The structure of human interferon- ? : implications for activity

Karpusas, Michael; Whitty, Adrian; Runkel, Laura; Hochman, Paula S.

doi:10.1007/s000180050248

Cited by 108 publications

(62 citation statements)

References 64 publications

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“…PEGylated Interferon ␤-1a Pharmacology and Toxicology 993 ing site (Karpusas et al, 1998;Runkel et al, 2000;Baker et al, 2006). Using the same site-specific N-terminal PEGylation procedure, a similar PEG-IFN ␤-1a molecule has been synthesized previously with 20-kDa mPEG-propionaldehyde.…”

Section: Discussionmentioning

confidence: 99%

In Vivo Pharmacology and Toxicology Evaluation of Polyethylene Glycol-Conjugated Interferon β-1a

Hu¹,

Olivier²,

Polack³

et al. 2011

J Pharmacol Exp Ther

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Human interferon (IFN) ␤ has well established beneficial effects in treating relapsing forms of multiple sclerosis, but current first-line treatment requires frequent (from daily to weekly) parenteral administration. A 20-kDa polyethylene glycol (PEG)-conjugated IFN ␤-1a (PEG-IFN ␤-1a) is being developed to decrease the frequency of administration and improve patient convenience and compliance. We present pharmacokinetic (PK) and pharmacodynamic (PD) parameters, immunogenicity, and safety of PEG-IFN ␤-1a in Rhesus monkeys in support of a phase 1 clinical trial. Two single-dose PK/PD studies and one 5-week repeat-dose toxicity study compliant with good laboratory practice were conducted. The PK of IFN ␤-1a and PEG-IFN ␤-1a were modeled with a two-compartment model, and the link between drug concentration and neopterin response (PD marker) was described with an indirect stimulatory model. PEG-IFN ␤-1ashowed greater exposure, longer half-life, lower clearance, and reduced volume of distribution than unmodified IFN ␤-1a. Consistent with the pharmacology of type I IFNs, PEG-IFN ␤-1a resulted in the elevation of neopterin concentration, a transient body temperature increase, and a reversible lymphocyte count decrease. As expected, neutralizing antibodies to PEG-IFN ␤-1a formed in almost all monkeys after 5 weeks of treatment, which resulted in significantly reduced drug exposure and abrogation of neopterin induction. There were no drug-related adverse effects at doses up to 100 g/kg (11 MIU/kg) given subcutaneously or intramuscularly once weekly for 5 weeks. The no-observed-adverse-effect level was determined to be 100 g/kg (11 MIU/kg), the highest dose tested.

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Section: Discussionmentioning

confidence: 99%

In Vivo Pharmacology and Toxicology Evaluation of Polyethylene Glycol-Conjugated Interferon β-1a

Hu¹,

Olivier²,

Polack³

et al. 2011

J Pharmacol Exp Ther

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“…1). Although Xt-IFN5, Xt-IFNi1.2, Xt-IFNi2.1 and Xt-IFNi3.1 share relative low identity, being 12.9e19.7%, 9.4e17.1%, 11.0e15.7%, and 8.8e15.3%, with type I IFNs in human, chicken, green anole lizard and zebrafish, respectively (Table 2), three important structural characteristics known in type I IFNs are conserved in predicted proteins of above Xt-IFNs, including a predicted signal peptide, putative N-glycosylation sites which are involved in post-translational modifications (Karpusas et al, 1998), two or four cysteine residues participated in the formation of disulfide bonds (Wetzel, 1981) (Fig. 1).…”

Section: Sequence Analysis Of Type I Ifn Genes In X Tropicalismentioning

confidence: 99%

Intronless and intron-containing type I IFN genes coexist in amphibian Xenopus tropicalis : Insights into the origin and evolution of type I IFNs in vertebrates

Gan

Chen

Huang

et al. 2017

Developmental & Comparative Immunology

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“…The biological effects of type I IFNs, however, are cell type-specific; thus, for many cell types, IFN␣ and IFN␤ inhibit proliferation and are proapoptotic but promote survival of memory T cells (Platanias, 2005). Type I IFN␤ (Karpusas et al, 1998) signals by binding to cognate receptors, IFN␤ receptor ␣ (IFN␤R␣), and IFN␤R␤, leading to the activation of the Janus kinases JAK1 and Tyk2, which promote signal transducer and activator of transcription 1 (STAT1) and STAT2 activation. Subsequent dimerization and translocation into the nucleus of JAK/STAT complex regulate the transcription of target genes, several of which encode proteins that have tumor suppressor activity (Takaoka and Taniguchi, 2003).…”

mentioning

confidence: 99%

Interferon β Augments Tuberous Sclerosis Complex 2 (TSC2)-Dependent Inhibition of TSC2-Null ELT3 and Human Lymphangioleiomyomatosis-Derived Cell Proliferation

Goncharova¹,

Goncharov²,

Chisolm³

et al. 2007

Mol Pharmacol

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Lymphangioleiomyomatosis (LAM), a rare pulmonary disorder, manifests as an abnormal neoplastic growth of smooth musclelike cells within the lungs. Mutational inactivation of tumor suppressor tuberous sclerosis complex 2 (TSC2) in LAM constitutively activates the mammalian target of rapamycin (mTOR)/p70 S6 kinase 1 (S6K1) signaling pathway and promotes neoplastic growth of LAM cells. In many cell types, type I interferon ␤ (IFN␤) inhibits proliferation and induces apoptosis through signal transducers and activators of transcription (STAT)-dependent and STAT-independent signaling pathways, one of which is the mTOR/S6K1 signaling pathway. Our study shows that IFN␤ is expressed in LAM tissues and LAM-derived cell cultures; however, IFN␤ attenuates LAM-derived cell proliferation only at high concentrations, 100 and 1000 U/ml (IC 50 value for IFN␤ is 20 U/ml compared with 1 U/ml for normal human mesenchymal cells, human bronchus fibroblasts and human airway smooth muscle cells). Likewise, IFN␤ only attenuates proliferation of smooth muscle TSC2-null ELT3 cells. Analysis of IFN␤ signaling in LAM cells showed expression of IFN␤ receptor ␣ (IFN␤R␣) and IFN␤R␤, activation and nuclear translocation of STAT1, and phosphorylation of STAT3 and p38 mitogen-activated protein kinase (MAPK), but IFN␤ had little effect on S6K1 activity. However, the re-expression of TSC2 or inhibition of mTOR/S6K1 with rapamycin (sirolimus) augmented antiproliferative effects of IFN␤ in LAM and TSC2-null ELT3 cells. Our study demonstrates that IFN␤-dependent activation of STATs and p38 MAPK is not sufficient to fully inhibit proliferation of cells with TSC2 dysfunction and that TSC2-dependent inhibition of mTOR/S6K1 cooperates with IFN␤ in inhibiting human LAM and TSC2-null ELT3 cell proliferation.

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The structure of human interferon- ? : implications for activity

Cited by 108 publications

References 64 publications

In Vivo Pharmacology and Toxicology Evaluation of Polyethylene Glycol-Conjugated Interferon β-1a

In Vivo Pharmacology and Toxicology Evaluation of Polyethylene Glycol-Conjugated Interferon β-1a

Intronless and intron-containing type I IFN genes coexist in amphibian Xenopus tropicalis : Insights into the origin and evolution of type I IFNs in vertebrates

Interferon β Augments Tuberous Sclerosis Complex 2 (TSC2)-Dependent Inhibition of TSC2-Null ELT3 and Human Lymphangioleiomyomatosis-Derived Cell Proliferation

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