Development of anti-amyloid fibril-reactive monoclonal antibodies for treatment of AL amyloidosis
Al Amyloidosis is characterized by the pathologic deposition of light chain fibrils in vital organs that leads to their eventually failure and, ultimately, results in death. All established therapies in amyloidosis focus on the destruction of plasma cells and subsequently the stop of the production of light chains forming the amyloid. Hence new accumulation of amyloid will be prohibited, but unfortunately existing amyloid will not be affected by the treatment resulting in continuous impairment of the organ function. Immunotherapy using monoclonal antibodies targeting directly the amyloid fibrills and subsequently destroying the existing amyloid is a very innovative and exciting approach. The amyloid fibril-reactive monoclonal antibody (mAb) 11-1F4 binds to a structure only present on human light-chain amyloid fibrils and initiates cell-mediated phagocytosis. In our ongoing Phase 1a/b clinical trial at Columbia University Medical Center, chimeric IgG1 11-1F4 (Ch 11-1F4)mAb shows amyloidolysis in 67% of patients. Antibody-dependent phagocytosis is a major mechanism of action of many antibodies against cancer through the interaction between Fc region on antibodies with its receptors on the macrophage surface. Macrophage and neutrophil mediated phagocytosis is a critical step for amyloid elimination as confirmed by in vivo studies. Therfore our research focuses on the development of bispecific antibodies, which target well-identified macrophage/neutrophil cell surface markers as well as AL Amyloid, to further enhance amyloid elimination. The use of antibody immunotherapy aiming at reversing fibril deposition will result in a more favorable outcome due to improved organ function, as compared to chemotherapy which only targets the amyloid-precursor producing plasma cell clone.