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

Monoclonal antibodies specific for the p185(HER2/neu) growth factor recepto r represent a significant advance in receptor-based therapy for p185(HER2/n eu)-expressing human cancers, We have used a structure-based approach to de velop a small (1.5 kDa) exocyclic anti-HER2/neu peptide mimic (AHNP) functi onally similar to an anti-p185(HER2/neu) monoclonal antibody, 4D5 (Hercepti n), The AHNP mimetic specifically binds to p185(HER2/neu) with high affinit y (K-D = 300 nM). This results in inhibition of proliferation of p185(HER2/ neu)-overexpressing tumor cells, and inhibition of colony formation in vitr o and growth of p185(HER2/neu)-expressing tumors in athymic mice, In additi on, the mimetic sensitizes the tumor cells to apoptosis when used in conjun ction with ionizing radiation or chemotherapeutic agents. A comparison of t he molar quantities of the Herceptin antibody and the AHNP mimetic required for inhibiting cell growth and anchorage-independent growth showed general ly similar activities. The structure-based derivation of the AHNP represent s a novel strategy for the design of receptor-specific tumor therapies.