NZ751610B2 - Subcutaneous administration of adamts13 - Google Patents

Subcutaneous administration of adamts13 Download PDF

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Publication number
NZ751610B2
NZ751610B2 NZ751610A NZ75161014A NZ751610B2 NZ 751610 B2 NZ751610 B2 NZ 751610B2 NZ 751610 A NZ751610 A NZ 751610A NZ 75161014 A NZ75161014 A NZ 75161014A NZ 751610 B2 NZ751610 B2 NZ 751610B2
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var
adamtsl3
ufv73
mammal
administered
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NZ751610A
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NZ751610A (en
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Werner Hoellriegl
Alexandra Nathalie Kopic
Evamaria Muchitsch
Barbara Plaimauer
Hanspeter Rottensteiner
Eva Maria Muchitsch
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Baxalta GmbH
Baxalta Incorporated
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
    • A61K38/4886—Metalloendopeptidases (3.4.24), e.g. collagenase
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
    • C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
    • C12N9/64—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue
    • C12N9/6421—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue from mammals
    • C12N9/6489—Metalloendopeptidases (3.4.24)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
    • C12Y304/24—Metalloendopeptidases (3.4.24)
    • C12Y304/24087—ADAMTS13 endopeptidase (3.4.24.87)

Abstract

This invention relates to methods of subcutaneous administration of ADAMTS13 formulations to a treat a disease or condition associated with ADAMTS13 and VWF dysfunction. Furthermore, evidence of the unexpectedly high bioavailability of ADAMTS13 formulations administered subcutaneously is provided herein. rein.

Description

SUBCUTANEOUS ADMINISTRATION OF ADAMTS13 CROSS-REFERENCES TO RELATED ATIONS This application claims priority to US. Provisional Patent Application Serial Nos. 61/794,659 filed March 15, 2013, the disclosure of which is hereby incorporated herein by reference in its entirety for all purposes.
BACKGROUND OF THE ION The ADAMTS (a disintegrin and metalloproteinase with thrombospondin type I motifs) proteins are a family of metalloproteinases containing number of conserved domains, including a zinc-dependant catalytic domain, a cystein-rich domain, a egrin-like domain, and at least one, and in most cases multiple, thrombospondin type I s (for review, see Nicholson et al., BMC Evol Biol. 2005 Feb. 4; 5(1): 1 1). These proteins, which are evolutionarily d to the ADAM and MMP families of metalloproteinases (Jones G C, Curr Pharm Biotechnol. 2006 February ;7(1):25-31), are secreted enzymes that have been linked to a number of diseases and conditions including thrombotic thrombocytopenic purpura (TTP) (Moake J L, Semin l. 2004 January ;41(1):4-14), connective tissue disorders, cancers, inflammation (Nicholson et al.), and severe plasmodium falciparum malaria (Larkin et al., PLoS Pathog. 2009 March ;5(3):e1000349). Because of these associations, the ADAMTS enzymes have been recognized as potential eutic targets for a number of pathologies (Jones G C, Curr Pharm hnol. 2006 February;7(1):25-31).
One ADAMTS family member, ADAMTSl3, cleaves von Willebrand factor (vWF) between residues Tyr 1605 and Met 1606. Loss ofADAMTSl3 activity has been linked to a number of conditions, such as TTP (Moake J L, Semin Hematol. 2004 January ;41(1):4-14), acute and chronic inflammation (Chauhan et al., J Exp Med. 2008 Sep. 1 ;205(9):2065-74), and most recently, severe plasmodium falciparum malaria (Larkin et al., PLoS Pathog. 2009 (3):e1000349).
Thrombotic thrombocytopenic a (TTP) is a er characterized by thrombotic microangiopathy, thrombocytopenia and microvascular thrombosis that can cause various degrees of tissue ischemia and infarction. Clinically, TTP patients are diagnosed by ms such as thrombocytopenia, schistocytes ents of erythrocytes) and ed levels of lactate dehydrogenase (Moake J L. Thrombotic microangiopathies. N Engl J Med. 2002 ; 347:5 89-600; Moake J L. von Willebrand factor, ADAMTS-l3, and thrombotic thrombocytopenic purpura. Semin Hematol. 2004 ; 41:4-14; Sadler J E, Moake J L, Miyata T, George J N. Recent advances in thrombotic thrombocytopenic purpura. Hematology (Am Soc Hematol Educ Program). 2004 : 407-423; Sadler J E. New concepts in von Willebrand disease.
Annu Rev Med. 2005; 56:173-l9l).
There are two major types of TTP: ed (noninherited/idopathic) and familial (inherited) (Tsai H M, Lian E C. Antibodies to von Willebrand -cleaving protease in acute thrombotic thrombocytopenic purpura. N Engl J. Med. 1998; 339: 1585-1594; Furlan M, Lammle B. Deficiency of von Willebrand factor-cleaving protease in familial and acquired thrombotic thrombocytopenic purpura. Baillieres Clin Haematol. 1998; 11:509-514). Genetic mutations in the ADAMTSl3 gene cause the familial form of TTP s people with acquired TTP do not have the mutations. Rather, acquired TTP is terized by the production of specific antibodies.
In 1982, Moake et al. found unusually large von Willebrand factor (UL-vWF) ers in the plasma of the patients with chronic relapsing TTP (Moake J L, Rudy C K, Troll J H, Weinstein M J, Colannino N M, Azocar J, Seder R H, Hong S L, Deykin D. Unusually large plasma factor VIII:von Willebrand factor multimers in chronic relapsing thrombotic thrombocytopenic purpura. N Engl J Med. 1982 ; 307: 435). The link between UL-vWF and TTP gained support with independent findings by Furlan et al. and Tsai and Lian that most patients suffering from TTP are deficient in a plasma metalloprotease, now known to be ADAMTSl3, that s vWF (Furlan M, Robles R, Solenthaler M, Wassmer M, Sandoz P, Laemmle B. Deficient activity of von Willebrand factor-cleaving protease in chronic relapsing thrombotic thrombocytopenic purpura. Blood. 1997 ; 89:3097-3103; Tsai H M, Sussman, I I, Ginsburg D, Lankhof H, Sixma J J, Nagel R L. Proteolytic cleavage of recombinant type 2A von Willebrand factor mutants R834W and R834Q: inhibition by doxycycline and by monoclonal antibody VP-l. Blood. 1997 ; 89: 1954-1962; Tsai H M, Lian E C. Antibodies to von Willebrand WO 51968 factor-cleaving protease in acute thrombotic thrombocytopenic purpura. N Engl J Med. 1998 ; 339:1585-1594).
The 13 protease is a 190 kDa glycosylated protein produced predominantly by the liver (Levy G G, Nichols W C, Lian E C, Foroud T, McClintick J N, McGee B M, Yang A Y, Siemieniak D R, Stark K R, Gruppo R, Sarode R, Shurin S B, Chandrasekaran V, Stabler S P, Sabio H, Bouhassira E E, Upshaw J D, Jr., Ginsburg D, Tsai H M. Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura. . 2001 ; 413 :488-494; Fujikawa K, Suzuki H, McMullen B, Chung D. ation of human von Willebrand factor-cleaving protease and its identification as a new member of the metalloproteinase family. Blood. 2001 ; 98: 1662-1666; Zheng X, Chung D, Takayama T K, s E M, Sadler J E, Fujikawa K. Structure of von Willebrand factor- cleaving protease (ADAMTS13), a metalloprotease involved in thrombotic thrombocytopenic purpura. J Biol Chem. 2001 ; 276:41059-41063; Soejima K, Mimura N, Hirashima M, Maeda H, Hamamoto T, Nakagaki T, Nozaki C. A novel human metalloprotease synthesized in the liver and secreted into the blood: possibly, the von Willebrand factor-cleaving protease; J Biochem (Tokyo). 2001 ; 130:475-480; Gerritsen H E, Robles R, Lammle B, Furlan M. Partial amino acid ce of purified von Willebrand factor-cleaving protease. Blood. 2001 ; 98: 1654-1661).
Mutations in the ADAMTS13 gene have been shown to cause TTP (Levy G G, Nichols W C, Lian E C, Foroud T, McClintick J N, McGee B M, Yang A Y, niak D R, Stark K R, Gruppo R, Sarode R, Shurin S B, Chandrasekaran V, Stabler S P, Sabio H, Bouhassira E E, Upshaw J D, Jr., Ginsburg D, Tsai H M. Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura. Nature. 2001 ; 413 :488- 494). Idiopathic TTP, often caused by autoantibodies inhibiting ADAMTS-13 activity, is a more common disorder that occurs in adults and older children and can recur at regular intervals in 11- 36% of patients (Tsai H M, Lian E C. Antibodies to von Willebrand -cleaving protease in acute thrombotic thrombocytopenic purpura. N Engl J Med. 1998 ; 339: 1585-1594; Furlan M, Lammle B. Deficiency ofvon Willebrand -cleaving protease in al and acquired thrombotic thrombocytopenic purpura. Baillieres Clin Haematol. 1998 ; 11:509-514).
Non neutralizing autoantibodies could also inhibit ADAMTS activity by inducing nce from circulation (Scheiflinger F, Knobl P, Trattner B, Plaimauer B, Mohr G, Dockal M, Domer F, Rieger M. Nonneutralizing IgM and IgG antibodies to von Willebrand factor- cleaving protease (ADAMTS-13) in a patient with thrombotic thrombocytopenic purpura. Blood. 2003 ; 102:3241-3243). Plasma ADAMTS13 activity in healthy adults ranges from 50% to 178% (Moake J L. Thrombotic thrombocytopenic purpura and the hemolytic uremic syndrome. Arch Pathol Lab Med. 2002 ; 126: 1430-1433). In most patients with familial or acquired TTP, plasma ADAMTS13 activity is absent or less than 5% of the . Without treatment the mortality rate exceeds 90%, but plasma therapy has reduced mortality to about 20% (Moake J L.
Thrombotic thrombocytopenic purpura and the tic uremic syndrome. Arch Pathol Lab Med. 2002; 126:1430-1433). vWF synthesized in megakaryocytes and endothelial cells is stored in platelet-- granules and Weibel-Palade bodies, respectively, as ultra large vWF (UL-VWF) (Moake J L, Rudy C K, Troll J H, Weinstein M J, Colannino N M, Azocar J, Seder R H, Hong S L, Deykin D. Unusually large plasma factor VIII:von Willebrand factor multimers in chronic relapsing thrombotic thrombocytopenic purpura. N Engl J Med. 1982 ; 307: 1432-1435; Wagner D D, d J B, Marder V J. localization of von Willebrand protein in Weibel-Palade bodies of human elial cells. J Cell Biol. 1982; 95:355-360; Wagner D D, Bonfanti R. von rand factor and the endothelium. Mayo Clin Proc. 1991 ; 66:621-627; Spom L A, Marder V J, Wagner D D. von Willebrand factor released from Weibel-Palade bodies binds more avidly to extracellular matrix than that ed constitutively. Blood. 1987 ; 69: 153 1-1534; Tsai H M, Nagel R L, Hatcher V B, Sussman, I I. Endothelial cell-derived high molecular weight von Willebrand factor is converted into the plasma multimer pattern by granulocyte proteases.
Biochem Biophys Res . 1989 ; 158:980-985; Tsai H M, Nagel R L, Hatcher V B, n, I I. Multimeric composition of endothelial cell-derived von Willebrand factor. Blood. 1989 ; 73:2074-2076). Once secreted from endothelial cells, these UL-vWF multimers are cleaved by ADAMTS13 in circulation into a series of smaller multimers at specific cleavage sites within the vWF molecule (Tsai H M, Nagel R L, Hatcher V B, Sussman, I I. Endothelial cell-derived high molecular weight von Willebrand factor is converted into the plasma er pattern by granulocyte proteases. Biochem Biophys Res Commun. 1989 ; 158:980-985; Dent J 2014/026747 A, Galbusera M, Ruggeri Z M. Heterogeneity of plasma von Willebrand factor multimers resulting from proteolysis of the constituent subunit. J Clin Invest. 1991 ; 88:774-782; Furlan M, Robles R, Affolter D, Meyer D, Baillod P, Lammle B. Triplet structure of von Willebrand factor reflects proteolytic degradation of high molecular weight multimers. Proc Natl Acad Sci USA. 1993 ; 90:7503-7507).
ADAMTS13 cleaves at the Tyr842-Met843 bond in the central A2 domain of the mature vWF t and requires zinc or m for activity (Dent J A, Berkowitz S D, Ware J, Kasper C K, i Z M. Identification of a cleavage site directing the immunochemical ion of molecular abnormalities in type IIA von Willebrand factor. Proc Natl Acad Sci USA. 1990 ; 87:6306-6310). VWF exists in "ball-of—yam" and filamentous form as seen by electron microscopy (Slayter H, Loscalzo J, Bockenstedt P, Handin R 1. Native conformation of human von Willebrand protein. Analysis by electron microscopy and quasi-elastic light scattering. J Biol. Chem. 1985 ; 260:8559-8563). Furthermore, atomic force microscopy confirms that VWF exits in a globular conformation under static conditions and an unfolded filamentous state after re to shear stress (Siedlecki C A, Lestini B J, Kottke-Marchant K K, Eppell S J, Wilson D L, Marchant R E. Shear-dependent changes in the dimensional structure of human von Willebrand factor. Blood. 1996 ; 88:2939-2950). This could occur also in vivo when one end of the VWF filament is anchored to a surface.
Thrombi of TTP patients consist of little fibrin and mainly ofvWF and platelets, suggesting VWF-mediated platelet aggregation as a cause of thrombosis (Asada Y, Sumiyoshi A, Hayashi T, Suzumiya J, Kaketani K. Immunohistochemistry of vascular lesion in thrombotic ocytopenic purpura, with special nce to factor VIII related antigen. Thromb Res. 1985 ; 38:469-479). ts with relapsing TTP have large multimers in the plasma. The UL-vWF multimers accumulate over time because the persistence of the inhibitor (Anti- ADAMTS 13 Ab) decreases ADAMTS13 activity. The UL-vWF multimers are hyperactive and unfold as a result of shear stress causing et aggregation, resulting in intravascular thrombosis (Tsai H M. Von Willebrand factor, ADAMTS13, and otic thrombocytopenic purpura. J Mol Med. 2002 ; 80:639-647; Tsai H M. Deficiency TS-13 in thrombotic and thrombocytopenic purpura. J Thromb Haemost. 2003; 1:203 8-2040; discussion 2040-2035).
It is believed that the presence of reactive UL-vWF multimers in the plasma due to ADAMTSl3 deficiency could be ated with an increased risk of arterial thrombosis linked to ry heart disease. Furthermore, ADAMTSl3 has been linked to cerebral infarction, myocardial infarction, ischemic/reperfusion injury, deep vein thrombosis, and disseminated intravascular coagulation. Accordingly, there is a need for pharmaceutical formulations ofADAMTSl3 proteins suitable for the treatment of various diseases and conditions associated with ADAMTSl3 and VWF dysfilnction.
However, pharmaceutical ations comprising very large and labile molecules such as l3 can generally only be administered intravenously. This is because such pharmaceutical ations normally exhibit a very low bioavailablity due to insufficient absorption and severe degradation when given subcutaneously, intramuscularly, and ermally. Accordingly, due to the low bioavailability, large and labile proteins are normally administered enously to provide direct availability to the blood stream.
While ADAMTSl3 can be administered intravenously to treat various diseases and conditions associated with ADAMTSl3 and VWF dysfilnction, it is inconvenient and not easy for patients to handle. Particularly, ADAMTSl3 formulations are often stered regularly throughout a t’s life. For example, patients with familial (inherited) TTP begin treatment with intravenous l3 in their first year of life. Accordingly, it would be advantageous to subcutaneously administer a pharmaceutical composition ofADAMTSl3.
However, low bioavailabilities of subcutaneously administered large and labile protein formulations has prevented the development of such subcutaneous formulations.
Previous studies have reported that certain ation factors VII, VIII, and IX that are suitable for subcutaneous administration. For example, PCT/SE95/00348 reports a Factor VIII formulation that is highly purified that contains additives such as hydrolyzed gelatin, hyaluronic acid, and soybean oil emulsion. The purification and additives allowed for the Factor VIII formulation to be highly concentrated. This highly concentrated formulation resulted in a ilability of at least about 15% and ly at least about 30% after subcutaneous, intramuscular, or intradermal administration compared to the bioavailability after intravenous administration. r, 15-30% bioavailability of subcutaneous administration compared to 2014/026747 intravenous administration is still very low and would not be ive at treating ADAMTSl3 disorders.
Furthermore, the prior studies do not provide a general principle for subcutaneous administration of large and labile ns. , prior studies present evidence of that it is subcuntaneous ceutical compositions of large and labile proteins are difficult to prepare because the compositions lack the requisite bioavailability for aneous administration.
Described herein is a method of subcutaneously administering an ADAMTSl3 ation to a treat a disease or condition associated with ADAMTSl3 and VWF dysfilnction.
Specifically, evidence of the unexpectedly high ilability, up to approximately 70%, of ADAMTSl3 ations administered subcutaneously is provided herein.
BRIEF SUMMARY OF THE INVENTION In one aspect, the present disclosure provides a method for treating a blood clotting disorder in a mammal, the method sing subcutaneously administering a therapeutically effective amount of a composition comprising isolated ADAMTSl3 to the mammal in need thereof, wherein the therapeutically effective amount ofADAMTSl3 comprises -4000 actiVity units per kilogram.
In one embodiment of the methods ed herein, the ng disorder is selected from the group consisting of inherited TTP, acquired TTP, cerebral infarction, myocardial infarction. ischemic/reperfusion injury, deep vein thrombosis, and sepsis-related disseminated intravasular coagulation.
In one embodiment of the methods provided herein, the bioavailability of the ADAMTSl3 after subcutaneous administration is 50-80% as compared to intravenous administration normalized for the same dose.
In one embodiment of the methods provided herein, the bioavailability of the ADAMTSl3 after subcutaneous administration is at least 50% as compared to intravenous stration normalized for the same dose.
In one ment of the methods provided herein, the bioavailability of the ADAMTSl3 after subcutaneous administration is at least 55% as compared to intravenous administration normalized for the same dose.
In one embodiment of the methods ed herein, the bioavailability of the ADAMTSl3 after subcutaneous administration is at least 60% as compared to intravenous administration normalized for the same dose.
In one embodiment of the methods provided herein, the bioavailability of the ADAMTSl3 after subcutaneous administration is at least 65% as compared to enous administration ized for the same dose.
In one embodiment of the s provided herein, the bioavailability of the ADAMTSl3 after subcutaneous administration is at least 70% as compared to enous administration normalized for the same dose.
In one embodiment of the methods provided herein, the ilability of the ADAMTSl3 after subcutaneous administration is at least 75% as compared to intravenous administration normalized for the same dose.
In one ment of the methods provided herein, the ilability of the ADAMTSl3 after subcutaneous administration is at least 80% as compared to intravenous administration normalized for the same dose.
In one embodiment of the methods provided herein, the bleeding episode is inherited TTP.
In one embodiment of the methods provided herein, the therapeutically effective amount comprises at least 20-160 activity units per kilogram.
In one embodiment of the methods ed herein, the bleeding episode is acquired TTP.
In one embodiment of the methods provided herein, the therapeutically effective amount comprises at least 40-2000 activity units per kilogram.
] In one embodiment of the methods provided herein, the bleeding episode is cerebral tion and/or ischemia reperfilsion injury.
In one ment of the s provided herein, the therapeutically effective amount comprises at least 40-4000 activity units per kilogram In one embodiment of the methods provided herein, the bleeding episode is dial infarction and/or ischemia reperfilsion injury.
In one embodiment of the methods provided , the therapeutically effective amount comprises at least 40-2000 activity units per kilogram.
In one ment of the methods provided herein, the l3 is administered in a single bolus injection, monthly, every two weeks, weekly, twice a week, daily, every 12 hours, every 8 hours, every six hours, every four hours, or every two hours.
In one embodiment of the methods provided herein, the ADAMTSl3 is recombinant.
In one embodiment of the methods provided herein, the ADAMTSl3 is plasma derived.
In one embodiment of the methods provided herein, the mammal is a human.
In one embodiment of the methods provided herein, the composition is a stable aqueous solution ready for administration.
In one embodiment of the methods provided herein, the composition is lyophilized.
In one embodiment of the methods provided herein, the composition is reconstituted with a pharmaceutically able vehicle suitable for injection.
In one aspect, the t disclosure provides a method for treating a bleeding episode in a mammal, the method comprising aneously administering a therapeutically effective amount of a composition sing isolated ADAMTSl3 to the mammal in need thereof, wherein the therapeutically effective amount ofADAMTSl3 comprises at least 120- 300% of the amount of a rd intravenous dose for a specific indication as measured in activity units per kilogram.
In one embodiment of the methods ed herein, the specific indication is inherited TTP and the standard intravenous dose is 10-80 activity units per kilogram.
In one ment of the methods ed herein, the specific indication is acquired TTP and the standard intravenous dose is 20-1000 activity units per kilogram.
In one embodiment of the methods provided , the specific indication is myocardial infarction and/or ischemia reperfiasion injury and the standard enous dose is 20- 2000 activity units per kilogram.
In one embodiment of the methods provided herein, the specific tion is cerebral infarction and/or ischemia reperfiasion injury and the standard intravenous dose is 20- 2000 activity units per kilogram.
In one embodiment of the methods provided , the bioavailability of the ADAMTSI3 after subcutaneous administration is 50-80% as compared to intravenous stration normalized for the same dose.
In one embodiment of the methods provided herein, the bioavailability of the ADAMTSl3 after subcutaneous administration is at least 50% as compared to intravenous administration normalized for the same dose.
In one embodiment of the methods provided herein, the bioavailability of the l3 after aneous administration is at least 55% as compared to intravenous administration normalized for the same dose.
In one embodiment of the methods provided herein, the bioavailability of the ADAMTSl3 after subcutaneous administration is at least 60% as ed to intravenous administration normalized for the same dose.
In one embodiment of the methods provided herein, the bioavailability of the ADAMTSl3 after subcutaneous administration is at least 65% as compared to intravenous administration normalized for the same dose.
In one ment of the s provided , the bioavailability of the ADAMTSl3 after subcutaneous administration is at least 70% as compared to intravenous administration normalized for the same dose.
In one embodiment of the methods provided herein, the bioavailability of the ADAMTSl3 after subcutaneous administration is at least 75% as compared to enous administration normalized for the same dose.
In one ment of the methods provided herein, the bioavailability of the ADAMTSl3 after subcutaneous administration is at least 80% as compared to intravenous administration normalized for the same dose.
In one embodiment of the methods provided herein, the ADAMTSI3 is administered in a single bolus injection, monthly, every two weeks, weekly, twice a week, daily, every 12 hours, every 8 hours, every six hours, every four hours, or every two hours.
In one embodiment of the methods provided herein, the I3 is recombinant.
In one embodiment of the methods provided herein, the ADAMTSI3 is plasma derived.
] In one embodiment of the methods provided herein, the mammal is a human.
In one embodiment of the methods provided herein, the composition is a stable aqueous solution ready for administration.
In one embodiment of the methods ed , the composition is lyophilized.
] In one embodiment of the methods provided herein, the composition is reconstituted with a pharmaceutically acceptable vehicle suitable for injection.
BRIEF DESCRIPTION OF THE DRAWINGS FIG 1. Figure 1 shows the mean plasma concentrations ofADAMTSl3 acitivity.
Median Tmax after so. stration was 24h for l3 ty.
FIG 2. Figure 2 shows the mean plasma trations ofADAMTSl3 acitivity.
Median Tmax after so. administration was 28h for ADAMTSl3 antigen ] FIG 3. Figure 3 shows observed (circles) and predicted concentrations (solid lines) for individual animals. Concentrations following i.v. administration were fitted using a two-compartmental model whereas concentrations following s.c. stration were fitted using a one-compartmental model with first-order absorption and first order elimination. Both models were modified by ion of an additional ate to model the assumed constant endogenous ADAMTS l 3 activity.
FIG 4. Figure 4 shows the concentrations observed adjusted for borderline values and corresponding ted concentrations for individual animals. Concentrations following i.v. administration were predicted using a two-compartmental model whereas concentrations following s.c. administration were predicted using a one-compartmental model with first-order absorption and first-order elimination.
DETAILED DESCRIPTION OF THE INVENTION 1. INTRODUCTION ADAMTSl3 (A13) is a plasma metalloprotease which cleaves von Willebrand factor (VWF) multimers and down tes their activity in platelet aggregation. ADAMTSl3 is associated clotting disorders such as inherited thrombotic thrombocytopenic purpura (TTP), acquired TTP, cerebral infarction, myocardial infarction, ischemic/reperfusion injury, deep vein thrombosis, and disseminated intravascular coagulation (DIC) such as sepsis-related DIC.
Current treatment of these clotting disorders involves intravenous administration Sl3 formulations. Treatment is currently limited to intravenous administration because ADAMTSl3 is a large protein and large proteins are generally not stable in formulations with high bioavailabilities suitable for subcutaneous administration. The mature ADAMTSl3 has a ated molecular mass of about 145 kDa whereas d plasma-derived ADAMTSl3 has an apparent molecular mass of about 180 kDa probably due to post-translational modifications consisting with present consensus ces for 10 potential N-glycosylation sites, and l O-glycosylation sites and one C-mannosylation site in the TSPl repeats. ns and molecules that are large and labile such as ADAMTSl3, are generally limited to intravenous administration due to the low bioavailability of the formulations when administered subcutaneously. For example, previous studies report that Factor VIII, a 170 to 300kDa protein, is typically administered intravenously because Factor VIII ations normally exhibit a very low bioavailability due to insufficient absorption and severe degradation when administered subcutaneously, intramuscularly or intradermally. See PCT/SE95/00348.
For e, it has been reported that Factor VIII concentrate injected intramuscularly d a maximum circulating level of only 1.4% of the normal plasma level with and without sodium e as an additive to used to prevent degradation and increase absorption (Pool et al, New England J. Medicine, vol. 275, no. 10, p. 547-548, 1966). The s further revealed that there was no significant difference in the activity recovered in the circulation regardless of whether such citrate was added to the preparation. In a later study, a high-purity factor VIII was administered intramuscularly to haemophilic dogs and human eers on et al, Br. J. Hematology, vol. 21, p. 21-41, 1971). Although, the doses were much larger than used by Pool et al., neither the dogs nor the human volunteers showed a significant rise in plasma factor VIII levels. In fact, the plasma factor VIII concentration in the haemophilic human volunteers remained below 1% of the normal plasma level, i.e. the severe haemophilia A prevailed even after stration in the absence of additives increasing the bioavailability.
There has been some success at subcutaneous delivery of small proteins such as Factor IX that do not degrade and aggregate like large, labile proteins such as Factor VIII and 2014/026747 ADAMTSl3. For e, subcutaneous administration of factor IX without additives is known from Berettini et al., “Subcutaneous factor IX administration to ts with hemophilia B,” Am. J. Hematology, 47(1):6l-62, 1994. r, even Factor IX, which is only 56 kDa, exhibited poor and very slow transport into the circulation.
Due to the low bioavailability of proteins such as Factors VIII and IX as described above, s of subcutaneous delivery of large and labile proteins are not generally pursued.
Rather, such proteins are normally given intravenously so that the formulation is directly available in the blood stream. It would however be advantageous if a ment could be given subcutaneously because subcutaneous administration is a minimally invasive mode of administration. Subcutaneous administration is also the most versatile mode of administration that can be used for short term and long term therapies. Subcutaneous administration can be performed by injection or by implantation of a sustained or timed release device beneath the surface of the skin. The site of the injection or device can be rotated when multiple injections or devices are needed.
Accordingly, subcutaneous formulations much easier to handle for the patient, especially since the formulation may have to be taken rly during the whole life (e.g., starting as early as a child’s first year of life). Furthermore, the easy and speed of subcutaneous delivery allows sed patient compliance and quicker access to medication when needed.
Thus, there is a benefit and need for aneous formulations ofADAMTSl3.
The present invention is based on the unexpected discovery of a successful method of subcutaneously administering liquid and lyophilized formulations of purified ADAMTS proteins.
II. DEFINITIONS ] As used herein, "ADAMTSl3" or "A13" refer to a metalloprotease of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin type I motifs) family that cleaves von Willebrand factor (vWF) between residues Tyr 1605 and Met 1606. In the context of the present ion, an “ADAMTSl3 protein” embraces any ADAMTSl3 protein, for example, ADAMTSl3 from a mammal such as a e, human (NP6205 94), monkey, rabbit, pig, bovine (XP610784), rodent, mouse (NP001001322), rat (XP3423 96), hamster, gerbil, canine, feline, frog (NP001083331), chicken (XP415435), and biologically active derivatives f. As used herein, “ADAMTS13 proteins” refer to recombinant and plasma derived 13 proteins. Mutant and variant ADAMTS13 ns having activity are also embraced, as are functional fragments and fusion proteins of the ADAMTS13 proteins.
Furthermore, the ADAMTS13 proteins of the invention may r comprise tags that facilitate purification, detection, or both. The ADAMTS13 proteins described herein may r be modified with a therapeutic moiety or a moiety suitable imaging in vitro or in vivo.
Human ADAMTS13 proteins include, t limitation, polypeptides comprising the amino acid sequence of GenBank accession number NP 620594 or a processed polypeptide thereof, for example a ptide in which the signal peptide (amino acids 1 to 29) and/or propeptide (amino acids 30-74) have been removed. Many natural variants of human ADAMTS13 are known in the art, and are embraced by the formulations of the present invention, some of which include mutations selected from R7W, V88M, H96D, R102C, R193W, T1961, H234Q, A250V, R268P, W390C, R398H, Q448E, Q456H, P457L, P475S, C508Y, R528G, P6 1 8A, R625H, I673F, R692C, A732V, E740K, A900V, S903L, C908Y, C951G, G982R, C1024G, A1033T, R1095W, R1095W, R1 l23C, Cl2l3Y, Tl226l, G1239V, and R1336W. Additionally, ADAMTS13 ns include natural and recombinant proteins that have been mutated, for example, by one or more conservative mutations at a non-essential amino acid.
Preferably, amino acids essential to the enzymatic activity ofADAMTS13 will not be d.
These include, for example, residues known or presumed to be essential for metal g such as residues 83, 173, 224, 228, 234, 281, and 284, and residues found in the active site of the enzyme, e.g., residue 225. Similarly, in the context of the present invention, ADAMTS13 ns include alternate isoforms, for example, isoforms lacking amino acids 275 to 305 and/or 1 135 to 1 190 of the filll-length human protein.
Likewise, ADAMTS13 proteins may be further modified, for e, by post- translational modifications (e. g., glycosylation at one or more amino acids selected from human residues 142, 146, 552, 579, 614, 667, 707, 828, 1235, 1354, or any other natural or engineered modification site) or by ex vivo chemical or tic modification, including without limitation, glycosylation, modification by water soluble polymer (e. g., PEGylation, sialylation, HESylation, etc.), tagging, and the like.
As used , “blood clotting disorder” is defined as a disorder that includes dysfianctional platelet recruitment as well as dysfunctional neutrophil recruitment. Non-limiting es of “blood clotting disorders” e inherited thrombotic thrombocytopenic purpura (TTP), acquired TTP, cerebral infarction, myocardial infarction, ischemic/reperfusion injury, deep vein thrombosis, and disseminated ascular coagulation (DIC) such as sepsis-related DIC.
As used herein, "one unit ofADAMTS13 activity" is defined as the amount of activity in 1 ml of pooled normal human plasma, regardless of the assay being used. For example, one unit ofADAMTSl3 FRETS-VWF73 activity is the amount of activity needed to cleave the same amount of FRETS-VWF73 substrate (Kokame et al., Br J ol. 2005 April ):93-100) as is cleaved by one ml of pooled normal human plasma. Additional activity assays can also be used to determine the activity of one unit ofADAMTS13. For example, direct ADAMTSl3 activity assays can be performed to detect the cleavage of either full-length VWF molecules or VWF fragments using SDS agrose gel electrophoresis and indirect ion ofADAMTS13 activity can be detected with collagen binding assays.
] As used herein, the terms "ADAMTS13" and "biologically active derivative", respectively, also include polypeptides obtained via recombinant DNA technology. atively, ADAMTS 13 can also refer to the plasma derived ADAMTS l3 purified from pooled human blood. The recombinant ADAMTSl3 ("rADAMTSl3"), e. g. recombinant human ADAMTSl3 ("r-hu-ADAMTSl3"), may be ed by any method known in the art. One specific example is disclosed in WO 41 which is incorporated herein by nce with respect to the method of producing recombinant ADAMTSl3. This may include any method known in the art for (i) the production of recombinant DNA by genetic engineering, e.g. via reverse transcription ofRNA and/or amplification of DNA, (ii) introducing recombinant DNA into prokaryotic or otic cells by transfection, i.e. via electroporation or microinj ection, (iii) cultivating said transformed cells, e.g. in a continuous or batchwise manner, (iv) expressing ADAMTSl3, e.g. constitutively or upon induction, and (v) isolating said ADAMTSl3, e.g. from the culture medium or by harvesting the transformed cells, in order to (vi) obtain substantially purified recombinant ADAMTSl3, e.g. via anion exchange chromatography or affinity chromatography. The term "biologically active derivative" includes also ic molecules such as, e.g. ADAMTSl3 (or a biologically active derivative thereof) in combination with Ig, in order to improve the biological/pharmacological properties such as, e. g. half life ofADAMTSl3 in the circulation system of a , particularly human. The Ig could have also the site of binding to an optionally mutated Fc receptor.
As used herein, the term "thrombus" refers to a blood clot, especially a platelet- comprising blood clot, a microthrombus, and/or an embolus. Said thrombus may be attached to an arterial or venous blood vessel or not, and may partially or completely block the blood flow in an arterial or venous blood vessel.
As used herein, a "therapeutically effective amount or dose" or "sufficient amount or dose" refers to a dose that produces s for which it is administered. The exact dose will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e. g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding ; Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of cy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).
As used herein, a "physiological concentration" of salt refers to a salt concentration of n about 100 mM and about 200 mM of a pharmaceutically acceptable salt. Non-limiting examples of pharmaceutically acceptable salts include, without limitation, sodium and potassium chloride, sodium and potassium acetate, sodium and potassium e, sodium and potassium phosphate.
As used herein, a hysiological tration" of salt refers to a salt concentration of less than about 100 mM of a pharmaceutically acceptable salt. In red embodiments, a sub-physiological tration of salt is less than about 80 mM of a pharmaceutical salt. In another preferred ment, a sub-physiological concentration of salt is less than about 60 mM of a pharmaceutical salt.
As used herein, the term "about" denotes an approximate range of plus or minus % from a specified value. For instance, the language "about 20%" encompasses a range of 18- 22%. As used herein, about also includes the exact amount. Hence "about 20%" means "about %" and also "20%." III. ADAMTSI3 COMPOSITIONS AND FORMULATION In one aspect, the t invention provides stabilized formulations of plasma derived ADAMTSl3 and recombinant ADAMTSl3 (rADAMTSl3) proteins as described in US. Patent ation Publication No. 201 l/0229455. In other embodiments, the ations provided herein retain significant ADAMTSl3 activity when stored for extended periods of time.
In yet other embodiments, the formulations of the invention reduce or retard dimerization, oligomerization, and/or aggregation of an ADAMTSl3 protein.
In one embodiment, the present ion provides formulations ofADAMTSl3 comprising a therapeutically effective amount or dose of an ADAMTSl3 protein, a subphysiological to physiological concentration of a pharmaceutically acceptable salt, a stabilizing concentration of one or more sugars and/or sugar alcohols, a non-ionic surfactant, a buffering agent providing a neutral pH to the formulation, and optionally a calcium and/or zinc salt.
Generally, the stabilized ADAMTSl3 formulations ed herein are suitable for pharmaceutical administration. In a preferred embodiment, the l3 protein is human ADAMTSl3 or a biologically active tive or fragment thereof as described in US. Patent ation Publication No. 201 455.
In certain ments, the ADAMTSl3 formulations are liquid formulations. In other embodiments, the ADAMTSl3 formulations are lyophilized formulations that are lyophilized from a liquid formulation as bed in US. Patent ation Publication No. 201 l/0229455. In certain embodiments of the formulations provided herein, the ADAMTSl3 protein is a human ADAMTSl3 or recombinant human ADAMTSl3, or a biologically active derivative or fragment thereof as described in US. Patent Application Publication No. 2011/0229455.
WO 51968 In n embodiments, ADAMTSl3 is provided in a therapeutically effective dose between about 0.05 mg/mL and about 10 mg/mL. In other embodiments, ADAMTS13 is present at a tration of between about 0.1 mg/mL and about 10 mg/mL. In yet other embodiments, ADAMTSl3 is present at a concentration of between about 0.1 mg/mL and about mg/mL. In another embodiment, ADAMTSl3 is present at a concentration of between about 0.1 mg/mL and about 2 mg/mL. In yet other embodiments, ADAMTSl3 may be t at about 0.01 mg/mL, or at about 0.02 mg/mL, 0.03 mg/mL, 0.04 mg/mL, 0.05 mg/mL, 0.06 mg/mL, 0.07 mg/mL, 0.08 mg/mL, 0.09 mg/mL, 0.1 mg/mL, 0.2 mg/mL, 0.3 mg/mL, 0.4 mg/mL, 0.5 mg/mL, 0.6 mg/mL, 0.7 mg/mL, 0.8 mg/mL, 0.9 mg/mL, 1.0 mg/mL, 1.1 mg/mL, 1.2 mg/mL, 1.3 mg/mL, 1.4 mg/mL, 1.5 mg/mL, 1.6 mg/mL, 1.7 mg/mL, 1.8 mg/mL, 1.9 mg/mL, 2.0 mg/mL, 2.5 mg/mL, 3.0 mg/mL, 3.5 mg/mL, 4.0 mg/mL, 4.5 mg/mL, 5.0 mg/mL, 5.5 mg/mL, 6.0 mg/mL, 6.5 mg/mL, 7.0 mg/mL, 7.5 mg/mL, 8.0 mg/mL, 8.5 mg/mL, 9.0 mg/mL, 9.5 mg/mL, .0 mg/mL, or a higher concentration. In one embodiment, the concentration of a relatively pure ADAMTS13 formulation may be determined by spectroscopy (i.e., total n measured at A280) or other bulk determination (e.g., Bradford assay, silver stain, weight of a lyophilized powder, etc.). In other embodiments, the concentration ofADAMTS13 may be determined by an ADAMTSl3 ELISA assay (e. g., mg/mL antigen).
In yet other embodiments, the concentration ofADAMTSl3 in a formulation provided by the t invention may be expressed as a level of enzymatic activity. For example, in one embodiment an ADAMTSl3 formulation may contain between about 10 units of FRETS-VWF73 activity and about 10,000 units of FRETS-VWF73 activity or other suitable l3 enzymatic unit (IU). In other embodiments, the formulation may contain between about 20 units of FRETS-VWF73 (UFV73) ty and about 8,000 units of FRETS-VWF73 activity, or between about 30 UFV73 and about 6,000 UFV73, or between about 40 UFV73 and about 4,000 UFV73, or between about 50 UFV73 and about 3,000 UFV73, or between about 75 UFV73 and about 2,500 UFV73, or between about 100 UFV73 and about 2,000 UFV73, or between about 200 UFV73 and about 1,500 UFV73, or n about other ranges therein. In a preferred embodiment, an ADAMTS13 formulation provided herein contains between about 20 and about 10,000. UFV73.
In n embodiments, a formulation contains about 10 units of FRETS-VWF73 activity, or about 20, 30, 40, 50, 60, 70, 80, 90, 100, 150,200,250, 300, 350,400,450, 500, 600, 700, 800, 900, 1,000, 1,100, 1,200, 1,300, 1,400, 1,500, 1,600, 1,700, 1,800, 1,900, 2,000, 2,100, 2,200, 2,300, 2,400, 2,500, 2,600, 2,700, 2,800, 2,900, 3,000, 3,100, 3,200, 3,300, 3,400, 3,500, 3,600, 3,700, 3,800, 3,900, 4,000, 4,100, 4,200, 4,300, 4,400, 4,500, 4,600, 4,700, 4,800, 4,900, 5,000, ,100, 5,200, 5,300, 5,400, 5,500, 5,600, 5,700, 5,800, 5,900, 6,000, 6,100, 6,200, 6,300, 6,400, 6,500, 6,600, 6,700, 6,800, 6,900, 7,000, 7,100, 7,200, 7,300, 7,400, 7,500, 7,600, 7,700, 7,800, 7,900, 8,000, 8,100, 8,200, 8,300, 8,400, 8,500, 8,600, 8,700, 8,800, 8,900, 9,000, 9,100, 9,200, 9,300, 9,400, 9,500, 9,600, 9,700, 9,800, 9,900, 10,000 or more units ofFRETS-VWF73 activity. rly, in certain embodiments, the concentration ofADAMTS13 may be expressed as an enzymatic activity per unit volume, for example, ADAMTS13 enzymatic units per mL (IU/mL). For example, in one embodiment an ADAMTS13 formulation may contain between about 10 IU/mL and about 10,000 IU/mL. In other embodiments, the formulation may contain between about 20 IU/mL and about 10,000 IU/mL, or between about 20 IU/mL and about 8,000 IU/mL, or n about 30 IU/mL and about 6,000 IU/mL, or between about 40 IU/mL and about 4,000 IU/mL, or between about 50 IU/mL and about 3,000 IU/mL, or between about 75 IU/mL and about 2,500 IU/mL, or between about 100 IU/mL and about 2,000 IU/mL, or between about 200 IU/mL and about 1,500 IU/mL, or between about other ranges therein. In a preferred embodiment, an ADAMTS13 ation provided herein contains between about 150 IU/mL and about 600 IU/mL. In another preferred embodiment, an ADAMTS13 formulation provided herein contains between about 100 IU/mL and about 1,000 IU/mL. In certain embodiments, a formulation ns about 10 IU/mL, or about 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1,000, 1,100, 1,200, 1,300, 1,400, 1,500, 1,600, 1,700, 1,800, 1,900, 2,000, 2,100, 2,200, 2,300, 2,400, 2,500, 2,600, 2,700, 2,800, 2,900, 3,000, 3,100, 3,200, 3,300, 3,400, 3,500, 3,600, 3,700, 3,800, 3,900, 4,000, 4,100, 4,200, 4,300, 4,400, 4,500, 4,600, 4,700, 4,800, 4,900, 5,000, 5,100, 5,200, 5,300, 5,400, 5,500, ,600, 5,700, 5,800, 5,900, 6,000, 6,100, 6,200, 6,300, 6,400, 6,500, 6,600, 6,700, 6,800, 6,900, 7,000, 7,100, 7,200, 7,300, 7,400, 7,500, 7,600, 7,700, 7,800, 7,900, 8,000, 8,100, 8,200, 8,300, 8,400, 8,500, 8,600, 8,700, 8,800, 8,900, 9,000, 9,100, 9,200, 9,300, 9,400, 9,500, 9,600, 9,700, 9,800, 9,900, 10,000 or more IU/mL.
In some embodiments, the ADAMTS13 formulations provided herein may r comprise one or more pharmaceutically acceptable excipients, rs, and/or diluents as described in US. Patent Application No. 20110229455. Furthermore, in one embodiment, the ADAMTSl3 formulations provided herein will have a tonicity in a range described in as described in US. Patent ation Publication No. 2011/0229455.
In fiarther embodiments, the present invention provides formulations of ADAMTSl3 comprising the exemplary formulations described in Section III (“ADAMTSl3 Compositions and Formulations”) ofUS. Patent Application ation No. 2011/0229455.
In certain embodiments ADAMTSl3 formulations are produced and comprise the additives. The methods ofADAMTSl3 production and compositions f as described in US. Patent Application Publication No. 2011/0229455, Sections IV and V, are incorporated herein by reference.
IV. METHODS OF TREATMENT The formulations described herein can be subcutaneously administered for therapeutic or prophylactic treatments. Generally, for therapeutic applications, formulations are administered to a subject with a disease or condition associated with ADAMTSl3 or VWF dysfilnction or ise in need thereof, in a "therapeutically effective dose." ations and amounts effective for these uses will depend upon the severity of the disease or condition and the general state of the patient's health. Single or multiple strations of the formulations may be administered depending on the dosage and frequency as required and tolerated by the patient.
A nt" or "subject" for the purposes of the present invention includes both humans and other animals, particularly s. Thus the itions, formulations, and s are applicable to both human therapy and nary applications. In a particular embodiment the patient is a mammal, and in one embodiment, is a human. Other known treatments and therapies for conditions associated with ADAMTSl3 or VWF dysfilnction can be used in combination with the formulations and methods provided by the invention.
In certain ments, the subcutaneous ADAMTSl3 formulation is administered by subcutaneous injection. In specific embodiments, the subcutaneous ADAMTSl3 formulation is subcutaneously ed into the same site of a patient (e.g., stered to the upper arm, anterior surface of the thigh, lower portion of the abdomen, or upper back) for repeat or continuous injections. In other embodiments, the subcutaneous ADAMTS13 formulation is subcutaneously injected into the different or rotating sites of a patient. In certain embodiments, the subcutaneous ADAMTS13 formulation is administered by subcutaneously ted deVice. In certain embodiments, the implanted deVice provides a timed release of an ADAMTS13 formulation. In certain embodiments, the implanted deVice provides a continuous release of an ADAMTS13 formulation.
In certain embodiments, an ADAMTS13 formulation bed herein is used for the treatment and prophylaxis ofADAMTS13 and VWF dysfunction. In certain embodiments, an ADAMTS13 formulation described herein is used for the treatment and prophylaxis of otic diseases and conditions. In certain embodiments, an ADAMTS13 formulation described herein is used for the treatment and laxis of an infarction.
In one embodiment, ADAMTS13 is administered at a dose of from 20 UFV73/kg body weight to 4000 UFV73/kg body weight. In one embodiment, ADAMTS13 is administered at a dose of from 20 UFV73/kg body weight to 2000 UFV73/kg body weight. In one embodiment, 13 is administered at a dose of from 20 UFV73/kg body weight to 1000 UFV73/kg body weight. In one embodiment, ADAMTS13 is administered at a dose of from 20 UFV73/kg body weight to 500 UFV73/kg body weight. In one embodiment, 13 is administered at a dose of from 20 UFV73/kg body weight to 200 UFV73/kg body weight. In one embodiment, ADAMTS13 is administered at a dose of from 20 UFV73/kg body weight to 100 UFV73/kg body weight. In one ment, 13 is administered at a dose of from 40 UFV73/kg body weight to 200 UFV73/kg body weight. In one embodiment, ADAMTS13 is administered at a dose of from 40 kg body weight to 100 UFV73/kg body . In other ments, ADAMTS13 is administered at about 20 UFV73/kg body weight, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1,000, 1,100, 1,200, 1,300, 1,400, 1,500, 1,600, 1,700, 1,800, 1,900, 2,000, 2,100, 2,200, 2,300, 2,400, 2,500, 2,600, 2,700, 2,800, 2,900, 3,000, 3,100, 3,200, 3,300, 3,400, 3,500, 3,600, 3,700, 3,800, 3,900, 4,000 UFV73/kg body weight, or at an intermediate concentration or concentration range thereof Generally, the dose ofADAMTSl3 stered to a mammal will depend upon, among other factors, the disease or condition being d, the s of the mammal, the age of the mammal, and the overall health of the mammal. The skilled person will readily be able to translate dosages between different mammals, for example from a mouse dose to a human dose.
One means for extrapolating a human dose from an animal dose includes the use of body surface area, which is known to correlate well with several metabolic parameters, e.g., blood volume, circulating plasma, and renal fianction, in diverse mammals. Thus, a conversion factor (e.g., Km) correlating an average weight of a mammal to an average body surface area can be used to correlate a drug dosage (e.g., a dosage ofADAMTSl3), sed in units of protein (e. g., mass or ty) per body weight of the mammal (e. g., kg), used for a first type ofmammal (e. g., a mouse) with a corresponding dose in a second type ofmammal (e.g., a human). For review, see -Shaw et al., FASEB, 22:659-62 (2007). For example, this can be done by first multiplying the drug dosage administered to the first type ofmammal by the conversion factor determined for that mammal, and then ng the product by the conversion factor determined for the second type of mammal. Examples of such conversion factors are given below in Table 1, adopted from the US. Department of Health and Human Services guidelines for estimating the maximum safe starting dose in initial clinical trials for eutics in adult healthy volunteers .
Table 1. Conversion of animal doses to human equivalent doses based on body surface area.
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In certain embodiments, the bioavailability of the ADAMTSl3 after subcutaneous administration is between at least 50% and at least 80% as compared to intravenous administration normalized for the same dose. In certain embodiments, the bioavailability of the ADAMTSl3 after subcutaneous stration is between at least 60% and at least 80% as compared to intravenous administration normalized for the same dose. In certain embodiments, the bioavailability of the ADAMTSl3 after subcutaneous administration is n at least 50% and 70% as compared to intravenous administration normalized for the same dose. In certain 2014/026747 embodiments, the bioavailability of the ADAMTSl3 after subcutaneous administration is between at least 55% and 65% as compared to intravenous stration normalized for the same dose. In certain embodiments, the bioavailability of the ADAMTSl3 after subcutaneous administration is between at least 55% and 70% as compared to intravenous administration normalized for the same dose.
In certain embodiments, the bioavailability of the ADAMTSl3 after subcutaneous administration is at least 40%, or at least 45%, or at least 50%, or at least 5 l%, or at least 52%, or at least 53%, or at least 54%, or at least 55%, or at least 56%, or at least 57%, or at least 58%, or at least 59%, or at least 60%, or at least 61%, or at least 62%, or at least 63%, or at least 64%, or at least 65%, or at least 66%, or at least 67%, or at least 68%, or at least 69%, or at least 70%, or at least 71%, or at least 72%, or at least 73%, or at least 74%, or at least 75%, or at least 76%, or at least 77%, or at least 78%, or at least 79%, or at least 80%, or at least 81%, or at least 82%, or at least 83%, or at least 84%, or at least 85% as compared to intravenous administration normalized for the same dose.
] In certain embodiments, the ADAMTSl3 formulation is subcutaneously administered in a single bolus injection. In n embodiments, the ADAMTSl3 formulation is subcutaneously administered monthly. In certain embodiments, the ADAMTSl3 formulation is subcutaneously administered every two weeks. In certain embodiments, the ADAMTSl3 formulation is subcutaneously administered weekly. In certain embodiments, the ADAMTSl3 formulation is subcutaneously stered twice a week. In n embodiments, the ADAMTSl3 formulation is subcutaneously subcutaneously stered daily. In certain embodiments, the ADAMTSl3 formulation is subcutaneously administered every 12 hours. In n embodiments, the l3 formulation is subcutaneously administered every 8 hours. In certain embodiments, the ADAMTSl3 formulation is subcutaneously administered every six hours. In certain embodiments, the ADAMTSl3 formulation is subcutaneously administered every four hours. In n embodiments, the ADAMTSl3 formulation is subcutaneously administered every two hours.
In one embodiment, the ADAMTSl3 formulation is subcutaneously administered in a dose and frequency combination selected from variations 1 to 1133 in Table 2. Generally, the dose and frequency ofADAMTS13 administered to a mammal will depend upon, among other factors, the disease or condition being treated, the species of the mammal, the age of the mammal, and the overall health of the mammal.
Table 2. Useful combinations ofADAMTS13 dosage and frequency for aneous stration.
Every One ' (UFV73/kg Time Other Time body weight) Monthl Monthly Monthly Weekly Weekly Day Daily Daily Daily 516 619 722 825 928 517 620 723 826 929 1032 518 621 724 827 930 1033 519 622 725 828 931 1034 520 623 726 829 932 1035 521 624 727 830 933 1036 522 625 728 831 934 1037 523 626 729 832 935 1038 524 627 730 833 936 1039 525 628 731 834 937 1040 526 629 732 835 938 1041 527 630 733 836 939 1042 528 631 734 837 940 1043 529 632 735 838 941 1044 530 633 736 839 942 1045 531 634 737 840 943 532 635 738 841 944 533 636 739 842 945 534 637 740 843 946 535 638 741 844 947 536 639 742 845 948 1051 537 640 743 846 949 1052 538 641 744 847 950 1053 539 642 745 848 951 1054 540 643 746 849 952 1055 541 644 747 850 953 1056 60-2000 Var. 27 Var. 130 Var. 233 Var. Var. Var. 542 645 -Var. 748 851 954 1057 60-1000 Var. 28 Var. 131 Var. 234 Var. 337 Var. 440 Var. Var. Var. Var. Var. Var. 543 646 749 852 955 1058 60-750 Var. 29 Var. 132 Var. 235 Var. 338 Var. 441 Var. Var. Var. Var. Var. 544 647 750 853 956 60-500 Var. 30 Var. 133 Var. 236 Var. 339 Var. 442 Var. Var. Var. Var. Var. 545 648 751 854 957 60-250 Var. 31 Var. 134 Var. 237 Var. 340 Var. 443 Var. Var. Var. Var. Var. 546 649 855 958 60-200 Var. 32 Var. 135 Var. 238 Var. 341 Var. 444 Var. Var. Var. Var. Var. 547 650 856 959 60-150 Var. 33 Var. 136 Var. 239 Var. 342 Var. 445 Var. Var. Var. Var. Var. 548 651 857 960 60-100 Var. 34 Var. 137 Var. 240 Var. 343 Var. 446 Var. Var. Var. Var. Var. Var. 549 652 755 858 961 1064 550 653 756 859 962 1065 551 654 757 860 963 1066 -----2000 Var. 37 Var. 140 Var. 243 Var. 346 Var. 449 Var. Var. Var. Var. Var. Var. -----------1000 Var. 38 Var. 141 Var. 244 Var. 347 Var. 450 Var. Var. Var. Var. Var. Var. -----------750 Var. 39 Var. 142 Var. 245 Var. 348 Var. 451 Var. Var. Var. Var. Var. Var. -----------500 Var. 40 Var. 143 Var. 246 Var. 349 Var. 452 Var. Var. Var. Var. Var. Var. -----------250 Var. 41 Var. 144 Var. 247 Var. 350 Var. 453 Var. Var. Var. Var. Var. Var. -----------200 Var. 42 Var. 145 Var. 248 Var. 351 Var. 454 Var. Var. Var. Var. Var. Var. -----------150 Var. 43 Var. 146 Var. 249 Var. 352 Var. 455 Var. Var. Var. Var. Var. Var. -----------100 Var. 44 Var. 147 Var. 250 Var. 353 Var. 456 Var. Var. Var. Var. Var. Var. 100-4000 Var. 45 Var. 148 Var. 251 Var. 354 Var. 457 Var. Var. Var. Var. Var. Var. 100-3000 Var. 46 Var. 149 Var. 252 Var. 355 Var. 458 Var. Var. Var. Var. Var. Var. 100-2000 Var. 47 Var. 150 Var. 253 Var. 356 Var. 459 Var. Var. Var. Var. Var. Var. 563 666 769 872 975 1078 564 667 770 873 976 1079 565 668 771 874 977 1080 566 669 772 875 978 1081 567 670 773 876 979 H O 00 N 100-150 Var. 53 ------Var. Var. Var. Var. 568 671 774 877 980 H O 00 U.) 200-4000 Var. 54 Var. 157 Var. 260 Var. Var. Var. Var. 569 672 775 878 981 200-3000 Var. 55 Var. 158 Var. 261 Var. 364 Var. 467 Var. Var. Var. Var. Var. 570 673 776 879 982 200-2000 Var. 56 Var. 159 Var. 262 Var. 365 Var. 468 Var. Var. Var. Var. Var. 571 674 777 880 983 00 Var. 57 Var. 160 Var. 263 Var. 366 Var. 469 Var. Var. Var. Var. Var. 572 675 778 881 984 200-750 Var. 58 Var. 161 Var. 264 Var. 367 Var. 470 Var. Var. Var. Var. Var. 573 676 779 882 985 200-500 Var. 59 Var. 162 Var. 265 Var. 368 Var. 471 Var. Var. Var. Var. Var. 574 677 780 883 986 200-250 Var. 60 Var. 163 Var. 266 Var. 369 Var. 472 Var. Var. Var. Var. Var. 575 678 781 884 987 400-4000 Var. 61 Var. 164 Var. 267 Var. 370 Var. 473 Var. Var. Var. Var. Var. 576 679 782 885 988 577 680 783 886 989 1092 578 681 784 887 990 1093 -----------1000 Var. 64 Var. 167 Var. 270 Var. 373 Var. 476 Var. Var. Var. Var. Var. Var. -----------750 Var. 65 Var. 168 Var. 271 Var. 374 Var. 477 Var. Var. Var. Var. Var. Var. -----------500 Var. 66 Var. 169 Var. 272 Var. 375 Var. 478 Var. Var. Var. Var. Var. Var. -----------4000 Var. 67 Var. 170 Var. 273 Var. 376 Var. 479 Var. Var. Var. Var. Var. Var. -----------3000 Var. 68 Var. 171 Var. 274 Var. 377 Var. 480 Var. Var. Var. Var. Var. Var. -----------2000 Var. 69 Var. 172 Var. 275 Var. 378 Var. 481 Var. Var. Var. Var. Var. Var. -----------1000 Var. 70 Var. 173 Var. 276 Var. 379 Var. 482 Var. Var. Var. Var. Var. Var. -----750 Var. 71 Var. 174 Var. 277 Var. 380 Var. 483 Var. Var. Var. Var. Var. Var. 1000-4000 Var. 72 Var. 175 Var. 278 Var. 381 Var. 484 Var. Var. Var. Var. Var. Var. 1000-3000 Var. 73 Var. 176 Var. 279 Var. 382 Var. 485 Var. Var. Var. Var. Var. Var. 1000-2000 Var. 74 Var. 177 Var. 280 Var. 383 Var. 486 Var. Var. Var. Var. Var. Var. 590 693 796 899 1002 1105 591 694 797 900 1003 1106 592 695 798 901 1004 1107 593 696 799 902 1005 1108 594 697 800 903 1006 1109 60::10% Var. 80 ------Var. Var. Var. Var. 595 698 801 904 1007 ._. ._. ._. O % Var.81Var.184 Var. 287 ---Var. Var. Var. Var. 596 699 802 905 1008 3§>—‘>—~: H. 100::10% Var. 82 Var. 185 Var. 288 Var. 391 Var. 494 Var. Var. Var. Var. Var. .3 597 700 803 906 1009 0% Var. 83 Var. 186 Var. 289 Var. 392 Var. 495 Var. Var. Var. Var. Var. 598 701 804 907 1010 200::10% Var. 84 Var. 187 Var. 290 Var. 393 Var. 496 Var. Var. Var. Var. Var. 599 702 805 908 101 1 250::10% Var. 85 Var. 188 Var. 291 Var. 394 Var. 497 Var. Var. Var. Var. Var. 600 703 806 909 1012 300::10% Var. 86 Var. 189 Var. 292 Var. 395 Var. 498 Var. Var. Var. Var. Var. 601 704 807 910 1013 350::10% Var. 87 Var. 190 Var. 293 Var. 396 Var. 499 Var. Var. Var. Var. Var. 602 705 808 91 1 1014 400::10% Var. 88 Var. 191 Var. 294 Var. 397 Var. 500 Var. Var. Var. Var. Var. 603 706 809 912 1015 450::10% Var. 89 Var. 192 Var. 295 Var. 398 Var. 501 Var. Var. Var. Var. Var. Var. 500::10% Var. 90 Var. 193 Var. 296 Var. 399 Var. 502 Var. Var. Var. Var. 606 709 812 915 1018 1121 607 710 813 916 1019 1122 ------------800::10% Var. 93 Var. 196 Var. 299 Var. 402 Var. 505 Var. Var. Var. Var. Var. Var. ------------900::10% Var. 94 Var. 197 Var. 300 Var. 403 Var. 506 Var. Var. Var. Var. Var. Var. ------------1000::10% Var. 95 Var. 198 Var. 301 Var. 404 Var. 507 Var. Var. Var. Var. Var. Var. ------------1250::10% Var. 96 Var. 199 Var. 302 Var. 405 Var. 508 Var. Var. Var. Var. Var. Var. ------------1500::10% Var. 97 Var. 200 Var. 303 Var. 406 Var. 509 Var. Var. Var. Var. Var. Var. ------------1750::10% Var. 98 Var. 201 Var. 304 Var. 407 Var. 510 Var. Var. Var. Var. Var. Var. 2000::10% Var. 99 Var. 202 Var. 305 Var. 408 Var. 511 Var. Var. Var. Var. Var. Var. 2500::10% Var. Var. 203 Var. 306 Var. 409 Var. 512 Var. Var. Var. Var. Var. Var. 3000::10% Var. Var. 204 Var. 307 Var. 410 Var. 513 Var. Var. Var. Var. Var. Var. 3500::10% Var. Var. 205 Var. 308 Var. 411 Var. 514 Var. Var. Var. Var. Var. Var. 102 617 720 823 926 1029 1132 4000::10% Var. Var. 206 Var. 309 Var. 412 Var. 515 Var. Var. Var. Var. Var. Var. 103 618 721 824 927 1030 1133 In certain embodiments, about 120-300% of the amount of a standard intravenous dose of an ADAMTS13 formulation for a specific tion as measured in activity units per kilogram is administered subcutaneously. In a specific embodiment, about 120% of the amount of a standard intravenous dose of an ADAMTS13 formulation for a specific indication as measured in activity units per kilogram is administered subcutaneously. In a specific embodiment, about 130% of the amount of a standard intravenous dose of an ADAMTS13 formulation for a specific indication as measured in activity units per kilogram is administered subcutaneously. In a specific embodiment, about 140% of the amount of a standard intravenous dose of an ADAMTS13 formulation for a specific indication as measured in activity units per kilogram is administered subcutaneously. In a specific embodiment, about 150% of the amount of a standard intravenous dose of an ADAMTS13 formulation for a specific indication as measured in ty units per kilogram is administered subcutaneously. In a specific embodiment, about 160% of the amount of a rd intravenous dose of an ADAMTS13 formulation for a specific indication as measured in activity units per kilogram is administered subcutaneously. In a specific embodiment, about 170% of the amount of a standard intravenous dose of an 13 formulation for a specific indication as measured in ty units per kilogram is administered aneously. In a specific ment, about 180% of the amount of a standard intravenous dose of an ADAMTS13 formulation for a specific indication as measured in activity units per kilogram is stered subcutaneously. In a specific ment, about 190% of the amount of a rd enous dose of an 13 formulation for a specific indication as measured in activity units per kilogram is administered subcutaneously. 8] In a specific ment, about 200% of the amount of a standard intravenous dose of an ADAMTS13 formulation for a specific indication as ed in activity units per kilogram is administered subcutaneously. In a specific embodiment, about 210% of the amount of a standard intravenous dose of an ADAMTS13 formulation for a specific indication as measured in activity units per kilogram is administered subcutaneously. In a specific embodiment, about 220% of the amount of a standard intravenous dose of an ADAMTS13 formulation for a specific tion as measured in activity units per kilogram is administered subcutaneously. In a specific embodiment, about 230% of the amount of a standard intravenous dose of an ADAMTS13 ation for a specific indication as measured in activity units per am is administered subcutaneously. In a specific embodiment, about 240% of the amount of a standard intravenous dose of an ADAMTS13 formulation for a specific indication as measured in activity units per am is administered subcutaneously. In a specific embodiment, about 250% of the amount of a standard intravenous dose of an 13 formulation for a specific indication as measured in activity units per kilogram is administered subcutaneously. In a specific embodiment, about 260% of the amount of a standard intravenous dose of an ADAMTS13 formulation for a specific indication as measured in activity units per kilogram is administered subcutaneously. In a specific embodiment, about 270% of the amount of a standard intravenous dose of an 13 formulation for a specific indication as measured in activity units per kilogram is administered subcutaneously. In a c embodiment, about 280% of the amount of a standard intravenous dose of an ADAMTS13 formulation for a specific indication as measured in activity units per kilogram is administered subcutaneously. In a specific embodiment, about 290% of the amount of a standard enous dose of an 13 formulation for a specific indication as measured in activity units per kilogram is administered subcutaneously. In a specific ment, about 300% of the amount of a standard intravenous dose of an ADAMTS13 formulation for a specific indication as measured in activity units per kilogram is administered subcutaneously.
In n embodiments, about 120%, about 122%, about 125%, about 127%, about 130%, about 132%, about 135%, about 137%, about 140%, about 142%, about 145%, about 147%, about 150%, about 152%, about 155%, about 157%, about 160%, about 162%, about 165%, about 167%, about 170%, about 172%, about 175%, about 177%, about 180%, about 182%, about 185%, about 187%, about 190%, about 192%, about 195%, about 97%, about 200%, about 202%, about 205%, about 207%, about 210%, about 212%, about 215%, about 217%, about 220%, about 222%, about 225%, about 227%, about 230%, about 232%, about 235%, about 237%, about 240%, about 242%, about 245%, about 247%, about 250%, about 252%, about 255%, about 257%, about 260%, about 262%, about 265%, about 267%, about 270%, about 272%, about 275%, about 277%, about 280%, about 282%, about 285%, about 287%, about 290%, about 292%, about 295%, about 297%, or about 300% of the amount of a standard intravenous dose of an l3 formulation for a specific indication as measured in activity units per kilogram is administered subcutaneously.
In one embodiment, an l3 formulation is administered subcutaneously to reduce inflammation caused by the clotting disorder (e.g., an infarction), thereby preventing or reducing tissue damage (e.g., damage to the cerebral damage) and/or to reduce reperfusion injury by preventing leukocyte ration and damage. In one ment, an ADAMTSl3 formulation is administered aneously to protect against secondary injury to infarct tissue (e.g., cerebral tissue and myocardial tissue) caused by reperfusion.
INHERITED TTP In one embodiment, an ADAMTS13 formulation described herein is used for the treatment and prophylaxis of inherited TTP. Inherited TTP is due to genetic mutations of the ADAMTSl3 gene. Inherited TTP can lead to neurologic stations (e.g. mental status, , seizures, hemiplegia, paresthesias, visual disturbance, and aphasia), fatigue, and severe bleeding. If left untreated, acquired TTP can be fatal or can cause lasting physiological damage.
Furthermore, because inherited TTP is due to a c mutation, life-long treatment is needed and patient compliance is required. While intravenous delivery ofADAMTSl3 formulations is effective at ng inherited TTP, intravenous delivery of drugs is not easy for patients to handle (especially en with inherited TTP) and decreases patient compliance. Accordingly, it would be beneficial to p a subcutaneous ADAMTS13 formulation and a method of ADAMTS13 subcutaneous delivery.
In one embodiment, the disclosure provides a method for treating inherited TTP in a mammal in need f, the method including subcutaneously administering a therapeutically effective amount of a composition comprising isolated ADAMTSl3 to the mammal, where the therapeutically effective amount ofADAMTSl3 is from 20 to 4000 units of FRETS-VWF73 activity per kilogram body weight of the mammal (UFV73/kg). In a specific ment, the mammal is a human. In one ment, the 20 UFV73 to 4000 UFV73/kg ADAMTS13 is administered about once a month. In one embodiment, the 20 to 4000 UFV73/kg ADAMTS13 is administered about twice a month. In one ment, the 20 to 4000 UFV73/kg ADAMTS13 is administered about once a week. In one embodiment, the 20 to 4000 UFV73/kg ADAMTS13 is administered about twice a week. In one embodiment, the 20 to 4000 UFV73/kg ADAMTS13 is administered about once every 48 hours. In one embodiment, the 20 to 4000 UFV73/kg ADAMTS13 is administered about once every 24 hours. In one embodiment, the 20 to 4000 UFV73/kg 13 is administered about once every 12 hours.
In one embodiment, the disclosure provides a method for treating inherited TTP in a mammal in need thereof, the method including subcutaneously administering a therapeutically effective amount of a composition comprising isolated ADAMTS13 to the mammal, where the eutically ive amount TS13 is from 20 to 2000 units of FRETS-VWF73 activity per kilogram body weight of the mammal (UFV73/kg). In a specific embodiment, the mammal is a human. In one ment, the 20 UFV73 to 2000 UFV73/kg ADAMTS13 is administered about once a month. In one embodiment, the 20 to 2000 UFV73/kg ADAMTS13 is administered about twice a month. In one ment, the 20 to 2000 UFV73/kg ADAMTS13 is administered about once a week. In one embodiment, the 20 to 2000 UFV73/kg ADAMTS13 is administered about twice a week. In one embodiment, the 20 to 2000 UFV73/kg ADAMTS13 is administered about once every 48 hours. In one embodiment, the 20 to 2000 UFV73/kg ADAMTS13 is administered about once every 24 hours. In one ment, the 20 to 2000 UFV73/kg ADAMTS13 is administered about once every 12 hours.
In one embodiment, the disclosure provides a method for treating inherited TTP in a mammal in need thereof, the method including subcutaneously administering a therapeutically effective amount of a ition comprising isolated ADAMTS13 to the mammal, where the therapeutically effective amount ofADAMTS13 is from 20 to 1000 units of FRETS-VWF73 activity per kilogram body weight of the mammal (UFV73/kg). In a specific embodiment, the mammal is a human. In one embodiment, the 20 UFV73 to 1000 kg ADAMTS13 is administered about once a month. In one embodiment, the 20 to 1000 UFV73/kg ADAMTS13 is administered about twice a month. In one embodiment, the 20 to 1000 UFV73/kg 13 is stered about once a week. In one embodiment, the 20 to 1000 UFV73/kg ADAMTS13 is administered about twice a week. In one embodiment, the 20 to 1000 UFV73/kg ADAMTS13 is administered about once every 48 hours. In one embodiment, the 20 to 1000 kg ADAMTSl3 is administered about once every 24 hours. In one embodiment, the 20 to 1000 UFV73/kg ADAMTSl3 is administered about once every 12 hours.
In one embodiment, the disclosure provides a method for treating ted TTP in a mammal in need thereof, the method including aneously administering a therapeutically effective amount of a composition comprising isolated ADAMTSl3 to the mammal, where the therapeutically effective amount ofADAMTSl3 is from 20 to 500 units of FRETS-VWF73 activity per kilogram body weight of the mammal (UFV73/kg). In a specific embodiment, the mammal is a human. In one embodiment, the 20 UFV73 to 500 UFV73/kg ADAMTSl3 is administered about once a month. In one embodiment, the 20 to 500 UFV73/kg ADAMTSl3 is administered about twice a month. In one embodiment, the 20 to 500 UFV73/kg ADAMTSl3 is administered about once a week. In one embodiment, the 20 to 500 UFV73/kg ADAMTSl3 is administered about twice a week. In one ment, the 20 to 500 UFV73/kg ADAMTSl3 is administered about once every 48 hours. In one embodiment, the 20 to 500 UFV73/kg l3 is administered about once every 24 hours. In one embodiment, the 20 to 500 UFV73/kg ADAMTSl3 is administered about once every 12 hours.
In one embodiment, the disclosure provides a method for treating inherited TTP in a mammal in need thereof, the method including subcutaneously stering a therapeutically effective amount of a composition comprising isolated ADAMTSl3 to the mammal, where the eutically effective amount TSl3 is from 20 to 200 units of FRETS-VWF73 activity per kilogram body weight of the mammal (UFV73/kg). In a specific embodiment, the mammal is a human. In one embodiment, the 20 UFV73 to 200 UFV73/kg ADAMTSl3 is administered about once a month. In one embodiment, the 20 to 200 UFV73/kg l3 is administered about twice a month. In one embodiment, the 20 to 200 UFV73/kg ADAMTSl3 is administered about once a week. In one embodiment, the 20 to 200 UFV73/kg ADAMTSl3 is administered about twice a week. In one embodiment, the 20 to 200 UFV73/kg ADAMTSl3 is administered about once every 48 hours. In one embodiment, the 20 to 200 UFV73/kg ADAMTSl3 is administered about once every 24 hours. In one embodiment, the 20 to 200 UFV73/kg ADAMTSl3 is administered about once every 12 hours.
In one ment, the disclosure provides a method for treating inherited TTP in a mammal in need thereof, the method including subcutaneously administering a therapeutically effective amount of a composition comprising isolated l3 to the mammal, where the therapeutically effective amount ofADAMTSl3 is from 20 to 100 units of FRETS-VWF73 ty per kilogram body weight of the mammal (UFV73/kg). In a specific embodiment, the mammal is a human. In one embodiment, the 20 UFV73 to 100 kg ADAMTSl3 is stered about once a month. In one embodiment, the 20 to 100 UFV73/kg ADAMTSl3 is administered about twice a month. In one embodiment, the 20 to 100 UFV73/kg ADAMTSl3 is administered about once a week. In one embodiment, the 20 to 100 UFV73/kg ADAMTSl3 is administered about twice a week. In one embodiment, the 20 to 100 UFV73/kg ADAMTSl3 is administered about once every 48 hours. In one embodiment, the 20 to 100 UFV73/kg ADAMTSl3 is administered about once every 24 hours. In one embodiment, the 20 to 100 UFV73/kg ADAMTSl3 is administered about once every 12 hours.
In one embodiment, the disclosure provides a method for treating inherited TTP in a mammal in need thereof, the method ing subcutaneously administering a therapeutically effective amount of a composition comprising isolated ADAMTSl3 to the mammal, where the therapeutically effective amount ofADAMTSl3 is from 40 to 200 units of VWF73 activity per kilogram body weight of the mammal (UFV73/kg). In a specific embodiment, the mammal is a human. In one embodiment, the 40 UFV73 to 200 UFV73/kg ADAVITSl3 is administered about once a month. In one embodiment, the 40 to 200 UFV73/kg ADAVITSl3 is administered about twice a month. In one embodiment, the 40 to 200 UFV73/kg ADAVITSl3 is administered about once a week. In one embodiment, the 40 to 200 UFV73/kg ADAVITSl3 is administered about twice a week. In one embodiment, the 40 to 200 kg ADAVITSl3 is administered about once every 48 hours. In one embodiment, the 40 to 200 kg l3 is administered about once every 24 hours. In one embodiment, the 40 to 200 UFV73/kg ADAMTSl3 is administered about once every 12 hours.
In one embodiment, the disclosure provides a method for treating inherited TTP in a mammal in need thereof, the method including subcutaneously administering a therapeutically effective amount of a composition sing isolated ADAMTSl3 to the mammal, where the therapeutically effective amount TSl3 and frequency of the dosing is selected from variations 1 to 1133 in Table 2. In a specific embodiment, the mammal is a human.
ACQUIRED TTP In specific embodiments, an l3 formulation described herein is used for the treatment and prophylaxis of acquired TTP. In acquired TTP, patients have a low ADAMTSl3 activity due to the development of autoimmune antibodies directed at l3.
Immune-complexed ADAMTSl3 is inactivated, neutralized and/or cleared from the blood stream and patient plasma. Reduced ADAMTSl3 activity leads to the accumulation of large uncleaved VWF multimers which can spontaneously adhere to platelets and leading to platelet- ch thrombi in the microcirculation. Like inherited TTP, acquired TTP can also lead to neurologic stations (e.g., mental status, stroke, seizures, hemiplegia, paresthesias, visual disturbance, and aphasia), fatigue, and severe bleeding. If left untreated, acquired TTP can be fatal or can cause g logical damage. Accordingly, patient compliance of ADAMTSl3 administration is necessary to prevent permanent damage and eventual fatalities.
Thus, it would be beneficial to develop a subcutaneous l3 ation and a method ofADAMTSl3 subcutaneous delivery to increase patient ease and compliance as bed above.
In one embodiment, the disclosure provides a method for treating ed TTP in a mammal in need thereof, the method including subcutaneously stering a therapeutically effective amount of a composition comprising isolated ADAMTSl3 to the mammal, where the therapeutically effective amount ofADAMTSl3 is from 20 to 4000 units of FRETS-VWF73 activity per kilogram body weight of the mammal (UFV73/kg). In a specific embodiment, the mammal is a human. In one ment, the 20 UFV73 to 4000 kg ADAMTSl3 is administered about once a month. In one embodiment, the 20 to 4000 UFV73/kg ADAMTSl3 is administered about twice a month. In one embodiment, the 20 to 4000 UFV73/kg ADAMTSl3 is administered about once a week. In one embodiment, the 20 to 4000 UFV73/kg ADAMTSl3 is administered about twice a week. In one embodiment, the 20 to 4000 UFV73/kg ADAMTSl3 is administered about once every 48 hours. In one embodiment, the 20 to 4000 UFV73/kg ADAMTSl3 is administered about once every 24 hours. In one embodiment, the 20 to 4000 UFV73/kg ADAMTSl3 is administered about once every 12 hours.
In one embodiment, the disclosure provides a method for treating acquired TTP in a mammal in need thereof, the method including subcutaneously administering a therapeutically effective amount of a composition comprising isolated ADAMTSl3 to the mammal, where the therapeutically effective amount ofADAMTSl3 is from 20 to 2000 units of VWF73 ty per kilogram body weight of the mammal (UFV73/kg). In a specific embodiment, the mammal is a human. In one embodiment, the 20 UFV73 to 2000 UFV73/kg ADAMTSl3 is administered about once a month. In one embodiment, the 20 to 2000 UFV73/kg ADAMTSl3 is administered about twice a month. In one embodiment, the 20 to 2000 UFV73/kg ADAMTSl3 is administered about once a week. In one embodiment, the 20 to 2000 UFV73/kg ADAMTSl3 is administered about twice a week. In one embodiment, the 20 to 2000 UFV73/kg ADAMTSl3 is administered about once every 48 hours. In one ment, the 20 to 2000 UFV73/kg ADAMTSl3 is administered about once every 24 hours. In one embodiment, the 20 to 2000 UFV73/kg ADAMTSl3 is administered about once every 12 hours.
In one embodiment, the sure provides a method for treating acquired TTP in a mammal in need thereof, the method including subcutaneously administering a therapeutically effective amount of a composition comprising ed ADAMTSl3 to the mammal, where the therapeutically ive amount TSl3 is from 20 to 1000 units of FRETS-VWF73 activity per kilogram body weight of the mammal (UFV73/kg). In a specific embodiment, the mammal is a human. In one embodiment, the 20 UFV73 to 1000 UFV73/kg ADAMTSl3 is stered about once a month. In one embodiment, the 20 to 1000 UFV73/kg ADAMTSl3 is stered about twice a month. In one embodiment, the 20 to 1000 UFV73/kg ADAMTSl3 is administered about once a week. In one embodiment, the 20 to 1000 UFV73/kg ADAMTSl3 is administered about twice a week. In one embodiment, the 20 to 1000 UFV73/kg ADAMTSl3 is stered about once every 48 hours. In one embodiment, the 20 to 1000 kg ADAMTSl3 is administered about once every 24 hours. In one embodiment, the 20 to 1000 UFV73/kg ADAMTSl3 is administered about once every 12 hours. 2014/026747 In one embodiment, the sure provides a method for ng acquired TTP in a mammal in need thereof, the method including subcutaneously administering a therapeutically effective amount of a ition comprising isolated ADAMTSl3 to the , where the therapeutically effective amount ofADAMTSl3 is from 20 to 500 units of FRETS-VWF73 actiVity per kilogram body weight of the mammal (UFV73/kg). In a specific embodiment, the mammal is a human. In one embodiment, the 20 UFV73 to 500 UFV73/kg ADAMTSl3 is administered about once a month. In one embodiment, the 20 to 500 kg ADAMTSl3 is administered about twice a month. In one embodiment, the 20 to 500 UFV73/kg ADAMTSl3 is administered about once a week. In one embodiment, the 20 to 500 UFV73/kg ADAMTS13 is administered about twice a week. In one embodiment, the 20 to 500 kg ADAMTS13 is administered about once every 48 hours. In one embodiment, the 20 to 500 UFV73/kg ADAMTS13 is administered about once every 24 hours. In one embodiment, the 20 to 500 UFV73/kg ADAMTS13 is administered about once every 12 hours.
In one embodiment, the disclosure provides a method for treating acquired TTP in a mammal in need thereof, the method including subcutaneously administering a therapeutically effective amount of a ition sing isolated ADAMTSl3 to the mammal, where the therapeutically effective amount ofADAMTSl3 is from 20 to 200 units of FRETS-VWF73 actiVity per kilogram body weight of the mammal (UFV73/kg). In a specific embodiment, the mammal is a human. In one embodiment, the 20 UFV73 to 200 UFV73/kg l3 is administered about once a month. In one embodiment, the 20 to 200 UFV73/kg ADAMTSl3 is administered about twice a month. In one embodiment, the 20 to 200 UFV73/kg ADAMTSl3 is administered about once a week. In one ment, the 20 to 200 UFV73/kg ADAMTS13 is administered about twice a week. In one embodiment, the 20 to 200 UFV73/kg ADAMTS13 is administered about once every 48 hours. In one embodiment, the 20 to 200 kg ADAMTS13 is administered about once every 24 hours. In one embodiment, the 20 to 200 UFV73/kg ADAMTS13 is administered about once every 12 hours.
In one embodiment, the disclosure provides a method for treating acquired TTP in a mammal in need thereof, the method including subcutaneously administering a therapeutically effective amount of a composition comprising isolated ADAMTSl3 to the mammal, where the eutically effective amount ofADAMTSl3 is from 20 to 100 units of FRETS-VWF73 activity per kilogram body weight of the mammal (UFV73/kg). In a specific embodiment, the mammal is a human. In one embodiment, the 20 UFV73 to 100 UFV73/kg ADAMTSl3 is administered about once a month. In one embodiment, the 20 to 100 UFV73/kg ADAMTSl3 is administered about twice a month. In one embodiment, the 20 to 100 UFV73/kg ADAMTSl3 is administered about once a week. In one embodiment, the 20 to 100 UFV73/kg l3 is administered about twice a week. In one ment, the 20 to 100 UFV73/kg l3 is administered about once every 48 hours. In one embodiment, the 20 to 100 UFV73/kg ADAMTSl3 is administered about once every 24 hours. In one ment, the 20 to 100 UFV73/kg ADAMTSl3 is administered about once every 12 hours.
In one embodiment, the disclosure provides a method for treating acquired TTP in a mammal in need thereof, the method including subcutaneously administering a therapeutically effective amount of a composition comprising isolated ADAMTSl3 to the mammal, where the therapeutically effective amount ofADAMTSl3 is from 40 to 200 units of FRETS-VWF73 actiVity per kilogram body weight of the mammal (UFV73/kg). In a specific embodiment, the mammal is a human. In one embodiment, the 40 UFV73 to 200 UFV73/kg ADAMTSl3 is administered about once a month. In one ment, the 40 to 200 UFV73/kg ADAMTSl3 is administered about twice a month. In one embodiment, the 40 to 200 UFV73/kg ADAMTSl3 is stered about once a week. In one embodiment, the 40 to 200 UFV73/kg ADAMTSl3 is administered about twice a week. In one embodiment, the 40 to 200 UFV73/kg ADAMTSl3 is administered about once every 48 hours. In one ment, the 40 to 200 UFV73/kg ADAMTSl3 is administered about once every 24 hours. In one embodiment, the 40 to 200 UFV73/kg ADAMTSl3 is administered about once every 12 hours. 8] In one ment, the disclosure provides a method for treating acquired TTP in a mammal in need thereof, the method including subcutaneously administering a therapeutically effective amount of a composition sing isolated ADAMTSl3 to the mammal, where the therapeutically effective amount ofADAMTSl3 and frequency of the dosing is selected from variations 1 to 1133 in Table 2. In a specific embodiment, the mammal is a human.
MYOCARDIAL INFARCT[ONAND REPERFUSIONINJURY In specific embodiments, an ADAMTSl3 formulation described herein is used for the treatment and prophylaxis of myocardial infarction. In specific embodiments, an ADAMTSl3 formulation described herein is used for the treatment and laxis of ischemic/reperfusion injury. Reperfusion is the ation of blood supply to tissue that is ischemic, due to decrease in blood supply. Reperfusion is a procedure for treating infarction (e.g. , myocardial infarction and cerebral infarction) or other ischemia, by enabling viable ischemic tissue to recover, thus limiting fiarther necrosis. However, reperfiJsion can itself fiarther damage the ic , causing reperfusion injury. For e, acute myocardial infarction (AMI) is caused by thrombotic ion of a coronary artery. In addition to the immediate injury that occurs during deprivation of blood flow, ischemic/reperfusion injury involves tissue injury that occurs after blood flow is restored from the reperfusion.
Furthermore, it has been reported that ADAMTSl3 has an anti-inflammatory effect that prevents or decreases secondary injury during ischemic reperfusion. De Meyer et al.
(“Protective anti-inflammatory effect ofADAMTSl3 on dial ischemia/reperfusion injury in mice,” Blood, 2012, 120(26):5217-5223). As described by De Meyer et al., VWF and ADAMTSl3 are involved in platelet adhesion and thrombus formation because ADAMTSl3 cleaves the most thrombogenic VWF ers into smaller and less hemostatically active VWF fragments. De Meyer et al. also describe ADAMTS’s role in down-regulating inflammatory responses. It has also been shown that ADAMTS 13 can reduce thrombosis and inflammation (e.g., atherosclerosis). Chauhan et al. (“ADAMTSl3: a new link between thrombosis and ation,” J Exp Med., 2008, 205:2065-2074); Chauhan et a]. (“Systemic antithrombotic effects ofADAMTSl3,” J Exp Med., 2006, 203:767-776; Gandhi et al. (“ADAMTSl3 reduces vascular inflammation and the development of early sclerosis in mice,” Blood, 2012, 119(10):2385-2391.
De Meyer et al. suggest that l3 prevents excessive VWF-mediated et and leukocyte recruitment in the ischemic myocardium by cleaving VWF. Based on this hypothesis, De Meyer et al. show that phil infiltration in the myocardium of animals with induced myocardial infarction was nine times lower when the s were treated ADAMTSl3. 2014/026747 Accordingly, De Meyer et al. show that ADAMTSl3 s atory responses in ischemic myocardium. This reduced inflammation also reduces reperfilsion injury by preventing leukocyte ation and damage. Thus, it would be beneficial to subcutaneously administer an l3 formulation to patients to avoid inflammation that results in tissue damage during infarction (e.g., myocardial tion and cerebral infaction) and reperfiJsion because subcutaneous administration is easier and faster to administer than intravenous compositions that are lly administered by a medical professional.
In some embodiments, the pharmaceutical composition is administered immediately upon discovery of a myocardial infarction, e.g., Within 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, 60 minutes, 90 minutes, 110 minutes, 120 minutes, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, 25 or more hours, or any combination thereof, for treatment of the infarction and/or reperfilsion injury.
Accordingly, it is important to have a pharmaceutical composition that can be quickly and easily administered.
In one embodiment, the sure provides a method for treating myocardial infarction in a mammal in need thereof, the method including subcutaneously administering a therapeutically effective amount of a composition sing isolated ADAMTSl3 to the mammal, Where the therapeutically effective amount ofADAMTSl3 is from 20 to 4000 units of FRETS-VWF73 actiVity per kilogram body weight of the mammal (UFV73/kg). In a specific embodiment, the mammal is a human. In one embodiment, the 20 UFV73 to 4000 UFV73/kg ADAMTSl3 is administered Within 10 minutes of ery of a myocardial infarction in the mammal. In one embodiment, the 20 to 4000 UFV73/kg l3 is administered Within 30 minutes of discovery of a dial infarction in the mammal. In one embodiment, the 20 to 4000 UFV73/kg ADAMTSl3 is administered Within 60 minutes of discovery of a myocardial infarction in the mammal. In one embodiment, the 20 to 4000 kg l3 is administered Within 4 hours of discovery of a myocardial infarction in the mammal. In one embodiment, the 20 to 4000 UFV73/kg ADAMTSl3 is administered Within 12 hours of discovery of a myocardial infarction in the mammal. In one embodiment, the 20 to 4000 UFV73/kg ADAMTSl3 is administered Within 24 hours of discovery of a myocardial infarction in the mammal.
In one embodiment, the disclosure provides a method for treating myocardial infarction in a mammal in need thereof, the method including subcutaneously administering a therapeutically effective amount of a ition comprising isolated ADAMTSl3 to the mammal, Where the therapeutically effective amount ofADAMTSl3 is from 20 to 2000 units of FRETS-VWF73 activity per kilogram body weight of the mammal (UFV73/kg). In a specific embodiment, the mammal is a human. In one embodiment, the 20 UFV73 to 2000 kg ADAMTSl3 is administered Within 10 minutes of discovery of a myocardial infarction in the . In one embodiment, the 20 to 2000 UFV73/kg ADAMTSl3 is stered Within 30 minutes of discovery of a myocardial infarction in the mammal. In one embodiment, the 20 to 2000 UFV73/kg ADAMTSl3 is administered Within 60 minutes of discovery of a myocardial infarction in the mammal. In one embodiment, the 20 to 2000 UFV73/kg ADAMTSl3 is administered Within 4 hours of discovery of a myocardial infarction in the mammal. In one embodiment, the 20 to 2000 UFV73/kg l3 is administered Within 12 hours of discovery of a myocardial infarction in the . In one embodiment, the 20 to 2000 UFV73/kg ADAMTSl3 is administered Within 24 hours of discovery of a myocardial infarction in the mammal.
] In one embodiment, the disclosure provides a method for treating myocardial infarction in a mammal in need thereof, the method including subcutaneously administering a therapeutically effective amount of a composition comprising isolated ADAMTSl3 to the mammal, Where the therapeutically ive amount ofADAMTSl3 is from 20 to 1000 units of FRETS-VWF73 ty per kilogram body weight of the mammal (UFV73/kg). In a specific embodiment, the mammal is a human. In one embodiment, the 20 UFV73 to 1000 UFV73/kg ADAMTSl3 is administered Within 10 minutes of discovery of a myocardial tion in the mammal. In one embodiment, the 20 to 1000 kg ADAMTSl3 is stered Within 30 minutes of discovery of a myocardial infarction in the mammal. In one embodiment, the 20 to 1000 UFV73/kg ADAMTSl3 is administered Within 60 minutes of discovery of a myocardial tion in the mammal. In one ment, the 20 to 1000 UFV73/kg ADAMTSl3 is administered Within 4 hours of discovery of a myocardial infarction in the mammal. In one 2014/026747 embodiment, the 20 to 1000 UFV73/kg ADAMTSl3 is administered Within 12 hours of discovery of a dial infarction in the mammal. In one embodiment, the 20 to 1000 UFV73/kg l3 is administered Within 24 hours of discovery of a myocardial infarction in the mammal.
In one embodiment, the disclosure es a method for treating myocardial infarction in a mammal in need thereof, the method including subcutaneously administering a therapeutically effective amount of a composition sing isolated ADAMTSl3 to the mammal, Where the therapeutically ive amount ofADAMTSl3 is from 20 to 500 units of FRETS-VWF73 activity per kilogram body weight of the mammal (UFV73/kg). In a specific embodiment, the mammal is a human. In one embodiment, the 20 UFV73 to 500 UFV73/kg ADAMTSl3 is stered Within 10 minutes of discovery of a myocardial tion in the mammal. In one embodiment, the 20 to 500 UFV73/kg ADAMTSl3 is administered Within 30 minutes of discovery of a myocardial infarction in the mammal. In one embodiment, the 20 to 500 UFV73/kg ADAMTSl3 is administered Within 60 minutes of discovery of a myocardial infarction in the mammal. In one embodiment, the 20 to 500 UFV73/kg ADAMTSl3 is stered Within 4 hours of discovery of a myocardial infarction in the mammal. In one embodiment, the 20 to 500 UFV73/kg ADAMTSl3 is administered Within 12 hours of discovery of a myocardial infarction in the mammal. In one embodiment, the 20 to 500 UFV73/kg ADAMTSl3 is administered Within 24 hours of discovery of a myocardial infarction in the mammal.
In one embodiment, the disclosure es a method for treating myocardial infarction in a mammal in need thereof, the method including subcutaneously administering a therapeutically effective amount of a composition comprising isolated ADAMTSl3 to the mammal, Where the therapeutically effective amount ofADAMTSl3 is from 20 to 200 units of FRETS-VWF73 activity per kilogram body weight of the mammal (UFV73/kg). In a specific embodiment, the mammal is a human. In one embodiment, the 20 UFV73 to 200 UFV73/kg ADAMTSl3 is administered Within 10 minutes of discovery of a myocardial infarction in the mammal. In one embodiment, the 20 to 200 kg l3 is administered Within 30 minutes of discovery of a myocardial infarction in the mammal. In one embodiment, the 20 to 200 kg ADAMTSl3 is administered Within 60 s of discovery of a myocardial infarction in the mammal. In one embodiment, the 20 to 200 UFV73/kg ADAMTSl3 is stered Within 4 hours of ery of a myocardial infarction in the mammal. In one embodiment, the 20 to 200 UFV73/kg ADAMTSl3 is administered Within 12 hours of discovery of a myocardial infarction in the mammal. In one ment, the 20 to 200 UFV73/kg ADAMTSl3 is administered Within 24 hours of discovery of a myocardial infarction in the mammal.
In one ment, the disclosure provides a method for treating myocardial infarction in a mammal in need thereof, the method including subcutaneously administering a eutically effective amount of a composition comprising isolated ADAMTSl3 to the mammal, Where the therapeutically effective amount ofADAMTSl3 is from 20 to 100 units of FRETS-VWF73 activity per kilogram body weight of the mammal (UFV73/kg). In a specific embodiment, the mammal is a human. In one embodiment, the 20 UFV73 to 100 UFV73/kg l3 is administered Within 10 minutes of discovery of a myocardial infarction in the mammal. In one embodiment, the 20 to 100 UFV73/kg ADAMTSl3 is administered Within 30 minutes of discovery of a dial infarction in the mammal. In one embodiment, the 20 to 100 UFV73/kg ADAMTSl3 is administered Within 60 s of discovery of a myocardial infarction in the mammal. In one embodiment, the 20 to 100 UFV73/kg ADAMTSl3 is administered Within 4 hours of discovery of a myocardial infarction in the . In one embodiment, the 20 to 100 UFV73/kg ADAMTSl3 is administered Within 12 hours of discovery of a myocardial infarction in the mammal. In one embodiment, the 20 to 100 UFV73/kg ADAMTSl3 is administered Within 24 hours of discovery of a myocardial infarction in the mammal.
In one embodiment, the disclosure provides a method for treating myocardial infarction in a mammal in need thereof, the method including subcutaneously administering a therapeutically effective amount of a composition comprising isolated ADAMTSl3 to the , Where the therapeutically effective amount ofADAMTSl3 is from 40 to 200 units of FRETS-VWF73 activity per kilogram body weight of the mammal /kg). In a ic ment, the mammal is a human. In one embodiment, the 40 UFV73 to 200 UFV73/kg ADAMTSl3 is administered Within 10 minutes of discovery of a myocardial infarction in the mammal. In one embodiment, the 40 to 200 UFV73/kg ADAMTSl3 is administered Within 30 s of ery of a myocardial infarction in the mammal. In one embodiment, the 40 to 200 UFV73/kg ADAMTSl3 is administered Within 60 minutes of discovery of a myocardial infarction in the mammal. In one embodiment, the 40 to 200 UFV73/kg l3 is administered Within 4 hours of ery of a myocardial infarction in the mammal. In one embodiment, the 40 to 200 UFV73/kg ADAMTSl3 is stered Within 12 hours of discovery of a myocardial infarction in the mammal. In one embodiment, the 40 to 200 UFV73/kg ADAMTSl3 is administered Within 24 hours of discovery of a myocardial infarction in the mammal.
CEREBRAL INFARCTI0N 0] In one ment, an ADAMTSl3 formulation described herein is used for the treatment and/or prophylaxis of cerebral infarction. Cerebral infarction, commonly referred to as a stroke, occurs when blood flow to part of the brain is prevented. Cerebral infarctions can occur, for example, when a blood vessel that supplies blood to the brain is blocked by a blood clot. A Cerebral infarction can also be the result of a blunt force trauma and mechanical .
This can either be caused by a clot in an artery of the brain (thrombotic stroke) or by a clot from another part of the body that travels to the brain (embolic stroke). Accordingly, in some embodiments, the invention provides a method of improving the recovery of (or reducing the damage to) sensory and/or motor function in a patient after a cerebral infarction, comprising the step of administering to the individual a ceutical composition comprising a therapeutically effective amount of an ADAMTSl3 n or a biologically active derivative thereof, thereby improving the recovery of (or reducing the damage to) sensory and/or motor function in the individual post-cerebral infarction. 1] In some embodiments, the pharmaceutical composition is administered immediately upon discovery of a cerebral infarction, e.g., Within 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, 60 minutes, 90 s, 110 minutes, 120 minutes, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, 25 or more hours, or any combination thereof Accordingly, it is important to have a ceutical composition that can be quickly and easily stered.
In one embodiment, the disclosure provides a method for treating cerebral infarction in a mammal in need thereof, the method including subcutaneously administering a therapeutically ive amount of a composition comprising isolated ADAMTSl3 to the mammal, Where the therapeutically effective amount ofADAMTSl3 is from 20 to 4000 units of VWF73 activity per kilogram body weight of the mammal (UFV73/kg). In a specific embodiment, the mammal is a human. In one embodiment, the 20 UFV73 to 4000 UFV73/kg ADAMTSl3 is administered Within 10 minutes of discovery of a cerebral infarction in the mammal. In one embodiment, the 20 to 4000 UFV73/kg ADAMTSl3 is administered Within 30 minutes of discovery of a cerebral infarction in the mammal. In one embodiment, the 20 to 4000 UFV73/kg ADAMTSl3 is administered Within 60 minutes of discovery of a cerebral infarction in the mammal. In one ment, the 20 to 4000 UFV73/kg ADAMTSl3 is administered Within 4 hours of discovery of a cerebral infarction in the mammal. In one embodiment, the 20 to 4000 UFV73/kg ADAMTSl3 is administered Within 12 hours of discovery of a cerebral infarction in the mammal. In one embodiment, the 20 to 4000 UFV73/kg ADAMTSl3 is stered Within 24 hours of discovery of a cerebral infarction in the mammal.
In one embodiment, the sure provides a method for treating cerebral infarction in a mammal in need thereof, the method including subcutaneously stering a therapeutically effective amount of a ition comprising isolated ADAMTSl3 to the mammal, Where the therapeutically effective amount ofADAMTSl3 is from 20 to 2000 units of FRETS-VWF73 ty per kilogram body weight of the mammal (UFV73/kg). In a specific embodiment, the mammal is a human. In one embodiment, the 20 UFV73 to 2000 UFV73/kg ADAMTSl3 is administered Within 10 minutes of ery of a cerebral infarction in the . In one embodiment, the 20 to 2000 UFV73/kg ADAMTSl3 is administered Within 30 minutes of discovery of a cerebral infarction in the mammal. In one embodiment, the 20 to 2000 UFV73/kg ADAMTSl3 is administered Within 60 minutes of discovery of a cerebral infarction in the mammal. In one embodiment, the 20 to 2000 kg ADAMTSl3 is administered Within 4 hours of discovery of a cerebral tion in the mammal. In one embodiment, the 20 to 2000 UFV73/kg ADAMTSl3 is administered Within 12 hours of discovery of a cerebral infarction in the . In one embodiment, the 20 to 2000 UFV73/kg ADAMTSl3 is administered Within 24 hours of discovery of a cerebral infarction in the mammal.
In one embodiment, the disclosure provides a method for treating cerebral infarction in a mammal in need thereof, the method including subcutaneously administering a therapeutically effective amount of a composition comprising isolated ADAMTSl3 to the mammal, Where the therapeutically effective amount ofADAMTSl3 is from 20 to 1000 units of FRETS-VWF73 activity per kilogram body weight of the mammal (UFV73/kg). In a specific embodiment, the mammal is a human. In one ment, the 20 UFV73 to 1000 UFV73/kg ADAMTSl3 is administered Within 10 minutes of discovery of a al tion in the mammal. In one embodiment, the 20 to 1000 UFV73/kg ADAMTSl3 is administered Within 30 minutes of ery of a cerebral infarction in the mammal. In one embodiment, the 20 to 1000 UFV73/kg ADAMTSl3 is stered Within 60 minutes of discovery of a cerebral tion in the mammal. In one embodiment, the 20 to 1000 UFV73/kg ADAMTSl3 is administered Within 4 hours of discovery of a cerebral infarction in the mammal. In one embodiment, the 20 to 1000 UFV73/kg ADAMTSl3 is administered Within 12 hours of discovery of a cerebral infarction in the mammal. In one embodiment, the 20 to 1000 UFV73/kg ADAMTSl3 is stered Within 24 hours of discovery of a cerebral infarction in the mammal.
In one embodiment, the sure es a method for treating cerebral infarction in a mammal in need thereof, the method including subcutaneously administering a therapeutically effective amount of a ition comprising isolated ADAMTSl3 to the mammal, Where the therapeutically effective amount ofADAMTSl3 is from 20 to 500 units of FRETS-VWF73 activity per kilogram body weight of the mammal (UFV73/kg). In a specific embodiment, the mammal is a human. In one embodiment, the 20 UFV73 to 500 UFV73/kg ADAMTSl3 is administered Within 10 minutes of discovery of a cerebral tion in the . In one embodiment, the 20 to 500 kg l3 is administered Within 30 minutes of discovery of a cerebral infarction in the mammal. In one embodiment, the 20 to 500 UFV73/kg ADAMTSl3 is administered Within 60 minutes of discovery of a cerebral infarction in the mammal. In one embodiment, the 20 to 500 UFV73/kg ADAMTSl3 is administered Within 4 hours of discovery of a cerebral infarction in the mammal. In one embodiment, the 20 to 500 UFV73/kg ADAMTSl3 is administered Within 12 hours of discovery of a cerebral infarction in the mammal. In one embodiment, the 20 to 500 kg ADAMTSl3 is administered Within 24 hours of discovery of a cerebral infarction in the mammal.
In one embodiment, the sure provides a method for treating cerebral infarction in a mammal in need thereof, the method including subcutaneously administering a eutically effective amount of a composition comprising isolated ADAMTSl3 to the mammal, Where the therapeutically effective amount ofADAMTSl3 is from 20 to 200 units of FRETS-VWF73 activity per am body weight of the mammal (UFV73/kg). In a specific embodiment, the mammal is a human. In one embodiment, the 20 UFV73 to 200 UFV73/kg ADAMTSl3 is administered Within 10 minutes of discovery of a cerebral infarction in the mammal. In one embodiment, the 20 to 200 UFV73/kg ADAMTSl3 is administered Within 30 minutes of discovery of a cerebral tion in the mammal. In one embodiment, the 20 to 200 UFV73/kg ADAMTSl3 is administered Within 60 minutes of discovery of a cerebral infarction in the mammal. In one ment, the 20 to 200 UFV73/kg ADAMTSl3 is stered Within 4 hours of discovery of a cerebral infarction in the mammal. In one embodiment, the 20 to 200 UFV73/kg ADAMTSl3 is administered Within 12 hours of discovery of a cerebral infarction in the mammal. In one embodiment, the 20 to 200 UFV73/kg ADAMTSl3 is administered Within 24 hours of discovery of a cerebral infarction in the mammal.
In one embodiment, the disclosure provides a method for treating cerebral infarction in a mammal in need thereof, the method including subcutaneously administering a therapeutically effective amount of a composition comprising ed ADAMTSl3 to the mammal, Where the therapeutically effective amount ofADAMTSl3 is from 20 to 100 units of FRETS-VWF73 activity per kilogram body weight of the mammal (UFV73/kg). In a specific embodiment, the mammal is a human. In one embodiment, the 20 UFV73 to 100 UFV73/kg ADAMTSl3 is administered Within 10 minutes of discovery of a cerebral infarction in the . In one ment, the 20 to 100 UFV73/kg ADAMTSl3 is administered Within 30 minutes of discovery of a cerebral infarction in the mammal. In one ment, the 20 to 100 kg l3 is administered Within 60 minutes of discovery of a cerebral infarction in the mammal. In one embodiment, the 20 to 100 UFV73/kg ADAMTSl3 is administered Within 4 hours of discovery of a cerebral infarction in the mammal. In one embodiment, the 20 to 100 UFV73/kg l3 is administered Within 12 hours of discovery of a al infarction in the mammal. In one embodiment, the 20 to 100 UFV73/kg ADAMTSl3 is administered within 24 hours of discovery of a cerebral infarction in the mammal.
In one embodiment, the disclosure es a method for treating cerebral infarction in a mammal in need thereof, the method including subcutaneously administering a therapeutically ive amount of a composition comprising isolated ADAMTSl3 to the mammal, where the therapeutically effective amount ofADAMTSl3 is from 40 to 200 units of FRETS-VWF73 activity per am body weight of the mammal (UFV73/kg). In a ic embodiment, the mammal is a human. In one embodiment, the 40 UFV73 to 200 UFV73/kg l3 is administered within 10 minutes of discovery of a cerebral infarction in the mammal. In one embodiment, the 40 to 200 UFV73/kg ADAMTSl3 is administered within 30 s of ery of a cerebral infarction in the mammal. In one embodiment, the 40 to 200 UFV73/kg ADAMTSl3 is administered within 60 minutes of discovery of a al infarction in the mammal. In one embodiment, the 40 to 200 UFV73/kg ADAMTSl3 is administered within 4 hours of discovery of a cerebral infarction in the mammal. In one embodiment, the 40 to 200 UFV73/kg ADAMTSl3 is administered within 12 hours of discovery of a cerebral infarction in the mammal. In one embodiment, the 40 to 200 UFV73/kg ADAMTSl3 is administered within 24 hours of discovery of a cerebral tion in the mammal.
DEEP VEIN OSIS In one embodiment, an ADAMTSl3 formulation described herein is used for the treatment and/or laxis of deep vein thrombosis (DVT). DVT is a blood clot that forms in a vein, deep in the body. While most deep vein clots occur in the lower leg or thigh, they can occur throughout the body. DVT is a particularly dangerous disease because a blood clot can break off and travel through the bloodstream (an embolus) to the heart, lungs, or brain, for example. Such embolisms can cause damage to organs and may result in death. Accordingly, as described above, ADAMTSl3 formulations can be used to treat DVT and resulting sms. rmore, because DVT can develop and cause damage quickly, it is important to have a pharmaceutical composition that can be quickly and easily administered. Thus, it would be beneficial to develop a subcutaneous ADAMTSl3 formulation and a method ofADAMTSl3 subcutaneous delivery. 2014/026747 In some embodiments, an ADAMTSl3 pharmaceutical composition is stered immediately upon discovery of a deep vein thrombosis, e.g., within 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, 60 s, 90 minutes, 110 minutes, 120 minutes, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, or more hours, or any combination thereof. Accordingly, it is important to have a pharmaceutical ition that can be quickly and easily stered.
In one embodiment, the disclosure provides a method for ng deep vein thrombosis in a mammal in need thereof, the method including subcutaneously administering a therapeutically effective amount of a composition sing isolated ADAMTSl3 to the mammal, where the therapeutically effective amount ofADAMTSl3 is from 20 to 4000 units of FRETS-VWF73 activity per am body weight of the mammal (UFV73/kg). In a specific embodiment, the mammal is a human. In one embodiment, the 20 UFV73 to 4000 UFV73/kg l3 is administered within 10 minutes of discovery of a deep vein thrombosis in the mammal. In one ment, the 20 to 4000 UFV73/kg ADAMTSl3 is administered within 30 minutes of discovery of a deep vein thrombosis in the mammal. In one embodiment, the 20 to 4000 UFV73/kg ADAMTSl3 is administered within 60 minutes of discovery of a deep vein thrombosis in the mammal. In one embodiment, the 20 to 4000 UFV73/kg ADAMTSl3 is administered within 4 hours of discovery of a deep vein thrombosis in the mammal. In one embodiment, the 20 to 4000 UFV73/kg ADAMTSl3 is administered within 12 hours of discovery of a deep vein thrombosis in the mammal. In one embodiment, the 20 to 4000 UFV73/kg ADAMTSl3 is administered within 24 hours of discovery of a deep vein thrombosis in the mammal. 2] In one embodiment, the disclosure provides a method for treating deep vein thrombosis in a mammal in need thereof, the method including subcutaneously administering a therapeutically effective amount of a ition comprising isolated ADAMTSl3 to the mammal, where the therapeutically effective amount ofADAMTSl3 is from 20 to 2000 units of FRETS-VWF73 activity per am body weight of the mammal (UFV73/kg). In a specific embodiment, the mammal is a human. In one embodiment, the 20 UFV73 to 2000 UFV73/kg ADAMTSl3 is administered within 10 minutes of discovery of a deep vein thrombosis in the mammal. In one embodiment, the 20 to 2000 UFV73/kg ADAMTSl3 is administered within 30 minutes of discovery of a deep vein thrombosis in the mammal. In one embodiment, the 20 to 2000 UFV73/kg ADAMTSl3 is stered within 60 minutes of discovery of a deep vein thrombosis in the mammal. In one embodiment, the 20 to 2000 UFV73/kg ADAMTSl3 is administered within 4 hours of discovery of a deep vein thrombosis in the mammal. In one embodiment, the 20 to 2000 UFV73/kg ADAMTSl3 is administered within 12 hours of discovery of a deep vein osis in the mammal. In one embodiment, the 20 to 2000 UFV73/kg ADAMTSl3 is administered within 24 hours of discovery of a deep vein thrombosis in the mammal.
In one embodiment, the disclosure provides a method for treating deep vein osis in a mammal in need thereof, the method including subcutaneously administering a therapeutically effective amount of a composition comprising isolated ADAMTSl3 to the , where the eutically ive amount ofADAMTSl3 is from 20 to 1000 units of FRETS-VWF73 activity per kilogram body weight of the mammal (UFV73/kg). In a specific embodiment, the mammal is a human. In one embodiment, the 20 UFV73 to 1000 UFV73/kg ADAMTSl3 is administered within 10 s of discovery of a deep vein thrombosis in the mammal. In one ment, the 20 to 1000 UFV73/kg ADAMTSl3 is administered within 30 minutes of discovery of a deep vein thrombosis in the mammal. In one embodiment, the 20 to 1000 UFV73/kg ADAMTSl3 is administered within 60 minutes of discovery of a deep vein thrombosis in the mammal. In one embodiment, the 20 to 1000 UFV73/kg ADAMTSl3 is administered within 4 hours of ery of a deep vein thrombosis in the mammal. In one embodiment, the 20 to 1000 UFV73/kg ADAMTSl3 is administered within 12 hours of discovery of a deep vein thrombosis in the mammal. In one embodiment, the 20 to 1000 UFV73/kg ADAMTSl3 is administered within 24 hours of discovery of a deep vein thrombosis in the mammal.
In one embodiment, the disclosure provides a method for treating deep vein thrombosis in a mammal in need f, the method including subcutaneously administering a therapeutically effective amount of a composition sing ed l3 to the mammal, where the therapeutically effective amount ofADAMTSl3 is from 20 to 500 units of FRETS-VWF73 activity per kilogram body weight of the mammal (UFV73/kg). In a specific embodiment, the mammal is a human. In one embodiment, the 20 UFV73 to 500 UFV73/kg ADAMTSl3 is administered within 10 minutes of discovery of a deep vein thrombosis in the mammal. In one embodiment, the 20 to 500 UFV73/kg ADAMTSl3 is administered within 30 minutes of discovery of a deep vein thrombosis in the mammal. In one embodiment, the 20 to 500 UFV73/kg ADAMTSl3 is stered within 60 minutes of discovery of a deep vein thrombosis in the mammal. In one embodiment, the 20 to 500 UFV73/kg ADAMTSl3 is administered within 4 hours of discovery of a deep vein thrombosis in the mammal. In one embodiment, the 20 to 500 UFV73/kg ADAMTSl3 is administered within 12 hours of discovery of a deep vein thrombosis in the . In one embodiment, the 20 to 500 kg ADAMTSl3 is administered within 24 hours of discovery of a deep vein thrombosis in the In one embodiment, the sure provides a method for treating deep vein thrombosis in a mammal in need thereof, the method including subcutaneously administering a therapeutically effective amount of a composition comprising isolated ADAMTSl3 to the mammal, where the therapeutically effective amount ofADAMTSl3 is from 20 to 200 units of FRETS-VWF73 activity per kilogram body weight of the mammal (UFV73/kg). In a specific ment, the mammal is a human. In one embodiment, the 20 UFV73 to 200 UFV73/kg l3 is stered within 10 minutes of discovery of a deep vein thrombosis in the mammal. In one embodiment, the 20 to 200 UFV73/kg ADAMTSl3 is administered within 30 minutes of ery of a deep vein thrombosis in the mammal. In one embodiment, the 20 to 200 UFV73/kg ADAMTSl3 is administered within 60 minutes of ery of a deep vein thrombosis in the mammal. In one embodiment, the 20 to 200 UFV73/kg ADAMTSl3 is administered within 4 hours of discovery of a deep vein thrombosis in the mammal. In one embodiment, the 20 to 200 UFV73/kg ADAMTSl3 is administered within 12 hours of discovery of a deep vein thrombosis in the mammal. In one embodiment, the 20 to 200 UFV73/kg ADAMTSl3 is administered within 24 hours of discovery of a deep vein thrombosis in the mammal.
In one embodiment, the sure es a method for treating deep vein thrombosis in a mammal in need thereof, the method including subcutaneously administering a therapeutically effective amount of a composition comprising isolated ADAMTSl3 to the mammal, where the therapeutically effective amount ofADAMTSl3 is from 20 to 100 units of FRETS-VWF73 activity per kilogram body weight of the mammal (UFV73/kg). In a specific embodiment, the mammal is a human. In one embodiment, the 20 UFV73 to 100 UFV73/kg ADAMTSl3 is administered within 10 s of ery of a deep vein thrombosis in the mammal. In one embodiment, the 20 to 100 UFV73/kg ADAMTSl3 is administered within 30 minutes of discovery of a deep vein thrombosis in the . In one embodiment, the 20 to 100 UFV73/kg ADAMTSl3 is stered within 60 minutes of discovery of a deep vein thrombosis in the mammal. In one embodiment, the 20 to 100 UFV73/kg ADAMTSl3 is administered within 4 hours of discovery of a deep vein thrombosis in the . In one embodiment, the 20 to 100 UFV73/kg ADAMTSl3 is administered within 12 hours of discovery of a deep vein thrombosis in the mammal. In one embodiment, the 20 to 100 UFV73/kg ADAMTSl3 is administered within 24 hours of discovery of a deep vein thrombosis in the In one embodiment, the disclosure provides a method for treating deep vein thrombosis in a mammal in need thereof, the method including subcutaneously stering a therapeutically effective amount of a composition sing isolated l3 to the mammal, where the therapeutically effective amount ofADAMTSl3 is from 40 to 200 units of FRETS-VWF73 activity per am body weight of the mammal /kg). In a specific embodiment, the mammal is a human. In one embodiment, the 40 UFV73 to 200 UFV73/kg ADAMTSl3 is stered within 10 minutes of discovery of a deep vein thrombosis in the mammal. In one embodiment, the 40 to 200 UFV73/kg ADAMTSl3 is administered within 30 minutes of discovery of a deep vein thrombosis in the mammal. In one embodiment, the 40 to 200 UFV73/kg ADAMTSl3 is administered within 60 minutes of discovery of a deep vein thrombosis in the mammal. In one embodiment, the 40 to 200 UFV73/kg ADAMTSl3 is administered within 4 hours of discovery of a deep vein thrombosis in the mammal. In one embodiment, the 40 to 200 UFV73/kg ADAMTSl3 is stered within 12 hours of discovery of a deep vein thrombosis in the mammal. In one embodiment, the 40 to 200 UFV73/kg ADAMTSl3 is administered within 24 hours of discovery of a deep vein thrombosis in the mammal. 8] [0001] In one embodiment, the sure es a method for prophylactic treatment of a mammal at risk for developing deep vein thrombosis, the method ing subcutaneously administering a therapeutically effective amount of a composition comprising isolated ADAMTSl3 to the mammal in need therein, where the therapeutically effective amount ofADAMTSl3 is from 20 to 4000 units of FRETS-VWF73 ty per kilogram body weight of the mammal (UFV73/kg). In a specific embodiment, the mammal is a human. In one embodiment, the 20 UFV73 to 4000 UFV73/kg ADAMTSl3 is administered about once a month. In one embodiment, the 20 to 4000 UFV73/kg ADAMTSl3 is administered about twice a month. In one embodiment, the 20 to 4000 UFV73/kg ADAMTSl3 is stered about once a week. In one embodiment, the 20 to 4000 kg ADAMTSl3 is administered about twice a week. In one embodiment, the 20 to 4000 UFV73/kg ADAMTSl3 is stered about once every 48 hours. In one embodiment, the 20 to 4000 UFV73/kg ADAMTSl3 is administered about once every 24 hours. In one embodiment, the 20 to 4000 UFV73/kg ADAMTSl3 is administered about once every 12 hours.
[0002] In one embodiment, the disclosure provides a method for prophylactic treatment of a mammal at risk for developing deep vein thrombosis, the method including subcutaneously administering a therapeutically effective amount of a composition comprising isolated ADAMTSl3 to the mammal, where the therapeutically effective amount of ADAMTSl3 is from 20 to 2000 units of FRETS-VWF73 activity per kilogram body weight of the mammal (UFV73/kg). In a specific embodiment, the mammal is a human. In one embodiment, the 20 UFV73 to 2000 UFV73/kg ADAMTSl3 is administered about once a month. In one embodiment, the 20 to 2000 UFV73/kg ADAMTSl3 is stered about twice a month. In one embodiment, the 20 to 2000 UFV73/kg ADAMTSl3 is administered about once a week. In one ment, the 20 to 2000 UFV73/kg ADAMTSl3 is administered about twice a week. In one embodiment, the 20 to 2000 kg ADAMTSl3 is administered about once every 48 hours. In one embodiment, the 20 to 2000 UFV73/kg ADAMTSl3 is administered about once every 24 hours. In one embodiment, the 20 to 2000 UFV73/kg ADAMTSl3 is administered about once every 12 hours.
[0003] In one embodiment, the disclosure provides a method for prophylactic treatment of a mammal at risk for ping deep vein thrombosis, the method including subcutaneously administering a therapeutically effective amount of a composition comprising isolated l3 to the mammal, where the therapeutically effective amount of ADAMTSl3 is from 20 to 1000 units of FRETS-VWF73 actiVity per kilogram body weight of the mammal (UFV73/kg). In a specific embodiment, the mammal is a human. In one ment, the 20 UFV73 to 1000 UFV73/kg ADAMTSl3 is administered about once a month. In one embodiment, the 20 to 1000 UFV73/kg ADAMTSl3 is administered about twice a month. In one embodiment, the 20 to 1000 kg ADAMTSl3 is administered about once a week. In one embodiment, the 20 to 1000 UFV73/kg ADAMTSl3 is administered about twice a week. In one embodiment, the 20 to 1000 UFV73/kg ADAMTSl3 is administered about once every 48 hours. In one embodiment, the 20 to 1000 kg l3 is administered about once every 24 hours. In one embodiment, the 20 to 1000 UFV73/kg ADAMTSl3 is administered about once every 12 hours.
[0004] In one embodiment, the disclosure provides a method for prophylactic treatment of a mammal at risk for developing deep vein thrombosis, the method including subcutaneously administering a therapeutically effective amount of a composition sing ed ADAMTSl3 to the mammal, where the therapeutically effective amount of ADAMTSl3 is from 20 to 500 units of FRETS-VWF73 actiVity per kilogram body weight of the mammal (UFV73/kg). In a specific embodiment, the mammal is a human. In one embodiment, the 20 UFV73 to 500 UFV73/kg ADAMTSl3 is administered about once a month. In one ment, the 20 to 500 UFV73/kg ADAMTSl3 is administered about twice a month. In one ment, the 20 to 500 UFV73/kg ADAMTSl3 is administered about once a week. In one embodiment, the 20 to 500 UFV73/kg ADAMTSl3 is stered about twice a week. In one embodiment, the 20 to 500 UFV73/kg ADAMTSl3 is administered about once every 48 hours.
In one embodiment, the 20 to 500 UFV73/kg ADAMTSl3 is administered about once every 24 hours. In one embodiment, the 20 to 500 UFV73/kg ADAMTSl3 is administered about once every 12 hours. 2] [0005] In one embodiment, the sure provides a method for prophylactic treatment of a mammal at risk for developing deep vein thrombosis, the method including subcutaneously administering a therapeutically effective amount of a composition comprising isolated ADAMTSl3 to the mammal, where the therapeutically effective amount of WO 51968 ADAMTSl3 is from 20 to 200 units of FRETS-VWF73 ty per kilogram body weight of the mammal (UFV73/kg). In a specific embodiment, the mammal is a human. In one embodiment, the 20 UFV73 to 200 UFV73/kg l3 is administered about once a month. In one embodiment, the 20 to 200 kg ADAMTSl3 is administered about twice a month. In one embodiment, the 20 to 200 UFV73/kg ADAMTSl3 is administered about once a week. In one embodiment, the 20 to 200 UFV73/kg ADAMTSl3 is administered about twice a week. In one embodiment, the 20 to 200 UFV73/kg ADAMTSl3 is administered about once every 48 hours.
In one embodiment, the 20 to 200 UFV73/kg ADAMTSl3 is administered about once every 24 hours. In one ment, the 20 to 200 UFV73/kg ADAMTSl3 is administered about once every 12 hours.
[0006] In one embodiment, the disclosure provides a method for prophylactic treatment of a mammal at risk for developing deep vein thrombosis, the method including aneously administering a therapeutically effective amount of a composition comprising isolated ADAMTSl3 to the mammal, where the therapeutically effective amount of ADAMTSl3 is from 20 to 100 units of FRETS-VWF73 activity per kilogram body weight of the mammal (UFV73/kg). In a specific embodiment, the mammal is a human. In one embodiment, the 20 UFV73 to 100 UFV73/kg ADAMTSl3 is administered about once a month. In one embodiment, the 20 to 100 UFV73/kg ADAMTSl3 is stered about twice a month. In one embodiment, the 20 to 100 UFV73/kg l3 is administered about once a week. In one embodiment, the 20 to 100 UFV73/kg ADAMTSl3 is administered about twice a week. In one embodiment, the 20 to 100 UFV73/kg ADAMTSl3 is administered about once every 48 hours.
In one embodiment, the 20 to 100 UFV73/kg ADAMTSl3 is administered about once every 24 hours. In one embodiment, the 20 to 100 UFV73/kg ADAMTSl3 is administered about once every 12 hours.
In one embodiment, the disclosure provides a method for lactic treatment of a mammal at risk for developing deep vein thrombosis, the method ing subcutaneously administering a therapeutically effective amount of a composition comprising isolated ADAMTSl3 to the , where the therapeutically effective amount of ADAMTSl3 is from 40 to 200 units of FRETS-VWF73 activity per kilogram body weight of the mammal (UFV73/kg). In a specific embodiment, the mammal is a human. In one embodiment, the 40 UFV73 to 200 UFV73/kg ADAMTSl3 is administered about once a month. In one embodiment, the 40 to 200 UFV73/kg ADAMTSl3 is administered about twice a month. In one embodiment, the 40 to 200 UFV73/kg ADAMTSl3 is administered about once a week. In one embodiment, the 40 to 200 UFV73/kg ADAMTSl3 is stered about twice a week. In one embodiment, the 40 to 200 UFV73/kg ADAMTSl3 is administered about once every 48 hours. In one embodiment, the 40 to 200 UFV73/kg ADAMTSl3 is administered about once every 24 hours.
In one embodiment, the 40 to 200 kg ADAMTSl3 is stered about once every 12 hours.
In one embodiment, the disclosure provides a method for prophylactic treatment of a mammal at risk for developing deep vein thrombosis, the method including subcutaneously administering a therapeutically effective amount of a composition comprising isolated ADAMTSl3 to the mammal, where the therapeutically effective amount of ADAMTSl3 and frequency of the dosing is selected from variations 1 to 1133 in Table 2. In a specific embodiment, the mammal is a human.
DISSEMINATED INTRA VASCULAR ATI0N In specific embodiments, an ADAMTSl3 ation described herein is used for the treatment and prophylaxis of disseminated intravascular coagulation (DIC), specifically, -related DIC. DIC is a condition in which blood clots form throughout the body's small blood vessels. These blood clots can reduce or block blood flow throughout the body and can result in damage to tissues and organs. The blood clots in the small blood vessels results from an increase in ng activity. This se in activity over uses available platelets and clotting factors, thereby also increasing the chance of serious internal and external bleeding by depleting the ble source of platelets and clotting s. Accordingly, a patient with DIC will often suffer from blood clots and severe bleeding disorders.
Certain es such as sepsis, surgery/trauma, cancer, complications of childbirth/pregnancy, venomous snake bites esnakes and vipers), frostbite, and burns can cause clotting factors to become overactive and can lead to DIC. DIC can also be acute (developing quickly over hours or days) or chronic (developing over weeks or months). While both types of DIC require medical treatment, acute DIC must be treated immediately to prevent excessive blood clotting in the small blood vessels that quickly lead to severe bleeding.
Accordingly, it is important to have a pharmaceutical composition that can be quickly and easily administered to treat DIC, especially acute DIC such as -related DIC. Thus, it would be beneficial to develop a aneous ADAMTSl3 ation and a method ofADAMTSl3 subcutaneous delivery.
In some embodiments, the pharmaceutical composition is administered immediately upon discovery of disseminated ascular coagulation, e.g., within 5 minutes, 10 s, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, 60 minutes, 90 minutes, 110 minutes, 120 minutes, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, ll hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, or more hours, or any combination thereof. Accordingly, it is important to have a pharmaceutical composition that can be quickly and easily administered.
In one embodiment, the disclosure provides a method for treating disseminated intravascular coagulation in a mammal in need thereof, the method including aneously administering a eutically ive amount of a composition comprising isolated ADAMTSl3 to the , where the therapeutically effective amount of ADAMTSl3 is from to 4000 units of FRETS-VWF73 activity per kilogram body weight of the mammal (UFV73/kg). In a specific embodiment, the mammal is a human. In one embodiment, the 20 UFV73 to 4000 UFV73/kg ADAMTSl3 is administered within 10 minutes of discovery of inated intravascular coagulation in the mammal. In one embodiment, the 20 to 4000 UFV73/kg ADAMTSl3 is administered within 30 minutes of discovery of disseminated intravascular coagulation in the . In one embodiment, the 20 to 4000 UFV73/kg ADAMTSl3 is administered within 60 minutes of discovery of disseminated ascular coagulation in the mammal. In one embodiment, the 20 to 4000 UFV73/kg ADAMTSl3 is administered within 4 hours of discovery of inated intravascular coagulation in the mammal. In one embodiment, the 20 to 4000 UFV73/kg ADAMTSl3 is administered within 12 hours of discovery of disseminated intravascular coagulation in the mammal. In one embodiment, the 20 to 4000 UFV73/kg l3 is administered within 24 hours of discovery of disseminated intravascular coagulation in the mammal.
In one embodiment, the disclosure provides a method for treating disseminated intravascular coagulation in a mammal in need thereof, the method ing subcutaneously administering a therapeutically effective amount of a composition comprising isolated ADAMTSl3 to the mammal, where the therapeutically ive amount of ADAMTSl3 is from to 2000 units of FRETS-VWF73 activity per kilogram body weight of the mammal (UFV73/kg). In a specific embodiment, the mammal is a human. In one embodiment, the 20 UFV73 to 2000 UFV73/kg ADAMTSl3 is administered within 10 minutes of discovery of disseminated ascular coagulation in the . In one embodiment, the 20 to 2000 UFV73/kg ADAMTSl3 is administered within 30 minutes of discovery of disseminated intravascular coagulation in the mammal. In one embodiment, the 20 to 2000 UFV73/kg ADAMTSl3 is stered within 60 minutes of ery of disseminated ascular coagulation in the mammal. In one embodiment, the 20 to 2000 UFV73/kg ADAMTSl3 is administered within 4 hours of discovery of disseminated intravascular coagulation in the mammal. In one embodiment, the 20 to 2000 kg ADAMTSl3 is administered within 12 hours of discovery of disseminated intravascular coagulation in the mammal. In one embodiment, the 20 to 2000 UFV73/kg ADAMTSl3 is administered within 24 hours of discovery of disseminated intravascular coagulation in the .
In one embodiment, the disclosure es a method for ng disseminated intravascular coagulation in a mammal in need thereof, the method ing subcutaneously stering a therapeutically effective amount of a composition comprising isolated ADAMTSl3 to the mammal, where the eutically effective amount of ADAMTSl3 is from to 1000 units of FRETS-VWF73 activity per kilogram body weight of the mammal (UFV73/kg). In a specific embodiment, the mammal is a human. In one embodiment, the 20 UFV73 to 1000 UFV73/kg ADAMTSl3 is administered within 10 minutes of discovery of disseminated intravascular coagulation in the mammal. In one embodiment, the 20 to 1000 UFV73/kg ADAMTSl3 is administered within 30 minutes of discovery of disseminated intravascular coagulation in the mammal. In one embodiment, the 20 to 1000 UFV73/kg ADAMTSl3 is administered within 60 minutes of discovery of disseminated intravascular coagulation in the mammal. In one embodiment, the 20 to 1000 UFV73/kg l3 is administered within 4 hours of discovery of disseminated intravascular coagulation in the . In one embodiment, the 20 to 1000 UFV73/kg ADAMTSl3 is administered within 12 hours of discovery of disseminated intravascular coagulation in the mammal. In one embodiment, the 20 to 1000 UFV73/kg ADAMTSl3 is stered within 24 hours of discovery of disseminated intravascular coagulation in the mammal.
In one embodiment, the disclosure provides a method for treating disseminated intravascular coagulation in a mammal in need thereof, the method including subcutaneously administering a therapeutically effective amount of a ition comprising isolated ADAMTSl3 to the mammal, where the therapeutically effective amount of ADAMTSl3 is from to 500 units of VWF73 activity per kilogram body weight of the mammal (UFV73/kg).
In a specific embodiment, the mammal is a human. In one embodiment, the 20 UFV73 to 500 UFV73/kg ADAMTSl3 is stered within 10 minutes of ery of disseminated intravascular coagulation in the mammal. In one embodiment, the 20 to 500 UFV73/kg ADAMTSl3 is administered within 30 minutes of ery of disseminated intravascular coagulation in the mammal. In one embodiment, the 20 to 500 UFV73/kg ADAMTSl3 is administered within 60 minutes of discovery of disseminated intravascular coagulation in the mammal. In one embodiment, the 20 to 500 UFV73/kg ADAMTSl3 is administered within 4 hours of discovery of disseminated intravascular ation in the mammal. In one embodiment, the 20 to 500 UFV73/kg ADAMTSl3 is administered within 12 hours of discovery of disseminated intravascular coagulation in the mammal. In one embodiment, the 20 to 500 kg ADAMTSl3 is administered within 24 hours of discovery of inated intravascular coagulation in the mammal.
In one embodiment, the disclosure es a method for treating disseminated intravascular coagulation in a mammal in need f, the method including subcutaneously administering a therapeutically effective amount of a composition comprising isolated l3 to the mammal, where the therapeutically effective amount of l3 is from to 200 units of FRETS-VWF73 activity per kilogram body weight of the mammal (UFV73/kg).
In a specific embodiment, the mammal is a human. In one embodiment, the 20 UFV73 to 200 UFV73/kg ADAMTSl3 is administered within 10 minutes of discovery of disseminated intravascular coagulation in the mammal. In one embodiment, the 20 to 200 UFV73/kg ADAMTSl3 is administered within 30 minutes of discovery of disseminated intravascular 2014/026747 ation in the . In one embodiment, the 20 to 200 UFV73/kg ADAMTSl3 is administered within 60 minutes of discovery of disseminated intravascular coagulation in the mammal. In one embodiment, the 20 to 200 UFV73/kg ADAMTSl3 is administered within 4 hours of ery of disseminated intravascular coagulation in the mammal. In one embodiment, the 20 to 200 UFV73/kg ADAMTSl3 is administered within 12 hours of discovery of disseminated intravascular coagulation in the mammal. In one embodiment, the 20 to 200 UFV73/kg ADAMTSl3 is administered within 24 hours of ery of disseminated intravascular coagulation in the mammal.
In one embodiment, the disclosure provides a method for treating disseminated intravascular coagulation in a mammal in need thereof, the method including subcutaneously administering a therapeutically effective amount of a composition comprising isolated ADAMTSl3 to the mammal, where the therapeutically effective amount of ADAMTSl3 is from to 100 units of FRETS-VWF73 activity per kilogram body weight of the mammal (UFV73/kg).
In a specific embodiment, the mammal is a human. In one embodiment, the 20 UFV73 to 100 UFV73/kg l3 is administered within 10 minutes of discovery of disseminated intravascular ation in the mammal. In one embodiment, the 20 to 100 UFV73/kg ADAMTSl3 is administered within 30 s of discovery of disseminated intravascular coagulation in the . In one embodiment, the 20 to 100 UFV73/kg ADAMTSl3 is administered within 60 minutes of discovery of disseminated intravascular coagulation in the mammal. In one embodiment, the 20 to 100 UFV73/kg ADAMTSl3 is administered within 4 hours of discovery of disseminated intravascular ation in the mammal. In one embodiment, the 20 to 100 kg ADAMTSl3 is administered within 12 hours of discovery of disseminated ascular coagulation in the mammal. In one embodiment, the 20 to 100 UFV73/kg l3 is administered within 24 hours of discovery of disseminated intravascular coagulation in the .
In one embodiment, the disclosure provides a method for treating disseminated intravascular coagulation in a mammal in need f, the method including subcutaneously administering a therapeutically effective amount of a composition comprising isolated ADAMTSl3 to the mammal, where the therapeutically effective amount of ADAMTSl3 is from 40 to 200 units of FRETS-VWF73 activity per kilogram body weight of the mammal (UFV73/kg).
In a specific embodiment, the mammal is a human. In one embodiment, the 40 UFV73 to 200 UFV73/kg ADAMTSl3 is administered within 10 minutes of discovery of disseminated intravascular ation in the . In one embodiment, the 40 to 200 UFV73/kg ADAMTSl3 is stered within 30 minutes of discovery of disseminated intravascular coagulation in the . In one embodiment, the 40 to 200 UFV73/kg ADAMTSl3 is administered within 60 minutes of discovery of disseminated intravascular coagulation in the mammal. In one embodiment, the 40 to 200 UFV73/kg ADAMTSl3 is administered within 4 hours of discovery of disseminated intravascular coagulation in the mammal. In one ment, the 40 to 200 UFV73/kg ADAMTSl3 is administered within 12 hours of discovery of disseminated intravascular coagulation in the mammal. In one embodiment, the 40 to 200 UFV73/kg l3 is administered within 24 hours of discovery of disseminated intravascular coagulation in the mammal.
V. ADAMTSl3 KITS In another , kits are provided for the treatment of a disease or condition associated with ADAMTSl3 or VWF dysfunction. In one embodiment, the kit comprises a formulation ofrADAMTSl3. In some embodiments, the kits provided herein may n one or more dose of a liquid or lyophilized formulation as provided herein. When the kits comprise a lyophilized rADAMTSl3 formulation, generally the kits will also contain a le liquid for reconstitution of the liquid formulation, for example, sterile water or a pharmaceutically acceptable buffer. In some embodiments, a kit includes an ADAMTSl3 formulation prepackaged in a syringe for subcutaneous administration by a health care professional or for home use.
In one embodiment, a kit is provided comprising between about 10 units of VWF73 activity and about 10,000 units of FRETS-VWF73 ty. In other embodiments, the kit may provide, for example, between about 20 units of VWF73 (UFV73) activity and about 8,000 units of FRETS-VWF73 activity, or between about 30 UFV73 and about 6,000 UFV73, or between about 40 UFV73 and about 4,000 UFV73, or between about 50 UFV73 and about 3,000 UFV73 Dr between about 75 UFV73 and about 2,500 UFV73 or n about 100 , , UFV73 and about 2,000 UFV73 or between about 200 UFV73 and about 1,500 UFV73 or between , , WO 51968 about other ranges therein. In certain embodiments, a kit may provide about 10 units of FRETS- VWF73 activity, or about 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1,000, 1,100, 1,200, 1,300, 1,400, 1,500, 1,600, 1,700, 1,800, 1,900, 2,000, 2,100, 2,200, 2,300, 2,400, 2,500, 2,600, 2,700, 2,800, 2,900, 3,000, 3,100, 3,200, 3,300, 3,400, 3,500, 3,600, 3,700, 3,800, 3,900, 4,000, 4,100, 4,200, 4,300, 4,400, 4,500, 4,600, 4,700, 4,800, 4,900, 5,000, 5,100, 5,200, 5,300, 5,400, 5,500, 5,600, 5,700, 5,800, 5,900, 6,000, 6,100, 6,200, 6,300, 6,400, 6,500, 6,600, 6,700, 6,800, 6,900, 7,000, 7,100, 7,200, 7,300, 7,400, 7,500, 7,600, 7,700, 7,800, 7,900, 8,000, 8,100, 8,200, 8,300, 8,400, 8,500, 8,600, 8,700, 8,800, 8,900, 9,000, 9,100, 9,200, 9,300, 9,400, 9,500, 9,600, 9,700, 9,800, 9,900, 10,000, 11,000, 12,000, 13,000, 14,000, 15,000, 16,000, , 18,000, 19,000, 20,000 or more units ofFRETS-VWF73 activity. 8] In certain ments, the kit is for a single administration or dose of ADAMTS13. In other embodiments, the kit may contain multiple doses ofADAMTS13 for subcutaneous administration. In one embodiment, the kit may comprise an ADAMTS13 formulation prepackaged in a syringe for subcutaneous administration by a health care professional or for home use.
VI. EXAMPLES Example I .' The Pharmacokinetic Properties ofrADAMTSI3 with Intravenous and Subcutaneous Administration 9] This study was conducted to evaluate the pharmacokinetic ties of recombinant ADAMTS13 in Gottingen minipigs after intravenous (iv) or subcutaneous (s.c.) administration. In this study, 4 male Gottingen minipigs were administered i.v. ADMTS13 (the “intravenous group”) and 4 male Gottingen minipigs were administered s.c. 3 (the “subcutaneous group”).
Male Gottingen minipigs were d before the start of the study to cooperate with the study procedures. Thus, the animals were not restrained during administration of anesthetics or the test item and blood sampling.
The animals were anesthetized for catheter implantation using a Zoletil mix consisting of 1.11 mg/kg tiletamine, 1.11 mg/kg zolazepam, 0.56 mg/kg xylazine, 0.56 mg/kg ketamine, and 0.11 mg/kg butorphanole (i.m.). ane was used for anesthesia maintenance when necessary. The animals received pure oxygen via a mask or an endotracheal tube during surgery. The jugular region was shaved and disinfected. A central catheter was ed into the cranial V. cava using the Seldinger technique. 4 mg/kg carprofene was administered for analgesia before recovery from anesthesia.
The intravenous group received a nominal dose of 200 FRETS-U/kg rADAMTS13 i.v. (0.085 mL/kg). The subcutaneous group ed a nominal dose of 1000 FRETS-U/kg rADAMTS 13 s.c. (0.456 mL/kg). Blood was sampled via the central venous catheter before stration of the test item and 5 min, 1 h, 3 h, 6 h, 9 h. 24 h, 32 h, 48 h, 56 h and 72 h after administration of the test item. Blood samples were prepared as follows: the first 0.5-0.7 mL were discarded to avoid dilution with the catheter lock solution (saline). Then, 0.8 mL blood was collected and mixed with 0.2 mL sodium citrate. The blood sample was centrifuged with 5700 rpm (1x 10 min, 1x 5 min). The plasma was stored at < -60 °C.
ADAMTS13 activity was determined by a FRETS assay and antigen by an ELISA. rmore, the potential development of binding antibodies against human rADAMTS13 and the influence ofrADAMTS13 on the multimer pattern of endogenous VWF were assessed. 4] As expected, after i.v. administration the median Tmax (time to Cmax) was 5min, ting immediate bioavailability. Median Tmax after s.c. administration was 24h for ADAMTS13 activity and 28h for ADAMTS13 antigen. Mean plasma concentrations of ADAMTS13 activity are summarized in Figure 1 and the averaged concentrations of ADAMTS13 antigen are summarized in Figure 2.
The dose-adjusted last[h*U/1’IIL/U/l{g and h"< ug/kg] after i.v. administration was 0.306 for activity and 0.373 for antigen. AUCO—tlast was ed using the trapezoidal rule from time point 0 to the last sampling time (tlast) hke et al. 2007). The dose-adjusted AUCO—tlast following s.c. administration was 0.198 for activity and 0.243 for antigen. Thus, the ratio of the dose-adjusted AUCO—tlast ing s.c. and iv. administration was 0.646 for activity and 0.651 for antigen. IVR [%] was 55.8 (activity) and 79.3 (antigen) after i.v. administration and 13.8 (activity) and 17.3 (antigen) after s.c. administration.
Since the plasma level of rADAMTS13 did not decline sufficiently during the observation period, the estimation of the al and initial half-lives has to be viewed with caution. Thus, the dependent parameters (MRT, Vss, Cls, AUCO—inf) may be unreliable as well. A follow-up study will be conducted to assess these parameters. Assessment of binding antibodies t rADAMTS13 was negative for all samples from all animals.
Results of the assessment of the minipigs’ VWF multimer pattern were tive for a very limited cleavage of nous VWF by recombinant ADAMTS13 (Table 3). The satellite band close to a low VWF-mer ly increased in intensity over time in animals ing s.c. administration, but not in animals receiving i.v. administration. The height of the VWF multimer patterns did not change in either group.
Table 3. Multimer analysis of inant ADAMTS13 from low and high resolution agarose gels.
Subcutaneous Group (1000 Eli/kg SC Slight increase in one satellite band intensity Sli ht increase in one satellite band intensit Example 2.‘ The Pharmacokinetic Properties ofrADAMTSI3 with Intravenous and aneous Administration This study was conducted to evaluate the pharmacokinetic ties of recombinant ADAMTS13 in gen minipigs after intravenous (iv) or subcutaneous (s.c.) administration. In this study, 4 male Gottingen minipigs were administered i.v. ADMTS13 (the “intravenous group”) and 4 male Gottingen minipigs were administered s.c. ADMTS13 (the “subcutaneous group”).
The male Gottingen minipigs were acclimated to study ures and anesthetized for catheter implantation as bed in Example 1.
This study was a trial using 3 and 5 male Gottingen minipigs per group. Both groups received a nominal dose of 200 FRETS-U/kg rADAMTS13. Three animals were dosed iv, the other five animals were dosed s.c.. Blood was sampled via the central venous catheter before administration of the test item and 5min, 1h, 2h, 6h, 5h, 23h, 30h, 47h, 54h, 71h, 78h, 95h and 102h after stration of the test item.
Blood samples were prepared as follows: The first 0.5-0.7 mL were discarded to avoid dilution with the catheter lock solution (saline). Then, 0.8 mL blood was ted and mixed with 0.2 mL sodium citrate. The blood sample was fuged with 5700 rpm (1x 10min, 1x 5min). The plasma was stored at < -60°C.
ADAMTS13 activity was ined by a FRETS assay and antigen by an ELISA.
As expected, after i.v. administration the median Tmax (time to Cmax) was 5min, indicating immediate bioavailability. Median Tmax after so. administration was 30h. Mean plasma concentrations ofADAMTS13 activity are summarized in Figure 3 and the averaged concentrations ofADAMTS13 antigen are summarized in Figure 4.
The AUCO—tlast[U/1’IlL/*h and ug/mL*h] after i.v. administration was 68.25 for activity and 39.81 for antigen. The AUCO—tlast following s.c. administration was 47.16 for activity and 26.23 for antigen. IVR [%] was 61.0 (activity) and 45.6 (antigen) after i.v. administration and 13.0 (activity) and 9.6 (antigen) after so. stration.
Terminal half-life [h] after i.v. administration was 46.96 for activity and 48.83 for antigen. Terminal half-life after so. administration was 56.76 for activity and 41.25 for antigen.
MRT [h] was 64.08 (activity) and 66.26 en) after i.v. administration and 104.2 ity) and 77.52 (antigen) after so. administration.
In summary, the bioavailability of the so. administration relative to the i.V. stration was 65.9% and 69.1% for ADAMTSI3 antigen and ADAMTSI3 activity, respectively.

Claims (61)

Claims 1.
1. Use of a composition comprising ed ADAMTS13 in the manufacture of a ment for subcutaneous administration of a therapeutically effective amount of ADAMTS13 in the treatment of a disease or condition associated with ADAMTS13 and/or VWF dysfunction in a subject in need thereof, wherein the composition further comprises at least one ed from the group consisting of a pharmaceutically acceptable salt, sugar, sugar alcohol, non-ionic surfactant, and buffering agent.
2. The use of claim 1, wherein the disease or condition associated with ADAMTS13 and/or VWF dysfunction is a blood clotting disorder, acute inflammation, c inflammation, plasmodium falciparum malaria, hemolytic uremic syndrome, arterial osis, coronary heart e, or atherosclerosis.
3. The use of claim 2, wherein the acute and/or chronic inflammation is caused by a blood clotting disorder.
4. The use of claim 2 or claim 3, wherein the blood clotting disorder is selected from the group consisting of inherited TTP, acquired TTP, cerebral infarction, myocardial infarction, ischemic/reperfusion injury, deep vein thrombosis, and disseminated intravasular ation.
5. The use according to any one of claims 2 to 4, wherein the blood clotting disorder is inherited TTP.
6. The use according to any one of claims 2 to 4, wherein the blood clotting disorder is acquired TTP.
7. The use according to any one of claims 2 to 4, wherein the blood ng disorder is al infarction.
8. The use according to any one of claims 2 to 4, wherein the blood clotting disorder is ischemia reperfusion injury.
9. The use according to any one of claims 2 to 4, n the blood clotting disorder is myocardial infarction.
10. The use according to any one of claims 2 to 4, wherein the blood clotting disorder is disseminated intravasular ation.
11. The use according to any one of claims 1 to 10, wherein the therapeutically effective amount comprises at least 20 to 160 activity units per kilogram body weight.
12. The use according to any one of claims 1 to 10, wherein the therapeutically effective amount is from 20 to 4,000 activity units per kilogram body weight.
13. The use according to any one of claims 1 to 10, wherein the therapeutically effective amount is from 20 to 2,000 activity units per kilogram body weight.
14. The use according to any one of claims 1 to 10, wherein the eutically effective amount is from 40 to 4,000 activity units per kilogram body weight.
15. The use according to any one of claims 1 to 10, wherein the eutically effective amount is from 40 to 2,000 activity units per kilogram body weight.
16. The use according to any one of claims 1 to 15, wherein the ment is to be administered in a single bolus injection, monthly, every two weeks, weekly, twice a week, daily, every 12 hours, every 8 hours, every six hours, every four hours, or every two hours.
17. The use according to any one of claims 1 to 16, wherein the ADAMTS13 is recombinant.
18. The use according to any one of claims 1 to 16, wherein the ADAMTS13 is plasma derived.
19. The use according to any one of claims 1 to 18, wherein the ADAMTS13 is human ADAMTS13.
20. The use according to any one of claims 1 to 1, wherein the composition is a stable aqueous solution ready for administration.
21. The use according to any one of claims 1 to 1, wherein the ition is lyophilized.
22. The use of claim 21, wherein the composition is reconstituted with a ceutically acceptable vehicle suitable for injection prior to administration.
23. Use of a composition comprising isolated ADAMTS13 in the manufacture of a ment for subcutaneous administration of a eutically effective amount of ADAMTS13 for the prevention or reduction of tissue damage in a subject in need thereof.
24. The use of claim 23, wherein the tissue damage is a secondary injury to infarct tissue.
25. Use of a composition comprising isolated ADAMTS13 in the manufacture of a medicament for subcutaneous administration of a therapeutically effective amount of 13 for improving the recovery of and/or reducing the damage to sensory and/or motor function after a cerebral infarction in a t in need thereof.
26. The use of claim 23, wherein the tissue damage is caused by a blood clotting disorder.
27. The use of claim 24, wherein the t is caused by a blood clotting disorder.
28. The use of claim 24, n the infarct is caused by blunt force trauma or mechanical
29. The use of claim 25, wherein the cerebral infarction is caused by a blood clotting disorder.
30. The use of claim 25, wherein the cerebral infarction is caused by blunt force trauma or mechanical injury.
31. The use according to any one of claims 26, 27, or 29, wherein the blood clotting disorder is selected from the group consisting of inherited TTP, acquired TTP, cerebral infarction, dial infarction, ic/reperfusion injury, deep vein thrombosis, and disseminated intravasular coagulation.
32. The use of claim 31, wherein the blood clotting disorder is inherited TTP.
33. The use of claim 31, wherein the blood clotting disorder is acquired TTP.
34. The use of claim 31, wherein the blood clotting disorder is cerebral infarction.
35. The use of claim 31, wherein the blood clotting disorder is ischemia reperfusion injury.
36. The use of claim 31, wherein the blood clotting disorder is myocardial infarction.
37. The use of claim 31, wherein the blood clotting er is disseminated intravasular coagulation.
38. Use of a ition comprising isolated ADAMTS13 in the manufacture of a medicament for subcutaneous administration of a therapeutically effective amount of ADAMTS13 for reducing a neurological manifestation associated with otic thrombocytopenic purpura (TTP) in a subject in need thereof.
39. The use according to claim 38, wherein the neurological manifestation is an alteration of mental status, stroke, seizures, hemiplegia, paresthesias, visual disturbance, and/or aphasia.
40. Use of a composition comprising isolated ADAMTS13 in the manufacture of a medicament for subcutaneous stration of a therapeutically effective amount of 13 for reducing fatigue associated with thrombotic thrombocytopenic purpura (TTP) in a subject in need thereof.
41. Use of a composition sing isolated ADAMTS13 in the manufacture of a medicament for subcutaneous administration of a therapeutically effective amount of ADAMTS13 for reducing severe bleeding associated with thrombotic thrombocytopenic purpura (TTP) in a subject in need thereof.
42. The use according to any one of claims 38 to 41, wherein the TTP is inherited TTP.
43. The use according to any one of claims 38 to 41, wherein the TTP is acquired TTP.
44. The use according to any one of claims 23 to 43, wherein the therapeutically effective amount comprises at least 20 to 160 activity units per kilogram body weight.
45. The use according to any one of claims 23 to 43, wherein the therapeutically effective amount is from 20 to 4,000 activity units per kilogram body .
46. The use ing to any one of claims 23 to 43, wherein the therapeutically effective amount is from 20 to 2,000 activity units per kilogram body weight
47. The use according to any one of claims 23 to 43, n the therapeutically ive amount is from 40 to 4,000 activity units per am body weight.
48. The use ing to any one of claims 23 to 43, wherein the therapeutically effective amount is from 40 to 2,000 activity units per kilogram body weight.
49. The use according to any one of claims 23 to 48, wherein the medicament is to be stered in a single bolus injection, monthly, every two weeks, weekly, twice a week, daily, every 12 hours, every 8 hours, every six hours, every four hours, or every two hours.
50. The use according to any one of claims 23 to 49, wherein the ADAMTS13 is recombinant.
51. The use according to any one of claims 23 to 49, wherein the ADAMTS13 is plasma derived.
52. The use according to any one of claims 23 to 51, n the ADAMTS13 is human ADAMTS13.
53. The use ing to any one of claims 23 to 1, wherein the composition is a stable aqueous on ready for administration.
54. The use according to any one of claims 23 to 1, wherein the composition is lyophilized.
55. The use of claim 54, wherein the composition is reconstituted with a pharmaceutically acceptable vehicle suitable for injection prior to administration.
56. The use according to any one of claims 1 to 55, wherein the therapeutically effective amount of ADAMTS13 comprises at least 120-300% of the amount of a standard intravenous dose for the disease or condition associated with ADAMTS13 and/or VWF dysfunction, for the prevention or reduction of tissue damage, for the protection against secondary injury to infarct tissue, or for the improvement of the recovery of and/or ng the damage to sensory and/or motor function, or TTP as measured in activity units per kilogram body weight.
57. The use of claim 56, wherein the standard intravenous dose for inherited TTP is from 10 to 80 activity units per kilogram body weight.
58. The use of claim 56, wherein the rd intravenous dose for acquired TTP is from 20 to 1,000 activity units per am body weight.
59. The use of claim 56, wherein and the standard intravenous dose for myocardial infarction is from 20 to 2,000 activity units per kilogram body weight.
60. The use of claim 56, n the standard intravenous dose for cerebral infarction is from 20 to 2,000 activity units per kilogram body weight.
61. The use of claim 56, wherein and the standard intravenous dose for ischemia reperfusion injury is from 20 to 2,000 activity units per kilogram body weight.
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