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Treatment of CD19+ leukemia by targeted calicheamicin theta specifically eradicates established disease



Treatment of CD19+ leukemia by targeted calicheamicin theta specifically eradicates established disease



Blood 102(11): 621a, November 16



The CD19 B-cell epitope similar to CD20 may provide an excellent target for the treatment of leukemia and non-Hodgkin lymphoma. One limitation of tumor targeting strategies using drug conjugates is the potency of the cytotoxic compound used for immunoconjugation. Therefore, we tested the hypothesis that a Calicheamicin theta anti-CD19-immunoconjugate circumvents this limitation and provides an effective treatment for CD19 positive malignancies. Calicheamicin theta is a rationally designed prodrug of the natural enediyene Calicheamicin g, obtained by total synthesis, which is up to 3 logs more potent than the natural analogue. Here, we report in vitro and in vivo efficacy and specificity of CD19 targeted Calicheamicin theta and resolve the mechanisms involved in Calicheamicin theta mediated anti-leukemic effects. First, we demonstrate high efficacy of Calicheamicin theta against primary bcr/abl positive Pre-B leukemic cells and multidrug resistant leukemia cell lines (IC50 10-9 to 10-12 M). Second, effective conjugation of Calicheamicin theta to an internalizing murine anti-CD19 monoclonal antibody was accomplished using heterobifunctional linkers. Third, anti-CD19-calicheamicin theta immunoconjugates were evaluated in vivo. Findings revealed a maximum tolerated dose of about 10mg/kg conjugated Calicheamicin theta in mice, which is ten fold higher than that of the free drug. Furthermore we demonstrate long lasting eradication of established leukemia in a xenograft model as indicated by a doubling of life span with all animals alive 100 days after tumor cell injection only in mice (n=6) treated with 10mg/kg conjugated Calicheamicin theta. This finding was in contrast to controls treated with an equivalent amount of non-specific ch14.18-Calicheamicin theta conjugate (all animals dead after 60 days) and animals receiving no treatment (all animals dead after 40 days). Finally, we determined the mechanism of action involved in calicheamicin theta mediated anti-tumor effects. Induction of apoptosis was mediated by the mitochondrial pathway and was independent of CD95/Fas signaling. This was demonstrated by Calicheamicin theta mediated decrease in mitochondrial membrane potential, release of cytochrome C, processing of caspase 3 and DNA fragmentation. Importantly, these effects were observed in picomolar concentrations of Calicheamicin theta, further supporting the strong potential of this compound for immunoconjugation. In summary, we demonstrate for the first time that Calicheamicin theta targeted to CD19 is highly potent and provides specific eradication of CD19 positive leukemia in vivo. These findings were extended by the first description of the mechanisms of apoptosis involved in calichemicin theta mediated cell death. Based on these findings, we conclude that anti-CD19-Calicheamicin theta immunoconjugates may offer a novel and highly effective approach for the treatment of CD19 positive malignancies.

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Accession: 035980353

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