Discovery of Pyrophosphate Diesters as Tunable, Soluble, and Bioorthogonal Linkers for Site-Specific Antibody-Drug Conjugates
Discovery of Pyrophosphate Diesters as Tunable, Soluble, and Bioorthogonal Linkers for Site-Specific Antibody-Drug Conjugates
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DOI：
10.1021/jacs.5b12547
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发表时间：
2016-02-03
影响因子：
15
通讯作者：
Garbaccio, Robert M.
中科院分区：
文献类型：
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作者：
Kern, Jeffrey C.;Cancilla, Mark;Garbaccio, Robert M.
为了检验抗体药物偶联物（adc）在肿瘤适应症之外的效用，研究人员发现了一种新型焦磷酸酯连接物，可以靶向递送糖皮质激素。作为小分子，这些高可溶性磷酸酯药物连接物被发现具有理想的正交特性：强大的血浆稳定性以及在溶酶体环境中快速释放有效载荷。在这些发现的基础上，在这种药物连接体组合和一种针对人类CD70的抗体之间制备了位点特异性adc， CD70是一种在免疫细胞中特异性表达的受体，但也发现在多种人类癌症中异常表达。通过糖皮质激素受体介导的基因mRNA水平的变化，研究人员证明了adc 1-22和1-37能够有效地将糖皮质激素靶向递送到具有代表性的细胞系。这些活性被发现是抗体、连接体和有效载荷依赖的。初步的机制研究支持溶酶体运输和酶连接物切割是活性所必需的这一观点，焦磷酸盐连接物的用途可能是adc内化以及其他靶向递送平台的一般用途。
As part of an effort to examine the utility of antibody drug conjugates (ADCs) beyond oncology indications, a novel pyrophosphate ester linker was discovered to enable the targeted delivery of glucocorticoids. As small molecules, these highly soluble phosphate ester drug linkers were found to have ideal orthogonal properties: robust plasma stability coupled with rapid release of payload in a lysosomal environment. Building upon these findings, site-specific ADCs were made between this drug linker combination and an antibody against human CD70, a receptor specifically expressed in immune cells but also found aberrantly expressed in multiple human carcinomas. Full characterization of these ADCs enabled procession to in vitro proof of concept, wherein ADCs 1-22 and 1-37 were demonstrated to afford potent, targeted delivery of glucocorticoids to a representative cell line, as measured by changes in glucocorticoid receptor-mediated gene mRNA levels. These activities were found to be antibody-, linker-, and payload-dependent. Preliminary mechanistic studies support the notion that lysosomal trafficking and enzymatic linker cleavage are required for activity and that the utility for the pyrophosphate linker may be general for internalizing ADCs as well as other targeted delivery platforms.