39 results about "Clotting factors" patented technology

The invention relates to the technical field of biomedical materials, and discloses an antibacterial hemostatic material and a preparation method thereof, the antibacterial hemostatic material comprises the following components by weight: 2-3 parts of amino acid terminated polyurethane, 1-3 parts of thiolated chitosan, 3-5 parts of sodium alginate, and 2-4 parts of a polyvinyl alcohol solution. Through the synergistic effect of amino acid terminated polyurethane-sulfhydrylated chitosan-sodium alginate, a dual hemostatic mechanism of physical adsorption-chemical coagulation promotion is constructed: sodium alginate as a natural polysaccharide has strong hydrophilicity and cation adsorption capacity, can quickly absorb moisture in wound blood, concentrate platelets and coagulation factors, and has a good hemostatic effect; thrombin activation is accelerated, and the blood coagulation time is shortened; the antibacterial hemostatic material disclosed by the invention has relatively good antibacterial and hemostatic effects.

Embodiments provide devices, preparations and methods for delivering therapeutic agents (TAs) such as clotting factors (CFs, e.g., Factor 8) within the GI tract. Many embodiments provide a swallowable device e.g., a capsule for delivering TAs into the intestinal wall (IW). Embodiments also provide TA preparations configured to be contained within the capsule, advanced from the capsule into the IW and / or surrounding tissue (ST) and degrade to release the TA into the bloodstream to produce a therapeutic effect (e.g., improved clotting). The preparation can be operably coupled to delivery means having a first configuration where the preparation is contained in the capsule and a second configuration where the preparation is advanced out of the capsule into the IW or ST (e.g., the peritoneal cavity). Embodiments are particularly useful for delivery of CFs for treatment of clotting disorders (e.g., hemophilia) where such CFs are poorly absorbed and / or degraded within the GI tract.

Variants of coagulation factor VIII (FVIII) and expression cassettes encoding the FVIII variants thereof are described. A variant FVIII includes a glycoepitope of the FVIII protein including an N2118Q mutation. The N2118Q mutation can be combined with other mutations including a BDD-FVIII, N6, V3, RH, furin-cleavage site deletion. X10, K12, and / or F309S mutation to form additional FVIII variants. The FVIII variants with the N2118Q mutation and expression cassettes thereof can result in reduced immunogenicity of the resulting protein. When combined with other FVIII mutations, higher gene expression, increased secretion, increased stability, and higher FVIII functional activity can be achieved by the expressed FVIII variants. The variant FVIII and expression cassettes described here can be useful in protein replacement therapy and / or gene therapy for the treatment of hemophilia A.

The present application relates to the technical field of medicine, and provides a kind of haena polysaccharide and its preparation method and application and target endogenous coagulation pathway anticoagulant and / or antithrombotic drug.The haena polysaccharide provided by the present application is fucosylated chondroitin sulfate polysaccharide, the weight average molecular weight is 9-13 million, the molar ratio of glucuronic acid, N-acetylglucosamine and fucose is 1:0.8-1.2:0.5-0.8, and the mass percentage content of sulfate group is 25-40%.The haena polysaccharide provided by the present application can target endogenous coagulation pathway terminal rate-limiting enzyme (iFXase), and has no obvious effect on coagulation factors in other coagulation pathways, realizes the effect of anticoagulation and non-hemorrhage, and can be widely applied in acute and recovery period treatment of ischemic stroke, solves the safety problem of using anticoagulant and antithrombotic drug for clinical ischemic stroke patients, and opens up a new field of research and development of target endogenous coagulation pathway rate-limiting enzyme anticoagulant drug.

The invention relates to the technical field of freeze-drying preparations, in particular to a plasma protective agent, a freeze-drying method for keeping the pH of plasma and freeze-dried plasma, and the plasma protective agent comprises the following components: an instant protective agent which comprises 5mg / ml of glycine; the feed additive is prepared from sodium dihydrogen phosphate, trehalose, hydroxyethyl starch, polyethylene glycol, mannitol, taurine, tryptophan lysine or glutamic acid. The sustained-release protective agent comprises antioxidant components encapsulated by lipidosome, wherein the antioxidant components comprise glutathione, adenosine and vitamin C. The invention also discloses a preparation method of the sustained-release protective agent. The novel protective agent vitamin C is adopted, the plasma pH adjusting operation is remarkably simplified, and the vitamin C is composed of multiple components with different functions, so that the stability of key components such as blood coagulation factors in plasma is greatly improved.

The present disclosure provides methods inducing immune tolerance in a human, comprising administering to the human an effective amount of a composition or a chimeric protein comprising a clotting factor and an Fc region.

To provide a method for treating reversible hemophilic arthropathy of a joint in a human having hemophilia.SOLUTION: Uses of a chimeric protein or composition comprising a coagulation factor and an Fc region are provided. The coagulation factor is selected from the group consisting of Factor VII (FVII), Factor VIIa (FVIIa), Factor VIII (FVIII), Factor IX (FIX), Factor X (FX), von Willebrand Factor (VWF), an antigen-binding portion thereof that specifically binds to FIX and FX, or any combination thereof.SELECTED DRAWING: None

Modified human factor VIII polypeptides with enhanced factor VIII activity are described. In some embodiments, the modified human factor VIII polypeptides comprise one or more amino acid substitutions at positions A20, T21, F57, L69, I80, L178, R199, H212, I215, R269, I310, L318, S332, R378, I610 and / or I661. Such polypeptides and viral vectors encoding such polypeptides may be used for treatment of FVIII deficiencies, such as hemophilia A.

Disclosed are a modified FIX (Factor IX) polypeptide comprising a leucine, cysteine, aspartic acid, glutamic acid, histidine, lysine, asparagine, glutamine or tyrosine in position 338; pharmaceutical preparations containing said modified FIX polypeptide; a nucleotide sequence coding for the modified FIX polypeptide; and a method for producing the modified FIX polypeptide.

This invention relates to a wholly recombinant four factor hemostatic complex concentrate (4F-PCC) composition, human liver cell-produced product. Methods of producing a hemostatic composition using a hepatocyte cell line and a CRISPR / Cas9 gene activation multiplexing, which allows for simultaneous and high level expression of the FII, FVII, FIX, and FX clotting factors. The resultant product is a recombinant resuscitation solution to aid in mitigation of coagulopathy, reversal of coagulopathic states, and fluid resuscitation.

A method for treating cancer is provided. The method includes administering a combination of a Prolidase, also known as peptidase D (PEPD), in combination with a monoclonal antibody or antigen binding fragment thereof that binds with specificity to a clotting factor, such as Factor XII (FXII). A single dose of the monoclonal antibody is sufficient to enable a therapeutic effect of the PEPD.

Embodiments provide devices, preparations and methods for delivering therapeutic agents (TAs) such as clotting factors (CFs, e.g., Factor 8) within the GI tract. Many embodiments provide a swallowable device e.g., a capsule for delivering TAs into the intestinal wall (IW). Embodiments also provide TA preparations configured to be contained within the capsule, advanced from the capsule into the IW and / or surrounding tissue (ST) and degrade to release the TA into the bloodstream to produce a therapeutic effect (e.g., improved clotting). The preparation can be operably coupled to delivery means having a first configuration where the preparation is contained in the capsule and a second configuration where the preparation is advanced out of the capsule into the IW or ST (e.g., the peritoneal cavity). Embodiments are particularly useful for delivery of CFs for treatment of clotting disorders (e.g., hemophilia) where such CFs are poorly absorbed and / or degraded within the GI tract.

The present disclosure provides methods of administering chimeric and hybrid Factor VIII (FVIII) polypeptides comprising FVIII and Fc to subjects at risk of developing inhibitory FVIII immune responses, including anti-FVIII antibodies and / or cell-mediated immunity. The administration is sufficient to promote coagulation and to induce immune tolerance to FVIII. The chimeric polypeptide can comprise full-length FVIII or a FVIII polypeptide containing a deletion, e.g., a full or partial deletion of the B domain.

The present invention relates to RNAi agents, e.g., double stranded RNAi agents, targeting the Kallikrein B, Plasma (Fletcher Factor) 1 (KLKB1) gene, the Factor XII (Hageman Factor (F12) gene, or the Kininogen 1 (KNG1) gene, and methods of using such RNAi agents to inhibit expression of a KLKB1 gene, an F12 gene, and / or a KNG1 gene, and methods of treating subjects having an hereditary angioedema (HAE) and / or a contact activation pathway-associated disorder.

The present disclosure provides nucleic acid molecules comprising a first inverted terminal repeat (ITR), a second ITR, and a genetic cassette encoding a target sequence. In some embodiments, the target sequence encodes a miRNA and / or a therapeutic protein. In certain embodiments, the therapeutic protein comprises a clotting factor, a growth factor, a hormone, a cytokine, an antibody, a fragment thereof, and a combination thereof. In some embodiments, the first ITR and / or the second ITR is an ITR of a non-adeno-associated virus (AAV). The present disclosure also provides methods of treating a metabolic disorder of the liver in a subject comprising administering to the subject the nucleic acid molecule or a polypeptide encoded thereby.

Compositions and methods use one or more feline circulating proteins as markers for early chronic kidney disease (CKD) to diagnose and / or treat CKD. A method of diagnosing chronic kidney disease (CKD) in a feline can include measuring an amount of each of at least one circulating protein from the feline. The at least one circulating protein is one or more of adiponectin (ADIPOQ), antibacterial peptide (CAMP), kinetin-like protein (KIF12), plasma retinol binding protein (RBP4), Ig-like domain containing protein (ZKSCAN1), blood coagulation factor X (F10), fibronectin (FN1), and mixtures thereof. The method further comprises comparing the amount of each of the at least one circulating protein from the feline to a respective predetermined value or a respective predetermined range. The method further comprises diagnosing the feline as having or not having early CKD based on the comparison.

This disclosure provides nucleic acid molecules comprising a first inverted terminal repeat (ITR), a second ITR, and a gene cassette encoding a target sequence. In some embodiments, the target sequence encodes a microRNA and / or a therapeutic protein. In certain embodiments, the therapeutic protein comprises a clotting factor, a growth factor, a hormone, a cytokine, an antibody, a fragment thereof, and a combination thereof. In some embodiments, the first ITR and / or the second ITR is an ITR of a non-adeno-associated virus (AAV). This disclosure also provides methods of treating a metabolic liver disorder in a subject comprising administering to the subject the nucleic acid molecule or a polypeptide so encoded.

To provide an FVIII formulation requiring less frequent administration, i.e., an FVIII formulation with a half-life longer than 1.5 to 2 times the half-life limitation.SOLUTION: The present invention provides a chimeric protein comprising (i) a first polypeptide which comprises FVIII fused to a first immunoglobulin (Ig) constant region or a portion thereof and (ii) a second polypeptide which comprises a von Willebrand factor (VWF) protein comprising a D' domain and a D3 domain of VWF fused to a second Ig constant region or a portion thereof by an XTEN sequence in between, where the XTEN sequence contains less than 288 amino acid residues, and where the first polypeptide is linked to or associated with the second polypeptide. Certain embodiments include the chimeric protein as described herein, where the XTEN sequence in the second polypeptide consists of an amino acid sequence having a length between 12 amino acids and 287 amino acids.SELECTED DRAWING: Figure 1

The invention provides an antibody or an antigen binding fragment thereof. The antibody comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprises an HFR1 as shown in an amino acid sequence SEQ ID NO: 7, an HFR2 as shown in an amino acid sequence SEQ ID NO: 8, an HFR3 as shown in an amino acid sequence SEQ ID NO: 9 or a mutant thereof, and an HFR4 as shown in an amino acid sequence SEQ ID NO: 10; the light chain variable region comprises an LFR1 shown as an amino acid sequence of SEQ ID NO: 13, an LFR2 shown as an amino acid sequence of SEQ ID NO: 14 or a mutant thereof, an LFR3 shown as an amino acid sequence of SEQ ID NO: 15 or a mutant thereof, and an LFR4 shown as an amino acid sequence of SEQ ID NO: 16 or a mutant thereof. The antibody or the antigen binding fragment thereof can improve the expression quantity of the antibody while ensuring the antigen binding activity.

Production was attempted for antibodies that neutralize the activity of a bispecific antibody having F.VIII function-substituting activity, for use in a method for measuring the reactivity of F.VIII in the presence of a bispecific antibody having F.VIII function-substituting activity. As a result, it was discovered that by using the produced antibodies, F.VIII activity in the plasma of a hemophilia A patient can be evaluated accurately by performing APTT-based one-stage clotting assay on a wide range of bispecific antibodies having F.VIII function-substituting activity. It was also discovered that F.VIII inhibitor titer in the plasma of a hemophilia A patient carrying F.VIII inhibitor can be evaluated accurately by APTT-based Bethesda assay.

Methods of accelerating clot formation and increasing clot deposition in a hemophiliac subject. A vagal nerve stimulator (VNS) may be implanted in a hemophiliac subject. The hemophiliac subject may have developed antibodies to factor VIII and not been administered a clotting factor within the last 48 hours. The vagus nerve of the subject may be stimulated in a manner that increases platelet intracellular calcium and / or activates splenic acetylcholine-synthesizing T lymphocytes using the implanted VNS.

The present disclosure provides nucleic acid molecules comprising a first inverted terminal repeat (ITR), a second ITR, and a genetic cassette encoding a target sequence. In some embodiments, the target sequence encodes a miRNA and / or a therapeutic protein. In certain embodiments, the therapeutic protein comprises a clotting factor, a growth factor, a hormone, a cytokine, an antibody, a fragment thereof, and a combination thereof. In some embodiments, the first ITR and / or the second ITR is an ITR of a non-adeno-associated virus (AAV). The present disclosure also provides methods of treating a metabolic disorder of the liver in a subject comprising administering to the subject the nucleic acid molecule or a polypeptide encoded thereby.

The invention belongs to the technical field of biological medicine, and discloses application of an active substance in preparation of a VKOR inhibitor and / or a vitamin K antagonist and an anticoagulant drug. The invention provides application of an active substance shown in a formula (1) or pharmaceutically acceptable salt thereof in preparation of a vitamin K epoxide reductase inhibitor. The active substance has VKOR inhibitory activity, can prevent liver from synthesizing blood coagulation factors and activating anticoagulant factors by blocking reduction of oxidized vitamin K and inhibiting circulation of vitamin K, has potential anticoagulant activity, and has the advantages of mild anticoagulant effect, low probability of occurrence of adverse hemorrhage events, good anticoagulant effect, high safety and the like. The compound has a good application prospect in preparation of anticoagulants and / or medicines for treating thromboembolic diseases.

The application relates to the technical field of biomedical materials, and discloses an antibacterial hemostatic material and a preparation method thereof, which comprises the following components by weight: 2-3 parts of amino acid-terminated polyurethane, 1-3 parts of thiolated chitosan, 3-5 parts of sodium alginate and 2-4 parts of polyvinyl alcohol solution. Through the synergistic effect of the amino acid-terminated polyurethane-thiolated chitosan-sodium alginate, a double hemostatic mechanism of physical adsorption-chemical coagulation is constructed: the sodium alginate, as a natural polysaccharide, has strong hydrophilicity and cation adsorption capacity, can quickly absorb the moisture in the wound blood, concentrate the platelets and coagulation factors, accelerate the activation of thrombin, and shorten the coagulation time; the antibacterial hemostatic material has good antibacterial and hemostatic effects.

This invention relates to a gene encoding coagulation factor IX. F9 This study investigates animal models of nonsense mutations, methods for screening hemophilia drugs using these models, and the application of the screened stRNAs in the preparation of hemophilia drugs. Based on an analysis of the probability of nonsense mutations in coagulation factor IX in hemophilia patients, the study verifies that stRNAs can read the coagulation factor IX encoding gene. F9 The function and efficiency of the premature termination codon (PTC) were investigated. Seven Arg-stRNAs were designed to target the coagulation factor IX R75* mutation, and readthrough efficiency was tested at the cellular level. A mouse model of the coagulation factor IX R75* mutation was constructed, and Arg-stRNA was delivered via AAV, restoring the expression of endogenous coagulation factor IX and reducing clotting time, demonstrating the effectiveness of stRNA in treating hemophilia B.

The present invention relates to a method and application for targeted knock-in of human coagulation factor VII and VIII coding genes at pig coagulation factor VII and VIII gene loci, and belongs to the field of gene editing technology. The present invention provides a group of sgRNAs for targeted knock-in of human coagulation factor coding genes at pig coagulation factor gene loci. Targeting the specific sites of the first intron of pig coagulation factor VII coding gene F7 and pig coagulation factor VIII coding gene F8, sgRNA and targeting vectors are designed respectively, and human coagulation factor FVII and FVIII protein coding genes are site-specifically knocked in, and human coagulation factor FVII protein expression is initiated by the endogenous promoter of pig F7 gene, and human coagulation factor FVIII protein expression is initiated by the endogenous promoter of pig F8 gene. The expression level is equivalent to the physiological level, and will not have a significant impact on the health status of the prepared gene-edited pigs, and is used for large-scale production of human coagulation factor FVII and FVIII protein products.

The application discloses a kind of alginate macroporous hemostatic material constructed with calcium carbonate as sacrifice template, comprising the following steps: (1) sodium alginate is dissolved with calcium carbonate powder in ultrapure water, and stirring is carried out until the mixture becomes uniform paste;(2) L-galactonic acid-1, 4-lactone is added to the paste, and stirring is uniformly carried out;(3) the mixture is placed at 4 DEG C to form hydrogel, and then immersed in hydrochloric acid solution to obtain macroporous hydrogel.By using calcium carbonate as a sacrificial template to prepare a macroporous system, the uniform pore structure can be used to load bioactive clotting factors, which can accelerate platelet aggregation and initiate the coagulation cascade, ensuring excellent hemostatic performance of the material. The gel material is soft, and can fully meet the requirements of complex wound environment for the form of hemostatic material.

The invention belongs to the technical field of medical treatment, and discloses a preparation method and application of a preoperative storage autoblood preparation composition, and the preparation method comprises the following steps: S1, collecting autologous whole blood; s2, carrying out first centrifugation on the whole blood; s3, transferring the platelet-rich plasma into a transfer bag; s4, introducing the erythrocyte preservative solution into the packed erythrocytes to obtain autologous suspension erythrocytes; s5, centrifuging the platelet-rich plasma for the second time; s6, the platelet-poor plasma is transferred into an empty bag to be frozen at a deep low temperature, and autologous frozen plasma is obtained; and S7, retaining the plasma in the blood bag with the concentrated platelets, standing the platelet-rich plasma, and uniformly shaking after natural depolymerization to obtain the autologous platelet-rich plasma. Through separation and preservation, the activity of red blood cells, blood coagulation factors and platelets is effectively reserved, intraoperative blood and PRP adjuvant therapy can be provided for patients, and tissue repair is promoted; the method is simple and convenient to operate and suitable for clinical popularization.

This invention discloses an isolated anti-FXI and / or anti-FXIa antibody or its antigen-binding fragment, which specifically binds to human FXI or FXIa, and provides a drug targeting FXI that effectively prevents or treats thrombosis with minimal side effects to meet medical needs. Because currently approved anticoagulants interfere with hemostasis, leading to an increased risk of bleeding, there is a significant unmet medical need for safer anticoagulants. Although thrombosis can be treated or prevented with anticoagulants (e.g., heparin, warfarin, aspirin, or factor Xa inhibitors), these treatments have significant adverse effects. Genetic and pharmacological evidence in humans and animals suggests that lowering coagulation factor XI (FXI) can successfully prevent and manage thrombosis with minimal bleeding.

The present invention provides a compound of Formula (I) and pharmaceutical compositions comprising one or more said compounds, and methods for using said compounds for treating or preventing thromboses, embolisms, hypercoagulability or fibrotic changes. The compounds are selective Factor XIa inhibitors or dual inhibitors of Factor XIa and plasma kallikrein.