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CD47-SIRPα-targeted therapeutics: status and prospects
R Maute1, J Xu1, I L Weissman2
1Gilead Sciences, Inc., Foster City, USA.
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.
Insights
Blocking the CD47 "don't eat me" signal shows promise in cancer therapy. Combination treatments with anti-CD47 antibodies, like Magrolimab, are demonstrating encouraging results in early clinical trials for various cancers.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- CD47 is a transmembrane protein overexpressed on tumor cells, acting as a "don't eat me" signal to inhibit phagocytosis by immune cells.
- The CD47-SIRPα axis is a critical pathway for immune evasion by cancer cells, making it a significant therapeutic target.
- Preclinical studies demonstrate the potential of blocking the CD47-SIRPα interaction to enhance anti-tumor immunity.
Purpose of the Study:
- To review the therapeutic potential of targeting the CD47-SIRPα pathway in cancer treatment.
- To discuss the development and clinical progress of agents blocking CD47 or SIRPα.
- To evaluate the efficacy and safety of CD47-SIRPα blockade in combination therapies.
Main Methods:
- Review of preclinical data and clinical trial findings for CD47-blocking agents.
- Analysis of combination strategies involving CD47-SIRPα blockade with other immunotherapies or standard treatments.
- Assessment of adverse events, particularly anemia, and mitigation strategies.
Main Results:
- Therapeutic antibodies and fusion proteins targeting CD47 or SIRPα have shown preclinical activity against hematologic and solid tumors.
- Anemia, a known side effect, has been managed effectively with strategies like low-dose priming.
- Early clinical studies of combination therapies, including Magrolimab, show promising response rates and good tolerability.
Conclusions:
- CD47-SIRPα blockade represents a promising novel therapeutic approach in oncology.
- Combination strategies are key to overcoming the limitations of single-agent therapy and improving clinical efficacy.
- Ongoing clinical trials will define the role of CD47-SIRPα blockade in standard cancer treatment protocols.
