Combination Therapy of Hepatocellular Carcinoma by GPC3-Targeted Bispecific Antibody and Irinotecan is Potent in Suppressing Tumor Growth in Mice.

Abstract

Hepatocellular carcinoma (HCC) is a world leading cause of cancer-related mortality, and currently no curative treatment for advanced HCC is available. Glypican-3 (GPC3) is an attractive target for HCC immunotherapy. This study explored the efficacy of six GPC3-targeted bispecific antibodies, alone or in combination with chemotherapeutic drug Irinotecan, for the treatment of HCC. The bispecific antibodies were constructed using three different structures, knob-into-hole (KH), scFv-scFv-hFc, and scFv-hFc-scFv, where CD3-targeting mAb OKT3 (scFv) was paired with two representative GPC3 mAbs hYP7 (scFv) and HN3 (VH only) that target different epitopes. The In vitro cell killing assay revealed that all bispecific antibodies efficiently killed GPC3 positive cancer cells, with hYP7-KH, hYP7-OKT3-hFc, and HN3-KH being most potent. In vivo xenograft mouse studies demonstrated that all bispecific antibodies suppressed tumor growth similarly, with hYP7-OKT3-hFc performing slightly better. Combination of hYP7-OKT3-hFc with Irinotecan dramatically improved the efficacy and arrested tumor growth of HepG2, Hep3B, and G1 in xenograft mice. Our results demonstrated that the cell surface proximal bispecific antibody hYP7-OKT3-hFc was superior in terms of potency and the GPC3-targeted bispecific antibody combined with Irinotecan was much potent to control HCC growth.

• Authors: Xin Chen, Yanmin Chen, Rong Liang, Lanxin Xiang, Jingwen Li, Yuankui Zhu, Huixia He, Le Huang, Dianbao Zuo, Weihang Li, Xinjun Liang, Shuang Dong, Sheng Hu, Mitchell Ho, Mingqian Feng
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 21 Issue 1 Pg. 149-158 (01 2022) ISSN: 1538-8514 [Electronic] United States
• PMID: 34725191 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2021 American Association for Cancer Research.

Chemical References

• Antibodies, Bispecific
• Irinotecan

Topics

• Animals
• Antibodies, Bispecific (pharmacology, therapeutic use)
• Antineoplastic Combined Chemotherapy Protocols (pharmacology, therapeutic use)
• Carcinoma, Hepatocellular (drug therapy, mortality, pathology)
• Humans
• Immunotherapy (methods)
• Irinotecan (pharmacology, therapeutic use)
• Liver Neoplasms (drug therapy, mortality, pathology)
• Mice
• Survival Analysis