Abstract
The success of the targeting of amyloid-β (Aβ) 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-Aβ 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 Aβ peptide-containing neurons in the early phase post-injection, and was colocalized with the Aβ peptide almost exclusively in glial cells in the late phase post-injection. Aβ peptide levels in the brain decreased simultaneously with an increase in scFv-h3D6 levels. This observation in addition to the increased tumor necrosis factor-α levels in the late phase post-injection suggested that the engulfment of Aβ peptide/scFv-h3D6 complex extruded from large neurons by phagocytic cells was the mechanism underlying Aβ peptide withdrawal. The mechanism of action of scFv-h3D6 demonstrates the effectivity of Aβ-immunotherapy and lays the background for other studies focused on the finding of a treatment for AD.
Highlights
The beneficial effects of a single intraperitoneal injection of 100 μg single-chain variable fragment (scFv)-h3D6 have already been demonstrated in young 3xTg-Alzheimer’s disease (AD) female mice [27,28,29]
We analyzed the pharmacokinetic parameters of scFv-h3D6 by studying variations in the plasma concentrations of the original version of the molecule and its elongated and thermodynamically more stable version [24,26]
Specific immunostaining is the most suitable methodology to classify cell types, we are confident that glial cells are actual because we previously showed them by glial fibrillary acidic protein (GFAP) and ionized calcium binding adaptor molecule 1 (Iba1) immunostaining [38]
Summary
The currently available therapies for Alzheimer’s disease (AD) include the use of cholinesterase inhibitors (donepezil, galantamine, and rivastigmine) that partially compensate the pathological reduction in acetylcholine and an NMDA receptor antagonist (memantine) that prevents. The effect of the increased glutamate levels in the synaptic cleft [1] Because these treatments palliate the symptoms of AD rather than targeting its underlying causes, the implementation of novel therapeutic strategies has become a necessity [2]. Solanezumab (Eli Lilly), albeit resulted safe, showed a benefit that was not higher than that associated with the palliative acetylcholinesterase inhibitors drugs, and the studies were terminated [12]. This has recently been the case for aducanumab (Biogen Idec) [13]. ScFv-h3D6 has been incorporated with different mutations to enhance its thermodynamic stability for improving its pharmacokinetic parameters and its therapeutic effect [25]. ScFv-h3D6 pharmacokinetics and mechanism of action containing these molecules as well as its effect on tumor necrosis factor- α (TNF-α) levels were examined to determine the mechanism of action of scFv-h3D6
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.