Abstract 6074: INCA33890, a bispecific antibody targeting PD-1 and TGFβR2, shows enhanced immune responses in models of ovarian cancer

Although immune checkpoint inhibitors (ICIs) targeting pathways involving programmed cell death 1 (PD-1) and its ligand (PD-L1) are promising for some diseases, they have shown modest responses in ovarian cancer patients. Multiple studies have shown that ICI resistance is associated with the prevalence of transforming growth factor (TGF)-β signaling in the tumor microenvironment (TME). In patients with ovarian cancer, TGF-β expression is associated with immunosuppressive features in the TME and poor prognosis. PD-1 and TGF-β inhibitory pathways play independent yet complementary roles in immunosuppression, providing rationale for simultaneous targeting of both pathways. However, agnostic inhibition of the TGF-β pathway has historically led to detrimental side effects. Therefore, we developed a bispecific Biclonics® antibody that conditionally blocks the TGF-β pathway through TGFβR2, only on immunosuppressed T cells that coexpress PD-1. In this study, we tested the efficacy of the dual PD-1- and TGFβR2-binding Biclonics® antibody, INCA33890, in models of ovarian cancer. We used patient ascites (N=6) as a model of ovarian TME. INCA33890 treatment resulted in significantly higher levels of secreted interferon (IFN)-γ compared with control antibodies targeting only PD-1 (pembrolizumab) or TGFβR2 (TGF-1). A significant increase in T-cell activation markers, such as CD137, CD25, and CD69, was also observed in some samples treated with INCA33890 compared with controls. Next, we tested INCA33890 in an autologous coculture of tumor-infiltrating lymphocytes expanded from an enzymatically digested-patient tumor and enriched tumor cells from the same patient. In these cocultures, IFN-γ levels were significantly higher with INCA33890 treatment compared with pembrolizumab; levels were similar compared with TGF-1. For an in vivo assessment, we used double huPD1/huTGFβR2 knock-in mice implanted with ovalbumin (ova) and luciferase-expressing murine ovarian cancer ID8 cells. Mice treated with INCA33890 showed a significant reduction in tumor burden and improved survival compared with controls. A significant increase in tumor-associated ova-specific CD8+ T cells was observed with INCA33890 treatment compared with controls. Phenotypic analysis of CD8+ T cells revealed a skew toward an effector memory subset (CD44high; CD62Llow expression) with INCA33890 treatment. Thus, INCA33890 showed favorable results in a humanized ovarian cancer model and demonstrated a tumor antigen-specific T-cell response resulting in reduced tumor burden. Altogether, we show that INCA33890 presents a promising immunotherapy option for patients with advanced ovarian cancer by targeting 2 prominent immunosuppressive pathways, leading to a coordinated immune response. Clinical assessment of INCA33890 for various advanced malignancies, including ovarian cancer, is ongoing (NCT05836324). Citation Format: Veethika Pandey, Kay M. Foos, Isabella Pargiolas, Mathilde Poussin, Ashwini Kulkarni, Liang-Chuan Wang, Patrick Mayes, Daniel J. Powell Jr. INCA33890, a bispecific antibody targeting PD-1 and TGFβR2, shows enhanced immune responses in models of ovarian cancer [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 6074.