METHODS AND COMPOSITIONS FOR TREATING COMPLEMENT-ASSOCIATED DISORDERS

• US 20120225056A1
• Filed: 11/10/2009
• Published: 09/06/2012
• Est. Priority Date: 11/10/2008
• Status: Active Grant

• Current Assignee: Alexion Pharmaceuticals Incorporated (Astrazeneca PLC)
• Original Assignee: Alexion Pharmaceuticals Incorporated (Astrazeneca PLC)
• Inventors: Rother, Russell P., Squinto, Stephen P., Bell, Leonard, Bedrosian, Camille
• Granted Patent: US 9,447,176 B2
• Time in Patent Office: Days
• US Class Current: 424/133.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2039/54 characterised by the route of administration
• CPC Class Codes: A61K 2039/545 characterised by the dose, timing or administration schedule
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 21/02 Muscle relaxants, e.g. for tetanus or cramps
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 7/04 Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: A61P 9/14 Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• CPC Class Codes: C07K 16/18 against material from animals or humans
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/34 : Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues

Abstract

The present disclosure relates to, inter alia, compositions containing an inhibitor of human complement and use of the compositions in methods for treating or preventing complement-associated disorders. In some embodiments, the inhibitor is chronically administered to patients. In some embodiments, the inhibitor is administered to a patient in an amount and with a frequency to maintain systemic complement inhibition and prevent breakthrough. In some embodiments, the compositions contain an antibody, or antigen-binding fragment thereof, that binds to a human complement component C5 protein or a fragment of the protein such as C5a or C5b.

Claims

1. (canceled)

2. A method for transplanting an allogeneic organ or tissue, the method comprising transplanting an organ or tissue into a patient in need thereof, wherein prior to and following the transplanting a complement inhibitor is administered to the patient in an amount and with a frequency effective to substantially inhibit systemic complement activity in the patient.

3. The method of claim 2, wherein the organ or tissue is selected from the group consisting of a liver, a kidney, a heart, a lung, skin, eye, bone marrow, and vascular tissue.

7. The method of claim 2, wherein the complement inhibitor is selected from the group consisting of a polypeptide, a polypeptide analog, a nucleic acid, a nucleic acid analog, and a small molecule.

8. The method of claim 2, wherein the complement inhibitor is selected from the group consisting of soluble CRI, LEX-CRI, MCP, OAF, CD59, Factor H, cobra venom factor, FUT-175, complestatin, and K76 COOH.

10. The method of claim 2, wherein the complement inhibitor inhibits the cleavage of human complement component C5, C4, C3, or C2.

12. The method of claim 10, wherein the complement inhibitor is an antibody or antigen-binding fragment thereof that binds to a human complement component protein.

13. The method of claim 12, wherein the antibody or antigen-binding fragment thereof binds to a human complement component C5 protein.

14. The method of claim 13, wherein the antibody binds to the alpha chain of the complement component C5 protein.

15. The method of claim 14, wherein the antibody binds to the alpha chain of human complement component C5, and wherein the antibody (i) inhibits complement activation in a human body fluid, (ii) inhibits the binding of purified human complement component C5 to either human complement component C3b or human complement component C4b, and (iii) does not bind to the human complement activation product free C5a.

4-6. -6. (canceled)

9. (canceled)

11. (canceled)

16-56. -56. (canceled)

57. A method for reducing the occurrence or severity of thrombotic microangiopathy (TMA) in a patient who has, is suspected of having, or at risk of developing TMA, the method comprising administering to a patient in need thereof an inhibitor of human complement to thereby reduce the occurrence or severity of TMA in the patient.

58. The method of claim 57, wherein the patient has a complement-associated disorder.

59. The method of claim 58, wherein administration of the inhibitor reduces the occurrence or severity of TMA in the brain of the patient.

60. The method of claim 59, wherein administration of the inhibitor reduces the occurrence or severity of TMA in the kidney.

61. The method of claim 60, wherein administration of the inhibitor to the patient promotes the resolution of pre-existing TMA in the patient.

62. A method for ameliorating one or more symptoms associated with a complement-associated disorder, the method comprising administering to a patient in need thereof an inhibitor of human complement in an amount effective to ameliorate one or more symptoms associated a complement-associated disorder, wherein the symptoms are ameliorated within less than 14 days after administering the inhibitor and with the proviso that the complement-associated disorder is not paroxysmal nocturnal hemoglobinuria.

63-71. -71. (canceled)

72. A method for treating a complement-associated disorder, the method comprising administering to a patient afflicted with a complement-associated disorder an inhibitor of human complement in an amount effective to treat the complement-associated disorder, wherein the inhibitor is administered to the patient even after one or more symptoms of the disorder have been ameliorated and with the proviso that the complement-associated disorder is not paroxysmal nocturnal hemoglobinuria.

74. The method of claim 72, wherein the inhibitor is administered to the patient even after the patient has entered clinical remission.

79. The method of claim 72, wherein the inhibitor is chronically administered to the patient.

80. The method of claim 72, wherein the complement-associated disorder is selected from the group consisting of membranoproliferative glomerulonephritis, atypical hemolytic uremic syndrome, antibody-mediated rejection, HELLP syndrome, and catastrophic antiphospholipid syndrome.

73. (canceled)

75-78. -78. (canceled)

81. A method for treating aHUS, the method comprising administering to a patient in need thereof an inhibitor of complement component C5a in an amount effective to treat aHUS in the patient.

82. The method of claim 81, wherein the inhibitor is:

(i) an antibody that binds to C5a;

or (ii) an antigen-binding fragment of the antibody.

90. The method of claim 81, wherein the inhibitor is chronically administered to the patient.

83-89. -89. (canceled)

91-93. -93. (canceled)