Abstract
Monoclonal antibodies specific for the p185HER2/neu growth factor receptor represent a significant advance in receptor-based therapy for p185HER2/neu-expressing human cancers. We have used a structure-based approach to develop a small (1.5 kDa) exocyclic anti-HER2/neu peptide mimic (AHNP) functionally similar to an anti-p185HER2/neu monoclonal antibody, 4D5 (Herceptin). The AHNP mimetic specifically binds to p185HER2/neu with high affinity (KD=300 nM). This results in inhibition of proliferation of p185HER2/neu-overexpressing tumor cells, and inhibition of colony formation in vitro and growth of p185HER2/neu-expressing tumors in athymic mice. In addition, the mimetic sensitizes the tumor cells to apoptosis when used in conjunction with ionizing radiation or chemotherapeutic agents. A comparison of the molar quantities of the Herceptin antibody and the AHNP mimetic required for inhibiting cell growth and anchorage-independent growth showed generally similar activities. The structure-based derivation of the AHNP represents a novel strategy for the design of receptor-specific tumor therapies.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Slamon, D.J. et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235, 177–182 (1987).
Cohen, J.A. et al. 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 (1989).
Drebin, J.A., Link, V.C., Stern, D.F., Weinberg, R.A. & Greene, M.I. Development of monoclonal antibodies reactive with the product of the neu oncogene. Symp. Fund. Cancer Res. 38, 277–289 (1986).
Drebin, J.A., Link, V.C. & Greene, M.I. Monoclonal antibodies specific for the neu oncogene product directly mediate anti-tumor effects in vivo. Oncogene 2, 387–394 (1988).
Baselga, J., Norton, L., Albanell, J., Kim, Y.M. & Mendelsohn, J. Recombinant humanized anti-HER2 antibody (Herceptin) enhances the antitumor activity of paclitaxel and doxorubicin against HER2/neu overexpressing human breast cancer xenografts. Cancer Res. 58, 2825–2831 (1998).
Carter, P. et al. Humanization of an anti-p185HER2 antibody for human cancer therapy. Proc. Natl. Acad. Sci. USA 89, 4285–4289 (1992).
Fendly, B.M. et al. Characterization of murine monoclonal antibodies reactive to either the human epidermal growth factor receptor or HER2/neu gene product. Cancer Res. 50, 1550–1558 (1990).
Hudziak, R.M. et al. p185HER2 monoclonal antibody has antiproliferative effects in vitro and sensitizes human breast tumor cells to tumor necrosis factor. Mol. Cell Biol. 9, 1165–1172 (1989).
Drebin, J.A., Stern, D.F., Link, V.C., Weinberg, R.A. & Greene, M.I. Monoclonal antibodies identify a cell-surface antigen associated with an activated cellular oncogene. Nature 312, 545–548 (1984).
Drebin, J.A., Link, V.C., Weinberg, R.A. & Greene, M.I. Inhibition of tumor growth by a monoclonal antibody reactive with an oncogene-encoded tumor antigen. Proc. Natl. Acad. Sci. USA 83, 9129–9133 (1986).
Cho, M.J. & Juliano, R. Macromolecular versus small-molecule therapeutics: drug discovery, development and clinical considerations. Trends Biotechnol. 14, 153–158 (1996).
Hruby, V.J. Conformational and topographical considerations in the design of biologically active peptides. Biopolymers 33, 1073–1082 (1993).
Langston, S. Peptidomimetics and small molecule design. Drug Discov. Today 2, 254–256 (1997).
Qabar, M., Urban, J., Sia, C., Klein, M. & Kahn, M. Pharmaceutical applications of peptidomimetics. Lett. Pept. Sci. 3, 25–30 (1996).
Murali, R. & Greene, M.I. Structure-based design of immunologically active therapeutic peptides. Immunol. Res. 17, 163–169 (1998).
Moore, G.J. Designing peptide mimetics. Trends Pharmacol. Sci. 15, 124–129 (1994).
KieberEmmons, T., Murali, R. & Greene, M.I. Therapeutic peptides and peptidomimetics. Curr. Opin. Biotechnol. 8, 435–441 (1997).
Saragovi, H.U. et al. Design and synthesis of a mimetic from an antibody complementarity-determining region. Science 253, 792–795 (1991).
Zhang, X. et al. Synthetic Cd4 exocyclic peptides antagonize Cd4 holoreceptor binding and T-cell activation. Nat. Biotechnol. 14, 472–475. (1996).
Takasaki, W., Kajino, Y., Kajino, K., Murali, R. & Greene, M.I. Structure-based design and characterization of exocyclic peptidomimetics that inhibit TNF alpha binding to its receptor. Nat. Biotechnol. 15, 1266–1270 (1997).
Chothia, C. & Lesk, A.M. Canonical structures for the hypervariable regions of immunoglobulins. J. Mol. Biol. 196, 901–917 (1987).
MacCallum, R.M., Martin, A.C. & Thornton, J.M. Antibody-antigen interactions: contact analysis and binding site topography. J. Mol. Biol. 262, 732–745 (1996).
Mariuzza, R.A., Phillips, S.E. & Poljak, R.J. The structural basis of antigen-antibody recognition. Annu. Rev. Biophys. Biophys. Chem. 16, 139–159 (1987).
Bruck, C. et al. Nucleic acid sequence of an internal image-bearing monoclonal anti-idiotype and its comparison to the sequence of the external antigen. Proc. Natl. Acad. Sci. USA 83, 6578–6582 (1986).
Eigenbrot, C., Randal, M., Presta, L., Carter, P. & Kossiakoff, A.A. X-ray structures of the antigen-binding domains from three variants of humanized anti-p185HER2 antibody 4D5 and comparison with molecular modeling. J. Mol. Biol. 229, 969–995 (1993).
Eigenbrot, C. et al. X-ray structures of fragments from binding and nonbinding versions of a humanized anti-CD18 antibody: structural indications of the key role of VH residues 59 to 65. Proteins 18, 49–62 (1994).
Zhang, H. et al. Pathobiological features of shared antigenic epitopes and biological functions of distinct and humanized anti-p185her2/neu monoclonal antibodies. Exp. Mol. Pathol. 67, 15–25 (1999).
Zhang, X. et al. Synthetic Cd4 exocyclics inhibit binding of human-immunodeficiency-virus type-1 envelope to Cd4 and virus-replication in T-lymphocytes. Nat. Biotechnol. 15, 150–154. (1997).
Adang, A.E.P., Hermkens, P.H.H., Linders, J.T.M., Ottenheijm, H.C.J. & van Staveren, C.J. Case histories of peptidomimetics: progression from peptides to drugs. Recl. Trav. Chim. Pays-Bas. 113, 63–78 (1994).
Akamatsu, M. et al. Potent inhibition of protein-tyrosine phosphatase by phosphotyrosine-mimic containing cyclic peptides. Bioorg. Med. Chem. 5, 157–163 (1997).
Graciani, N.R., Tsang, K.Y., McCutchen, S.L. & Kelly, J.W. Amino acids that specify structure through hydrophobic clustering and histidine-aromatic interactions lead to biologically active peptidomimetics. Bioorg. Med. Chem. 2, 999–1006 (1994).
McDonnell, J.M., Fushman, D., Cahill, S.M., Sutton, B.J. & Cowburn, D. Solution structures of Fc epsilon RI alpha-chain mimics: a beta-hairpin peptide and its retroenantiomer. J. Am. Chem. Soc. 119, 5321–5328 (1997).
Yiallouros, I. et al. Phosphinic peptides, the first potent inhibitors of astacin, behave as extremely slow-binding inhibitors. Biochem. J. 331, 375–379 (1998).
Benveniste, M. & Mayer, M.L. Structure-activity analysis of binding kinetics for NMDA receptor competitive antagonists: the influence of conformational restriction. Br. J. Pharmacol. 104, 207–221 (1991).
Moosmayer, D. et al. Characterization of different soluble TNF receptor (TNFR80) derivatives: positive influence of the intracellular domain on receptor/ligand interaction and TNF neutralization capacity. J. Interf. Cytok. Res. 16, 471–477 (1996).
Drebin, J.A., Link, V.C., Stern, D.F., Weinberg, R.A. & Greene, M.I. Down-modulation of an oncogene protein product and reversion of the transformed phenotype by monoclonal antibodies. Cell 41, 697–706 (1985).
Qian, X. et al. Identification of p185neu sequences required for monoclonal antibody- or ligand-mediated receptor signal attenuation. DNA Cell Biol. 16, 1395–1405 (1997).
Hansen, M.B., Nielsen, S.E. & Berg, K. Re-examination and further development of a precise and rapid dye method for measuring cell growth/cell kill. J. Immunol. Methods 119, 203–210 (1989).
Shepard, H.M. et al. Monoclonal antibody therapy of human cancer: taking the HER2 protooncogene to the clinic. [Review]. J. Clin. Immunol. 11, 117–127 (1991).
O'Rourke, D.M. et al. Conversion of a radioresistant phenotype to a more sensitive one by disabling erbB receptor signaling in human cancer cells. Proc. Natl. Acad. Sci. USA 95, 10842–10847 (1998).
Waldman, T. et al. Cell-cycle arrest versus cell death in cancer therapy. Nat. Med. 3, 1034–1036 (1997).
Katsumata, M. et al. Prevention of breast tumour development in vivo by downregulation of the p185neu receptor. Nat. Med. 1, 644–648 (1995).
Qian, X., Dougall, W.C., Hellman, M.E. & Greene, M.I. Kinase-deficient neu proteins suppress epidermal growth factor receptor function and abolish cell transformation. Oncogene 9, 1507–1514 (1994).
Acknowledgements
This work was supported by grants awarded to M.I.G. from the Abramson Cancer Institute, National Cancer Institute, NIH, and the US Army.
Author information
Authors and Affiliations
Corresponding authors
Rights and permissions
About this article
Cite this article
Park, BW., Zhang, HT., Wu, C. et al. Rationally designed anti-HER2/neu peptide mimetic disables P185HER2/neu tyrosine kinases in vitro and in vivo. Nat Biotechnol 18, 194–198 (2000). https://doi.org/10.1038/72651
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/72651
This article is cited by
-
Transformable peptide nanoparticles arrest HER2 signalling and cause cancer cell death in vivo
Nature Nanotechnology (2020)
-
Polyethylene glycol-conjugated HER2-targeted peptides as a nuclear imaging probe for HER2-overexpressed gastric cancer detection in vivo
Journal of Translational Medicine (2018)
-
Identification of a novel antagonist of the ErbB1 receptor capable of inhibiting migration of human glioblastoma cells
Cellular Oncology (2013)