Mechanistic Modeling of Soluble Aß Dynamics and Target Engagement in the Brain by Anti-Aß mAbs in Alzheimer's Disease.

ABSTRACT

BACKGROUND: Anti-amyloid-ß (Aß) monoclonal antibodies (mAbs) are currently in development for treating Alzheimer's disease. OBJECTIVES: To address the complexity of Aß target engagement profiles, improve the understanding of crenezumab Pharmacokinetics (PK) and Aß Pharmacodynamics (PD) in the brain, and facilitate comparison of anti-Aß therapies with different binding characteristics. METHODS: A mechanistic mathematical model was developed describing the distribution, elimination, and binding kinetics of anti-Aß mAbs and Aß (monomeric and oligomeric forms of Aß1-40 and Aß1-42) in the brain, Cerebrospinal Fluid (CSF), and plasma. Physiologically meaningful values were assigned to the model parameters based on the previous data, with remaining parameters fitted to clinical measurements of Aß concentrations in CSF and plasma, and PK/PD data of patients undergoing anti-Aß therapy. Aß target engagement profiles were simulated using a Monte Carlo approach to explore the impact of biological uncertainty in the model parameters. RESULTS: Model-based estimates of in vivo affinity of the antibody to monomeric Aß were qualitatively consistent with the previous data. Simulations of Aß target engagement profiles captured observed mean and variance of clinical PK/PD data. CONCLUSION: This model is useful for comparing target engagement profiles of different anti-Aß therapies and demonstrates that 60 mg/kg crenezumab yields a significant increase in Aß engagement compared with lower doses of solanezumab, supporting the selection of 60 mg/kg crenezumab for phase 3 studies. The model also provides evidence that the delivery of sufficient quantities of mAb to brain interstitial fluid is a limiting step with respect to the magnitude of soluble Aß oligomer neutralization.