1. Beyond Antibodies Sanjeev Kumar Cadila Healthcare Ltd. September 1, 2012

2. Beyond Antibodies Chapter 1 Conventional Antibodies Antibodies Structure Structure-Function Correlation Evolution Terminology

3. Structure of an Antibody Molecule Nature Reviews Drug Discovery 9, 325-338 (April 2010)

4. Structure / Function Relationship of an Antibody Molecule Antigen NATURE REVIEWS | Immunology, Vol 10 | MAY 2010 | pp 317-327

5. Evolution of Antibody Generation Platforms over 35+ years Decreasing Immunogenicity Increasing Humanziation Therapeutic and Diagnostic Antibody Sector:-Current Status and Future Directions-March 2006 TRENDS in Biotechnology Vol.23 No.10 October 2005, pp 514-522

6. Therapeutic Antibodies and Fusion Proteins: Terminology PK/PD Predictions for monoclonal Antibodies, October 09, 2008,Genentech

7. More than 35 Antibodies Approved by FDA so far and ~250 in clinical development NATURE REVIEWS | Immunology, Vol 10 | MAY 2010 | pp 345-52 Therapeutic and Diagnostic Antibody Sector:-Current Status and Future Directions-March 2006

8. Emerging trends and developments in the mAbs sector, Antibody Engineering & Design July 28, 2010 Boston

9. Beyond Antibodies Chapter 2 Antibody Sequence can be modified to make better Therapeutic Antibodies Antibodies Structure Structure-Function Correlation Evolution Terminology

10. Changes in Amino acid sequence to improve function Lucentis Antitope platform Elusys platform Teplizumab (MGA031; MacroGenics/Eli lilly)) otelixizumab (TRX4; Tolerx/GlaxoSmithKline)) Xencor, Biowa [MEDi-563], Potelligent, GA-101 [Glycart] Metmab; Natalizumab Reslizumab (SCH55700; Ception Therapeutics) Zevalin, Bexxar SGN-35, T-DM1 Cimzia NATURE REVIEWS | Immunology, Vol 10 | MAY 2010 | pp 345-52 Medi-557 [Numax-YTE]

11. Biosimilars – A Wall Street Perspective, RBC Capital Markets, LLC, Jason Kantor, Ph.D. (Analyst), May 26, 2011

12. Beyond Antibodies Chapter 3 Antibody Drug Conjugates

13. Pay Load Pay Load can be chemotherapeutic; radioisotope, cytokine, or a protein based toxin Antibody-Drug Conjugates: Guided Missiles Deployed Against Cancerous Cells

14. NATURE REVIEWS | DRUG DISCOVERY, VOL 5 | FEB 2006 | pp- 147-159 Hari Hariharan, D.V.M., Ph.DAntibody Therapeutics Meeting December 9, 2010 Mechanism of Action of Chemolabelled ADCs

15. Chemolabelled ADCs

17. Radiolabelled ADCs Ibritumomab tiuxetan [(Zevalin)], Murine IgG1/ 90 Y Anti-CD20 Indication - Relapsed or refractory NHL Tositumomab and 131I tositumomab (Bexxar) Murine IgG2a /131 I Anti-CD20 Indication - NHL refractory to Rituximab and relapsed following chemotherapy http://canceres.info/?farmaco=ibritumomab-tiuxetan http://www.lymphomation.org/treatment-rit.htm http://cewilton.blogspot.in/2007_06_01_archive.html

18. Cytokine-conjugated ADCs  EMD273066 [huKS-IL2 IC (EMD 273066) - IgG1 mAb specific for the human epithelial cell adhesion molecule (EpCAM) antigen, linked to two molecules of interleukin-2]  DI-Leu16-IL-2 [de-immunized and humanized anti-CD20 monoclonal antibody Leu16 fused to human cytokine interleukin-2 (IL2)]  F16–IL2 [Recombinant fusion protein composed of the antibody fragment scFv(F16) (specific to the alternatively spliced domain A1 of tenascin-C) and of human interleukin-2 (IL-2)]  hu14.18-IL2 (EMD 273063) - EMD Lexigen Research Center Corp [EMD-273063 is an antibody/cytokine fusion protein comprised of a humanized version of the murine anti-GD2 antibody 14.18 coupled to two molecules of IL-2] NATURE REVIEWS | DRUG DISCOVERY, VOL 5 | FEB 2006 | pp- 147-159

19. ADCs in Development

21. Beyond Antibodies Chapter 4 Antibody Structure can be modified to make dramatically different Therapeutics Multispecific Antibody formats Types and Features BITE technology [Micromet] Antibody-ligand fusion proteins [Apoptosis inducing] Terminology

22. Dual variable domain-Ig, multispecific, two antigen combining sites with different specificity in tandem on an IgG Two scFvs genetically fused to a human Immunoglobulin G (IgG), stability engineered, prokaryotic expression system and favourable biophysical properties Amino acids in the interface of CH3 domains, which form homodimers naturally, are mutated at sites where two chains interact, such that one of them has a small side chain (hole), while the other has a large side chain (knob). The more favorable protein interaction between knobs and holes led to the almost exclusive heterodimerization of two different CH3 domains Germaine Fuh, Genentech, IBC Antibody Engineering 2009 Diverse variety of multi-specific antibody formats available

23. BiTE ;MT103 [Rabbit anti-CD19 scFv fragment x scFv fragment of a murine anti-CD3 mAb] rM28; [Murine anti-M-AP scFv fragment x scFV fragment of a murine anti-CD28 mAb] Patrick A. Baeuerle, Micromet, Inc. San Diego, December, 2009 BiTE Technology Platform

24. Blinatumomab (MT103; Micromet/Medimmune), a BiTE specific for CD19 and CD3 Patrick A. Baeuerle, Micromet, Inc. San Diego, December, 2009 BiTE Technology – Mechanism of Action

25. Biosimilars – A Wall Street Perspective, RBC Capital Markets, LLC, Jason Kantor, Ph.D. (Analyst), May 26, 2011 Bispecific Antibodies in Development

26. Beyond Antibodies Chapter 5 Non-Antibody Scaffolds – Natural proteins that are not antibodies but can work like them Alternative non-antibody scaffolds/Antibody mimetics Types and Features Characteristics Commercial scope

27. Diverse Variety of Scaffolds can bind Antigens Company – Pieris Scaffold – Lipocalin Source - Human/insect Company – Adnexus Scaffold – Adnectin Company - Molecular Partners-JnJ Scaffold – Ankyrin Source – Designed, synthetic Company – Affibody Scaffold – Z domain of Protein A isolated from S.aureus Source - Bacteria Company – Pieris Scaffold – Lipocalin Company – Adalta Scaffold – single domain antibody Source - Shark Scaffold – variable lymphocyte receptors, Source - Jawless vertebrates Scaffold - Escherichia coli colicin E7 immunity protein Im7 Current Opinion in Pharmacology 2008, 8:609–615

28. Prof Dr. Anne Skerra, Therapeutic Antibodies Europe 2010 Diverse Antibody-like scaffolds in Development

29. Desired properties and advantages over antibodies Prof Dr. Anne Skerra, Therapeutic Antibodies Europe 2010

30. NATURE REVIEWS | DRUG DISCOVERY, VOL 5 | FEB 2006 | pp- 147-159 THANK YOU