Compositions comprising bacterial strains

• US 10,493,112 B2
• Filed: 08/17/2017
• Issued: 12/03/2019
• Est. Priority Date: 06/15/2015
• Status: Active Grant

• Current Assignee: CJ Bioscience Incorporated
• Original Assignee: 4D Pharma Research Limited (4D Pharma PLC)
• Inventors: Grant, George, Patterson, Angela Margaret, Mulder, Imke, McCluskey, Seanin, Raftis, Emma
• Primary Examiner(s): Ogunbiyi, Oluwatosin A
• Application Number:
  US15/679,857
• Publication Number:
  US 20170354695A1
• Time in Patent Office: 838 Days
• Field of Search: None
• CPC Class Codes: A23L 33/135 Bacteria or derivatives thereof, e.g. probiotics
• CPC Class Codes: A23L 33/30 Dietetic or nutritional methods, e.g. for losing weight A23L33/10 takes precedence
• CPC Class Codes: A23V 2002/00 Food compositions, function of food ingredients or processes for food or foodstuffs
• CPC Class Codes: A61K 2035/11 Medicinal preparations comprising living procariotic cells
• CPC Class Codes: A61K 35/74 Bacteria therapeutic use of a bacterial protein A61K38/00
• CPC Class Codes: A61K 35/747 Lactobacilli, e.g. L. acidophilus or L. brevis
• CPC Class Codes: A61K 9/19 lyophilised , i.e. freeze-dried, solutions or dispersions lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/04 Antipruritics
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/02 : for peripheral neuropathies
• 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 27/00 : Drugs for disorders of the senses
• CPC Class Codes: A61P 27/02 : Ophthalmic agents
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 35/04 : specific for metastasis
• CPC Class Codes: A61P 37/00 : Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• 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: C12N 1/205 : Bacterial isolates
• CPC Class Codes: C12R 2001/01 : Bacteria or Actinomycetales ; using bacteria or Actinomycetales
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The invention provides compositions comprising bacterial strains for treating and preventing inflammatory and autoimmune diseases.

Claims

1. A method of treating a condition mediated by the Th17 pathway in a subject, comprising:

administering to the subject a therapeutically effective amount of a pharmaceutical composition that contains a single Parabacteroides bacterial strain that comprises a 16s rRNA gene sequence with;

(a) at least 96% sequence identity to the sequence of SEQ ID NO;

1,

(b) at least 97% sequence identity to the sequence of SEQ ID NO;

2,

(c) at least 97% sequence identity to the sequence of SEQ ID NO;

3,

(d) at least 97% sequence identity to the sequence of SEQ ID NO;

4,

(e) at least 97% sequence identity to the sequence of SEQ ID NO;

5,

(f) at least 97% sequence identity to the sequence of SEQ ID NO;

6, or

(g) at least 97% sequence identity to the sequence of SEQ ID NO;

9, as determined by the Smith-Waterman homology search algorithm using an affine gap search with a gap open penalty of 12 and a gap extension penalty of 2, and a BLOSUM matrix of 62,

wherein said bacterial strain is live and viable; and

a pharmaceutically acceptable excipient, diluent, or carrier;

wherein said single Parabacteroides bacterial strain is lyophilized, wherein the single Parabacteroides bacterial strain is present in an amount that comprises from about 1×

10³ to about 1×

10¹¹ CFU/g of the single Parabacteroides bacterial strain with respect to a total weight of the pharmaceutical composition; and

wherein said pharmaceutical composition is in solid dose tablet or capsule form.

2. The method of claim 1, wherein the bacterial strain comprises a 16s rRNA gene sequence with at least 99.9% sequence identity to the sequence shown in SEQ ID NO:

9.

3. The method of claim 1, wherein the bacterial strain is of the species Parabacteroides distasonis.

4. The method of claim 1, wherein the administering results in a reduction of at least one cytokine of the Th17 pathway that comprises IL-17A, IL-17B, IL-17C, IL-17D, IL-17E, IL-17F, IFN-γ

, IL-10, IL-6, or TNFα

.

5. The method of claim 1, wherein the subject has a condition that comprises uveitis, multiple sclerosis, an arthritis, neuromyelitis optica, psoriasis, systemic lupus erythematosus, celiac disease, an asthma, allergic asthma, neutrophilic asthma, chronic obstructive pulmonary disease (COPD), scleritis, vasculitis, Behcet'"'"'s disease, atherosclerosis, atopic dermatitis, emphysema, periodontitis, allergic rhinitis, and allograft rejection.

6. The method of claim 5, wherein the condition is uveitis;

and wherein the administering results in a reduction in retinal damage in uveitis.

7. The method of claim 5, wherein the condition is asthma;

and wherein the administering results in a reduction in neutrophilia or eosinophilia.

8. The method of claim 5, wherein the condition is arthritis, wherein the arthritis comprises osteoarthritis, psoriatic arthritis, spondyloarthritis, ankylosing spondylitis, and juvenile idiopathic arthritis.

9. The method of claim 1, wherein the condition mediated is not ulcerative colitis, colitis, Crohn'"'"'s disease, irritable bowel disease, or rheumatoid arthritis.

10. A pharmaceutical composition that contains:

a single Parabacteroides bacterial strain that comprises a 16s rRNA gene sequence with;

(a) at least 96% sequence identity to the sequence of SEQ ID NO;

1,

(b) at least 97% sequence identity to the sequence of SEQ ID NO;

2,

(c) at least 97% sequence identity to the sequence of SEQ ID NO;

3,

(d) at least 97% sequence identity to the sequence of SEQ ID NO;

4,

(e) at least 97% sequence identity to the sequence of SEQ ID NO;

5,

(f) at least 97% sequence identity to the sequence of SEQ ID NO;

6, or

(g) at least 97% sequence identity to the sequence of SEQ ID NO;

9,

as determined by the Smith-Waterman homology search algorithm using an affine gap search with a gap open penalty of 12 and a gap extension penalty of 2, and a BLOSUM matrix of 62, wherein said single Parabacteroides bacterial strain is live and viable; and

a pharmaceutically acceptable excipient, diluent, or carrier;

wherein said single Parabacteroides bacterial strain is lyophilized, wherein the single Parabacteroides bacterial strain is present in an amount that comprises from about 1×

10³ to about 1×

10¹¹ CFU/g of the single Parabacteroides bacterial strain with respect to a total weight of the pharmaceutical composition; and

wherein said pharmaceutical composition is in solid dose tablet or capsule form.

11. The pharmaceutical composition of claim 10, wherein the single Parabacteroides bacterial strain comprises a 16s rRNA gene sequence with at least 99.9% sequence identity to the sequence shown in SEQ ID NO:

9 as determined by the Smith-Waterman homology search algorithm using an affine gap search with a gap open penalty of 12 and a gap extension penalty of 2, and a BLOSUM matrix of 62.

12. The pharmaceutical composition of claim 10, wherein the single Parabacteroides bacteria strain has a Sau3AI DNA restriction pattern that is the same as a Sau3AI DNA restriction pattern for the Parabacteroides distasonis strain MRX005 deposited as NCIMB 42382 as determined by amplified ribosomal DNA restriction analysis;

and

wherein administration of said bacterial strain in a Collagen II stimulated mouse model results in a reduction in a level of IL-6, IL-10, IL-17A, IFN-γ

, or TNF-α

.

13. The pharmaceutical composition of claim 10, wherein the single Parabacteroides bacterial strain is of the species Parabacteroides distasonis.

14. The pharmaceutical composition of claim 10, wherein the single Parabacteroides bacterial strain is the Parabacteroides distasonis strain MRX005 deposited as NCIMB 42382.

15. The pharmaceutical composition of claim 10, wherein at least 50% of the single Parabacteroides bacterial strain as measured by an amount of CFU, remains viable after about 1 year of storage when the pharmaceutical composition is stored in a closed container at 25°

C. at 95% relative humidity.

16. The pharmaceutical composition of claim 10, wherein the single Parabacteroides bacteria strain is present in an amount that comprises from about 1×

10⁶ to about 1×

10¹¹ CFU/g of the single Parabacteroides bacterial strain with respect to a total weight of the pharmaceutical composition.

17. The pharmaceutical composition of claim 10, wherein the single Parabacteroides bacterial strain totally or partially colonises the intestine when administered to a subject.

18. The pharmaceutical composition of claim 10, wherein the single Parabacteroides bacterial strain comprises a 16s rRNA gene sequence with at least 99% sequence identity to the sequence shown in SEQ ID NO:

9 as determined by the Smith-Waterman homology search algorithm using an affine gap search with a gap open penalty of 12 and a gap extension penalty of 2, and a BLOSUM matrix of 62.

19. The pharmaceutical composition of claim 10, wherein the pharmaceutical composition is encapsulated.

20. The pharmaceutical composition of claim 10, wherein the pharmaceutical composition comprises the 16s rRNA gene sequence of SEQ ID NO:

1, SEQ ID NO;

2, SEQ ID NO;

3, SEQ ID NO;

4, SEQ ID NO;

5, SEQ ID NO;

6, or SEQ ID NO;

9.