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Anti-Id Antibodies in Murine Tumor Models Anti-Id Antibodies and Human Cancer Network Antigens in Lymphoma and Leukemia Formats of Anti-Id Antibodies

Immune Pathways Induced by Anti-Idiotypic Antibodies Conclusion and Future Directions of Anti-Id Cancer Vaccines References

1. introduction

Active specific immunotherapy (ASI) is an attractive approach to cancer therapy, especially in an adjuvant setting. ASI is intended to boost or induce a host antitumor response, in contrast to passive immunotherapy, where large doses of preformed antitumor antibodies, or T cells with predetermined specificity, are infused. In classical ASI, patients are vaccinated with purified tumor-specific or tumor-associated antigens (TAAs). This approach has a number of major limitations. The tumor antigens are usually weakly immunogenic due to the induction of tolerance. This tolerance can be broken by presentation of the critical epitope in a different molecular environment (1). Secondly, it is difficult to obtain the purified antigen in sufficient quantities for vaccination. Although this limitation can be overcome by the synthesis of well-defined antigens by use of recombinant DNA technology, the recombinant molecule may not resemble the native structure of the protein. Moreover, mass production of nonprotein antigens, such as carbohydrates or lipids, is not possible by recombinant DNA technology. These limitations can be overcome by using an elegant approach to ASI, with the use of anti-idiotypic (Id) antibodies.

From: Handbook of Cancer Vaccines Edited by: M. A. Morse, T. M. Clay, and H. K. Lyerly © Humana Press Inc., Totowa, NJ

Anti-Id antibody approach is based on the internal-image concept (2,3). This concept proposes that the idiotypes represent links between the outside world of the antigens and the inner immune repertoire. The antigen receptor of T and B lymphocytes expresses antigenic determinants that can be recognized and can elicit humoral or cellular immune responses. Anti-Id concept for the induction of humoral responses can be summarized as follows. A given antibody, Ab1, can recognize a specific determinant on an antigen (Fig. 1A), such as a tumor antigen. The interaction of Ab1 to the antigenic epitope takes place through its variable regions. The variable regions of the Ab1 can also serve as a determinant that induces the synthesis of a heterogeneous population of antibodies, referred to as Ab2 or anti-Id antibodies (Fig. 1B). There can be three classes of Ab2 antibodies based on the region of the variable domain of Ab1 they recognize (4). Ab2a recognize idiotopes that are outside the antigen-binding site. If the target idiotope is close to the binding site and interferes with the antigen binding, it is called Ab2y. Ab2p recognize the binding site of Ab1 and resemble the epitope recognized by Ab1 (Fig. 1B). Ab2p, thus, can act as a surrogate for the nominal antigen and can be used as vaccines. Ab2p antibody is defined by three criteria (5):

1. Immunochemical criterion: its ability to block the binding of Ab1 to its antigen. Antigen binding by Ab1 is not affected by Ab2a; may be partially blocked by Ab2y

2. Functional criterion: The functional criterion is based on its ability to mimic a given antigen and, therefore, to induce the synthesis of antibody specific for the same antigen in various species (genetically unrestricted). Immunization of an animal with Ab2p elicits a polyclonal anti-anti-Id antibody or Ab3 response (Fig. 1B). A subset of Ab3 is expected to recognize the nominal antigen. This Ab3 subtype is called Ab1' to indicate that it might differ in its other idiotopes from Ab1 (Fig. 1B).

3. Structural criterion: Structural identity between an epitope of the antigen and a segment of the variable region of the antibody may represent the most faithful criterion to define an Ab2p.

Whereas the structural criterion may be the best for designation of Ab2p raised by immunization with antibodies specific for protein antigens, the immunochemical and functional criteria can be used to define Ab2p raised against antibodies specific for polysacchrides, lipoproteins, nucleotides, or synthetic drugs (5). The cascade of complementary idiotopes is the basis of making anti-Id antibody vaccines for cancer and a number of infectious diseases (5). The efficacy of anti-Id vaccination has been demonstrated in a number of murine tumor models as well as in cancer patients.

2. anti-id antibodies in murine tumor models

In a number of studies, Kennedy et al. (6,7) demonstrated the efficacy of anti-Id vaccines in a model of SV40-transformed tumor cells. An anti-Id antibody, 58D, was raised against a monoclonal antibody, PAb 405. Pab 405 recognizes the carboxy terminus of SV40 T-antigen. Immunization of BALB/c mice with 58D induced high-titer anti-Tantigen antibodies (Ab1') in 6 of 10 mice. Three of the mice with the highest anti-Tantigen titers were completely protected against challenge with lethal doses of live SV40-transformed mKSA tumor cells. Nepom et al. (8) raised anti-Id antibodies against murine monoclonal antibody 8.2, an antibody specific for a human melanoma-associated cell-surface marker called p97. They demonstrated that these anti-Id antibodies can

Fig. 1. Idiotype network. (A) Binding of monoclonal antibody to an epitope of a tumor antigen, T. (B) Generation of Ab2P, Ab3 and Ab1'. See text for details.

prime animals for immunity with specificity that mimics 8.2 itself. Sera from mice immunized with anti-8.2 (Ab2) contained anti-anti-8.2 antibodies (Ab3), some of which have the same idiotype as 8.2 itself (Ab1'). In another model, Raychaudhuri et al. (9) generated a number of anti-Id antibodies using 11C1 as the Ab1 antibody. 11C1 recognizes the gp52 envelope of mouse mammary tumor virus. Immunizing DBA/2 mice with monoclonal anti-Id antibodies induced immune responses related to gp52. Dunn et al. (10) studied the anti-Id cascade in a rat sarcoma model, HSN. The Ab2 antibody (HIM/ 1/230) was developed using the Ab1 11/160, a monoclonal antibody against HSN tumor cells. Tumor progression was evaluated by a lung colonization assay. Compared to untreated mice, those treated with this Ab2 had significantly reduced number of surface colonies following challenge with intravenous injection of rat sarcoma HSN tumor cells. Anti-Id antibody prepared against anti-BCG (bacille Calmette-Guerin) monoclonal antibody (11) exhibited vaccine activity against Meth A fibrosarcoma that shared a common antigen(s) with BCG. Mice vaccinated with the anti-Id antibody were partially protected against Meth A tumor, and the presence of Ab3 type antibody was detected in the sera of immunized mice. To determine whether the pulmonary metastases of melanoma cells could be inhibited by anti-Id therapy, C57BL/6 mice were immunized with an anti-Id antibody, 7C4, which mimics a mouse melanoma antigen. Vaccination of mice with 7C4 significantly reduced lung metastasis (p < 0.01) and increased survival (p < 0.01) following challenge with live BL6 cells into their caudal (12). An anti-Id monoclonal antibody, D704, was established that bore the internal image of the determinant defined by the monoclonal antibody, M2590, against the sialic acid residue on ganglioside, GM3. Significant suppression of tumor growth and prolongation of survival were achieved by immunization with D704 followed by challenge with 1 x 104 melanoma cells per mouse, but not in a group inoculated with 5 x 104 melanoma cells/mouse. D704 induced humoral anti-anti-Id (anti-GM3) response as well as cellular antitumor responses (13).

We developed a murine monoclonal anti-Id antibody, designated 3H1, which mimics a specific epitope of carcino embryonic antigen (CEA) (see Subheading 2.1.1. for details). The efficacy of 3H1 as a tumor vaccine was evaluated in a murine model (14). In this model, the murine colorectal cancer cell line MC-38 was transduced with human CEA gene and injected into syngeneic C57BL/6 mice. Immunization of naive mice with 3H1 induced humoral and cellular anti-3H1 as well as anti-CEA immunity. Mice immunized with 3H1 were protected against a challenge with lethal doses of MC-38cea cells, whereas no protection was observed with CEA-negative MC-38 cells, or when mice were vaccinated with an unrelated anti-Id antibody and challenged with MC-38cea cells (p < 0.003). To demonstrate the efficacy of 3H1 vaccine against established tumors, MC38cea tumors were first implanted into the mice and they were treated with 3H1 or a control anti-Id antibody. At first tumors developed in both groups at the same rate. On completion of six courses of treatment, tumors of six of nine mice treated with 3H1 became necrotic and regressed. In the control group, only one of eight mice showed regression. These data demonstrate that 3H1 induced CEA-specific antitumor protective immunity in this murine model (14).

Overall, these results in murine systems suggest that anti-Id vaccines bearing internal images of protein and nonprotein antigens induce humoral and cellular immunities directed against the nominal antigens. The vaccinated mice are protected against subsequent challenge with live tumor cells. These results stimulated interest in the development of anti-Id vaccines for the treatment of cancer patients.

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