Artificial Internalizing Receptors for Targeted Degradation of Extracellular Proteins

Abstract Artificial internalizing receptors are developed, and it is demonstrated that these small organic molecules are powerful agents for capturing and removing the cognate protein of interest from the extracellular space. Toward the overall goal, a range of candidate receptor molecules is synthesized, and the leads are selected based on the highest efficacy of protein capture and internalization by the receptor‐engineered cells. Receptor performance is validated in model T lymphoblasts, donor‐derived peripheral blood mononuclear cells, and hepatocytes. The capture and depletion are achieved over successive additions of the extracellular target protein. In contrast to pan‐IgG degraders, artificial receptors depleted the one, cognate immunoglobulin, leaving the pool of non‐cognate proteins un‐altered. In an in vitro model system, mimicking hepatic removal of the target protein, receptor‐engineered scavenger hepatocytes captured the protein of interest and prevented its association with the cognate receptor on the responder lymphoblasts.