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.