Abstract 6673: B7-H3-targeted 4-1BB activation potentiates CD8 T cell-dependent antitumor immunity without systemic toxicity

4-1BB is a costimulatory receptor on activated T and NK cells, and the stimulation of 4-1BB by the natural ligand or agonistic mAb enhances cellular proliferation and effector functions. Immunotherapy targeting 4-1BB has been tested for cancer patients; however, dose-limiting toxicities of 4-1BB agonists restrict further clinical development. B7-H3 (CD276) is overexpressed on the cell surface of multiple cancers and tumor-associated endothelial cells, yet barely on healthy adult tissues. To restrict 4-1BB stimulation activity in tumors, we have developed an FcγR-binding null bispecific IgG1 antibody consisting of B7-H3-targeting IgG and two anti-4-1BB single-chain variable fragments. The B7-H3x4-1BB bispecific antibody (B5x1D8) shows a potent in vitro T cell costimulatory activity in the presence of B7-H3 on the tumor cells. B5x1D8 rapidly accumulates in B7-H3-overexpressing tumors compared to 4-1BB agonistic mAb. B5x1D8 elicits a 4-1BB-dependent anti-tumor response in three different B7-H3-overexpressing murine tumor models. More importantly, in contrast to 4-1BB mAb, B5x1D8 does not induce any observable systemic abnormalities. Treatment of B5x1D8 increases the density, cytokine production, and proliferation of CD8 T cells in the tumor. Characterization of TILs indicates that B5x1D8 increases the number of PD-1+TIM-3+ “terminal effector” CD8 T cells for eliminating tumor cells. Furthermore, a combination of B5x1D8 and immune checkpoint blockade (ICB), anti-PD1, synergistically inhibits tumor growth. The human 4-1BB-targeting bispecific antibody also induces B7-H3-dependent 4-1BB costimulation and inhibits tumor growth in human 4-1BB transgenic mice. In sum, our data suggest that the B7-H3x4-1BB bispecific antibody represents an alternative form of IgG-based 4-1BB agonistic mAb for effective and safe cancer immunotherapy against B7-H3 positive cancers as monotherapy and combination therapy with other immunotherapy, like ICB. Citation Format: Gihoon You, Yangsoon Lee, Yeon-Woo Kang, Han Wook Park, Kyeongsu Park, Jaeho Jung, Seung-Woo Lee. B7-H3-targeted 4-1BB activation potentiates CD8 T cell-dependent antitumor immunity without systemic toxicity [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 6673.