The development of amyloid subtype-specific CAR-phagocytes for AL Amyloidosis therapy

Description

Light chain (AL) amyloidosis is a fatal plasma cell disorder related to multiple myeloma, characterized by clonal plasma cells that produce excess misfolded immunoglobulin light chains—either the κ or λ subtype—which aggregate into amyloid fibrils, causing organ damage and ultimately leading to death. Current therapies targeting plasma cells can suppress further fibril production but do not eliminate existing deposits, which continue to cause organ damage. Monoclonal antibodies that specifically recognize amyloid fibrils are under clinical investigation for their ability to drive organ responses. Since antibody-mediated amyloid clearance relies on Fc-Fc receptor interactions to recruit phagocytes, we aimed to enhance this mechanism by engineering amyloid-targeting chimeric antigen receptor (CAR) phagocyte therapy. These CAR constructs direct effector cell engagement and phagocytosis specifically to amyloid deposits, enabling efficient amyloid clearance in tissues. Using CAR-engineered hematopoietic stem cells, we developed a scalable platform to generate CAR phagocytes. These cells demonstrated strong binding to AL amyloid and robust phagocytic activity in vitro, and significantly accelerated amyloid clearance in a humanized mouse model. Furthermore, we have developed novel monoclonal antibodies that specifically target λ light chain amyloid, which accounts for the majority of AL amyloidosis cases. In this proposal, we aim to advance subtype-specific CAR constructs and validate their in vivo efficacy in amyloid clearance. This personalized, subtype-directed approach holds promise for transforming AL amyloidosis treatment and addressing urgent clinical needs.