Enhanced <em>in vivo</em> efficacy using a novel long-life type I Interferon variant in a mouse model of multiple sclerosis — ASN Events
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Enhanced in vivo efficacy using a novel long-life type I Interferon variant in a mouse model of multiple sclerosis (#73)

Daniel Harari 1 , Nadine Kallweit 2 , Renne Abramovich 1 , Keren Sasson 1 , Alla Zozulya 3 , Paul Smith 3 , Martin Schlapschy 2 , Rina Aharoni 1 , Mario Köster 4 , Raya Eliam 1 , Arne Skerra 2 5 , Gideon Schreiber 1
  1. Weizmann Institute of Science, Rehovot, Israel
  2. Lehrstuhl für Biologische Chemie, Universitaet Muenchen, Freising-Weihenstephan, Germany
  3. TA Neurodegenerative Diseases, Merck Serono S.A, Geneva, Switzerland
  4. Gene Regulation and Differentiation, Helmholtz Centre for Infection Research, Braunschweig, Germany
  5. XL-protein GmbH, Freising, Germany

IFNβ is a common therapeutic option to treat multiple sclerosis (MS). It is unique amongst 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 IFN, but modified to exhibit higher receptor affinity than IFNβ. Here, YNSα8was fused with a 600-residue hydrophilic, unstructured N-terminal polypeptide chain, comprising Proline, Alanine and Serine (PAS), in order to prolong its plasma half-life via "PASylation". PAS-IFNα8exhibited a 10-fold increased half-life in both pharmacodynamic and pharmacokinetic assays in a transgenic mouse model harboring the human receptors1, notably without any detectable loss in biological potency or bioavailability. This long-life superagonist conferred significantly improved protection from MOG35-55peptide-induced experimental autoimmune encephalomyelitis (EAE) compared to IFNβ, despite being injected with a 4-fold decrease in frequency and at an overall 16-fold lower dosage. These data were corroborated by FACS and immunohistochemistry, showing a decrease of myeloid lineage cells in the central nervous system (CNS) for PAS-YNSα8 treated animals. Importantly, PAS-IFNα8 did not induce antibodies upon repeated administration, and its biological efficacy remained unchanged after 21 days of treatment. We next  extracted RNA from spleen-derived CD4+ cells andperformed high throughput qPCR for ~200 IFN-response genes enriched for immune function.A striking strong correlation of gene expression andEAEclinical response was observed for two genes - CD274 (PD-L1) and CXCR3.  An IFN-responsive role for PD-L1 in EAE clinical response has been recently reported elsewhere2. This preclinical study thus supports that we have generated a novel, potent and pharmacologically long-acting IFN-variant with potential to treat multiple sclerosis with greater efficacy than current IFN therapies available for use today. It is also provides us with a means to unravel the central IFN-response genes that are providing clinical benefit in EAE and potentially for MS.

  1. Harari, D., Abramovich, R., Zozulya, A., Smith, P., Pouly, S., Köster, M., Hauser, H., and Schreiber, G. (2014) Bridging the species divide: transgenic mice humanized for type-I interferon response. PloS One 9, e84259
  2. Liu, Y., Carlsson, R., Comabella, M., Wang, J., Kosicki, M., Carrion, B., Hasan, M., Wu, X., Montalban, X., Dziegiel, M. H., Sellebjerg, F., Sørensen, P. S., Helin, K., and Issazadeh-Navikas, S. (2014) FoxA1 directs the lineage and immunosuppressive properties of a novel regulatory T cell population in EAE and MS. Nat. Med. 20, 272–282