Sulfatase-cleavable linkers for antibody-drug conjugates.
Sulfatase-cleavable linkers for antibody-drug conjugates.
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DOI：
10.1039/c9sc06410a
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发表时间：
2020-01-27
期刊：
影响因子：
8.4
通讯作者：
Spring DR
中科院分区：
文献类型：
--
作者：
Bargh JD;Walsh SJ;Isidro-Llobet A;Omarjee S;Carroll JS;Spring DR
抗体-药物结合物(ADC)是一类结合了单抗的细胞选择性和小分子的细胞毒性的靶向给药制剂。这两个组分由共价连接物连接，其性质对ADC的有效性和安全性至关重要。酶可裂解的二肽连接物由于能够选择性地释放靶细胞溶酶体中的有效载荷而成为一种特别有效的ADC连接物类型。然而，这些接头有一些缺点，包括在啮齿动物血浆中不稳定，以及它们固有的高疏水性。在这里，我们展示了含有芳基硫酸盐的ADC连接体被溶酶体硫酸盐酶切割以无痕迹地释放它们的有效载荷，同时绕过了与二肽连接体相关的不稳定问题。当与曲妥珠单抗和高效的单甲基金黄色E(MMAE)有效载荷相结合时，含有芳基硫酸盐的ADC2和ADC3对HER2阳性细胞的细胞毒性比不可切割的ADC4更强，同时保持了对HER2阴性细胞的选择性。我们认为，我们的芳基硫酸盐连接体的稳定性、溶解性和合成可操作性使其成为可切割ADC连接体的一个有吸引力的新基序，与广泛使用的二肽连接体相比具有明显的优势。含有芳基硫酸盐的接头被溶酶体硫酸盐酶切割，以释放靶向癌细胞的ADC的有效载荷。
Antibody-drug conjugates (ADCs) are a class of targeted drug delivery agents combining the cell-selectivity of monoclonal antibodies (mAbs) and the cytotoxicity of small molecules. These two components are joined by a covalent linker, whose nature is critical to the efficacy and safety of the ADC. Enzyme-cleavable dipeptidic linkers have emerged as a particularly effective ADC linker type due to their ability to selectively release the payload in the lysosomes of target cells. However, these linkers have a number of drawbacks, including instability in rodent plasma and their inherently high hydrophobicity. Here we show that arylsulfate-containing ADC linkers are cleaved by lysosomal sulfatase enzymes to tracelessly release their payload, while circumventing the instability problems associated with dipeptide-linkers. When incorporated with trastuzumab and the highly potent monomethyl auristatin E (MMAE) payload, the arylsulfate-containing ADC 2 and ADC 3 were more cytotoxic than the non-cleavable ADC 4 against HER2-positive cells, while maintaining selectivity over HER2-negative cells. We propose that the stability, solubility and synthetic tractability of our arylsulfate linkers make them an attractive new motif for cleavable ADC linkers, with clear benefits over the widely used dipeptidic linkers. Arylsulfate-containing linkers are cleaved by lysosomal sulfatases to release payloads from ADCs at targeted cancer cells.
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