ArticleCancer research communications2026
CRB-701: A Second-generation Nectin-4-Targeted Antibody-Drug Conjugate with Optimized Stability and Pharmacokinetics for the Treatment of Solid Tumors.
Article in Cancer research communications, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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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 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.
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