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Functional Idiotopes: Tumor Antigen–Directed Expression of CD8⁺ T-Cell Epitopes Nested in Unique NH₂-terminal V_H Sequence of Antiidiotypic Antibodies?

Departments of ¹ Gynecologic Oncology and ² Immunology, M.D. Anderson Cancer Center, Houston, Texas and ³ Department of Immunology, Roswell Park Cancer Institute, Buffalo, New York

Requests for reprints: Soldano Ferrone, Department of Immunology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263. Phone: 716-845-8534; Fax: 716-845-7613; E-mail: soldano.ferrone{at}roswellpark.org.

Abstract

Antiidiotypic antibodies have been and are being used for cancer immunotherapy based on the rationale that Ab2 carrying an "internal image" of the corresponding tumor antigen can induce tumor antigen–specific antibodies (i.e., Ab3 and inhibit tumor growth). Recent evidence indicates that Ab2 also induces cellular responses by CD4⁺ and CD8⁺ T cells. This finding has raised the question of where the short peptides, which express CD8⁺ T-cell–defined epitopes, are located and their relationship with the tumor antigen. We found that two of the four known Ab2 associated with tumor antigen, with known amino acid sequence, express unique NH₂-terminal V_H sequences which precede the framework regions. Both the unique and the shared NH₂-terminal V_H sequences are nested MHC class I antigen–binding peptides. These peptides were highly homologous with peptides from corresponding tumor antigen (carcinoembryonic antigen, CD55, and human high molecular weight melanoma–associated antigen) but differed from the tumor antigen peptides by the presence of the side chain known to mediate stronger forces of interaction with other atoms. The presence of candidate CTL epitopes in NH₂-terminal V_H of Ab2 homologous with tumor antigen may be important for the development of novel immunotherapeutic strategies for cancer.

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