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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\u2010fluoro\u20104\u2010(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\u2010thiol\u2010reactive system enables rapid initial thiol substitution followed by proximity\u2010accelerated 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\u2010fluorophore conjugates, demonstrating high plasma stability and efficient internalization into target cell lines, and antibody\u2013drug 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\u2010containing biomolecules under mild conditions.<\/jats:p>","DOI":"10.1002\/anie.3744091","type":"journal-article","created":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T07:32:05Z","timestamp":1790926325000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Proximity\u2010Induced Disulfide Rebridging Enables Modular Construction of Stable Antibody\u2013Drug Conjugates"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1841-3001","authenticated-orcid":false,"given":"Bin\u2010Bin","family":"Pan","sequence":"first","affiliation":[{"name":"State Key Laboratory of Elemento\u2010Organic Chemistry Frontiers Science Center For New Organic Matter College of Chemistry Nankai University  Tianjin 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