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- Title
Rationally designed anti-HER2/neu peptide mimetic disables P185<sup>HER2/neu</sup> tyrosine kinases in vitro and in vivo.
- Authors
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
- Abstract
Monoclonal antibodies specific for the p185[SUPHER2/neu] growth factor receptor represent a significant advance in receptor-based therapy for p185[SUPHER2/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[SUPHER2/neu] monoclonal antibody, 4D5 (Herceptin). The AHNP mimetic specifically binds to p185[SUPHER2/neu] with high affinity (K[SUBD] = 300 nM). This results in inhibition of proliferation of p185[SUPHER2/neu]-over-expressing tumor cells, and inhibition of colony formation in vitro and growth of p185[SUPHER2/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.
- Subjects
MONOCLONAL antibodies; CANCER
- Publication
Nature Biotechnology, 2000, Vol 18, Issue 2, p194
- ISSN
1087-0156
- Publication type
Article
- DOI
10.1038/72651