Abeta targets of the biosimilar antibodies of Bapineuzumab, Crenezumab, Solanezumab in comparison to an antibody against N-truncated Abeta in sporadic Alzheimer disease cases and mouse models
Abeta targets of the biosimilar antibodies of Bapineuzumab, Crenezumab, Solanezumab in comparison to an antibody against N-truncated Abeta in sporadic Alzheimer disease cases and mouse models
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DOI：
10.1007/s00401-015-1489-x
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发表时间：
2015-11-01
影响因子：
12.7
通讯作者：
Bayer, Thomas A.
中科院分区：
文献类型：
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作者：
Bouter, Yvonne;Noguerola, Jose Socrates Lopez;Bayer, Thomas A.
Solanezumab和Crenezumab是两种针对β淀粉样蛋白（A β）的人源化抗体，目前正在多项临床试验中进行测试，用于预防阿尔茨海默病。然而，关于这些抗体的靶向作用正在进行科学讨论。在此，我们报告了Solanezumab、Crenezumab和Bapineuzumab生物类似药抗体在福尔马林固定、石蜡包埋组织和人新鲜冷冻组织中的免疫组织化学染色特征。此外，我们在不同的小鼠模型（包括5XFAD、Tg 4 -42、TBA 42、APP/PS1 KI、3xTg）中对人源化抗体的生物类似药版本进行了直接比较免疫组织化学分析。这些人源化抗体的染色模式显示出令人惊讶的相似特征。所有三种抗体都以类似的方式检测斑块、脑淀粉样血管病和神经元内A β。值得注意的是，Solanezumab显示出对斑块的强结合亲和力。我们还重申，Bapineuzumab不识别N-截短或修饰的A β，而Solanezumab和Crenezumab确实检测N-末端修饰的A β肽A β 4-42和焦谷氨酸A β 3-42。此外，我们将结果与特异性识别A β 4-42和焦谷氨酸A β 3-42但不识别全长A β 1-42的小鼠NT 4X抗体的染色模式进行了比较。与Solanezumab、Crenezumab和Bapineuzumab的生物类似药抗体相比，鼠NT 4X抗体显示出独特的靶向结合。NT 4X几乎不与人体组织中的淀粉样蛋白斑块发生交叉反应。然而，它确实可以检测人体组织中的脑淀粉样血管病。在阿尔茨海默病小鼠模型中，NT 4X检测神经元内A β和斑块，与人源化抗体相当。总之，生物仿制药抗体Solanezumab、Crenezumab和Bapineuzumab与淀粉样蛋白斑块强烈反应，这与NT 4X抗体形成对比，NT 4X抗体几乎不识别人体组织中的斑块。因此，NT 4X是第一种新型治疗性抗体。
Solanezumab and Crenezumab are two humanized antibodies targeting Amyloid-beta (A beta) which are currently tested in multiple clinical trials for the prevention of Alzheimer's disease. However, there is a scientific discussion ongoing about the target engagement of these antibodies. Here, we report the immunohistochemical staining profiles of biosimilar antibodies of Solanezumab, Crenezumab and Bapineuzumab in human formalin-fixed, paraffin-embedded tissue and human fresh frozen tissue. Furthermore, we performed a direct comparative immunohistochemistry analysis of the biosimilar versions of the humanized antibodies in different mouse models including 5XFAD, Tg4-42, TBA42, APP/PS1KI, 3xTg. The staining pattern with these humanized antibodies revealed a surprisingly similar profile. All three antibodies detected plaques, cerebral amyloid angiopathy and intraneuronal A beta in a similar fashion. Remarkably, Solanezumab showed a strong binding affinity to plaques. We also reaffirmed that Bapineuzumab does not recognize N-truncated or modified A beta, while Solanezumab and Crenezumab do detect N-terminally modified A beta peptides A beta 4-42 and pyroglutamate A beta 3-42. In addition, we compared the results with the staining pattern of the mouse NT4X antibody that recognizes specifically A beta 4-42 and pyroglutamate A beta 3-42, but not full-length A beta 1-42. In contrast to the biosimilar antibodies of Solanezumab, Crenezumab and Bapineuzumab, the murine NT4X antibody shows a unique target engagement. NT4X does barely cross-react with amyloid plaques in human tissue. It does, however, detect cerebral amyloid angiopathy in human tissue. In Alzheimer mouse models, NT4X detects intraneuronal A beta and plaques comparable to the humanized antibodies. In conclusion, the biosimilar antibodies Solanezumab, Crenezumab and Bapineuzumab strongly react with amyloid plaques, which are in contrast to the NT4X antibody that hardly recognizes plaques in human tissue. Therefore, NT4X is the first of a new class of therapeutic antibodies.