CRB-701: A Second-generation Nectin-4-Targeted Antibody-Drug Conjugate with Optimized Stability and Pharmacokinetics for the Treatment of Solid Tumors.

UNLABELLED: The adhesion protein nectin-4 is a clinically validated tumor-selective antigen that is overexpressed across multiple cancer types and has been successfully exploited as a target for antibody-drug conjugates (ADCs), most notably enfortumab vedotin (EV), which is approved for the treatment of urothelial carcinoma. In this study, we report the design and preclinical characterization of a second-generation nectin-4-targeted ADC, CRB-701 (also identified as SYS6002). CRB-701 was synthesized using microbial transglutaminase technology to conjugate two molecules of monomethyl auristatin E (MMAE) via a cleavable linker to a highly selective, high-affinity anti-nectin-4 monoclonal antibody. CRB-701 exhibited potent in vitro cytotoxicity in nectin-4-expressing cell lines and in vivo antitumor activity in cell line-derived and patient-derived murine xenograft models of human cancer (cell line-derived models: PC-3-NECTIN4 prostate cancer, MDA-MB-468 breast cancer, and HT1376 bladder cancer; patient-derived model: BL0597 bladder cancer), exhibiting efficacy similar to or greater than EV across tumors with varying levels of nectin-4 expression. CRB-701 delivered high levels of MMAE upon internalization in tumor cells and was markedly more stable in circulation than EV, with lower systemic MMAE release, an approximately twofold longer half-life, and at least a twofold higher safety margin in monkeys. These results suggest that CRB-701 may be a promising alternative therapeutic for the treatment of nectin-4-expressing tumors, providing a more favorable therapeutic window and potentially enabling regimens with higher doses and less frequent dosing than those required for EV, the only currently approved nectin-4-targeting ADC.

SIGNIFICANCE: CRB-701 is a nectin-4-targeted ADC. CRB-701 showed similar or superior antitumor activity, better stability in plasma, and was associated with lower systemic MMAE release than EV, the only approved nectin-4-targeted ADC. CRB-701 offers a promising alternative for treatment of nectin-4-expressing tumors.