Novel methods and antibodies for treating coagulapathy

A technology for coagulation disorders and antibodies, applied in the fields of antibodies, gene therapy, chemical instruments and methods, etc., can solve problems such as lack of high blood clots

Inactive Publication Date: 2016-06-22
NOVO NORDISK AS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] However, severe thromboembolic disease has been observed in individuals with homozygous protein S deficiency, and it has been demonstrated that hybrid protein S deficiency results in a high incidence of thrombosis in persons with an otherwise normal coagulation system (Marlar and Neumann , SeminThrombHemost. (1990) 16:299-309; Schwarz et al., Blood (1984) 64:1297-1300)

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  • Novel methods and antibodies for treating coagulapathy
  • Novel methods and antibodies for treating coagulapathy
  • Novel methods and antibodies for treating coagulapathy

Examples

Experimental program
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Embodiment approach

[0267] The following embodiments are provided to aid understanding of the present invention, however, the present invention is not limited to the following embodiments.

[0268] In one embodiment, the invention relates to inhibitors (such as but not limited to antibodies, Fab or other fragments, peptides or aptamers) that bind to protein S and inhibit the interaction of protein S with APCs.

[0269] In one embodiment, the invention relates to an antibody or antigen-binding fragment thereof that binds to protein S and inhibits the interaction of protein S with APC.

[0270] In one embodiment, the invention relates to an antibody or antigen-binding fragment thereof that binds to protein S and inhibits the interaction of protein S with APCs without interfering with known non-coagulation functions of protein S.

[0271] In one embodiment, the present invention relates to the use of an antibody or antigen-binding fragment thereof that binds to protein S and inhibits the interaction...

Embodiment 1

[0472] Example 1: Polyclonal Antibodies Against Protein S Improve APTT in Human Hemophiliac Plasma

[0473] In FVIII-deficient human plasma, polyclonal anti-Protein S antibody concentration-dependently shortened clotting time in the presence of APC ( figure 1 ). Congenitally FVIII-deficient human plasma (George King Biomedical Inc.) was treated with 0.3 μg / ml APC (Innovative Research) and indicated levels of polyclonal anti-protein S (DAKO #A0384) together with APTT reagent (APTT-SP, IL) before recalcification. Incubate at 37°C for 300 sec. The time to fibrin clot formation was measured using an ACL9000 (ILS). Average EC 50 It was 37.1 μg / ml (SD=2.4, n=3 experiments), corresponding to about 250 nM.

Embodiment 2

[0474] Example 2: Procoagulant effect of anti-Protein S antibody compared to FVIII in hemophilia A plasma

[0475] The maximum effect of anti-Protein S antibody in FVIII-deficient plasma was compared with the clotting times of normal human plasma and human plasma with 1%, 5% and 10% FVIII (internal), respectively ( figure 2 ). The data indicated that the complete response with anti-protein S was similar to the clotting time of plasma with 5-10% FVIII. The effect of complete neutralization of protein S was confirmed by establishing the clotting time of protein S-deficient plasma (HaemochromDiagnostica) with excess neutralizing FVIII antibody (internal), similar to protein S and FVIII doubly deficient plasma.

[0476]Plasma was mixed with APC (0.3 μg / ml) and antiprotein S (DAKO, #A0384) or FVIII in various combinations together with APTT reagent (APTT-SP, IL) and incubated at 37°C before recalcification 300sec. The time to fibrin clot formation was measured using an ACL9000 ...

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Abstract

The present invention relates to pro-coagulant human Protein S inhibitors, such as antibodies or antigen-binding fragments thereof that can be administered subcutaneously as prophylactic treatment for haemophilia patients regardless of inhibitor status and without interfering with non-coagulant functions of Protein S.

Description

[0001] Incorporation by Reference of Sequence Listings [0002] The Sequence Listing entitled "Sequence Listing" was created on November 6, 2014 and is incorporated herein by reference. technical field [0003] The present invention relates to inhibitors, such as antibodies, that specifically bind protein S. Background technique [0004] In subjects with coagulopathy, such as humans with hemophilia types A and B, multiple steps of the coagulation cascade are dysfunctional due to, for example, the absence or insufficient presence of coagulation factors. This dysfunction of part of the coagulation cascade results in inadequate blood clotting and potentially life-threatening bleeding, or damage to internal organs such as joints. Subjects with hemophilia A and B, such as humans, may receive replacement therapy with coagulation factors such as exogenous Factor VIII (FVIII) or Factor IX (FIX), respectively. However, such patients are at risk of developing "inhibitors" (antibodi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K16/18C12N15/13A61K45/06A61K48/00A61K31/7088A61K39/395A61P7/04
CPCA61K31/7088A61K45/06A61K48/005A61K2039/505C07K16/18C07K2317/56C07K2317/565A61P7/04C07K16/36C07K2317/24C07K2317/34C07K2317/55C07K2317/76C07K2317/522C07K2317/54
Inventor H.海布罗奇佩特森M.B.赫米特H.L.霍姆伯格B.O.克罗格K.克贾尔加亚尔德M.D.安德森R.萨博E.瓦特斯L.M.安德森K.W.巴尔林格
Owner NOVO NORDISK AS
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