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Antibody-based delivery of interleukin-2 to neovasculature has potent activity against acute myeloid leukemia.

Abstract
Acute myeloid leukemia (AML) is a rapidly progressing disease that is accompanied by a strong increase in microvessel density in the bone marrow. This observation prompted us to stain biopsies of AML and acute lymphoid leukemia (ALL) patients with the clinical-stage human monoclonal antibodies F8, L19, and F16 directed against markers of tumor angiogenesis. The analysis revealed that the F8 and F16 antibodies strongly stained 70% of AML and 75% of ALL bone marrow specimens, whereas chloroma biopsies were stained with all three antibodies. Therapy experiments performed in immunocompromised mice bearing human NB4 leukemia with the immunocytokine F8-IL2 [consisting of the F8 antibody fused to human interleukin-2 (IL-2)] mediated a strong inhibition of AML progression. This effect was potentiated by the addition of cytarabine, promoting complete responses in 40% of treated animals. Experiments performed in immunocompetent mice bearing C1498 murine leukemia revealed long-lasting complete tumor eradication in all treated mice. The therapeutic effect of F8-IL2 was mediated by both natural killer cells and CD8(+) T cells, whereas CD4(+) T cells appeared to be dispensable, as determined in immunodepletion experiments. The treatment of an AML patient with disseminated extramedullary AML manifestations with F16-IL2 (consisting of the F16 antibody fused to human IL-2, currently being tested in phase 2 clinical trials in patients with solid tumors) and low-dose cytarabine showed significant reduction of AML lesions and underlines the translational potential of vascular tumor-targeting antibody-cytokine fusions for the treatment of patients with leukemia.
AuthorsKatrin L Gutbrodt, Christoph Schliemann, Leonardo Giovannoni, Katharina Frey, Thomas Pabst, Wolfram Klapper, Wolfgang E Berdel, Dario Neri
JournalScience translational medicine (Sci Transl Med) Vol. 5 Issue 201 Pg. 201ra118 (Sep 04 2013) ISSN: 1946-6242 [Electronic] United States
PMID24005158 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • F8 monoclonal antibody
  • Fibronectins
  • Interleukin-2
  • Cytarabine
Topics
  • Adult
  • Aged
  • Aged, 80 and over
  • Animals
  • Antibodies, Monoclonal (administration & dosage)
  • Antibodies, Monoclonal, Humanized
  • Biopsy
  • CD4-Positive T-Lymphocytes (cytology)
  • CD8-Positive T-Lymphocytes (cytology)
  • Cell Line, Tumor
  • Cytarabine (administration & dosage)
  • Disease Progression
  • Female
  • Fibronectins (metabolism)
  • HL-60 Cells
  • Humans
  • Interleukin-2 (administration & dosage)
  • Leukemia, Myeloid, Acute (therapy)
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Nude
  • Mice, SCID
  • Middle Aged
  • Neoplasm Transplantation
  • Neovascularization, Pathologic (drug therapy)
  • Young Adult

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