Abstract
Monoclonal antibodies (mAbs) are currently the largest and most dominant class of therapeutic proteins. Inter-individual variability has been observed for several mAbs; however, an understanding of the underlying mechanisms and factors contributing to inter-subject differences in mAb disposition is still lacking. In this review, we analyze the mechanisms of antibody disposition and the putative mechanistic determinants of inter-individual variability. Results from in vitro, preclinical, and clinical studies were reviewed evaluate the role of the neonatal Fc receptor and Fc gamma receptors (expression and polymorphism), target properties (expression, shedding, turnover, internalization, heterogeneity, polymorphism), and the influence of anti-drug antibodies. Particular attention is given to the influence of co-administered drugs and disease, and to the physiological relevance of covariates identified by population pharmacokinetic modeling, as determinants of variability in mAb pharmacokinetics.
Highlights
Monoclonal antibodies are generally found to exhibit desirable pharmacokinetic (PK)characteristics such as slow clearance and long biological half-lives; significant inter-individual variability (IIV) in PK is often noted
A similar experimental evaluation for Monoclonal antibodies (mAbs) has not been yet conducted; it is likely that the incomplete bioavailability observed with slower rate of absorption may be due to catabolism that may occur at the injection site or/and during lymphatic transport
FcγRs may play a minor role in mAb clearance [112]; the influence of gamma receptors would be expected to be increased in conditions of depleted concentrations of endogenous IgG, the development of immune complexes, and in conditions when mAb has been engineered for high affinity binding to gamma receptors [113]
Summary
Monoclonal antibodies (mAb) are generally found to exhibit desirable pharmacokinetic (PK). Anthropometric variables (weight, body surface area), demographic variables (age, gender, and race), anti-drug antibodies (ADA), serum albumin, dose, co-administered drugs, and co-morbidities are often considered as covariates in clinical population modeling of antibody PK. Despite inclusion of these covariates, much of the IIV remains to be explained. Few dedicated studies have been undertaken to examine determinants of variability in mAb PK, and little effort has been placed on the identification of mechanistic biomarkers of IIV. We discuss (a) mechanisms of mAb pharmacokinetics, (b) variability in determinants of mAb disposition, (c) common covariates identified through population PK modeling, and (d) factors contributing to IIV. We assess and analyze evidence from in vitro, pre-clinical, and clinical studies to understand the sources of IIV and their implications on mAb disposition
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