Abstract:
:Manipulation of binding affinity between monoclonal antibodies (mAbs) and the neonatal Fc receptor (FcRn) has been leveraged to extend mAb half-life; however, the steps required for success remain ambiguous and experimental observations are inconsistent. Recent models have considered the time course of endosomal transit a major contributor to the relationship between FcRn affinity and antibody half-life. Our objective was to develop a minimal physiologically based pharmacokinetic model to explain how changes in IgG-FcRn association rate constant (Kon), dissociation rate constant (Koff), and endosomal transit time [T(w)] translate to improved IgG clearance across mice, monkeys and humans. By simulating mAb clearance across physiological values of Kon, Koff, and T(w), we found that lowering Koff improves clearance only until the dissociation half-life reaches endosomal transit time. In contrast, Kon influenced clearance independently of T(w).The model was then applied to fit 66 mAb plasma profiles across species digitized from the literature, and clearance of mAb (CLIgG) and vascular fluid-phase endocytosis rate (CLup) were estimated. We found that CLIgG scaled well with body weight (allometric exponent of 0.90). After accounting for mAbs with significant FcRn binding at physiological pH, CLup was allometrically scalable (exponent 0.72). For the antibodies surveyed, Kon was more highly correlated with CLIgG across all species. The relationship between Koff and KD with CLIgG was largely inconsistent. Taken together, this model provides a parsimonious approach to evaluate endosomal transit kinetics using only mAb plasma concentrations. These findings reinforce the idea that endosomal transit kinetics should be considered when modeling FcRn salvage.
journal_name
MAbsjournal_title
mAbsauthors
Maas BM,Cao Ydoi
10.1080/19420862.2018.1506648subject
Has Abstractpub_date
2018-11-01 00:00:00pages
1322-1331issue
8eissn
1942-0862issn
1942-0870journal_volume
10pub_type
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