Designing non-clinical safety evaluation programmes for interferons and interleukins: A personal view

  • Grushenka H. I. Wolfgang
  • Sharon Chen
  • Martin Giedlin
  • Rene Braeckman
  • Dale Johnson
Part of the CMR International Workshop Series book series (CMRW)


1. Toxicity of interferons and interleukins is produced only in animal models that are pharmacologically responsive to the molecule. Studies in a pharmacologically active species have been able to predict most human toxicities. However, when design issues, such as early neutralisation of biological effects, limit the value of animal studies in responsive species, the use of homologous proteins in a species not sensitive to the recombinant human protein may allow prediction of toxic effects.


Safety Evaluation Human Toxicity Personal View Allometric Scaling Recombinant Human Protein 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Anderson PM and Sorenson MA (1994). Effects of route and formulation on clinical pharmacokinetics of interleukin-2. Clinical Pharmacokinetics, 27:19–31.PubMedCrossRefGoogle Scholar
  2. Anderson TD, Arceco R and Hayes TJ (1993). Comparative toxicity and pathology associated with administration of recombinant HuIL-1 alpha to animals. International Review of Experimental Pathology, 34A: 9–36.Google Scholar
  3. Bargetzi MJ, Gluckman E, Tichelli A et al. (1995). Recombinant human interleukin-3 in refractory severe aplastic anaemia: a phase I/II trial. British Journal of Haematology, 91: 306–312.PubMedCrossRefGoogle Scholar
  4. Bocci V (1985). Distribution, catabolism and pharmacokinetics of interferons. In Finter NB and Oldham RK (eds.) In Vivo and Clinical Fluids. Elsevier, New York, Vol 4, pp. 47–72.Google Scholar
  5. Bocci V, Muscettola M and Naldini A (1986). The lymphatic route-III. Pharmacokinetics of human natural interferon-beta injected with albumin as a retarder in rabbits. General Pharmacology, 17: 445–449.PubMedCrossRefGoogle Scholar
  6. Bocci V, Pessina GP, Nicoletti C et al. (1990). The lymphatic route-VII. Distribution of recombinant human interleukin-2 in rabbit plasma and lymph. Journal of Biological Regulation and Homeostatic Agents, 4: 25–28.Google Scholar
  7. Bradley EC and Grimm E (1993). Interleukins. In Holland JF, Frei E, Bast RC, Kufe DW, Morton DL and Weichselbaum RR (eds.) Cancer Medicine. Lea & Febiger, Philadelphia, 3rd edn, pp. 941–947.Google Scholar
  8. Caligiuri MA (1993). Low-dose recombinant interleukin-2 therapy: rational and potential clinical applications. Seminars in Oncology, 20: 3–10.PubMedGoogle Scholar
  9. Carone FA and Peterson DR (1980). Hydrolysis and transport of small peptides by the proximal tubule. American Journal of Physiology, 238: F151–F158.PubMedGoogle Scholar
  10. Chiu PJS, Radwanski E, Tetintoff G, Monge A and Swanson SJ (1996). Interleukin-10 pharmacokinetics in intact and nephrectomized mice. European Cytokine Network, 7: 67–69.PubMedGoogle Scholar
  11. Djeu HY, Hui JH, Wei S, Rui H, Pearson CA, Leonard WJ and Blanchard DK (1993). Function associated with interleukin-2 receptor-b on human neutrophils. Journal of Immunology, 150(3): 960–970.Google Scholar
  12. Dodds WJ (1982). The pig model for biomedical research. Federation Proceedings, 41: 247–256.Google Scholar
  13. Dong HD, Kimoto Y and Taguchi T (1992). Pokeweed mitogen induces p55 interleukin-2 receptor on human monocytes and its effect on interleukin-2 activated monocyte toxicity. Immunological Investigations, 21: 663–670.PubMedCrossRefGoogle Scholar
  14. Espinoza-Delgado I, Bosco MC, Musso T, Gusella GL, Longo DL and Aresio L (1995). Interleukin-2 and human monocyte activation. Journal of Leukocyte Biology, 57: 13–19.PubMedGoogle Scholar
  15. Freireich EJ, Gehan EA, Rail DP et al. (1966). Quantitative comparison of toxicity of anticancer agents in mouse, rat, hamster, dog, monkey and man. Cancer Chemotherapy Reports, 50: 219–244.Google Scholar
  16. Gibbons JA, Luo Z-P and Harmon ER et al. (1995). Quantitation of the renal clearance of interleukin-2 using nephrectomized and ureter-ligated rats. Journal of Pharmacology and Experimental Therapy, 272: 119–125.Google Scholar
  17. Green JD and Terrell TG (1992). Utilization of homologous proteins to evaluate the safety of recombinant proteins — case study: recombinant human interferon-gamma (rhIFN-y). Toxicology Letters, 64: 321–327.PubMedCrossRefGoogle Scholar
  18. Gutterman JU (1994). Cytokine therapeutics: Lessons from interferon a. Proceedings of the National Academy Science USA, 91: 1198–1205.CrossRefGoogle Scholar
  19. Harada Y and Yahara I (1993). Pathogenesis of toxicity with human-derived interleukin-2 in experimental animals. International Review of Experimental Pathology, 34A: 37–55.Google Scholar
  20. Hu CJ, Ozes ON, Klein SB, Blatt LM and Taylor MW (1995). Comparison of the in vitro host range of recombinant met-interferon-coni, Interferon-(X2a, and Interferon-β. Journal of Interferon Cytokine Research, 15: 231–234.PubMedCrossRefGoogle Scholar
  21. Jensen LT, Olesen HP, Risteli J et al. (1990). External thoracic duct-venous shunt in conscious pigs for long-term studies of connective tissue metabolites in lymph. Laboratory Animal Science, 40: 620–624.PubMedGoogle Scholar
  22. Jusko WJ and Ko HC (1994). Physiologic indirect response models characterize diverse types of pharmacodynamic effects. Clinical Pharmacology and Therapeutics, 56: 406–418.PubMedCrossRefGoogle Scholar
  23. Kammuller M (1995). Recombinant human interleukin-6: safety issues of a pleiotropic growth factor. Toxicology, 105: 91–107.PubMedCrossRefGoogle Scholar
  24. Kawasaki H, Moriyama M, Nariuchi H (1992). Mechanism of augmentation of endotoxin fever by Beta Interferon in rabbits: Possible participation of Tumor Necrosis Factor (Cachectin). Infection and Immunity, 60(3): 933–936.PubMedGoogle Scholar
  25. Klapproth J, Castell J, Geiger T, Andus T and Heinrich PC (1989). Fate and biological action of human recombinant interleukin 1β in the rat in vivo. European Journal of Immunology, 19: 1485–1490.CrossRefGoogle Scholar
  26. Leach M, Snyder E, Sinha D et al. (1996). Pathologic findings in cynomolgus monkeys administered interleukin-4. Fundamental and Applied Toxicology, 30: 1,107.Google Scholar
  27. Metcalf D and Nicola NA (1988). Tissue localization and fate in mice of injected multipotential colony-stimulating factor. Proceedings of the National Academy of Science USA, 85: 3160–3164.CrossRefGoogle Scholar
  28. Montero-Julian FA, Klein B, Gautherot E and Braintly H (1995). Pharmaco-kinetic study of anti-interleukin-6 (interleukin-6) therapy with monoclonal antibodies: Enhancement of interleukin-6 clearance by cocktails of anti-interleukin-6 antibodies. Blood, 85: 917–924.PubMedGoogle Scholar
  29. Mordenti J, Chen SA and Ferraiolo BL (1993). Pharmacokinetics of interferon-gamma. In King AHC, Larrick JW and Baughman RA (eds.) Protein Therapeutics: Pharmacokinetics and Pharmacodynamics. Stockton Press, New York, pp. 187–199.Google Scholar
  30. Oka T, Iwata J, Furihata M, Sonobe H, Miyoshi I, Ohtsuki Y (1992). Inhibitory effects of human interferons on the immortalization of human, but not rabbit, T lymphocytes by human T-lymphotropic virus type-1 (HTLV-I). International Journal of Cancer, 51: 915–920.CrossRefGoogle Scholar
  31. Physicians’ Desk Reference (PDR) (1996). 50th edition, Medical Economics Company Inc.Google Scholar
  32. Piscitelli SC, Forrest A, Vogel S et al. (1996). A novel PK/PD model for infused interleukin-2 (interleukin-2) in HIV-infected patients. 97th Annual Meeting of the American Society for Clinical Pharmacology and Therapeutics, March 20-22, Lake Buena Vista, FL.Google Scholar
  33. Rabkin R and Kitaji J (1983). Renal metabolism of peptide hormones. Mineral Electrolyte Metabolism, 9: 212–226.Google Scholar
  34. Reiner G, Ronneberger and Hintz-Obertreis (1993). Comparative toxicity of Escherichia coli and yeast rhIL-3 in cynomolgus and rhesus monkeys. International Review of Experimental Pathology, 34A: 119–147.Google Scholar
  35. Ryffel B (1996). Unanticipated human toxicology of recombinant proteins. Archives of Toxicology Suppl., 18: 333–341.PubMedCrossRefGoogle Scholar
  36. Ryffel B, Mihatsch MJ and Woerly G (1993). Pathology induced by interleukin-6. International Review of Experimental Pathology, 34A: 79–89.Google Scholar
  37. Sarmiento UM, Riley JH, Knaack PA et al. (1994). Biologic effects of recombinant human interleukin-12 in squirrel monkeys (Sciureus saimiri). Laboratory Investigation, 71: 862–873.PubMedGoogle Scholar
  38. Scharenberg JGM, Stam AGM, von Blumberg BME, Roest GJ, Palmer PA, Franks CR, Meijer CJLM and Scheper RJ (1994). The development of anti-interleukin-2 (IL-2) antibodies in cancer patients treated with recombinant IL-2. European Journal of Cancer, 30: 1804–1809.CrossRefGoogle Scholar
  39. Scheibenbogen C, Keintholz U, Richter M, Andreesen R and Hunstein W (1992). The interleukin-2 receptor in human monocytes and macrophages: Regulation of expression and release of the a and b chains (p55 and p75). Research Immunology, 143: 33–37.CrossRefGoogle Scholar
  40. Snyder E, Leach M, Sinha D et al. (1996). Effects of subcutaneous rhuIL-4 in cynomolgus monkeys. Fundamental and Applied Toxicology, 30: 1, 107.CrossRefGoogle Scholar
  41. Stites DP, Terr AI and Parslow TG (1994). In Basic and Clinical Immunology, 8th Edition. Norwalk, Connecticut, Appleton & Lange Paramount Publishing Business and Professional Group.Google Scholar
  42. Taniguchi T and Minami Y (1993). The IL2/IL2 receptor system: A current overview. Cell, 73: 5–8.PubMedCrossRefGoogle Scholar
  43. Terrell TG and Green JD (1993). Comparative pathology of recombinant murine interferon-γ in mice and recombinant human interferon-γ in cynomolgus monkey. International Review of Experimental Pathology, 34B: 73–101.Google Scholar
  44. Terrell TG and Green JD (1994). Issues with biotechnology products in toxicologic pathology. Toxicologic Pathology, 22: 187–193.PubMedCrossRefGoogle Scholar
  45. Vial T and Descotes J (1992). Clinical toxicity of interleukin-2. Drug Safety, 7: 417–433.PubMedCrossRefGoogle Scholar
  46. Vial T and Descotes J (1995). Clinical toxicology of cytokines used as haemopoietic growth factors. Drug Safety, 13: 371–406.PubMedCrossRefGoogle Scholar
  47. Wheeler VS (1996). Interleukins: The search for an anticancer therapy. Seminars in Nursing Oncology, 12: 106–114.CrossRefGoogle Scholar
  48. Whittingdon R and Faulds D (1993). Interleukin-2. A review of its pharmacological properties and therapeutic use in patients with cancer. Drugs, 46: 446–514.CrossRefGoogle Scholar
  49. Zbinden G (1990a). Effects of recombinant human alpha-interferon in a rodent cardiotoxicity model. Toxicology Letters, 50: 25–35.PubMedCrossRefGoogle Scholar
  50. Zbinden G (1990b). Safety evaluation of biotechnology products. Drug Safety, 5: (Suppl. 1), 58–64.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 1998

Authors and Affiliations

  • Grushenka H. I. Wolfgang
  • Sharon Chen
  • Martin Giedlin
  • Rene Braeckman
  • Dale Johnson

There are no affiliations available

Personalised recommendations