Amyloid Targeting CAR Macrophage Therapy Against AL Amyloidosis

Description

Amyloid light chain (AL) amyloidosis is an incurable rare monoclonal plasma cell dyscrasia closely related to multiple myeloma. The clonal plasma cells produce excessive misfolded monoclonal immunoglobulin light chains, forming extracellular insoluble fibrils, destroying tissue architecture, causing functional organ damage, and eventually leading to death. Current chemotherapies only target clonal plasma cells to suppress the synthesis of new amyloidogenic light chains, however, the already formed fibrillar deposits are not affected and keep causing persistent organ damage. Therefore, direct fibrillar targeting therapy is urgently needed to resolve the amyloid deposit and cure this ultimately fatal disease. We designed amyloid-targeting chimeric antigen receptors (CARs) engineered macrophage therapy to induce amyloid fibril deposit-specific macrophage recruitment and phagocytosis for amyloid clearance. We have successfully built a first-generation AL amyloid-specific CAR macrophage which selectively engulfed AL amyloid fibrils in vitro detected by pHrodo red fluorescence-based phagocytosis assay. We hereby propose to further improve the anti-amyloid CAR-M design with additional costimulatory signaling domains and optimized culture conditions and validate the in vivo AL amyloid targeting and clearance of the amyloid-specific CAR macrophages in a humanized AL amyloidosis mice model.