tissue factor x TLT1

Last update 01 Nov 2024

Basic Info

Related Targets

tissue factorTLT1

Drugs associated with tissue factor x TLT1

CN113891896

Patent Mining

Target

TLT1 x tissue factor

Mechanism-

Active Org.

Beijing Neoletix Biological Technology

Originator Org.

Beijing Neoletix Biological Technology

Active Indication

Hemorrhage

Inactive Indication-

Drug Highest PhaseDiscovery

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with tissue factor x TLT1

100 Translational Medicine associated with tissue factor x TLT1

0 Patents (Medical) associated with tissue factor x TLT1

Literatures (Medical) associated with tissue factor x TLT1

01 Jan 2020·Journal of Thrombosis and HaemostasisQ2 · MEDICINE

Enhanced potency of recombinant factor VIIa with increased affinity to activated platelets

Q2 · MEDICINE

Article

Author: Egebjerg, Thomas ; Kjelgaard-Hansen, Mads ; Krogh, Thomas N ; Sanfridson, Annika ; Jensen, Mette S ; Holmberg, Heidi ; Enoksson, Mari ; Brophy, Donald F ; Demuth, Helle ; Martin, Erika J ; Kjalke, Marianne ; Buchardt, Jens ; Hilden, Ida

BACKGROUNDRecombinant factor VIIa (rFVIIa) enhances thrombin generation in a platelet-dependent manner; however, rFVIIa binds activated platelets with relatively low affinity. Triggering receptor expressed on myeloid cells (TREM)-like transcript (TLT)-1 is expressed exclusively on activated platelets.OBJECTIVETo enhance the potency of rFVIIa via binding TLT-1.METHODSRecombinant FVIIa was conjugated to a TLT-1 binding Fab. In vitro potency of this platelet-targeted rFVIIa (PT-rFVIIa) was evaluated using factor X activation assays and by measuring viscoelastic changes in whole blood. In vivo potency was evaluated using a tail vein transection model in F8^-/- mice expressing human TLT-1.RESULTSPT-rFVIIa and rFVIIa had similar dissociation constant values for tissue factor binding and similar tissue factor-dependent factor X activation. However, PT-rFVIIa had increased catalytic efficiency on TLT-1-loaded vesicles and activated platelets. The in vitro potency in normal human blood with antibody-induced hemophilia A was dependent on assay conditions used; with maximally activated platelets, the half maximal effective concentration for clot time for PT-rFVIIa was 49-fold lower compared with rFVIIa. In the murine bleeding model, a 53-fold lower half maximal effective concentration was observed for blood loss for PT-rFVIIa, supporting the relevance of the assay conditions with maximally activated platelets. In vitro analysis of blood from subjects with hemophilia A confirmed the data obtained with normal blood.CONCLUSIONSIncreasing the affinity of rFVIIa to activated platelets resulted in approximately 50-fold increased potency both in vitro and in the mouse model. The correlation of in vivo with in vitro data using maximally activated platelets supports that these assay conditions are relevant when evaluating platelet-targeted hemostatic concepts.

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