Figure 1. Ubiquibodies. Portnoff et al. have demonstrated a strategy for targeted destruction of intracellular proteins using engineered intracellular antibodies that deliver ubiquitin to a target protein. Ubiquitin is a small protein that tags intracellular proteins for degradation by the proteasome, a cellular garbage disposal system.

The team constructed a transgene encoding the E3 ubiquitin ligase domain of STIP1 homology and U-box containing protein 1 (STUB1; CHIP) fused to a mAb-derived designer binding protein (DBP) that targets a model substrate (a). The resulting fusion protein is called a ubiquibody.

In cell culture, DBP trapped a model target protein (b), and the CHIP domain of the fusion protein added ubiquitin to the captive target (c), triggering the addition of further ubiquitin molecules (d) and degradation of the target by the proteasome (e).

Arvinas Inc. and GlaxoSmithKline plc are independently developing proteolysis-targeting chimeric molecules, or PROTACs, that recruit a different E3 ubiquitin ligase to target disease-linked proteins. PROTAC compounds from Arvinas are in lead optimization to treat cancer, and GSK has PROTACs in lead discovery for undisclosed indications.