Beyond antibodies-final-31aut
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The document discusses various types of antibody therapeutics beyond conventional antibodies, including: 1) Antibody drug conjugates that link cytotoxic payloads like chemotherapy agents to antibodies to target cancer cells. 2) Multispecific antibody formats that bind two or more antigens, like bispecific T-cell engagers that recruit T cells to kill cancer cells. 3) Non-antibody protein scaffolds that mimic the binding properties of antibodies but have advantages like smaller size and greater stability. These include domains from lipocalins, adnectins, and affibodies. 4) Various engineered antibody formats like antibody fragments, conjugated antibodies, and common light chain antibodies that modify properties like half-
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Beyond antibodies-final-31aut
- 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 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 Cimzia Lucentis Medi-557 [Numax-YTE] Zevalin, Bexxar Antitope platform SGN-35, Elusys platform T-DM1 Teplizumab (MGA031; MacroGenics/Eli lilly)) Metmab; otelixizumab (TRX4; Natalizumab Tolerx/GlaxoSmithKline)) Reslizumab Xencor, (SCH55700; Biowa [MEDi-563], Ception Potelligent, Therapeutics) GA-101 [Glycart] NATURE REVIEWS | Immunology, Vol 10 | MAY 2010 | pp 345-52
- 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. 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
- 17. Radiolabelled ADCs Tositumomab and 131I tositumomab (Bexxar) Ibritumomab tiuxetan [(Zevalin)], Murine IgG2a/131I Murine IgG1/90Y Anti-CD20 Anti-CD20 Indication - NHL refractory to Rituximab Indication - Relapsed or refractory NHL 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
- 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. 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
- 23. 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
- 24. 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
- 25. Bispecific Antibodies in Development Biosimilars – A Wall Street Perspective, RBC Capital Markets, LLC, Jason Kantor, Ph.D. (Analyst), May 26, 2011
- 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 – variable lymphocyte Scaffold - Escherichia Company – Adalta Scaffold – Lipocalin receptors, coli colicin E7 immunity Scaffold – single domain Source - Jawless vertebrates protein Im7 antibody Source - Shark Company – Pieris Company – Adnexus Company - Molecular Partners-JnJ Company – Affibody Scaffold – Lipocalin Scaffold – Adnectin Scaffold – Ankyrin Scaffold – Z domain of Protein A Source - Human/insect Source – Designed, synthetic isolated from S.aureus Source - Bacteria Current Opinion in Pharmacology 2008, 8:609–615
- 28. Diverse Antibody-like scaffolds in Development Prof Dr. Anne Skerra, Therapeutic Antibodies Europe 2010
- 29. Desired properties and advantages over antibodies Prof Dr. Anne Skerra, Therapeutic Antibodies Europe 2010
- 30. THANK YOU NATURE REVIEWS | DRUG DISCOVERY, VOL 5 | FEB 2006 | pp- 147-159
Editor's Notes
- Figure 1 | Igg structure and function. a | IgG is composed of two heavy (H) and two light (L) chains. These chains comprise constant (C) regions, which constitute the Fc domain, and variable (V) regions, which constitute the Fab domain and allow antigen specificity. b | Antigen coated with IgG can bind Fc receptors and initiate signalling through immunoreceptor tyrosine-based activation motifs (ITAMs) or immunoreceptor tyrosine-based inhibitory motifs (ITIMs). c | IgG can bind neonatal Fc receptors (FcRn) on endothelial cells to maintain serum IgG levels. d | IgG can also bind to tumour cells and recruit complement component 1q (C1q) to initiate the complement cascade, resulting in tumour cell lysis by the membrane attack complex (MAC). FcγR, Fc receptor for IgG.
- Brentuximabvedotin(Adcetris; Seattle Genetics)Approved by the FDA for the treatment of Hodgkin lymphoma (HL) and systemic anaplastic large cell lymphoma (ALCL) in August 2011, brentuximab is the first new drug for the treatment of HL in more than 30 years. It consists of an anti-CD30 antibody conjugated to the antimitotic agent monomethylauristatin E (MMAE). CD30 is a cell membrane protein of the tumor necrosis factor receptor family.It was granted accelerated approval based on two single-arm multicenter clinical trials of patients with CD30-positive HL after failure of autologous stem cell transplant and patients with CD30-positive systemic ALCL who had previously received chemotherapy. The objective response rates (ORR) were 73% and 86%, respectively, while the complete remission (CR) rates were 32% and 57%, respectively, and the partial remission (PR) rates were 40% and 29%,
- Trastuzumabemtansine(T-DM1; Genentech)T-DM1 combines the anti-HER2 antibody trastuzumab (Herceptin) with a derivative of the cytotoxinmaytansine, called DM1. It is designed to selectively bind to HER2 receptors that are often overexpressed on tumor cells, particularly in patients with breast cancer.In the phase III EMILIA trial, T-DM1 extended median progression-free survival by 3.2 months in women with HER2-positive locally advanced or metastatic breast cancer compared with standard therapy of capecitabine plus lapatinib (9.6 months vs 6.4 months, respectively), according to findings presented at the American Society of Clinical Oncology (ASCO) annual meeting in June.Genentech has announced its intention to submit a biologics license application to the FDA, and its European counterpart, Roche, plans to submit a marketing authorization application to the European Medicines Agency.