Receptor-mediated abeta amyloid antibody targeting to Alzheimer's disease mouse brain.
Receptor-mediated abeta amyloid antibody targeting to Alzheimer's disease mouse brain.
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DOI：
10.1021/mp1003515
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发表时间：
2011-02-07
影响因子：
4.9
通讯作者：
Pardridge WM
中科院分区：
文献类型：
--
作者：
Zhou QH;Fu A;Boado RJ;Hui EK;Lu JZ;Pardridge WM
这项工作的目的是减少阿尔茨海默病（AD）转基因小鼠脑中的A β淀粉样肽负荷，而不伴随血浆A β淀粉样肽的升高。抗A β淀粉样蛋白抗体（AAA）被重新设计为与血脑屏障（BBB）分子特洛伊木马的融合蛋白。将AAA改造为单链抗体（ScFv），并将ScFv与针对小鼠转铁蛋白受体（TfR）的嵌合单克隆抗体（MAb）的重链融合，并且将该融合蛋白命名为cTfRMAb-ScFv。cTfRMAb-ScFv蛋白通过在BBB TfR上的转运从血液渗透小鼠脑，并且在静脉内施用后脑摄取为注射剂量/克脑的3.5%。在12月龄时研究双转基因APPswe、PSEN 1dE 9小鼠。基于免疫细胞化学，显示小鼠在大脑皮层中具有广泛的A β淀粉样蛋白斑块。每3-4天通过静脉内注射盐水或注射剂量为lmg/kg的cTfRMAb-ScFv融合蛋白治疗小鼠，连续12周。在融合蛋白处理的小鼠中，脑Aβ1-42浓度降低40%，而血浆Aβ1-42浓度没有任何升高。在给药小鼠中未观察到脑微出血。这些结果表明，脑穿透抗体药剂可以开发用于脑疾病，如AD后，抗体的再工程改造为融合蛋白，通过受体介导的运输，运输通过BBB。
The goal of this work is the reduction in the Abeta amyloid peptide burden in brain of Alzheimer’s disease (AD) transgenic mice without the concomitant elevation in plasma Abeta amyloid peptide. An anti-Abeta amyloid antibody (AAA) was re-engineered as a fusion protein with a blood-brain barrier (BBB) molecular Trojan horse. The AAA was engineered as a single chain Fv (ScFv) antibody, and the ScFv was fused to the heavy chain of a chimeric monoclonal antibody (MAb) against the mouse transferrin receptor (TfR), and this fusion protein was designated cTfRMAb-ScFv. The cTfRMAb-ScFv protein penetrates mouse brain from blood via transport on the BBB TfR, and the brain uptake is 3.5 % of injected dose/gram brain following an intravenous administration. Double transgenic APPswe,PSEN1dE9 mice were studied at 12 months of age. The mice were shown to have extensive Abeta amyloid plaques in cerebral cortex based on immunocytochemistry. The mice were treated every 3–4 days by intravenous injections of either saline or the cTfRMAb-ScFv fusion protein at an injection dose of 1 mg/kg for 12 consecutive weeks. The brain Aβ1–42 concentration was reduced 40% in the fusion protein treated mice, without any elevation in plasma Aβ1–42 concentration. No cerebral micro-hemorrhage was observed in the treated mice. These results show that brain-penetrating antibody pharmaceutics can be developed for brain disorders such as AD following the re-engineering of the antibody as a fusion protein that is transported across the BBB via receptor-mediated transport.
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影响因子：
3.8
作者：
Boado, Ruben J.;Zhang, Yun;Wang, Yuntao;Pardridge, William M.
通讯作者：
Pardridge, William M.
DOI：
10.1016/s0006-291x(84)80190-4
发表时间：
1984-01-01
影响因子：
3.1
作者：
GLENNER, GG;WONG, CW
通讯作者：
WONG, CW
影响因子：
4.8
作者：
Hinton, PR;Johlfs, MG;Tsurushita, N
通讯作者：
Tsurushita, N
影响因子：
120.7
作者：
Näslund, J;Haroutunian, V;Buxbaum, JD
通讯作者：
Buxbaum, JD
影响因子：
6
作者：
Janelsins, Michelle C.;Mastrangelo, Michael A.;Bowers, William J.
通讯作者：
Bowers, William J.