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

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.