SIRPα variants with high CD47 affinity enhance the antitumor activity of therapeutic antibodies.
Major finding: SIRPα variants with high CD47 affinity enhance the antitumor activity of therapeutic antibodies.
Concept: Blockade of antiphagocytic CD47 signaling lowers the threshold for macrophage activation.
Impact: High-affinity SIRPα monomers may act as universal adjuvants for tumor-specific antibodies.
Cancer cells can evade detection by the immune system by co-opting normal self-tolerance mechanisms. For example, many cancers avoid macrophage detection by expressing high levels of CD47, which binds to a macrophage inhibitory receptor, signal-regulatory protein alpha (SIRPα), and prevents phagocytosis. Blockade of the interaction between CD47 and SIRPα is therefore being investigated as a way to increase phagocytosis of cancer cells by macrophages. Weiskopf and colleagues sought to use the SIRPα binding domain as a CD47 antagonist, but it had poor activity due to the weak affinity of the native CD47–SIRPα interaction. The authors therefore created mutant libraries of the SIRPα binding domain and used yeast surface display to identify SIRPα variants with increased affinity for CD47. These variants maintained a highly similar structure and CD47 binding mode as wild-type SIRPα but with an approximately 50,000-fold increase in CD47 affinity. The high-affinity SIRPα variants bound and blocked CD47 expressed on cancer cells but did not increase phagocytosis of cancer cells in vitro unless the prophagocytic stimulus of an antibody Fc chain was present. However, these molecules caused red blood cell destruction and anemia, prompting the authors to evaluate the ability of SIRPα variants to increase phagocytosis of cancer cells when combined with tumor-specific antibodies. In several tumor models, high-affinity SIRPα variant monomers synergized with all clinically available therapeutic antibodies tested, including rituximab, alemtuzumab, and trastuzumab, to induce significant tumor regression in association with increased macrophage infiltration. Moreover, the antitumor effects persisted even after treatment cessation and were not toxic. Lowering the threshold for macrophage activation by blocking CD47 signaling with high-affinity SIRPα variant may be a universally effective approach for potentiating the efficacy of tumor-specific antibodies.
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