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

IF 3 Q3 IMMUNOLOGY

Antibodies Pub Date : 2024-06-07 DOI:10.3390/antib13020045

Guangyu Zhou, Shengyu Fu, Yunsen Zhang, Shuang Li, Ziang Guo, D. Ouyang, Tianlei Ying, Yinying Lu, Qi Zhao

引用次数: 0

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.

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人表皮生长因子受体-2 (HER2) 共膜域的抗体识别增强嵌合抗原受体 (CAR)-T 细胞的抗肿瘤反应

嵌合抗原受体（CAR）T细胞疗法有望治疗恶性肿瘤。然而，由于人类表皮生长因子受体-2（HER2）CAR-T细胞对HER2的 "靶向非肿瘤 "识别，其使用存在严重毒性风险，包括细胞因子释放综合征。提高 HER2 CAR 的质量和功能可大大提高 CAR-T 细胞的治疗潜力。在这项研究中，我们开发了一种新型抗HER2单克隆抗体Ab8，它的靶点是HER2的III结构域，有别于曲妥珠单抗的IV结构域识别。尽管两种抗HER2 mAbs诱导的抗体依赖性细胞毒性水平相似，但基于曲妥珠单抗的CAR-T细胞对HER2阳性癌细胞表现出了强大的抗肿瘤活性。总之，我们的研究结果为抗体识别膜近端结构域促进 HER2 特异性 CAR-T 细胞的抗肿瘤反应提供了科学证据。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Antibodies IMMUNOLOGY-

CiteScore

7.10

自引率

6.40%

发文量

审稿时长

11 weeks

期刊介绍： Antibodies (ISSN 2073-4468), an international, peer-reviewed open access journal which provides an advanced forum for studies related to antibodies and antigens. It publishes reviews, research articles, communications and short notes. Our aim is to encourage scientists to publish their experimental and theoretical results in as much detail as possible. There is no restriction on the length of the papers. Full experimental and/or methodical details must be provided. Electronic files or software regarding the full details of the calculation and experimental procedure - if unable to be published in a normal way - can be deposited as supplementary material. This journal covers all topics related to antibodies and antigens, topics of interest include (but are not limited to): antibody-producing cells (including B cells), antibody structure and function, antibody-antigen interactions, Fc receptors, antibody manufacturing antibody engineering, antibody therapy, immunoassays, antibody diagnosis, tissue antigens, exogenous antigens, endogenous antigens, autoantigens, monoclonal antibodies, natural antibodies, humoral immune responses, immunoregulatory molecules.