PASylation of IL-1 receptor antagonist (IL-1Ra) retains IL-1 blockade and extends its duration in mouse urate crystal-induced peritonitis.

Autor:	Powers NE; Department of Medicine, University of Colorado, Aurora, Colorado 80045 nicholas.e.powers@CUAnschutz.edu., Swartzwelter B; Department of Medicine, University of Colorado, Aurora, Colorado 80045., Marchetti C; Department of Medicine, University of Colorado, Aurora, Colorado 80045., de Graaf DM; Department of Medicine, University of Colorado, Aurora, Colorado 80045.; Department of Internal Medicine, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GA Nijmegen, The Netherlands., Lerchner A; XL-protein GmbH, Lise-Meitner-Strasse 30, 85354 Freising, Germany., Schlapschy M; Lehrstuhl für Biologische Chemie, Technische Universität München, Emil-Erlenmeyer-Forum 5, 85354 Freising, Germany., Datar R; DNX Biopharmaceuticals, Inc., San Diego, California 92121., Binder U; XL-protein GmbH, Lise-Meitner-Strasse 30, 85354 Freising, Germany., Edwards CK 3rd; DNX Biopharmaceuticals, Inc., San Diego, California 92121., Skerra A; Lehrstuhl für Biologische Chemie, Technische Universität München, Emil-Erlenmeyer-Forum 5, 85354 Freising, Germany., Dinarello CA; Department of Medicine, University of Colorado, Aurora, Colorado 80045.; Department of Internal Medicine, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GA Nijmegen, The Netherlands.
Jazyk:	angličtina
Zdroj:	The Journal of biological chemistry [J Biol Chem] 2020 Jan 17; Vol. 295 (3), pp. 868-882. Date of Electronic Publication: 2019 Dec 09.
DOI:	10.1074/jbc.RA119.010340
Abstrakt:	Interleukin-1 (IL-1) is a key mediator of inflammation and immunity. Naturally-occurring IL-1 receptor antagonist (IL-1Ra) binds and blocks the IL-1 receptor-1 (IL-1R1), preventing signaling. Anakinra, a recombinant form of IL-1Ra, is used to treat a spectrum of inflammatory diseases. However, anakinra is rapidly cleared from the body and requires daily administration. To create a longer-lasting alternative, PASylated IL-1Ra (PAS-IL-1Ra) has been generated by in-frame fusion of a long, defined-length, N-terminal Pro/Ala/Ser (PAS) random-coil polypeptide with IL-1Ra. Here, we compared the efficacy of two PAS-IL-1Ra molecules, PAS600-IL-1Ra and PAS800-IL-1Ra (carrying 600 and 800 PAS residues, respectively), with that of anakinra in mice. PAS600-IL-1Ra displayed markedly extended blood plasma levels 3 days post-administration, whereas anakinra was undetectable after 24 h. We also studied PAS600-IL-1Ra and PAS800-IL-1Ra for efficacy in monosodium urate (MSU) crystal-induced peritonitis. 5 days post-administration, PAS800-IL-1Ra significantly reduced leukocyte influx and inflammatory markers in MSU-induced peritonitis, whereas equimolar anakinra administered 24 h before MSU challenge was ineffective. The 6-h pretreatment with equimolar anakinra or PAS800-IL-1Ra before MSU challenge similarly reduced inflammatory markers. In cultured A549 lung carcinoma cells, anakinra, PAS600-IL-1Ra, and PAS800-IL-Ra reduced IL-1α-induced IL-6 and IL-8 levels with comparable potency. In human peripheral blood mononuclear cells, these molecules suppressed Candida albicans -induced production of the cancer-promoting cytokine IL-22. Surface plasmon resonance analyses revealed significant binding between PAS-IL-1Ra and IL-1R1, although with a slightly lower affinity than anakinra. These results validate PAS-IL-1Ra as an active IL-1 antagonist with marked in vivo potency and a significantly extended half-life compared with anakinra. (© 2020 Powers et al.)
Databáze:	MEDLINE
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