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- W2273890207 abstract "IFN β 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 YNS α 8) that is built on the backbone of a low affinity IFN, but modified to exhibit higher receptor affinity than IFN β . Here, YNS α 8 was 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-IFN α 8 exhibited a 10-fold increased half-life in both pharmacodynamic and pharmacokinetic assays in a transgenic mouse model harboring the human receptors [1] , notably without any detectable loss in biological potency or bioavailability. This long-life superagonist conferred significantly improved protection from MOG35–55 peptide-induced experimental autoimmune encephalomyelitis (EAE) compared to IFN β , 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-YNS α 8 treated animals. Importantly, PAS-IFN α 8 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 and performed high throughput qPCR for ∼ 200 IFN-response genes enriched for immune function. A striking strong correlation of gene expression and EAE clinical 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 elsewhere [2] . 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." @default.
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- W2273890207 date "2014-11-01" @default.
- W2273890207 modified "2023-09-27" @default.
- W2273890207 title "73" @default.
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- W2273890207 doi "https://doi.org/10.1016/j.cyto.2014.07.080" @default.
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