<i>In Vitro</i>Characterization of the Anti-PD-1 Antibody Nivolumab, BMS-936558, and<i>In Vivo</i>Toxicology in Non-Human Primates
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- Changyu Wang
- 1Biologics Discovery California, Bristol-Myers Squibb Company, Redwood City, California;
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- Kent B. Thudium
- 1Biologics Discovery California, Bristol-Myers Squibb Company, Redwood City, California;
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- Minhua Han
- 1Biologics Discovery California, Bristol-Myers Squibb Company, Redwood City, California;
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- Xi-Tao Wang
- 1Biologics Discovery California, Bristol-Myers Squibb Company, Redwood City, California;
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- Haichun Huang
- 1Biologics Discovery California, Bristol-Myers Squibb Company, Redwood City, California;
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- Diane Feingersh
- 1Biologics Discovery California, Bristol-Myers Squibb Company, Redwood City, California;
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- Candy Garcia
- 1Biologics Discovery California, Bristol-Myers Squibb Company, Redwood City, California;
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- Yi Wu
- 1Biologics Discovery California, Bristol-Myers Squibb Company, Redwood City, California;
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- Michelle Kuhne
- 1Biologics Discovery California, Bristol-Myers Squibb Company, Redwood City, California;
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- Mohan Srinivasan
- 1Biologics Discovery California, Bristol-Myers Squibb Company, Redwood City, California;
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- Sujata Singh
- 1Biologics Discovery California, Bristol-Myers Squibb Company, Redwood City, California;
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- Susan Wong
- 1Biologics Discovery California, Bristol-Myers Squibb Company, Redwood City, California;
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- Neysa Garner
- 1Biologics Discovery California, Bristol-Myers Squibb Company, Redwood City, California;
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- Heidi Leblanc
- 1Biologics Discovery California, Bristol-Myers Squibb Company, Redwood City, California;
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- R. Todd Bunch
- 2Bristol-Myers Squibb Company, Mount Vernon, Indiana; and
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- Diann Blanset
- 3Medarex, Princeton, New Jersey
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- Mark J. Selby
- 1Biologics Discovery California, Bristol-Myers Squibb Company, Redwood City, California;
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- Alan J. Korman
- 1Biologics Discovery California, Bristol-Myers Squibb Company, Redwood City, California;
説明
<jats:title>Abstract</jats:title><jats:p>The programmed death-1 (PD-1) receptor serves as an immunologic checkpoint, limiting bystander tissue damage and preventing the development of autoimmunity during inflammatory responses. PD-1 is expressed by activated T cells and downmodulates T-cell effector functions upon binding to its ligands, PD-L1 and PD-L2, on antigen-presenting cells. In patients with cancer, the expression of PD-1 on tumor-infiltrating lymphocytes and its interaction with the ligands on tumor and immune cells in the tumor microenvironment undermine antitumor immunity and support its rationale for PD-1 blockade in cancer immunotherapy. This report details the development and characterization of nivolumab, a fully human IgG4 (S228P) anti-PD-1 receptor-blocking monoclonal antibody. Nivolumab binds to PD-1 with high affinity and specificity, and effectively inhibits the interaction between PD-1 and its ligands. In vitro assays demonstrated the ability of nivolumab to potently enhance T-cell responses and cytokine production in the mixed lymphocyte reaction and superantigen or cytomegalovirus stimulation assays. No in vitro antibody-dependent cell-mediated or complement-dependent cytotoxicity was observed with the use of nivolumab and activated T cells as targets. Nivolumab treatment did not induce adverse immune-related events when given to cynomolgus macaques at high concentrations, independent of circulating anti-nivolumab antibodies where observed. These data provide a comprehensive preclinical characterization of nivolumab, for which antitumor activity and safety have been demonstrated in human clinical trials in various solid tumors. Cancer Immunol Res; 2(9); 846–56. ©2014 AACR.</jats:p>
収録刊行物
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- Cancer Immunology Research
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Cancer Immunology Research 2 (9), 846-856, 2014-09-01
American Association for Cancer Research (AACR)