Methods and Compositions for the Prevention and Treatment of Sepsis

• US 20070274989A1
• Filed: 05/14/2004
• Published: 11/29/2007
• Est. Priority Date: 05/15/2003
• Status: Active Grant

• Current Assignee: Genentech, Inc. (Roche Holding AG)
• Original Assignee: Genentech, Inc. (Roche Holding AG)
• Inventors: Mollnes, Tom, Fung, Sek
• Granted Patent: US 8,329,169 B2
• Time in Patent Office: Days
• US Class Current: 424/136.100
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 37/04 Immunostimulants
• 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: C07K 16/18 against material from animals or humans
• CPC Class Codes: C07K 16/2896 against molecules with a "CD"-designation, not provided for elsewhere

Abstract

The present invention includes compositions comprising one or more complement inhibitors and one or more CD14 pathway inhibitors for the prevention or treatment of sepsis. The complement inhibitors may be antibodies that bind to and inhibit complement proteins such as C5a and the CD14 pathway inhibitors may be antibodies that bind to and inhibit CD14 pathway components, such as CD14 and LPS. The invention also relates to methods of treating subjects suffering from sepsis comprising administering these compositions, as well as kits for supplying the compositions for treatment.

Claims

1-39. -39. (canceled)

40. A composition for the prevention or treatment of sepsis comprising one or more complement inhibitors and one or more CD14 pathway inhibitors.

41. The composition of claim 40, wherein the complement inhibitor comprises an antibody or a binding fragment thereof.

42. The composition of claim 41, wherein the complement inhibitor comprises an anti-C5 antibody or a binding fragment thereof, an anti-C5a antibody or a binding fragment thereof, an anti-C5a receptor antibody or a binding fragment thereof, an anti-C3a antibody or a binding fragment thereof, an anti-C3a receptor antibody or a binding fragment thereof, an anti-C6 antibody or a binding fragment thereof, an anti-C7 antibody or a binding fragment thereof, an anti-C8 antibody or a binding fragment thereof, an anti-C9 antibody or a binding fragment thereof, an anti-properdin antibody or a binding fragment thereof, or an anti-Factor D antibody or a binding fragment thereof.

43. The composition of claim 41, wherein the complement inhibitor comprises an anti-C5a antibody or binding fragment thereof.

44. The composition of claim 40, wherein the complement inhibitor comprises a C5a receptor antagonist.

45. The composition of claim 40, wherein the complement inhibitor comprises compstatin, a C1q inhibitor, a C1 inhibitor, a C1r inhibitor, a C1s inhibitor, sCR1, Membrane Cofactor Protein (MCP), Decay Accelerating Factor (DAF), MCP-DAF fusion protein (CAB-2), C4bp, Factor H, Factor I, Carboxypeptidase N, vitronectin (S Protein), clusterin, or CD59.

46. The composition of claim 40, wherein the CD14 pathway inhibitor comprises an LPS antagonist, an LBP antagonist, an CD14 antisense nucleic acid sequence, a CD14 siRNA, or a CD14 RNAi.

47. The composition of claim 40, wherein the CD14 pathway inhibitor comprises an antibody or a binding fragment thereof.

48. The composition of claim 42 or claim 47, wherein the composition comprises an antibody having altered effector functions.

49. The composition of claim 47, wherein the CD14 pathway inhibitor comprises an anti-LPS antibody or a binding fragment thereof, an anti-LBP antibody or a binding fragment thereof, an anti-CD14 antibody or a binding fragment thereof, an anti-TLR4 antibody or a binding fragment thereof, an anti-MD2 antibody or a binding fragment thereof, an anti-TLR2 antibody or a binding fragment thereof, or an anti-TLR6 antibody or a binding fragment thereof.

50. The composition of claim 47, wherein the CD14 pathway inhibitor comprises an anti-CD14 antibody or a binding fragment thereof.

51. The composition of claim 47, wherein the CD14 pathway inhibitor comprises an anti-LPS antibody or binding fragment thereof.

52. The composition of claim 40, wherein the complement inhibitor comprises an anti-C5a antibody or binding fragment thereof and the CD14 pathway inhibitor comprises an anti-CD14 antibody or binding fragment thereof.

53. The composition of claim 40, wherein the complement inhibitor comprises an anti-C5a antibody or binding fragment thereof and the CD14 pathway inhibitor comprises an anti-LPS antibody or binding fragment thereof.

57. The composition of claim 40, further comprising one or more pharmaceutically acceptable adjuvants, carriers, excipients, and/or diluents.

58. A kit comprising the composition of claim 40.

59. The kit of claim 58, wherein the complement inhibitor and the CD-14 pathway inhibitor are supplied separately.

60. The kit of claim 58, wherein the complement inhibitor comprises an anti-C5a antibody.

61. The kit of claim 58, wherein the CD14 pathway inhibitor comprises an anti-CD14 antibody.

62. The kit of claim 58, wherein the amount of complement inhibitor or CD14 pathway inhibitor is sufficient for dosages of about 1 to about 200 milligrams per kilogram of body weight per day.

80. The method according to claim 40 or 77, further comprising one or more pharmaceutically acceptable adjuvants, carriers, excipients, and/or diluents.

54. The composition comprising a bispecific antibody comprising a first binding element that is a complement inhibitor and a second binding element that is a CD14 pathway inhibitor

55. The composition of claim 54, wherein the first binding element binds C5a.

56. The composition of claim 54, wherein the second binding element binds CD14.

63. A method for the prevention or treatment of sepsis comprising administering one or more complement inhibitors and one or more CD14 pathway inhibitors to a patient in need thereof.

64. The method according to claim 63, wherein the complement inhibitor comprises an antibody or a binding fragment thereof.

65. The method according to claim 64, wherein the complement inhibitor comprises an anti-C5 antibody or a binding fragment thereof, an anti-C5a antibody or a binding fragment thereof, an anti-C5a receptor antibody or a binding fragment thereof, an anti-C3a antibody or a binding fragment thereof, an anti-C3a receptor antibody or a binding fragment thereof, an anti-C6 antibody or a binding fragment thereof, an anti-C7 antibody or a binding fragment thereof, an anti-C8 antibody or a binding fragment thereof, an anti-C9 antibody or a binding fragment thereof, an anti-properdin antibody or a binding fragment thereof, or an anti-Factor D antibody or a binding fragment thereof.

66. The method according to claim 63, wherein the complement inhibitor comprises an anti-C5a antibody or binding fragment thereof.

67. The method according to claim 63, wherein the complement inhibitor comprises a C5a receptor antagonist.

68. The method according to claim 63, wherein the complement inhibitor comprises compstatin, a C1q inhibitor, a C1 inhibitor, a C1r inhibitor, a C1s inhibitor, sCR1, Membrane Cofactor Protein (MCP), Decay Accelerating Factor (DAF), MCP-DAF fusion protein (CAB-2), C4bp, Factor H, Factor I, Carboxypeptidase N, vitronectin (S Protein), clusterin, or CD59.

69. The method according to claim 63, wherein the CD14 pathway inhibitor comprises an LPS antagonist, an LBP antagonist, an CD14 antisense nucleic acid sequence, a CD14 siRNA, or a CD14 RNAi.

70. The method according to claim 63, wherein the CD14 pathway inhibitor comprises an antibody or a binding fragment thereof.

71. The method according to claim 63 or claim 70, wherein the composition comprises an antibody having altered effector functions.

72. The method according to claim 63, wherein the CD14 pathway inhibitor comprises an anti-LPS antibody or a binding fragment thereof, an anti-LBP antibody or a binding fragment thereof, an anti-CD14 antibody or a binding fragment thereof, an anti-TLR4 antibody or a binding fragment thereof, an anti-MD2 antibody or a binding fragment thereof, an anti-TLR2 antibody or a binding fragment thereof, or an anti-TLR6 antibody or a binding fragment thereof.

73. The method according to claim 70, wherein the CD14 pathway inhibitor comprises an anti-CD14 antibody or a binding fragment thereof.

74. The method according to claim 70, wherein the CD14 pathway inhibitor comprises an anti-LPS antibody or binding fragment thereof.

75. The method according to claim 63, wherein the complement inhibitor comprises an anti-C5a antibody or binding fragment thereof and the CD14 pathway inhibitor comprises an anti-CD14 antibody or binding fragment thereof.

76. The method according to claim 63, wherein the complement inhibitor comprises an anti-C5a antibody or binding fragment thereof and the CD14 pathway inhibitor comprises an anti-LPS antibody or binding fragment thereof.

77. A method for the prevention or treatment of sepsis comprising administering a bispecific antibody comprising a first binding element that is a complement inhibitor and a second binding element that is a CD14 pathway inhibitor to a patient in need thereof.

78. The method according to claim 77, wherein the first binding element binds C5a.

79. The method according to claim 77, wherein the second binding element binds CD14.