Skip to main content
SpringerLink
Log in

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

  • Original Articles
  • Chimeric Antibody, Anti-(EGF Receptor) Immunotherapy, Metastasis, Melanoma
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Aboud-Pirak E, Hurwitz E, Pirak ME, Bellot F, Schlessinger J, Sela M (1988) Efficacy of antibodies to epidermal growth factor receptor against KB carcinoma in vitro and in nude mice. J Natl Cancer Inst 80: 1605

    PubMed  Google Scholar 

  2. Barker E, Mueller BM, Handgretinger R, Herter M, Yu AL, Reisfeld RA (1991) Effect of a chimeric antr-ganglioside GD2 antibody on cell-mediated lysis of human neuroblastoma cells. Cancer Res 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 (1990) Treatment of malignant gliomas with125I-labeled monoclonal antibody against epidermal growth factor receptor. Antibody Immunoconj Radiopharmacol 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 (1992) Humanization of an anti-p185HER2 antibody for human cancer therapy. Proc Natl Acad Sci USA 89: 4285

    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 (1991) 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 83: 97

    PubMed  Google Scholar 

  6. Elder DE, Rodeck U, Thurin, J, Cardillo F, Clark WH, Stewart R, Herlyn M (1989) Antigenic profile of tumor progression stages in human melanocytic nevi and melanomas. Cancer Res 49: 5091

    PubMed  Google Scholar 

  7. Gillies SD, Lo KM, Wesolowski J (1989) High-level expression of chimeric antibodies using adapted cDNA variable region cassettes. J Immunol Methods 125: 191

    PubMed  Google Scholar 

  8. Herlyn D, Koprowski H (1982) IgG2a monoclonal antibodies inhibit human tumor growth through interaction with effector cells. Proc Natl Acad Sci USA 79: 4761

    PubMed  Google Scholar 

  9. Kawamoto T, Sato JD, Le A, Polikoff J, Sato GH, Mendelsohn J (1983) 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 80: 1337

    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 (1991) Pharmacokinetics and immune response of131I-chimeric mouse/human B72.3 (human γ4) monoclonal antibody in humans. Cancer Res 51: 5461

    PubMed  Google Scholar 

  11. Kipps TJ, Parham P, Punt J, Herzenberg LA (1985) Importance of immunoglobulin isotype in human antibody-dependent, cell-mediated cytotoxicity directed by murine monoclonal antibodies. J Exp Med 161: 1

    PubMed  Google Scholar 

  12. Liu AY, Robinson RR, Hellström KE, Murray ED Jr, Chang, CP, Hellström I (1987) Chimeric mouse-human IgGI antibody that can mediate lysis of cancer cells. Proc Natl Acad Sci USA 84: 3439

    PubMed  Google Scholar 

  13. Liu AY, Robinson RR, Murray ED Jr, Ledbetter JA, Hellström I, Hellström KE (1987) Production of a mouse-human chimeric monoclonal antibody to CD20 with potent Fc-dependent biologic activity. J Immunol 139: 3521

    PubMed  Google Scholar 

  14. LoBuglio AF, Wheeler RH, Trang, J, Haynes A, Rogers K, Harvey EB, Sun L, Ghrayeb J, Khazaeli MB (1989) Mouse/human chimeric monoclonal antibody in man: kinetics and immune response. Proc Natl Acad Sci USA 86: 4220

    PubMed  Google Scholar 

  15. Masui H, Kawamoto T, Sato JD, Wolf B, Sato G, Mendelsohn J (1984) Growth inhibition of human tumor cells in athymic mice by anti-epidermal growth factor receptor monoclonal antibodies. Cancer Res 44: 1002

    PubMed  Google Scholar 

  16. Masui H, Moroyama T, Mendelsohn J (1986) Mechanism of antitumor activity in mice for anti-epidermal growth factor receptor monoclonal antibodies with different isotypes. Cancer Res 46: 5592

    PubMed  Google Scholar 

  17. Mendelsohn J (1988) Growth factor receptors as targets for antitumor therapy with monoclonal antibodies. In: Waldmann H (ed) Monoclonal antibody therapy Prog Allergy Karger, Basel, p 147

    Google Scholar 

  18. Morrison SL (1992) In vitro antibodies: strategies for production and application. Annu Rev Immunol 10: 239

    PubMed  Google Scholar 

  19. Mueller BM, Romerdahl CA, Gillies SD, Reisfeld RA (1990) Enhancement of antibody-dependent cytotoxicity with a chimeric anti-GD2 antibody. J Immunol 144: 1382

    PubMed  Google Scholar 

  20. Mueller BM, Romerdahl CA, Trent JM, Reisfeld RA (1991) Suppression of spontaneous melanoma metastasis in SCID mice with an antibody to the epidermal growth factor receptor. Cancer Res 51: 2193

    PubMed  Google Scholar 

  21. Real FX, Rettig WJ, Chesa PG, Melamed MR, Old LJ, Mendelsohn J (1986) Expression of epidermal frowth factor receptor in human cultured cells and tissues: relationship to cell lineage and stage of differentiation. Cancer Res 46: 4726

    PubMed  Google Scholar 

  22. Rodeck, U, Herlyn M, Herlyn D, Molthoff C, Atkinson B, Varello M, Steplewski Z, Koprowski H (1987) Tumor growth modulation by a monoclonal antibody to the epidermal growth factor receptor: immunologically mediated and effector cell-independent effects. Cancer Res 47: 3692

    PubMed  Google Scholar 

  23. Rodeck U, Herlyn M, Menssen HD, Furlanetto RW, Korprowski H (1987) Metastatic but not primary melanoma cell lines grow in vitro independently of exogenous growth factors. Int J Cancer 40: 687

    PubMed  Google Scholar 

  24. Steplewski Z, Spira G, Blaszczyk M, Lubeck MD, Radbruch A, Illges H, Herlyn D, Rajewsky K, Scharff M (1985) Isolation and characterization of anti-monosialoganglioside monoclonal antibody 19-9 class-switch variants. Proc Natl Acad Sci USA 82: 8652

    Google Scholar 

  25. Steplewski Z, Sun LK, Shearman CW, Ghrayeb J, Daddona P, Koprowski H (1988) Biological activity of human-mouse IgG1, IgG2, IgG3, and IgG4 chimeric monoclonal antibodies with anti-tumor specificity. Proc Natl Acad Sci USA 85: 4852

    PubMed  Google Scholar 

  26. Ullrich A, Schlessinger J (1990) Signal transduction by receptors with tyrosine kinase activity. Cell 61: 203

    PubMed  Google Scholar 

  27. Van de Vijver MJ, Kumar R, Mendelsohn J (1991) 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 266: 7503

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Dept. of Immunology, The Scripps Research Institute, IMM13, 10666 N. Torrey Pines Road, 92037, La Jolla, CA, USA

    Mayumi Naramura, Ralph A. Reisfeld & Barbara M. Mueller

  2. Fuji Immuno Pharmaceuticals Corp., 02173, Lexington, MA, USA

    Stephen D. Gillies

  3. Memorial Sloan-Kettering Cancer Center, 10021, New York, NY, USA

    John Mendelsohn

Authors
  1. Mayumi Naramura
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Stephen D. Gillies
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. John Mendelsohn
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ralph A. Reisfeld
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Barbara M. Mueller
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

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

Rights and permissions

Reprints and permissions

About this article

Cite this article

Naramura, M., Gillies, S.D., Mendelsohn, J. et al. Therapeutic potential of chimeric and murine anti-(epidermal growth factor receptor) antibodies in a metastasis model for human melanoma. Cancer Immunol Immunother 37, 343–349 (1993). https://doi.org/10.1007/BF01518458

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01518458

Key words

Search

Navigation