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Org Biomol Chem. 2019 Sep 21;17(35):8115-8124. doi: 10.1039/c9ob01639b. Epub 2019 Aug 28.
We report a modular approach to synthesize maleimido group containing hydrophilic dolastatin 10 (Dol10) derivatives as drug-linkers for the syntheses of antibody-drug conjugates (ADCs). Discrete polyethylene glycol (PEG) moieties of different chain lengths were introduced as part of the linker to impart hydrophilicity to these drug linkers. The synthesis process involved construction of PEG maleimido derivatives of the tetrapeptide intermediate (N-methylvaline-valine-dolaisoleucine-dolaproine), which were subsequently coupled with dolaphenine to generate the desired drug linkers. The synthetic method reported in this manuscript circumvents the use of highly cytotoxic Dol10 in its native form. By using trastuzumab (Herceptin®) as the antibody we have synthesized Dol10 containing ADCs. The presence of a discrete PEG chain in the drug linkers resulted in ADCs free from aggregation. The effect of PEG chain length on the biological activities of these Dol10 containing ADCs was investigated by in vitro cytotoxicity assays. ADCs containing PEG and PEG spacers exhibited the highest level of in vitro anti-proliferative activity against HER2-positive (SK-BR-3) human tumor cells. ADCs derived from Herceptin® and PEG-Dol10, at a dose of 10 mg kg, effectively delayed the tumor growth and prolonged the survival time in mice bearing human ovarian SKOV-3 xenografts.
我们报告了一种模块化方法，用于合成含有马来酰亚胺基的亲水性 dolastatin 10（Dol10）衍生物作为用于抗体药物偶联物（ADC）的药物接头。不同链长的离散聚乙二醇（PEG）部分被引入作为接头的一部分，以使这些药物接头具有亲水性。该合成过程涉及构建四肽中间体（N-甲基缬氨酸-缬氨酸-二亮氨酸-二亮氨酸）的 PEG 马来酰亚胺衍生物，随后与 dolaphenine 偶联生成所需的药物接头。本文报道的合成方法避免了在其天然形式下使用高度细胞毒性的 Dol10。我们使用曲妥珠单抗（赫赛汀®）作为抗体合成了含有 Dol10 的 ADC。药物接头中存在离散的 PEG 链可使 ADC 无聚集。通过体外细胞毒性测定研究了 PEG 链长对这些含有 Dol10 的 ADC 的生物学活性的影响。含有 PEG 和 PEG 间隔物的 ADC 对 HER2 阳性（SK-BR-3）人肿瘤细胞表现出最高水平的体外增殖抑制活性。用赫赛汀®和 PEG-Dol10 衍生的 ADC，剂量为 10 mg/kg，可有效延迟荷有人卵巢 SKOV-3 异种移植瘤小鼠的肿瘤生长并延长生存时间。
