Compositions and methods for treating coagulation related disorders

• US 20060159675A1
• Filed: 12/19/2005
• Published: 07/20/2006
• Est. Priority Date: 06/19/2003
• Status: Abandoned Application

• Current Assignee: Genentech, Inc. (Roche Holding AG)
• Original Assignee: Genentech, Inc. (Roche Holding AG)
• Inventors: Wong, Hing C., Jiao, Jin-An, Egan, Jack O.
• Application Number:
  US11/311,702
• Publication Number:
  US 20060159675A1
• Time in Patent Office: Days
• US Class Current: 424/133.100
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07K 16/36 against blood coagulation factors
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/55 Fab or Fab'

Abstract

Disclosed are methods for preventing or treating sepsis, a sepsis-related condition or an inflammatory disease in a mammal. In one embodiment, the method includes administering to the mammal a therapeutically effective amount of at least one humanized antibody, chimeric antibody, or fragment thereof that binds specifically to tissue factor (TF) to form a complex in which factor X or factor IX binding to the complex is inhibited and the administration is sufficient to prevent or treat the sepsis in the mammal. The invention has a wide spectrum of useful applications including treating sepsis, disorders related to sepsis, and inflammatory diseases such as arthritis.

Claims

1. A method for preventing or treating a sepsis or inflammatory disease in a mammal, the method comprising administering to the mammal a therapeutically effective amount of at least one humanized antibody, chimeric antibody, or fragment thereof that binds specifically to tissue factor (TF) to form a complex, wherein factor X or factor IX binding to the complex is inhibited and the administration is sufficient to prevent or treat the sepsis in the mammal.

3. The method of claims 1-2, wherein the humanized antibody, chimeric antibody or fragment thereof is further characterized by having a binding specificity for the TF about equal or greater than the antibody obtained from cell line H36.D2.B7 deposited under ATCC Accession No. HB-12255.

4. The method of claims 1-3, wherein the humanized antibody, chimeric antibody or fragment thereof is further characterized in that factor X or factor IX activation by the TF-factor VIIa complex is blocked.

5. The method of claims 14, wherein administration of the humanized antibody, chimeric antibody or fragment to the mammal increases survival time by at least about 2-fold as determined by a standard in vivo septic shock assay.

6. The method of claims 1-5, wherein administration of the humanized antibody, chimeric antibody or fragment to the mammal attenuates at least one of inflammatory cytokine (interleukin-6 (IL-6) and interleukin-8 (IL-8), interleukin-1beta (IL-1β

), tumor necrosis factor-alpha (TNFα

) or tumor necrosis factor receptor (TNFR)) levels in the mammal after at least about 5 hours.

7. The method of claims 1-6, wherein about 5 minutes after administration of the humanized antibody, chimeric antibody or fragment, the mammal exhibits a blood clotting time of between from about 30 to about 350 seconds as determined by a standard prothrombin time assay.

8. The method of claims 1-7, wherein the amount of the administered humanized antibody, chimeric antibody, or fragment is sufficient to inhibit platelet deposition by at least about 50% as determined by a standard platelet deposition assay.

9. The method of claims 1-8, wherein the humanized antibody has an IgG1 or IgG4 isotype.

10. The method of claims 1-9, wherein the human TF binding fragment is Fab, Fab′

, or F(ab)₂.

11. The method of claims 1-10, wherein the humanized antibody is a monoclonal antibody.

12. The method of claims 1-10, wherein the humanized antibody or fragment thereof is a single-chain.

13. The method of claims 1-28, wherein the mammal is a primate.

14. The method of claim 13, wherein the primate is a human patient.

15. The method of claims 1-14, wherein the sepsis is associated with at least one of disseminated intravascular coagulation (DIC), fibrin deposition, thrombosis, and lung injury.

16. The method of claims 1-14, wherein the inflammatory disease is associated with at least one of arthritis, preferably rheumatoid arthritis, glomerulonephritis, multiple sclerosis, psoriasis, Sjogren'"'"'s syndrome and inflammatory bowel disease.

17. The method of claims 1-28, wherein the amount of the humanized antibody, chimeric antibody or fragment administered to the mammal is between about 0.01 to about 25 (mg/kg).

18. A kit for performing the method of claims 1-16, wherein the kit includes at least one humanized antibody, chimeric antibody, or fragment thereof that binds specifically to human TF to form a complex, wherein factor X or factor 1×

binding to the complex is inhibited.

19. The kit of claim 17, wherein the humanized antibody, chimeric antibody, or fragment thereof is provided in a pharmaceutically acceptable vehicle.

20. The kit of claims 17-18, wherein the humanized antibody, chimeric antibody, or fragment thereof is lyophilized and the kit further includes a pharmaceutically acceptable vehicle for dissolving the humanized antibody, chimeric antibody or fragment.

26. The method of claims 22-25, wherein the administered antibody, chimeric antibody or fragment there of is encompassed by any one of claims 2-12.

28. The method of claim 27, wherein the administered antibody, chimeric antibody or fragment there of is encompassed by any one of claims 2-12.

21. A method for reducing an inflammatory cytokine production in a mammal, the method comprising administering to the mammal a therapeutically effective amount of at least one humanized antibody, chimeric antibody, or fragment thereof that binds specifically to TF to form a complex, wherein factor X or factor IX binding to the complex is inhibited and the administration is sufficient to reduce the inflammatory cytokine production in the mammal.

22. The method of claim 21, wherein the inflammatory cytokine is at least one of inflammatory cytokine (interleukin-6 (IL-6) and interleukin-8 (IL-8), interleukin-1 beta (IL-1β

), tumor necrosis factor-alpha (TNFα

) or tumor necrosis factor receptor (TNFR)).

2. The method of claim 1, wherein the humanized antibody, chimeric antibody or the fragment exhibits at least one of:

1) a dissociation constant (K_d) for the TF of less than about 0.5 nM;

or

     2) an affinity constant (K_d) for the TF of less than about 10×

10¹⁰ M<sup>−

1</sup>.

23. The method of claims 21-22, wherein the administered antibody, chimeric antibody or fragment there of is encompassed by any one of claims 2-12.

24. The method of claim 23, wherein the lung injury is acute lung injury (ALI), or acute respiratory distress syndrome (ARDS).

25. The method of claim 23, wherein the sepsis-associated renal disorder is acute tubular necrosis (ACN).

22-1. A method for preventing or treating a sepsis-related condition in a mammal, the method comprising administering to the mammal a therapeutically effective amount of at least one humanized antibody, chimeric antibody, or fragment thereof that binds specifically to tissue factor (TF) to form a complex, wherein factor X or factor IX binding to the complex is inhibited and the administration is sufficient to prevent or treat the condition in the mammal.

23-2. The method of claim 22, wherein the sepsis-related condition is one or more of disseminated intravascular coagulation (DIC), fibrin deposition, thrombosis, lung injury, or sepsis-associated renal disorder.

27. A method for preventing or treating sepsis-induced anemia in a mammal, the method comprising administering to the mammal a therapeutically effective amount of at least one humanized antibody, chimeric antibody, or fragment thereof that binds specifically to tissue factor (TF) to form a complex, wherein factor X or factor IX binding to the complex is inhibited and the administration is sufficient to prevent or treat the condition in the mammal.