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 ( BR idged A ctivation by I ntra/intermolecular D ivision) 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/β-catenin signaling system, demonstrating that a multivalent WNT agonist molecule divided into two inactive components assembled from different epitopes via the hepatocyte receptor βKlotho 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.
Competing Interests: HC, SL, NS, TS, CL, YP The authors are current full-time employees and shareholders of Surrozen, Inc, RL, AS, AD, YP, MV The authors were former full-time employees and shareholders of Surrozen, Inc, YL The author is a current full-time employee and shareholder of Surrozen, Inc. YL is Executive Vice President of Research at Surrozen, Inc
(© 2023, Chen, Lee et al.)