1F10, a λ Light Chain Amyloid-Specific Monoclonal Antibody for Targeted Therapy of AL Amyloidosis.

Light chain (AL) amyloidosis is a fatal plasma cell dyscrasia characterized by the overproduction of misfolded l or k immunoglobulin light chains (LCs) produced by clonal plasma cells, which aggregate into amyloid fibrils that deposit in tissues and cause progressive organ damage. While current anti-plasma cell therapies reduce the production of new amyloidogenic LCs, pre-existing fibrils persist and continue to drive organ damage. Amyloid-targeting monoclonal antibodies birtamimab and anselamimab were developed and tested for active AL amyloid clearance; however, they failed to meet the primary endpoint in Phase 3 trials, presumably due to insufficient binding affinity for l LC amyloid, which occurs in ~80% of patients. Here, we reported the development of 1F10, a novel high-affinity l subtype-specific amyloid-binding monoclonal antibody that does not cross-react with soluble native l or k LCs. 1F10 exhibits superior binding affinity to l AL amyloid fibrils and significantly enhances antibody-dependent phagocytosis (ADP) of l AL amyloid compared with birtamimab and anselamimab. Specific binding of 1F10 to l amyloid is confirmed by immunohistochemical staining of patient-derived tissue biopsies. Importantly, 1F10 demonstrates robust in vivo activity, significantly accelerating the resolution of l amyloid fibrils in an AL amyloidoma mouse model. Together, these findings establish 1F10 antibody as a promising subtype-specific immunotherapeutic candidate for targeting l LC amyloid, addressing a critical unmet need for the majority of patients with AL amyloidosis.