复旦大学吴艳玲课题组近日取得一项新成果。经过不懈努力，他们的最新研究揭示了抗5T4的人种系样单克隆抗体可用于实体瘤的有效ADC和CAR-T治疗。该研究于2026年1月27日发表于国际一流学术期刊《中国药理学报》杂志上。

在本研究中，该研究组鉴定了高亲和力的针对人5T4的种系样人单克隆抗体，其中抗体m603对乳腺癌、胰腺癌、卵巢癌、肺癌和肝癌等多种肿瘤细胞具有优异的细胞结合活性。随后，课题组研究人员构建了基于m603的抗体-药物偶联物（ADCs）和嵌合抗原受体(CAR)-T细胞。通过将抗体与细胞毒性载荷DM4或MMAE偶联，得到的ADCs在体外表现出有效的抗原依赖性细胞杀伤活性。ADC结合MMAE有效载荷在胰腺癌异种移植模型中引起持久的肿瘤抑制。

此外，来自m603的第三代CAR-T细胞（603z-CAR-T）含有4-1BB和CD28共刺激结构域，可有效诱导IFN-γ和IL-2分泌，并显著根除肿瘤。种系样抗体作为5t4靶向治疗的通用平台，为治疗实体瘤提供了有前景的免疫疗法。

据了解，5T4是一种肿瘤胎儿抗原，在广泛的实体肿瘤中过表达，在正常成人组织中很少存在，突出了其作为治疗靶点的前景。

附：英文原文

Title: Human germline-like monoclonal antibody against 5T4 enables potent ADC and CAR-T therapies for solid tumors

Author: Jiang, Yi-qing, Ma, Xiao-jie, Wang, Yin-man, Feng, Yi, Kong, Yu, Huang, Ai-ling, Jin, Zi-xuan, Ying, Tian-lei, Wu, Yan-ling

Issue&Volume: 2026-01-27

Abstract: 5T4 is an oncofetal antigen overexpressed in a wide range of solid tumors with minimal presence in normal adult tissues, highlighting its promise as a therapeutic target. In this study, we identified germline-like human monoclonal antibodies targeting human 5T4 with high affinity, among which antibody m603 exhibits superior cell binding activity to various cancer cells including breast, pancreatic, ovarian, lung and liver cancer cell lines. Subsequently, we constructed antibody-drug conjugates (ADCs) and chimeric antigen receptor (CAR)-T cell based on m603. By conjugating the antibody with cytotoxic payload DM4 or MMAE, the resulting ADCs demonstrated potent and antigen-dependent cell killing activity in vitro. The ADC conjugated with MMAE payload elicited durable tumor suppression in pancreatic cancer xenograft models. Furthermore, third-generation CAR-T cells derived from m603 (603z-CAR-T), incorporating 4-1BB and CD28 costimulatory domains, effectively induced IFN-γ and IL-2 secretion and remarkable tumor eradication. The germline-like antibody as a versatile platform for 5T4-targeted therapies offers promising immunotherapies for treating solid tumors.

DOI: 10.1038/s41401-025-01731-3

Source: https://www.nature.com/articles/s41401-025-01731-3