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Overexpression of nectin cell adhesion protein 4 correlates with cancer progression and poor prognosis in many human malignancies. Enfortumab vedotin (EV) is the first nectin-4-targeting antibody drug conjugate approved by the US Food and Drug Administration for treatment of urothelial cancer. However, inadequate efficacy has limited progress in the treatment of other solid tumors with EV. Furthermore, ocular, pulmonary, and hematological toxic side effects are common in nectin-4-targeted therapy, which frequently results in dose reduction and/or treatment termination. Thus, we designed a second generation nectin-4-specific drug, 9MW2821, based on interchain-disulfide drug conjugate technology. This novel drug contained a site-specifically conjugated humanized antibody and the cytotoxic moiety monomethyl auristatin E. The homogenous drug-antibody ratio and novel linker chemistry of 9MW2821 increased the stability of conjugate in the systemic circulation, enabling highly efficient drug delivery and avoiding off-target toxicity. In preclinical evaluation, 9MW2821 exhibited nectin-4 specific cell binding, efficient internalization, bystander killing, and equivalent or superior antitumor activity compared with EV in both cell-line-derived xenograft and patient-derived xenograft models. In addition, 9MW2821 demonstrated a favorable safety profile; the highest non-severely toxic dose in monkey toxicological studies was 6 mg/kg, with milder adverse events compare to EV. Overall, 9MW2821 is a nectin-4-directed, investigational antibody-drug conjugate based on innovative technology that endowed the drug with compelling preclinical antitumor activity and a favorable therapeutic index. The 9MW2821 antibody-drug conjugate is being investigated in a Phase I/II clinical trial (NCT05216965) in patients with advanced solid tumors.