Targeted inhibition of CD47-SIRPα requires Fc-FcγR interactions to maximize activity in T-cell lymphomas.

Blood
Salvia JainDavid M Weinstock

Abstract

Antibodies that bind CD47 on tumor cells and prevent interaction with SIRPα on phagocytes are active against multiple cancer types including T-cell lymphoma (TCL). Here we demonstrate that surface CD47 is heterogeneously expressed across primary TCLs, whereas major histocompatibility complex (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. In vivo treatment of multiple human TCL patient-derived xenografts or an immunocompetent murine TCL model with a short course of anti-CD47 mAb markedly reduced lymphoma burden and extended survival. Depletion of macrophages reduced efficacy in vivo, whereas depletion of neutrophils had no effect. F(ab')2-only fragments of anti-CD47 antibodies failed to induce phagocytosis by human macrophages, indicating a requirement for Fc-Fcγ receptor interactions. In contrast, F(ab')2-only fragments increased phagocytosis by murine macrophages ...Continue Reading

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Citations

Nov 8, 2019·Blood·Owen A O'Connor
Apr 7, 2020·Nature Reviews. Cancer·Danilo FioreGiorgio Inghirami
Jul 18, 2020·Journal of Hematology & Oncology·Entsar EladlHong Chang
Oct 7, 2020·Journal for Immunotherapy of Cancer·Hongfei WangYanfeng Gao
Jan 13, 2021·The Journal of Immunology : Official Journal of the American Association of Immunologists·Gabriela AndrejevaDaniel S Pereira
Jan 29, 2021·Journal for Immunotherapy of Cancer·Chunxiao LiUNKNOWN Senior Correspondence
Apr 29, 2021·Seminars in Hematology·John C Reneau, Ryan A Wilcox
Sep 15, 2021·Cancer Immunology, Immunotherapy : CII·Oleg KruglovOleg E Akilov

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