Untitled

Runkel, Laura; Meier, Werner; Pepinsky, R. Blake; Karpusas, Michael; Whitty, Adrian; Kimball, Kathleen; Brickelmaier, Margot; Muldowney, Celine; Jones, W. E.; Goelz, S

doi:10.1023/a:1011974512425

Cited by 279 publications

(56 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Similar to our results with IL-24, they concluded that specific sugar modifications in hemagglutinin act together to maintain a hydrophilic surface to promote trimer formation and to discourage non-productive aggregation. A similar conclusion was also reached with recombinant interferon-␤ (IFN-␤) (35). In the crystal structure of IFN␤-1a (Avonex), N-linked glycan modification screened the hydrophobic surface of the IFN-␤ from aggregation by forming hydrogen bonds between the glycan moiety and the peptide backbone of the cytokine.…”

Section: Discussionmentioning

confidence: 60%

Structural Mapping of Post-translational Modifications in Human Interleukin-24

Fuson

Zheng

Craxton

et al. 2009

Journal of Biological Chemistry

View full text Add to dashboard Cite

Human interleukin-24 (IL-24) is unique among the IL-10 superfamily as there is considerable evidence that it possesses multiple anti-cancer properties, including direct tumor cell cytotoxicity, helper T cell (TH1) immune stimulation, and anti-angiogenic activities. The primary sequence of human IL-24 differs from homologous cytokines, because it possesses three consensus N-linked glycosylation sites and the potential for a single disulfide bond. To address the significance of these modifications in human IL-24, we analyzed the relationship between post-translational modifications and the cytokine activity of the human IL-24 protein. In contrast to related interleukins, we identified a relationship between net glycosylation, protein solubility, and cytokine activity. In addition, abrogation of the two cysteine residues by mutagenesis dramatically altered the ability of IL-24 to secrete from host cells and resulted in the concomitant loss of IL-24 activity. We conclude that, unlike other IL-10 family members, human IL-24 must be glycosylated to maintain solubility and bioavailability. Further, a single, unique disulfide bond is required for secretion and activity. These structure-function relationships show that, although IL-24 is a member of the IL-19 subfamily of IL-10-like cytokines by sequence similarity, its surface properties and its distinctive disulfide arrangement make it unique. These observations could explain the novel biological activities measured of this cytokine. Understanding the structural basis of IL-24 activity will be important in the interpretation of the function of this cytokine and in the development of scale-up strategies for biophysical and clinical applications.

show abstract

Section: Discussionmentioning

confidence: 60%

Structural Mapping of Post-translational Modifications in Human Interleukin-24

Fuson

Zheng

Craxton

et al. 2009

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Molarities of interferons based on biological activity referenced to fully glycosylated, purified IFN-␤1a were always less than those estimated by enzyme-linked immunosorbent assay. Experiments to investigate the effect of glycosylation on IFN-␤ activity suggest a 2-fold lower specific activity of unglycosylated versus glycosylated forms (53). All the results presented in this report compare mutant and wild-type preparations that had similar proportions of glycosylated interferon.…”

Section: Methodsmentioning

confidence: 68%

“…The eukaryotic cos cell expressed IFN-␤ mutants described in this study were soluble, highly glycosylated, and retained full activity over many months in conditioned medium. The importance of glycosylation for IFN-␤ stability and solubility have been recently described (53).…”

Section: Discussionmentioning

confidence: 99%

Differences in Activity between α and β Type I Interferons Explored by Mutational Analysis

Runkel¹,

Pfeffer²,

Lewerenz³

et al. 1998

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Type I interferon (IFN) subtypes ␣ and ␤ share a common multicomponent, cell surface receptor and elicit a similar range of biological responses, including antiviral, antiproliferative, and immunomodulatory activities. However, ␣ and ␤ IFNs exhibit key differences in several biological properties. For example, IFN-␤, but not IFN-␣, induces the association of tyrosine-phosphorylated receptor components ifnar1 and ifnar2, and has activity in cells lacking the IFN receptor-associated, Janus kinase tyk2. To define the structural basis for these functional differences we produced human IFN-␤ with point mutations and compared them to wild-type IFN-␤ in assays that distinguish ␣ and ␤ IFN subtypes. IFN-␤ mutants with charged residues (N86K, N86E, or Y92D) introduced at two positions in the C helix lost the ability to induce the association of tyrosine-phosphorylated receptor chains and had reduced activity on tyk2-deficient cells. The combination of negatively charged residues N86E and Y92D (homologous with IFN-␣8) increased the cross-species activity of the mutant IFN-␤s on bovine cells to a level comparable to that of human IFN-␣s. In contrast, point mutations in the AB loop and D helix had no significant effect on these subtypespecific activities. A subset of these latter mutations did, however, reduce activity in a manner analogous to IFN-␣ mutations. The effects of these mutations on IFN-␤ activity are discussed in the context of a family of related ligands acting through a common receptor and signaling pathway.The mammalian type I IFNs, 1 produced in response to viral infection and other inducers, are divided into ␣ and ␤ subtypes on the basis of their reactivity with antisera raised against IFNs derived, respectively, from leukocytes and fibroblasts (1). The human IFN-␣s are encoded by a family of at least 15 different genes, while IFN-␤ is the unique member of its subtype (2). Primary sequence comparison between the ␣ and ␤ subtypes reveal an approximately 50% amino acid homology, while the amino acid homologies between the IFN-␣ subtypes are approximately 80% (2, 3), reinforcing the division between IFN-␣ and -␤ subtypes.As the pleiotropic nature of these cytokines became apparent, with both subtypes eliciting a similar range of biological activities (3), differences between ␣ subtypes, and between IFN-␣ and -␤s, in potency and cell type specific activities were noted (4). In particular, IFN-␤ elicits a markedly higher antiproliferation response in some cell types such as (5), embryonal carcinoma, melanoma and melanocytes than do IFN-␣s (6, 7, and references therein). Higher potency of IFN-␤ in treatment of multiple sclerosis and certain cancers has been observed (7).The entire class of type I IFNs elicit their biological activities through engagement of a common cell surface receptor (8 -10). Two chains of the receptor, ifnar1 and ifnar2, both members of the type two cytokine receptor family, have been identified (11-15). Both components are necessary for function and in the absence of either there is neither...

show abstract

“…142 Natural IFN-β is a 166 amino acid glycoprotein that can be produced by most cells in response to viral infections or other biological inducers. 18 There are two types of recombinant IFN-β, known as IFN-β-1a and IFN-β-1b. IFN-β-1a is a glycosylated form that is structurally indistinguishable from natural IFN-β;…”

Section: Beta-interferonsmentioning

confidence: 99%

“…143 Several in vitro studies have concluded that the biological activity of some IFN-β-1a formulations is greater than that of IFN-β-1b, 18,143,144 but the clinical implications of such differences are unknown. Furthermore, these studies have not compared all of the approved formulations of recombinant IFN-β.…”

Section: Beta-interferonsmentioning

confidence: 99%

Clinical effectiveness and cost-effectiveness of beta-interferon and glatiramer acetate for treating multiple sclerosis: systematic review and economic evaluation

Melendez‐Torres

Auguste

Armoiry

et al. 2017

Health Technol Assess

View full text Add to dashboard Cite

Background At the time of publication of the most recent National Institute for Health and Care Excellence (NICE) guidance [technology appraisal (TA) 32] in 2002 on beta-interferon (IFN-β) and glatiramer acetate (GA) for multiple sclerosis, there was insufficient evidence of their clinical effectiveness and cost-effectiveness. Objectives To undertake (1) systematic reviews of the clinical effectiveness and cost-effectiveness of IFN-β and GA in relapsing–remitting multiple sclerosis (RRMS), secondary progressive multiple sclerosis (SPMS) and clinically isolated syndrome (CIS) compared with best supportive care (BSC) and each other, investigating annualised relapse rate (ARR) and time to disability progression confirmed at 3 months and 6 months and (2) cost-effectiveness assessments of disease-modifying therapies (DMTs) for CIS and RRMS compared with BSC and each other. Review methods Searches were undertaken in January and February 2016 in databases including The Cochrane Library, MEDLINE and the Science Citation Index. We limited some database searches to specific start dates based on previous, relevant systematic reviews. Two reviewers screened titles and abstracts with recourse to a third when needed. The Cochrane tool and the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) and Philips checklists were used for appraisal. Narrative synthesis and, when possible, random-effects meta-analysis and network meta-analysis (NMA) were performed. Cost-effectiveness analysis used published literature, findings from the Department of Health’s risk-sharing scheme (RSS) and expert opinion. A de novo economic model was built for CIS. The base case used updated RSS data, a NHS and Personal Social Services perspective, a 50-year time horizon, 2014/15 prices and a discount rate of 3.5%. Outcomes are reported as incremental cost-effectiveness ratios (ICERs). We undertook probabilistic sensitivity analysis. Results In total, 6420 publications were identified, of which 63 relating to 35 randomised controlled trials (RCTs) were included. In total, 86% had a high risk of bias. There was very little difference between drugs in reducing moderate or severe relapse rates in RRMS. All were beneficial compared with BSC, giving a pooled rate ratio of 0.65 [95% confidence interval (CI) 0.56 to 0.76] for ARR and a hazard ratio of 0.70 (95% CI, 0.55 to 0.87) for time to disability progression confirmed at 3 months. NMA suggested that 20 mg of GA given subcutaneously had the highest probability of being the best at reducing ARR. Three separate cost-effectiveness searches identified > 2500 publications, with 26 included studies informing the narrative synthesis and model inputs. In the base case using a modified RSS the mean incremental cost was £31,900 for pooled DMTs compared with BSC and the mean incremental quality-adjusted life-years (QALYs) were 0.943, giving an ICER of £33,800 per QALY gained for people with RRMS. In probabilistic sensitivity analysis the ICER was £34,000 per QALY gained. In sensitivity analysis, using the assessment group inputs gave an ICER of £12,800 per QALY gained for pooled DMTs compared with BSC. Pegylated IFN-β-1 (125 µg) was the most cost-effective option of the individual DMTs compared with BSC (ICER £7000 per QALY gained); GA (20 mg) was the most cost-effective treatment for CIS (ICER £16,500 per QALY gained). Limitations Although we built a de novo model for CIS that incorporated evidence from our systematic review of clinical effectiveness, our findings relied on a population diagnosed with CIS before implementation of the revised 2010 McDonald criteria. Conclusions DMTs were clinically effective for RRMS and CIS but cost-effective only for CIS. Both RCT evidence and RSS data are at high risk of bias. Research priorities include comparative studies with longer follow-up and systematic review and meta-synthesis of qualitative studies. Study registration This study is registered as PROSPERO CRD42016043278. Funding The National Institute for Health Research Health Technology Assessment programme.

show abstract

Untitled

Abstract: Together these results suggest that the greater biological activity of IFN-beta-1a is due to a stabilizing effect of the carbohydrate on structure.

Cited by 279 publications

References 30 publications

Structural Mapping of Post-translational Modifications in Human Interleukin-24

Structural Mapping of Post-translational Modifications in Human Interleukin-24

Differences in Activity between α and β Type I Interferons Explored by Mutational Analysis

Clinical effectiveness and cost-effectiveness of beta-interferon and glatiramer acetate for treating multiple sclerosis: systematic review and economic evaluation

Contact Info

Product

Resources

About