BRAIDing receptors for cell specific targeting

Abstract

AbstractSystemic toxicity is a major challenge to therapeutic development, consequently, cell-type specific targeting is highly desirable to improve on-target cell efficacy while reducing off-target toxicity. Here, we describe a cell targeting system we called BRAID (BRidgedActivation byIntra/intermolecularDivision) where an active molecule is divided into two inactive or less active parts that are subsequently brought together via a bridging receptor on target cell. We tested this hypothesis using WNT/β-catenin signaling system and demonstrated that a multivalent WNT agonist molecule divided into two inactive components induced signaling specifically on hepatocytes assembled via two different epitopes on a hepatocyte receptor, βKlotho. These data provided proof-of-concept for a cell specific targeting approach and also demonstrated the feasibility of combining different signaling pathways where desirable. This approach has broad applications to other receptor systems.