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: Changyu Wang, Kent B Thudium, Minhua Han, Xi-Tao Wang, Haichun Huang, Diane Feingersh, Candy Garcia, Yi Wu, Michelle Kuhne, Mohan Srinivasan, Sujata Singh, Susan Wong, Neysa Garner, Heidi Leblanc, R Todd Bunch, Diann Blanset, Mark J Selby, Alan J Korman
• Journal: Cancer immunology research (Cancer Immunol Res) Vol. 2 Issue 9 Pg. 846-56 (Sep 2014) ISSN: 2326-6074 [Electronic] United States
• PMID: 24872026 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

• Antibodies, Monoclonal
• Programmed Cell Death 1 Receptor
• Nivolumab

Topics

• Animals
• Antibodies, Monoclonal (biosynthesis, immunology)
• Antigen-Presenting Cells (immunology)
• Cell Line, Tumor
• Female
• Humans
• Immunotherapy
• Lymphocyte Activation (immunology)
• Lymphocytes, Tumor-Infiltrating (immunology)
• Macaca fascicularis
• Male
• Mice
• Mice, Transgenic
• Neoplasms (therapy)
• Nivolumab
• Programmed Cell Death 1 Receptor (immunology)
• Toxicity Tests
• Tumor Microenvironment