Degrader-antibody conjugates move past a rocky debut

The recent Roche-C4 and Gyre-Cullgen deals suggest interest in degrader-antibody conjugates is picking up, after a quiet year for the emerging modality and the discontinuation of the first clinical DAC following a fatal adverse event.

The appeal of DACs is that they could pair the tissue-targeting logic of ADCs with the catalytic activity of protein degraders. DACs comprise antibodies linked to small-molecule degraders, using the antibody to deliver the payload to cells bearing a chosen surface antigen. Structurally, a DAC looks like an ADC, but instead of a cytotoxic payload, it carries a degrader molecule designed to hijack an E3 ligase and send an intracellular protein to the proteasome for destruction...