6BIT

SIRPalpha antibody complex

Summary for 6BIT

• Entry DOI: 10.2210/pdb6bit/pdb
• Descriptor: KWAR23 Fab heavy chain, KWAR23 Fab light chain, Tyrosine-protein phosphatase non-receptor type substrate 1, ... (4 entities in total)
• Functional Keywords: macrophage, neutrophil, phagocytosis, myeloid, immune checkpoint, cd47, sirp, cancer immunotherapy, immune system
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 6
• Total formula weight: 117590.84

Authors

Ring, N.G.,Herndler-Brandstetter, D.,Weiskopf, K.,Shan, L.,Volkmer, J.P.,George, B.M.,Lietzenmayer, M.,McKenna, K.M.,Naik, T.J.,McCarty, A.,Zheng, Y.,Ring, A.M.,Flavell, R.A.,Weissman, I.L. (deposition date: 2017-11-03, release date: 2017-12-06, Last modification date: 2024-10-16)

Primary citation

Ring, N.G.,Herndler-Brandstetter, D.,Weiskopf, K.,Shan, L.,Volkmer, J.P.,George, B.M.,Lietzenmayer, M.,McKenna, K.M.,Naik, T.J.,McCarty, A.,Zheng, Y.,Ring, A.M.,Flavell, R.A.,Weissman, I.L.
Anti-SIRP alpha antibody immunotherapy enhances neutrophil and macrophage antitumor activity.
Proc. Natl. Acad. Sci. U.S.A., 114:E10578-E10585, 2017

PubMed 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 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.

PubMed: 29158380
DOI: 10.1073/pnas.1710877114

Experimental method

X-RAY DIFFRACTION (2.191 Å)