Abstract 7299: CS2009: A first-in-class trispecific antibody targeting PD-1, CTLA-4, and VEGFA with potential to be a next-generation backbone therapy with combined checkpoint inhibition and anti-angiogenesis

Abstract Background: CS2009 is a first-in-class trispecific antibody designed to target PD-1, CTLA-4, and VEGFA, with potential to replace current anti-PD(L)1 therapies. CS2009 consists of three functional arms including anti-PD-1, anti-CTLA-4, and anti-VEGFA. Clinical evaluations of bispecific molecules and combination therapies targeting PD-1/CTLA-4 and PD-1/VEGFA have shown favorable synergistic effects. For instance, cadonlimab (targeting PD-1/CTLA-4) and ivonescimab (targeting VEGFA/PD-1) have been approved in China for the treatment of advanced cervical carcinoma, gastric or gastroesophageal junction adenocarcinoma, and EGFR-mutant non-small cell lung cancer, respectively. Here, we present preclinical data that demonstrate CS2009 preferentially targets and reinvigorate PD-1/CTLA-4 double-positive tumor-infiltrating T lymphocytes (TILs); and its anti-VEGFA arm inhibits tumor angiogenesis and promotes vascular normalization, helping to convert an immune-suppressive tumor microenvironment (TME) to an immune-active TME, hence enhancing the tumor growth inhibition mediated by effector TILs. Methods & Results: The lead molecule of CS2009, J30, was constructed with a bivalent anti-VEGFA arm, a monovalent anti-PD-1 arm, and a monovalent anti-CTLA-4 arm. Preclinical characteristics of J30 have been published previously. To further validate J30 as the lead molecule, J30 was assessed in primary PBMCs assays, which demonstrated its potent checkpoint inhibitory function. Its cross-species binding to PD-1, CTLA-4, and VEGFA were evaluated by Octet (BLI). Its functionality of interrupting the interaction of PD-1/PD-L1, CD80/CTLA4, and VEGFR2/VEGFA was evaluated in the competitive ELISA assays. Its cross-reactivity supported selection of cynomolgus monkey as the relevant species for nonclinical safety assessment. A single-dose PK study (5, 15, or 50 mg/kg, 30-minute IV infusion) and a GLP-compliant 4-week repeat-dose toxicity and safety pharmacology study (0, 25, 50, or 100 mg/kg, 30-minute IV infusion, QW*5) with a 4-week recovery were conducted in cynomolgus monkeys. J30 demonstrated a monoclonal antibody-like PK profile, with terminal half-lives (t1/2) around 4 days, with no observed gender differences. All dose levels were well tolerated with the highest non-severely toxic dose (HNSTD) at 100 mg/kg. Further pharmacodynamic analysis demonstrated J30’s biological activity in periphery with dose dependency. Both ICOS/Ki67 expression level on CD8 & CD4 T cells were upregulated. Conclusion: CS2009 is a promising trispecific antibody for the treatment of various advanced solid tumors, with potential to be a next-generation backbone therapy with combined checkpoint inhibition and anti-angiogenesis. Current preclinical data support further clinical investigation of CS2009. Citation Format: Chuan Wang, Ning Zhang, Yilin Huo, Xinling Zhang, Yongwang Li, Jingyu Sun, Xuelian Liu, Yongli Yang, Xueqin Dai, Yuxin Qian, Fei Ma, Yi Sun, Yujuan La, Jianxin Yang. CS2009: A first-in-class trispecific antibody targeting PD-1, CTLA-4, and VEGFA with potential to be a next-generation backbone therapy with combined checkpoint inhibition and anti-angiogenesis [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 7299.