Synthesis of a heterotrifunctional linker for the site-specific preparation of antibody-drug conjugates with two distinct warheads
Synthesis of a heterotrifunctional linker for the site-specific preparation of antibody-drug conjugates with two distinct warheads
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DOI：
10.1016/j.bmcl.2018.10.043
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发表时间：
2018-12-15
影响因子：
2.7
通讯作者：
Dimasi, Nazzareno
中科院分区：
文献类型：
--
作者：
Kumar, Amit;Kinneer, Krista;Dimasi, Nazzareno
具有不同抗癌机制的多种治疗药物共给药可以克服耐药性，并产生相加或协同的抗癌效应，可能会增强抗肿瘤效果。抗体-药物结合物(ADC)可用于多种具有不同抗癌机制的治疗药物的高度特异性递送，但需要更多的研究来设计可在其上制备双药物ADC的灵活平台。在这里，我们描述了一种可用于构建柔性平台的异三官能连接物的合成，该连接物可用于以位置特异性的方式制备双细胞毒性药物结合物。作为概念验证，我们合成了携带单甲基金黄色E(MMAE，微管蛋白聚合抑制剂)和吡咯洛苯并二氮杂二聚体(PBD，DNA小沟槽烷化剂)的双重药物ADC。然后，我们评估了双重药物ADCs的体外疗效，并确认了双重作用机制。
Codelivery of multiple therapeutic agents with different anticancer mechanisms can overcome drug resistance as well as generate additive or synergistic anticancer effects that may enhance the antitumor efficacy. Antibody-drug conjugates (ADCs) can be used for highly specific delivery of multiple therapeutic agents with different anticancer mechanisms, though more research is required towards designing flexible platforms on which dual drug ADCs could be prepared. Herein, we describe the synthesis of a heterotrifunctional linker that could be used to construct flexible platforms for preparing dual-cytotoxic drug conjugates in a site-specific manner. As a proof of concept, we synthesized dual drug ADCs carrying monomethyl auristain E (MMAE, tubulin polymerization inhibitor) and pyrrolobenzodiazepine dimer (PBD, DNA minor groove alkylator). We then evaluated the dual drug ADCs for in vitro efficacy and confirmed the dual mechanism of action.