Eradication of CD19+ leukemia by targeted calicheamicin θ.
Children with relapsed and refractory acute lymphoblastic leukemia (ALL) still face a critical prognosis. We tested the hypothesis that targeted calicheamicin theta (θ) using an anti-CD19-immunoconjugate may provide an effective treatment strategy for CD19(+) ALL. Calicheamicin θ is a rationally designed prodrug of the natural enediyene calicheamicin γ, obtained by total synthesis. It offers the advantage of increased in vivo stability and 1000-fold higher antitumor potency over calicheamicin γ. First, we demonstrate efficacy of calicheamicin θ against primary pre-B leukemic cells and multidrug-resistant leukemia cell lines (IC(50) = 10(-9) to 10(-12) M). Second, conjugation of calicheamicin θ to an internalizing murine anti-CD19 monoclonal antibody was demonstrated to affect neither calicheamicin θ mediated cytotoxicity nor binding of the antibody to the target molecule. Third, anti-CD19-calicheamicin θ immunoconjugate revealed a maximum tolerated dose of 10 μg/kg and CD19-specific and long-lasting eradication of established leukemia was demonstrated in a xenograft model. Finally, we show that the antileukemic effect of anti-CD19-calicheamicin θ is mediated by induction of apoptosis proceeding through the caspase-mediated mitochondrial pathway. On the basis of these results, we conclude that anti-CD19-calicheamicin θ immunoconjugates may offer a novel and effective approach for the treatment of relapsed CD19(+) ALL.
Bernt
Kathrin M
KM
Charité Universitätsmedizin Berlin, Department of Pediatrics, Experimental Oncology, Berlin, Germany.
Prokop
Aram
A
Huebener
Nicole
N
Gaedicke
Gerhard
G
Wrasidlo
Wolfgang
W
Lode
Holger N
HN
D000617:Aminoglycosides / Q000737:chemistry / Q000627:therapeutic use*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000276:immunology; D018941:Antigens, CD19 / Q000276:immunology / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000627:therapeutic use*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D053281:Enediynes / Q000737:chemistry / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D018796:Immunoconjugates / Q000737:chemistry* / Q000276:immunology / Q000627:therapeutic use*; D051379:Mice; D016513:Mice, SCID; D015394:Molecular Structure; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism* / Q000473:pathology
D000617:Aminoglycosides; D000911:Antibodies, Monoclonal; D018941:Antigens, CD19; D000970:Antineoplastic Agents; D053281:Enediynes; D018796:Immunoconjugates; C113504:calicheamicin theta(1)I