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[Proc Amer Assoc Cancer Res, Volume 45, 2004]


Experimental and Molecular Therapeutics 34: Genes, Drugs, and Novel Agents

Abstract #3802

Preclinical in vitro characterization of anti-CTLA4 therapeutic antibody CP-675,206.

Douglas C. Hanson, Paul C. Canniff, Michael J. Primiano, Carol B. Donovan, Joseph P. Gardner, Edward J. Natoli, Rodney W. Morgan, Robert J. Mather, David H. Singleton, Paul A. Hermes, Mark J. Neveu, Glenn C. Andrews, Christopher D. Castro, Eileen A. Elliott and Vahe Bedian

Pfizer Global Research & Development, Groton, CT.

Cytotoxic T lymphocyte-associated antigen 4 (CTLA4; CD152) is a cell surface receptor expressed on activated T cells. The natural ligands for CTLA4, B7.1 (CD80) and B7.2 (CD86), are expressed on antigen-presenting cells. Experimental evidence indicates that binding of B7 to CTLA4 delivers a potent negative regulatory signal to T cells, and that blocking this negative signal markedly enhances T cell-mediated killing of various murine tumors, including established tumors, and can induce antitumor immunity. CP-675,206 is a fully human anti-huCTLA4 antagonist IgG2 antibody that was generated in XenoMouse® mice at Abgenix, Inc. An IgG2 isotype was selected to minimize Fc receptor binding and complement activation. Flow cytometric studies of activated T cells demonstrated that CP-675,206 binds to human and cynomolgus monkey CTLA4, but it does not bind to mouse, hamster, rat, or rabbit CTLA4. BIAcore binding studies indicated that CP-675,206 binds to immobilized human and monkey CTLA4-Ig with average affinities of 0.28 and 0.98 nM, respectively. Binding studies demonstrated that CP-675,206 displayed >500-fold selectivity for human CTLA4-Ig compared to human CD28-Ig, B7.2-Ig, and IgG1. Human whole blood studies showed that CP-675,206 alone does not induce release of cytokines, and Fc receptor binding studies demonstrated that this antibody does not bind to human leukocyte Fc receptors. Competition binding studies demonstrated that CP-675,206 blocks binding of human CTLA4-Ig to immobilized B7.1 and B7.2 with average IC50 values of 0.65 and 0.50 nM, respectively. This anti-CTLA4 antagonist antibody consistently enhanced IL-2 and interferon-gamma production in human T cell blasts stimulated with B7-positive Raji cells. CP-675,206 also enhanced IL-2 production in a concentration dependent manner in human and cynomolgus monkey whole blood (WB) and peripheral blood mononuclear cells (PBMC) stimulated with staphylococcal enterotoxin A (SEA) superantigen. In summary, CP-675,206 is a potent fully human anti-CTLA4 antagonist antibody that enhances T cell activation in vitro and is currently being evaluated in cancer patient clinical trials.







HOME HELP FEEDBACK HOW TO CITE ABSTRACTS ARCHIVE CME INFORMATION SEARCH
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Cancer Epidemiology Biomarkers & PreventionMolecular Cancer Therapeutics
Molecular Cancer ResearchCancer Prevention Research
Cancer Prevention Journals PortalCancer Reviews Online
Annual Meeting Education BookMeeting Abstracts Online
Copyright © 2004 by the American Association for Cancer Research.