CD47 is a widely expressed transmembrane protein and represents the ligand for the signal regulatory protein alpha (SIRPo), which is identified on macrophages and dendritic cells.[1] The activation of SIRPo triggers a signal transduction cascade, leading to the inhibition of phagocytosis.[2–4] In a preclinical model, the expression of mouse CD47 in a human acute myeloid leukemia (AML) cell line resulted in the inhibition of phagocytosis.[5] Moreover, CD47 was overexpressed on myeloid leukemia cells, mediating cancer cell evasion of phagocytosis by the innate immune system.[6] Thus, through its interaction with SIRPo, CD47 on the surface of tumor cells (or leukemic cells) appears to be an essential molecule in allowing tumor and potentially cancer stem cells to overcome intrinsic expression of their prophagocytic ‘‘eat me’’signals, and thereby escape phagocytosis. As a macrophage inhibitory checkpoint, CD47-SiRPa interaction may be amenable to targeted strategies. In mouse xenograft models, a monoclonal antibody (mAb) targeting CD47 was able to enhance phagocytosis, leading to the inhibition of tumor growth and metastasis. This allowed the elimination of cancer cells from various hematologic malignancies and solid cancers.[7–12] Although macrophage phagocytosis of the malignant cells represented the major mechanism of antitumor activity, different studies demonstrated that phagocytic cells further triggered a downstream antitumor and cytotoxic, CD8+ T-cell immune response. These findings suggest that anti-CD47 antibody-mediated phagocytosis also may mediate downstream T-cell elimination of tumor cells.[13, 14]

A key principle to the success of anti-CD47 therapies is the potential specificity of the CD47/SIRPo signaling pathway blockade, leading to the elimination of cancer cells, while leaving most normal cell counterparts unaffected. The selective targeting of tumor cells by anti-CD47 mAb is attributed to the significantly higher expression potent prophagocytic signal on the surface of cancer cells. These prophagocytic signals, which serve as a second hit that is required to induce phagocytosis in addition to interruption of the CD47-SiRPa axis, are minimally expressed on normal healthy cells. Calreticulin was identified as prophagocytic molecule present on the surface of multiple hematologic and solid malignancies.[9]