Beyond antibodies-final-31aut
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Transcript of Beyond antibodies-final-31aut
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Beyond Antibodies
Sanjeev Kumar
Cadila Healthcare Ltd.September 1, 2012
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Beyond AntibodiesChapter 1
Conventional Antibodies
AntibodiesStructureStructure-Function CorrelationEvolution
Terminology
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Structure of an Antibody Molecule
Nature Reviews Drug Discovery 9, 325-338 (April 2010)
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Structure / Function Relationship of an Antibody Molecule
Antige
n
NATURE REVIEWS | Immunology, Vol 10 | MAY 2010 | pp 317-327
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Evolution of Antibody Generation Platforms over 35+ years
De
cre
as
ing
Im
mu
no
ge
nic
ity
Incr
easi
ng
Hu
man
ziat
ion
Therapeutic and Diagnostic Antibody Sector:-Current Status and Future Directions-March 2006TRENDS in Biotechnology Vol.23 No.10 October 2005, pp 514-522
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Therapeutic Antibodies and Fusion Proteins: Terminology
PK/PD Predictions for monoclonal Antibodies, October 09, 2008,Genentech
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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
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Emerging trends and developments in the mAbs sector, Antibody Engineering & Design July 28, 2010 Boston
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Beyond AntibodiesChapter 2
Antibody Sequence can be modified to make better Therapeutic Antibodies
AntibodiesStructureStructure-Function CorrelationEvolution
Terminology
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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]
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Biosimilars – A Wall Street Perspective, RBC Capital Markets, LLC, Jason Kantor, Ph.D. (Analyst), May 26, 2011
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Beyond AntibodiesChapter 3
Antibody Drug Conjugates
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Pay Load
Pay Load can be chemotherapeutic; radioisotope, cytokine, or a protein based toxin
Antibody-Drug Conjugates: Guided Missiles Deployed Against Cancerous Cells
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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
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Chemolabelled ADCs
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Chemolabelled ADCs
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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
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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
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ADCs in Development
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ADCs in Development
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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
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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
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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
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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
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Biosimilars – A Wall Street Perspective, RBC Capital Markets, LLC, Jason Kantor, Ph.D. (Analyst), May 26, 2011
Bispecific Antibodies in Development
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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
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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
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Prof Dr. Anne Skerra, Therapeutic Antibodies Europe 2010
Diverse Antibody-like scaffolds in Development
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Desired properties and advantages over antibodies
Prof Dr. Anne Skerra, Therapeutic Antibodies Europe 2010
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NATURE REVIEWS | DRUG DISCOVERY, VOL 5 | FEB 2006 | pp- 147-159
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