Abstract:
:Several different monoclonal antibodies (mAbs) have been actively developed in the field of Alzheimer's disease (AD) for basic science and clinical applications; however, the binding kinetics of many of the mAbs with the beta-amyloid peptides (Abeta) are poorly understood. A panel of mAbs with different Abeta recognition sites, including our plaque-binding antibody (IgG4.1), a peptide-capturing antibody (11A50), and two classical mAbs (6E10 and 4G8) used for immunohistochemistry, were chosen for characterization of their kinetics of binding to monomeric and fibrillar forms of Abeta40 using surface plasmon resonance and their amyloid plaque binding ability in AD mouse brain sections using immunohistochemistry. The plaque-binding antibody (IgG4.1) with epitope specificity of Abeta(2-10) showed a weaker affinity (512 nM) for monomeric Abeta40 but a higher affinity (1.5 nM) for Abeta40 fibrils and labeled dense core plaques better than 6E10 as determined by immunohistochemistry. The peptide-capturing antibody (11A50) showed preferential affinity (32.5 nM) for monomeric Abeta40 but did not bind to Abeta40 fibrils, whereas antibodies 6E10 and 4G8 had moderate affinity for monomeric Abeta40 (22.3 and 30.1 nM, respectively). 4G8, which labels diffuse plaques better than 6E10, had a higher association rate constant than 6E10 but showed similar association and dissociation kinetics compared to those of 11A50. Enzymatic digestion of IgG4.1 to the F(ab')(2)4.1 fragments or their polyamine-modified derivatives that enhance blood-brain barrier permeability did not affect the kinetic properties of the antigen binding site. These differences in kinetic binding to monomeric and fibrillar Abeta among various antibodies could be utilized to distinguish mAbs that might be useful for immunotherapy or amyloid plaque imaging versus those that could be utilized for bioanalytical techniques.
journal_name
Biochemistryjournal_title
Biochemistryauthors
Ramakrishnan M,Kandimalla KK,Wengenack TM,Howell KG,Poduslo JFdoi
10.1021/bi900523qsubject
Has Abstractpub_date
2009-11-03 00:00:00pages
10405-15issue
43eissn
0006-2960issn
1520-4995journal_volume
48pub_type
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