Germline humanization of a murine Aβ antibody and crystal structure of the humanized recombinant Fab fragment

Abstract

Alzheimer's disease is the most common form of dementia, affecting 26 million people worldwide. The Aβ peptide (39–43 amino acids) derived from the proteolytic cleavage of the amyloid precursor protein is one of the main constituents of amyloid plaques associated with disease pathogenesis and therefore a validated target for therapy. Recently, we characterized antibody fragments (Fab and scFvs) derived from the murine monoclonal antibody WO-2, which bind the immunodominant epitope (₃EFRH₆) in the Aβ peptide at the N-terminus. In vitro, these fragments are able to inhibit fibril formation, disaggregate preformed amyloid fibrils, and protect neuroblastoma cells against oligomer-mediated toxicity. In this study, we describe the humanization of WO-2 using complementary determining region loop grafting onto the human germline gene and the determination of the three-dimensional structure by X-ray crystallography. This humanized version retains a high affinity for the Aβ peptide and therefore is a potential candidate for passive immunotherapy of Alzheimer's disease.