Functional selection of protease inhibitory antibodies

Abstract

Significance Proteases precisely control a wide variety of physiological processes and thus are important drug targets. Compared with small-molecule inhibitors, monoclonal antibodies (mAbs) are attractive, as they provide required specificity. However, finding inhibitory mAbs is often a bottleneck, largely due to lack of a function-based selection method. We overcame this obstacle and successfully isolated mAbs that effectively inhibited 5 therapeutic targets spanning 4 basic classes of proteases. Our mAb inhibitors are highly selective and deliver desired biochemical and biological actions, including reduction of amyloid beta formation in vitro and pain relief in animal behavioral tests. Thus, the technique described here can be readily applied to many pathophysiologically important proteases for the discovery and engineering of therapeutic mAbs.