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

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 beta (A beta) and its related molecules have failed, with the exception of aducanumab, an anti-A beta 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 A beta are correlated with AD pathogenesis. Moreover, A beta and tau pathologies initially proceed independently. At a certain point in the progression of AD symptoms, the A beta 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 A beta-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.

Automated summary

Alzheimer's disease is a neurodegenerative disease with increasing global prevalence, for which the etiology and pathological mechanisms are not yet clear. There are currently no definitive therapies available for AD, although targeting tau and A beta have shown promise as treatment approaches.