期刊
JOURNAL OF NEUROSCIENCE
卷 32, 期 28, 页码 9677-9689出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.4742-11.2012
关键词
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Passive immunization against beta-amyloid (A beta) has become an increasingly desirable strategy as a therapeutic treatment for Alzheimer's disease (AD). However, traditional passive immunization approaches carry the risk of Fc gamma receptor-mediated overactivation of microglial cells, which may contribute to an inappropriate proinflammatory response leading to vasogenic edema and cerebral microhemorrhage. Here, we describe the generation of a humanized anti-A beta monoclonal antibody of an IgG4 isotype, known as MABT5102A(MABT). An IgG4 subclass was selected to reduce the risk of Fc gamma receptor-mediated overactivation of microglia. MABT bound with high affinity to multiple forms of A beta, protected against A beta 1-42 oligomer-induced cytotoxicity, and increased uptake of neurotoxic A beta oligomers by microglia. Furthermore, MABT-mediated amyloid plaque removal was demonstrated using in vivo live imaging in hAPP((V717I))/PS1 transgenic mice. When compared with a human IgG1 wild-type subclass, containing the same antigen-binding variable domains and with equal binding to A beta, MABT showed reduced activation of stress-activated p38MAPK(p38 mitogen-activated protein kinase) in microglia and induced less release of the proinflammatory cytokine TNF alpha. We propose that a humanized IgG4 anti-A beta antibody that takes advantage of a unique A beta binding profile, while also possessing reduced effector function, may provide a safer therapeutic alternative for passive immunotherapy for AD. Data from a phase I clinical trial testing MABT is consistent with this hypothesis, showing no signs of vasogenic edema, even in ApoE4 carriers.
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