title: The novel calicheamicin-conjugated CD22 antibody inotuzumab ozogamicin (CMC-544) effectively kills primary pediatric acute lymphoblastic leukemia cells.
abstract: 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.
authors.affiliation: Department of Immunology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.
authors.forename: J F
authors.initials: JF
authors.lastname: de Vries
authors.forename: C M
authors.initials: CM
authors.lastname: Zwaan
authors.forename: M
authors.initials: M
authors.lastname: De Bie
authors.forename: J S A
authors.initials: JS
authors.lastname: Voerman
authors.forename: M L
authors.initials: ML
authors.lastname: den Boer
authors.forename: J J M
authors.initials: JJ
authors.lastname: van Dongen
authors.forename: V H J
authors.initials: VH
authors.lastname: van der Velden
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002648:Child; D006801:Humans; D000080045:Inotuzumab Ozogamicin; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000276:immunology / Q000473:pathology*; D051918:Sialic Acid Binding Ig-like Lectin 2 / Q000276:immunology
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D051918:Sialic Acid Binding Ig-like Lectin 2; D000080045:Inotuzumab Ozogamicin