Skip to main content
PMC home page
Cancer Science logoLink to Cancer Science
. 2005 Aug 31;95(8):621–625. doi: 10.1111/j.1349-7006.2004.tb03319.x

Monoclonal antibodies as effective therapeutic agents for solid tumors

Yuji Hinoda 1,✉, Shigeru Sasaki 2, Tadao Ishida 2, Kohzoh Imai 2
PMCID: PMC11159998  PMID: 15298722

Abstract

Monoclonal antibodies (mAbs) against growth factors or their receptors have been revealed to be effective therapeutic agents for solid tumors. Trastuzumab (humanized anti‐HER2 mAb) is the first mAb approved for the treatment of a solid tumor, metastatic breast cancer. Large‐scale phase III clinical trials are now ongoing to further evaluate the additive effects on chemotherapy and the efficacy as a maintenance monotherapy. Another anti‐HER2 mAb CH401 that we developed also seems to have good potential. This chimeric mAb completely suppressed the growth of established human tumor xenografts in SCID mice after a single injection. Furthermore, CH401 characteristically showed much stronger induction of apoptosis in HER2‐overexpressing gastric cancer cells compared to trastuzumab. Additional targets now being intensively evaluated are epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF). Both cetuximab (chimeric anti‐EGFR mAb) and bevacizumab (humanized anti‐VEGF mAb) have recently been shown to be of clinical value for metastatic colorectal cancer. Anti‐idiotype mAbs are unique as active immunotherapeutic agents, and survival benefits have been observed in clinical trials for solid tumors.

Abbreviations:

mAb

monoclonal antibody

HER2

human epidermal growth factor receptor 2

ADCC

antibody‐dependent cell‐mediated cytotoxicity

SCID

severe combined immunodeficiency

MARK

mitogen‐activated protein kinase

JNK

c‐Jun N‐terminal kinase

EGFR

epidermal growth factor receptor

VEGF

vascular endothelial growth factor

VEGFR

VEGF receptor

5‐FU

5‐fluorouracil

LV

leucovorin

References

  • 1. Köhler G, Milstein C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 1975; 256: 495–7. [DOI] [PubMed] [Google Scholar]
  • 2. Maloney DG, Grillo‐Lopez AJ, White CA, Bodkin D, Schilder RJ, Neidhart JA, Janakiraman N, Foon KA, Liles TM, Dallaire BK, Wey K, Royston I, Davis T, Levy R. IDEC‐C2B8 (Rituximab) anti‐CD20 monoclonal antibody therapy in patients with relapsed low‐grade non‐Hodgkin's lymphoma. Blood 1997; 90: 2188–95. [PubMed] [Google Scholar]
  • 3. Pegram MD, Lipton A, Hayes DF, Weber BL, Baselga JM, Tripathy D, Baly D, Baughman SA, Twaddell T, Glaspy JA, Slamon DJ. Phase II study of receptor‐enhanced chemosensitivity using recombinant humanized anti‐p185HER2/neu monoclonal antibody plus cisplatin in patients with HER2/neu‐overexpressing metastatic breast cancer refractory to chemotherapy treatment. J Clin Oncol 1998; 16: 2659–71. [DOI] [PubMed] [Google Scholar]
  • 4. Ishida T, Tsujisaki M, Hanzawa Y, Hirakawa T, Hinoda Y, Imai K, Yachi A. Significance of erbB‐2 gene product as a target molecule for cancer therapy. Scand J Immunol 1994; 39: 459–66. [DOI] [PubMed] [Google Scholar]
  • 5. Nahta R, Hung MC, Esteva FJ. The HER‐2‐targeting antibodies trastuzumab and pertuzumab synergistically inhibit the survival of breast cancer cells. Cancer Res 2004; 64: 2343–6. [DOI] [PubMed] [Google Scholar]
  • 6. Lum LG, Rathore R, Cummings F, Colvin GA, Radie‐Keane K, Maizel A, Quesenberry PJ, Elfenbein GJ. Phase I/II study of treatment of stage IV breast cancer with OKT3×trastuzumab‐armed activated T cells. Clin Breast Cancer 2003; 4: 212–7. [DOI] [PubMed] [Google Scholar]
  • 7. Repp R, van Ojik HH, Valerius T, Groenewegen G, Wieland G, Oetzel C, Stockmeyer B, Becker W, Eisenhut M, Steininger H, Deo YM, Blijham GH, Kalden JR, van de Winkel JG, Gramatzki M. Phase I clinical trial of the bispecific antibody MDX‐H210 (anti‐FcgammaRI×anti‐HER‐2/neu) in combination with Filgrastim (G‐CSF) for treatment of advanced breast cancer. Br J Cancer 2003; 89: 2234–43. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8. Mendelsohn J. Antibody‐mediated EGF receptor blockade as an anticancer therapy: from the laboratory to the clinic. Cancer Immunol Immunother 2003; 52: 342–6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9. Modjtahedi H, Hickish T, Nicolson M, Moore J, Styles J, Eccles S, Jackson E, Salter J, Sloane J, Spencer L, Priest K, Smith I, Dean C, Gore M. Phase I trial and tumour localisation of the anti‐EGFR monoclonal antibody ICR62 in head and neck or lung cancer. Br J Cancer 1996; 73: 228–35. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10. Yang XD, Jia XC, Corvalan JR, Wang P, Davis CG. Development of ABX‐EGF, a fully human anti‐EGF receptor monoclonal antibody, for cancer therapy. Crit Rev Oncol Hematol 2001; 38: 17–23. [DOI] [PubMed] [Google Scholar]
  • 11. Crombet T, Torres L, Neninger E, Catala M, Solano ME, Perera A, Torres O, Iznaga N, Torres F, Perez R, Lage A. Pharmacological evaluation of humanized anti‐epidermal growth factor receptor, monoclonal antibody h‐R3, in patients with advanced epithelial‐derived cancer. J Immunother 2003; 26: 139–48. [DOI] [PubMed] [Google Scholar]
  • 12. Vanhoefer U, Tewes M, Rojo F, Dirsch O, Schleucher N, Rosen O, Tillner J, Kovar A, Braun AH, Trarbach T, Seeber S, Harstrick A, Baselga J. Phase I study of the humanized antiepidermal growth factor receptor monoclonal antibody EMD72000 in patients with advanced solid tumors that express the epidermal growth factor receptor. J Clin Oncol 2004; 22: 175–84. [DOI] [PubMed] [Google Scholar]
  • 13. Curnow RT. Clinical experience with CD64‐directed immunotherapy. An overview. Cancer Immunol Immunother 1997; 45: 210–5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14. Fernando NH, Hurwitz HI. Inhibition of vascular endothelial growth factor in the treatment of colorectal cancer. Semin Oncol 2003; 30: 39–50. [DOI] [PubMed] [Google Scholar]
  • 15. Jayson GC, Zweit J, Jackson A, Mulatero C, Julyan P, Ranson M, Broughton L, Wagstaff J, Hakannson L, Groenewegen G, Bailey J, Smith N, Hastings D, Lawrance J, Haroon H, Ward T, McGown AT, Tang M, Levitt D, Marreaud S, Lehmann FF, Herold M, Zwierzina H European Organisation for Research and Treatment of Cancer Biological Therapeutic Development Group. Molecular imaging and biological evaluation of HuMV833 anti‐VEGF antibody: implications for trial design of antiangiogenic antibodies. J Natl Cancer Inst 2002; 94: 1484–93. [DOI] [PubMed] [Google Scholar]
  • 16. Posey JA, Ng TC, Yang B, Khazaeli MB, Carpenter MD, Fox F, Needle M, Waksal H, LoBuglio AF. A phase I study of anti‐kinase insert domain‐containing receptor antibody, IMC‐1C11, in patients with liver metastases from colorectal carcinoma. Clin Cancer Res 2003; 9: 1323–32. [PubMed] [Google Scholar]
  • 17. Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE, Levin WJ, Stuart SG, Udove J, Ullrich A et al. Studies of the HER‐2/neu proto‐on‐cogene in human breast and ovarian cancer. Science 1989; 244: 707–12. [DOI] [PubMed] [Google Scholar]
  • 18. Clark GM, McGuire WL. Follow‐up study of HER‐2/neu amplification in primary breast cancer. Cancer Res 1991; 51: 944–8. [PubMed] [Google Scholar]
  • 19. Tan AR, Swain SM. Ongoing adjuvant trials with trastuzumab in breast cancer. Semin Oncol 2003; 30: 54–64. [DOI] [PubMed] [Google Scholar]
  • 20. Sawaki M, Ito Y, Tada K, Mizunuma N, Takahashi S, Horikoshi N, Kasumi F, Akiyama F, Sakamoto G, Imai T, Nakao A, Hatake K. Efficacy and safety of trastuzumab as a single agent in heavily pretreated patients with HER‐2/neu‐overexpressing metastatic breast cancer. Tumori 2004; 90: 40–3. [DOI] [PubMed] [Google Scholar]
  • 21. Perez EA, Rodeheffer R. Clinical cardiac tolerability of trastuzumab. J Clin Oncol 2004; 22: 322–9. [DOI] [PubMed] [Google Scholar]
  • 22. Seidman A, Hudis C, Pierri MK, Shak S, Paton V, Ashby M, Murphy M, Stewart SJ, Keefe D. Cardiac dysfunction in the trastuzumab clinical trials experience. J Clin Oncol 2002; 20: 1215–21. [DOI] [PubMed] [Google Scholar]
  • 23. Crone SA, Zhao YY, Fan L, Gu Y, Minamisawa S, Liu Y, Peterson KL, Chen J, Kahn R, Condorelli G, Ross J Jr, Chien KR, Lee KF. ErbB2 is essential in the prevention of dilated cardiomyopathy. Nat Med 2002; 8: 459–65. [DOI] [PubMed] [Google Scholar]
  • 24. Langer CJ, Stephenson P, Thor A, Vangel M, Johnson DH. Eastern Cooperative Oncology Group Study 2598. 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: 1180–7. [DOI] [PubMed] [Google Scholar]
  • 25. Hwang JJ, Sinicrope F, Safran H, Earle M, Wong MKK, Brufsky A, Warnick E, Troetschel M, Ramanathan RK. A Phase II trial of irinotecan and trastuzumab (“Herceptin”) in patients (Pts) overexpressing HER‐2/neu in metastatic colorectal cancer (CRC). Proc Am. Soc Clin Oncol 2001; 20: abstr 565. [Google Scholar]
  • 26. Safran H, Steinhoff M, Mangray S, Rathore R, King TC, Chai L, Berzein K, Moore T, Iannitti D, Reiss P, Pasquariello T, Akerman P, Quirk D, Mass R, Goldstein L, Tantravahi U. Overexpression of the HER‐2/neu oncogene in pancreatic adenocarcinoma. Am J Clin Oncol 2001; 24: 496–9. [DOI] [PubMed] [Google Scholar]
  • 27. Endo K, Yoon BI, Pairojkul C, Demetris AJ, Sirica AE. ERBB‐2 Overexpression and cyclooxygenase‐2 up‐regulation in human cholangiocarcinoma and risk conditions. Hepatology 2002; 36: 439–50. [DOI] [PubMed] [Google Scholar]
  • 28. Allgayer H, Babic R, Gruetzner KU, Tarabichi A, Schildberg FW, Heiss MM. c‐erbB‐2 is of independent prognostic relevance in gastric cancer and is associated with the expression of tumor‐associated protease systems. J Clin Oncol 2000; 18: 2201–9. [DOI] [PubMed] [Google Scholar]
  • 29. Ishida T, Tsujisaki M, Hinoda Y, Imai K, Yachi A. Establishment and characterization of mouse‐human chimeric monoclonal antibody to erbB‐2 product. Jpn J Cancer Res 1994; 85: 172–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30. Yamamura M, Hinoda Y, Sasaki S, Tsujisaki M, Oriuchi N, Endo K, Imai K. A human/mouse chimeric monoclonal antibody against intercellular adhesion molecule‐1 for tumor radioimmunoimaging. Jpn J Cancer Res 1996; 87: 405–11. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31. Sasaki S, Tsujisaki M, Jinnohara T, Ishida T, Sekiya M, Adachi M, Takahashi S, Hinoda Y, Imai K. Human tumor growth suppression by apoptosis induced with anti‐ErbB‐2 chimeric monoclonal antibody. Jpn J Cancer Res 1998; 89: 562–70. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32. 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 Dl, and antitumor action. Cancer Res 2002; 62: 4132–41. [PubMed] [Google Scholar]
  • 33. Nahta R, Hung MC, Esteva FJ. The HER‐2‐targeting antibodies trastuzumab and pertuzumab synergistically inhibit the survival of breast cancer cells. Cancer Res 2004; 64: 2343–6. [DOI] [PubMed] [Google Scholar]
  • 34. Kono K, Takahashi A, Ichihara F, Sugai H, Fujii H, Matsumoto Y. Impaired antibody‐dependent cellular cytotoxicity mediated by herceptin in patients with gastric cancer. Cancer Res 2002; 62: 5813–7. [PubMed] [Google Scholar]
  • 35. Herbst RS, Shin DM. Monoclonal antibodies to target epidermal growth factor receptor‐positive tumors: a new paradigm for cancer therapy. Cancer 2002; 94: 1593–611. [DOI] [PubMed] [Google Scholar]
  • 36. Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A, Bets D, Mueser M, Harstrick A, Van Cutsem E. Cetuximab (C225) alone or in combination with irinotecan (CPT‐11) in patients with epidermal growth factor receptor (EGFR)‐positive, irinotecan‐refractory metastatic colorectal cancer (MCRC). Proc Am Soc Clin Oncol 2003; 22: 252 (abstr 1012). [Google Scholar]
  • 37. Mendelsohn J. Targeting the epidermal growth factor receptor for cancer therapy. J Clin Oncol 2002; 20: 1S–13S. [PubMed] [Google Scholar]
  • 38. Scappaticci FA. Mechanisms and future directions for angiogenesis‐based cancer therapies. J Clin Oncol 2002; 20: 3906–27. [DOI] [PubMed] [Google Scholar]
  • 39. Hurwitz H, Fehrenbacher L, Cartwright T, Hainsworth J, Heim W, Berlin J, Griffing S, Novotny W, Holmgren E, Kabbinavar F. Bevacizumab (a monoclonal antibody to vascular endothelial growth factor) prolongs survival in first‐line colorectal cancer (CRC): results of a phase III trial of bevacizumab in combination with bolus IFL (irinotecan, 5‐fluorouracil, leucovorin) as first‐line therapy in subjects with metastatic CRC. Proc Am Soc Clin Oncol 2003; 22: abstr 3646. [Google Scholar]
  • 40. Jerne NK. Towards a network theory of the immune system. Ann Immunol (Paris) 1974; 125: 373–89. [PubMed] [Google Scholar]
  • 41. Tsujisaki M, Imai K, Tokuchi S, Hanzawa Y, Ishida T, Kitagawa H, Hinoda Y, Yachi A. Induction of antigen‐specific immune response with use of anti‐idiotypic monoclonal antibodies to anti‐carcinoembryonic antigen antibodies. Cancer Res 1991; 51: 2599–604. [PubMed] [Google Scholar]
  • 42. Tsujisaki M, Hinoda Y, Tokuchi S, Hanzawa Y, Arimura Y, Masuya J, Kitagawa H, Okochi E, Shimamura T, Hamuro J, Imai K, Yachi A. The analysis of internal image‐bearing anti‐idiotypic monoclonal antibody in relation to carcinoembryonic antigen. J Immunol 1993; 150: 508–16. [PubMed] [Google Scholar]
  • 43. Hinoda Y, Tsujisaki M, Imai K, Yachi A. Internal image‐bearing anti‐idiotypic monoclonal antibodies. Tumour Biol 1995; 16: 48–55. [DOI] [PubMed] [Google Scholar]
  • 44. Jinnohara T, Tsujisaki M, Sasaki S, Hinoda Y, Taniguchi M, Imai K. Anti‐tumor effect of internal image bearing anti‐idiotypic monoclonal antibody in relation to GM3 ganglioside. Int J Cancer 1998; 76: 345–53. [DOI] [PubMed] [Google Scholar]
  • 45. Foon KA, John WJ, Chakraborty M, Sherratt A, Garrison J, Flett M, Bhattacharya‐Chatterjee M. Clinical and immune responses in advanced colorectal cancer patients treated with anti‐idiotype monoclonal antibody vaccine that mimics the carcinoembryonic antigen, Clin Cancer Res 1997; 3: 1267–76. [PubMed] [Google Scholar]
  • 46. Wagner U, Kohler S, Reinartz S, Giffels P, Huober J, Renke K, Schlebusch H, Biersack HJ, Mobus V, Kreienberg R, Bauknecht T, Krebs D, Wallwiener D. Immunological consolidation of ovarian carcinoma recurrences with monoclonal anti‐idiotype antibody ACA125: immune responses and survival in palliative treatment. See The biology behind: K. A. Foon and M. Bhattacharya‐Chatterjee, Are solid tumor anti‐idiotype vaccines ready for prime time Clin Cancer Res 2001; 7: 1154–62. [PubMed] [Google Scholar]
  • 47. Foon KA, Lutzky J, Baral RN, Yannelli JR, Hutchins L, Teitelbaum A, Kashala OL, Das R, Garrison J, Reisfeld RA, Bhattacharya‐Chatterjee M. Clinical and immune responses in advanced melanoma patients immunized with an anti‐idiotype antibody mimicking disialoganglioside GD2. J Clin Oncol 2000; 18: 376–84. [DOI] [PubMed] [Google Scholar]
  • 48. Miotti S, Negri DR, Valota O, Calabrese M, Bolhuis RL, Gratama JW, Colnaghi MI, Canevari S. Level of anti‐mouse‐antibody response induced by bi‐specific monoclonal antibody OC/TR in ovarian‐carcinoma patients is associated with longer survival. Int J Cancer 1999; 84: 62–8. [DOI] [PubMed] [Google Scholar]
  • 49. Frodin JE, Faxas ME, Hagstrom B, Lefvert AK, Masucci G, Nilsson B, Steinitz M, Unger P, Mellstedt H. Induction of anti‐idiotypic (ab2) and anti‐anti‐idiotypic (ab3) antibodies in patients treated with the mouse monoclonal antibody 17‐1A (abl). Relation to the clinical outcome‐an important antitu‐moral effector function Hybridoma 1991; 10: 421–31. [DOI] [PubMed] [Google Scholar]
  • 50. Cheung NK, Guo HF, Heller G, Cheung IY. Induction of Ab3 and Ab3′ antibody was associated with long‐term survival after anti‐G(D2) antibody therapy of stage 4 neuroblastoma. Clin Cancer Res 2000; 6: 2653–60. [PubMed] [Google Scholar]

Articles from Cancer Science are provided here courtesy of Wiley

RESOURCES