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

2012; Society for Neuroscience; Volume: 32; Issue: 28 Linguagem: Inglês

10.1523/jneurosci.4742-11.2012

1529-2401

Oskar Adolfsson, Maria Pihlgren, Nicolas Toni, Yvan Varisco, Anna Lucia Buccarello, Katia Antoniello, Sophie Lohmann, Katarzyna Piórkowska, Valérie Gafner, Jasvinder K. Atwal, Janice Maloney, Mark Chen, Alvin Gogineni, Robby M. Weimer, Deborah L. Mortensen, Michel Friesenhahn, Carole Ho, Robert Paul, Andrea Pfeifer, A. Muhs, Richard J. Watts,

Glycosylation and Glycoproteins Research

Passive immunization against β-amyloid (Aβ) has become an increasingly desirable strategy as a therapeutic treatment for Alzheimer9s 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.