Summary
An immunoconjugate composed of natural interferon α (nIFNα) bound in a noncleavable fashion to a monoclonal antibody (MoAb) recognizing a breast epithelial membrane mucin (Mc5) was used to treat xenografts of a human mammary carcinoma cell line (MCF-7) growing in nude mice. The immunoconjugate (nIFNα/Mc5) was administered as 20 intralesional (i.l.) injections to 1 of 2 xenografts in each animal. It was found that nIFNα/Mc5 produced a significant enhancement of the growth inhibitory actions of nIFNα on the injected tumors. Further enhancement was obtained when nIFNγ or nIFNγ together with Mc5 (at a dose 10 times larger than that present in nIFNα/Mc5) were added to the immunoconjugate. Biodistribution experiments showed that the uptake of125I-nIFNα/Mc5 by the tumors was greater and its elimination slower than for125I-nIFNα alone or conjugated to irrelevant mouse IgG1. In addition, the immunoconjugate up-regulated the antigenic expression of a breast epithelial membrane mucin by the carcinoma cells, an up-regulation which was not significantly different from that produced by nIFNα alone. The contralateral noninjected tumors exposed to systemic levels of the immunoconjugate showed an enhancement of antitumor effects, but to a lesser extent than the injected tumors. These findings suggest that the enhancement of the growth inhibitory action of the immunoconjugate was related to the specific binding of Mc5 which targeted the IFN to the carcinoma cells and impeded its elimination. It is likely that the targeting was favored by the IFN-mediated up-regulation of antigenic expression by the carcinoma cells, thereby producing a cascade of interrelated effects. The results of this study point out the feasibility and potential usefulness of IFN treatment by means of immunoconjugates as well as the worth of pursuing and improving this form of therapy.
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References
Balkwill FR, Moodie EM, Freedman V, Fantes KH: Human interferon inhibits the growth of established human breast tumors in the nude mouse. Int J Cancer 30: 231–235, 1982
Borden EC, Balkwill FR: Preclinical and clinical studies of interferons and interferon inducers in breast cancer. Cancer 53: 783–789, 1984
Ozzello L, Habif DV, De Rosa CM, Cantell K: Effects of intralesional injections of interferon-α on xenografts of human mammary carcinoma cells (BT20 and MCF-7). J Interferon Res 8: 207–215, 1988
Ozzello L, Habif DV, De Rosa CM, Cantell K: Treatment of human breast cancer xenografts using natural interferons-α and -γ injected singly or in combination. J Interferon Res 8: 679–690, 1988
Ozzello L, Habif DV, De Rosa CM, Cantell K: Cellular events accompanying regression of skin recurrences of breast carcinomas treated with intralesional injections of natural interferons alpha and gamma. Cancer Res 52: 4571–4581, 1992
Goldstein D, Laszlo J: Interferon therapy in cancer: from imaginon to interferon. Cancer Res 46: 4315–4329, 1986
Borden EC: Effects of interferons in neoplastic diseases of Man. Pharmac Ther 37: 213–229, 1988
Willis RJ: Clinical pharmacokinetics of interferons. Clin Pharmacokinet 19: 390–399, 1990
Kirkwood JM, Ernstoff MS: Interferons in the treatment of human cancer. J Clin Oncol 2: 336–352, 1984
Ceriani RL, Blank EW, Peterson JA: Experimental immunotherapy of human breast carcinomas implanted in nude mice with a mixture of monoclonal antibodies against human milk fat globule components. Cancer Res 47: 532–540, 1987
Ozzello L, De Rosa CM, Blank EW, Cantell K, Habif DV, Ceriani RL: Potentiation of anti-tumor efficacy resulting from the combined administration of interferon α and of an anti-breast epithelial monoclonal antibody in the treatment of breast cancer xenografts. In: Ceriani RL (ed.) Breast Cancer Immunodiagnosis and Immunotherapy. Plenum Press, New York, 1989, pp. 195–201
Cantell K, Hirvonen S, Kauppinen H-L, Myllyla G: Production of interferon in human leukocytes from normal donors with the use of Sendai virus. Methods Enzymol 78: 29–38, 1981
Cantell K, Hirvonen S, Kauppinen H-L: Prduction and partial purification of human immune interferon. Methods Enzymol 119: 54–63, 1986
Kauppinen H-L, Hirvonen S, Cantell K: Effect of purification procedures on the composition of human leukocyte interferon preparations. Methods Enzymol 119: 27–35, 1986
Kauppinen H-L, Bang B, Eronen J, Majuri R, Myllyla G, Tolo H, Hirvonen S, Cantell K: Preparation of natural human gamma interferon for clinical use. In: Stewart WE, Schellekens H (eds) The Biology of the Interferon System. Elsevier, Amsterdam, 1986, pp. 221–227
Ceriani RL, Blank EW: Experimental therapy of human breast tumors with131I-labeled monoclonal antibodies prepared against the human milk fat globule. Cancer Res 48: 4664–4672, 1988
Ceriani RL, Peterson JA, Lee JY, Moncada R, Blank EW: Characterization of cell surface antigens of human mammary epithelial cells with monoclonal antibodies prepared against human milk fat globule. Somat Cell Genet 9: 415–427, 1983
Soule HD, Vazquez J, Long A, Albert S, Brennan M: A human cell line from a pleural effusion derived from a breast carcinoma. J Natl Cancer Inst 51: 1409–1416, 1973
Ozzello L, Sordat M: Behavior of tumors produced by transplantation of human mammary cell lines in athymic nude mice. Eur J Cancer 16: 553–559, 1980
Inoue K, Fujimoto S, Ogawa M: Antitumor efficacy of seventeen anticancer drugs in human breast cancer xenograft (MX-1) transplanted in nude mice. Cancer Chemother Pharmacol 10: 182–186, 1983
Alkan SS, Miescher Granger S, Braun DG, Hochkeppel HK: Antiviral and antiproliferative effects of interferons delivered via monoclonal antibodies. J Interferon Res 4: 355–363, 1984
Tran R, Horan Hand P, Greiner JW, Pestka S, Schlom J: Enhancement of surface antigen expression on human breast carcinoma cells by recombinant human interferons. J Interferon Res 8: 75–88, 1988
Leon JA, Mesa-Tejada R, Gutierrez CM, Estabrook A, Greiner JW, Schlom J, Fisher PB: Increased surface expression and shedding of tumor associated antigens by human breast carcinoma cells treated with recombinant human interferons or phorbol ester tumor promoters. Anticancer Res 9: 1639–1648, 1989
Greiner JW, Guadagni F, Noguchi P, Pestka S, Colcher D, Fisher PB, Schlom J: Recombinant interferon enhances monoclonal antibody targeting of carcinoma lesionsin vivo. Science 235: 895–898, 1987
Schiller JH, Groveman DS, Schmid SM, Willson JKV, Cummings KB, Borden EC: Synergistic antiproliferative effects of human recombinant α54- or βser-interferons with γ-interferon on human cell lines of various histogenesis. Cancer Res 46: 483–488, 1986
von Wussow P, Block B, Hartmann F, Deicher H: Intralesional interferon-alpha therapy in advanced malignant melanoma. Cancer 61: 1071–1074, 1988
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Ozzello, L., De Rosa, C., Blank, E. et al. The use of natural interferon alpha conjugated to a monoclonal antibody anti mammary epithelial mucin (Mc5) for the treatment of human breast cancer xenografts. Breast Cancer Res Tr 25, 265–276 (1993). https://doi.org/10.1007/BF00689841
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DOI: https://doi.org/10.1007/BF00689841