OprF/I AGENTS AND USE THEREOF IN HOSPITALIZED AND OTHER PATIENTS

• US 20130266575A1
• Filed: 03/12/2013
• Published: 10/10/2013
• Est. Priority Date: 12/23/2010
• Status: Abandoned Application

• Current Assignee: Valneva Austria Gmbh (Valneva SE)
• Original Assignee: Intercell Austria AG (Valneva SE)
• Inventors: Klade, Christoph, Schlegl, Robert, Westritschnig, Kerstin
• Application Number:
  US13/795,448
• Publication Number:
  US 20130266575A1
• Time in Patent Office: Days
• US Class Current: 424/139.1
• CPC Class Codes: A61K 39/104 Pseudomonadales, e.g. Pseudomonas
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: C07K 14/21 from Pseudomonadaceae (F)

Abstract

The present invention relates to a new use of a vaccine comprising a fusion protein that comprises the Pseudomonas aeruginosa outer membrane protein I (OprI or OMPI) which is fused with its amino terminal end to the carboxy-terminal end of a carboxy-terminal portion of the Pseudomonas aeruginosa outer membrane protein F (OprF or OMPF), as well as to a new use of a monoclonal or polyclonal antibody against this fusion protein or a pharmaceutical composition thereof.

Claims

1. A method of reducing mortality in a subject, comprising administering to said subject a therapeutically effective amount of an OprF/I agent, wherein said subject is selected from the group consisting of:

i) a hospitalized patient or a subject who is at risk of being hospitalized;

ii) an ICU patient or a subject who is at risk of being admitted to ICU;

iii) a ventilated ICU patient or a subject who is at of risk being ventilated;

iv) a burn victim patient; and

v) a cystic fibrosis patient.

2. The method of claim 1, comprising co-administration of a therapeutically effective amount of an OprF/I agent and a second drug substance, wherein said second drug substance is an antimicrobial or antifungal drug.

3. The method of claim 1, wherein the OprF/I agent is administered twice to the subject at an amount of 100 mcg.

4. The method of claim 1, wherein the OprF/I agent is administered to the subject at least 2 weeks before admission to the hospital.

5. The method of claim 1, wherein the OprF/I agent comprises a polypeptide selected from the group consisting of polypeptides with SEQ ID NOs:

1 to 13.

6. The method of claim 1, wherein the OprF/I agent comprises a polypeptide a polypeptide of SEQ ID NO:

1.

7. The method of claim 1, wherein the OprF/I agent comprises a protein complex, wherein the protein complex is a trimer of OprF/I fusion proteins of SEQ ID NO:

1 or functional active variants thereof having at least 85% identity to the amino acid sequence of SEQ ID NO;

1.

8. The method of claim 7, wherein at least 80% of the OprF/I agent consists of the protein complex according to claim 7.

9. The method of claim 7, wherein the OprF/I fusion protein is selected from the group consisting of

(a) the OprF/I fusion protein of SEQ ID NO:

1 with a Cys18-Cys27-bond (SEQ ID NO;

     11), and

(b) the OprF/I fusion protein of SEQ ID NO;

1 with a Cys18-Cys27-bond and Cys33-Cys47-bond (SEQ ID NO;

     12), and

(c) the OprF/I fusion protein of SEQ ID NO;

1 with a Cys18-Cys47-bond and Cys27-Cys33-bond (SEQ ID NO;

     13),

or functional active variants thereof having at least 85% identity to the amino acid sequence of SEQ ID NO;

1 and the same disulfide bond pattern as specified in (a), (b) or (c).

10. The method of claim 9, wherein the sum of a) the OprF/I fusion protein of SEQ ID NO:

1 with a Cys18-Cys27-bond (SEQ ID NO;

     11), b) the OprF/I fusion protein of SEQ ID NO;

1 with a Cys18-Cys27-bond and Cys33-Cys47-bond (SEQ ID NO;

     12), and c) the OprF/I fusion protein of SEQ ID NO;

1 with a Cys18-Cys47-bond and Cys27-Cys33-bond (SEQ ID NO;

     13) is equal or greater than 75% of the total OprF/I fusion protein of SEQ ID NO;

1.

11. The method of claim 7, wherein the OprF/I agent is the OprF/I fusion protein of SEQ ID NO:

1 with a Cys18-Cys27-bond (SEQ ID NO;

     11) or a functional active variant thereof having at least 85% identity to the amino acid sequence of SEQ ID NO;

1, and the same disulfide bond pattern as specified in SEQ ID NO;

11.

12. The method of claim 7, wherein the OprF/I agent is the OprF/I fusion protein of SEQ ID NO:

1 with a Cys18-Cys27-bond and Cys33-Cys47-bond (SEQ ID NO;

     12) or a functional active variant thereof having at least 85% identity to the amino acid sequence of SEQ ID NO;

1, and the same disulfide bond pattern as specified in SEQ ID NO;

12.

13. The method of claim 7, wherein the OprF/I agent is the OprF/I fusion protein of SEQ ID NO:

1 with a Cys18-Cys47-bond and Cys27-Cys33-bond (SEQ ID NO;

     13) or a functional active variant thereof having at least 85% identity to the amino acid sequence of SEQ ID NO;

1, and the same disulfide bond pattern as specified in SEQ ID NO;

13.

14. The method of claim 1, wherein the OprF/I agent is a hybrid protein comprising the Pseudomonas aeruginosa outer membrane protein I fused with its amino-terminal end to the carboxy-terminal end of a carboxy-terminal portion of the Pseudomonas aeruginosa outer membrane protein F, particularly

(i) wherein the Pseudomonas aeruginosa outer membrane protein I is the full length outer membrane protein I;

especially SEQ ID NO;

5;

(ii) wherein the Pseudomonas aeruginosa outer membrane protein F is the full length outer membrane protein F, especially SEQ ID NO;

6;

(iii) wherein the OprF/I agent consists of or comprises SEQ ID NO;

1;

(iv) wherein the OprF/I agent is a functional active variant and/or has at least 85% sequence identity to SEQ ID NO;

1;

(v) wherein the OprF/I agent forms a trimer comprising or consisting of a polypeptide with SEQ ID NO;

1 or functional active variants thereof with at least 85% identity to SEQ ID NO;

1;

(vi) wherein the OprF/I agent forms a trimer comprising or consisting of a polypeptide of SEQ ID NO;

1 with (a) a Cys18-Cys27-bond (see e.g. SEQ ID NO;

     11), or (b) a Cys18-Cys27-bond and a Cys33-Cys47-bond (see e.g. SEQ ID NO;

     12), or (c) Cys18-Cys47-bond and Cys27-Cys33-bond (see e.g. SEQ ID NO;

     13), or (d) functional active variants with at least 85% identity to SEQ ID NO;

1 and the same disulfide bond pattern as specified in (a), (b) or (c), or e) combinations of (a), (b), (c) and/or (d);

(vii) wherein the OprF/I agent comprises or consist of i) SEQ ID NO;

2, 3, 7 to 10, and/or ii) SEQ ID NO;

4;

(viii) wherein the OprF/I agent comprises the carboxy terminal portion of outer membrane protein F with the sequence from amino acid 190 to amino acid 342 of the native OprF protein (SEQ ID NO;

     3) or the carboxy terminal portion of outer membrane protein F with the sequence from amino acid 190 to amino acid 350 of the native OprF protein (SEQ ID NO;

     2);

(ix) wherein the OprF/I agent comprises the amino-terminal end of outer membrane protein I with the sequence from amino acid 21 to amino acid 83 of the native OprI protein (SEQ ID NO;

     4);

(x) wherein the OprF/I agent comprises or consists of the carboxy terminal portion of outer membrane protein F with the sequence from amino acid 190 to amino acid 342 of the native OprF protein (SEQ ID NO;

     3) or the carboxy terminal portion of outer membrane protein F with the sequence from amino acid 190 to amino acid 350 of the native OprF protein (SEQ ID NO;

     2) fused to the amino-terminal end of outer membrane protein I with the sequence from amino acid 21 to amino acid 83 of the native OprI protein (SEQ ID NO;

     4); and

/or

(xi) wherein the OprF/I agent comprises an Ala-(His)₆ tag such as e.g. in the OprF/I agent of SEQ ID NO;

1.

16. The method of claim 1, wherein the OprF/I agent comprises optionally at least one additive or adjuvant.

17. The method of claim 16, wherein the adjuvant is aluminium hydroxide, preferably formulated in an isotonic phosphate buffer (pH 7.4).

18. A method of reducing mortality in a subject comprising

administering to said subject a therapeutically effective amount of an antibody or antigen-binding portions thereof specifically binding the OprF/I agent, wherein said subject is selected from the group consisting of:

i) a hospitalized patient or a subject who is at risk of being hospitalized;

ii) an ICU patient or a subject who is at risk of being admitted to ICU;

iii) a ventilated ICU patient or a subject who is at of risk being ventilated;

iv) a burn victim patient; and

v) a cystic fibrosis patient.

19. The method of claim 18, wherein the OprF/I agent comprises a polypeptide selected from the group consisting of polypeptides with SEQ ID NOs:

1 to 13.

20. The method of claim 18, wherein the OprF/I agent comprises polypeptide a polypeptide of SEQ ID NO:

1.

21. The method of claim 18, wherein the OprF/I agent is selected from the group consisting of

(a) the OprF/I fusion protein of SEQ ID NO:

1 with a Cys18-Cys27-bond (SEQ ID NO;

     11), and

(b) the OprF/I fusion protein of SEQ ID NO;

1 with a Cys18-Cys27-bond and Cys33-Cys47-bond (SEQ ID NO;

     12), and

(c) the OprF/I fusion protein of SEQ ID NO;

1 with a Cys18-Cys47-bond and Cys27-Cys33-bond (SEQ ID NO;

     13),

or a functional active variants thereof having at least 85% identity to the amino acid sequence of SEQ ID NO;

1 and the same disulfide bond pattern as specified in (a), (b) or (c).

22. The method of claim 18, wherein the OprF/I agent is a hybrid protein comprising the Pseudomonas aeruginosa outer membrane protein I fused with its amino-terminal end to the carboxy-terminal end of a carboxy-terminal portion of the Pseudomonas aeruginosa outer membrane protein F, particularly

(i) wherein the Pseudomonas aeruginosa outer membrane protein I is the full length outer membrane protein I;

especially SEQ ID NO;

5;

(ii) wherein the Pseudomonas aeruginosa outer membrane protein F is the full length outer membrane protein F, especially SEQ ID NO;

6;

(iii) wherein the OprF/I agent consists of or comprises SEQ ID NO;

1;

(iv) wherein the OprF/I agent is a functional active variant and/or has at least 85% sequence identity to SEQ ID NO;

1;

(v) wherein the OprF/I agent forms a trimer comprising or consisting of a polypeptide with SEQ ID NO;

1 or functional active variants thereof with at least 85% identity to SEQ ID NO;

1;

(vi) wherein the OprF/I agent forms a trimer comprising or consisting of a polypeptide of SEQ ID NO;

1 with (a) a Cys18-Cys27-bond (see e.g. SEQ ID NO;

     11), or (b) a Cys18-Cys27-bond and a Cys33-Cys47-bond (see e.g. SEQ ID NO;

     12), or (c) Cys18-Cys47-bond and Cys27-Cys33-bond (see e.g. SEQ ID NO;

     13), or (d) functional active variants with at least 85% identity to SEQ ID NO;

1 and the same disulfide bond pattern as specified in (a), (b) or (c), or e) combinations of (a), (b), (c) and/or (d);

(vii) wherein the OprF/I agent comprises or consist of i) SEQ ID NO;

2, 3, 7 to 10, and/or ii) SEQ ID NO;

4;

(viii) wherein the OprF/I agent comprises the carboxy terminal portion of outer membrane protein F with the sequence from amino acid 190 to amino acid 342 of the native OprF protein (SEQ ID NO;

     3) or the carboxy terminal portion of outer membrane protein F with the sequence from amino acid 190 to amino acid 350 of the native OprF protein (SEQ ID NO;

     2);

(ix) wherein the OprF/I agent comprises the amino-terminal end of outer membrane protein I with the sequence from amino acid 21 to amino acid 83 of the native OprI protein (SEQ ID NO;

     4); and

/or

(x) wherein the OprF/I agent comprises or consists of the carboxy terminal portion of outer membrane protein F with the sequence from amino acid 190 to amino acid 342 of the native OprF protein (SEQ ID NO;

     3) or the carboxy terminal portion of outer membrane protein F with the sequence from amino acid 190 to amino acid 350 of the native OprF protein (SEQ ID NO;

     2) fused to the amino-terminal end of outer membrane protein I with the sequence from amino acid 21 to amino acid 83 of the native OprI protein (SEQ ID NO;

     4).