Identification and characterization of TSR-042, a novel anti-human PD-1 therapeutic antibody

• Published in: European journal of cancer (1990) 2016-12, Vol.69, p.S102-S102
• Main Authors: Laken, H, Kehry, M, McNeeley, P, Neben, T, Zhang, J, Jenkins, D, Wilcoxen, K
• Format: Article
• Language: English
• Subjects: Apoptosis; Binding; Biocompatibility; Bladder; Bladder cancer; Cancer; CD4 antigen; Cell death; Cross-reactivity; Cytometry; Flow cytometry; Gene expression; Hematology, Oncology and Palliative Medicine; Human behavior; Identification methods; Immune checkpoint; Immune response; Immune system; Immunoglobulin G; Immunoglobulins; Immunotherapy; In vivo methods and tests; Intravenous administration; Leukocytes (mononuclear); Lung cancer; Lymphocytes; Lymphocytes T; Melanoma; Mixed leukocyte reaction; Molecular chains; Monoclonal antibodies; Non-small cell lung carcinoma; PD-1 protein; Peripheral blood mononuclear cells; Proteins; Safety programs; Surface plasmon resonance; Toxicology; Tumors
• ISSN: 0959-8049; 1879-0852
• DOI: 10.1016/S0959-8049(16)32902-1

Background: The recognition of tumors by the immune system has long been appreciated and the presence of tumor associated lymphocytes has been reported as a positive prognostic indicator in multiple tumor types. However, despite evidence of immune reactivity, tumors are still able to grow suggesting a sub-optimal response. Programmed cell death-i (PD-i) is an immune checkpoint receptor expressed by T-cells that, through interactions with its ligands, PD-Li and PD-L2, has been demonstrated to suppress cancer-specific immune responses. Clinical evaluation of anti- PD1 and anti-PD-Li antibodies is ongoing in multiple tumor types, including non-small cell lung cancer, melanoma and bladder cancer and to date, two anti-PD-i antibodies and one anti-PD-Li antibody have been approved for the treatment of human cancers. Here, we describe the identification of TSR-042, a novel investigational anti-PDi antibody. Materials and Methods: TSR-042 is a potent, selective, IgG4 humanized monoclonal antibody generated from a mouse hybridoma using the SHM- XEL system. It was characterized in a number of in vitro and in vivo studies and completed ND-enabling preclinical activities. Results: TSR-042 displays high affinity to both human and cynomolgus monkey PD-i, as assessed by surface plasmon resonance to recombinant PD-i and flow cytometry using cell lines overexpressing recombinant PD-I or binding to native protein on peripheral blood mononuclear cells. TSR- 042 does not cross-react to the mouse species orthologue. In addition to binding to PD-i, TSR-042 also inhibits the interaction of both PD-Li and PD-L2 with PD-i. The functional antagonist activity of TSR-042 to augment in vitro responses of primary human CD4+ T-cells was assessed in a human CD4+ mixed lymphocyte reaction assay. TSR-042 was found to be a potent functional antagonist in this system, resulting in increased lL-2 production. Furthermore, TSR-042 was also found to have increased activity in the presence of either anti-TIM3 or anti-L.AG3 antibodies. TSR- 042 was also shown to not induce significant stimulation of cytokine release from human PBMCs when incubated as a single agent. Owing to its lack of cross-reactivity to rodent PD-i, a comprehensive safety program in cynomolgus monkey was performed. Results from single dose and repeat-dose intravenous toxicology studies indicated that TSR-042 was well-tolerated and displayed a profile that supported assessment of the molecule in the clinic. Conclusion: Taken tog