An Effector-Reduced Anti- -Amyloid (A) Antibody with Unique A Binding Properties Promotes Neuroprotection and Glial Engulfment of A

Jul 13, 2012The Journal of neuroscience : the official journal of the Society for Neuroscience

A modified anti-amyloid antibody with special binding helps protect brain cells and boosts support cell clearance of amyloid

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Abstract

A humanized anti-β-amyloid monoclonal antibody, MABT5102A (MABT), exhibits a safer profile with no signs of vasogenic edema in a phase I clinical trial.

MABT binds with high affinity to various forms of β-amyloid (Aβ).
It protects against cytotoxicity induced by Aβ1-42 oligomers.
MABT increases the uptake of neurotoxic Aβ oligomers by microglia.
In vivo imaging in transgenic mice demonstrated MABT-mediated removal of amyloid plaques.
Compared to a human IgG1 subclass, MABT showed reduced activation of stress-related pathways in microglia.
MABT induced less release of the proinflammatory cytokine TNFα.

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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.

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An Effector-Reduced Anti- -Amyloid (A) Antibody with Unique A Binding Properties Promotes Neuroprotection and Glial Engulfment of A

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