Immunotherapy in Systemic Primary (AL) Amyloidosis Using Amyloid-Reactive Monoclonal Antibodies

Abstract

Heretofore, treatment of patients with primary or light chain-associated (AL) amyloidosis has been directed toward reducing the synthesis of the amyloidogenic precursor protein through conventional or high-dose cytotoxic antiplasma cell chemotherapy. Although such efforts have extended survival, most often the prognosis remains exceedingly poor due to the persistence (or progression) of the pathologic deposits. The development of murine amyloid-reactive monoclonal antibodies (mAbs) has provided another therapeutic approach; namely, passive immunotherapy. These reagents, prepared against human light chain-related fibrils, recognize an epitope common to the β-pleated structure of AL and other types of amyloid proteins and can effect rapid amyloidolysis when administered to mice injected with human AL amyloid extracts. One such prototypic antibody, the IgG1κ mAb 11-1F4, has now been chimerized and is undergoing GMP production for an eventual phase I and II clinical trial in patients with AL amyloidosis. Demonstration of the therapeutic efficacy of this amyloid-reactive mAb would provide an important proof-of-principle that this form of immunotherapy also could benefit individuals with other types of inherited or acquired amyloid-associated disease.