Combinations of anti-staphylococcus aureus antibodies

Abstract

The present disclosure is directed to anti-Staphylococcus aureus antibody combinations including combinations of antibodies that bind to S. aureus alpha toxin (AT) protein, clumping factor A protein (ClfA), and/or at least one leukotoxin protein. Methods of treating and preventing infections comprising administering the antibody combinations are also provided herein.

1 . A method of preventing a  Staphylococcus aureus  ( S. aureus ) infection in a subject comprising administering to the subject (a) an antibody or antigen-binding fragment thereof that binds to  S. aureus  alpha toxin (AT), (b) an antibody or antigen-binding fragment thereof that binds to  S. aureus  clumping factor A (ClfA), and (c) an antibody or antigen-binding fragment thereof that binds to at least one  S. aureus  leukotoxin. 
     
     
         2 . A method of treating or preventing a  Staphylococcus aureus  ( S. aureus ) infection in a subject comprising administering to the subject an antibody or antigen-binding fragment thereof that binds to at least one  S. aureus  leukotoxin and (a) an antibody or antigen-binding fragment thereof that binds to  S. aureus  alpha toxin (AT) or (b) an antibody or antigen-binding fragment thereof that binds to  S. aureus  clumping factor A (ClfA). 
     
     
         3 . A composition comprising (a) an antibody or antigen-binding fragment thereof that binds to  S. aureus  AT, (b) an antibody or antigen-binding fragment thereof that binds to  S. aureus  ClfA, and (c) an antibody or antigen-binding fragment thereof that binds to at least one  S. aureus  leukotoxin. 
     
     
         4 . A composition comprising an antibody or antigen-binding fragment thereof that binds to at least one  S. aureus  leukotoxin and (a) an antibody or antigen-binding fragment thereof that binds to  S. aureus  AT or (b) an antibody or antigen-binding fragment thereof that binds to  S. aureus  ClfA. 
     
     
         5 - 12 . (canceled) 
     
     
         13 . The method of  claim 1 , wherein the antibody or antigen-binding fragment thereof that binds to  S. aureus  AT binds to the same  S. aureus  AT epitope as an antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:19 and a VL comprising the amino acid sequence of SEQ ID NO:33. 
     
     
         14 . The method of  claim 1 , wherein the antibody or antigen-binding fragment thereof that binds to  S. aureus  AT competitively inhibits binding of an antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:19 and a VL comprising the amino acid sequence of SEQ ID NO:33 to  S. aureus  AT. 
     
     
         15 . The method of  claim 1 , wherein the antibody or antigen-binding fragment thereof that binds to  S. aureus  AT comprises a variable heavy chain (VH) complementarity determining region (CDR) 1 comprising the amino acid sequence of SEQ ID NO:1, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:2, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:3, a variable light chain (VL) CDR1 comprising the amino acid sequence of SEQ ID NO:10, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:11, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:12. 
     
     
         16 - 19 . (canceled) 
     
     
         20 . The method of  claim 1 , wherein the antibody or antigen-binding fragment thereof that binds to  S. aureus  AT comprises the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 of MEDI4893. 
     
     
         21 - 34 . (canceled) 
     
     
         35 . The method of  claim 1 , wherein the antibody or antigen-binding fragment thereof that binds to  S. aureus  AT has an affinity of 80-100 pM for  S. aureus  AT. 
     
     
         36 . The method of  claim 1 , wherein the antibody or antigen-binding fragment thereof that binds to  S. aureus  ClfA binds to the same  S. aureus  ClfA epitope as an antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:20 and a VL comprising the amino acid sequence of SEQ ID NO:34. 
     
     
         37 . The method of  claim 1 , wherein the antibody or antigen-binding fragment thereof that binds to  S. aureus  ClfA competitively inhibits binding of an antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:20 and a VL comprising the amino acid sequence of SEQ ID NO:34 to  S. aureus  ClfA. 
     
     
         38 . The method of  claim 1 , wherein the antibody or antigen-binding fragment thereof that binds to  S. aureus  ClfA comprises a VH CDR1 comprising the amino acid sequence of SEQ ID NO:4, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:5, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:6, a VL CDR1 comprising the amino acid sequence of SEQ ID NO:13, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:14, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:15. 
     
     
         39 - 40 . (canceled) 
     
     
         41 . The method of  claim 1 , wherein the antibody or antigen-binding fragment thereof that binds to  S. aureus  ClfA comprises a heavy chain constant domain comprising the amino acid sequence of CSYHLC (SEQ ID NO:55). 
     
     
         42 . The method of  claim 41 , wherein said heavy chain constant domain comprises the amino acid sequence of MHEACSYHLCQKSLSLS (SEQ ID NO:56). 
     
     
         43 - 45 . (canceled) 
     
     
         46 . The method of  claim 1 , wherein the antibody or antigen-binding fragment thereof that binds to  S. aureus  ClfA comprises the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 of SAR114-N3Y, 11H10, SAR72, SAR80, SAR113, SAR132, SAR352, SAR372, SAR510, SAR547, SAS1, SAS19, or SAS203. 
     
     
         47 - 65 . (canceled) 
     
     
         66 . The method of  claim 1 , wherein the antibody or antigen-binding fragment thereof that binds to  S. aureus  ClfA has binding affinities (K D ) of less than 1 nM for all ClfA genotypes. 
     
     
         67 - 69 . (canceled) 
     
     
         70 . The method of  claim 1 , wherein the antibody or antigen-binding fragment thereof that binds to at least one  S. aureus  leukotoxin binds to the same  S. aureus  leukotoxin epitope as an antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:32 and a VL comprising the amino acid sequence of SEQ ID NO:46. 
     
     
         71 . The method of  claim 1 , wherein the antibody or antigen-binding fragment thereof that binds to at least one  S. aureus  leukotoxin competitively inhibits binding of an antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:32 and a VL comprising the amino acid sequence of SEQ ID NO:46 to the  S. aureus  leukotoxin. 
     
     
         72 . The method of  claim 1 , wherein the antibody or antigen-binding fragment thereof that binds to at least one  S. aureus  leukotoxin comprises a VHCDR1 comprising the amino acid sequence of SEQ ID NO:7, a VH CDR2 comprising the amino acid sequence of SEQ ID NO:8, a VH CDR3 comprising the amino acid sequence of SEQ ID NO:9, a VL CDR1 comprising the amino acid sequence of SEQ ID NO:16, a VL CDR2 comprising the amino acid sequence of SEQ ID NO:17, and a VL CDR3 comprising the amino acid sequence of SEQ ID NO:18. 
     
     
         73 - 76 . (canceled) 
     
     
         77 . The method of  claim 1 , wherein the antibody or antigen-binding fragment thereof that binds to at least one  S. aureus  leukotoxin comprises the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 of SAN481-SYT. 
     
     
         78 - 93 . (canceled) 
     
     
         94 . The method of  claim 1 , wherein the  S. aureus  infection is sepsis, bacteremia, pneumonia, ICU pneumonia, skin or soft tissue infection (SSTI), diabetic infection of the lower limbs, a diabetic foot ulcer (DFU), a bone infection, joint infection, a device infection, a wound infection, a surgical site infection, osteomyelitis, and/or antibiotic-resistant  S. aureus.    
     
     
         95 - 109 . (canceled) 
     
     
         110 . The method of  claim 1 , wherein the treating or preventing an  S. aureus  infection comprises inhibiting  S. aureus  agglutination, toxin neutralization, inducing opsonophagocytosis, inhibiting  S. aureus  fibrinogen binding, inhibiting  S. aureus  agglutination, inhibiting thromboembolic lesion formation, inhibiting  S. aureus -associated sepsis, or any combination of the foregoing. 
     
     
         111 - 118 . (canceled) 
     
     
         119 . The method of  claim 1 , wherein the antibody or antigen-binding fragment thereof that binds to  S. aureus  AT, the antibody or antigen-binding fragment thereof that binds to  S. aureus  ClfA, and/or the antibody or antigen-binding fragment thereof that binds to at least one  S. aureus  leukotoxin are administered in the same pharmaceutical composition. 
     
     
         120 . A method of treating or preventing a  S. aureus  infection in a subject with diabetes comprising administering to the subject an antibody or antigen-binding fragment thereof that binds to  S. aureus  AT. 
     
     
         121 - 160 . (canceled)