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.