| Autor: |
de Vries JF; Department of Immunology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands., Zwaan CM, De Bie M, Voerman JS, den Boer ML, van Dongen JJ, van der Velden VH |
| Jazyk: |
angličtina |
| Zdroj: |
Leukemia [Leukemia] 2012 Feb; Vol. 26 (2), pp. 255-64. Date of Electronic Publication: 2011 Aug 26. |
| DOI: |
10.1038/leu.2011.206 |
| Abstrakt: |
We investigated whether the newly developed antibody (Ab) -targeted therapy inotuzumab ozogamicin (CMC-544), consisting of a humanized CD22 Ab linked to calicheamicin, is effective in pediatric primary B-cell precursor acute lymphoblastic leukemia (BCP-ALL) cells in vitro, and analyzed which parameters determine its efficacy. CMC-544 induced dose-dependent cell kill in the majority of BCP-ALL cells, although IC(50) values varied substantially (median 4.8 ng/ml, range 0.1-1000 ng/ml at 48 h). The efficacy of CMC-544 was highly dependent on calicheamicin sensitivity and CD22/CMC-544 internalization capacity of BCP-ALL cells, but hardly on basal and renewed CD22 expression. Although CD22 expression was essential for uptake of CMC-544, a repetitive loop of CD22 saturation, CD22/CMC-544 internalization and renewed CD22 expression was not required to achieve intracellular threshold levels of calicheamicin sufficient for efficient CMC-544-induced apoptosis in BCP-ALL cells. This is in contrast to studies with the comparable CD33 immunotoxin gemtuzumab ozogamicin (Mylotarg) in acute myeloid leukemia (AML) patients, in which complete and prolonged CD33 saturation was required for apoptosis induction. These data suggest that CMC-544 treatment may result in higher response rates in ALL compared with response rates obtained in AML with Mylotarg, and that therefore clinical studies in ALL, preferably with multiple low CMC-544 dosages, are warranted. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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