Antibody capture of soluble Abeta does not reduce cortical Abeta amyloidosis in the PDAPP mouse.
BACKGROUND
In vivo administration of antibodies against the amyloid-beta (Abeta) peptide has been shown to reduce and reverse the progressive amyloidosis that develops in a variety of mouse models of Alzheimer's disease (AD). This work has been extended to clinical trials where subsequent autopsy cases of AD subjects immunized against Abeta showed similar reductions in parenchymal amyloid plaques, suggesting this approach to reduce neuropathology in man is feasible.


OBJECTIVE
Multiple hypotheses have been advanced to explain how anti-Abeta antibodies may lower amyloid burden. In this report, we compare approaches utilizing either plaque-binding or peptide-capturing anti-Abeta antibodies for effectiveness in reducing amyloidosis in a mouse model of AD.


METHODS
A plaque-binding monoclonal antibody (3D6) and an Abeta peptide-capturing monoclonal antibody (266) were compared in chronic treatment and prevention paradigms using a transgenic mouse model of AD. The effects of antibody therapy on plaque burden and plasma clearance of Abeta were investigated by quantitative imaging and clearance studies of intravenously injected (125)I-Abeta.


RESULTS
The plaque-binding antibody 3D6 was highly effective in either treatment or prevention of amyloidosis. In these studies, the peptide-capture antibody 266 showed no reduction in amyloidosis in either paradigm and showed trends towards increasing amyloidosis. Antibody 266 was also found to greatly prolong (>180-fold) the normally rapid peripheral clearance of Abeta, in contrast to that found with 3D6 (>24-fold).


CONCLUSIONS
Reversing and preventing Alzheimer's type amyloidosis is most effectively accomplished with anti-amyloid antibodies that avidly bind plaque.
Seubert
Peter
P
Elan Pharmaceuticals, Inc., South San Francisco, Calif. 94080, USA. Peter.Seubert@elan.com
Barbour
Robin
R
Khan
Karen
K
Motter
Ruth
R
Tang
Pearl
P
Kholodenko
Dora
D
Kling
Kristin
K
Schenk
Dale
D
Johnson-Wood
Kelly
K
Schroeter
Sally
S
Gill
Davinder
D
Jacobsen
J Steven
JS
Pangalos
Menelas
M
Basi
Guriqbal
G
Games
Dora
D
D016229:Amyloid beta-Peptides / Q000097:blood / Q000276:immunology*; D000686:Amyloidosis / Q000097:blood / Q000276:immunology* / Q000628:therapy; D000818:Animals; D000906:Antibodies / Q000378:metabolism / Q000627:therapeutic use*; D002540:Cerebral Cortex / Q000276:immunology* / Q000473:pathology; D005260:Female; D051379:Mice; D008822:Mice, Transgenic; D058225:Plaque, Amyloid / Q000276:immunology* / Q000473:pathology; D011485:Protein Binding / Q000276:immunology; D012995:Solubility
D016229:Amyloid beta-Peptides; D000906:Antibodies