Abstract 2117: GenSciP107, a MICA/B-directed and Fc-enhanced antibody, potently inhibits tumor growth via ADCC and stimulation of immune response

Abstract Background: The expression of major histocompatibility complex class I polypeptide-related sequence A and B (MICA/B) is induced in normal cells under stress and in tumor cells including hepatocellular carcinoma (HCC), non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), and urothelial cancer (UC), etc. Membrane-bound MICA/B (mMICA/B) interacts and activates NKG2D, a stimulatory receptor on NK cells, γδ T cells and a subset of CD8+ T cell. Shed MICA/B (sMICA/B), however, inhibits the function of NK and other NKG2D+ immune cells. Thus, an anti-MICA/B antibody can be an intriguing immuno-oncology therapy for cancer, by inhibiting MICA/B shedding from tumor cells and by stimulating NK and CD8+ T cell functions, resulting in potent killing of tumor cells. Methods: GenSciP107 is an anti-MICA/B monoclonal antibody isolated from immunized mice and then humanized and affinity matured. The Fc region of GenSciP107 was mutated for enhanced effector functions and for extended half-life. A set of in vitro assays were conducted to examine the impact of GenSciP107 on the MICA/B-NKG2d axis in immune cells. In vivo anti-tumor activity of GenSciP107 was evaluated in CDX models of NSCLC and HCC in mice. Pharmacokinetic properties of GenSciP107 were assessed following an intravenous administration in cynomolgus monkeys. Results: GenSciP107 bound to recombinant human MICA/B proteins with single digit nanomolar affinity, as analyzed using SPR technology. It stimulated NK cells and macrophages to lyse MICA/B+ tumor cells with an EC50 in the double digit picomolar range in the LDH release-based ADCC assay and in the single digit nanomolar range in the ADCP assay, respectively. GenSciP107 also increased the apparent expression levels of MICA/B on tumor cells by preventing their shedding, resulting in excellent stimulation of NK cells and subsequent cytotoxicity of tumor cells. Furthermore, GenSciP107 reversed the inhibitory effect of sMICA/B on NK cells and on PBMCs in an in vitro ADCC assay. GenSciP107 significantly inhibited tumor growth in the CDX models of human HCC and NSCLC. Half-life of GenSciP107 was determined to be about 377 hours following an intravenous injection at the dose of 10 mg/kg in non-human primates. Conclusion: These data highlight the potential of GenSciP107 as a novel cancer therapy with multiple mechanisms of action and support its further evaluation in IND-enabling studies. Citation Format: Ming Lei, Jiuhe Sun, Hanxi Yu, Li Tong, Yihui Lin, Chunsheng Zhang, Lei Song, Yanshuang Liu, Yanhou Liu, Jiyuan Zhao, Yingxin Bi, Weiqing Li, Yunna Gao, Yuanyuan Yuan, Bo Guo, Fu Li, John L. Xu. GenSciP107, a MICA/B-directed and Fc-enhanced antibody, potently inhibits tumor growth via ADCC and stimulation of immune response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2117.