Method of treating a staphylococcus infection in a patient having a low-level pathogenic
View Patent ↗This invention provides methods of treating patients having a Staphylococcus infection where the patient also has a low level of Pseudomonas aeruginosa . The methods comprise administering an antagonist of the Pseudomonas Type III Secretion System, e.g., an anti-PcrV antibody antagonist.
1. A method of treating a Staphylococcus aureus infection in a patient who has a low level of Pseudomonas aeruginosa infection, the method comprising administering an anti-PcrV antibody that comprises a V H region and a V L region and is an antagonist of the Pseudomonas aeruginosa Type III secretion system (TTSS), to the patient in an amount to effectively reduce the Staphylococcus aureus load in the patient.
2. The method of claim 1 , wherein the patient has cystic fibrosis, is on a mechanical ventilator, is a neutropenic cancer patient, or is a burn patient.
3. The method of claim 1 , wherein the level of TTSS-expressing Pseudomonas aeruginosa is 10% or greater of the Pseudomonas aeruginosa burden.
4. The method of claim 1 , further comprising administering a penicillinase-resistant penicillin.
5. The method of claim 1 , further comprising administering a Gram-positive selective antibiotic.
6. The method of claim 5 , wherein the Gram-positive-selective antibiotic is vancomycin or daptomycin.
7. The method of claim 1 , wherein the patient has cystic fibrosis and the method further comprises administering an antibiotic with the proviso that the antibiotic is not an aminoglyocoside.
8. The method of claim 1 , wherein the anti-PcrV antibody competes with Mab166 for binding to PcrV.
9. The method of claim 8 , wherein the antibody has a V H region that has a CDR1 that comprises NYPMH (SEQ ID NO:56), a CDR2 that comprises VISYDGSEKWYADSVKG (SEQ ID NO:57), and a CDR3 that comprises NRGDIYYDFTYAMDI (SEQ ID NO:50); and a V L region that has a CDR1 that comprises RASEGVDRWLA (SEQ ID NO:58), a CDR2 that comprises DASTLQS (SEQ ID NO:59), and a CDR3 that comprises QHFWGTPYT (SEQ ID NO:48).
10. The method of claim 1 , wherein the V H region has the amino acid sequence of SEQ ID NO:1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 26, or 35.
11. The method of claim 1 , wherein the V L region has the amino acid sequence of SEQ ID NO:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 28, 30, 32, 34, 36, 37, 43, or 44.
12. The method of claim 1 , wherein the antibody is a Fab′.
13. The method of claim 1 , wherein the antibody is PEGylated.
14. A method of treating a mechanically ventilated patient infected with Staphylococcus aureus and Pseudomonas aeruginosa , where the levels of Staphylococcus aureus and Pseudomonas aeruginosa are each 10 3 cfu/ml, or less, in an endotracheal aspirate; or 10 2 cfu/ml, or less, in a bronchoalveolar lavage, the method comprising administering a therapeutically effective dose of an anti-PcrV antibody to the patient, wherein the anti-PcrV antibody comprises a VH region and a VL region and is an antagonist of the Type III secretion system.
15. The method of claim 14 , wherein the anti-PcrV antibody competes with Mab166 for binding to PcrV.
16. The method of claim 15 , wherein the antibody has a V H region that has a CDR1 that comprises NYPMH (SEQ ID NO:56), a CDR2 that comprises VISYDGSEKWYADSVKG (SEQ ID NO:57), and a CDR3 that comprises NRGDIYYDFTYAMDI (SEQ ID NO:50); and a V L region that has a CDR1 that comprises RASEGVDRWLA (SEQ ID NO:58), a CDR2 that comprises DASTLQS (SEQ ID NO:59), and a CDR3 that comprises QHFWGTPYT (SEQ ID NO:48).
17. The method of claim 14 , wherein the V H region has the amino acid sequence of SEQ ID NO:1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 26, or 35.
18. The method of claim 14 , wherein the antibody comprises a V L region that has the amino acid sequence of SEQ NO:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 28, 30, 32, 36, 37, 43, or 44.
19. A method of treating a patient with a wound infected with Staphylococcus aureus and Pseudomonas aeruginosa , where the levels of Staphylococcus aureus and Pseudomonas aeruginosa are each less than 10 3 cfu/g of tissue or less than 10 3 cfu/ml of exudate, the method comprising administering a therapeutically effective dose of an anti-PcrV antibody to the patient, wherein the anti-PcrV antibody comprises a VH region and a VL region and is an antagonist of the Type III secretion system.
20. The method of claim 19 , wherein the anti-PcrV antibody competes with Mab166 for binding to PcrV.
21. The method of claim 20 , wherein the antibody has a V H region that has a CDR1 that comprises NYPMH (SEQ ID NO:56), a CDR2 that comprises VISYDGSEKWYADSVKG (SEQ ID NO:57), and a CDR3 that comprises NRGDIYYDFTYAMDI (SEQ ID NO:50); and a V L region that has a CDR1 that comprises RASEGVDRWLA (SEQ ID NO:58), a CDR2 that comprises DASTLQS (SEQ ID NO:59), and a CDR3 that comprises QHFWGTPYT (SEQ ID NO:48).
22. The method of claim 19 , wherein the V H region has the amino acid sequence of SEQ ID NO:1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 26, or 35.
23. The method of claim 19 , wherein the V L region has the amino acid sequence of SEQ ID NO:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 28, 30, 32, 36, 37, 43, or 44.
24. The method of claim 1 , wherein the antibody comprises a V H region having the amino acid sequence of SEQ ID NO:26 and a V L region having the amino acid sequence of SEQ ID NO:24.
25. The method of claim 14 , wherein the antibody comprises a V H region having the amino acid sequence of SEQ ID NO:26 and a V L region having the amino acid sequence of SEQ ID NO:24.
26. The method of claim 19 , wherein the antibody comprises a V H region having the amino acid sequence of SEQ ID NO:26 and a V L region having the amino acid sequence of SEQ ID NO:24.