An Effector-Reduced Anti-β-Amyloid (Aβ) Antibody with Unique Aβ Binding Properties Promotes Neuroprotection and Glial Engulfment of Aβ
An Effector-Reduced Anti-β-Amyloid (Aβ) Antibody with Unique Aβ Binding Properties Promotes Neuroprotection and Glial Engulfment of Aβ
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DOI：
10.1523/jneurosci.4742-11.2012
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发表时间：
2012-07-11
影响因子：
5.3
通讯作者：
Watts, Ryan J.
中科院分区：
文献类型：
--
作者：
Adolfsson, Oskar;Pihlgren, Maria;Watts, Ryan J.
针对β-淀粉样蛋白（A β）的被动免疫已经成为阿尔茨海默病（AD）治疗性治疗的一种越来越理想的策略。然而，传统的被动免疫方法存在Fc γ受体介导的小胶质细胞过度活化的风险，这可能导致不适当的促炎反应，导致血管源性水肿和脑微出血。在这里，我们描述了IgG 4同种型的人源化抗A β单克隆抗体的产生，称为MABT 5102 A（MABT）。选择IgG 4亚类以降低Fc γ受体介导的小胶质细胞过度活化的风险。MABT以高亲和力结合多种形式的A β，保护免受A β 1-42寡聚体诱导的细胞毒性，并增加小胶质细胞对神经毒性A β寡聚体的摄取。此外，在hAPP（（V717 I））/PS1转基因小鼠中使用体内活体成像证实MABT介导的淀粉样斑块去除。当与人IgG 1野生型亚类（含有相同的抗原结合可变结构域且与A β具有相等的结合力）相比时，MABT显示小胶质细胞中应激激活的p38 MAPK（p38丝裂原激活蛋白激酶）的激活减少，并诱导促炎细胞因子TNF α的释放减少。我们提出，人源化IgG 4抗A β抗体利用独特的A β结合特性，同时还具有降低的效应子功能，可以为AD的被动免疫治疗提供更安全的治疗替代方案。来自一项测试MABT的I期临床试验的数据与这一假设一致，显示即使在ApoE 4携带者中也没有血管源性水肿的迹象。
Passive immunization against beta-amyloid (A beta) 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 gamma 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 beta monoclonal antibody of an IgG4 isotype, known as MABT5102A(MABT). An IgG4 subclass was selected to reduce the risk of Fc gamma receptor-mediated overactivation of microglia. MABT bound with high affinity to multiple forms of A beta, protected against A beta 1-42 oligomer-induced cytotoxicity, and increased uptake of neurotoxic A beta 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 beta, MABT showed reduced activation of stress-activated p38MAPK(p38 mitogen-activated protein kinase) in microglia and induced less release of the proinflammatory cytokine TNF alpha. We propose that a humanized IgG4 anti-A beta antibody that takes advantage of a unique A beta 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.