Enhanced in vivo efficacy of a long-life type I Interferon superagonist in a mouse model of multiple sclerosis

Daniel Harari, Nadine Kallweit, Renne Abramovich, Keren Sasson, Alla Zozulya, Paul Smith, Martin Schlapschy, Rina Aharoni, Mario Koester, Raya Eliam, Arne Skerra, Gideon Schreiber

Research output: Contribution to journalMeeting Abstractpeer-review


IFN-Beta (IFNB) has been a major therapeutic option to treat multiple sclerosis (MS) for more than two decades. Newer drugs have more recently been accepted for patient use with clinical trial data often suggesting superior therapeutic efficacy but with the price of a less favorable safety profile. We have recently reported the generation of an interferon superagonist (dubbed YNSa8) that behaves like a potent form of IFNB as demonstrated in transgenic mice harboring humanized receptors to the Type-I Interferons. For this protein we have used a novel technology named “PASylation” to convert YNSa8 into a long-acting drug when injected into animals. PAS-YNSa8 demonstrated a 10-fold increased half-life in mice, but notably without any detectable loss in biological potency or bioavailability. Furthermore, in comparison to both human and mouse IFNB, this long-living superagonist conferred improved protection from MOG35–55 peptide-induced experimental autoimmune encephalomyelitis (EAE), a mouse model commonly used to emulate human MS. The improved therapeutic effect of PAS-YNSa8 relative to IFNB took place despite the 4-fold decrease in frequency of injection and at an overall 16-fold lower dosage used. The phenotypic activity of this improved functioning IFN-variant is in line with that published by others regarding the role of IFN signaling in EAE — We detected a decrease in monocytes, possibly infiltrating macrophages into the CNS as a consequence to IFN therapy. Furthermore, a direct correlation between improvement in IFN-therapeutic response and the upregulation of the T-cell immune-tolerance factor PD-L1 and the chemokine receptor CXCR3 were detected in CD4-isolated spleen cells, implicating these factors as major player in transducing the therapeutic response to IFN therapy. The possible implications of our findings for treating MS will be discussed.
Original languageEnglish
Pages (from-to)219-219
Number of pages1
JournalJournal of Neuroimmunology
Issue number2-Jan
StatePublished - Oct 2014
Event12th International Congress of Neuroimmunology (ISNI) - Mainz, GERMANY
Duration: 9 Nov 201413 Nov 2014


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