Passive Immunotherapies Targeting Amyloid-β in Alzheimer's Disease: A Quantitative Systems Pharmacology Perspective.

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by amyloid-β (Aβ) protein accumulation in the brain. Passive immunotherapies using monoclonal antibodies for targeting Aβ 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 Aβ with antibodies. We first reviewed the contradicting results associated with the amyloid hypothesis and the pharmacological basis of Aβ immunotherapy. Subsequently, we developed a quantitative systems pharmacology (QSP) model that describes the non-linear progression of Aβ pathology and the pharmacologic actions of the Aβ-targeting antibodies. Using the QSP model, we analyzed various scenarios for effective passive immunotherapy for AD. The model revealed that binding exclusively to the Aβ monomer has minimal effect on Aβ aggregation and plaque reduction, making the antibody affinity toward Aβ 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 Aβ species but lack effector function exhibited moderate effects in plaque reduction. Our model highlights the importance of binding aggregate Aβ species and incorporating effector functions for efficient and early plaque reduction, guiding the development of more effective therapies for this devastating disease. SIGNIFICANCE STATEMENT: Despite previous unsuccessful attempts spanning several decades, passive immunotherapies utilizing monoclonal antibodies for targeting amyloid-beta (Aβ) have demonstrated promise with two recent FDA approvals. However, the pharmacological basis that differentiates clinically effective therapies from ineffective ones remains elusive. Our study offers a quantitative systems pharmacology perspective, emphasizing the significance of selectively targeting specific Aβ species and importance of antibody effector functions. This perspective sheds light on the development of more effective therapies for this devastating disease.