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Improving macrophage responses to therapeutic antibodies by molecular engineering of SIRPα variants
Kipp Weiskopf1, Aaron M Ring, Peter J Schnorr
1Institute for Stem Cell Biology and Regenerative Medicine; Stanford University School of Medicine; Stanford, CA USA ; Ludwig Center for Cancer Stem Cell Research and Medicine; Stanford University School of Medicine; Stanford, CA USA ; Stanford Cancer Institute; Stanford University School of Medicine; Stanford, CA USA.
Abstract:
CD47 transduces inhibitory signals through signal-regulatory protein α (SIRPα), a plasma membrane receptor expressed by macrophages. Many cancers upregulate CD47 to evade immunosurveillance. We have recently engineered SIRPα variants that potently antagonize CD47 for use as anticancer immunotherapeutics. These high-affinity SIRPα variants synergize with antineoplastic antibodies by lowering the threshold for macrophage-mediated destruction of malignant cells.
Insights
Engineered SIRPα variants block cancer
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- CD47 is a protein on cancer cells that helps them evade immune detection by signaling through SIRPα on macrophages.
- Upregulation of CD47 is a common immune evasion strategy in many cancers.
Purpose of the Study:
- To develop novel SIRPα variants as potential anticancer immunotherapeutics.
- To investigate the synergistic effects of engineered SIRPα variants with existing cancer therapies.
Main Methods:
- Engineering of signal-regulatory protein α (SIRPα) variants with enhanced affinity for CD47.
- Testing the efficacy of these variants in antagonizing CD47-mediated inhibitory signals.
- Evaluating the synergy between engineered SIRPα variants and antineoplastic antibodies in promoting cancer cell destruction.
Main Results:
- Engineered SIRPα variants effectively antagonize CD47.
- These variants lower the activation threshold for macrophages.
- Synergy observed between SIRPα variants and antineoplastic antibodies enhances macrophage-mediated cancer cell destruction.
Conclusions:
- Engineered SIRPα variants represent a promising strategy for cancer immunotherapy.
- These variants can enhance the effectiveness of antibody-based cancer treatments by overcoming CD47-mediated immune evasion.
