CMC-544 (inotuzumab ozogamicin) shows less effect on multidrug resistant cells: analyses in cell lines and cells from patients with B-cell chronic lymphocytic leukaemia and lymphoma.
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.
Takeshita
Akihiro
A
Laboratory and Internal Medicine, Hamamatsu University School of Medicine, Higashiku, Hamamatsu, Japan. akihirot@hama-med.ac.jp
Shinjo
Kaori
K
Yamakage
Nozomi
N
Ono
Takaaki
T
Hirano
Isao
I
Matsui
Hirotaka
H
Shigeno
Kazuyuki
K
Nakamura
Satoki
S
Tobita
Tadasu
T
Maekawa
Masato
M
Ohnishi
Kazunori
K
Sugimoto
Yoshikazu
Y
Kiyoi
Hitoshi
H
Naoe
Tomoki
T
Ohno
Ryuzo
R
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002452:Cell Count; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D003524:Cyclosporins / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D005434:Flow Cytometry; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D000080045:Inotuzumab Ozogamicin; D019169:Jurkat Cells; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D011804:Quinolines / Q000627:therapeutic use; D051918:Sialic Acid Binding Ig-like Lectin 2 / Q000032:analysis / Q000276:immunology; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D003524:Cyclosporins; D007166:Immunosuppressive Agents; D011804:Quinolines; D051918:Sialic Acid Binding Ig-like Lectin 2; C087719:dofequidar; D000080045:Inotuzumab Ozogamicin; C070272:valspodar