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Use of Anti-factor xi antibodies for prevention of thrombus formation

a technology of anti-thrombosis and anti-factor xi, applied in the field of haematology, can solve problems such as disease symptoms

Inactive Publication Date: 2011-06-30
HACK ERIK
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0095]In a further embodiment, a binding molecule of the invention, when administered to a human patient via intravenous infusion, provides therapeutic benefits at dosages below 0.005 or 0.003 g / kg.

Problems solved by technology

Pathological thrombosis refers to clot formation that is not part of a normal hemostatic process and that may result in disease symptoms.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

Chromogenic assay for factor XIa

[0137]A mixture of 75 μL phosphate-buffered saline (PBS), pH 7.4, containing the chromogenic substrate S-2366 1 mmol / L (final concentration), 5 μL of factor XIa at different final concentrations (range, 0.01-10 nmol / L) and 20 μL, PBS are added to wells of microtiter plates (Dynatech, Plochingen, Germany). Conversion of the substrate is measured by using a spectrophotometer. Microtiter plates are read on a Multiskan plate reader (Labsystems, Helsinki, Finland) after incubation for various time intervals at room temperature at 405 nm. The effect of monoclonal antibodies on the chromogenic activity is achieved by pre-incubation 5 μL of factor XIa at a final concentration of 1 nmol / L with 20 μL PBS containing various concentrations of monoclonal antibody to be tested for 15 minutes at room temperature. Seventy-five μL of PBS containing S2366 is added and the conversion of the substrate is measured as described above. A reference consisting of various dilu...

example 2

Chromogenic assay for factor XI activation by factor XIIa

[0138]Five μL of PBS containing 10 nm factor XI is incubated with 5 μL of 1 nMol / L factor XIIa for 30 minutes at room temperature. Thereafter, 75 μL phosphate-buffered saline (PBS), pH 7.4, containing the chromogenic substrate S-2366 1 mmol / L (final concentration), and 15 μL of PBS are added to wells of microtiter plates (Dynatech, Plochingen, Germany). Conversion of the substrate is measured by using a spectrophotometer. Microtiter plates are read on a Multiskan plate reader (Labsystems, Helsinki, Finland) after incubation for various time intervals at room temperature at 405 nm. The effect of monoclonal antibodies on the activation is tested by adding 15 μL of PBS containing the antibody to be tested to the mixture of factor XI and factor XIIa, in a way that first the antibody is added to factor XI, and after 15 minutes incubation factor XIIa is added. Dilutions of factor XIIa are tested as control. Seventy-five μL of PBS co...

example 3

Chromogenic Assay for Factor IX Activation by Factor XIa

[0139]This assay is performed essentially as described by T Ogawa et al., J Biol Chem 2005; 280:23523-30. Briefly, factor IX (1000 nM) in 50 mM Tris-HCl pH 7.5 buffer containing 0.1 mg per ml BSA containing 5 mM CaCl2 was activated by addition of factor XIa (1 nM active sites, 0.5 nM protein). At various time points (0-240 minutes), 50 μl aliquots were removed and supplemented with aprotinin (final concentration 15 μM) to inhibit factor XIa. The steady-state kinetics of hydrolysis of S299 (1 mM) by quenched samples was studied in Tris-BSA buffer containing 5 mM CaCl2 and 33% ethylene glycol. Changes in absorbance at 405 nm were measured. Duplicate assays were run. The factor IX concentration tested in the assay was 1000 nM. Generation of factor IXa as a function of time was determined by interpolation from the linear dependence of the initial rate of 5299 hydrolysis on known concentrations of factor IXa. Initial steady-state ra...

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Abstract

The present invention relates to binding molecules such as antibodies that specifically bind plasma coagulation factor XI and that inhibit factor XI activation and / or activity. The factor XI-binding molecules of the invention may used in methods for preventing or treating diseases, disorders and / or conditions that are mediated by factor XI activation and / or wherein inhibition of factor XI has a beneficial effect.

Description

FIELD OF THE INVENTION[0001]The present invention is in the field of haematology, in particular the field of coagulation. The invention relates to methods for inhibiting the formation of blood clots using binding molecules that specifically bind and inhibit the activation and / or activity of factor XI. The antigen binding molecule may or may not be specific for the activated conformation of factor XI and is preferably used in methods for reducing or preventing thrombus formation on synthetic grafts, atherosclerotic plaques or in other pathological thrombotic and thrombo-embolic processes.BACKGROUND OF THE INVENTION[0002]Coagulation consists of a humoral and a cellular response. The former leads to the conversion of soluble fibrinogen into insoluble fibrin, the latter consists of activation of platelets leading to a platelet plug. Platelet plugs, fibrin threads and included red blood cells together constitute a blood clot. A key molecule in clot formation is thrombin. This protease co...

Claims

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Application Information

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IPC IPC(8): A61K39/395C07K16/36A61P9/10A61P7/02
CPCA61K2039/505C07K2316/96C07K16/36A61P7/02A61P9/10C07K2317/76
Inventor HACK, ERIK
Owner HACK ERIK
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