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Rationally designed anti-HER2/neu peptide mimetic disables P185HER2/neu tyrosine kinases in vitro and in vivo

Nature Biotechnology volume 18, pages 194–198 (2000)Cite this article

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.

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Figure 1: Structural and kinetic binding analyses of AHNP.
Figure 2: Inhibition of cell proliferation and anchorage-independent growth by AHNP.
Figure 3: Combined cytotoxicity of doxorubicin and AHNP.
Figure 4: AHNP enhances γ-irradiation-induced apoptosis.
Figure 5: Inhibition of in vivo tumor growth by administration of AHNP.

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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.

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Author notes

  1. Byeong-Woo Park, Hong-Tao Zhang and Chuanjin Wu: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, Center for Receptor Biology and Cell Growth, University of Pennsylvania School of Medicine, 36th and Hamilton Walk, Philadelphia, 19104, PA

    Byeong-Woo Park, Hong-Tao Zhang, Chuanjin Wu, Alan Berezov, Xin Zhang, Qiang Wang, Donald M. O'Rourke, Mark I. Greene & Ramachandran Murali

  2. Xcyte Therapeutics, Inc., Seattle, 98122, WA

    Raj Dua

  3. Department of Radiation Oncology, University of Pennsylvania School of Medicine, 36th and Hamilton Walk, Philadelphia, 19104, PA

    Gary Kao

  4. Department of Neurosurgery, University of Pennsylvania School of Medicine, 36th and Hamilton Walk, Philadelphia, 19104, PA

    Donald M. O'Rourke

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Correspondence to Mark I. Greene or Ramachandran Murali.

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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

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