Low, immune enhancing, dose mtor inhibitors and uses thereof

• US 10,004,803 B2
• Filed: 10/12/2016
• Issued: 06/26/2018
• Est. Priority Date: 11/13/2013
• Status: Expired due to Fees

• Current Assignee: Novartis Ag
• Original Assignee: Novartis Ag
• Inventors: Mannick, Joan, Glass, David, Murphy, Leon
• Primary Examiner(s): Gill, Rachel B
• Application Number:
  US15/292,088
• Publication Number:
  US 20170281753A1
• Time in Patent Office: 622 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, for example, with low, immune enhancing, doses of an mTOR inhibitor, such as RAD001.

Claims

1. A method of promoting an immune response in an immunosenescent human subject, comprising administering to the immunosenescent human subject a low, immune enhancing, dose of about 0.1 mg of RAD001, orally and once daily, thereby enhancing or promoting an immune response in the immunosenescent human subject.

2. The method of claim 1, wherein the immunosenescent human subject is immunocompromised.

3. The method of claim 1, wherein the immunosenescent human subject has an infectious disease.

4. The method of claim 1, wherein the immunosenescent human subject has an impaired immune response.

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

6. The method of claim 5, 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, cognitive decline, memory impairment, tendon stiffness, heart dysfunction, cancer, obesity, and diabetes.

9. The method of claim 6, wherein the aging-related mobility disability is frailty.

10. The method of claim 6, wherein the dementia is age-related dementia.

11. The method of claim 6, wherein the heart dysfunction is cardiac hypertrophy or systolic or diastolic dysfunction.

7. A method of evaluating an immunosenescent human subject for treatment with a low, immune enhancing, dose of RAD001 to promote or enhance an immune response to an influenza vaccine or antigen, comprising:

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

measuring a baseline or pre-immunization level of anti-influenza antibody in the immunosenescent human subject, and

comparing the baseline or pre-immunization level of anti-influenza antibody in the immunosenescent human subject to the reference value,

wherein a baseline or pre-immunization level of anti-influenza antibody in the immunosenescent human subject less than the reference value is predictive of a greater RAD001 associated increase in antibody titer for the influenza antigen,

and wherein the immunosenescent human subject, once evaluated, is then treated with a low, immune enhancing dose of RAD001,

wherein treatment comprises administering a dose of about 0.1 mg of RAD001, orally and once daily.

8. A composition comprising

(a) a vaccine antigen;

and

(b) about 0.1 mg of RAD001.