Compositions and methods for treatment of autoimmune and inflammatory diseases and disorders

Patent metadata

Field	Value
Publication number	US-2016304574-A1
Application number	US-201415026927-A
Country	US
Kind code	A1
Filing date	Sep 22, 2014
Priority date	Sep 20, 2013
Publication date	Oct 20, 2016
Grant date	—

Abstract

The present application discloses a novel fusion peptide of IL-2 and IL-33 and its use. It comprises a biologically active domain of Interleukin-2 (IL-2) or a biologically active fragment or homolog thereof, and a biologically active domain of Interleukin-33 (IL-33) or a biologically active fragment or homolog thereof. The two portions can be linked by a linker sequence. The application discloses that combination therapies using IL-2 and IL-33 or a therapy using the IL233 fusion protein are effective in preventing or treating diseases and disorders such as autoimmune diseases and disorders, inflammation, etc. Depending on the subject's disease or disorder, the compositions of the invention are useful for preventing certain symptoms, treating the disease, and alleviating at least some of the symptoms.

First claim

What is claimed is:

1 . A fusion protein comprising a biologically active domain of Interleukin-2 (IL-2) or a biologically active fragment or homolog thereof, wherein said domain binds with the IL-2 receptor, and a biologically active domain of Interleukin-33 (IL-33) or a biologically active fragment or homolog thereof, wherein said IL-33 domain binds with the IL-33 receptor, further wherein said IL-2 domain is linked to said IL-33 domain with a linker sequence.

2 . The fusion protein of claim 1 , wherein said protein comprises the amino acid sequence of SEQ ID NO:2 or SEQ ID NO:11 or a biologically active substantially homologous sequence.

3 . The fusion protein of claim 1 , wherein said linker comprises the sequence of SEQ ID NO:5 or a substantially homologous sequence.

4 . The fusion protein of claim 1 , wherein said IL-2 comprises the sequence of SEQ ID NO:6 or SEQ ID NO:8 and said IL-33 comprises the sequence of SEQ ID NO:7 or SEQ ID NO:9, or biologically active fragments or homologs thereof.

5 . The fusion protein of claim 4 , wherein said fragment of IL-2 comprises the sequence of SEQ ID NO:3, and said fragment of IL-33 comprises the sequence of SEQ ID NO:4, or biologically active fragments or homologs thereof.

6 . The fusion protein of claim 5 , wherein said homolog of SEQ ID NO:3 is selected from a group comprising at least 75, 80, 85, 90, and 95% homology with SEQ ID NO:3 and said homolog of SEQ ID NO:4 is selected from a group comprising at least 75, 80, 85, 90, and 95% homology with SEQ ID NO:4.

7 . The fusion protein of claim 1 , wherein said protein is a synthetic protein.

8 . An isolated nucleic acid comprising a nucleic acid sequence encoding a fusion protein of claim 1 .

9 . An isolated nucleic acid comprising a nucleic acid sequence encoding a fusion protein of claim 6 .

10 . An isolated nucleic acid comprising the sequence of SEQ ID NO:1.

11 . A vector comprising the isolated nucleic acid of claim 10 and optionally a promoter.

12 . The vector of claim 11 , wherein said vector is selected from the group consisting of a bacterial vector, a viral vector, and a mammalian vector.

13 . A recombinant host cell comprising the isolated nucleic acid of claim 10 .

14 . A recombinant host cell comprising the vector of claim 11 .

15 . A fusion protein encoded by the isolated nucleic acid of claim 10 .

16 . A transgenic non-human mammal comprising an isolated nucleic acid encoding an IL2/IL33 fusion protein or fragment or homolog thereof.

17 . The transgenic non-human mammal of claim 16 , wherein said isolated nucleic acid comprises the sequence of SEQ ID NO:1.

18 . A method for stimulating proliferation, activation, mobilization, and recruitment of T-regulatory (Treg), Thelper2 (Th2), and innate lymphoid cells (ILC) and activating Treg, Th2 and ILC, said method comprising contacting said cells with an effective amount of an IL233 fusion protein or a combination of Interleukin-2 (IL-2) and Interleukin-33 (IL-33) proteins, or biologically active fragments or homologs thereof.

19 . The method of claim 18 , wherein a pharmaceutical composition comprising a pharmaceutically acceptable carrier and said effective amount of IL233 fusion protein or a combination of Interleukin-2 (IL-2) and Interleukin-33 (IL-33) proteins, or biologically active fragments or homologs thereof, and optionally an additional therapeutic agent is administered at least once to a subject in need thereof.

20 . The method of claim 18 , wherein said IL233 fusion protein, or a biologically active homolog or fragment thereof, comprises a fragment of IL-2 that binds to an IL-2 receptor and a fragment of IL-33 that binds with the IL-33 receptor.

21 . The method of claim 20 , wherein said IL233 protein comprises the amino acid sequence of SEQ ID NO:2 or SEQ ID NO:11.

22 . The method of claim 18 , wherein said IL233 protein comprises the amino acid sequence of SEQ ID NO:2 or SEQ ID NO:11, said IL-2 protein comprises the sequence of SEQ ID NO:6 or SEQ ID NO:8, and said IL-33 protein comprises the sequence of SEQ ID NO:7 or SEQ ID NO:9, or biologically active fragments or homologs thereof.

23 . The method of claim 19 , wherein said method treats a disease or disorder selected from the group consisting of diabetic nephropathy, pancreatitis, type 1 diabetes, type 2 diabetes, insulitis, lupus, lupus glomerulonephritis, obesity, acute kidney injury, renal ischemia reperfusion injury, multiple sclerosis, diabetic retinopathy, ankylosing spondylitis, autoimmune cardiomyopathy, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune lymphoproliferative syndrome, autoimmune pancreatitis, autoimmune polyendocrine syndrome, autoimmune urticaria, autoimmune uveitis, Crohn's disease, dermatomyositis, Graft versus host (GVH) disease, Hashimoto's thyroiditis, inflammatory demyelinating diseases, interstitial cystitis, juvenile idiopathic arthritis aka Juvenile rheumatoid arthritis, lupus erythematosus, Multiple sclerosis, Myasthenia gravis, microscopic colitis, polymyositis Primary biliary cirrhosis, Primary sclerosing cholangitis, Progressive inflammatory neuropathy, rheumatoid arthritis, Sjögren's syndrome, Systemic lupus Erythematosus Transplant rejection, ulcerative colitis (one of two types of idiopathic inflammatory bowel disease “IBD”), vasculitis, and Wegener's granulomatosis.

24 . The method of claim 19 , wherein said method treats inflammation.

25 . The method of claim 19 , wherein said IL233 fusion protein or a combination of Interleukin-2 (IL-2) and Interleukin-33 (IL-33) proteins are administered at a dosage ranging from about 1 μg/kg body weight to about 1000 μg/kg body weight.

26 . The method of claim 25 , wherein said dosage is from about 10 μg/kg body weight to about 500 μg/kg body weight.

27 . The method of claim 26 , wherein said dosage is from about 20 μg/kg body weight to about 100 μg/kg body weight.

28 . The method of claim 27 , wherein said dosage is from about 30 μg/kg body weight to about 50 μg/kg body weight.

29 . The method of claim 25 , wherein said dosage is selected from the group consisting of 5.0, 15, 50, and 150 μg/kg of body weight.

30 . The method of claim 23 , wherein when said subject is being treated for obesity said method inhibits weight gain, inhibits hyperglycemia, inhibits proteinuria, and restores glucose tolerance.

31 . The method of claim 19 , wherein said method promotes anti-inflammatory M2 macrophages and inhibits proinflammatory M1 macrophages.

32 . The method of claim 31 , wherein said M2 macrophages inhibit inflammation.

33 . The methods of claim 32 , wherein said M2 macrophages inhibit inflammation in a tissue or organ selected from the group consisting of pancreas, liver, kidneys, adipose tissue, salivary glands, central nervous system (CNS), and related organs.

34 . The method of claim 19 , wherein said method increases Treg levels in said subject.

35 . A method of treating inflammation associated with a disease or disorder, wherein said disease or disorder is selected from the group consisting of diabetic nephropathy, pancreatitis, type 1 diabetes, type 2 diabetes, insulitis, lupus, lupus glomerulonephritis, obesity, acute kidney injury, renal ischemia reperfu

Assignees

• Sharma Rahul
• Okusa Mark D
• Univ Virginia Patent Foundation

Inventors

• Sharma Rahul
• Okusa Mark D

Classifications

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title

• C07K14/54

  Interleukins [IL] · CPC title

• C07K2319/74

  containing a fusion for binding to a cell surface receptor · CPC title

• C07K14/55 Primary

  IL-2 · CPC title