Synergistic efficacy of simultaneous anti-TGF-β/VEGF bispecific antibody and PD-1 blockade in cancer therapy.

Abstract

BACKGROUND:

Recently, therapeutic antibodies against programmed cell death 1 (PD-1) and its ligand (PD-L1) have exerted potent anticancer effect in a variety of tumors. However, blocking the PD-1/PD-L1 axis alone is not sufficient to restore normal immune response. Other negative regulators of antitumor immunity, like TGF-β and VEGFA, are also involved in immune escape of tumor cells and induce immunotherapy resistance.

METHODS:

We developed a novel anti-TGF-β/VEGF bispecific antibody Y332D based on the Nano-YBODY™ technology platform. The CCK-8, flow cytometry, SBE4 luciferase reporter assay, western blotting and transwell assays were used to measure the biological activities of the anti-TGF-β moiety. The NFAT luciferase reporter assay, luminescent cell viability assay and tube formation assay were used to measure the biological activities of the anti-VEGF moiety. The in vivo anticancer efficacy of Y332D alone or in combination with PD-1 blockade was evaluated in H22, EMT-6, 4T1, and AKT/Ras-driven murine hepatocellular carcinoma tumor models. Immunofluorescent staining, flow cytometry, RNA-seq and quantitative RT-PCR were adopted to analyze the alterations in the tumor microenvironment.

RESULTS:

Y332D could maintain specific binding affinities for TGF-β and VEGFA. Y332D almost entirely counteracted the in vitro biological functions of TGF-β and VEGFA, including immunosuppression, activated TGF-β signaling, epithelial-mesenchymal transition (EMT), activated VEGF/VEGFR signaling, HUVEC proliferation and tube formation. The in vivo experiment data demonstrated that Y332D was more effective in inhibiting tumor growth and metastasis than anti-TGF-β and anti-VEGF monotherapies. In combination therapies, Y332D plus PD-1 blockade exhibited the most potent and durable anticancer effect. Mechanistically, Y332D plus PD-1 blockade upregulated the density and function of tumor-infiltrating lymphocytes and exerted reinvigorated antitumor immunity.

CONCLUSION:

Y332D could simultaneously block TGF-β and VEGF signalings. In comparison with the monotherapies, Y332D combined with PD-1 blockade exerts superior antitumor effect through improving immune microenvironment.

• Authors: Mengke Niu, Ming Yi, Yuze Wu, Lijuan Lyu, Qing He, Rui Yang, Liang Zeng, Jian Shi, Jing Zhang, Pengfei Zhou, Tingting Zhang, Qi Mei, Qian Chu, Kongming Wu
• Journal: Journal of hematology & oncology (J Hematol Oncol) Vol. 16 Issue 1 Pg. 94 (08 12 2023) ISSN: 1756-8722 [Electronic] England
• PMID: 37573354 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2023. BioMed Central Ltd., part of Springer Nature.

Chemical References

• B7-H1 Antigen
• Programmed Cell Death 1 Receptor
• Transforming Growth Factor beta
• Antibodies, Bispecific

Topics

• Humans
• Animals
• Mice
• B7-H1 Antigen
• Programmed Cell Death 1 Receptor
• Transforming Growth Factor beta (metabolism)
• Antibodies, Bispecific (pharmacology, therapeutic use)
• Carcinoma, Hepatocellular (drug therapy)
• Liver Neoplasms (drug therapy)
• Tumor Microenvironment
• Cell Line, Tumor