Abstract 6071: PD-1xTGFβR2 bispecific Biclonics® antibody INCA33890 augments human T-cell effector functions in vitro and ex vivo

Abstract Anti-programmed cell death (PD)-1 and anti PD-ligand1 antibodies have produced durable clinical responses in a wide variety of solid and hematologic malignancies; however, their clinical benefits are often limited to a subset of patients. One of the immune resistance mechanisms that limits the activity of PD-1 axis pathway blockers involves activation of the transforming growth factor beta (TGFβ) pathway within the tumor microenvironment (TME). To overcome this immune suppression, a PD-1 and TGFβ receptor 2 (TGFβR2) dual targeting bispecific Biclonics® antibody, INCA33890, was developed. INCA33890 inhibits TGFβR2 preferentially on PD-1-positive cells (Wang L-C, et al. AACR 2023. Abs 2936). In this study, various in vitro and ex vivo cell-based systems were used to evaluate changes in T-cell effector function induced by INCA33890 compared with the anti-PD-1 antibodies, nivolumab or pembrolizumab. We observed that INCA33890 induced higher interferon gamma (IFNγ) levels than nivolumab with and without exogenous TGFβ in an exhausted T-cell mixed lymphocyte reaction (MLR) assay. Additionally, INCA33890 was superior to nivolumab in enhancing T-cell proliferation in the presence of TGFβ. RNAseq analysis of samples from the exhausted MLR assay revealed that, compared with nivolumab, expression of cytotoxic genes (GZMB, GNLY), proinflammatory cytokines (IFNG), and T-cell activation markers (CD25, 4-1BB) were elevated following INCA33890 treatment in the presence of TGFβ. We next co-cultured T-cell receptor-engineered T cells with non-small cell lung cancer tumor digests to examine the impact of the TME on antigen-specific T-cell responses. INCA33890 increased the percentage of IFNγ-producing T cells compared with pembrolizumab over 72 hours. In summary, our data suggest that co-inhibition of both PD-1 and TGFβR2 by INCA33890 may provide greater therapeutic benefits than an anti-PD-1 antibody alone. Citation Format: Jun Guan, Aidan Gilmartin, Kenji Kimura, Estela Noguera-Ortega, Ashwini Kulkarni, Pat Feldman, Michelle Kinder, Cynthia Timmers, Alejandro Amador Arjona, Patrick Mayes, Steven M. Albelda, Evgeniy Erulasnov, Liang-Chuan Wang. PD-1xTGFβR2 bispecific Biclonics® antibody INCA33890 augments human T-cell effector functions in vitro and ex vivo [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 6071.