RT Journal Article
SR Electronic
T1 <em>In Vitro</em> Characterization of the Anti-PD-1 Antibody Nivolumab, BMS-936558, and <em>In Vivo</em> Toxicology in Non-Human Primates
JF Cancer Immunology Research
JO Cancer Immunol Res
FD American Association for Cancer Research
SP 846
OP 856
DO 10.1158/2326-6066.CIR-14-0040
VO 2
IS 9
A1 Wang, Changyu
A1 Thudium, Kent B.
A1 Han, Minhua
A1 Wang, Xi-Tao
A1 Huang, Haichun
A1 Feingersh, Diane
A1 Garcia, Candy
A1 Wu, Yi
A1 Kuhne, Michelle
A1 Srinivasan, Mohan
A1 Singh, Sujata
A1 Wong, Susan
A1 Garner, Neysa
A1 Leblanc, Heidi
A1 Bunch, R. Todd
A1 Blanset, Diann
A1 Selby, Mark J.
A1 Korman, Alan J.
YR 2014
UL http://cancerimmunolres.aacrjournals.org/content/2/9/846.abstract
AB 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.