Programmable Drug Control of Receptor Valency Modulates the Potency of Cell Therapeutics.

An increasing number of preclinical and clinical studies are exploring the use of receptor-engineered cells that can respond to disease states for the treatment of cancer, infectious disease, autoimmunity, and regeneration. However, receptor-based cell therapies, including chimeric antigen receptor (CAR), face many critical issues including target recognition escape, adverse side effects, and lack of in vivo control. Drug-controllable receptors offer a promising solution to overcome these issues through precise in vivo tuning of cells via enhanced sensing and therapeutic efficacy. Here we develop a novel class of modular and tunable receptors, termed valency-controlled receptors (VCRs), which can leverage customized small molecules to mediate cell signaling strength via controlled spatial clustering. We first develop DNA origami activated VCRs to demonstrate that receptor valency is a core mechanism that modulates immune cell activation. We design a series of customized valency-control ligands (VCLs) by transforming small molecule drugs into a multivalency format and modularly fusing VCR onto the CAR architecture. We demonstrate that VCL induction allows enhanced target sensitivity of engineered cells. Using medicinal chemistry, we develop programmable bioavailable VCL drugs to demonstrate that the VCR system enables drug-induced highly potent responses towards low antigen cancers in vitro and in vivo . Valency controlled receptors and customizable drug ligands provide a new synthetic biology platform to precisely tune engineered cell therapeutic potency, which can address existing safety and efficacy barriers in cell therapy.