Conclusions

The results we have summarized provide convincing evidence that mouse and human anti-id antibodies which bear the internal image of human TAA are more effective than the corresponding TAA in breaking unresponsiveness to a self-antigen in patients with malignant diseases. The cellular and/or humoral anti-anti-id response appears to be associated with a favorable clinical response. Whether this association reflects a cause-effect relationship requires double blind, mul-

ticenter clinical trials with a large number of patients with malignant diseases.

The clinical trials performed with anti-id antibodies have also identified two major limitations of active specific immunotherapy with anti-id antibodies, i.e., the low reactivity of anti-anti-id antibodies with TAA used as a target and the lack of induction of HLA class I antigen restricted, TAA specific CTL. We will conclude this review by discussing approaches we have been developing in order to overcome these two limitations of active specific immunotherapy with anti-id antibodies

As already mentioned, in at least four antigenic systems, antigen binding anti-anti-id mAb have been found to have a high degree, but not complete homology in the amino acid sequence of their heavy and light chain variable regions with the corresponding Abl mAb used to trigger the idiotypic cascade [49-52]. The limited number of residue differences between Abl mAb and anti-anti-id mAb is likely to underlie their reduced reactivity with the nominal antigen. Therefore it is our working hypothesis that somatic mutations which occur in the course of an immune response may increase the homology in the amino acid sequence of the heavy and light chain variable regions of antibodies elicited by anti-id antibodies with those of antibodies elicited by the corresponding TAA. As a result, the mutated antibodies may display a much stronger reactivity with the TAA. Boosters with the original TAA are expected to expand the B-cell pop-ulation(s) which secrete the mutated antibodies. This working hypothesis suggests the following immunization strategy. A host is first immunized with a mimic of the TAA to break unresponsiveness to a self-antigen. The host is then boosted with the original TAA to expand the population of B-cells secreting antibodies that because of somatic hypermutations display a high, if not complete homology in the amino acid sequence of the heavy and/or light chain variable regions with the antibody elicited by the original TAA (Figure 4). As a result, this immunization strategy is expected to overcome the unresponsiveness to a self-TAA and the weak immune response to a self-TAA elicited by a mimic of this antigen. Our working hypothesis is supported by our recent findings. HMW-MAA bearing human melanoma cells do not induce anti-HMW-MAA antibodies in rabbits which express HMW-MAA with an antigenic profile and a tissue distribution similar to those in humans (Figure. 5).

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