Specific inhibition of the reaction between a tumor-inhibitory antibody and the ErbB-2 receptor by a mimotope derived from a phage display library.
Overexpression of ErbB-2, a coreceptor for stroma-derived growth factors, is involved in malignancies of epithelial tissues, and a humanized antibody to ErbB-2 was shown to be therapeutic in a clinical setting. In an effort to understand and enhance immunotherapy, the laboratory has raised several tumor inhibitory monoclonal antibodies (mAb), including mAb L26 that blocks inter-receptor interactions. Here the application of the phage display methodology for the isolation of a phage clone that specifically recognizes mAb L26 is described. The isolated mimetic peptide (mimotope) specifically inhibited the binding of mAb L26 to ErbB-2 overexpressing cells. No sequence homology was found between the mimotope and ErbB-2. implying that it mimics a conformational structure of the receptor. Preliminary studies showed that the lead peptide can be truncated by removal of two to three amino acids from either the N- or C-terminal end without drastically affecting the inhibitory properties of the mimotope. A tryptophan'glycine residue at the C-terminus and a lysine at the N-terminus of the peptide seemed to play a role in its ability to compete with L26 antibody for binding to ErbB-2 overexpressing cells. These results highlight the potential of active immunization with conformation mimicking peptides in ErbB-2 overexpressing tumors.
Vaisman
N
N
Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
Nissim
A
A
Klapper
L N
LN
Tirosh
B
B
Yarden
Y
Y
Sela
M
M
D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000378:metabolism*; D000912:Antibodies, Neoplasm / Q000276:immunology / Q000378:metabolism*; D001667:Binding, Competitive; D016466:CHO Cells; D006224:Cricetinae; D000939:Epitopes; D006801:Humans; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D019151:Peptide Library; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D011487:Protein Conformation; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm; D000939:Epitopes; D019151:Peptide Library; D010455:Peptides; D018719:Erb-b2 Receptor Tyrosine Kinases