Abstract
In response to the need to treat disorders such as Crohn’s disease, rheumatoid arthritis, allergies, and diabetes, the pharmaceutical industry has pursued the development of cytokines as therapeutic agents. Cytokines possess unique characteristics that are distinctly different than small molecule drugs. These hormone-like proteins possess complex structural features, demonstrate unique binding specificities and, in many cases, share overlapping physiological functions. These characteristics make development of cytokine therapeutics a challenge to drug-development scientists. Preclinical development of these molecules is complicated by the challenge of differentiating between toxicity and exaggerated immunopharmacology and understanding and analyzing the impact of antidrug antibody on the pharmacodynamics and pharmacokinetics of the parent compound. Regulatory agencies have recognized these issues and established guidance documents to address the nonclinical development of biological products. Several examples, including the nonclinical development of interleukin (IL)-, IL-5 antagonists, IL-6, IL-10, and IL-18 are reviewed in the context of these issues.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Bloom B, Bennett B. Mechanism of a reaction in vitro associated with delayedtype hypersensitivity. Science 1966;153:80–82.
Cohen S, Bigazzi P, Yoshida T. Similarities of T-cell function in cell-mediated immunity and antibody production. Cell Immunol 1974; 12:150–159.
Mantovani A. Cytokines: A World Apart. In: Pharmacology of Cytokines. Oxford University Press New York, 2000, pp. 1–18.
Oppmann B, Lesley R, Blom B, et al. Novel pl9 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity 2000;13:715–725.
Nicola NA. Cytokine pleiotropy and redundancy: a view from the receptor. Stem Cells 1994;12:(Suppl 1) 3–12.
Vilcek J. The cytokines: an overview. In: Thompson A, ed. The Cytokine Handbook. 3rd ed. San Diego: Academic Press; 1998; 1–20.
Homey B. Chemokines and chemokine receptors as targets in the therapy of psoriasis. Curr Drug Targets 2004;3:169–174.
Hendrick J, Zlotnick A. Chemokines and lymphocyte biology. Curr Opin Immunol 1996;8:343–347.
Baggiolini M, Dewald B, Moser B. Human chemokines: an update. Annu Rev Immunol 1997;15:675–705.
Romagnani S. New therapeutic strategies in allergic diseases. Drugs Today 2003;39:849–865.
Schooltink H, Rose-John S. Cytokines as therapeutic drugs. J. Interferon and Cytokine Research 2002;22:505–516.
International Conference on Harmonisation. Guidance S7A. Safety Pharmacology Studies for Human Pharmaceuticals; July 2001.
Weir A. Preclinical safety assessment of therapeutic proteins and monoclonal antibodies. In: Mathieu, M, ed. Biologies Development: A Regulatory Overview. 3rd ed. Waltham MA Parexel; 2004; 17–24.
Rosenblum I, Dayan, A. Carcinogenicity testing of IL-10: principles and practicalities. Human Exp Toxicol 2002;21:347–358.
Ryan A, Terrell T. Biotechnology and its products. In: Haschek WM, Rousseaux CG, Wallig M, eds. Handbook of Toxicologic Pathology, 2nd ed., Vol 1. San Diego Academic Press; 2002, pp. 479–500.
Thomas PT. Nonclinical evaluation of therapeutic cytokines: immunotoxicologic Issues. Toxicology 2002; 174:27–35.
Vilcek J. The cytokines: an overview. In: Thompson A, ed. The Cytokine Handbook. 3rd ed. San Diego Academic Press; 1998, pp. 1–20.
Bazan J. A novel family of growth factor receptors: a common binding domain in the growth hormone prolactin, erythropoietin and IL-6 receptors and the p75 IL-2 receptor B-chain. Biochem Biophys Research Commun 1989;164:788–795.
Ihle J. Cytokine receptor signaling. Nature 1995;377:591–594.
Hirano T, Akira S, Taga T, Hishimoto T. Biological and clinical aspects of interleukin-6. Immunol Today 1990; 11:443–449.
Van Snick J. Interleukin-6: an overview. Ann Rev Immunol 1990;8:253–278.
Kammuler M, Ryffel B. Extrapolation of experimental safety data to humans: the interleukin-6 case. Clin Immunol Immunopathol 1997;83:5–17.
Ryffel B, Car B, Gunn H, Roman D, Hiestand P, Mihatsch M. Interleukin-6 exacerbates glomerulonephritis in (NZBxNZW) Fl mice. Am J Pathol 1994; 144:927–937.
Carson W, Yu H, Dierksheide J, et al. A fatal cytokine-induced systemic inflammatory response reveals a critical role for NK cells. J Immunol 1999; 162: 4943–4951.
Carson WE, Dierksheide JE, Jabbour S, et al. Coadministration of interleukin-18 and interleukin-12 induces a fatal inflammatory response in mice: critical role of natural killer cell interferon-gamma production and STAT-mediated signal transduction. Blood 2000;96:1465–1473.
Talmadge J. Pharmacodynamic aspects of peptide administration of biological response modifiers. Adv Drug Delivery Rev 1998;33:241–252.
Ammaan A, Beck S, DeGutzman L, et al. Transforming growth factor beta. Effect on soft tissue repair. Ann NY Acad Sci 1990;593:124–134.
Schellekens H. Immunogenicity of therapeutic proteins: clinical implications and future prospects. Clin Ther 2002;24:1720–1740.
Herzyk D. The immunogenicity of therapeutic cytokines. Curr Opinion Mol Ther 2003;5:167–171.
Yeung V, Chang J, Miller J, Barnett C, Stickler M, Harding F. Elimination of an immunodominant CD4+ T-cell epitope in human IFN-β does not result in an in vivo response directed at the subdominant epitope. J Immunol 2004; 172: 6658–6665.
Vial T, Descotes J. Immune-mediated side effects of cytokines in humans. Toxicology 1995; 105:31–57.
House R. Theory and practice of cytokine assessment in immunotoxicology. Methods 1999; 19:17–27.
Griffiths SA, Lumley CE. Non-clinical safety studies for biotechnologicallyderived Pharmaceuticals: Conclusions from an international workshop. Hum Exp Toxicol 1998; 17:63–83.
International Conference on Harmonization. Guidance S6. Preclinical safety evaluation of biotechnology-derived Pharmaceuticals; July 1997.
U.S. Food and Drug Administration. CDER Guidance for Industry. Immunotoxicology Evaluation of Investigational New Drugs; October 2002.
EMEA Committee for Proprietary Medicinal Products. Note for Guidance on Repeat Dose Toxicity. Appendix B. Guidance on Immunotoxicity. CPMP/ SWP/1042/99. July 2000.
International Conference on Harmonization Steering Committee Meeting. ICH 2004 Press Release June 9–10, 2004.
Old L. Tumor necrosis factor (TNF). Science 1985;230:630–632.
Gamble JR, Harlan JM, Klebanoff SJ, Vadas MA. Stimulation of the adherence of neutrophils to umbilical vein endothelium by human recombinant tumor necrosis factor. Proc Natl Acad Sci USA 1985;82:8667–8671.
Vilcek J, Lee TH. Tumor necrosis factor. New insights into the molecular mechanisms of its multiple actions. J Biol Chem 1991;266:7313–7316.
Mease PJ, Kivitz AJ, Burch FX, et al. Etanercept treatment of psoriatic arthritis: safety, efficacy, and effect on disease progression. Arthritis Rheum 2004;50:2264–2272.
Borish LC, Nelson HS, Corren J, Bensch G, Busse WW, Whitmore JB, Agosti JM, for the IL-R Asthma Study Group. Efficacy of soluble IL-receptor for the treatment of adults with asthma. J Allergy Clin Immunol 2001; 107:963–970.
Zavorotinskaya T, Tomkinson A, Murphy JE. Treatment of experimental asthma by long-term gene therapy directed against IL-and IL-13. Mol Ther 2003;7:155–162.
Ito H. I1-6 and Crohn’s disease. Curr Drug Targets Inflamm Allergy 2003;2: 125–130.
Nishimoto N, Kishimoto T. Inhibition of IL-6 for the treatment of inflammatory diseases. Curr Opin Pharmacol 2004;4:386–391.
Moore K, de Waal Malefyt R, Coffmann R, O’Garra A. Interleukin-10 and the interleukin-10 receptor. Ann Rev Immunol 2001;19:683–765.
Li M, He S. IL-10 and its related cytokines for treatment of inflammatory bowel disease. World J Gastroenterol 2004; 10:620–625.
Herzyk D, Soos J, Maier C, et al. Immunopharmacology of recombinant human interleukin-18 in nonhuman primates. Cytokine 2002;20:38–48.
Braddock M, Quinn A, Canvin J. Therapeutic potential of targeting IL-1 and IL-18 in inflammation. Expert Opin Biol Ther 2004;4:847–860.
Okamura H, Tsutsui H. Kashiwamura S, Yoshimoto T, Nakanish K. Interleukin-18: A novel cytokine that augments both innate and acquired immunity. Adv Immunol 1998;70:281–312.
Hashimoto W, Osaki T, Okamura H, et al. Differential antitumor effects of administration of recombinant interleukin-18 (rIL-18) or rIL-12 are mediated by Fas-Fas ligand and perforin-induced tumor apoptosis. J Immunol 1999; 163: 583–589.
Herzyk D, Bugelski P, Hart T, Wier P. Preclinical safety of recombinant human interleukin-18. Toxicol Pathol 2003;31:554–561.
Hart TK, Cook RM, Zia-Amirhosseini P, et al. Preclinical efficacy and safety of mepolizumab (SB-240563), a humanized monoclonal antibody to IL-5 in cynomolgus monkeys. J Allerg Clin Immunol 2001; 108:250–257.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2007 Humana Press Inc., Totowa, NJ
About this protocol
Cite this protocol
Thomas, P.T., Beck-Westermeyer, M.S. (2007). Preclinical Approaches for the Safety Assessment of Cytokines. In: House, R.V., Descotes, J. (eds) Cytokines in Human Health. Methods in Pharmacology and Toxicology. Humana Press. https://doi.org/10.1007/978-1-59745-350-9_9
Download citation
DOI: https://doi.org/10.1007/978-1-59745-350-9_9
Publisher Name: Humana Press
Print ISBN: 978-1-58829-467-8
Online ISBN: 978-1-59745-350-9
eBook Packages: Springer Protocols