WO2002031515A2 - Xenogeneic antibody containing plasma reagents and associated methods - Google Patents
Xenogeneic antibody containing plasma reagents and associated methods Download PDFInfo
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- WO2002031515A2 WO2002031515A2 PCT/EP2001/011310 EP0111310W WO0231515A2 WO 2002031515 A2 WO2002031515 A2 WO 2002031515A2 EP 0111310 W EP0111310 W EP 0111310W WO 0231515 A2 WO0231515 A2 WO 0231515A2
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- animal species
- factor
- plasma
- antibody containing
- containing plasma
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6854—Immunoglobulins
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/86—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving blood coagulating time or factors, or their receptors
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/96—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving blood or serum control standard
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
- G01N2333/745—Assays involving non-enzymic blood coagulation factors
- G01N2333/755—Factors VIII, e.g. factor VIII C [AHF], factor VIII Ag [VWF]
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/90—Enzymes; Proenzymes
- G01N2333/914—Hydrolases (3)
- G01N2333/948—Hydrolases (3) acting on peptide bonds (3.4)
- G01N2333/95—Proteinases, i.e. endopeptidases (3.4.21-3.4.99)
- G01N2333/964—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue
- G01N2333/96425—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from mammals
- G01N2333/96427—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from mammals in general
- G01N2333/9643—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from mammals in general with EC number
- G01N2333/96433—Serine endopeptidases (3.4.21)
- G01N2333/96441—Serine endopeptidases (3.4.21) with definite EC number
- G01N2333/9645—Factor IX (3.4.21.22)
Definitions
- the present invention provides plasma derived from a first animal species that contains antibodies from a second animal species (xenogeneic antibodies). Specifically, the present invention provides xenogeneic antibody containing plasma that is useful as biological assay (bioassay) reagents. More specifically, the present invention provides a bioassay reagent, methods for making the reagent and methods for using the reagent in an assay intended to determine the biological activity of compounds used to treat autoimmune and hematological disorders
- Hemophilia is a disease characterized by blood clotting (hemostasis) disorders caused by deficiencies in coagulation factors. Hemostasis is a complex biological process involving numerous diverse enzymes, co-factors, macromolecules and cell signaling compounds. Hemophilia can be inherited or acquired and both vary in severity. Inherited hemophilia usually involves only one hemostatic component or pathway whereas acquired hemophilia generally involves multiple hemostatic pathways Generally, hemophilia is treated using coagulation factor concentrates derived from donor plasma or through recombinant DNA technologies.
- the most frequently used replacement coagulation factors include Factor V, Factor NTH, von Willebrand Factor (vWF), Factor IX, and Factor X.
- vWF von Willebrand Factor
- IX Factor IX
- Factor X One of the most serious side effects of treating hemophilia with replacement coagulation factor concentrates is the development of inhibitory antibodies against one or more of these coagulation factors.
- inhibitory antibodies can be associated with various autoimmune diseases including systemic lupus erythematosus (SLE).
- SLE systemic lupus erythematosus
- the inhibitory factor found in SLE patients is not directed at a specific coagulation factor, but rather it is an anti-phospholipid antibody that non-specifically interferes with many coagulation pathway reactions.
- inhibitory antibodies form when the recipient's immune system reacts to the replacement coagulation factor as it would a foreign substance (antigen) such as a virus.
- FEIBA Factor Eight Inhibition Bypassing Activity
- FEIBA is made from pooled human plasma and contains Factor II, activated Factor Nil, Factor VII, Factor IX and Factor X.
- FEIBA bypasses the need for Factors NIII and IX by acting simultaneously at different points in the blood coagulation cascade (hemophilia A patients most often have Factor NIII inhibitor whereas hemophilia B patents most often have Factor IX inhibitor). All biological reagents and therapeutics must be stringently evaluated prior to their in vitro diagnostic or in vivo therapeutic use.
- anti-inhibitory blood clotting therapeutics have been evaluated in vivo using experimental animals such as hemophilic dogs, which exhibit a genetic defect similar to human hemophilia, or animals in which a transient hemophilia has been established by administering blood coagulation factor antibodies to such animals.
- experimental animals such as hemophilic dogs, which exhibit a genetic defect similar to human hemophilia, or animals in which a transient hemophilia has been established by administering blood coagulation factor antibodies to such animals.
- side effects from hemophilia make these animal models difficult to establish and maintain.
- animal models do not completely simulate human hemophilia and/or may show biased results due to normalization of the transient hemophilic state. Examples of successful animal models for human blood coagulation disorders are described in J.Clin. Invest 82 (1988), 206-211, WO 95/01570 and AT 404 429 B. Therefore, non-human animal test systems have proven to be less than ideal for evaluating the therapeutic efficacy of anti-clotting factor inhibitory antibody treatments
- a blood clotting deficiency therapeutic's efficacy can be accurately evaluated in vitro providing adequate standards have been established in vivo and sufficeient consistant testing reagents having appropriate sensitivity and specificity are available.
- plasma that exhibit specific blood coagulation disorders.
- plasma are, especially samples from patients having inhibitor antibodies, are rare. Consequently, standardized testing reagents derived from human plasma are extremely difficult to provide on a consistent basis.
- hemophiliacs blood factor concentrates derived from pooled human plasma for decades. Consequently, they may have been exposed to products contaminated with human immunodeficiency virus (HIN), human T-cell lymphotropic virus type I (HTLN I), human T-cell lymphotropic virus type II (HTLN II), hepatitis virus type B 5 hepatitis virus type C and other, potentially unidentified viral and/or non-viral pathogens. Therefore, not only is human plasma having blood-clotting deficiencies rare, especially inhibitory antibody disorders, but available sources are also frequently contaminated with infectious agents. Consequentially, there is a need for constant, well characterized, non-infectious human plasma suitable for in vitro testing of therapeutic argents intended to treat blood clotting disorders, autoimmune diseases, and especially, anti-clotting factor inhibitory antibody therapeutics.
- HIN human immunodeficiency virus
- HNLN I human T-cell lymphotropic virus type I
- HTLN II human T-cell lymphotropic virus type II
- hepatitis virus type B hepatitis virus type C.
- Another object of the present invention is to provide an anti-blood clotting factor antibody containing plasma suitable of the in vitro testing of therapeutics used to treat hemophiliacs having anti-blood clotting factor antibodies (inhibitory antibodies).
- the present invention is a bioassay reagent made by blending the plasma of one animal with antibodies derived from at least one other different animal (xenogeneic antibody containing plasma).
- the xenogeneic antibodies recognize antigens indigenous to the animal used as the plasma source (the first animal species).
- the normal, healthy animal immune system generally does not recognize indigenous antigens, consequently, these antigens must be inoculated into a second animal species to produce the xenogeneic antibodies of the present invention.
- Suitable antigens recognized by the xenogeneic antibodies of the present invention include, but are not limited to lipids, phospholipids, glycolipids, proteins, amino acids, glycoproteins, carbohydrates, and nucleic acids.
- the antigens recognized by the xenogeneic antibodies are blood coagulation factor antigens including, but not limited to Factor N, Factor VIII, Factor IX, factor X and von Willebrand Factor.
- the plasma source is derived from the animal to be treated using the therapeutic that the present invention is intended to test.
- the bioassay is intended to test the efficacy of therapeutics used to treat human autoimmune diseases, therefore, a human (the first animal, order Primate) is the optimum plasma source.
- suitable animal orders include, but are not limited to Artiodactyla, Perissodactyla, Rodentia, and Lagomorpha.
- the xenogeneic antibody is produced in a second animal species for reasons briefly explained above.
- Suitable second animal orders include, but are not limited to Artiodactyla, Perissodactyla, Rodentia, Lagomorpha and Primates, providing that the second animal species is different from the first animal species, and that the second animal will immunologically recognize the antigens administered.
- a goat order Artiodactyla, species Capra
- Suitable Capra species include, but are not limited to aegagrus, ibex, pyrenaica, cylindricornis, hircus, andfalconeri.
- the present invention is directed to a bioassay reagent comprising plasma of a first animal species that contains antibodies from at least one other animal species (xenogeneic antibodies). These xenogeneic antibodies are directed against antigens indigenous to the species from which the plasma component was derived. In one embodiment of the present invention autoimmune antibodies present in the plasma component are removed (immunodepleted) before the xenogeneic antibodies are added.
- the present invention provides a consistent, standardized bioassay reagent that is ideally suited for testing autoimmune therapeutics for efficacy prior to use in animals.
- the bioassay reagents of the present invention can be prepared using human plasma that is free of detectable blood borne infectious agents
- compositions are easy to produce using methods known to those of ordinary skill in the art of immunology (Thromb. Haemost. 68 (2) (1992), 155-159; British Journal of Hematology 46 (1980) 471-481).
- normal human plasma the first animal species
- xenogeneic antibodies from a second animal species such as, but not limited to cattle, horses, goats, rabbits, mice, and rats that recognized antigen indigenous to the fist animal species is not known. Consequently, the present invention provides novel methods and reagents for the in vitro efficacy analysis of therapeutics using xenogeneic antibody containing plasma.
- FIG.1 graphically compares the clotting time reduction of (a) human Factor NIII deficient plasma containing naturally occurring auto antibodies against Factor VIII (patient plasma containing inhibitory antibodies), (b) human Factor VIII deficient (immunodepleted) plasma with added inhibitor against Factor VIII (the xenogeneic antibodies of the present invention) and (c) human normal plasma with added inhibitor against Factor VIII (the xenogeneic antibodies of the present invention).
- the present invention is generally directed at bioassay reagents consisting of normal plasma from one animal species that is mixed with antibodies derived from at least one other different animal species (xenogeneic antibodies) to form a xenogeneic antibody containing plasma.
- the bioassay reagents disclosed contain plasma from a first animal species and antibodies derived from at least one second different animal species that recognize antigens indigenous to the first animal species.
- associated methods for making and using the bioassay reagents disclosed are also provided.
- the proteins, glycoproteins, lipids, glycolipids, carbohydrates, nucleic acids and other structural components (antigens) of a normal animal's body do not elicit a humoral immune response (that part of the immune system made of plasma cells that produce antibodies). That is, our immune systems generally do not make antibodies against our. However, in rare cases an animal's immune system will produce antibodies against its own antigens resulting in "autoantibodies” and an "autoimmune" disease. In severe cases, aggressive autoimmune diseases can be life threatening.
- Autoantibodies generally form in one of several ways.
- the most common cause of autoimmune diseases is genetically based.
- the immune systems of genetically predisposed persons respond to their own antigens as if they were foreign antigens and form antibodies against them.
- Systemic lupus Erythematosus (SLE) is an example of a genetically based autoimmune disease where the body's humoral immune system forms autoantibodies against its own nucleic acids, nuclear proteins, and phosolipids (40% to 60% of SLE patents form anti-phospholipid antibodies).
- Autoimmune disease can also be drug induced, or the result of prolonged immune system stimulation resulting from repeated injections of therapeutics derived from a closely related species.
- hemophiliacs that receive blood clotting factor concentrates derived from pooled human plasma that produce antibodies against blood clotting factors (inhibitory antibodies) including, but not limited to, Factor VIII, Factor IX, Factor X, von Willebrand Factor (vWF), and/or phospholipids.
- autoantibody containing human plasma especially plasma containing inhibitory factor
- pathogens include, but not limited to human immunodeficiency virus (HIN), human T-cell lymphotropic virus type I (HTLV I), human T-cell lymphotropic virus type II (HTLV II), hepatitis virus type B, hepatitis virus type C and other, potentially unidentified viral and/or non- viral pathogens. Therefore, the ability to produce large quantities of plasma containing autoantibodies free from detectable blood borne pathogen would be a significant scientific advance.
- the inventors of the present invention have overcome the aforementioned obstacle by devising a system whereby detectable blood borne pathogen free animal plasma from one species (the plasma donor) is mixed with antibodies that react with antigens indigenous to the plasma donor.
- antigens from the plasma donor are extracted from the plasma donor species and used to immunize a different animal species (the immunized animal) using methods known to those of ordinary skill in the art.
- the immunized animal's humoral immune system reacts to the extracted plasma donor antigens as foreign antigens resulting in xenogeneic antibody production.
- the xenogeneic antibody-producing animals must be sufficiently taxonomically different from the plasma donor animal so that their immune systems will respond immunologically to the antigens. For example, if the plasma donor is a goat (belonging to the subfamily "Caprinae" of the "Bovidae” family of the "Artiodactyla” order), then the animals used to produce the xenogeneic antibodies have to be members of another family or subfamily e.g.
- the plasma donor is a human (Homo sapien; family Hominidae; order Primate) and the immunized animal is a goat (Capra sp; species selected from the group including aegagrus, ibex, pyrenaica, cylindricornis, hircus, and falconer i).
- any antigen indigenous to the plasma donor may be administered to one or more different animals (the “second animal species") so that xenogeneic antibodies against this antigen(s) are induced.
- the xenogeneic antibodies may be extracted and combined with the donor plasma from healthy noninfected individuals.
- the antibody extraction method is not critical and depends on the nature of the xenogeneic antibody preparation that is to be supplied to the donor plasma. If a xenogeneic polyclonal antibody preparation is combined with the donor plasma, then ascites fluid, plasma, plasma fractions, plasma preparations, or serum containing the antibodies of the second group of animal(s) is provided.
- immunoglobulin preparations may be obtained by purifying the plasma or ascites fluid using methods known to those in the art, such as, but not limited to immunoprecipitation, gel electrophoresis and affinity chromatography (Arch. Biochem. Biophys. 134, (1969), 279-284; Vox. Sang. 23, (1972), 279-290).
- xenogeneic monoclonal antibodies may be prepared using methods known to those of ordinary skill in the art (Methods Enzymol. 73, (1981), 3- 46). All methods for providing such xenogeneic (polyclonal and monoclonal) antibody prepai-ations are in principle suited for the present invention. However, reproducibility and consistency of the present invention is enhanced when highly specific and purified xenogeneic antibodies are used.
- the composition according to the present invention is provided in lyophilized form, which is reconstitutable upon demand but stably stored for long time periods.
- the xenogeneic antibody containing plasma is free of inhibitory antibodies of the first group of animals thus reducing the risk that the added xenogeneic antibodies may interfere with indigenous antibodies already present in the donor plasma.
- the presence of indigenous autoantibodies may be determined in advance using immunoassays known to those of ordinary skill in the art.
- compositions according to the present invention are especially suited for testing the efficacy of therapeutics used to treat autoimmune diseases; especially hemophiliacs having inhibitor antibodies.
- an in vitro method for evaluating auto-antibody disease therapeutic efficacy include mixing the autoantibody disease therapeutic with the xenogeneic antibody containing plasma of the present invention to form a mixture. Next, the effect of the autoantibody disease therapeutic on the xenogeneic antibody containing plasma is detected.
- the autoantibody disease therapeutic is an anti-blood clotting factor antibody therapeutic and a blood coagulation assay is used to determine the effects of the xenogeneic antibody containing plasma on the therapeutic. This method is especially suited for evaluating substances for their ability to treat blood coagulation disorders in human patients.
- FIG. 1 graphically compares the clotting time reduction of human factor VIII deficient plasma that has been treated using Factor Eight Inhibition Bypassing Activity (FEIBA).
- Curve (a) is the control and depicts the clotting time reduction of human factor VIII deficient plasma containing naturally occurring autoantibodies against factor VIII (patient plasma containing inhibitory antibodies).
- Curve (b) depicts human factor VIII deficient (immunodepleted) plasma with the xenogeneic antibodies of the present invention added.
- curve (c) depicts human normal plasma with the xenogeneic antibodies of the present invention added.
- the effects of FEIBA is nearly identical in all examples. Therefore, it can be concluded that the xenogeneic antibody containing plasma of the present invention closely simulates plasma having naturally occurring autoantibodies and inhibitory factor.
- xenogeneic antibodies are produced from indigenous antigens derived using recombinant DNA technology as known to those of ordinary skill in the art of molecular biology.
- Recombinant antigen preparations can be tailored to exacting specifications permitting the production of xenogeneic antibody containing plasma having potencies equal to or greater than naturally occurring inhibitory antibody containing plasma.
- the present invention is suitable for high throughput routine testing or for single batch control of bioassay reagents which vary in biological activity, concentration and/or composition due to their biological origins.
- a kit is provided for the evaluation of substances for their ability to be applied to patients suffering from an autoantibody disease, especially inhibitor patients.
- This kit according to the present invention comprises a composition according to the present invention and a substance to be evaluated.
- such a kit preferably contains reagents for measuring coagulation time as well as standard preparations and reference samples, which may also be provided in lyophilized form.
- a goat is immunized with human recombinant FVIII by the following protocol. Primary immunization by subcutaneous injection of 32.5 ⁇ g human recombinant FVIII with complete Freund's adjuvant and two booster injections with
- the goat-anti- human-FVIII-antiplasma is heated to 56°C for 70 minutes, the resulting insoluble material removed by centrifugation and the supernatant measured with a functional assay (Bethesda-assay) for anti-FVIII antibody titer.
- a functional assay Bethesda-assay for anti-FVIII antibody titer.
- Approximately 1.8 ml of the supernatant is mixed with 57 ml of human normal plasma and 6 ml of HEPES/glycine-buffer (10 %(w/v) HEPES, 10 %(w/v) glycine in aqua dest, pH 6.6. The mixture is freeze dried and stored at 2 - 8°C until reconstitution.
- Goat-anti-human-FVIII-antiplasma is heated to 56°C for 70 minutes, the resulting insoluble material removed by centrifugation and the supernatant measured with a functional assay (Bethesda-assay) for anti-FVIII antibody titer. Approximately 0.3 ml of the supernatant is mixed with 15 ml of FVIII-deficient plasma (immunodepleted). The mixture is freeze dried and stored at 2 - 8°C until reconstitution.
- Example 3 Preparation of the Xenogeneic Antibody Containing Plasma Using Goat-anti-human Factor VIII Goat-anti-human-FVIII-antiplasma is heated to 56°C for 120 minutes, the resulting insoluble material removed by centrifugation and the supernatant measured with a functional assay (Bethesda-assay) for anti-FVIII titer. Approximately 0.63 ml of the supernatant is mixed with 20 ml of human normal plasma, and 1.5 ml of
- HEPES/glycine-buffer (10 %(w/v) HEPES, 10 %(w/v) glycine in aqua des , pH 6.6). The mixture is freeze dried and stored at 2 - 8°C until reconstitution.
- Goat-anti-human-FVIII-antiplasma is subjected to immunoglobulin fractionation according to Kistler et al. (Vox Sang, 1962, 7; 414-424) with some modifications. Briefly, the cryosupernatant is precipitated two times with 20 % ethanol, the resulting precipitate is dissolved and brought to 17 % ethanol. After separation, the supernatant is precipitated with 25 % ethanol, the pellet is dissolved. The resulting immunoglobulin solution contains 12 mg protein/ml and is stored frozen.
- the immunoglobulin solution (1 ml) is mixed with 13.5 ml immunodepleted FVIII deficient plasma and 1.5 ml HEPES/glycine-buffer (10 %(w/v) HEPES, 10 %(w/v) glycine in aqua dest., pH 6.6) is added.
- the mixture is freeze dried and stored at 2 - 8 °C.
- FIX Factor IX
- a goat is immunized with purified human plasma derived FIX by the following protocol. Primary immunization by subcutaneous injection of 90 ⁇ g human pd FIX with complete Freund's adjuvant and two booster injections with 90 ⁇ g of protein with incomplete Freund's adjuvant 3 and 8 weeks later. Blood samples are taken in intervals and the anti-FIX-inhibitor titer is measured with a functional assay (Bethesda assay). Two weeks after the second booster, citrated antiplasma with an inhibitor antibody titer of 1100 Bethesda-Units/ml is obtained by plasmapheresis. The plasma pool is stored frozen in aliquots at ⁇ -20°C.
- the goat-anti- human-FIX-antiplasma is heated to 56°C for 120 minutes, the resulting insoluble material removed by centrifugation and the supernatant measured with a functional assay (Bethesda-assay) for anti-FIX titer.
- a functional assay Bethesda-assay
- Two ml of the supernatant is mixed with 34 ml of human normal plasma and 4 ml of HEPES/glycine-buffer (10 %(w/v) HEPES, 10 %(w/v) glycine in aqua dest., pH 6.6.
- the mixture is freeze dried and stored at 2 - 8°C until reconstitution.
- Example 6 Preparation of the Xenogeneic Antibody Containing Plasma Using Goat-anti-human von Willebrand factor A goat is immunized with human plasma derived von Willebrand factor.
- the goat-anti- human- von Willebrand factor-antiplasma is heated to 56°C for 70 minutes, the resulting insoluble material removed by centrifugation and the supernatant measured with an ELISA. 10 ml of the supernatant is mixed with 35 ml of human normal plasma and 5 ml of HEPES/glycine-buffer (10 %(w/v) HEPES, 10 %(w/v) glycine in aqua dest., pH 6.6. The mixture is frozen and stored at ⁇ -20°C.
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Abstract
Description
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Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2002534849A JP2004514117A (en) | 2001-10-01 | 2001-10-01 | Plasma reagents containing heterologous antibodies and related methods |
EP01978391A EP1325342A2 (en) | 2000-10-13 | 2001-10-01 | Xenogeneic antibody containing plasma reagents and associated methods |
AU2002210517A AU2002210517A1 (en) | 2000-10-13 | 2001-10-01 | Xenogeneic antibody containing plasma reagents and associated methods |
CA002424794A CA2424794A1 (en) | 2000-10-13 | 2001-10-01 | Xenogeneic antibody containing plasma reagents and associated methods |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US68782300A | 2000-10-13 | 2000-10-13 | |
US09/687,823 | 2000-10-13 |
Publications (2)
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WO2002031515A2 true WO2002031515A2 (en) | 2002-04-18 |
WO2002031515A3 WO2002031515A3 (en) | 2003-03-13 |
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ID=24762001
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PCT/EP2001/011310 WO2002031515A2 (en) | 2000-10-13 | 2001-10-01 | Xenogeneic antibody containing plasma reagents and associated methods |
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EP (1) | EP1325342A2 (en) |
AU (1) | AU2002210517A1 (en) |
CA (1) | CA2424794A1 (en) |
WO (1) | WO2002031515A2 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8068853B2 (en) * | 2009-01-06 | 2011-11-29 | Chi Mei Communication Systems, Inc. | System and method for automatically recording position information |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5202264A (en) * | 1989-10-27 | 1993-04-13 | Health Research, Incorporated | ELISA using multi-species antibodies for detection of von Willebrand factor in multiple species |
US5804159A (en) * | 1995-06-09 | 1998-09-08 | Immuno Aktiengesellschaft | Antiplasma animal model |
WO1999058680A2 (en) * | 1998-05-08 | 1999-11-18 | Stichting Sanquin Bloedvoorziening | Method for diagnosis and treatment of haemophilia a patients with an inhibitor |
-
2001
- 2001-10-01 WO PCT/EP2001/011310 patent/WO2002031515A2/en not_active Application Discontinuation
- 2001-10-01 EP EP01978391A patent/EP1325342A2/en not_active Withdrawn
- 2001-10-01 AU AU2002210517A patent/AU2002210517A1/en not_active Abandoned
- 2001-10-01 CA CA002424794A patent/CA2424794A1/en not_active Abandoned
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5202264A (en) * | 1989-10-27 | 1993-04-13 | Health Research, Incorporated | ELISA using multi-species antibodies for detection of von Willebrand factor in multiple species |
US5804159A (en) * | 1995-06-09 | 1998-09-08 | Immuno Aktiengesellschaft | Antiplasma animal model |
WO1999058680A2 (en) * | 1998-05-08 | 1999-11-18 | Stichting Sanquin Bloedvoorziening | Method for diagnosis and treatment of haemophilia a patients with an inhibitor |
Non-Patent Citations (1)
Title |
---|
SULTAN Y ET AL: "IN VITRO EVALUATION OF FACTOR VIII-BYPASSING ACTIVITY OF ACTIVATED PROTHROMBIN COMPLEX CONCENTRATE, PROTHROMBIN COMPLEX CONCENTRATE, AND FACTOR VLLA IN THE PLASMA OF PATIENTS WITH FACTOR VIII INHIBITORS: THROMBIN GENERATION TEST IN THE PRESENCE OF COLLAGEN- ACTIVATED PLATELETS" JOURNAL OF LABORATORY AND CLINICAL MEDICINE, ST. LOUIS, MO, US, vol. 121, no. 3, 1 March 1993 (1993-03-01), pages 444-452, XP000611305 ISSN: 0022-2143 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8068853B2 (en) * | 2009-01-06 | 2011-11-29 | Chi Mei Communication Systems, Inc. | System and method for automatically recording position information |
Also Published As
Publication number | Publication date |
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WO2002031515A3 (en) | 2003-03-13 |
EP1325342A2 (en) | 2003-07-09 |
CA2424794A1 (en) | 2002-04-18 |
AU2002210517A1 (en) | 2002-04-22 |
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