A multi-pronged approach to treat cancer

Jonathan Rios-Doria, Ph.D.

Bite of Science

Towson University, Baltimore, MD

September 10th, 2014

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Outline of my talk

1 My career path

3 MedImmune’s approach to cancer therapy

4 A day in the life at MedImmune and critical skills needed

2 Fundamentals of cancer biology and why cancer is hard to treat

Education and Experience

Eisenhower H.S, Shelby Twp., MI

University of Michigan, B.S., Cellular and Molecular Biology

University of Michigan, Ph.D. Cellular and Molecular Biology

– Cancer Biology focus Postdoctoral fellowship at Moffitt

Cancer Center in Tampa, FL

Employed at startup biotech company in Tampa, FL

– Nanomedicines to treat cancer

Joined MedImmune in 2011

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Hallmarks of Cancer

4Hanahan and Weinberg, Cell. Volume 144, Issue 5, 2011, 646 - 674

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Cancer Statistics, 2014

Siegel R., et all. CA Cancer J Clin. 2014 Jan-Feb;64(1):9-29

Why is cancer hard to treat?

Cancer is not one disease, it is a collection of diseases

Cancer is heterogeneous

– Identifying which patients will respond to a therapy is challenging

Cancer cells are good at avoiding death

Most cancers recur and are develop drug resistance

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MedImmune Headquarters, Gaithersburg

Fast Facts: MedImmune and AstraZeneca

MedImmune: a world-leading biologics company

– Founded 25 years ago– Combines several former biotechs; merged with CAT in

2008– Biologics subsidiary of AstraZeneca

MedImmune “Firsts”

– First approved fully human MAb drug: Humira (world’s top selling drug)

– First FDA-approved MAb for infectious disease: Synagis

– First VLP technology for HPV vaccines

– First advance in flu technology in 60+ yrs: FluMist

AstraZeneca: world leading oncology company

– tamoxifen (Nolvadex), bicalutimide (Casodex), gefitinib (Iressa), fulvestrant (Faslodex), anastrozole (Arimidex)

Tumor Targeted Therapies

Activating and shaping a potent and durable anti-tumor immune response

Directly and specifically attacking tumor cells with powerful biologics

Immune Mediated Therapies

Two major areas of focus

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Target Cell

Bi-SpecificAntibody Drug Conjugate

ADCC enhanced

TM(effector null)

YTE(half life

extension)LigandMimetic

NK

Th

e b

iolo

gic

s IM

ED

s

We Match the Target to the Best Therapeutic Technologies

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• MedImmune is a world leader in the development of antibody drugs

• Multiple sophisticated biologics platforms within our tool kit

ADC Mechanism of Action

11Schrama et al 2006. Nat Rev. Drug Disc

Target– High expression in tumors

– Very limited normal expression

Antibody– Target specific

– Internalized to lysosome

– Site-specific conjugation technology

Anatomy of ADCs

Linker– Non-cleavable, cleavable

– Stable to prevent release of the warhead

Cytotoxic warhead– Highly potent small molecule

– Chemically-modifiable to attach linker

– Payload = Linker + Warhead

http://www.biooncology.com/research-education/adc/about-adcs/index.html

Cancer Stem Cells: A paradigm shift

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Targeting cancer stem cells may provide a durable clinical response

Cancer Immunotherapy – 2013 Breakthrough of the year*

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*as chosen by the editors of SciencePardoll., et al. Nat Rev Cancer. 2012 Mar 22;12(4):252-64

My primary role at MedImmune

In vivo pharmacology

– New model development

Evaluating in vivo efficacy of various anti-cancer drugs in the pipeline

Determining pharmacokinetics and mechanisms of action of drugs

Identifying which tumor models and types in which the drugs work

Identifying molecular markers of drug response

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Drug Development Timeline

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Approval

Clinical Trials (~10 years)Preclinical Research (~3-5 years)

TargetDiscovery

IND

Where most of my work is

Example of evaluating efficacy of a candidate anti-cancer drug

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8 13 18 23 28 33 38 43 48 53 58 63 68 73 78 830

100

200

300

400

500

600

700

800

900

1000

1100

1200

1300

Antibody 1Antibody 2Antibody 1+2

last dose

Days Post Implant

Mea

n T

um

or

Vo

lum

e (m

m3 )

Control

Patient-Derived Xenograft (PDX) models

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-Tumor is directly from patient-Never cultured in vitro

Determining pharmacokinetics of antibodies in mice

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Days

Co

nce

ntr

atio

n (

ug

/mL

)

0.01

0.1

1

10

100

1000

0 4 7 10 13 16

3 mg/kg

0 4 7 10 13 16

10 mg/kg

0 4 7 10 13 16

0.01

0.1

1

10

100

100030 mg/kg

10.3 2C5

Exploring mechanism of action of antibodies

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pAktAkt

3mg/kg 30

pSrc

Src

NonspecificIgG

10 30

Antibody X

Fluorescent imaging of ovarian cancer

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Untreated Untreated

B07 B07

Antibody 1 Antibody 1

Why I chose this career

Patient is the primary focus

Discovery is exciting

Opportunities for innovation and novel therapies

– New technologies

Variety and dynamic nature of work

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Example of typical day

7:30-9:00am – catch up on emails, prepare for meetings

9:00-10:00am – meeting with project team

10-11am – seminar from invited speaker or candidate interview

11-11:30am – chat in hallway around cool idea or recent piece of data

11:30-12:30pm – lunch

12:30-1:00pm – respond to emails received in the morning

1:00-2:00pm – meeting with another project team

2-3:30pm – individual or team meetings with members of staff

3:30-4:00pm – teleconference or video chats with colleagues or external partners

4-5:00pm – catch up on emails and start to prepare for next day’s activities

5:00pm- Leave

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What I look for in a job candidate

Creative thinker and intellectually sharp

Evidence of problem solving ability

Good educational background and record of accomplishment

The ability to work in a team environment

Good communication skills

Any questions?

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