title: In vitro characterization of the anti-PD-1 antibody nivolumab, BMS-936558, and in vivo toxicology in non-human primates.
abstract: 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.
authors.affiliation: Biologics Discovery California, Bristol-Myers Squibb Company, Redwood City, California;
authors.forename: Changyu
authors.initials: C
authors.lastname: Wang
authors.affiliation: Biologics Discovery California, Bristol-Myers Squibb Company, Redwood City, California;
authors.forename: Kent B
authors.initials: KB
authors.lastname: Thudium
authors.affiliation: Biologics Discovery California, Bristol-Myers Squibb Company, Redwood City, California;
authors.forename: Minhua
authors.initials: M
authors.lastname: Han
authors.affiliation: Biologics Discovery California, Bristol-Myers Squibb Company, Redwood City, California;
authors.forename: Xi-Tao
authors.initials: XT
authors.lastname: Wang
authors.affiliation: Biologics Discovery California, Bristol-Myers Squibb Company, Redwood City, California;
authors.forename: Haichun
authors.initials: H
authors.lastname: Huang
authors.affiliation: Biologics Discovery California, Bristol-Myers Squibb Company, Redwood City, California;
authors.forename: Diane
authors.initials: D
authors.lastname: Feingersh
authors.affiliation: Biologics Discovery California, Bristol-Myers Squibb Company, Redwood City, California;
authors.forename: Candy
authors.initials: C
authors.lastname: Garcia
authors.affiliation: Biologics Discovery California, Bristol-Myers Squibb Company, Redwood City, California;
authors.forename: Yi
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Biologics Discovery California, Bristol-Myers Squibb Company, Redwood City, California;
authors.forename: Michelle
authors.initials: M
authors.lastname: Kuhne
authors.affiliation: Biologics Discovery California, Bristol-Myers Squibb Company, Redwood City, California;
authors.forename: Mohan
authors.initials: M
authors.lastname: Srinivasan
authors.affiliation: Biologics Discovery California, Bristol-Myers Squibb Company, Redwood City, California;
authors.forename: Sujata
authors.initials: S
authors.lastname: Singh
authors.affiliation: Biologics Discovery California, Bristol-Myers Squibb Company, Redwood City, California;
authors.forename: Susan
authors.initials: S
authors.lastname: Wong
authors.affiliation: Biologics Discovery California, Bristol-Myers Squibb Company, Redwood City, California;
authors.forename: Neysa
authors.initials: N
authors.lastname: Garner
authors.affiliation: Biologics Discovery California, Bristol-Myers Squibb Company, Redwood City, California;
authors.forename: Heidi
authors.initials: H
authors.lastname: Leblanc
authors.affiliation: Bristol-Myers Squibb Company, Mount Vernon, Indiana; and.
authors.forename: R Todd
authors.initials: RT
authors.lastname: Bunch
authors.affiliation: Medarex, Princeton, New Jersey.
authors.forename: Diann
authors.initials: D
authors.lastname: Blanset
authors.affiliation: Biologics Discovery California, Bristol-Myers Squibb Company, Redwood City, California;
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Selby
authors.affiliation: Biologics Discovery California, Bristol-Myers Squibb Company, Redwood City, California; alan.korman@bms.com.
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Korman
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000096:biosynthesis / Q000276:immunology*; D000938:Antigen-Presenting Cells / Q000276:immunology; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007167:Immunotherapy; D008213:Lymphocyte Activation / Q000276:immunology*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009369:Neoplasms / Q000628:therapy; D000077594:Nivolumab; D061026:Programmed Cell Death 1 Receptor / Q000276:immunology*; D018675:Toxicity Tests; D059016:Tumor Microenvironment
chemical_list: D000911:Antibodies, Monoclonal; D061026:Programmed Cell Death 1 Receptor; D000077594:Nivolumab