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Germline humanization of a murine Aβ antibody and crystal structure of the humanized recombinant Fab fragment
Author(s) -
Robert Remy,
Streltsov Victor A.,
Newman Janet,
Pearce Lesley A.,
Wark Kim L.,
Dolezal Olan
Publication year - 2010
Publication title -
protein science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.353
H-Index - 175
eISSN - 1469-896X
pISSN - 0961-8368
DOI - 10.1002/pro.312
Subject(s) - humanized antibody , peptide , antibody , epitope , monoclonal antibody , recombinant dna , chemistry , conformational epitope , microbiology and biotechnology , immunotherapy , p3 peptide , amyloid precursor protein , biochemistry , biology , gene , alzheimer's disease , medicine , immunology , disease , immune system , pathology
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 ( 3 EFRH 6 ) 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.