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1. WO2008003327 - IMMUNOTOXINES POUR TRAITER DES MALADIES ASSOCIÉES À UNE I NFECTION PAR LE CYTOMEGALOVIRUS (CMV)

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Claims

1. An immunotoxin comprising (a) a ligand that binds a constitutively
internalizing receptor encoded by human CMV and expressed on the CMV infected cell and (b) a toxin that is cytotoxic to the CMV infected cell, wherein the immunotoxin is not SEQ ID NO: 1

2. The immunotoxin according to claim 1, wherein the receptor is selected from the group consisting of human CMV encoded proteins US28, US27, UL33 and UL78 or any naturally occurring variants thereof

3. The immunotoxin according to claim 2, wherein the receptor is US28.

4. The immunotoxin according to any of the preceding claims, wherein the ligand is selected from the group consisting of a chemokine or a variant thereof or an antibody or a fragment thereof.

5. The immunotoxin according to any of the preceding claims, wherein the ligand is a chemokine or a variant thereof.

6. The immunotoxin according to any of the preceding claims, wherein the ligand is selected from the group consisting of a chemokine or a variant thereof originating from human, mouse, rat, rabbit, fowl, pig, horse, rhesus monkey, orangutan, cow, dog, or virus.

7. The immunotoxin according to any of the preceding claims, wherein the ligand is a chemokine selected from the group consisting of CC-chemokines, XC- chemokines, CXC-chemokines and CXsC-chemokines or variants thereof.

8. The immunotoxin according to claim 7, wherein the ligand is a CC-chemokine selected from the group consisting of CCLl, CCL2, CCL3, CCL4, CCL5, CCL6, CCL7, CCL8, CCL9, CCLlO, CCLU, CCL12, CCL13, CCL14, CCL15, CCL16, CCL17, CCL18, CCL19, CCL20, CCL21, CCL22, CCL23, CCL24, CCL25, CCL26, CCL27 and CCL28 or variants thereof.

9. The immunotoxin according to claim 8, wherein the ligand is a CC-chemokine or a variant thereof originating from human or mouse.

5 10. The immunotoxin according to claim 7, wherein the ligand is a XC-chemokine selected from the group consisting of XCLl and XCL2 or variants thereof.

11. The immunotoxin according to claim 7, wherein the ligand is a CXC-chemokine selected from the group consisting of CXCLl, CXCL2, CXCL3, CXCL4, CXCL5,

10 CXCL6, CXCL7, CXCL8, CXCL9, CXCLlO, CXCLIl, CXCL12, CXCL13, CXCL14,

CXCL15 and CXCL16 or variants thereof.

12. The immunotoxin according to claim 7, wherein the ligand is a CX3C
chemokine or a variant thereof.
15
13. The immunotoxin according to claim 12, wherein the ligand is a variant which has at least 67% amino acid sequence identity to human CX3CLI (SEQ ID
NO:2).

20 14. The immunotoxin according to claim 12, wherein the ligand is a variant which has at least 67% amino acid sequence identity to the chemokine domain
(positions 25-100 of SEQ ID NO:2) of human CX3CLl.

15. The immunotoxin of claim 14, wherein the ligand binds to the US28 receptor 25 with a Kd of 10"8 M or less.

16. The immunotoxin of any of claims 14 and 15, wherein the ligand binds to the CX3CR1 receptor with a Kd of 10"6 M or more.

30 17. The immunotoxin according to any of claims 14-16, wherein the ligand is
selected from the group consisting of the following variants: A variant mutated in position 31 of SEQ ID NO:2, a variant in position 38 of SEQ ID NO:2, a variant mutated in position 42 of SEQ ID NO:2, a variant mutated in position 60 of SEQ ID NO:2, a variant mutated in position 61 of SEQ ID NO:2, a

35 variant mutated in position 68 of SEQ ID NO:2, a variant mutated in position 71 of SEQ ID NO:2, a variant mutated in position 72 of SEQ ID NO:2 and a variant mutated in position 73 of SEQ ID NO:2.

18. The immunotoxin according to any of claims 14-17, wherein the ligand is

5 selected from the group consisting of the following variants: A variant mutated in position 31 of SEQ ID NO:2 to an Alanine, a variant mutated in position 31 of SEQ ID NO:2 to an Glutamate, a variant in position 38 of SEQ ID NO:2 to an Alanine, a variant mutated in position 38 of SEQ ID NO:2 to a Glutamate, a variant mutated in position 42 of SEQ ID NO:2 to an Alanine, a variant

10 mutated in position 42 of SEQ ID NO:2 to a Glutamate, a variant mutated in position 60 of SEQ ID NO:2 to a Alanine, a variant mutated in position 60 of
SEQ ID NO:2 to a Glutamate, a variant mutated in position 61 of SEQ ID NO:2 to a Alanine, a variant mutated in position 61 of SEQ ID NO:2 to a Glutamate, a variant mutated in position 68 of SEQ ID NO:2 to a Alanine, a variant

15 mutated in position 68 of SEQ ID NO:2 to a Glutamate, a variant mutated in position 71 of SEQ ID NO:2 to a Alanine, a variant mutated in position 71 of
SEQ ID NO:2 to a Glutamate, a variant mutated in position 71 of SEQ ID NO:2 to a Glutamine, a variant mutated in position 72 of SEQ ID NO:2 to a Alanine, a variant mutated in position 73 of SEQ ID NO:2 to a Alanine and a variant

20 mutated in position 73 of SEQ ID NO:2 to a Leucine.

19. The immunotoxin according to any of claims 14-16, wherein the ligand is
variant wherein one or more amino acid residues in position 33, 34 and 35 of SEQ ID NO:2 are mutated.
25
20. The immunotoxin according to any of claims 1-7, wherein the ligand is the
Kaposi Sarcoma associated herpesvirus (KSHV) encoded CC-chemokine vCCL2 (SEQ ID NO:7) or a variant thereof.

30 21. The immunotoxin according to any of claims 1-3 wherein the ligand is a
chimera between two or more different chemokines, wherein the chemokine is selected from the group consisting of CC-chemokines, XC-chemokines, CXC- chemokines and CXsC-chemokines.

22. The immunotoxin according to claim 4, wherein the ligand is an antibody or a fragment thereof selected from the group consisting of an antibody against
US28 or a fragment of said antibody, an antibody against US27 or a fragment of said antibody, an antibody against UL33 or a fragment of said antibody and

5 an antibody against UL78 or a fragment of said antibody.

23. The immunotoxin according to claim 23, wherein the ligand is an antibody against US28 or a fragment of said antibody.

10 24. The immunotoxin according to any of the preceding claims, wherein the toxin is selected from the group consisting of gelonin, bouganin, saporin, ricin, ricin A chain, bryodin, diphtheria, restrictocin, diphtheria toxin, Pseudomonas
exotoxin A and variants thereof.

15 25. The immunotoxin according to claim 24, wherein the toxin is Pseudomonas exotoxin A or a variant thereof.

26. The immunotoxin according to claim 25, wherein the toxin is PE38KDEL (SEQ ID NO:9).
20
27. The immunotoxin according to claim 26 comprising the ligand of any of claims 12-19 and PE38KDEL (SEQ ID NO:9).

28. The immunotoxin according to claim 27 comprising the chemokine domain

25 CX3CLl (positions 25-100 of SEQ ID NO:2) and PE38KDEL (SEQ ID NO:9), the immunotoxin having SEQ ID NO: 11.

29. Use of the immunotoxin according to any of claims 1-28 as a medicament.

30 30. Use of the immunotoxin according to any of claims 1-28 for the manufacture of a medicament for the treatment or prevention of a CMV infection.

31. Use of the immunotoxin according to any of claims 1-28 for the manufacture of a medicament for preventing the establishment or progress of the CMV 35 infection, or of any symptom of the CMV infection.

32. Use of the immunotoxin according to any of claims 1-28 for the manufacture of a medicament for preventing the establishment or progress of the CMV infection, or of any symptom of the CMV infection in HIV infected patients.

5
33. Use according to any of claims 29-32, wherein the CMV infection is localised in a tissue selected from the group consisting of retina, heart, liver, lung, spleen or blood cells.

10 34. Use according to any of claims 29-33, wherein the individual for the treatment or prevention of the CMV infection is an immuno-compromised patient
selected from the group consisting of HIV-patients, neonates and
immunosuppressive patients, bona marrow transplant patients and solid organ transplants.
15
35. Use according to claim 29-34, wherein the individual for the treatment or prevention of the CMV infection is a patient suffering from a coronary disease.

36. A pharmaceutical composition comprising an immunotoxin according to any of 20 claims 1-28 or any physiological acceptable salt thereof.

37. The pharmaceutical composition according to claim 36 further comprising a pharmaceutical acceptable carrier.

25 38. The pharmaceutical composition according to any of claims 36 and 37,
wherein the composition is administered simultaneous, separate or sequential with one or more anti-viral therapeutics.

39. The pharmaceutical composition according to any of claims 36-38, wherein the 30 composition is administered simultaneous, separate or sequential with one or more immunosuppressive therapeutics.

40. A kit for treatment or prevention of CMV infection comprising (a) an effective amount of an immunotoxin according to any of claims 1-28 and (b) a
35 therapeutic selected from the group of antiviral therapeutics and immuno- suppressive therapeutics for simultaneous, separate or sequential
administration.

41. A nucleic acid sequence comprising a sequence encoding an immunotoxin 5 according to any of the claims 1-28.

42. A nucleic acid sequence according to claim 41, wherein the immunotoxin is
SEQ ID NO: 11 or a variant thereof, the nucleic acid sequence having SEQ ID NO:22.
10
43. A nucleic acid construct comprising a nucleotide sequence according to claims 41 or 42 operably linked to one or more control sequences that direct the production of the immunotoxin in a suitable host.

15 44. A recombinant expression vector comprising the nucleic acid construct as defined in claim 39.

45. A recombinant host cell comprising the nucleic acid construct as defined in claim 39 or the recombinant expression vector as defined in claim 40.
20
46. A recombinant host cell according to claim 41, wherein said host cell is a
prokaryotic host cell.
47. A method of treatment or prophylaxis of a CMV infection comprising
administering an effective amount of an immunotoxin according to any of

25 claims 1-28 to an individual in the need thereof.

48. The method according to claim 42, wherein the individual is an immunocompromised patient selected from the group consisting of HIV-patients, neonates and immunosuppressive patients, bona marrow transplant patients

30 and solid organ transplant patients.

49. The method according to claim 42, wherein the individual is a patient suffering from a coronary disease.

50. The method according to any of claims 42-44, wherein the CMV infection is localised in a tissue selected from the group consisting of retina, heart, liver, lung, spleen and blood cells.