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Antibody Capture of Soluble Aβ Does Not Reduce Cortical Aβ Amyloidosis in the PDAPP Mouse

Seubert P.a · Barbour R.a · Khan K.a · Motter R.a · Tang P.a · Kholodenko D.a · Kling K.a · Schenk D.a · Johnson-Wood K.a · Schroeter S.a · Gill D.b · Jacobsen J.S.c · Pangalos M.c · Basi G.a · Games D.a
aElan Pharmaceuticals, Inc., South San Francisco, Calif., bWyeth, Wyeth Research, Cambridge, Mass., and cDiscovery Neuroscience, Wyeth Research, Princeton, N.J., USA Neurodegenerative Dis 2008;5:65–71 (DOI:10.1159/000112834)

Abstract

Background: In vivo administration of antibodies against the amyloid-β (Aβ) 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 Aβ 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-Aβ antibodies may lower amyloid burden. In this report, we compare approaches utilizing either plaque-binding or peptide-capturing anti-Aβ antibodies for effectiveness in reducing amyloidosis in a mouse model of AD. Methods: A plaque-binding monoclonal antibody (3D6) and an Aβ 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 Aβ were investigated by quantitative imaging and clearance studies of intravenously injected 125I-Aβ. 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 Aβ, in contrast to that found with 3D6 (>24-fold). Conclusion: Reversing and preventing Alzheimer’s type amyloidosis is most effectively accomplished with anti-amyloid antibodies that avidly bind plaque.

 

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