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, i s 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 t o understand and enhance immunotherapy, the laboratory has raised several t urner inhibitory monoclonal antibodies (mAb), including mAb L26 that blocks inter-receptor interactions. Here the application of the phage display met hodology for the isolation of a phage clone that specifically recognizes mA b L26 is described. The isolated mimetic peptide (mimotope) specifically in hibited 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 tha t 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 inhi bitory properties of the mimotope. A tryptophan/glycine residue at the C-te rminus 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 overexpre ssing cells. These results highlight the potential of active immunization w ith conformation mimicking peptides in ErbB-2 overexpressing tumors. (C) 20 00 Elsevier Science B.V. All rights reserved.