Pharmacokinetic parameters and mechanism of action of an efficient anti-Aβ single chain antibody fragment
Pharmacokinetic parameters and mechanism of action of an efficient anti-Aβ single chain antibody fragment
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DOI：
10.1371/journal.pone.0217793
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发表时间：
2019-05-31
期刊：
影响因子：
3.7
通讯作者：
Villegas, Sandra
中科院分区：
文献类型：
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作者：
Esquerda-Canals, Gisela;Marti-Clua, Joaquim;Villegas, Sandra
通过免疫治疗在阿尔茨海默病(AD)小鼠模型中靶向淀粉样β蛋白(Aβ)寡聚体的成功尚未转化为临床。已提出使用单链可变区(ScFv)来阻止可结晶组分介导的小胶质细胞激活，从而防止全长mAbs潜在的严重影响。Bapineuzumab衍生的抗Aβ单链抗体scFv-h3D6的有效性已被广泛证明。在这项工作中，我们将scFv-h3D6-EL-scFv-h3D6-EL与其原始版本进行了比较，以评估其较高的热力学稳定性是否改善了其药代动力学参数。虽然ScFv-h3D6-EL的半衰期比原始版本长，但其从腹膜腔到全身的吸收却低于原始版本。此外，我们还试图确定scFv-h3D6保护作用的机制。我们发现scFv-h3D6呈室内分布，更有趣的是它跨越了血脑屏障。在脑内，ScFv-h3D6在注射后早期被胶质细胞吞噬或被含Aβ肽的神经元内化，在注射后晚期几乎完全与Aβ肽共定位于神经胶质细胞。脑内Aβ多肽水平下降，同时scFv-h3D6水平上升。这一观察结果，加上注射后晚期肿瘤坏死因子-α水平的升高，表明吞噬细胞吞噬从大神经元中排出的Aβ肽/ScFv-h3D6复合体是Aβ肽退出的机制。ScFv-h3D6的作用机制证明了Aβ免疫治疗的有效性，并为其他专注于AD治疗的研究奠定了基础。
The success of the targeting of amyloid-beta (A beta) oligomers through immunotherapy in Alzheimer's disease (AD) mouse models has not been translated into the clinics. The use of single-chain variable fragments (scFvs) has been proposed to prevent the potential severe effects of full-length mAbs by precluding crystallizable fraction-mediated microglia activation. The efficacy of scFv-h3D6, a bapineuzumab-derived anti-A beta scFv, has been extensively proven. In this work, we compared scFv-h3D6-EL, an elongated variant of the scFv-h3D6, with its original version to assess whether its characteristic higher thermodynamic stability improved its pharmacokinetic parameters. Although scFv-h3D6-EL had a longer half-life than its original version, its absorption from the peritoneal cavity into the systemic compartment was lower than that of the original version. Moreover, we attempted to determine the mechanism underlying the protective effect of scFv-h3D6. We found that scFv-h3D6 showed compartmental distribution and more interestingly crossed the blood-brain barrier. In the brain, scFv-h3D6 was engulfed by glial cells or internalized by A beta peptide-containing neurons in the early phase post-injection, and was colocalized with the A beta peptide almost exclusively in glial cells in the late phase post-injection. A beta peptide levels in the brain decreased simultaneously with an increase in scFv-h3D6 levels. This observation in addition to the increased tumor necrosis factor-a levels in the late phase post-injection suggested that the engulfment of A beta peptide/scFv-h3D6 complex extruded from large neurons by phagocytic cells was the mechanism underlying A beta peptide withdrawal. The mechanism of action of scFv-h3D6 demonstrates the effectivity of A beta-immunotherapy and lays the background for other studies focused on the finding of a treatment for AD.