7st5 | pdb_00007st5
Structure of Fab CC-95251 in complex with SIRP-alpha
Structural highlights
FunctionSHPS1_HUMAN Immunoglobulin-like cell surface receptor for CD47. Acts as docking protein and induces translocation of PTPN6, PTPN11 and other binding partners from the cytosol to the plasma membrane. Supports adhesion of cerebellar neurons, neurite outgrowth and glial cell attachment. May play a key role in intracellular signaling during synaptogenesis and in synaptic function (By similarity). Involved in the negative regulation of receptor tyrosine kinase-coupled cellular responses induced by cell adhesion, growth factors or insulin. Mediates negative regulation of phagocytosis, mast cell activation and dendritic cell activation. CD47 binding prevents maturation of immature dendritic cells and inhibits cytokine production by mature dendritic cells.[1] [2] Publication Abstract from PubMedIn normal cells, binding of the transmembrane protein CD47 to signal regulatory protein-alpha (SIRPalpha) 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-SIRPalpha signaling axis and inducing a prophagocytic signal via tumor-opsonizing antibodies. We identified a novel, fully human mAb (BMS-986351) that binds SIRPalpha with high affinity. BMS-986351 demonstrated broad binding coverage across SIRPalpha polymorphisms and potently blocked CD47-SIRPalpha 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). SIGNIFICANCE: Increasing the phagocytotic capabilities of tumor-associated macrophages by modulating macrophage-tumor cell surface signaling via the CD47-SIRPalpha axis is a novel strategy. Molecules targeting CD47 have potential but its ubiquitous expression necessitates higher therapeutic doses to overcome potential antigen sink effects. The restricted expression pattern of SIRPalpha may limit toxicities and lower doses of the SIRPalpha antibody BMS-986351 may overcome target mediated drug disposition while maintaining the desired pharmacology. Discovery and Preclinical Activity of BMS-986351, an Antibody to SIRPalpha That Enhances Macrophage-mediated Tumor Phagocytosis When Combined with Opsonizing Antibodies.,Chan H, Trout CV, Mikolon D, Adams P, Guzman R, Mavrommatis K, Abbasian M, Hadjivassiliou H, Dearth L, Fox BA, Sivakumar P, Cho H, Hariharan K Cancer Res Commun. 2024 Feb 22;4(2):505-515. doi: 10.1158/2767-9764.CRC-23-0634. PMID:38319147[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
| ||||||||||||||||||||
