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首页> 外文期刊>Molecular pharmaceutics >Design, Synthesis, and Evaluation of Linker-Duocarmycin Payloads: Toward Selection of HER2-Targeting Antibody-Drug Conjugate SYD985
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Design, Synthesis, and Evaluation of Linker-Duocarmycin Payloads: Toward Selection of HER2-Targeting Antibody-Drug Conjugate SYD985

机译：连接子-杜卡霉素有效负载的设计，合成和评估：HER2靶向抗体-药物偶联物SYD985的选择

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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.
机译：当前市场上或临床试验中的抗体-药物偶联物（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物，并通过有丝分裂阻断细胞的进程。我们着手开发基于杜卡霉素的新型接头药物，杜卡霉素是由DNA烷基化和DNA结合部分组成并结合到DNA小沟中的有效DNA烷基化剂。通过减少的链间二硫键与抗HER2抗体曲妥珠单抗偶联，将连接物药物评估为ADC。选择带有基于咪唑并[1,2-a]吡啶的DNA结合单元的杜卡霉素3b作为药物部分，尤其是由于其在血浆中的快速降解。该药物以其非活性前药形式，即山高杜卡霉素3a掺入接头药物中。与第一种方法相比，DNA烷基化部分的羟基上的连接子连接优于与DNA结合部分的连接，因为第一种方法在体外细胞毒性方面产生了更一致的结果，并且生成的ADC具有出色的人血浆稳定性。最终根据相应的曲妥珠单抗偶联物SYD983的特性选择了接头药物2，该药物的平均药物与抗体之比（DAR）为约2。SYD983对多种人类癌细胞系显示亚纳摩尔效价，非常有效在BT-474异种移植模型中，在食蟹猴中具有较长的半衰期，这与猴和人血浆中的高稳定性相符。比较具有不同平均DAR的ADC的研究表明，较高的平均DAR会提高功效，但也会导致不利的理化和毒理学特性。用疏水相互作用色谱分级分离SYD983，得到SYD985，其由大约95％的DAR2和DAR4以大约2∶1的比例组成，并且平均DAR为大约2.8。 SYD985结合了来自未分级ADC的多个有利特性，并提高了均一性。它被选作进一步开发，并于近期进入临床I期评估。

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