Targeted Inhibition of CD47-SIRPα Requires Fc-FcγR Interactions to Maximize Activity in T-cell Lymphomas

Antibodies that bind CD47 on tumor cells and prevent interaction with SIRPα on phagocytes are active against multiple cancer types including T-cell lymphomas (TCL). Here we demonstrate that surface CD47 is heterogeneously expressed across primary TCLs whereas MHC class I, which can also suppress phagocytosis, is ubiquitous. Multiple monoclonal antibodies (mAbs) that block CD47-SIRPα interaction promoted phagocytosis of TCL cells, which was enhanced by cotreatment with antibodies targeting MHC class I. Expression levels of surface CD47 and genes that modulate CD47 pyroglutamation did not correlate with the extent of phagocytosis induced by CD47 blockade in TCL lines. Treatment of multiple human TCL patient-derived xenografts (PDXs) or an immunocompetent murine TCL model in vivo with a short course of anti-CD47 mAb markedly reduced lymphoma burden and extended survival. In vivo depletion of macrophages antagonized efficacy while depletion of neutrophils had no effect. F(ab9)2-only fragments of anti-CD47 antibodies failed to induce phagocytosis by human macrophages, indicating a requirement for Fc-FcγR interactions. In contrast, F(ab9)2-only fragments increased phagocytosis by murine macrophages independent of SLAMF7-Mac-1 interaction. Full-length anti-CD47 mAbs also induced phagocytosis by FcγR-deficient, murine macrophages. An IgG1 anti-CD47 mAb induced phagocytosis and NK cell-mediated cytotoxicity of TCL cells that was augmented by co-treatment with the anti-CCR4 mAb, mogamulizumab or a mAb blocking MHC class I. These studies help explain the disparate activity of monotherapy with agents that block CD47 in murine models compared to patients. They also have direct translational implications for the deployment of anti-CD47 mAbs alone or in combination.