Anti-SIRPα antibody immunotherapy enhances neutrophil and macrophage antitumor activity

Nan Guo Ring, Dietmar Herndler-Brandstetter, Kipp Weiskopf, Liang Shan, Jens Peter Volkmer, Benson M. George, Melanie Lietzenmayer, Kelly M. McKenna, Tejaswitha J. Naik, Aaron McCarty, Yunjiang Zheng, Aaron M. Ring, Richard A. Flavell, Irving L. Weissman

Research output: Contribution to journalArticlepeer-review

70 Scopus citations

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.

Original languageEnglish
Pages (from-to)E10578-E10585
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number49
DOIs
StatePublished - Dec 5 2017
Externally publishedYes

Keywords

  • Bispecific antibody
  • Cancer immunotherapy
  • Humanized mouse
  • Myeloid cells
  • SIRPA

Fingerprint Dive into the research topics of 'Anti-SIRPα antibody immunotherapy enhances neutrophil and macrophage antitumor activity'. Together they form a unique fingerprint.

Cite this