Abstract 2359: New insights into targeting the CD200R1 pathway in T and NK cells using 23ME-00610 as a single agent or in combination
Authors: Mithra R. Kumar, Shiteng Duan, Shruti Yadav, Abigail Jarret, Zhonghao Yan, Jill Fenaux, Martin Kinisu, Zuoan Yi, Mauro Poggio, Patrick Collins, Antony Symons, Lorena Riol Blanco, Maike Schmidt, Sophia Majeed, Anh Diep, Clarissa Lee
Journal: Cancer Research (2024)

Abstract 23ME-00610 is a monoclonal antibody that is being evaluated as a single agent in a Phase 1/2a clinical trial for advanced solid malignancies (NCT05199272). It binds with high affinity (KD &amp;lt; 0.1 nM) to CD200R1, a promising immune-oncology (IO) target identified by surveying the 23andMe genetic and health survey database. CD200R1 is an inhibitory receptor that when bound to its ligand CD200, reduces pro-inflammatory cytokine production, and leads to an immunosuppressive tumor environment. To gain further insight into the mechanism of action of 23ME-00610 and its potential for combination therapy, we profiled CD200R1 and other immune inhibitory receptors in human dissociated solid tumor samples using spectral flow cytometry. CD200R1 was broadly expressed across tumor-infiltrating immune cells, including T cells and NK cells, cytotoxic cell types with known antitumor functions. Notably, CD200R1 expression pattern was differentiated from PD-1, which is mostly restricted to T cells, indicating differences in patient populations that could potentially benefit from anti-CD200R1 and anti-PD-1 treatments. The ligand, CD200 was broadly expressed, including on tumor cells and endothelial cells. The differential expression profiles of CD200R1 and PD-1 on immune cells, along with CD200 expression on endothelial cells, suggest that combining 23ME-00610 with other clinically validated immunomodulatory agents could enhance antitumor responses. Follow-up experiments were conducted to validate and extend these findings. In an in vitro assay with cancer patient-derived PBMCs, 23ME-00610 promoted higher production of IFNγ, a key functional antitumor cytokine, compared to anti-PD-1 in 9 of 10 donors. Subsequent attempts were made to pinpoint immune cells responsible for 23ME-00610's anti-tumor activity. 23ME-00610 reversed CD200-mediated suppression of chronically stimulated primary T cells and CD200-mediated inhibition of NK cell degranulation, suggesting that 23ME-00610 can mediate tumor cell killing through at least two different cell types. To test the potential of 23ME-00610 to combine with anti-PD-1 to enhance T cell function, an artificial antigen-presenting cell (aAPC) line overexpressing PD-L1 and CD200 was co-cultured with chronically stimulated primary human T cells. Anti-PD-1 and 23ME-00610 each independently enhanced IFNy secretion levels compared to isotype control, yet their combination resulted in a more than additive effect. Taken together, these data demonstrate that 23ME-00610 can enhance both NK and T cell antitumor effector functions, and 23ME-00610 could synergize with anti-PD-1 to further increase the activity of T cells against cancer cells. The results of this study provide evidence that 23ME-00610 could expand IO treatment options for patients with advanced solid malignancies as a single agent or in combination with other anti-tumor therapeutics. Citation Format: Mithra R. Kumar, Shiteng Duan, Shruti Yadav, Abigail Jarret, Zhonghao Yan, Jill Fenaux, Martin Kinisu, Zuoan Yi, Mauro Poggio, Patrick Collins, Antony Symons, Lorena Riol Blanco, Maike Schmidt, Sophia Majeed, Anh Diep, Clarissa Lee. New insights into targeting the CD200R1 pathway in T and NK cells using 23ME-00610 as a single agent or in combination [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2359.