单克隆抗体
细胞毒性
药品
抗体
体内
药物发现
重组DNA
小分子
共轭体系
肽
体外
作者
Ronald Christiaan Elgersma,Ruud Coumans,Tijl Huijbregts,Wiro Michaël Petrus Bernardus Menge,John Joosten,Henri Johannes Spijker,Franciscus M. H. de Groot,Miranda M.C. van der Lee,Ruud Ubink,Diels van den Dobbelsteen,David F. Egging,Wim H. A. Dokter,GF Verheijden,Jacques M. Lemmens,C. Marco Timmers,Patrick Henry Beusker
摘要
Antibody–drug conjugates (ADCs) that are currently on the market or in clinical trials are predominantly based on two drug classes: auristatins and maytansinoids. Both are tubulin binders and block the cell in its progression through mitosis. We set out to develop a new class of linker-drugs based on duocarmycins, potent DNA-alkylating agents that are composed of a DNA-alkylating and a DNA-binding moiety and that bind into the minor groove of DNA. Linker-drugs were evaluated as ADCs by conjugation to the anti-HER2 antibody trastuzumab via reduced interchain disulfides. Duocarmycin 3b, bearing an imidazo[1,2-a]pyridine-based DNA-binding unit, was selected as the drug moiety, notably because of its rapid degradation in plasma. The drug was incorporated into the linker-drugs in its inactive prodrug form, seco-duocarmycin 3a. Linker attachment to the hydroxyl group in the DNA-alkylating moiety was favored over linking to the DNA-binding moiety, as the first approach gave more consistent results for in vitro c...
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