US2009208512A1PendingUtilityA1

Catalytic anti-factor VIII allo-antibodies

Assignee: KAVERI SRINIVASPriority: Jul 21, 1999Filed: Jan 16, 2009Published: Aug 20, 2009

Est. expiryJul 21, 2019(expired)· nominal 20-yr term from priority

Inventors:Srinivas Kaveri Sébastien Lacroix-Desmazes Michel Kazatchkine

A61P 7/00A61P 7/04A61P 7/02A61P 43/00C07K 14/755G01N 33/86G01N 33/6854A61K 38/00G01N 33/68

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References

Claims

Abstract

The present invention relates to a method of determining the presence of catalytic anti-Factor VIII allo-antibodies capable of degrading Factor VIII in a mammal, and of characterising the cleavage sites in said Factor VIII molecule by said catalytic anti-Factor VIII allo-antibodies. It also relates to an anti-Factor VIII allo-antibody-catalysed Factor VIII degradation inhibitor; and to a pharmaceutical composition comprising said catalytic anti-Factor VIII allo-antibodies which are capable of degrading Factor VIII and which originate from said method of determination; and further to a pharmaceutical composition comprising said anti-Factor VIII allo-antibody-catalysed Factor VIII degradation inhibitor. Finally, the present invention relates to the application in therapeutics of said anti-Factor VIII allo-antibody-catalysed Factor VIII degradation inhibitor, of a pharmaceutical composition comprising said catalytic anti-Factor VIII allo-antibodies which are capable of degrading Factor VIII and which originate from said method of determination, and of a pharmaceutical composition comprising said anti-Factor VIII allo-antibody-catalysed Factor VIII degradation inhibitor.

Claims

exact text as granted — not AI-modified

1 - 27 . (canceled)

28 . An isolated amino acid sequence:

SEQ. ID No. 1:
Ser Val Ala Lys Lys His Pro.

1 5

29 . An isolated amino acid sequence:

SEQ. ID No. 2:
Asp Glu Asp Glu Asn Gln Ser.

1 5

30 . An isolated amino acid sequence:

SEQ. ID No. 3:
Asp Gln Arg Gln Gly Ala Glu.

1 5

31 . A peptide or non-peptide analogue of an amino acid sequence of claim 28 , which is capable of inhibiting any site in the Factor VIII molecule which is susceptible to being lysed by an anti-Factor VIII allo-antibody.

32 . A peptide or non-peptide analogue of an amino acid sequence of claim 29 , which is capable of inhibiting any site in the Factor VIII molecule which is susceptible to being lysed by an anti-Factor VIII allo-antibody.

33 . A peptide or non-peptide analogue of an amino acid sequence of claim 30 , which is capable of inhibiting any site in the Factor VIII molecule which is susceptible to being lysed by an anti-Factor VIII allo-antibody.

34 . A method of neutralising catalytic anti-Factor VIII allo-antibodies comprising using an anti-Factor VIII allo-antibody-catalysed Factor VIII degradation inhibitor.

35 . The method of claim 34 , wherein said inhibitor comprises a protease inhibitor.

36 . The method of claim 35 , wherein said protease inhibitor is 4-(2-aminoethyl)benzenesulphonyl fluoride hydrochloride.

37 . The method of claim 34 , wherein said inhibitor inhibits cleavage of the scissile bonds: Arg 372 -Ser 373 , located between the A1 and A2 domains, Tyr 1680 -Asp 1681 , located on the N-terminus of the A3 domain, and Glu 1794 -Asp 1795 located within the A3 domain of the Factor VIII molecule.

38 . The method of claim 34 , wherein said inhibitor comprises a peptide or non-peptide analogue of the isolated amino acid sequence:

SEQ. ID No. 1:
Ser Val Ala Lys Lys His Pro.

1 5

39 . The method of claim 34 , wherein said inhibitor comprises a peptide or non-peptide analogue of the isolated amino acid sequence:

SEQ. ID No. 2:
Asp Glu Asp Glu Asn Gln Ser.

1 5

40 . The method of claim 34 , wherein said inhibitor comprises a peptide or non-peptide analogue of the isolated amino acid sequence:

SEQ. ID No. 3:
Asp Gln Arg Gln Gly Ala Glu.

1 5

41 . A pharmaceutical composition which comprises a pharmaceutically effective amount of a pharmaceutically active ingredient selected from the group consisting of an anti-Factor VIII allo-antibody capable of degrading Factor VIII, and a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable excipient, vehicle or carrier.

42 . The pharmaceutical composition of claim 41 , wherein said anti-Factor VIII allo-antibody capable of degrading Factor VIII is as obtainable from a method which comprises:
i) isolating the plasma from a sample of blood taken from said mammal, ii) isolating anti-Factor VIII allo-antibodies from said plasma; iii) placing said anti-Factor VIII allo-antibodies in contact with Factor VIII for a period of time sufficient to permit any degradation of said Factor VIII by said anti-Factor VIII allo-antibodies; and iv) determining, after said period of time, whether said Factor VIII has been degraded by said anti-Factor VIII allo-antibodies.

43 . A method of therapeutic treatment of a mammal suffering from a pathology resulting from abnormal level of Factor VIII in the blood thereof, wherein a therapeutically effective amount of a pharmaceutically active ingredient selected from the group consisting of at least one anti-Factor VIII allo-antibody capable of degrading Factor VIII, and a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable excipient, vehicle or carrier, is administered to said mammal.

44 . The method of claim 43 , wherein said pathology results from the presence of an excess of Factor VIII in the blood thereof.

45 . The method of claim 44 , wherein said pathology is of thrombotic nature.

46 . The method of claim 45 , which is a therapeutic treatment of a mammal suffering from thrombosis.

47 . A pharmaceutical composition which comprises a pharmaceutically effective amount of a pharmaceutically active ingredient selected from the group consisting of a Factor VIII degradation inhibitor of claim 34 , and a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable excipient, vehicle or carrier.

48 . A method of therapeutic treatment of a mammal suffering from a pathology resulting from the sub-physiological level of Factor VIII in the blood thereof, wherein a therapeutically effective amount of a pharmaceutically active ingredient selected from the group consisting of at least one Factor VIII degradation inhibitor, and a pharmaceutically acceptable salt thereof, is administered to said mammal.

49 . The method of claim 48 , wherein said inhibitor comprises a protease inhibitor.

50 . The method of claim 49 , wherein said protease inhibitor is 4-(2-aminoethyl)benzenesulphonyl fluoride hydrochloride.

51 . The method of claim 48 , wherein said inhibitor inhibits cleavage of the scissile bonds: Arg 372 -Ser 373 , located between the A1 and A2 domains, Tyr 1680 -Asp 1681 , located on the N-terminus of the A3 domain, and Glu 1794 -Asp 1795 located within the A3 domain of the Factor VIII molecule.

52 . The method of claim 48 , which comprises a peptide or non-peptide analogue of the amino acid sequence:

Ser Val Ala Lys Lys His Pro.

53 . The method of claim 48 , which comprises a peptide or non-peptide analogue of the amino acid sequence:

Asp Glu Asp Glu Asn Gln Ser.

54 . The method of claim 48 , which comprises a peptide or non-peptide analogue of the amino acid sequence:

Asp Gln Arg Gln Gly Ala Glu.

55 . The method of claim 48 , wherein said pathology is of haemophilic nature.

56 . The method of claim 55 , wherein said pathology of haemophilic nature is a disease involving coagulation defects due to Factor VIII insufficiency.

57 . The method of claim 55 , which is a method of therapeutic treatment of a mammal suffering from haemophilia A.

58 . An anti-Factor VIII allo-antibody-catalysed Factor VIII degradation inhibitor, which comprises a peptide or non-peptide analogue of the isolated amino acid sequence:

SEQ. ID No. 1:
Ser Val Ala Lys Lys His Pro.

1 5

59 . An anti-Factor VIII allo-antibody-catalysed Factor VIII degradation inhibitor, which comprises a peptide or non-peptide analogue of the isolated amino acid sequence:

SEQ. ID No. 2:
Asp Glu Asp Glu Asn Gln Ser.

1 5

60 . An anti-Factor VIII allo-antibody-catalysed Factor VIII degradation inhibitor, which comprises a peptide or non-peptide analogue of the isolated amino acid sequence:

SEQ. ID No. 3:
Asp Gln Arg Gln Gly Ala Glu.

1 5

61 . A pharmaceutical composition, which comprises a pharmaceutically effective amount of an anti-Factor VIII allo-antibody-catalysed Factor VIII degradation inhibitor.

62 . The pharmaceutical composition of claim 61 , which comprises a protease inhibitor.

63 . The pharmaceutical composition of claim 62 , wherein said protease inhibitor is 4-(2-aminoethyl)benzenesulphonyl fluoride hydrochloride.

64 . The pharmaceutical composition of claim 61 , wherein said inhibitor inhibits cleavage of the scissile bonds: Arg 372 -Ser 373 , located between the A1 and A2 domains, Tyr 1680 -Asp 1681 , located on the N-terminus of the A3 domain, and Glu 1794 -Asp 1795 located within the A3 domain of the Factor VIII molecule.

65 . The pharmaceutical composition of claim 61 , which comprises a peptide or non-peptide analogue of the amino acid sequence:

Ser Val Ala Lys Lys His Pro.

66 . The pharmaceutical composition of claim 61 , which comprises a peptide or non-peptide analogue of the amino acid sequence:

Asp Glu Asp Glu Asn Gln Ser.

67 . The pharmaceutical composition of claim 61 , which comprises a peptide or non-peptide analogue of the amino acid sequence:

Asp Gln Arg Gln Gly Ala Glu.

68 . An isolated anti-Factor VIII allo-antibody, which has a catalytic activity capable of catalysing degradation of Factor VIII.

69 . An isolated anti-Factor VIII allo-antibody which is obtainable by a method of determining the presence of anti-Factor VIII allow-antibodies capable of degrading Factor VIII in a mammal, which comprises:
i) isolating the plasma from a sample of blood taken from said mammal, ii) isolating anti-Factor VIII allo-antibodies from said plasma; v) placing said anti-Factor VIII allo-antibodies in contact with Factor VIII for a period of time sufficient to permit any degradation of said Factor VIII by said anti-Factor VIII allo-antibodies; and vi) determining, after said period of time, whether said Factor VIII has been degraded by said anti-Factor VIII allo-antibodies.

70 . The isolated anti-Factor VIII allo-antibody of claim 68 , which cleaves the following scissile bonds in the Factor VIII molecule: Arg 372 -Ser 373 , located between the A1 and A2 domains, Tyr 1680 -Asp 1681 , located on the N-terminus of the A3 domain, and Glu 1794 -Asp 1795 located within the A3 domain of the Factor VIII molecule.

71 . The isolated anti-Factor VIII allo-antibody of claim 69 , which cleaves the following scissile bonds in the Factor VIII molecule: Arg 372 -Ser 373 , located between the A1 and A2 domains, Tyr 1680 -Asp 1681 , located on the N-terminus of the A3 domain, and Glu 1794 -Asp 1795 located within the A3 domain of the Factor VIII molecule.

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