Abstract CN07-03: CD47 is an adverse prognostic factor and therapeutic antibody target on human AML stem cells

Abstract

Abstract Human acute myeloid leukemia (AML) is organized as a cellular hierarchy initiated and maintained by rare self-renewing leukemia stem cells (LSC), which must be eliminated in order to cure the patient. We identified increased expression of CD47 on human AML LSC compared to their normal counterparts. CD47 is a cell surface molecule that serves as the ligand for SIRP-alpha on the surface of phagocytes, which in turn transmits a dominant inhibitory signal for phagocytosis. In this way, CD47 essentially functions as a “don't eat me” signal. We hypothesized that increased CD47 expression contributes to pathogenesis by inhibiting phagocytosis of AML LSC. Consistent with this hypothesis, we found that increased CD47 expression predicted worse overall survival in 3 independent cohorts of adult AML patients. Furthermore, we predicted that disruption of the interaction of CD47 with SIRP-alpha would result in phagocytosis and elimination of AML LSC. We found that blocking monoclonal antibodies directed against CD47 enabled phagocytosis of AML LSC, but not normal CD34+ human bone marrow progenitor cells, by human macrophages in vitro. Additionally, coating of human AML LSC with anti-CD47 monoclonal antibodies inhibited their engraftment in vivo in a xenotransplantation assay. Finally, analogous to a clinical therapy, treatment of human AML-engrafted mice with anti-CD47 antibody eliminated AML cells in the peripheral blood and bone marrow and targeted LSC. In summary, increased CD47 expression is an independent poor prognostic factor that can be targeted on human AML stem cells with monoclonal antibodies capable of stimulating phagocytosis and elimination of LSC. Targeting of CD47 with blocking monoclonal antibodies to induce phagocytosis is a novel mechanism for antibody cancer therapy. While anti-CD47 antibodies can be effective monotherapy for human AML, such antibodies may be equally, if not more, effective as part of a combination strategy. The combination of an anti-CD47 antibody, able to block a strong inhibitory signal for phagocytosis, with a second antibody able to bind an LSC-specific molecule and engage Fc receptors on phagocytes, thereby delivering a strong positive signal for phagocytosis, may result in a synergistic stimulus for phagocytosis and specific elimination of AML LSC. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):CN07-03.