The Methylene Alkoxy Carbamate Self‐Immolative Unit: Utilization for the Targeted Delivery of Alcohol‐Containing Payloads with Antibody–Drug Conjugates,Angewandte Chemie International Edition

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The Methylene Alkoxy Carbamate Self‐Immolative Unit: Utilization for the Targeted Delivery of Alcohol‐Containing Payloads with Antibody–Drug Conjugates
Angewandte Chemie International Edition ( IF 16.1 ) Pub Date : 2016-05-20 , DOI: 10.1002/anie.201601506
Robert V. Kolakowski ₁ , Karl T. Haelsig ₁ , Kim K. Emmerton ₁ , Chris I. Leiske ₁ , Jamie B. Miyamoto ₁ , Julia H. Cochran ₁ , Robert P. Lyon ₁ , Peter D. Senter ₁ , Scott C. Jeffrey ₁

Affiliation

A strategy for the conjugation of alcohol‐containing payloads to antibodies has been developed and involves the methylene alkoxy carbamate (MAC) self‐immolative unit. A series of MAC β‐glucuronide model constructs were prepared to evaluate stability and enzymatic release, and the results demonstrated high stability at physiological pH in a substitution‐dependent manner. All the MAC model compounds efficiently released alcohol drug surrogates under the action of β‐glucuronidase. To assess the MAC technology for ADCs, the potent microtubule‐disrupting agent auristatin E (AE) was incorporated through the norephedrine alcohol. Conjugation of the MAC β‐glucuronide AE drug linker to the anti‐CD30 antibody cAC10, and an IgG control antibody, gave potent and immunologically specific activities in vitro and in vivo. These studies validate the MAC self‐immolative unit for alcohol‐containing payloads within ADCs, a class that has not been widely exploited.

中文翻译：

亚甲基氨基甲酸酯氨基甲酸酯自焚单元：用于抗体-药物结合物的含酒精有效负载的目标递送

已经开发出一种将含酒精的有效载荷与抗体结合的策略，该策略涉及亚甲基烷氧基氨基甲酸酯（MAC）自消灭单元。制备了一系列MACβ-葡糖醛酸苷模型构建体以评估稳定性和酶促释放，结果证明了在生理pH下以取代依赖性方式具有很高的稳定性。所有的MAC模型化合物都在β-葡萄糖醛酸苷酶的作用下有效地释放了醇类药物替代物。为了评估用于ADC的MAC技术，通过去甲麻黄碱醇掺入了有效的微管破坏剂auristatin E（AE）。MACβ-葡糖醛酸苷AE药物接头与抗CD30抗体cAC10和IgG对照抗体的结合在体外和体内均具有强大的免疫学特异性活性。

更新日期：2016-05-20

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