Abstract 2375: 23ME-01473, a novel anti-ULBP6/2/5 monoclonal antibody, reinvigorates anti-tumor NK cell function through NKG2D and FcγRIIIa activation

Abstract Using genome-wide association studies (GWAS) of the 23andMe genetic and healthy survey database across all phenotypes as part of our unique target discovery platform, we identified immuno-oncology (I/O) -related genetic variants as those with opposing directionality of effects on cancer and immunological phenotypes, which comprise the I/O signature. This I/O signature identified ULBP6 as a potential cancer therapeutic target. ULBP6 is a stress-induced cell surface ligand found on cancer cells, that binds to the activating receptor, NKG2D, on NK and T cells to induce tumor cell killing. However, as a mechanism of immune escape, tumors shed ULBP6 to produce a soluble form that attenuates NKG2D activation and is elevated in cancers. Given that the 2 allelic variants of ULBP6 have the highest binding affinity to NKG2D of all human NKG2D ligands, ULBP6 may be the most immunosuppressive soluble NKG2D ligand and a critical regulator of anti-tumor response. Accordingly, soluble ULBP6 exhibited significant suppression of IFNγ release and detectable cell surface NKG2D expression on healthy donor PBMCs using in vitro cell-based assays. Moreover, the overexpression of human ULBP6 in a genetically modified MC38 murine model resulted in decreased infiltration of NK, NKT, and CD8 T cells in vivo. As such, we developed a novel humanized monoclonal antibody, 23ME-01473, that binds with high affinity to ULBP6, and due to the high sequence homology, to ULBP2 and ULBP5, to block their interaction with NKG2D. By preventing the binding of soluble ULBP6 to NKG2D on PBMCs in vitro, 23ME-01473 restored NKG2D activation as measured by increased detectable cell surface NKG2D expression, IFNγ and granzyme B release, and tumor cell killing by PBMCs. To further leverage the binding of 23ME-01473 to ULBP6/2/5, 23ME-01473 was designed to have an afucosylated Fc domain that enhances its binding affinity to the activating Fc receptor, FcγRIIIa, on NK cells to induce ADCC against tumor cells. The combination of NKG2D and FcγRIIIa activation resulted in synergistic PBMC-mediated IFNγ secretion and enhanced tumor cell killing, compared to activation of either NKG2D or FcγRIIIa. Taken together, these results reveal ULBP6 as a novel cancer therapeutic target, and given the dual activation of NKG2D and FcγRIIIa, suggest the potential of 23ME-01473 to activate NK cells and elicit anti-tumor immunity. Citation Format: Joel Benjamin, Abigail Jarret, Shashank Bharill, Shruti Yadav, Dina Ayupova, Clifford Hom, Zahra Bahrami Dizicheh, I-Ling Chen, Anh Diep, Shi Shi, Caroline Bonnans, Danielle Kellar, Germaine Fuh, Maike Schmidt, Kimberline Gerrick, Patrick Koenig, Mauro Poggio. 23ME-01473, a novel anti-ULBP6/2/5 monoclonal antibody, reinvigorates anti-tumor NK cell function through NKG2D and FcγRIIIa activation 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 (6Suppl): Abstract nr 2375.