Abstract
Passive immunization against β-amyloid (Aβ) has become an increasingly desirable strategy as a therapeutic treatment for Alzheimer's disease (AD). However, traditional passive immunization approaches carry the risk of Fcγ 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-Aβ monoclonal antibody of an IgG4 isotype, known as MABT5102A (MABT). An IgG4 subclass was selected to reduce the risk of Fcγ receptor-mediated overactivation of microglia. MABT bound with high affinity to multiple forms of Aβ, protected against Aβ1-42 oligomer-induced cytotoxicity, and increased uptake of neurotoxic Aβ 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 Aβ, MABT showed reduced activation of stress-activated p38MAPK (p38 mitogen-activated protein kinase) in microglia and induced less release of the proinflammatory cytokine TNFα. We propose that a humanized IgG4 anti-Aβ antibody that takes advantage of a unique Aβ 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.
Publication types
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Clinical Trial, Phase I
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Multicenter Study
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Randomized Controlled Trial
MeSH terms
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Aged
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Aged, 80 and over
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Alzheimer Disease / blood
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Alzheimer Disease / immunology
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Alzheimer Disease / pathology
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Alzheimer Disease / therapy*
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Amyloid beta-Peptides / immunology*
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Amyloid beta-Peptides / metabolism
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Amyloid beta-Protein Precursor / genetics
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Animals
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Animals, Newborn
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CX3C Chemokine Receptor 1
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Cells, Cultured
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Cerebral Cortex / cytology
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Disease Models, Animal
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Dose-Response Relationship, Drug
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Dose-Response Relationship, Immunologic
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Double-Blind Method
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Enzyme-Linked Immunosorbent Assay
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Female
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Gene Expression Regulation / drug effects
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Gene Expression Regulation / genetics
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Gene Expression Regulation / immunology
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Green Fluorescent Proteins / genetics
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Hippocampus / cytology
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Humans
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Immunoglobulin G / metabolism
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Immunoglobulin G / pharmacology*
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Male
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Mice
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Mice, Transgenic
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Microglia / drug effects*
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Microglia / metabolism*
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Microscopy, Confocal
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Middle Aged
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Mutation / genetics
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Neurons / drug effects
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Neurons / metabolism
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Neuroprotective Agents / metabolism
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Neuroprotective Agents / pharmacology*
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Peptide Fragments / metabolism*
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Plaque, Amyloid / immunology
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Plaque, Amyloid / metabolism
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Plaque, Amyloid / pathology
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Presenilin-1 / genetics
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Protein Binding / drug effects
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Rats
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Rats, Sprague-Dawley
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Receptors, Chemokine / genetics
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Statistics, Nonparametric
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Time Factors
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Tumor Necrosis Factor-alpha / metabolism
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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Amyloid beta-Peptides
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Amyloid beta-Protein Precursor
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CX3C Chemokine Receptor 1
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Cx3cr1 protein, mouse
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Immunoglobulin G
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Neuroprotective Agents
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PSEN1 protein, human
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Peptide Fragments
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Presenilin-1
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Receptors, Chemokine
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Tumor Necrosis Factor-alpha
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amyloid beta-protein (1-42)
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Green Fluorescent Proteins
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p38 Mitogen-Activated Protein Kinases