Although antibody–drug conjugates (ADCs) find increasing applications in cancer treatment, de novo or treatment-emergent resistance mechanisms may impair clinical benefit. Two resistance mechanisms that emerge under prolonged exposure include upregulation of transporter proteins that confer multidrug resistance (MDR+) and loss of cognate antigen expression. New technologies that circumvent these resistance mechanisms may serve to extend the utility of next-generation ADCs. Recently, we developed the quaternary ammonium linker system to expand the scope of conjugatable payloads to include tertiary amines and applied the linker to tubulysins, a highly potent class of tubulin binders that maintain activity in MDR+ cell lines. In this work, tubulysin M, which contains an unstable acetate susceptible to enzymatic hydrolysis, and two stabilized tubulysin analogues were prepared as quaternary ammonium-linked glucuronide-linkers and assessed as ADC payloads in preclinical models. The conjugates were potent across a panel of cancer cell lines and active in tumor xenografts, including those displaying the MDR+ phenotype. The ADCs also demonstrated potent bystander activity in a coculture model comprised of a mixture of antigen-positive and -negative cell lines, and in an antigen-heterogeneous tumor model. Thus, the glucuronide–tubulysin drug-linkers represent a promising ADC payload class, combining conjugate potency in the presence of the MDR+ phenotype and robust activity in models of tumor heterogeneity in a structure-dependent manner. Mol Cancer Ther; 17(8); 1752–60. ©2018 AACR.

中文翻译：

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葡萄糖醛酸连接的抗体-微管溶素偶联物在 MDR+ 和异质肿瘤模型中显示活性

尽管抗体药物偶联物 (ADC) 在癌症治疗中的应用越来越多，但从头或治疗中出现的耐药机制可能会损害临床获益。在长期暴露下出现的两种耐药机制包括赋予多药耐药性 (MDR+) 的转运蛋白上调和同源抗原表达的丧失。绕过这些阻力机制的新技术可能有助于扩展下一代 ADC 的效用。最近，我们开发了季铵连接器系统，以扩大可结合有效载荷的范围，包括叔胺，并将连接器应用于微管溶素，微管蛋白结合剂是一种在 MDR+ 细胞系中保持活性的高效微管蛋白结合剂。在这项工作中，微管溶素 M 含有一种易受酶水解影响的不稳定醋酸盐，和两种稳定的微管溶素类似物被制备为季铵连接的葡糖苷酸接头，并在临床前模型中作为 ADC 有效载荷进行评估。这些偶联物在一组癌细胞系中是有效的，并且在肿瘤异种移植物中具有活性，包括那些显示 MDR+ 表型的移植物。在由抗原阳性和阴性细胞系的混合物组成的共培养模型中，以及在抗原异质肿瘤模型中，ADC 还表现出强大的旁观者活性。因此，葡糖苷酸-微管溶素药物接头代表了一种有前途的 ADC 有效载荷类别，以结构依赖性方式将 MDR+ 表型存在下的偶联物效力与肿瘤异质性模型中的稳健活性相结合。摩尔癌症治疗; 17(8); 1752-60 年。©2018 AACR。