Ioannides Sequence of Antiidiotypic Antibodies ? H-terminal V 2 T-Cell Epitopes Nested in Unique NH + CD 8 Directed Expression of − Functional Idiotopes : Tumor Antigen

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 VH sequences which precede the framework regions. Both the unique and the shared NH2-terminal VH 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 VH of Ab2 homologous with tumor antigen may be important for the development of novel immunotherapeutic strategies for cancer. (Cancer Res 2005; 65(14): 6002-5) The Idiotype Network Theory in the Context of Cancer Immunotherapy Active specific immunotherapy with well-defined moieties represents an attractive approach to cancer therapy. A number of immunogens are being tested in patients with various types of malignant diseases. Among them are idiotype-specific antibodies (i.e., antiidiotypic antibodies), which mimic tumor antigen. The use of antiidiotypic antibodies as immunogens is based on the rationale put forward by the idiotype network theory (1, 2). According to this theory, an antigen induces an antibody specifically recognizing a defined amino acid sequence/structural motif unique to this antigen. This antibody is designated as Ab1. In hematologic malignancies (myeloma, lymphoma, and leukemia) the Ab1 bound on B-cell idiotype is a specific tumor antigen and, due to mutations in VH regions, is also patient specific. Because the antigen-binding amino acid sequence of Ab1 is unique, Ab1 is seen as foreign by the immune system which has produced it. As a consequence, the immunized host generates another antibody, which specifically recognizes the antigen-binding amino acid sequence of Ab1. This antibody is designated as Ab2 or antiidiotypic antibody. Because only certain amino acid sequences in antibody-binding regions differ between Ab1 and antibody of other specificities present in the host, it is believed that Ab2 recognizes only the antigen-binding amino acid sequence on Ab1. The antigen-binding amino acid sequence of Ab1 recognizes several amino acids of the antigen and is recognized by Ab2. Due to similarity between antigen and Ab1-binding amino acid sequence of Ab2, it is generally believed that Ab2 carries the ‘‘internal image’’ of the antigen (1, 2). Based on this rationale, a number of immunotherapy studies have used Ab2 as immunogens to elicit tumor antigen–specific immunity (3). The role of idiotype-specific immune responses in regulation of tumor proliferation and metastasis is poorly understood. One rationale for these studies is that Ab2 stimulates the immune system to generate new antibodies to the internal image of the antigen. These antibodies, generally defined as Ab3, will interact with the inducing antigen on the tumor cell. The antigen-Ab3 interaction may mediate immune destruction of tumor cells and/or inhibit a number of functions attributed to the tumor antigen. A number of antibody found to be bound to tumor cells by the SEREX approach (4) probably belong to both Ab1 and Ab3 categories. There is also concern that Ab2 and Ab3 neutralize each other. A second rationale for the use of Ab2 as an immunogen in immunotherapy is that Ab2 can induce T cells interacting with novel epitopes on Ab2 (3). The question of how this happens is more complex than it initially seems. If the tumor antigen and the Ab2 share linear amino acid sequence homology, then the resulting T cells, as self-reactive T cells, should be tolerized or deleted. However, if the homology is partial, Ab2-specific T cells which recognize the tumor antigen, although with lower affinity than Ab2 peptides, may be activated. Most human tumor antigen peptides recognized by CTL are weak and partial inducers of differentiation. The differentiation of Ab2-specific T cells and their presence in large numbers account for their ability to mediate an antitumor response. Structure of Antibody Variable Regions The NH2-terminal regions of the heavy (H) and light (L) chains of an antibody are implicated in antigen recognition (5, 6). Because these regions recognize diverse amino acid sequences, and maintain their folding, the first 120 to 140 NH2-terminal amino acids define the variable region of the heavy (VH) and light (VL) chains. Each contains three complementarity-determining regions designated as CDR1, CDR2, and CDR3. These three regions are more mutated compared with the intervening regions, which are designated as framework regions. Differences in the antigen 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@roswellpark.org. I2005 American Association for Cancer Research. Cancer Res 2005; 65: (14). July 15, 2005 6002 www.aacrjournals. org Perspectives in Cancer Research American Association for Cancer Research Copyright © 2005 on February 23, 2013 cancerres.aacrjournals. org Downloaded from DOI:10.1158/0008-5472.CAN-04-3400