Abstract 5811: ABL103, a bispecific antibody targeting B7-H4 and 4-1BB, shows synergistic immune responses with combination of pembrolizumab in the immunosuppressive tumor microenvironment

Abstract B7-H4 (B7x, VTCN1) is overexpressed in many types of cancers, including breast, ovarian, and endometrial cancers. B7-H4 expression is also observed in tumor associated macrophages and implicated as an immune checkpoint regulating T cell responses. 4-1BB (CD137/TNFRSF9) is an inducible co-stimulatory receptor and expressed in a wide variety of immune cell types, including activated T cells, natural killer (NK) cells, dendritic cells (DCs). Previously, we demonstrated that ABL103, B7-H4x4-1BB bispecific antibody, induced in vitro T cell activation only in the presence of B7-H4-expressing tumor cells through B7-H4-dependent 4-1BB clustering, resulting in strong in vivo antitumor effects. While ABL103 augmented T cell infiltration and the ratio of intra-tumoral CD8+ T/Treg in tumor microenvironment (TME), no systemic immune response was observed. Mutually exclusive expression pattern of B7-H4 and PD-L1 raised the question on combination effect of ABL103 and PD(L)-1 inhibitors. While most ovarian and triple negative breast cancer patient tissues showed B7-H4 expression, only a few tissues showed PD-L1 expression. To understand how ABL103 modifies TME alone or in combination with immune checkpoint inhibitors, ABL103 was treated alone or in combination with pembrolizumab in two mouse models including MC38/hB7-H4 (immune hot tumors) and B16F10/hB7-H4 (immune cold tumors). In the advanced murine tumor model of MC38/hB7-H4, ABL103 strongly suppressed tumor progression alone or in combination with pembrolizumab. Marked increase of T cell infiltration was observed in the combination group compared to ABL103 alone or pembrolizumab alone. In the rapidly growing B16F10/hB7-H4 tumor model, pembrolizumab alone failed to suppress tumor progression and did not induce T cell infiltration. However, combination of pembrolizumab and ABL103 showed a marked increase of intra-tumoral CD8+ T cells. Interestingly, pembrolizumab induced 4-1BB expression on CD8 T cells, whereas ABL103 induced PD-L1 expression in CD11b+ cells when combined with pembrolizumab. The combination group also showed an increased proportion of MHC I/II double positive macrophages. These results support the interactive immune activation of ABL103 and pembrolizumab, which leads to synergistic activation of T cells and transition of cold TME to inflammatory TME. Overall, our study suggests that ABL103 could be a promising therapeutic antibody as monotherapy as well as combination strategy with pembrolizumab by reinvigorating immune responses in the immunosuppressive TME. Citation Format: Chorong Yang, Eunhee Lee, Yangsoon Lee, Daehae Song, Byungje Sung, Jiseon Yoo, Kyungjin Park, Jonghwa Won. ABL103, a bispecific antibody targeting B7-H4 and 4-1BB, shows synergistic immune responses with combination of pembrolizumab in the immunosuppressive tumor microenvironment [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 5811.