Abstract 602: 23ME-00610 is a first-in-class monoclonal antibody that targets the CD200R1 immune checkpoint to enhance T cell-mediated antitumor activity

Abstract

Abstract In the 23andMe genetic database, associations were observed for CD200R1 variants and autoimmune and cancer traits with opposing directionality. These data suggest that CD200R1 may be a pivotal checkpoint in immunosurveillance of cancer and a promising therapeutic target. CD200R1 is expressed widely on human T cells and myeloid cells; and binds to its cognate ligand CD200 to suppress the activity of immune cells. Elevated expression of CD200R1 was observed on tumor-infiltrating lymphocytes relative to peripheral blood mononuclear cells (PBMCs) from cancer patients. While the expression of CD200R1 and its ligand CD200 are well characterized, the downstream immunosuppressive role for CD200R1 in human tumors or the potentiation of anti-tumor T cell function by targeting of CD200R1 is not well understood. To test the therapeutic potential of inhibiting the CD200R1 pathway we developed 23ME-00610, a fully humanized monoclonal antibody that binds to all functionally relevant isoforms and haplotypes of CD200R1 with high affinity (KD values < 0.1 nM), to target tumors that are reliant on the CD200R1 immunosuppressive pathway. 23ME-00610 completely displaced the ligand CD200 from CD200R1 in cell-based flow cytometry assays with blocking IC50 values that ranged from 0.32 to 1.04 nM depending on the concentration of CD200 ligand present, and inhibited downstream signaling through the adaptor protein DOK2 in a reporter-based assay. Functionally, 23ME-00610 reversed CD200-mediated suppression of chronically stimulated primary T cells. In addition, 23ME-00610 enhanced PBMC-mediated tumor killing with a mean EC50 of 2.09 nM using methods of real-time measurement of cytotoxicity of human CD200-expressing tumor cells when compared to control antibodies. Moreover, 23ME-00610 promoted IFNγ production, a key functional anti-tumor T cell cytokine, in cancer patients’-derived PBMCs. Taken together, these results demonstrate that 23ME-00610 has the potential to reverse CD200-mediated immunosuppression in the TME to enhance anti-tumor T-cell functions in cancer patients. Citation Format: Jill Fenaux, Yao-ming Huang, Cristina Melero, Wei-Jen Chung, Suk Lee, Dina Ayupova, Mauro Poggio, Dylan Glatt, Zuoan Yi, Cecilia Lay, Maike Schmidt, Sophia R. Majeed, Germaine Fuh, Alice Chen, Sushil Kumar. 23ME-00610 is a first-in-class monoclonal antibody that targets the CD200R1 immune checkpoint to enhance T cell-mediated antitumor activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 602.