An in vitro FcRn-dependent transcytosis assay as a screening tool for predictive assessment of non-specific clearance of antibody therapeutics in humans
2019
AbstractA cell-based assay employing Madin-Darby canine kidney cells stably expressing human
neonatal Fc receptor(FcRn) heavy chain and β2-microglobulin genes was developed to measure
transcytosisof monoclonal antibodies (mAbs) under conditions relevant to the FcRn-mediated IgG salvage pathway. The FcRn-dependent
transcytosisassay is modeled to reflect combined effects of non-specific interactions between mAbs and cells, cellular uptake via
pinocytosis, pH-dependent interactions with FcRn, and dynamics of intracellular trafficking and sorting mechanisms. Evaluation of 53 mAbs, including 30 marketed mAb drugs, revealed a notable correlation between the
transcytosisreadouts and clearance in humans. FcRn was required to promote efficient
transcytosisof mAbs and contributed directly to the observed correlation. Furthermore, the
transcytosisassay correctly predicted rank order of clearance of glycosylation and Fv charge variants of Fc-containing proteins. These results strongly support the utility of thi...
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