The preclinical development of roferon®-A

Trown, P. W.; Wills, Robert J.; Kamm, Jerome J.

doi:10.1002/1097-0142(19860415)57:8+<1648::aid-cncr2820571303>3.0.co;2-o

Cited by 62 publications

(25 citation statements)

References 30 publications

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“…However, in contrast to mouse IFN-a, 100 000 IU of human IFN-a (as a control group for mouse IFN-a), a dose which is 10 times that of the mouse IFN-a, had no stimulatory effect on the expression of these IFN-regulated genes (Figure 1), consistent with the species-restricted activity of IFN-a. 32,33 Very similar results were obtained in two other experiments. Moreover, as expected, heat inactivation (1001C for 10 min) completely abolished the stimulatory effect of the IFN-a on IFN-regulated gene expression (data not shown), excluding contamination by endotoxin as a possible causative factor.…”

Section: Resultssupporting

confidence: 80%

Systemic interferon-α regulates interferon-stimulated genes in the central nervous system

2007

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The prime anti-viral cytokine interferon-a (IFN-a) has been implicated in several central nervous system (CNS) disorders in addition to its beneficial effects. Systemic IFN-a treatment causes severe neuropsychiatric complications in humans, including depression, anxiety and cognitive impairments. While numerous neuromodulatory effects by IFN-a have been described, it remains unresolved whether or not systemic IFN-a acts directly on the brain to execute its CNS actions. In the present study, we have analyzed the genes directly regulated in post-IFN-a receptor signaling and found that intraperitoneal administration of mouse IFN-a, but not human IFN-a, activated expression of several prototypic IFN-stimulated genes (ISGs), in particular signal transducers and activators of transcription (STAT1), IFN-induced 15 kDa protein (ISG15), ubiquitin-specific proteinase 18 (USP18) and guanylate-binding protein 3 (GBP3) in the brain. A similar temporal profile for the regulated expression of these IFN-aactivated ISG genes was observed in the brain compared with the peripheral organs. Dual labeling in situ hybridization combined with immunocytochemical staining demonstrated a wide distribution of the key IFN-regulated gene STAT1 transcripts in the different parenchyma cells of the brain, particularly neurons. The overall response to IFN-a challenge was abolished in STAT1 knockout mice. Together, our results indicate a direct, STAT1-dependent action of systemic IFN-a in the CNS, which may provide the basis for a mechanism in humans for neurological/neuropsychiatric illnesses associated with IFN-a therapy.

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Section: Resultssupporting

confidence: 80%

Systemic interferon-α regulates interferon-stimulated genes in the central nervous system

2007

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“…The emergence of anti-Albuferon antibodies was expected on the basis of published reports of IFN-␣ administration in monkeys (Trown et al, 1986). In the study reported here, the development of antibodies in 10 of 12 animals coincided with the observed increase in clearance of Albuferon from the circulation.…”

Section: Discussionsupporting

confidence: 76%

“…The development of antibodies after IFN-␣ injection was expected on the basis of reports by Trown et al (1986) and Bailon et al (2001). Therefore, in this study, serum samples were assessed for the development of anti-Albuferon antibodies using an ELISA method.…”

Section: Immunogenicity Analysismentioning

confidence: 99%

Pharmacokinetic and Pharmacodynamic Studies of a Human Serum Albumin-Interferon-α Fusion Protein in Cynomolgus Monkeys

Osborn¹,

Olsen²,

Nardelli³

et al. 2002

J Pharmacol Exp Ther

192

105

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Interferon-␣ (IFN-␣) is indicated for the treatment of certain viral infections including hepatitis B and C, and cancers such as melanoma. The short circulating half-life of unmodified IFN-␣ makes frequent dosing (daily or three times weekly) over an extended period (6 -12 months or more) necessary. To improve the pharmacokinetics of IFN-␣ and decrease dosing frequency, IFN-␣ was fused to human serum albumin producing a new protein, Albuferon. In vitro comparisons of Albuferon and IFN-␣ showed similar antiviral and antiproliferative activities, although Albuferon was less potent on a molar basis than IFN-␣. Pharmacokinetic and pharmacodynamic properties of the fusion protein were enhanced in monkeys. After a single intravenous injection (30 g/kg,) clearance was 0.9 ml/h/kg, and the terminal half-life was 68 h. After 30 g/kg subcutaneous injection, apparent clearance (clearance divided by bioavailability) was 1.4 ml/h/kg, the terminal half-life was 93 h, and bioavailability was 64%. The rate of clearance of Albuferon was approximately 140-fold slower, and the half-life 18-fold longer, than for IFN-␣ given by the subcutaneous route in other monkey studies. Sera from Albuferon-treated monkeys demonstrated doserelated antiviral activity for Ն8 days based on an in vitro bioassay, whereas antiviral activity from IFN-␣-treated animals was only slightly elevated relative to vehicle on day 0. Significant increases in 2Ј,5Ј-oligoadenylate synthetase mRNA relative to IFN-␣-or vehicle-treated animals were maintained for Ն10 days after subcutaneous dosing. The improved pharmacokinetics of Albuferon are accompanied by an improved pharmacodynamic response suggesting that Albuferon may offer the benefits of less frequent dosing and a potentially improved efficacy profile compared with IFN-␣.

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“…The use of IFN-ot alone and in combination with AZT in other mammalian retrovirus infections is limited, but similar to its application for HIV infections, these agents act synergistically to prophylactically prevent murine and feline retrovirus infections (42,51). Phase I studies in humans have indicated a half-life of IFN-oa in plasma of 2 to 3 h following subcutaneous injection, with dose limitations related to pyrexia, lethargy, myalgia, and hematological toxicity (38,48). Initial clinical trials with IFN-cx against HIV-associated Kaposi sarcoma have been encouraging in terms of antiviral and antitumor responses, significant increases in CD4+ cells, and decreases in circulating viral antigen in those patients who respond to therapy (4,10,23).…”

mentioning

confidence: 99%

Alpha interferon (2b) in combination with zidovudine for the treatment of presymptomatic feline leukemia virus-induced immunodeficiency syndrome

Zeidner

Myles

Mathiason-DuBard

et al. 1990

Antimicrob Agents Chemother

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The therapeutic efficacies of human recombinant alpha interferon (IFN-alpha), IFN-alpha plus zidovudine (AZT), and AZT alone were evaluated in presymptomatic cats with established feline leukemia virus (FeLV)-acquired immunodeficiency syndrome (FAIDS) infection and high levels of persistent antigenemia. Subcutaneous injection of 1.6 x 10(6) U of human recombinant IFN-alpha 2b per kg delivered peak concentrations in plasma of 3,600 U/ml at 2 h postadministration with a half-life of elimination of 2.9 h. This dosage of IFN-alpha could be delivered to cats for up to 12 weeks without significant clinical toxicity. Oral administration of AZT (20 mg/kg three times daily) resulted in peak concentrations in plasma of 3 micrograms/ml at 2 h with a half-life of elimination of approximately 1.60 h. Treatment of FeLV-FAIDS-infected cats with IFN-alpha, either alone or in combination with orally administered AZT, resulted in significant decreases in circulating p27 core antigen beginning 2 weeks after the initiation of therapy. AZT alone had no effect on circulating virus antigen. Depending upon whether high (1.6 x 10(6) U/kg)- or low (1.6 x 10(4) to 1.6 x 10(5) U/kg)-dosage IFN-alpha was used, cats became refractory to therapy 3 or 7 weeks after the beginning of treatment. At these times, IFN-alpha-treated animals developed antibodies to IFN-alpha that were neutralizing, specific for human recombinant IFN-alpha, and dose dependent in magnitude. The results of this study indicate that human recombinant IFN-alpha is effective in reducing circulating virus antigenic load in cats persistently infected with FeLV-FAIDS. However, the continued efficacy of IFN-alpha therapy appeared to be limited by the formation of cytokine-specific neutralizing antibodies.

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The preclinical development of roferon®-A

Cited by 62 publications

References 30 publications

Systemic interferon-α regulates interferon-stimulated genes in the central nervous system

Systemic interferon-α regulates interferon-stimulated genes in the central nervous system

Pharmacokinetic and Pharmacodynamic Studies of a Human Serum Albumin-Interferon-α Fusion Protein in Cynomolgus Monkeys

Alpha interferon (2b) in combination with zidovudine for the treatment of presymptomatic feline leukemia virus-induced immunodeficiency syndrome

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