Antigens And Therapy

There are two aspects to antigens and antibodies and their usefulness in therapy. First, antibodies to carefully selected antigens expressed by the leukemic cells are used for ex vivo purification of autologous bone marrow grafts or for in vivo treatment. Second, therapy may be determined by the specific phenotype of the leukemic cell population. In this case, we speak about phe-notype-specific therapy.

The choice of antibodies for bone marrow purging focuses on attacking the leukemic clonogenic cells while sparing the pluripotent hematopoietic stem cells. Some candidate reagents for the elimination of residual blast cells in autologous marrow grafts have been CD33 and CD65s antibodies in AML, CD7 in T-cell lymphoblastic leukemia, and CD10 (CALLA) and CD52 (CAMPATH) in B-cell lymphoblastic leukemia.45-49

In vivo therapy with monoclonal antibodies aims at a specific antigen, which otherwise may be a part of very diverse immunophenotypes. Clinical trials with humanized CD33 monoclonal antibody linked to a cell toxin, such as calicheamycin, constitute one promising ongoing example for that kind of therapeutic approach.50,51 A major requirement for the success of antigen-targeted therapy is exact knowledge of antigen distribution in normal tissues and of the kind of antigen response to antibody binding. Whereas CD33 is rapidly internalized after antibody binding, which makes this antigen an ideal candidate for conjugation with intracellularly active cytotoxic agents,52 CD20 antigen, another target of antibody therapy,53 does not modulate or internalize. The effectiveness of rituximab, a chimeric monoclonal antibody to the CD20 antigen in the chronic lymphoid malignancies tested predominantly to date, results from various mechanisms of action, including activation of the complement cascade, apoptosis, and recruitment of cytotoxic T cells.53

The ultimate goal of immunophenotyping is the establishment of phenotypes or phenotypic characteristics with known therapeutic sensitivity. The best, and currently the only, example for phenotype-specific therapy is given by APL with its characteristic immunophenotype54 and exquisite response to ATRA.9

As we learn more about possible physiological consequences of hematopoietic antigen expression, our approach to the overall classification of leukemias may change. Rather than delineating lineage- or maturation-related phenotypes, the power of immunophenotyping may lie in the characterization of functional leukemia subsets, defined by the expression of molecules with specific functional significance, such as adhesion molecules, cytokine receptors, or surface enzymes. This is already suggested by evidence that the presence of a single functional antigen across FAB or immunophenotypic subtypes may guide therapeutic modalities. For instance, the demonstration of P-glycoprotein (Pgp), a unidirectional membrane drug-efflux pump, which is one potential mediator of multidrug resistance (MDR), has led to the identification of Pgp inhibitors such as cyclosporin and their inclusion in clinical trials.55 Immunophe-notyping may indeed provide important information on potential targets for future therapeutic strategies. Once recognized, the disruption of cell regulatory processes due to the presence or overexpression of certain antigens may lead to rational drug design aimed at modulating the activity of such target molecules, as is already being attempted in the case of Pgp.

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