Stabilized liquid and lyophilized ADAMTS13 formulations

{
  "publication_number": "US10758599B2",
  "country": "US",
  "kind": "B2",
  "title": "Stabilized liquid and lyophilized ADAMTS13 formulations",
  "abstract": "The present invention relates to formulations of ADAMTS13 with enhanced or desirable properties. As such, the invention provides liquid and lyophilized formulations of ADAMTS13 that are suitable for pharmaceutical administration. Among other aspects, the present invention also provides methods of treating various diseases and conditions related to VWF and/or ADAMTS13 dysfunction in a subject. Also provided herein are kits comprising ADAMTS13 formulations useful for the treatment of various diseases and conditions.",
  "claims": [
    "1. A method of treating or preventing thrombocytopenic purpura (TTP), the method comprising administering to a subject in need thereof a therapeutically effective dose of an ADAMTS13 formulation, wherein said subject suffers from TTP or at risk of suffering from TTP and said formulation comprises: (a) 0.05 mg/ml to 10.0 mg/ml ADAMTS13; (b) 0 mM to 100 mM of a pharmaceutically acceptable salt (c) 0.5 mM to 20 mM calcium; (d) a sugar and/or sugar alcohol; (e) a nonionic surfactant; and (f) a buffering agent for maintaining a pH between 6.0 and 8.0.",
    "2. The method of treating or preventing of claim 1, wherein said formulation comprises between about 50 units and about 1000 units of ADAMTS13 activity per mL.",
    "3. The method of treating or preventing of claim 1, wherein said pharmaceutically acceptable salt is sodium chloride (NaCl).",
    "4. The method of treating or preventing of claim 1, wherein said formulation comprises between 1.0 and 10.0 mM calcium.",
    "5. The method of treating or preventing of claim 1, wherein said formulation comprises between 2% and 6% of a sugar and/or sugar alcohol.",
    "6. The method of treating or preventing of claim 1, wherein said sugar and/or sugar alcohol is selected from the group consisting of sucrose, trehalose, mannitol, and a combination thereof.",
    "7. The method of treating or preventing of claim 1, wherein said sugar and/or sugar alcohol is a combination of sucrose and mannitol.",
    "8. The method of treating or preventing of claim 1, wherein said formulation comprises between 0.01% and 0.1% of a non-ionic surfactant.",
    "9. The method of treating or preventing of claim 1, wherein said surfactant is selected from the group consisting of Polysorbate 20, Polysorbate 80, Pluronic F-68, and BRIJ 35.",
    "10. The method of treating or preventing of claim 1, wherein said formulation comprises between 5 mM and 100 mM of a buffering agent.",
    "11. The method of treating or preventing of claim 1, wherein said formulation comprises between 10 mM and 50 mM of a buffering agent.",
    "12. The method of treating or preventing of claim 1, wherein said buffering agent is histidine or HEPES.",
    "13. The method of treating or preventing of claim 1, wherein said formulation has a pH between 6.5 and 7.5.",
    "14. The method of treating or preventing of claim 1, wherein said pH of the formulation is 7.0±0.2.",
    "15. The method of treating or preventing of claim 1, wherein said formulation further comprises between 0.5 μM and 20 μM zinc.",
    "16. The method of treating or preventing of claim 1, wherein said formulation comprises between 0 mM and 90 mM of a pharmaceutically acceptable salt.",
    "17. The method of treating or preventing of claim 1, wherein said formulation comprises between 0 mM and 60 mM of a pharmaceutically acceptable salt.",
    "18. The method of treating or preventing of claim 1, wherein said formulation comprises between 0 mM and 30 mM of a pharmaceutically acceptable salt.",
    "19. The method of treating or preventing of claim 1, wherein said formulation comprises between 30 mM and 60 mM of a pharmaceutically acceptable salt.",
    "20. The method of treating or preventing of claim 1, wherein said formulation comprises between 30 mM and 90 mM of a pharmaceutically acceptable salt.",
    "21. The method of treating or preventing of claim 1, wherein said formulation comprises between 60 mM and 90 mM of a pharmaceutically acceptable salt.",
    "22. The method of treating or preventing of claim 1, wherein said formulation comprises monomeric ADAMTS13 protein and a content of ADAMTS13 aggregates of less than 5% total protein.",
    "23. The method of treating or preventing of claim 1, wherein the specific activity of the ADAMTS13 protein is at least about 600 U of FRETS-VWF73 activity per mg ADAMTS13 protein.",
    "24. The method of treating or preventing of claim 1, wherein said formulation comprises: (a) 0.05 mg/ml to 10.0 mg/ml ADAMTS13; (b) 0 mM to 60 mM NaCl; (c) 2 mM to 4 mM calcium; (d) 2% to 4% mannitol; (e) 0.5% to 2% sucrose; (f) 0.025% to 0.1% Polysorbate 80; (g) 10 mM to 50 mM histidine; and (h) a pH of 7.0.+−.0.2.",
    "25. The method of treating or preventing of claim 1, wherein said formulation comprises: (a) 0.05 mg/ml to 10.0 mg/ml ADAMTS13; (b) 0 mM to 100 mM of a pharmaceutically acceptable salt; (c) 0.5 mM to 20 mM calcium; (d) a sugar and/or sugar alcohol; (e) a nonionic surfactant; (f) 5 mM to 100 mM of a buffering agent selected from the group consisting of histidine and HEPES; and (g) a pH between 6.0 and 8.0.",
    "26. The method of treating or preventing of claim 1, wherein said formulation comprises: (a) 0.05 mg/ml to 10.0 mg/ml ADAMTS13; (b) 0 mM to 100 mM of a pharmaceutically acceptable salt; (c) 0.5 mM to 20 mM calcium; (d) 2% to 6% of a sugar and/or sugar alcohol; (e) a nonionic surfactant; (f) 5 mM to 100 mM of a buffering agent selected from the group consisting of histidine and HEPES; and (g) a pH between 6.0 and 8.0.",
    "27. The method of treating or preventing of claim 1, wherein the TTP is acquired TTP.",
    "28. The method of treating or preventing of claim 1, wherein the TTP is hereditary TTP."
  ],
  "description_excerpt": "Not Applicable\n\nNot Applicable\n\nThe 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 disintegrin-like domain, and at least one, and in most cases multiple, thrombospondin type I repeats (for review, see Nicholson et al., BMC Evol Biol. 2005 Feb. 4; 5(1):11). These proteins, which are evolutionarily related 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 Hematol. 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 therapeutic targets for a number of pathologies (Jones G C, Curr Pharm Biotechnol. 2006 February; 7(1):25-31).\n\nOne ADAMTS family member, ADAMTS13, cleaves von Willebrand factor (vWF) between residues Tyr 1605 and Met 1606. Loss of ADAMTS13 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 March; 5(3): e1000349).",
  "cpc": [
    "A61K 38/4886",
    "A61K 38/00",
    "A61K 47/02",
    "A61K 47/10",
    "A61K 47/183",
    "A61K 47/22",
    "A61K 47/26",
    "A61K 9/0019",
    "A61K 9/08",
    "A61K 9/19",
    "A61P 7/02",
    "A61P 9/10",
    "C12Y 304/24087",
    "Y02A 50/30"
  ],
  "ipc": [
    "A61K 38/48",
    "A61K 47/02",
    "A61K 47/10",
    "A61K 47/18",
    "A61K 47/22",
    "A61K 47/26",
    "A61K 9/08",
    "A61K 9/19"
  ],
  "assignees": [
    "Baxalta GmbH",
    "Baxalta Inc"
  ],
  "inventors": [
    "Peter Matthiessen",
    "Peter L. Turecek",
    "Hans-Peter Schwarz"
  ],
  "filing_date": "2019-02-14",
  "publication_date": "2020-09-01",
  "grant_date": "2020-09-01",
  "priority_date": "2009-09-21",
  "application_number": "US-201916275690-A",
  "family_id": "43598388",
  "cited_by_count": 10,
  "citations": [
    "US20060205661A1",
    "JP2001227510A",
    "US20090017467A1",
    "US20080176312A1",
    "US6926894B2",
    "US20050266528A1",
    "US7501117B2",
    "WO2002042441A2",
    "US7361748B2",
    "WO2002088366A1",
    "US7112666B2",
    "US20060233784A1",
    "US7517522B2",
    "US7037658B2",
    "WO2003016492A2",
    "US7780831B2",
    "US20070280924A1",
    "US20070015703A1",
    "JP2007174978A",
    "US8623352B2",
    "US9572778B2",
    "US9937244B2",
    "US10238720B2"
  ]
}