Bw. Park et al., Rationally designed anti-HER2/neu peptide mimetic disables p185(HER2/neu) tyrosine kinases in vitro and in vivo, NAT BIOTECH, 18(2), 2000, pp. 194-198
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.