A bispecific antibody targeting HER2 and CLDN18.2 eliminates gastric cancer cells expressing dual antigens by enhancing the immune effector function

• Published in: Investigational new drugs Vol. 42; no. 1; pp. 106 - 115
• Main Authors: Yue, Jingying, Shao, Shuai, Zhou, Jie, Luo, Wenting, Xu, Yanling, Zhang, Qinbin, Jiang, Jing, Zhu, Marie M
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.02.2024; Springer Nature B.V
• Subjects: Antibodies; Antibodies, Bispecific - pharmacology; Antibodies, Bispecific - therapeutic use; Antibodies, Monoclonal - pharmacology; Antibodies, Monoclonal - therapeutic use; Antibody-dependent cell-mediated cytotoxicity; Antigens; Biocompatibility; Bispecific antibodies; Cancer; Cell Line, Tumor; Claudins; Cytotoxicity; ErbB-2 protein; Gastric cancer; Growth factors; Humans; Medicine; Medicine & Public Health; Monoclonal antibodies; Oncology; Pharmacology/Toxicology; Receptor, ErbB-2 - metabolism; Spheroids; Stomach Neoplasms - drug therapy; Thermal stability; Trastuzumab; Trastuzumab - pharmacology; Trastuzumab - therapeutic use; Tumors; CLDN18.2; HER2; Bispecific antibody; Gastric cancer; ADCC
• ISSN: 0167-6997; 1573-0646
• DOI: 10.1007/s10637-024-01417-3

Gastric cancer (GC) is widely regarded as one of the toughest cancers to treat. Trastuzumab, which targets the human epidermal growth factor receptor 2 (HER2) for GC treatment, has demonstrated clinical success. However, these patients have a high likelihood of developing resistance. Additionally, Claudin18.2 (CLDN18.2) is a promising emerging target for GC treatment. Therefore, therapies that simultaneously target both HER2 and CLDN18.2 targets are of great significance. Here, we constructed a bispecific antibody targeting both HER2 and CLDN18.2 (HC-2G4S; BsAb), which displayed satisfactory purity, thermostability and enhancing antibody-dependent cell-mediated cytotoxicity (ADCC) activity. In a tumor spheroids model of GC, BsAb demonstrated greater therapeutic efficacy than monoclonal antibodies (mAb) or combination treatment strategies. We propose that the enhanced anti-tumor potency of BsAbs in vivo is due to the monovalent binding of single-chain antibodies to more targets due to weaker affinity, resulting in a more potent immune effect function. Therefore, HC-2G4S could be a productive agent for treating GC that is HER2-positive, CLDN18.2-positive, or both, with the potential to overcome trastuzumab resistance and provide significant clinical benefits and expanded indications.