Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 114, Issue 49, Pages E10578-E10585Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1710877114
Keywords
cancer immunotherapy; SIRPA; myeloid cells; bispecific antibody; humanized mouse
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Funding
- Howard Hughes Medical Institute Medical Research Fellowship
- Erwin Schrdinger Fellowship (Austrian Science Fund) [J3220-B19]
- Stanford Medical Scientist Training Program [T32 GM07365]
- Mathilde Krim Fellowship (amfAR, The Foundation for AIDS Research)
- NIH [1K99AI125065-01, T32 AI07019]
- Bill and Melinda Gates Foundation
- Howard Hughes Medical Institute
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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 (SIRP alpha) 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 SIRP alpha 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/SIRP alpha antibody outperforms individually delivered antibodies in specific types of cancers. These studies demonstrate that SIRP alpha blockade induces potent antitumor activity by targeting multiple myeloid cell subsets that frequently infiltrate tumors. Thus, KWAR23 represents a promising candidate for combination therapy.
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