Tumour necrosis factor alpha single domain antibodies, and use thereof

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to immunology and biotechnology. There are offered versions of a TNF-alpha polypeptide wherein a number of heavy-chain single domain antibodies is equal to two. What is described is coding nucleic acid. There are disclosed versions of the compositions, a polypeptide-based kit, as well as versions of using it. What is described is a method for producing the polypeptide with using nucleic acid.

EFFECT: use of the invention provides the substantial growth of cytotoxicity lC50 (of the order of 10-9) that can find further application in therapy of TNFα-mediated disorders.

52 cl, 18 dwg, 11 tbl, 9 ex

 

The text descriptions are given in facsimile form.

1. Polypeptide capable of binding TNF-alpha, containing at least one single domain antibody against TNF-alpha, chosen from:
(a) single-domain antibodies against TNF-alpha, containing a sequence represented by any of SEQ ID nos: 1-5 and 14,
(b) single domain antibodies against TNF-alpha, containing a sequence that is more than 85% identical to any of the sequences represented by SEQ ID NO: 1-5 and 14, and
in which the number of single-domain antibodies against TNF-alpha is at least two.

2. The polypeptide according to claim 1, additionally containing at least one single domain antibody directed against cyberotic the CSOs protein.

3. The polypeptide according to claim 2, where the specified whey protein is any protein from a number of serum albumin, serum immunoglobulins, tyrosinaemia protein, transferrin or fibrinogen.

4. The polypeptide according to claim 2, in which at least one single domain antibody against whey protein contains the sequence of any of SEQ ID nos: 26-29 and 85-97.

5. The polypeptide according to claim 1, containing at least one single domain antibody against TNF-alpha, which has an IC50 of 100 nm or lower when the colorimetric method of analysis using MTT.

6. The polypeptide according to claim 1, additionally containing at least one single domain antibody is selected from the group consisting of single-domain antibodies against IFN-gamma, single-domain antibodies against the receptor of TNF-alpha and single-domain antibodies against the receptor for IFN-gamma.

7. The polypeptide according to claim 1, containing at least one single domain antibody against TNF-alpha, including the sequence of which more than 85% identical to SEQ ID NO: 1.

8. The polypeptide according to claim 1, where at least one single domain antibody is humanitariannet Camelidae VHH.

9. The polypeptide of claim 8 in which at least one humanitariannet Camelidae VHH contains the sequence of any of SEQ ID nos: 17-19 21-24.

10. The polypeptide according to claim 6, where at least one single domain antibody against IFN-gamma contains the sequence any of SEQ ID NO: 44-72.

11. The polypeptide according to claim 1, where at least one single domain antibody is a Camelidae VHH.

12. The polypeptide according to any one of claims 1 to 11, are suitable for treating and/or preventing and/or alleviating disorders relating to inflammatory processes.

13. The polypeptide according to item 12, where these disorders represent any disorder of inflammation, rheumatoid arthritis, Crohn's disease, ulcerative colitis, syndrome inflamed colon cancer, multiple sclerosis, Addison's disease, autoimmune hepatitis, autoimmune parotitis, diabetes type I, epididymitis, glomerulonephritis, graves disease, Guillain-Barre syndrome, Hashimoto's disease, hemolytic anemia, systemic lupus erythematosus, male infertility, weakness bulbar palsy, bladderworts, psoriasis, rheumatic fever, sarcoidosis, scleroderma, Sjogren syndrome, spondyloarthropathy, thyroiditis and vasculitis.

14. The polypeptide according to any one of claims 1 to 11, are suitable for treating and/or preventing and/or alleviating disorders susceptible to modulation by a substance that modulates TNF-alpha, can pass through a medium of the stomach without inactivation of the substance.

15. The polypeptide according to 14, where these disorders represent any disorder of inflammation, rheumatoid arthritis, is aesni Crown, ulcerative colitis syndrome inflamed colon cancer, multiple sclerosis, Addison's disease, autoimmune hepatitis, autoimmune parotitis, diabetes type I, epididymitis, glomerulonephritis, graves disease, Guillain-Barre syndrome, Hashimoto's disease, hemolytic anemia, systemic lupus erythematosus, male infertility, weakness bulbar palsy, bladderworts, psoriasis, rheumatic fever, sarcoidosis, scleroderma, Sjogren syndrome, spondyloarthropathy, thyroiditis and vasculitis.

16. The polypeptide according to any one of claims 1 to 11, are suitable for treating and/or preventing and/or alleviating disorders susceptible to modulation by a substance that modulates TNF-alpha, which are delivered into the vagina or rectum.

17. The polypeptide according to item 16, where these disorders represent any disorder of inflammation, rheumatoid arthritis, Crohn's disease, ulcerative colitis, syndrome inflamed colon cancer, multiple sclerosis, Addison's disease, autoimmune hepatitis, autoimmune parotitis, diabetes type I, epididymitis, glomerulonephritis, graves disease, Guillain-Barre syndrome, Hashimoto's disease, hemolytic anemia, systemic lupus erythematosus, male infertility, weakness bulbar palsy, bladderworts, psoriasis, rheumatic fever, Sarko the oz, scleroderma, Sjogren syndrome, spondyloarthropathy, thyroiditis and vasculitis.

18. The polypeptide according to any one of claims 1 to 11, are suitable for treating and/or preventing and/or alleviating disorders susceptible to modulation by a substance that modulates TNF-alpha, and delivered to the nose, upper respiratory tract and/or lungs.

19. The polypeptide according p where these disorders represent any disorder of inflammation, rheumatoid arthritis, Crohn's disease, ulcerative colitis, syndrome inflamed colon cancer, multiple sclerosis, Addison's disease, autoimmune hepatitis, autoimmune parotitis, diabetes type I, epididymitis, glomerulonephritis, graves disease, Guillain-Barre syndrome, Hashimoto's disease, hemolytic anemia, systemic lupus erythematosus, male infertility, weakness bulbar palsy, bladderworts, psoriasis, rheumatic fever, sarcoidosis, scleroderma, Sjogren syndrome, spondyloarthropathy, thyroiditis and vasculitis.

20. The polypeptide according to any one of claims 1 to 11, are suitable for treating and/or preventing and/or alleviating disorders susceptible to modulation by a substance that modulates TNF-alpha, delivered to the intestinal mucosa, where the specified disorder increases the permeability of the intestinal mucosa.

21. The polypeptide according to claim 20, where indicated the disorder are any disorder among inflammation, rheumatoid arthritis, Crohn's disease, ulcerative colitis, syndrome inflamed colon cancer, multiple sclerosis, Addison's disease, autoimmune hepatitis, autoimmune parotitis, diabetes type I, epididymitis, glomerulonephritis, graves disease, Guillain-Barre syndrome, Hashimoto's disease, hemolytic anemia, systemic lupus erythematosus, male infertility, weakness bulbar palsy, bladderworts, psoriasis, rheumatic fever, sarcoidosis, scleroderma, Sjogren syndrome, spondyloarthropathy, thyroiditis and vasculitis.

22. The polypeptide according to any one of claims 1 to 11, are suitable for treating and/or preventing and/or alleviating disorders susceptible to modulation by a substance that modulates TNF-alpha, able to effectively pass through tissues under the tongue.

23. The polypeptide according to item 22, where these disorders represent any disorder of inflammation, rheumatoid arthritis, Crohn's disease, ulcerative colitis, syndrome inflamed colon cancer, multiple sclerosis, Addison's disease, autoimmune hepatitis, autoimmune parotitis, diabetes type I, epididymitis, glomerulonephritis, graves disease, Guillain-Barre syndrome, Hashimoto's disease, hemolytic anemia, systemic lupus erythematosus, male infertility, weakness bulbar palsy, pusy is chutki, psoriasis, rheumatic fever, sarcoidosis, scleroderma, Sjogren syndrome, spondyloarthropathy, thyroiditis and vasculitis.

24. The polypeptide according to any one of claims 1 to 11, are suitable for treating and/or preventing and/or alleviating disorders susceptible to modulation by a substance that modulates TNF-alpha, able to effectively pass through the skin.

25. The polypeptide according to paragraph 24, where these disorders represent any disorder of inflammation, rheumatoid arthritis, Crohn's disease, ulcerative colitis, syndrome inflamed colon cancer, multiple sclerosis, Addison's disease, autoimmune hepatitis, autoimmune parotitis, diabetes type I, epididymitis, glomerulonephritis, graves disease, Guillain-Barre syndrome, Hashimoto's disease, hemolytic anemia, systemic lupus erythematosus, male infertility, weakness bulbar palsy, bladderworts, psoriasis, rheumatic fever, sarcoidosis, scleroderma, Sjogren syndrome, spondyloarthropathy, thyroiditis and vasculitis.

26. A composition comprising an effective amount of the polypeptide according to any one of claims 1 to 9 and at least one single domain antibody is selected from single-domain antibodies against IFN-gamma, single-domain antibodies against the receptor of TNF-alpha and single-domain antibodies against the receptor for IFN-gamma, and pharmaceutically when memy media suitable for treating and/or preventing and/or alleviating disorders susceptible to modulation by a substance that modulates TNF-alpha.

27. The composition according to p, where at least one single domain antibody against IFN-gamma contains the sequence of any of SEQ ID NO: 44-72.

28. The composition according to p, where at least one single domain antibody is a Camelidae VHH.

29. The composition according to p or 27, are suitable for treating and/or preventing and/or alleviating disorders relating to inflammatory processes.

30. The composition according to p suitable for treating and/or preventing and/or alleviating disorders susceptible to modulation by a substance that modulates TNF-alpha, can pass through a medium of the stomach without inactivation of the substance.

31. The composition according to p suitable for treating and/or preventing and/or alleviating disorders susceptible to modulation by a substance that modulates TNF-alpha, which are delivered into the vagina or rectum.

32. The composition according to p suitable for treating and/or preventing and/or alleviating disorders susceptible to modulation by a substance that modulates TNF-alpha, and delivered to the nose, upper respiratory tract and/or lungs.

33. The composition according to p suitable for treating and/or preventing and/or alleviating disorders susceptible to modulation prophetic is STV, modulating TNF-alpha, delivered to the intestinal mucosa, where the specified disorder increases the permeability of the intestinal mucosa.

34. The composition according to p suitable for treating and/or preventing and/or alleviating disorders susceptible to modulation by a substance that modulates TNF-alpha, able to effectively pass through tissues under the tongue.

35. The composition according to p suitable for treating and/or preventing and/or alleviating disorders susceptible to modulation by a substance that modulates TNF-alpha, able to effectively pass through the skin.

36. Nucleic acid encoding a polypeptide according to any one of claims 1 to 11.

37. Nucleic acid p suitable for treating and/or preventing and/or alleviating disorders relating to inflammatory processes.

38. A kit for identifying an agent that reduces the intensity of the disorder mediated by tumor necrosis factor alpha, containing the polypeptide according to any one of claims 1-11, tumor necrosis factor alpha, and packaging materials and instructions for use.

39. Set in § 38, where these disorders represent any disorder of inflammation, rheumatoid arthritis, Crohn's disease, ulcerative colitis, syndrome inflamed colon cancer, multiple sclerosis, disease Ad is the Eason, autoimmune hepatitis, autoimmune parotitis, diabetes type I, epididymitis, glomerulonephritis, graves disease, Guillain-Barre syndrome, Hashimoto's disease, hemolytic anemia, systemic lupus erythematosus, male infertility, weakness bulbar palsy, bladderworts, psoriasis, rheumatic fever, sarcoidosis, scleroderma, Sjogren syndrome, spondyloarthropathy, thyroiditis and vasculitis.

40. A composition comprising an effective amount of nucleic acid in p, polypeptide according to any one of claims 1 to 11, and a suitable pharmaceutical carrier suitable for treating and/or preventing and/or alleviating disorders susceptible to modulation by a substance that modulates TNF-alpha.

41. The in vitro method for the diagnosis of disorders characterized by dysfunction of tumor necrosis factor alpha, including:
(a) bringing into contact of the sample with a polypeptide according to any one of claims 1-11,
(b) detection of binding of the specified polypeptide with the specified sample, and
(c) comparing the binding detected in stage (b), with the standard, where the difference in binding relative to the specified sample is the diagnosis of disorders characterized by dysfunction of tumor necrosis factor alpha.

42. The kit for screening for the disorder, where the specified disorder is any one of a number of inflammation, rheumatoid arthritis, pain is FDI Crown, ulcerative colitis syndrome inflamed colon cancer, multiple sclerosis, Addison's disease, autoimmune hepatitis, autoimmune parotitis, diabetes type I, epididymitis, glomerulonephritis, graves disease, Guillain-Barre syndrome, Hashimoto's disease, hemolytic anemia, systemic lupus erythematosus, male infertility, weakness bulbar palsy, bladderworts, psoriasis, rheumatic fever, sarcoidosis, scleroderma, Sjogren syndrome, spondyloarthropathy, thyroiditis and vasculitis, comprising the polypeptide according to any one of claims 1 to 11, packaging materials and instructions for use.

43. The method of producing the polypeptide according to any one of claims 1 to 11, comprising the stage of:
(a) obtaining a DNA that encodes a Camelidae VHH directed against tumor necrosis factor alpha,
(b) cloning and expression of DNA obtained in stage (a).

44. The method of producing the polypeptide according to any one of claims 1 to 11, including:
(a) culturing host cells containing nucleic acid encoding the polypeptide according to any one of claims 1 to 11, under conditions that allow expression of the polypeptide, and
(b) extraction of the resulting polypeptide from the culture.

45. The method according to item 44, in which these cells-the hosts are bacterial or yeast.

46. The use of the polypeptide according to any one of claims 1 to 11, nucleic acid pH or composition p is p to obtain drugs for the treatment and/or prevention, and/or alleviating disorders relating to inflammatory processes.

47. The use of the polypeptide according to any one of claims 1 to 11 or the composition of p to obtain drugs for treating, preventing and/or alleviating the symptoms of disorders susceptible to modulation by a substance that modulates TNF-alpha, can pass through a medium of the stomach without inactivation of the substance.

48. The use of the polypeptide according to any one of claims 1 to 11 or the composition of p to obtain drugs for treating, preventing and/or alleviating the symptoms of disorders susceptible to modulation by a substance that modulates TNF-alpha, which are delivered into the vagina or rectum.

49. The use of the polypeptide according to any one of claims 1 to 11 or the composition of p to obtain drugs for treating, preventing and/or alleviating the symptoms of disorders susceptible to modulation by a substance that modulates TNF-alpha, and delivered to the nose, upper respiratory tract and/or lungs.

50. The use of the polypeptide according to any one of claims 1 to 11 or the composition of p to obtain drugs for treating, preventing and/or alleviating the symptoms of disorders susceptible to modulation by a substance that modulates TNF-alpha, delivered to the intestinal mucosa, where the specified disorder increases the permeability of clisis the second membrane of the intestine.

51. The use of the polypeptide according to any one of claims 1 to 11 or the composition of p to obtain drugs for treating, preventing and/or alleviating the symptoms of disorders susceptible to modulation by a substance that modulates TNF-alpha, able to effectively pass through tissues under the tongue.

52. The use of the polypeptide according to any one of claims 1 to 11 or the composition of p to obtain drugs for treating, preventing and/or alleviating the symptoms of disorders susceptible to modulation by a substance that modulates TNF-alpha, able to effectively pass through the skin.



 

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