肿瘤细胞治疗研究
英文原题：Human germline-like monoclonal antibody against 5T4 enables potent ADC and CAR-T therapies for solid tumors.
5T4 是一种癌胚抗原，在多种实体瘤中过表达，而在正常成人组织中表达极少，凸显了其作为治疗靶点的前景。
5T4是一种胎儿癌抗原，在多种实体瘤中过表达，而在正常成人组织中仅少量存在，因而是有前景的治疗靶点。本研究鉴定出多种靶向人5T4的类生殖系人源单克隆抗体，具有高亲和力；其中抗体m603对多种癌细胞具有更强结合活性，包括乳腺癌、胰腺癌、卵巢癌、肺癌和肝癌细胞系。随后，我们基于m603构建抗体药物偶联物（ADC）和嵌合抗原受体（CAR）T细胞。将抗体与细胞毒载荷DM4或MMAE偶联后，所得ADC在体外显示强效、抗原依赖性细胞杀伤。MMAE载荷ADC在胰腺癌异种移植模型中诱导持久肿瘤抑制。此外，源自m603的第三代CAR-T细胞（603z-CAR-T）含4-1BB和CD28共刺激结构域，可有效诱导IFN-γ和IL-2分泌，并显著清除肿瘤。作为可灵活应用于5T4靶向疗法的平台，该类生殖系抗体为实体瘤治疗提供了有前景的免疫疗法。
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- 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.
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