7ST5

Structure of Fab CC-95251 in complex with SIRP-alpha

Summary for 7ST5

• Entry DOI: 10.2210/pdb7st5/pdb
• Descriptor: Fab CC-95251 anti-SIRP-alpha heavy chain, Fab CC-95251 anti-SIRP-alpha light chain, Tyrosine-protein phosphatase non-receptor type substrate 1, ... (6 entities in total)
• Functional Keywords: cell surface receptor, immune system
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 6
• Total formula weight: 122338.78

Authors

Fenalti, G. (deposition date: 2021-11-12, release date: 2023-05-17, Last modification date: 2024-10-16)

Primary citation

Chan, H.,Trout, C.V.,Mikolon, D.,Adams, P.,Guzman, R.,Mavrommatis, K.,Abbasian, M.,Hadjivassiliou, H.,Dearth, L.,Fox, B.A.,Sivakumar, P.,Cho, H.,Hariharan, K.
Discovery and Preclinical Activity of BMS-986351, an Antibody to SIRP alpha That Enhances Macrophage-mediated Tumor Phagocytosis When Combined with Opsonizing Antibodies.
Cancer Res Commun, 4:505-515, 2024

PubMed Abstract: In normal cells, binding of the transmembrane protein CD47 to signal regulatory protein-α (SIRPα) on macrophages induces an antiphagocytic signal. Tumor cells hijack this pathway and overexpress CD47 to evade immune destruction. Macrophage antitumor activity can be restored by simultaneously blocking the CD47-SIRPα signaling axis and inducing a prophagocytic signal via tumor-opsonizing antibodies. We identified a novel, fully human mAb (BMS-986351) that binds SIRPα with high affinity. BMS-986351 demonstrated broad binding coverage across SIRPα polymorphisms and potently blocked CD47-SIRPα binding at the CD47 binding site in a dose-dependent manner. In vitro, BMS-986351 increased phagocytic activity against cell lines from solid tumors and hematologic malignancies, and this effect was markedly enhanced when BMS-986351 was combined with the opsonizing antibodies cetuximab and rituximab. A phase I dose-escalation/-expansion study of BMS-986351 for the treatment of advanced solid and hematologic malignancies is underway (NCT03783403).

PubMed: 38319147
DOI: 10.1158/2767-9764.CRC-23-0634

Experimental method

X-RAY DIFFRACTION (2.2 Å)