Discovery On Target - Cover 16th Disc very · 2020. 9. 16. · Drug Targets »» NK Cell-Based...

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Conference At-A-Glance

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» » Small Molecules for Cancer Immunotherapy

» » Autoimmune»and»Inflammation»Drug Targets

» » NK Cell-Based Cancer Immunotherapy

» » Targeting Tumor Myeloid Cells» » Targeting the Ubiquitin-Proteasome System

» » Kinase Inhibitor Discovery » » CNS and Neurodegenerative Targets

» » GPCR-Based Drug Discovery » » Constrained Peptides and Macrocyclics

» » Lead Generation Strategies» » Target»Identification»and»Validation - Part 1 & Part 2

» » Antibacterial Discovery and Development

» » Targeting Gram-Negative Pathogens

» » NASH and Fibrosis » » Targeting the Microbiome» » Antibody Discovery Forum - Part 1 & Part 2

» » Antibodies Against Membrane Protein Targets - Part 1 & Part 2

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CliCk Here to registerDiscoveryOnTarget.com

A Division of Cambridge Innovation Institute

eVent FeatURes

350+ Speakers

20 Conference Tracks

1 Training Seminar

2 Symposia

13 Short Courses

80+ Exhibiting Companies

1,300+ Attendees

TARGETDisc veryon

16th Annual

September 25-28, 2018Sheraton BostonBoston, MA

The Industry’s Preeminent Event on Novel Drug Targets

DiscoveryonTARGET.com

• Small Molecules for Cancer Immunotherapy

• Autoimmune and Inflammation Drug Targets

• NK Cell-Based Cancer Immunotherapy

• Targeting Tumor Myeloid Cells

immunotherapy

• Antivirals: Targeting HBV and Beyond

• Targeting Autophagy• Antibacterial Discovery

and Development• Targeting Gram-Negative

Pathogens• NASH and Fibrosis• Targeting the Microbiome

Hot & emerging

• Antibody Discovery Forum - Part 1 & Part 2

• Antibodies Against Membrane Protein Targets - Part 1 & Part 2

Antibodies

• Targeting the Ubiquitin- Proteasome System

• Kinase Inhibitor Discovery • CNS and Neurodegenerative

Targets • GPCR-Based Drug Discovery • Constrained Peptides and

Macrocyclics• Lead Generation Strategies• Target Identification and

Validation - Part 1 & Part 2

target-Based Discovery & Validation

COnFeRenCe tRaCks & sYMPOsia

Final Agenda

Premier Sponsors:

http://www.discoveryontarget.com/offerings


http://www.healthtech.com/

http://discoveryontarget.com

DiscoveryOnTarget.com • 2CoNfERENCE AT-A-GlANCE

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ABoUT THE EVENT Cambridge Healthtech Institute’s 16th Annual Discovery on Target, “The Industry’s Preeminent Event on Novel Drug Targets,” will once again gather over 1,300 drug discovery professionals in Boston, MA, this September 25-28, 2018. The event brings forth current and emerging “hot” targets, technologies and validation strategies for the development of novel small molecules and biologics.

immunotherapy target-Based Discovery & Validation Hot & emerging Antibodies training seminars

WEDNESDAY September 26

Small Molecules for Cancer Immuno-therapy

NK Cell-Based

Cancer Immuno-therapy

Targeting the

Ubiquitin-Proteasome

System

CNS and Neurode-generative

Targets

Constrained Peptides and Mac-rocyclics

Target Identifica-tion and

Validation - PART 1

Antibacteri-al Discovery and Devel-

opment

NASH and Fibrosis

Antibody Discovery

Forum - PART 1

Antibodies Against

Membrane Protein

Targets - PART 1

TS1: Machine Learning

for Effective Drug

Discovery Decisions

THURSDAY September 27

Small Molecules for Cancer Immuno-therapy

NK Cell-Based

Cancer Immuno-therapy

Targeting the

Ubiquitin-Proteasome

System

CNS and Neurode-generative

Targets

Constrained Peptides and Mac-rocyclics


Validation - PART 1

Anti-bacterial

Discovery and Devel-

opment

NASH and

Fibrosis

Antibody Discovery

Forum - PART 1

Antibodies Against

Membrane Protein

Targets - PART 1

Plenary Keynote Program

Autoim-mune and Inflamma-tion Drug Targets

Targeting Tumor

Myeloid Cells

Kinase Inhibitor

Discovery

GPCR- Based Drug Discovery

Lead Generation Strategies


Validation - PART 2

Targeting Gram-

Negative Pathogens

Targeting the

Microbi-ome

Antibody Discovery

Forum - PART 2

Antibodies Against

Membrane Protein

Targets - PART 2

TS2: Introduction

to Small Molecule Drug Dis-

covery and Development

Dinner Short Courses

FRIDAY September 28

Autoim-mune and Inflamma-tion Drug Targets

Targeting Tumor

Myeloid Cells

Kinase Inhibitor

Discovery

GPCR- Based Drug Discovery

Lead Generation Strategies


Validation - PART 2

Targeting Gram-

Negative Pathogens

Targeting the

Microbi-ome

Antibody Discovery

Forum - PART 2

Antibodies Against

Membrane Protein

Targets - PART 2

Pre-Conference symposia

TUESDAY September 25

Antivirals: Targeting HBV and Beyond

Targeting Autophagy Regenerative Medicine

Pre-Conference Short Courses

CoNFereNCe CHANNels

Target-Based Discovery & Validation

Hot & emerging

Antibodies

immunotherapy

Disc very TARGETon

September 25-28, 2018 • Sheraton Boston • Boston, MA

#BostonDoT18The Industry’s Preeminent Event on Novel Drug Targets

16th Annual

CoNfERENCE AT-A-GlANCE

TS2: Introduction

to Small Molecule Drug Dis-

covery and Development




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®

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sPOnsOR, eXHiBit anD leaD gen OPPORtUnities

Podium Presentations—Available within Main Agenda!Showcase your solutions to a guaranteed, targeted audience through a 15- or 30-minute presentation during a specific conference program, breakfast, lunch, or separate from the main agenda within a pre-conference workshop. Package includes exhibit space, on-site branding, and access to cooperative marketing efforts by CHI. For the luncheon option, lunches are delivered to attendees who are already seated in the main session room. Presentations will sell out quickly, so sign on early to secure your talk!

One-on-One MeetingsSelect your top prospects from the pre-conference registration list. CHI will reach out to your prospects and arrange the meeting for you. A minimum number of meetings will be guaranteed, depending on your marketing objectives and needs. A very limited number of these packages will be sold.

Invitation-Only VIP Dinner/Hospitality SuiteSponsors will select their top prospects from the conference pre-registration list for an evening of network-ing at the hotel or at a choice local venue. CHI will extend invitations and deliver prospects, helping you to make the most out of this invaluable opportunity. The evening will be customized according to sponsor’s objectives (i.e., Purely social, Focus group, Reception style, Plated dinner with specific conversation focus)

Additional branding & promotional opportunities include:• Hotel Room Keys• Footprint Trails• Conference Tote Bags

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(Tote Bag Insert or Chair Drop)

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Looking for additional ways to drive leads to your sales team?

CHI’s Lead Generation Programs will help you obtain more targeted, quality leads throughout the year. We will mine our database of 800,000+ life science professionals to your specific needs. We guarantee a minimum of 100 leads per program! Opportunities include:

• Live Webinars• White Papers

• Market Surveys • Podcasts and More!

Comprehensive sponsorship packages allow you to achieve your objectives

before, during, and long after the event. Signing on earlier will allow you

to maximize exposure to hard-to-reach decision-makers.

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US BREAKDOWN

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2017 attenDee DeMOgRaPHiCs

Rod EymaelBusiness Development [email protected]

For more information regarding exhibit and sponsorship, please contact:

eXHiBitExhibitors will enjoy facilitated networking opportunities with 1,300+ qualified delegates, making it the perfect platform to launch a new product, collect feedback, and generate new leads from around the world. Exhibit space sells out quickly, so reserve yours today!

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A Division of Cambridge Innovation Institute SHoRT CoURSES | HoTEl & TRAVEl

PRE-CONFERENCE SHORT COURSES | TUESDAY, SEPTEMBER 25 | 2:00 - 5:00 PM

SC1: INTRODUCTION TO GPCR-BASED DRUG DISCOVERYThis course will provide an understanding for some of the pharmacological complexities of G protein-coupled receptors (GPCRs) as well as for the tools used to study them in a drug discovery setting. The course is well suited for biologists, pharmacologists and medicinal chemists who have recently started working with GPCRs or for those who need a refresher on the latest technological advances and newest paradigms.Instructor: Annette Gilchrist, PhD, Professor, Pharmacology, Midwestern University

SC2: DRUG METABOLISM AND ITS ROLE IN DISCOVERY AND DRUG DEVELOPMENTThis short course will focus on concepts important for those wanting to understand how drug metabolism is applied to drug discovery and development. Topics will include how drugs are metabolized, what enzymes are involved, how drug metabolism concepts are applied during lead optimization, how drug metabolites are identified in preclinical studies and human clinical trials, the role of bioactivation in drug toxicity and the growing application of in silico tools in drug metabolism. Those scientists involved in medicinal chemistry, pharmacology and drug metabolism will benefit from this overview.Instructor: John C. L Erve, PhD, DABT, Consultant, Jerve Scientific Consulting, Inc.

SC3: HOW TO BEST UTILIZE 3D CELLS, SPHEROIDS, AND PDX MODELS IN ONCOLOGYThe course will provide an overview of 3D cell culture and spheroid models currently available and where and how these models are being used, specifically for oncology research. The instructors will share their experiences on how they tested and evaluated various cell culture reagents and growth matrices,

what worked, what didn’t and what you need to consider when setting up low- and high-throughput screening experiments using 3D cell cultures in your lab. The challenges working with 3D cell cultures, from experimental design to data analysis will be discussed.Instructors: Madhu Lal-Nag, PhD, Group Leader, Trans-NIH RNAi Facility, National Center for Advancing Translational Sciences, National Institutes of HealthGeoffrey Bartholomeusz, PhD, Associate Professor and Director, Target Identification and Validation Program, Department of Experimental Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center

PRE-CONFERENCE DINNER SHORT COURSES | TUESDAY, SEPTEMBER 25 | 6:00 - 8:30 PM

SC8: TARGETING OF ION CHANNELS WITH MONOCLONAL ANTIBODIESIon channels are important therapeutic targets and currently represent the second largest target class addressed by therapeutic drugs. Significant opportunities exist for targeting ion channels with antibodies, but to date it has been challenging to discover therapeutic antibodies against them. This course will examine emerging technologies and strategies for enabling the isolation of functional anti-ion channel antibodies and highlight progress via case studies. The topics to be covered include: 1) antibody discovery, including methods to generate monoclonal antibodies and antigen preparation strategies; 2)

assays to enable isolation of binding antibodies, including use of recombinant stable cell lines; 3) in vitro assays to measure functional activity of the antibody, including use of electrophysiology platforms and ion flux methods; and 4) review of promising ligand-gated and voltage-gated ion channel targets and antibodies in development. Open discussion will be actively encouraged.Instructor: Trevor Wilkinson, PhD, Associate Director, Antibody Discovery and Protein Engineering, Medimmune Ltd., United Kingdom

SC9: CNS TRANSLATIONAL STRATEGIESA greater understanding of CNS-related disease biology and the emergence of new, improved targets and technologies has bought renewed interest in neuroscience. This short course describes the critical stages needed to translate an exciting CNS target into an effective CNS therapy by addressing challenges in biomarkers design and validation, modelling, imaging and methods to bridge the preclinical/clinical translation gap.Instructors: Chongzhao Ran, PhD., Assistant Professor of Radiology, Massachusetts General Hospital, Harvard Medical SchoolChangning Wang, PhD, Assistant Professor, Radiology, Massachusetts General Hospital, Harvard Medical SchoolVanita Chopra, PhD., Assistant Professor, Neurology, Massachusetts General Hospital, Harvard Medical School

SHORT COURSES* » September 25 & 27

* Separate registration required

HOTEL & TRAVELSheraton Boston Hotel39 Dalton StreetBoston, MA 02199T: 617-236-2000

Discounted Room Rate: $329Reservation Cutoff: August 29, 2018

For more information, visit DiscoveryOnTarget.com

Our short courses are designed to be instructional, interactive and provide in-depth information on a specific topic. They allow for one-on-one interaction and provide a great way to explain more technical aspects that would otherwise not be covered during our main presentations.




http://www.discoveryontarget.com/travel


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SC10: APPLICATIONS OF ARTIFICIAL INTELLIGENCE AND MACHINE LEARNING IN DRUG DISCOVERY AND DEVELOPMENTThis course aims to educate a diverse group of scientists-chemists, biologists, toxicologists, and those involved in translational and clinical research, about the growing use and applications of AI and ML. Talks start with explaining the basic terminology used and what it means, followed by discussions separating the hope from the hype. It goes into the caveats and limitations in AI and ML, while exploring ways in which it can be successfully applied in the drug discovery and development pipeline. There will be experts from various areas presenting case studies on how they have used AI/ML tools for lead optimization, target discovery, visualizing and classifying large datasets, patient stratification and more.Instructors: Arvind Rao, PhD, Associate Professor, Department of Computational Medicine and Bioinformatics, University of MichiganJin Yao, PhD, Scientific Investigator, Computational Biology and Statistics, Target Sciences, GSKAnna Basile, PhD, Postdoctoral Research Scientist Department of Biomedical Informatics Columbia University

SC11: MECHANISTIC UNDERSTANDING OF PHARMACOLOGICAL PROBES FOR THE UBIQUITIN-PROTEASOME SYSTEMThis course is intended for the audience interested in drug discovery programs aimed to develop PROTACs (molecular degraders) and/or small molecule inhibitors targeting components of the ubiquitin-proteasome system (UPS). This course will cover basic mechanistic biochemistry of the ubiquitin-proteasome system, which includes E1, E2, E3, and deubiquitinating enzymes, and their macromolecular architecture. Subsequently, the course will transition into a general discussion of existing biochemical assays and technologies to discover PROTACs and small molecule inhibitors of E1, E2, E3, and deubiquitinating enzymes. Finally, existing PROTACs and pharmacological probes targeting E1, E2, E3, and deubiquitinating enzymes, their pharmacological properties, and basic control experiments that need to be done to inform a better

design of these probes for preclinical and clinical studies will also be discussed.Instructor: Alexander Statsyuk, PhD, Assistant Professor, Department of Pharmacological and Pharmaceutical Sciences, University of Houston

DINNER SHORT COURSES | THURSDAY, SEPTEMBER 27 | 7:00 - 9:30 PM

SC13: GPCR STRUCTURE-BASED DRUG DISCOVERYRecent breakthroughs in obtaining high-resolution structures of G protein-coupled receptors (GPCRs) by both X-ray crystallography and Cryo-EM, are rapidly impacting the pharmaceutical industry. This course will review how GPCR structures elucidated to date have informed our current understanding of GPCR function. The course will also provide examples of how GPCR structural information is being applied to guide rational approaches for GPCR drug discovery. Another course focus is on new biophysical techniques that provide complementary information on GPCR dynamics and function. Recent examples of nuclear magnetic resonance (NMR) and the impact of other biophysical techniques on drug discovery will be shared.Instructors: Matthew Eddy, PhD, Assistant Professor, Chemistry, University of FloridaHuixian Wu, PhD, Principal Scientist, Structural and Molecular Sciences, Discovery Sciences, Pfizer, Inc. Groton

SC14: ADVANCING TOOLS AND TECHNOLOGIES FOR FRAGMENT-BASED DESIGNThis course aims to introduce the fundamentals of Fragment-Based Lead Discovery (FBLD) to attendees. The first section will focus on the concepts of using fragments for hit generation. Special emphasis will be placed on practical pitfalls and the many ways to advance fragments to leads and drugs. The second part of the course will discuss the variety of fragment screening methods and when they are best applied. The composition of fragment libraries will also be discussed in detail. The attendees should come away from this course with a solid understanding of what FBLD is and how to apply it.Instructors: Daniel A. Erlanson, PhD, Co-Founder, Carmot Therapeutics, Inc.Mary Harner, PhD, Research Investigator II, Mechanistic Biochemistry, Bristol-Myers Squibb R&D

SC15: INTRODUCTION TO TARGETED COVALENT INHIBITORSCovalent inhibitors of kinases have re-emerged as a drug design strategy due to more examples of their safety and efficacy in patients. Covalent inhibitors have the advantage of increased selectivity and longer action of duration but there are still important issues about their design and application that need to be better understood. This course will cover practical as well as theoretical issues that a medicinal chemist needs to keep in mind in developing covalent inhibitors.Instructor: Mark Schnute, PhD, Associate Research Fellow, Medicine Design, Inflammation & Immunology Research, Pfizer, Inc.

SC16: IMMUNOLOGY BASICSImmunology is a difficult subject to master, even for immunologists. Newly discovered cell types and their associated function in human health and disease have been continuously revealed over the last decade. In this course immunologists (non-physicians) with extensive experience in the biopharmaceutical drug discovery and development will break it down for you by filling the gaps that most chemists have. It’s not a comprehensive course – but hopefully better – a useful course. The focus will range from basic background biology and terminology that immunologists take for granted and then jump to the biological underpinnings of the areas and targets a lot of medicinal chemists are developing compounds against.Instructors: Songqing Na, PhD, Senior Scientist, Biotechnology & Autoimmunity Res-AME, Eli Lilly and CompanyThomas Sundberg, PhD, Senior Research Scientist I, Center for Development of Therapeutics, Broad Institute of MIT and Harvard

SC17: TECHNOLOGIES TO ASSESS PERMEABILITY AND EFFLUX IN GRAM-NEGATIVE BACTERIAL PATHOGENSOur lack of understanding of the molecular basis for compound penetration into and efflux out of gram-negative bacteria has been identified as a key bottleneck for the rational discovery of novel antibacterial compounds. A main driver of this knowledge gap is the historical lack of assays, tools, and/or predictive models to provide medicinal chemists with structure-activity relationships that






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could guide optimization of whole cell penetration (and efflux avoidance). However, there have been some recent, promising advances in the field which set the stage for future innovative approaches.Instructors: David Six, PhD, Investigator III, Infectious Diseases, Novartis Institutes for BioMedical ResearchRam Iyer, PhD, Principal Scientist (Bacteriology), Entasis Therapeutics, Inc.

SC18: PRACTICAL PHENOTYPIC SCREENINGPhenotypic drug discovery is experiencing a Renaissance in the pharmaceutical industry, based on its successful track record in delivering first-in-class medicines. This approach offers the promise of delivering both novel targets and chemical matter modulating a disease phenotype of interest. Although phenotypic screening may appear at first sight to be similar to target-based screening, there are some significant differences between the two approaches. These need to be properly considered and addressed to ensure the greatest likelihood of success for phenotypic drug discovery programs. This presentation will cover a range of relevant topics with a goal of providing practical information to help prosecute such programs more effectively.Instructor: Fabien Vincent, PhD, Associate Research Fellow, Hit Discovery and Lead Profiling Group, Pfizer, Inc.





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SYMPOSIA » September 25

2nd Annual | September 25

Antivirals: Targeting HBV and Beyond New Drug Development for Infectious Diseases

Antiviral drug development is shifting its focus to hepatitis B virus (HBV) after the encouraging success of developing direct-acting antivirals against the hepatitis C virus. Both viruses cause liver disease and represent major global health problems that can lead to death from liver failure. Progress has been made in several HBV-specific approaches such as RNAi to silence HBV gene production, or inhibitors of the virus’s capsid assembly, some of which are in early-stage clinical trials. Advances are also occurring in more broadly applicable antiviral approaches, especially those that modulate the host immune system. Join this symposium to stay abreast of new drug development in the HBV and broader infectious disease field and to share insights and strategies with fellow researchers.

RECOMMENDED ALL ACCESS PACKAGE: Choose 2 Short Courses or 1 Symposium and 2 Conferences/Training Seminars • September 25 Symposium: Antivirals:

Targeting HBV and Beyond • September 26-27 Conference:

NASH and Fibrosis • September 27-28 Conference: Autoimmune

and Inflammation Drug Targets

TUESDAY, SEPTEMBER 258:00 am Pre-Conference Symposia and Short Course Registration8:00 Morning Coffee

TARGETING THE RNA AND PROTEINS OF HEPATITIS B VIRUS9:00 Welcome RemarksAnjani Shah, PhD, Conference Director, Cambridge Healthtech Institute9:05 Chairperson’s Opening RemarksDavid B. Smith, PhD, Vice President, Global Research and Development Leader, Hepatitis, Alios BioPharma Inc., part of the Janssen Pharmaceutical Companies

9:15 KEYNOTE PRESENTATION: New Directions towards a Functional Cure for Chronic Hepatitis BJan Martin Berke, PhD, Principal Scientist, Hepatitis Discovery, Janssen Research & Development, Beerse, BelgiumWhile approximately 260 million individuals worldwide are chronically infected with the Hepatitis B virus, current regimens provide only a fraction of patients with functional cure, loss of S-antigen and suppression of the virus in the absence of continued treatment. With the goal of developing finite duration combination regimens that deliver a higher rate of functional cure, multiple mechanism of action agents are currently in development. This presentation will overview progress to date in this area.

9:45 Antiviral Activities of AB-506, a Next Generation HBV Capsid Inhibitor, in Combination with AB-452, an HBV RNA Destabilizer, Nucleos(t)ide Analogs and the RNAi Agent ARB-1467René Rijnbrand, PhD, Vice President, Biology, Arbutus Biopharma Inc.Increasing HBV cure rates will require a combination regimen that blocks viral replication, reduce s antigen levels, starve cccDNA formation and activate immune responses to eliminate cccDNA. Capsid inhibitor AB-506 in combination with RNA destabilizer AB-452, NAs or the RNAi agent ARB-1467 using HBV cell culture and animal models showed additive to synergistic antiviral activity. These data suggest that these agents are mechanistically compatible and may be used for treatment in a combination regimen.

10:15 Preclinical Antiviral Profile of the Novel HBV Core Inhibitor EP-027367Michael Vaine, PhD, Principal Scientist, Virology, Enanta PharmaceuticalsEP-027367 is a novel HBV inhibitor that modulates capsid assembly and other core protein functions. In vitro, it inhibits rcDNA production with low double digit nanomolar activity, is active across HBV genotypes A-H, nucleos(t)ide resistant variants, and inhibits nascent cccDNA formation in infectable cell lines. In a human liver, chimeric mouse model, EP-027367 can reduce circulating HBV titers by up to 3-logs with 28 days of treatment.10:45 Sponsored Presentation (Opportunity Available)11:00 Networking Coffee Break with Poster Viewing

DIRECT-ACTING ANTIVIRALS FOR HBV11:30 AB-452: A Selective Small-Molecule Destabilizer of HBV Viral RNAMin Gao, PhD, Senior Scientist, Biology, Arbutus Biopharma, Inc.AB-452 is a potent HBV RNA destabilizer. It is inactive against a panel of DNA and RNA viruses, demonstrating the specificity of AB-452. Since AB-452 promotes the degradation of HBV RNAs, especially sRNA and consequently, inhibits multiple stages of viral life cycle in vitro and in vivo, combination regimens containing AB-452 could not only further inhibit HBV DNA replication and potentially increase the cure rate, but also provide an opportunity to shorten the treatment duration.12:00 pm Using siRNA to Target the HBV TranscriptomeJames C. Hamilton, MD, MBA, Vice President Clinical Development, Arrowhead PharmaceuticalsHepatocyte targeted siRNA therapeutics can be used to silence HBV viral mRNA transcripts leading to reduction in serum antigen levels and inhibition of viral replication. This mRNA silencing effect applies to the entire viral transcriptome including transcripts derived from integrated DNA and cccDNA which may be important in generating functional cures

Back by popular demand are focused, one-day pre-conference symposia, designed to highlight areas of discovery research currently capturing the interest of developers, and poised to grow in importance over the next few years. Pre-conference symposia complement topics covered during main conference meetings, and can be combined to provide a robust and comprehensive four days of unique programing based on personal interest.





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12:30 HBV Ribonuclease H: Drug Discovery and Target ValidationJohn Tavis, PhD, Professor of Molecular Virology, Department of Molecular Microbiology and Immunology, St. Louis University School of MedicineHBV replication requires the viral ribonuclease H (RNaseH), but no anti-RNaseH drugs exist. We developed assays to measure RNaseH activity and identify HBV replication inhibitors. >100 inhibitors were found, the best having an EC50 of 110 nM and a therapeutic index of 390. RNaseH inhibitors are synergistic with nucleos(t)ide analogs, insensitive to HBV’s genetic diversity, and can suppress HBV viremia in infected humanized mice, so the RNaseH is a promising target for novel drug development.1:00 Sponsored Presentation (Opportunity Available)1:00 Pre-Conference Short Course RegistrationClick here for details on short courses offered.1:15 Enjoy Lunch on Your Own

STIMULATING HOST RESPONSES AND TARGETING EMERGING VIRUSES2:45 Chairperson’s RemarksRené Rijnbrand, PhD, Vice President, Biology, Arbutus Biopharma Inc.2:55 Achieving Functional Cure of Chronic HBV Infection with REP 2139-Based Combination TherapyAndrew Vaillant, PhD, CSO, Replicor, Inc.HBsAg loss during treatment of chronic HBV infection predicts functional remission persisting after the completion of therapy but is rarely achieved with approved therapies. REP 2139 uniquely allows HBsAg clearance in most patients, dramatically potentiating the ability of immunotherapy to restore host control of infection. Follow-up data from the latest clinical trials with REP 2139-based combination therapy demonstrating the achievement of long term functional cure in HBV and HDV infection will be featured.3:25 Targeting TLR7 for Emerging Infectious DiseasesJames B. Whitney, PhD, Professor, Center for Virology and Vaccine Research, Harvard Medical School and Ragon Institute of MGH, MIT, and Harvard3:55 Small Molecule Inhibitors of Flavivirus Entry Inspired by the Humural Immune ResponsePriscilla L. Yang, PhD, Professor, Department of Microbiology and Immunobiology, Harvard Medical School

4:25 Closing Comments4:30 Close of Symposium5:00 Pre-Conference Dinner Short Course RegistrationClick here for details on short courses offered.

2nd Annual | September 25

Targeting Autophagy Understanding and Modulating Autophagy Pathways for Drug Discovery

Autophagy has been shown to play a role in many diseases, such as cancer, autoimmune, CNS, metabolic and infectious disorders. However, targeting autophagy is complex because there are different types of autophagy and they all involve various cellular pathways that are not well understood. Many studies have shown that autophagy can also have a binary function, for instance, acting as a tumor suppressor or a tumor enhancer in cancer. Despite such complexities, it is promising to see many preclinical and clinical studies underway using already approved autophagy drugs and novel inhibitors. Cambridge Healthtech Institute’s symposium on Targeting Autophagy taps into the recent excitement in this field by bringing together a group of experts who are uncovering new mechanisms and inhibitors to help drug discovery.

RECOMMENDED ALL ACCESS PACKAGE: Choose 2 Short Courses or 1 Symposium and 2 Conferences/Training Seminars• September 25 Symposium:

Targeting Autophagy• September 25 Short Course 11: Mechanistic

Understanding of Pharmacological Probes for the Ubiquitin-Proteasome System

• September 26-27 Conference: Targeting the Ubiquitin-Proteasome System

• September 27-28 Conference: Kinase Inhibitor Discovery

• September 27 Short Course 18: Practical Phenotypic Screening

TUESDAY, SEPTEMBER 258:00 am Pre-Conference Symposia and Short Course Registration8:00 Morning Coffee

UNDERSTANDING THE CELLULAR EFFECTS OF TARGETING AUTOPHAGY9:00 Welcome RemarksTanuja Koppal, PhD, Conference Director, Cambridge Healthtech Institute9:05 Chairperson’s Opening RemarksJeff MacKeigan, PhD, Professor of Cancer Biology and Complex Diseases, College of Human Medicine, Michigan State University9:15 Autophagy in Cancer: Known and Unique TargetsJeff MacKeigan, PhD, Professor of Cancer Biology and Complex Diseases, College of Human Medicine, Michigan State UniversityOur lab uses predictive computational modeling and cell-based measurements to accurately model the autophagic process. We are now extending our models to predict the therapeutic benefit of inhibiting autophagy in cancer. Our research suggests that targeting known and unique kinases in the autophagy pathway can uncover more selective and potent small molecule inhibitors as compared to current lysomotropic agents.9:45 Downregulation of Autophagy by a Cancer-Specific Ubiquitin Ligase Targeting AMPKRyan Potts, PhD, Associate Member, Department of Cell and Molecular Biology, St. Jude Children’s Research HospitalAMP-activated protein kinase (AMPK) is a master sensor and regulator of cellular energy status. Upon metabolic stress, AMPK suppresses anabolic and promotes catabolic processes, including autophagy, to regain energy homeostasis. Here, I will discuss a widespread mechanism to suppress AMPK through its ubiquitination and degradation by the cancer-specific MAGE-A3/6-TRIM28 ubiquitin ligase. Recent findings on the regulation of MAGE-A3/6 protein stability under nutrient deprivation will also be discussed.10:15 Targeting Autophagy in Colorectal Cancer Cells: A Relevant Strategy?Steve Jean, PhD, Assistant Professor, Department of Anatomy and Cell Biology, Université de SherbrookeAPC loss, and KRAS activation, two hallmarks of CRC, are linked to increased autophagic flux, suggesting a





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potential involvement of autophagy in CRC. Through in vivo approaches on CRC cell lines, we found that the outcome of autophagy inhibition in a complex system is unpredictable. Hence, the relationship between autophagy inhibition and cancer driver/passenger mutations must be clarified before autophagy inhibition can be considered as a therapeutic avenue in CRC.

10:45 Sponsored Presentation (Opportunity Available)11:00 Networking Coffee Break with Poster Viewing11:30 Leveraging Autophagy’s Ability to Regulate Apoptosis to Improve Cancer TherapyAndrew Thorburn, DPhil, Chair, Department of Pharmacology, University of Colorado, School of MedicineIn this presentation, I will discuss how autophagy inhibition sensitizes tumor cells to undergo apoptosis and necroptosis and how this can be leveraged to enhance the activity of other anti-cancer agents.12:00 pm Regulation of Innate Immunity by Selective AutophagyAditya Murthy, PhD, Scientist, Cancer Immunology, Genentech, Inc.Molecular mechanisms by which autophagy limits inflammation remain poorly understood. We have recently shown that loss of the autophagy gene Atg16L1 promotes interferon-mediated pathology via accumulation of the signaling adaptor TRIF. Multiplexed proteomics identified SQSTM1/p62 and Tax1BP1 as autophagy receptors for TRIF. Human macrophages harboring the Crohn’s disease-associated ATG16L1 variant (T300A) exhibited elevated cytokine production upon TLR3/4 stimulation. These findings implicate selective autophagy as a key immunoregulatory node in innate immunity.12:30 Extrinsic Roles of Tumor-Intrinsic AutophagyChristina H. Eng, PhD, Senior Principal Scientist, Pfizer Oncology R&DThe role of autophagy in cancer has been extensively examined, yet the impact of autophagy inhibition on neoplastic disease varies greatly and depends on a number of factors such as genetic context and tumor landscape. Metabolic stress such as nutrient and oxygen limitation, oncogenic mutations, and chemotherapeutic treatment are all situations that may fuel the dependence on autophagy in tumorigenic

cells. Our findings indicate that autophagic activity in malignant cells does not promote tumorigenesis in a cancer-cell intrinsic manner, but alters extrinsic host responses to tumor growth.1:00 Sponsored Presentation (Opportunity Available)1:00 Pre-Conference Short Course RegistrationClick here for details on short courses offered.1:15 Enjoy Lunch on Your Own

EXPLORING TOOLS & ASSAYS TO PROBE AND QUANTIFY THE AUTOPHAGY CASCADE2:45 Chairperson’s RemarksIan Ganley, PhD, Programme Leader, The MRC Protein Phosphorylation and Ubiquitylation Unit, The Sir James Black Centre, School of Life Sciences, University of Dundee2:55 Illuminating Mitochondrial Autophagy in VivoIan Ganley, PhD, Programme Leader, The MRC Protein Phosphorylation and Ubiquitylation Unit, The Sir James Black Centre, School of Life Sciences, University of DundeeMitophagy, the autophagy of mitochondria, is an essential quality control (QC) mechanism of pathophysiological relevance with strong links to Parkinson’s disease, cancer and inflammatory disorders. However, if and how mitophagy proceeds within specific cellular subtypes in vivo has remained unclear, largely due to a lack of tractable models. To address this, we developed “mito-QC”, a fluorescent reporter mouse that allows the facile assessment of mitophagy and mitochondrial architecture in vivo.3:25 Phenotypic Screening Paradigms for Autophagy Pathway RegulatorsPhilip A. Bergman, BS, Investigator III, Chemical Biology and Therapeutics, Novartis Institutes for BioMedical Research, Inc.To identify novel autophagy pathway nodes, we established phenotypic pooled CRISPR screening paradigms and mapped regulators of autophagy cargo and cargo receptors in mammalian cells. As proof of concept, we performed a genome-wide screen for the autophagy cargo receptor p62 and validated mTOR signaling and the entire macroautophagy machinery as key regulators of p62 turnover. Here, we will

present our progress in applying phenotypic screening paradigms to identify novel autophagy pathway nodes.

GOING BEYOND AUTOPHAGY3:55 Regulation and Consequences of Autophagy and Non-Canonical Autophagy Resembling LC3-Associated Phagocytosis or LAPMichael Overholtzer, PhD, Associate Member, Cell Biology Program, Memorial Sloan Kettering Cancer CenterAutophagy proteins have parallel functions in non-autophagic processes that involve LC3 lipidation. Notably, LC3-Associated Phagocytosis or LAP was discovered as a parallel function of core autophagy proteins that lipidate LC3 onto phagosomes and other endocytic membranes. Here I will discuss new data uncovering regulation of LAP and the consequences of this process that differ from macroautophagy. The engagement of LAP by lysosomotropic drugs, including chloroquine, will also be discussed.4:25 Roles for Autophagy Genes beyond Autophagy: Control of Exosome Release and Exosome-Mediated MetastasisDerrick Gibbings, PhD, Assistant Professor, Cellular and Molecular Medicine, University of OttawaAutophagy and autophagy-related genes (Atg) have been attributed prominent roles in tumorigenesis, tumor growth, and metastasis. Extracellular vesicles called exosomes are also implicated in cancer metastasis. Here, we demonstrate that exosome production is strongly reduced in cells lacking Atg5 and Atg16L1, but this is independent of Atg7 and canonical autophagy. These findings uncover mechanisms controlling exosome release and identify means by which autophagy-related genes can contribute to metastasis in autophagy-independent pathways.4:55 Closing CommentsTanuja Koppal, PhD, Conference Director, Cambridge Healthtech Institute5:00 Close of Symposium5:00 Pre-Conference Dinner Short Course RegistrationClick here for details on short courses offered.




DiscoveryOnTarget.com • 11TRAINING SEmINARS

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A Division of Cambridge Innovation Institute TRAINING SEmINARS

DAY 1: THURSDAY, SEPTEMBER 27 | 12:20 PM - 7:00 PM DAY 2: FRIDAY, SEPTEMBER 28 | 7:30 AM - 4:00 PM

DAY 1 - THURSDAY12:20 - 2:00 pm Plenary Keynote Program2:00 - 2:45 pm Refreshment Break in the Exhibit Hall with Poster Viewing3:00 - 7:00 pm Training Seminar 2 in Session 7:00 pm Training Seminar 2 Close of Day

DAY 2 - FRIDAY7:30 - 8:30 am Interactive Breakfast Breakout Discussion Groups8:30 am - 4:00 pm Training Seminar 2 in Session 12:30 - 1:30 pm Lunch Provided4:00 pm Training Seminar 2 Concludes

TS2: INTRODUCTION TO SMALL MOLECULE DRUG DISCOVERY AND DEVELOPMENT

Instructor: H. James Harwood Jr., PhD, Founder and CEO, Delphi BioMedical Consultants, LLCThis 1.5-day lecture-based interactive seminar focuses on strategies for identifying drug discovery targets, discovering and characterizing small molecule hits, and developing structure-activity relationships to advance

hits through lead optimization, preclinical development, and clinical evaluation. Participants will learn the stages and processes required to advance programs from idea to clinic, through examples and case studies. This seminar is intended for scientists in either academia or industry who would like to become more familiar with small molecule drug discovery and development.

* For detailed agendas and further details, please visit the conference website

TRAINING SEMINAR INFORMATIONEach CHI Training Seminar offers 1.5 days of instruction with start and stop times for each day shown above and on the Event-at-a-Glance published in the onsite Program & Event Guide. Training Seminars will include morning and afternoon refreshment breaks, as applicable, and lunch will be provided to all registered attendees on the full day of the class.

Each person registered specifically for the Training Seminar will be provided with a hard copy handbook for the Seminar in which they are registered. A limited number of additional handbooks will be available for other delegates who wish to attend the Seminar, but after these have been distributed, no additional books will be available.

Though CHI encourages track hopping between conference programs, we ask that Training Seminars not be disturbed once they have begun. In the interest of maintaining the highest quality learning environment for Training Seminar attendees, and because Seminars are conducted differently than conference programming, we ask that attendees commit to attending the entire program, and not engage in track hopping, as to not disturb the hands-on style instruction being offered to the other participants.

TRAINING SEMINAR » September 27-28

Cambridge Healthtech Institute Training Seminars offer real-life case studies, problems encountered and solutions applied, along with extensive coverage of the academic theory and background. Each Training Seminar offers a mix of formal lecture and interactive discussions and activities to maximize the learning experience. These Training Seminars are led by experienced instructors who will focus on content applicable to your current research and provide important guidance to those new to their fields.

By Cambridge Healthtech Institute




The 16th Annual Discovery on Target, “The Industry’s Preeminent Event on Novel Drug Targets,” will once again gather over 1,300 drug discovery professionals in Boston, MA, this September 25-28, 2018. The event brings forth current and emerging “hot” targets, technologies and validation strategies for the development of novel small molecules and biologics.

2018 eVeNt FeAtUres

• Over 350+ speakers presenting across 20 conference tracks, 2 training seminars and 3 symposia

• 16 Short Courses to provide additional training and education to brush up on your knowledge or expand your horizons

• Exhibit hall of 80+ companies with novel technologies and solutions

• Plenary keynote program unified by an underlying theme on meeting the new challenges of novel drug development

• Poster sessions featuring cutting-edge, ongoing research

• Student fellowships offering discounted registration for young researchers looking to make a difference

• 1,300+ international delegates focusing on preclinical research and the challenges and opportunities in early drug discovery and development

• Sponsored talks by leading technology and service providers showcasing new offerings

• Dedicated poster viewing and interactive panel discussions for active networking

New Approaches to Challenging Targets in CancerThe development of new anti-cancer therapies continues to be massively outpaced by the rapidly expanding knowledge into the biological mechanisms that underpin the development of cancer. One major obstacle is that many potentially interesting targets are challenging to drug. This lecture will focus on strategies using covalent inhibitors and small molecule degraders which hold the promise of making many previously challenging targets druggable. In particular, we will focus on the use of these approaches to target kinases and present some key advantages of small molecule degraders including potency, selectivity and abrogation of non-kinase activity dependent functions. We will also describe efforts to target KRAS – a notorious and frequent oncogene that has been recalcitrant to small molecule approaches.

Nathanael S. Gray, PhD, Professor of Biological Chemistry and Molecular Pharmacology, Dana-Farber Cancer InstituteNathanael Gray spent his childhood in Zambia, Yemen, India and Sudan before returning to the US to attend high school at Berkeley High in California. During his PhD at University of California at

Berkeley, he discovered Purvalanol, one of the first selective inhibitors of cyclin-dependent kinases. After receiving the PhD in 1999, Dr. Gray moved to the Genomics Institute of the Novartis Research Foundation in San Diego, where he was named Director of Biological Chemistry in 2001. Dr. Gray’s research team was responsible for the development of several clinical candidates, including BAF312 which is currently undergoing Phase III clinical trials for the treatment of Multiple Sclerosis. Dr. Gray joined the faculty of Harvard Medical School and the Dana-Farber Cancer Institute in 2006 to continue his research using synthetic chemistry and functional small molecule discovery to modulate biological pathways important in cancer. His research group has been responsible for the discovery of novel inhibitors of wild-type and mutant forms of EGFR (WZ4002), mTor (Torin1 and Torin 2), Bcr-Abl (GNF-2, GNF-5, HG-7-85-01), Mps1 (Mps1-IN-1 Mps1-IN-2), Erk5 (XMD8-92), b-Raf, LRRK2 (LRRK2-IN-1), Jnk1,2,3 (JNK-IN-7) and Ephrin kinases which have become widely used research tools and have inspired several drug discovery programs.

The 2018 Plenary Keynote Program will provide a unified underlying theme on meeting the new challenges of novel drug development.

PlenaRY keYnOte PROgRaM Thursday, September 27, 12:20 - 2:00 pm

DiscoveryOnTarget.com • 12PlENARy KEyNoTES & EVENT fEATURES

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DiscoveryOnTarget.com • 13AGENDA

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Antibodies September 26-28

· Antibody Discovery Forum - PART 1

· Antibodies Against Membrane Protein Targets - PART 1

· Antibody Discovery Forum - PART 2

· Antibodies Against Membrane Protein Targets - PART 2

Hot & emerging September 26-28

· Antibacterial Discovery and Development

· NASH and Fibrosis

· Targeting Gram-Negative Pathogens

· Targeting the Microbiome

September 26-28target-Based Discovery & Validation · Targeting the Ubiquitin-Proteasome System

· CNS and Neurodegenerative Targets

· Constrained Peptides and Macrocyclics

· Target Identification and Validation - PART 1

· Kinase Inhibitor Discovery

· GPCR-Based Drug Discovery

· Lead Generation Strategies

· Target Identification and Validation - PART 2

immunotherapy September 26-28

· Small Molecules for Cancer Immunotherapy

· NK Cell-Based Cancer Immunotherapy

· Autoimmune and Inflammation Drug Targets

· Targeting Tumor Myeloid Cells

symposia September 25

· Antivirals: Targeting HBV and Beyond

· Targeting Autophagy

· Regenerative Medicine

COnFeRenCe CHannels & sYMPOsiaTake advantage of Discovery on Target’s program channels to explore the 1.5-day main program conferences and pre-conference symposia that align with your research. Conference and Symposia details below. Also, supplement your education with short courses and training seminars. Click here for details on short courses offered and click here for details on training seminars. As part of the (best value) All Access registration choose from 2 Short Courses or 1 Symposium, and 2 Conferences/Training Seminars.




http://www.discoveryontarget.com/short-courses

http://www.discoveryontarget.com/training-seminars

DiscoveryOnTarget.com • 14SmAll molECUlES foR CANCER ImmUNoTHERAPy

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IMMUNOTHERAPY

First-generation cancer immunotherapy agents being developed or approved are engineered T cells targeting tumors or mostly antibody-based biologics that target the immune checkpoint cascade. The success of these biologics in the clinic is now inspiring the discovery and development of small molecules that act on intracellular targets affecting immuno-modulatory pathways in cancer. Cambridge Healthtech Institute’s 2nd Annual Small Molecules for Cancer Immunotherapy conference brings together discovery chemists and biologists to talk about these new intracellular oncology targets and immuno-modulatory small molecule inhibitors that are being developed to act alone or in combination with existing treatments.


Targeting Autophagy • September 25 Short Course 3: How to

Best Utilize 3D Cells, Spheroids, and PDX Models in Oncology

• September 26-27 Conference: Small Molecules for Cancer Immunotherapy

• September 27-28 Conference: Targeting Tumor Myeloid Cells

• September 27 Short Course 16: Immunology Basics

WEDNESDAY, SEPTEMBER 267:00 am Registration Open and Morning Coffee

UPDATE ON SMALL MOLECULES IN DEVELOPMENT FOR IMMUNOONCOLOGY8:00 Welcome RemarksTanuja Koppal, PhD, Conference Director, Cambridge Healthtech Institute8:05 Chairperson’s Opening RemarksPaul Kassner, PhD, Vice President, Quantitative Biology, FLX Bio Inc.

8:10 Beyond PD-1 Axis: The Next Generation Oral Checkpoint Inhibitor Targeting the CD47/SIRPα Pathway for Cancer ImmunotherapyPottayil G. Sasikumar, PhD, Associate Research Director and Head of the Peptide Chemistry group, Aurigene Discovery Technologies LimitedEncouraged by our success in discovering small molecule immune checkpoint inhibitors predominantly impacting T cells, we are now focusing on next generation checkpoint inhibitors. In this presentation, we will discuss successful identification of oral agents targeting the CD47/signal regulatory protein alpha (SIRPα) axis, a critical regulator of myeloid cell activation and a checkpoint for macrophage and dendritic-cell mediated phagocytosis and antigen presentation.8:40 Small Molecule Immune Oncology Therapies from Ubiquitin Proteasome SystemSuresh Kumar, PhD, Senior Director R&D, Progenra, Inc.Progenra is developing small molecule inhibitors targeting deubiquitinases and ubiquitin ligases that promote tumor growth and immune evasion. The deubiquitylase (DUB) USP7 stabilizes several pro-tumorigenic proteins and plays an essential in Treg function by regulating post-translational modification of Foxp3 and TIP60. Progenra has developed potent USP7 inhibitors that exhibit direct anti-tumor activity in multiple xenograft tumor models. Most importantly, USP7 inhibitors also impair Treg functions and are efficacious in syngeneic solid tumor models.9:10 Purine Nucleoside Phosphorylase Inhibitors as Novel, First-in-Class Small Molecule ImmunotherapyShanta Bantia, PhD, President and CEO, Nitor TherapeuticsWe have discovered, contrary to all previous literature, that purine nucleoside phosphorylase (PNP) inhibitors

are immune potentiators and represent a new class of orally bioavailable, small molecule immuno-oncology therapeutics. Increase in the endogenous metabolite, guanosine, with PNP inhibition leads to activation of TLR2, 4 and 7. Potential attributes for differentiation of PNP inhibitor (NTR001) are: less adverse events from targeted immune activation in tumor micro-environment; human safety known and doses defined, and immune activation in clinical/preclinical studies confirmed.9:40 Grand Opening Coffee Break in the Exhibit Hall with Poster Viewing10:25 The Network-Driven Drug Discovery (NDD) Approach and Lead Generation: Novel Immune-Modulatory Small Molecules Case StudySree Vadlamudi, PhD, Programme Manager, e Therapeutics plcThe majority of drug discovery approaches involve the search for a single binding target in a well-characterized pathway. But while pathways are easy to envisage, they do not reflect the complexity of biological systems. A more realistic way to describe the underlying interactions which occur is as a network. We have implemented and validated a highly productive NDD approach to identify NCEs in diverse areas of biology. We will describe a case study highlighting the discovery and optimizationof small molecules modulating tumor micro environment (TME) with a novel mechanism of action.10:55 Epigenetic Control of Immune Checkpoint Inhibitor ResponsesDiana Hargreaves, PhD, Assistant Professor, Molecular and Cell Biology, Salk Institute for Biological SciencesMutations in subunits of the SWI/SNF chromatin remodeling complex are known to potentiate responses to checkpoint therapies and are thus attractive targets for the development of small molecules for cancer therapy. Here we describe a key role for the SWI/SNF subunit ARID1A in controlling chromatin accessibility and histone modifications at transcriptional enhancers and discuss our efforts to identify novel SWI/SNF complex inhibitors.

2nd Annual | September 26-27

Small Molecules for Cancer Immunotherapy Unraveling the Chemistry and Biology for Next-Generation Therapies





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11:25 Development of CCR4 Antagonists for Cancer ImmunotherapyPaul Kassner, PhD, Vice President, Quantitative Biology, FLX Bio Inc.Regulatory T cells (Treg) suppress anti-tumor immunity in the tumor microenviroment (TME). CCR4 is highly expressed on Treg and responsible for recruitment of Treg to the TME. FLX475 is a potent and selective CCR4 antagonist in Phase I clinical trials. The preclinical development, patient selection strategy and biomarker plan for FLX475 will be discussed.11:55 PANEL DISCUSSION12:25 pm Session Break12:35 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own1:15 Refreshment Break in the Exhibit Hall with Poster Viewing

IMPACTING TLRs, CYTOKINES AND PRO-INFLAMMATORY PATHWAYS1:50 Chairperson’s RemarksDavid Ferguson, PhD, Professor, Medicinal Chemistry, University of Minnesota1:55 Targeting Myeloid Cell Suppressor Function through Inhibition of GCN2Buvana Ravishankar, PhD, Scientist, Discovery Biology, FLX Bio Inc.Myeloid-derived suppressor cells (MDSC) are a major component of the tumor microenvironment with potent immune-suppressive activity. MDSC within the tumor mediate local depletion of amino-acids that induce suppression of T cell proliferation and activation. GCN2 kinase is a stress response kinase

that detects amino-acid deprivation leading to T cell anergy and apoptosis. GCN2 inhibitors abrogated the suppressive function of MDSCs leading to restoration of proliferation and effector function of CD8 T cells.2:25 Discovery of Small Molecule AhR Antagonists to Overcome Local Tumor ImmunosuppressionChristoph Steeneck, PhD, Director Medicinal Chemistry, Phenex Pharmaceuticals AGThe Aryl Hydrocarbon Receptor (AhR) is widely known for mediating toxicity and tumor-promoting activities of halogenated hydrocarbons and polycyclic aromatic hydrocarbons. However in recent years, ample evidence emerged that AhR activation causes immunosuppression and that AhR antagonism could represent a treatment for cancer complementary to checkpoint inhibitors. An overview on Phenex` series of small molecule AhR antagonists and their optimization will be given. The lead molecules show high potency, favorable ADME/PK and in vivo efficacy.2:55 Sponsored Presentation (Opportunity Available)3:25 Refreshment Break in the Exhibit Hall with Poster Viewing and Poster Competition Winner Announced4:05 IDO1 as a Promoter of Inflammatory NeovascularizationAlexander J. Muller, PhD, Associate Professor, Lankenau Institute for Medical ResearchIDO1 is a tryptophan catabolizing enzyme implicated in maintaining pregnancy and tumoral immune escape. This may, however, be just one aspect of a multifaceted role for IDO1. Our studies have determined that, by triggering the integrated stress response, IDO1 can support inflammatory neovascularization through its positioning at the regulatory interface between the inflammatory

cytokines IFNγ and IL6. These insights have important ramifications for the therapeutic development of IDO1 inhibitors.4:35 Toll-Like Receptor 7 and 8 Agonists with Direct Inflammasome ActivationDavid Ferguson, PhD, Professor, Medicinal Chemistry, University of MinnesotaThe basic structural features of small molecule ligands that confer selectivity to Toll-like receptors 7 and 8 will be discussed in the context of immunomodulation and the design of cancer vaccines. An SAR analysis will be presented to identify structural features that confer selectivity to TLR7 and TLR8 and ligand specific activation of key cytokines in producing antigen-specific cellular responses in model systems. Finally, in vivo data will be shown that demonstrates the potential of TLR7/8 stimulation in designing advanced vaccines for cancer treatment.

5:05 Interactive Breakout Discussion GroupsJoin a breakout discussion group. These are informal, moderated discussions with brainstorming and interactive problem solving, allowing participants from diverse backgrounds to exchange ideas and experiences and develop future collaborations around a focused topic. Details on the topics and moderators are available on the conference website.

Sponsored by6:05 Welcome Reception in the Exhibit Hall with Poster Viewing7:10 Close of Day

THURSDAY, SEPTEMBER 277:30 am Registration Open and Morning Coffee

Media Partners

Official Publications

Sponsoring Publications

Lead Sponsoring Publications

Web PartnersDiagnostics World





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EMERGING TARGETS AND COMBINATIONS FOR CANCER IMMUNOTHERAPY8:00 Chairperson’s RemarksAmar Natarajan, PhD, Professor, Eppley Institute for Cancer Research, Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center8:05 Exhausted CD8 Cells May Predict Response to Immune Checkpoint Inhibitors in Breast CancerPamela Munster, MD, Professor, Department of Medicine; Director, Early Phase Clinical Trials Unit, and Leader, Developmental Therapeutics Program, University of California San FranciscoImmune checkpoint inhibitors have limited efficacy in estrogen receptor (ER)+ breast cancer. Implicated factors include scarcity of tumor infiltrating lymphocytes (TILs), low PD-L1 expression, female gender and liver involvement. Evaluation of in vitro and in vivo effects of epigenetic modulation with HDACi on Tregs, change in TIL composition and data from a clinical trial in patients with (ER)+ metastatic breast cancer suggests that HDACi induced Treg regulation and the presence of exhausted CD8+ cells in a small subset of patients (ER)+ breast cancer patients were predictive of response.8:35 Chemical Genetic Screens Identify Kinase Inhibitor Combinations that Target Anti-Apoptotic Proteins for Cancer TherapyAmar Natarajan, PhD, Professor, Eppley Institute for Cancer Research, Fred and Pamela Buffett Cancer Center, University of Nebraska Medical CenterSystematic CRISPR studies defined signaling arms in the apoptosis network that can be targeted for cancer therapy. Using a pair of doxycycline (Dox)-inducible cell lines that specifically report on targeting either the Mcl-1 arm or the Bcl-2/Bcl-xL/Bcl-w arm we identified unique combination of inhibitors that synergistically induce apoptosis. Here we will present preclinical studies that validate these combinations that can be rapidly translated to the clinics.

9:05 Discovery of Scaffold/Platform for the Development of Dual Kinase/Epigenetic Inhibitors for the Activation of Innate and Adaptive Antitumor ImmunityDonald Durden, MD, PhD, Professor, Department of Pediatrics, University of California, San Diego; Director of Operations, SignalRx PharmaceuticalsA novel thienopyranone molecular scaffold has been discovered to selectively inhibit PI3 kinase as well as the bromodomain protein BRD4. Molecular modeling studies and a robust PI-3K and BRD4 BD1 homology model has been developed and will be presented to describe how these single small molecules can bind to inhibit such distinctly different proteins and their functions. As a cancer therapeutic, this dual inhibition mechanism allows for a unique and powerful way to modulate critical components of cancer cells. Finally, other inhibitors developed in silico against other targeted kinases e.g. BTK in combination with PI3K-gamma and PI3K-delta will be presented as novel immuno-oncological agents.9:35 Coffee Break in the Exhibit Hall with Poster Viewing10:20 Plate-Based Approach to Identify PROTACS Molecules and Protein DegradersDavide Gianni, PhD, Team Leader, Discovery Sciences, AstraZenecaPROTACS provide a new modality to drug previously challenging targets and much evidence indicates that protein degraders are a mode of inhibition that can be pursued post HTS. Western Blot is mostly used to characterize PROTACS molecules, but it has a number of obvious limitations. The adoption of plate-based approaches is essential in PROTACS and several options are available such as, antibody-based and non-antibody based approaches. We will present two case studies building plate-based, HTS-friendly protein degradation assays potentially applicable for PROTACS identification campaigns.

10:50 PROTACS: The Chemical Equivalent of CRISPRShanique Alabi, Graduate Student, Laboratory of Dr. Craig Crews, Department of Molecular, Cellular and Developmental Biology, Yale UniversityInduced protein degradation offers several advantages over traditional inhibition strategies and has emerged recently as a potential therapeutic option. For the past 16 years, we have helped develop this fast-growing field, shepherding our initial chemical biology concept into a drug development strategy that is on the verge of clinical validation. PROTACs with high target selectivity, potency, and oral bioavailability will be discussed as well as a system to address the ‘PROTACability’ of particular E3 ligases.11:20 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own11:50 Conference Registration Open

12:20 pm Plenary Keynote ProgramClick here for details.

2:00 Refreshment Break in the Exhibit Hall with Poster Viewing2:45 Close of Conference




DiscoveryOnTarget.com • 17AUToImmUNE AND INflAmATIoN DRUG TARGETS

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IMMUNOTHERAPY

This conference focuses on small molecule, peptide or macrocyclic-based agents that have the potential to be developed into oral-based therapies for the treatment of autoimmune diseases and chronic inflammation disorders. The success of biologics for autoimmune diseases coupled with rapid advances in basic research has validated many immunology-relevant signaling pathways and uncovered new intracellular molecules to target for potential new drug agents that can enter the cell. Discovering oral-based therapies, which offer patient convenience is a high priority in the drug discovery industry because of the chronic nature of many autoimmune and inflammation conditions and the fact that their incidence is predicted to steadily increase due to the growing aging population.

RECOMMENDED ALL ACCESS PACKAGE: Choose 2 Short Courses or 1 Symposium and 2 Conferences/Training Seminars• September 25 Symposium: Antivirals:

Targeting HBV and Beyond• September 25 Short Course 11: Mechanistic


• September 26-27 Conference: NASH and Fibrosis

• September 27-28 Conference: Autoimmune and Inflammation Drug Targets


THURSDAY, SEPTEMBER 2711:50 am Conference Registration Open


2:00 Refreshment Break in the Exhibit Hall with Poster Viewing

NEW INTRACELLULAR DRUG TARGETS FOR INFLAMMATION2:45 Welcome RemarksAnjani Shah, PhD, Conference Director, Cambridge Healthtech Institute

2:50 Chairperson’s Opening RemarksShruti Sharma, PhD, Assistant Professor, Department of Immunology, Tufts2:55 Discovery and Investigation of Selective Immunoproteasome InhibitorsMichael Siu, PhD, Senior Scientist, Discovery Chemistry, Genentech, Inc.The importance of the immunoproteasome for immune cell function has led to efforts to selectively inhibit this target to deplete pathogenic immune cells for the potential treatment of autoimmune diseases. Herein, we describe the discovery of β5i (LMP7) selective inhibitors and their effects on immune cells. These inhibitors have provided new understanding of immunoproteasome inhibition that suggests selective inhibition may have limited potential for immune cell depletion.3:25 The Anti-inflammatory Effect of SINE (Selective Inhibitors of Nuclear Export) Compounds in the Context of IBDDouglas Widman, Phd, Research and Development Program Manager, Karyopharm Therapeutics, Inc.Karyopharm Therapeutics has developed a class of compounds known as Selective Inhibitors of Nuclear Export (SINE), which reversibly bind to and inhibit the function of nuclear export protein, exportin-1 (XPO1). In murine DSS induced c olitis, longer, less inflamed colons and more normal stool consistency was observed in mice treated with SINE compound. SINE compounds demonstrate the ability to reduce chronic inflammation by multiple mechanisms including inhibiting NF-kB activity even in presence of TNF-α.

3:55 Identification of Two Novel Chemical Series for the Irreversible Inhibition of Myeloperoxidase (MPO)Andrew W. Patterson, PhD, Senior Investigator I, Global Discovery Chemistry, Novartis Institutes for Biomedical Research, Inc.4:25 Refreshment Break in the Exhibit Hall with Poster Viewing5:00 Role of STING in Innate Immunity and Implications for Drug DiscoveryShruti Sharma, PhD, Assistant Professor, Department of Immunology, Tufts5:30 Inhibitor of NCK, a First-in-Class TCR Signaling Adaptor for Combatting AutoimmunityBalbino Alarcon, PhD, Professor, Center for Molecular Biology Severo Ochoa, National Research Council of Spain, MadridAntigen binding to the T cell receptor (TCR) triggers the recruitment of the cytosolic adaptor protein Nck to a proline-rich sequence (PRS) in the cytoplasmic tail of the TCR’s CD3ε subunit. We have generated an orally-available, inhibitor of the TCR-Nck interaction that selectively inhibits TCR-triggered T cell activation at subnanomolar concentrations. The inhibitor is not immunosuppressive and exerts a long-lasting protective effect in several models of autoimmunity even when the compound is no longer present.6:00 Targeting the Keap1-NRF2 System to Combat InflammationMichelangelo Campanella, PhD, PharmD, Professor and Unit Head, Mitochondrial Cell Biology and Pharma-cology Research Group RVC and University College London Consortium for Mitochondrial ResearchMy talk will report upon Nrf2 inducers as pharmacological tolls in mitochondrial quality control operated by targeted autophagy and its impact on autoimmunity and inflammation. The presentation will also elaborate on the prominent biological activity in cellular homeostasis of the non-covalent Keap1-Nrf2 protein-protein interaction (PPI) inhibitor PMI, which is structurally distinct from the covalent Keap1 modifiers (e.g., sulforaphane) and amenable to therapeutic exploitation.6:30 Dinner Short Course RegistrationClick here for details on short courses offered.9:30 Close of Day

3rd Annual | September 27-28

Autoimmune and Inflammation Drug Targets Towards Oral-Based Therapeutics




DiscoveryOnTarget.com • 18AUToImmUNE AND INflAmATIoN DRUG TARGETS

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IMMUNOTHERAPY

FRIDAY, SEPTEMBER 287:00 am Registration Open

7:30 Interactive Breakfast Breakout Discussion GroupsGrab a cup of coffee and join a breakout discussion group. These are informal, moderated discussions with brainstorming and interactive problem solving, allowing participants from diverse backgrounds to exchange ideas and experiences and develop future collaborations around a focused topic.Details on the topics and moderators are available on the conference website.

THE MICROBIOME, AUTOIMMUNITY AND INFLAMMATION8:30 Chairperson’s RemarksThomas Sundberg, PhD, Senior Research Scientist I, Center for Development of Therapeutics, Broad Institute of MIT and Harvard

8:35 KEYNOTE PRESENTATION: Bacterial Transformations in Autoimmune Drug MetabolismJason Michael Crawford, PhD, Maxine F. Singer ’57 Ph.D. Associate Professor of Chemistry and Associate Professor of Microbial Pathogenesis, Yale UniversityPhotorhabdus asymbiotica is a gammaproteobacterial pathogen that causes systemic and severe soft tissue infections in humans. During infection, it produces tapinarof, an immunomodulatory drug developed to treat psoriasis and atopic dermatitis. We show that bacteria transform tapinarof into other novel metabolites that regulate arylhydrocarbon receptor and Nrf2 antioxidant signaling, phenotypes responsible for tapinarof’s clinical efficacy. We also show that closely related dietary metabolites associated with “alternative” IBD treatments undergo similar novel transformations.

9:05 Reverse Translation for Therapeutic Development in the Human MicrobiomeUlrich Thienel, MD, PhD, CMO, Finch Therapeutics, Inc.A major challenge in microbiome research is interpreting correlations observed in human cohort studies or murine models. However, with the increasing abundance of clinical interventional data from experience with fecal microbiota transplantation, there is an opportunity to develop therapeutic insights directly from clinical observations. Finch Therapeutics identifies microbial therapies by observing patterns of microbial engraftment that drive clinical responses. We plan to use the patterns to develop a new generation of rationally selected microbiota therapies for Inflammatory Bowel Disease.9:35 NOD2, Innate Immunity and the MicrobiomeKlare Lazor, Graduate Student, Laboratory of Catherine Grimes, Department of Chemistry and Biochemistry, University of Delaware 10:05 Coffee Break in the Exhibit Hall with Poster Viewing and Poster Competition Winner Announced

INTRACELLULAR KINASE INHIBITORS FOR INFLAMMATION/AUTOIMMUNITY10:45 Considerations in the Generation of Covalent BTK InhibitorsNoel S. Wilson, PhD, Senior Scientist II, Discovery Chemistry and Technology, AbbVie 11:15 Evobrutinib (BTK inhibitor) in Autoimmunity: Preclinical UpdatesAndrew Bender, PhD, Senior Scientist, Discovery Biology, EMD Serono11:45 Sponsored Presentation (Opportunity Available)12:15 pm Session Break12:25 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own1:15 Refreshment Break in the Exhibit Hall with Poster Viewing

ORAL-BASED APPROACHES FOR AUTOIMMUNITY1:55 Chairperson’s RemarksSongqing Na, PhD, Senior Scientist, Biotechnology & Autoimmunity Res-AME, Eli Lilly and Company

2:00 FEATURED PRESENTATION: PTG-200, An Oral Peptide Antagonist of the IL-23 Receptor, for the Treatment of IBDDavid Y. Liu, PhD, CSO, Protagonist Therapeutics

2:30 Identification of a First-in-Class RIP1 Kinase Inhibitor in Clinical Trials for Immuno-Inflammatory Diseases via DNA-Encoded LibrariesPhilip A. Harris, PhD, Senior Director, Pattern Recognition Receptor DPU, GlaxoSmithKlineRIP1 kinase activity is a critical driver of cell death and pro-inflammatory cytokine production downstream of multiple signaling pathways including TNFR1. Hence RIP1 inhibitors have the potential to result in a broad therapeutic benefit in inflammatory diseases. This talk will describe the identification of a novel and selective RIP1 inhibitor series from a DNA-encoded library, and the lead optimization leading to identification of development candidate GSK2982772, now in Phase IIa clinical evaluation in psoriasis, rheumatoid arthritis and ulcerative colitis patients.3:00 Targeting TLRs in Fibrotic DiseaseGlenda Trujillo, PhD, Principal Scientist, Translational Research for Fibrosis Discovery Biology, Bristol-Myers Squibb Company 3:30 Identification of Two Novel Chemical Series for the Irreversible Inhibition of Myeloperoxidase (MPO)Andrew W. Patterson, PhD, Senior Investigator I, Global Discovery Chemistry, Novartis Institutes for Biomedical Research, Inc.MPO is a peroxidase present in phagocytic cells that participates in innate immune response, with a primary anti-microbial function of generating powerful oxidants (i.e. HOCl). MPO activation is also associated with generating oxidants within tissues. As such, plasma MPO levels have been linked to several chronic inflammatory diseases including cardiovascular disease. Here we describe two novel series of irreversible, mechanism-based MPO inhibitors that are orally bioavailable and active in vivo in a peritonitis model of acute inflammation.4:00 Close of Conference




DiscoveryOnTarget.com • 19NK CEll-BASED CANCER ImmUNoTHERAPy

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IMMUNOTHERAPY

A growing number of studies into pathways elucidating NK cell biology, activating and suppressing NK cell function, the development of pharmacological and genetic methods to enhance NK cell anti-tumor immunity, and the ability to expand NK cells ex vivo have set the stage for a new generation of cancer immunotherapies. As preclinical and clinical studies continue, there is a clear need to better understand the mechanisms underlying the regulation of NK cell phenotype and function within the tumor environment to accelerate the development of NK cell-targeting therapeutics.

Cambridge Healthtech Institute’s 3rd Annual NK Cell-Based Cancer Immunotherapy conference will once again convene immuno-oncology researchers, cancer immunotherapy developers, and technology providers to discuss current challenges and opportunities - from discovery NK immuno-oncology to clinical studies, share latest technologies and development approaches, as well as to provide updates on preclinical, clinical, and combination studies.


Targeting Autophagy• September 25 Short Course 3: How to


• September 26-27 Conference: NK Cell-Based Cancer Immunotherapy




MODULATING NK CELLS FOR HIGHER SPECIFICITY AND POTENCY8:00 Welcome RemarksNgoc Emily Le, PhD, Associate Producer, Cambridge Healthtech Institute8:05 Chairperson’s Opening RemarksBahram (Bob) Valamehr, PhD, MBA, Vice President, Cancer Immunotherapy, Fate Therapeutics, Inc.

8:10 KEYNOTE PRESENTATION: Novel Strategies to Produce Better NK Cells to Treat CancerJeffrey Miller, MD, Professor, Medicine, Division of Hematology, Oncology and

Transplantation, University of MinnesotaWe have developed a trispecific killer engagers (TriKE) platform to make NK cells antigen specific and enrich for a unique population of adaptive NK cells that kill better, mediate enhanced antibody-dependent cellular cytotoxicity, can resist immune suppression mechanisms and exhibit properties of immunologic memory. To overcome limitation of single cell infusions, a platform to deliver off-the-shelf NK cells derived from clonal, genetically modified induced pluripotent stem cells (iPSC) was developed. These strategies alone or in combination with checkpoint blockade are key to the future.

8:40 Pluripotent Cell-Derived NK Cells as a Cornerstone Approach for Off-the-Shelf Cancer ImmunotherapyBahram (Bob) Valamehr, PhD, MBA, Vice President, Cancer Immunotherapy, Fate Therapeutics, Inc.I will discuss our progress towards translating a unique and effective strategy to create a renewable source of “off-the-shelf” engineered NK cells derived from a single-cell derived master pluripotent cell line. The derived master pluripotent cell line is

banked, characterized and repeatedly applied to our stage-specific directed differentiation process to reproducibly and reliably generate NK cells. Preclinical data highlight the therapeutic value of pluripotent-derived NK cells including anti-tumor capacity, manufacturing reliability and preclinical efficacy.9:10 Inhibition of MICA and MICB Shedding by Tumor Cells Elicits NK Cell-Mediated Tumor ImmunityKai W. Wucherpfennig, MD, PhD, Professor and Chair, Cancer Immunology and Virology, Dana-Farber Cancer Institute; Professor, Neurology and Microbiology/Immunobiology, Harvard Medical SchoolWe rationally designed antibodies targeting the MICA α3 domain, the site of proteolytic shedding, and found that these antibodies prevent loss of cell surface MICA/B by human cancer cells. These antibodies inhibit tumor growth in multiple fully immunocompetent mouse models and reduce human melanoma metastases in a humanized mouse model.9:40 Grand Opening Coffee Break in the Exhibit Hall with Poster Viewing

MODULATING NK CELLS FOR HIGHER SPECIFICITY AND POTENCY (CONT.)10:25 NKTR-255: Accessing the Immunotherapeutic Potential of IL-15 for NK Cell TherapiesSaul Kivimae, PhD, In Vivo Pharmacology Function Lead, Nektar TherapeuticsIL-15 has long been recognized for its potential as an immunotherapeutic agent. Exploiting this potential has been challenging due to unfavorable pharmacokinetic properties. NKTR-255 is a novel polymer-conjugated IL-15 that shows prolonged plasma exposure and IL-15 pathway activation while retaining high affinity IL-15Rα binding. NKTR-255 treatment expands and sustains activation of NK and CD8 memory T cell populations. High level of NK cell dependent anti-tumor efficacy is demonstrated in NKTR-255 treated mouse models of tumor metastasis.

3rd Annual | September 26-27

NK Cell-Based Cancer Immunotherapy Engineering Strategies and Clinical Evidence





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10:55 Engineering NK Cells for Enhanced Potency and PersistenceJames B. Trager, PhD, Senior Vice President, Research and Development, Nkarta TherapeuticsNK cells form a first line of defense against cancer, and they can be effective mediators of cytotoxicity and adaptive immunity. Efforts to maximize their potential as cancer therapeutics are hampered by difficulty in expanding NK cells, relatively short in vivo persistence, and the ability of tumor cells to evade NK recognition. We will discuss recent progress in overcoming these barriers to successful therapeutic application of NK cells.11:25 Engineered, Off-the-Shelf NK Cell Lines for Patient Specific Cancer TreatmentHans Klingemann, MD, PhD, Vice President, Research & Development, NantKwest, Inc.aNK and haNK have completed Phase I studies, taNK (her-2 CAR) for glioma is currently accruing patients. Further genetic modifications of the haNK platform include additional CARs as well as homing receptors and molecules that can positively affect the tumor microenvironment. The off-the-shelf character of these cells is reflected in the fact that they can be cryopreserved and irradiated in bulk and shipped to the treatment site overnight.11:55 PANEL DISCUSSION12:25 pm Session Break12:35 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own1:15 Refreshment Break in the Exhibit Hall with Poster Viewing

CLINICAL DEVELOPMENTS OF NK CELL-BASED THERAPIES1:50 Chairperson’s RemarksHans Klingemann, MD, PhD, Vice President, Research & Development, NantKwest, Inc.1:55 Genetic Modification of NK Cells to Retarget and Sustain Anti-Tumor Activity in Patients with Multiple MyelomaEvren Alici, MD, PhD, Head, Gene and Cell Therapy Group, Division of Hematology, Medicine, Karolinska University Hospital, SwedenIn this talk, I will comparatively discuss various strategies for NK cell gene modification, modulation of degranulation using small molecules, as well as decreasing NK cell time-to-next-kill via modulation of intracellular RNA sensing pathways. I will also discuss results of a first-in-man autologous ex vivo expanded NK cell clinical trial in patients with multiple myeloma

which showed the cells to be safe with some signs of efficacy and an interesting manageable side effect.2:25 NK Cell Subsets and Their Plasticity – Implications for Cell TherapyKarl-Johan Malmberg, MD, PhD, Professor, Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, NorwayIn this talk, I will discuss new insights into the underlying mechanisms behind the functional diversification of human NK cells, including the formation of a molecular memory, evidence for subset plasticity and dynamic imprints caused by NK cell responses to cytomegalovirus infection. In terms of clinical translation, we are currently exploring new strategies to selectively expand such “adaptive” NK cells for cancer therapies.2:55 Fuelling Robust Anti-Tumor NK Cell ResponsesDavid Finlay, Assistant Professor, School of Biochemistry and Immunology, School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, IrelandFor robust anti-tumour functions NK cells increase the uptake of cellular fuels and the flux through metabolic pathways. We have characterised these metabolic responses in activated NK cells, discovered the metabolic regulators involved and their importance for NK cell effector function. NK cells have profound metabolic defects in various disease states where NK cell functional responses are impaired. These discoveries have important implications for NK cell immunotherapies.3:25 Refreshment Break in the Exhibit Hall with Poster Viewing and Poster Competition Winner Announced

CLINICAL DEVELOPMENTS OF NK CELL-BASED THERAPIES (CONT.)4:05 Harnessing NK Cell Memory for Leukemia ImmunotherapyRizwan Romee, MD, Member Faculty and Director, Haploidentical Donor Transplant Program, Oncology/ BMT and Leukemia Program, Dana Farber Cancer Institute, Harvard Medical SchoolWe identified human cytokine induced memory-like cells induced by brief activation of conventional NK cells with IL-12 and IL-18. These memory-like NK cells have enhanced anti-leukemia responses and we recently completed first-in-human Phase I clinical trial of these memory-like NK cells in patients with advanced AML/MDS with very promising safety and efficacy signal. We are now working on several approaches to expand the use of these memory-like

NK cells in combination with other novel agents in transplant and non-transplant settings.

DISCOVERY PLATFORMS AND TECHNOLOGIES FOR NK CELLS4:35 Dynamic Analysis of Human Natural Killer Cell Response at Single-Cell ResolutionTania (Tali) Konry, PhD, Assistant Professor, Pharmaceutical Sciences, Northeastern UniversityWe have developed a high throughput droplet based microfluidic platform to investigate the key features of NK cells associated with rapid, slow or inactive tumor killing kinetics in NHL. We are working on identifying NK cell heterogeneity and bio-functional characteristics to discover novel drug combinations for NK cell dependent immunotherapy via an integrated droplet platform. We identified significant variability in NK-lymphoma cell contact duration, frequency, and subsequent cytolysis. We extended this technique to characterize functional heterogeneity in cytolysis of primary cells from b-NHL patients




DISCOVERY PLATFORMS AND TECHNOLOGIES FOR NK CELLS (CONT.)8:00 Chairperson’s RemarksHans Klingemann, MD, PhD, Vice President, Research & Development, NantKwest, Inc.8:05 NK Cells and GlioblastomaMichael A. Caligiuri, MD, President and Physician-in-Chief, City of Hope National Medical CenterGlioblastoma remains an incurable malignancy, presenting as late-stage disease with a very poor





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overall survival. Oncolytic viral therapy is currently being explored in clinical trials, but in some instances, natural killer (NK) cells present a barrier to effective viral replication and tumor lysis. We have discovered how NK cells “see” human herpes virus – a mechanism we have named Fc bridged cellular cytotoxicity – and have therefore devised strategies to circumvent this barrier for this deadly disease.8:35 New Insights into Requirements for Human NK Cell DevelopmentEmily Mace, PhD, Assistant Professor, Pediatric Immunology, American Society for Hematology Scholar, Pediatrics, Columbia University Irving Medical CenterIn this talk, I will discuss recent developments in understanding the requirements for the differentiation and expansion of functionally mature human NK cells from immature precursors. In particular, I will focus on insights derived from in vitro differentiation systems that hold promise for better understanding and improving the efficiency and specificity of clinically relevant NK cell subsets.9:05 Reports from Wednesday Evening Breakout Discussions9:35 Coffee Break in the Exhibit Hall with Poster Viewing

DISCOVERY PLATFORMS AND TECHNOLOGIES FOR NK CELLS (CONT.)10:20 Discovering Novel Therapeutic Antibody to Modulate NK Cells for Cancer ImmunotherapyZhengmao Ye, PhD, Biochemical and Cellular Pharmacology, GenentechNatural Killer cell is a critical immune cell subset mediating tumor killing. In this proposal, I plan to discuss a drug discovery project targeting a cell surface protein that mediates the suppression of NK and CD8+ T cell activity. I will discuss the functional assay development/antibody screening strategy for lead identification as well as pharmacological characterization of the lead molecule and its MOA elucidation.10:50 Engineering Human Pluripotent Stem Cells to Produce NK Cells with Improved Targeted Anti-Cancer ActivityDan Kaufman, MD, PhD, Professor, Director of Cell Therapy Program, University of California, San DiegoOur studies have designed novel chimeric antigen receptors optimized to enhance NK cell-mediated anti-tumor activity. We use human induced pluripotent stem cells (iPSCs) as a platform to express these NK-CARs and can efficiently produce iPSC-derived NK cells with stable CAR expression. NK-CAR-

expressing iPSC-NK cells demonstrate improved anti-tumor activity in vitro and in vivo. We are now translating these NK-CAR-iPSC-NK cells to produce a standardized, targeted “off the shelf” anti-cancer immunotherapy.11:20 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own11:50 Conference Registration Open






DiscoveryOnTarget.com • 22TARGETING TUmoR myEloID CEllS

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IMMUNOTHERAPY

Recently, our understanding of the Tumor Microenvironment (TME) has shed light onto the importance of tumor-infiltrating myeloid cells, such as tumor-associated neutrophils (TANs), myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), and tumor-associated dendritic cells (TADCs), as critical contributors to the suppression of innate and adaptive immune responses. Importantly, these cells exist in various states within the TME, producing either immunosuppressive or immunostimulatory responses. Therapeutically targeting of tumor myeloid cells to eliminate or to convert them to their immunostimulatory state has emerged as a new and complementary strategy in the suite of cancer immunotherapy approaches. However, our understanding of tumor-resident myeloid cell phenotype and their possible divergent function in the tumor microenvironment is still not elaborated.

Cambridge Healthtech Institute’s 2nd Annual Targeting Tumor Myeloid Cells conference will bring together experts in the field to examine their phenotypic complexity and possible functions in connection with the tumor microenvironment. We will also discuss evidences for their contribution to cancer pathogenesis from new clinical studies along with regulation mechanisms of myeloid cells by tumors.


Targeting Autophagy• September 25 Short Course 3: How to


• September 26-27 Conference: NK Cell-Based Cancer Immunotherapy






TUMOR MICROENVIRONMENT AND THE IMMUNE SYSTEM2:45 Welcome RemarksNgoc Emily Le, PhD, Conference Producer, Cambridge Healthtech Institute2:50 Chairperson’s Opening RemarksKipp Weiskopf, MD, PhD, Resident Physician, Internal Medicine, Brigham and Women’s Hospital

2:55 KEYNOTE PRESENTATION: Reprogramming Tumor Microenvironment to Enhance ImmunotherapyDai Fukumura, MD, PhD, Deputy

Director of Edwin L. Steele Laboratory and Investigator, Massachusetts General Hospital; Associate Professor, Harvard Medical SchoolImmune checkpoint blocker immunotherapy has revolutionized oncology. However, its efficacy is limited to small fraction of patients. Our laboratory has been dissecting the role of tumor microenvironment (TME) in tumor progression and therapeutic response. We found that TME suppresses anti-tumor immunity via two components – abnormal ECM and infiltrated myeloid cells – resulting in hypoperfusion, hypoxia and immunosuppression. We developed strategies to reprogram immune TME and enhance immunotherapy by targeting these mechanisms.

3:25 Chemotherapy-Induced Metastasis: Mechanisms and Translational OpportunitiesGeorge S. Karagiannis, DVM, PhD, Anatomy and Structural Biology, Albert Einstein College of Medicine Anatomy and Structural BiologyA better understanding of the mechanistic underpinnings of chemotherapy-induced metastasis will allow us to better predict which patients are more likely to exhibit pro-metastatic responses to chemotherapy and will help develop new therapeutic strategies to neutralize chemotherapy-driven prometastatic changes.3:55 Talk Title to be AnnouncedKipp Weiskopf, MD, PhD, Resident Physician, Internal Medicine, Brigham and Women’s Hospital4:25 Refreshment Break in the Exhibit Hall with Poster Viewing

TUMOR MICROENVIRONMENT AND THE IMMUNE SYSTEM (CONT.)5:00 Targeting the ATP: Adenosine Pathway in CancerTim Sullivan, PhD, Vice President, Business Development, Arcus Biosciences, Inc.In many tumors, extracellular adenosine contributes to an immunosuppressed tumor micro-environment (TME) via activation of the A2a receptor (A2aR), expressed on lymphocytes, and the A2b receptor (A2bR), expressed on myeloid cells. AB928 is a novel and selective dual A2aR/A2bR antagonist designed to potently block the immunosuppressive effects of adenosine in the TME.5:30 Inhibition of STAT3 by Antisense Oligonucleotide Treatment Decreases the Immune Suppressive Tumor Microenvironment in Syngeneic Tumor ModelsTheresa Proia, PhD, Associate Principal Scientist, In Vivo Bioscience, Oncology IMED Biotech Unit, AstraZenecaWe explored the ability of a mouse STAT3 targeted antisense oligonucleotide (ASO) to enhance the antitumor activity of an anti-PD-L1 mAb in syngeneic murine tumor models. Our data indicate that inhibition of STAT3 has immunomodulatory activity, specifically through reduction of suppressive CD163+ cells and in combination with anti-PDL1, increased cytotoxic activity of CD8+ T cells in CT26 tumors, leading to significant tumor growth inhibition. These


Targeting Tumor Myeloid Cells Successful Strategies and Clinical Advancement





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IMMUNOTHERAPY

data demonstrate the opportunity to effectively combine STAT3 ASO with antibodies such as those targeting PD-L1 to enhance the activity of immune checkpoint inhibitors.6:00 Targeting Myeloid Cells in the MicroenvironmentDavid C. Linehan, MD, Seymour I. Schwartz Professor, Chairman, Surgery, University of Rochester Medical Center ObjectiveTargeting tumour-associated CXCR2+neutrophils (TAN) or tumour-associated CCR2+ macrophages (TAM) alone improves antitumour immunity in preclinical models. However, a compensatory influx of an alternative myeloid subset may result in a persistent immunosuppressive TME and promote therapeutic resistance. Here, we show CCR2 and CXCR2 combined blockade reduces total tumour-infiltrating myeloids, promoting a more robust antitumour immune response in PDAC compared with either strategy alone.6:30 Dinner Short Course RegistrationClick here for details on short courses offered.9:30 Close of Day


7:30 Interactive Breakfast Breakout Discussion GroupsGrab a cup of coffee and join a breakout discussion group. These are informal, moderated discussions with brainstorming and interactive problem solving, allowing participants from diverse backgrounds to exchange ideas and experiences and develop future collaborations around a focused topic. Details on the topics and moderators are available on the conference website.

TARGETING MYELOID CELLS IN CANCER – CLINICAL APPROACHES8:30 Chairperson’s RemarksJeffery Kutok, MD, PhD, CSO, Infinity Pharmaceuticals8:35 A Drug Development Perspective on Targeting Tumor-Associated Myeloid CellsMajety Meher Vinay Krishna Mohan, PhD, Principal Scientist, Cancer Immunotherapy, Discovery Oncology, Pharma Research and Early Development (pRED), Roche Innovation Center MunichMyeloid cells represent one of the most abundant immune cell populations within the tumor stroma and

are equipped with a broad functional repertoire that promotes tumor growth by suppressing cytotoxic T cell activity, stimulating neo-angiogenesis and tissue remodeling. There are several pharmacological approaches to therapeutically target tumor-associated myeloid cells, each of which has unique advantages and challenges that need to be considered to achieve clinical benefit.9:05 Targeting Tumor Infiltrating Myeloid Cells for Effective ImmunotherapyAlan Wang, PhD, Associate Professor, Cancer Biology, The University of Texas MD Anderson Cancer CenterBoth human cancers and mouse tumors are heavily infiltrated with various types of myeloid cells. Their immune suppressive roles in GEM models, including castration resistance prostate cancer, colon cancer, pancreatic cancer and GBM will be discussed. Results on combinations of MDSCs targeting agents and immune checkpoint blockade will be presented.9:35 Reprogramming Tumor-Associated Macrophages by Targeting PI3K- γ with IPI-549Jeffery Kutok, MD, PhD, CSO, Infinity PharmaceuticalsIPI-549 is a first-in-class, oral, selective PI3K-γ inhibitor that in preclinical studies reprograms macrophages from an immune-suppressive to an immune-activating phenotype and can overcome resistance to checkpoint inhibitors. We are conducting a Ph 1/1b study IPI-549-01 (NCT02637531) evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics, and immunomodulatory activity of IPI-549 to determine its recommended Phase II dose and preliminary efficacy, as monotherapy and combined with nivolumab, in ~200 advanced solid tumor patients.10:05 Coffee Break in the Exhibit Hall with Poster Viewing and Poster Competition Winner Announced10:45 Blocking the CD47 “Do Not Eat” Signal with SIRPaFc Fusion ProteinsBob Uger, PhD, CSO, Trillium Therapeutics, Inc.CD47 is an innate immune checkpoint that binds to SIRPα and delivers a “do not eat” signal to suppress macrophage phagocytosis. Many tumors express high levels of CD47 to escape macrophage-mediated immune surveillance. Trillium Therapeutics is developing SIRPaFc fusion proteins to block the CD47 “do not eat” signal. The preclinical rationale and emerging clinical data for this novel class of innate immune system checkpoint inhibitors will be discussed.

11:15 The Development of ARRY382John E. Robinson, PhD, Director, Array BioPharma, Inc.There is growing interest in the role of CSF1 in cancer. CSF1 driven M2 macrophages mediate immune suppression in the tumor microenvironment and therefore CSF1R inhibition provides a viable therapeutic strategy for augmenting established tumor immunotherapeutics such as anti-PD-1 and anti-CTLA4. ARRY-382 is a potent, selective CSF1R kinase inhibitor that could have utility in immune-oncology. In a phase I study in cancer patients ARRY-382 induced a 28X increase in circulating CSF-1 while simultaneously reducing non-classical (M2) macrophages by 96% from baseline. The design and discovery of ARRY-382 along with additional clinical results will be presented.

EMERGING TECHNOLOGIES AND MODEL ADVANCEMENT11:45 Chairperson’s RemarksDonald L. Durden, MD, PhD, Director, SignalRx Pharmaceuticals, Inc.11:45 Macrophage Syk-PI3Kγ-HIF Axis Controls Tumor Immune SuppressionDonald L. Durden, MD, PhD, Director, SignalRx Pharmaceuticals, Inc.12:15 pm Session Break12:25 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own1:15 Refreshment Break in the Exhibit Hall with Poster Viewing

EMERGING TECHNOLOGIES AND MODEL ADVANCEMENT (CONT.)1:55 Chairperson’s RemarksDonald L. Durden, MD, PhD, Director, SignalRx Pharmaceuticals, Inc.2:00 Cancer Immunotherapy Getting Brainy: Visualizing the Distinctive CNS Metastatic Niche to Illuminate Therapeutic ResistanceBryan Ronain Smith, PhD, Associate Professor, Instructor, Radiology and Molecular Imaging Program, Stanford UniversityCurrent methods to examine the immunobiology of metastases in the brain are constrained by tissue processing methods that limit spatial data collection, omit dynamic information, and cannot recapitulate the heterogeneity of the tumor microenvironment. In the current review, we describe how high-resolution, live imaging tools, particularly intravital microscopy (IVM), are instrumental in answering these questions.





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2:30 Sialyl Tn: A Novel Therapeutic Target for Myeloid Derived Suppressor CellsDavid A. Eavarone, PhD, Senior Scientist, Siamab TherapeuticsTumor expression of the glycan Sialyl Tn (STn) is well established and can be leveraged for therapeutic intervention. We have detected the presence of STn on the surface of infiltrating myeloid derived suppressor cells (MDSCs) in a panel of human tumor samples. Data from in vivo tumor models links tumor and MDSC STn expression and supports the use of anti-STn therapeutics for targeting MDSCs and reducing tumor immune suppression.

3:00 TIM-3 Regulates CD103+ Dendritic Cell Function and Response to Chemotherapy in Breast CancerBrian Ruffell, Assistant Member, Immunology, H. Lee Moffitt Cancer Center and Research InstituteImmunotherapeutic approaches are particularly lacking in breast cancer. Here we describe that TIM-3 expression by intratumoral CD103+ DCs regulates chemokine expression during paclitaxel treatment, with anti-TIM-3 antibody administration leading to an immune-mediated response to chemotherapy in murine models. These findings expand upon the potential targets of TIM-3 antibodies currently in clinical trials and offer a rationale for combinatorial studies with chemotherapy.

3:30 Re-Programming Tumor Myeloid CompartmentKarrie Wong, PhD, Investigator II, Exploratory Immuno-Oncology, Novartis Institutes for BioMedical Research, Inc.Granulocyte-macrophage colony-stimulating factor (GM-CSF), a pleiotropic cytokine that modulates the differentiation and maturation of innate immune cells, has a complex role in cancer immunotherapy. In the tumor microenvironment, GM-CSF contributes to immunosuppression in the tumor microenvironment in a context dependent manner by inducing myeloid suppressor cells and regulatory T cells. Using an in vitro assay and in vivo syngeneic tumor models, we explored targets of GM-CSF mediated myeloid cell immunosuppression.4:00 Close of Conference




DiscoveryOnTarget.com • 25TARGETING THE UBIqUITIN-PRoTEASomE SySTEm

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TARGET-BASED DISCOVERY & VALIDATION

The ubiquitin-proteasome system (UPS) is a well-controlled, selective mechanism for intracellular protein degradation and turnover. New understanding of the role and molecular mechanisms involved in the dysregulation of the UPS has led to its emergence as a key regulator of protein function and stability. Although implicated to play a role in cancer, CNS, infectious diseases and more, the multi-step processes involved, and the diversity of substrates, make it difficult to target the UPS. However, in recent years, the development of high-quality chemical probes and assay technologies has turned it into one of the most exciting targets for discovering novel drugs. In the UPS, the ligases and deubiquitinases (DUBs) have recently attracted a lot of attention as possible targets for clinical intervention. Cambridge Healthtech Institute’s Targeting the Ubiquitin-Proteasome System conference will bring together a diverse group of chemists and biologists to discuss the promise and challenges in modulating the UPS.


Targeting Autophagy• September 25 Short Course 11: Mechanistic






EMERGING ASSAYS & APPROACHES TO STUDY AND MODULATE THE UBIQUITIN CASCADE8:00 Welcome RemarksTanuja Koppal, PhD, Conference Director, Cambridge Healthtech Institute8:05 Chairperson’s Opening RemarksDaniel Finley, PhD, Professor, Department of Cell Biology, Harvard Medical School

8:10 USP14: Mechanism, Specificity, and InhibitionDaniel Finley, PhD, Professor, Department of Cell Biology, Harvard Medical SchoolUSP14, a proteasomal deubiquitinating enzyme, can rapidly remove ubiquitin prior to substrate commitment to degradation, thus rescuing substrates from a fate of degradation. Accordingly, small-molecule USP14 inhibitors that we have identified can stimulate the degradation of specific proteasome targets. USP14 shows a novel principle of selectivity in that it only deubiquitinates proteins carrying multiple ubiquitin chains. USP14 is activated ~1000-fold by the proteasome. We will discuss interesting new mutants that prevent this activation.8:40 Conformational Remodeling of USP7 Catalytic Domain to Promote Deubiquitinating ActivityAyşegül Özen, PhD, Scientist II, Blueprint MedicinesUSP7 catalytic domain (USP7cd) shows limited activity alone and is regulated by intramolecular domains. Structural features stabilizing the inactive state and atomistic mechanism of activation remain unclear. By comparative structural analyses, molecular dynamics simulations, and in silico sequence re-engineering, we identified key determinants of USP7cd activation, engineered USP7cd for improved activity, and show that electrostatics in a distal loop and local packing in the core together modulate USP7cd activation.9:10 Targeting the Deubiquitinase STAMBP Inhibits Inflammasome ActivityJoseph S. Bednash, MD, Postdoctoral Scholar, Division of Pulmonary and Critical Care Medicine, University of PittsburghInflammasomes regulate innate immune responses by facilitating maturation of inflammatory cytokines,

interleukin (IL)-1β and IL-18. The deubiquitinase enzyme, STAM-binding protein (STAMBP) is necessary for inflammasome activation and IL-1β secretion after Toll-like receptor (TLR) agonism. A small-molecule inhibitor of STAMBP suppresses IL-1β release after TLR agonism in both cell and tissue models. These findings describe a unique pathway of inflammasome regulation with the identification of STAMBP as a potential therapeutic target.9:40 Grand Opening Coffee Break in the Exhibit Hall with Poster Viewing10:25 New Screening Technologies and Chemical Probes Targeting the Ubiquitin System: Inhibitors, Activators, and DegradersAlexander Statsyuk, PhD, Assistant Professor, Department of Pharmacological and Pharmaceutical Sciences, University of HoustonThe Ubiquitin System has emerged as promising system for drug discovery. Two major principles of targeting the ubiquitin system have emerged: direct targeting of the enzymes that control protein ubiquitination, and hijacking E3 ligases to induce protein degradation. In this lecture I will outline novel screening tools and technologies to discover small molecule inhibitors/activators and hijackers for RBR/HECT E3 ligases.10:55 A Targeted Quantitative Proteomic Assay for Parkinson’s Disease That Measures the Dynamics of Ubiquitin Events on Mitochondria and Their Modulation by Small MoleculesAlban Ordureau, PhD, Postdoctoral Fellow, Laboratory of Dr. Wade Harper, Department of Cell Biology, Harvard Medical SchoolThe kinase PINK1 and Ub ligase Parkin, both mutated in Parkinson’s disease, promote mitochondrial outer membrane ubiquitylation and mitophagy. We have developed a quantitative proteomics approach that allows the dynamics and site specificity of Parkin-dependent mitochondrial ubiquitylation to be assessed in model systems and ES cell-derived neurons. We demonstrate that this approach can be used to monitor the activity of activators, inhibitors and regulators of the pathway with precision.

6th Annual | September 26-27

Targeting the Ubiquitin-Proteasome System Small Molecules and Assays for Modulating DUBs, Ligases and More





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11:25 Mass Spectrometry Analysis of Linkage-Specific Ubiquitin Sites in Response to Oxidative StressGustavo M. Silva, PhD, Assistant Professor, Department of Biology, Duke UniversityOxidative stress is a prevalent condition that can lead to cell death, causing a variety of human diseases. To combat the harmful effects of oxidative stress, protein ubiquitination plays a significant role in regulating function, location, and fate of the proteome. Although the ubiquitin system is highly complex, here we used mass spectrometry to tease out a distinct ubiquitin signal, revealing new pathways relevant for stress response.

Sponsored by11:55 Drugging the Undruggable: Discovering Novel Drugs for the Ubiquitin-Proteasome SystemPeter Foote, PhD, Senior Scientist II, Research & Development, LifeSensorsWhile ubiquitin regulates critical disease pathways, few FDA-approved drugs target the UPS, due to a lack of physiological HTS tools and PD markers for cellular activity. We have developed assays enabled by Tandem Ubiquitin Binding Entities (TUBEs) to quantitate cellular substrate ubiquitylation and help accelerate successful compounds to the clinic.12:10 Sponsored Presentation (Opportunity Available)12:25 pm Session Break12:35 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own1:15 Refreshment Break in the Exhibit Hall with Poster Viewing

NOVEL STRATEGIES FOR TARGETING USP7 AND PROTEASOME1:50 Chairperson’s Remarks1:55 Targeting the Nrf1-mediated Proteasome Recovery Pathway in CancerSenthil K. Radhakrishnan, PhD, Assistant Professor, Department of Pathology, Virginia Commonwealth UniversityInhibition of cellular proteasome results in transcriptional upregulation of proteasome subunit genes eventually leading to the recovery of proteasome activity. In mammalian cells, this recovery pathway is mediated by the transcription factor Nrf1.

Consistent with this observation, depletion of Nrf1 enhances proteasome inhibitor-mediated apoptosis in multiple cancer cells. In this presentation, I will describe a strategy to target the Nrf1 pathway to potentiate the action of proteasome inhibitor drugs in cancer. 2:25 Small Molecule Activation of Proteasome ActivityJetze Tepe, PhD, Associate Professor of Chemistry, Department of Chemistry, Michigan State UniversityIntrinsically disordered proteins are important, low-abundant signaling proteins targeted for degradation by the 20S proteasome. When over-expressed, these disordered proteins are directly implicated in many human diseases, including neurodegenerative diseases and cancer. Our work demonstrates that small molecules can enhance the catalytic degradation of intrinsically disordered proteins by the 20S proteasome, which represents a new therapeutic strategy to combat human diseases.2:55 Sponsored Presentation (Opportunity Available)3:25 Refreshment Break in the Exhibit Hall with Poster Viewing and Poster Competition Winner Announced4:05 USP7 Inhibition Impairs FOXP3+ Treg Function and Promotes Antitumor ImmunityWayne W. Hancock, MD, PhD, Professor, Pathology and Chief of Transplant Immunology, Children’s Hospital of Philadelphia and University of PennsylvaniaFOXP3+ T-regulatory (Treg) cells are present in increased numbers and display significantly enhanced suppressive function compared to Tregs isolated from adjacent lung, lymph node or blood of the same individual, leading to potent suppression of host anti-tumor immunity. USP7 inhibition is able to preferentially impair FOXP3+ Treg function while maintaining host-anti-tumor immunity, leading to beneficial effects when used alone or in conjunction with checkpoint blockade, vaccination or other therapeutic approaches.4:35 Potent and Selective USP7 Inhibitors Target Multiple Tumor Types through Diverse MechanismsPaul Kassner, PhD, Vice President, FLX Bio, Inc.USP7 is a deubiquitinase with multiple downstream targets. Inhibitors of USP7 are expected to decrease function of oncogenes, increase tumor suppressor function, enhance immune function and sensitize tumor cells to DNA damaging agents. FLX Bio has

developed potent and selective inhibitors of USP7 as a novel approach to cancer therapy.




NEW PROBES AND INHIBITORS TARGETING DUBS AND LIGASES8:00 Chairperson’s RemarksStephanos Ioannidis, Ph.D., Head, Early Portfolio, FORMA Therapeutics

Maximize your experience on-site at Discovery on Target 2018!The Intro-Net offers you the opportunity to set up meetings with selected attendees before, during and after this conference, allowing you to connect to the key people you want to meet. This online system was designed with your privacy in mind and is available only to registered session attendees of this event. Registered conference attendees will receive more information on accessing the Intro-Net in the weeks leading up to the event.





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8:05 DUBing The UndruggableStephanos Ioannidis, Ph.D., Head, Early Portfolio, FORMA Therapeutics FORMA Therapeutics deploys multiple drug discovery screening platforms to explore the DUB family (DUBome) and along with DUB scaffold repurposing, automated parallel synthesis, and computational / crystallographic insights specific and selective inhibitors within the DUBome have been identified. As part of a fully-integrated R&D strategy, DUB alliances which include FORMA and key collaborative networks have been forged to assist in the interrogation of previous undruggable targets via specific DUB inhibition. In this presentation FORMA’s novel approach to DUBs and drugging the undruggable will be described.8:35 Ubiquitin Code-Reading, Writing and Editing: Future of Breakthrough TherapiesTauseef R. Butt, PhD, President and CEO, Progenra, Inc.We are currently developing small molecules that inhibit the cancer-supporting DUBs and ubiquitin ligases. The DUB inhibitors are capable of both killing tumor cells directly and suppressing regulatory T cells, thereby unleashing effector T cells, which identify and kill tumor cells. These results constitute the first example of a small molecule single agent that works by targeting both the tumor itself and the tumor’s ability to escape surveillance and killing by the host immune system and, in addition, by eliminating tumor metastasis.

9:05 Ubiquitination-Deubiquitination: A Friend and foe in Cellular HomeostasisSayantanee Niyogi, PhD, Scientist, Membrane Biology Section, National Institutes of Health (NIH)We performed a screen knocking down about 100 deubiquitinating enzymes to screen for DUBs that had an effect on traffic of proteins, upregulated during Cancer. We identified two DUBs; USP3 and USP6 that decreased the half-life of long-lived proteins routing them to degradation. We also discovered that over-expression of USP6 could counter the effect of an E3-Ligase MARCH8 induced degradation. This study demonstrates that cycles of ubiquitylation and deubiquitylation can determine whether specific proteins are degraded or recycled.9:35 Coffee Break in the Exhibit Hall with Poster Viewing10:20 Plate-Based Approach to Identify PROTACS Molecules and Protein DegradersDavide Gianni, PhD, Team Leader, Discovery Sciences, AstraZenecaPROTACS provide a new modality to drug previously challenging targets and much evidence indicates that protein degraders are a mode of inhibition that can be pursued post HTS. Western Blot is mostly used to characterize PROTACS molecules, but it has a number of obvious limitations. The adoption of plate-based approaches is essential in PROTACS and several options are available such as, antibody-based

and non-antibody based approaches. We will present two case studies building plate-based, HTS-friendly protein degradation assays potentially applicable for PROTACS identification campaigns.10:50 PROTACS: The Chemical Equivalent of CRISPRShanique Alabi, Graduate Student, Laboratory of Dr. Craig Crews, Department of Molecular, Cellular and Developmental Biology, Yale UniversityInduced protein degradation offers several advantages over traditional inhibition strategies and has emerged recently as a potential therapeutic option. For the past 16 years, we have helped develop this fast-growing field, shepherding our initial chemical biology concept into a drug development strategy that is on the verge of clinical validation. PROTACS with high target selectivity, potency, and oral bioavailability will be discussed as well as a system to address the ‘PROTACability’ of particular E3 ligases.11:20 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own11:50 Conference Registration Open






DiscoveryOnTarget.com • 28KINASE INHIBIToR DISCoVERy

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In 2017 we saw several kinase inhibitors approved by the FDA. Case studies of approved, clinically advanced or promising inhibitors will be presented at this year’s Kinase Inhibitor Discovery conference at the Discovery on Target event in Boston. Special coverage will be given to work dedicated to binding kinetic studies with kinases and other issues that remain a challenge, including selectivity. Attend to learn more.


Targeting Autophagy• September 25 Short Course 1: Introduction to

GPCR-Based Drug Discovery• September 25 Short Course 10: Applications of

Artificial Intelligence and Machine Learning in Drug Discovery and Development



• September 27 Short Course 15: Introduction to Targeted Covalent Inhibitors




CLINICAL AND ADVANCED INHIBITORS2:45 Welcome RemarksVictoria Mosolgo, Conference Producer, Cambridge Healthtech Institute

2:50 Chairperson’s Opening RemarksCampbell McInnes, PhD, Professor, Drug Discovery and Biomedical Sciences, University of South Carolina2:55 Cancer Drug Resistance, Challenge and Opportunity – The Osimertinib StoryStephen Fawell, PhD, Vice President, Head Oncology iScience, AstraZenecaFirst line EGFR inhibitors like gefitinib are highly active in EGFRmt NSCLC, however most patients eventually relapse with drug resistant disease of which the majority are driven by a second T790M mutation. Osimertinib, a potent and selective covalent inhibitor was specifically designed to target this form of the receptor. The combination of a well designed active drug and a clear patient selection strategy led to one of the fastest approvals of an Oncology drug.3:25 Illuminating the Darkness…PKC Inhibitors for Metastatic Uveal MelanomaMichael Visser, PhD, Group Leader, Senior Investigator, Novartis Institutes for BioMedical Research, Inc.Uveal Melanoma (UM) is the most common primary intraocular malignancy of the adult eye, with an incidence of five to six cases per million. Despite aggressive local management of primary UM, the development of metastases is common and occurs in ~50% of patients. There are currently no effective treatment options for metastatic disease and median survival is around nine months. Genetic analysis of UM samples reveals the presence of activating mutations in the Gq alpha subunits, GNAQ and GNA11. One of the key downstream targets of the constitutively active Gq alpha subunits is the protein kinase C (PKC) signaling pathway. We describe the discovery of NVP-LXS196, a potent, selective PKC inhibitor. The lead series was optimized for kinase and off target selectivity to afford a compound that is rapidly absorbed and well tolerated in pre-clinical species. NVP-LXS196 is currently in Phase I clinical trials to assess the safety, tolerability and pharmacokinetic profile in metastatic uveal melanoma

patients where encouraging early activity has been observed.

Sponsored by

®

3:55 Sensors for Continuous Monitoring of Protein Kinase & Phosphatase ActivityErik Schaefer, President, AssayQuant TechnologiesAssayQuant® is combining chelation-enhanced fluorescence, using the sulfonamido-oxine (Sox) chromophore, with high-throughput peptide synthesis methods to identify optimized physiologically-based substrates for measuring the activity of protein kinases and phosphatases. The result is a simple yet powerful method that allows continuous, quantitative and homogenous detection of activity using recombinant enzymes or crude cell or tissue lysates. This approach provides a quantum improvement in assay performance and productivity needed to accelerate discovery and drug development efforts.4:25 Refreshment Break in the Exhibit Hall with Poster Viewing

CLINICAL AND ADVANCED INHIBITORS (CONT.)5:00 ARQ 531, a Reversible BTK Inhibitor Exhibits Distinct Kinase Selectivity and Demonstrates Potent Anti-Tumor Activity in Ibrutinib Resistant Tumor ModelsSudharshan Eathiraj, PhD, Senior Lead Investigator, Translational Medicine, ArQule, Inc.ARQ 531 is an ATP competitive reversible inhibitor of BTK. Kinase selectivity profile combined with pathway analysis data suggests that ARQ 531 targets multiple oncogenic signaling pathways and potently inhibits tumor growth in the mouse xenografts of cell lines primarily resistant to previously approved BTK inhibitor, ibrutinib. ARQ 531 monotherapy is currently being investigated in a Phase 1 dose-escalation study in B-cell hematologic malignancies.5:30 Full Kinome and Cancer Cell Panel Profiling of All Kinase Inhibitor Drugs Approved for Clinical UseGuido Zaman, PhD, Managing Director & Head of Biology, Netherlands Translational Research Center B.V.All small molecule kinase inhibitors approved for clinical use were profiled on a panel of 275 biochemical kinase assays and 102 cancer cell line


Kinase Inhibitor Discovery Emerging Targets, Tools, and Development Strategies





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proliferation assays (Oncolines). Novel genomic biomarkers predictive of drug response in human tumor cells were discovered. Comparative analyses of biochemical and cellular profiling data yielded new insight into the mechanism of action of different kinase inhibitor drugs acting via the same primary target or signaling pathway.

COVALENT INHIBITORS6:00 The Meisenheimer Complex as a Novel Paradigm in Drug Discovery: Targeting PLK1 through a Novel Covalent MechanismCampbell McInnes, PhD, Professor, Drug Discovery and Biomedical Sciences, University of South CarolinaThis talk will describe novel inhibitors of PLK1 kinase activity that inhibit through the unique covalent strategy that reversibly inhibits kinase activity by formation of a Meisenheimer Complex. The discovery and optimization of these inhibitors is described in addition to confirmation of their on-target anti-tumor mode of action through selective PLK1 inhibition.6:30 Dinner Short Course RegistrationClick here for details on short courses offered.9:30 Close of Day



SELECTIVE INHIBITORS & PROMISING CANDIDATES8:30 Chairperson’s RemarksIstvan Enyedy, PhD, Computational Chemistry, Biogen8:35 Discovery of ATR Inhibitor BAY 1895344 with Favorable PK Properties and Promising Anti-

Tumor Efficacy in Monotherapy and Combination in Preclinical Tumor ModelsUlrich Luecking, PhD, Principal Scientist, Medicinal Chemistry, BayerThe identification of ATR inhibitor BAY 1895344 is reported. In vitro, BAY 1895344 was shown to be a very potent and highly selective ATR inhibitor, which potently inhibits proliferation of a broad spectrum of human tumor cell lines. BAY 1895344 revealed good bioavailability across species. Moreover, BAY 1895344 demonstrated potent anti-tumor efficacy in monotherapy in DNA damage response deficient tumor models as well as in combination treatment with DNA damage-inducing and DNA repair-compromising therapies.9:05 Discovery of Novel, Soft JAK Kinase Inhibitors for Topical Treatment of PsoriasisDaniel R. Greve, PhD, Senior Manager, Head of Medicinal Chemistry, LEO Pharma A/SThe presentation covers our efforts in a recent research project aiming for novel, selective pan-JAK inhibitors to treat psoriasis topically. The small molecule inhibitors have a pharmacokinetic profile that allows for high local exposure combined with low systemic exposure, by optimizing human hepatic clearance. The best compounds are efficacious in our mouse xenograft model of plaque psoriasis, while being rapidly cleared from systemic circulation.9:35 Discovery of AS-871, a Selective and Non-Covalent BTK Inhibitor for the Treatment of Rheumatoid ArthritisMasaaki Sawa, PhD, CSO, Carna Biosciences, Inc.We have developed a novel non-covalent inhibitor of BTK through the optimization of a lead compound which was derived from our SYK/BTK dual inhibitor program. During the lead optimization, we employed a dual screening approach using two conformationally different BTK proteins, an activated form of BTK and an unactivated form of BTK to enhance the selectivity. AS-871 displayed potent inhibitory activities in cellular assays and demonstrated significant efficacies in several in vivo models.10:05 Coffee Break in the Exhibit Hall with Poster Viewing and Poster Competition Winner Announced

PHOSPHATASES10:45 A Genomic Perspective on Protein and Lipid PhosphatasesGerard Manning, PhD, Director, Bioinformatics and Computational Biology GenentechKinases and phosphatases jointly control most biological pathways. Many phosphatases are altered in disease but have been challenging to target. We have cataloged all human protein and lipid phosphatases (the phosphatome) to serve as a global resource for understanding all phosphorylation events, and to derive new targets and biomarkers. I will review our findings and potential for new therapeutic development..11:15 Novel Inhibitor Design Concepts for Protein Kinases and PhosphatasesGerhard Mueller, PhD, CSO, Gotham TherapeuticsThe last 20 years of research on small molecule protein kinase inhibitors resulted in approximately 40 small molecule kinase inhibitors that received market approval. Apart from the traditional design paradigm, i.e. optimizing compounds to competitively bind into the ATP site, a number of allosteric inhibitor binding modalities have been discovered that allow to engineer molecular properties such as target residence time. In contrast to the kinase field, the target family of protein phosphatases is and remains an underexplored area even though individual members are well-validated drug targets for therapeutic intervention into a number of disease states. The medicinal chemistry approaches that have been chosen to inhibit protein phosphatases will be highlighted, again emphasizing the relevance of allosteric binding mechanisms over traditional active site-directed design approaches.

Sponsored by11:45 Exploring Kinase Inhibitor Selectivity and Affinity in Live Cells Using NanoBRETMatthew Robers, Senior Research Scientist, Group Leader, Biology, Promega CorporationYuren Wang, Director, Pharmacology and QC, Cell-Based Assay Group, Reaction Biology Corp.We will describe the application of an energy transfer technique (NanoBRET) that enables the first quantitative approach to broadly profile fractional occupancy and compound affinity for kinases in live cells. Through a collaboration with Reaction Biology Corp (RBC), the NanoBRET technology has been scaled into a high-throughput cell-based profiling format. The validated Promega’s NanoBRET cell-based assay technology platform is compatible with RBC’s





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broad spectrum in vitro biochemical radioactive kinase assay platform. 12:15 pm Session Break12:25 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own1:15 Refreshment Break in the Exhibit Hall with Poster Viewing

BINDING KINETICS AND PROFILING1:55 Chairperson’s RemarksGuido Zaman, PhD, Managing Director & Head of Biology, Netherlands Translational Research Center B.V.2:00 Kinetic Selectivity and Target Vulnerability in Drug DiscoveryPeter Tonge, PhD, Professor, Chemistry, Stony Brook UniversitySince a drug can bind to two targets with the same affinity but different on and off rates, drug selectivity has both a thermodynamic and a kinetic component. Using systems such as Bruton’s tyrosine kinase as an example, we discuss the utility of kinetic selectivity, and the role of target turnover and target vulnerability in the translation of kinetic selectivity to in vivo drug activity.

2:30 Conformational Adaption May Explain the Slow Dissociation Kinetics of Roniciclib (BAY 1000394), a Type I CDK Inhibitor with Kinetic Selectivity for CDK2 and CDK9Christian Stegmann, PhD, Management Support, Research & Development, Pharmaceuticals, Bayer AGRoniciclib (BAY 1000394) is a type I pan-CDK (cyclin-dependent kinase) inhibitor which has revealed potent efficacy in xenograft cancer models. We could show that roniciclib displays prolonged residence times on CDK2 and CDK9, whereas residence times on other CDKs are transient, thus giving rise to a kinetic selectivity of roniciclib. In tumor cells, the prolonged residence times of roniciclib on CDK2 and CDK9 are reflected in a sustained inhibitory effect on retinoblastoma protein (RB) phosphorylation, indicating that the target residence time on CDK2 may contribute to sustained target engagement and antitumor efficacy.3:00 A Kinase Platform for the Discovery of Reversible and Covalent Kinase InhibitorsIgor Mochalkin, PhD, Associate Director, EMD SeronoProtein kinases play an important role in signaling pathways that control cell growth, metabolism, proliferation and apoptosis, and the dysregulation of kinase functions can fuel cancers and other diseases.

To identify novel, potent and selective kinase inhibitors for the treatment of oncological and immunological disorders, we established a Kinase Platform Project team to leverage kinase-target profiling, de novo design, fragment screening and covalent approaches targeted to individual kinases and kinase mini-panels. In this presentation, we highlight our implementation of drug discovery technologies that led to the identification and development of two clinical candidates, evobrutinib and M2698.3:30 Strategies for Designing Selective Kinase InhibitorsIstvan Enyedy, PhD, Computational Chemistry, BiogenDesigning selective kinase inhibitors has been challenging. The desired selectivity of a kinase inhibitor depends on the therapeutic area. Polypharmacology is often desired in oncology, while highly selective inhibitors are usually needed for other therapeutic areas. Strategies for designing selective inhibitors vary from targeting residues that are less conserved to exploiting differences in the flexibility of the kinase domain when selectivity among isoforms is desired.4:00 Close of Conference




DiscoveryOnTarget.com • 31CNS AND NEURoDEGENERATIVE TARGETS

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The identification of therapeutic targets based on novel mechanistic approaches is urgently needed for CNS and neurodegenerative diseases, particularly for conditions such as Alzheimer’s and Parkinson’s which represent extensive unmet medical need and blockbuster potential for the right therapy. Driven by an improving understanding of CNS disease biology and the emergence of new mechanisms and targets, Cambridge Healthtech Institute’s CNS and Neurodegenerative Targets conference profiles the latest tools, targets and platforms driving today’s CNS drug discovery strategies, with critical updates and findings in key areas such as new targets for misfolded proteins, tau, GCPRs, gene therapy, and neuroinflammation.


Regenerative Medicine• September 25 Short Course 9: CNS

Translational Strategies• September 26-27 Conference: CNS and

Neurodegenerative Targets • September 27-28 Conference: Lead

Generation Strategies• September 27 Short Course 16:

Immunology Basics


LATEST BIOLOGY, PATHWAYS AND CHALLENGES FOR CNS THERAPEUTICS8:00 Welcome RemarksDaniel Barry, Senior Conference Director, Cambridge Healthtech Institute8:05 Chairperson’s Opening RemarksDario Doller, PhD, Senior Director, Exploratory Science, SAGE Therapeutics

8:10 KEYNOTE PRESENTATION: Progress in Deciphering Alzheimer’s and Parkinson’s Diseases Predicts New Therapeutic ApproachesDennis J. Selkoe, MD, The Vincent and

Stella Coates Professor of Neurologic Diseases, Harvard Medical School; Co-Director, Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s HospitalThere are specific reasons for the failure of certain clinical trials in AD, and the underlying biological understanding of the disease is sound and steadily improving. Here, we will review the basic science of AD pathogenesis. We will also discuss a new hypothesis for the initiation of dopaminergic neurodegeneration in Parkinson’s disease.

8:40 Translating Targets into Therapeutic Candidates for Alzheimer’s DiseaseStephen Wood, PhD, Director, Neuroscience Discovery Research, Amgen, Inc.Information coming from human genetic studies has implicated several key pathways in the pathogenesis of Alzheimer’s disease (AD). These include processing of the Amyloid Precursor Protein and activation of the innate immune response. Here we describe efforts to understand the biology of targets in each of these pathways in order to help translate that into potential, disease-modifying therapeutics for the treatment of AD.

MACHINE LEARNING, AI AND SCREENING TO IMPROVE CNS DRUG DISCOVERY9:10 Machine Learning Models in CNS Drug DiscoveryIstvan Enyedy, PhD, Principal Scientist, BiogenFor CNS targets, the design of modulators that permeate the blood-brain barrier is challenging. The promiscuity of efflux transporters is the main reason for stopping the blood-brain barrier penetration of a large variety of compounds. Machine learning methods have been used for building models for predicting substrates of efflux transporters. The performance of several models will be presented.9:40 Grand Opening Coffee Break in the Exhibit Hall with Poster Viewing10:25 Phenotypic Screening for Novel Inhibitors of Tau Aggregation in Human iPSC-Derived NeuronsBhavya Voleti, PhD, Associate Principal Scientist, Neurodegenerative Diseases Discovery WP, Merck Research LaboratoriesTauopathies are neurodegenerative diseases characterized by the presence of aggregates of abnormally hyperphosphorylated tau. Due to the intrinsic differences in clearance mechanisms between neuronal and non-neuronal cells, human iPSC-derived neurons were used to develop a biologically relevant tau model. The goal of this work is to uncover key targets/MOAs of interest involved in the clearance of tau aggregates that could become potential strategies to cure neurodegenerative disorders associated with tau.10:55 Evolving the Concept of Phenotypic Screening to a New Level of Data-Driven, Systems Oriented Drug DiscoveryPeder Svensson, PhD, Director, Comp Chem & Biol, CIO, Integrative Research LaboratoriesISP represents a systems-oriented approach to CNS drug discovery, with the potential to significantly improve the discovery process, reducing resource needs, and development risks. The technology emanates from an integrative view on disease states and drug-induced states. Hence, pharmacological evaluation is focused on comprehensive, phenotypic characterization. We discuss theoretical considerations, as well as practical


CNS and Neurodegenerative Targets Targets and Tools for Developing CNS Therapies





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applications of ISP, illustrating with compounds discovered and characterized by the principles outlined.11:25 Mechanistic Insights into the Use of Mevalonate Pathway Modulators as Cognitive EnhancersAngela Mabb, PhD, Assistant Professor, Georgia State University, Neuroscience InstituteTo identify specific targets in the mevalonate pathway that promote AMPAR abundance, we established a high-content surface AMPAR assay in mouse primary hippocampal neurons. Using this assay, we found that tocotrienols increased surface AMPAR expression. Tocotrienol-mediated upregulation of surface AM-PARs was also associated with reduced expression of Arc protein, suggesting a mechanistic link of tocotri-enol action on AMPAR abundance.

Sponsored by11:55 Applications of AI in Drug Target DiscoveryJane Yu, Technical Pre-Sales, IBM Watson for Drug Discovery, IBM Watson HealthWith millions of scientific research articles published each year, innovation in the life sciences suffers from knowledge waste and lack of knowledge integration. IBM Watson for Drug Discovery addresses this issue by extensively mining literature and data to help scientists accelerate biomedical research. Using advanced analytics and machine learning, the platform can also predict novel relationships, as demonstrated through our recent work with Barrow Neurological in ALS disease, and Pfizer in immuno-oncology, among many projects.12:25 pm Session Break12:35 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own1:15 Refreshment Break in the Exhibit Hall with Poster Viewing

TARGETING AND DEVELOPING NOVEL CNS TARGETS1:50 Chairperson’s RemarksDaniel Klamer, PhD, MBA, Vice President, Business Development & Scientific Strategy, Anavex Life Sciences Corp.

1:55 ANAVEX 2-73, a Sigma-1 Receptor Agonist, in Phase IIb/III for the Treatment of Alzheimer’s DiseaseDaniel Klamer, PhD, MBA, Vice President, Business Development & Scientific Strategy, Anavex Life Sciences Corp.Anavex Life Sciences Corp.’s lead drug candidate, ANAVEX 2-73, recently completed a successful Phase IIa clinical trial for Alzheimer’s disease. ANAVEX 2-73 is an orally available drug candidate that restores cellular homeostasis by activating the sigma-1 receptor. Full genomic analysis of the study participants resulted in the identification of genetic mutations linked to treatment response. Clinical studies in several indications are planned or underway utilizing a precision medicine approach.2:25 M3 Biotechnology: Neuro-Regenerative Disease-Modifying TherapiesLeen Kawas, PhD, CEO, M3 BiotechnologyA clinical-stage biotechnology company with a platform of novel small molecule therapeutics for neurodegeneration with a focus on Alzheimer’s disease. M3’s lead therapeutic is a modulator of a novel neurotrophic growth factor shown to slow disease progression, exhibit neuroprotective and regenerative properties and restore cognitive function in preclinical studies of AD. Currently in human clinical trials, the lead is assessed for safety, tolerability, pharmacokinetics and EEG as a pharmacodynamic biomarker.2:55 Sponsored Presentation (Opportunity Available)3:25 Refreshment Break in the Exhibit Hall with Poster Viewing and Poster Competition Winner Announced4:05 Non-Fibrillar Amyloid-Beta Oligomers – It’s Time to Intercept the Most Relevant AD TargetGrant A. Krafft, PhD, Chairman and Chief Scientist, Acumen Pharmaceuticals, Inc.Alzheimer’s disease (AD) affects more than 45M people worldwide, yet no treatment affords meaningful symptomatic or disease modifying benefits. Recent failures of amyloid-directed therapeutics have cast doubt on the amyloid hypothesis; however, none of the failed drugs directly targeted non-fibrillar amyloid β oligomers (AbOs), now widely recognized as the AD-relevant Aβ structures. This presentation will highlight the AbO-AD linkage and profile ACU193, the first AbO-selective AD immunotherapeutic.

4:35 Oligomerix - Targeting Tau in Alzheimer’s Disease and Related DementiasJames Moe, PhD, MBA, President and CEO, Oligomerix, Inc.Oligomerix is discovering and developing small molecule disease modifying drugs for Alzheimer’s disease that target the initial step in tau aggregation leading to the formation of tau oligomers, the toxic tau aggregates responsible for neuronal loss, impairment of memory formation and transmission of tau pathology during disease progression. The lead compound from our program inhibited tau aggregation in transgenic mice expressing human tau, best representing tau aggregation in AD.



THURSDAY, SEPTEMBER 277:30 am Registration Open and Morning Coffee8:00 Chairperson’s RemarksStephan Schann, Head of Research & Development, Domain Therapeutics8:05 Targeting Protein Degradation Pathways in Neurodegenerative DiseaseMichael K. Ahlijanian, PhD, Head, Neuroscience, FORMA TherapeuticsOver the past several years, mutations in genes associated with genetic or familial forms of these diseases have been identified. Several of these genes are components of cellular protein degradation networks including autophagy and the unfolded protein response (UPR). This talk will describe the links between genes associated with genetic forms of neurodegenerative diseases, including Parkinson’s disease and Amylotrophic Lateral Sclerosis, protein degradation networks and the potential for developing novel therapeutics that target discrete components of protein degradation in neurons.





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8:35 FEATURED PRESENTATION: Effects of USP14 Inhibition on Proteasomal Degradation in Mammalian CellsQi Wang, PhD, Director, Discovery Biology Neuroscience IMED Biotech Unit, AstraZenecaInhibition of the proteasome-associated deubiquitinase (DUB) USP14 has been considered a therapeutic strategy for accelerating degradation of aggregation-prone proteins involved in neurodegenerative diseases. In the attempt to validate this target, we studied the effects of inhibiting proteasomal DUBs on protein degradation in mammalian cells. I will present these data and discuss the limitation of USP14 as a target to accelerate proteasomal degradation.

9:05 Sponsored Presentation (Opportunity Available)9:35 Coffee Break in the Exhibit Hall with Poster Viewing10:20 Update on Merck’s LRRK2 Parkinson’s Disease ProgramMatt Fell, PhD, Principal Scientist, Neuroscience, Merck10:50 Discovery of Foliglurax, an mGluR4 PAM for the Treatment of Parkinson’s DiseaseStephan Schann, Head of Research & Development, Domain TherapeuticsmGluR4 is an emerging target for the treatment of Parkinson’s disease (PD). However, since the discovery of its therapeutic potential, no ligand has been successfully developed. Starting from the (-) PHCCC, medicinal chemistry efforts lead to the discovery of

a novel series of potent mGluR4 PAMs and to the nomination of Foliglurax, the first mGluR4 PAM clinical candidate currently evaluated in a Phase II study for the treatment of PD.11:20 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own11:50 Conference Registration Open






DiscoveryOnTarget.com • 34GPCR-BASED DRUG DISCoVERy

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G protein-coupled receptors (GPCRs), which relay chemical signals such as hormones from outside to the inside of cells, are the targets of approximately a third of the medicines on the market today. The receptors’ signaling complexities due to their ability to couple to a variety of G proteins (biased signaling) are now more understood and capitalized upon to design more selective drugs. CHI’s well-established GPCR-Based Drug Discovery conference will continue to convene prominent scientists in both academia and industry to share and discuss the latest advances in applied GPCR research. Presentations will touch on a range of topics, such as new screening assays, biophysical techniques, structure-based drug development, medicinal chemistry optimization case studies and examples of GPCR-targeted compounds in development.

RECOMMENDED ALL ACCESS PACKAGE: Choose 2 Short Courses or 1 Symposium and 2 Conferences/Training Seminars• September 25 Short Course 1: Introduction to

GPCR-Based Drug Discovery• September 26-27 Conference: Antibodies

Against Membrane Protein Targets - Part 1• September 27-28 Conference: GPCR-Based

Drug Discovery• September 27 Short Course 13: GPCR

Structured-Based Drug Discovery




GPCR STRUCTURES AND TARGETED DRUG DESIGN IMPLICATIONS2:45 Welcome RemarksAnjani Shah, PhD, Conference Director, Cambridge Healthtech Institute2:50 Chairperson’s Opening RemarksDean G. Brown, PhD, Director of External Chemistry, Hit Discovery, Discovery Sciences, IMED Biotech Unit, AstraZeneca

2:55 Structural Pharmacology of GPCRs in Asthma and Structure-Based Drug DevelopmentCheng Zhang, PhD, Assistant Professor, Pharmacology and Chemical Biology, University of Pittsburgh School of MedicineThe commonly used medication for controlling asthma includes bronchodilators and anti-inflammation drugs. Almost all bronchodilators are the agonists of beta2 adrenergic receptor (beta2AR). We report a crystal structure of human beta2AR bound to the most widely used asthma drug salmeterol, which reveals the bitopic nature of salmeterol and an additional ligand binding site in the receptor. The results provide a structural explanation for the prominent pharmacological characteristics of salmeterol including high receptor-subtype selectivity and long-lasting action. We also present the first crystal structures of a lipid GPCR, the CRTH2, as a new target for developing small molecule anti-inflammation drugs for asthma. The structures reveal critical features for the binding of CRTH2 antagonists including a Phase III drug candidate, fevipiprant. They also suggest a novel mechanism for the recognition of endogenous lipid mediators by GPCRs. Based on the structures, we have identified compounds with novel structural scaffolds as potential antagonists of CRTH2, and propose new strategies for further drug development.3:25 Apelin Receptor Structure and SignalingLiaoyuan Hu, PhD, Scientific Director, Discovery Pharmacology, Amgen Asia R&D CenterThe apelin receptor (APJ) is a potential target for the treatment of a variety of diseases. We will report the high-resolution structure of APJ, especially in ligand binding pocket, and the molecular mechanism on receptor activation and signaling pathways. We identified a critical residue for signaling selectivity (biased receptor) and rationalized the structure

mechanism using molecular dynamics simulation. These results shed light on the general mechanism of class A receptor activation and functional selectivity.

Sponsored by3:55 Biophysical Methods in Drug Discovery Dedicated to Membrane Protein TargetsMichael Hennig, PhD, CEO, leadXpro AGleadXpro combines high-quality transmembrane protein generation with structure determination methods like X-ray (SwissFEL/SLS) and cryo-EM as well as wave-guided interferometry to characterize molecular interactions with drug targets. Examples will illustrate the high sensitivity of Creoptix’ instruments and the accurate measurement of ligand binding and kinetics to support drug design.

Sponsored by4:10 Complexity Simplified: Using Smart Drug Discovery Software to Manage Disperse Assay DataDan Robinhold, Research Informatics, Collaborative Drug Discovery, Inc.Research of tomorrow is moving quickly toward a more collaborative, open source and platform-independent environment. CDD Vault (Assay Reg/ELN/Viz) now incorporates “BioAssay Express” that utilizes machine learning to scan and catalog libraries of human-readable assay text into computer-readable format to better access private, collaborative and public assay data.4:25 Refreshment Break in the Exhibit Hall with Poster Viewing

NEW GPCR-TARGETED ASSAYS AND COMPOUNDS5:00 Identification and Optimization of a CGRP Receptor Antagonist of Novel ChemotypeBrendan Crowley, PhD, Associate Principal Scientist, Neuroscience, Merck Research LabsI describe our strategy to rapidly evolve a series of CGRP receptor antagonists utilizing physical property, ligand efficiency, and diversity-guided iterative library design as well as evidence that these molecules make novel interactions in the binding site (from receptor mutagenesis, X-ray crystallography, and NMR data). I also discuss lead optimization efforts that led to an advanced candidate with high affinity for the receptor,


GPCR-Based Drug Discovery Exploiting Signaling Complexities for Better Therapeutics





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potent in vivo activity, good off-target selectivity, and a low potential human dose.5:30 TruPath: An Open-Source Platform for Comprehensive Screening of GPCR Signal Transduction PathwaysRyan T. Strachan, PhD, Research Assistant Professor, Pharmacology, University of North Carolina – Chapel HillOur understanding of G Protein-Coupled Receptor (GPCR) signaling remains incomplete and likely conceals therapeutically useful bias. Here we present an open source, optimized BRET-based Transducer Pathway screening platform (dubbed ‘TruPath’) that measures activation of 18 different G-protein signaling pathways. When combined with our GPCRome library, TruPath enables potency and efficacy profiling for both established (e.g., opioid) and understudied (e.g., MRGPRX2) receptors and their ligands, thereby revealing the full extent of transducer promiscuity and bias. We hope that such a panoramic understanding of GPCR signaling reveals new biology and therapeutic strategies.6:00 Exploration of Endosomal GPCR Signaling Using Electron MicroscopyAlex Thomsen, PhD, Assistant Professor, Department of Surgery, Columbia UniversityWe recently demonstrated that a class of GPCRs promotes endosomal signaling by forming “megaplexes” composed of a single GPCR that interacts simultaneously with β-arrestin, which drives the receptor internalization, and G protein, which initiates signaling from internalized compartments. Now we are applying a variety of electron microscopy (EM) and computational methods to obtain high-resolution structural information about the megaplex (cryo-EM), and to visualize GPCR signaling on the endosomal surface within living cells.6:30 Dinner Short Course RegistrationClick here for details on short courses offered.9:30 Close of Day



RECEPTOR PHARMACOLOGY, BIASED SIGNALING AND STRUCTURAL INSIGHTS8:30 Chairperson’s RemarksLakshmi Devi, PhD, Professor, Department of Pharmacology, Mount Sinai School of Medicine

8:35 FEATURED PRESENTATION: Mu Opioid Receptor Pharmacology: A Window into Another Dimension of GPCR FunctionGavril Pasternak, MD, PhD, Chair and Professor of Neurology, Neuroscience, Pharmacology and Psychiatry, Weill Cornell Medical College; Laboratory Head, Molecular Pharmacology Program, Memorial Sloan Kettering Cancer CenterThe mu opioid receptor Oprm1 is a member of the G-protein coupled receptor family. First demonstrated in 1973, it led to the discovery of the endogenous opioids and the ‘sodium effect’ in which sodium ions allosterically transition receptors between agonist and antagonist conformations – now established with most GPCRs. Cloning the receptor uncovered a vast array of Oprm1 splice variants, including an atypical target capable of eliciting analgesia without the side effects associated with classical opioids.

9:05 GPCR Dimerization and Deorphanization: Impact on Drug DiscoveryLakshmi Devi, PhD, Professor, Department of Pharmacology, Mount Sinai School of MedicineStudies in Dr. Lakshmi Devi’s laboratory aim at unraveling the molecular mechanisms of signal transduction mediated by G-protein coupled receptors (GPCRs) and their regulation in health and disease. Recent studies have focused on the identification of compounds targeting opioid receptor heteromers as well as ligands targeting recently deorphanized hypothalamic neuropeptide GPCRs. This presentation

will focus on different approaches used in novel ligand identification for the treatment of pain and addiction.9:35 Angiotensin Receptor Structure and Implications for Biased SignalingLaura M. Wingler, PhD, Postdoctoral Researcher, Howard Hughes Medical Institute, Lefkowitz Lab, Department of Medicine, Duke University Medical CenterThe angiotensin II type 1 receptor is a premier model system for studies of biased agonism in GPCRs, as it has both Gq-biased and β-arrestin-biased agonists that have been exceptionally well characterized. Here we use multiple structural techniques to elucidate the distinct angiotensin receptor conformations stabilized by functionally diverse ligands. Our findings suggest mechanisms by which biased agonists induce the receptor to couple selectively to particular transducers and achieve their different biological profiles.10:05 Coffee Break in the Exhibit Hall with Poster Viewing and Poster Competition Winner Announced

RECEPTOR KINETICS AND ALLOSTERIC MODULATION

10:45 FEATURED PRESENTATION: Receptor Kinetics for Probing Allosteric Modulation and Biased SignalingTerry Kenakin, PhD, Professor, Department of Pharmacology, University of North Carolina School of MedicineI will compare the muscarinic receptor Gq protein activation profiles of five exemplar molecules (slow binding agonists, partial agonists, inverse agonists, PAM-Agonists and Beta-PAMs) in calcium and IP1 assays to illustrate how quantitative comparisons to pharmacological models can both identify mechanisms of action and also convert descriptive findings to predict data for therapeutic systems. Using these models optimally allows the identification of consistent and simple scales of activity that can guide medicinal chemistry.

11:15 Drug-Target Binding Kinetics - A Case for GPCRsDong Guo, PhD, Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, ChinaThe success rate of a candidate drug moving through the clinical development phase is disappointingly low despite the fact that properties of drug candidates for a given therapeutic target are mostly optimized with respect to standard pharmacological parameters of





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affinity, potency and intrinsic activity. Determining drug target binding kinetics, next to traditional potency measures, may increase the rate of success. Our work provides new insights in ligand-GPCR interactions and underlines the importance of measuring binding kinetics of both drug candidates and competing endogenous ligands.

Sponsored by11:45 Biortus Delivers Cryo-EM Service to Drug DiscoveryXiaodong Yan, Executive Director, Biology, BiortusWuxi Biortus Biosciences Co. Ltd (founded in 2009) is located in Wuxi within the greater Shanghai area of China. As an innovation-driven CRO, Biortus is the first and the only company available in China who delivers the cutting-edge cryo-EM service to drug discovery industry.12:15 pm Session Break

Sponsored by12:25 Luncheon Presentation: Measure β-Arrestin Signaling Through Native GPCRs In High ThroughputLisa Minor, Scientific Consultant, Business Development, Multispan, Inc.Screening compounds for biased signaling using native GPCR in one cellular environment may lead to selective perturbation of disease-specific pathways. Our newly developed proprietary MultiScreenTM β-arrestin technology overcomes the receptor-tagging

drawback of other existing technologies, enabling high-throughput detection of β-arrestin translocation induced by native GPCRs in vitro and in vivo for the first time. This presentation will highlight these novel features and the robustness of this assay among other updates of our portfolio.1:15 Refreshment Break in the Exhibit Hall with Poster Viewing

BIOPHYSICAL APPROACHES1:55 Chairperson’s RemarksBrian J. Murphy, PhD, Senior Principal Scientist, Metabolic Disease Biology, Bristol-Myers Squibb Co.

2:00 Discovery of Small Molecule Protease-Activated Receptor 2 (PAR2) Antagonists Using a Stabilized GPCR, Fragment-Based Lead Generation and DNA-Encoded Library ScreeningDean G. Brown, PhD, Director of External Chemistry, Hit Discovery, Discovery Sciences, IMED Biotech Unit, AstraZenecaWe employed two screening strategies to identify antagonists at protease activated receptor (PAR2), one being a DNA-encoded library screen on PAR2 and the second a fragment screen using a stabilized PAR2 GPCR receptor. From these efforts, we identified two lead series of compounds, each of which bind to distinct and previously unknown allosteric sites.

These results illustrate the power of integrating stabilized GPCR technologies into established screening paradigms.2:30 Integrating Biophysical and Structural Data Provides Comprehensive View of GPCR FunctionMatthew Eddy, PhD, Assistant Professor, Department of Chemistry, University of Florida and Affiliated Faculty, National High Magnetic Field Laboratory3:00 Characterization of Wild Type GPCRs Using Surface Plasmon ResonanceIva Navratilova, PhD, Staff Scientist, Department of Molecular Biology, University of DundeeExpressing, purifying and analysing membrane proteins using SPR is routinely challenging. In this presentation, we will present our latest results demonstrating a scalable method for the successful development of SPR assays for a wide range of wild-type GPCRs. The SPR assays can be exploited for fragment screening and kinetic characterization to discover novel ligands.3:30 Nanodiscs for Membrane Protein Drug Discovery ApplicationsNasr Mahmoud, PhD, Postdoctoral Fellow, Laboratory of Gerhard Wagner, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School4:00 Close of Conference

INTERACTIVE BREAKOUT DISCUSSION GROUPSJoin a breakout discussion group. These are informal, moderated discussions with brainstorming and interactive problem solving, allowing participants from diverse backgrounds to exchange ideas and experiences and develop future collaborations around a focused topic. Details on the topics and moderators are available on the conference website.




DiscoveryOnTarget.com • 37CoNSTRAINED PEPTIDES AND mACRoCyClICS

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This meeting covers the progress and challenges of accessing new chemical space – the middle space – to find molecules with drug potential that are bigger than small molecules but smaller than biologics. The hope is that these middle-sized molecules are big enough for more specific interactions with protein-protein interaction surfaces but small enough to penetrate the cell, reach intracellular drug targets and be orally bioavailable. However, theory is still meeting practice. Researchers continue to refine the ‘rules’ and properties for the best design of this class of molecules which mainly consist of constrained peptides and synthetic macrocyclics.




• September 26-27 Conference: Constrained Peptides and Macrocyclics

• September 27 Short Course 14: Advancing Tools and Technologies for Fragment-Based Design

• September 27-28 Conference: Lead Generation Strategies


INHIBITING INTRACELLULAR PROTEIN-PROTEIN INTERACTIONS8:00 Welcome RemarksAnjani Shah, PhD, Conference Director, Cambridge Healthtech Institute8:05 Chairperson’s Opening RemarksScott Lokey, PhD, Professor, Chemistry and Biochemistry, University of California, Santa Cruz

8:10 KEYNOTE PRESENTATION: Peptide Drug Hunter: An Extraordinary Trek into Intracellular Target SpaceTomi K. Sawyer, PhD, Distinguished

Scientist, Peptide Drug Discovery & Innovative Technologies, Merck & Co., Inc.Macrocyclic peptides can modulate intracellular protein-protein interaction target space; however, achieving cell permeability is challenging and is hindering their therapeutic potential. Accordingly, we have focused a multidisciplinary effort on macrocyclic peptides to understand their structure-cell permeability relationships. As a benchmark and model system, we have studied a series of analogs of ATSP-7041, a stapled peptide dual antagonist of MDM2 and MDMX, to evaluate and correlate their biological, biophysical, permeability and metabolic stability properties.

8:40 Modulation of Intracellular Protein-Protein Interactions with Bicyclic PeptidesDehua Pei, PhD, Professor of Chemistry and Biochemistry, The Ohio State UniversityWe are developing bicyclic peptides as a novel class of inhibitors against intracellular protein-protein interactions (PPIs), which are challenging targets for conventional drug modalities. These bicycles feature highly active cell-penetrating peptides (CPPs) in one ring for cellular entry and specific target-binding sequences in the second ring. Potent, selective, proteolytically stable, and cell-permeable bicyclic peptidyl inhibitors have been generated against a variety of intracellular proteins including protein tyrosine phosphatases, peptidyl-prolyl isomerase, K-Ras, and NFkB essential modulator.

9:10 Targeting a Metabolic Vulnerability in Parasitic Nematodes with Nucleic Acid-Encoded Peptide LibrariesJames Inglese, PhD, Director, Assay Development and Screening Technologies, National Center for Advancing Translational Sciences (NCATS), NIHiPGM is the nematode isozyme of the human glycolytic enzyme, phosphoglycerate mutase, and represents a potential drug target for tropical diseases. Small molecule high throughput screening efforts by others have failed to identify inhibitors. We used mRNA-display affinity selection to identify isozyme-selective phosphoglycerate mutase ligands, termed Ipglycermides that potently inhibit the catalytic activity of all nematode iPGM orthologs tested to date. Progress in the pharmacological evaluation of ipglycermide analogs aimed at developing a therapeutics agent will be discussed.9:40 Grand Opening Coffee Break in the Exhibit Hall with Poster Viewing10:25 Stapled Peptides Targeting MCL-1 and BFL-1 to Reactivate Apoptosis in CancerLoren D. Walensky, MD, PhD, Professor, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston Children’s Hospital, Harvard Medical SchoolThe “helix-in-groove” mode of protein-protein interaction underlies a series of oncogenic signaling events that drive human cancer. Indeed, a nearly universal mechanism of apoptotic suppression in cancer is governed by the entrapment of pro-death helices by the surface grooves of anti-apoptotic BCL-2 family proteins. Here, we developed both non-covalent and covalent stapled peptide inhibitors to dissect and target the apoptotic blockades imposed by MCL-1 and BFL-1, yielding new drug prototypes for cancer therapy.10:55 Discovery of ALRN-6924, a first-in-class MDMX and MDM2 Dual Inhibitor Stapled Peptide in Clinical TrialsVincent Guerlavais, PhD, Director, Medicinal Chemistry, Aileron Therapeutics11:25 Late Breaking Presentation11:55 Sponsored Presentation (Opportunity Available)12:25 pm Session Break


Constrained Peptides and Macrocyclics Cell-Penetrating Middle-Sized Molecules for Better Therapeutics





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12:35 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own1:15 Refreshment Break in the Exhibit Hall with Poster Viewing

NON-PEPTIDIC SYNTHETIC MACROCYCLICS1:50 Chairperson’s RemarksAlec Flyer, PhD, Senior Scientist, Global Discovery Chemistry, Novartis Institutes Biomedical Research1:55 Advances in the Synthesis and Applications of MacrocyclesAndrei K. Yudin, PhD, Professor, Department of Chemistry, University of TorontoSynthetic tools that allow one not only to cyclize linear precursors but also to exercise control over conformation-driven cellular permeability are in high demand. This lecture will summarize our ongoing efforts in this area and will highlight key experimental findings obtained in the past few months.2:25 Structure-Based Design of Small-Molecule MacrocyclesMaxwell D. Cummings, PhD, Senior Principal Scientist, Computational Chemistry, Discovery Sciences, Janssen R&DDespite having diverse chemical structures, macrocycles are often considered as a single chemotype. A recent survey covering macrocyclic drugs and clinical candidates captures their diversity in both chemical structure and discovery provenance. We are interested in the structure-based design of purely synthetic small-molecule macrocycles, an area of drug discovery that has not been heavily explored. We present simple metrics that facilitate the detection and prioritization of bound ligands that may be particularly suited to macrocyclization. Representative examples of such macrocyclic-like compounds will be presented for discussion.2:55 Sponsored Presentation (Opportunity Available)3:25 Refreshment Break in the Exhibit Hall with Poster Viewing and Poster Competition Winner Announced4:05 Discovery of Potent and Orally Bioavailable Macrocyclic Peptide-Peptoid Hybrid CXCR7 ModulatorsMarkus Boehm, PhD, Associate Research Fellow, Medicinal Chemistry, PfizerWhile several small molecules have been identified that modulate the activity of CXCR7, an attractive drug

target for a variety of disease indications, peptidic macrocycles may provide additional advantages in terms of potency, selectivity, and reduced off-target activity. We report on a series of peptidic macrocycles that bind to CXCR7 and also incorporate an N-linked peptoid functionality in order to overcome the poor permeability associated with peptides. The peptoid group also enabled us to explore side chain diversity well beyond that of natural amino acids.4:35 Lessons for the Design of Synthetic Macrocycles from Machine LearningAdrian Whitty, PhD, Professor, Biochemistry, Boston UniversityWe identified several novel macrocycle-specific molecular descriptors based on structural or physicochemical features, for assessing macrocyclic chemotype diversity and predicting the key ADME property of membrane permeability. These descriptors should help inform the design of pharmaceutically useful macrocycles or macrocycle libraries, which because they contain non-traditional drug chemotypes, need rules beyond those considered in traditional assessments of drug likeness. I also describe various machine learning techniques we used for evaluating the utility of the descriptors we identified.




CYCLIC PEPTIDE DESIGN CHALLENGES8:00 Chairperson’s RemarksSusanne Saalau, PhD, Senior Director, Chemistry, FOG Pharma

8:05 The Permeability Landscape around Lariat Cyclic PeptidesScott Lokey, PhD, Professor, Chemistry and Biochemistry, University of California, Santa CruzHeterodetic cyclic peptides (lariat peptides) differ from simple homodetic cyclic peptides by the addition of a tail extending from the cyclic portion. Although lariat peptides comprise a large portion of bioactive cyclic peptide natural products, exploration of permeability in this space has been limited. We recently discovered a simple lariat scaffold based on a natural product, Xentrivalpeptide A, composed entirely of non-N-methylated alpha amino acids. I describe the synthesis and properties of several passively permeable lariat peptides with six H-bond donors and molecular weights greater than 800.8:35 Measuring Cytosolic Penetration Using the Chloroalkane Penetration AssayJoshua A. Kritzer, PhD, Associate Professor, Department of Chemistry, Tufts UniversityCell penetration is a major obstacle for developing peptide, protein and nucleic acid therapeutics. Most commonly used techniques for measuring cell penetration are qualitative, and most cannot distinguish cytosolic material from material trapped at the cell surface or in endosomes. We have devised a new technique, the chloroalkane penetration assay (CAPA), that measures penetration to the cytosol in a high-throughput, quantitative manner. Here, we describe the advantages and disadvantages of CAPA and demonstrate some of its applications.9:05 Sponsored Presentation (Opportunity Available)9:35 Coffee Break in the Exhibit Hall with Poster Viewing10:20 Identification of Novel Constrained Peptides and Scaffolds against Cap-Dependent TranslationChristopher J. Brown, PhD, Research Scientist, p53lab, A*STARThe eIF4F complex is frequently dysregulated in human cancers leading to an increase in cap-dependent translation, which causes the upregulation of key oncogenic related proteins. Rational stapled peptide design and constrained peptide phage display have identified new modalities that inhibit eIF4F activity. These activi-ties have enabled an alternative interaction motif against the eIF4E:4G interface critical for eIF4F assembly to be discovered, enabling the exploration of new chemical space.





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10:50 Artificial Intelligence Designed TLR4 Peptide ActivatorsImmanuel Lerner, PhD, CEO, PepticomThe use of artificial intelligence (AI) for the target based discovery of novel peptides. Relevant results and background regarding discovery projects will be presented with emphasis on the discovery and validation of TLR4 agonist cyclic peptides (composed of D,L and non natural amino acids).11:20 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own11:50 Conference Registration Open






DiscoveryOnTarget.com • 40lEAD GENERATIoN STRATEGIES

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Finding new drug leads as fast as possible, but also as accurately as possible, in other words compounds with high drug potential, has always been the goal in early drug discovery. Often the process is separated into two steps: ‘hit’ generation which focuses on quickly finding large numbers of compounds with questionable drug potential followed by ‘lead’ optimization to whittle down the number of hits into promising, high-drug potential leads. However, automation and other advances in biophysical approaches have married the two processes to enable smaller numbers but higher quality drug leads to be found from the start. After the successful launch of CHI’s Lead Generation Strategies conference last year, we return to convene discovery biologists and chemists to share best practices and discuss how to implement new approaches towards faster and higher quality lead generation for drug discovery.




• September 26-27 Conference: Constrained Peptides and Macrocyclics

• September 27-28 Conference: Lead Generation Strategies

• September 27 Short Course 14: Advancing Tools and Technologies for Fragment-Based Design




NEW APPROACHES FOR BETTER HIT ASSESSMENT2:45 Welcome RemarksAnjani Shah, PhD, Conference Director, Cambridge Healthtech Institute2:50 Chairperson’s Opening RemarksJoe Patel, PhD, Director, Structural Biology, C4 Therapeutics

2:55 KEYNOTE PRESENTATION: Mechanistic Pharmacology-Driven Lead DiscoveryPeter Tummino, PhD, Vice President, Global Head, Lead Discovery, Janssen

Research and DevelopmentDecades of effort in small molecule screening has focused on increasing throughput and com-pound library size. Generally, these large efforts have not yielded major advancements in providing quality lead molecules. An alternative approach is to design screening assays that are more disease-relevant, incorporate knowledge from detailed mechanistic studies, and possess multiparametric readouts. This approach, combined application of machine learning to data analysis, may provide a stronger engine for lead ID.

3:25 Do We Need to Change the Definition of Drug-Like Properties?Michael Shultz, PhD, Associate Director and Group Leader, Cardiovascular and Metabolism, Medicinal Chemistry, Novartis Institutes for Biomedical Research

Sponsored by3:55 Integrated Drug Discovery Engine for the Development of the Next-Generation Kinase Inhibitors Alexis Denis, Head, Discovery Division, OncodesignNanocyclix is a medicinal chemistry technology based on the macrocyclization of small Lead-like molecules. It is a kinase-focused library designed in a chemocentric approach to identify drug-like and selective inhibitors across the kinome. Nanocyclix leads have potential application in several indications: Oncology, Immuno-inflammation and Parkinson disease. 4:10 Sponsored Presentation (Opportunity Available)4:25 Refreshment Break in the Exhibit Hall with Poster Viewing5:00 Targeted Degradation Strategies for New Drug LeadsJoe Patel, PhD, Director, Structural Biology, C4 TherapeuticsTargeted protein degradation has emerged as an exciting new approach for drug discovery. This talk will provide a brief overview of the technology and how degraders exploit the ubiquitin-proteasome system before describing therapeutic applications of targeted protein degradation to BET bromodomain proteins and to the control of tumor cell-killing by CAR T-cells.5:30 Encoded Library Technology (ELT): A Platform for Lead Discovery at GSKSvetlana Belyanskaya, PhD, Scientific Leader, Encoded Library Technologies, R&D Platform Technology & Science, GSK BostonDNA Encoded Library Technology is an affinity-based screening platform that is routinely used for lead discovery at GSK. It was successfully applied for discovery of potent and selective inhibitors to multiple challenging targets. The platform has evolved and a quantitative on-DNA binding assay has recently been developed for simultaneous characterization of billions of compounds in the selection. A case study will be presented to illustrate its application for a hit identification program.


Lead Generation Strategies Biophysical Techniques and New Methods for Drug Discovery





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6:00 CETSA (Cellular Thermal Shift Assay) HT to Measure Intracellular Target Engagement with the Androgen ReceptorJoseph Shaw, PhD, Senior Scientist, Lead Generation, AstraZenecaCETSA (Cellular Thermal Shift Assay) is an exciting technology increasingly being used to determine in-cell target engagement in early drug discovery campaigns in a label-free and disease relevant manner. We report a new high-throughput CETSA assay for the high value oncology target Androgen Receptor, and demonstrate a novel application of CETSA enabling determination of intracellular binding affinities. Application of high-throughout CETSA technology can guide lead generation campaigns using direct measures of binding to the desired target in cells.6:30 Dinner Short Course RegistrationClick here for details on short courses offered.9:30 Close of Day



BIOPHYSICAL METHODS FOR MORE EFFICIENT LEAD GENERATION8:30 Chairperson’s RemarksDaniel A. Erlanson, PhD, Co-Founder, Carmot Therapeutics, Inc.8:35 Novel Approaches in Using NMR and SPR for Fragment Hit Identification and ValidationAnil Padyana, PhD, Associate Director, Structural Biology and Biophysics, Department of Biochemistry, Agios Pharmaceuticals

9:05 AbbVie’s Fragment-Based Drug Design Platform for Tool and Lead GenerationAshley Adams, Ph.D., Senior Scientist, Discovery Chemistry and Technology, AbbVie, Inc.This presentation will cover a recent application of AbbVie’s revamped fragment library featuring an example where a fragment with high fsp3 character was quickly advanced to lead with high BEI, LE, and LipE as well as good oral bioavailability. The unique properties associated with fragments with high sp3 character and some lessons learned on the efficiency of chemistry to iterate 3D fragment hits will also be discussed.9:35 Solid-State NMR for Peptide Drug OptimizationYongchao Su, PhD, Associate Principal Scientist and Head of the Pharmaceutical NMR Lab in Preclinical Sciences, Merck & Co., Inc.We used solid state (ss) NMR to determine the high-resolution structure of fibrils from a pharmaceutical peptide. This is the first time in pharmaceutical sciences that a high resolution molecular structure of insoluble aggregate of a peptide drug has been determined. The structure enabled us to identify and test residues in the fibril core that lead to backbone rearrangement, which should facilitate optimization of peptide drugs with lower risks of aggregation.10:05 Coffee Break in the Exhibit Hall with Poster Viewing and Poster Competition Winner Announced10:45 Using Stable Isotope Tracers to Interrogate Pathway Biology and Differentiate Potential HitsNathan Hatcher, PhD, Principal Scientist, Department of Neuroscience, Movement Disorders and Translational Capabilities, Merck & Co., Inc.This presentation will consider how to probe biochemical flux via stable isotope tracer methods. Focus will be placed on differentiation of possible lead candidates. Attention will be directed towards cell-based screening efforts; however, we will discuss the potential for translational opportunities using in vivo models. Example problems will be described which consider “classical” metabolic pathways, e.g., glucose flux, as well. We will consider problems regarding protein kinetics.11:15 New Gas-Phase Tools for the Simultaneous Determination of Protein Complex Structure, Stability and SequenceBrandon Ruotolo, PhD, Associate Professor, Department of Chemistry, University of MichiganThe next generation of medicines will rely heavily upon our ability to quickly assess the structures

and stabilities of large, complex macromolecular machines, as well as the influence of large libraries of conformationally-selective small molecule binders and protein-based biotherapeutics. Such endeavours are nearly insurmountable with current tools. In this presentation, I will discuss recent developments surrounding the activation of gas-phase protein complex ions aimed at bridging this gap in basic technology.11:45 Every Compound Counts – Virtual Screening and Computer-Aided Drug Design for a More Efficient Route to Drug DiscoveryTrevor Perrior, CSO, DomainexDomainex clients have seen the benefit of its efficient approach, which significantly increases the speed from drug target to candidate molecule. An important part of this philosophy is the use of computational techniques for the selection of screening libraries, and for the design of compounds during lead optimisation.12:15 pm Session Break

Sponsored by12:25 Luncheon Presentation: Protein Domain Trapping - Large Scale Protein Engineering Enables Biophysics and Structural Biology in Drug DiscoveryJan Schultz, Director, Business Development, ZoBioWith novel targets the rate limiting step in small molecule drug discovery often becomes the availability of protein in an appropriate, well-behaved form. Standard methods for generating constructs are far too slow and sample only a fraction of the great number of possibilities. ZoBio has developed PDT to screen millions of protein variations for those that express high levels of soluble, well-behaved protein with the desired biological activity. Initial feasibility studies require only 4-6 weeks. 1:15 Refreshment Break in the Exhibit Hall with Poster Viewing

BIOPHYSICAL APPROACHES FOR MEMBRANE PROTEINS1:55 Chairperson’s RemarksBrian J. Murphy, PhD, Senior Principal Scientist, Metabolic Disease Biology, Bristol-Myers Squibb Co.





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2:00 Discovery of Small Molecule Protease-Activated Receptor 2 (PAR2) Antagonists Using a Stabilized GPCR, Fragment-Based Lead Generation and DNA-Encoded Library ScreeningDean G. Brown, PhD, Director of External Chemistry, Hit Discovery, Discovery Sciences, IMED Biotech Unit, AstraZenecaWe employed two screening strategies to identify antagonists at protease activated receptor (PAR2), one being a DNA-encoded library screen on PAR2 and the second a fragment screen using a stabilized PAR2 GPCR receptor. From these efforts, we identified two lead series of compounds, each of which bind to distinct and previously unknown allosteric sites.

These results illustrate the power of integrating stabilized GPCR technologies into established screening paradigms.2:30 Integrating Biophysical and Structural Data Provides Comprehensive View of GPCR FunctionMatthew Eddy, PhD, Assistant Professor, Department of Chemistry, University of Florida and Affiliated Faculty, National High Magnetic Field Laboratory3:00 Characterization of Wild Type GPCRs Using Surface Plasmon ResonanceIva Navratilova, PhD, Staff Scientist, Department of Molecular Biology, University of DundeeExpressing, purifying and analysing membrane proteins using SPR is routinely challenging. In this

presentation, we will present our latest results demonstrating a scalable method for the successful development of SPR assays for a wide range of wild- type GPCRs. The SPR assays can be exploited for fragment screening and kinetic characterization to discover novel ligands.3:30 Nanodiscs for Membrane Protein Drug Discovery ApplicationsNasr Mahmoud, PhD, Postdoctoral Fellow, Laboratory of Gerhard Wagner, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School4:00 Close of Conference




DiscoveryOnTarget.com • 43TARGET IDENTIfICATIoN AND VAlIDATIoN - PART 1

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Finding novel, druggable targets for therapeutic intervention remains a top priority for the pharma/biotech industry, especially when it comes to building a robust drug discovery pipeline. It also remains a formidable challenge and companies continue to invest a lot of time and resources in identifying and validating good drug targets to pursue. What are the challenges in target discovery? What tools and strategies are being used and how well are they working? What’s being done to ensure that validated targets lead to better and safer therapies? Cambridge Healthtech Institute’s conference on Target Identification and Validation will bring together leading experts to discuss some of these critical questions.

Part 1: Focus on Functional Genomics and Computational ScreeningThis part of the Target Identification and Validation conference will highlight some of the existing and emerging functional genomics, artificial intelligence and machine learning tools that are being used for generating novel drug targets. The use of such tools and screens for validating existing targets or associating them with new disease indications will also be discussed.


Targeting Autophagy• September 25 Short Course 10: Applications of


• September 26-27 Conference: Target Identification and Validation - Part 1




USE OF CRISPR, RNAi AND OTHER GENOMIC SCREENS FOR FINDING NOVEL TARGETS8:00 Welcome RemarksTanuja Koppal, PhD, Conference Director, Cambridge Healthtech Institute

8:05 Chairperson’s Opening RemarksRoderick Beijersbergen, PhD, Group Leader, Division of Molecular Carcinogenesis and NKI Robotics and Screening Center, The Netherlands Cancer Institute8:10 Exploring New Biology and Targets Identified through Big CRISPR DataScott Martin, PhD, Group Lead, Functional Genomics, GenentechCRISPR screening has rapidly transformed our approaches towards new target discovery. A major hope for these efforts is to identify new dependencies in cancer that remain undiscovered by analogous RNAi-based screens. I will discuss efforts to leverage large-scale CRISPR screening data for this purpose, including both computational and bench-level approaches.8:40 Leveraging Functional Genomics to Identify and Characterize Novel TargetsLauren Drowley, PhD, Functional Genomics Lead, Translational Medicine, UCB PharmaFunctional genomics provides tools that enable identification and interrogation of complex disease mechanisms in patient samples and relevant cellular models, improving disease understanding. Using a suite of functional genomic capabilities including CRISPR, investigation/modulation of regulatory elements and examining chromatin structure, UCB is improving understanding of the role of genome structure and function in health and disease allowing for more directed and improved therapies in the future.

9:10 Building CRISPR/Cas9-Based Platforms for Therapeutic Target Identification and ValidationRui Wang, PhD, Senior Scientist, Department of Immunology, AbbVie Bioresearch CenterTo better understand the immune system and discover novel therapeutics for autoimmune diseases, we have built CRISPR/Cas9-based platforms for new target identification, target exploration and validation, and evaluation of the efficacy and toxicity for early targets. With those platforms, we aim to build a mechanism to continuously screen new targets from various data sources and to explore novel biology involved in the immunological diseases.9:40 Grand Opening Coffee Break in the Exhibit Hall with Poster Viewing10:25 Target Deconvolution Using CRISPR Mutagenesis ScanningDirk Daelemans, PhD, Associate Professor, Rega Institute - Laboratory of Virology and Chemotherapy, KU LeuvenDeconvoluting and validating the molecular target of small-molecule hits from a screen is still a major challenge but is a must for further drug development. The discovery of mutations that confer resistance is recognized as the gold standard proof for a drug’s target. We will present a high-density tiling CRISPR genetic screening approach to rapidly deconvolute the target protein and binding site of small-molecule inhibitors based on drug resistance mutations.10:55 Investigating Cancer Drug Specificity with CRISPR/Cas9 MutagenesisJason Sheltzer, PhD, Principal Investigator, Cold Spring Harbor LaboratoryCRISPR/Cas9 gene editing can be applied to characterize potential genetic dependencies in cancer. We show that cancer cells can tolerate CRISPR/Cas9 mutagenesis of many reported cancer drug targets with no loss in cell fitness. In contrast, RNAi hairpins and small-molecules designed against those targets continue to kill cancer cells, even when their putative target is knocked out using CRISPR. We suggest that many RNAi constructs and clinical compounds exhibit greater target-independent killing than previously realized.


Target Identification and Validation Part 1 Focus on Functional Genomics and Computational Screening




Reasons you should present your research poster at this conference:

• Your poster will be available to 1,300+ delegates

• You’ll automatically be entered into our poster competition where two winners each will receive an

American Express Gift Certificate • $50 off your registration fee • Your research will be seen by leaders

from pharmaceutical, biotech, academic and government institutes

Cambridge Healthtech Institute encourages attendees to gain further exposure by presenting their work in the poster sessions. To secure a poster board and inclusion in the conference materials, your abstract must be submitted, approved and your registration paid in full by August 10, 2018.

More information available at DiscoveryOnTarget.com

Dedicated Poster Sessions for Symposia and Conference Tracks

TARGET IDENTIfICATIoN AND VAlIDATIoN - PART 1

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A Division of Cambridge Innovation Institute DiscoveryOnTarget.com • 44


11:25 TECHNOLOGY PANEL DISCUSSION: Do We Have the Right Tools to Find Drug Targets That Are Difficult to Identify and Validate?This panel will bring together speakers and 3-5 technical experts from leading technology and service companies to discuss improvements and limitations in assays, platforms, and data analysis tools available for target discovery and validation.Roderick Beijersbergen, PhD, Group Leader, Division of Molecular Carcinogenesis and NKI Robotics and Screening Center, The Netherlands Cancer Institute (Moderator)

Sponsored by11:55 Efficient Tools to Enable Drug Target and Biomarker DiscoveryPaul Diehl, PhD, COO, Cellecta, Inc.Cellecta’s technologies allow for precise and convenient analysis of the genes responsible for driving biological responses. Using NGS with multiplex RT-PCR in our DriverMap Genome-wide Expression Profiling Assay enables rapid association of gene expression changes in large numbers of cell, tissue, and blood samples. Examples of this approach will be discussed.

Sponsored by12:10 pm Development of High- Throughput Cellular Thermal Shift Assays: Cellular Mechanistic Assays in Early Drug DiscoveryMarc Holbert, PhD, Scientific Leader Protein, Cellular and Structural Sciences, GSKA problem in early drug discovery is lack of rank-order correlation between biochemical potencies from initial screens and diminished potency and efficacy in cellular phenotypic assays. Cellular thermal shift assays bridge this gap, enabling assessment of drug target engagement in live cells based on ligand-induced changes in protein thermal stability.12:25 Session Break

Sponsored by12:35 Luncheon Presentation: Enabling Arrayed CRISPR Screens in Primary T Cells, iPSCs & Immortalized Cell LinesAbhi Saharia, PhD, Director, Product Management, SynthegoLoss-of-function screens in primary & stem cells can be incredibly valuable in identifying novel drug targets or uncovering functional complexity within the human genome. To date, loss-of-function CRISPR-Cas9 screens have largely been conducted using pooled lentiviral libraries and/or in immortalized cell

lines. Although valuable, these limit the type of assay, model system or phenotype that one can screen. We have developed ready-to-transfect chemically modified single guide CRISPR libraries, that simplify high-fidelity arrayed screening in a wide variety of cell types, including Primary T cells & induced Pluripotent Stem Cells (iPSCs). Here, we discuss various screens in T cells, iPSCs & immortalized cell lines where we monitor a variety of assays. High efficiency protein knockouts were confirmed by genotypic, protein and functional analyses, indicating that these screens are capable of producing high confidence hits with low false negatives. These results highlight the ease & power of arrayed screening in immortalized cell lines, or biologically relevant primary & stem cells using chemically modified single guide RNAs.1:15 Refreshment Break in the Exhibit Hall with Poster Viewing

NEW FUNCTIONAL GENOMICS ASSAYS, LIBRARIES & PLATFORMS FOR TARGET IDENTIFICATION1:50 Chairperson’s RemarksScott Martin, PhD, Group Lead, Functional Genomics, Genentech

http://www.discoveryontarget.com/posters





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1:55 FEATURED PRESENTATION: Dissecting Functional GenomicsMichael T. McManus, PhD, Professor, University of California, San FranciscoThe field of human genetics and epigenetics has been rife with scientific debate as scientists struggle to understand the complex nature of population and familial incidence patterns and their relationships to molecular mechanism of gene expression. A cornerstone in the debate is the unresolved genetic architecture of complex disease and the functional relationship between genes. We have developed powerful tools and methodologies to dissect polygenic architecture and dissect functional genomics as related to genetic epistasis, in both cells and in vivo models.

2:25 Up, Down, and Out: Complementary CRISPR Technologies for Genetic ScreensJohn Doench, PhD, Associate Director, Genetic Perturbation Platform, Broad Institute of Harvard and MITThe ease of programming Cas9 with an sgRNA presents an abundance of potential target sites, but the on-target activity and off-target effects of individual sgRNAs can vary. We will discuss the design and use of libraries for conventional CRISPR-based knockout screens, as well as activation (CRISPRa) and interference (CRISPRi) approaches.

Sponsored by2:55 CRISPR Technology Mimicking the Fibrosis ProcessLieke Geerts, PhD, Senior Scientist, Biology, Charles RiverCRISPR technology is an asset for target validation in the drug discovery process with its ability to generate full gene knockouts. Using an adenovirus delivery system, efficient CRISPR-mediated gene knockout was obtained in a complex cellular assay mimicking the fibrosis process.3:25 Refreshment Break in the Exhibit Hall with Poster Viewing and Poster Competition Winner Announced4:05 The Screen Drives the Targets: Development of Clinically Relevant Screening ModelsRoderick Beijersbergen, PhD, Group Leader, Division of Molecular Carcinogenesis and NKI Robotics and Screening Center, The Netherlands Cancer InstituteA major challenge is the large genomic and epigenomic diversity of human cancers. The development of appropriate cell line models for large scale in vitro screens with strong predictive powers to clinical utility remains crucial. This will be crucial for the discovery of novel targets, elucidation of potential

resistance mechanisms and novel combinations. The development and implementation of such models will be presented and discussed.4:35 3’-Digital Gene Expression Transcriptional ScreeningSarah Boswell, PhD, Director of Sequencing Technologies, Laboratory of Systems Pharmacology and Director, Single-Cell Sequencing Core, Harvard Medical School3’ Digital Gene Expression (3’-DGE) was developed by the Broad Institute as a single-cell sequencing method. Here, we implement 3’-DGE as a low-read density transcriptome (mRNA) profiling method. A few thousand cells are plated and treated in 384-well format. 3’-DGE libraries sequenced at 1-2 million reads per sample yield 4,000-6,000 transcripts per well all for roughly $4000. Using 3’-DGE we obtain information about drug targets, polypharmacology, and toxicity in one assay.




NEW SCREENING PLATFORMS AND COMPUTATIONAL TOOLS FOR FINDING NOVEL TARGETS8:00 Chairperson’s RemarksDeepak K. Rajpal, PhD, Senior Scientific Director, Computational Biology, GlaxoSmithKline R&D8:05 Target Identification & Validation for Immune-Mediated IndicationsDeepak K. Rajpal, PhD, Senior Scientific Director, Computational Biology, GlaxoSmithKline R&DWe share an overview of our computational approaches to identify targets. Additionally, we share application of disease signatures in our drug discovery approaches, along with some thoughts on creating a

validation approach for generating further evidence on targets. We conclude by sharing a conceptual approach that may be broadly applied for target identification and validation.8:35 A High-Throughput Imaging-Genetic Screen Identifies MEK-PI3K Modulation for TNBCArvind Rao, PhD, Associate Professor, Department of Computational Medicine and Bioinformatics, The University of Michigan, Ann ArborAs combination therapies enter mainstream clinical oncology, there is now a need for infrastructure to integrate multiple modalities of data to prioritize drug combinations rationally. In this vein, we examine a scenario using machine learning methods to prioritize drug combinations selected based on phenotypic screening via RNAi, coupled with known genetic vulnerabilities in Triple Negative Breast Cancer cells. Such a strategy leverages imaging and genetic information to prioritize the MEKi+PI3Ki combination as a possible regimen.

Sponsored by9:05 Applications of AI in Drug Target DiscoveryEric Baldwin, Solutions Executive, IBM Watson for Drug Discovery, IBM Watson HealthWith millions of scientific research articles published each year, innovation in the life sciences suffers from knowledge waste and lack of knowledge integration. IBM Watson for Drug Discovery addresses this issue by extensively mining literature and data to help scientists accelerate biomedical research. Using advanced analytics and machine learning, the platform can also predict novel relationships, as demonstrated through our recent work with Barrow Neurological in ALS disease, and Pfizer in immuno-oncology, among many projects.9:35 Coffee Break in the Exhibit Hall with Poster Viewing10:20 Development of a Biologically Intelligent High-Throughput Assay Platform for Phenotypic Screening - Redefining the Screening ToolboxMadhu Lal-Nag, PhD, Team Leader, RNAi Screening, National Center for Advancing Translational Sciences, National Institutes of HealthDeveloping physiologically relevant assays with predictive, measurable phenotypic end points has been the pain point for high-throughput screening in drug discovery. Here we describe the development of a platform of physiologically relevant screenable phenotypes and biologically intuitive analysis algorithms that capture and define these phenotypes





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in a physiologically relevant context. This also encompasses the development of a biologist’s toolbox designed to target a majority of diverse biological phenotypes.10:50 Patient-Derived Xenograft-Derived ex vivo (PDXEx) Model for Evaluation of Tumor-Specific TherapiesGeoffrey Bartholomeusz, PhD, Associate Professor and Director, Target Identification and Validation Program, Department of Experimental Therapeutics, Division of

Cancer Medicine, The University of Texas MD Anderson Cancer CenterWe have developed a PDXEx model that closely replicates the tissue architecture of the original tumor and has a gene expression profile showing a high degree of correlation to that of the original tumor. Our model has great application as a screening platform exhibiting a high predictive value in identifying effective tumor-specific therapies in a resource-, time-, and cost-efficient manner.

11:20 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own11:50 Conference Registration Open







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Finding novel, druggable targets for therapeutic intervention remains a top priority for the pharma/biotech industry, especially when it comes to building a robust drug discovery pipeline. It also remains a formidable challenge and companies continue to invest a lot of time and resources in identifying and validating good drug targets to pursue. What are the challenges in target discovery? What tools and strategies are being used and how well are they working? What’s being done to ensure that validated targets lead to better and safer therapies? Cambridge Healthtech Institute’s conference on Target Identification and Validation will bring together leading experts to discuss some of these critical questions. The conference will help attendees meet and interact with experts and peers from around the world to share ideas and hear about new strategies and technologies helping target discovery.

Part 2: Focus on Chemical Biology and Phenotypic ScreeningThis part of the Target Identification and Validation conference will describe how phenotypic screening and chemical biology can be used to find new drug targets, validate existing targets for new indications, and better understand how inhibiting or activating these targets could impact other cellular pathways.


Targeting Autophagy• September 25 Short Course 10: Applications of








EXPLORING VARIOUS ASSAYS & PLATFORMS FOR HIGH-THROUGHPUT SCREENING2:45 Welcome RemarksTanuja Koppal, PhD, Conference Director, Cambridge Healthtech Institute2:50 Chairperson’s Opening RemarksJames Inglese, PhD, Head, Assay Development & Screening Technologies, National Center for Advancing Translational Sciences, NIH2:55 Strategies for the Development of Quantitative HTS Assays Targeting Rare DiseasesJames Inglese, PhD, Head, Assay Development & Screening Technologies, National Center for Advancing Translational Sciences, NIHPhenotypic assays enabled by genome editing in combination with novel reporter gene and high content imaging technology were integrated to create quantitative HTS assays. The assays were designed to target pathophysiology arising from gene duplication, haploinsufficiency, defective organelle biogenesis or genes with implied protective properties, associated with CMT, Dravet syndrome, Parkinson’s and more. Our goal was to identify transcriptional and post-translationally active pharmacological agents acting by a variety of mechanisms, including chromatin co-regulators accessible by our assay.

3:25 Comprehensive Proteomics Characterization of a Selective Cyclin-Dependent Kinase InhibitorJ. Adam Hendricks, PhD, Associate Principal Scientist, Discovery Biology, Discovery Sciences, IMED Biotech Unit, AstraZenecaWe describe a comprehensive characterization of a cyclin-dependent kinase inhibitor using a combination of affinity enrichment-based chemoproteomics and thermal proteome profiling strategies. Application of these orthogonal approaches enabled “static and dynamic” proteome characterization of a CDK9 inhibitor. This case study highlights the advantages and limitations of different proteomics readouts and their applications in drug discovery toward understanding the mechanism of action of clinical candidates.

Sponsored by3:55 Preclinical Strategies for Evaluating Treatment Efficacy to Prevent or Cure Auditory DisordersSylvie Cosnier-Pucheu, CSO, CILcareNo effective treatment exists to cure hearing loss (affecting 360 million persons worldwide) and tinnitus (which affects around 10–15% of the general population). This presentation provides an overview of current animal models of hearing disorders and potential targets for new therapies.

Sponsored by4:10 ZeCardio: A Zebrafish-Based Screening Platform for Genetic Association Studies in Cardiovascular DiseaseVincenzo Di Donato, PhD, Project Manager, Genome Editing Platform, ZeClinicsThe advent of CRISPR/Cas9 methodologies has greatly expanded the possibilities of in vivo target identification and validation. However, the generation of knockout animal models is a low-throughput and time-consuming process. Here, we will present a zebrafish-based mutagenesis platform allowing high-throughput phenotypical validation of candidate genes readily in the F0 generation.4:25 Refreshment Break in the Exhibit Hall with Poster Viewing


Target Identification and Validation Part 2 Focus on Chemical Biology and Phenotypic Screening





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5:00 A Membranome cDNA Library for Biologics Discovery and Phenotypic ScreeningXi Ai, PhD, Associate Principal Scientist, Screening & Compound Profiling, Merck Research LaboratoriesAbout 20-30% of all proteins are membrane proteins, which accounts for over 50% of marketed drug targets. We have established a human membranome cDNA library consisting of 2900 membrane protein genes and developed a live-cell assay for screening. The library will enable us to study novel cell surface receptor/ligand interaction for early target identification and cell surface receptor de-orphanization, as well as antibody specificity profiling.5:30 Novel Targets and Compounds for Lung Fibrosis: Screening for Genes and Compounds that Control Fibroblast YAP/TAZ ActivationDaniela M. Santos, PhD, Postdoctoral Fellow, Division of Pulmonary and Critical Care Medicine, The Andrew M. Tager Fibrosis Research Center and Center for Immunology and Inflammatory Diseases, Department of Medicine, Massachusetts General Hospital and Harvard Medical SchoolIdiopathic Pulmonary Fibrosis is a lethal disease driven by pathological fibroblast accumulation and differentiation. Recent evidence indicates that transcription co-activators YAP and TAZ integrate the chemical and mechanical signals that activate fibroblasts. We designed a small molecule and siRNA screen to identify YAP inhibitors and new pathways controlling YAP activation in human fibroblasts. The resulting hits may lead to the development of novel anti-fibrotic therapies.6:00 Building Precision in vivo Models Using CRISPR-Based EditingMaria Paz Zafra Martin, PhD, Postdoctoral Fellow, Department of Medicine, Hematology and Medical Oncology, Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine The development of animal models that precise reflect the genetic changes that occur in human tumors is a key step in developing immunocompetent pre-clinical models. I will discuss our efforts using CRISPR to engineer single nucleotide variants (SNVs) in animal models, to understand the impact of defined genetic changes on tumor initiation, progression and therapy response.6:30 Dinner Short Course RegistrationClick here for details on short courses offered.9:30 Close of Day



PHENOTYPIC SCREENING FOR TARGET DISCOVERY AND MECHANISM-OF-ACTION STUDIES8:30 Chairperson’s RemarksFabien Vincent, PhD, Associate Research Fellow, Hit Discovery and Lead Profiling Group, Pfizer8:35 Hit Triage and Validation for Phenotypic Screening: Considerations and StrategiesFabien Vincent, PhD, Associate Research Fellow, Hit Discovery and Lead Profiling Group, PfizerPhenotypic screening is a validated approach to identify novel therapeutic targets. However, significant differences exist between target-based and phenotypic screening, prompting a need to re-assess our strategies and processes to most effectively prosecute phenotypic projects. The hit triage and validation process was critically re-evaluated in light of the unique characteristics of phenotypic screening. Key considerations and specific strategies will be shared and illustrated by in house and literature examples.9:05 Understanding the Mechanism of Kinase InhibitorsLyn Jones, PhD, Vice President, Chemistry and Chemical Biology, Jnana TherapeuticsAdvances in the development of chemoproteomic profiling technologies are enabling a deeper understanding of the selectivity and hence mechanism of action of small molecule kinase inhibitors. Additionally, many ATP-site binders have been found to degrade their cognate target kinases. The drug discovery impact of kinase profiling and MoA studies will be presented.

9:35 Chemo-Genomic Screening in AML: A New Approach to Identify Therapeutic StrategiesAnne Marinier, PhD, Principal Investigator and Director of Medicinal Chemistry, IRIC and Associate Professor, Department of Chemistry, Université de MontréalCapitalizing on new leukemia stem cell culture conditions, we developed a chemo-genomic screening approach using genetically and clinically characterized acute myeloid leukemia (AML) specimens and a structurally diverse compound collection. Clustering of hits demonstrating similar specimen inhibition patterns generated CCCs (Compound Correlation Clusters) which reveal sensitized target pathways essential to tumor survival. The CCCs’ therapeutic relevance will be exemplified by the identification of a novel target for poor prognosis AML.10:05 Coffee Break in the Exhibit Hall with Poster Viewing and Poster Competition Winner Announced10:45 Phenotypic High-Content Approach to Identify Novel Targets of AutophagyStephen Walker, PhD, Senior Research Scientist III, High Throughput Screening, AbbVieWe have established various phenotypic screening approaches and conducted small molecule screens for diverse indications using physiologically relevant disease models. This presentation will highlight the workflow performed for a screen combining autophagy specific cellular models with high content multi-parametric analysis to identify autophagic regulators for clearance of accumulated proteins. Hits from a screen utilizing a focused library of annotated compounds are being further characterized in disease-specific models and prioritized for target identification.11:15 Identification of Essential Genes for Cancer Immunotherapy Using High-Throughput Genome EngineeringNeville Sanjana, PhD, Assistant Professor, Departments of Biology, Neuroscience and Physiology, New York University; Core Faculty Member, New York Genome CenterWe have developed two-cell type whole-genome CRISPR screens to dissect the complex interactions between tumor cells and primary immune cells in cancer immunotherapy. Using primary human cytotoxic T cells, we identify loss-of-function mutations genome-wide that drive resistance to immunotherapy with transgenic TCR T cells and validate several novel immunotherapy resistance mechanisms across different melanomas, cancers, and antigens (in collaboration with N. Restifo’s, National Cancer Institute).





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11:45 Computational Methods to Help Find Chemical Matter to Uncover Novel BiologyYuan Wang, PhD, Investigator III, Data Science, Chemical Biology & Therapeutics, Novartis Institutes for BioMedical ResearchTo explore new targets and biology, phenotypic screens are increasingly utilized in drug discovery. Potent and selective chemical tool compounds against well-defined targets can be used as probes in disease-relevant phenotypes. In Novartis we have designed an evidence-based metric to systematically rank tool compounds and collected over 4000 compounds (“MOAbox”) to connect targets with novel biology. We are also exploring algorithms that can connect previously un-drugged targets to known ones.12:15 pm Session Break12:25 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own1:15 Refreshment Break in the Exhibit Hall with Poster Viewing

CASE STUDIES ON HOW TO DECONVOLUTE EXISTING TARGETS & TACKLE CHALLENGING ONES1:55 Chairperson’s RemarksPaul Brennan, PhD, Associate Professor, Medicinal Chemistry, University of Oxford; Principal Investigator, Target Discovery Institute, Structural Genomics Consortium

2:00 Chemical Probes in Target DiscoveryPaul Brennan, PhD, Associate Professor, Medicinal Chemistry, University of Oxford; Principal Investigator, Target Discovery Institute, Structural Genomics ConsortiumChemical probes are selective small molecule inhibitors that can be used in cellular assays to induce a phenotype and link it to a small set of protein targets. Chemical probes have been developed for many bromodomains, the principal epigenetic readers of histone lysine acetylation, and been used to decipher the biology of bromodomains in cancer and inflammation. We are current developing chemical probes for new protein families.2:30 Target Validation in the IL17 Signaling Pathway: Challenges and OpportunitiesAlex Lipovsky, PhD, Senior Scientist, Foundational Immunology, AbbVieThe IL23/IL17 signaling axis plays a key role in the pathophysiology of psoriasis. We conducted a small molecule and a CRISPR screen in primary human keratinocytes to identify druggable targets in the IL17 signaling pathway. I will discuss functional genomics approaches, technology platforms, and target validation strategies to confirm and prioritize screen hits. Examples of successful gene perturbation in primary cells with CRISPR RNPs and RNAi will be highlighted.

3:00 Small Molecule Modulators of Conformationally Dynamic Protein TargetsEvripidis (Evris) Gavathiotis, PhD, Associate Professor, Department of Biochemistry and Medicine, Albert Einstein College of MedicineMy presentation will discuss approaches for targeting two conformationally dynamic protein targets that critically control cell death and cell survival pathways converging at the mitochondria. Validation of novel targets and mechanisms go hand-in-hand with the discovery of small molecules. Structure-based drug design, biochemical, cell-based and in vivo proof-of-concept studies provided lead compounds and insights on modulating dynamic protein targets.3:30 Small Molecule Modulators of InflammationSinu John, PhD, Staff Scientist, Signaling Systems Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of HealthRecent studies have shown that a macrophage-driven inflammatory signature is common to a large majority of the diseases. We have developed a TNF reporter assay that can be used to identify small molecule modulators of the human macrophage inflammatory response. We have conducted a screen of biologically active small molecules and identified several compounds that have substantial modulatory effects on the TNF response. In validation studies, we find that these molecules can be grouped into classes with both negative and positive effects on the inflammatory response, with therapeutic potential.4:00 Close of Conference




DiscoveryOnTarget.com • 50ANTIBACTERIAl DISCoVERy AND DEVEloPmENT

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New discovery platforms, novel screens and approaches are vital for the discovery of new antibacterials and for ceasing the dangerous trend of multidrug microbial resistance. Cambridge Healthtech Institute’s 5th Annual Antibacterial Discovery and Development track will focus on the general, strategic issues and solutions that would allow new antibacterial development to move forward. The conference will be held as part of the 5th Annual Re-Entering Antibacterial Discovery and Development Summit, and it will be followed by Targeting Gram-Negative Pathogens.

Advisors: Lynn Silver, LL Silver Consulting; Ruben Tommasi, Entasis Therapeutics; Joyce Sutcliffe, Formerly Tetraphase; Todd Black, Merck

RECOMMENDED ALL ACCESS PACKAGE: Choose 2 Short Courses or 1 Symposium and 2 Conferences/Training Seminars• September 25 Short Course 10: Applications of


• September 26-27 Conference: Antibacterial Discovery and Development

• September 27-28 Conference: Targeting Gram-Negative Pathogens

• September 27 Short Course 17: Technologies to Assess Permeability and Efflux in Gram-Negative Bacterial Pathogens


DISCOVERY PLATFORMS: NATURAL PRODUCTS AND GENOME MINING8:00 Welcome RemarksMana Chandhok, Associate Conference Producer, Cambridge Healthtech Institute8:05 Chairperson’s Opening RemarksZachary Zimmerman, PhD, CEO, Co-Founder, Forge Therapeutics, Inc.

8:10 KEYNOTE PRESENTATION: Culture Independent Discovery of New AntibioticsSean Brady, PhD, Associate Professor, The Laboratory of Genetically

Encoded Small Molecules, Rockefeller UniversityUncultivated microorganisms are an attractive source of potentially new antibiotics. Although there is no easy way to culture most environmental bacteria, it is possible to clone microbial DNA directly from environmental samples and study this DNA in the lab. We are using both functional and sequence-based metagenome screening strategies to identify antibiotics encoded by environmental bacteria. Antibiotics isolated in these studies will be discussed.

8:40 Forging Novel Classes of AntibioticsZachary Zimmerman, PhD, CEO, Co-Founder, Forge Therapeutics, Inc.Forge Therapeutics is focused on developing small molecule, direct-acting, novel antibiotics that inhibit select metalloenzymes to treat infections caused from high priority drug-resistant bacteria. We are currently in late lead optimization for the first-ever non-hydroxamate inhibitor of LpxC, a bacterial Zn2+ hydrolase, for IV/oral treatment of urinary tract infection (‘FG-LpxC-UTI’).9:10 Antimicrobials for Unmet Medical NeedsKim Lewis, PhD, University Distinguished Professor, Biology; Director of Antimicrobial Discovery Center, Biology, Northeastern UniversityWe identified compounds with no detectable resistance (Teixobactin, Novo29), and capable of

killing persister cells (ADEP, lassomycin). ADC56 is a novel antimicrobial with coverage of Gram negative ESKAPE pathogens. Lyme disease is caused by B. burgdorferi, and we identified compounds acting selectively against this pathogen. Selectively killing pathobionts of the human microbiome is a new area for antimicrobial drug discovery, and we will discuss it as well.9:40 Grand Opening Coffee Break in the Exhibit Hall with Poster Viewing

DISCOVERY PLATFORMS (CONT.)10:25 Mining the Actinomycete Armamentarium for Novel AntibioticsLaurence E. Reid, PhD, CEO, Warp Drive BioWarp Drive Bio is deploying state-of-the- art, genome mining technologies to access natural molecules that have been historically “hidden” within microbes. We have built databases of genomic sequence from over 135,000 strains, encoding more than four million biosynthetic gene clusters. We are exploiting this database to isolate clusters that synthesize natural products that have not been previously studied and which have predicted antimicrobial activity. We will review our results to date regarding discovery of novel antimicrobials.10:55 Near Future Prospects from Natural ProductsJose Ruben Tormo, PhD, Associate Area Head & Collection Manager, Chemistry, Fundacion MEDINAMicrobial natural products (NPs) are one of the most prolific sources of new leads for the discovery of novel antibiotics with a large number of molecules and analogs still today in the clinic. NPs present a unique chemical space with potency and selectivity being the result of an extended evolutionary selection. New integrated NPs discovery approaches are playing a key role in the identification of new molecules to be developed to fill the antibiotic pipeline.11:25 Progress toward Selective Bacterial Protein Synthesis AntibacterialsChad Testa, PhD, Vice President, Cūrza Global, LLCInspired by a natural product, Cūrza is developing antibiotics that selectively inhibit bacterial protein synthesis by acting on a clinically undrugged binding site on the ribosome. CZ-02s have excellent drug-like properties, do not show cross-resistance to other


Antibacterial Discovery and Development Helping Antibacterial Development to Move Forward





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protein synthesis inhibitors (e.g., aminoglycosides, tetracyclines), are efficacious in murine E. coli infection models, have potent selective inhibition of bacterial protein synthesis and are not cytotoxic.11:55 Fixing the Broken Antibiotics Business Model through Molecular DiagnosticsAndreas E. Posch, PhD, Founder & Managing Director, Ares Genetics GmbHAres Genetics’ vision is to revolutionize infectious disease diagnostics and therapeutics by translating success stories from treatment response prediction in cancer to microbial infections. To achieve this, Ares Genetics makes use of high-resolution Next Generation Sequencing (NGS) technology in combination with a proprietary pathogen and drug resistance biomarker database, ARESdb, for result interpretation. In this talk, we will present how ARESdb can be used for (a) diagnosing microbial infections and drug response prediction, as well as, (b) accelerating and informing antibiotic drug development across the product life cycle.12:25 pm Session Break12:35 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own1:15 Refreshment Break in the Exhibit Hall with Poster Viewing

ALTERNATIVE THERAPIES1:50 Chairperson’s RemarksNeeraj (Neil) Surana, MD, PhD, Instructor, Infectious Diseases, Boston Children’s Hospital1:55 The Efficacy, Safety, and Tolerability of Gepotidacin (GSK2140944)David Gardiner, Medicine Development Leader, Gepotidacin, GSKGepotidacin is a novel, first-in-class, triazaacenaphthylene antibacterial agent which has in vitro activity against causative pathogens of acute bacterial skin and skin structure infections (ABSSSIs).2:15 Cloudbreak Antibody-Drug Conjugates for Treatment of MDR Gram Negative Bacterial InfectionsJames Levin, PhD, Director of Preclinical Development, Cidara TherapeuticsCloudbreak ADCs physically link the pathogen and the immune component to eradicate pathogens via dual killing mechanisms. The engagement of specific innate immune system components confers potential to largely limit resistance development in target pathogens. Furthermore, by linking to an antibody Fc, ADCs possess extended half-lives to support

once-weekly or bi-weekly dosing, making them well suited as immunotherapeutic agents to prevent and treat life-threatening multidrug-resistant Gram-negative infections.2:35 Anti-Persister Strategy for the Treatment of Chronic, Recurrent InfectionsDiane Joseph-McCarthy, PhD, Vice President, Translational Science, EnBiotixBacteria can enter into a persister state in response to various stresses including antibiotic treatment. In this metabolically dormant state, bacteria become tolerant or “transiently resistant” to antibiotics, which can lead to chronic, recurrent infections including persistent lung infections. Combinations of aminoglycosides with bacterial metabolites as proton-motive force enhancing potentiators were investigated. Pairwise combinations were screened using the time-kill method as well as biofilm assays. Eliminating bacterial persisters early may be a key to limiting further resistance and prolonging the lifetime of clinically important anti-infective agents.2:55 Predicting Antibiotic Resistance with Bacterial Synthetic BiologyÁkos Nyerges, Project leader, Csaba Pál Lab, Synthetic and Systems Biology Unit, Hungarian Academy of SciencesForecasting resistance evolution at an early stage of drug development would be useful to identify less resistance-prone antimicrobials. To this aim, by building on synthetic biology, we developed a method (DIvERGE) that enables precise mutagenesis of drug targets, directly in pathogenic bacteria. This method allowed us to predict resistance evolution to antibiotics in a high-throughput manner. With DIvERGE, we also predicted probable resistance processes for antibiotics that are in clinical trials3:25 Refreshment Break in the Exhibit Hall with Poster Viewing and Poster Competition Winner Announced

UTILIZING THE MICROBIOME4:05 Exploiting Host–Microbiome Interactions to Treat Infectious DiseasesNeeraj (Neil) Surana, MD, PhD, Assistant Professor of Pediatrics, Molecular Genetics and Microbiology, Duke UniversityAlthough investigators are working on developing new antibiotics, the history of the past ~75 years suggests that success will be short-lived before confronting resistance. An alternative to drugs that directly target the pathogen is to augment the host immune response—in a pathogen agnostic manner—to better

contain the infection. Improved understanding of cause-effect relationships between the microbiome and immunity will lead to new treatment modalities that complement conventional antibiotics.4:35 Mining the Human Microbiome for Novel Gram-Negative AntibioticsJessica Ferreyra, PhD, Scientist, Biology, NGM BiopharmaceuticalsWe have identified human microbiota-derived peptides that exhibit antimicrobial activity against human pathogens. Using two bioinformatics discovery pipelines, we identified 1,204 candidate antimicrobial products from 2,161 microbial genomes of bacteria associated with human gut, mouth, skin and urogenital sites.




FUNDERS AND ACCELERATORS8:00 Chairperson’s RemarksVikas Goyal, Associate, SR One8:05 Replenishing and Enabling the Pipeline for Anti-Infective Resistance (REPAIR)Aleks Engel, PhD, Partner, Novo Seeds, Nova HoldingsThe REPAIR Impact Fund will invest $165m over 3-5 years in novel anti-infective therapies between lead optimization and end of Phase I.8:25 Funding Opportunities with CARB-XKevin Outterson, Professor of Law, N. Neal Pike Scholar in Health and Disability Law, Boston University; Executive Director, CARB-XCARB-X is a $455M public-private partnership funded by BARDA, the Wellcome Trust, and NIAID. We provide non-dilutive awards to companies to support innovative preclinical and Phase I development focused on priority bacterial pathogens.





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8:45 How BARDA Is Addressing the Global Threat of Antimicrobial Resistance by Stimulating the End-to-End Research and Development of Novel Antibacterial ProductsMark Albrecht, Acting Branch Chief, Antibacterials Program, Biomedical Advanced Research and Development AuthoritySince 2010, the Biomedical Advanced Research and Development Authority (BARDA) has addressed the rising threat of antimicrobial resistance by providing direct funding, access to core development and manufacturing services, and technical and business support to small biotechs and large, global pharmaceutical companies supporting the clinical development of new antibiotics. In 2016, BARDA, along with the Wellcome Trust and the National Institutes of Health, established the Combatting Antibiotic Resistant Bacteria Accelerator, or CARB-X, a public-private partnership managed by Boston University accelerating the preclinical research and development innovative products addressing the AMR threat. Together, BARDA is providing end-to-end support to developers of novel diagnostics, preventatives and treatments to beat back the growing global threat of antibacterial resistant bacteria.9:05 Global Antibiotic Research and Development Partnership (GARDP)François Franceschi, PhD, Project Leader, Antimicrobial Memory Recovery and Exploratory Programme (AMREP), Global Antibiotic R&D Partnership (GARDP)The Global Antibiotic Research and Development Partnership (GARDP) – a not-for-profit drug developer

– addresses global public health needs by developing affordable new or improved antibiotic treatments. Initiated by the World Health Organization (WHO) and the Drugs for Neglected Disease initiative (DNDi) in 2016, GARDP is an important element of WHO’s Global Action Plan on antimicrobial resistance that calls for new public-private partnerships to encourage research and development (R&D) of new antimicrobial agents and diagnostics. GARDP capitalizes on DNDi’s track record of developing, delivering, and implementing seven new treatments since 2003 for neglected diseases, and a pipeline of new chemical entities, as well as from WHO’s technical expertise and leadership. GARDP prioritizes its R&D strategies based on global health priorities, clear target product profiles and R&D roadmaps. This approach creates a favourable environment for equitable access by developing a sustainable and fair pricing system. Partnerships are key to GARDP programmes and include contractual arrangements with pharmaceutical companies, research institutions, and academic partners. Current programmes comprise neonatal sepsis, sexually-transmitted infections, paediatric antibiotics and the antimicrobial memory recovery and exploratory programme, which includes REVIVE – an online resource connecting and supporting the antimicrobial R&D community. A key component of GARDP’s model is a tailored approach to ensuring sustainable access – embedding stewardship and conservation within an access approach.9:35 Coffee Break in the Exhibit Hall with Poster Viewing

10:20 PANEL DISCUSSION: Filling in the Funding GapsVikas Goyal, Associate, SR One (Moderator)Mark Albrecht, Acting Branch Chief, Antibacterials Program, Biomedical Advanced Research and Development Authority Kevin Outterson, Professor of Law, N. Neal Pike Scholar in Health and Disability Law, Boston University; Executive Director, CARB-X Aleks Engel, PhD, Partner, Novo Seeds, Nova HoldingsFrançois Franceschi, PhD, Project Leader ¦ Antimicrobial Memory Recovery and Exploratory Programme (AMREP), Global Antibiotic R&D Partnership (GARDP)With the past years filled with energetic activism from the antibacterial community, the world is joining together to fight antibacterial drug resistance. This panel will discuss current funding opportunities, challenges to overcome and hope for the future.







DiscoveryOnTarget.com • 53TARGETING GRAm-NEGATIVE PATHoGENS

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Multidrug-resistant Gram-negative bacteria are one of the main challenges for the healthcare system and public health in general. Gram-negative bacteria have specific scientific problems, such as low permeability of the outer membrane that must be overcome, complicated and multiple resistance mechanisms, etc. Cambridge Healthtech Institute’s 2nd Annual Targeting Gram-Negative Pathogens conference will be taking place as a part of the 5th Annual Re-Entering Antibacterial Discovery and Development Summit. It will be preceded by the more general Antibacterial Discovery and Development.

Advisors: Lynn Silver, LL Silver Consulting; Ruben Tommasi, Entasis Therapeutics; Joyce Sutcliffe, Formerly Tetraphase; Todd Black, Merck

RECOMMENDED ALL ACCESS PACKAGE: Choose 2 Short Courses or 1 Symposium and 2 Conferences/Training Seminars• September 25 Short Course 10: Applications of


• September 26-27 Conference: Antibacterial Discovery and Development

• September 27-28 Conference: Targeting Gram-Negative Pathogens

• September 27 Short Course 17: Technologies to Assess Permeability and Efflux in Gram-Negative Bacterial Pathogens




BREAKING OPEN BARRIERS2:45 Welcome RemarksMana Chandhok, Associate Conference Producer, Cambridge Healthtech Institute

2:50 Chairperson’s Opening RemarksTodd A. Black, PhD, Executive Director, Infectious Diseases, Basic Research, Merck Research Laboratories

2:55 KEYNOTE PRESENTATION: Staphylococcus aureus mAbs in DevelopmentSteven Projan, PhD, Former Senior Vice President, MedImmune; Beat

the Reaper, LLCThere has been an increasing focus on the potential use of immunotherapies for bacterial infections (in what can best be called a back to the future approach as immune anti sera were raised in large animals in the latter part of the nineteenth century with Emil von Behring winning first Nobel Prize for Physiology or Medicine). Now in the 21st century the use of (fully human) monoclonal antibodies are being aggressively investigated in human clinical studies with Staphylococcus aureus being the prime pathogen being target. Can the neutralization of one or a handful of the 300 plus virulence factors that Staph produces have a therapeutic or prophylactic effect? The role of many of these virulence factors is evading the host response to infection but does the bacterium have an achilles heal? Preclinical data suggest this is the case with alpha toxin being one of the prime targets.

EXTENDED-SPECTRUM BETA-LACTAMASE INHIBITORS: UPDATES3:55 Sponsored Presentation (Opportunity Available)

4:25 Refreshment Break in the Exhibit Hall with Poster Viewing5:00 In vitro Activity of Imipenem-Relebactam against Gram-Negative ESKAPE PathogensKatherine Young, MS, Senior Principal Scientist, Richard T. Clark Fellow for Global Health, Infectious Diseases, MerckRelebactam (formerly MK-7655) is an inhibitor of class A and C β-lactamases, including Klebsiella pneumoniaecarbapenemase (KPC), and is currently in clinical development in combination with imipenem-cilastatin. Using Clinical and Laboratory Standards Institute (CLSI)-defined broth microdilution methodology, we evaluated the in vitro activities of imipenem-relebactam, imipenem, and seven routinely tested parenteral antimicrobial agents against Gram-negative ESKAPE pathogens.5:30 Innovation and Challenges in the Development of Beta-Lactamase Inhibitor CombinationsMichael N. Dudley, PharmD, FIDSA, Senior Vice President, CSO, Head of Infectious Disease Global Innovation, The Medicines CompanyDevelopment of new antibiotics for resistant gram-negative infections has been most successful by restoring the activity of proven β-lactam antibiotics through use of novel β-lactamase inhibitors. However, combination therapy presents challenges in getting the right partner agent as well as getting the PK-PD right. Examples of successes and failures will be discussed.6:00 Restoring β-Lactam Efficacy against Methicillin-Resistant StaphylococciHolly Sutterlin, PhD, Director of Biology, Prokaryoticsβ-lactam antibiotics have served as the most impactful class of antibiotics but their efficacy has been eroded by the emergence of MRSA/E. To re-establish β-lactams as a standard of care therapy for MRSA/E infections, we are developing inhibitors of wall teichoic acid biosynthesis that exhibit bactericidal synergy in combination with broad-spectrum β-lactam antibiotics against diverse MRSA/E clinical isolates and show robust efficacy in a murine MRSA infection model.6:30 Dinner Short Course RegistrationClick here for details on short courses offered.9:30 Close of Day


Targeting Gram-Negative Pathogens Small Molecules, Biologics and More





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GRAM-NEGATIVE BIOLOGICS8:30 Chairperson’s RemarksAntonio DiGiandomenico, PhD, Principal Scientist, Microbial Sciences, MedImmune8:35 Immunotherapeutics Targeting Antibiotic-Resistant Pseudomonas aeruginosaAntonio DiGiandomenico, PhD, Principal Scientist, MedImmuneP. aeruginosa is a major challenge for new antimicrobial drug discovery efforts because of its versatile lifestyle and ability to develop antibiotic resistance. This rise in resistance coupled with the dearth in discovery of new antibiotic classes requires development of alternative antimicrobials, such as pathogen-specific monoclonal antibodies (mAbs). In this presentation, I will introduce novel anti-Pseudomonal mAbs and discuss their mechanisms of action in multiple infection models.9:05 Monoclonal Antibody Targeting the β-barrel Assembly Machine of Escherichia coli Is BactericidalSteven Rutherford, PhD, Scientist, GenentechFolding β-barrel proteins into the outer membrane is essential in Gram-negative bacteria. We discovered an antibody, MAB1, that inhibits BamA, an outer membrane protein required for β-barrel assembly in Escherichia coli. MAB1 is bactericidal when the LPS is truncated and it inhibits β-barrel folding, induces periplasmic stress, and disrupts outer membrane integrity. MAB1 highlights the potential for new mechanisms of antibiotics to inhibit bacterial growth by targeting extracellular epitopes.

9:35 Next-Generation Approaches to Antibody Discovery for Treatment and Prevention of Infections Caused by Gram-Negative MDR PathogensDante Ricci, PhD, Scientist, Early Research, AchaogenCases of neonatal infection are increasingly attributed to Gram-negative pathogens, with multi-drug-resistant Acinetobacter baumannii emerging as a major underlying cause of neonatal sepsis and consequent mortality. I will discuss the advantages of antibody-based approaches to prevention and treatment of Gram-negative infections, and describe a platform for the efficient identification of broadly cross-reactive anti-Acinetobacter mAbs that bind live bacteria and forestall infection.10:05 Coffee Break in the Exhibit Hall with Poster Viewing and Poster Competition Winner Announced

ANTI-GRAM NEGATIVE SMALL MOLECULES: DISCOVERY AND DEVELOPMENT10:45 Phenotypic Screening Strategies and Outcomes Directed towards Novel Gram-Negative TargetsCarl Balibar, PhD, Principal Scientist, Infectious Diseases, MerckThe emergence of multi-drug resistant bacteria is eroding the efficacy of existing antibiotics. Although genomics has greatly contributed to the identification of novel antibacterial targets, it has failed to exploit such targets to impact antibiotic discovery. Phenotypic screening remains the primary source for new antibacterial compounds; however, it is imperative to design screens with intent, target bias, and hit-prioritization strategies if high potential inhibitors and targets are to be discovered.11:15 On the Design and Optimization of the PyrrolocytosinesErin M. Duffy, PhD, CSO, Melinta Therapeutics, Inc.Our approach to the design of new antibiotics is unique, proprietary, and powerful, combining X-ray crystallography of the bacterial ribosome with a structure-based design process that we have refined over many antibiotic programs and that allows us to exploit existing as well as novel binding sites. The pyrrolocytosines represent completely novel small-molecule ribosome inhibitors from a de novo design effort targeting a validated but unexploited binding site, rationally designed to enhance bacterial influx and minimize bacterial efflux. The net result is robust coverage of ESKAPE pathogens as well as other urgent and serious threats on the CDC and WHO priority lists. Lead compounds are unaffected by

resistance to current therapies, consistent with novel chemistry and mechanism, including ESBLs, KPCs, NDMs, mcr-1 and high-efflux-expressing P. aeruginosa. The structure-based design process has allowed us to problem-solve in the areas of in vitro activity, animal efficacy and preclinical safety. Herein, we present the dossiers of several pyrrolocytosine leads in preclinical development with credentials for addressing drug-resistant Neisseria gonorrhoeae, carbapenem-resistant Enterobacteriaceae and infections caused by pathogens across the full ESKAPE spectrum.11:45 Sponsored Presentation (Opportunity Available)12:15 pm Session Break12:25 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own1:15 Refreshment Break in the Exhibit Hall with Poster Viewing

CASE STUDIES AND COMPUTATIONAL APPROACHES1:55 Chairperson’s RemarksSharookh Bomi Kapadia, Senior Scientist, Infectious Diseases, Genentech2:00 Bacterial Chemical Genomics: A Path of Ceased ResistanceEric Brown, PhD, Professor, Biochemistry and Biomedical Sciences, McMaster UniversityAntibiotic drug resistance has reached crisis proportions, owing to a dearth of new antibiotics. In the Brown lab, we are developing chemical-genomic approaches with utility in exploring complex biology and enigmatic processes that are essential for bacterial survival. Efforts to date have resulted in new understanding, platforms, chemical probes and lead compounds for antibacterial research. The ultimate goal is to contribute fresh directions for new antibacterial therapies.2:30 The Grim Reaper Is Lurking, What Matters More Death, Efficacy, or Safety?Gary Eldridge, President & CEO, Sequoia Sciences, Inc.Sepsis from UTI leads to more deaths annually than breast cancer. Sequoia Sciences is developing a vaccine to reduce the recurrences of UTI. Sequoia has evaluated its vaccine in women with and without a history of recurrent UTI. The vaccine has been well-tolerated and highly immunogenic, and elicited functional antibody responses. The results of these human studies, including preliminary clinical evidence of efficacy, and the design of future clinical studies will be presented.





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3:00 Gram-Negative Lipoprotein Biosynthesis and TransportSharookh Bomi Kapadia, Senior Scientist, Infectious Diseases, GenentechAntibiotic discovery for Gram-negative bacteria pose further challenges due to the impermeability of the asymmetric LPS-containing outer membrane. Here, we will discuss our efforts to better understand the bacterial lipoprotein synthesis and transport pathways and highlight the success and challenges associated with targeting them.3:30 Bacterial Outer Membranes and Interactions with Membrane ProteinsWonpil Im, PhD, Presidential Endowed Chair in Health, Science and Engineering, Professor of Biological Sciences and Bioengineering, Lehigh UniversityThe outer membrane of Gram-negative bacteria is a unique asymmetric membrane bilayer: phospholipids in the inner leaflet and lipopolysaccharides in the outer leaflet. Its function as a selective barrier is crucial for the survival of bacteria, and it also renders gram-negative bacteria resistant to antibiotics. I will present our ongoing molecular modeling and simulation studies on various bacterial outer membranes and their interactions with outer membrane proteins.4:00 Close of Conference




DiscoveryOnTarget.com • 56NASH AND fIBRoSIS

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Non-alcoholic Steatohepatitis (NASH) is a disease of the liver that starts with an accumulation of fat and proceeds to inflammation and scarring of the liver. The scarring begins as fibrosis, but can worsen to cirrhosis and eventual liver failure. The global incidence of NASH is rapidly rising and no medical treatments exist. Advances in the scientific understanding of the fibrotic disease process in other organs are also rapidly occurring. This conference convenes discovery scientists in academics, biotech and pharma who work in the area of fibrosis, inflammation or liver disease to share insights, tools and stay abreast of this emerging and rapidly progressing field.


Targeting HBV and Beyond• September 25 Short Course 2: Drug

Metabolism and Its Role in Discovery and Drug Development

• September 26-27 Conference: NASH and Fibrosis

• September 27-28 Conference: Autoimmune and Inflammation Drug Targets



NASH DRUG CANDIDATES8:00 Welcome RemarksAnjani Shah, PhD, Conference Director, Cambridge Healthtech Institute8:05 Chairperson’s Opening RemarksBryan C. Fuchs, PhD, Assistant Professor of Surgery, Harvard Medical School

8:10 KEYNOTE PRESENTATION: NASH Basic Science Overview and Medical LandscapeBrent Tetri, MD, Director, Division of Gastroenterology and Hepatology;

Professor of Internal Medicine, Saint Louis University School of MedicineNASH is histologic phenotype that represents the consequences of stress on multiple metabolic, inflammatory and fibrogenic pathways. It can thus be expected that patients develop NASH due to environmental, metabolic, genetic and epigenetic reasons that vary among individuals. This talk will provide a high-level overview of the pathways thought to be mechanistically important in both the pathogenesis of NASH and the resulting fibrosis and how these pathways might be targeted with pharmacotherapy.

9:10 Thyroid Hormone Receptor Agonists for Treating NASHRebecca Taub, MD, CMO & Executive Vice President, Research & Development, Madrigal Pharmaceuticals9:40 Grand Opening Coffee Break in the Exhibit Hall with Poster Viewing

NASH DRUG CANDIDATES AND TARGETS10:25 Therapeutic Approaches to Cirrhotic versus Pre-cirrhotic NASHPeter Traber, MD, Partner, Alacrita Consulting; Adjunct Professor of Medicine, University of Pennsylvania School of Medicine10:55 ACC Inhibitor for NASHJamie Bates, PhD, Senior Research Scientist, I Fibrosis, GileadACC1 and 2 catalyze the rate-limiting step of de novo lipogenesis (DNL) and inhibit mitochondrial fatty acid oxidation, respectively. GS-0976, a liver-directed acetyl-CoA carboxylase (ACC) inhibitor is currently in

Phase II for NASH. We demonstrate that DNL inhibition suppresses the activation of hepatic stellate cells (HSCs) in vitro and reduces liver fibrosis in two rodent models. These data demonstrate that, in addition to decreasing lipotoxicity in hepatocytes, ACC inhibition directly inhibits HSC activation.11:25 LXR Inverse Agonists for the Treatment of NASHClaus Kremoser, PhD, CEO, PhenexNuclear Receptor targeted drugs such as FXR, TRbeta or PPAR agonists have emerged as effective approaches to combat NASH but they all come with limitations. LXR is known as a functional counterplayer of FXR and as such, inhibiting LXR function by inverse agonist ligands should yield similar effects than activating FXR. Animal data show that beyond strong anti-steatotic properties, LXR inverse agonists demonstrate novel, unprecendeted antidiabetic effects.

Sponsored by11:55 How HepQuant Tests May Aid Drug DevelopmentSteve Helmke, CSO, HepQuant, LLCHepquant tests are minimally invasive, blood-based and use cholates as probes to measure the effects of disease on liver function and physiology. The main output, Disease Severity Index (DSI), is a liver score from 0 to 50 that is reproducible and can quantify disease severity and track changes over time.12:25 pm Session Break12:35 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own1:15 Refreshment Break in the Exhibit Hall with Poster Viewing

EMERGING TARGETS FOR LIVER FIBROSIS1:50 Chairperson’s RemarksH. James Harwood Jr., PhD, Founder and CEO, Delphi BioMedical Consultants, LLC1:55 Is Combination Therapy the Future of NASH Treatment?Star Seyedkazemi, PharmD, Associate Vice President, Clinical Development, Liver Therapeutic Area, Allergan


NASH and Fibrosis Drug Development for the Fatty Liver




DiscoveryOnTarget.com • 57NASH AND fIBRoSIS

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2:25 A Bispecific Antibody Mimetic of FGF21 for Metabolic Diseases and NASHJames A. Ernst, PhD, Senior Scientist, Department of Protein Science, Genentech, Inc.Activation of the FGF21 pathway has been shown to improve several features of metabolic disease in animals. Here we describe a novel bispecific antibody that mimics the function and metabolic effects of FGF21. Treatment with this antibody improves glycemic and lipid profiles in mouse disease models and reduces body weight in mice and non-human primates. These effects mimic the activity of FGF21 on both mice and non-human primates, suggesting that antibody-mediated activation of FGF21 pathway would be an effective treatment for type 2 diabetes.2:55 Sponsored Presentation (Opportunity Available)3:25 Refreshment Break in the Exhibit Hall with Poster Viewing and Poster Competition Winner Announced4:05 Targeting Liver Fibrosis through Modulating the Wnt PathwayWeilin Xie, PhD, Senior Principal Scientist, Biotherapeutics, Celgene4:35 CSTI-100, a Melanin-Concentrating Hormone Receptor 1 (MCHR1) Antagonist, for the Treatment of NASHPete Guzzo, PhD, Founder and CEO, ConSynance Therapeutics, Inc.MCHR1 antagonism is a new target approach for the treatment of NASH and CSTI-100 appears to be the furthest advanced compound in the industry. Emerging evidence from studies with CSTI-100 and the literature suggest this approach may have advantages over current clinical approaches. In addition, Jim Harwood has been a consultant to this program for about 10 years, and he recommended we apply to present at this prestigious forum.




TOOLS AND TARGETS FOR FIBROSIS8:00 Chairperson’s RemarksRebecca Taub, MD, CMO & Executive Vice President, Research & Development, Madrigal Pharmaceuticals

8:05 FEATURED PRESENTATION: Animal Models for NASHBryan C. Fuchs, PhD, Assistant Professor of Surgery, Harvard Medical SchoolGenerating robust fibrosis in the setting of a metabolic syndrome that resembles human clinical NASH remains a challenge for preclinical animal models. Despite these limitations, a plethora of animal models have been utilized in the NASH drug development landscape. Here, we will summarize the most commonly used models and discuss their relevance to the human disease and how they might be better utilized to enhance translation into the clinic.

8:35 NASH and Fibrosis Serum BiomakersSaurabh Gupta, PhD, Director, Translational Medicine and Early Clinical, Takeda Pharmaceuticals Interational Co.Clinical Diagnosis of NASH and evaluation of anti-fibrotic activity in clinical trials heavily relies on the histological readouts based on liver biopsy, a highly

invasive, variable and a non-representative technique. We will summarize soluble biomarkers which have shown most promising results in terms of fibrosis and NASH staging, and measuring the anti-fibrotic activity in clinical trials.9:05 Sponsored Presentation (Opportunity Available)9:35 Coffee Break in the Exhibit Hall with Poster Viewing10:20 Targeting Integrins for the Treatment of FibrosisScott M. Turner, PhD, Vice President, Translational Sciences, PLIANT TherapeuticsIntegrin receptors regulate multiple processes involved in inflammation, cell adhesion and fibrosis. αv integrins are of interest as antifibrotic targets due to their role in cell-specific TGFβ activation and promotion of fibrosis. Selective targeting of specific integrins with small molecule inhibitors can interrupt the pro-fibrotic TGFβ pathway, without the risks associated with systemic TGFβ inhibition. We have developed oral small molecule integrin inhibitors with demonstrated antifibrotic activity in primary human tissue slices and preclinical models of fibrosis.

10:50 FEATURED PRESENTATION: Development of a Novel Targeted HSP47 siRNA Lipid Nanoparticle for the Treatment of Hepatic FibrosisEdgar D. Charles, MD, Clinical Development Lead, Liver Fibrosis, Bristol-Myers Squibb







DiscoveryOnTarget.com • 58TARGETING THE mICRoBIomE

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Basic and applied biomedical research from the Human Microbiome Project and other independent studies prove that a disruption of a stable microbiome ecosystem results in dysbiosis. This imbalance leads to chronic disease and health conditions. There is great promise in correlating the microbiome compositions with these diseases and using the microbiome as a tool for therapeutic development. Cambridge Healthtech Institute’s 4th Annual Targeting the Microbiome tracks both the scientific and clinical progress being made to discover and develop microbiome-derived biomarkers, drug targets, and bioactive molecules as potential treatments for chronic disease and health conditions. Through interactive sessions and panel discussions, leading researchers and thought leaders will explore how the microbiome can become a potential point of intervention to impact progression to disease.


Targeting Autophagy• September 25 Short Course 9: CNS

Translational Strategies• September 26-27 Conference: CNS and

Neurodegenerative Targets• September 27-28 Conference: Targeting

the Microbiome• September 27 Short Course 16:

Immunology Basics




TARGETING THE MICROBIOME IN OBESITY AND METABOLIC DISORDERS2:45 Welcome RemarksCindy Crowninshield, RDN, LDN, HHC, Senior Conference Director, Cambridge Healthtech Institute

2:50 Chairperson’s Opening Remarks2:55 Targeting the Human Host-Microbiome Interface in Metabolic DiseaseJames R. Brown, MSc, PhD, GSK Senior Fellow and Director in Computational Biology for Infectious Disease and Oncology, GlaxoSmithKline, Collegeville PARecent studies have highlighted the role of gastrointestinal tract microbial communities in metabolic health and disease. The microbiome, the collective genomic and metabolic potential of the gut microbiota, has a key role in many chronic diseases through its mitigation of host immune-inflammatory responses. In this presentation, we provide a pharmaceutical industry perspective on the importance of the gut microbiome in metabolic and inflammatory diseases, its impact on drug pharmacology and the promise and challenges of exploiting human host-microbiome cross-talk pathways and networks for novel therapeutic targets.3:25 Gut Microbiome Mediates Sex Differences in the Obesity and Metabolic Syndrome in MiceKanakaraju “Raj” Kaliannan, MD, Instructor, Medicine, Harvard Medical School; Senior Research Fellow, Laboratory for Lipid Medicine and Technology (LLMT), Massachusetts General HospitalGut microbiome mediates sex differences in the obesity and metabolic syndrome. Estrogen or estrogen-like compounds-induced elevated intestinal alkaline phosphatase levels and subsequent gut microbiome changes lower bacterial lipopolysaccharide production and gut permeability, resulting in reduced metabolic endotoxemia and systemic low-grade chronic inflammation with subsequent reduction in the susceptibility to develop western-diet-induced metabolic syndrome in estrogen treated males and post-menopausal women.

Sponsored by3:55 Small Molecules at the Intersection of Health and MicrobiotaKaren DeBalsi, PhD, Senior Study, Director, MetabolonMetabolites serve as a language that mediates cross-species relationships and Metabolon’s unbiased global metabolomics approach provides a great tool to decipher the complex biological story. This talk will cover how one can best leverage this technology to address their microbiome research questions as supported by case studies.4:25 Refreshment Break in the Exhibit Hall with Poster Viewing

TARGETING THE MICROBIOME IN ORAL HEALTH & NUTRITION5:00 The Oral Microbiome as a Gateway to Systemic HealthBonnie Feldman, DDS, MBA, Digital Health Analyst and Chief Growth Officer, DrBonnie360The oral cavity is home to an immensely diverse microbiome: an estimated 20 billion microbes (more than 700 species) live in our mouths, with distinct populations predominating in different oral habitats. The status of our oral microbiome and health may provide an early indicator of systemic diseases such as diabetes, heart disease, stroke, rheumatoid arthritis and other autoimmune diseases. As advances in big data analytics, next-generation sequencing, and systems immunology advance our knowledge about the human microbiome, our understanding of and approach toward oral health, systemic immunity, and systemic health will also evolve. Learn about the latest research connecting the oral microbiome and gut with chronic and autoimmune diseases and systemic health.5:30 Nutrition and the Gut Microbiome: Where Are We Now? Where Are We Going?Leigh A. Frame, PhD, MHS, Program Director, Integrative Medicine, The George Washington University School of Medicine and Health SciencesWhen the gut microbiome (gBiome) is in an unhealthy state, an individual is in dysbiosis, which may be related to their diet and its nutritional value. The role of nutrition and the gBiome in health and disease has


Targeting the Microbiome Microbiota-Targeted Therapies to Treat and Prevent Disease





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rapidly grown with the understanding of each, their interactions, and the links to gastrointestinal disease, obesity, and chronic disease. In the last decade, the availability of affordable next-generation sequencing and gnotobiotics (germ-free animal models) has facilitated a major advancement in our understanding of the gBiome and the interaction with nutrition.6:00 Oral Blis - Streptococcus salivarius Probiotics to Promote a Healthy Oral MicrobiomeJohn Hale, PhD, Chief Technology Officer, Blis Technologies LtdStreptococcus salivarius is a commonly-occurring commensal bacterium found both exclusively in humans. S. salivarius strains K12 and M18 have been characterized and developed as probiotics providing many benefits to consumers by promoting microbial equilibrium. This talk will present examples of how application of these probiotics has led to the promotion of improved health. Future studies embracing microbiome technology will further validate the specific roles probiotics have in improving oral health.6:30 Dinner Short Course RegistrationClick here for details on short courses offered.9:30 Close of Day



TARGETING THE MICROBIOME IN AUTOIMMUNITY AND INFLAMMATORY BOWEL DISEASE8:30 Chairperson’s RemarksThomas Sundberg, PhD, Senior Research Scientist I, Center for Development of Therapeutics, Broad Institute of MIT and Harvard

8:35 KEYNOTE PRESENTATION: Bacterial Transformations in Autoimmune Drug MetabolismJason Michael Crawford, PhD, Maxine F. Singer ’57 Ph.D. Associate Professor of Chemistry and Associate Professor of Microbial Pathogenesis, Yale UniversityPhotorhabdus asymbiotica is a gammaproteobacterial pathogen that causes systemic and severe soft tissue infections in humans. During infection, it produces tapinarof, an immunomodulatory drug developed to treat psoriasis and atopic dermatitis. We show that bacteria transform tapinarof into other novel metabolites that regulate arylhydrocarbon receptor and Nrf2 antioxidant signaling, phenotypes responsible for tapinarof’s clinical efficacy. We also show that closely related dietary metabolites associated with “alternative” IBD treatments undergo similar novel transformations.

9:05 Reverse Translation for Therapeutic Development in the Human MicrobiomeUlrich Thienel, MD, PhD, CMO, Finch Therapeutics, Inc.A major challenge in microbiome research is interpreting correlations observed in human cohort studies or murine models. However, with the increasing abundance of clinical interventional data from experience with fecal microbiota transplantation, there is an opportunity to develop therapeutic insights directly from clinical observations. Finch Therapeutics identifies microbial therapies by observing patterns of microbial engraftment that drive clinical responses. We plan to use the patterns to develop a new generation of rationally selected microbiota therapies for Inflammatory Bowel Disease.9:35 NOD2, Innate Immunity and the MicrobiomeKlare Lazor, Graduate Student, Laboratory of Catherine Grimes, Department of Chemistry and Biochemistry, University of Delaware 10:05 Coffee Break in the Exhibit Hall with Poster Viewing and Poster Competition Winner Announced

COMMERCIALIZING TRANSLATIONAL APPLICATIONS & MICROBIOME PRODUCTS10:45 Standards for Microbiome and Metagenomics: Supporting the Commercial Translation of Microbiome ScienceScott A. Jackson, PhD, Leader, Complex Microbial Systems Group, Biosystems and Biomaterials Division, National Institute of Standards and TechnologyAt NIST, we are improving microbiome science and supporting the National Microbiome Initiative by developing standards for microbiome measurements that will enable federal, academic, and industry labs to reliably reproduce and advance each other’s results. Microbiome standards will support research investigations and commercial translation of microbiome science by providing measurement assurance tools: standardized protocols, reference materials, validated measurements and critically evaluated reference data.11:15 Considerations in Developing a Microbiome TherapeuticJeannie Rojas, PhD, MBA, Portfolio Leader, Research and Development, Janssen R&DWhen developing a commercial microbiome product, the development pathway and regulatory submission strategy will be different depending on whether the product is a medical food, dietary supplement or prescription drug. Microbiome-based products are novel and available guidelines are open to interpretation. In this talk, I will walk through the process of bringing a microbiome-based therapeutic to the clinic, with emphasis on key considerations, hurdles and challenges that must be factored into the development process.11:45 Sponsored Presentation (Opportunity Available)12:15 pm Session Break12:25 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own1:15 Refreshment Break in the Exhibit Hall with Poster Viewing

MICROBIOME MARKET, DEVELOPMENT & INVESTMENT OPPORTUNITIES1:55 Chairperson’s RemarksKeith F. Batchelder, MD, CEO and Founder, Genomic Healthcare Strategies





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2:00 Human Microbiome Growth Opportunities and PredictionsMadhumitha Rangesa, Department of Chemical and BioMolecular Engineering, NYU: Tandon School of Engineering; (formerly Senior Analyst, Frost & Sullivan)This presentation focuses on recent development in the areas of microbiome-driven therapeutics. An overview of key research groups, disease focus areas and trends will be provided. The discussion will encompass a review of select technologies, markets and products as well.

2:30 PANEL DISCUSSION: From Microbiome to Market: Exploring Business Development Opportunities and Investment ModelsKeith F. Batchelder, MD, CEO and Founder, Genomic Healthcare Strategies (Moderator)David Donabedian, PhD, Venture Partner, Longwood Fund; CEO and Co-Founder of Longwood portfolio Company Axial Biotherapeutics, Inc.Gail H. Javitt, JD, Member of the Firm, Health Care and Life Sciences Practice, Epstein Becker GreenJeannie Rojas, PhD, MBA, Portfolio Leader, Research and Development, Janssen R&DThis panel discussion is appropriate for you if you are working in research, science or industry and have questions about translation opportunities or the kinds of business and financial models that investors find attractive. We will discuss the areas of the microbiome investors are looking at and why. We will explore the global scope of microbiome and successful collaboration, reimbursement, and business investment models between science, business, healthcare, and government in bringing live microbial products to market. We will also discuss balancing venture activities, external R&D, and long-term market opportunities. Join us for a lively and interactive discussion.

4:00 Close of Conference




DiscoveryOnTarget.com • 61ANTIBoDy DISCoVERy foRUm - PART 1

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Discovery on Target’s new Antibody Discovery Forum conference offers research scientists working at the R&D stage the opportunity to participate in a novel meeting format that will encourage discussion and the exchange of information on the application of new science and technology for the discovery of new biotherapeutics.Part 1 will focus on the discovery workflow, and explore best practices for identifying and using new and legacy technologies to discover novel and functional drug candidates in an environment where speed and efficiency is now a mandate. The meeting will consider new approaches to the essential steps in the discovery process and how to make these more efficient by selectively and intelligently integrating the many new tools now available on the market. A key focus of the agenda will be a discussion of methods used to discover well-performing candidates and leads as early as possible – and to accomplish this goal at the lowest possible cost needed to achieve a high-quality outcome.

RECOMMENDED ALL ACCESS PACKAGE: Choose 2 Short Courses or 1 Symposium and 2 Conferences/Training Seminars• September 25 Short Course 8: Targeting of Ion

Channels with Monoclonal Antibodies• September 26-27 Conference: Antibody

Discovery Forum - Part 1• September 27-28 Conference: Antibody

Discovery Forum - Part 2• September 27 Short Course 13: GPCR

Structure-Based Drug Discovery


OPTIMIZING THE DISCOVERY WORKFLOW8:00 Welcome RemarksKent Simmons, Senior Conference Director, Cambridge Healthtech Institute8:05 Chairperson’s Opening RemarksAvinash Gill, PhD, Senior Scientific Manager, Genentech8:10 High Throughput Generation of Challenging AntigensMedha Tomlinson, PhD, Principal Research Scientist, AbbVieGeneration of proprietary therapeutics in disease requires recombinant protein antigen or a cell-based immunogen. Target antigens are challenging to

produce since they have to maintain secondary and tertiary structures to maintain functionality. Here we describe the design and production of a challenging antigen and strategies we have set up to increase throughput to support our discovery workflow.8:40 Meeting the Needs of Antibody Discovery and Engineering Campaigns with Automated WorkflowsAvinash Gill, PhD, Senior Scientific Manager, GenentechAn increasing need for high-throughput (HTP) processes to rapidly produce large numbers of antibodies has accompanied the rising scale and complexity of antibody discovery and engineering. Automated HTP workflows have been put in place to combine highly productive small-scale mammalian expression and purification platforms for generating antibodies and other therapeutic formats. The availability of purified material has enabled unambiguous identification of “hits” in biological and functional screening assays.

Sponsored by9:10 Optimizing Therapeutic Antibody Discovery with OmniAbBill Harriman, PhD, MBA, Vice President, Antibody Discovery Services LigandShelley Izquierdo, PhD, Director, Antibody Discovery, LigandThe OmniAb® portfolio of transgenics leverages 3 species to generate the OmniMouse®, OmniRat® and OmniChicken™ antibody discovery platforms, enhancing the diversity of immunological responses to therapeutically relevant targets and potentially uncovering novel epitopes for improved biological activity. Due to precise transgene design and effective in vivo affinity maturation, typical programs yield large cohorts of developable antibody candidates. Next

generation transgenic animals and recent case studies will be discussed.9:40 Grand Opening Coffee Break in the Exhibit Hall with Poster Viewing10:25 Applying Fully Automated Antibody Discovery Workflows for Finding the Needle in the HaystackStefan Zahn, PhD, Principal Scientist, Antibody Technology, Novo Nordisk AS, DenmarkThe discovery of therapeutic antibodies depends on finding the right antibody with proper functionality, affinity and developability within a highly diverse B-cell repertoire. In vivo antibody platforms have proven to efficiently deliver on these parameters. We will present a highly automated antibody discovery workflow based on traditional hybridoma technology and discuss emerging technologies for deeper mining of the B-cell repertoire providing eventually greater and faster success.10:55 Enhancing Antibody Discovery Methods and Maximizing Throughput in the Absence of AutomationColby Souders, PhD, Senior Scientist - Antibody and Protein Engineering, KanyosThe way in which therapeutic antibodies are discovered has rapidly progressed in the past decade. New methods allow us to find potent human clinical candidates at an accelerated pace; however, proprietary technology and fully automated platforms are not available for every campaign to facilitate discovery efforts. Here we address ways of finding the optimal drug candidate by exploring multiple discovery techniques and integrating the most current technology available to every researcher, such as single B-cell sorting and next-generation sequencing.

11:25 INTERACTIVE PANEL AND AUDIENCE DISCUSSION: Best Practices for Improving the Discovery WorkflowAvainash Gill, PhD, Senior Scientific Manager, Genentech (Moderator)Colby Souders, PhD, Senior Scientist - Antibody and Protein Engineering, Kanyos BioMedha Tomlinson, PhD, Principal Research Scientist, AbbVie Bioresearch CenterStefan Zahn, PhD, Principal Scientist, Antibody Technology, Novo Nordisk AS, Denmark

Inaugural | September 26-27

Antibody Discovery Forum Part 1 Discovery Technologies and Methods





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12:25 pm Session Break12:35 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own1:15 Refreshment Break in the Exhibit Hall with Poster Viewing

SCREENING AND SELECTION1:50 Chairperson’s RemarksAndrew Bradbury, PhD, MB BS (MD), CSO, Specifica, Inc.1:55 Best Practices for Evolving in House Screening Libraries and Discovery PlatformsAndrew Nixon, PhD, Vice President, Biotherapeutics Molecule Discovery, Boehringer IngelheimThe choices that we make early in the discovery process have a profound impact on the quality of the antibodies that are advanced into development and the subsequent speed to the clinic. Here we will discuss how to approach and iterate during the early screening stages to ensure successful identification of therapeutic candidates.2:25 How Can NGS Support Library Production, Selection and Screening?Bradbury_AndrewAndrew Bradbury, PhD, MB BS (MD), CSO, Specifica, Inc.The use of next-generation sequencing (NGS) as a routine tool during antibody library generation, selection and screening provides deep understanding of all aspects of in vitro antibody generation. NGS analysis of the PCR products generated by primers used to create a naive antibody library from lymphocytes, for example, revealed that primers are far more promiscuous than anticipated and amplify many other V genes, even when the primers have been designed to be V gene or family specific. This talk will discuss other insights gained from the routine use of NGS in antibody library production and selection.

Sponsored by2:55 Leveraging Computational Modeling Methods to De-Risk the Development of BiologicsHubert Li, PhD, Senior Scientist, SchrödingerComputational approaches applied upstream can play vital complementary roles in reducing failure rates, development delays, and the cost of advancing biologic drug candidates. We present in silico methods for detecting protein liabilities early in the discovery phase and describe how to integrate these approaches to screen and mitigate common issues like instability and aggregation propensity. These approaches are designed to guide experimentalists in making triage decisions by identifying classes of hits for continued exploration.

3:25 Refreshment Break in the Exhibit Hall with Poster Viewing and Poster Competition Winner Announced

4:05 PANEL DISCUSSION: Best Practices for Phenotypic and Functional Antibody ScreeningAndrew Bradbury, PhD, MB BS (MD), CSO, Specifica, Inc. (Moderator)Andrew Nixon, PhD, Vice President, Biotherapeutics Molecule Discovery, Boehringer IngelheimSai Reddy, PhD, Assistant Professor, Biosystems Science and Engineering, ETH Zurich, Switzerland




IMPLEMENTING EMERGING DISCOVERY TECHNOLOGIES8:00 Chairperson’s RemarksJane Seagal, PhD, Senior Scientist, Biologics Generation Group, AbbVie Bioresearch Center8:05 High-Throughput Antibody Engineering in Mammalian Cells by CRISPR/Cas9-Mediated Homology-Directed MutagenesisSai Reddy, PhD, Assistant Professor, Biosystems Science and Engineering, ETH Zurich, SwitzerlandHomology-directed mutagenesis (HDM) extends the concept of CRISPR/Cas9-mediated homology-directed repair to generate site-directed mutagenesis libraries in mammalian cells. Following cleavage by the Cas9 protein, single-stranded oligonucleotides containing degenerate codons serve as the repair template, providing integration of sequence diversity into the genome. We used HDM to generate libraries in the antibody CDRH3 and combined this with a mammalian surface display platform for high-throughput screening.

8:35 Developments in Computational-Based Methods for Antibody DesignAndrew Wollacott, PhD, Principal Scientist, Visterra, Inc.Over the last decade, there have been notable developments in computational protein design methods, high throughput protein characterization, and availability of antibody repertoire data. The convergence of these methods has led to significant advances in structure-guided design and antibody engineering. Here we provide an overview of recent developments and applications in the field of protein design and offer our perspective on best practices for applying these tools for antibody discovery.9:05 Sponsored Presentation (Opportunity Available)9:35 Coffee Break in the Exhibit Hall with Poster Viewing10:20 Engineering Cells at the Protein Level with Intracellular AntibodiesAndrea Marschall, PhD, Postdoctoral Researcher, Biochemistry, Brandeis UniversityIntracellular antibodies (intrabodies) can knock down functions by acting at the protein level and allow gradual quantitative tuning of membrane-receptors. We demonstrated gradual reductions of vascular adhesion molecule 1 (VCAM1) in vitro. In the world’s first transgenic intrabody mouse that we generated, ablation of VCAM1 by an intracellular antibody resulted in aberrant localization of B cells in adult animals. Intrabody mice were viable although genetic knockouts of VCAM1 are lethal.10:50 Best Practices for Evaluation and Implementing New Technology PlatformsShiv Krishnan, PhD, Head, Business Development & Licensing, Technology Platforms, SanofiAccess to cutting edge technologies is critical for sustaining innovation and productivity in drug discovery. The advent of high throughput technologies powered by miniaturization and computation has increased access to a large variety of molecular modalities. With the large variety of options in the marketplace, the objective selection of the right technologies is a major challenge. This presentation covers strategies and methodologies used for identifying, evaluating and implementing technologies for drug discovery and development.11:20 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own11:50 Conference Registration Open





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The second part of the program will address the challenging circumstance of identifying novel approaches that can be used to enter the thriving immune-oncology space. The meeting will begin with a broad look at current understandings of the biology of immune-oncology and what has been learned from the many recent clinical studies in the space – and then explore specific opportunities related to new and underexplored targets, improvements in target selectivity and unmet medical needs. Special consideration will also be given to the translation of academic and clinical stage findings into commercial development programs. A discussion format will offer those in attendance a novel opportunity to explore strategies in this space with colleagues.


Channels with Monoclonal Antibodies• September 26-27 Conference: Antibody

Discovery Forum - Part 1• September 27-28 Conference: Antibody

Discovery Forum - Part 2• September 27 Short Course 13: GPCR

Structure-Based Drug Discovery




FUTURE DIRECTIONS FOR CANCER IMMUNOTHERAPY2:45 Welcome RemarksKent Simmons, Senior Conference Director, Cambridge Healthtech Institute2:50 Chairperson’s Opening RemarksThomas Bouquin, PhD, Head, Biologics Research, Sanofi, France

2:55 KEYNOTE PRESENTATION: Diverse Biologics Modalities Underpin ‘Third Wave’ Cancer Immunology TherapeuticsJonathon Sedgwick, PhD, Vice

President and Global Head, Cancer Immunology and Immune Modulation, Boehringer Ingelheim PharmaceuticalsDespite over a century of research, it has only been in the current decade that using the patient’s own immune system to attack and remove cancer as a reliable and effective therapeutic approach has succeeded, through use of so-called “checkpoint inhibitor” monoclonal antibodies. Additional approaches to enable the immune system to recognize and kill cancer cells are being investigated. Diverse biologics modalities dominate the field, and these will be discussed.

3:25 Emerging Technologies for Personalizing Cancer ImmunotherapyAaron Goldman, PhD, Instructor in Medicine, Harvard Medical SchoolThe ability to predict whether a patient will respond to treatment is a ‘holy grail’ for oncologists. The vision and strategy for the 21st century treatment of cancer calls for a personalized approach in which therapy selection is designed for each individual patient. Here, we profile emerging models, systems and platforms that seek to harness the complexity of the tumor microenvironment to provide solutions for the clinic.

3:55 Agonist Bispecific Antibodies Delivering the Next Immuno-Oncology BreakthroughJohn Haurum, PhD, CEO, F-Star, United KingdomTargeting T cells via TNFRSF costimulatory pathways has the potential to strongly activate the immune system due to broad expression across multiple immune cells. However, FcR-mediated crosslinking is often required for optimal activity, limiting clinical efficiency, due to low affinity of Fc:FcR interactions and ADCC-mediated T cell depletion. We will present novel bispecific programmes that do not bind to FcR, but instead crosslink their two targets, resulting in a potent and controlled T cell activation.4:25 Refreshment Break in the Exhibit Hall with Poster Viewing

OPPORTUNITIES IN NEW TARGET DISCOVERY5:00 Droplet-Microfluidics as a Powerful Tool for Cancer ImmunotherapyChristoph Merten, PhD, Group Leader, Microfluidics, European Molecular Biology Laboratory (EMBL), GermanyDroplet-microfluidics allows assays to be carried out at high throughput, using minute amounts of sample material (e.g., patient biopsies). In this talk, I will show how these conceptual advantages can be exploited in cancer immunology, e.g., for the discovery of tumor-associated antigens (TAAs) and personalized therapy approaches.5:30 Antibody Discovery for Novel Multi-Targeting Strategy in Immuno-OncologyThomas Bouquin, PhD, Head, Biologics Research, Sanofi, FranceTargeting the first generation of immune checkpoints pathways has revolutionized cancer treatment leading to durable responses in previously not curable patients. However, many patients and cancer types do not respond to these treatments, prompting the discovery of new classes of immunotherapies. The presentation will focus on our strategy to discover antibodies against next-generation targets in the immune oncology space and their combination in our proprietary multi-specific format.

Inaugural | September 27-28

Antibody Discovery Forum Part 2 Discovery of Novel Cancer Immunotherapies





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6:00 Genome-Wide Networks of Stem Cell-Associated Retroviral Sequences Define Novel Diagnostic and Therapeutic Targets in Clinically Lethal MalignanciesGennadi V. Glinsky, MD, PhD, Research Scientist, Institute of Engineering in Medicine, University of California, San DiegoStem cell-associated retroviral sequences (SCARS) define thousands of genetic regulatory elements that emerged during human genomes’ evolution from endogenous retroviruses, and genome-wide, SCARS shaped the evolution of human-specific genomic regulatory networks (GRNs). Experimental and clinical evidence documenting the critical role of SCARS and associated GRNs in pathogenesis of clinically intractable human malignancies will be reported with an emphasis on molecular and genetic definitions of novel diagnostic and therapeutic targets.6:30 Dinner Short Course RegistrationClick here for details on short courses offered.9:30 Close of Day



OPPORTUNITIES IN IMPROVED TARGETING AND SPECIFICITY8:30 Chairperson’s RemarksJoseph Rucker, PhD, Vice President, Research and Development, Integral Molecular, Inc.8:35 ErbB Targeted CAR-T Cell Immunotherapy of Head and Neck Cancer: T4 ImmunotherapyJohn Maher, PhD, Clinical Senior Lecturer in Immunology, Kings College London, United KingdomT4 immunotherapy consists of a CD28+CD3 zeta-based chimeric antigen receptor (CAR), targeted against the extended ErbB network, and which is co-expressed with an IL-4 responsive chimeric cytokine receptor. Preclinical efficacy and safety

has been demonstrated in models of head and neck, ovarian, breast cancer and mesothelioma. Phase I clinical evaluation is now ongoing in patients with locally advanced or recurrent head and neck cancer, employing intra-tumoral delivery to minimize toxicity.9:05 Development of DART and TRIDENT Molecules to Target Costimulatory and Checkpoint Receptors for Immuno-Oncology ApplicationsGundo Diedrich, PhD, Director, Antibody Engineering, MacroGenicsBispecific molecules offer unique opportunities for the treatment of cancer that cannot be replicated with monospecific antibodies. The development of bispecific DART and TRIDENT molecules for dual checkpoint inhibition (PD-1 x LAG3, PD-1 x CTLA4) and tumor localized immune cell agonism (HER2 x CD137) will be presented. A synthesis of how these novel agents can be combined with other cancer treatments in an integrated immune stimulatory approach will be discussed.9:35 Targeting the Innate Immune System to Improve the Outcomes of PD-1/PD-L1 TherapyKathleen M. Mahoney, M.D., Ph.D., Clinical Instructor, Beth Israel Deaconess Medical Center; Research Associate, Dana Farber Cancer InstituteBlocking either the PD-1 receptor or its ligand PD-L1 has improved overall survival in Phase III trials in patients across tumor types. While some tumors fail to response due to a lack of immune cells infiltrating the tumor, others fail despite immune cells in the tumor. The microenvironment of many “hot” tumors is hostile to antitumor lymphocyte activity, in part due to the myeloid cell population, including tumor-associated macrophage and myeloid-derived suppressor cells. By targeting these innate immune cells via pathways such as CSFR1 or VISTA, we may be able to improve the responses and durable outcomes of PD-1/PD-L1 therapy for patients with these “hot” tumors.10:05 Coffee Break in the Exhibit Hall with Poster Viewing and Poster Competition Winner Announced10:45 A Microbiome-Derived Dual Checkpoint Inhibitor with Anti PD-1 Activity Enhances T Cell Activation and Antitumor ImmunityMarc Mansour, PhD, Senior Consultant, Leidos HealthLD01, is a microbiome-derived small peptide with dual checkpoint activity against PD1 and one other synergistic receptor. LD01 increases T cell proliferation in the presence of PDL-1. In challenge models, systemic LD01 reduced B16-F10 lung metastases, protected animals from sepsis, and enhanced vaccine-induced malaria specific T cells leading to enhanced

survival from malaria. LD01 has broad utility as a stand-alone immunotherapeutic and as a genetically engineered component of other therapies.11:15 T-DM1-Resistant Cells Gain High Metastatic Potential: Identifying Novel Therapeutic Targets for the Treatment of T-DM1-Resistant DiseaseWen Jin Wu, MD, PhD, Senior Investigator, Office of Biotechnology Products, Center for Drug Evaluation and Research, FDAT-DM1 is an ADC approved to treat trastuzumab-resistant breast cancers. Despite initial favorable outcomes, most patients eventually progress disease due to development of acquired resistance to T-DM1. We found that T-DM1-resistant cells gain high metastatic potential with significantly increased cell motility and invasion and that integrin proteins play critical roles in the regulation of cell invasion. We proposed that targeting integrins may be a novel therapeutic approach to treat T-DM1-resistant disease.11:45 Completing the Immunity Cycle by Developing Myeloid ImmunotherapiesTatiana Novobrantseva, PhD, Co-Founder, Head, Research and Development, Verseau TherapeuticsMacrophages/DCs are biologically optimized to either induce or suppress an immune response. Targeting pro-tumorigenic macrophages has been repeatedly identified as a very important next step of development for the field of immuno-oncology. Similarly, myeloid cell suppression has been long realized to be fueling the vicious cycle of the autoimmune disease. The talk will describe Verseau Therapeutics approaches to tweaking myeloid cell functionality in human disease.12:15 pm Session Break12:25 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own1:15 Refreshment Break in the Exhibit Hall with Poster Viewing

TRANSLATIONAL RESEARCH1:55 Chairperson’s RemarksKris F. Sachsenmeier, PhD, Associate Director, Translational Science, AstraZeneca2:00 The TGFb Pathway as a Resistance Mechanism of Immune-Checkpoint Inhibitors and Novel Targets in the TGFb PathwayKuldeep Neote, PhD, Senior Director, New Ventures/Scout J&J Innovation Center BostonThe hallmarks of resistance to PD-1/PD-L1 blockade is a low mutational burden, T cell exclusion or a TGFb activated stroma. TGFb has been shown as an





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important driver of checkpoint blockade re-sistance in metastatic melanoma and urothelial cancers, but development of TGFb antagonist-based therapies has been hampered by systemic toxicity. The presentation discusses strategies to neutralize TGFb in the tumor microenvironment that have the potential of limiting systemic toxicity and reverse immune evasion typified by a T cell exclusion phenotype.2:30 Overcoming Specific Mechanisms of Resistance to Immuno-Oncology TherapiesKris F. Sachsenmeier, PhD, Associate Director, Translational Science, AstraZenecaAs the clinical use of immunotherapies increases, knowledge of specific mechanisms of resistance are coming into focus. A review will be presented which summarizes a number of widely-accepted immuno-oncology resistance mechanisms, including tumor micro-environmental immunosuppression, activation or inactivation of specific signaling pathways

and changes in tumor HLA status and antigen presentation. Theoretical means of addressing each resistance mechanism will also be reviewed within the current context of preclinical and clinical experience.3:00 Indirect Immunization with Antigen-Specific Monoclonal IgG & IgE: Schedule-Dependent Interactions with Cytotoxic Agents and Immune ModulatorsChristopher F. NIcodemus, MD, Chairman, Clinical & Scientific Advisory Board, OncoQuest, Inc., CanadaWe examined the properties of Fc-gamma and Fc-epsilon constructs and identified molecules to initiate CD8 T cell Immunity that translates into promising preclinical and clinical antitumor activity in a schedule-dependent fashion linked to administration of cytotoxic and select immune adjuvants. IgE shows additional promise in mobilizing NK cell activity at low doses and influencing tissue perfusion of solid tumor

tissue matrix. Lead products targeting Muc1 and Muc16 for a range of indications are discussed.3:30 Selection of Antibody-Drug Conjugate Targets Using Expression Data, Glycoproteomics, and Functional ScreensJennifer J. Hill, PhD, Team Lead, MS & NMR Analytics, National Research Council CanadaAntibody-drug conjugates (ADCs) are a promising therapeutic class for cancer therapy. We describe our approach to identify new ADC targets, incorporating gene expression data mining and glycoproteomic profiling, followed by in vitro screening through a surrogate ADC assay. Based on these target selection methods, we are producing thousands of monoclonal and single-domain antibodies generated against a variety of cancer-associated targets and screening them for ADC activity, in vitro and in vivo.4:00 Close of Conference




DiscoveryOnTarget.com • 67ANTIBoDIES AGAINST mEmBRANE PRoTEIN TARGETS - PART 1

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Part 1 surveys solutions to research and development challenges specific to the ion channel and GPCR target families and offers presentations of biotherapeutics now advancing through development and clinical studies. The segment also includes an in-depth session focusing on new ion channel and GPCR structures, new tools for structural biology and the key characterization assays used to understand binding and functional activity in these targets.


Channels with Monoclonal Antibodies• September 26-27 Conference: Antibodies

Against Membrane Protein Targets - Part 1• September 27-28 Conference: Antibodies

Against Membrane Protein Targets - Part 2• September 27 Short Course 18: Practical

Phenotypic Screening


ION CHANNEL TARGETS8:00 Welcome RemarksKent Simmons, Senior Conference Director, Cambridge Healthtech Institute8:05 Chairperson’s Opening RemarksPravien Abeywickrema, Senior Scientist, Target Protein Design, Janssen Research & Development8:10 Nanobodies to Ion Channel Targets; What Do We Know and Where Do We Want to Go?Diane Van Hoorick, PhD, Senior Project Leader, Ablynx, BelgiumNanobodies, based on single-domain antibody fragments, retain target selectivity of full-length antibodies and in addition are easily engineered into multi-valents and multi-specifics. Based on these aspects, Nanobodies are ideal biologics for flexible targets such as ion channels. Multiple functionally active Nanobodies modifying particular conformational and functional states in different channels were

generated. Furthermore, multivalent engineering demonstrated that electrophysiological profiles can be improved and combined into new modes of action.8:40 Discovery of Functional Monoclonal Antibodies Targeting Ion Channels: Challenges and SolutionsTrevor Wilkinson, PhD, Associate Director, Antibody Discovery and Protein Engineering, MedImmune Ltd., United KingdomComplex multi-spanning membrane proteins, such as GPCRs and ion channels, are attractive targets for therapeutics. Discovery of functional monoclonal antibodies targeting these proteins is challenging although advances in this area are being realized. We will review the challenges in targeting ion channels with antibodies and provide an overview of the solutions being developed. We will illustrate progress in this field with case studies of ion channel antibody discovery.

9:10 KEYNOTE PRESENTATION: The High-Resolution Crystal Structure of the NavMs Sodium Channel Provides Information on Drug Binding and Mutations Associated

with Human DiseasesBonnie Ann Wallace, PhD, Professor, Institute of Structural and Molecular Biology, Birkbeck College, United KingdomOur high resolution crystal structures of Nav mutations, along with molecular dynamics and spectroscopic, mutational and electrophysiology studies of the channel, have enabled visualization of the binding sites of channel-blocking drugs and the transmembrane fenestrations that enable drug ingress into the channel, the changes in the voltage sensor and the channel gate associated with ion transport and the channel opening and closing, and the roles of mutations associated with human diseases.

9:40 Grand Opening Coffee Break in the Exhibit Hall with Poster Viewing10:25 Exploration of New Methods to Improve and Streamline Expression of Difficult to Express Membrane Proteins to Support Drug DiscoveryPravien Abeywickrema, Senior Scientist, Target Protein Design, Janssen Research & DevelopmentIntegral membrane proteins represent more than 60% of current drug targets. Despite the clinical significance, therapeutic agents that target membrane proteins have been difficult to develop. Poor expression in recombinant systems is the most critical challenge to producing functional membrane proteins for antibody discovery, structural and functional studies. The results from the exploration of different technologies for streamlined, efficient stable cell-line generation and transient expression in mammalian cells for several GPCRs and ion channels will be presented.10:55 A Multiplatform Strategy for the Discovery of Conventional Monoclonal Antibodies that Inhibit the Voltage-Gated Potassium Channel Kv1.3Paul Colussi, PhD, Vice President, Research, TetraGeneticsWe have isolated conventional antibodies that potently and selectively block the activity of Kv1.3, a voltage-gated potassium channel widely recognized as a therapeutic target for a variety of autoimmune diseases. We developed a general strategy to achieve our goals by combining high-level expression of recombinant voltage-gated ion channels in Tetrahymena thermophila with immunization of phylogenetically diverse species and screening tools that allow deep-mining of the immune repertoire.11:25 Exploiting TRP Channels for Targeted Drug EntryBruce P. Bean, PhD, Professor, Neurobiology, Harvard Medical SchoolMany neurons mediating pain express TRPV1 or TRPA1 channels or both. The pores formed by these channels are unusual in allowing entry of very large cations, up to 450 Daltons. This property can be exploited to deliver cationic drug molecules into the neurons. This mechanism can be used to produce long-lasting inhibition of pain, and can also be used to


Antibodies Against Membrane Protein Targets Part 1 Characterization and Structural Biology; The Development of Biotherapeutics for Ion Channel and GPCR Targets




[ ]• Full-time graduate and PhD candidates qualify for a student rate. Students are

encouraged to present a research poster and receive an additional $50 off their registration fee. Students with a research poster will be recognized as a student fellow at the event.

• Student rates cannot be combined with any other discount offers. Students must present a valid/current student ID to qualify for the student rate. Limited to the first 100 students that apply.

• The deadline to submit a poster is Friday, August 10, 2018. Those who submit a poster after this date will not receive recognition in the conference materials. The final deadline to register as a student fellow is Friday, August 10, 2018.

Full-time graduate students and PhD candidates are encouraged to apply for the Discovery on Target Student Fellowship. Applications are due by August 10, 2018.

STUDENT FELLOWSHIPMore information available at DiscoveryOnTarget.com


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inhibit itch, cough, and inflammation involving release of inflammatory neuropeptides.

Sponsored by11:55 Efficient Membrane Protein Targeting Antibodies Discovery Using Synthetic Antibody Libraries and CIS DisplayGuy Hermans, PhD, CSO, Isogenica Ltd.12:25 pm Session Break

Sponsored by12:35 Luncheon Presentation: Discovery of Highly Specific Claudin 6 Antibodies for Targeting CancerJoseph Rucker, Vice President, Research and Development, Integral MolecularOncology target Claudin 6 is upregulated in cancer and is not expressed in normal human tissue, unlike its closely related homolog Claudin 9. Integral Molecular has discovered specific Claudin 6 antibodies using its MPS Antibody Discovery Engine. High-resolution epitope mapping, together with specificity analysis using the Membrane Proteome Array allowed selection of lead candidates mAbs. These mAbs bind unique residues on Claudin 6, creating novel intellectual property, and lack reactivity for other cell surface proteins.


GPCR TARGETS1:50 Chairperson’s RemarksCatherine Hutchings, PhD, Independent Consultant, United Kingdom1:55 Pipeline Update on GPCR and Ion Channel AntibodiesCatherine Hutchings, PhD, Independent Consultant, United KingdomG protein-coupled receptors (GPCRs) and ion channels represent some of the most important target classes for therapeutic drug discovery across a wide range of diseases. The progress made by antibody-based therapeutics directed to these target classes will be reviewed outlining the breadth and diversity of antibody molecules, target opportunities in R&D and the clinical pipeline, including recent development to the expansion of opportunities afforded by next-generation modalities.2:25 i-bodies against the Chemokine Receptor CXCR4 as a Treatment for FibrosisMick Foley, PhD, CSO, AdAlta, Australiai-bodies are small, stable, human scaffolds containing a long CDR3 that enable better access to proteins

such as GPCRs and ion channels. We have obtained a panel of high affinity single domain antibodies specific for the chemokine receptor CXCR4 which is a therapeutic target in fibrosis. The lead i-body AD-114 blocked SDF-1-induced leukocyte recruitment in an air pouch model of inflammation and the recruitment of fibrocytes into the lungs of mice with bleomycin induced pulmonary fibrosis.2:55 Overcoming Tolerance by Deep Mining of Natural Immune RepertoiresKevin Heyries, PhD, Co-Founder, Business Development and Strategy Lead, AbCelleraAntibodies from natural immune responses are widely regarded as superior to those generated by display technologies; however, immune tolerance poses a serious challenge for targets with high inter-species homology. Insoluble and poorly immunogenic targets such as membrane proteins exacerbate this challenge. We show how AbCellera’s ultra-deep screening technology overcomes these challenges, producing hundreds of diverse rodent antibodies against targets with 100% rodent-human homology, including G protein-coupled receptors.

3:25 Refreshment Break in the Exhibit Hall with Poster Viewing and Poster Competition Winner Announced

http://register.healthtech.com/reg?DOT18&ID=17867&CO=53





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4:05 Targeting Membrane Proteins in their Native ContextIwan Zimmermann, PhD, Postdoctoral Fellow, Institute of Medical Microbiology, University of Zurich, SwitzerlandAntibody generation against native conformations of membrane proteins remains challenging and suffers from poor translation to binding in the native membrane context. We have established an in vitro selection procedure using three differently shaped synthetic nanobody libraries called sybodies. This enabled us to rapidly generate conformation-selective high affinity binders against challenging membrane protein targets. Furthermore, we have developed NestLink, a selection/screening hybrid technology centred on barcoding peptides that allows for deep mining of binder pools directly on cells.4:35 Structural Insights into the Extracellular Recognition of the Human Serotonin 2B Receptor by an AntibodyAndrii Ishchenko, PhD, Senior Research Associate, Structural Biology, USCGiven the importance of G protein-coupled receptors (GPCRs) as pharmaceutical targets, there has been an immense interest in therapeutic mAbs that act on GPCRs. We present the structure of a complex between the human 5-HT2B receptor and a Fab fragment bound to the extracellular side of the receptor and highlight the structural determinants of Fab binding. The structure sheds light on the mechanism of selectivity in extracellular recognition of GPCRs by mAbs.


Sponsored by6:05 Welcome Reception in the Exhibit Hall with Poster Viewing

7:10 Close of Day


CHARACTERIZATION AND STRUCTURAL BIOLOGY8:00 Chairperson’s RemarksMariana Lemos-Duarte, PhD, Postdoctoral Researcher, Icahn School of Medicine at Mount Sinai8:05 Confobody Enabled Structure Based Drug Discovery: Locking GPCRs in Functional ConformationsSarah Triest, PhD, Scientist, Confo Therapeutics, BelgiumCamelid single domain antibodies are excellent tools to stabilize conformational states of GPCRs. Confo Therapeutics uses such conformation sensitive antibodies (Confobodies) to constrain GPCRs in the desired disease-linked conformer as a starting point for drug discovery. The Confobody technology allows fragment screening of conformer-selective agonists with the desired efficacy profile and potency. A case study will be shown for the µ-opioid receptor. 8:35 Novel Uses of FT-ICR for Membrane Protein, Nanodisc, mAb and ADC AnalysisIain D. G. Campuzano, Principal Scientist, Discovery Attribute Sciences, AmgenMembrane proteins make up approximately 50% of possible “druggable” targets, making them very attractive molecules for many research groups. Native-MS analyses for accurate antibody, protein and nanodisc MW and drug-to-antibody ratio (DAR) confirmation have traditionally been performed using oa-ToF instrumentation and more recently the extended mass range Orbitrap analyser with incremental improvements in data quality. Herein we present the analysis of mAbs, ADCs, nanodiscs and PEGylated biotherapeutics using FT-ICR MS, with a specific focus for enabling membrane protein characterization.9:05 Sponsored Presentation (Opportunity Available)

9:35 Coffee Break in the Exhibit Hall with Poster Viewing10:20 Conformation-Specific Antibodies to Study GPCR SignalingMariana Lemos-Duarte, PhD, Postdoctoral Researcher, Icahn School of Medicine at Mount SinaiActivation of G-protein-coupled receptors such as opioid receptors lead to initiation of signaling cascades resulting in enhanced protein phosphorylation. Among the various kinases, protein kinase C is thought to play a crucial role in the desensitization of opioid receptors. To explore this, I am using conformation-sensitive antibodies as unique tools to explore the role of protein kinase C in opioid receptor desensitization.10:50 Characterization of Targeted Engineered Toxin Bodies (ETBs), Designed to Provide a Novel Mechanism of Action in OncologyErin Willert, PhD, Senior Vice President, R&D, Molecular TemplatesMolecular Templates, a clinical stage biopharmaceutical company, develops highly potent, specific, next-generation immunotoxins. Engineered Toxin Bodies (ETBs) destroy cancer cells by enzymatic inactivation of ribosomes, a mechanism of action distinct from other therapeutics, facilitating activity in the refractory/relapsed setting and in combination with other treatment modalities. Molecular Templates’ pipeline ETBs, proprietarily de-immunized to avoid both innate and adaptive immune recognition, target cell surface receptors expressed on hematological and solid tumors.11:20 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own11:50 Conference Registration Open







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Part 2 offers an examination of state-of-the-art approaches for the expression of high quality membrane protein antigens and antibody generation, then explores selection and screening strategies that can be applied to discover binders with functional activity against GPCR and ion channel targets.


Channels with Monoclonal Antibodies• September 26-27 Conference: Antibodies

Against Membrane Protein Targets - Part 1• September 27-28 Conference: Antibodies

Against Membrane Protein Targets - Part 2• September 27 Short Course 18: Practical

Phenotypic Screening




DISCOVERY OF FUNCTIONAL ANTIBODIES2:45 Welcome RemarksKent Simmons, Senior Conference Director, Cambridge Healthtech Institute2:50 Chairperson’s Opening RemarksIain D. G. Campuzano, Principal Scientist, Discovery Attribute Sciences, Amgen

2:55 Droplet-Microfluidics for the Discovery of Antibodies Binding or Modulating Receptors on Target CellsChristoph Merten, PhD, Group Leader, Microfluidics, European Molecular Biology Laboratory (EMBL), GermanyDroplet microfluidics has become a powerful tool for antibody screening. After giving a general overview on the technology, I will introduce our new 2-cell platform, facilitating assays involving two different cell types. This allows screening hybridoma cells or even primary plasma cells (from mice and humans) for the secretion of antibodies binding or modulating membrane receptors on specific target cells. Approximately 100,000 antibodies can be screened in a single experiment in less than 24 hours.3:25 Strategies for Antibody Discovery to Integral Membrane ProteinsRobert Pejchal, PhD, Associate Director, Antibody Discovery, Adimab LLCDiscovery of antibodies that target integral membrane proteins at the cell surface represent a unique challenge. Using yeast presentation of large synthetic human antibody libraries, Adimab has developed methods for isolation of target specific binders utilizing whole cells selection, NGS, and high-throughput screening. Considerations for utilization of solubilized protein are also discussed.3:55 Integrating New Visualization and Analysis Tools for Large Antibody Datasets from Single-Cell ScreeningMaia Smith, MSc, Data Visualization Lead, AbCelleraHigh throughput discovery technologies enable the rapid generation of large panels of antibody candidates. The resulting volume of data is complex and multidimensional, making it exceedingly difficult to analyze with conventional workflows in order to select leads. We will show how AbCellera’s pipeline integrates a dynamic, interactive visualization software to easily

explore large panels of antibodies and select lead candidates with specific properties for development.

4:10 Sponsored Presentation (Opportunity Available)4:25 Refreshment Break in the Exhibit Hall with Poster Viewing5:00 Conformational Display Selection of Functional Antibodies against GPCRsJohn Burg, PhD, Head, Biochemistry, Ab Initio BiotherapeuticsG protein-coupled receptors (GPCRs) are critical signaling mediators for both endogenous ligands and therapeutics. By combining next-generation synthetic antibody libraries with novel selection techniques, we have enabled the facile discovery of functional antibodies against GPCRs. Our selections have yielded antibodies that recognize native extracellular GPCR epitopes, with the ability to modulate receptor signaling. Our technology opens the door to routine discovery in this important new class of biologics.5:30 Generation of Positive Allosteric Modulators of TRPV1 Using Affimer ReagentsDarren Tomlinson, PhD, Associate Professor, University of Leeds, United KingdomAffimers are scaffolding proteins that constrain variable regions for molecular recognition and can be used as alternatives to antibodies in many applications. In this talk, I will focus on the isolation of Affimer reagents against TRPV1, an ion channel implicated in pain disorders. The reagents act as positive allosteric modulators, and we have mimicked the interaction with small molecules through in silico drug design based on a co-crystal structure.6:00 Interrogation of Surface Ig-Bearing and Ig-Secreting Cells using Fluorescence Activated Cell SortingJohn S. Kenney, PhD, President, Antibody SolutionsSurface immunoglobulin (SIg)-bearing B cells and antibody secreting cells (ASCs) e.g., plasmablasts or plasmacytes, are two populations within the germinal center for isolating high-affinity, antigen specific antibodies. Using Fluorescence-activated Cell Sorting (FACS), SIg cells may be identified by


Antibodies Against Membrane Protein Targets Part 2 Antigen and Antibody Generation, Discovery of Functional Antibodies





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Ag-staining of SIg, whereas, ASCs require capture of antibody secreted by the cell prior to Ag-staining. I’ll demonstrate the utility of a FACS-based approach for isolating cells from either population. 6:30 Dinner Short Course RegistrationClick here for details on short courses offered.9:30 Close of Day



ANTIBODY GENERATION8:30 Chairperson’s RemarksChristopher Murawsky, PhD, Principal Scientist, Amgen8:35 Tag-on-Demand – Exploiting ‘Switchable’ Expression Technology for the Enrichment of High-Expressing Membrane Protein Cell Lines Zachary T. Britton, PhD, Scientist, Antibody Discovery and Protein Engineering, MedImmune, LLCPoor expression and detection of membrane protein therapeutic targets have hampered drug discovery and screening efforts. To address this issue, we have developed a “Tag-on-Demand” approach to exploit ‘switchable’ expression of ‘tagged’ membrane proteins for detection and selection steps that can be turned off for ‘untagged’ expression of native proteins and used directly in whole-cell drug discovery efforts. Validation of this approach using model membrane proteins will be presented.9:05 Antibody Generation for Membrane Proteins and Complex EpitopesChristopher Murawsky, PhD, Principal Scientist, AmgenMany of the most therapeutically interesting targets are multi-pass or multi-subunit membrane proteins that have nominal surface area exposed that can serve as epitopes for antibody binding. The extracellular regions may interact to form complex, non-linear epitopes that are required for activity and are the

targets of function-modifying antibodies. We present case studies describing strategies to discover antibodies to these targets, focusing on antigen engineering, generation of large and diverse antibody repertoires and high throughput screening.9:35 Improving Antibody Discovery against Challenging TargetsRajesh Vij, Senior Scientific Researcher, Antibody Engineering, GenentechThe generation of large and diverse panels of monoclonal antibodies against multi-transmembrane or integral membrane proteins has proven challenging, thus hindering the discovery of rare functional clones. Focusing on a case study, we will discuss how antigen format, immunization scheme, and downstream expression and screening strategies can be optimized to identify antibodies with novel activities.10:05 Coffee Break in the Exhibit Hall with Poster Viewing and Poster Competition Winner Announced10:45 Cell Membrane Preparation to Enable Immunization, Antigen-Specific B-Cell Sorting and Screening for Antibodies against Cell Surface TargetsHabtom Hapte, PhD, Principal Scientist, Biotherapeutics Discovery, Boehringer IngelheimHere we report a strategy that resulted in identification of antigen-specific B cells using membrane prep as bait and a membrane prep based Meso-Scale Discovery (MSD) screening. Single B-cell sorting using membrane prep as bait generated 118 target-1-specific hits. This strategy will enable us to generate immune responses against targets that are difficult to express and purify using membrane prep based immunization, sort and screen.11:15 So Long Llamas: Rapid Discovery of Synthetic GPCR-Targeted NanobodiesConor McMahon, PhD, Postdoctoral Fellow, Biological Chemistry and Molecular Pharmacology, Harvard Medical SchoolSingle-domain camelid antibody fragments (‘nanobodies’) are broadly used as tools for biological research and have therapeutic potential. However, nanobody discovery typically requires animal immunization, presenting a host of barriers to their production. We developed a fully synthetic yeast displayed nanobody library, which circumvents animal immunization and also allows rapid isolation of conformation-specific binders. From this library, we generated a range of functional nanobodies targeting GPCRs, including conformational stabilizers and ligands.11:45 Sponsored Presentation (Opportunity Available)

12:15 pm Session Break12:25 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own1:15 Refreshment Break in the Exhibit Hall with Poster Viewing

GENERATION AND OPTIMIZATION OF MEMBRANE PROTEIN ANTIGENS1:55 Chairperson’s RemarksDan Rohrer, PhD, Senior Director, Biologics Discovery, Bristol-Myers Squibb2:00 Advances in Target Expression and Display for Discovery of Biological TherapeuticsIvan Correia, MBA, PhD, Research Fellow, Head, Global Protein Sciences, AbbVie Bioresearch CenterGeneration of specific immune response to a target protein is dependent on correct fold and conformation state of the antigen and must represent its natural state in vivo. Other important considerations include post-translational modifications and genetic polymorphism. Progress is continuously being made, and in this presentation, we introduce new perspectives and advances. We highlight many options available and successfully applied to a large number of target proteins.2:30 Beyond Detergents: Nanoencapsulation of Membrane Proteins for Drug DiscoveryTim Dafforn, PhD, Professor, Biotechnology, University of Birmingham, United KingdomFor more than 40 years, the only way to extract membrane proteins from cells was to use a detergent. However, this approach was far from successful, producing samples with low stability and activity. The recent emergence of nanoencapsulation systems like MSP and SMALP now provide membrane protein samples with high stability. In this talk, I will summarize these approaches and new developments that have occurred in the SMALP field.3:00 Expression and Screening of Human Integral Membrane Protein TargetsNicola Burgess-Brown, PhD, Principal Investigator, Structural Genomics Consortium, University of Oxford, United KingdomThe SGC promotes research advancement through our open access policy, and in the absence of IP. Globally, we have solved more than 2000 human protein structures and 10 novel integral membrane proteins (IMPs). Although we have made a significant contribution to structural biology and protein production for functional studies, IMPs and





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protein-protein complexes still remain a challenge to produce. Here, I present our established approaches for eukaryotic expression and screening IMPs using baculovirus/insect cells and BacMam technology.3:30 Emerging Strategies for Membrane Protein Presentation in Antibody DiscoveryPawel Dominik, PhD, Senior Scientist, Cancer Immunology Discovery, PfizerPhage display enables the discovery of high affinity antibodies to a variety of antigens. While discovering antibodies has become routine for most proteins, it is still challenging for transmembrane proteins. Nanodiscs have emerged as powerful tools to study membrane proteins in a more natural lipid environment. By combining phage display and nanodiscs, we improved our ability to discover antibodies to multi-pass transmembrane proteins. This approach expands the toolbox for the rapid discovery of therapeutic antibodies.4:00 Close of Conference




Pricing & Registration InformationAll Access (Choose 2 Short Courses or 1 Symposium and 2 Conferences/Training Seminars)

Academic, Government, Commercial Hospital-Affiliated

Registrations After August 31, 2018 and On-Site $3,399 $2,049

stAndArd PAckAge (Choose 2 Conferences/Training Seminars, excludes Short Courses and Symposia)


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symPosiA Pricing

One Symposium $999 $699

short course Pricing

One Short Course $699 $399

Two Short Courses $999 $699

Three Short Courses $1,199 $899

SympoSia

September 25S1: Antivirals: Targeting HBV and BeyondS2: Targeting Autophagy

immunotherapy

September 26–27C7A: Small Molecules for Cancer ImmunotherapyC8A: NK Cell-Based Cancer Immunotherapy

September 27–28 C7B: Autoimmune and Inflammation Drug TargetsC8B: Targeting Tumor Myeloid Cells

target-BaSeddiScovery&validation

September 26–27C2A: Targeting the Ubiquitin-Proteasome SystemC3A: CNS and Neurodegenerative TargetsC4A: Constrained Peptides and MacrocyclicsC5A: Target Identification and Validation - Part 1

September 27–28 C2B: Kinase Inhibitor DiscoveryC3B: GPCR-Based Drug DiscoveryC4B: Lead Generation StrategiesC5B: Target Identification and Validation - Part 2

hot&emerging

September 26–27C6A: Antibacterial Discovery and DevelopmentC1A: NASH and Fibrosis

September 27–28 C6B: Targeting Gram-Negative PathogensC1B: Targeting the Microbiome

antiBodieS

September 26–27C9A: Antibody Discovery Forum - Part 1C10A: Antibodies Against Membrane Protein Targets - Part 1

September 27–28 C9B: Antibody Discovery Forum - Part 2C10B: Antibodies Against Membrane Protein Targets - Part 2

trainingSeminarS

September 27–28 TS2: Introduction to Small Molecule Drug Discovery and Development

ShortcourSeS

September 25SC1: Introduction to GPCR-Based Drug DiscoverySC2: Drug Metabolism and Its Role in Discovery and Drug DevelopmentSC3: How to Best Utilize 3D Cells, Spheroids, and PDX Models in OncologySC8: Targeting of Ion Channels with Monoclonal AntibodiesSC9: CNS Translational StrategiesSC10: Applications of Artificial Intelligence and Machine Learning in Drug Discovery and DevelopmentSC11: Mechanistic Understanding of Pharmacological Probes for the Ubiquitin-Proteasome System

September 27 SC13: GPCR Structure-Based Drug DiscoverySC14: Advancing Tools and Technologies for Fragment-Based DesignSC15: Introduction to Targeted Covalent InhibitorsSC16: Immunology BasicsSC17: Technologies to Assess Permeability and Efflux in Gram-Negative Bacterial PathogensSC18: Practical Phenotypic Screening

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How to Register: [email protected] | P: 781.972.5400 or Toll-free in the U.S. 888.999.6288

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ADDITIONAL REGISTRATION DETAILSEach registration includes all conference sessions, posters and exhibits, food functions, and access to the conference proceedings link.Handicapped Equal Access: In accordance with the ADA, Cambridge Healthtech Institute is pleased to arrange special accommodations for attendees with special needs. All requests for such assistance must be submitted in writing to CHI at least 30 days prior to the start of the meeting.To view our Substitutions/Cancellations Policy, go to healthtech.com/regdetails. Video and or audio recording of any kind is prohibited onsite at all CHI events.

conference discountsRegister 3 – 4th is FREE: Individuals must register for the same conference or conference combination and submit completed registration form together for discount to apply.

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