Passive Immunotherapies Targeting Amyloid-β in Alzheimer’s Disease: A Quantitative Systems Pharmacology PerspectiveS

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by amyloid-b (Ab) protein accumulation in the brain. Passive immunotherapies using monoclonal antibodies for targeting Ab have shown promise for AD treatment. Indeed, recent US Food and Drug Administration approval of aducanumab and lecanemab, alongside positive donanemab Phase III results demonstrated clinical efficacy after decades of failed clinical trials for AD. However, the pharmacological basis distinguishing clinically effective from ineffective therapies remains unclear, impeding development of potent therapeutics. This study aimed to provide a quantitative perspective for effectively targeting Ab with antibodies. We first reviewed the contradicting results associated with the amyloid hypothesis and the pharmacological basis of Ab immunotherapy. Subsequently, we developed a quantitative systems pharmacology (QSP) model that describes the non-linear progression of Ab pathology and the pharmacologic actions of the Ab-targeting antibodies. Using the QSP model, we analyzed various scenarios for effective passive immunotherapy for AD. The model revealed that binding exclusively to the Ab monomer has minimal effect on Ab aggregation and plaque reduction, making the antibody affinity toward Ab monomer unwanted, as it could become a distractive mechanism for plaque reduction. Neither early intervention, high brain penetration, nor increased dose could yield significant improvement of clinical efficacy for antibodies targeting solely monomers. Antibodies that bind all Ab species but lack effector function exhibited moderate effects in plaque reduction. Our model highlights the importance of binding aggregate Ab species and incorporating effector functions for efficient and early plaque reduction, guiding the development of more effective therapies for this devastating disease.