Method for preventing or treating M tuberculosis infection

• US 8,470,338 B2
• Filed: 04/27/2006
• Issued: 06/25/2013
• Est. Priority Date: 04/29/2005
• Status: Expired due to Fees

• Current Assignee: Glaxosmithkline Biologicals SA (GlaxoSmithKline PLC), Infectious Disease Research Institute
• Original Assignee: Glaxosmithkline Biologicals SA (GlaxoSmithKline PLC), Infectious Disease Research Institute
• Inventors: Coler, Rhea, Lobet, Yves, Reed, Steven
• Primary Examiner(s): Swartz, Rodney P.
• Application Number:
  US11/912,730
• Publication Number:
  US 20090123491A1
• Time in Patent Office: 2,616 Days
• Field of Search: 424/9.1, 424/9.2, 424/234.1, 424/248.1, 536/23.1, 536/23.7
• US Class Current: 424/248.1
• CPC Class Codes: A61K 2039/523 expressing foreign proteins
• CPC Class Codes: A61K 2039/53 DNA (RNA) vaccination
• CPC Class Codes: A61K 2039/55566 Emulsions, e.g. Freund's adjuvant, MF59
• CPC Class Codes: A61K 2039/55572 Lipopolysaccharides; Lipid A; Monophosphoryl lipid A
• CPC Class Codes: A61K 2039/55577 Saponins; Quil A; QS21; ISCOMS
• CPC Class Codes: A61K 2039/575 humoral response
• CPC Class Codes: A61K 31/4409 only substituted in position 4, e.g. isoniazid, iproniazid
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 39/04 Mycobacterium, e.g. Mycobacterium tuberculosis
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 31/06 for tuberculosis
• CPC Class Codes: A61P 37/04 Immunostimulants
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 14/35 from Mycobacteriaceae (F)

Abstract

The present invention is directed to methods of preventing reactivation of active and latent M. tuberculosis infections by administering a pharmaceutical composition comprising a nucleic acid encoding a Mtb72f fusion protein, or a Mtb72f fusion protein or an immunogenic fragment thereof, for example together with an adjuvant. The Mtb72f nucleic acid or fusion protein can be administered with one or more chemotherapeutic agents effective against a M. tuberculosis infection. The methods also provide for shortening the time course of a chemotherapeutic regimen against a M. tuberculosis infection.

Claims

1. A method for preventing or delaying tuberculosis reactivation in a subject, the method comprising the step of administering to a subject without clinical tuberculosis who tests positive for Mycobacterium tuberculosis an immunologically effective amount of a pharmaceutical composition comprising a Mtb72f fusion protein comprising an amino acid sequence that is at least 95% identical to residues 4-725 of SEQ ID NO:

4 and an adjuvant, wherein the Mtb72f fusion protein induces an immune response against M. tuberculosis, thereby preventing or delaying tuberculosis reactivation.

2. The method of claim 1, wherein the subject is infected with a multi-drug resistant strain of M. tuberculosis.

3. The method of claim 1, wherein the subject was previously immunized with Bacillus Calmette-Guerin (BCG).

4. The method of claim 1, wherein the Mtb72f is from Mycobacterium tuberculosis.

5. The method of claim 1, wherein the Mtb72f is a polypeptide comprising residues 8-729 of SEQ ID NO:

2.

6. The method of claim 5, wherein the Mtb72f is a polypeptide comprising SEQ ID NO:

2.

7. The method of claim 5, wherein the Mtb72f is a polypeptide comprising SEQ ID NO:

6.

8. The method of claim 1, wherein the Mtb72f is a polypeptide comprising residues 4-725 of SEQ ID NO:

4.

9. The method of claim 1, wherein the adjuvant comprises 3D-MPL and QS21.

10. The method of claim 1, further comprising the administration of one or more chemotherapeutic agents effective in treating a M. tuberculosis infection.

11. The method of claim 10, wherein the one or more chemotherapeutic agents is selected from the group consisting of isoniazid and rifampin.

12. The method of claim 1, further comprising administering the pharmaceutical composition of claim 1 one or more subsequent times.

13. The method of claim 1, further comprising a method of prime and boost by subsequently administering a nucleic acid encoding a Mtb72f fusion protein comprising an amino acid sequence that is at least 95% identical to residues 4-725 of SEQ ID NO:

4.

14. A method for preventing or delaying tuberculosis reactivation in a subject, the method comprising the step of administering to a subject without clinical tuberculosis who tests positive for Mycobacterium tuberculosis an immunologically effective amount of a pharmaceutical composition comprising a nucleic acid encoding a Mtb72f fusion protein-comprising an amino acid sequence that is at least 95% identical to residues 4-725 of SEQ ID NO:

4, wherein after administration, the Mtb72f fusion protein is expressed and induces an immune response against M. tuberculosis, thereby preventing or delaying tuberculosis reactivation.

15. The method of claim 14, wherein the nucleic acid is SEQ ID NO:

1.

16. The method of claim 14, wherein the nucleic acid comprises nucleotides 63-2222 of SEQ ID NO:

1.

17. The method of claim 14, wherein the nucleic acid comprises nucleotides 10-2175 of SEQ ID NO:

3.

18. The method of claim 14, wherein the nucleic acid is delivered in an adenovirus vector.

19. The method of claim 14, wherein the nucleic acid is delivered in a mutant Mycobacterium or Bacillus host cell vector.

20. The method of claim 14, further comprising a method of prime and boost by subsequently administering a Mtb72f fusion protein—

from a Mycobacterium species of the tuberculosis complex.

21. The method of claim 1, wherein said Mtb72f fusion protein consists of an amino acid sequence that is at least 95% identical to residues 4-725 of SEQ ID NO:

4.

22. The method of claim 1, wherein said Mtb72f fusion protein comprises an amino acid sequence comprising residues 1 and 4-725 of SEQ ID NO:

4.

23. The method of claim 5, wherein said Mtb72f fusion protein comprises an amino acid sequence comprising residues 1 and 8-729 of SEQ ID NO:

2.

24. The method of claim 14, wherein said Mtb72f fusion protein consists of an amino acid sequence that is at least 95% identical to residues 4-725 of SEQ ID NO:

4.

25. The method of claim 14, wherein said Mtb72f fusion protein comprises an amino acid sequence comprising residues 1 and 4-725 of SEQ ID NO:

4.

26. A method for preventing or delaying tuberculosis reactivation in a subject, the method comprising the step of administering to a subject without clinical tuberculosis who tests positive for Mycobacterium tuberculosis an immunologically effective amount of a pharmaceutical composition comprising a Mtb72f fusion protein comprising an amino acid sequence comprising residues 4-725 of SEQ ID NO:

4 and an adjuvant comprising 3D-MPL and QS21,

wherein the Mtb72f fusion protein induces an immune response against M. tuberculosis, thereby preventing or delaying tuberculosis reactivation.

27. The method of claim 26, wherein the Mtb72f fusion protein has the amino acid sequence of residues 4-725 of SEQ ID NO:

4.

28. The method of claim 1, wherein the subject is a human subject.

29. The method of claim 14, wherein the subject is a human subject.