全癌唾液酸-Tn靶向治疗将嵌合抗原受体（CAR）疗法扩展至实体瘤。

Pan-carcinoma sialyl-Tn-targeting expands CAR therapy to solid tumors.

作者信息

Abrantes Rafaela, Forcados Christopher, Warren David J, Santos-Ferreira Liliana, Fleten Karianne Giller, Senra Emanuel, Costa Ana Filipa, Krpina Klara, Henrique Rui, Liberg Ann Magritt, Rawat Puneet, Gelebart Pascal, McCormack Emmet, Bjørge Line, Davidson Ben, Greiff Victor, Costea Daniela Elena, Pinto Filipe, Flatmark Kjersti, Gomes Catarina, Inderberg Else Marit, Reis Celso A, Wälchli Sébastien

机构信息

i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal; IPATIMUP - Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Rua Júlio Amaral de Carvalho 45, 4200-135 Porto, Portugal; ICBAS - Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal.

Translational Research Unit, Department of Cellular Therapy, Oslo University Hospital, Sognsvannsveien 20, 0372 Oslo, Norway; Faculty of Medicine, University of Oslo, Sognsvannsveien 9, 0372 Oslo, Norway.

出版信息

Cell Rep Med. 2025 Sep 16;6(9):102350. doi: 10.1016/j.xcrm.2025.102350. Epub 2025 Sep 8.

DOI:10.1016/j.xcrm.2025.102350

PMID:40925376

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12490251/

Abstract

Accurate identification of tumor-specific markers is vital for developing chimeric antigen receptor (CAR)-based therapies. While cell surface antigens are seldom cancer-restricted, their post-translational modifications (PTMs), particularly aberrant carbohydrate structures, offer attractive alternatives. Among these, the sialyl-Tn (STn) antigen stands out for its prevalent presence in various epithelial tumors. Although monoclonal antibodies (mAbs) against STn have been developed, their clinical application has been hindered by concerns regarding specificity. Herein, we describe AM52.1, a mAb with unprecedented specificity for STn and lack of reactivity with healthy tissues. The single-chain variable fragment (scFv) of AM52.1 was assembled into a second-generation CAR scaffold. AM52.1CAR T cells efficiently targeted STn-expressing cancer cell lines and patient-derived organoids (PDOs), while sparing STn-negative cells. In further preclinical models, AM52.1CAR T cells robustly controlled gastric and tubo-ovarian tumors, as well as colorectal cancer mucinous peritoneal metastases, highlighting their strong therapeutic potential for targeting and managing complex solid tumors.

摘要

准确识别肿瘤特异性标志物对于开发基于嵌合抗原受体（CAR）的疗法至关重要。虽然细胞表面抗原很少是癌症特异性的，但其翻译后修饰（PTM），特别是异常的碳水化合物结构，提供了有吸引力的替代方案。其中，唾液酸化Tn（STn）抗原因其在各种上皮肿瘤中的普遍存在而备受关注。尽管已经开发出针对STn的单克隆抗体（mAb），但其临床应用因对特异性的担忧而受到阻碍。在此，我们描述了AM52.1，一种对STn具有前所未有的特异性且与健康组织无反应性的单克隆抗体。AM52.1的单链可变片段（scFv）被组装成第二代CAR支架。AM52.1 CAR T细胞有效地靶向表达STn的癌细胞系和患者来源的类器官（PDO），同时不损伤STn阴性细胞。在进一步的临床前模型中，AM52.1 CAR T细胞有力地控制了胃和输卵管卵巢肿瘤以及结直肠癌黏液性腹膜转移，突出了它们在靶向和管理复杂实体瘤方面的强大治疗潜力。