BRAIDing receptors for cell specific targeting
Systemic toxicity is a major challenge in the development of therapeutics. Consequently, cell-type-specific targeting is needed to improve on-target efficacy while reducing off-target toxicity. Here, we describe a cell-targeting system we have termed BRAID (BRidged Activation by Intra/intermolecular Division) whereby an active molecule is divided into two inactive or less active parts that are subsequently brought together via a so-called bridging receptor on the target cell. This concept was validated using the WNT/{beta}-catenin signaling system, demonstrating that a multivalent WNT agonist molecule divided into two inactive components assembled from different epitopes via the hepatocyte receptor {beta}Klotho induces signaling specifically on hepatocytes. These data provide proof-of-concept for this cell-specific targeting strategy and in principle, this may also allow activation of multiple signaling pathways where desirable. This approach has broad application potential for other receptor systems.