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Proc Natl Acad Sci U S A. 2017 Dec 5;114(49):E10578-E10585. doi: 10.1073/pnas.1710877114. Epub 2017 Nov 20.

Anti-SIRPα antibody immunotherapy enhances neutrophil and macrophage antitumor activity.

Author information

1
Institute for Stem Cell Biology and Regenerative Medicine, and Ludwig Center for Cancer Stem Cell Research, Stanford University School of Medicine, Stanford, CA 94305.
2
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520.
3
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520; richard.flavell@yale.edu irv@stanford.edu.
4
Howard Hughes Medical Institute, New Haven, CT 06520.
5
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.

Abstract

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-α (SIRPα) 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 SIRPα 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/SIRPα antibody outperforms individually delivered antibodies in specific types of cancers. These studies demonstrate that SIRPα blockade induces potent antitumor activity by targeting multiple myeloid cell subsets that frequently infiltrate tumors. Thus, KWAR23 represents a promising candidate for combination therapy.

KEYWORDS:

SIRPA; bispecific antibody; cancer immunotherapy; humanized mouse; myeloid cells

PMID:
29158380
PMCID:
PMC5724266
DOI:
10.1073/pnas.1710877114
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

Conflict of interest statement: K.W., A.M.R., and I.L.W. are shareholders of Forty Seven, Inc., and have filed a patent application that describes the human anti-SIRPα antibody KWAR23. I.L.W. is co-inventor of the patent, and co-founder and director of the company that has licensed the antibody.

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