Abstract
Cancer patients were given a recombinant mutant interferon β by alternating IM and IV injections with weekly escalation of doses from 0.1 to 400 million U. Antibodies specific to the interferon of the IgG class were detected in 24 of 30 patients using an indirect enzyme-linked immunosorbent assay. Serum from only 1 of the 30 patients had detectable ability to neutralize interferon biological activity. Thein vivo interferon serum level, assayed as antiviral activity immediately after IV injection, was not lower than levels seen in the absence of antibodies. Antibodies did not alter the kinetics of clearance of interferon from the serum after IV administration. Antibody levels progressively decreased when interferon administration was discontinued. In most patients antibody levels decreased during a maintenance period when interferon was being administered only by the IV route. In a subsequent trial interferon was given IV, and antibody developed in only 2 of 36 patients. In contrast, in a trial in which interferon was given IM, 20 of 25 patients developed antibody. No antibody-related clinical sequelae could be detected in any of these patients.
Similar content being viewed by others
References
Khosrovi B: The production, characterization, and testing of a modified recombinant human interferon beta.In Interferon: Research, Clinical Application, and Regulatory Consideration, K Zoon, P Noguchi, and TY Liu (eds). New York, Elsevier, 1984, pp 89–100
Mark DF, Lu SD, Creasey AA, Yamamoto R, Lins LS: Site-specific mutagenesis of the human fibroblast interferon gene. Proc Natl Acad Sci USA 81:5662–5666, 1984
Hawkins M, Horning S, Konrad M, Anderson S, Sielaff K, Rosno S, Schiesel J, Davis T, DeMets D, Merigan T, Borden E: Phase I evaluation of a synthetic mutant of β-interferon. Cancer Res 45:5914–5920, 1985
Banting FG, Franks WR, Gaitus S: Physiological studies in metrazol shock. VII. Anti-insulin activity of insulin-treated patients. Am J Psychiat 95:562–566, 1938
Yalow RS, Berson SA: Immunologic aspects of insulin. Am J Med 31:882–891, 1961
Prout TE: The antigenicity of insulin: A review. J Chron Dis 15:879–885, 1962
Kahn CR, Rosenthal AS: Immunologic reactions to insulin: Insulin allergy, insulin resistance, and the autoimmune insulin syndrome. Diabetes Care 2:283–295, 1979
Shapiro SS: Antibodies to blood coagulation factors. Clin Haematol 8:207–214, 1979
Vallbracht A, Treuner J, Flehmig B, Joester KE, Niethammer D: Interferon-neutralizing antibodies in a patient treated with human fibroblast interferon. Nature 289:496–497, 1981
Trown PW, Kramer MJ, Dennin RA, Connell EV, Palleroni AV, Quesada J, Gutterman JV: Antibodies to human leucocyte interferons in cancer patients. Lancet 8316:81–84, 1983
Morgensen KC, Daubas P, Gresser I, Sereni D, Varet B: Patient with circulating antibodies to alpha interferon. Lancet 2:1227–1228, 1981
Panem S, Vilcek J: Antibodies to interferon in man.In The Biology of the Interferon System, E DeMaeyer, H Schellekens (eds). Amsterdam, Elsevier, 1983, pp 369–378
Moore WV, Leppert P: Role of aggregated human growth hormone (hGH) in development of antibodies to hGH. J Clin Endocrinol Metab 51:691–697, 1980
Thorner MD, Reschke J, Chitwood J, Rogol AD, Furlanetto R, Rivier J, Vale W, Blizzard RM: Development of antibody to growth hormone-releasing factor. N Engl J Med 312:994, 1985
Fireman P, Fineberg SE, Galloway JA: Development of IgE antibodies to human (recombinant DNA), porcine, and bovine insulins in diabetic subjects. Diabetes Care 5:119–125, 1982
Velcovsky HG, Federlin KF: Insulin-specific IgG and IgE antibody response in type I diabetic subjects exclusively treated with human insulin (recombinant DNA). Diabetes Care 5:126–128, 1982
Guttermann JV, Fine S, Quesada J, Horning SJ, Levine JF, Alexanian R, Bernhardt L, Kramer M, Spiegel H, Colburn W, Trown P, Merigan T, Dziewanoski Z: Recombinant leukocyte A interferon: Pharmacokinetics, single-dose tolerance, and biologic effects in cancer patients. Ann Intern Med 96:549–556, 1982
Voller A, Bidwell D: Enzyme-linked immunosorbent assay.In Manual of Clinical Laboratory Immunology, 3rd ed, WR Rose, H Friedman, JL Fahey (eds). Washington, DC, American Society for Microbiology, 1986, pp 99–109
Jaton JC, Brandt D, Vassalli P: The isolation and characterization of immunoglobulins, antibodies, and their constituent polypeptide chains.In Immunological Methods, I Lefkovits, B Pernin (eds). New York, Academic Press, 1979, pp 44–66
McPherson TA, Tan YH: Phase I pharmacotoxicological study of human fibroblast interferon in human cancers. J Natl Cancer Inst 65:75–79, 1980
Hawkins MJ, Krown SE, Borden EC, Krim M, Real FX, Edwards BS, Anderson SA, Cunningham-Rundles S, Oettgen HF: American cancer society phase I trial of naturally produced beta interferon. Cancer Res 44:5934–5938, 1984
Edy VG, Billiau A, DeSomer P: Non-appearance of injected fibroblast interferon in circulation. Lancet 1:451–452, 1978
Hanley DF, Wiranowska-Stewart M, Stewart WE II: Pharmacology of interferons I. Pharmacologic distinctions between human leukocyte and fibroblast interferons. J Immunopharmacol 1:219–226, 1979
Rosenblum MG, Unger BW, Gutterman JV, Hersh EM, David GS, Frincke JM: Modification of human leukocyte interferon pharmacology with a monoclonal antibody. Cancer Res 45:2421–2424, 1985
Bino T, Madar Z, Gertler A, Rosenberg H: The kidney is the main site of interferon degradation. J Interferon Res 2:301–308, 1982
Tokazewski-Chen SA, Marafino BJ, Stebbing N: Effects of nephrectomy on the pharmacokinetics of various cloned human interferons in the rat. J Pharmacol Exp Ther 227:9–15, 1983
Kruse V: Effect of insulin-binding antibodies on free insulin in plasma and tissue after subcutaneous injection. A model study.In Basic and Clinical Aspects of Immunity to Insulin, K Keck, P Erb (eds). Berlin, Walter de Gruyter, 1981, pp 319–334
Innis M, McCormick F: Procedures for expression, modification and analysis of human beta interferon in heterologous cells.In Interferons, Part C, Methods of Enzymology, S Peska (ed). New York, Academic Press, 1986, Vol 119, pp 397–403
Colby CB, Inoue M, Thompson M, Tan YH: Immunologic differentiation betweenE. coli and CHO cell-derived recombinant and natural human interferons. J Immunol 133:3091–3095, 1984
Abdi EA, Kamitomo VJ, McPherson TA, Konrad MW, Inoue M, Tan YH: Extended phase I study of human beta interferon in human cancer. Clin Invest Med 9:33–40, 1986
Cunningham AJ: Large numbers of cells in normal mice produce antibody components of isologous erythrocytes. Nature 252:749–751, 1974
Martin SE, Martin WJ: Interspecies brain antigen detected by naturally occurring mouse anti-brain auto-antibody. Proc Natl Acad Sci USA 72:1036–1040, 1975
Dresser DW: Most IgM producing cells in the mouse secrete autoantibodies. Nature 274:480–482, 1978
DeMaeyer-Grignard J, Cachard-Thomas A, DeMaeyer E: Naturally occurring anti-interferon antibodies in Lou/c rats. J Immunol 133:775–778, 1984
Guilbert B, Dighiero G, Arrameas, S: Naturally occurring antibodies against nine common antigens in human sera. I. Detection, isolation, and characterization. J Immunol 128:2779–2787, 1982
Dighiero G, Guilbert B, Arrameas S: Naturally occurring antibodies against nine common antigens in human sera. II. High incidence of monoclonal Ig exhibiting antibody activity against action and tubulin and sharing antibody specificities with natural antibodies. J Immunol 128:2788–2792, 1982
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Konrad, M.W., Childs, A.L., Merigan, T.C. et al. Assessment of the antigenic response in humans to a recombinant mutant interferon beta. J Clin Immunol 7, 365–375 (1987). https://doi.org/10.1007/BF00917014
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00917014