Data from Preclinical Evaluation of 9MW2821, a Site-Specific Monomethyl Auristatin E-based Antibody-Drug Conjugate for treatment of Nectin-4-expressing Cancers

• DOI: 10.1158/1535-7163.c.6769268.v2
• Publication Date: 2024-09-16T13:32:20Z
• Authors: Wei Zhou; Peng Fang; Dongan Yu; Hongyuan Ren; Meng You; Long Yin; Fei Mei; Huikai Zhu; Zhenzhen Wang; Hui Xu; Yuxia Cao; Xiaowei Sun; Xiaohong Xu; Jianjun Bi; Jin Wang; Lanping Ma; Xin Wang; Lin Chen; Yongliang Zhang; Xiaowei Cen; Xi Zhu; Liguang Lou; Datao Liu; Xiaoding Tan; Jinliang Yang; Tao Meng; Jingkang Shen
• Keywords: Conjugate; Antibody-drug conjugate

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