Antibody Therapy for Solid Tumors

  • Cristina I. Truica
  • Dorinda Rouch
  • Carlos L. Arteaga
Part of the Cancer Drug Discovery and Development book series (CDD&D)


Over the last several years the use of monoclonal antibody (MAb) therapy for the treatment of human malignancy has advanced from experimental therapy to standard of care for some malignancies. The success of MAb therapy stems not only from the ability to humanize the antibody, thus, decreasing the inherent immunogenicity of the approach but also from targeting appropriate proteins. Human cancers associated with the overexpression of particular growth factor receptors such as HER-2/neu, epidermal growth factor receptor, and vascular endothelial growth factor, have been impacted by commercially available antibodies. This review focuses on the mechanisms of action and clinical benefit of MAb therapy against common growth factor receptors.

Key Words

Monoclonal antibody EGFR HER-2/neu VEGF growth factor receptors 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Harris M. Monoclonal antibodies as therapeutic agents for cancer. Lancet Oncol 2004; 5:292–302.PubMedCrossRefGoogle Scholar
  2. 2.
    Holbro T, Hynes NE. ErbB receptors: directing key signaling networks throughout life. Annu Rev Pharmacol Toxicol 2004; 44:195–217.PubMedCrossRefGoogle Scholar
  3. 3.
    Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2001; 2:127–137.PubMedCrossRefGoogle Scholar
  4. 4.
    Normanno N, Bianco C, De Luca A, Salomon DS. The role of EGF-related peptides in tumor growth. Front Biosci 2001; 6:D685–D707.PubMedCrossRefGoogle Scholar
  5. 5.
    Graus-Porta D, Beerli RR, Daly JM, Hynes NE. ErbB-2, the preferred heterodimerization partner of all ErbB receptors, is a mediator of lateral signaling. EMBO J 1997; 16:1647–1655.PubMedCrossRefGoogle Scholar
  6. 6.
    Holbro T, Beerli RR, Maurer F, Koziczak M, Barbas CF III, Hynes NE. The ErbB2/ErbB3 heterodimer functions as an oncogenic unit: ErbB2 requires ErbB3 to drive breast tumor cell proliferation. Proc Natl Acad Sci USA 2003; 100:8933–8938.PubMedCrossRefGoogle Scholar
  7. 7.
    Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004; 304:1497–1500.PubMedCrossRefGoogle Scholar
  8. 8.
    Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004; 350:2129–2139.PubMedCrossRefGoogle Scholar
  9. 9.
    Pao W, Miller V, Zakowski M, et al. EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci USA 2004; 101:13,306–13,311.PubMedCrossRefGoogle Scholar
  10. 10.
    Slamon DJ, Godolphin W, Jones LA, et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 1989; 244:707–712.PubMedCrossRefGoogle Scholar
  11. 11.
    Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 1987; 235:177–182.PubMedCrossRefGoogle Scholar
  12. 12.
    Sliwkowski MX, Schaefer G, Akita RW, et al. Coexpression of erbB2 and erbB3 proteins reconstitutes a high affinity receptor for heregulin. J Biol Chem 1994; 269:14,661–14,665.PubMedGoogle Scholar
  13. 13.
    Petit AM, Rak J, Hung MC, et al. Neutralizing antibodies against epidermal growth factor and ErbB-2/neureceptor tyrosine kinases down-regulate vascular endothelial growth factor production by tumor cells in vitro and in vivo: angiogenic implications for signal transduction therapy of solid tumors. Am J Pathol 1997; 151:1523–1530.PubMedGoogle Scholar
  14. 14.
    Benz CC, Scott GK, Sarup JC, et al. Estrogen-dependent, tamoxifen-resistant tumorigenic growth of MCF-7 cells transfected with HER2/neu. Breast Cancer Res Treat 1993; 24:85–95.CrossRefGoogle Scholar
  15. 15.
    Carter P, Presta L, Gorman CM, et al. Humanization of an anti-p185HER2 antibody for human cancer therapy. Proc Natl Acad Sci USA 1992; 89:4285–4289.PubMedCrossRefGoogle Scholar
  16. 16.
    Lewis GD, Figari I, Fendly B, et al. Differential responses of human tumor cell lines to anti-p185HER2 monoclonal antibodies. Cancer Immunol Immunother 1993; 37:255–263.PubMedCrossRefGoogle Scholar
  17. 17.
    Arteaga CL. Trastuzumab, an appropriate first-line single-agent therapy for HER2-overexpressing metastatic breast cancer. Breast Cancer Res 2002; 5:96–100.CrossRefGoogle Scholar
  18. 18.
    Hudziak RM, Lewis GD, Winget M, Fendly BM, Shepard HM, Ullrich A. p185HER2 monoclonal antibody has antiproliferative effects in vitro and sensitizes human breast tumor cells to tumor necrosis factor. Mol Cell Biol 1989; 9:1165–1172.PubMedGoogle Scholar
  19. 19.
    Drebin JA, Link VC, Stern DF, Weinberg RA, Greene MI. Down-modulation of an oncogene protein product and reversion of the transformed phenotype by monoclonal antibodies. Cell 1985; 41:697–706.PubMedCrossRefGoogle Scholar
  20. 20.
    Klapper LN, Waterman H, Sela M, Yarden Y. Tumor-inhibitory antibodies to HER-2/ErbB-2 may act by recruiting c-Cbl and enhancing ubiquitination of HER-2. Cancer Res 2000; 60:3384–3388.PubMedGoogle Scholar
  21. 21.
    Yakes FM, Chinratanalab W, Ritter CA, King W, Seelig S, Arteaga CL. Herceptin-induced inhibition of phosphatidylinositol-3 kinase and Akt Is required for antibody-mediated effects on p27, cyclin D1, and antitumor action. Cancer Res 2002; 62:4132–4141.PubMedGoogle Scholar
  22. 22.
    Clynes RA, Towers TL, Presta LG, Ravetch JV. Inhibitory Fc receptors modulate in vivo cytoxicity against tumor targets. Nat Med 2000; 6:443–446.PubMedCrossRefGoogle Scholar
  23. 23.
    Gennari R, Menard S, Fagnoni F, et al. Pilot study of the mechanism of action of preoperative trastuzumab in patients with primary operable breast tumors overexpressing HER2. Clinical Cancer Res 2004; 10:5650–5655.CrossRefGoogle Scholar
  24. 24.
    Mass R. The role of HER-2 expression in predicting response to therapy in breast cancer. Semin Oncol 2000; 27:46–52; discussion 92–100.PubMedGoogle Scholar
  25. 25.
    Jacobs TW, Gown AM, Yaziji H, Barnes MJ, Schnitt SJ. Comparison of fluorescence in situ hybridization and immunohistochemistry for the evaluation of HER-2/neu in breast cancer. J Clin Oncol 1999; 17:1974–1982.PubMedGoogle Scholar
  26. 26.
    Leyland-Jones B, Gelmon K, Ayoub JP, et al. Pharmacokinetics, safety, and efficacy of trastuzumab administered every three weeks in combination with paclitaxel. J Clin Oncol 2003; 21:3965–3971.PubMedCrossRefGoogle Scholar
  27. 27.
    Suter TM, Cook-Bruns N, Barton C. Cardiotoxicity associated with trastuzumab (Herceptin) therapy in the treatment of metastatic breast cancer. Breast 2004; 13:173–183.PubMedCrossRefGoogle Scholar
  28. 28.
    Cobleigh MA, Vogel CL, Tripathy D, et al. Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol 1999; 17:2639–2648.PubMedGoogle Scholar
  29. 29.
    Vogel CL, Cobleigh MA, Tripathy D, et al. Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol 2002; 20:719–726.PubMedCrossRefGoogle Scholar
  30. 30.
    Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001; 344:783–792.PubMedCrossRefGoogle Scholar
  31. 31.
    Pegram MD, Konecny GE, O’Callaghan C, Beryt M, Pietras R, Slamon DJ. Rational combinations of trastuzumab with chemotherapeutic drugs used in the treatment of breast cancer. J Natl Cancer Inst 2004; 96:739–749.PubMedCrossRefGoogle Scholar
  32. 32.
    Pegram MD, Pienkowski T, Northfelt DW, et al. Results of two open-label, multicenter phase II studies of docetaxel, platinum salts, and trastuzumab in HER2-positive advanced breast cancer. J Natl Cancer Inst 2004; 96:759–769.PubMedGoogle Scholar
  33. 33.
    Burstein HJ, Harris LN, Marcom PK, et al. Trastuzumab and vinorelbine as first-line therapy for HER2-overexpressing metastatic breast cancer: multicenter phase II trial with clinical outcomes, analysis of serum tumor markers as predictive factors, and cardiac surveillance algorithm. J Clin Oncol 2003; 21:2889–2895.PubMedCrossRefGoogle Scholar
  34. 34.
    Van Pelt AE, Mohsin S, Elledge RM, et al. Neoadjuvant trastuzumab and docetaxel in breast cancer: preliminary results. Clin Breast Cancer 2003; 4:348–353.PubMedCrossRefGoogle Scholar
  35. 35.
    Langer CJ, Stephenson P, Thor A, Vangel M, Johnson DH. Trastuzumab in the treatment of advanced non-small-cell lung cancer: is there a role? Focus on Eastern Cooperative Oncology Group study 2598. J Clin Oncol 2004; 22:1180–1187.PubMedCrossRefGoogle Scholar
  36. 36.
    Ziada A, Barqawi A, Glode LM, et al. The use of trastuzumab in the treatment of hormone refractory prostate cancer; phase II trial. Prostate 2004; 60:332–337.PubMedCrossRefGoogle Scholar
  37. 37.
    Salomon DS, Brandt R, Ciardiello F, Normanno N. Epidermal growth factor-related peptides and their receptors in human malignancies. Crit Rev Oncol Hematol 1995; 19:183–232.PubMedCrossRefGoogle Scholar
  38. 38.
    Arteaga CL, Baselga J. Clinical trial design and end points for epidermal growth factor receptor-targeted therapies: implications for drug development and practice. Clin Cancer Res 2003; 9:1579–1589.PubMedGoogle Scholar
  39. 39.
    Arteaga CL. ErbB-targeted therapeutic approaches in human cancer. Exp Cell Res 2003; 284:122–130.PubMedCrossRefGoogle Scholar
  40. 40.
    Goldstein NI, Prewett M, Zuklys K, Rockwell P, Mendelsohn J. Biological efficacy of a chimeric antibody to the epidermal growth factor receptor in a human tumor xenograft model. Clin Cancer Res 1995; 1:1311–1318.PubMedGoogle Scholar
  41. 41.
    Saltz L, Rubin M, Hochster H, et al. Cetuximab (IMC-225) plus irinotecan (CPT-11) is active in CPT-11-refractory colorectal cancer that expresses epidermal growth factor receptors. Proc Am Soc Clin Oncol 2001; 20:3a.Google Scholar
  42. 42.
    Saltz L, Meropol NJ, Loehrer PJ, Waksal H, Needle MN, Mayer RJ. Single agent IMC-C225 (Erbitux) has activity in CPT-11-refractory colorectal cancer (CRC) that expresses the epidermal growth factor receptor (EGFR). Proc Am Soc Clin Oncol 2002; 21:127a.Google Scholar
  43. 43.
    Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and cetuximab plus Irinotecan in Irinotecan-refractory Metastatic Colorectal Cancer. N Engl J Med 2004; 351:337–345.PubMedCrossRefGoogle Scholar
  44. 44.
    Gatzemeieer U, Rosell R, Ramlau R, et al. Cetuximab (c225) in combination with cisplatin/vinorelbine vs. cisplatin/vinorelbine alone in the first-line treatment of patients with epidermal growth factor receptor positive advanced non-small cell lung cancer. Proc Am Soc Clin Oncol 2003; 22:642.Google Scholar
  45. 45.
    Kim ES, Mauer Am, Tran HT, et al. A Phase II study of cetuximab, an epidermal growth factor receptor (EGFR) blocking antibody, in combination with docetaxel in chemotherapy refractory/resistant patients with advanced non-small cell lung cancer. Proc Am Soc Clin Oncol 2003; 22:642.Google Scholar
  46. 46.
    Robert F, Ezekiel MP, Spencer SA, et al. Phase I study of an anti-epidermal growth factor receptor antibody cetuximab in combination with radiation therapy in patients with advanced head and neck cancer. J Clin Oncol 2001; 19:3234–3243.PubMedGoogle Scholar
  47. 47.
    Tabernero J, Rojo F, Jimenez E, et al. A phase I pharmacokinetic (PK) and serial tumor and skin pharmacodynamic (PD) study of weekly, every 2 weeks or every 3 weeks 1-hour (h) infusion EMD72000, an humanized monoclonal anti-epidermal growth factor receptor (EGFR) antibody, in patients (pt) with advanced tumors. Proc Am Soc Clin Oncol 2003; 22:192.Google Scholar
  48. 48.
    Lynch DH, Yang XD. Therapeutic potential of ABX-EGF: a fully human anti-epidermal growth factor receptor monoclonal antibody for cancer treatment. Semin Oncol 2002; 29:47–50.PubMedCrossRefGoogle Scholar
  49. 49.
    Carmeliet P. Angiogenesis in health and disease. Nat Med 2003; 9:653–660.PubMedCrossRefGoogle Scholar
  50. 50.
    Ferrara N. VEGF and the quest for tumour angiogenesis factors. Nat Rev Cancer 2002; 2:795–803.PubMedCrossRefGoogle Scholar
  51. 51.
    Ferrara N. Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev 2004; 25:581–611.PubMedCrossRefGoogle Scholar
  52. 52.
    Willett CG, Boucher Y, di Tomaso E, et al. Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med 2004; 10:145–147.PubMedCrossRefGoogle Scholar
  53. 53.
    Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004; 350:2335–2342.PubMedCrossRefGoogle Scholar
  54. 54.
    George DJ, Kaelin WG Jr. The von Hippel-Lindau protein, vascular endothelial growth factor, and kidney cancer. N Engl J Med 2003; 349:419–421.PubMedCrossRefGoogle Scholar
  55. 55.
    Yang JC, Haworth L, Sherry RM, et al. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 2003; 349:427–434.PubMedCrossRefGoogle Scholar
  56. 56.
    Chen HX. Expanding the clinical development of bevacizumab. Oncologist 2003; 9(Suppl 1):27–35.Google Scholar
  57. 57.
    Riethmuller G, Holz E, Schlimok G, et al. Monoclonal antibody therapy for resected Dukes’ C colorectal cancer: seven-year outcome of a multicenter randomized trial. J Clin Oncol 1998; 16:1788–1794.PubMedGoogle Scholar

Copyright information

© Humana Press Inc., Totowa, NJ 2006

Authors and Affiliations

  • Cristina I. Truica
    • 1
  • Dorinda Rouch
    • 1
  • Carlos L. Arteaga
    • 1
  1. 1.Departments of Medicine and Cancer Biology and Breast Cancer Program, Vanderbilt-Ingram Comprehensive Cancer CenterVanderbilt University School of MedicineNashville

Personalised recommendations