Pandemic Prevention Platform (P3) Proposers Day West: Lightning

Talks

NOTE: These slides are the property of the organizations listed, and are presented here with the permission of the authors. Content may not be repurposed without the permission of the authors.

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Aridis

MabIgX Technology Aridis Pharmaceuticals, Inc5941 Optical Court

San Jose, CA95138

Human convalesce

nt donor

B-cell fusion &

screening

Cell line characteriz

ation

GMPmanufacturing

Human convalesce

nt donor

B-cell fusion &

screeningManufacturing

MabIgX® Process – stable B-cell fusion cell lines

• FAST – Reach Phase I in 6-8 months• SAFE – Fully human mAbs• POTENT – mAb optimized by human immune system• APPROVED – 2 mAbs passed Phase IIa clinical (FDA/EMA)

P3 MabIgX® Improved Process

Take cell line from screening directly to production run: <60 days• Concurrent screening of mAbs, upscale & cell line testing• Single cell/microfluidics technology

In-vivo potency optimization of mAb (human immune system) prior to fusion

Anti-infective immunotherapy using human monoclonal antibodies is a promising therapeutic option to treat infectious disease outbreaks

Conventional mAb Discovery & Development Process: 18-24 monthsImmunizatio

n of miceB-cell

screeningAntibody

(genome)sequencing

Humanization& vectorconstruction

Antibody vector transfection &

clonal selection

Cell line process development &

process scale up

Release testing &

fill/finish to DP

Ichor

Ichor Medical Systems:DNA Based Antibody Delivery

• Participated in DARPA ADEPT-PROTECT program.• Developed an electroporation based delivery platform for delivery of DNA

encoded monoclonal antibodies (mAb) to provide sustained endogenous expression from a single administration.

• Established collaborations with mAb developers and demonstrated sustained mAb serum levels and protection against viral challenge in non-clinical studies.

Delivery System (TDS-IM)

+DNA

Vector encoding

mAb Intramuscular TriGrid

CandidateAntibody

0 1 2 3 4 5 6

Time (months)

Seru

m m

Ab

Conventional Recombinant mAb Pharmacokinetics

DNA mAb Pharmacokinetics in NHP

LLNL #1

LLNL-PRES-6968941

Simulations using an agent-based model and molecular dynamics will predict successful antibody interactions in the germinal center

Mutation

Proliferation

Affinity selection

Survivalmemory B cells, plasma cells

B cell internalizes antigen with probability determined by MD

helper T-cell

antigen

simulations (1000s ofmutation-specific binding free energy calculated using HPC)

Transport simulated via random hopping process

Bind with a probability determined by MD simulations

Death if B cell fails to internalize antigen after 10 hours

Cell death

Mutations (probability of 10-3 per base pair per division)• prob. of functionally silent mutation = 0.5• prob. of lethal mutation = 0.3• rest are mutations that affect affinity between B cell receptor and antigen

activated naïve B cell

CollaboratorsA. Chakraborty (MIT)M. Karplus (Harvard)

Addresses: Rapidly identify and evolve antibody candidate

NNSA

LLNL-PRES-7251768

Bioprinting Next Generation Tissue System: Instrumented Lymph Nodes

Key Features Needed: - Dynamic Vasculature

(lymphatic and blood vessels)

- Innervation- Highly organized 3D stromal

and lymphoid structure

Printed vascularized tissue = building blocks to creating functional tissue

PARC

MicroJet Particle Drug Delivery • Direct needle-free delivery of

powder payloads to tissue – physical penetration of particles

• Tunable array of collimated jets

– disposable ejector & drug cartridge• Advantages

– High patient throughput, mass population delivery

• Quiet, microjets• No –efield or custom biochem needed

– High dosing with single array scan over large area

– Simple formulations– Precision multi-particle delivery– Tunable dosing

• Showed transdermal delivery of nucleic acid-based dry particles

– Biological response comparable to intradermal injections

High speed jetGas inlet

Skin

Air accelerated post-Venturi nozzle

Drug particlesentrainment inlet

Drug reservoir

Contact: Eugene.Chow@parc.com

serum SEAP activity

Pulmotect

Boosting the Respiratory Immune System to Provide Rapid, Broad Spectrum Protection

PUL- 042-12 h

% S

urvi

val

Vehicle Only

PUL- 042+12 h

H7N9 Pandemic Influenza H3N2 Influenza

Contact: Brenton Scott, PhD

30

20

10

0

80

70

60

50

40

90

100

PUL- 042-72 h

Vehicle Only

PUL- 042+24 h

PUL- 042+24 h, +72 h

PUL- 042+48 h

% S

urvi

val

➢ Clinical-stage drug➢ Immediate lung activity➢ Long-term stability

Pre- and post-exposure of PUL-042 shows activity against H7N9 and H3N2 viral challenges in mouse models

N=15/group N=15/group

Technology Benefits:➢ Broad spectrum – every pathogen tested to date➢ Host-targeted – reduce pathogen resistance➢ Large scale/ease of manufacturing

bscott@pulmotect.com 713-579-9226

Twist Bioscience

COMBINATORIAL LIBRARIES

• TA2: Evolving Antibodies

• Libraries are:• Rationally designed• Precisely controlled• Large search space

(~10^10 and higher!)• No unintended stop

codons• Bias-free• NGS-verified

• 2-3 design/construct/test:• Improve potency• Improve specificity

• Cost effective• Fast turn-around time

UCSD #1

Hybrid tandem peptide/porous Si

nanoparticle

Tandem peptide nanocomplex

(TPNC)CARG peptide targetingS.aureus infected trachea

Targeting groups: peptides identified by in vivo phage display

Nanoparticles: Porous Si and tandem peptide nanocomplexes

Payload: oligonucleotide or protein

DARPA P3: Nanoparticle Delivery SystemsTeam: Sailor, Bhatia, Ruoslahti, Spinnaker Biosciences

GOAL: Develop means of efficiently delivering nucleic-acid-based protective treatments PROBLEM: Current methods to deliver nucleic acid therapies suffer from inadequate efficacy SOLUTION: Targeted, fusogenic nanoparticle-based nucleic acid delivery vehicles

(1) Build on previous success in treatment of bacterial infections (DARPA ADEPT/PROTECT)(2) Harness peptides that target b cells or macrophages(3) Effectively deliver treatments with safe, proven nanoparticle systems(4) Partner with Spinnaker Biosciences for GMP formulation work

targeting peptides hollow nanoparticles therapeutic payloads

VIRAPUR

• Growth and titration experience with100s of human viruses

• Rapid production of 100s of liters of many high titer viruses for pharma

• Banks of common human and primatecell lines

• Cell selection methodologies for improved virus production

• Protein and nucleic acid based assays for all viruses

• Previous DARPA contract• BSL2 and BSL3

• mggibson@virapur.com• 858 824-9000

1

• Zika Virus• Influenza viruses• Rhinovirus, Picorna viruses• RSV and Coronaviruses• Vaccinia and Poxviruses

virapur.comSan Diego, CA

• Herpesviruses• Adenoviruses• Parvoviruses• Enteroviruses• Bacteriophage

AbCellera

ABCELLERAABCELLERA

• Therapeutic antibody discovery & development• 14 partnered therapeutic programs since 2015, 100% successful• 5 programs in infectious disease: Ebola, ETEC, Flu, Klebsiella • State-of-the-art capabilities in Human mAb discovery & Immune Profiling• Founded in 2012, 32 employees and rapidly growing

ANTIBODY DISCOVERY PLATFORM • Microfluidic-based single B cell screening• Throughput of >1,000,000 cells per screen• Any species, any tissue• Single cell assay capabilities: cross-reactivity, affinity, cell binding, blocking…• Cells to hundreds of functional antibody sequences in 5 days• High-throughput antibody expression/characterization

ANTIBODY OPTIMIZATION & ENGINEERING• Deep screening of antibody libraries in mammalian cells• Ig-Seq and Bioinformatics • High-throughput affinity ranking (>100,000 mAbs per run)• Early ranking of mAbs in final format – avoid liabilities of display approaches

www.abcellera.com

Scripps

The Scripps Research Institute• Member of DARPAs Autonomous Diagnostics to

Enable Prevention and Therapeutics consortium• High-throughput and rapid isolation and

characterization of mAb during Zika pandemic using whole virus memory B cell isolation technology

Virus expansion to 10^11 PFU

whole virus antigen-specificB cell isolation

Generation of broadly neutralizing and highly potent mAb

Rapid characterization of ~300 mAb

LLNL #2

LLNL-PRES-72517624

Bioprinting Next Generation Tissue System: Instrumented Lymph Nodes

Key Features Needed: - Dynamic Vasculature

(lymphatic and blood vessels)

- Innervation- Highly organized 3D stromal

and lymphoid structure

Printed vascularized tissue = building blocks to creating functional tissue

Vanderbilt

DARPA Pandemic Prevention Platform (P3) Primary Deliverable: Provide a Platform Technology to Provide Pandemic Protection Within 60 Days Following Pathogen Identification

Proposed Platform: Selective TLR3 Agonist to Provide Immediate Immunity Against Any Viral Pathogen within Area of Contagion Risk (Primary Contacts) Prior to Identification and Promote Immune Responses for Antigen Induced Long Term Immunity Against Any Specific Pathogen (Herd Immunity)

Platform Specifics:• Rintatolimod (RNA: Poly I:Poly C12U) proven effective prior to and post exposure to viruses

in all viral classes - DNA, RNA (+ strand), RNA (- strand), and retroviruses in multiple animal models

• Proven efficacious in animal models against select agents (Ebola, SARS-CoV, WEE/VEE)• ~100,000 human doses administered to ~1,000 subjects in multiple open label and blinded

clinical trials including phase 2 and 3 double-blind, placebo-controlled trials • Drug generally well-tolerated with long-term administration with no difference in severe

adverse events between drug and placebo in Phase 2/3 trials• Currently manufactured in 4,000 unit lots (2 units per dose) with at least 4 years of stability

at 40 C (can be stockpiled for immediate availability under common storage conditions)• Regulatory rapid approval potential using FDA animal rule program • Powerful immune driver of mucosal and IM/SC delivery with proven antigen spreading

Duke

• Antigen-specific cell isolation

• Structure/function-based immunogen design

• Broadly neutralizing Abs• Nucleic acid delivery

• GMP/development • CHO and mRNA platforms• Phase I isolation unit• Domestic and International

Clinical Trial sites

• Elucidate immune response to priority pathogens

• Antibody ID & Evolution• Programs in HIV, Flu, TB,

Zika, Dengue, WNV, chlamydia, gonorrhea

• Pathogen Identification• Comprehensive Virology• Mouse, Ferret, Rabbit, NHP• Containment Cell-sorting BSL2/3

ContainmentFacility

HostPathogenInteraction

Vaccine &

Therapeutic Discovery

GMP &

ClinicalTrials

frederick.porter@duke.edu - greg.sempowski@duke.edu

dhvi.duke.edu

Integrated Infectious Disease Research & DevelopmentTo Improve Global Health

Discover

EvolveTranslate

Identify

Synthetic Genomics

| 0C O P Y R I G H T © S Y N T H E T I C G E N O M I C S , I N C.

Combination of synthetic technologies to enable viral rescue and recoveryAnticipated P3 role for Synthetic Genomics

Integrated and rapid manufacturing of RNA-Ab platform once sequence identified

Replicon platform with improved persistent, high gene expression in vivo

● Lead: (1) Synthesis of known Ab genes; (2) Assembly of genes into SGI RNA replicon vector; (3) Synthetically amplify DNA; (4)RNA formulation testing/analysis

● Partners: (1) Grow virus; (2) Affinity mature Ab genes; (3) Conduct in vivo efficacy studies; (4) Manufacture RNA

● SGI technologies can rapidly sequence emerging pathogens

● SGI synthesis technologies allow for assembly of large DNA fragments in days using automation (BioXP)

● Synthetic, purified virus can be rescued in partner labs

● Superior RNA platforms created by experienced team that are capable of elevated expression of reporter genes in vivo (left panel) and multigenic expression of antibodies in vitro (right panel)

Rapid, fully synthetic, self-amplifying RNA expression platforms

0 10 20 30104

105

106

107

108

109

Days

Tota

l Flu

x (p

hoto

ns/s

econ

d)

SGIOriginal

***

*** *

Alphavirus replicon

10/1010/10

10/1010/10

10/1010/10 10/10

10/109/1010/10

8/109/10

3/102/10

BioXp™ 3200

SGI WT DNA100

101

102

103

Ab

expr

essi

on (p

g/ce

ll/da

y)

Alphavirus replicons

Day 5Day 4Day 3Day 2Day 1

Oligos designed and synthesized 24 hours

Ab replicon assembled 12 hours

Ab gene sequence received

Ab gene cassette synthesized and error-corrected 24 hours

DNA amplificationsynthetically 24 hours

DNA template delivered to RNA manufacturer24 hours

RNA manufacture initiated

NSP Cas9 AA…A

NSP Cas9 AA…A

NSP Cas9 AA…A

UCSD #2

Adaptive Laboratory Evolution (ALE)

Harnessing the power of biology to “self-optimize” through mutation and selection

The ALE Process

Starting Strain

Optimized Strain

Adam Feistafeist@ucsd.edu

The Proprietary ALE Technology PlatformLaboratory Automation Process Control Bioinformatics & Databases

>10,000 Mutations from>50 Projects - Identified and

categorized through a bioinformatics pipeline

Clear Plateaus

Sequence & Characterize Here!

• Strict Selection Pressures• Quantitative Data Throughout

• Rapid Mutation Analysis• ALE simulator for Prediction

• Parallel Replicates• Around the clock operation

• Multiple Tunable Parameters

ALE Mutation Database

thrAS357R (AGC→CGC)Y356C (TAC→TGC)

• Previously Found and Context• Structural Implications• Functional Enrichment