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[Cancer Research 65, 6001-6004, July 15, 2005]
© 2005 American Association for Cancer Research

Perspectives in Cancer Research

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

Kouichiro Kawano1, Soldano Ferrone3 and Constantin G. Ioannides1,2

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 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.

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 structure translate in amino acid differences in these regions. These differences are more evident in the CDR3.

Early studies have proposed that only the complementarity-determining regions of an antibody are involved in antigen recognition. This model seemed to be correct for small molecules (i.e., phenols or short sugars). Traditionally, the antibody epitopes (B-cell idiotopes) forming internal images of the nominal antigen are located in the CDR3. Epitopes recognized by CD4+ cells are also present in CDR3 (7, 8). When an antibody recognizes a protein in its native form, framework regions are likely to be involved in antigen binding (5, 6). Considering that an antibody against a protein has high affinity for its ligand, the specific recognition is due to involvement of both framework region and CDR3. Then, the idiotopes/internal images of the antigen should be present in framework region and in CDR3 of Ab2. Because framework region 1 (FR1) is less diverse than the complementarity-determining region but is the NH2-terminal sequence of VH, it is possible that unique sequences are added to the FR1 to sense antigen. In the Ab2 they will share homology with the antigen amino acid sequence.

Tumor Antigen and Ab2 Amino Acid Sequence Comparison

There is no information available regarding homology between tumor antigen amino acid sequences and unique NH2-terminal V-region amino acid sequences of Ab2. We investigated whether epitopes, which can be recognized by CD8+ T cells because they bind MHC class I molecules, are present in the NH2-terminal V regions preceding FR1. To date, there are only four published amino acid sequences of Ab2/antiidiotypic antibody associated with human tumor antigen with known amino acid sequence. Two Ab2 have been generated and sequenced by one of us, and they bear the internal image of distinct determinants of human high molecular weight melanoma–associated antigen (HMW-MAA), which is expressed in a high percentage of melanoma lesions (9). These Ab2 are designated as MF11-30 and MK2-23, respectively (10). The third Ab2, designated 105AD7, bears the internal image of CD55 antigen. CD55 is widely expressed by colorectal carcinoma cells (11, 12). The fourth Ab2, designated 3H1, bears the internal image of carcinoembryonic antigen (CEA; refs. 5, 13).

First, we searched for unique VH peptides preceding FR1. Then, utilizing proteomics programs available at http://bimas.dcrt.nih.gov/molbio/hla_bind, we searched for HLA-A2 binding motifs in the unique VH peptides we had identified. To identify homologous amino acid sequences in the tumor antigen, the sequences of the identified unique VH peptides containing HLA-A2 binding motifs were compared with the amino acid sequences of the corresponding tumor antigen (HMW-MAA, CD55, and CEA). Peptides from Ab2 CDR3, which lacked or showed minimal homology with other immunoglobulin amino acid sequences, were analyzed in parallel. We found that two of the four Ab2 [i.e., monoclonal antibodies (mAb) MF11-30 and 105AD7] contain unique amino acid sequences located before FR1. FR1 starts with a distinctive motif: EVQ, QVQ, EDQ in position 17 to 19. These unique VH peptides encompass the first 18 and 24 amino acids of mAb MF11-30 and 105AD7 VH, respectively (Fig. 1). The other two Ab2 (i.e., mAb MK2-23 and 3H1) do not contain unique VH peptides preceding FR1. The unique VH peptides with HLA-A2 binding motifs from mAb 105AD7 and MF11-30 are shown in Table 1. Two of mAb 105AD7 peptides, designated as 105AD7 (7-16) and 105AD7 (2-10), showed significant homology, 6/10 (60%) and 5/9 (55%), respectively, with CD55 (14-23) and CD55 (373-381) amino acid sequences (Table 2). Results for the pair HMW-MAA and mAb MF11-30 have been published and are not repeated here (14).



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  		Figure 1. Immunoglobulin VH region structure.

 

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  		Table 1. Unique NH2-terminal amino acid sequences of VH antiidiotypic mAb 105AD7 and MF11-30

 

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  		Table 2. Amino acid sequence homology between VH of Ab2 and tumor antigens HMW-MAA, CD55, and CEA

 
mAb MK2-23 and 3H1 do not express unique NH2-terminal VH amino acid sequences. However, two mAb MK2-23 peptides, MK2-23(12-20) and MK2-23(37-46), show significant homology with HMW-MAA (1020-1028) and (825-834) amino acid sequences. mAb MK2-23 amino acid sequence in CDR3 shows poor homology with other VH amino acid sequences. It should be noted that the VH CDR3 (100-117) amino acid sequence is 50% homologous with HMW-MAA (690-706) amino acid sequence. The CDR3 amino acid sequence resembles an MHC class II epitope due to the presence of hydrophobic aliphatic and aromatic amino acids, which are known to form MHC class II anchors. Peptides with this sequence may activate CD4+ T cells as reported for CDR3 peptides from mAb 3H1. Surprisingly, we found significant homology between the NH2-terminal VH 3H1 peptide (12-20) and CEA isoform 1 (100-108). The two nonamers, 3H1 (12-20) and CEA-1(100-108), are 55% homologous and can bind to HLA class I antigens.

The homology between tumor antigen and Ab2 amino acid sequences is not random. It was not observed with amino acid sequences from the immunoglobulin light chain. Also, VH of human myelomas which contain unique FR1 (15) did not show such extensive homology with HMW-MAA and CD55 as the one reported here (data not shown). To summarize, two Ab2 carry unique NH2-terminal VH sequences whereas two Ab2 do not. All four NH2-terminal VH are more than 50% homologous with the inducer tumor antigen. We have designated these Ab2/antiidiotypic antibody NH2-terminal VH sequences as T-cell idiotopes because they are homologous with somatic antigen.

Evaluation of Antigen-Ab2 Similarities in Energy Terms

The major structural differences between the tumor antigen peptides and the corresponding T-cell idiotopes include (a) introduction or removal of charged residues; (b) insertion of groups which lead to misalignments; and (c) introduction of polar residues which form H-bonds. Of the eight pairs of Ab2-tumor antigen shown in Table 2, changes in charged residues are present in the pairs mAb 105AD7 (7-16)/CD55 (14-23), mAb MK2-23 (37-46)/HMW-MAA (825-834), and mAb 3H1 (12-20)/CEA (100-108). Misalignments are generated by insertion of (a) Ser7 in mAb 105AD7 (7-16), which shifts the almost identical group (RVL) with the CD55 (14-23) group: RLL; (b) Ser6 in mAb MD2-23, which also shifts the almost identical group: RKL with the HMW-MAA group RRL; and (c) Asp6 in mAb MK2-23, which also shifts the almost identical group KKG with the group RKG in HMW-MAA (825-833). The Ab2-tumor antigen peptide pairs which lack changes in charged residues show changes in polar residues such as Ser7->Gly7 (pair 1), Thr5->Phe5 (pair 2), as well as Cys3->Val3 (pair 3).

These findings raise important questions regarding the effects of changes in VH amino acid sequence on T-cell activation. If a self-antigen such as CD55 fails to induce CTL specific for the peptide CD55 (14-23), this may be due to T-cell deletion or to ignorance because of repulsion of T-cell receptor by negative charges on side chains. In energy terms, electrostatic forces are the strongest between atoms. In this case, stimulation with peptide 105AD7 (7-16) may activate cross-reactive CD8+ T cells. Similarly, if the CEA (100-108) is not sufficiently activating CD8+ T cells, the peptide 3H1 may be a stronger immunogen because Lys4 can induce 10-fold stronger electrostatic forces than Tyr4 (see pair 8, Table 2). Generation of tumor antigen–specific CTL should be enhanced if proinflammatory/inflammatory cytokines are administered. In the clinical trial with mAb MF11-30(3-11), Bacillus Calmette-Guerin was used as an adjuvant (14). Therefore, Ab2 can be used to activate humoral or cellular responses to cancer according to disease (i.e., myeloma/lymphoma or solid tumors).

Proposed Model

The reasons for the presence of unique NH2-terminal VH sequences with high frequency in Ab2 (anti-idiotype) are unclear. During the class switch to immunoglobulin G (IgG), novel VH families are used by antibody to increase the binding affinity for the antigen (16). It is unknown how these VH families are selected and whether unique NH2-terminal VH inserts are associated with a particular VH gene. Based on alignment with IMGT program (http://imgt.cines.fr), the VH of mAb MF11-30 and 105AD7 belong to VH families Q52 and IgG VHII, respectively. The first 23 amino acids of mAb MF11-30 VH are absent from all other IgGs. The first six NH2-terminal amino acids of mAb 105-AD7 VH are absent from most IgGs. Compared with the few more homologous IgG or hypothetical proteins, the following 11 amino acids had one deletion, which resulted in a misalignment plus at least four to five nonconservative changes. The only partial match for mAb 105AD7H/DTLCYT was found in a rearranged VH pseudogene (DILCST) that has deleted the CDR2 (17). One possibility is that changes are selected by Ab2 to enhance contact with antigen. Another possibility is that unique NH2-terminal VH inserts may have been selected based on the Ab2 CDR3 amino acid sequence. If this is the case, CDR3 determines whether the Ab2 will induce antigen-specific CD8+ T cells. CD8+ T-cell responses induced by antiidiotypic antibodies in myelomas have been recently observed (18). Mutations consisted in introduction of polar and charged residues. This amino acid sequence was followed by conserved FR1. Naturally occurring CTL precursors with specificity for Ab2 as well as suppressor T cells induced by Ab2 have been reported (19, 20). Is Ab2 directing the response to tumor antigen by determining whether CD8+ cells will be activated or not? Further studies determining the affinity of Ab2/antiidiotypic antibody peptide and tumor Ag for TCR of CD8+ T cells will be useful to clarify this issue.

The functional T-cell idiotope approach to tumor immunity suggests that CTL epitopes are generated from the nascent VH chains of Ab2 and are presented by B cells directly to T cells. A unique amino acid sequence is formed by joining three to five amino acids of the leader with the new insert and the first amino acids of the FR1. Endogenous peptides of this sequence can be presented by various MHC molecules. A recent report on activation of CD4+T cells by mutated FR1 supports this hypothesis (21). This mechanism of antigen generation and presentation differs from the mechanism of generation of novel candidate CTL epitopes by modification of HLA-A2 anchor residues in FR1 of Ab1 reported in myelomas (22, 23). The functional T-cell idiotope approach to tumor antigen discovery differs from the phage-display antibody library and SEREX approaches (i.e., refs. 24, 25), because it searches for CTL epitopes in antiidiotypic antibody/Ab2. The phage display and SEREX identify tumor antigen recognized by Ab1 and/or Ab3 but not the sequence of the CTL epitope of the tumor antigen nested in Ab2.

Ab2 which induces CD8+ T-cell responses should lead to discovery of novel tumor antigen. Isolated B cells with blocked Fc receptors can be identified after reaction with the IgG fraction of the same patient serum. Isolated mRNA could be amplified with IgG primers and sequenced. The unique NH2-terminal VH sequence of Ab2 could be compared with those of tumor proteins to identify candidate CTL epitopes. If the peptide corresponding to the T-cell idiotope activates, and expands CTLs, which recognize tumor cells, it will indicate that idiotope-specific CTLs are functional The presence of CTL epitopes in the T-cell idiotopes raise the possibility of using peptides corresponding to these idiotopes and even Ab2 to elicit effector CTL targeting the corresponding tumor.

In conclusion, we found significant similarities (50-60%) between candidate CTL epitopes mapped to a new NH2-terminal sequence of VH of Ab2/antiidiotypic antibody and the tumor antigen which induced Ab1. The differences between Ab2 and tumor antigen consisted mainly in charged residues in the former. Unique NH2-terminal VH sequences seemed to be generated either by nucleotide insertion or from a highly mutated germ line preceding the constant amino acid sequence of FR1. Ab2 peptides homologous with tumor antigen peptides may be stronger immunogens than the tumor antigen peptides for induction of CTL recognizing tumors expressing these antigen. Ongoing studies in our laboratory aim to address whether CD8+ cell idiotypes are immunogenic and induce protection from tumor growth in transgenic animals.

Acknowledgments

Grant support: Public Health Service grants P01 CA89480 and R01 CA105500 awarded by the National Cancer Institute, Department of Health and Human Services, the Harry J. Lloyd Charitable Trust, DOD grant 1-01-0299, the Keck Foundation and Grant No. P50 CA93459 (MDACC-melanoma SPORE). Its contents do not necessarily reflect the views of the NIH.

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.

Received 9/20/04. Revised 3/ 9/05. Accepted 4/20/05.

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