Modulating SIRP-alpha, a Myeloid-Specific Immune Checkpoint, for Immunotherapeutic Treatment of Malignancy
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BACKGROUND: CD47 is a "don't-eat-me" signal upregulated by many types of cancer that signals through its receptor SIRPα to inhibit macrophage-mediated destruction. Recent studies have demonstrated the efficacy of anti-CD47 blockade in synergizing with traditional monoclonal antibodies (mAbs) to enhance phagocytosis of cancer cells. We proposed targeting SIRPα as an alternative strategy and as a bridge to creating a single format bispecific macrophage-enhancing antibody (BiME). OBJECTIVE: The focus of this project was to test the therapeutic efficacy of SIRPα-blockade in combination treatment with other anti-tumor mAbs and in a single agent format as BiMEs. METHODS: We created KWAR23, a SIRPα-blocking monoclonal antibody, and from it, we derived several BiMEs in the dual-variable-domain immunoglobulin format to target CD20, Her2, and CD70. We tested these agents in high-throughput phagocytosis assays. We have also begun testing the therapeutic efficacy of KWAR23 in combination with rituximab in a xenograft mouse model of B cell lymphoma. RESULTS: KWAR23 significantly enhanced the efficacy and potency of phagocytosis of mAb-opsonized cancer cells when compared to the mAbs alone in B cell lymphoma and breast adenocarcinoma. BiMEs resulted in greater efficacy of phagocytosis of cancer cells when compared to their parent mAbs for B cell lymphoma, breast adenocarcinoma, and renal cell carcinoma. SIRPα-blockade in combination with rituximab also appeared to significantly reduce tumor burden in mice engrafted with a B cell lymphoma cell line. CONCLUSIONS: The therapeutic role of check-point inhibitors has become increasingly apparent and important in the treatment of cancer in recent years, but the role played by macrophages remains unclear. We have now demonstrated multiple strategies for targeting the CD47-SIRPα pathway to harness macrophages in antibody-mediated cell killing. This research may further benefit the field of immunotherapy as we learn more about the intricate interplay between innate and adaptive immunity in cancer biology.
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