Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
WuXi AppTec , 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China.
J Med Chem. 2018 Feb 8;61(3):989-1000. doi: 10.1021/acs.jmedchem.7b01430. Epub 2017 Dec 21.
Antibody-drug conjugates (ADCs) have become an important therapeutic modality for oncology, with three approved by the FDA and over 60 others in clinical trials. Despite the progress, improvements in ADC therapeutic index are desired. Peptide-based ADC linkers that are cleaved by lysosomal proteases have shown sufficient stability in serum and effective payload-release in targeted cells. If the linker can be preferentially hydrolyzed by tumor-specific proteases, safety margin may improve. However, the use of peptide-based linkers limits our ability to modulate protease specificity. Here we report the structure-guided discovery of novel, nonpeptidic ADC linkers. We show that a cyclobutane-1,1-dicarboxamide-containing linker is hydrolyzed predominantly by cathepsin B while the valine-citrulline dipeptide linker is not. ADCs bearing the nonpeptidic linker are as efficacious and stable in vivo as those with the dipeptide linker. Our results strongly support the application of the peptidomimetic linker and present new opportunities for improving the selectivity of ADCs.
抗体偶联药物（ADCs）已成为肿瘤学的一种重要治疗方式，已有三种 ADC 获得 FDA 批准，还有六十多种处于临床试验阶段。尽管取得了这些进展，但人们仍希望提高 ADC 的治疗指数。由溶酶体蛋白酶切割的基于肽的 ADC 接头在血清中具有足够的稳定性，并能在靶细胞中有效释放有效载荷。如果接头可以被肿瘤特异性蛋白酶优先水解，那么安全性可能会提高。然而，基于肽的接头的使用限制了我们调节蛋白酶特异性的能力。在这里，我们报告了基于结构指导的新型非肽 ADC 接头的发现。我们表明，含有环丁烷-1,1-二羧酸酰胺的接头主要被组织蛋白酶 B 水解，而缬氨酸-瓜氨酸二肽接头则不会。带有非肽接头的 ADC 在体内与带有二肽接头的 ADC 一样有效且稳定。我们的结果强烈支持肽模拟接头的应用，并为提高 ADC 的选择性提供了新的机会。
