PEGylation of a glycosaminoglycan-binding, dominant-negative CXCL8 mutant retains bioactivity in vitro and in vivo.

Autor: Gerlza T; Karl-Franzens-University Graz, Schubertstrasse 1, 8010 Graz, Austria; ProtAffin Biotechnology AG, Reininghausstrasse 13a, 8020 Graz, Austria., Trojacher C; Karl-Franzens-University Graz, Schubertstrasse 1, 8010 Graz, Austria; ProtAffin Biotechnology AG, Reininghausstrasse 13a, 8020 Graz, Austria., Jeremic D; ProtAffin Biotechnology AG, Reininghausstrasse 13a, 8020 Graz, Austria., Krieger E; YASARA Biosciences GmbH & CMBI, Wagramer Strasse 25/3/45, 1220 Vienna, Austria., Adage T; ProtAffin Biotechnology AG, Reininghausstrasse 13a, 8020 Graz, Austria., Kungl A; Karl-Franzens-University Graz, Schubertstrasse 1, 8010 Graz, Austria; ProtAffin Biotechnology AG, Reininghausstrasse 13a, 8020 Graz, Austria. Electronic address: andreas.kungl@uni-graz.at.
Jazyk: angličtina
Zdroj: Cytokine [Cytokine] 2020 Mar; Vol. 127, pp. 154942. Date of Electronic Publication: 2019 Nov 30.
DOI: 10.1016/j.cyto.2019.154942
Abstrakt: We have recently shown that a dominant-negative mutant of CXCL8, dnCXCL8, with increased glycosaminoglycan (GAG) binding affinity and inactivated GPCR signaling function is able to efficiently prevent neutrophil infiltration into murine lungs (Adage et al., 2015). Here we present evidence that chemical PEGylation of dnCXCL8 with 20 kDa and 40 kDa PEG does not significantly interfere with GAG binding affinity, nor does it influence the mutant's disabled chemotaxis function, while it strongly improved bioavailability and serum half-life of the chemokine mutant. In a murine model of lung inflammation, only the 40 kDa PEGylated dnCXCL8 showed a significant reduction of neutrophils in bronchoalveolar lavage (BAL) fluid. In combination with an almost three-fold increase (compared to non-PEGylated dnCXCL8) in plasma half-life after intravenous administration, our results prove that PEGylation of chemokine-derived biologics is an amenable way for the treatment of chronic inflammatory conditions.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2019 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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