CD47–SIRPα-targeted therapeutics: status and prospects

Abstract

CD47 is a “don’t eat me” signal to phagocytes that is overexpressed on many tumor cells as a potential mechanism for immune surveillance evasion. CD47 and its interaction with signal-regulating protein alpha (SIRPα) on phagocytes is therefore a promising cancer target. Therapeutic antibodies and fusion proteins that block CD47 or SIRPα have been developed and have shown activity in preclinical models of hematologic and solid tumors. Anemia is a common adverse event associated with anti-CD47 treatment, but mitigation strategies—including use of a low ‘priming’ dose—have substantially reduced this risk in clinical studies. While efficacy in single-agent clinical studies is lacking, findings from studies of CD47–SIRPα blockade in combination with agents that increase ‘eat me’ signals or with antitumor antibodies are promising. Magrolimab, an anti-CD47 antibody, is the furthest along in clinical development among agents in this class. Magrolimab combination therapy in phase Ib/II studies has been well tolerated with encouraging response rates in hematologic and solid malignancies. Similar combination therapy studies with other anti-CD47–SIRPα agents are beginning to report. Based on these early clinical successes, many trials have been initiated in hematologic and solid tumors testing combinations of CD47–SIRPα blockade with standard therapies. The results of these studies will help determine the role of this novel approach in clinical practice and are eagerly awaited.

Highlights

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  CD47 is a “don’t eat me” signal overexpressed on cancer cells.

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  Blockade of the CD47–SIRPα signaling pathway leads to phagocytosis of tumor cells.

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  CD47–SIRPα blockade plus standard treatment shows promising clinical efficacy.

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  Clinically, CD47–SIRPα blockade plus standard treatment is well tolerated.

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  Clinical trials targeting CD47–SIRPα in hematologic and solid tumors are ongoing.