Article
Kim L. Wark and Olan Dolezal contributed equally to this work.
Received: 23 October 2009; Revised: 26 November 2009; Accepted: 30 November 2009
10.1002/pro.312 About DOI
Germline humanization of a murine A  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 |
| CSIRO Molecular and Health Technologies, 343 Royal Parade, Parkville, Victoria 3052, Australia |
| email: Remy Robert (remy.robert@csiro.au) |
*Correspondence to Remy Robert, CSIRO Molecular and Health Technologies, 343 Royal Parade, Parkville, Victoria 3052, Australia
Kim L. Wark and Olan Dolezal contributed equally to this work.| Keywords |
| antibody engineering humanization SPR crystal structure Alzheimer's disease |
| Abstract |
Alzheimer's disease is the most common form of dementia, affecting 26 million people worldwide. The A 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 A 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 A peptide and therefore is a potential candidate for passive immunotherapy of Alzheimer's disease. |
Received: 23 October 2009; Revised: 26 November 2009; Accepted: 30 November 2009
| Digital Object Identifier (DOI) |
10.1002/pro.312 About DOI
