Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 61, Issue 36, Pages -Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.202204132
Keywords
Acyl Transfer; Anti-Tumor; One-Step Synthesis; Site-Specific ADCs; Thioester
Categories
Funding
- Natural Science Foundation of China (NSFC) [21877116, 92153301, 82003574]
- Shanghai Sail Program [19YF1457100, 22YF1457400]
- Shanghai Municipal Science and Technology Major Project, Hangzhou innovation and entrepreneurship leading team project [TD2020005]
- Lingang Laboratory [LG-QS202206-03]
- Special Research Assistant Program (Chinese Academy of Sciences, CAS)
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In this paper, a strategy for the facile and efficient one-step synthesis of site-specific antibody-drug conjugates (ADCs) using a thioester-based acyl transfer reagent is reported. This strategy allows for the selective modification of antibodies and demonstrates excellent homogeneity, stability, and anti-tumor activity.
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.
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