Abstract 5186: Human stem cell humanized mouse model for in vivo evaluation of bispecific antibody efficacy and drug-induced cytokine release

Abstract

Abstract Bispecific antibodies have shown several promising advantages over monoclonal antibodies and are emerging as one of the growing cancer immunotherapies. Preclinical in vivo models to assess efficacy and cytokine release associated with immune cell engagement are needed. We have developed a human stem cell (HSC) humanized mouse model for testing efficacy and for quantifying cytokine release in response to bispecific antibody treatment. Here we evaluated an EGFR bispecific T cell engager (BiTE), using EGFR-positive MDA-MB-231 orthotopic breast cancer model in CD34+ HSC humanized NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG™) mice. BiTE treatment for 2 weeks resulted in complete tumor regression when dosing was initiated at an average tumor volume of around 100 mm3. In addition, BiTE treatment for 4 weeks effectively inhibited the tumor growth when dosing mice bearing larger tumors of around 400mm3 in volume. Sixteen hours after the first two doses as compared to PBS control, human cytokines IFN-γ, IL-6, and IL-10 were elevated. Cytokine levels then returned to the baselines following continuous dosing. We observed a similar time course and levels of cytokine release between these two BiTE-treated groups with different tumor sizes. T cell activation in the peripheral blood after the last dose was assessed by flow cytometry analysis. In the BiTE-treated group, T cell percentage decreased, as compared to the PBS control. Both CD4+ and CD8+ T cell subsets showed an increased frequency of CD69+ cells after BiTE treatment. Evaluation of drug efficacy and cytokine release in response to BiTE treatment using PBMC-humanized NSG™ mice with and without MDA-MB-231 tumors are underway and results will be discussed. Citation Format: Li-Chin Yao, Danying Cai, Roberta Aliperta, Allison Colthart, Werner Meier, Mingshan Cheng, James G. Keck. Human stem cell humanized mouse model for in vivo evaluation of bispecific antibody efficacy and drug-induced cytokine release [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5186.