Disulfide rebridging platforms for site-specific ADC conjugation

Antibody-drug conjugates (ADCs) have emerged as a transformative class of targeted therapeutics, combining the exquisite specificity of monoclonal antibodies with the potency of small-molecule cytotoxic payloads. While numerous strategies exist to generate ADCs, site-specific conjugation methods have gained prominence due to their ability to produce homogeneous constructs with defined drug-antibody ratios, improved stability, and predictable pharmacokinetics. Among these, disulfide rebridging chemistries have recently attracted considerable attention as an elegant and versatile platform for precise antibody modification. By exploiting native interchain disulfide bonds, rebridging approaches restore structural integrity while introducing functional handles for payload attachment, enabling the generation of reproducible and structurally well-defined ADCs from native antibodies. This review provides a systematic and comprehensive overview of the chemical methodologies developed for disulfide rebridging, tracing the evolution of rebridging reagents and strategies from early maleimide and bissulfone scaffolds to modern dibromopyridazinediones, and other bridging frameworks. Beyond chemistry, we discuss the biological implications of rebridged ADCs, including their translational potential, supported by emerging preclinical and clinical data. Providing a dual chemical and biological perspective, this review aims to serve as a practical guide for researchers seeking to navigate the expanding landscape of site-specific ADC development, ultimately contributing to the rational design of next-generation targeted therapeutics.