Abstract
The incidence and clinical significance of therapy-induced neutralizing interferon β (IFNß) antibodies was studied in a group of 21 melanoma patients treated with natural IFNß and 7 patients treated with recombinant IFNß. They were treated subcutaneously with 3×106 IU three times per week in an adjuvant open trial for 24 weeks after surgical removal of all detectable metastases. Of the 21 patients treated with natural IFNß, 95% developed significant levels of neutralizing antibodies after 24 weeks. In comparison, 28% of the 7 patients treated with recombinant IFNß developed neutralizing IFNß antibodies. Cross-reactivity of the antibodies could be demonstrated. Persistence of antibody titers was seen in 80% of the patients 24 weeks after cessation of treatment with natural IFNß. No correlation between the maximum antibody titers and the antibody persistence after cessation of therapy could be established. We detected a clear correlation between the formation of neutralizing antibodies and the decrease in β2-microglobulin and 2′,5′-oligoadenylate synthease and therefore the drop in biological activity. In this adjuvant trial there was no difference in relapse rate and time until relapse between antibody-positive and antibody-negative patients. No difference in clinical outcome could be established between the patients treated with natural IFNß and recombinant IFNß.
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References
Antenelli G, currenti M Turriziani MO, Dianzani F (1990) Neutralizing antibodies to IFN-α: relative frequency in patients treated with different interferon preparations. J Interferon Res 163: 882–885
Conrad HS, Egge H, Katalinic JP, Reiser W, Siklosi T, Schaper K (1987) Structure of the carbohydrate moiety of human interferon-β secreted by a recombinant Chinese hamster ovary cell line. J Biol Chem 262: 14600–14605
Dummer R, Müller W, Nestle F, Wiede J, Dues J, Lechner W, Haubitz I, Wolf W, Bill E, Burg G (1991) Formation of neutralizing antibodies against natural interferon β but not against recombinant interferon γ during adjuvant therapy for high-risk malignant melanoma patients. Cancer 67: 2300–2304
Fierlbeck G, Hoedt B d', Stroebel W, Mayer P, Rassner G (1993) Adjuvante Therapie des malignen Melanoms mit IFN-beta im klinischen Stadium II Zentralbl Haut 162: 115
Figlin R, Itri L (1988): Anti interferon antibodies: A perspective. Sem Hematol 25: 9–15
Fineberg SE, Galloway JA, Fineberg NS, Fineberg NS, Rathbun MJ, Hufferad S (1983) Immunogenicity of recombinant DNA human insulin. Diabetologica 25: 465–469
Hirata Y (1979) Insulin and autoimmunity in a case of spontaneous hypoglycaemia. J Jpn Diabetic Soc 13: 31
Kaplan S, Sarvag D, Suter S (1973) Antibodies to hGH arising in patients treated with hGH: incidence, characteristics and effect on growth, In: Rati S (ed) Advances in hGH research. DHEW 74-612. US Government Printing Office Washington, DC, pp 725–744
Kirkwood IM, Ernstoff MS (1990) Role of INFs in the therapy of melanoma. J Invest Dermatol 95: 180–184
Larocca A, Leung SC, Marcus SG (1989) Evaluation of neutralizing antibodies in patients treated with recombinant interferon betaser. J Interferon Res 9: 551–560
Laruso A (1990) Natural antibodies to IFNγ in man and their increase during viral infection. J Immunol 144: 685–690
Lee J, Vilcek J (1989) Biology of disease, Interleukin-6: a multifunctional cytokine regulating immune reactions and the acute phase protein response. Lab Invest. 61: 588–602
Monson RT (1989) Malignant melanoma: a plaque of our times. Br J Surg 76: 997–998
Moosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. Immunol Methods 65: 55–63
Oberg K, Magnusson A, Lundquist G, Theodorson E, Wide L, Wilander E (1989) Treatment of malignant carcinoid tumors with recombinant interferon alpha 2b: Development of neutralizing interferon antibodies and possible loss of antitumor activity. J Natl Cancer Inst 81: 531–534
Prümmer O (1993) Interferon alpha antibodies in patients with renal cell carcinoma treated with recombinant interferon alpha 2A in an adjuvant multicenter trial. Cancer 71: 1828–1834
Quesada JR (1985) Antitumor activity of recombinant-derived Interferon α in metastatic renal cell carcinoma. J Clin Oncol 3: 1522–1528
Quesada JR, Itri L, Gutterman J (1987) Alpha interferons in hairy cell leukaemia. A five year follow-up in 100 patients J Interferon Res 7: 678
Reiser W, Hauser H (1987) Recombinant human interferon-β from mammalian cell lines. Arzneimittelforschung 37: 482–485
Robbins J, Rall JE, Rawson RW (1956) An unusual instance of thyroxin binding by human serum gamma globulin. J Clin Endocrinol Metab 16: 573–579
Ross C, Hansen MB, Schyberg T, Berg K (1990) Autoantibodies to crude human leucocyte interferon (IFN), native human IFN, recombinant human IFNα 2b and human IFNγ in healthy blood donors Clin Exp Immunol 82: 57–62
Steinberg IJ, Huang P, Ljubich P, Lee Huang S (1990) Antierythropoetin antibodies in hypervisosity syndrome associated with giant lymph-node hyperplasia (GLNA: Castleman's disease). Br J Haematol 74: 543–544
Steis RG, Smith JW, Urban WJ (1988) Resistance of recombinant interferon α 2a in hairy cell leukemia associated with neutralizing anti interferon antibodies. N Engl J Med 318: 1409–1413
Vallbracht A, Treuner J, Flehmig B, Joesster KE, Niethammer D (1981) Interferon-neutralizing antibodies in a patient treated with human fibroblast interferon. Nature 289: 496–497
Wilkinson M, McElduff A, Wilson J, Haber P, Freeman A, Robertson M, Mathews P (1990) Spontaneously occurring antibodies to parathyroid hormone. J Clin Endocrinol Metab 70: 1744–1749
Wolvekamp MC, Marquet RL (1990) Interleukin-6: historical background, genetics and biological significance> Immunol Lett 24: 1–10
Wussow P von, Jakschies D (1990) Interferon-Antikörper-Phantasie oder Faktum. In: Niederle N, Wussow P von (eds) Interferone: präklinische und klinische Befunde. Springer, Berlin Heidelberg New York, pp 79–91
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Fierlbeck, G., Schreiner, T., Schaber, B. et al. Neutralizing interferon β antibodies in melanoma patients treated with recombinant and natural interferon β. Cancer Immunol Immunother 39, 263–268 (1994). https://doi.org/10.1007/BF01525990
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DOI: https://doi.org/10.1007/BF01525990