Clinical and Translational Science (Jul 2022)
Application of quantitative protein mass spectrometric data in the early predictive analysis of target engagement by monoclonal antibodies
Abstract
Abstract Model‐informed drug discovery is endorsed by the US Food and Drug Administration (FDA) to improve the flow of medicines from bench to bedside. In the case of monoclonal antibodies, this necessitates taking into account not only the pharmacokinetic (PK) properties of the drug, but also the tissue distribution, concentration, and turnover of the target to guide dose and affinity selection, as well as serve as a link to downstream pharmacology. Relevant information (e.g., tissue proteomic data from quantitative mass spectrometry), is increasingly available from public domain data repositories, although not necessarily in the form that is directly usable for the purpose of quantitative, predictive, and mechanistic PK/pharmacodynamic (PD) modeling based on molarity or similar frameworks instead. Using secreted plasma protein concentrations measured both by immunochemical methods and mass spectrometry, we addressed this gap and derived an optimized nonlinear empirical function that establishes the correlation between the two data sets and validated the approach taken using a wider data set of all proteins found in plasma. In addition, we present a semimechanistic framework for the plasma half‐life of soluble proteins where clearance is expressed as a nonlinear function of the molecular weight of the protein. Finally, we apply the approach to two established therapeutic antibody targets: complement factor C5 and PCSK9 to demonstrate how the described framework can be applied to predictive PK/PD modeling.