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.
Highlights
Cancer can be considered as an inability of the host to eliminate transformed cells
The affinity of nivolumab for recombinant human programmed death-1 (PD-1) protein was 3.06 nmol/L when the chip was coated with low antigen density, and 2.64 nmol/L when antibody was captured on the chip using anti-IgG, in good agreement with the Scatchard analysis
Positive control anti-CD3 antibody potently increased cytokine release (Supplementary Table S2). These results demonstrate that nivolumab does not cause nonspecific lymphocyte activation
Summary
Cancer can be considered as an inability of the host to eliminate transformed cells. The immune system is the principal mechanism of cancer prevention, transformed cells counteract immunosurveillance. Natural control mechanisms that limit T-cell activation, thereby preventing collateral damage from unrestrained T-cell activity, may be exploited by tumors to evade immune responses [1]. Restoring the capacity of immune effector cells—especially T cells—to recognize and eliminate cancer is the goal of immunotherapy. The concept of inhibitory receptor blockade, known as checkpoint blockade, has been validated in humans with the approval of the antiCTLA-4 antibody ipilimumab for metastatic melanoma [2, 3]. Note: Supplementary data for this article are available at Cancer Immunology Research Online (http://cancerimmunolres.aacrjournals.org/)
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