Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
Mabwell (Shanghai) Bioscience Co., Ltd., Shanghai, China.
Mol Cancer Ther. 2023 Aug 1;22(8):913-925. doi: 10.1158/1535-7163.MCT-22-0743.
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 (ADC) approved by the FDA for the treatment of urothelial cancer. However, inadequate efficacy has limited progress in the treatment of other solid tumors with EV. Furthermore, ocular, pulmonary, and hematologic 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 (PDX) models. In addition, 9MW2821 demonstrated a favorable safety profile; the highest nonseverely toxic dose in monkey toxicologic studies was 6 mg/kg, with milder adverse events compared with EV. Overall, 9MW2821 is a nectin-4-directed, investigational ADC based on innovative technology that endowed the drug with compelling preclinical antitumor activity and a favorable therapeutic index. The 9MW2821 ADC is being investigated in a phase I/II clinical trial (NCT05216965 and NCT05773937) in patients with advanced solid tumors.
黏附蛋白 4 过表达与许多人类恶性肿瘤的癌症进展和不良预后相关。Enfortumab vedotin（EV）是首个获 FDA 批准用于治疗膀胱癌的 nectin-4 靶向抗体药物偶联物（ADC）。然而，EV 在治疗其他实体瘤方面的疗效不足限制了其进展。此外，nectin-4 靶向治疗常见眼部、肺部和血液学毒性副作用，常导致剂量减少和/或治疗终止。因此，我们基于双硫键药物偶联技术设计了第二代 nectin-4 特异性药物 9MW2821。该新药包含一个特异性连接的人源化抗体和细胞毒药物单甲基澳瑞他汀 E。9MW2821 的均一药物-抗体比和新型连接子化学提高了在体循环中偶联物的稳定性，从而实现高效的药物递送并避免脱靶毒性。在临床前评估中，9MW2821 表现出与 EV 相比具有 nectin-4 特异性细胞结合、高效内化、旁观者杀伤和等效或更优的抗肿瘤活性，无论是在细胞系衍生的异种移植模型还是患者来源的异种移植（PDX）模型中。此外，9MW2821 表现出良好的安全性特征；在猴子毒理学研究中，最高非严重毒性剂量为 6mg/kg，与 EV 相比，不良反应更轻微。总体而言，9MW2821 是一种基于创新技术的 nectin-4 定向、研究性 ADC，赋予该药物具有引人注目的临床前抗肿瘤活性和良好的治疗指数。9MW2821 ADC 正在一项晚期实体瘤患者的 I/II 期临床试验（NCT05216965 和 NCT05773937）中进行研究。
