LOW, IMMUNE ENHANCING, DOSE MTOR INHIBITORS AND USES THEREOF

• US 20170281753A1
• Filed: 10/12/2016
• Published: 10/05/2017
• Est. Priority Date: 11/13/2013
• Status: Active Grant

• Current Assignee: Novartis Ag
• Original Assignee: Novartis Institutes for BioMedical Research, Inc. (Novartis Ag)
• Inventors: MANNICK, Joan, GLASS, David, MURPHY, Leon
• Granted Patent: US 10,004,803 B2
• Time in Patent Office: Days
• 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 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.

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

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

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

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

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

13. 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 andsystolic and diastolic dysfunction, immunosenescence, cancer, obesity, and diabetes.

14. 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.

15. 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