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

Remy Robert, Victor A Streltsov, Janet Newman, Lesley A Pearce, Kim L Wark, Olan Dolezal

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23 Citations (Scopus)

Abstract

Alzheimer s disease is the most common form of dementia, affecting 26 million people worldwide. The Abeta 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 ((3)EFRH(6)) in the Abeta 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 Abeta peptide and therefore is a potential candidate for passive immunotherapy of Alzheimer s disease.
Original languageEnglish
Pages (from-to)299 - 308
Number of pages10
JournalProtein Science
Volume19
Issue number2
DOIs
Publication statusPublished - 2010
Externally publishedYes

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