Abstract
Four monoclonal antibodies (MAbs) specific for the extracellular domain of the human erbB-2/HER2 protein (FRP5, FSP16, FWP51 and FSP77) have been isolated (Harwerth et al., J. Biol. Chem., 267, 15160-15167, 1992). In this paper we describe the effects of erbB-2 specific MAb administration on the tumorigenic growth of human erbB-2 transformed NIH3T3 cells implanted into athymic nude mice. Two antibodies, FWP51 and FSP77, inhibited the onset of tumour growth, while the administration of FRP5 and FSP16 did not affect tumour growth. In addition, administration of MAbs FWP51 and FSP77 led to a retardation in the growth of established tumours. Treatment was not curative in that tumours regrew within two weeks of the final treatment. The administration of a combination of MAbs FWP51 and FSP77 which react with two distinct regions on the erbB-2 molecule was more effective than treatment with either MAb alone. The two growth-inhibitory antibodies were also effective in the treatment of tumours established from SKOV3 cells, a human ovarian tumour cell line with high levels of the erbB-2 protein. The effect of the MAbs on the anchorage-independent growth of erbB-2 transformed cells and on erbB-2 receptor turnover was also measured.
Full text
PDF





Images in this article
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Bargmann C. I., Weinberg R. A. Increased tyrosine kinase activity associated with the protein encoded by the activated neu oncogene. Proc Natl Acad Sci U S A. 1988 Aug;85(15):5394–5398. doi: 10.1073/pnas.85.15.5394. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Batra J. K., Kasprzyk P. G., Bird R. E., Pastan I., King C. R. Recombinant anti-erbB2 immunotoxins containing Pseudomonas exotoxin. Proc Natl Acad Sci U S A. 1992 Jul 1;89(13):5867–5871. doi: 10.1073/pnas.89.13.5867. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Berger M. S., Locher G. W., Saurer S., Gullick W. J., Waterfield M. D., Groner B., Hynes N. E. Correlation of c-erbB-2 gene amplification and protein expression in human breast carcinoma with nodal status and nuclear grading. Cancer Res. 1988 Mar 1;48(5):1238–1243. [PubMed] [Google Scholar]
- Coussens L., Yang-Feng T. L., Liao Y. C., Chen E., Gray A., McGrath J., Seeburg P. H., Libermann T. A., Schlessinger J., Francke U. Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene. Science. 1985 Dec 6;230(4730):1132–1139. doi: 10.1126/science.2999974. [DOI] [PubMed] [Google Scholar]
- Di Fiore P. P., Pierce J. H., Kraus M. H., Segatto O., King C. R., Aaronson S. A. erbB-2 is a potent oncogene when overexpressed in NIH/3T3 cells. Science. 1987 Jul 10;237(4811):178–182. doi: 10.1126/science.2885917. [DOI] [PubMed] [Google Scholar]
- Drebin J. A., Link V. C., Stern D. F., Weinberg R. A., Greene M. I. Down-modulation of an oncogene protein product and reversion of the transformed phenotype by monoclonal antibodies. Cell. 1985 Jul;41(3):697–706. doi: 10.1016/s0092-8674(85)80050-7. [DOI] [PubMed] [Google Scholar]
- Harwerth I. M., Wels W., Marte B. M., Hynes N. E. Monoclonal antibodies against the extracellular domain of the erbB-2 receptor function as partial ligand agonists. J Biol Chem. 1992 Jul 25;267(21):15160–15167. [PubMed] [Google Scholar]
- Hudziak R. M., Lewis G. D., Winget M., Fendly B. M., Shepard H. M., Ullrich A. p185HER2 monoclonal antibody has antiproliferative effects in vitro and sensitizes human breast tumor cells to tumor necrosis factor. Mol Cell Biol. 1989 Mar;9(3):1165–1172. doi: 10.1128/mcb.9.3.1165. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hynes N. E. Amplification and overexpression of the erbB-2 gene in human tumors: its involvement in tumor development, significance as a prognostic factor, and potential as a target for cancer therapy. Semin Cancer Biol. 1993 Feb;4(1):19–26. [PubMed] [Google Scholar]
- Hynes N. E., Gerber H. A., Saurer S., Groner B. Overexpression of the c-erbB-2 protein in human breast tumor cell lines. J Cell Biochem. 1989 Feb;39(2):167–173. doi: 10.1002/jcb.240390208. [DOI] [PubMed] [Google Scholar]
- Kasprzyk P. G., Song S. U., Di Fiore P. P., King C. R. Therapy of an animal model of human gastric cancer using a combination of anti-erbB-2 monoclonal antibodies. Cancer Res. 1992 May 15;52(10):2771–2776. [PubMed] [Google Scholar]
- Kraus M. H., Popescu N. C., Amsbaugh S. C., King C. R. Overexpression of the EGF receptor-related proto-oncogene erbB-2 in human mammary tumor cell lines by different molecular mechanisms. EMBO J. 1987 Mar;6(3):605–610. doi: 10.1002/j.1460-2075.1987.tb04797.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Marth C., Müller-Holzner E., Greiter E., Cronauer M. V., Zeimet A. G., Doppler W., Eibl B., Hynes N. E., Daxenbichler G. Gamma-interferon reduces expression of the protooncogene c-erbB-2 in human ovarian carcinoma cells. Cancer Res. 1990 Nov 1;50(21):7037–7041. [PubMed] [Google Scholar]
- Masuko T., Sugahara K., Kozono M., Otsuki S., Akiyama T., Yamamoto T., Toyoshima K., Hashimoto Y. A murine monoclonal antibody that recognizes an extracellular domain of the human c-erbB-2 protooncogene product. Jpn J Cancer Res. 1989 Jan;80(1):10–14. doi: 10.1111/j.1349-7006.1989.tb02237.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- McKenzie S. J., Marks P. J., Lam T., Morgan J., Panicali D. L., Trimpe K. L., Carney W. P. Generation and characterization of monoclonal antibodies specific for the human neu oncogene product, p185. Oncogene. 1989 May;4(5):543–548. [PubMed] [Google Scholar]
- Meyer T., Regenass U., Fabbro D., Alteri E., Rösel J., Müller M., Caravatti G., Matter A. A derivative of staurosporine (CGP 41 251) shows selectivity for protein kinase C inhibition and in vitro anti-proliferative as well as in vivo anti-tumor activity. Int J Cancer. 1989 May 15;43(5):851–856. doi: 10.1002/ijc.2910430519. [DOI] [PubMed] [Google Scholar]
- Peles E., Levy R. B., Or E., Ullrich A., Yarden Y. Oncogenic forms of the neu/HER2 tyrosine kinase are permanently coupled to phospholipase C gamma. EMBO J. 1991 Aug;10(8):2077–2086. doi: 10.1002/j.1460-2075.1991.tb07739.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Pierce J. H., Arnstein P., DiMarco E., Artrip J., Kraus M. H., Lonardo F., Di Fiore P. P., Aaronson S. A. Oncogenic potential of erbB-2 in human mammary epithelial cells. Oncogene. 1991 Jul;6(7):1189–1194. [PubMed] [Google Scholar]
- Press M. F., Cordon-Cardo C., Slamon D. J. Expression of the HER-2/neu proto-oncogene in normal human adult and fetal tissues. Oncogene. 1990 Jul;5(7):953–962. [PubMed] [Google Scholar]
- Schechter A. L., Stern D. F., Vaidyanathan L., Decker S. J., Drebin J. A., Greene M. I., Weinberg R. A. The neu oncogene: an erb-B-related gene encoding a 185,000-Mr tumour antigen. Nature. 1984 Dec 6;312(5994):513–516. doi: 10.1038/312513a0. [DOI] [PubMed] [Google Scholar]
- Segatto O., King C. R., Pierce J. H., Di Fiore P. P., Aaronson S. A. Different structural alterations upregulate in vitro tyrosine kinase activity and transforming potency of the erbB-2 gene. Mol Cell Biol. 1988 Dec;8(12):5570–5574. doi: 10.1128/mcb.8.12.5570. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Slamon D. J., Clark G. M., Wong S. G., Levin W. J., Ullrich A., McGuire W. L. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987 Jan 9;235(4785):177–182. doi: 10.1126/science.3798106. [DOI] [PubMed] [Google Scholar]
- Slamon D. J., Godolphin W., Jones L. A., Holt J. A., Wong S. G., Keith D. E., Levin W. J., Stuart S. G., Udove J., Ullrich A. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science. 1989 May 12;244(4905):707–712. doi: 10.1126/science.2470152. [DOI] [PubMed] [Google Scholar]
- Stancovski I., Hurwitz E., Leitner O., Ullrich A., Yarden Y., Sela M. Mechanistic aspects of the opposing effects of monoclonal antibodies to the ERBB2 receptor on tumor growth. Proc Natl Acad Sci U S A. 1991 Oct 1;88(19):8691–8695. doi: 10.1073/pnas.88.19.8691. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Suda Y., Aizawa S., Furuta Y., Yagi T., Ikawa Y., Saitoh K., Yamada Y., Toyoshima K., Yamamoto T. Induction of a variety of tumors by c-erbB2 and clonal nature of lymphomas even with the mutated gene (Val659----Glu659). EMBO J. 1990 Jan;9(1):181–190. doi: 10.1002/j.1460-2075.1990.tb08094.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Varley J. M., Swallow J. E., Brammar W. J., Whittaker J. L., Walker R. A. Alterations to either c-erbB-2(neu) or c-myc proto-oncogenes in breast carcinomas correlate with poor short-term prognosis. Oncogene. 1987;1(4):423–430. [PubMed] [Google Scholar]
- Wels W., Harwerth I. M., Mueller M., Groner B., Hynes N. E. Selective inhibition of tumor cell growth by a recombinant single-chain antibody-toxin specific for the erbB-2 receptor. Cancer Res. 1992 Nov 15;52(22):6310–6317. [PubMed] [Google Scholar]
- Wels W., Harwerth I. M., Zwickl M., Hardman N., Groner B., Hynes N. E. Construction, bacterial expression and characterization of a bifunctional single-chain antibody-phosphatase fusion protein targeted to the human erbB-2 receptor. Biotechnology (N Y) 1992 Oct;10(10):1128–1132. doi: 10.1038/nbt1092-1128. [DOI] [PubMed] [Google Scholar]
- Wright C., Angus B., Nicholson S., Sainsbury J. R., Cairns J., Gullick W. J., Kelly P., Harris A. L., Horne C. H. Expression of c-erbB-2 oncoprotein: a prognostic indicator in human breast cancer. Cancer Res. 1989 Apr 15;49(8):2087–2090. [PubMed] [Google Scholar]
- Yamamoto T., Ikawa S., Akiyama T., Semba K., Nomura N., Miyajima N., Saito T., Toyoshima K. Similarity of protein encoded by the human c-erb-B-2 gene to epidermal growth factor receptor. Nature. 1986 Jan 16;319(6050):230–234. doi: 10.1038/319230a0. [DOI] [PubMed] [Google Scholar]
- Yarden Y. Agonistic antibodies stimulate the kinase encoded by the neu protooncogene in living cells but the oncogenic mutant is constitutively active. Proc Natl Acad Sci U S A. 1990 Apr;87(7):2569–2573. doi: 10.1073/pnas.87.7.2569. [DOI] [PMC free article] [PubMed] [Google Scholar]
- van de Vijver M., van de Bersselaar R., Devilee P., Cornelisse C., Peterse J., Nusse R. Amplification of the neu (c-erbB-2) oncogene in human mammmary tumors is relatively frequent and is often accompanied by amplification of the linked c-erbA oncogene. Mol Cell Biol. 1987 May;7(5):2019–2023. doi: 10.1128/mcb.7.5.2019. [DOI] [PMC free article] [PubMed] [Google Scholar]