Development and characterization of chimeric antigen receptor macrophages for amyloid clearance

Systemic amyloidosis is a protein folding disorder characterized by the extracellular deposition of protein fibrils in tissues and vital organs, leading to dysfunction and mortality. While there are monoclonal antibody-based therapies that promote cell-mediated amyloid clearance in various stages of clinical development, there are currently no treatment options which focus on reducing the tissue amyloid burden. Therefore, the urgent need for a transformative approach to facilitate amyloid clearance and restore organ function remains paramount. We demonstrate that a short, polybasic peptide (p5) can serve as a versatile recognition motif for chimeric antigen receptors in macrophages, enabling pan-amyloid binding and uptake. By comparing CH2- and CH3-spacer designs, quantifying glycan interactions, and establishing opsonization- and complement-dependent enhancement, we provide a blueprint for peptide-targeted CAR-M engineering beyond conventional scFv recognition. These findings broaden the repertoire of CAR targeting strategies and motivate translational studies of CAR-M for systemic amyloidosis, where established fibrils persist despite precursor-lowering therapies.