Antibody composition and passive immunization against pregnancy-induced hypertension

• US 20060134106A1
• Filed: 12/23/2005
• Published: 06/22/2006
• Est. Priority Date: 07/25/2002
• Status: Active Grant

• Current Assignee: Velo Bio, LLC
• Original Assignee: Glenveigh Pharmaceuticals, LLC
• Inventors: Adair, Charles David
• Granted Patent: US 7,794,716 B2
• Time in Patent Office: Days
• US Class Current: 424/133.100
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2039/545 characterised by the dose, timing or administration schedule
• CPC Class Codes: A61K 2039/55 characterised by the host/recipient, e.g. newborn with maternal antibodies
• CPC Class Codes: A61P 15/06 Antiabortive agents; Labour repressants
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: C07K 16/44 against material not provided for elsewhere , e.g. haptens, metals, DNA, RNA, amino acids
• CPC Class Codes: C07K 2317/55 Fab or Fab'

Abstract

A composition is provided to prevent, limit the effects of, delay the onset of, or treat one or more of the causes, symptoms or complications of gestational hypertension, preeclampsia, eclampsia and/or intrauterine growth restriction. The composition comprises a therapeutically effective amount of an antibody that reacts immunologically with or binds digoxin and has a high dose of digoxin binding capacity as the active ingredient. There is also provided a method of preventing, limiting the effects of, delaying the onset of, or treating a cause, symptom or complication of gestational hypertension, preeclampsia, eclampsia or intrauterine growth restriction, comprising the step of administering to a mammal a composition comprising a therapeutically effective amount of an antibody that reacts immunologically with or binds digoxin and has a high dose of digoxin binding capacity.

Claims

1. A pharmaceutical composition of digoxin antibody for administration to a mammal who is not intoxicated by an exogenous cardenolide or bufadienolide, comprising a high dose digoxin antibody as an active ingredient, wherein said high dose digoxin antibody is therapeutically effective for treating gestational hypertension, preeclampsia, eclampsia or intrauterine growth restriction

5. The composition of any one of claims 1-4, wherein said high dose comprises between approximately 0.5 mg and 100 mg digoxin binding capacity.

6. The composition of any one of claims 1-4, wherein said high dose comprises between approximately 0.5 mg and 50 mg digoxin binding capacity.

7. The composition of any one of claims 1-4, wherein said high dose comprises between approximately 0.5 mg and 15 mg digoxin binding capacity.

8. The composition of any one of claims 1-4, wherein said high dose comprises between greater than 0.006mg and 10.0 mg digoxin binding capacity per kilogram of the weight of a mammal to be administered said composition.

9. The composition of any one of claims 1-4, wherein said high dose comprises between greater than 0.006mg and 5.0 mg digoxin binding capacity per kilogram of the weight of a mammal to be administered said composition

10. The composition of any one of claims 1-4, wherein said high dose comprises between 0.01 mg and 1.0 mg digoxin binding capacity per kilogram of the weight of a mammal to be administered said composition.

11. The composition of any one of claims 1-4, wherein said high dose comprises between 0.01 mg and 0.5 mg digoxin binding capacity per kilogram of the weight of a mammal to be administered said composition.

12. The composition of any one of claims 1-4, wherein said digoxin antibody comprises a binding fragment.

13. The composition of any one of claims 1-4, wherein said digoxin antibody is specific for digoxin or a conjugate of digoxin.

14. The composition of any one of claims 1-4, wherein said digoxin antibody is digoxin immune Fab (ovine) or is produced or derived from a sheep or from a cell line, a polypeptide or nucleic acid of ovine source.

15. The composition of any one of claims 1-4, wherein the digoxin antibody is a monoclonal antibody.

16. The composition of any one of claims 1-4, wherein the composition is therapeutically effective to cause a reduction in systolic blood pressure, diastolic blood pressure or mean arterial pressure.

17. The composition of any one of claims 1-4, wherein the composition is therapeutically effective to cause a decrease in vasoconstriction, vasospasm, exaggerated myocardial function or intravascular volume contraction.

18. The composition of any one of claims 1-4, wherein the composition is therapeutically effective to cause a decrease in proteinuria, a serum creatinine level or a liver enzyme level.

19. The composition of any one of claims 1-4, wherein the composition is therapeutically effective to cause an increase in urinary output or creatinine clearance.

20. The composition of any one of claims 1-4, wherein the composition is therapeutically effective to cause an increase in blood flow in a middle cerebral artery, an umbilical artery or an umbilical vein.

21. The composition of any one of claims 1-4, wherein the composition is therapeutically effective to cause a normalization in the systolic/diastolic ratio of a middle cerebral artery or a reduction in the systolic/diastolic ratio of an umbilical artery or an umbilical vein.

22. The composition of any one of claims 1-4, wherein the composition is therapeutically effective to cause normalization in the resistance index of a middle cerebral artery or a reduction in the resistance index of an umbilical artery or an umbilical vein.

23. The composition of any one of claims 1-4, wherein the composition is therapeutically effective to cause an improvement in the diastolic pressure of a middle cerebral artery, an umbilical artery or an umbilical vein.

24. The composition of any one of claims 1-4, wherein the composition is therapeutically effective to improve clonus, hyper reflexia, central nervous system irritability, eclamptic seizure, ocular function, or fetal periventricular or intraventricular hemorrhage.

25. The composition of any one of claims 1-4, wherein the composition is therapeutically effective to cause a reduction in systolic blood pressure, diastolic blood pressure or mean arterial pressure, vasoconstriction, vasospasm, exaggerated myocardial function or intravascular volume contraction, and wherein said reduction is clinically beneficial.

26. The composition of any one of claims 1-4, wherein the composition is therapeutically effective to cause a reduction in systolic blood pressure, diastolic blood pressure or mean arterial pressure, vasoconstriction, vasospasm, exaggerated myocardial function or intravascular volume contraction, and wherein said reduction is statistically significant.

27. The composition of any one of claims 1-4, wherein the composition is therapeutically effective to cause a reduction in proteinuria, a serum creatinine level or a liver enzyme level and wherein said reduction is clinically beneficial.

28. The composition of any one of claims 1-4, wherein the composition is therapeutically effective to cause a reduction in proteinuria, a serum creatinine level or a liver enzyme level and wherein said reduction is statistically significant.

29. The composition of any one of claims 1-4, wherein the composition is therapeutically effective to cause an increase in urinary output or creatinine clearance and wherein said increase is clinically beneficial.

30. The composition of any one of claims 1-4, wherein the composition is therapeutically effective to cause an increase in urinary output or creatinine clearance, and wherein said increase is statistically significant.

31. The composition of any one of claims 1-4, wherein the composition is therapeutically effective to cause an improvement or normalization in the blood flow or in the systolic/diastolic ratio or in the resistance index of in a middle cerebral artery, an umbilical artery or an umbilical vein, and wherein said improvement or normalization is clinically beneficial.

32. The composition of any one of claims 1-4, wherein the composition is therapeutically effective to cause an improvement or normalization in the blood flow or in the systolic/diastolic ratio or the resistance index or in the diastolic pressure of a middle cerebral artery, an umbilical artery or an umbilical vein, and wherein said improvement or normalization is clinically beneficial.

33. The composition of any one of claims 1-4, wherein the composition is therapeutically effective to cause an increase or normalization in the blood flow or in the systolic/diastolic ratio or in the resistance index or in the diastolic pressure of a middle cerebral artery, an umbilical artery or an umbilical vein, and wherein said increase is statistically significant.

34. The composition of any one of claims 1-4, wherein the composition is therapeutically effective to cause an improvement in clonus, hyper reflexia, central nervous system irritability, eclamptic seizure, ocular function, or fetal periventricular or intraventricular hemorrhage, and wherein said improvement is clinically beneficial.

35. The composition of any one of claims 1-4, wherein the composition is therapeutically effective to cause an improvement in clonus, hyper reflexia, central nervous system irritability, eclamptic seizure, ocular function, or fetal periventricular or intraventricular hemorrhage, and wherein said improvement is statistically significant.

36. The composition of any one of claims 1-4, wherein said composition is sufficient to cause a reduction or improvement in diastolic blood pressure, systolic blood pressure or mean arterial pressure, and wherein said statistically significant reduction or improvement commences at a time that is less than four hours after commencing administration of said composition.

37. The composition of claim 36, wherein said statistically significant reduction or improvement continues for a period of time that is more than four hours after commencing administration of said composition.

38. The composition of any one of claims 1-4, wherein said composition is diluted or solubilized with an excipient, diluent or solvent.

39. The composition of claim 37, wherein said excipient, diluent or solvent comprises a sterile aqueous solution, and wherein said sterile aqueous solution is selected from among the group consisting of sterile water, sterile water for injection, physiological saline, phosphate buffered saline, 0.5% dextrose, lactated Ringer'"'"'s solution and Ringer'"'"'s solution.

40. A method for treating gestational hypertension, preeclampsia, eclampsia or intrauterine growth restriction, comprising the step of administering the composition of any one of claims 1-4 to a mammal in need thereof.

41. The method of claim 40, wherein said composition is solubilized or diluted with a suitable solvent, diluent or excipient prior to the administration.

42. The method of claim 40, further comprising the step of evaluating the mammal for one or more risk factors, diagnostic indicators, causes, symptoms or complications of gestational hypertension, preeclampsia, eclampsia or intrauterine growth restriction.

43. The method of claim 42, further comprising the step of determining that the mammal exhibits one or more of said risk factors, diagnostic indicators, causes, symptoms or complications.

44. The method of claim 40, further comprising the step of repeating the administration of a composition of any one of claims 1-4.

45. The method of claim 44, wherein the repeat administration occurs at an interval of between approximately one hour and approximately thirty-six hours, or between approximately one hour and approximately twenty-four hours, or between approximately one hour and approximately fifteen hours, or between approximately three hours and approximately eight hours.

46. The method of claim 44, wherein the repeat administration occurs at approximately six hours.

47. The method of claim 40, wherein the composition is administered intravenously.

48. The method of claim 40, wherein the composition is administered over a period of thirty-six hours or less.

49. The method of claim 40, wherein the composition is administered over a period of twenty-four hours or less.

50. The method of claim 40, wherein the composition is administered over a period of twelve hours or less.

51. The method of claim 40, wherein the composition is administered by intravenous bolus infusion.

52. The method of claim 40, wherein the composition is administered by intravenous bolus injection.

53. The method of claim 40, further comprising the step of administering at least one therapeutically effective amount of a corticosteroid.

54. The method of claim 53, wherein the corticosteroid is administered at least thirty minutes prior to administration of said composition.

55. The method of claim 40, further comprising the step of administering at least one therapeutically effective amount of an antihypertensive drug.

56. The method of claim 55, wherein said antihypertensive drug is selected from among the group consisting of labetalol, altenolol, nifedipine, 1-methyldopa and hydralazine.

57. The method of claim 40, further comprising the step of administering at least one therapeutically effective amount of magnesium sulfate or phenytoin.

58. A method for treating gestational hypertension, preeclampsia, eclampsia or intrauterine growth restriction, comprising the steps of:

(a) evaluating a mammal for one or more risk factors, diagnostic indicators, causes, symptoms, or complications of gestational hypertension, preeclampsia, eclampsia or intrauterine growth restriction;

(b) determining that said subject exhibits one or more of said risk factors, diagnostic indicators, causes, symptoms or complications;

(c) providing a composition of any one of claims 1-4;

(d) solubilizing or diluting the composition with a solvent, diluent or excipient; and

(e) administering said solubilized or diluted composition to said mammal.

59. The method of claim 58, further comprising the step of repeating steps (c) through (e).

60. The method of claim 58, wherein said steps (c), (d), and (e) are repeated between approximately every four and approximately every eight hours.

61. The method of claim 58, wherein said solubilized composition is administered by intravenous bolus infusion.

62. The method of claim 58, further comprising the step of administering to said mammal at least one therapeutically effective amount of a corticosteroid, an antihypertensive, an anti-convulsant or any combination thereof.

2. A pharmaceutical composition of digoxin antibody for administration to a mammal who is not intoxicated by an exogenous cardenolide or bufadienolide, comprising a high dose digoxin antibody as an active ingredient, wherein said high dose digoxin antibody is therapeutically effective for treating a symptom or condition associated with the presence of an endogenous inhibitor of Na⁺/K⁺ ATPase.

3. A pharmaceutical composition comprising a high dose digoxin antibody as an active ingredient in a single application dose, wherein said high dose digoxin antibody is therapeutically effective for treating gestational hypertension, preeclampsia, eclampsia, or intrauterine growth restriction.

4. A composition of digoxin antibody as a single application dose, comprising as an active ingredient an amount of digoxin antibody having greater than 0.006 mg digoxin binding capacity per kilogram of weight of a mammal to whom the composition is to be administered, wherein said mammal is not intoxicated by an exogenous cardenolide or bufadienolide, and wherein said high dose digoxin antibody is therapeutically effective for treating gestational hypertension, preeclampsia, eclampsia, or intrauterine growth restriction.

63. A method of treating gestational hypertension, preeclampsia, eclampsia or intrauterine growth restriction, comprising the steps of:

(a) selecting a composition from Table II.A, Table II.B or Table III; and

(b) administering the composition to a mammal in need thereof.

65. The method of either of claims 63 or 64, further comprising the step of administering at least one therapeutically effective amount of a corticosteroid, an antihypertensive drug or an anti-convulsant or any combination thereof.

64. A method of treating gestational hypertension, preeclampsia, eclampsia or intrauterine growth restriction, comprising the steps of:

(a) selecting a composition from Table II.A, Table II.B or Table III;

(b) administering the composition to a mammal in need thereof;

(c) monitoring the mammal'"'"'s blood pressure; and

(d) repeating steps (a) and (b) or steps (a), (b) and (c) at least once.

66. A method of treating gestational hypertension, preeclampsia, eclampsia or intrauterine growth restriction in a mammal comprising the steps of:

(a) providing a serum “

digoxin”

concentration;

(b) selecting a composition of digoxin antibody from Table II.A, Table II.B or Table III, wherein the composition is selected based upon said serum “

digoxin”

concentration;

(c) administering the composition to a mammal; and

(d) repeating steps (b) and (c) at least once.

67. The method of claim 66, wherein said serum “

digoxin”

concentration is from among the range of serum “

digoxin”

concentrations known to be present in pregnant women.

68. The method of claim 66, wherein said serum “

digoxin”

concentration is quantified in the mammal before the initial administration of said composition.

69. A method for determining a composition of digoxin antibody to be administered to a mammal at risk for developing or demonstrating one or more causes or symptoms or complications of gestational hypertension, preeclampsia, eclampsia or intrauterine growth restriction, comprising:

(a) providing the weight of a mammal;

(b) selecting a serum “

digoxin”

concentration between 0.1 ng/mL and 2.0 ng/mL;

(c) selecting a digoxin antibody composition from among the range of compositions described in Table II.A, Table II.B or Table III, wherein said composition is selected based upon the values obtained in steps (a) and (b).

70. A method for treating gestational hypertension, preeclampsia, eclampsia or intrauterine growth restriction in mammal, comprising the step of administering at least one composition of digoxin antibody to a subject mammal, wherein said composition has a digoxin binding capacity between greater than 0.006 and approximately 10 milligrams per kilogram of the weight of said mammal.

71. The method of claim 70, wherein the composition has digoxin binding capacity between greater than 0.006 and approximately 5.0 milligrams per kilogram of the mammal'"'"'s weight.

72. The method of claim 70, wherein the composition has digoxin binding capacity between approximately 0.01 mg and approximately 1.0 mg per kilogram of the mammal'"'"'s weight.

73. The method of claim 70, wherein the composition has digoxin binding capacity between approximately 0.01 and approximately 0.5 milligrams per kilogram of the mammal'"'"'s weight.

74. The method of claim 70, wherein the composition has digoxin binding capacity of at least 0.032 milligrams per kilogram of the mammal'"'"'s weight, and wherein said composition is administered over a period of 30 hours or less.

75. The method of claim 70, wherein said composition has digoxin binding capacity that is between approximately 0.032 and approximately 0.171 milligrams per kilogram of said mammal'"'"'s weight, and wherein said composition is administered over a period 30 hours or less.

76. The method of claim 70, wherein said composition has digoxin binding capacity between approximately 0.066 and approximately 0.171 milligrams per kilogram of said mammal'"'"'s weight, and wherein said composition is administered over a period of 30 hours or less.

77. The method of claim 70, wherein said composition has digoxin binding capacity between approximately 0.081 and approximately 0.171 milligrams per kilogram of said mammal'"'"'s weight, and wherein said composition is administered over a period of 30 hours or less.

78. The method of claim 70, wherein said composition has digoxin binding capacity between approximately 0.122 and approximately 0.171 milligrams per kilogram of said mammal'"'"'s weight, and wherein said composition is administered over a period of 30 hours or less.

79. A method for treating gestational hypertension, preeclampsia, eclampsia or intrauterine growth restriction in a mammal, comprising the step of administering to a mammal a composition capable of interfering with an effect of an endogenous Na⁺/K⁺ ATPase inhibitor on said mammal, wherein said administration is for a time and in an amount therapeutically effective to treat gestational hypertension, preeclampsia, eclampsia or intrauterine growth restriction.

80. A pharmaceutical composition comprising a compound capable of binding digoxin, digitoxin, digitoxigenin, digoxigenin, or gitoxingenin, wherein said composition has the ability to bind greater than 0.006 mg of digoxin digitoxin, digitoxigenin, digoxigenin, or gitoxingenin per kilogram body weight of a mammal to whom the composition will be administered, and wherein said composition is therapeutically effective for treating a cause, a symptom or a complication of a condition associated with an endogenous inhibitor of Na⁺/K⁺ ATPase.