Article

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

AC Immune SA, 1015 Lausanne, Switzerland.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 07/2012; 32(28):9677-89. DOI: 10.1523/JNEUROSCI.4742-11.2012
Source: PubMed

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.

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    • "The study aims to test patients 30 years and older using Genetech's Crenezumab mAb. This antibody interacts with multiple species of Ab (Adolfsson et al., 2012). The effector function of Crenezumab is reduced by using a IgG4 backbone. "
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    • "Activation of FcγR can result in a pro-inflammatory response including the release of cytokines and other mediators (Carbone et al., 2013). Experimental models of AD and observations from clinical trials have provided evidence that activating FcγRs may be responsible for the activation of microglia following immunotherapy, and the associated side effects (Wilcock et al., 2006; Adolfsson et al., 2012; Freeman et al., 2012). There are a number of inflammatory changes within the CNS during ageing, which are further affected by AD, including increased expression of all FcγRs on microglial cells and/or perivascular macrophages (Peress et al., 1993; Cribbs et al., 2012). "
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    • "Furthermore, TREM2 overexpression in the brain of APPswe/PS1dE9 mice significantly attenuated neuronal and synaptic losses, which was accompanied by an improvement in spatial cognitive function. The neurotoxicity of Ab and proinflammatory cytokines led to the neuronal and synaptic damage in cellular and animal models of AD (Calkins and Reddy, 2011; Gouras et al, 2010; Kapadia and Sakic, 2011), which could be effectively prevented by Ab-targeting therapy or anti-inflammatory treatment (Adolfsson et al, 2012; Varvel et al, 2009). On consideration of this evidence, the attenuation of neuronal and synaptic losses by TREM2 overexpression was likely attributed to the amelioration of Ab neuropathology and neuroinflammation in this scenario. "
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