LOW, IMMUNE ENHANCING, DOSE MTOR INHIBITORS AND USES THEREOF

• US 20150140036A1
• Filed: 11/13/2014
• Published: 05/21/2015
• Est. Priority Date: 11/13/2013
• Status: Abandoned Application

• Current Assignee: Novartis Ag
• Original Assignee: Novartis Institutes for BioMedical Research, Inc. (Novartis Ag)
• Inventors: Glass, David, Mannick, Joan, Murphy, Leon
• Application Number:
  US14/540,867
• Publication Number:
  US 20150140036A1
• Time in Patent Office: Days
• US Class Current: 424/209.1
• CPC Class Codes: A61K 2039/55511 Organic adjuvants
• CPC Class Codes: A61K 31/436 the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
• CPC Class Codes: A61K 31/4745 condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 39/00 Medicinal preparations containing antigens or antibodies materials for immunoassay G01N33/53
• CPC Class Codes: A61K 39/09 Lactobacillales, e.g. aerococcus, enterococcus, lactobacillus, lactococcus, streptococcus
• CPC Class Codes: A61K 39/092 Streptococcus
• CPC Class Codes: A61K 39/12 Viral antigens
• CPC Class Codes: A61K 39/145 Orthomyxoviridae, e.g. influenza virus
• CPC Class Codes: A61K 39/39 characterised by the immunostimulating additives, e.g. chemical adjuvants
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/14 : for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/28 : for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/12 : for cataracts
• CPC Class Codes: A61P 27/16 : Otologicals
• CPC Class Codes: A61P 3/04 : Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/04 : Antibacterial agents
• CPC Class Codes: A61P 31/16 : for influenza or rhinoviruses
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 35/02 : specific for leukemia
• 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 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 : Antihypertensives
• CPC Class Codes: C12N 2760/16034 : Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
• CPC Class Codes: C12N 7/00 : Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof preparing medicinal viral antigen or antibody compositions, e.g. virus vaccines, A61K39/00
• CPC Class Codes: G01N 33/6854 : Immunoglobulins

Abstract

The present invention relates, in part, to compositions and methods for enhancement of an immune response by partial mTOR inhibition, e.g., with low, immune enhancing, doses of an mTOR inhibitor, such as RAD001.

Claims

1. A method of promoting an immune response in a subject, comprising,

administering to the subject a low, immune enhancing, dose of an mTOR inhibitor,

thereby enhancing or promoting an immune response in the subject.

2. The method of claim 1, wherein the mTOR inhibitor is an allosteric mTOR inhibitor or a catalytic inhibitor.

3. The method of claim 1, wherein the mTOR inhibitor is RAD001 or rapamycin.

4. The method of claim 2, wherein the catalytic inhibitor is a kinase inhibitor.

5. The method of claim 4, wherein the kinase inhibitor is selective for mTOR or is selected from BEZ235 and CCG168.

6. The method of claim 1, wherein the dose comprises an allosteric and a catalytic mTOR inhibitor.

7. The method of claim 1, wherein the mTOR inhibitor is administered for an amount of time sufficient one or more of the following to occur:

i) a decrease in the number of PD-1 positive immune effector cells;

ii) an increase in the number of PD-1 negative immune effector cells;

iii) an increase in the ratio of PD-1 negative immune effector cells/PD-1 positive immune effector cells;

iv) an increase in the number of naive T cells;

v) an increase in the expression of one or more of the following markers;

CD62L^high, CD127^high, CD27⁺, and BCL2, e.g., on memory T cells, e.g., memory T cell precursors;

vi) a decrease in the expression of KLRG1, e.g., on memory T cells, e.g., memory T cell precursors;

or

vii) an increase in the number of memory T cell precursors, e.g., cells with any one or combination of the following characteristics;

increased CD62L^high increased CD127^high, increased CD27⁺, decreased KLRG1, and increased BCL2;

and wherein i), ii), iii), iv), v), vi), or vii) occurs at least transiently, as compared to a non-treated subject.

8. The method of claim 1, wherein the method comprises inhibiting a negative immune response mediated by the engagement of PD-1 with PD-L1 or PD-L2.

9. The method of claim 1, which comprises increasing the number of T cells capable of proliferation, cytotoxic function, secreting cytokines, or activation.

10. The method of claim 1, wherein the administering results in the partial, but not total, inhibition of mTOR for at least 1, 5, 10, 20, 30, or 60 days.

11. The method of claim 1, wherein the dose of an mTOR inhibitor is associated with mTOR inhibition of at least 5% but no more than 90%, as measured by p70 S6K inhibition.

12. The method of claim 11, wherein the mTOR inhibitor comprises RAD001.

13. The method of claim 1, wherein administering comprises administering, once per week, in an immediate release dosage form, 0.1 to 20, 0.5 to 10, 2.5 to 7.5, 3 to 6, or about 5 mgs of RAD001, or a bioequivalent dose of a different mTOR inhibitor.

14. The method of claim 1, wherein administering comprises administering, once per week, in an immediate release dosage form, about 5 mgs of RAD001, or a bioequivalent dose of a different mTOR inhibitor.

15. The method of claim 1, wherein administering comprises administering, once per week, in a sustained release dosage form, 0.3 to 60, 1.5 to 30, 7.5 to 22.5, 9 to 18, or about 15 mgs of RAD001, or a bioequivalent dose of a different mTOR inhibitor.

16. The method of claim 1, wherein administering comprises administering, once per week, in a sustained release dosage form, about 15 mgs of RAD001 or a bioequivalent dose of a different mTOR inhibitor.

17. The method of claim 1, wherein administering comprises administering, once per day, in an immediate release dosage form, 0.005 to 1.5, 0.01 to 1.5, 0.1 to 1.5, 0.2 to 1.5, 0.3 to 1.5, 0.4 to 1.5, 0.5 to 1.5, 0.6 to 1.5, 0.7 to 1.5, 0.8 to 1.5, 1.0 to 1.5, 0.3 to 0.6, or about 0.5 mgs of RAD001, or a bioequivalent dose of a different mTOR inhibitor.

18. The method of claim 1, wherein administering comprises administering once per day, in an immediate release dosage form, about 0.5 mgs of RAD001, or a bioequivalent dose of a different mTOR inhibitor.

19. The method of claim 1, wherein administering comprises administering, once per day, in a sustained release dosage form, 0.015 to 4.5, 0.03 to 4.5, 0.3 to 4.5, 0.6 to 4.5, 0.9 to 4.5, 1.2 to 4.5, 1.5 to 4.5, 1.8 to 4.5, 2.1 to 4.5, 2.4 to 4.5, 3.0 to 4.5, 0.9 to 1.8, or about 1.5 mgs mgs of RAD001, or a bioequivalent dose of a different mTOR inhibitor.

20. The method of claim 1, wherein administering comprises administering, once per week, in a sustained release dosage form, 0.1 to 30, 0.2 to 30, 2 to 30, 4 to 30, 6 to 30, 8 to 30, 10 to 30, 1.2 to 30, 14 to 30, 16 to 30, 20 to 30, 6 to 12, or about 10 mgs of RAD001 or a bioequivalent dose of a different mTOR inhibitor.

21. The method of claim 1, wherein the mTOR inhibitor is RAD001 and the dose provides for a trough level of RAD001 in a range of between about 0.1 and 3 ng/ml, between 0.3 or less and 3 ng/ml, or between 0.3 or less and 1 ng/ml, or a bioequivalent dose of a different mTOR inhibitor.

22. The method of claim 1, wherein the subject has cancer and the method comprises

promoting the subject'"'"'s immune response to the cancer.

23. The method of claim 22, wherein the subject was selected on the basis of having cancer.

24. The method of claim 22, wherein a cell of the cancer expresses PD-L1 or PD-L2.

25. The method of claim 22, wherein a cell in the cancer microenvironment expresses PD-L1 or PD-L2.

26. The method of claim 22, wherein the cancer comprises a solid tumor.

27. The method of claim 22, wherein the cancer is a hematological cancer.

28. The method of claim 22, wherein the cancer is selected from Table 1.

29. The method of claim 22, wherein the cancer is melanoma.

30. The method of claim 22, further comprising administering a second treatment to the subject.

31. The method of claim 30, wherein the second treatment is a chemotherapeutic, radiation, a cellular therapy, or bone marrow transplant.

32. The method of claim 30, comprising administering a second treatment that kills T cells.

33. The method of claim 32, wherein the second treatment is radiation or cytotoxic chemotherapy.

34. The method of claim 30, wherein the mTOR inhibitor is administered prior to, simultaneously with, or after the initiation of the second treatment.

35. The method of any of claim 22, comprising treating a cancer from Table 1, and administering a treatment listed in Table 1 for that cancer.

36. The method of claim 1, wherein the subject is immunocompromised.

37. The method of claim 1, wherein the subject is HIV+ or has AIDs.

38. The method of claim 1, wherein the subject has an infectious disease.

39. The method of claim 1, wherein the subject has an impaired immune response.

40. The method of claim 1, wherein the subject is immunoscenescent.

41. The method of claim 1, comprising treating the subject for an age related condition.

42. The method of claim 41, wherein the age related condition is selected from the group consisting of sarcopenia, skin atrophy, muscle wasting, brain atrophy, atherosclerosis, arteriosclerosis, pulmonary emphysema, osteoporosis, osteoarthritis, high blood pressure, erectile dysfunction, dementia, Huntington'"'"'s disease, Alzheimer'"'"'s disease, cataracts, age-related macular degeneration, prostate cancer, stroke, diminished life expectancy, impaired kidney function, and age-related hearing loss, aging-related mobility disability (e.g., frailty), cognitive decline, age-related dementia, memory impairment, tendon stiffness, heart dysfunction such as cardiac hypertrophy and systolic and diastolic dysfunction, immunosenescence, cancer, obesity, and diabetes.

43. The method of claim 1, comprising, enhancing an immune response to an antigen in the subject.

44. The method of claim 43, further comprising administering the antigen or a vaccine to the subject.

45. The method of claim 44, wherein prior to the step of administering, the method comprises a step of identifying a subject having an impaired immune response to an antigen.

46. The method of claim 44, wherein the antigen is an influenza antigen.

47. The method of claim 46, wherein the antigen is selected from the influenza subgroup consisting of H1N1, H2N3, and B influenza subtypes.

48. The method of claim 44, wherein the antigen is a pneumococcal antigen.

49. The method of claim 44, wherein the antigen and the mTOR inhibitor are co-administered.

50. The method of any of claim 44, wherein the antigen and the mTOR inhibitor are administered sequentially.

51. The method of claim 1, wherein the subject is less than 65 years old.

52. The method of claim 1, wherein the subject does not receive a vaccine while the mTOR inhibitor is present at levels which promote the immune response.

53. The method of claim 52, wherein the vaccine is an anti-cancer vaccine or a vaccine against an infectious agent.

54. The method of claim 52, wherein the vaccine is a therapeutic vaccine for a neurological disorder or Alzheimer'"'"'s disease.

55. The method of claim 1, wherein the subject does not receive a vaccine within 10, 20, 30, 40, 50, 60, 70, 80, or 90 days prior to or after initiation of the low, immune enhancing, dose of the mTOR inhibitor.

56. The method of claim 1, wherein the low, mTOR inhibitor is administered at the time of, or after vaccination.

63. The method of claim 1, wherein the subject is a human.

57. A method of evaluating a subject for treatment with a low, immune enhancing, dose of mTOR inhibitor, to promote or enhance an immune response to an influenza vaccine or antigen, comprising:

determining a baseline or pre-immunization level of anti-influenza antibody,

wherein a relatively low baseline or pre-immunization level of anti-influenza antibody is predictive of a greater mTOR inhibitor-associated increase in antibody titer for the influenza antigen,

thereby evaluating the subject.

58. The method of claim 57, further comprising comparing the determined level with a reference value, wherein a value less than or equal to the reference value is indicative of a greater mTOR inhibitor-associated increase in antibody titer.

59. The method of claim 57, wherein responsive to a determined level of antibody titer the subject is classified as to likelihood of benefiting from a low, immune enhancing, dose of mTOR inhibitor.

60. The method of claim 57, wherein responsive to a determined level of antibody titer the subject is administered a low, immune enhancing, dose of mTOR inhibitor.

61. The method of claim 57, wherein the determining step comprises

determining if the baseline or pre-immunization titer of anti-influenza antibody of the subject is equal to or less than 1:

40; and

responsive to said determination, classifying the subject as to the likelihood of benefiting from a low, immune enhancing, dose of an mTOR inhibitor, or selecting a course of therapy for said subject.

62. The method of claim 57, wherein the mTOR inhibitor is RAD001.

64. A vaccine adjuvant comprising about 0.005 mg to 1.5 mg of the mTOR inhibitor RAD001, or a bioequivalent dose of a different mTOR inhibitor.

65. The vaccine adjuvant of claim 64, comprising an amount of an mTOR inhibitor sufficient to inhibit P70 S6 kinase activity in a cell by no greater than 80%.

66. The vaccine adjuvant of claim 64, wherein said mTOR inhibitor is a rapamycin or a rapalog.

67. The vaccine adjuvant of any of claim 64, comprising a 0.01-1 mg, 0.01-0.7 mg, 0.01-0.5 mg, or 0.1-0.5 mg of RAD001 or a bioequivalent dose of a different mTOR inhibitor.

68. The vaccine adjuvant of any of claim 64, comprising 0.5 mg of RAD001 or a bioequivalent dose of a different mTOR inhibitor.

69. A composition comprising

(a) a vaccine antigen;

and

(b) about 0.005 mg to 1.5 mg of the mTOR inhibitor RAD001, or a bioequivalent dose of a different mTOR inhibitor

70. The composition of claim 69, wherein said composition comprises about 0.01-1 mg, about 0.01-0.7 mg, about 0.01-0.5 mg, or about 0.1-0.5 mg of RAD001, or a bioequivalent dose of a different mTOR inhibitor.

71. The composition of claim 69, comprising about 0.5 mg of RAD001 or a bioequivalent dose of a different mTOR inhibitor.

72. The composition of claim 69, wherein said composition comprises an amount of an mTOR inhibitor sufficient to inhibit P70 S6 kinase activity by no greater than 80% in a subject to which said composition is administered.

73. The composition of claim 69, wherein said composition produces at least a 1.2 fold increase in immune response as compared to placebo in a subject to which said composition is administered.

74. The composition of claim 69, wherein said mTOR inhibitor is a rapamycin or a rapalog.

75. The composition of claim 69, wherein said vaccine antigen is derived from influenza.

76. The composition of claim 69, wherein said vaccine antigen is selected from the group consisting of H1N1, H2N3, and B influenza subtypes.

77. The composition of claim 69, wherein said vaccine antigen is derived from pneumococcus.