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J. E. Janik
responsible for the cleavage of CD25 in vivo is unknown, but matrix metalloprotease 9 is capable of releasing soluble CD25 from the cell surface [6]. The level of serum soluble CD25 or any soluble tumor marker is dependent upon the rate of its production and its catabolism [5]. In the mouse, cell surface shedding of CD25 is not affected over two orders of magnitude of substrate expression. Two factors known to impact serum sIL2R levels are kidney function and administration of a monoclonal anti- body that binds to CD25. The low molecular weight of sIL2R, 23 kDa, allows it to be filtered by the kidney. Thus, the kidney is primarily responsible for its catabolism, with 90% of serum sIL2R catabolized in 1 h. The majority is excreted as amino acids that are generated in the kidney through degradation of the filtered molecule, and a small portion, 1–3%, is excreted intact. A decrease in renal function results in an increase in serum sIL2R level without a change in tumor burden. The other factor that alters serum sIL2R levels is administration of a monoclonal antibody that binds to CD25. Under normal condi- tions, sIL2R is filtered by the kidney, but antibody binding increases its effective molecular weight and prevents its filtration, significantly extending its serum half-life. Use of serum sIL2R levels to follow disease status is not possible after administration of an antibody that binds CD25. This principle applies to other shed receptors, and attempts to measure their levels following administration of an antibody targeted to that receptor yield unreliable data. Serum sIL2R levels were found to be elevated in
patients with hairy cell leukemia by multiple groups, and administration of effective therapy resulted in a significant reduction in sIL2R levels [7,8]. Changes in serum sIL2R levels correlated with response to therapy, but it was not possible to distinguish complete and partial responders based on the sIL2R level in some studies. The reduction in serum sIL2R levels was accompanied by improvement or resolution of cytopenias and clinical recovery. Persis- tently elevated levels of serum sIL2R identify patients with suboptimally treated disease. Many of these studies were performed at a time when the only effective pharmacologic therapy for hairy cell leuke- mia was interferon a. It was customary to administer a limited course of treatment, usually 12–18 months. With this approach, the vast majority of patients relapse and require other therapies. Based on the high relapse rate associated with a limited duration treatment course, prolonged continuous interferon a was administered in an attempt to prevent relapses and improve the complete remission rate [9]. Serum sIL2R levels continued to decrease in association with increases in median granulocyte and platelet counts over the treatment course, suggesting that
continued interferon treatment eliminated more hairy cells. Serum sIL2R levels correlate with total body burden of disease and provide a useful marker for response to treatment and to follow patients for clinical relapse. In a study of patients treated with cladrabine, the serum sIL2R levels doubled 18 months before granulocyte counts decreased by 50%, and provided an early warning of the risk of clinical relapse [10]. Although sIL2R levels correlate well with disease
activity in classic hairy cell leukemia, variant hairy cell leukemia is CD25-negative, and serum sIL2R levels are not useful in following disease activity [2]. Furthermore, serum sIL2R levels can be elevated with immune reactions associated with T cell proliferation, such as acute infections or other inflammatory conditions, hindering interpretation of single values of serum sIL2R as measures of active hairy cell leukemia. Other assays to monitor for the presence of active hairy cell leukemia have been developed. CD22 is highly expressed on mature B cells and,
like CD25, has provided a target for therapeutic intervention. Its internalization in response to anti- body binding provided the rationale for immunotox- in therapy that is effective in relapsed and refractory hairy cell leukemia. CD22 is a transmembrane protein that exists as a 135 kDa membrane bound form and is proteolytically processed to release its 100 kDa extracellular domain. This fragment is further processed in the serum to an 80 kDa form. Both low molecular weight forms of CD22 can be detected in the serum by Western blotting and quantitated with an enzyme-linked immunosorbent assay (ELISA). Normal controls have serum soluble CD22 (sCD22) levels of less than 2 ng/mL, whereas among 93 patients with hairy cell leukemia serum sCD22 levels ranged from 2.1 to 163 ng/mL. As with serum sIL2R levels, sCD22 levels decreased with administration of effective therapy, but in contrast to sIL2R it was possible to distinguish patients who achieved a complete response from those with a partial response. The level of serum sCD22 more accurately reflected disease response in variant hairy cell leukemia compared with sIL2R levels where the malignant cells are CD25-negative. A comparison of serum sCD22 and sIL2R levels in classic hairy cell leukemia has not been reported. Such a comparison would be helpful in determining the optimal tumor marker for following patients with classic hairy cell leukemia. CD307 is expressed on the surface of B cells and a small fraction is released into the serum due to proteolytic cleavage, but the majority of the protein is generated as a result of alternative message splicing to generate a secreted soluble form [1]. Serum soluble CD307 levels were elevated in the
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