Peptide vaccines of the HER-2/neu dimerization loop are effective in inhibiting mammary tumor growth in vivo.
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.
Allen
Stephanie D
SD
Ohio State Biochemistry Program, and Department of Obstetrics and Gynecology, The Ohio State University, Columbus, OH 43210, USA.
Garrett
Joan T
JT
Rawale
Sharad V
SV
Jones
Audra L
AL
Phillips
Gary
G
Forni
Guido
G
Morris
John C
JC
Oshima
Robert G
RG
Kaumaya
Pravin T P
PT
D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000138:chemical synthesis / Q000276:immunology* / Q000378:metabolism; D001943:Breast Neoplasms / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000138:chemical synthesis / Q000276:immunology* / Q000378:metabolism; D045744:Cell Line, Tumor; D003429:Cross Reactions / Q000235:genetics; D019281:Dimerization; D005260:Female; D006131:Growth Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000276:immunology / Q000473:pathology* / Q000517:prevention & control*; D008459:Measles virus / Q000235:genetics / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000008:administration & dosage / Q000138:chemical synthesis / Q000276:immunology* / Q000378:metabolism; D017433:Protein Structure, Secondary; D011817:Rabbits; D051381:Rats; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000008:administration & dosage / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D022223:Vaccines, Subunit / Q000008:administration & dosage / Q000138:chemical synthesis / Q000276:immunology* / Q000378:metabolism; D014760:Viral Fusion Proteins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology
D000970:Antineoplastic Agents; D019496:Cancer Vaccines; D006131:Growth Inhibitors; D010446:Peptide Fragments; D018719:Erb-b2 Receptor Tyrosine Kinases; D022223:Vaccines, Subunit; D014760:Viral Fusion Proteins