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

Autor:	Ferl GZ; Department of Translational & Systems Pharmacology, Genentech Research & Early Development, Genentech, Inc., South San Francisco, California, CA 94048, United States., Fuji RN; Department of Translational & Systems Pharmacology, Genentech Research & Early Development, Genentech, Inc., South San Francisco, California, CA 94048, United States., Atwal JK; Department of Translational & Systems Pharmacology, Genentech Research & Early Development, Genentech, Inc., South San Francisco, California, CA 94048, United States., Sun T; Department of Translational & Systems Pharmacology, Genentech Research & Early Development, Genentech, Inc., South San Francisco, California, CA 94048, United States., Ramanujan S; Department of Translational & Systems Pharmacology, Genentech Research & Early Development, Genentech, Inc., South San Francisco, California, CA 94048, United States., Quartino AL; Department of Translational & Systems Pharmacology, Genentech Research & Early Development, Genentech, Inc., South San Francisco, California, CA 94048, United States.
Jazyk:	angličtina
Zdroj:	Current Alzheimer research [Curr Alzheimer Res] 2020; Vol. 17 (4), pp. 393-406.
DOI:	10.2174/1567205017666200302122307
Abstrakt:	Background: Anti-amyloid-β (Aβ) monoclonal antibodies (mAbs) are currently in development for treating Alzheimer's disease. Objectives: To address the complexity of Aβ target engagement profiles, improve the understanding of crenezumab Pharmacokinetics (PK) and Aβ Pharmacodynamics (PD) in the brain, and facilitate comparison of anti-Aβ therapies with different binding characteristics. Methods: A mechanistic mathematical model was developed describing the distribution, elimination, and binding kinetics of anti-Aβ mAbs and Aβ (monomeric and oligomeric forms of Aβ1-40 and Aβ1-42) 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 Aβ concentrations in CSF and plasma, and PK/PD data of patients undergoing anti-Aβ therapy. Aβ 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 Aβ were qualitatively consistent with the previous data. Simulations of Aβ 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-Aβ therapies and demonstrates that 60 mg/kg crenezumab yields a significant increase in Aβ 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 Aβ oligomer neutralization. (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)
Databáze:	MEDLINE
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