7urx

SJ25C1 Fab in complex with soluble CD19

spinqualitylabelsall models 7urx, resolution 3.40Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7urx is a 3 chain structure with sequence from Homo sapiens and Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 3.4Å Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease CD19_HUMAN Common variable immunodeficiency. The disease is caused by mutations affecting the gene represented in this entry. Function CD19_HUMAN Assembles with the antigen receptor of B-lymphocytes in order to decrease the threshold for antigen receptor-dependent stimulation. Publication Abstract from PubMed Chimeric antigen receptor (CAR) T cell therapy relies on T cells that are guided by synthetic receptors to target and lyse cancer cells. CARs bind to cell surface antigens through an scFv (binder), the affinity of which is central to determining CAR T cell function and therapeutic success. CAR T cells targeting CD19 were the first to achieve marked clinical responses in patients with relapsed/refractory B cell malignancies and to be approved by the U.S. Food and Drug Administration (FDA). We report cryo-EM structures of CD19 antigen with the binder FMC63, which is used in four FDA-approved CAR T cell therapies (Kymriah, Yescarta, Tecartus, and Breyanzi), and the binder SJ25C1, which has also been used extensively in multiple clinical trials. We used these structures for molecular dynamics simulations, which guided creation of lower- or higher-affinity binders, and ultimately produced CAR T cells endowed with distinct tumor recognition sensitivities. The CAR T cells exhibited different antigen density requirements to trigger cytolysis and differed in their propensity to prompt trogocytosis upon contacting tumor cells. Our work shows how structural information can be applied to tune CAR T cell performance to specific target antigen densities. CD19 CAR antigen engagement mechanisms and affinity tuning.,He C, Mansilla-Soto J, Khanra N, Hamieh M, Bustos V, Paquette AJ, Garcia Angus A, Shore DM, Rice WJ, Khelashvili G, Sadelain M, Meyerson JR Sci Immunol. 2023 Mar 10;8(81):eadf1426. doi: 10.1126/sciimmunol.adf1426. Epub , 2023 Mar 3. PMID:36867678 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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