Abstract 2122: FS-8002, a bifunctional antibody fusion protein of anti-VEGF and anti-TGF-β, exhibits significant anti-tumor activity in preclinical studies

Abstract Background: FS-8002 is a bifunctional antibody fusion protein targeting vascular endothelial growth factor (VEGF) and transforming growth factor β (TGF-β), which is generated by fusing a humanized IgG1 antibody against VEGF and the extracellular domain of TGF-β receptor II (TGF-βRII). FS-8002 can simultaneously bind to and neutralize VEGF and TGF-β, thus achieving anti-tumor effects through the following proposed mechanisms: 1) inhibiting tumor neovascularization and normalizing tumor blood vessels; 2) relieving the suppression of anti-tumor immune cells in the tumor microenvironment (TME); 3) inhibiting the formation of the immune barrier or extracellular matrix (ECM) and promoting cytotoxic T cell infiltration into tumors, and 4) blocking the invasion and metastasis of tumor cells. Methods: The mechanism of action (MOA) and anti-tumor effects of FS-8002 were evaluated in a series of studies including in vitro target binding, biological activity assays, and in vivo efficacy study in xenograft tumor models. Results: in vitro, FS-8002 binds to VEGF and TGF-β simultaneously. FS-8002 bound to VEGF165 and VEGF121 and thus inhibited VEGF-induced human umbilical vein endothelial cell (HUVEC) proliferation. FS-8002 also specifically bound to TGF-β1 and TGF-β3, but only had weak affinity to TGF-β2. By neutralizing TGF-β, FS-8002 could block TGF-β/Smad signaling pathway, inhibit TGF-β1-induced tumor cell metastasis, and relieve immunosuppression in the TME by activating NK cells and inhibiting Treg proliferation. FS-8002 exhibited significant anti-tumor effect in two "cold tumor" xenograft models (human PBMC reconstituted MDA-MB-231 model and HT-29 cells model) as single agent or in combination with anti-PD-1 antibody (Keytruda®). IHC analysis of the tumors from the two mouse xenograft models revealed that FS-8002 treatment could inhibit the tumor neovascularization, inhibit the formation of the immune barrier by reducing fibrosis formation in tumor tissues, and promote T cells infiltration into tumor tissue to kill tumor cells, therefore exhibit anti-tumor effect. The results of GLP repeat-dose toxicity study in cynomolgus monkeys combined with safety pharmacology assessment indicated that FS-8002 was well tolerated under the doses ranged from 15 to 135 mg/kg/dose (HNSTD) after four weeks of weekly intravenous infusion administration, and the adverse effects were within expectations and can be managed in clinical trials. FS-8002 is currently under clinical evaluation for safety and activity in both US (IND approved) and China. Conclusion: All the preclinical data supported FS-8002 to be studied in clinical trials. Citation Format: Libo Zhou, Qiran Guo, Ruxia Zhou, Hua Jiang, Chaoyi Xu, Xinzhong Jon Wang. FS-8002, a bifunctional antibody fusion protein of anti-VEGF and anti-TGF-β, exhibits significant anti-tumor activity in preclinical studies [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 2122.