Site-Selective Antibody-Drug Conjugation by a Proximity-Driven S to N Acyl Transfer Reaction on a Therapeutic Antibody br
JOURNAL OF MEDICINAL CHEMISTRY(2022)
摘要
Immunoglobulin Gs (IgGs) contain many Lys and Cysresidues, which results in an unwanted complex product mixture withconventional drug conjugation methods. We selectively acylated the epsilon-NH2of K248 on trastuzumab using an IgG Fc-binding peptide (FcBP)equipped with a 5-norbornene-2-carboxylic acid thioester (AbClick-1).AbClick-1 locates its thioester close to the epsilon-NH2of K248 whilebinding to trastuzumab. Consequently, the thioester underwentproximity-driven selective acylation of epsilon-NH2through anStoNacyl transfer reaction. Furthermore,N-tert-butyl maleimide acceleratedthe cross-linking reaction with an approximately 95% yield of thedesired product by scavenging the byproduct (FcBP-SH). Only K248was modified selectively with the 5-norbornene-2-carbonyl group,which was further modified by click reaction to afford an antibody-drug conjugate (ADC) with two drugs per antibody. Theresulting ADCs showed remarkablein vitroandin vivoanticancer activity. Our results demonstrate that a thioester is a promising chemical entity for proximity-driven site-selective conjugation of antibodies
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