Abstract 266: Antitumor activity of REGN2810, a fully human anti-PD-1 monoclonal antibody, against MC38.Ova tumors grown in immune-competent humanized PD-1 mice

Abstract

Abstract Programmed Cell Death Protein 1 (PD-1), is an inhibitory checkpoint receptor, expressed in an activation-induced manner on T cells. PD-1 signals upon binding to its ligands PD-L1 and PD-L2, expressed on APCs and some types of cancer cells, and delivers inhibitory signals to T cells, promoting T-cells functional exhaustion in a tumor microenvironment. Clinically, antibodies (Abs) that block the interaction between PD-1 and PD-L1 can release the cytotoxic function of tumor-specific T cells, yielding durable objective responses in multiple cancer types. REGN2810 is a fully human hinge-stabilized IgG4P monoclonal Ab that binds to the extracellular domain of human PD-1 with high affinity and specificity. REGN2810 was selected using a combination of binding studies (Surface Plasmon Resonance [SPR]-Biacore), enzyme-linked immunosorbent assays (ELISA), novel engineered cell-based bioassays, and preclinical studies in mouse models. REGN2810 was investigated in PD-1 humanized mice, an approach that allows direct testing of clinical PD-1 Ab that does not cross-react with mouse PD-1. Humanized PD-1 mice were created by Velocigene technology to express a humanized hybrid PD-1 protein comprising the extracellular portion of human PD-1 and the transmembrane and intracellular portion of mouse PD-1. Humanized PD-1 mice were validated for inducible cell surface expression of hybrid PD-1 protein on activated T-cells, intact PD-1/PD-L1 signaling and immune responses. A weakly immunogenic murine colorectal cancer cell line MC38 was engineered to express ovalbumin (MC38.Ova) in order to increase tumor immunogenicity and allow monitoring of T-cell immune responses to well-defined antigenic ovalbumin peptides. Prophylactic treatment with REGN2810 PD-1 Ab significantly suppressed growth of subcutaneous syngeneic MC38.Ova tumors in humanized PD-1 mice in a dose dependent manner, and improved mouse survival. Therapeutic treatment with REGN2810 also promoted dose dependent regression of established MC38.Ova tumors in humanized PD-1 mice. Treatment with REGN2810 induced CD8 T cells proliferation and cytokine production in spleens of tumor bearing huPD-1 mice. The mechanism of action and robust anti-tumor efficacy of REGN2810 support its clinical development for the treatment of human cancers. Citation Format: Elena Burova, Omaira Allbritton, William Poueymirou, Venus Lai, Janelle White, Dimitris Skokos, Nicholas Papadopoulos, Drew Murphy, Israel Lowy, Ella Ioffe, Gavin Thurston. Antitumor activity of REGN2810, a fully human anti-PD-1 monoclonal antibody, against MC38.Ova tumors grown in immune-competent humanized PD-1 mice. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 266. doi:10.1158/1538-7445.AM2015-266