title: 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.
authors.affiliation: Department of Chemistry and Applied Biosciences, ETH Zürich, Wolfgang-Pauli-Strasse 10, CH-8093 Zurich, Switzerland.
authors.forename: Katrin L
authors.initials: KL
authors.lastname: Gutbrodt
authors.forename: Christoph
authors.initials: C
authors.lastname: Schliemann
authors.forename: Leonardo
authors.initials: L
authors.lastname: Giovannoni
authors.forename: Katharina
authors.initials: K
authors.lastname: Frey
authors.forename: Thomas
authors.initials: T
authors.lastname: Pabst
authors.forename: Wolfram
authors.initials: W
authors.lastname: Klapper
authors.forename: Wolfgang E
authors.initials: WE
authors.lastname: Berdel
authors.forename: Dario
authors.initials: D
authors.lastname: Neri
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized; D001706:Biopsy; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology; D045744:Cell Line, Tumor; D003561:Cytarabine / Q000008:administration & dosage; D018450:Disease Progression; D005260:Female; D005353:Fibronectins / Q000378:metabolism; D018922:HL-60 Cells; D006801:Humans; D007376:Interleukin-2 / Q000008:administration & dosage*; D015470:Leukemia, Myeloid, Acute / Q000628:therapy*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D016513:Mice, SCID; D008875:Middle Aged; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C528643:F8 monoclonal antibody; D005353:Fibronectins; D007376:Interleukin-2; D003561:Cytarabine