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

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.

• Authors: Daniel Harari, Nadine Kuhn, Renne Abramovich, Keren Sasson, Alla L Zozulya, Paul Smith, Martin Schlapschy, Rina Aharoni, Mario Köster, Raya Eilam, Arne Skerra, Gideon Schreiber
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 289 Issue 42 Pg. 29014-29 (Oct 17 2014) ISSN: 1083-351X [Electronic] United States
• PMID: 25193661 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• Interferon Type I
• PAS-YNSalpha8 peptide
• Peptides
• Recombinant Proteins
• Interferon-beta

Topics

• Animals
• Cell Separation
• Encephalomyelitis, Autoimmune, Experimental (drug therapy, metabolism)
• Female
• Flow Cytometry
• Humans
• Interferon Type I (agonists, pharmacology)
• Interferon-beta (pharmacology)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Multiple Sclerosis (drug therapy)
• Peptides (chemistry)
• Protein Engineering (methods)
• Recombinant Proteins (chemistry)
• Surface Plasmon Resonance
• Treatment Outcome