The tubulysins are promising anticancer cytotoxic agents due to the clinical validation of their mechanism of action (microtubule inhibition) and their particular activity against multidrug-resistant tumor cells. Yet their high potency and subsequent systemic toxicity make them prime candidates for targeted therapy, particularly in the form of antibody–drug conjugates (ADCs). Here we report a strategy to prepare stable and bioreversible conjugates of tubulysins to antibodies without loss of activity. A peptide trigger along with a quaternary ammonium salt linker connection to the tertiary amine of tubulysin provided ADCs that were potent in vitro. However, we observed metabolism of a critical acetate ester of the drug in vivo, resulting in diminished conjugate activity. We were able to circumvent this metabolic liability with the judicious choice of a propyl ether replacement. This modified tubulysin ADC was stable and effective against multidrug-resistant lymphoma cell lines and tumors.

中文翻译：

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稳定Tubulysin抗体-药物结合物以使抗多药耐药肿瘤活性

由于其作用机理（微管抑制）及其对多药耐药性肿瘤细胞的特殊活性的临床验证，微管溶素是有前途的抗癌细胞毒剂。然而，它们的高功效和随后的全身毒性使其成为靶向治疗的主要候选药物，尤其是以抗体-药物偶联物（ADC）的形式。在这里，我们报告了一种制备微管溶素与抗体稳定且生物可逆的偶联物而又不损失活性的策略。肽触发剂与季铵盐接头连接到微管溶素的叔胺一起提供了在体外有效的ADC 。但是，我们观察到该药物的一种重要的乙酸酯在体内代谢，导致缀合物活性降低。通过明智地选择丙醚替代品，我们能够规避这种代谢责任。这种改良的微管溶素ADC稳定且有效抵抗多药耐药性淋巴瘤细胞系和肿瘤。