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

文献类型：期刊论文

作者Zhou, Wei1,2,3,4; Fang, Peng3; Yu, Dongan3,5; Ren, Hongyuan3; You, Meng3,5; Yin, Long3,5; Mei, Fei3,5; Zhu, Huikai3; Wang, Zhenzhen3; Xu, Hui3
刊名MOLECULAR CANCER THERAPEUTICS
出版日期2023-08-01
卷号22期号:8页码:913-925
ISSN号1535-7163
DOI10.1158/1535-7163.MCT-22-0743
通讯作者Tan, Xiaoding(xiaoding.tan@mabwell.com) ; Yang, Jinliang(jinliangyang@scu.edu.cn) ; Meng, Tao(tmeng@simm.ac.cn)
英文摘要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 specifi- cally 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.
WOS关键词NECTIN FAMILY ; EXPRESSION ; STABILITY ; MOLECULES ; TARGET ; POTENT
资助项目Mabwell (Shanghai) Bioscience Co., Ltd
WOS研究方向Oncology
语种英语
出版者AMER ASSOC CANCER RESEARCH
WOS记录号WOS:001045277200001
源URL[http://119.78.100.183/handle/2S10ELR8/306887]  
专题中国科学院上海药物研究所
通讯作者Tan, Xiaoding; Yang, Jinliang; Meng, Tao
作者单位1.Sichuan Univ, West China Hosp, Canc Ctr, Collaborat Innovat Ctr Biotherapy, Chengdu 610041, Peoples R China
2.Sichuan Univ, West China Hosp, Collaborat Innovat Ctr Biotherapy, State Key Lab Biotherapy, Chengdu 610041, Peoples R China
3.Mabwell Shanghai Biosci Co Ltd, Shanghai 201203, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med, 555 Zu Chong Zhi Rd, Shanghai 201203, Peoples R China
5.Jiangsu Mabwell Hlth Pharmaceut R&D Co Ltd, Taizhou, Peoples R China
推荐引用方式
GB/T 7714		 Zhou, Wei,Fang, Peng,Yu, Dongan,et al. Preclinical Evaluation of 9MW2821, a Site-Specific Monomethyl Auristatin E-based Antibody-Drug Conjugate for Treatment of Nectin-4-expressing Cancers[J]. MOLECULAR CANCER THERAPEUTICS,2023,22(8):913-925.
APA Zhou, Wei.,Fang, Peng.,Yu, Dongan.,Ren, Hongyuan.,You, Meng.,...&Shen, Jingkang.(2023).Preclinical Evaluation of 9MW2821, a Site-Specific Monomethyl Auristatin E-based Antibody-Drug Conjugate for Treatment of Nectin-4-expressing Cancers.MOLECULAR CANCER THERAPEUTICS,22(8),913-925.
MLA Zhou, Wei,et al."Preclinical Evaluation of 9MW2821, a Site-Specific Monomethyl Auristatin E-based Antibody-Drug Conjugate for Treatment of Nectin-4-expressing Cancers".MOLECULAR CANCER THERAPEUTICS 22.8(2023):913-925.

入库方式： OAI收割

来源：上海药物研究所

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