title: Rationally designed anti-HER2/neu peptide mimetic disables P185HER2/neu tyrosine kinases in vitro and in vivo.
abstract: Monoclonal antibodies specific for the p185HER2/neu growth factor receptor represent a significant advance in receptor-based therapy for p185HER2/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-p185HER2/neu monoclonal antibody, 4D5 (Herceptin). The AHNP mimetic specifically binds to p185HER2/neu with high affinity (KD=300 nM). This results in inhibition of proliferation of p185HER2/neu-overexpressing tumor cells, and inhibition of colony formation in vitro and growth of p185HER2/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.
authors.affiliation: Department of Pathology and Laboratory Medicine, Center for Receptor Biology and Cell Growth, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: B W
authors.initials: BW
authors.lastname: Park
authors.forename: H T
authors.initials: HT
authors.lastname: Zhang
authors.forename: C
authors.initials: C
authors.lastname: Wu
authors.forename: A
authors.initials: A
authors.lastname: Berezov
authors.forename: X
authors.initials: X
authors.lastname: Zhang
authors.forename: R
authors.initials: R
authors.lastname: Dua
authors.forename: Q
authors.initials: Q
authors.lastname: Wang
authors.forename: G
authors.initials: G
authors.lastname: Kao
authors.forename: D M
authors.initials: DM
authors.lastname: O'Rourke
authors.forename: M I
authors.initials: MI
authors.lastname: Greene
authors.forename: R
authors.initials: R
authors.lastname: Murali
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000737:chemistry*; D017209:Apoptosis; D001254:Astrocytoma; D015374:Biosensing Techniques; D004317:Doxorubicin / Q000627:therapeutic use; D015195:Drug Design; D004359:Drug Therapy, Combination; D005720:Gamma Rays; D051379:Mice; D008819:Mice, Nude; D018716:Molecular Mimicry; D011485:Protein Binding; D018714:Radiotherapy, Adjuvant; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*; D000068878:Trastuzumab; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000528:radiation effects
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D004317:Doxorubicin; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C404542:anti-HER2-neu peptide mimic, 1.5 kDa