Proximity-Induced Disulfide Rebridging Enables Modular Construction of Stable Antibody-Drug Conjugates.

Authors

Bin-Bin Pan, Xiao-Hui Zhou, Xing Zhang, Mo-Han Li, Jia-Long Zhao, Ping Du, Chan Cao, Bin Zou, Xun-Cheng Su

Published in

Angewandte Chemie (International ed. in English). Pages e3744091. Oct 02, 2026. Epub Oct 02, 2026.

Abstract

Disulfide rebridging chemistry is a promising strategy for site-specific modification of native antibodies. Current disulfide rebridging strategies using homofunctional rebridging reagents typically favor either rapid conjugation with compromised stability or stable linkage formation with reduced reaction efficiency. Here, we report a kinetically differentiated rebridging strategy using a class of heterotrifunctional rebridging reagents, 5-fluoro-4-(phenylsulfonyl)pyridine derivatives, which can efficiently rebridge reduced disulfide bonds in antibodies to construct diverse types of antibody conjugates under physiological conditions. The kinetically differentiated bis-thiol-reactive system enables rapid initial thiol substitution followed by proximity-accelerated subsequent conjugation, in which the spatially vicinal cysteine thiols generated upon disulfide reduction sequentially replace fluorine and phenylsulfonyl groups on the pyridine derivatives, thereby combining efficient disulfide rebridging with high linkage stability. The resulting pyridyl aldehyde in the rebridged antibodies enables conjugation of functional probes or payloads, yielding multifunctional antibody conjugates. Based on this method, we have constructed antibody-fluorophore conjugates, demonstrating high plasma stability and efficient internalization into target cell lines, and antibody-drug conjugates (ADCs) with potent cytotoxicity in vitro. This method provides robust linkage stability and expands the toolkit of disulfide bridging reagents for constructing stable antibody conjugates and disulfide-containing biomolecules under mild conditions.

PMID:
42823879
Bibliographic data and abstract were imported from PubMed on 02 Oct 2026.

Read full publication at:
Please sign in to see all details.

Stats

1-terrible, 9-excellent. How would you rate this publication? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.