Design, Synthesis, and Evaluation of Linker-Duocarmycin Payloads: Toward Selection of HER2-Targeting Antibody-Drug Conjugate SYD985
Design, Synthesis, and Evaluation of Linker-Duocarmycin Payloads: Toward Selection of HER2-Targeting Antibody-Drug Conjugate SYD985
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DOI：
10.1021/mp500781a
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发表时间：
2015-06-01
影响因子：
4.9
通讯作者：
Beusker, Patrick H.
中科院分区：
文献类型：
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作者：
Elgersma, Ronald C.;Coumans, Ruud G. E.;Beusker, Patrick H.
目前市场上或临床试验中的抗体-药物缀合物（ADC）主要基于两种药物类别：澳瑞他汀和美登木素生物碱。两者都是微管蛋白结合剂，并阻止细胞通过有丝分裂的进展。我们着手开发一类新的基于倍癌霉素的接头药物，倍癌霉素是由DNA烷基化和DNA结合部分组成的有效DNA烷基化剂，并结合到DNA的小沟中。通过经还原的链间二硫键与抗HER 2抗体曲妥珠单抗偶联，将接头-药物作为ADC进行评价。选择带有咪唑并[1，2-a]吡啶基DNA结合单元的多卡霉素3b作为药物部分，特别是因为其在血浆中快速降解。该药物以其非活性前药形式seco-duocarmycin 3a掺入接头-药物中。与DNA烷基化部分中的羟基连接的接头优于与DNA结合部分连接，因为第一种方法给出了体外细胞毒性的更一致的结果，并产生了具有优异的人血浆稳定性的ADC。最终基于相应曲妥珠单抗缀合物SYD 983的性质选择接头-药物2，SYD 983具有约2的平均药物与抗体比率（DAR）。SYD 983对多种人癌细胞系显示出亚纳摩尔效力，在BT-474异种移植模型中高度有效，并且在食蟹猴中具有长半衰期，与猴和人血浆中的高稳定性一致。比较具有不同平均DAR的ADC的研究表明，较高的平均DAR导致功效增加，但也导致物理化学和毒理学性质稍差。用疏水性相互作用色谱法对SYD 983进行分级得到SYD 985，其由约95%的DAR 2和DAR 4物质组成，比例约为2：1，平均DARs约为2.8。SYD 985结合了普通ADC的几个有利特性，并改善了均匀性。它被选中进行进一步开发，最近进入临床I期评价。
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 cytotoxicity and generated ADCs with excellent human plasma stability. Linker-drug 2 was eventually selected based on the properties of the corresponding trastuzumab conjugate, SYD983, which had an average drug-to-antibody ratio (DAR) of about 2. SYD983 showed subnanomolar potencies against multiple human cancer cell lines, was highly efficacious in a BT-474 xenograft model, and had a long half-life in cynomolgus monkeys, in line with high stability in monkey and human plasma. Studies comparing ADCs with a different average DAR showed that a higher average DAR leads to increased efficacy but also to somewhat less favorable physicochemical and toxicological properties. Fractionation of SYD983 with hydrophobic interaction chromatography resulted in SYD985, consisting of about 95% DAR2 and DAR4 species in an approximate 2:1 ratio and having an average DAR of about 2.8. SYD985 combines several favorable properties from the unfractionated ADCs with an improved homogeneity. It was selected for further development and recently entered clinical Phase I evaluation.