Gantenerumab: A Novel Human Anti-Aβ Antibody Demonstrates Sustained Cerebral Amyloid-β Binding and Elicits Cell-Mediated Removal of Human Amyloid-β
Gantenerumab: A Novel Human Anti-Aβ Antibody Demonstrates Sustained Cerebral Amyloid-β Binding and Elicits Cell-Mediated Removal of Human Amyloid-β
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DOI：
10.3233/jad-2011-110977
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发表时间：
2012-01-01
影响因子：
4
通讯作者：
Loetscher, Hansruedi
中科院分区：
文献类型：
--
作者：
Bohrmann, Bernd;Baumann, Karlheinz;Loetscher, Hansruedi
在阿尔茨海默病(AD)的转基因模型和AD患者中，已证明抗Aβ抗体具有降低淀粉样β蛋白的能力。虽然免疫治疗去除淀粉样蛋白的机制存在争议，但抗体介导的外周Aβ与小胶质细胞吞噬活性和大脑淀粉样蛋白的分解(或两者的组合)的隔离已被提出。对于成功的Aβ免疫治疗，我们假设高亲和力抗体与淀粉样β蛋白斑块结合并募集脑效应细胞是最有效地清除淀粉样蛋白所必需的。在这里，我们报道了一种新型的全人抗Aβ抗体Gantenerumab的产生，该抗体在体外进行了优化，利用HuCal(R)噬菌体展示技术以亚纳摩尔亲和力与表达在淀粉样β纤维上的构象表位结合。在肽图中，Aβ的N末端和中心部分均可被甘特纳单抗识别。值得注意的是，通过对Gantenerumab Fab-Aβ(1-11)复合体的X射线分析，确定了N-末端Aβ与互补决定区结合的新方向。在功能分析中，当Gantenerumab与原代人类巨噬细胞共同培养时，Gantenerumab诱导AD脑片中人淀粉样β沉积的细胞吞噬，并中和寡聚体Aβ(42)介导的对大鼠大脑长时程增强的抑制作用。在APP751(瑞典)xPS2(N141I)转基因小鼠中，Gantenerumab显示出持续与脑淀粉样β蛋白结合，在慢性治疗时，通过招募小胶质细胞显著减少小的淀粉样β蛋白斑块，并防止新的斑块形成。与其他Aβ抗体不同，Gantenerumab不改变血浆Aβ，提示未受干扰的全身清除可溶性Aβ。这些研究表明，Gantenerumab优先与大脑中聚集的Aβ相互作用，并通过诱导效应细胞介导的清除来降低淀粉样β蛋白。
The amyloid-beta lowering capacity of anti-A beta antibodies has been demonstrated in transgenic models of Alzheimer's disease (AD) and in AD patients. While the mechanism of immunotherapeutic amyloid-beta removal is controversial, antibody-mediated sequestration of peripheral A beta versus microglial phagocytic activity and disassembly of cerebral amyloid (or a combination thereof) has been proposed. For successful A beta immunotherapy, we hypothesized that high affinity antibody binding to amyloid-beta plaques and recruitment of brain effector cells is required for most efficient amyloid clearance. Here we report the generation of a novel fully human anti-A beta antibody, gantenerumab, optimized in vitro for binding with sub-nanomolar affinity to a conformational epitope expressed on amyloid-beta fibrils using HuCAL (R) phage display technologies. In peptide maps, both N-terminal and central portions of A beta were recognized by gantenerumab. Remarkably, a novel orientation of N-terminal A beta bound to the complementarity determining regions was identified by x-ray analysis of a gantenerumab Fab-A beta(1-11) complex. In functional assays gantenerumab induced cellular phagocytosis of human amyloid-beta deposits in AD brain slices when co-cultured with primary human macrophages and neutralized oligomeric A beta(42)-mediated inhibitory effects on long-term potentiation in rat brain. In APP751(swedish)xPS2(N141I) transgenic mice, gantenerumab showed sustained binding to cerebral amyloid-beta and, upon chronic treatment, significantly reduced small amyloid-beta plaques by recruiting microglia and prevented new plaque formation. Unlike other A beta antibodies, gantenerumab did not alter plasma A beta suggesting undisturbed systemic clearance of soluble A beta. These studies demonstrated that gantenerumab preferentially interacts with aggregated A beta in the brain and lowers amyloid-beta by eliciting effector cell-mediated clearance.