A Physiologically-Based Pharmacokinetic Model for the Prediction of 'Half-Life Extension' and 'Catch and Release' Monoclonal Antibody Pharmacokinetics
| Autor: | Nicole Piche-Nicholas, Rob Webster, Gregory Weber, John Tolsma, Kerry Kelleher, Haobin Luo, Katherine Wright, Robert D. Bell, Dean Messing, Joel Bard, Hannah M. Jones, Zhiwei Zhang, Paul Jasper |
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| Rok vydání: | 2020 |
| Předmět: |
Physiologically based pharmacokinetic modelling
medicine.drug_class Druggability Mice Transgenic Computational biology Receptors Fc HIV Antibodies Monoclonal antibody Antibodies Monoclonal Humanized Protein Engineering Article Mice Neonatal Fc receptor Pharmacokinetics Drug Development Drug Discovery medicine Animals Humans Pharmacology (medical) Computer Simulation biology Drug discovery Chemistry Research lcsh:RM1-950 Histocompatibility Antigens Class I Homozygote Models Immunological Antibodies Monoclonal Articles lcsh:Therapeutics. Pharmacology Modeling and Simulation Mutation biology.protein Antibody Intracellular Broadly Neutralizing Antibodies Half-Life Protein Binding |
| Zdroj: | CPT: Pharmacometrics & Systems Pharmacology CPT: Pharmacometrics & Systems Pharmacology, Vol 9, Iss 9, Pp 534-541 (2020) |
| ISSN: | 2163-8306 |
| Popis: | Monoclonal antibodies (mAbs) can be engineered to have “extended half‐life” and “catch and release” properties to improve target coverage. We have developed a mAb physiologically‐based pharmacokinetic model that describes intracellular trafficking, neonatal Fc receptor (FcRn) recycling, and nonspecific clearance of mAbs. We extended this model to capture target binding as a function of target affinity, expression, and turnover. For mAbs engineered to have an extended half‐life, the model was able to accurately predict the terminal half‐life (82% within 2‐fold error of the observed value) in the human FcRn transgenic (Tg32) homozygous mouse and human. The model also accurately captures the trend in pharmacokinetic and target coverage data for a set of mAbs with differing catch and release properties in the Tg32 mouse. The mechanistic nature of this model allows us to explore different engineering techniques early in drug discovery, potentially expanding the number of “druggable” targets. |
| Databáze: | OpenAIRE |
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