内化
癌症研究
抗体-药物偶联物
细胞毒性T细胞
细胞毒性
酪氨酸激酶
癌症
药理学
受体
受体酪氨酸激酶
抗体
体外
结合
单克隆抗体
医学
化学
内科学
免疫学
生物化学
数学分析
数学
作者
Barbara Akla,Matthieu Broussas,Noureddine Loukili,Robert Ahrends,Charlotte Beau‐Larvor,Martine Malissard,Nicolas Boute,Thierry Champion,Jean‐François Haeuw,Alain Beck,Michel Perez,Cyrille Dreyfus,Mariya Pavlyuk,Eric Chetaille,Nathalie Corvaı̈a
出处
期刊:Molecular Cancer Therapeutics
[American Association for Cancer Research]
日期:2020-01-01
卷期号:19 (1): 168-177
被引量:21
标识
DOI:10.1158/1535-7163.mct-19-0219
摘要
Abstract The insulin-like growth factor type 1 receptor (IGF-1R) is important in tumorigenesis, and its overexpression occurs in numerous tumor tissues. To date, therapeutic approaches based on mAbs and tyrosine kinase inhibitors targeting IGF-1R have only shown clinical benefit in specific patient populations. We report a unique IGF-1R–targeted antibody–drug conjugate (ADC), W0101, designed to deliver a highly potent cytotoxic auristatin derivative selectively to IGF-1R overexpressing tumor cells. The mAb (hz208F2-4) used to prepare the ADC was selected for its specific binding properties to IGF-1R compared with the insulin receptor, and for its internalization properties. Conjugation of a novel auristatin derivative drug linker to hz208F2-4 did not alter its binding and internalization properties. W0101 induced receptor-dependent cell cytotoxicity in vitro when applied to various cell lines overexpressing IGF-1R, but it did not affect normal cells. Efficacy studies were conducted in several mouse models expressing different levels of IGF-1R to determine the sensitivity of the tumors to W0101. W0101 induced potent tumor regression in certain mouse models. Interestingly, the potency of W0101 correlated with the expression level of IGF-1R evaluated by IHC. In an MCF-7 breast cancer model with high-level IGF-1R expression, a single injection of W0101 3 mg/kg led to strong inhibition of tumor growth. W0101 provides a potential new therapeutic option for patients overexpressing IGF-1R. A first-in-human trial of W0101 is currently ongoing to address clinical safety.
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