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The Role of FcRn in the Disposition, Metabolism and Pharmacokinetics of Soluble Non‐Crosslinking Immune Complexes
Author(s) -
Alvarez Hamsell M.,
So OnYee,
Hsieh SuChun,
ShinskyBjorde Natalie,
Ma Huiping,
Song Yaoli,
Pang Yinuo,
Marian Melinda,
Escandón Enrique
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.270.7
Subject(s) - pegylation , pharmacokinetics , immune system , chemistry , biodistribution , cytokine , pharmacology , antibody , kidney , in vivo , biotransformation , biochemistry , in vitro , immunology , medicine , biology , polyethylene glycol , enzyme , microbiology and biotechnology
Human interleukin 10 (hIL‐10) is a potent cytokine homodimer that has been investigated in the clinic for inflammatory indications. We have characterized the effects of IL‐10 pegylation and formation of IL‐10/αIL‐10 immune complexes in the pharmacokinetics (PK), biodistribution and biotransformation of IL‐10 in mice. Plasma size exclusion analysis indicated that fluorolabeled native and pegylated murine IL‐10 are stable in the circulation without evidence of biotransformation. Pegylation of IL‐10 resulted in increased exposure, ~2.7‐fold increase in half‐life from 0.098 to 0.26 days and ~20‐fold reduction in clearance. Kidney is the major organ of disposition for both native and pegylated mIL‐10 with renal uptake directly related to systemic clearance. hIL‐10/αIL‐10 complexes were characterized in plasma without evidence of free or degraded hIL‐10 fragments. The hIL‐10 exposure in immune complexes vs. hIL‐10 alone, increased from 0.53 to 11.28 ug*day/ml, with a half‐life of 1.16 days and a ~23‐fold reduction in clearance. In contrast to free interleukin 10, antibody bound hIL‐10 was targeted mainly to the liver with minimal renal distribution. In vitro analysis of FcRn interactions shows a ~10‐fold reduction in binding affinity for the antibody when present as IL‐10/αIL‐10 immune complexes. The changes in FcRn binding and increased liver uptake of IL‐10/αIL‐10 immune complexes may explain in part the unique PK properties of soluble antibody‐bound IL‐10.