Anti-PcrV antibodies that bind PcrV, compositions comprising anti-PcrV antibodies, and methods of use thereof
The present disclosure provides antibodies and antigen-binding fragments of antibodies that bind to Pseudomonas aeruginosa PcrV, and methods of using the same. According to certain embodiments, the disclosure includes antibodies and antigen-binding fragments of antibodies that bind PcrV. The anti-PcrV antibodies and antigen-binding fragments are useful for the prevention and treatment of P. aeruginosa infections.
1. An isolated recombinant antibody or antigen-binding fragment thereof that specifically binds to P. aeruginosa PcrV, wherein the antibody or antigen-binding fragment thereof comprises:
(a) three heavy chain complementarity determining regions (CDRs) (HCDR1, HCDR2 and HCDR3) contained within a heavy chain variable region (HCVR) amino acid sequence of SEQ ID NO: 34; and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within a light chain variable region (LCVR) amino acid sequence of SEQ ID NO: 42;
(b) three HCDRs (HCDR1, HCDR2 and HCDR3) contained within an HCVR amino acid sequence of SEQ ID NO: 50; and three light chain LCDRs (LCDR1, LCDR2 and LCDR3) contained within an LCVR amino acid sequence of SEQ ID NO: 58;
(c) three HCDRs (HCDR1, HCDR2 and HCDR3) contained within an HCVR amino acid sequence of SEQ ID NO: 2; and three light chain LCDRs (LCDR1, LCDR2 and LCDR3) contained within an LCVR amino acid sequence of SEQ ID NO: 10; or
(d) three HCDRs (HCDR1, HCDR2 and HCDR3) contained within an HCVR amino acid sequence of SEQ ID NO: 18; and three light chain LCDRs (LCDR1, LCDR2 and LCDR3) contained within an LCVR amino acid sequence of SEQ ID NO: 26.
2. The isolated antibody or antigen-binding fragment thereof of claim 1 , which is a fully human monoclonal antibody.
3. The isolated antibody or antigen-binding fragment thereof of claim 1 , comprising an HCVR having an amino acid sequence of SEQ ID NO: 34 and an LCVR having an amino acid sequence of SEQ ID NO: 42.
4. The isolated antibody or antigen-binding fragment thereof of claim 1 , comprising an HCVR having an amino acid sequence of SEQ ID NO: 50 and an LCVR having an amino acid sequence of SEQ ID NO: 58.
5. The isolated antibody or antigen-binding fragment thereof of claim 1 , comprising an HCVR having an amino acid sequence of SEQ ID NO: 2 and an LCVR having an amino acid sequence of SEQ ID NO: 10.
6. The isolated antibody or antigen-binding fragment thereof of claim 1 , comprising an HCVR having an amino acid sequence of SEQ ID NO: 18 and an LCVR having an amino acid sequence of SEQ ID NO: 26.
7. The isolated antibody or antigen-binding fragment thereof of claim 1 , comprising:
an HCDR1 comprising an amino acid sequence of SEQ ID NO: 36; an HCDR2 comprising an amino acid sequence of SEQ ID NO: 38; an HCDR3 comprising an amino acid sequence of SEQ ID NO: 40; an LCDR1 comprising an amino acid sequence of SEQ ID NO: 44; an LCDR2 comprising an amino acid sequence of SEQ ID NO: 46; and an LCDR3 comprising an amino acid sequence of SEQ ID NO: 48.
8. The isolated antibody or antigen-binding fragment thereof of claim 1 , comprising:
an HCDR1 comprising an amino acid sequence of SEQ ID NO: 52; an HCDR2 comprising an amino acid sequence of SEQ ID NO: 54; an HCDR3 comprising an amino acid sequence of SEQ ID NO: 56; an LCDR1 comprising an amino acid sequence of SEQ ID NO: 60; an LCDR2 comprising an amino acid sequence of SEQ ID NO: 62 and an LCDR3 comprising an amino acid sequence of SEQ ID NO: 64.
9. The isolated antibody or antigen-binding fragment thereof of claim 1 , comprising:
an HCDR1 comprising an amino acid sequence of SEQ ID NO: 4; an HCDR2 comprising an amino acid sequence of SEQ ID NO: 6; an HCDR3 comprising an amino acid sequence of SEQ ID NO: 8; an LCDR1 comprising an amino acid sequence of SEQ ID NO: 12; an LCDR2 comprising an amino acid sequence of SEQ ID NO: 14; and an LCDR3 comprising an amino acid sequence of SEQ ID NO: 16.
10. The isolated antibody or antigen-binding fragment thereof of claim 1 , comprising:
an HCDR1 comprising an amino acid sequence of SEQ ID NO: 20; an HCDR2 comprising an amino acid sequence of SEQ ID NO: 22; an HCDR3 comprising an amino acid sequence of SEQ ID NO: 24; an LCDR1 comprising an amino acid sequence of SEQ ID NO: 28; an LCDR2 comprising an amino acid sequence of SEQ ID NO: 30; and an LCDR3 comprising an amino acid sequence of SEQ ID NO: 32.
11. A pharmaceutical composition comprising one or more isolated antibodies or antigen-binding fragments thereof according to claim 1 and a pharmaceutically acceptable carrier or diluent.
12. The pharmaceutical composition of claim 11 , wherein the one or more isolated antibodies or antigen-binding fragments thereof comprise the HCVR/LCVR amino acid sequence pair selected from the group consisting SEQ ID NOs: 34/42, 50/58, 2/10, and 18/26.
13. The pharmaceutical composition of claim 12 , wherein the one or more isolated antibodies or antigen-binding fragments thereof comprise the HCVR/LCVR amino acid sequence pair selected from the group consisting of SEQ ID NOs: 34/42 and 50/58.
14. The pharmaceutical composition of claim 11 , wherein the isolated antibody or antigen binding fragment thereof comprises:
(a) an HCDR1 comprising an amino acid sequence of SEQ ID NO: 36; an HCDR2 comprising an amino acid sequence of SEQ ID NO: 38; an HCDR3 comprising an amino acid sequence of SEQ ID NO: 40; an LCDR1 comprising an amino acid sequence of SEQ ID NO: 44; an LCDR2 comprising an amino acid sequence of SEQ ID NO: 46; and an LCDR3 comprising an amino acid sequence of SEQ ID NO: 48;
(b) an HCDR1 comprising an amino acid sequence of SEQ ID NO: 52; an HCDR2 comprising an amino acid sequence of SEQ ID NO: 54; an HCDR3 comprising an amino acid sequence of SEQ ID NO: 56; an LCDR1 comprising an amino acid sequence of SEQ ID NO: 60; an LCDR2 comprising an amino acid sequence of SEQ ID NO: 62 and an LCDR3 comprising an amino acid sequence of SEQ ID NO: 64;
(c) an HCDR1 comprising an amino acid sequence of SEQ ID NO: 4; an HCDR2 comprising an amino acid sequence of SEQ ID NO: 6; an HCDR3 comprising an amino acid sequence of SEQ ID NO: 8; an LCDR1 comprising an amino acid sequence of SEQ ID NO: 12; an LCDR2 comprising an amino acid sequence of SEQ ID NO: 14; and an LCDR3 comprising an amino acid sequence of SEQ ID NO: 16; or
(d) an HCDR1 comprising an amino acid sequence of SEQ ID NO: 20; an HCDR2 comprising an amino acid sequence of SEQ ID NO: 22; an HCDR3 comprising an amino acid sequence of SEQ ID NO: 24; an LCDR1 comprising an amino acid sequence of SEQ ID NO: 28; an LCDR2 comprising an amino acid sequence of SEQ ID NO: 30; and an LCDR3 comprising an amino acid sequence of SEQ ID NO: 32.
15. A method of decreasing bacterial load in a subject with a P. aeruginosa infection, a method of increasing the survival, or the likelihood of survival of a subject suffering from infection with P. aeruginosa , or a method of ameliorating or reducing the severity, duration, or frequency of occurrence of at least one symptom of a P. aeruginosa infection in a subject, the method comprising therapeutically administering a pharmaceutical composition comprising one or more antibodies of claim 1 to the subject.
16. The method of claim 15 , wherein the subject is selected from the group consisting of a subject undergoing surgery, a subject being treated for a major illness, a trauma patient, an intravenous drug user, a subject having severe burns, a subject using a breathing machine, a subject with a catheter, a subject undergoing chemotherapy, a subject having diabetes, a subject with cystic fibrosis, a subject with tuberculosis, a subject with HIV, or a subject with a compromised immune system.
17. The method of claim 15 , wherein the antibody or antigen-binding fragment thereof, or the pharmaceutical composition comprising the antibody or antigen-binding fragment thereof, is administered in combination with a second therapeutic agent selected from the group consisting of an antibiotic, an anti-inflammatory drug, and a different antibody to P. aeruginosa.
18. The method of claim 15 , wherein the antibody or antigen-binding fragment thereof, or the pharmaceutical composition comprising the antibody or antigen-binding fragment thereof, is administered subcutaneously, intravenously, intradermally, intramuscularly, intranasally, or orally.
19. The method of claim 15 , wherein the subject has pneumonia, bacteremia, a bone infection, a joint infection, a skin infection, a burn infection, a wound infection, or any combination thereof.
20. The method of claim 15 , wherein the P. aeruginosa is resistant or partially resistant to an antibiotic.
21. The method of claim 17 , wherein the anti-inflammatory is a corticosteroid or non-steroidal anti-inflammatory drug.
22. A method of decreasing bacterial load in a subject with a P. aeruginosa infection, a method of increasing the survival, or the likelihood of survival of a subject suffering from infection with P. aeruginosa , or a method of ameliorating or reducing the severity, duration, or frequency of occurrence of at least one symptom of a P. aeruginosa infection in a subject, the method comprising prophylactically administering a pharmaceutical composition comprising one or more antibodies of claim 1 to the subject.
23. The method of claim 22 , wherein the antibody or antigen-binding fragment thereof, or the pharmaceutical composition comprising the antibody or antigen-binding fragment thereof, is administered in combination with a second therapeutic agent selected from the group consisting of an antibiotic, an anti-inflammatory drug, and a different antibody to P. aeruginosa.
24. The method of claim 23 , wherein the anti-inflammatory is a corticosteroid or non-steroidal anti-inflammatory drug.
25. The method of claim 22 , wherein the antibody or antigen-binding fragment thereof, or the pharmaceutical composition comprising the antibody or antigen-binding fragment thereof, is administered subcutaneously, intravenously, intradermally, intramuscularly, intranasally, or orally.
26. The method of claim 22 , wherein the subject is selected from the group consisting of a subject undergoing surgery, a subject being treated for a major illness, a trauma patient, an intravenous drug user, a subject having severe burns, a subject using a breathing machine, a subject with a catheter, a subject undergoing chemotherapy, a subject having diabetes, a subject with cystic fibrosis, a subject with tuberculosis, a subject with HIV, or a subject with a compromised immune system.
27. The method of claim 22 , wherein the P. aeruginosa is resistant or partially resistant to an antibiotic.