Compound for stimulating signal pathways through il-15rbeta/gamma for purposes of inducing and/or stimulating activation and/or proliferation of il-15rbeta/gamma-positive cells such as nk- and/or t-cells, nucleic acid coding compound, expression vector, host cell, adjuvant for immunotherapeutic composition, pharmaceutical composition and therapeutic agent for treating condition or disease which requires higher activity of il-15, method for inducing and/or stimulating in vitro proliferation and/or activation of il-15rbeta/gamma-positive cells and method for making in vitro activated nk-and/or t-cells

FIELD: medicine.

SUBSTANCE: compound contains IL-15 indirectly bound by covalent links with a polypeptide containing a sushi domain of an extra-cellular region of the alpha IL-15R subunit.

EFFECT: invention allows inducing and stimulating activation and proliferation of said cells, and effectively treating the conditions and diseases which requires higher activity of IL-15.

44 cl, 42 dwg, 4 tbl, 1 ex

 

The text descriptions are given in facsimile form.

1. The connection is designed to stimulate the path of signal transmission through 1L-15R/gamma, with the aim to induce and/or stimulate the activation and/or proliferation 1L-15R/gamma-positive cells, such as NK and/or T cells, characterized in that it contains an element linking 1L-15R/gamma indirectly linked by covalent bonds with the polypeptide containing the sushi domain of the extracellular region of subunit alpha, IL-15R, and:
- the specified element connecting 1L-15R/gamma, is an IL-15, and
the amino acid sequence of the specified polypeptide containing sushi domain,
- represents the amino acid sequence of the extracellular region of subunit alpha, IL-15R, or
- represents the amino acid sequence of a fragment of the extracellular region of subunit alpha, IL-15R, where specified in the fragment preserved sushi domain specified extracellular region subunit alpha, IL-15R, with the specified domain sushi is defined as beginning with the first encoded by exon 2 of the cysteine residue (C1) and ending on the fourth encoded by exon 2 of the cysteine residue (C4), and C1 remains the C4 is also included in the specified domain sushi, or
represents a variant amino acid sequence that is at least 85% identical to the amino acid sequence of such extracellular region subunit alpha, IL-15R, or a fragment of the extracellular region of subunit alpha, IL-15R, along the entire length of the amino acid sequence of the extracellular region or a fragment of the extracellular region, provided that each of the four cysteine residues (C1, C2, C3 and C4) of the specified domain sushi preserved in the specified variant sequence.

2. The compound according to claim 1, characterized in that the specified alpha subunit of IL-15R represents the alpha subunit of IL-15R person, or the alpha subunit of IL-15R monkey, or the alpha subunit of IL-15R mouse, or the alpha subunit of IL-15R rabbit, or the alpha subunit of IL-15R pigs.

3. The compound according to claim 1 or 2, wherein the specified sequence of amino acids specified extracellular region subunit alpha, IL-15R is a sequence of the extracellular region of subunit alpha, IL-15R human SEQ ID NO:40, the sequence of the extracellular region of subunit alpha, IL-15R chimpanzees SEQ ID NO:80, the sequence of the extracellular region of subunit alpha, IL-15R house mouse SEQ ID NO:74 or the sequence of the extracellular region of subunit alpha, IL-15R gray rat SEQ ID NO:86.

4. The compound according to claim 1 or 2 characterized in that that a specified sequence of amino acids specified domain sushi is a sequence of the sushi domain subunit alpha, IL-15R human SEQ ID NO:14, sushi domain subunit alpha, IL-15R Pan troglodytes SEQ ID NO:81, sushi domain subunit alpha, IL-15R Mus musculus SEQ ID NO:75 or sushi domain subunit alpha, IL-15R gray rat SEQ ID NO:87.

5. The compound according to claim 1 or 2, characterized in that the fragment of the extracellular region of subunit alpha, IL-15R includes:
- part of the extracellular region of subunit alpha, IL-15R, encoded by exons 2 and 3 of this subunit alpha, IL-15R, or
the fragment part is encoded by exons 2 and 3, in which are preserved the specified domain sushi.

6. The compound according to claim 5, characterized in that the specified encoded by exon 2 sequence is:
is encoded by exon 2 part of the extracellular region of subunit alpha, IL-15R person that has the sequence of SEQ ID NO:24, encoded by exon 2 part of the extracellular region of subunit alpha, IL-15R chimpanzees, which has the sequence of SEQ ID NO:98,
is encoded by exon 2 part of the extracellular region of subunit alpha, IL-15R house mouse, which has the sequence of SEQ ID NO:97, encoded by exon 2 part of the extracellular region of subunit alpha, IL-15R gray rat, which has the sequence of SEQ ID NO:99.

7. The compound according to claim 5, characterized in that toksana encoded by exon 3 sequence is:
is encoded by exon 3 of the extracellular region of subunit alpha, IL-15R person that has the sequence of SEQ ID NO:93,
is encoded by exon 3 of the extracellular region of subunit alpha, IL-15R chimpanzees, which has the sequence of SEQ ID NO:95,
is encoded by exon 3 of the extracellular region of subunit alpha, IL-15R house mouse, which has the sequence of SEQ ID NO:94,
is encoded by exon 3 of the extracellular region of subunit alpha, IL-15R gray rat, which has the sequence of SEQ ID NO:96.

8. The compound according to any one of claims 1, 2, 6, characterized in that the fragment of the extracellular region of subunit alpha, IL-15R consists of:
- part of the extracellular region of subunit alpha, IL-15R, encoded by exon 2 of the same subunit alpha, IL-15R, or
- fragment of such encoded by exon 2 parts, in which are preserved the specified domain sushi.

9. The compound according to any one of claims 1, 2, 6, 7, characterized in that the fragment of the extracellular region of subunit alpha, IL-15R includes part of the extracellular region of subunit alpha, IL-15R, encoded by exon 2 of the same subunit alpha, IL-15R, and additionally includes at least one amino acid sequence encoded by exon 3 of said subunit alpha, IL-15R.

10. The connection according to claim 9, characterized in that the fragment of the extracellular region the t subunit alpha, IL-15R consists of:
- part of the extracellular region of subunit alpha, IL-15R, encoded by exons 2 and 3 of this subunit alpha, IL-15R, or
- part of the extracellular region of subunit alpha, IL-15R, encoded by exon 2 of the same subunit alpha, IL-15R, and the fragment of the extracellular region of subunit alpha, IL-15R, encoded by exon 3 of said subunit alpha, IL-15R.

11. The compound according to any one of claims 1, 2, 6, 7, 10, characterized in that the fragment of the extracellular region of subunit alpha, IL-15R is a fragment of a subunit alpha, IL-15R, which further includes:
- the hinge area specified subunit alpha, IL-15R, or
a fragment of such a hinge region,
where the amino acid sequence specified hinge region subunit alpha, IL-15R is a:
- articulated sequence of subunit alpha, IL-15R human SEQ ID NO:20,
- articulated sequence of subunit alpha, IL-15R chimpanzees SEQ ID NO:82,
- articulated sequence of subunit alpha, IL-15R house mouse SEQ ID NO:76, or
- articulated sequence of subunit alpha, IL-15R gray rat SEQ ID NO:88.

12. The connection according claim 11, characterized in that the polypeptide containing the sushi domain is a polypeptide having the sequence of SEQ ID NO:30.

13. The connection according claim 11, characterized in that the amino acid sequence pointed to by the first fragment of the hinge region subunit alpha, IL-15R person includes i, or ir, or ird.

14. The connection 13, characterized in that the polypeptide containing the sushi domain is a polypeptide having the sequence of SEQ ID NO:22, 24, 26, 28.

15. The compound according to any one of claims 1, 2, 6, 7, 10, characterized in that the fragment of the extracellular region of subunit alpha, IL-15R person further includes:
is encoded by exon 3 of the area subunit alpha, IL-15R man, rich in glycosylation sites where the specified encoded by exon 3 part represents the sequence of SEQ ID NO:34, or
- the fragment of sequence SEQ ID NO:34.

16. The connection 15, characterized in that the polypeptide containing the sushi domain is a polypeptide having the sequence of SEQ ID NO:36.

17. The compound according to any one of p, 7, 10, 13, 14, characterized in that the fragment of the extracellular region of subunit alpha, IL-15R further includes:
- part of the extracellular region of subunit alpha, IL-15R, single or multiple exons, encoding the extracellular region of subunit alpha, IL-15R, different from exons 1, 2, 3, or
a fragment of such a part.

18. The compound according to any one of claims 1 to 2, 6-7, 10, 12-14, 16, characterized in that it includes a signal peptide, indirectly associated with the specified polypeptide containing sushi domain, or with the specified element, binding the m 1L-15R/gamma.

19. The compound according to any one of claims 1 to 2, 6-7, 10, 12-14, 16, characterized in that the IL-15 is an IL-15 human.

20. The connection according to claim 19, wherein the specified sequence of amino acids specified IL-15 person represents a sequence of SEQ ID NO:48.

21. The compound according to any one of claims 1 to 2, 6-7, 10, 12-14, 16, 20, characterized in that the specified element connecting 1L-15R/gamma, does not bind to the alpha subunit of IL-2R.

22. The compound according to any one of claims 1 to 2, 6-7, 10, 12-14, 16, 20, characterized in that the polypeptide containing the domain sushi, indirectly associated with the specified element connecting 1L-15R/gamma.

23. Connection p.22, characterized in that the polypeptide containing the sushi domain, is associated with the specified element that binds IL-15R/gamma, via a peptide linker that includes at least one, but less than 30 amino acids.

24. The connection to item 23, wherein the amino acid sequence of the indicated peptide linker is a sequence of SEQ ID NO:50 or SEQ ID NO:52.

25. The compound according to any one of claims 1 to 2, 6-7, 10, 12-14, 16, 20, 23-24, characterized in that the polypeptide containing the domain sushi, is located in N-terminal position relative to the specified element connecting 1L-15R/gamma.

26. The compound according to any one of claims 1 to 2, 6-7, 10, 12-14, 16, 20, 23-24, characterized in that decree the config polypeptide, containing the domain sushi, is located in the C-terminal position relative to the specified element connecting 1L-15R/gamma.

27. The compound according to any one of claims 1 to 2, 6-7, 10, 12, 16, 20, 23-24, characterized in that its amino acid sequence is the sequence SEQ ID NO:60.

28. The compound according to any one of claims 1 to 2, 6-7, 10, 12, 16, 20, 23-24, characterized in that its amino acid sequence is the sequence SEQ ID NO:62.

29. Nucleic acid encoding connection, which is designed to stimulate the path of signal transmission through EL-15R/gamma, with the aim to induce and/or stimulate the activation and/or proliferation of IL-15R/gamma-positive cells, such as NK and/or T cells, characterized in that it encodes a compound according to any one of claims 1 to 28 in accordance with the universal genetic code, given its degeneracy.

30. The expression vector, characterized in that it includes a nucleic acid according to clause 29.

31. A host cell for producing compounds according to any one of claims 1 to 28, transformed or transfected with a nucleic acid according to clause 29 and/or a vector according to item 30.

32. A host cell according p, characterized in that it is a cell of a mammal.

33. Adjuvant for immunotherapy composition for treating a condition or disease in which VC is positive, the increase in the activity of IL-15, characterized in that it contains at least one element of the following elements:
connection according to any one of claims 1 to 28,
- nucleic acid according to clause 29,
the vector according to item 30,
cell host according to any one of p-32.

34. Adjuvant on p, characterized in that it is designed to improve the response of the memory cells CD8, and said treatment is the treatment, alleviation or prevention.

35. Pharmaceutical composition for treatment of conditions or diseases in which it is desirable increase in the activity of IL-15, characterized in that it contains at least one element of the following elements:
connection according to any one of claims 1 to 28,
- nucleic acid according to clause 29,
the vector according to item 30,
cell host according to any one of p-32.

36. Drug for the treatment of conditions or diseases in which it is desirable increase in the activity of IL-15, characterized in that it includes at least one element of the following elements:
connection according to any one of claims 1 to 28,
- nucleic acid according to clause 29,
the vector according to item 30,
cell host according to any one of p-32.

37. Drug for p, characterized in that it is a composition of the vaccine, and said treatment is the treatment, alleviation or prevention.

38. Drug for p or 37, characterized in that h is about, it is intended for the treatment of tumors, and said treatment is the treatment, alleviation or prevention.

39. Drug at § 38, characterized in that it additionally contains at least one antigen of a tumor.

40. Drug for p or 37, characterized in that it is intended for the treatment of infectious diseases, and said treatment is the treatment, alleviation or prevention.

41. Drug for p or 37, characterized in that it is intended for the treatment of immunodeficiency, and said treatment is the treatment, alleviation or prevention.

42. Drug for p or 37, characterized in that it is intended to treat X-linked severe combined immunodeficiency (SCID-X), and said treatment is the treatment, alleviation or prevention.

43. The in vitro method of inducing and/or stimulating the proliferation and/or activation 1L-15R/gamma-positive cells, characterized in that it includes:
bringing the sample cell, which includes 1L-15R/gamma-positive cells, in contact with at least one of the following items:
connection according to any one of claims 1 to 28,
- nucleic acid according to clause 29, the expression vector according to item 30,
- the host-cell according to any one of p-32, during the period of time when the external conditions, which are specified contact causes the induction and/or stimulation of proliferation and/or activation of these IL-15R/gamma-positive cells.

44. The method of obtaining in vitro activated NK and/or T cells, characterized in that it includes:
bring the sample cell, which includes resting NK and/or T cells, in contact with at least one of the following items:
connection according to any one of claims 1 to 28, nucleic acid according to clause 29,
- expression vector according to item 30,
- the host-cell according to any one of p-32, during the period of time when the external environment in which the specified contact leads to induction of the indicated activation of resting NK and/or T-cells contained in the specified pattern.



 

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