7ahv

Anti-FIXa Fab of mim8 in complex with human FIXa

spinqualitylabelsall models 7ahv, resolution 3.11Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7ahv is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 3.11Å Ligands: 0GJ, CA, SO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease FA9_HUMAN Defects in F9 are the cause of recessive X-linked hemophilia B (HEMB) [MIM:306900; also known as Christmas disease. Note=Mutations in position 43 (Oxford-3, San Dimas) and 46 (Cambridge) prevents cleavage of the propeptide, mutation in position 93 (Alabama) probably fails to bind to cell membranes, mutation in position 191 (Chapel-Hill) or in position 226 (Nagoya OR Hilo) prevent cleavage of the activation peptide. Defects in F9 are the cause of thrombophilia due to factor IX defect (THPH8) [MIM:300807. A hemostatic disorder characterized by a tendency to thrombosis. Function FA9_HUMAN Factor IX is a vitamin K-dependent plasma protein that participates in the intrinsic pathway of blood coagulation by converting factor X to its active form in the presence of Ca(2+) ions, phospholipids, and factor VIIIa. Publication Abstract from PubMed Hemophilia A is a bleeding disorder resulting from deficient factor VIII (FVIII), which normally functions as a cofactor to activated factor IX (FIXa) that facilitates activation of factor X (FX). To mimic this property in a bispecific antibody format, a screening was conducted to identify functional pairs of anti-FIXa and anti-FX antibodies, followed by optimization of functional and biophysical properties. The resulting bispecific antibody (Mim8) assembled efficiently with FIXa and FX on membranes, and supported activation with an apparent equilibrium dissociation constant of 16 nM. Binding affinity with FIXa and FX in solution was much lower, with equilibrium dissociation constant values for FIXa and FX of 2.3 and 1.5 microM, respectively. In addition, the activity of Mim8 was dependent on stimulatory activity contributed by the anti-FIXa arm, which enhanced the proteolytic activity of FIXa by 4 orders of magnitude. In hemophilia A plasma and whole blood, Mim8 normalized thrombin generation and clot formation, with potencies 13 and 18 times higher than a sequence-identical analogue of emicizumab. A similar potency difference was observed in a tail vein transection model in hemophilia A mice, whereas reduction of bleeding in a severe tail-clip model was observed only for Mim8. Furthermore, the pharmacokinetic parameters of Mim8 were investigated and a half-life of 14 days shown in cynomolgus monkeys. In conclusion, Mim8 is an activated FVIII mimetic with a potent and efficacious hemostatic effect based on preclinical data. A factor VIIIa-mimetic bispecific antibody, Mim8, ameliorates bleeding upon severe vascular challenge in hemophilia A mice.,Ostergaard H, Lund J, Greisen PJ, Kjellev S, Henriksen A, Lorenzen N, Johansson E, Roder G, Rasch MG, Johnsen LB, Egebjerg T, Lund S, Rahbek-Nielsen H, Gandhi PS, Lamberth K, Loftager M, Andersen LM, Bonde AC, Stavenuiter F, Madsen DE, Li X, Holm TL, Ley CD, Thygesen P, Zhu H, Zhou R, Thorn K, Yang Z, Hermit MB, Bjelke JR, Hansen BG, Hilden I Blood. 2021 Oct 7;138(14):1258-1268. doi: 10.1182/blood.2020010331. PMID:34077951 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Antibody 3D structures Factor IX 3D structures

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