A multi-pronged approach to treat cancer

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

2. Outline of my talk 1 My career path 2 Fundamentals of cancer biology and why cancer is hard to treat 3 MedImmune’s approach to cancer therapy 4 A day in the life at MedImmune and critical skills needed

3. 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

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

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

6. 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

7. MedImmune Headquarters, Gaithersburg

8. 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)

9. Two major areas of focus Tumor Targeted Therapies Immune Mediated Therapies Directly and specifically attacking tumor cells with powerful biologics • Activating and shaping a potent and durable anti-tumor immune response

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

11. ADC Mechanism of Action Schrama et al 2006. Nat Rev. Drug Disc

12. Anatomy of ADCs • http://www.biooncology.com/research-education/adc/about-adcs/index.html Target • High expression in tumors • Very limited normal expression Antibody • Target specific • Internalized to lysosome • Site-specific conjugation technology 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

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

14. Cancer Immunotherapy – 2013 Breakthrough of the year* Pardoll., et al. Nat Rev Cancer. 2012 Mar 22;12(4):252-64 *as chosen by the editors of Science

15. 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

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

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

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

19. Determining pharmacokinetics of antibodies in mice

20. Exploring mechanism of action of antibodies Nonspecific IgG Antibody X mg/kg 30 10 3 30 pAkt Akt pSrc Src

21. Untreated Untreated B07 B07 Antibody 1 Antibody 1 Fluorescent imaging of ovarian cancer

22. 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

23. 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

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

25. Any questions?