Ring et al. developed KWAR23, an antibody that targets the SIRPα receptor on myeloid cells, to disrupt binding to the CD47 “don’t eat me” signal expressed on tumor (and normal) tissue to prevent macrophage phagocytosis. In combination with tumor-opsonizing antibodies, KWAR23 induced macrophages and neutrophils to phagocytose target tumor cells (from various tumor cell lines) in vitro. In human sirpa knock-in mice on an SRG background (lacking T, B, and NK cells), this combination elicited partial and complete responses.

Cancer immunotherapy has emerged as a promising therapeutic intervention. However, complete and durable responses are only seen in a fraction of patients who have cancer. A key factor that limits therapeutic success is the infiltration of tumors by cells of the myeloid lineage. The inhibitory receptor signal regulatory protein-alpha (SIRPalpha) is a myeloid-specific immune checkpoint that engages the "don't eat me" signal CD47 expressed on tumors and normal tissues. We therefore developed the monoclonal antibody KWAR23, which binds human SIRPalpha with high affinity and disrupts its binding to CD47. Administered by itself, KWAR23 is inert, but given in combination with tumor-opsonizing monoclonal antibodies, KWAR23 greatly augments myeloid cell-dependent killing of a collection of hematopoietic and nonhematopoietic human tumor-derived cell lines. Following KWAR23 antibody treatment in a human SIRPA knockin mouse model, both neutrophils and macrophages infiltrate a human Burkitt's lymphoma xenograft and inhibit tumor growth, generating complete responses in the majority of treated animals. We further demonstrate that a bispecific anti-CD70/SIRPalpha antibody outperforms individually delivered antibodies in specific types of cancers. These studies demonstrate that SIRPalpha blockade induces potent antitumor activity by targeting multiple myeloid cell subsets that frequently infiltrate tumors. Thus, KWAR23 represents a promising candidate for combination therapy.

Author Info: (1) Institute for Stem Cell Biology and Regenerative Medicine, and Ludwig Center for Cancer Stem Cell Research, Stanford University School of Medicine, Stanford, CA Department

Author Info: (1) Institute for Stem Cell Biology and Regenerative Medicine, and Ludwig Center for Cancer Stem Cell Research, Stanford University School of Medicine, Stanford, CA Department of Immunobiology, Yale University School of Medicine, New Haven, CT (2) Department of Immunobiology, Yale University School of Medicine, New Haven, CT (3) Institute for Stem Cell Biology and Regenerative Medicine, and Ludwig Center for Cancer Stem Cell Research, Stanford University School of Medicine, Stanford, CA (4) Department of Immunobiology, Yale University School of Medicine, New Haven, CT (5) Institute for Stem Cell Biology and Regenerative Medicine, and Ludwig Center for Cancer Stem Cell Research, Stanford University School of Medicine, Stanford, CA (6) Institute for Stem Cell Biology and Regenerative Medicine, and Ludwig Center for Cancer Stem Cell Research, Stanford University School of Medicine, Stanford, CA (7) Department of Immunobiology, Yale University School of Medicine, New Haven, CT (8) Institute for Stem Cell Biology and Regenerative Medicine, and Ludwig Center for Cancer Stem Cell Research, Stanford University School of Medicine, Stanford, CA (9) Institute for Stem Cell Biology and Regenerative Medicine, and Ludwig Center for Cancer Stem Cell Research, Stanford University School of Medicine, Stanford, CA (10) Institute for Stem Cell Biology and Regenerative Medicine, and Ludwig Center for Cancer Stem Cell Research, Stanford University School of Medicine, Stanford, CA (11) Department of Immunobiology, Yale University School of Medicine, New Haven, CT (12) Department of Immunobiology, Yale University School of Medicine, New Haven, CT (13) Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520; richard.flavell@yale.edu irv@stanford.edu. Howard Hughes Medical Institute, New Haven, CT 06520. (14) Institute for Stem Cell Biology and Regenerative Medicine, and Ludwig Center for Cancer Stem Cell Research, Stanford University School of Medicine, Stanford, CA 94305; richard.flavell@yale.edu irv@stanford.edu.

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