| Effects of Pegylation and Immune Complex Formation on the Pharmacokinetics and Biodistribution of Recombinant Interleukin 10. | |
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MedLine Citation:
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PMID: 22083830 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Interleukin 10 (IL-10) is a potent cytokine homodimer with multiple immunoregulatory functions. Here, we have characterized the effects of pegylation and formation of hIL-10/hαhIL-10 (humanized anti-hIL-10) immune complexes in the pharmacokinetics (PK), biodistribution and biotransformation of IL-10 in mice. In order to assess the fate of native, pegylated and antibody bound IL-10; we implemented an analytical set of fluorescent-emission-linked assays (FELA). Plasma size exclusion chromatography analysis indicated that fluoro-labeled native and pegylated murine IL-10 (mIL-10 and PEG-mIL-10) are stable in the circulation. Pegylation of IL-10 resulted in a 21-fold increased exposure, 2.7-fold increase in half-life and a 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. Fluorescent signal in the kidneys reached tissue-to-blood ratios up to 150 and 20 for native and PEG-mIL10, respectively. hIL-10/hαhIL-10 immune complexes are detectable in the circulation without evidence of unbound or degraded hIL-10. The exposure of hIL-10 present in immune complexes vs. hIL-10 alone, increased from 0.53 to 11.28 μg*day/ml, with a half-life of 1.16 days and a 23-fold reduction in clearance. Unlike hIL-10 alone, antibody bound hIL-10 was targeted mainly to the liver with minimal renal distribution. In addition, we found an 11-fold reduction (from 9.9 to 113 nM) in binding to the Neonatal Fc Receptor (FcRn) when the hαhIL10 antibody is conjugated to hIL-10. The potential changes in FcRn binding in vivo and increased liver uptake may explain the unique PK properties of hIL-10/hαhIL-10 immune complexes. |
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Authors:
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Hamsell M Alvarez; On-Yee So; Suchun Hsieh; Natasha Shinsky-Bjorde; Huiping Ma; Yaoli Song; Yinuo Pang; Melinda Marian; Enrique Escandon |
Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-11-14 |
Journal Detail:
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Title: Drug metabolism and disposition: the biological fate of chemicals Volume: - ISSN: 1521-009X ISO Abbreviation: - Publication Date: 2011 Nov |
Date Detail:
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Created Date: 2011-11-15 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9421550 Medline TA: Drug Metab Dispos Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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1 Merck Research Laboratories; |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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