Treatment of corticosteroid-dependent asthma with anti-TSLP antibodies

Abstract

This disclosure relates to a method for treating corticosteroid-dependent asthma, such as oral corticosteroid (OCS)-dependent asthma, using antibodies that are generally specific to thymic interstitial lymphocyte necrosis factor (TSLP).

Claims

1. A method for treating corticosteroid-dependent asthma in a subject, comprising administering a therapeutically effective dose of anti-TSLP at a dose of 140 to 420 mg at intervals of every two weeks or every four weeks, wherein the antibody is a. Light chain variable domain, i. Light chain CDR1 sequence containing the amino acid sequence shown in Sequence ID No. 3; ii. Light chain CDR2 sequence containing the amino acid sequence shown in Sequence ID No. 4; iii. Light chain CDR3 sequence containing the amino acid sequence shown in Sequence ID No. 5 Light chain variable domains, including, b. A heavy chain variable domain, i. A heavy chain CDR1 sequence containing the amino acid sequence shown in Sequence ID No. 6; ii. A heavy chain CDR2 sequence containing the amino acid sequence shown in Sequence ID No. 7, and iii. Heavy chain CDR3 sequence containing the amino acid sequence shown in Sequence ID No. 8 Heavy chain variable domains A method comprising the following, wherein the antibody specifically binds to the TSLP polypeptide represented by amino acids 29-159 of SEQ ID NO: 2, and the antibody is an IgG2 antibody.

2. A method for treating corticosteroid-dependent asthma in a subject, comprising administering a therapeutically effective dose of anti-TSLP antibody at a dose of 140 to 420 mg at intervals of every two weeks or every four weeks, wherein the antibody is a. Light chain variable domain, i. An amino acid sequence that is at least 80% identical to SEQ ID NO: 12; ii. A sequence of amino acids encoded by a polynucleotide sequence that is at least 80% identical to sequence number 11; iii. The sequence of amino acids encoded by a polynucleotide that hybridizes with the complement of the polynucleotide consisting of SEQ ID NO: 11 under moderately stringent conditions. A light chain variable domain selected from the group consisting of, b. A heavy chain variable domain, i. An amino acid sequence that is at least 80% identical to SEQ ID NO: 10; ii. An amino acid sequence encoded by a polynucleotide sequence that is at least 80% identical to sequence number 9; iii. The sequence of amino acids encoded by a polynucleotide that hybridizes with the complement of the polynucleotide consisting of SEQ ID NO: 9 under moderately stringent conditions. A heavy chain variable domain selected from the group consisting of, c. Light chain variable domain of (a) and heavy chain variable domain of (b) A method comprising the antibody, wherein the antibody specifically binds to the TSLP polypeptide represented by amino acids 29 to 159 of SEQ ID NO:

2.

3. The method according to claim 1 or 2, wherein the light chain variable domain is described in Sequence ID No. 12 and the heavy chain variable domain is described in Sequence ID No.

10.

4. The method according to any one of claims 1 to 3, wherein the antibody is administered every two weeks or every four weeks.

5. The method according to any one of claims 1 to 4, wherein the antibody is an IgG2 antibody.

6. The method according to any one of claims 1 to 5, wherein the antibody is administered in a dose of 210 mg.

7. The method according to any one of claims 1 to 6, wherein the antibody is tezeperumab.

8. A method for treating corticosteroid-dependent asthma in a subject comprising administering a therapeutically effective dose of anti-TSLP antibody at a dose of 210 mg at intervals of four weeks, wherein the antibody is a. Light chain variable domain, i. Light chain CDR1 sequence containing the amino acid sequence shown in Sequence ID No. 3; ii. Light chain CDR2 sequence containing the amino acid sequence shown in Sequence ID No. 4; iii. Light chain CDR3 sequence containing the amino acid sequence shown in Sequence ID No. 5 Light chain variable domains, including, b. A heavy chain variable domain, i. A heavy chain CDR1 sequence containing the amino acid sequence shown in Sequence ID No. 6; ii. A heavy chain CDR2 sequence containing the amino acid sequence shown in Sequence ID No. 7, and iii. Heavy chain CDR3 sequence containing the amino acid sequence shown in Sequence ID No. 8 Heavy chain variable domains A method comprising the antibody, wherein the antibody specifically binds to the TSLP polypeptide represented by amino acids 29 to 159 of SEQ ID NO:

2.

9. A method for treating corticosteroid-dependent asthma in a subject comprising administering a therapeutically effective dose of anti-TSLP antibody at a dose of 210 mg at intervals of four weeks, wherein the antibody is a. Light chain variable domain, i. An amino acid sequence that is at least 80% identical to SEQ ID NO: 12; ii. A sequence of amino acids encoded by a polynucleotide sequence that is at least 80% identical to sequence number 11; iii. The sequence of amino acids encoded by a polynucleotide that hybridizes with the complement of the polynucleotide consisting of SEQ ID NO: 11 under moderately stringent conditions. A light chain variable domain selected from the group consisting of, b. A heavy chain variable domain, i. An amino acid sequence that is at least 80% identical to SEQ ID NO: 10; ii. An amino acid sequence encoded by a polynucleotide sequence that is at least 80% identical to sequence number 9; iii. The sequence of amino acids encoded by a polynucleotide that hybridizes with the complement of the polynucleotide consisting of SEQ ID NO: 9 under moderately stringent conditions. A heavy chain variable domain selected from the group consisting of, c. Light chain variable domain of (a) and heavy chain variable domain of (b) A method comprising the antibody, wherein the antibody specifically binds to the TSLP polypeptide represented by amino acids 29 to 159 of SEQ ID NO:

2.

10. The method according to claim 8 or 9, wherein the light chain variable domain is described in Sequence ID No. 12 and the heavy chain variable domain is described in Sequence ID No.

10.

11. The method according to any one of claims 1 to 10, wherein the antibody is administered for a period of at least 4 months, 6 months, 9 months, 1 year, 2 years or longer.

12. The method according to any one of claims 1 to 11, wherein the anti-TSLP antibody is bivalent and selected from the group consisting of human antibody, humanized antibody, chimeric antibody, monoclonal antibody, recombinant antibody, IgG1 antibody, IgG2 antibody, IgG3 antibody, and IgG4 antibody.

13. The method according to any one of claims 8 to 13, wherein the antibody is an IgG2 antibody.

14. The method according to any one of claims 6 to 11, wherein the antibody is tezeperumab.

15. The method according to any one of claims 1 to 14, wherein the antibody is a human antibody.

16. The method according to any one of claims 1 to 15, wherein the antibody is administered to the subject in a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient.

17. The method according to any one of claims 1 to 16, wherein the corticosteroid-dependent asthma is severe or asthma.

18. The method according to any one of claims 1 to 17, wherein the corticosteroid-dependent asthma is oral corticosteroid-dependent asthma.

19. The method according to any one of claims 1 to 18, wherein the subject is an adult.

20. The method according to any one of claims 1 to 19, wherein the subject is a child or an adolescent.

21. The aforementioned administration is based on forced expiratory volume (FEV), FEV １ Reversibility, forced vital capacity (FVC), FeNO, ACQ-6 score and AQLQ(S)+12 score, pre-BD administration FEV １ The method according to any one of claims 1 to 20, which improves one or more measures of corticosteroid-dependent asthma selected from the group consisting of: change from baseline, reduction from baseline of the daily maintenance OCS dose, daily maintenance OCS dose of 5 mg or less, and reduction of 50% or more from baseline of the daily maintenance OCS dose, time to asthma exacerbation and first asthma exacerbation as measured by AAER, asthma exacerbation rate associated with emergency room (ER) visit, emergency clinic visit or hospitalization, and the proportion of participants who did not experience an asthma exacerbation, weekly mean home PEF (morning and evening), adrenal insufficiency, and / or St. George Respiratory Questionnaire (SGRQ) score.

22. The method according to any one of claims 1 to 21, wherein the administration improves one or more symptoms of corticosteroid-dependent asthma as measured by a patient symptom diary.

23. The method according to any one of claims 1 to 22, wherein the antibody is administered every four weeks.

24. The method according to any one of claims 1 to 23, wherein the antibody is tezeperumab.

25. The method according to claim 24, wherein the antibody is an IgG2 antibody and has the full-length heavy chain and light chain sequences described in SEQ ID NOs: 13 and 14, respectively.

26. The method according to any one of claims 1 to 25, wherein the antibody variant has pK characteristics substantially similar to tezepermab-ekko in humans.

27. A method for reducing the frequency of asthma exacerbations in a subject having corticosteroid-dependent asthma, comprising administering a therapeutically effective dose of anti-TSLP antibody at a dose of 140 mg to 420 mg at intervals of two weeks or four weeks, wherein the antibody is a. Light chain variable domain, i. Light chain CDR1 sequence containing the amino acid sequence shown in Sequence ID No. 3; ii. Light chain CDR2 sequence containing the amino acid sequence shown in Sequence ID No. 4; iii. Light chain CDR3 sequence containing the amino acid sequence shown in Sequence ID No. 5 Light chain variable domains, including, b. A heavy chain variable domain, i. A heavy chain CDR1 sequence containing the amino acid sequence shown in Sequence ID No. 6; ii. A heavy chain CDR2 sequence containing the amino acid sequence shown in Sequence ID No. 7, and iii. Heavy chain CDR3 sequence containing the amino acid sequence shown in Sequence ID No. 8 Heavy chain variable domains A method comprising the antigen-binding protein, wherein the antigen-binding protein specifically binds to the TSLP polypeptide represented by amino acids 29-159 of SEQ ID NO:

2.

28. A method for reducing the frequency of asthma exacerbations in a subject having corticosteroid-dependent asthma, comprising administering a therapeutically effective dose of anti-TSLP antibody at a dose of 140 mg to 420 mg at intervals of two weeks or four weeks, wherein the antibody is a. Light chain variable domain, i. An amino acid sequence that is at least 80% identical to SEQ ID NO: 12; ii. A sequence of amino acids encoded by a polynucleotide sequence that is at least 80% identical to sequence number 11; iii. The sequence of amino acids encoded by a polynucleotide that hybridizes with the complement of the polynucleotide consisting of SEQ ID NO: 11 under moderately stringent conditions. A light chain variable domain selected from the group consisting of, b. A heavy chain variable domain, i. An amino acid sequence that is at least 80% identical to SEQ ID NO: 10; ii. An amino acid sequence encoded by a polynucleotide sequence that is at least 80% identical to sequence number 9; iii. The sequence of amino acids encoded by a polynucleotide that hybridizes with the complement of the polynucleotide consisting of SEQ ID NO: 9 under moderately stringent conditions. A heavy chain variable domain selected from the group consisting of, c. Light chain variable domain of (a) and heavy chain variable domain of (b) Methods that include...

29. The method according to claim 27 or 28, wherein the light chain variable domain is described in Sequence ID No. 12 and the heavy chain variable domain is described in Sequence ID No.

10.

30. The method according to any one of claims 27 to 29, wherein the antibody is administered every four weeks.

31. The method according to any one of claims 27 to 30, wherein the antibody is administered in a dose of 210 mg.

32. The method according to any one of claims 27 to 31, wherein the administration is performed for a period of at least four months, six months, nine months, one year, two years or longer.

33. The method according to any one of claims 27 to 32, wherein the anti-TSLP antibody is selected from the group consisting of human antibodies, humanized antibodies, chimeric antibodies, monoclonal antibodies, recombinant antibodies, IgG1 antibodies, IgG2 antibodies, IgG3 antibodies, and IgG4 antibodies.

34. The method according to any one of claims 27 to 33, wherein the antibody is an IgG2 antibody.

35. The method according to any one of claims 27 to 34, wherein the antibody is a human antibody.

36. The method according to any one of claims 27 to 35, wherein the antibody is tezeperumab.

37. The method according to any one of claims 27 to 36, wherein the antibody is administered to the subject in a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient.

38. The method according to any one of claims 27 to 37, wherein the administration delays the time to asthma exacerbation compared to subjects who have not received the anti-TSLP antibody.

39. The method according to any one of claims 27 to 38, wherein the administration reduces the frequency or level of co-administration therapy in the subject.

40. The method according to claim 39, wherein the administration eliminates the need for oral corticosteroid therapy or inhaled corticosteroid therapy.

41. The method according to any one of claims 27 to 40, wherein the method comprises reducing the dose of the corticosteroid received by the subject during the tapering phase of treatment, and maintaining the subject at a maintenance dose of the corticosteroid.

42. The method according to claim 41, wherein the dose of the corticosteroid is reduced every four weeks for approximately 20 weeks.

43. The method according to claim 41 or 42, wherein the dose of the corticosteroid is reduced by 5 mg / day or 2.5 mg / day.

44. A method for eliminating the need for oral corticosteroids in a subject having asthma, comprising administering a therapeutically effective dose of anti-TSLP antibody to the subject at a dose of 210 mg at intervals of four weeks for at least two years, wherein the antibody comprises a light chain variable domain comprising i. a light chain CDR1 sequence containing the amino acid sequence shown in SEQ ID NO: 3; ii. a light chain CDR2 sequence containing the amino acid sequence shown in SEQ ID NO: 4; iii. a light chain CDR3 sequence containing the amino acid sequence shown in SEQ ID NO: 5; and b. a heavy chain variable domain comprising i. a heavy chain CDR1 sequence containing the amino acid sequence shown in SEQ ID NO: 6; ii. a heavy chain CDR2 sequence containing the amino acid sequence shown in SEQ ID NO: 7; and iii. a heavy chain CDR3 sequence containing the amino acid sequence shown in SEQ ID NO: 8, wherein the antigen-binding protein specifically binds to the TSLP polypeptide shown in amino acids 29-159 of SEQ ID NO:

2.

45. A method for eliminating the need for oral corticosteroids in a subject with asthma, comprising administering a therapeutically effective dose of anti-TSLP antibody at a dose of 210 mg at intervals of four weeks for at least two years, wherein the antibody comprises: a. a light chain variable domain, selected from the group consisting of i. an amino acid sequence at least 80% identical to SEQ ID NO: 12; ii. an amino acid sequence encoded by a polynucleotide sequence at least 80% identical to SEQ ID NO: 11; iii. an amino acid sequence encoded by a polynucleotide that hybridizes with the polynucleotide complement of SEQ ID NO: 11 under moderately stringent conditions; and b. a heavy chain variable domain, selected from the group consisting of i. an amino acid sequence at least 80% identical to SEQ ID NO: 10; ii. an amino acid sequence encoded by a polynucleotide sequence at least 80% identical to SEQ ID NO: 9; iii. an amino acid sequence encoded by a polynucleotide that hybridizes with the polynucleotide complement of SEQ ID NO: 9 under moderately stringent conditions; or c. A method comprising the light chain variable domain of (a) and the heavy chain variable domain of (b).

46. A method for reducing the daily maintenance oral corticosteroid dose to 5 mg / day or less in a subject having asthma, comprising administering a therapeutically effective dose of anti-TSLP antibody to the subject at a dose of 210 mg at 4-week intervals for at least 2 years, wherein the antibody comprises a. a light chain variable domain comprising i. a light chain CDR1 sequence containing the amino acid sequence shown in SEQ ID NO: 3; ii. a light chain CDR2 sequence containing the amino acid sequence shown in SEQ ID NO: 4; iii. a light chain CDR3 sequence containing the amino acid sequence shown in SEQ ID NO: 5; and b. a heavy chain variable domain comprising i. a heavy chain CDR1 sequence containing the amino acid sequence shown in SEQ ID NO: 6; ii. a heavy chain CDR2 sequence containing the amino acid sequence shown in SEQ ID NO: 7; and iii. a heavy chain CDR3 sequence containing the amino acid sequence shown in SEQ ID NO: 8, wherein the antigen-binding protein specifically binds to the TSLP polypeptide shown by amino acids 29-159 of SEQ ID NO:

2.

47. A method for reducing the daily maintenance oral corticosteroid dose to 5 mg / day or less in a subject with asthma, comprising administering a therapeutically effective dose of anti-TSLP antibody at a dose of 210 mg at 4-week intervals for at least 2 years, wherein the antibody comprises: a. a light chain variable domain, selected from the group consisting of i. an amino acid sequence at least 80% identical to SEQ ID NO: 12; ii. an amino acid sequence encoded by a polynucleotide sequence at least 80% identical to SEQ ID NO: 11; iii. an amino acid sequence encoded by a polynucleotide that hybridizes with the complement of the polynucleotide consisting of SEQ ID NO: 11 under moderately stringent conditions; and b. a heavy chain variable domain, consisting of i. an amino acid sequence at least 80% identical to SEQ ID NO: 10; ii. an amino acid sequence encoded by a polynucleotide sequence at least 80% identical to SEQ ID NO: 9; iii. A heavy chain variable domain selected from the group consisting of a polynucleotide complement of sequence number 9 and an amino acid sequence encoded by a polynucleotide that hybridizes under moderately stringent conditions, or a method comprising the light chain variable domain of (a) and the heavy chain variable domain of (b).

48. The method according to any one of claims 44 to 47, wherein the light chain variable domain is described in Sequence ID No. 12 and the heavy chain variable domain is described in Sequence ID No.

10.

49. The method according to any one of claims 27 to 48, wherein the anti-TSLP antibody is tezeperumab.

50. The method according to claim 49, wherein the antibody is an IgG2 antibody and has the full-length heavy chain and light chain sequences described in SEQ ID NOs: 13 and 14, respectively.

51. The method according to any one of claims 27 to 50, wherein the subject has oral corticosteroid-dependent asthma.

52. The method according to any one of claims 1 to 51, wherein the administration is subcutaneous or intravenous.

53. An anti-TSLP antibody for treating corticosteroid-dependent asthma in a subject, comprising administering a therapeutically effective dose of an anti-TSLP antibody or antibody variant to the subject at a dose of 140 to 420 mg every two weeks or every four weeks, wherein the antibody is a. Light chain variable domain, i. Light chain CDR1 sequence containing the amino acid sequence shown in Sequence ID No. 3; ii. Light chain CDR2 sequence containing the amino acid sequence shown in Sequence ID No. 4; iii. Light chain CDR3 sequence containing the amino acid sequence shown in Sequence ID No. 5 Light chain variable domains, including, b. A heavy chain variable domain, i. A heavy chain CDR1 sequence containing the amino acid sequence shown in Sequence ID No. 6; ii. A heavy chain CDR2 sequence containing the amino acid sequence shown in Sequence ID No. 7, and iii. Heavy chain CDR3 sequence containing the amino acid sequence shown in Sequence ID No. 8 Heavy chain variable domains An anti-TSLP antibody comprising the above, wherein the antibody specifically binds to the TSLP polypeptide represented by amino acids 29-159 of SEQ ID NO: 2, and the antibody is an IgG2 antibody.

54. An anti-TSLP antibody for treating corticosteroid-dependent asthma in a subject, comprising administering a therapeutically effective dose of an anti-TSLP antibody or antibody variant to the subject at a dose of 140 to 420 mg every two weeks or every four weeks, wherein the antibody is a. Light chain variable domain, i. An amino acid sequence that is at least 80% identical to SEQ ID NO: 12; ii. A sequence of amino acids encoded by a polynucleotide sequence that is at least 80% identical to sequence number 11; iii. The sequence of amino acids encoded by a polynucleotide that hybridizes with the complement of the polynucleotide consisting of SEQ ID NO: 11 under moderately stringent conditions. A light chain variable domain selected from the group consisting of, b. A heavy chain variable domain, i. An amino acid sequence that is at least 80% identical to SEQ ID NO: 10; ii. An amino acid sequence encoded by a polynucleotide sequence that is at least 80% identical to sequence number 9; iii. The sequence of amino acids encoded by a polynucleotide that hybridizes with the complement of the polynucleotide consisting of SEQ ID NO: 9 under moderately stringent conditions. A heavy chain variable domain selected from the group consisting of, c. Light chain variable domain of (a) and heavy chain variable domain of (b) An anti-TSLP antibody comprising the above, wherein the antibody specifically binds to the TSLP polypeptide represented by amino acids 29-159 of SEQ ID NO:

2.

55. The use of an anti-TSLP antibody for the manufacture of a pharmaceutical product for use in the treatment of corticosteroid-dependent asthma in a subject, comprising administering a therapeutically effective dose of the anti-TSLP antibody to the subject at a dose of 140 to 420 mg at intervals of every two weeks or every four weeks, wherein the antibody is a. Light chain variable domain, i. Light chain CDR1 sequence containing the amino acid sequence shown in Sequence ID No. 3; ii. Light chain CDR2 sequence containing the amino acid sequence shown in Sequence ID No. 4; iii. Light chain CDR3 sequence containing the amino acid sequence shown in Sequence ID No. 5 Light chain variable domains, including, b. A heavy chain variable domain, i. A heavy chain CDR1 sequence containing the amino acid sequence shown in Sequence ID No. 6; ii. A heavy chain CDR2 sequence containing the amino acid sequence shown in Sequence ID No. 7, and iii. Heavy chain CDR3 sequence containing the amino acid sequence shown in Sequence ID No. 8 Heavy chain variable domains The invention includes a method in which the antibody specifically binds to the TSLP polypeptide represented by amino acids 29-159 of SEQ ID NO: 2, and the antibody is an IgG2 antibody.

56. The use of an anti-TSLP antibody for the manufacture of a pharmaceutical product for use in the treatment of corticosteroid-dependent asthma in a subject, comprising administering a therapeutically effective dose of the anti-TSLP antibody to the subject at a dose of 140 to 420 mg at intervals of every two weeks or every four weeks, wherein the antibody is a. Light chain variable domain, i. An amino acid sequence that is at least 80% identical to SEQ ID NO: 12; ii. A sequence of amino acids encoded by a polynucleotide sequence that is at least 80% identical to sequence number 11; iii. The sequence of amino acids encoded by a polynucleotide that hybridizes with the complement of the polynucleotide consisting of SEQ ID NO: 11 under moderately stringent conditions. A light chain variable domain selected from the group consisting of, b. A heavy chain variable domain, i. An amino acid sequence that is at least 80% identical to SEQ ID NO: 10; ii. An amino acid sequence encoded by a polynucleotide sequence that is at least 80% identical to sequence number 9; iii. The sequence of amino acids encoded by a polynucleotide that hybridizes with the complement of the polynucleotide consisting of SEQ ID NO: 9 under moderately stringent conditions. A heavy chain variable domain selected from the group consisting of, c. Light chain variable domain of (a) and heavy chain variable domain of (b) The antibody contains a substance that specifically binds to the TSLP polypeptide represented by amino acids 29-159 of SEQ ID NO:

2.

57. The antibody for use or use according to any one of claims 53 to 56, wherein the light chain variable domain is described in Sequence ID No. 12 and the heavy chain variable domain is described in Sequence ID No.

10.

58. The antibody for use or use according to any one of claims 53 to 57, wherein the antibody is administered every two weeks or every four weeks.

59. The antibody for use or use according to any one of claims 53 to 58, wherein the antibody is an IgG2 antibody.

60. The antibody for use or use according to any one of claims 53 to 59, wherein the antibody is administered in a dose of 210 mg.

61. The antibody for use or use according to any one of claims 53 to 60, wherein the antibody is tezeperumab.

62. The antibody for use or use according to any one of claims 53 to 61, wherein the light chain variable domain is described in Sequence ID No. 12 and the heavy chain variable domain is described in Sequence ID No.

10.

63. The antibody for use or use according to any one of claims 53 to 62, wherein the antibody is administered every two weeks or every four weeks.

64. The antibody for use or use according to any one of claims 53 to 63, wherein the antibody is an IgG2 antibody.

65. The antibody for use or use according to any one of claims 53 to 64, wherein the antibody is administered in a dose of 210 mg.

66. The antibody for use or use according to any one of claims 53 to 65, wherein the antibody is tezepermab.

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