Anti-SIRPα antibody immunotherapy enhances neutrophil and macrophage antitumor activity

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Bispecific / pharmacology*
  • Antibodies, Monoclonal / pharmacology*
  • Antibodies, Neoplasm / pharmacology*
  • Antigens, Differentiation / genetics
  • Antigens, Differentiation / immunology*
  • Burkitt Lymphoma / genetics
  • Burkitt Lymphoma / immunology
  • Burkitt Lymphoma / pathology
  • Burkitt Lymphoma / therapy*
  • CD27 Ligand / genetics
  • CD27 Ligand / immunology
  • CD47 Antigen / genetics
  • CD47 Antigen / immunology
  • Cell Line, Tumor
  • Combined Modality Therapy / methods
  • Gene Expression
  • Gene Knock-In Techniques
  • Humans
  • Immunotherapy / methods
  • Macrophages / cytology
  • Macrophages / drug effects
  • Macrophages / immunology
  • Mice
  • Mice, Transgenic
  • Neutrophils / cytology
  • Neutrophils / drug effects
  • Neutrophils / immunology
  • Phagocytosis / drug effects*
  • Protein Binding
  • Receptors, Immunologic / genetics
  • Receptors, Immunologic / immunology*
  • Transgenes
  • Xenograft Model Antitumor Assays


  • Antibodies, Bispecific
  • Antibodies, Monoclonal
  • Antibodies, Neoplasm
  • Antigens, Differentiation
  • CD27 Ligand
  • CD47 Antigen
  • CD47 protein, human
  • CD70 protein, human
  • Receptors, Immunologic
  • SIRPA protein, human