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Identification of an Antigenic and Immunogenic Motif Expressed by Two 7-Mer Rituximab-Specific Cyclic Peptide Mimotopes: Implication for Peptide-Based Active Immunotherapy¹

Department of Internal Medicine and Clinical Oncology, University of Bari Medical School, Bari, Italy

Two 7-mer cyclic peptides—Rp15-C and Rp13-C—which bear the antigenic motif recognized by the anti-CD20 mAb rituximab, but have different motif-surrounding amino acids, show a comparable avidity for rituximab and inhibit the binding of rituximab to raft-associated CD20 and rituximab-induced membrane ceramide on human lymphoid Daudi cells. Their immunogenic profiles differed: Abs recognizing CD20 were induced in two and five of five BALB/c mice immunized with Rp15-C and Rp13-C, respectively. Analysis of immunogenic motif, performed by panning a 7-mer phage-display peptide library with purified anti-peptide IgGs, showed that the motif defined by anti-Rp15-C mostly included amino acids surrounding the rituximab-specific antigenic motif <aNPS>, whereas that defined by anti-Rp13-C was <NPS>. These data indicate that their motif-surrounding amino acids can markedly influence the specificity of Abs, even when elicited with a short 7-mer peptide. Because these anti-peptide Abs are of IgG isotype, their specificity is likely to reflect how peptides are processed at the T cell level and suggest that, within a short peptide, the motifs defined by T cells during the initial phase and upon their stimulation may be different. Our findings may account for the failure of most forms of peptide-based immunotherapy in cancer and autoimmune diseases in which anti-mimotope Abs are expected to play a relevant therapeutic effect. They also suggest strategies to implement the specificity of peptide-induced Abs against the target Ag.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by a grant from Associazione Italiana per la Ricerca sul Cancro (Milan, Italy).

² Address correspondence and reprint requests to Dr. Federico Perosa, Department of Internal Medicine and Clinical Oncology, University of Bari Medical School, Piazza G. Cesare 11, 70124-Bari, Italy. E-mail address: f.perosa{at}dimo.uniba.it

³ Abbreviations used in this paper: PIT, passive immunotherapy; PDPL, phage-display peptide library; CTB, cholera toxin subunit B; KLH, keyhole limpet hemocyanin; HMW-MAA, high m.w. melanoma-associated Ag.