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

Byeongwoo 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

Research output: Contribution to journalArticle

150 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 languageEnglish
Pages (from-to)194-198
Number of pages5
JournalNature Biotechnology
Volume18
Issue number2
DOIs
Publication statusPublished - 2000 Feb 1

Fingerprint

Protein-Tyrosine Kinases
Peptides
Tumors
Monoclonal antibodies
Neoplasms
Monoclonal Antibodies
Cells
Growth
Growth Factor Receptors
Ionizing radiation
Cell growth
Cell death
Antibodies
Anti-Idiotypic Antibodies
Ionizing Radiation
Nude Mice
Apoptosis
In Vitro Techniques
Therapeutics
Trastuzumab

All Science Journal Classification (ASJC) codes

  • Biotechnology
  • Bioengineering
  • Applied Microbiology and Biotechnology
  • Molecular Medicine
  • Biomedical Engineering

Cite this

Park, Byeongwoo ; Zhang, Hong Tao ; Wu, Chuanjin ; Berezov, Alan ; Zhang, Xin ; Dua, Raj ; Wang, Qiang ; Kao, Gary ; O'Rourke, Donald M. ; Greene, Mark I. ; Murali, Ramachandran. / Rationally designed anti-HER2/neu peptide mimetic disables p185(HER2/neu) tyrosine kinases in vitro and in vivo. In: Nature Biotechnology. 2000 ; Vol. 18, No. 2. pp. 194-198.
@article{7fdd5cddac1046fab8c7477f14ce0612,
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 = "Byeongwoo Park 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",
year = "2000",
month = "2",
day = "1",
doi = "10.1038/72651",
language = "English",
volume = "18",
pages = "194--198",
journal = "Nature Biotechnology",
issn = "1087-0156",
publisher = "Nature Publishing Group",
number = "2",

}

Park, B, Zhang, HT, Wu, C, Berezov, A, Zhang, X, Dua, R, Wang, Q, Kao, G, O'Rourke, DM, Greene, MI & Murali, R 2000, 'Rationally designed anti-HER2/neu peptide mimetic disables p185(HER2/neu) tyrosine kinases in vitro and in vivo', Nature Biotechnology, vol. 18, no. 2, pp. 194-198. https://doi.org/10.1038/72651

Rationally designed anti-HER2/neu peptide mimetic disables p185(HER2/neu) tyrosine kinases in vitro and in vivo. / Park, Byeongwoo; 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, 01.02.2000, p. 194-198.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Rationally designed anti-HER2/neu peptide mimetic disables p185(HER2/neu) tyrosine kinases in vitro and in vivo

AU - Park, Byeongwoo

AU - Zhang, Hong Tao

AU - Wu, Chuanjin

AU - Berezov, Alan

AU - Zhang, Xin

AU - Dua, Raj

AU - Wang, Qiang

AU - Kao, Gary

AU - O'Rourke, Donald M.

AU - Greene, Mark I.

AU - Murali, Ramachandran

PY - 2000/2/1

Y1 - 2000/2/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=0033953634&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0033953634&partnerID=8YFLogxK

U2 - 10.1038/72651

DO - 10.1038/72651

M3 - Article

C2 - 10657127

AN - SCOPUS:0033953634

VL - 18

SP - 194

EP - 198

JO - Nature Biotechnology

JF - Nature Biotechnology

SN - 1087-0156

IS - 2

ER -