Abstract A135: GS24-B057, a potential best-in-class Nectin-4- and Trop-2-directed bispecific ADC, for the treatment of multiple solid tumors

Abstract Background: Nectin-4 and Trop-2 are transmembrane proteins commonly co-overexpressed in various solid tumors and associated with tumor progression. ADCs targeting Nectin-4 or Trop-2 have shown promising therapeutic potential in urothelial carcinoma (UC), non-small cell lung cancer (NSCLC), and triple-negative breast cancer (TNBC). Notably, the combination of Padcev™ (a Nectin-4-directed ADC; also referred to as EV) and Trodelvy™ (a Trop-2-directed ADC; also referred to as SG) as second-line therapy for metastatic UC has demonstrated significantly improved efficacy, with the overall response rate (ORR) reaching 70%. However, the safety profile of this combination remains to be a concern, with ≥Grade 3 treatment-emergent adverse events (TEAEs) occurring in 78% of patients. To enhance clinical efficacy while minimizing toxicity, we developed GS24-B057, a dual Nectin-4- and Trop-2-targeting ADC with a drug-to-antibody ration (DAR) of 6, integrating an optimally engineered bispecific antibody, a tailored topoisomerase I inhibitor payload, and site-specific conjugation. Materials and Methods: The in vitro tumor cell binding and internalization activity of GS24-B057 were evaluated by flow cytometry in Nectin-4 and Trop-2 positive cell lines. Cytotoxicity and bystander killing effect were assessed in a Cell Titer-Glo assay and in a luciferase assay, respectively. The in vivo anti-tumor efficacy of GS24-B057 was systematically examined in a number of human cancer cell line-derived xenograft (CDX) models in mice. Results: In preclinical studies, GS24-B057 exhibited significantly stronger in vitro cell binding and internalization than EV and SG, as well as robust direct cytotoxicity and pronounced bystander killing effect in tumor cell lines. GS24-B057 demonstrated superior in vivo anti-tumor efficacy as compared to the EV and SG combination in a number of CDX models including UC and TNBC. A pilot non-GLP 4-week repeat dose toxicity study in cynomolgus monkeys has been planned. Conclusion: These data suggest the potential of GS24-B057 as an effective therapeutic option for patients with UC and TNBC and support its further evaluation in IND-enabling studies. Citation Format: Meihan Li, Fu Li, Qiuru Che, Dongxia Chu, Qiyang Zhang, Xiaojing Huang, Nan Li, Qingjuan Ma, Shaonan Liang, Weiming He, Yihui Lin, Wenqiang Zhai, Fanglong Yang, Siqing Wang, Lei Jin, John L. Xu. GS24-B057, a potential best-in-class Nectin-4- and Trop-2-directed bispecific ADC, for the treatment of multiple solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr A135.