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A human endothelial cell-based recycling assay for screening of FcRn targeted molecules

Algirdas Grevys,Jeannette Nilsen,Kine M. K. Sand,M. B. Daba,I. Øynebråten,Malin Bern,Martin B. McAdam,Stian Foss,Tilman Schlothauer,T. Michaelsen,G. Christianson,D. Roopenian,R. Blumberg,I. Sandlie,J. Andersen

Published 2018 in Nature Communications

ABSTRACT

Albumin and IgG have remarkably long serum half-lives due to pH-dependent FcRn-mediated cellular recycling that rescues both ligands from intracellular degradation. Furthermore, increase in half-lives of IgG and albumin-based therapeutics has the potential to improve their efficacies, but there is a great need for robust methods for screening of relative FcRn-dependent recycling ability. Here, we report on a novel human endothelial cell-based recycling assay (HERA) that can be used for such pre-clinical screening. In HERA, rescue from degradation depends on FcRn, and engineered ligands are recycled in a manner that correlates with their half-lives in human FcRn transgenic mice. Thus, HERA is a novel cellular assay that can be used to predict how FcRn-binding proteins are rescued from intracellular degradation. The development of IgG and albumin-based therapeutics with increased half-lives needs more efficient screening procedures. Here the authors report a human endothelial cell-based recycling assay enabling screening of IgG and albumin variants without chemical labelling and prior to animal testing.

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