Skip to main content
NCBI home page
Cancer Immunology, Immunotherapy : CII logoLink to Cancer Immunology, Immunotherapy : CII
. 1993 Sep;37(5):343–349. doi: 10.1007/BF01518458

Therapeutic potential of chimeric and murine anti-(epidermal growth factor receptor) antibodies in a metastasis model for human melanoma

Mayumi Naramura 1, Stephen D Gillies 2, John Mendelsohn 3, Ralph A Reisfeld 1, Barbara M Mueller 1,✉
PMCID: PMC11038331  PMID: 8402738

Abstract

On many tumors, high numbers of epidermal growth factor (EGF) receptors provide a target for antibody-mediated tumor therapy. We evaluate here the therapeutic potential of a mouse/human chimeric anti-(EGF receptor) antibody and compare it to the parental murine antibody in a xenograft model for metastatic melanoma. Our model is based on the human cell line M24met, which overexpresses the EGF receptor and metastasizes spontaneously in SCID mice. Both the chimeric anti-(EGF receptor) antibody (ch225) and the mouse monoclonal antibody (m225) exhibited saturable, high-affinity binding to M24met cells and were equivalent in their ability to target M24met tumors in mice. Neither anti-(EGF receptor) antibodies nor EGF modulated the growth of M24met cells in vitro. Further analysis revealed that the EGF receptor on these cells is not phosphorylated upon EGF binding, indicating an anomalous receptor on these cells. In antibodydependent cellular cytotoxicity experiments, ch225 and m225 were potent mediators of M24met cytolysis by effector cells. Antibody-mediated cytotoxicity revealed a marked species preference, with ch225 activating human peripheral blood mononuclear cells and m225 activating mouse splenocytes and to a lesser degree mouse macrophages. Neither antibody mediated cytolysis in the presence of human complement. In SCID mice, m225 suppressed spontaneous metastasis considerably while ch225 had only a modest effect. Our data indicate that in the M24met melanoma tumor model, anti-(EGF receptor) antibodies suppress spontaneous metastasis solely by activating immune effector cells.

Key words: Chimeric antibody, Anti-(EGF receptor) immunotherapy, Metastasis, Melanoma

Footnotes

Supported by NIH grants CA51946 (R.A.R., B.M.M., S.D.G.), CA42508 (R.A.R.), and CA37641 (J.M.) This is The Scripps Research Institute manuscript number 7960-IMM

References

  • 1.Aboud-Pirak E, Hurwitz E, Pirak ME, Bellot F, Schlessinger J, Sela M. Efficacy of antibodies to epidermal growth factor receptor against KB carcinoma in vitro and in nude mice. J Natl Cancer Inst. 1988;80:1605. doi: 10.1093/jnci/80.20.1605. [DOI] [PubMed] [Google Scholar]
  • 2.Barker E, Mueller BM, Handgretinger R, Herter M, Yu AL, Reisfeld RA. Effect of a chimeric antr-ganglioside GD2 antibody on cell-mediated lysis of human neuroblastoma cells. Cancer Res. 1991;51:144. [PubMed] [Google Scholar]
  • 3.Brady LW, Woo DV, Markoe A, Dadparvar S, Karlson U, Rackover M, Peyster P, Emrich J, Miyamoto C, Steplewski Z, Koprowski H. Treatment of malignant gliomas with125I-labeled monoclonal antibody against epidermal growth factor receptor. Antibody Immunoconj Radiopharmacol. 1990;3:169. [Google Scholar]
  • 4.Carter P, Presta L, Gorman CM, Ridgway JBB, Henner D, Wong WLT, Rowland AM, Kotts C, Carver ME, Shepard HM. Humanization of an anti-p185HER2 antibody for human cancer therapy. Proc Natl Acad Sci USA. 1992;89:4285. doi: 10.1073/pnas.89.10.4285. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Divgi CR, Welt S, Kris M, Real FX, Yeh SDJ, Gralla R, Merchant B, Schweighart S, Unger M, Larson SM, Mendelsohn J. Phase I and imaging trial of indium 111-labeled anti epidermal growth factor receptor monoclonal antibody 225 in patients with squamous cell lung carcinoma. J Natl Cancer Inst. 1991;83:97. doi: 10.1093/jnci/83.2.97. [DOI] [PubMed] [Google Scholar]
  • 6.Elder DE, Rodeck U, Thurin J, Cardillo F, Clark WH, Stewart R, Herlyn M. Antigenic profile of tumor progression stages in human melanocytic nevi and melanomas. Cancer Res. 1989;49:5091. [PubMed] [Google Scholar]
  • 7.Gillies SD, Lo KM, Wesolowski J. High-level expression of chimeric antibodies using adapted cDNA variable region cassettes. J Immunol Methods. 1989;125:191. doi: 10.1016/0022-1759(89)90093-8. [DOI] [PubMed] [Google Scholar]
  • 8.Herlyn D, Koprowski H. IgG2a monoclonal antibodies inhibit human tumor growth through interaction with effector cells. Proc Natl Acad Sci USA. 1982;79:4761. doi: 10.1073/pnas.79.15.4761. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Kawamoto T, Sato JD, Le A, Polikoff J, Sato GH, Mendelsohn J. Growth stimulation of A431 cells by EGF: identification of high affinity receptors for epidermal growth factor by an anti-receptor monoclonal antibody. Proc Natl Acad Sci USA. 1983;80:1337. doi: 10.1073/pnas.80.5.1337. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Khazaeli MB, Saleh MN, Liu TP, Meredith RF, Wheeler RH, Baker TS, King D, Secher D, Allen L, Rogers K, Colcher D, Schlom J, Shochat D, LoBuglio AF. Pharmacokinetics and immune response of131I-chimeric mouse/human B72.3 (human γ4) monoclonal antibody in humans. Cancer Res. 1991;51:5461. [PubMed] [Google Scholar]
  • 11.Kipps TJ, Parham P, Punt J, Herzenberg LA. Importance of immunoglobulin isotype in human antibody-dependent, cell-mediated cytotoxicity directed by murine monoclonal antibodies. J Exp Med. 1985;161:1. doi: 10.1084/jem.161.1.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Liu AY, Robinson RR, Hellström KE, Murray ED, Jr, Chang CP, Hellström I. Chimeric mouse-human IgGI antibody that can mediate lysis of cancer cells. Proc Natl Acad Sci USA. 1987;84:3439. doi: 10.1073/pnas.84.10.3439. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Liu AY, Robinson RR, Murray ED, Jr, Ledbetter JA, Hellström I, Hellström KE. Production of a mouse-human chimeric monoclonal antibody to CD20 with potent Fc-dependent biologic activity. J Immunol. 1987;139:3521. [PubMed] [Google Scholar]
  • 14.LoBuglio AF, Wheeler RH, Trang J, Haynes A, Rogers K, Harvey EB, Sun L, Ghrayeb J, Khazaeli MB. Mouse/human chimeric monoclonal antibody in man: kinetics and immune response. Proc Natl Acad Sci USA. 1989;86:4220. doi: 10.1073/pnas.86.11.4220. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Masui H, Kawamoto T, Sato JD, Wolf B, Sato G, Mendelsohn J. Growth inhibition of human tumor cells in athymic mice by anti-epidermal growth factor receptor monoclonal antibodies. Cancer Res. 1984;44:1002. [PubMed] [Google Scholar]
  • 16.Masui H, Moroyama T, Mendelsohn J. Mechanism of antitumor activity in mice for anti-epidermal growth factor receptor monoclonal antibodies with different isotypes. Cancer Res. 1986;46:5592. [PubMed] [Google Scholar]
  • 17.Mendelsohn J. Growth factor receptors as targets for antitumor therapy with monoclonal antibodies. In: Waldmann H, editor. Monoclonal antibody therapy Prog Allergy. Basel: Karger; 1988. p. 147. [DOI] [PubMed] [Google Scholar]
  • 18.Morrison SL. In vitro antibodies: strategies for production and application. Annu Rev Immunol. 1992;10:239. doi: 10.1146/annurev.iy.10.040192.001323. [DOI] [PubMed] [Google Scholar]
  • 19.Mueller BM, Romerdahl CA, Gillies SD, Reisfeld RA. Enhancement of antibody-dependent cytotoxicity with a chimeric anti-GD2 antibody. J Immunol. 1990;144:1382. [PubMed] [Google Scholar]
  • 20.Mueller BM, Romerdahl CA, Trent JM, Reisfeld RA. Suppression of spontaneous melanoma metastasis in SCID mice with an antibody to the epidermal growth factor receptor. Cancer Res. 1991;51:2193. [PubMed] [Google Scholar]
  • 21.Real FX, Rettig WJ, Chesa PG, Melamed MR, Old LJ, Mendelsohn J. Expression of epidermal frowth factor receptor in human cultured cells and tissues: relationship to cell lineage and stage of differentiation. Cancer Res. 1986;46:4726. [PubMed] [Google Scholar]
  • 22.Rodeck U, Herlyn M, Herlyn D, Molthoff C, Atkinson B, Varello M, Steplewski Z, Koprowski H. Tumor growth modulation by a monoclonal antibody to the epidermal growth factor receptor: immunologically mediated and effector cell-independent effects. Cancer Res. 1987;47:3692. [PubMed] [Google Scholar]
  • 23.Rodeck U, Herlyn M, Menssen HD, Furlanetto RW, Korprowski H. Metastatic but not primary melanoma cell lines grow in vitro independently of exogenous growth factors. Int J Cancer. 1987;40:687. doi: 10.1002/ijc.2910400520. [DOI] [PubMed] [Google Scholar]
  • 24.Steplewski Z, Spira G, Blaszczyk M, Lubeck MD, Radbruch A, Illges H, Herlyn D, Rajewsky K, Scharff M. Isolation and characterization of anti-monosialoganglioside monoclonal antibody 19-9 class-switch variants. Proc Natl Acad Sci USA. 1985;82:8652. doi: 10.1073/pnas.82.24.8653. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Steplewski Z, Sun LK, Shearman CW, Ghrayeb J, Daddona P, Koprowski H. Biological activity of human-mouse IgG1, IgG2, IgG3, and IgG4 chimeric monoclonal antibodies with anti-tumor specificity. Proc Natl Acad Sci USA. 1988;85:4852. doi: 10.1073/pnas.85.13.4852. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Ullrich A, Schlessinger J. Signal transduction by receptors with tyrosine kinase activity. Cell. 1990;61:203. doi: 10.1016/0092-8674(90)90801-k. [DOI] [PubMed] [Google Scholar]
  • 27.Van de Vijver MJ, Kumar R, Mendelsohn J. Ligand-induced activation of A431 cell epidermal growth factor receptors occurs primarily by an autocrine pathway that acts upon receptors on the surface rather than intracellularly. J Biol Chem. 1991;266:7503. [PubMed] [Google Scholar]

Articles from Cancer Immunology, Immunotherapy : CII are provided here courtesy of Springer

RESOURCES