"humanized" antibodies against human gp39, compositions containing these antibodies and their therapeutic use

 

The invention relates to the field of medical genetics. The essence of the invention comprise the "humanized" antibodies are able to bind with human GP39. These antibodies can be used for the treatment of autoimmune diseases, as well as immunosuppressants in transplantation of heterologous cells, tissues or organs. The invention contains a variable sequence of the aforementioned antibodies and corresponding pharmaceutical compositions containing them. The technical result is an expansion of the means of gene therapy. 10 C. and 24 C.p. f-crystals, 6 tab., 26 Il.

Description text in facsimile form (see graphic part). T TA

Claims

1. "Humanized" antibody that binds to the antigen Dr and inhibits the binding of antigen Dr with protein SV and which is capable of competing with the murine antibody 24-31 for the inhibition of binding of CD40 with Dr.

2. The antibody under item 1, containing hypervariable region of the antibody 24-31, shown in Fig.4-8, or its variants and equivalents, which contain one or more conservative amino acid substitutions.

3. "Humanized" antibody derived from the murine monochloroamine, at least about one-third of the affinity of binding to the antigen Dr mouse antibody 24-31.

5. "Humanized" antibody derived from a murine monoclonal antibody 24-31 and preserving premaxillary capacity for functional in vitro activity in b-cell analysis at a concentration which is not more than three times higher than the concentration of the parent murine antibody 24-31.

6. "Humanized" antibody under item 5, where In-cell analysis to measure T-cell-dependent production of antibodies.

7. "Humanized" antibody under item 1, where the specified antibody contains a "humanized" variable sequence of the light chain selected from the following group of sequence # 1. (see the graphical part), and their variants and equivalents, containing one or more conservative amino acid substitutions that do not have a significant impact on the ability of the obtained "humanized" antibodies to contact the antigen Dr.

8. "Humanized" antibody under item 1, where the specified antibody contains a "humanized" variable sequence of the heavy chain selected from the following group a sequence of N 2, (see graphic part), and their variants and equivalents, which contains the ability received "humanized" antibodies to contact the antigen Dr.

9. "Humanized" antibody under item 1, which contains a "humanized" variable sequence of the light chain selected from the following group a sequence of N 3, (see graphic part) and "humanized" variable sequence of the heavy chain selected from the following group a sequence of N 4, (see graphic part) and their variants and equivalents, containing one or more conservative amino acid substitutions that do not have a significant impact on the ability of the obtained "humanized" antibodies to contact the antigen Dr.

10. "Humanized" antibody under item 5, which contains a "humanized" variable sequence of the light chain (1) and "humanized" variable sequence of the heavy chain (1).

11. "Humanized" antibody under item 5, which contains a "humanized" variable sequence of the light chain (2) and "humanized" variable sequence of the heavy chain (1).

12. "Humanized" antibody under item 5, which contains a "humanized" variable sequence of the light chain (1) and "humanized" variable sequence of the heavy chain (2).

13. "Humanized" antibody under item 5, which contains a "humanized" VA is (2).

14. "Humanized" antibody under item 1, which contains a constant region light Kappa or lambda chain of human antibodies and the constant region of the heavy chain or gamma-1 or gamma 4 human antibodies.

15. A DNA sequence encoding a "humanized" antibody under item 1.

16. Expressing a vector containing a DNA sequence under item 15.

17. The pharmaceutical composition which is effective in the treatment of pathological conditions mediated by the interaction of antigen Dr with protein SV, and contains a "humanized" antibody derived from a murine monoclonal antibody 24-31.

18. The pharmaceutical composition according to p. 17, where the aforementioned "humanized" antibody contains a "humanized" variable sequence of the light chain selected from the following group a sequence of N 5, (see graphic part), and their variants and equivalents, containing one or more conservative amino acid substitutions that do not have a significant impact on the ability of the obtained "humanized" antibodies to contact the antigen Dr.

19. The pharmaceutical composition according to p. 18, where the aforementioned "humanized" antibody contains a "humanized" variable posledovatel yanti and equivalents, containing one or more conservative amino acid substitutions that do not have a significant impact on the ability of the obtained "humanized" antibodies to contact the antigen Dr.

20. The pharmaceutical composition according to p. 17, where the aforementioned "humanized" antibody contains a "humanized" variable sequence of the light chain selected from the following group a sequence of N 7, (see graphic part), and "humanized" variable sequence of the heavy chain selected from the following group a sequence of N 8, (see graphic part), and their variants and equivalents, containing one or more conservative amino acid substitutions that do not have a significant impact on the ability of the obtained "humanized" antibodies to contact the antigen Dr.

21. The pharmaceutical composition according to p. 20, where the "humanized" antibody contains a "humanized" variable sequence of the light chain (1) and "humanized" variable sequence of the heavy chain (1).

22. The pharmaceutical composition according to p. 20, where the specified antibody contains a "humanized" variable sequence of the light chain (2) and "humanized" variable successively the sequence of the light chain (1) and "humanized" variable sequence of the heavy chain (2).

24. The pharmaceutical composition according to p. 20, which contains a "humanized" variable sequence of the light chain (2) and "humanized" variable sequence of the heavy chain (2).

25. The method of treatment of a disease treatable by modulation of the expression of antigen Dr or inhibiting the interaction of gp39/CD40, introducing a therapeutically effective amount of "humanized" antibody, which binds to the antigen Dr and inhibits the binding of antigen Dr with protein CD40.

26. The method according to p. 25, where the specified disease is an autoimmune disease.

27. The method according to p. 26, where the specified autoimmune disease selected from the group consisting of rheumatoid arthritis, psoriasis, multiple sclerosis, diabetes, systemic lupus erythematosus and ETC.

28. The method according to p. 25, where the specified condition is neotominae disease.

29. The method according to p. 27, where the specified disease is graft versus host disease or graft rejection.

30. The method of suppression of the humoral and/or cellular immune response against cells or vectors introduced into the cell or gene therapy involving the administration before, during or PEFC sufficient to suppress humoral and/or cellular immune response against cells or vectors, enter in the process of cell or gene therapy.

31. The method according to p. 30, where the specified vector is a viral vector, DNA or antisense RNA.

32. The method according to p. 31, where the specified viral vector is an adenovirus or retrovirus.

33. The method according to p. 30, where the aforementioned "humanized" antibody contains the sequence represented by at least one of Fig.5-8.

34. An improved method of treatment to suppress unwanted immune response, mediated by the interaction of antigen Dr with protein CD40, after transplantation of cells, tissues or organs derived from the same species or from other species, the individual in need of such treatment, where the aforementioned improvement is the introduction of "humanized" antibodies against human antigen Dr, derived from the murine antibody 24-31, before, during or after transplantation, in a quantity sufficient to suppress immune responses against these transplanted cells, tissue or organ, or to suppress immune responses, stimulated the transplanted cell, tissue or organ against this host.

All sequences are given in the end of the description.

 

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