A multi-pronged approach to treat cancer Jonathan Rios-Doria, Ph.D. Bite of Science Towson University, Baltimore, MD September 10 th, 2014

2 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

Hallmarks of Cancer 4 Hanahan and Weinberg, Cell. Volume 144, Issue 5, 2011,

5 Cancer Statistics, 2014 Siegel R., et all. CA Cancer J Clin 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 6

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

10 Target Cell Bi-Specific Antibody Drug Conjugate ADCC enhanced TM (effector null) YTE (half life extension) Ligand Mimetic NK The biologics IMEDs We Match the Target to the Best Therapeutic Technologies 10 MedImmune is a world leader in the development of antibody drugs Multiple sophisticated biologics platforms within our tool kit

ADC Mechanism of Action 11 Schrama et al 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 12

Cancer Stem Cells: A paradigm shift 13 Targeting cancer stem cells may provide a durable clinical response

Cancer Immunotherapy – 2013 Breakthrough of the year* 14 *as chosen by the editors of Science Pardoll., et al. Nat Rev Cancer 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 15

Drug Development Timeline 16 Approval Clinical Trials (~10 years) Preclinical Research (~3-5 years) Target Discovery IND Where most of my work is

Example of evaluating efficacy of a candidate anti- cancer drug 17

Patient-Derived Xenograft (PDX) models 18 -Tumor is directly from patient -Never cultured in vitro

Determining pharmacokinetics of antibodies in mice 19

Exploring mechanism of action of antibodies 20 pAkt Akt 3 mg/kg 30 pSrc Src Nonspecific IgG Antibody X

Fluorescent imaging of ovarian cancer 21 Untreated B07 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 22

23 Example of typical day  7:30-9:00am – catch up on s, 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 s 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 s and start to prepare for next day’s activities  5:00pm- Leave

24 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? 25