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Alzheimer’s disease (AD) impacts more than half a million people worldwide, with no cure available. The regulatory approval of three anti-amyloid monoclonal antibodies (mAbs), including aducanumab, lecanemab, and donanemab, has established immunotherapy as a therapeutic approach to modify disease progression. Its multifactorial pathology, which involves amyloid-β (Aβ) plaques, tau neurofibrillary tangles, neuroinflammation, and cerebrovascular dysfunction, limits the efficacy of single-target therapies. The restricted blood–brain barrier (BBB) penetration and amyloid-related imaging abnormalities (ARIA), together with small treatment effects, demonstrate the necessity for advanced biologic therapies. Protein engineering advancements have created bispecific antibodies that bind to pathological proteins (e.g., Aβ, tau) and BBB shuttle receptors to boost brain delivery and dual therapeutic effects. This review combines existing information about antibody-based therapy in AD by focusing on bispecific antibody formats and their preclinical and clinical development, as well as biomarker-based patient selection and upcoming combination strategies. The combination of rationally designed bispecific antibodies with fluid and imaging biomarkers could show potential for overcoming existing therapeutic challenges and delivering significant clinical advantages. Full article

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. Full article