Probiotic compositions containing clostridiales for inhibiting inflammation

• US 9,610,307 B2
• Filed: 11/25/2015
• Issued: 04/04/2017
• Est. Priority Date: 11/25/2014
• Status: Active Grant

• Current Assignee: Flagship Pioneering, Inc., PharmaBiome AG
• Original Assignee: Evelo Biosciences, Inc.
• Inventors: Berry, David, Kaplan, Johanne, Rahman, Shaila
• Primary Examiner(s): JOHNSON, KARA D
• Application Number:
  US14/952,895
• Publication Number:
  US 20160143962A1
• Time in Patent Office: 496 Days
• CPC Class Codes: A61K 2035/115 Probiotics
• CPC Class Codes: A61K 31/7004 Monosaccharides having only carbon, hydrogen and oxygen atoms
• CPC Class Codes: A61K 31/7016 Disaccharides, e.g. lactose, lactulose lactobionic acid A61K31/7032
• CPC Class Codes: A61K 31/715 Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
• CPC Class Codes: A61K 35/39 Pancreas; Islets of Langerhans Langerhans cells of epidermis A61K35/36
• CPC Class Codes: A61K 35/74 Bacteria therapeutic use of a bacterial protein A61K38/00
• CPC Class Codes: A61K 35/741 Probiotics probiotic yeast, e.g. saccharomyces A61K36/06
• CPC Class Codes: A61K 35/742 Spore-forming bacteria, e.g. Bacillus coagulans, Bacillus subtilis, clostridium or Lactobacillus sporogenes
• CPC Class Codes: A61K 35/744 Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
• CPC Class Codes: A61K 35/745 Bifidobacteria
• CPC Class Codes: A61K 35/747 Lactobacilli, e.g. L. acidophilus or L. brevis
• CPC Class Codes: A61K 38/46 Hydrolases (3)
• CPC Class Codes: A61K 9/0031 Rectum, anus
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• 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 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• 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

Pharmaceutical compositions containing microbial entities are described herein. The pharmaceutical compositions may optionally contain or be used in conjunction with one or more prebiotics. Uses of the pharmaceutical compositions to treat or prevent disorders of the local or systemic microbiome in a subject are also provided.

Claims

1. A pharmaceutical composition comprising:

an isolated population of anti-inflammatory bacterial cells consisting essentially of 3 or more strains of anti-inflammatory bacteria, wherein the 3 or more strains comprise Blautia producta, Ruminococcus torques, and one or more strains selected from Eubacterium rectale, Ruminococcus obeum, and Eubacterium ventriosum, wherein each strain of anti-inflammatory bacteria selected for inclusion in the composition is capable of increasing secretion of Interleukin 10 (IL-10) by a population of human peripheral blood mononuclear cells (PBMCs) in vitro, and wherein the isolated population of anti-inflammatory bacterial cells increases IL-10 secretion by PBMCs by at least 80% or more relative to each strain individually; and

a pharmaceutically acceptable excipient.

2. The pharmaceutical composition of claim 1, wherein the isolated population of anti-inflammatory bacterial cells counteracts secretion of a pro-inflammatory cytokine induced by Enterococcus faecalis in a population of human PBMCs.

3. The pharmaceutical composition of claim 1, wherein the 3 or more strains of anti-inflammatory bacteria comprise Blautia producta, Ruminococcus torques, and Ruminococcus obeum.

4. The pharmaceutical composition of claim 1, wherein the 3 or more strains of anti-inflammatory bacteria comprise Blautia producta, Ruminococcus torques, and Eubacterium rectale.

5. The pharmaceutical composition of claim 1, wherein the 3or more strains of anti-inflammatory bacteria compromise Blautia producta, Ruminococcus torques, and Eubacterium ventriosum.

6. The pharmaceutical composition of claim 1, wherein the isolated population of anti-inflammatory bacterial cells comprises a bacterial cell in vegetative form.

7. The pharmaceutical composition of claim 1, wherein the isolated population of anti-inflammatory bacterial cells comprises a bacterial cell in spore form.

8. The pharmaceutical composition of claim 1, wherein the isolated population of anti-inflammatory bacterial cells increases IL-10 secretion by PBMCs by at least 100% or more relative to each strain individually.

9. The pharmaceutical composition of claim 1, further comprising a prebiotic.

10. The pharmaceutical composition of claim 9, wherein the prebiotic comprises a monomer or polymer selected from the group consisting of arabinoxylan, xylose, soluble fiber dextran, soluble corn fiber, polydextrose, lactose, N-acetyl-lactosamine, glucose, galactose, fructose, rhamnose, mannose, uronic acids, 3′

-fucosyllactose, 3′

-sialylactose, 6′

-sialyllactose, lacto-N-neotetraose, 2′

-2′

-fucosyllactose, and combinations thereof.

11. The pharmaceutical composition of claim 9, wherein the prebiotic comprises a sugar selected from the group consisting of arabinose, fructose, fucose, lactose, galactose, glucose, mannose, D-xylose, xylitol, ribose, xylobiose, sucrose, maltose, lactose, lactulose, trehalose, cellobiose, xylooligosaccharide, and combinations thereof.

12. The pharmaceutical composition of claim 1, wherein the isolated population of anti-inflammatory bacterial cells reduces the secretion of one or more pro-inflammatory cytokines selected from the group consisting of IFNγ

, IL-12p70, IL-1α

, IL-6, IL-8, MCP1, MIP1α

, MIP1β

, TNFα

, and combinations thereof, by a population of human PBMCs.

13. The pharmaceutical composition of claim 1, wherein the isolated population of anti-inflammatory bacterial cells increases the secretion of one or more anti-inflammatory cytokines selected from the group consisting of IL-13, IL-4, IL-5, TGFβ

, and combinations thereof, by a population of human PBMCs.

14. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is formulated for oral administration.

15. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is formulated for rectal administration.

16. A method for reducing inflammation in a subject having an autoimmune or inflammatory disorder, the method comprising administering the pharmaceutical composition of claim 1 to the subject, thereby reducing inflammation in the subject.

17. The method of claim 16, wherein the autoimmune or inflammatory disorder is selected from the group consisting of graft-versus-host disease (GVHD), an inflammatory bowel disease (IBD), ulcerative colitis, Crohn'"'"'s disease, multiple sclerosis (MS), systemic lupus erythematosus (SLE), type I diabetes, rheumatoid arthritis, Sjogren'"'"'s syndrome, and Celiac disease.

18. The method of claim 17, wherein the autoimmune or inflammatory disorder is GVHD.

19. The method of claim 16, wherein the pharmaceutical composition is administered orally.

20. The method of claim 16, wherein administration of the pharmaceutical composition reduces inflammation in the gastrointestinal tract of the subject.

21. The method of claim 16, wherein administration of the pharmaceutical composition reduces inflammation at a site distal to the gastrointestinal tract of the subject.

22. The method of claim 16, wherein the subject has a dysbiosis.

23. The method of claim 22, wherein the dysbiosis is a gastrointestinal dysbiosis.

24. The method of claim 22, wherein the dysbiosis is a distal dysbiosis.

25. The method of claim 16, wherein the anti-inflammatory bacterial cells of the pharmaceutical composition engraft in the gastrointestinal tract of the subject.

26. The method of claim 16, further comprising administering a prebiotic to the subject.

27. A pharmaceutical composition comprising:

an isolated population of anti-inflammatory bacterial cells consisting essentially of 3 or more strains of anti-inflammatory bacteria, wherein the 3 or more strains comprise Blautia producta, Eubacterium ventriosum and Coprococcus comes, wherein each strain of anti-inflammatory bacteria selected for inclusion in the composition is capable of increasing secretion of Interleukin 10 (IL-10) by a population of peripheral blood mononuclear cells (PBMCs) in vitro, and wherein the isolated population of anti-inflammatory bacterial cells increases IL-10 secretion by PBMCs by at least 80% or more relative to each strain individually; and

a pharmaceutically acceptable carrier.

28. The pharmaceutical composition of claim 27, wherein the 3or more strains of anti-inflammatory bacteria comprise Blautia producta, Eubacterium ventriosum, and Coprococcus comes.

29. A pharmaceutical composition comprising:

an isolated population of anti-inflammatory bacterial cells consisting essentially of 3 or more strains of anti-inflammatory bacteria, wherein the 3 or more strains comprise Ruminococcus torques, Eubacterium ventriosum and Blautia ovatus, wherein each strain of anti-inflammatory bacteria selected for inclusion in the composition is capable of increasing secretion of Interleukin 10 (IL-10) by a population of peripheral blood mononuclear cells (PBMCs) in vitro, and wherein the isolated population of anti-inflammatory bacterial cells increases IL-10secretion by PBMCs by at least 80% or more relative to each strain individually; and

a pharmaceutically acceptable carrier.

30. The pharmaceutical composition of claim 29, wherein the 3or more strains of anti-inflammatory bacteria comprise Ruminococcus torques, Eubacterium ventriosum, and Bacteroides ovatus.