Affinity-optimized TROP2 antibodies support potent antitumor activity in antibody–drug conjugates

Abstract Background Trophoblast cell surface antigen 2 (TROP2) is frequently overexpressed in epithelial tumors and is associated with poor prognosis, making it an attractive therapeutic target. Antibody–drug conjugates (ADCs) directed against TROP2 show clinical benefit, but expression in normal tissues such as skin raises concerns about on-target, off-tumor toxicity. Strategies that improve antitumor efficacy without increasing toxicity are needed. Methods Using an in-house phage library, we identified and characterized a novel fully human monoclonal antibody recognizing a unique conformational epitope of TROP2 with reduced binding affinity. This antibody was engineered into homogeneous ADCs carrying auristatin and/or duocarmycin payloads. Comparative studies with a surrogate of sacituzumab govitecan were performed in TROP2-expressing tumor models. Results The novel ADCs demonstrated remarkable antitumor activity in mouse xenograft and syngeneic tumor models. Despite lower binding affinity, the novel antibody exhibited potent efficacy, suggesting that epitope selection and affinity tuning can be leveraged to enhance therapeutic outcomes. Conclusions Novel anti-TROP2 ADCs offer a promising approach for assuring efficacy while potentially mitigating toxicity. Optimization of antibody binding properties may enable the development of safer and more effective TROP2-targeted therapeutics.