CRB-701: a Second-Generation Nectin-4 Targeted Antibody–Drug Conjugate with Optimized Stability and Pharmacokinetics for the Treatment of Solid Tumors

Vollständiger Abstract

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Abstract 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 treatment of urothelial carcinoma. Here, 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 (mTGase) 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 great than to 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 two-fold longer half-life, and at least two-fold 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 are required for EV, the only currently approved nectin-4 targeting ADC.