Beyond Antibodies

Sanjeev Kumar

Cadila Healthcare Ltd.September 1, 2012

Beyond AntibodiesChapter 1

Conventional Antibodies

AntibodiesStructureStructure-Function CorrelationEvolutionTerminology

Structure of an Antibody Molecule

Nature Reviews Drug Discovery 9, 325-338 (April 2010)

Structure / Function Relationship of an Antibody Molecule

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NATURE REVIEWS | Immunology, Vol 10 | MAY 2010 | pp 317-327

Evolution of Antibody Generation Platforms over 35+ years

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Therapeutic and Diagnostic Antibody Sector:-Current Status and Future Directions-March 2006TRENDS in Biotechnology Vol.23 No.10 October 2005, pp 514-522

Therapeutic Antibodies and Fusion Proteins: Terminology

PK/PD Predictions for monoclonal Antibodies, October 09, 2008,Genentech

More than 35 Antibodies Approved by FDA so far and ~250 in clinical development

NATURE REVIEWS | Immunology, Vol 10 | MAY 2010 | pp 345-52Therapeutic and Diagnostic Antibody Sector:-Current Status and Future Directions-March 2006

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

Beyond AntibodiesChapter 2

Antibody Sequence can be modified to make better Therapeutic Antibodies

AntibodiesStructureStructure-Function CorrelationEvolutionTerminology

Changes in Amino acid sequence to improve function

Lucentis

Antitope platformElusys 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, BexxarSGN-35, T-DM1

Cimzia

NATURE REVIEWS | Immunology, Vol 10 | MAY 2010 | pp 345-52

Medi-557 [Numax-YTE]

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

Beyond AntibodiesChapter 3

Antibody Drug Conjugates

Pay Load

Pay Load can be chemotherapeutic; radioisotope, cytokine, or a protein based toxin

Antibody-Drug Conjugates: Guided Missiles Deployed Against Cancerous Cells

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

Mechanism of Action of Chemolabelled ADCs

Chemolabelled ADCs

Chemolabelled ADCs

Radiolabelled ADCs

Ibritumomab tiuxetan [(Zevalin)], Murine IgG1/90Y Anti-CD20 Indication - Relapsed or refractory NHL

Tositumomab and 131I tositumomab (Bexxar) Murine IgG2a/131I Anti-CD20Indication - NHL refractory to Rituximab and relapsed following chemotherapy

http://canceres.info/?farmaco=ibritumomab-tiuxetanhttp://www.lymphomation.org/treatment-rit.htm

http://cewilton.blogspot.in/2007_06_01_archive.html

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

ADCs in Development

ADCs in Development

Beyond AntibodiesChapter 4

Antibody Structure can be modified to make dramatically different Therapeutics

Multispecific Antibody formatsTypes and FeaturesBITE technology [Micromet]Antibody-ligand fusion proteins [Apoptosis inducing]Terminology

Dual variable domain-Ig, multispecific, two antigen

combining sites with different specificity in tandem on an IgG

Two scFvs genetically fusedto 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 sidechain (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

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

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

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

Bispecific Antibodies in Development

Beyond AntibodiesChapter 5

Non-Antibody Scaffolds – Natural proteins that are not antibodies but can work like them

Alternative non-antibody scaffolds/Antibody mimetics

Types and FeaturesCharacteristicsCommercial scope

Diverse Variety of Scaffolds can bind Antigens

Company – PierisScaffold – Lipocalin Source - Human/insect

Company – AdnexusScaffold – Adnectin

Company - Molecular Partners-JnJScaffold – AnkyrinSource – Designed, synthetic

Company – Affibody Scaffold – Z domain of Protein A isolated from S.aureusSource - Bacteria

Company – PierisScaffold – 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

Prof Dr. Anne Skerra, Therapeutic Antibodies Europe 2010

Diverse Antibody-like scaffolds in Development

Desired properties and advantages over antibodies

Prof Dr. Anne Skerra, Therapeutic Antibodies Europe 2010

NATURE REVIEWS | DRUG DISCOVERY, VOL 5 | FEB 2006 | pp- 147-159

THANK YOU