+ Site Statistics
+ Search Articles
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ PDF Full Text
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn

+ Translate
+ Recently Requested

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.

(PDF emailed within 1 workday: $29.90)

Accession: 035980353

Download citation: RISBibTeXText

Related references

CD19 targeted calicheamicin THETA is effective against high risk ALL. Blood 96(11 Part 1): 467a, November 16, 2000

Eradication of CD19+ leukemia by targeted calicheamicin θ. Bioconjugate Chemistry 20(8): 1587-1594, 2011

Antitumour activity of Calicheamicin theta, Doxorubicin and anti-CD19 immunoconjugates in a human pre-B ALL cell line. Blood 98(11 Part 1): 105a, November 16, 2001

Targeted therapy of renal cell carcinoma xenografts with a chemoimmunoconjugate of mAb 138H11 and calicheamicin theta. Proceedings of the American Association for Cancer Research Annual Meeting (41): 79, March, 2000

Preclinical targeted therapy of renal cell carcinoma with conjugates of mAb 138H11 and calicheamicin theta. European Journal of Cancer 35(SUPPL 5): S55, 1999

Antibody-targeted chemotherapy with CMC-544: a CD22-targeted immunoconjugate of calicheamicin for the treatment of B-lymphoid malignancies. Blood 103(5): 1807-1814, 2003

Systemic IL-12 administration combined with gene-modified tumor cell vaccination eradicates pre-established leukemia and establishes long lasting immunity in a murine model of Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia. Blood 98(11 Part 1): 120a, November 16, 2001

A phase I trial for the treatment of purine analog-refractory chronic lymphocytic leukemia using autologous T cells genetically targeted to the B cell specific antigen CD19. Journal of Clinical Oncology 26(15_suppl): 3045-3045, 2016

Selective ablation of acute myeloid leukemia using antibody-targeted chemotherapy: a phase I study of an anti-CD33 calicheamicin immunoconjugate. Blood 93(11): 3678-3684, 1999

Novel cellular therapies for leukemia: CAR-modified T cells targeted to the CD19 antigen. Hematology. American Society of Hematology. Education Program 2012: 143-151, 2013

Antibody-targeted chemotherapy with the calicheamicin conjugate hu3S193-N-acetyl gamma calicheamicin dimethyl hydrazide targets Lewisy and eliminates Lewisy-positive human carcinoma cells and xenografts. Clinical Cancer Research 10(13): 4538-4549, 2004

Targeted therapy with arsenic trioxide and interferon alpha eradicates leukemic cells in SCID mice model of adult T-cell leukemia/lymphoma. 2007

CD19-targeted chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia. Blood 125(26): 4017-4023, 2015

CMC-544, an Anti-CD22 Antibody-Targeted Calicheamicin Therapeutic for the Treatment of B Lymphoid Malignancies. Blood 100(11): Abstract No 599, November 16, 2002