Beyond Antibodies
Sanjeev Kumar
Cadila Healthcare Ltd.
September 1, 2012
Beyond Antibodies
Chapter 1
Conventional Antibodies
Antibodies
Structure
Structure-Function Correlation
Evolution
Terminology
Structure of an Antibody Molecule
Nature Reviews Drug Discovery 9, 325-338 (April 2010)
Structure / Function Relationship of an Antibody Molecule
NATURE REVIEWS | Immunology, Vol 10 | MAY 2010 | pp 317-327
Increasing Humanziation
Decreasing Immunogenicity
Evolution of Antibody Generation Platforms over 35+ years
Therapeutic and Diagnostic Antibody Sector:-Current Status and Future Directions-March 2006
TRENDS 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 345-52
Therapeutic 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 Antibodies
Chapter 2
Antibody Sequence can be modified to make better Therapeutic Antibodies
Antibodies
Structure
Structure-Function Correlation
Evolution
Terminology
Changes in Amino acid sequence to improve function
Cimzia
Lucentis
Medi-557 [Numax-YTE]
Zevalin,
Bexxar
SGN-35,
T-DM1
Metmab;
Natalizumab
Reslizumab
(SCH55700;
Ception
Therapeutics)
Antitope platform
Elusys platform
Teplizumab (MGA031;
MacroGenics/Eli lilly))
otelixizumab (TRX4;
Tolerx/GlaxoSmithKline))
Xencor,
Biowa [MEDi-563],
Potelligent,
GA-101 [Glycart]
NATURE REVIEWS | Immunology, Vol 10 | MAY 2010 | pp 345-52
Biosimilars – A Wall Street Perspective, RBC Capital Markets, LLC, Jason Kantor, Ph.D. (Analyst), May 26, 2011
Beyond Antibodies
Chapter 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
Mechanism of Action of Chemolabelled ADCs
NATURE REVIEWS | DRUG DISCOVERY, VOL 5 | FEB 2006 | pp- 147-159
Hari Hariharan, D.V.M., Ph.DAntibody Therapeutics Meeting December 9, 2010
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-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
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 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
Diverse variety of multi-specific antibody formats available
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
Two scFvs genetically fused
to a human Immunoglobulin G
(IgG), stability engineered,
prokaryotic expression system and
favourable biophysical properties
Dual variable domain-Ig,
multispecific, two antigen
combining sites with different
specificity in tandem on an IgG
Germaine Fuh, Genentech, IBC Antibody Engineering 2009
BiTE Technology Platform
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 – Mechanism of Action
Blinatumomab (MT103; Micromet/Medimmune), a BiTE specific for CD19 and CD3
Patrick A. Baeuerle, Micromet, Inc. San Diego, December , 2009
Bispecific Antibodies in Development
Biosimilars – A Wall Street Perspective, RBC Capital Markets, LLC, Jason Kantor, Ph.D. (Analyst), May 26, 2011
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
Diverse Variety of Scaffolds can bind Antigens
Company – Pieris
Scaffold – Lipocalin
Company – Pieris
Scaffold – Lipocalin
Source - Human/insect
Company – Adalta
Scaffold – single domain
antibody
Source - Shark
Company – Adnexus
Scaffold – Adnectin
Scaffold – variable lymphocyte
receptors,
Source - Jawless vertebrates
Company - Molecular Partners-JnJ
Scaffold – Ankyrin
Source – Designed, synthetic
Scaffold - Escherichia
coli colicin E7 immunity
protein Im7
Company – Affibody
Scaffold – Z domain of Protein A
isolated from S.aureus
Source - Bacteria
Current Opinion in Pharmacology 2008, 8:609–615
Diverse Antibody-like scaffolds in Development
Prof Dr. Anne Skerra, Therapeutic Antibodies Europe 2010
Desired properties and advantages over antibodies
Prof Dr. Anne Skerra, Therapeutic Antibodies Europe 2010
THANK YOU
NATURE REVIEWS | DRUG DISCOVERY, VOL 5 | FEB 2006 | pp- 147-159