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


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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    ABSTRACT: Alzheimer's disease (AD) is the most prevalent form of dementia worldwide and is an emerging global epidemic. It is characterized by an imbalance between production and clearance of amyloid β (Aβ) and tau proteins. Oligomeric forms of Aβ and tau are believed to be the most toxic. Dramatic results from AD animal models showed great promise for active and passive immune therapies targeting Aβ. However, there is very limited evidence in human studies of the clinical benefits from these approaches. Immunotherapies targeting only tau pathology have had some success but are limited so far to mouse models. The majority of current methods is based on immunological targeting of a self-protein; hence, benefits need to be balanced against risks of stimulating excessive autoimmune toxic inflammation. For greater efficacy the next generation of vaccines needs to focus more on concurrently targeting all the intermediate toxic conformers of oligomeric Aβ and tau species. Copyright © 2015 Elsevier Inc. All rights reserved.
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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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    ABSTRACT: Triggering receptor expressed on myeloid cells 2 gene (TREM2) is a recently identified susceptibility gene for Alzheimer's disease (AD), since its low-frequency variants increase the risk of this disease with an odds ratio similar to that of one APOE ɛ4 allele. To date, the expression and biological functions of TREM2 under AD context remain largely unknown. Using APPswe/PS1dE9 mice, a transgenic model of AD, we showed that TREM2 was up-regulated in microglia during disease progression. For the first time, we provided in vitro and in vivo evidence that this up-regulation was attributed to the increased amyloid-β (Aβ) 1-42 levels in brain. By knockdown and overexpression of TREM2 in cultured primary microglia, we revealed that TREM2 modulated microglial functions under AD context, as it facilitated Aβ1-42 phagocytosis and inhibited Aβ1-42-triggered pro-inflammatory responses. Meanwhile, this modulation was depended on DAP12, the adapter protein of TREM2. More importantly, overexpression of TREM2 in brain of APPswe/PS1dE9 mice markedly ameliorated AD-related neuropathology including Aβ deposition, neuroinflammation and neuronal and synaptic losses, which was accompanied by an improvement in spatial cognitive functions. Taken together, our data suggest that the up-regulation of TREM2 serves as a compensatory response to Aβ1-42 and subsequently protects against AD progression via modulation of microglia functions. These findings provide insights into the role of TREM2 in AD pathogenesis, and highlight TREM2 as a potential therapeutic target for this disease.Neuropsychopharmacology accepted article preview online, 22 July 2014; doi:10.1038/npp.2014.164.
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