一种利用对MAGE-A4/HLA-A∗02:01复合物具有高度特异性的单链抗体片段(scFv)的新型嵌合抗原受体T细胞(CAR-T)疗法的临床前评估。

Preclinical evaluation of a novel CAR-T therapy utilizing a scFv antibody highly specific to MAGE-A4/HLA-A∗02:01 complex.

作者信息

Wang Linan, Matsumoto Masahiro, Akahori Yasushi, Seo Naohiro, Shirakura Kazuko, Kato Takuma, Katsumoto Yoichi, Miyahara Yoshihiro, Shiku Hiroshi

机构信息

Department of Personalized Cancer Immunotherapy, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan.

Tokyo Laboratory 11, R&D Center, Sony Group Corporation, Bunkyo-ku, Tokyo 113-8510, Japan.

出版信息

Mol Ther. 2024 Mar 6;32(3):734-748. doi: 10.1016/j.ymthe.2024.01.018. Epub 2024 Jan 18.

Abstract

Despite the revolutionary success of chimeric antigen receptor (CAR)-T therapy for hematological malignancies, successful CAR-T therapies for solid tumors remain limited. One major obstacle is the scarcity of tumor-specific cell-surface molecules. One potential solution to overcome this barrier is to utilize antibodies that recognize peptide/major histocompatibility complex (MHCs) in a T cell receptor (TCR)-like fashion, allowing CAR-T cells to recognize intracellular tumor antigens. This study reports a highly specific single-chain variable fragment (scFv) antibody against the MAGE-A4/human leukocyte antigen (HLA)-A∗02:01 complex (MAGE-A4 pMHC), screened from a human scFv phage display library. Indeed, retroviral vectors encoding CAR, utilizing this scFv antibody as a recognition component, efficiently recognized and lysed MAGA-A4 tumor cells in an HLA-A∗02:01-restricted manner. Additionally, the adoptive transfer of T cells modified by the CAR-containing glucocorticoid-induced tumor necrosis factor receptor (TNFR)-related receptor (GITR) intracellular domain (ICD), but not CD28 or 4-1BB ICD, significantly suppressed the growth of MAGE-A4 HLA-A∗02:01 tumors in an immunocompromised mouse model. Of note, a comprehensive analysis revealed that a broad range of amino acid sequences of the MAGE-A4p peptide were critical for the recognition of MAGE-A4 pMHC by these CAR-T cells, and no cross-reactivity to analogous peptides was observed. Thus, MAGE-A4-targeted CAR-T therapy using this scFv antibody may be a promising and safe treatment for solid tumors.

摘要

尽管嵌合抗原受体(CAR)-T疗法在治疗血液系统恶性肿瘤方面取得了革命性成功,但针对实体瘤的成功CAR-T疗法仍然有限。一个主要障碍是肿瘤特异性细胞表面分子的稀缺。克服这一障碍的一个潜在解决方案是利用以T细胞受体(TCR)样方式识别肽/主要组织相容性复合体(MHC)的抗体,使CAR-T细胞能够识别细胞内肿瘤抗原。本研究报告了一种从人单链可变片段(scFv)噬菌体展示文库中筛选出的针对MAGE-A4/人类白细胞抗原(HLA)-A∗02:01复合体(MAGE-A4 pMHC)的高度特异性scFv抗体。事实上,利用这种scFv抗体作为识别成分编码CAR的逆转录病毒载体,以HLA-A∗02:01限制性方式有效识别并裂解了MAGA-A4肿瘤细胞。此外,经含CAR的糖皮质激素诱导肿瘤坏死因子受体(TNFR)相关受体(GITR)细胞内结构域(ICD)修饰的T细胞的过继转移,而非CD28或4-1BB ICD修饰的T细胞,在免疫缺陷小鼠模型中显著抑制了MAGE-A4 HLA-A∗02:01肿瘤的生长。值得注意的是,全面分析表明,MAGE-A4p肽的广泛氨基酸序列对于这些CAR-T细胞识别MAGE-A4 pMHC至关重要,并且未观察到与类似肽的交叉反应性。因此,使用这种scFv抗体的靶向MAGE-A4的CAR-T疗法可能是一种有前景且安全的实体瘤治疗方法。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2abc/10928314/55eeea5e2b98/fx1.jpg

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