Shanghai, China, December 1, 2025—Shanghai Henlius Biotech, Inc. (2696.HK) today announced that the investigational new drug (IND) application for a Phase 1 clinical trial of HLX37, a recombinant humanized anti-PD-L1 and anti-VEGF bispecific antibody, has been approved by the China National Medical Products Administration (NMPA), for the treatment of advanced/metastatic solid tumors.

Programmed cell death-ligand 1 (PD-L1), also known as B7-H1 or CD274, is a key molecule in tumor immune evasion. It inhibits T-cell activation and proliferation by binding to the PD-1 receptor on T cells, thereby suppressing the body's immune surveillance of tumors ^[1]. Research indicates that programmed death-ligand 1 (PD-L1) is highly expressed in various solid tumors, including non-small cell lung cancer, gastric cancer, and ovarian cancer, and its expression level correlates with the efficacy of immunotherapy ^[2,3]. Although PD-1/PD-L1 inhibitors are widely used in clinical practice, two significant limitations remain: 1) a modest objective response rate to single-agent therapy, and 2) disease progression in many patients attributable to adaptive resistance and T-cell exhaustion ^[4]. Vascular endothelial growth factor A (VEGFA), commonly referred to as VEGF, is a central regulator of tumor angiogenesis. It promotes the formation of abnormal blood vessels that supply oxygen and nutrients to the tumor, simultaneously fostering an immunosuppressive microenvironment ^[5]. VEGF, a key member of the VEGF family (encompassing VEGFA, VEGFB, VEGFC, VEGFD, and PlGF), exerts its biological effects primarily by binding and activating its cognate receptors VEGFR1 and VEGFR2^[6]. In the tumor context, VEGF-induced aberrant angiogenesis results in hypoxic and acidic conditions that promote PD-L1 upregulation and recruit immunosuppressive cell populations, including regulatory T cells. This process intensifies T-cell exhaustion and compromises the effectiveness of anti-PD-1/L1 immunotherapy. Furthermore, immunosuppression mediated by PD-L1 can trigger the secretion of pro-angiogenic factors like IL-8 and VEGF, establishing a detrimental feed-forward loop between angiogenesis and immune evasion ^[7]. Consequently, co-targeting PD-L1 and VEGF represents a therapeutic strategy with significant synergistic potential.

HLX37 is a recombinant humanized anti-PD-L1 and anti-VEGF bispecific antibody developed by Henlius. Its mechanism of action integrates two therapeutic pathways: (1) Blocking PD-1/PD-L1 interaction: by inhibiting the binding of PD-L1 on tumor cells to the PD-1 receptor on immune cells (e.g., T cells), it reverses tumor-induced immunosuppression and restores T cell-mediated antitumor activity; (2) Anti-angiogenic pathway: by neutralizing VEGF, it suppresses tumor angiogenesis, thereby cutting off the blood supply essential for tumor growth and metastasis. This dual-targeting design is expected to generate a synergistic antitumor effect and may reduce the risk of drug resistance. Specifically, through its specific binding to PD-L1 on tumor cells, HLX37 achieves enhanced enrichment of the bispecific antibody within the tumor microenvironment, leading to superior efficacy compared to the combination of anti-PD-L1 and anti-VEGF monoclonal antibodies. Preclinical studies demonstrated that HLX37 has strong antitumor activity and favorable safety profile, with enhanced tumor enrichment, indicating its broad therapeutic potential across multiple tumor types. These findings were first presented at the 2025 American Association for Cancer Research (AACR) Annual Meeting ^[8].

By strategically prioritizing solid tumor domain as a core therapeutic area, Henlius continues to uphold its patient-centric mission, accelerating differentiated innovation to address unmet medical needs and delivering high-quality, affordable therapies to tumor patients worldwide.

【Reference】

[1] Parvez A, Choudhary F, et al. PD-1 and PD-L1: architects of immune symphony and immunotherapy breakthroughs in cancer treatment. Front Immunol. 2023; 14:1296341.

[2] Yu, H., Boyle, T. A., et al. (2016). PD-L1 Expression in Lung Cancer. Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer, 11(7), 964–975.

[3] Cozac-Szőke, A. R., Cozac, D. A., et al. (2025). Immune Cell Interactions and Immune Checkpoints in the Tumor Microenvironment of Gastric Cancer. International journal of molecular sciences, 26(3), 1156.

[4] Sun, J. Y., Zhang, D., et al. (2020). Resistance to PD1/PD-L1 blockade cancer immunotherapy: mechanisms, predictive factors, and future perspectives. Biomarker research, 8, 35.

[5] Pérez-Gutiérrez, L., & Ferrara, N. (2023). Biology and therapeutic targeting of vascular endothelial growth factor A. Nature reviews. Molecular cell biology, 24(11), 816–834.

[6] Khan, K. A., & Kerbel, R. S. (2018). Improving immunotherapy outcomes with anti-angiogenic treatments and vice versa. Nature reviews. Clinical oncology, 15(5), 310–324.

[7] Hack, S. P., Zhu, A. X., & Wang, Y. (2020). Augmenting Anticancer Immunity Through Combined Targeting of Angiogenic and PD-1/PD-L1 Pathways: Challenges and Opportunities. Frontiers in immunology, 11, 598877

[8] Song G, Chen Y-S, et al. Abstract 7303: A novel anti-PD-L1/VEGF bispecific antibody (HLX37) with immune checkpoint inhibition, anti-angiogenic, and antineoplastic activities. Cancer Res 15 April 2025; 85 (8_Supplement_1): 7303. AACR Annual Meeting 2025.