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J Biol Chem. 2014 Oct 17;289(42):29014-29. doi: 10.1074/jbc.M114.602474. Epub 2014 Sep 5.

Enhanced in vivo efficacy of a type I interferon superagonist with extended plasma half-life in a mouse model of multiple sclerosis.

Author information

1
From the Departments of Biological Chemistry, daniel.harari@weizmann.ac.il.
2
the Munich Center for Integrated Protein Science & Lehrstuhl für Biologische Chemie, Technische Universität München, 85350 Freising-Weihenstephan, Germany.
3
From the Departments of Biological Chemistry.
4
MS Platform, Merck-Serono, Geneva, GE 1279 Switzerland, and.
5
Immunology, and.
6
the Department of Gene Regulation and Differentiation, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany.
7
Veterinary Resources, Weizmann Institute of Science, Rehovot 76100, Israel.
8
the Munich Center for Integrated Protein Science & Lehrstuhl für Biologische Chemie, Technische Universität München, 85350 Freising-Weihenstephan, Germany, XL-protein GmbH, 85354 Freising, Germany.
9
From the Departments of Biological Chemistry, gideon.schreiber@weizmann.ac.il.

Abstract

IFNβ is a common therapeutic option to treat multiple sclerosis. It is unique among the family of type I IFNs in that it binds to the interferon receptors with high affinity, conferring exceptional biological properties. We have previously reported the generation of an interferon superagonist (dubbed YNSα8) that is built on the backbone of a low affinity IFNα but modified to exhibit higher receptor affinity than even for IFNβ. Here, YNSα8 was fused with a 600-residue hydrophilic, unstructured N-terminal polypeptide chain comprising proline, alanine, and serine (PAS) to prolong its plasma half-life via "PASylation." PAS-YNSα8 exhibited a 10-fold increased half-life in both pharmacodynamic and pharmacokinetic assays in a transgenic mouse model harboring the human receptors, notably without any detectable loss in biological potency or bioavailability. This long-lived superagonist conferred significantly improved protection from MOG35-55-induced experimental autoimmune encephalomyelitis compared with IFNβ, despite being injected with a 4-fold less frequency and at an overall 16-fold lower dosage. These data were corroborated by FACS measurements showing a decrease of CD11b(+)/CD45(hi) myeloid lineage cells detectable in the CNS, as well as a decrease in IBA(+) cells in spinal cord sections determined by immunohistochemistry for PAS-YNSα8-treated animals. Importantly, PAS-YNSα8 did not induce antibodies upon repeated administration, and its biological efficacy remained unchanged after 21 days of treatment. A striking correlation between increased levels of CD274 (PD-L1) transcripts from spleen-derived CD4(+) cells and improved clinical response to autoimmune encephalomyelitis was observed, indicating that, at least in this mouse model of multiple sclerosis, CD274 may serve as a biomarker to predict the effectiveness of IFN therapy to treat this complex disease.

KEYWORDS:

Autoimmune Disease; Biomarker; Drug Development; Interferon; Multiple Sclerosis; Transgenic Mice

PMID:
25193661
PMCID:
PMC4200257
DOI:
10.1074/jbc.M114.602474
[Indexed for MEDLINE]
Free PMC Article

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