Advertisement

Biotherapy

, Volume 10, Issue 1, pp 15–24 | Cite as

Treatment-induced antibodies to interleukin-2

  • Otto Prümmer
Article

Abstract

Interleukin-2 (IL-2) is a 15 kDa glycoprotein with proven activity as an immune stimulant in the treatment of malignant disorders, congenital and acquired immune deficiencies, infectious disorders, and as an adjuvant to vaccines. Both natural and recombinant type IL-2 preparations have been applied in clinical treatment trials and have turned out to be immunogenic, although to a varying extent. Enzyme immunoassays and western blotting are standard procedures for the detection of IL-2-binding antibodies, whereas the neutralizing capacity of these antibodies is frequently demonstrated by inhibition of IL-2-dependent cell growth in vitro. The rate of treatment-induced IL-2 antibodies has varied from 0% to 100% in reported trials and frequently exceeded 50% in patients exposed to recombinant IL-2, whereas natural type IL-2 appeared to be little immunogenic. Duration of treatment, cumulative IL-2 dose, and route of IL-2 administration are likely to determine both the rate of seroconversion as well as composition and properties of the anti-IL-2 antibodies. Interleukin-2 antibodies are polyclonal in nature and predominantly composed of IgM and IgG types. Frequently they react with both recombinant and natural IL-2 types. As a rule, neutralizing IL-2 antibodies are detected in serum samples with high IL-2-binding titers and are recognized later than their non-neutralizing predecessors. Neutralization in vitro, however, does not predict neutralization in vivo, and there are very rare patients with documented, antibody-mediated loss of response to IL-2 treatment. More frequently, IL-2 antibodies will limit the expression of IL-2-dependent proteins in vivo, but the opposite has also been observed. Although the precise mechanism of antibody induction by IL-2 is unknown, immunogenicity of some drug formulations rather than polyclonal B-cell activation appears to play a critical role. Approaches aiming at limiting the immunogenicity of IL-2 preparations are discussed, and strategies how to recognize and circumvent antibody-mediated IL-2 resistance are presented.

Key words

Interleukin-2 interleukin-2 antibodies interleukin-2 antagonists and inhibitors interleukin-2 treatment review 

Abbreviations

EIA

enzyme immunoassay

ELISA

enzyme-labelled immunosorbent assay

i.v.

intravenous

IFN

interferon

IL-2

interleukin-2

IL-2R

IL-2 receptor

IU

international unit

MTT

3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium

nIL-2

natural IL-2

NK cells

natural killer cells

PEG

polyethylene glycol

rIL-2

recombinant IL-2

s.c.

subcutaneous

sIL-2R

soluble IL-2R

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Smith KA: Interleukin 2: inception, impact, and implications. Science 1988; 240: 1169–1176.PubMedCrossRefGoogle Scholar
  2. 2.
    Morgan DA, Ruscetti FW, Gallo R: Selective in vitro growth of T-lymphocytes from normal bone marrows. Science 1976; 192: 1007–1008.CrossRefGoogle Scholar
  3. 3.
    Smith KA: Lowest dose interleukin-2 immunotherapy. Blood 1993; 81: 1414–1423.PubMedGoogle Scholar
  4. 4.
    Caliguri MA: Low-dose recombinant interleukin-2 therapy: rationale and potential clinical applications. Semin Oncol 1993; 20: 3–10.Google Scholar
  5. 5.
    Taniguchi T, Minami Y: The IL-2/IL-2 receptor system: a current overview. Cell 1993; 73: 5–8.PubMedCrossRefGoogle Scholar
  6. 6.
    Rubin LA, Nelson DL: The soluble interleukin-2 receptor: biology, function, and clinical application. Ann Intern Med 1990; 113: 619–627.PubMedGoogle Scholar
  7. 7.
    Taniguchi T, Matsui H, Fujita T, Takaoka C, Kashima N, Yoshimoto R, Hamuro J: Structure and expression of a cloned cDNA for human interleukin 2. Nature 1983; 302: 305–310.PubMedCrossRefGoogle Scholar
  8. 8.
    Parkinson DR: Interleukin-2 in cancer therapy. Semin Oncol 1988; 15, No.6, Suppl. 6: 10–26.PubMedGoogle Scholar
  9. 9.
    Sznol M, Parkinson DR: Interleukin-2 in therapy of hematologic malignancies. Blood 1994; 83: 2020–2022.PubMedGoogle Scholar
  10. 10.
    Voss SD, Hong R, Sondel PM: Severe combined immunodeficiency, interleukin-2 (IL-2), and the IL-2 receptor: Experiments of nature continue to point the way. Blood 1994; 83: 626–635.PubMedGoogle Scholar
  11. 11.
    Cunningham Rundles C, Mayer L, Sapira E, Mendelsohn L: Restoration of immunoglobulin secretion in vitro in common variable immunodeficiency by in vivo treatment with polyethylene glycol-conjugated human recombinant interleukin-2. Clin Immunol Immunopathol 1992; 64: 46–56.CrossRefGoogle Scholar
  12. 12.
    Cunningham Rundles C, Kazbay K, Hassett J, Zhou Z, Mayer L: Brief report: enhanced humoral immunity in common variable immunodeficiency after long-term treatment with polyethylene glycol-conjugated interleukin-2. N Engl J Med 1994; 331: 918–921.CrossRefGoogle Scholar
  13. 13.
    Lotze MT, Frana LW, Sharrow SO, Robb RJ, Rosenberg SA: In vitro administration of purified human interleukin 2: I. Half life and immunologic effects of the Jurkat cell line derived IL 2. J Immunol 1985; 134: 157–166.PubMedGoogle Scholar
  14. 14.
    Huland E, Huland H, Heinzer H: Interleukin-2 by inhalation: local therapy for metastatic renal cell carcinoma. J Urol 1992; 147: 344–348.PubMedGoogle Scholar
  15. 15.
    Huland E, Heinzer H, Huland H: Inhaled interleukin-2 in combination with low-dose systemic interleukin-2 and interferon alpha in patients with pulmonary metastatic renal-cell carcinoma: effectiveness and toxicity of mainly local treatment. J Cancer Res Clin Oncol 1994; 120: 221–228.PubMedCrossRefGoogle Scholar
  16. 16.
    Schwulera U, Huland E, Struff WG, et al: Antibody formation to interleukin-2 in renal cell carcinoma patients with pulmonary metastases treated by aerosol therapy; in Bergmann L, Mitrou PS (eds): Cytokines in cancer therapy. Basel, Karger, 1994, pp 224–231.Google Scholar
  17. 17.
    Knüver-Hopf J, Pohl U, Baumgarten E, et al: No antibody formation in cancer patients treated with natural interleukin-2 in combination with recombinant interferon-gamma; in Bergmann L, Mitrou PS (eds): Cytokines in cancer therapy. Basel, Karger, 1994, pp 232–237. 18. J Interferon Res 1994; 14: 147–226.Google Scholar
  18. 18.
    Bost KL, Hahn BH, Saag MS, Shaw GM, Weigent DA, Blalock JE: Individuals infected with HIV possess antibodies against IL-2. Immunology 1988; 65: 611–615.PubMedGoogle Scholar
  19. 19.
    Tiberio L, Caruso A, Pozzi A, Rivoltini L, Morelli D, Monti E, Balsari A: The detection and biological activity of human antibodies to IL-2 in normal donors. Scand J Immunol 1993; 38: 472–476.PubMedCrossRefGoogle Scholar
  20. 20.
    Monti E, Pozzi A, Tiberio L, Morelli D, Caruso A, Villa ML, Balsari A: Purification of interleukin-2 antibodies from healthy individuals. Immunol Lett 1993; 36: 261–266.PubMedCrossRefGoogle Scholar
  21. 21.
    Krigel RL, Padavic-Shaller KA, Rudolph AR, Litwin S, Konrad M, Bradley EC, Comis RL: A phase I study of recombinant interleukin 2 plus recombinantβ-interferon. Cancer Res 1988; 48: 3875–3881.PubMedGoogle Scholar
  22. 22.
    Kolitz JE, Wong GY, Welte K, Merluzzi VJ, Engert A, Bialas T, Polivka A, Bradley EC, Konrad M, Gnecco C, Oettgen HF, Mertelsmann R: Phase I trial of recombinant interleukin-2 and cyclophosphamide: augmentation of cellular immunity and T-cell mitogenic response with long-term administration of rIL-2. J Biol Resp Modif 1988; 7: 457–472.Google Scholar
  23. 23.
    Whitehead RP, Ward D, Hemingway L, Hemstreet GP, III, Bradley E, Konrad M: Subcutaneous recombinant interleukin 2 in a dose escalating regimen in patients with metastatic renal cell adenocarcinoma. Cancer Res 1990; 50: 6708–6715.PubMedGoogle Scholar
  24. 24.
    Scharenberg JG, Stam AG, von Blomberg BM, Roest GJ, Palmer PA, Franks CR, Meijer CJ, Scheper RJ: The development of anti-interleukin-2 (IL-2) antibodies in cancer patients treated with recombinant IL-2. Eur J Cancer 1994; 30A: 1804–1809.PubMedCrossRefGoogle Scholar
  25. 25.
    Ardizzoni A, Bonavia M, Viale M, Baldini E, Mereu C, Verna A, Ferrini S, Cinquegrana A, Molinari S, Mariani GL, et al: Biologic and clinical effects of continuous infusion interleukin-2 in patients with non-small cell lung cancer. Cancer 1994; 73: 1353–1360.PubMedCrossRefGoogle Scholar
  26. 26.
    Allegretta M, Atkins MB, Dempsey RA, Bradley EC, Konrad MW, Childs A, Wolfe SN, Mier JW: The development of anti-interleukin-2 antibodies in patients treated with recombinant human interleukin-2 (IL-2). J Clin Immunol 1986; 6: 481–490.PubMedCrossRefGoogle Scholar
  27. 27.
    Hänninen EL, Knüver-Hopf J, Atzpodien J: Immunogenicity of recombinant human interleukin-2: biological features and clinical relevance. Biotherapy 1994; 6: 251–261.CrossRefGoogle Scholar
  28. 28.
    Kirchner H, Körfer A, Evers P, Szamel M, Knüver-Hopf J, Mohr H, Franks CR, Pohl U, Resch K, Hadam M, Poliwoda H, Atzpodien J: The development of neutralizing antibodies in a patient receiving subcutaneous recombinant and natural interleukin-2. Cancer 1990; 67: 1862–1864.CrossRefGoogle Scholar
  29. 29.
    Kirchner H, Körfer A, Palmer PA, Evers P, De Riese W, Knüver-Hopf J, Hadam M, Goldman U, Franks CR, Poliwoda H, et al: Subcutaneous interleukin-2 and interferon-alpha 2b in patients with metastatic renal cell cancer: the German outpatient experience. Mol Biother 1990; 2: 145–154.PubMedGoogle Scholar
  30. 30.
    Prümmer O, Funke I, Heimpel H, Porzsolt F: Cytokine therapy in advanced renal cell carcinoma: immunogenicity of combined modality treatment with recombinant IL-2 plus recombinant IFN-α2a. J Interferon Cytokine Res 1995;15, Suppl 1:S219. (Abstract)Google Scholar
  31. 31.
    Mosmann T: Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 1983; 65: 55–63.PubMedCrossRefGoogle Scholar
  32. 32.
    Grossberg S: Human antibodies to interferons: report of a National Institutes of Health workshop held 25–26 July 1988 in Bethesda, MD. J Interferon Res 1988;8 (6):V-VII.Google Scholar
  33. 33.
    Grabstein KH, Eisenmann J, Shanebeck K, Rauch C, Srinivasan S, Fung V, Beers C, Richardson J, Schoenborn MA, Ahdie M, Johnson L, Alderson MR, Watson JD:, Anderson DM, Giri JG: Cloning of a T cell growth factor that interacts with theβ chain of the interleukin-2 receptor. Science 1994; 264: 965–968.PubMedCrossRefGoogle Scholar
  34. 34.
    Hardt C, Röllinghoff M, Pfizenmaier K, Mosmann H, Wagner H: Lyt-23+ cyclophosphamide-sensitive T cells regulate the activity of an interleukin 2 inhibitor in vivo. J Exp Med 1981; 154: 262–274.PubMedCrossRefGoogle Scholar
  35. 35.
    Male D, LeIchuk R, Curry S, Pryce G, Playfair HL: Serum IL-2 inhibitor in mice. II. Molecular characteristics. Immunology 1985; 56: 119–125.PubMedGoogle Scholar
  36. 36.
    Ohtsuka Y, Kobayashi K, Hirano T, Furukawa S, Nagano S, Takahashi T: Involvement of lipoproteins in suppression of interleukin 2-dependent cell proliferation by sera from aged humans. Gerontol 1990; 36: 268–275.CrossRefGoogle Scholar
  37. 37.
    Fukushima T, Kobayashi K, Kasama T, Kasahara K, Tabata M, Sekine F, Negishi M, Ide H, Takahashi T: Inhibition of interleukin 2 by serum in healthy individuals and in patients with autoimmune disease. Int Arch Allergy Appl Immunol 1987; 84: 135–141.PubMedGoogle Scholar
  38. 38.
    von Wussow P, Freund M, Block B, Diedrich H, Poliwoda H, Deicher H: Clinical significance of anti-IFN-α antibody titers during interferon therapy. Lancet 1989;ii:635–636.Google Scholar
  39. 39.
    Perez R, Padavic K, Krigel R, Weiner L: Antierythrocyte autoantibody formation after therapy with interleukin-2 and gamma-interferon. Cancer 1991; 67: 2512–2517.PubMedCrossRefGoogle Scholar
  40. 40.
    Sauter NP, Atkins MB, Mier JW, Lechan RM: Transient thyrotoxicosis and persistent hypothyroidism due to acute autoimmune thyroiditis after interleukin-2 and interferon-alpha therapy for metastatic carcinoma: a case report. Am J Med 1992; 92: 441–444.PubMedCrossRefGoogle Scholar
  41. 41.
    Schwartzentruber DJ, White DE, Zweig MH, Weintraub BD, Rosenberg SA: Thyroid dysfunction associated with immunotherapy for patients with cancer. Cancer 1991; 687: 2384–2390.CrossRefGoogle Scholar
  42. 42.
    Reid I, Sharpe I, McDevitt J, Maxwell W, Emmons R, Tanner WA, Monson JR: Thyroid dysfunction can predict response to immunotherapy with interleukin-2 and interferon-2 alpha. Br J Cancer 1991; 64: 915–918.PubMedGoogle Scholar
  43. 43.
    Figlin RA, Belldegrun A, Moldawer N, Zeffren J, deKernion J: Concomitant administration of recombinant human interleukin-2 and recombinant interferon alfa-2x an active outpatient regimen in renal cell carcinoma. J Clin Oncol 1992; 10: 414–421.PubMedGoogle Scholar
  44. 44.
    Bergmann CA, Landmeier BJ, Kaplan DR: Phase separation analysis of recombinant interleukin 2. Mol Immunol 1991; 28: 99–105.PubMedCrossRefGoogle Scholar
  45. 45.
    Abbas AK, Lichtman AH, Pober JS: Cellular and molecular immunology. Philadelphia, Saunders, 1994.Google Scholar
  46. 46.
    Prümmer O, Porzsolt F: Therapie-induzierte Zytokin-Antikörper beim Nierenzellkarzinom: Vorkommen, Eigenschaften, klinische Relevanz; in Hofstetter A, Kriegmair M (eds): Aktuelle Kontroversen in der Therapie des Nierenzell-karzinoms. München, Bern, Wien, New York, Zuckschwerdt, 1992, pp 56–66.Google Scholar
  47. 47.
    Atkins MB, Gould JA, Allegretta M, Li JJ, Dempsey RA, Rudders RA, Parkinson DR, Reichlin S, Mier JW: Phase I evaluation of recombinant interleukin-2 in patients with advanced malignant disease. J Clin Oncol 1986; 4: 1380–1391.PubMedGoogle Scholar
  48. 48.
    Kolitz JE, Welte K, Wong GY: Expansion of activated T-lymphocytes in patients treated with recombinant interleukin-2. J Biol Response Mod 1987; 6: 412–429.PubMedGoogle Scholar
  49. 49.
    Steis RG, Smith JW, Urba WJ, Venzon DJ, Longo DL, Barney R, Evans LM, Itri LM, Ewel CH: Loss of interferon antibodies during prolonged continuous interferon-alpha 2a therapy in hairy cell leukemia. Blood 1991; 77: 792–798.PubMedGoogle Scholar
  50. 50.
    Prümmer O, Trauschel B, Drees N, Güttler I, Pastor J, Bertels C, Drost K, Frohneberg D, Wenderoth U, Heinzl R, Hartmann K, Boeckmann W, Brandl H, Förster P, Karrasch M, Löhmer H, Fischer C, Lopez-Gamarra D, Hofmann J, Schaefer M, Schneider W, Ulm K, Klopfer E, Holdener EE, Porzsolt F: Antibodies to interferon (IFN)-α as a consequence of adjuvant IFN-α2a treatment of renal cell carcinoma. J Interferon Res 1989;9, Suppl. 2:S114.(Abstract)Google Scholar
  51. 51.
    Prümmer O, The Delta-P Study Group: Interferon-alpha antibodies in patients with renal cell carcinoma treated with recombinant interferon-alpha-2a in an adjuvant multicenter trial. Cancer 1993; 71: 1828–1834.PubMedCrossRefGoogle Scholar
  52. 52.
    Prümmer O, Porzsolt F, Delta-P Study Group: Recombinant interferon-α2 antibodies in renal cell carcinoma. J Interferon Res 1994; 14: 193–195.PubMedGoogle Scholar
  53. 53.
    Sato J, Hamaguchi N, Doken K, Iwasa S, Ogawa Y, Toguchi H: Pharmacokinetic alteration in rats of recombinant interleukin-2 (rIL-2) by immunocomplexing with a monoclonal antibody against rIL-2. Biol Pharm Bull 1994; 17: 535–538.PubMedGoogle Scholar
  54. 54.
    Courtney LP, Phelps JL, Karavodin LM: An anti-IL-2 antibody increases serum half-life and improves anti-tumor efficacy of human recombinant interleukin-2. Immunopharmacology 1994; 28: 223–232.PubMedCrossRefGoogle Scholar
  55. 55.
    Billiau A, Matthys P, Martens E, Heremans H: Effects of anti-interferon-gamma and anti-interleukin-6 antibodies in disease models in mice: antibodies as carriers of cytokines. J Interferon Res 1994; 14: 277–279.PubMedGoogle Scholar
  56. 56.
    Saurat J-H, Schifferli J, Steiger G, Dayer J-M, Didierjean L: Anti-interleukin-1α autoantibodies in humans: characterization, isotype distribution, and receptor-binding inhibition — higher frequency in Schnitzler’s syndrome (urticaria and macroglobulinemia). J Allergy Clin Immunol 1991; 88: 244–256.PubMedCrossRefGoogle Scholar
  57. 57.
    May LT, Neta R, Moldawer LL, Kenney JS, Patel K, Sehgal PB: Antibodies chaperone circulating IL-6: paradoxical effects of anti-IL-6 ‘neutralizing’ antibodies in vivo. J Immunol 1993; 151: 3225–3236.PubMedGoogle Scholar
  58. 58.
    Tomlinson-Jones A, Ziltener HJ: Enhancement of the biologic effects of interleukin-3 in vivo by anti-interleukin-3 antibodies. Blood 1993; 82: 1133–1141.Google Scholar
  59. 59.
    Finkelman FD, Madden KB, Morris SC, Holmes JM, Boiani N, Katona IM, Maliszewski CR: Anti-cytokine antibodies as carrier proteins: prolongation of in vivo effects of exogenous cytokines by injection of cytokine-anti-cytokine antibody complexes. J Immunol 1993; 151: 1235–1244.PubMedGoogle Scholar
  60. 60.
    Suzuki H, Takemura H, Yoshizaki K, Koishihara Y, Ohsugi Y, Okano A, Akiyama Y, Tojo T, Kishimoto T, Kashiwagi H: IL-6-anti-Il-6 autoantibody complexes with IL-6 activity in sera from patients with systemic sclerosis. J Immunol 1994; 152: 935–942.PubMedGoogle Scholar
  61. 61.
    Heremans H, Dillen C, Put W, Van Damme J, Billiau A: Protective effect of anti-interleukin (IL)-6 antibody against endotoxin, associated with paradoxically increased IL-6 levels. Eur J Immunol 1992; 22: 2395–2401.PubMedCrossRefGoogle Scholar
  62. 62.
    Lu ZY, Brochier J, Wijdenes J, Brailly H, Bataille R, Klein B: High amounts of circulating immune interleukin-6 (IL-6) in the form of monomeric immune complexes during anti-IL-6 therapy. Towards a new methodolgy for measuring overall cytokine production in human in vivo. Eur J Immunol 1992; 22: 2819–2824.PubMedCrossRefGoogle Scholar
  63. 63.
    Rosenblum MG, Unger BW, Gutterman JU, Hersh EM, David GS, Frincke JM: Modification of human leukocyte interferon pharmacology with a monoclonal antibody. Cancer Res 1985; 45: 2421–2424.PubMedGoogle Scholar
  64. 64.
    Montero-Julian FA, Gautherot E, Wijdenes J, Klein B, Brailly H: Pharmacokinetics of interleukin-6 during therapy with anti-interleukin-6 monoclonal antibodies: enhanced clearance of interleukin-6 by a combination of three anti-interleukin-6 antibodies. J Interferon Res 1994; 14: 301–302.PubMedGoogle Scholar
  65. 65.
    Katre NV: Immunogenicity of recombinant IL-2 modified by covalent attachment of polyethylene glycol. J Immunol 1990; 144: 209–213.PubMedGoogle Scholar
  66. 66.
    Menzel T, Schomburg A, Korfer A, Hadam M, Meffert M, Dallmann I, Casper S, Kirchner H, Poliwoda H, Atzpodien J: Clinical and preclinical evaluation of recombinant PEG-IL-2 in human. Cancer Biother 1993; 8: 199–212.PubMedGoogle Scholar

Copyright information

© Kluwer Academic Publishers 1997

Authors and Affiliations

  • Otto Prümmer
    • 1
  1. 1.Department of Medicine IIIUniversity of UlmUlmGermany

Personalised recommendations