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a Binding scores were determined using BIMAS (100).

a Binding scores were determined using BIMAS (100).

anti-id response elicited in healthy animals [46-48]. As discussed in a previous section of this paper, the low reactivity of TAA binding anti-anti-id antibodies with the original antigen reflects the similarity, but not identity with the original TAA, of the anti-id antibody used as an immunogen. If this interpretation is correct, the reactivity of antianti- id antibodies with the TAA used as a target of immunotherapy cannot be enhanced by augmenting the immunogenicity of anti-id antibodies used as immunogens. Furthermore, no information is available about the effect of the degree of antigen mimicry by anti-id antibodies on the characteristics of the anti-anti-id response. Therefore, one cannot predict whether amino acid substitutions in the heavy and/or light chain variable regions of an anti-anti-id antibody to enhance or reduce the degree of antigenic mimicry represents a viable approach to augment the reactivity of anti-anti-id antibodies with TAA.

(iv) The immunogenicity of anti-id antibodies in patients with malignant diseases is influenced by several variables. It has been a general experience that, in agreement with data obtained in animal model

Figure 4. Model for the generation of high affinity antibodies to a self-TAA by sequential immunization with a mimic of the self-TAA and with the original self-TAA. Mimics of self-TAA activate B-cell clones secreting antibodies which recognize poorly the epitope(s) on the self-TAA. Somatic hypermutations in the course of an immune response may result in the generation of B-cell clones secreting antibodies with high reactivity with self-TAA. Boosting with the original self-TAA leads to the expansion of these high affinity antibody producing B-cell clones.

Figure 4. Model for the generation of high affinity antibodies to a self-TAA by sequential immunization with a mimic of the self-TAA and with the original self-TAA. Mimics of self-TAA activate B-cell clones secreting antibodies which recognize poorly the epitope(s) on the self-TAA. Somatic hypermutations in the course of an immune response may result in the generation of B-cell clones secreting antibodies with high reactivity with self-TAA. Boosting with the original self-TAA leads to the expansion of these high affinity antibody producing B-cell clones.

systems, the immunogenicity of anti-id antibodies in patients with malignant diseases is enhanced by their administration with an adjuvant [38, 70, 71, 76, 77], Alum, BCG and QS21 have been used as adjuvants in patients [38, 41, 58-62, 64-72, 74-77]. Whether the three adjuvants differ in their efficacy to enhance the immunogenicity of anti-id antibodies remains to be determined. The dose/injection of anti-id antibodies injected to patients ranges between 0.1 mg and 8 mg. There is general consensus that the optimal dose for immunization is 2 mg of anti-idiotypic antibody/injection. This dose, which had been identified in a dose escalation trial with the anti-id mAb MF11 -30 in patients with melanoma [69], has been used for most of the anti-id mAb tested in clinical trials. The total dose of anti-id antibody injected to a patient ranges from 0.5 to 56 mg. The requirement for conjugation to a carrier differs among the anti-id antibodies tested. Keyhole limpet hemocyanin (KLH) which is the only carrier used in patients with malignant diseases, has been found to enhance the immunogenicity of some anti-id mAb [70], but to reduce or not to affect that of others [77]. Whether these differences reflect technical reasons and/or the characteristics of the TAA system and/or of the anti-id mAb tested remains to be determined. Different immunization schedules have been tested. The total number of immunizations/patient has ranged from 3 to 26. The frequency of the administrations has ranged between every 1 and 8 weeks. The effect of the immunization schedule on the immunogenicity of anti-id antibodies is not known, since this variable has not been investigated in patients with malignant diseases and has been investigated only to a limited extent in animal model systems [83],

(v) Immunotherapy with anti-id antibodies has been found to have a beneficial effect on the clinical course of the disease, as evidenced by regression of metastatic lesions in a limited number of patients [69, 71, 84] and by survival prolongation of the immunized patients [38,67,69,70,72,73], The latter has been assessed utilizing historical controls in a limited number of studies [67,77]. In many studies, survival prolongation has been found to be associated with the immune response elicited by anti-id antibodies [38,69-71,7375] or with the triggering of the idiotypic cascade by anti-TAA antibodies [85-87]. This association argues in favor of a clinical significance of the anti anti-id response elicited in patients with malignant diseases.

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