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1. (WO2012057904) MYCOBACTERIUM TUBERCULOSIS ANTIGENS AND COMBINATIONS THEREOF HAVING HIGH SEROREACTIVITY
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CLAIMS

1 . A diagnostic composition comprising a combination of three or more Mycobacterium tuberculosis seroreactive antigens, or immunogenic fragments thereof, wherein the antigens are selected from the group consisting of Rv0054 (SEQ ID NO: 1 ), Rv0164 (SEQ ID NO: 3), Rv0410 (SEQ ID NO: 5), Rv0455c (SEQ ID NO: 7), Rv0632 (SEQ ID NO: 9)Rv0655 (SEQ ID NO: 1 1 ), Rv0831 c (SEQ ID NO: 13), Rv0934 (SEQ ID NO: 15), Rv0952 (SEQ ID NO: 17), Rv1009 (SEQ ID NO: 19), Rv1099 (SEQ ID NO: 21 ), Rv1240 (SEQ ID NO: 23), Rv1288 (SEQ ID NO: 25), Rv1410c (SEQ ID NO: 27), ), Rv141 1 (SEQ ID NO: 29) Rv1569 (SEQ ID NO: 31 ), Rv1789 (SEQ ID NO: 33), Rv1813c (SEQ ID NO: 35), Rv1827 (SEQ ID NO: 37), Rv1837 (SEQ ID NO: 39), Rv1860 (SEQ ID NO: 41 ), Rv1886c (SEQ ID NO: 43), Rv1908 (SEQ ID NO: 45), Rv1980 (SEQ ID NO:47), Rv1984c (SEQ ID NO: 49), Rv2031 (SEQ ID NO: 51 ), Rv2032 (SEQ ID NO: 53), Rv2220 (SEQ ID NO: 55), Rv2450 (SEQ ID NO: 57), Rv2608 (SEQ ID NO: 59), Rv2623 (SEQ ID NO: 61 ), Rv2866 (SEQ ID NO: 63), Rv2873 (SEQ ID NO: 65), Rv2875 (SEQ ID NO: 67), Rv3020 (SEQ ID NO: 69), Rv3044 (SEQ ID NO: 71 ), Rv3310 (SEQ ID NO: 73), Rv3407 (SEQ ID NO: 75), Rv361 1 (SEQ ID NO: 77), Rv3614 (SEQ ID NO: 79), Rv3616 (SEQ ID NO: 81 ) Rv3619 (SEQ ID NO: 83), Rv3628 (SEQ ID NO: 85), Rv3804 (SEQ ID NO:87), Rv3841 (SEQ ID NO: 89), Rv3864 (SEQ ID NO:91 ), Rv3874 (SEQ ID NO: 93) and Rv3881 (SEQ ID NO: 95), and antigens having at least 90% identity to any of the foregoing sequences.

2. The diagnostic composition of claim 1 , wherein the seroreactive antigens are selected from the group consisting of Rv0455 (SEQ ID NO: 7), Rv0632 (SEQ ID NO:9), Rv0831 (SEQ ID NO: 13), Rv0934 (SEQ ID NO: 15), ), Rv1240 (SEQ ID NO: 23), Rv1410 (SEQ ID NO: 27), Rv1860 (SEQ ID NO: 41 ), Rv1980 (SEQ ID NO:47), Rv2031 (SEQ ID NO: 51 ), Rv2032 (SEQ ID NO: 53), Rv2875 (SEQ ID NO: 67), Rv3310 (SEQ ID NO: 73), ), Rv3619 (SEQ ID NO: 83), Rv3864 (SEQ ID NO:91 ), Rv3874 (SEQ ID NO: 93), Rv3881 (SEQ ID NO: 95), and antigens having at least 90% identity to any of the foregoing sequences.

3. The diagnostic composition of claim 1 , wherein the seroreactive antigens are selected from the group consisting of Rv0632 (SEQ ID NO:9), Rv0831 (SEQ ID NO: 13), Rv0934 (SEQ ID NO: 15), Rv1860 (SEQ ID NO: 41 ), Rv1980 (SEQ ID NO:47), Rv2031 (SEQ ID NO: 51 ), Rv2032 (SEQ ID NO: 53), Rv2875 (SEQ ID NO: 67), Rv3864 (SEQ ID NO:91 ), Rv3874 (SEQ ID NO: 93), Rv3881 (SEQ ID NO: 95), and antigens having at least 90% identity to any of the foregoing sequences.

4. The diagnostic composition of claim 1 , wherein seroreactive antigens, or immunogenic fragments thereof, are covalently linked in the form of a fusion polypeptide.

5. The diagnostic composition of claim 4, wherein the fusion polypeptide comprises an amino acid sequence selected from the group consisting of DID90A (SEQ ID NO: 97), DID90B (SEQ ID NO: 98), DID104 (SEQ ID NO: 99), DID64 (SEQ ID NO: 100), DID65 (SEQ ID NO:101 ), DID82 (SEQ ID NO: 102), DID96 (SEQ ID NO:103) and DID94 (SEQ ID NO: 104)or a sequence having at least 90% identity thereto.

6. The diagnostic composition of any one of claims 1 -5, wherein the seroreactive antigens are immobilized on a solid support.

7. The diagnostic composition of any one of claims 1 -5, wherein the seroreactive antigens are immobilized on a solid support in a lateral flow or dual path platform diagnostic assay format.

8. An isolated fusion polypeptide comprising a combination of three or more covalently linked Mycobacterium tuberculosis seroreactive antigens, or immunogenic fragments thereof, wherein the antigens are selected from the group consisting of Rv0054 (SEQ ID NO: 1 ), Rv0164 (SEQ ID NO: 3), Rv0410 (SEQ ID NO: 5), Rv0455c (SEQ ID NO: 7), Rv0632 (SEQ ID NO: 9)Rv0655 (SEQ ID NO: 1 1 ), Rv0831 c (SEQ ID NO: 13), Rv0934 (SEQ ID NO: 15), Rv0952 (SEQ ID NO: 17), Rv1009 (SEQ ID NO: 19), Rv1099 (SEQ ID NO: 21 ), Rv1240 (SEQ ID NO: 23), Rv1288 (SEQ ID NO: 25), Rv1410c (SEQ ID NO: 27), ), Rv141 1 (SEQ ID NO: 29) Rv1569 (SEQ ID NO: 31 ), Rv1789 (SEQ ID NO: 33), Rv1813c (SEQ ID NO: 35), Rv1827 (SEQ ID NO: 37), Rv1837 (SEQ ID NO: 39), Rv1860 (SEQ ID NO: 41 ), Rv1886c (SEQ ID NO: 43), Rv1908 (SEQ ID NO: 45), Rv1980 (SEQ ID NO:47), Rv1984c (SEQ ID NO: 49), Rv2031 (SEQ ID NO: 51 ), Rv2032 (SEQ ID NO: 53), Rv2220 (SEQ ID NO: 55), Rv2450 (SEQ ID NO: 57), Rv2608 (SEQ ID NO: 59), Rv2623 (SEQ ID NO: 61 ), Rv2866 (SEQ ID NO: 63), Rv2873 (SEQ ID NO: 65), Rv2875 (SEQ ID NO: 67), Rv3020 (SEQ ID NO: 69), Rv3044 (SEQ ID NO: 71 ), Rv3310 (SEQ ID NO: 73), Rv3407 (SEQ ID NO: 75), Rv361 1 (SEQ ID NO: 77), Rv3614 (SEQ ID NO: 79), Rv3616 (SEQ ID NO: 81 ) Rv3619 (SEQ ID NO: 83), Rv3628 (SEQ ID NO: 85), Rv3804 (SEQ ID NO:87), Rv3841 (SEQ ID NO: 89), Rv3864 (SEQ ID NO:91 ), Rv3874 (SEQ ID NO: 93) and Rv3881 (SEQ ID NO: 95), and antigens having at least 90% identity to any of the foregoing sequences.

9. The isolated fusion polypeptide of claim 8, wherein the seroreactive antigens are selected from the group consisting of Rv0455 (SEQ ID NO: 7), Rv0632 (SEQ ID NO:9), Rv0831 (SEQ ID NO: 13), Rv0934 (SEQ ID NO: 15), ), Rv1240 (SEQ ID NO: 23), Rv1410 (SEQ ID NO: 27), Rv1860 (SEQ ID NO: 41 ), Rv1980 (SEQ ID NO:47), Rv2031 (SEQ ID NO: 51 ), Rv2032 (SEQ ID NO: 53), Rv2875 (SEQ ID NO: 67), Rv3310 (SEQ ID NO: 73), ), Rv3619 (SEQ ID NO: 83), Rv3864 (SEQ ID NO:91 ), Rv3874 (SEQ ID NO: 93), Rv3881 (SEQ ID NO: 95), and antigens having at least 90% identity to any of the foregoing sequences.

10. The isolated fusion polypeptide of claim 8, wherein the seroreactive antigens are selected from the group consisting of Rv0632 (SEQ ID NO:9), Rv0831 (SEQ ID NO: 13), Rv0934 (SEQ ID NO: 15), Rv1860 (SEQ ID NO: 41 ), Rv1980 (SEQ ID NO:47), Rv2031 (SEQ ID NO: 51 ), Rv2032 (SEQ ID NO: 53), Rv2875 (SEQ ID NO: 67), Rv3864 (SEQ ID NO:91 ), Rv3874 (SEQ ID NO: 93), Rv3881 (SEQ ID NO: 95), and antigens having at least 90% identity to any of the foregoing sequences.

1 1 . An isolated fusion polypeptide comprising seroreactive sequences from Rv2031 (SEQ ID NO: 51 ), Rv0934 (SEQ ID NO: 15) and Rv2032 (SEQ ID NO: 53).

12. The isolated fusion polypeptide of claim 1 1 , wherein the fusion polypeptide comprising the amino acid sequence set forth in SEQ ID NO:

97, or a sequence having at least 90% identity to SEQ ID NO: 97.

13. An isolated fusion polypeptide comprising seroreactive sequences from Rv2875 (SEQ ID NO: 67), Rv0934 (SEQ ID NO: 15) and Rv2032 (SEQ ID NO: 53).

14. The isolated fusion polypeptide of claim 13, wherein the fusion polypeptide comprising the amino acid sequence set forth in SEQ ID NO:

98, or a sequence having at least 90% identity to SEQ ID NO: 98.

15. An isolated fusion polypeptide comprising seroreactive sequences from Rv0831 (SEQ ID NO: 13), Rv0934 (SEQ ID NO: 15) and Rv2032 (SEQ ID NO: 53).

16. The isolated fusion polypeptide of claim 15, wherein the fusion polypeptide comprising the amino acid sequence set forth in SEQ ID NO:

99, or a sequence having at least 90% identity to SEQ ID NO: 99.

17. An isolated fusion polypeptide comprising seroreactive sequences from Rv2031 (SEQ ID NO: 51 ), Rv0934 (SEQ ID NO: 15) and Rv3874 (SEQ ID NO: 93).

18. The isolated fusion polypeptide of claim 17, wherein the fusion polypeptide comprising the amino acid sequence set forth in SEQ ID NO:

100, or a sequence having at least 90% identity to SEQ ID NO: 100.

19. An isolated fusion polypeptide comprising seroreactive sequences from Rv2875 (SEQ ID NO: 67), Rv0934 (SEQ ID NO: 15) and Rv3874 (SEQ ID NO: 93).

20. The isolated fusion polypeptide of claim 17, wherein the fusion polypeptide comprising the amino acid sequence set forth in SEQ ID NO:

101 , or a sequence having at least 90% identity to SEQ ID NO: 101 .

21 . An isolated fusion polypeptide comprising seroreactive sequences from Rv2875 (SEQ ID NO: 67), Rv1860 (SEQ ID NO: 41 ) and Rv2032 (SEQ ID NO: 53).

22. The isolated fusion polypeptide of claim 17, wherein the fusion polypeptide comprising the amino acid sequence set forth in SEQ ID NO:

102, or a sequence having at least 90% identity to SEQ ID NO: 102.

23. An isolated fusion polypeptide comprising seroreactive sequences from Rv0632 (SEQ ID NO: 9), Rv1980 (SEQ ID NO: 47) and Rv3881 (SEQ ID NO: 95 ).

24. The isolated fusion polypeptide of claim 17, wherein the fusion polypeptide comprising the amino acid sequence set forth in SEQ ID NO:

103, or a sequence having at least 90% identity to SEQ ID NO: 103.

25. An isolated fusion polypeptide comprising seroreactive sequences from Rv1860 (SEQ ID NO: 41 ), Rv1980 (SEQ ID NO: 47) and Rv3864 (SEQ ID NO: 91 ).

26. The isolated fusion polypeptide of claim 17, wherein the fusion polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 104, or a sequence having at least 90% identity to SEQ ID NO: 104.

27. An isolated polynucleotide encoding a fusion polypeptide of any one of claims 8-26.

28. A method for detecting Mycobacterium tuberculosis in a biological sample, comprising

(a) contacting the biological sample with a combination of three or more Mycobacterium tuberculosis seroreactive antigens, or immunogenic fragments thereof, wherein the antigens are selected from the group consisting of Rv0054 (SEQ ID NO: 1 ), Rv0164 (SEQ ID NO: 3), Rv0410 (SEQ ID NO: 5), Rv0455c (SEQ ID NO: 7), Rv0632 (SEQ ID NO: 9)Rv0655 (SEQ ID NO: 1 1 ), Rv0831 c (SEQ ID NO: 13), Rv0934 (SEQ ID NO: 15), Rv0952 (SEQ ID NO: 17), Rv1009 (SEQ ID NO: 19), Rv1099 (SEQ ID NO: 21 ), Rv1240 (SEQ ID NO: 23), Rv1288 (SEQ ID NO: 25), Rv1410c (SEQ ID NO: 27), ), Rv141 1 (SEQ ID NO: 29) Rv1569 (SEQ ID NO: 31 ), Rv1789 (SEQ ID NO: 33), Rv1813c (SEQ ID NO: 35), Rv1827 (SEQ ID NO: 37), Rv1837 (SEQ ID NO: 39), Rv1860 (SEQ ID NO: 41 ), Rv1886c (SEQ ID NO: 43), Rv1908 (SEQ ID NO: 45), Rv1980 (SEQ ID NO:47), Rv1984c (SEQ ID NO: 49), Rv2031 (SEQ ID NO: 51 ), Rv2032 (SEQ ID NO: 53), Rv2220 (SEQ ID NO: 55), Rv2450 (SEQ ID NO: 57), Rv2608 (SEQ ID NO: 59), Rv2623 (SEQ ID NO: 61 ), Rv2866 (SEQ ID NO: 63), Rv2873 (SEQ ID NO: 65), Rv2875 (SEQ ID NO: 67), Rv3020 (SEQ ID NO: 69), Rv3044 (SEQ ID NO: 71 ), Rv3310 (SEQ ID NO: 73), Rv3407 (SEQ ID NO: 75), Rv361 1 (SEQ ID NO: 77), Rv3614 (SEQ ID NO: 79), Rv3616 (SEQ ID NO: 81 ) Rv3619 (SEQ ID NO: 83), Rv3628 (SEQ ID NO: 85), Rv3804 (SEQ ID NO:87), Rv3841 (SEQ ID NO: 89), Rv3864 (SEQ ID NO:91 ), Rv3874 (SEQ ID NO: 93) and

Rv3881 (SEQ ID NO: 95), and antigens having at least 90% identity to any of the foregoing sequences; and

(b) detecting in the biological sample the presence of antibodies that bind thereto.

29. The method of claim 28, wherein the seroreactive antigens are selected from the group consisting of Rv0455 (SEQ ID NO: 7), Rv0632 (SEQ ID NO:9), Rv0831 (SEQ ID NO: 13), Rv0934 (SEQ ID NO: 15), ), Rv1240 (SEQ ID NO: 23), Rv1410 (SEQ ID NO: 27), Rv1860 (SEQ ID NO: 41 ), Rv1980 (SEQ ID NO:47), Rv2031 (SEQ ID NO: 51 ), Rv2032 (SEQ ID NO: 53), Rv2875 (SEQ ID NO: 67), Rv3310 (SEQ ID NO: 73), ), Rv3619 (SEQ ID NO: 83), Rv3864 (SEQ ID NO:91 ), Rv3874 (SEQ ID NO: 93), Rv3881 (SEQ ID NO: 95), and antigens having at least 90% identity to any of the foregoing sequences.

30. The method of claim 28, wherein the seroreactive antigens are selected from the group consisting of Rv0632 (SEQ ID NO:9), Rv0831 (SEQ ID NO: 13), Rv0934 (SEQ ID NO: 15), Rv1860 (SEQ ID NO: 41 ), Rv1980 (SEQ ID NO:47), Rv2031 (SEQ ID NO: 51 ), Rv2032 (SEQ ID NO: 53), Rv2875 (SEQ ID NO: 67), Rv3864 (SEQ ID NO:91 ), Rv3874 (SEQ ID NO: 93), Rv3881 (SEQ ID NO: 95), and antigens having at least 90% identity to any of the foregoing sequences.

31 . The method of claim 28, wherein seroreactive antigens, or immunogenic fragments thereof, are covalently linked in the form of a fusion polypeptide.

32. The method of claim 31 , wherein the fusion polypeptide comprises an amino acid sequence selected from the group consisting of DID90A (SEQ ID NO: 97), DID90B (SEQ ID NO: 98), DID104 (SEQ ID NO: 99), DID64 (SEQ ID NO: 100), DID65 (SEQ ID NO: 101 ), DID82 (SEQ ID NO: 102), DID96 (SEQ ID NO: 103), and DID94 (SEQ ID NO:104) or a sequence having at least 90% identity thereto.

33. The method of any one of claims 28-32, wherein the seroreactive antigens are immobilized on a solid support.

34. The method of claim 33, wherein the seroreactive antigens are immobilized on a solid support in a lateral flow diagnostic test strip.

35. The method of claim 33, wherein the method is carried out in an assay format selected from the group consisting of an ELISA assay, a lateral flow strip test assay and a dual path platform assay.

36. The method of claim 33, wherein the method is a test-of-cure method for monitoring the status of infection in an infected individual over time or in response to treatment.

37. A diagnostic kit for detecting Mycobacterium tuberculosis infection in a biological sample, comprising:

(a) a combination of three or more Mycobacterium tuberculosis seroreactive antigens, or immunogenic fragments thereof, wherein the antigens are selected from the group consisting of Rv0054 (SEQ ID NO: 1 ), Rv0164 (SEQ ID NO: 3), Rv0410 (SEQ ID NO: 5), Rv0455c (SEQ ID NO: 7), Rv0632 (SEQ ID NO: 9)Rv0655 (SEQ ID NO: 1 1 ), Rv0831 c (SEQ ID NO: 13), Rv0934 (SEQ ID NO: 15), Rv0952 (SEQ ID NO: 17), Rv1009 (SEQ ID NO: 19), Rv1099 (SEQ ID NO: 21 ), Rv1240 (SEQ ID NO: 23), Rv1288 (SEQ ID NO: 25), Rv1410c (SEQ ID NO: 27), ), Rv141 1 (SEQ ID NO: 29) Rv1569 (SEQ ID NO: 31 ), Rv1789 (SEQ ID NO: 33), Rv1813c (SEQ ID NO: 35), Rv1827 (SEQ ID NO: 37), Rv1837 (SEQ ID NO: 39), Rv1860 (SEQ ID NO: 41 ), Rv1886c (SEQ ID NO: 43), Rv1908 (SEQ ID NO: 45), Rv1980 (SEQ ID NO:47), Rv1984c (SEQ ID NO: 49), Rv2031 (SEQ ID NO: 51 ), Rv2032 (SEQ ID NO: 53), Rv2220 (SEQ ID NO: 55), Rv2450 (SEQ ID NO: 57), Rv2608 (SEQ ID NO: 59), Rv2623 (SEQ ID NO: 61 ), Rv2866 (SEQ ID NO: 63), Rv2873 (SEQ ID NO: 65), Rv2875 (SEQ ID NO: 67), Rv3020 (SEQ ID NO: 69), Rv3044 (SEQ ID NO: 71 ), Rv3310 (SEQ ID NO: 73), Rv3407 (SEQ ID NO: 75), Rv361 1 (SEQ ID NO: 77), Rv3614 (SEQ

ID NO: 79), Rv3616 (SEQ ID NO: 81 ) Rv3619 (SEQ ID NO: 83), Rv3628 (SEQ ID NO: 85), Rv3804 (SEQ ID NO:87), Rv3841 (SEQ ID NO: 89), Rv3864 (SEQ ID NO:91 ), Rv3874 (SEQ ID NO: 93) and Rv3881 (SEQ ID NO: 95), and antigens having at least 90% identity to any of the foregoing sequences; and

(b) a detection reagent.

38. The diagnostic kit of claim 37, wherein the seroreactive antigens are selected from the group consisting of Rv0455 (SEQ ID NO: 7), Rv0632 (SEQ ID NO:9), Rv0831 (SEQ ID NO: 13), Rv0934 (SEQ ID NO: 15), ), Rv1240 (SEQ ID NO: 23), Rv1410 (SEQ ID NO: 27), Rv1860 (SEQ ID NO: 41 ), Rv1980 (SEQ ID NO:47), Rv2031 (SEQ ID NO: 51 ), Rv2032 (SEQ ID NO: 53), Rv2875 (SEQ ID NO: 67), Rv3310 (SEQ ID NO: 73), ), Rv3619 (SEQ ID NO: 83), Rv3864 (SEQ ID NO:91 ), Rv3874 (SEQ ID NO: 93), Rv3881 (SEQ ID NO: 95), and antigens having at least 90% identity to any of the foregoing sequences.

39. The diagnostic kit of claim 37, wherein the seroreactive antigens are selected from the group consisting of Rv0632 (SEQ ID NO:9), Rv0831 (SEQ ID NO: 13), Rv0934 (SEQ ID NO: 15), Rv1860 (SEQ ID NO: 41 ), Rv1980 (SEQ ID NO:47), Rv2031 (SEQ ID NO: 51 ), Rv2032 (SEQ ID NO: 53), Rv2875 (SEQ ID NO: 67), Rv3864 (SEQ ID NO:91 ), Rv3874 (SEQ ID NO: 93), Rv3881 (SEQ ID NO: 95), and antigens having at least 90% identity to any of the foregoing sequences.

40. The diagnostic kit of claim 37, wherein seroreactive antigens, or immunogenic fragments thereof, are covalently linked in the form of a fusion polypeptide.

41 . The diagnostic kit of claim 40, wherein the fusion polypeptide comprises an amino acid sequence selected from the group consisting of DID90A (SEQ ID NO: 97), DID90B (SEQ ID NO: 98), DID104 (SEQ ID NO: 99), DID64 (SEQ ID NO: 100), DID65 (SEQ ID NO: 101 ), DID82

(SEQ ID NO: 102), DID96 (SEQ ID NO: 103), and DID94 (SEQ ID NO:104) or a sequence having at least 90% identity thereto.

42. The diagnostic kit of claim 37, wherein the seroreactive antigens are immobilized on a solid support.

43. The diagnostic kit of claim 37, wherein the kit comprises an assay format selected from the group consisting of an ELISA assay, a lateral flow strip test assay and a dual path platform assay.

44. A lateral flow or dual path platform diagnostic test device comprising at least three Mycobacterium tuberculosis seroreactive antigens, or immunogenic portions thereof, immobilized on a solid support, wherein the seroreactive antigens are selected from the group consisting of Rv0632 (SEQ ID NO:9), Rv0831 (SEQ ID NO: 13), Rv0934 (SEQ ID NO: 15), Rv1860 (SEQ ID NO: 41 ), Rv1980 (SEQ ID NO:47), Rv2031 (SEQ ID NO: 51 ), Rv2032 (SEQ ID NO: 53), Rv2875 (SEQ ID NO: 67), Rv3864 (SEQ ID NO:91 ), Rv3874 (SEQ ID NO: 93), Rv3881 (SEQ ID NO: 95), and antigens having at least 90% identity to any of the foregoing sequences.

45. A lateral flow or dual path platform diagnostic test device comprising a fusion polypeptide selected from the group consisting of DID90A (SEQ ID NO: 97), DID90B (SEQ ID NO: 98), DID104 (SEQ ID NO: 99), DID64 (SEQ ID NO: 100), DID65 (SEQ ID NO: 101 ), DID82 (SEQ ID NO: 102), DID96 (SEQ ID NO: 103), and DID94 (SEQ ID NO:104) or a sequence having at least 90% identity thereto, immobilized on a solid support.