Rationally designed anti-HER2/neu peptide mimetic disables p185(HER2/neu) tyrosine kinases in vitro and in vivo

Byeong Woo Park; Hong Tao Zhang; Chuanjin Wu; Alan Berezov; Xin Zhang; Raj Dua; Qiang Wang; Gary Kao; Donald M. O'Rourke; Mark I. Greene; Ramachandran Murali

doi:10.1038/72651

Rationally designed anti-HER2/neu peptide mimetic disables p185(HER2/neu) tyrosine kinases in vitro and in vivo

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

Department of Surgery

Research output: Contribution to journal › Article › peer-review

155 Citations (Scopus)

Abstract

Monoclonal antibodies specific for the p185(HER2/neu) growth factor receptor represent a significant advance in receptor-based therapy for p185(HER2/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-p185(HER2/neu) monoclonal antibody, 4D5 (Herceptin). The AHNP mimetic specifically binds to p185(HER2/neu) with high affinity (K(D) = 300 nM). This results in inhibition of proliferation of p185(HER2/neu)-overexpressing tumor cells, and inhibition of colony formation in vitro and growth of p185(HER2/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.

Original language	English
Pages (from-to)	194-198
Number of pages	5
Journal	Nature Biotechnology
Volume	18
Issue number	2
DOIs	https://doi.org/10.1038/72651
Publication status	Published - 2000 Feb

Bibliographical note

Funding Information:
This work was supported by grants awarded to M.I.G. from the Abramson Cancer Institute, National Cancer Institute, NIH, and the US Army.

All Science Journal Classification (ASJC) codes

Biotechnology
Bioengineering
Applied Microbiology and Biotechnology
Molecular Medicine
Biomedical Engineering

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title = "Rationally designed anti-HER2/neu peptide mimetic disables p185(HER2/neu) tyrosine kinases in vitro and in vivo",

abstract = "Monoclonal antibodies specific for the p185(HER2/neu) growth factor receptor represent a significant advance in receptor-based therapy for p185(HER2/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-p185(HER2/neu) monoclonal antibody, 4D5 (Herceptin). The AHNP mimetic specifically binds to p185(HER2/neu) with high affinity (K(D) = 300 nM). This results in inhibition of proliferation of p185(HER2/neu)-overexpressing tumor cells, and inhibition of colony formation in vitro and growth of p185(HER2/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.",

author = "Park, {Byeong Woo} and Zhang, {Hong Tao} and Chuanjin Wu and Alan Berezov and Xin Zhang and Raj Dua and Qiang Wang and Gary Kao and O'Rourke, {Donald M.} and Greene, {Mark I.} and Ramachandran Murali",

note = "Funding Information: 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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Rationally designed anti-HER2/neu peptide mimetic disables p185(HER2/neu) tyrosine kinases in vitro and in vivo. / Park, Byeong Woo; Zhang, Hong Tao; Wu, Chuanjin; Berezov, Alan; Zhang, Xin; Dua, Raj; Wang, Qiang; Kao, Gary; O'Rourke, Donald M.; Greene, Mark I.; Murali, Ramachandran.

In: Nature Biotechnology, Vol. 18, No. 2, 02.2000, p. 194-198.

Research output: Contribution to journal › Article › peer-review

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AU - Berezov, Alan

AU - Zhang, Xin

AU - Dua, Raj

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AU - Kao, Gary

AU - O'Rourke, Donald M.

AU - Greene, Mark I.

AU - Murali, Ramachandran

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