Novel Amanitin-Based Antibody–Drug Conjugates Targeting TROP2 for the Treatment of Pancreatic Cancer

Trophoblast cell surface antigen 2 (TROP2) exhibits aberrant expression in pancreatic cancer, correlating with metastasis, advanced tumor stage, and poor prognosis in patients with pancreatic ductal adenocarcinoma. TROP2 has been recognized as a promising therapeutic target for antibody-drug conjugates (ADC), as evidenced by the approval of the anti-TROP2 ADC Trodelvy for the treatment of triple-negative breast cancer (TNBC). In this study, we report the generation of novel second-generation amanitin-based ADCs (ATAC) targeting TROP2, comprising the humanized RS7 antibody of Trodelvy (hRS7) and the highly potent payload amanitin. The specific in vitro binding, efficient antigen internalization, and high cytotoxicity of hRS7 ATACs with EC50 values in the picomolar range in TROP2-expressing cells constituted the foundation for preclinical in vivo evaluation. The hRS7 ATACs demonstrated a significant reduction in tumor growth in vivo in subcutaneous xenograft mouse models of pancreatic cancer and TNBC at well-tolerated doses. The antitumor efficacy correlated with the level of TROP2 expression on the tumors and the in vivo tumor uptake of the ATACs. The long half-life of 9.7 to 10.7 days of hRS7 ATACs without premature payload release in serum supported a high therapeutic index. Notably, the efficacy of the hRS7 ATACs was superior to that of Trodelvy with complete tumor eradication in both refractory pancreatic cancer and TNBC xenograft models. In summary, hRS7 ATACs represent a highly effective and well-tolerated targeted therapy, and our data support their development for pancreatic cancer and other TROP2-expressing tumors.