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Medicinal composition usable for preventing and/or treating blood coagulation factor ix abnormality, comprising multispecific antigen binding molecule replacing function of blood coagulation factor VIII

A technology of antigen-binding molecules and blood coagulation factors, which can be applied in drug combinations, anticoagulant factor immunoglobulins, peptide/protein components, etc., and can solve the problem of insufficient hemostatic activity to completely stop bleeding

Pending Publication Date: 2019-11-15
NARA MEDICAL UNIVERSITY +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

For bleeding in von Willebrand patients, FVIII preparations containing desmopressin (DDAVP) or plasma-derived vWF are administered, but again, the problem is that frequent IV injections are required and their hemostatic activity is not sufficient in some cases complete hemostasis

Method used

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  • Medicinal composition usable for preventing and/or treating blood coagulation factor ix abnormality, comprising multispecific antigen binding molecule replacing function of blood coagulation factor VIII
  • Medicinal composition usable for preventing and/or treating blood coagulation factor ix abnormality, comprising multispecific antigen binding molecule replacing function of blood coagulation factor VIII
  • Medicinal composition usable for preventing and/or treating blood coagulation factor ix abnormality, comprising multispecific antigen binding molecule replacing function of blood coagulation factor VIII

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Experimental program
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Effect test

Embodiment 1

[0198] In the present invention, the use of blood or plasma from FIX disorders other than Hemophilia A, Acquired Hemophilia A, Von Willebrand and Hemophilia C tests functionally replaces multispecific antigen binding of FVIII Blood / plasma procoagulant activity of the molecule. Specifically, using blood / plasma from hemophilia B patients and commercially available FIX-deficient human plasma (GeorgeKing Bio-Medical), ACE910 (Emicerizumab) was examined by each coagulation evaluation method, ROTEM and APTT. Blood / plasma procoagulant activity of anti-(Emicizumab), which is a bispecific antibody described in patent literature (WO2012 / 067176) and is one of the above-mentioned multispecific antigen-binding molecules.

Embodiment 2

[0200] Preparation of ACE910, which is an anti-FIXa / FX bispecific antibody that replaces the function of FⅧ

[0201] ACE910 was obtained by the methods described in WO 2005 / 035756, WO 2006 / 109592 and WO 2012 / 067176. The bispecific antibody was expressed by incorporating the antibody gene into an animal cell expression vector and transfecting it into CHO cells. The bispecific antibody contained in the cell culture supernatant is then purified.

[0202] The FVIII function displacement activity of the bispecific antibodies thus purified was measured by the enzymatic assay shown below. At room temperature, 1 nM human FIXa (Enzyme Research Laboratories), 140 nM human FX (Enzyme Research Laboratories), 20 μM phospholipids (10% phosphatidylserine, 60% phosphatidylcholine, 30% phosphatidylethanolamine) and bispecific antibodies were mixed with Contains 5mM CaCl 2 Mix with 0.1% bovine serum albumin in Tris-buffered saline and incubate for 2 minutes to proceed by FIXa-induced FX ac...

Embodiment 3

[0204] ROTEM measurement

[0205] ROTEM measurements were performed according to conventional methods using a ROTEM delta measuring device (Tem International GmbH). Use calcium solution star-tem reagent (Ref. No. 503-01, Tem International GmbH) as Ca trigger 3002

[0206] APTT measurement

[0207] Thrombocheck APTT-SLA (Sysmex) was used as APTT reagent. 50 μL of APTT reagent was added to 50 μL of FIX disorder patient-derived plasma or FIX-deficient human plasma containing ACE910 and / or anti-FIX-Gla antibodies (Thromb Res 2000; 100:73-79). After incubation at 37°C for 5 minutes, 50 μL of 0.02 mol / L calcium chloride solution was added to initiate the coagulation reaction, and APTT was measured with an automatic blood coagulation measurement device (CS-2000i, Sysmex) according to conventional methods.

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Abstract

The present inventors verified the coagulation promoting effect of multispecific antigen binding molecules, said molecules replacing the function of FVIII, using blood and plasma collected from patients with FIX abnormality. As a result, it is clarified that a multispecific antigen binding molecule replacing the function of FVIII is not only usable in a method for preventing and / or treating bleeding in hemophilia A, acquired hemophilia A, von Willebrand's disease and hemophilia C caused by the dysfunction of FVIII but also usable in a method for preventing and / or treating bleeding in FIX abnormality owing to the coagulation promoting activity thereof. It is also clarified that the effect of a FIX preparation can be enhanced by the combined use of the FIX preparation with the multispecificantigen binding molecule replacing the function of FVIII and this combined use appears promising as a combination therapy showing a stable hemostatic effect.

Description

technical field [0001] The present invention relates to a pharmaceutical composition for the prevention and / or treatment of coagulation factor IX (FIX) disorders comprising a multispecific antigen-binding molecule that replaces the function of coagulation factor VIII (FVIII) (functional replacement). Background technique [0002] FIX disorder is a rare bleeding disorder caused by a congenital defect or dysfunction of FIX (NPL 1). FIX disorder is also known as hemophilia B. FIX is an enzyme precursor that changes from a precursor to enzymatically active activated coagulation factor IX (FIXa) when the hemagglutination reaction begins. FIXa forms coagulation factor X-activation complex (tenase complex) together with activated coagulation factor VIII (FVIIIa), and plays an important role in promoting coagulation reaction by activating coagulation factor X (FX). Similarly, FVIII disorder is a bleeding disorder caused by a congenital defect or dysfunction of FVIII, also known as...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K39/395A61K38/36A61P7/04A61P43/00C07K16/46C07K16/36C12P21/08
CPCA61P7/04A61P43/00C07K16/36C07K2317/31A61K38/4846C12Y304/21022A61K2300/00C07K16/46A61K38/36A61K2039/505C07K2317/565C07K2317/75
Inventor 岛绿伦野上惠嗣荻原建一
Owner NARA MEDICAL UNIVERSITY
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