A phase I/II study of recombinant human interleukin-12 in patients with chronic hepatitis C

Zeuzem, Stefan; Hopf, U.; Carréño, Vicente; Diago, M.; Shiffman, Mitchell L.; Grüne, S.; Dudley, F. J.; Rakhit, Ashok; Rittweger, Karen; Yap, Sing Hiem; Koff, Raymond S.; Thomas, Howard

doi:10.1002/hep.510290429

Cited by 55 publications

(28 citation statements)

References 50 publications

(46 reference statements)

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“…Also, recently published phase 1 trials of rhIL-12 in non-HIV-infected patients with advanced malignancies or chronic hepatitis B or C infection reported MTD rhIL-12 ranges of 500-1500 ng/kg [10][11][12][13][14]. In these trials, rhIL-12 was well tolerated, with minimal side effects, at doses !100 ng/kg.…”

Section: Discussionmentioning

confidence: 96%

“…In the phase 1 trials conducted in patients with advanced malignancies, serum IFN-g levels increased significantly within 12 h after an intravenous or subcutaneous injection of rhIL-12, peaked at about day 3, and returned to baseline by day 7 when patients were given у30 ng/kg of rhIL-12 [10,[15][16][17]. In the phase 1 trials for chronic hepatitis B and C (which excluded HIV-seropositive patients), IFN-g levels increased in only 2 of 8 subjects given rhIL-12 at 250 ng/kg but in 7 of 10 given 500 ng/kg [13,14].…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Phase 1 Trial of a Single Dose of Recombinant Human Interleukin–12 in Human Immunodeficiency Virus–Infected Patients with 100–500 CD4 Cells/μL

et al. 2000

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A phase 1 dose-escalation trial of a single subcutaneous dose of recombinant human (rh) interleukin (IL)-12 was conducted in medically stable human immunodeficiency virus (HIV)-infected patients with 100-500/microL absolute CD4(+) T lymphocytes. Subjects at each dose level were randomly assigned (3:1) to receive rhIL-12 or placebo. Among the 47 subjects enrolled, rhIL-12 was well tolerated at doses of 3-300 ng/kg, but 4 of 5 subjects who received rhIL-12 at 1000 ng/kg had severe adverse events. Dose-related increases in serum interferon-gamma occurred after rhIL-12 administration at doses > or =30 ng/kg. There was no effect of rhIL-12 on plasma HIV RNA or absolute CD4(+) T cell counts. However, dose-related increases in absolute CD8(+) T and NK cells were observed in subjects assigned to rhIL-12 doses of 30-300 ng/kg. Single rhIL-12 doses of 30-300 ng/kg were well tolerated and had biologic activity that could potentially be of benefit in the treatment of HIV disease or its complications.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Phase 1 Trial of a Single Dose of Recombinant Human Interleukin–12 in Human Immunodeficiency Virus–Infected Patients with 100–500 CD4 Cells/μL

et al. 2000

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“…another phase I/II trial using a different formulation of IL-12 administered once weekly for 10 weeks, where no patients achieved viral clearance at any stage of the study [11]. IL-12 given alone for treatment of chronic hepatitis C does not appear to be efficacious and is poorly tolerated.…”

Section: Interleukin-12mentioning

confidence: 96%

Current status of immunomodulatory therapies in HCV infection

Pockros

2004

Curr hepatitis rep

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“…The sequence identity of rhesus IL-12 to hIL-12 is Ϸ95%, and therefore it is possible that EvIL-12 (88͞86% identity to human͞rhesus) may also be immunogenic in non-human primates and humans. On the other hand, a small percentage of patients receiving recombinant hIL-12 at doses considered efficacious and safe also developed antibodies but without adverse clinical effect (48)(49)(50). Antibody formation to other therapeutic human recombinant proteins such as IFN-␣, IFN-␤, IL2, GM-CSF, and GH have also been detected in patients without adverse consequences, but the clinical significance of the presence of non-neutralizing antibodies has not been fully established (51,52).…”

Section: Identification Of Clones With Biological Activity Greater Thmentioning

confidence: 99%

Optimized expression and specific activity of IL-12 by directed molecular evolution

Leong

Chang²,

Ong³

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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DNA delivery of IL-12 has shown promise in reducing the toxic side effects associated with administration of recombinant human (h)IL-12 protein while maintaining the ability to inhibit tumor growth and abolish tumor metastases in animal models. We have developed a more potent version of IL-12 by using DNA shuffling and screening to improve its expression in human cells and specific activity on human T cells. The most improved evolved IL-12 (EvIL-12) derived from seven mammalian genes encoding both the p35 and p40 subunits of IL-12 showed a 128-fold improvement in human T cell proliferation compared with native hIL-12 during the initial screening of supernatants from transected cells. When purified hIL-12 and EvIL-12 proteins were compared in vitro in human T cell proliferation and Th1 differentiation assays, it was demonstrated that EvIL-12 exhibited a concomitant 10-fold increase in the specific activity of the protein compared with hIL-12. Furthermore, DNA shuffling improved the level of expression and homogeneity of the heterodimer synthesized by 293 human embryonic kidney cells transfected with EvIL-12 by at least 10-fold. Molecular analysis of the variant revealed strategic placement of amino acid substitutions that potentially may facilitate heterodimer formation and product expression. The enhanced expression and biological activity of EvIL-12 may improve the effectiveness of IL-12 gene-based vaccines and therapeutics without the toxic side effects sometimes associated with hIL-12 protein administration.

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A phase I/II study of recombinant human interleukin-12 in patients with chronic hepatitis C

Abstract: Hepatitis C virus (HCV) infection often progresses to chronic hepatitis, cirrhosis, and possibly hepatocellular carcinoma.

Cited by 55 publications

References 50 publications

Phase 1 Trial of a Single Dose of Recombinant Human Interleukin–12 in Human Immunodeficiency Virus–Infected Patients with 100–500 CD4 Cells/μL

Phase 1 Trial of a Single Dose of Recombinant Human Interleukin–12 in Human Immunodeficiency Virus–Infected Patients with 100–500 CD4 Cells/μL

Current status of immunomodulatory therapies in HCV infection

Optimized expression and specific activity of IL-12 by directed molecular evolution

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