School of Pharmaceutical Science and Technology, Hangzhou Institute of Advanced Study, Hangzhou, 310024, China.
CAS Key Laboratory of Receptor Research, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, No. 555 Zuchongzhi Road, Pudong, Shanghai, 201203, China.
Angew Chem Int Ed Engl. 2022 Sep 5;61(36):e202204132. doi: 10.1002/anie.202204132. Epub 2022 Jul 27.
Direct chemical modification of native antibodies in a site-specific manner remains a great challenge. Ligand-directed conjugation can achieve the selective modification of antibodies, but usually requires multiple extra steps for ligand release and cargo assembly. Herein, we report a novel, traceless strategy to enable the facile and efficient one-step synthesis of site-specific antibody-drug conjugates (ADCs) by harnessing a thioester-based acyl transfer reagent. The designed reagent, consisting of an optimized Fc-targeting ligand, a thioester bridge and a toxin payload, directly assembles the toxin precisely onto the K251 position of native IgGs and simultaneously self-releases the affinity ligand in one step. With this method, we synthesized a series of K251-linked ADCs from native Trastuzumab. These ADCs demonstrated excellent homogeneity, thermal stability, and both in vitro and in vivo anti-tumor activity. This strategy is equally efficient for IgG1, IgG2, and IgG4 subtypes.
直接在特定位置对天然抗体进行化学修饰仍然是一个巨大的挑战。配体导向偶联可以实现抗体的选择性修饰，但通常需要多个额外的步骤来释放配体和组装有效载荷。在此，我们报告了一种新的无痕迹策略，通过利用基于硫酯的酰基转移试剂，可轻松高效地一步合成抗体药物偶联物（ADC）。该设计的试剂由优化的 Fc 靶向配体、硫酯桥和毒素有效载荷组成，可直接将毒素精确组装到天然 IgG 的 K251 位置，并在一步中同时自释放亲和配体。使用该方法，我们从天然曲妥珠单抗中合成了一系列 K251 连接的 ADC。这些 ADC 表现出优异的均一性、热稳定性以及体外和体内抗肿瘤活性。该策略对 IgG1、IgG2 和 IgG4 亚型同样有效。
