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- Title
An Effector-Reduced Anti-&bgr;-Amyloid (A&bgr;) Antibody with Unique A&bgr; Binding Properties Promotes Neuroprotection and Glial Engulfment of A&bgr;.
- Authors
Adolfsson, Oskar; Pihlgren, Maria; Toni, Nicolas; Varisco, Yvan; Buccarello, Anna Lucia; Antoniello, Katia; Lohmann, Sophie; Piorkowska, Kasia; Gafner, Valerie; Atwal, Jasvinder K.; Maloney, Janice; Chen, Mark; Gogineni, Alvin; Weimer, Robby M.; Mortensen, Deborah L.; Friesenhahn, Michel; Ho, Carole; Paul, Robert; Pfeifer, Andrea; Muhs, Andreas
- Abstract
Passive immunization against&bgr;-amyloid (A&bgr;) 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 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&bgr; 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 A&bgr;, protected against A&bgr;1- 42 oligomer-induced cytotoxicity, and increased uptake of neurotoxic A&bgr; 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&bgr;,MABTshowed reduced activation of stress-activatedp38MAPK(p38 mitogen-activated protein kinase) in microglia and induced less release of the proinflammatory cytokine TNF&agr;. We propose that a humanized IgG4 anti-A&bgr; antibody that takes advantage of a unique A&bgr; 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.
- Subjects
ALZHEIMER'S disease treatment; AMYLOID; IMMUNIZATION; FC receptors; IMMUNOGLOBULIN G; NEUROTOXIC agents; IMMUNOTHERAPY; EDEMA
- Publication
Journal of Neuroscience, 2012, Vol 32, Issue 28, p9677
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.4742-11.2012