Abstract 2129: An innovative multi-specific Fc fusion protein simultaneously targeting PD-L1, VEGF-A, and PLGF for pancreatic cancer treatment via reshaping the tumor microenvironment

Abstract Introduction: Pancreatic cancer is a notoriously cold tumor characterized by a dense extracellular matrix and an immunosuppressive microenvironment, resulting in the limited efficacy of many immune-oncology therapies. Here, we investigated the therapeutic potential of PB203, a novel multi-specific Fc fusion protein that simultaneously blocks PD-L1, VEGF-A, and PLGF, for the treatment of pancreatic cancer. Methods: PB203 was engineered and assessed for its binding affinities to the target molecules and its inhibitory capacity against ligand-mediated signaling in vitro at the cellular level. Its therapeutic efficacy was further evaluated in an orthotopic human pancreatic cancer model using humanized mice. Endpoints included anti-tumor effects, fibrosis modulation, and immune profile remodeling within the tumor microenvironment (TME). Results: PB203 demonstrated picomolar binding affinities to VEGF-A and PLGF and sub-nanomolar binding affinity to PD-L1. Remarkably, it maintained its binding affinities under conditions mimicking simultaneous target engagement, showing comparable efficacy to single-target interactions, regardless of binding sequence or target occupancy. The Fc fusion protein effectively inhibited ligand-mediated signaling without compromising the potency of its parental molecules. In an orthotopic pancreatic cancer model using humanized mice treated with gemcitabine, PB203 achieved significant anti-tumor efficacy, including cases of complete regression. Notably, gemcitabine treatment alone increased fibrosis within the TME; however, co-treatment with PB203 significantly reversed this effect. PB203-mediated fibrosis reduction correlated with a decreased abundance of several cancer-associated fibroblast (CAF) subsets, highlighting its potential to remodel the TME and enhance therapeutic synergy in pancreatic cancer. Conclusions: PB203 demonstrated substantial anti-tumor activity in an orthotopic pancreatic cancer model featuring an immunosuppressive TME, closely mirroring patient conditions. Its ability to inhibit CAFs and reduce fibrosis within the TME, likely driven by PLGF blockade, represents a unique mechanism of action. These findings suggest that beyond emerging PD-(L)1/VEGF-A bi-specific strategies, triple blockade of PD-(L)1, VEGF-A, and PLGF with PB203 could offer a novel therapeutic option for highly desmoplastic and hard-to-treat cancers like pancreatic cancer. Further clinical investigations are warranted to validate these findings. Citation Format: Hyungul (David) Yang, Jin A Shin, Hyeseong Lim, Eunbyul Cho, Daeseok Oh. An innovative multi-specific Fc fusion protein simultaneously targeting PD-L1, VEGF-A, and PLGF for pancreatic cancer treatment via reshaping the 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 2129.