Introduction of Monoclonal Antibodies Into Clinical Practice

Several problems have limited the successful introduction of monoclonal antibody therapies into clinical practice. These obstacles include (1) identification of tumor-specific antigens, (2) antigen surface density, (3) antibody production, (4) internalization of antigen or antigen-antibody complex, (5) antigenicity of the antibody resulting in host sensitization, (6) infusion toxicity from host humoral response, and (7) delivery of antibody to bulky tumors. An ideal antigen should be expressed at relatively high density on tumor cells, but not on most normal cells, and should not undergo shedding, internalization, or other modification. B-cell malignancies each express a unique immunoglobulin (Ig) idiotype (Id), which is generated by recombination of the genetic sequences for variable Ig light and heavy chains. Each clonal B-cell lymphoproliferative disorder produces a unique Id protein, and thus Id would be the ideal antigen for monoclonal antibody therapy. Early studies of immunotherapy focused on monoclonal antibodies directed against tumor-specific idiotype (anti-Id MAbs). These studies yielded promising results, and several patients with NHL achieved long-lasting remissions (24-28). However, relapse was common and was often accompanied by genetic mutation of the Id protein (29-31). Whereas anti-Id MAb therapy was tested primarily in patients with indolent B-cell NHL, anti-Id MAb therapy was given to several patients with CLL (32-34). In these case reports, individual patients with CLL received anti-Id MAb, with transient responses in two of three patients; immune deficiency was felt to contribute to the lack of response in the third patient (34).

Despite the theoretical advantages of using anti-Id MAb, identification of an individual patient's Id protein sequence and generation of an individualized anti-Id MAb are not feasible on a large scale with current available technology. Id vaccines may be an alternative approach if the immune deficiency of CLL can be overcome to allow generation of a primary and persistent secondary immune response. Id vaccines, which have shown promise in B-cell NHL, are now entering clinical trials in CLL. Development of monoclonal antibodies has become focused on the use of antigens specific for tumors, as opposed to patient-specific antigens, to allow broad therapeutic applicability of each monoclonal antibody. Monoclonal antibodies generated against several such antigens in CLL are reviewed in this chapter.

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