Peptide vaccines of the HER-2/neu dimerization loop are effective in inhibiting mammary tumor growth in vivo.

Abstract

Human epidermal growth factor receptor-2 (HER-2)/neu (ErbB2), a member of the epidermal growth factor family of receptors, is overexpressed in 20-30% of breast cancers. It is an attractive target for receptor-directed antitumor therapy using mAbs. Unlike other epidermal growth factor receptor family members, HER-2/neu does not bind a high-affinity ligand, but rather functions as the preferred dimerization partner. Pertuzumab (Omnitarg) is a humanized mAb directed against the HER-2/neu dimerization domain that inhibits receptor signaling. The recent definition of the crystal structure of the HER-2/neu-pertuzumab complex demonstrated that the receptor dimerization region encompassed residues 266-333. Based on the three-dimensional structure of the complex, we have designed three conformational peptide constructs (sequences 266-296, 298-333, and 315-333) to mimic regions of the dimerization loop of the receptor and to characterize their in vitro and in vivo antitumor efficacy. All the constructs elicited high-affinity peptide Abs that inhibited multiple signaling pathways including HER-2/neu-specific inhibition of cellular proliferation and cytoplasmic receptor domain phosphorylation. All the peptide Abs showed Ab-dependent cellular cytotoxicity to varying degrees with the 266-296 constructs being equally effective as compared with Herceptin. The 266-296 peptide vaccine had statistically reduced tumor onset in both transplantable tumor models (FVB/n and BALB/c) and significant reduction in tumor development in two transgenic mouse tumor models (BALB-neuT and VEGF(+/-)Neu2-5(+/-)). The 266-296 construct represents the most promising candidate for antitumor vaccination and could also be used to treat a variety of cancers with either normal or elevated expression of HER-2 including breast, lung, ovarian, and prostate.

• Authors: Stephanie D Allen, Joan T Garrett, Sharad V Rawale, Audra L Jones, Gary Phillips, Guido Forni, John C Morris, Robert G Oshima, Pravin T P Kaumaya
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 179 Issue 1 Pg. 472-82 (Jul 01 2007) ISSN: 0022-1767 [Print] United States
• PMID: 17579068 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Antineoplastic Agents
• Cancer Vaccines
• Growth Inhibitors
• Peptide Fragments
• Vaccines, Subunit
• Viral Fusion Proteins
• Receptor, ErbB-2

Topics

• Amino Acid Sequence
• Animals
• Antineoplastic Agents (administration & dosage, chemical synthesis, immunology, metabolism)
• Breast Neoplasms (immunology, pathology, prevention & control)
• Cancer Vaccines (administration & dosage, chemical synthesis, immunology, metabolism)
• Cell Line, Tumor
• Cross Reactions (genetics)
• Dimerization
• Female
• Growth Inhibitors (administration & dosage, chemical synthesis, immunology, metabolism)
• Humans
• Male
• Mammary Neoplasms, Experimental (immunology, pathology, prevention & control)
• Measles virus (genetics, immunology)
• Mice
• Mice, Inbred BALB C
• Mice, Transgenic
• Molecular Sequence Data
• Peptide Fragments (administration & dosage, chemical synthesis, immunology, metabolism)
• Protein Structure, Secondary
• Rabbits
• Rats
• Receptor, ErbB-2 (administration & dosage, chemistry, immunology, metabolism)
• Vaccines, Subunit (administration & dosage, chemical synthesis, immunology, metabolism)
• Viral Fusion Proteins (administration & dosage, genetics, immunology)