The document discusses opportunities for developing cutting-edge biomedical technologies and treatments at Skolkovo Institute of Translational Medicine in Russia. Some key areas discussed include immunotherapy for cancer, biomarkers for early disease detection, and developing biosimilars. Recruiting top international scientists and their breakthrough ideas is seen as important for generating new intellectual property at Skolkovo.

4. The “Cutting Edge” technologies

7. The “Hellstrom” Paradox”, Natur e, 1968; ? Anti-tumor T cells destroy tumor cells in vitro : The “Hellstrom-Schreiber” Paradox: -“ Equilibrium lesions ”(Nature, 2007) The Motivation: 1974, Moscow University In vivo tumor seems to be protected :

8. Adenosine puts anti-tumor T killer cells to sleep … The Solution Ohta and Sitkovsky, Nature 2001

11. Tumor Defense Countermeasures

12. Tumor Rejection Survival

13. Tumor Rejection Anti-Tumor Hypoxia Drug Competitive A2AR Antagonist Tumor Hypoxia [O 2 ] Low Ecto-Enzymes [CD39] High [CD73] High ATP-->[Adenosine] High Elimination or Blockade of CD73

14. Preclinical evidence of tumor rejection and immunological memory to rejected tumor due to the action of the A2AR antagonist in different animal models of cancer

15. The Anti-Tumor Hypoxia Drug enables anti-tumor T killer cells to reject lung tumors 21% 40% 60%

19. Some of the promising opportunities for Skolkovo Specific Examples…

22. S22-Fc - a multi-specific binder to EGFR, Her3 and Her2/neu Binding to T6-17 (Her2) and NE91(EGFR) cells by S22-Fc MCF7 NE91 T6-17 S22-Fc S22 Fc

23. “ Creation of a trivalent antibody like molecule with picomolar activity against EGFr, HER2/neu and HER3” The molecule is already fully “human” …; Has potential to help all HER+ breast cancer patients as compared with 25% for original herceptin Ab… as compared with Zero with no “old” herceptin. Is not it something that “ everybody wants and nobody has ”?

26. Chronology of Key Biotech Product Approvals 1982 - 2007 Fabrazyme Amevive Xolair Bexxar Raptiva 2003 1987 1998 1997 1995 1996 1988 1989 1990 1991 1992 1993 1994 1999 2001 2000 CBER (N=48) CDER (N=14) Activase 1986 1985 Nutropin Glucagon Thyrogen Mylotarg Ovidrel Natrecor Protropin Cerezyme Ceredase Follistim Forteo Epogen /Procrit Neupogen Leukine Actimmune Proleukin Pulmozyme Betaseron ReoPro Intron A Abatacept Galsulfase Avonex Retavase Benefix Infergen Neumega Rituxan Zenapax Regranex Simulect Synagis Remicade Herceptin Enbrel NovoSeven Ontak Refacto Zevalin Elitek Humira Rebif Humulin R (1982) Achieved $1 Billion Annually in International Sales 2002 Campath Kineret Xigris Aranesp 2004 2005 2006 Avastin Erbitux Tysabri Lucentis Myozyme Elaprase Vectibix Humatrope Increlex Products Most Likely Off Patent by 2018 2007 2018

33. Generation of the BSI mAb library against native human plasma proteins using mAb proteomics (patent pending) Patent pending proteome normalization (10,000 mABs / experiment) No translation bottleneck Record speed form bench to market

38. Contacts USA numbers 617-669-88-16 - works in Moscow 617-800-52-65

40. Molecular Weight hGH ~ 3000 atoms Factor VIII ~ 55,000 atoms Need for Trials Biosimilars – Complexity leads to unknowns - If you don’t run trials – you won’t know the safety or efficacy Aspirin 21 atoms Complexity of biotech products IgG Antibody ~ 25,000 atoms 0 200,000 350,000 250,000 50,000 150,000 100,000 300,000 COOH OCOCH 3

41. Drug Discovery from Uncultur-able before Microorganisms ● 99% of all species of microorganisms on the planet do not grow in the lab ● Millions of new species, an enormous untapped resource for drug discovery ● A general method to grow uncultured microorganisms developed based on cultivation in situ in diffusion chamber and subsequent “domestication” for growth in the lab ● Growth factors for many uncultured species identified, an additional tool for growing them in the lab Patent: US 7,011,957 Kaeberlein et al., Science 296:1127-1129. Schumacher et al., 2009. Science 323:396-401. Dörr et al., PLoS Biol 8(2): e1000317. Lewis, K. 2007. Nature Rev. Microbiol. 5:48-56. D’Onofrio et al., 2010. Chem. & Biol. 17: 254–264.

43. Generation of the BSI mAb library against native human plasma proteins using mAb proteomics (patent pending) Plasma Normalization Patent pending Shotgun Immunization Library characterization screening mAb Production mAb microarray Production QuantiPlasma™ PlasmaScan™ Microarray Libraries >600 mABs “ 10 000 mABs” Plasma Collection Nascent library generation HT Hybridoma Cloning mAb validation ELISA Characterization mAb/epitope/protein ID

44. An Open Forum on the Scientific and Regulatory Issues of Biosimilars and Follow-on Biologics Boston, MA USA Copley Marriott Hotel Address by: Senator Edward Kennedy Chairman of the Senate Health, Education, Labor and Pensions Committee Plenary by: Dr. Randall Lutter Acting Deputy Commissioner for Policy, US FDA Organizing Chair: Prof. Barry Karger Director, Barnett Institute, and James L. Waters Chair, Northeastern University Hosted by: A high level meeting of the international biotechnology and generics industries, together with government regulators and academic laboratories, for an open forum and collegial debate on the scientific and regulatory issues in the introduction of generic complex biological drugs. www.barnett.neu.edu/biogenerics/ For additional information or to receive updates, email Biogenerics2008@neu.edu BIOGENERICS March 2-4, 2008

45. BIOSYSTEMS INTERNATIONAL The antibody technology company