Electrocatalytic Reduction of Disulfide Bonds in Antibodies

In most FDA-approved antibody-drug conjugates, cysteines generated through reduction of the native interchain di-sulfide bonds in monoclonal antibodies (mAbs) are conjugated with maleimide-based cytotoxic payloads. Despite being key to efficiently producing well-defined conjugates, selective disulfide reduction strategies are severely underdevel-oped. Herein, we report a vitamin B12-catalyzed, electrochemically driven protocol that efficiently reduces disulfide bonds in various aqueous buffers and at a broad pH range. This robust and simple method is suitable for disulfide reduc-tions of substrates ranging from biologically relevant small molecules to large proteins. Finally, one-pot reduc-tion/conjugation of disulfide bonds in mAbs was achieved to access antibody conjugates.