Abstract
The effect of CMC-544, a calicheamicin-conjugated anti-CD22 monoclonal antibody, was analysed in relation to CD22 and P-glycoprotein (P-gp) in B-cell chronic lymphocytic leukaemia (CLL) and non-Hodgkin lymphoma (NHL) in vitro. The cell lines used were CD22-positive parental Daudi and Raji, and their P-gp positive sublines, Daudi/MDR and Raji/MDR. Cells obtained from 19 patients with B-cell CLL or NHL were also used. The effect of CMC-544 was analysed by viable cell count, morphology, annexin-V staining, and cell cycle distribution. A dose-dependent, selective cytotoxic effect of CMC-544 was observed in cell lines that expressed CD22. CMC-544 was not effective on Daudi/MDR and Raji/MDR cells compared with their parental cells. The MDR modifiers, PSC833 and MS209, restored the cytotoxic effect of CMC-544 in P-gp-expressing sublines. In clinical samples, the cytotoxic effect of CMC-544 was inversely related to the amount of P-gp (P = 0.003), and to intracellular rhodamine-123 accumulation (P < 0.001). On the other hand, the effect positively correlated with the amount of CD22 (P = 0.010). The effect of CMC-544 depends on the levels of CD22 and P-gp. Our findings will help to predict the clinical effectiveness of this drug on these B-cell malignancies, suggesting a beneficial effect with combined use of CMC-544 and MDR modifiers.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / analysis
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
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Antibodies, Monoclonal / therapeutic use*
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Antibodies, Monoclonal, Humanized
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Antineoplastic Agents / therapeutic use*
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Cell Count
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Cell Line, Transformed
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Cell Line, Tumor
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Cyclosporins / therapeutic use
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Dose-Response Relationship, Drug
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Drug Resistance, Multiple / drug effects
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Drug Resistance, Neoplasm
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Flow Cytometry
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Humans
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Immunosuppressive Agents / therapeutic use
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Inotuzumab Ozogamicin
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Jurkat Cells
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Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy*
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Leukemia, Lymphocytic, Chronic, B-Cell / immunology
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Leukemia, Lymphocytic, Chronic, B-Cell / metabolism
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Lymphoma, Non-Hodgkin / drug therapy*
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Lymphoma, Non-Hodgkin / immunology
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Lymphoma, Non-Hodgkin / metabolism
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Quinolines / therapeutic use
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Sialic Acid Binding Ig-like Lectin 2 / analysis
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Sialic Acid Binding Ig-like Lectin 2 / immunology
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Treatment Outcome
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Tumor Cells, Cultured
Substances
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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Antibodies, Monoclonal
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Antibodies, Monoclonal, Humanized
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Antineoplastic Agents
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Cyclosporins
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Immunosuppressive Agents
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Quinolines
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Sialic Acid Binding Ig-like Lectin 2
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dofequidar
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Inotuzumab Ozogamicin
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valspodar