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Review
. 2022 Feb 14;14(2):411.
doi: 10.3390/pharmaceutics14020411.

Delivery of Intravenously Administered Antibodies Targeting Alzheimer's Disease-Relevant Tau Species into the Brain Based on Receptor-Mediated Transcytosis

Toshihiko Tashima  1
Affiliations
Review

Delivery of Intravenously Administered Antibodies Targeting Alzheimer's Disease-Relevant Tau Species into the Brain Based on Receptor-Mediated Transcytosis

Toshihiko Tashima. Pharmaceutics. .

Abstract

Alzheimer's disease (AD) is a neurodegenerative disease that causes memory loss, cognitive decline, and eventually dementia. The etiology of AD and its pathological mechanisms remain unclear due to its complex pathobiology. At the same time, the number of patients with AD is increasing worldwide. However, no therapeutic agents for AD are currently available for definitive care. Several phase 3 clinical trials using agents targeting amyloid β (Aβ) and its related molecules have failed, with the exception of aducanumab, an anti-Aβ monoclonal antibody (mAb), clinically approved by the US Food and Drug Administration in 2021, which could be modified for AD drug development due to controversial approval. Neurofibrillary tangles (NFTs) composed of tau rather than senile plaques composed of Aβ are correlated with AD pathogenesis. Moreover, Aβ and tau pathologies initially proceed independently. At a certain point in the progression of AD symptoms, the Aβ pathology is involved in the alteration and spreading of the tau pathology. Therefore, tau-targeting therapies have attracted the attention of pharmaceutical scientists, as well as Aβ-targeting therapies. In this review, I introduce the implementations and potential of AD immunotherapy using intravenously administered anti-tau and anti-receptor bispecific mAbs. These cross the blood-brain barrier (BBB) based on receptor-mediated transcytosis and are subsequently cleared by microglia based on Fc-mediated endocytosis after binding to tau and lysosomal degradation.

Keywords: Alzheimer’s disease; Alzheimer’s disease-relevant tau species; anti-tau and anti-receptor bispecific monoclonal antibodies; drug delivery into the brain; immunotherapy; interactions between Aβ and tau; tau clearance in microglia; tau clearance in neurons; temporal-spatial pathological Aβ and tau distribution; transendothelium based on receptor-mediated transcytosis.

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Conflict of interest statement

The author declares no conflict of interest.

Figures

Figure 1
Figure 1
Structures of approved drugs and a tau imaging agent for Alzheimer’s disease.
Figure 2
Figure 2
Strategy used to eliminate tau species using anti-receptor and anti-tau bispecific monoclonal antibodies based on receptor-mediated endocytosis and lysosomal degradation in microglia to cure Alzheimer’s disease.
Figure 3
Figure 3
Schematic representation of the protein structures of tau.
Figure 4
Figure 4
Tau species enter the cells based on endocytosis such as receptor-mediated endocytosis.
Figure 5
Figure 5
Tau species in endosomes enter the recipient cells based on membrane fusion.
Figure 6
Figure 6
Amino acid sequence of human tau441 (2N4R). Lysines are shown in red and arginines are shown in light blue.
Figure 7
Figure 7
Tau in exosomes (40–100 nm in diameter) secreted from neurons.
Figure 8
Figure 8
Tau in ectosomes (50–1000 nm in diameter) secreted from the membrane of neurons, independently on the endolysosomal machinery.
Figure 9
Figure 9
Tau secreted from neurons based on the endolysosomal machinery.
Figure 10
Figure 10
Tau secreted from neurons through an unconventional non-vesicular mechanism.
Figure 11
Figure 11
Tau cell-to-cell transportation through tunneling nanotubes.
Figure 12
Figure 12
The structure of bispecific IgG against receptors and tau species.
Figure 13
Figure 13
Tau degradation by the ubiquitin-proteasome pathway through Fc receptor-mediated endocytosis in neurons using bispecific Abs against tau and receptors. TRIM21 stands for tripartite motif-containing protein 21.
Figure 14
Figure 14
Tau/pS422 species lysosomal degradation through membrane microdomain-mediated endocytosis in neurons using bispecific Abs against tau/pS422 and receptors.
Figure 15
Figure 15
Structures of neurodegenerative disease modulators.
See this image and copyright information in PMC

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