Abstract 7303: A novel anti-PD-L1/VEGF bispecific antibody (HLX37) with immune checkpoint inhibition, anti-angiogenic, and antineoplastic activities

Abstract Introduction: Dual blockade of PD-L1 and VEGF has demonstrated significant clinical benefits in advanced hepatocellular carcinoma (HCC) and non-small cell lung cancer (NSCLC). However, efficacy remains suboptimal in certain indications, potentially due to insufficient levels of anti-VEGF inhibitors within the tumor, as well as vascular dysfunction caused by the disruption of vascular homeostasis via the anti-VEGF inhibitor. The bispecific antibody targeting PD-L1 and VEGF enhances anti-VEGF delivery to the tumor site by binding to tumor PD-L1, promoting synergistic effects of blood vessel normalization and T cell activation within the tumor microenvironment, thus improving anti-tumor activity. Methods: Flow cytometry and Biacore were employed to evaluate the binding of the bispecific antibody. PD-L1 or VEGF blockade assays were conducted using PD-1-Jurkat cells/PD-L1-APC-CHOK1 or KDR cells. Efficacy was assessed in CDX models with immune humanization, including MDA-MB231 (human breast cancer cell line), NCI-H292 (human lung mucoepidermoid carcinoma cell line), HCT116 (human colon cancer cell line), and SK-MES-1 (human lung cancer cell line) tumor cell lines. Pilot pharmacokinetic and toxicity studies were performed in cynomolgus monkeys. Results: In vitro assays demonstrated that the anti-PD-L1/VEGF bispecific antibody exhibits high binding affinity for both PD-L1 and VEGF, showing dual blockade activity against PD-1/PD-L1 and VEGF/VEGFR2. The anti-PD-L1/VEGF bispecific antibody was shown to possess superior ability to reverse T cell exhaustion. It conferred robust tumor inhibition activity and dose-dependent tumor suppression in the MDA-MB231, NCI-H292, HCT116, and SK-MES-1 models. Compared to the combination group of anti-PD-1 monoclonal antibody and anti-VEGF monoclonal antibody, the anti-PD-L1/VEGF bispecific antibody showed enhanced tumor enrichment. The distribution of anti-PD-L1/VEGF is mediated by both PD-L1 and VEGF, HLX37 was well tolerated in cynomolgus monkeys after three weekly intravenous doses of 100 mg/kg. Conclusion: HLX37 is an anti-PD-L1/VEGF bispecific antibody with immune checkpoint inhibitory, anti-angiogenic, and antineoplastic properties. It demonstrated strong preclinical efficacy and a favorable safety profile, with enhanced tumor enrichment. It holds promising potential for further application in various types of tumors. Citation Format: Ge Song, Yu-Syuan Chen, Xiaoling Yuan, Chunlei Ge, Xiansong Xiong, Seng Zhu, Hongqing Wei, Jijun Yuan, Chen Hu, Qingyu Wang, Jun Zhu. A novel anti-PD-L1/VEGF bispecific antibody (HLX37) with immune checkpoint inhibition, anti-angiogenic, and antineoplastic activities [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 7303.