Antibody Recognition of Human Epidermal Growth Factor Receptor-2 (HER2) Juxtamembrane Domain Enhances Anti-Tumor Response of Chimeric Antigen Receptor (CAR)-T Cells

Guangyu Zhou; Shengyu Fu; Yunsen Zhang; Shuang Li; Ziang Guo; Defang Ouyang; Tianlei Ying; Yinying Lu; Qi Zhao

doi:10.3390/antib13020045

Antibody Recognition of Human Epidermal Growth Factor Receptor-2 (HER2) Juxtamembrane Domain Enhances Anti-Tumor Response of Chimeric Antigen Receptor (CAR)-T Cells

Antibodies (Basel). 2024 Jun 7;13(2):45. doi: 10.3390/antib13020045.

Authors

Guangyu Zhou^{1

2}, Shengyu Fu¹, Yunsen Zhang³, Shuang Li⁴, Ziang Guo¹, Defang Ouyang³, Tianlei Ying⁵, Yinying Lu⁴, Qi Zhao^{1

2}

Affiliations

¹ Institute of Translational Medicine, Cancer Centre, Faculty of Health Sciences, University of Macau, Taipa 999078, Macau SAR, China.
² MoE Frontiers Science Center for Precision Oncology, University of Macau, Taipa 999078, Macau SAR, China.
³ Institute of Chinese Medical Sciences, University of Macau, Taipa 999078, Macau SAR, China.
⁴ The Fifth Medical Center of the PLA General Hospital, Beijing 100036, China.
⁵ MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Engineering Research Center for Synthetic Immunology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.

Abstract

Chimeric antigen receptor (CAR) T cell therapy shows promise in treating malignant tumors. However, the use of human epidermal growth factor receptor-2 (HER2) CAR-T cells carries the risk of severe toxicity, including cytokine release syndrome, due to their "on-target off-tumor" recognition of HER2. Enhancing the quality and functionality of HER2 CARs could greatly improve the therapeutic potential of CAR-T cells. In this study, we developed a novel anti-HER2 monoclonal antibody, Ab8, which targets domain III of HER2, distinct from the domain IV recognition of trastuzumab. Although two anti-HER2 mAbs induced similar levels of antibody-dependent cellular cytotoxicity, trastuzumab-based CAR-T cells exhibited potent antitumor activity against HER2-positive cancer cells. In conclusion, our findings provide scientific evidence that antibody recognition of the membrane-proximal domain promotes the anti-tumor response of HER2-specific CAR-T cells.

Keywords: CAR-T cell; HER2; monoclonal antibody; trastuzumab.

Grants and funding

Authors appreciate the National Key R&D Program of China (2019YFA0904400), the Natural Science Foundation of Guangdong Province (2023A1515010549), the Science and Technology Development Fund of Macau (FDCT/0043/2021/A1, FDCT/0009/2023/RIC and FDCT/0002/2021/AKP), the University of Macau (MYRG2022-00143-FHS and MYRG-GRG2023-00158-FHS-UMDF).