Eradication of CD19+ leukemia by targeted calicheamicin θ.

Abstract

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.

• Authors: Kathrin M Bernt, Aram Prokop, Nicole Huebener, Gerhard Gaedicke, Wolfgang Wrasidlo, Holger N Lode
• Journal: Bioconjugate chemistry (Bioconjug Chem) Vol. 20 Issue 8 Pg. 1587-94 (Aug 19 2009) ISSN: 1520-4812 [Electronic] United States
• PMID: 19572629 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Aminoglycosides
• Antibodies, Monoclonal
• Antigens, CD19
• Antineoplastic Agents
• Enediynes
• Immunoconjugates
• calicheamicin theta(1)I

Topics

• Aminoglycosides (chemistry, therapeutic use)
• Animals
• Antibodies, Monoclonal (chemistry, immunology)
• Antigens, CD19 (immunology, metabolism)
• Antineoplastic Agents (chemistry, therapeutic use)
• Cell Line
• Cell Proliferation (drug effects)
• Drug Screening Assays, Antitumor
• Enediynes (chemistry, therapeutic use)
• Female
• Humans
• Immunoconjugates (chemistry, immunology, therapeutic use)
• Mice
• Mice, SCID
• Molecular Structure
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (drug therapy, immunology, metabolism, pathology)