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首页> 外文期刊>Molecular cancer therapeutics >Development of Novel Quaternary Ammonium Linkers for Antibody-Drug Conjugates
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Development of Novel Quaternary Ammonium Linkers for Antibody-Drug Conjugates

机译：新型抗体-药物偶联物季铵盐连接基的开发

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A quaternary ammonium-based drug-linker has been developed to expand the scope of antibody-drug conjugate (ADC) payloads to include tertiary amines, a functional group commonly present in biologically active compounds. The linker strategy was exemplified with a beta-glucuronidase-cleavable auristatin E construct. The drug-linker was found to efficiently release free auristatin E (AE) in the presence of beta-glucuronidase and provide ADCs that were highly stable in plasma. Anti-CD30 conjugates comprised of the glucuronide-AE linker were potent and immunologically specific in vitro and in vivo, displaying pharmacologic properties comparable with a carbamate-linked glucuronide-monomethylauristatin E control. The quaternary ammonium linker was then applied to a tubulysin antimitotic drug that contained an N-terminal tertiary amine that was important for activity. A glucuronide-tubulysin quaternary ammonium linker was synthesized and evaluated as an ADC payload, in which the resulting conjugates were found to be potent and immunologically specific in vitro, and displayed a high level of activity in a Hodgkin lymphoma xenograft. Furthermore, the results were superior to those obtained with a related tubulysin derivative containing a secondary amine N-terminus for conjugation using previously known linker technology. The quaternary ammonium linker represents a significant advance in linker technology, enabling stable conjugation of payloads with tertiary amine residues. (C) 2016 AACR.
机译：已经开发了基于季铵盐的药物接头，以扩大抗体-药物偶联物（ADC）负载的范围，使其包括叔胺，叔胺是生物活性化合物中通常存在的官能团。该连接子策略以β-葡萄糖醛酸苷酶可切割的auristatin E构建体为例。发现该药物接头在β-葡萄糖醛酸苷酶存在下能有效释放游离的澳瑞他汀E（AE），并提供在血浆中高度稳定的ADC。由葡萄糖醛酸-AE接头组成的抗CD30缀合物在体外和体内均具有强效和免疫学特异性，显示出与氨基甲酸酯连接的葡萄糖醛酸-单甲基auristatin E对照相当的药理特性。然后将季铵连接基应用于微管溶素抗有丝分裂药物，该药物含有对活性至关重要的N末端叔胺。合成了葡糖醛酸-微管蛋白溶血素季铵盐接头，并作为ADC有效载荷进行了评估，其中发现的缀合物在体外具有强效和免疫学特异性，并且在霍奇金淋巴瘤异种移植物中表现出高水平的活性。此外，结果优于使用包含仲胺N-末端的相关微管溶素衍生物通过先前已知的接头技术缀合获得的结果。季铵连接基代表了连接基技术的重大进步，可以使有效负载与叔胺残基稳定结合。 （C）2016 AACR。

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