Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Short Communication
  • Published:

Differential binding patterns of monoclonal antibody 2C4 to the ErbB3–p185her2/neu and the EGFR–p185her2/neu complexes

Oncogene volume 27, pages 3870–3874 (2008)Cite this article

Abstract

2C4 (Pertuzumab, Omnitarg) is a monoclonal antibody targeting p185her2/neu, which is overexpressed in 30% of invasive breast cancer. 2C4 is currently in phase II clinical trials for several types of cancers. This antibody has been reported to disrupt the association between p185her2/neu and ErbB3. In our studies of epidermal growth factor receptor (EGFR)–p185her2/neu heterodimerization, we noted that 2C4 formed associations with the EGFR–p185her2/neu receptor complex. Our data argue against 2C4 as a universal heterodimerization blocker for p185her2/neu, but indicate that cocktails of monoclonal antibodies binding distinct interaction surfaces of p185her2/neu will emerge as the most potent targeted therapy.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  • Agus DB, Akita RW, Fox WD, Lewis GD, Higgins B, Pisacane PI et al. (2002). Targeting ligand-activated ErbB2 signaling inhibits breast and prostate tumor growth. Cancer Cell 2: 127–137.

    Article  CAS  PubMed  Google Scholar 

  • Berezov A, Chen J, Liu Q, Zhang HT, Greene MI, Murali R . (2002). Disabling receptor ensembles with rationally designed interface peptidomimetics. J Biol Chem 277: 28330–28339.

    Article  CAS  PubMed  Google Scholar 

  • Carter P, Presta L, Gorman CM, Ridgway JB, Henner D, Wong WL et al. (1992). Humanization of an anti-p185HER2 antibody for human cancer therapy. Proc Natl Acad Sci USA 89: 4285–4289.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cho HS, Leahy DJ . (2002). Structure of the extracellular region of HER3 reveals an interdomain tether. Science 297: 1330–1333.

    Article  CAS  PubMed  Google Scholar 

  • Cho HS, Mason K, Ramyar KX, Stanley AM, Gabelli SB, Denney Jr DW et al. (2003). Structure of the extracellular region of HER2 alone and in complex with the Herceptin Fab. Nature 421: 756–760.

    Article  CAS  PubMed  Google Scholar 

  • Cohen JA, Weiner DB, More KF, Kokai Y, Williams WV, Maguire Jr HC et al. (1989). Expression pattern of the neu (NGL) gene-encoded growth factor receptor protein (p185neu) in normal and transformed epithelial tissues of the digestive tract. Oncogene 4: 81–88.

    CAS  PubMed  Google Scholar 

  • Drebin JA, Link VC, Greene MI . (1988). Monoclonal antibodies reactive with distinct domains of the neu oncogene-encoded p185 molecule exert synergistic anti-tumor effects in vivo. Oncogene 2: 273–277.

    CAS  PubMed  Google Scholar 

  • Drebin JA, Link VC, Stern DF, Weinberg RA, Greene MI . (1985). Down-modulation of an oncogene protein product and reversion of the transformed phenotype by monoclonal antibodies. Cell 41: 697–706.

    Article  CAS  PubMed  Google Scholar 

  • Drebin JA, Stern DF, Link VC, Weinberg RA, Greene MI . (1984). Monoclonal antibodies identify a cell-surface antigen associated with an activated cellular oncogene. Nature 312: 545–548.

    Article  CAS  PubMed  Google Scholar 

  • Ferguson KM, Berger MB, Mendrola JM, Cho HS, Leahy DJ, Lemmon MA . (2003). EGF activates its receptor by removing interactions that autoinhibit ectodomain dimerization. Mol Cell 11: 507–517.

    Article  CAS  PubMed  Google Scholar 

  • Franklin MC, Carey KD, Vajdos FF, Leahy DJ, De Vos AM, Sliwkowski MX . (2004). Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complex.[see comment]. Cancer Cell 5: 317–328.

    Article  CAS  PubMed  Google Scholar 

  • Guex N, Peitsch MC . (1997). SWISS-MODEL and the Swiss-PdbViewer: an environment for comparative protein modeling. Electrophoresis 18: 2714–2723.

    Article  CAS  PubMed  Google Scholar 

  • Jackson JG, St Clair P, Sliwkowski MX, Brattain MG . (2004). Blockade of epidermal growth factor- or heregulin-dependent ErbB2 activation with the anti-ErbB2 monoclonal antibody 2C4 has divergent downstream signaling and growth effects. Cancer Res 64: 2601–2609.

    Article  CAS  PubMed  Google Scholar 

  • Katsumata M, Okudaira T, Samanta A, Clark DP, Drebin JA, Jolicoeur P et al. (1995). Prevention of breast tumour development in vivo by downregulation of the p185neu receptor. Nat Med 1: 644–648.

    Article  CAS  PubMed  Google Scholar 

  • Kern JA, Schwartz DA, Nordberg JE, Weiner DB, Greene MI, Torney L et al. (1990). p185neu expression in human lung adenocarcinomas predicts shortened survival. Cancer Res 50: 5184–5187.

    CAS  PubMed  Google Scholar 

  • Kokai Y, Myers JN, Wada T, Brown VI, LeVea CM, Davis JG et al. (1989). Synergistic interaction of p185c-neu and the EGF receptor leads to transformation of rodent fibroblasts. Cell 58: 287–292.

    Article  CAS  PubMed  Google Scholar 

  • Kwak EL, Sordella R, Bell DW, Godin-Heymann N, Okimoto RA, Brannigan BW et al. (2005). Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib. Proc Natl Acad Sci USA 102: 7665–7670.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lodato RF, Maguire Jr HC, Greene MI, Weiner DB, LiVolsi VA . (1990). Immunohistochemical evaluation of c-erbB-2 oncogene expression in ductal carcinoma in situ and atypical ductal hyperplasia of the breast. Mod Pathol 3: 449–454.

    CAS  PubMed  Google Scholar 

  • Mendoza N, Phillips GL, Silva J, Schwall R, Wickramasinghe D . (2002). Inhibition of ligand-mediated HER2 activation in androgen-independent prostate cancer. Cancer Res 62: 5485–5488.

    CAS  PubMed  Google Scholar 

  • Ogiso H, Ishitani R, Nureki O, Fukai S, Yamanaka M, Kim JH et al. (2002). Crystal structure of the complex of human epidermal growth factor and receptor extracellular domains. Cell 110: 775–787.

    Article  CAS  PubMed  Google Scholar 

  • Romond EH, Perez EA, Bryant J, Suman VJ, Geyer Jr CE, Davidson NE et al. (2005). Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 353: 1673–1684.

    Article  CAS  PubMed  Google Scholar 

  • Sanner MF . (1999). Python: a programming language for software integration and development. J Mol Graph Model 17: 57–61.

    CAS  PubMed  Google Scholar 

  • Sergina NV, Rausch M, Wang D, Blair J, Hann B, Shokat KM et al. (2007). Escape from HER-family tyrosine kinase inhibitor therapy by the kinase-inactive HER3. Nature 445: 437–441.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE et al. (1989). Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 244: 707–712.

    Article  CAS  PubMed  Google Scholar 

  • Takai N, Jain A, Kawamata N, Popoviciu LM, Said JW, Whittaker S et al. (2005). 2C4, a monoclonal antibody against HER2, disrupts the HER kinase signaling pathway and inhibits ovarian carcinoma cell growth. Cancer 104: 2701–2708.

    Article  CAS  PubMed  Google Scholar 

  • van de Vijver M, van de Bersselaar R, Devilee P, Cornelisse C, Peterse J, Nusse R . (1987). Amplification of the neu (c-erbB-2) oncogene in human mammary tumors is relatively frequent and is often accompanied by amplification of the linked c-erbA oncogene. Mol Cell Biol 7: 2019–2023.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wada T, Myers JN, Kokai Y, Brown VI, Hamuro J, LeVea CM et al. (1990a). Anti-receptor antibodies reverse the phenotype of cells transformed by two interacting proto-oncogene encoded receptor proteins. Oncogene 5: 489–495.

    CAS  PubMed  Google Scholar 

  • Wada T, Qian XL, Greene MI . (1990b). Intermolecular association of the p185neu protein and EGF receptor modulates EGF receptor function. Cell 61: 1339–1347.

    Article  CAS  PubMed  Google Scholar 

  • Weiner DB, Liu J, Cohen JA, Williams WV, Greene MI . (1989). A point mutation in the neu oncogene mimics ligand induction of receptor aggregation. Nature 339: 230–231.

    Article  CAS  PubMed  Google Scholar 

  • Williams TM, Weiner DB, Greene MI, Maguire Jr HC . (1991). Expression of c-erbB-2 in human pancreatic adenocarcinomas. Pathobiology 59: 46–52.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was partially funded by a grant from NCI (5P01 CA 89480).

Author information

Authors and Affiliations

  1. Department of Pathology/Lab Medicine, University of Pennsylvania School of Medicine, Hamilton Walk, Philadelphia, PA, USA

    Z Cai, G Zhang, Z Zhou, K Bembas, M I Greene & H Zhang

  2. Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    J A Drebin

Authors
  1. Z Cai
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. G Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Z Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. K Bembas
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J A Drebin
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M I Greene
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. H Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to H Zhang.

Additional information

Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cai, Z., Zhang, G., Zhou, Z. et al. Differential binding patterns of monoclonal antibody 2C4 to the ErbB3–p185her2/neu and the EGFR–p185her2/neu complexes. Oncogene 27, 3870–3874 (2008). https://doi.org/10.1038/onc.2008.13

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2008.13

Keywords

This article is cited by

Search

Advanced search

Quick links