Type III secretion system targeting molecules
This invention relates generally to molecules that specifically bind bacterial V-tip proteins of the type III secretion system of Gram negative bacteria such as PcrV from Pseudomonas aeruginosa . More specifically, this invention relates to molecules that block the injection of effector molecules into target cells. This invention also relates to molecules that specifically bind to bacterial lipoproteins, such as OprI. The molecules of the present invention are monospecific or multispecific and can bind their target antigen in a monovalent or multivalent manner. The invention also relates generally to molecules that specifically bind bacterial cell surface proteins such as OprI, and to methods of use these molecules in a variety of therapeutic, diagnostic, and/or prophylactic indications.
1. A method for treating an infectious disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of an isolated polypeptide comprising a first VHH domain that binds PcrV from Pseudomonas aeruginosa , wherein the first VHH domain comprises the CDRs of SEQ ID NO: 41, as determined by Chothia numbering.
2. The method of claim 1 , wherein the first VHH domain is humanized.
3. The method of claim 1 , wherein the polypeptide comprises an immunoglobulin Fc region polypeptide.
4. The method of claim 3 , wherein the immunoglobulin Fc region polypeptide comprises the amino acid sequence of SEQ ID NO: 1, 2, 3, or 4.
5. The method of claim 1 , wherein the infectious disease is a Pseudomonas aeruginosa infection.
6. The method of claim 5 , wherein the Pseudomonas aeruginosa infection is a community acquired infection.
7. The method of claim 5 , wherein the Pseudomonas aeruginosa infection is a nosocomial infection.
8. The method of claim 1 , wherein the polypeptide comprises a second VHH domain that binds OprI from Pseudomonas aeruginosa.
9. The method of claim 8 , wherein the second VHH domain comprises the CDRs of SEQ ID NO: 62, as determined by Chothia numbering.
10. The method of claim 9 , wherein the first VHH domain and the second VHH domain are humanized.
11. The method of claim 9 , wherein the polypeptide comprises an immunoglobulin Fc region polypeptide.
12. The method of claim 11 , wherein the immunoglobulin Fc region polypeptide comprises the amino acid sequence of SEQ ID NO: 1, 2, 3, or 4.
13. The method of claim 8 , wherein the infectious disease is a Pseudomonas aeruginosa infection.
14. The method of claim 13 , wherein the Pseudomonas aeruginosa infection is a community acquired infection.
15. The method of claim 13 , wherein the Pseudomonas aeruginosa infection is a nosocomial infection.
16. The method of claim 9 , wherein the polypeptide comprises a third VHH domain that binds PcrV from Pseudomonas aeruginosa , wherein the first VHH domain and the third VHH domain bind different epitopes of PcrV.
17. The method of claim 16 , wherein the polypeptide comprises an immunoglobulin Fc region polypeptide.
18. The method of claim 17 , wherein the immunoglobulin Fc region polypeptide comprises the amino acid sequence of SEQ ID NO: 1, 2, 3, or 4.
19. The method of claim 16 , wherein the infectious disease is a Pseudomonas aeruginosa infection.
20. The method of claim 19 , wherein the Pseudomonas aeruginosa infection is a community acquired infection.
21. The method of claim 19 , wherein the Pseudomonas aeruginosa infection is a nosocomial infection.
22. A method for treating an infectious disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of an isolated polypeptide comprising a first VHH domain that binds OprI from Pseudomonas aeruginosa , wherein the first VHH domain comprises the CDRs of SEQ ID NO: 62, as determined by Chothia numbering.
23. The method of claim 22 , wherein the first VHH domain is humanized.
24. The method of claim 22 , wherein the polypeptide comprises an immunoglobulin Fc region polypeptide.
25. The method of claim 24 , wherein the immunoglobulin Fc region polypeptide comprises the amino acid sequence of SEQ ID NO: 1, 2, 3, or 4.
26. The method of claim 22 , wherein the polypeptide comprises a second VHH domain that binds PcrV from Pseudomonas aeruginosa.
27. The method of claim 26 , wherein the polypeptide comprises an immunoglobulin Fc region polypeptide.
28. The method of claim 27 , wherein the immunoglobulin Fc region polypeptide comprises the amino acid sequence of SEQ ID NO: 1, 2, 3, or 4.
29. The method of claim 22 , wherein the infectious disease is a Pseudomonas aeruginosa infection.
30. The method of claim 29 , wherein the Pseudomonas aeruginosa infection is a community acquired infection.
31. The method of claim 29 , wherein the Pseudomonas aeruginosa infection is a nosocomial infection.
32. A method for preventing an infectious disease, the method comprising administering to a subject at risk of developing an infectious disease an effective amount of an isolated polypeptide comprising a first VHH domain that binds PcrV from Pseudomonas aeruginosa , wherein the first VHH domain comprises the CDRs of SEQ ID NO: 41, as determined by Chothia numbering.
33. A method for preventing an infectious disease, the method comprising administering to a subject at risk of developing an infectious disease an effective amount of an isolated polypeptide comprising a first VHH domain that binds OprI from Pseudomonas aeruginosa , wherein the first VHH domain comprises the CDRs of SEQ ID NO: 62, as determined by Chothia numbering.