Cell and Virus Sensitivity Studies with Recombinant Human Alpha Interferons

Krämer, Manfred; Dennin, R; Krämer, Chiara; Jones, Gary J.; Connell, Edward V.; Rolon, N.; Gruarin, A.; Kale, Ramesh R.; Trown, P. W.

doi:10.1089/jir.1983.3.425

Cited by 60 publications

(34 citation statements)

References 10 publications

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“…1, Albuferon had considerable activity on all the cell lines, with a calculated EC 50 of 1.6 ng/ml in WISH cells, 0.12 ng/ml in MDBK cells, and 1.85 ng/ml in COS-1 cells. The results obtained with Albuferon were similar to those reported for various forms of recombinant IFN-␣ (Kramer et al, 1983;Runkel et al, 1998). Albuferon was most potent on MDBK cells, with a mean EC 50 of 0.15 Ϯ 0.05 ng/ml obtained from six independent experiments.…”

Section: Resultssupporting

confidence: 85%

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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Section: Resultssupporting

confidence: 85%

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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“…Lung homogenates from uninfected RAG1 Ϫ/Ϫ mice altered the morphology of Vero cells. This was apparently not due to the constitutive presence of IFN-␣ in the tissue, as suggested by previous reports (17)(18)(19)(20), because the effect could not be reproduced by treatment of the cells with recombinant mouse IFN-␣ at any of a range of concentrations 100-fold above and 100-fold below the IFN-␣ level we measured in RAG1…”

Section: Clearance Of Sars-cov In the Mouse Does Not Involve Nk Cellssupporting

confidence: 46%

Mechanisms of Host Defense following Severe Acute Respiratory Syndrome-Coronavirus (SARS-CoV) Pulmonary Infection of Mice

Glass¹,

Subbarao

Murphy

et al. 2004

The Journal of Immunology

331

325

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We describe a model of severe acute respiratory syndrome-coronavirus (SARS-CoV) infection in C57BL/6 mice. A clinical isolate of the virus introduced intranasally replicated transiently to high levels in the lungs of these mice, with a peak on day 3 and clearance by day 9 postinfection. Viral RNA localized to bronchial and bronchiolar epithelium. Expression of mRNA for angiotensin converting enzyme 2, the SARS-CoV receptor, was detected in the lung following infection. The virus induced production in the lung of the proinflammatory chemokines CCL2, CCL3, CCL5, CXCL9, and CXCL10 with differential kinetics. The receptors for these chemokines were also detected. Most impressively, mRNA for CXCR3, the receptor for CXCL9 and CXCL10, was massively up-regulated in the lungs of SARS-CoV-infected mice. Surprisingly Th1 (and Th2) cytokines were not detectable, and there was little local accumulation of leukocytes and no obvious clinical signs of pulmonary dysfunction. Moreover, beige, CD1−/−, and RAG1−/− mice cleared the virus normally. Infection spread to the brain as it was cleared from the lung, again without leukocyte accumulation. Infected mice had a relative failure to thrive, gaining weight significantly more slowly than uninfected mice. These data indicate that C57BL/6 mice support transient nonfatal systemic infection with SARS-CoV in the lung, which is able to disseminate to brain. In this species, proinflammatory chemokines may coordinate a rapid and highly effective innate antiviral response in the lung, but NK cells and adaptive cellular immunity are not required for viral clearance.

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“…The literature suggests that targeted IFN␣ might also induce an acute tumor-directed immune response and evoke immune memory. 21,22 Because murine cells are considerably less sensitive (ϳ 4 logs) than human cells to human IFN␣2b, 23,24 the antitumor activity of mAb-IFN␣ in murine models is primarily because of the direct action of IFN␣2b on the tumor cells and cannot be attributed to immunoactivation in the host. In the ex vivo studies, C2-2b-2b depleted normal B cells, monocytes, and DCs.…”

Section: Discussionmentioning

confidence: 99%

Preclinical studies on targeted delivery of multiple IFNα2b to HLA-DR in diverse hematologic cancers

Rossi

Cardillo

et al. 2011

Blood

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The short circulating half-life and side effects of IFN␣ affect its dosing schedule and efficacy. Fusion of IFN␣ to a tumortargeting mAb (mAb-IFN␣) can enhance potency because of increased tumor localization and improved pharmacokinetics. We used the Dock-and-Lock method to generate C2-2b-2b, a mAb-IFN␣ comprising tetrameric IFN␣2b site-specifically linked to hL243 (humanized anti-HLA-DR). In vitro, C2-2b-2b inhibited various B-cell lymphoma leukemia and myeloma cell lines. In most cases, this immunocytokine was more effective than CD20-targeted mAb-IFN␣ or a mixture comprising the parental mAb and IFN␣. Our findings indicate that responsiveness depends on HLA-DR expression/density and sensitivity to IFN␣ and hL243. C2-2b-2b induced more potent and longer-lasting IFN␣ signaling compared with nontargeted IFN␣. Phosphorylation of STAT1 was more robust and persistent than that of STAT3, which may promote apoptosis.C2-2b-2b efficiently depleted lymphoma and myeloma cells from whole human blood but also exhibited some toxicity to B cells, monocytes, and dendritic cells. C2-2b-2b showed superior efficacy compared with nontargeting mAb-IFN␣, peginterferonalfa-2a, or a combination of hL243 and IFN␣, using human lymphoma and myeloma xenografts. These results suggest that C2-2b-2b should be useful in the treatment of various hematopoietic malignancies. (Blood. 2011;118(7):1877-1884)

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Cell and Virus Sensitivity Studies with Recombinant Human Alpha Interferons

Cited by 60 publications

References 10 publications

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

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

Mechanisms of Host Defense following Severe Acute Respiratory Syndrome-Coronavirus (SARS-CoV) Pulmonary Infection of Mice

Preclinical studies on targeted delivery of multiple IFNα2b to HLA-DR in diverse hematologic cancers

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