JPWO2020076789A5 - - Google Patents

Description

Embodiments of the invention are further described in the following sections:
[Section 1]
A method of treating or preventing a Staphylococcus aureus (S. aureus) infection in a subject, comprising administering to the subject (a) an antibody that binds S. aureus alpha-toxin (AT) or an antigen-binding fragment thereof, (b) an antibody or antigen-binding fragment thereof that binds to S. aureus clumping factor A (ClfA), and (c) at least one S. aureus leuco A method comprising administering an antibody or antigen-binding fragment thereof that binds a toxin.
[Section 2]
A method of treating or preventing S. aureus infection in a subject, comprising administering to said subject at least one antibody or antigen-binding fragment thereof that binds to S. aureus leukotoxin and ( a) an antibody or antigen-binding fragment thereof that binds to S. aureus alpha-toxin (AT) or (b) an antibody that binds to S. aureus clumping factor A (ClfA) or an antigen thereof A method comprising administering a binding fragment.
[Section 3]
(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) at least one A composition comprising an antibody or antigen-binding fragment thereof that binds to S. aureus leukotoxin.
[Section 4]
at least one antibody or antigen-binding fragment thereof that binds to S. aureus leukotoxin and (a) an antibody or antigen-binding fragment thereof that binds to S. aureus AT or (b) yellow A composition comprising an antibody or antigen-binding fragment thereof that binds to S. aureus ClfA.
[Section 5]
5. The composition of paragraphs 3 or 4, above, for use in treating or preventing S. aureus infection in a subject.
[Section 6]
An antibody or antigen-binding fragment thereof that binds S. aureus ClfA and at least one species of S. aureus for use in treating or preventing S. aureus infection in a subject An antibody or antigen-binding fragment thereof that binds to S. aureus alpha-toxin (AT) in combination with an antibody or antigen-binding fragment thereof that binds to (S. aureus) leukotoxin.
[Section 7]
An antibody or antigen-binding fragment thereof that binds S. aureus AT and at least one species of S. aureus for use in treating or preventing S. aureus infection in a subject An antibody or antigen-binding fragment thereof that binds to S. aureus ClfA in combination with an antibody or antigen-binding fragment thereof that binds to (S. aureus) leukotoxin.
[Item 8]
An antibody or antigen-binding fragment thereof that binds S. aureus AT and/or S. aureus (S. aureus) for use in treating or preventing S. aureus infection in a subject at least one antibody or antigen-binding fragment thereof that binds to S. aureus leukotoxin in combination with an antibody or antigen-binding fragment thereof that binds to ClfA.
[Item 9]
5. Use of the composition of paragraphs 3 or 4 above in the preparation of a medicament for treating or preventing S. aureus infection in a subject.
[Item 10]
An antibody or antigen-binding fragment thereof that binds S. aureus ClfA and at least one species of S. aureus in the preparation of a medicament for treating or preventing S. aureus infection in a subject Use of an antibody or antigen-binding fragment thereof that binds to S. aureus alpha-toxin (AT) in combination with an antibody or antigen-binding fragment thereof that binds to (S. aureus) leukotoxin.
[Item 11]
An antibody or antigen-binding fragment thereof that binds S. aureus AT and at least one species of S. aureus in the preparation of a medicament for treating or preventing S. aureus infection in a subject Use of an antibody or antigen-binding fragment thereof that binds to S. aureus ClfA in combination with an antibody or antigen-binding fragment thereof that binds to (S. aureus) leukotoxin.
[Item 12]
An antibody or antigen-binding fragment thereof that binds S. aureus AT and/or S. aureus (S. aureus) in the preparation of a medicament for treating or preventing S. aureus infection in a subject Use of at least one antibody or antigen-binding fragment thereof that binds to S. aureus leukotoxin in combination with an antibody or antigen-binding fragment thereof that binds to ClfA.
[Item 13]
The antibody or antigen-binding fragment thereof that binds to S. aureus AT is the same S. aureus antibody as the 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. 13. The method, composition, antibody or antigen-binding fragment thereof or use of any one of the preceding clauses 1-12, which binds to a S. aureus AT epitope.
[Item 14]
The antibody or antigen-binding fragment thereof that binds to S. aureus AT is a S. aureus antibody comprising a VH comprising said amino acid sequence of SEQ ID NO: 19 and a VL comprising said amino acid sequence of SEQ ID NO: 33 ( 14. The method, composition, antibody or antigen-binding fragment thereof, or use of any one of paragraphs 1 to 13, which competitively inhibits binding to S. aureus AT.
[Item 15]
Said antibody or antigen-binding fragment thereof that binds to S. aureus AT comprises a variable heavy chain (VH) complementarity determining region (CDR) 1 comprising said amino acid sequence of SEQ ID NO: 1, said a VH CDR2 comprising an amino acid sequence, a VH CDR3 comprising said amino acid sequence of SEQ ID NO: 3, a variable light chain (VL) CDR1 comprising said amino acid sequence of SEQ ID NO: 10, a VL CDR2 comprising said amino acid sequence of SEQ ID NO: 11 and SEQ ID NO: 15. A method, composition, antibody or antigen-binding fragment thereof or use according to any one of the preceding paragraphs, comprising a VL CDR3 comprising said 12 amino acid sequences.
[Item 16]
16. The method or composition of any one of items 1 to 15, wherein the antibody or antigen-binding fragment thereof that binds to S. aureus AT comprises a VH comprising the amino acid sequence of SEQ ID NO: 19. products, antibodies or antigen-binding fragments thereof or uses.
[Item 17]
17. The method or composition of any one of items 1 to 16, wherein said antibody or antigen-binding fragment thereof that binds to S. aureus AT comprises a VL comprising said amino acid sequence of SEQ ID NO: 33. products, antibodies or antigen-binding fragments thereof or uses.
[Item 18]
18. The method of any one of paragraphs 1 to 17, wherein said antibody or antigen-binding fragment thereof that binds to S. aureus AT comprises a heavy chain comprising said amino acid sequence of SEQ ID NO:47. Compositions, antibodies or antigen-binding fragments thereof or uses.
[Item 19]
19. The method of any one of paragraphs 1 to 18, wherein said antibody or antigen-binding fragment thereof that binds to S. aureus AT comprises a light chain comprising said amino acid sequence of SEQ ID NO:52. Compositions, antibodies or antigen-binding fragments thereof or uses.
[Section 20]
15. Any of paragraphs 1 to 14 above, wherein said antibody or antigen-binding fragment thereof that binds to S. aureus AT comprises VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VL CDR3 of MEDI4893. A method, composition, antibody or antigen-binding fragment thereof, or use according to any one of claims 1 to 3.
[Section 21]
21. The method, composition, antibody or antigen-binding fragment thereof or use of paragraph 20, wherein said CDRs are Kabat defined CDRs, Chothia defined CDRs or AbM defined CDRs.
[Section 22]
The method or composition according to any one of items 1 to 17 and 19 to 21 above, wherein the antibody or antigen-binding fragment thereof that binds to S. aureus AT further comprises a heavy chain constant region. , antibodies or antigen-binding fragments thereof or uses.
[Section 23]
23. The method, composition, according to item 22 above, wherein said heavy chain constant region is selected from the group consisting of human immunoglobulin IgG ₁ , IgG ₂ , IgG ₃ , IgG ₄ , IgA ₁ and IgA ₂ heavy chain constant regions. Antibodies or antigen-binding fragments thereof or uses.
[Section 24]
23. The method, composition, antibody or antigen-binding fragment thereof, or use of paragraph 22, wherein said heavy chain constant region is a human IgG ₁ constant region.
[Section 25]
22. The method or composition according to any one of items 1 to 18, 20 and 21 above, wherein the antibody or antigen-binding fragment thereof that binds to S. aureus AT further comprises a light chain constant region. , antibodies or antigen-binding fragments thereof or uses.
[Section 26]
26. The method, composition, antibody or antigen-binding fragment thereof or use of Claim 25, wherein said light chain constant region is selected from the group consisting of human immunoglobulin IgGκ and IgGλ light chain constant regions.
[Section 27]
26. The method, composition, antibody or antigen-binding fragment thereof or use of paragraph 25, wherein said light chain constant region is a human IgG kappa light chain constant region.
[Section 28]
28. The method, composition, antibody according to any one of items 1 to 27, wherein the antibody or antigen-binding fragment thereof that binds to S. aureus AT is an IgG antibody or antigen-binding fragment thereof. or an antigen-binding fragment or use thereof.
[Section 29]
29. The antibody or antigen-binding fragment thereof that binds to S. aureus AT comprises an Fc region that has been genetically engineered for improved half-life. A method, composition, antibody or antigen-binding fragment thereof or use of.
[Item 30]
30. The method, composition, antibody of any one of paragraphs 1 to 29, wherein said antibody or antigen-binding fragment thereof that binds to S. aureus AT comprises an Fc region having a YTE mutation. or an antigen-binding fragment or use thereof.
[Item 31]
31. The method, composition, antibody or method according to any one of items 1 to 30, wherein the antibody or antigen-binding fragment thereof that binds to S. aureus AT is a monoclonal antibody or antigen-binding fragment. Antigen-binding fragments or uses thereof.
[Item 32]
32. The method, composition, antibody or antigen binding thereof of any one of the preceding paragraphs 1-31, wherein the antibody or antigen-binding fragment thereof that binds to S. aureus AT is a full-length antibody. fragment or use.
[Item 33]
32. The method, composition, antibody or antigen binding thereof according to any one of the preceding paragraphs 1 to 31, wherein said antibody or antigen binding fragment thereof that binds to S. aureus AT is an antigen binding fragment. fragment or use.
[Item 34]
Said antibodies or antigen-binding fragments thereof that bind S. aureus AT include Fab, Fab', F(ab') ₂ , single chain Fv (scFv), disulfide-linked Fv, intrabody, IgGΔCH2, mini 34. The method, composition, antibody of item 33, comprising a body, F(ab') ₃ , tetrabody, triabody, diabodies, DVD-Ig, Fcab, mAb ² , (scFv) ₂ or scFv-Fc or an antigen-binding fragment or use thereof.
[Item 35]
35. Any one of items 1 to 34 above, wherein the antibody or antigen-binding fragment thereof that binds to S. aureus AT has an affinity of 80 to 100 pM for S. aureus AT. A method, composition, antibody or antigen-binding fragment thereof, or use according to any one of claims 1 to 3.
[Item 36]
The antibody or antigen-binding fragment thereof that binds to S. aureus ClfA is the same S. aureus 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. 36. The method, composition, antibody or antigen-binding fragment thereof or use of any one of the preceding clauses 1-35, which binds to a S. aureus ClfA epitope.
[Item 37]
The antibody or antigen-binding fragment thereof that binds to S. aureus ClfA is a S. aureus 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, composition, antibody or antigen-binding fragment thereof, or use of any one of paragraphs 1 to 36, which competitively inhibits binding to S. aureus) ClfA.
[Item 38]
Said antibody or antigen-binding fragment that binds to S. aureus ClfA has a VH CDR1 comprising said amino acid sequence of SEQ ID NO:4, a VH CDR2 comprising said amino acid sequence of SEQ ID NO:5, said amino acid sequence of SEQ ID NO:6 VH CDR3 comprising the sequence, VL CDR1 comprising said amino acid sequence of SEQ ID NO: 13, VL CDR2 comprising said amino acid sequence of SEQ ID NO: 14, and VL CDR3 comprising said amino acid sequence of SEQ ID NO: 15. The method, composition, antibody or antigen-binding fragment thereof, or use of any one.
[Item 39]
39. The method, composition of any one of items 1 to 38, wherein said antibody or antigen-binding fragment thereof that binds to S. aureus ClfA comprises a VH comprising said amino acid sequence of SEQ ID NO: 20. products, antibodies or antigen-binding fragments thereof or uses.
[Item 40]
40. The method, composition of any one of items 1 to 39, wherein the antibody or antigen-binding fragment thereof that binds to S. aureus ClfA comprises a VL comprising the amino acid sequence of SEQ ID NO: 34. products, antibodies or antigen-binding fragments thereof or uses.
[Item 41]
41. Any one of paragraphs 1 to 40 above, wherein said antibody or antigen-binding fragment thereof that binds to S. aureus ClfA comprises a heavy chain constant domain comprising said amino acid sequence of CSYHLC (SEQ ID NO: 55). A method, composition, antibody or antigen-binding fragment thereof or use as described in .
[Item 42]
42. The method, composition, antibody or antigen-binding fragment thereof or use of Clause 41 above, wherein said heavy chain constant domain comprises said amino acid sequence of MHEACSYHLCQKSLSLS (SEQ ID NO: 56).
[Item 43]
43. The method of any one of paragraphs 1-42, wherein said antibody or antigen-binding fragment thereof that binds to S. aureus ClfA comprises a heavy chain comprising said amino acid sequence of SEQ ID NO:49; Compositions, antibodies or antigen-binding fragments thereof or uses.
[Item 44]
44. The method of any one of paragraphs 1 to 43, wherein said antibody or antigen-binding fragment thereof that binds to S. aureus ClfA comprises a light chain comprising said amino acid sequence of SEQ ID NO:53; Compositions, antibodies or antigen-binding fragments thereof or uses.
[Item 45]
Paragraphs 1 to 44 above, wherein said antibody or antigen-binding fragment thereof that binds to S. aureus ClfA comprises VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VL CDR3 of SAR114-N3Y The method, composition, antibody or antigen-binding fragment thereof or use according to any one of
[Section 46]
Said antibody or antigen-binding fragment thereof that binds to S. aureus ClfA comprises VH CDR1, VH CDR2 of 11H10, SAR72, SAR80, SAR113, SAR132, SAR352, SAR372, SAR510, SAR547, SAS1, SAS19 or SAS203 , VH CDR3, VL CDR1, VL CDR2 and VL CDR3.
[Section 47]
47. The method, composition, antibody or antigen-binding fragment thereof or use of paragraphs 45 or 46, wherein said CDRs are Kabat defined CDRs, Chothia defined CDRs or AbM defined CDRs.
[Item 48]
Said antibody or antigen-binding fragment thereof that binds to S. aureus ClfA comprises VH and VL, wherein said VH is said amino acid sequence according to any one of SEQ ID NOs: 21-31 and 68 47. The method, composition, antibody or antigen-binding fragment thereof or use of any one of paragraphs 1-35 or 46 above, comprising:
[Item 49]
The antibody or antigen-binding fragment thereof that binds to S. aureus ClfA comprises a VH and a VL, wherein the VL comprises the amino acid sequence according to any one of SEQ ID NOs: 35-45 and 69. 47. The method, composition, antibody or antigen-binding fragment thereof or use of any one of paragraphs 1-35 or 46 above, comprising:
[Item 50]
Said antibody, or antigen-binding fragment thereof, that binds to S. aureus ClfA comprises (a) SEQ ID NOs: 21 and 35, respectively; (b) SEQ ID NOs: 22 and 36, respectively; (c) SEQ ID NOs: 23 and 37, respectively; (d) SEQ. , (i) SEQ ID NOs: 29 and 43, respectively, (j) SEQ ID NOs: 30 and 44, respectively, (k) SEQ ID NOs: 31 and 45, respectively, or (l) SEQ ID NOs: 68 and 69, respectively, and 36. The method, composition, antibody or antigen-binding fragment thereof or use of any one of the preceding paragraphs 1-35, comprising a VL sequence.
[Section 51]
51. The method, composition according to any one of items 1 to 40 and 44 to 50 above, wherein said antibody or antigen-binding fragment thereof that binds to S. aureus ClfA further comprises a heavy chain constant region. , antibodies or antigen-binding fragments thereof or uses.
[Section 52]
52. The method, composition, according to paragraph 51 above, wherein said heavy chain constant region is selected from the group consisting of human immunoglobulin IgG ₁ , IgG ₂ , IgG ₃ , IgG ₄ , IgA ₁ and IgA ₂ heavy chain constant regions. Antibodies or antigen-binding fragments thereof or uses.
[Section 53]
52. The method, composition, antibody or antigen-binding fragment thereof or use of paragraph 51, wherein said heavy chain constant region is a human IgG ₁ constant region.
[Section 54]
54. The method, composition according to any one of items 1 to 43 and 45 to 53 above, wherein said antibody or antigen-binding fragment thereof that binds to S. aureus ClfA further comprises a light chain constant region. , antibodies or antigen-binding fragments thereof or uses.
[Section 55]
55. The method, composition, antibody or antigen-binding fragment thereof or use of Claim 54, wherein said light chain constant region is selected from the group consisting of human immunoglobulin IgGκ and IgGλ light chain constant regions.
[Section 56]
55. The method, composition, antibody or antigen-binding fragment thereof or use of paragraph 54, wherein said light chain constant region is a human IgG kappa light chain constant region.
[Section 57]
1, above, wherein said antibody or antigen-binding fragment that binds to S. aureus ClfA comprises a mutation that extends half-life in human FcRn mice compared to said same antibody without said mutation. 57. The method, composition, antibody or antigen-binding fragment thereof or use of any one of claims 1-56.
[Section 58]
Said antibody or antigen-binding fragment thereof that binds to S. aureus ClfA comprises a mutation that extends half-life relative to said same antibody without said mutation, said mutation comprising: 58. The method, composition, antibody or antigen-binding fragment thereof or use of any one of the preceding paragraphs, which does not inhibit OPK activity compared to said same antibody or antigen-binding fragment without mutation.
[Section 59]
59. A method, composition, antibody or Antigen-binding fragments or uses thereof.
[Section 60]
60. The method, composition, antibody or antigen binding thereof of any one of paragraphs 1 to 59, wherein said antibody or antigen-binding fragment thereof that binds to S. aureus ClfA is a full-length antibody. fragment or use.
[Section 61]
60. The method, composition, antibody or antigen binding thereof of any one of paragraphs 1 to 59, wherein said antibody or antigen binding fragment thereof that binds to S. aureus ClfA is an antigen binding fragment. fragment or use.
[Section 62]
Said antibodies or antigen-binding fragments thereof that bind to S. aureus ClfA include Fab, Fab', F(ab') ₂ , single chain Fv (scFv), disulfide-linked Fv, intrabody, IgGΔCH2, mini 62. The method, composition, antibody of paragraph 61, comprising a body, F(ab') ₃ , tetrabody, triabody, diabody, DVD-Ig, Fcab, mAb ² , (scFv) ₂ or scFv-Fc or an antigen-binding fragment or use thereof.
[Section 63]
Item 1 above, wherein said antibody or antigen-binding fragment thereof that binds to S. aureus ClfA has an IC50 that is within 2 μg/mL of each other for ClfA001, ClfA002 and ClfA004 in a fibrinogen binding inhibition assay. 62. The method, composition, antibody or antigen-binding fragment thereof or use of any one of claims 1-62.
[Section 64]
Said antibody or antigen-binding fragment thereof that binds to S. aureus ClfA has an IC50 against ClfA001, ClfA002 and ClfA004 all between 1 μg/mL and 5 μg/mL in a fibrinogen binding inhibition assay. 64. The method, composition, antibody or antigen-binding fragment thereof, or use of any one of the preceding paragraphs 1-63, comprising:
[Section 65]
1, wherein said antibody or antigen-binding fragment thereof that binds to S. aureus ClfA has binding affinities (K _D ) for ClfA001, ClfA002 and ClfA004 that are all between 200 and 350 pM. 64. The method, composition, antibody or antigen-binding fragment thereof or use of any one of claims 1-64.
[Section 66]
66. Any one of paragraphs 1-65 above, wherein said antibody or antigen-binding fragment thereof that binds to S. aureus ClfA has a binding affinity (K _D ) of less than 1 nM for all ClfA genotypes. The method, composition, antibody or antigen-binding fragment thereof, or use according to the clause.
[Section 67]
Said antibody or antigen-binding fragment that binds to S. aureus ClfA is reduced by 5% or less after exposure of said antibody or antigen-binding fragment to conventional white light at 2 kLux/hr at 23° C. for 14 days 67. The method, composition, antibody or antigen-binding fragment thereof or use of any one of paragraphs 1 to 66, having monomeric purity.
[Section 68]
Said antibody or antigen-binding fragment thereof binds to at least one S. aureus leukotoxin, binds LukF, LukD and/or HlgB, and/or said antibody or antigen-binding fragment thereof binds to LukF 68. The method, composition, antibody or antigen-binding fragment thereof or use of any one of the preceding paragraphs that neutralizes , LukD and/or HlgB.
[Section 69]
Said antibody or antigen-binding fragment thereof binds to at least one S. aureus leukotoxin, binds LukF, LukD and/or HlgB, and/or said antibody or antigen-binding fragment thereof binds to LukF 69. The method, composition, antibody or antigen-binding fragment thereof or use of paragraph 68 above which neutralizes , LukD and/or HlgB.
[Section 70]
The antibody or antigen-binding fragment thereof that binds to S. aureus leukotoxin has the same yellow color as the 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. 70. The method, composition, antibody or antigen-binding fragment thereof or use of any one of the preceding clauses 1-69 that binds to a S. aureus leukotoxin epitope.
[Section 71]
The antibody or antigen-binding fragment thereof that binds to S. aureus leukotoxin is the 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, composition, antibody or antigen-binding fragment thereof or use of any one of the preceding paragraphs, which competitively inhibits binding to S. aureus leukotoxin.
[Section 72]
Said antibody or antigen-binding fragment that binds to at least one S. aureus leukotoxin comprises VH CDR1 comprising said amino acid sequence of SEQ ID NO: 7, VH CDR2 comprising said amino acid sequence of SEQ ID NO: 8, SEQ ID NO: 9, VL CDR1 comprising said amino acid sequence of SEQ ID NO: 16, VL CDR2 comprising said amino acid sequence of SEQ ID NO: 17, and VL CDR3 comprising said amino acid sequence of SEQ ID NO: 18. 72. The method, composition, antibody or antigen-binding fragment thereof, or use of any one of 1-71.
[Section 73]
73. The above clauses 1-72, wherein said antibody or antigen-binding fragment thereof that binds to at least one S. aureus leukotoxin comprises a VH comprising said amino acid sequence of SEQ ID NO:32. A method, composition, antibody or antigen-binding fragment thereof or use as described.
[Section 74]
74. The above clauses 1-73, wherein said antibody or antigen-binding fragment thereof that binds to at least one S. aureus leukotoxin comprises a VL comprising said amino acid sequence of SEQ ID NO:46. A method, composition, antibody or antigen-binding fragment thereof or use as described.
[Section 75]
75. Any one of paragraphs 1-74 above, wherein said antibody or antigen-binding fragment thereof that binds at least one S. aureus leukotoxin comprises a heavy chain comprising said amino acid sequence of SEQ ID NO:50. A method, composition, antibody or antigen-binding fragment thereof or use as described in .
[Section 76]
76. Any one of the preceding paragraphs 1-75, wherein said antibody or antigen-binding fragment thereof that binds at least one S. aureus leukotoxin comprises a light chain comprising said amino acid sequence of SEQ ID NO:54. A method, composition, antibody or antigen-binding fragment thereof or use as described in .
[Section 77]
said antibody or antigen-binding fragment thereof that binds to at least one S. aureus leukotoxin comprises VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VL CDR3 of SAN481-SYT; 72. The method, composition, antibody or antigen-binding fragment thereof, or use of any one of paragraphs 1-71 above.
[Section 78]
78. The method, composition, antibody or antigen-binding fragment thereof or use of paragraph 77, wherein said CDRs are Kabat defined CDRs, Chothia defined CDRs or AbM defined CDRs.
[Section 79]
79. The above paragraphs 1-74 and 76-78, wherein said antibody or antigen-binding fragment thereof that binds at least one S. aureus leukotoxin further comprises a heavy chain constant region. A method, composition, antibody or antigen-binding fragment thereof or use of.
[Section 80]
_{80. The} method, composition, according to clause 79, wherein said heavy chain constant region is selected from the group consisting of human immunoglobulin IgG1, IgG2, IgG3 _{, IgG4} , _IgA1 and _IgA2 heavy chain constant regions. Antibodies or antigen-binding fragments thereof or uses.
[Section 81]
80. The method, composition, antibody or antigen-binding fragment thereof or use of paragraph 79, wherein said heavy chain constant region is a human IgG ₁ constant region.
[Section 82]
82. The above paragraphs 1-75 and 77-81, wherein said antibody or antigen-binding fragment thereof that binds at least one S. aureus leukotoxin further comprises a light chain constant region. A method, composition, antibody or antigen-binding fragment thereof or use of.
[Section 83]
83. The method, composition, antibody or antigen-binding fragment thereof or use of Claim 82, wherein said light chain constant region is selected from the group consisting of human immunoglobulin IgGκ and IgGλ light chain constant regions.
[Section 84]
83. The method, composition, antibody or antigen-binding fragment thereof, or use of Clause 82, wherein said light chain constant region is a human IgG kappa light chain constant region.
[Section 85]
85. The method of any one of the preceding paragraphs 1-84, wherein the antibody or antigen-binding fragment thereof that binds to at least one S. aureus leukotoxin is an IgG antibody or antigen-binding fragment thereof. , compositions, antibodies or antigen-binding fragments thereof or uses.
[Section 86]
86. Any of the above paragraphs 1-85, wherein said antibody or antigen-binding fragment thereof that binds at least one S. aureus leukotoxin comprises an Fc region that has been genetically modified for improved half-life. A method, composition, antibody or antigen-binding fragment thereof, or use according to any one of claims 1 to 3.
[Section 87]
87. The method of any one of paragraphs 1-86, wherein said antibody or antigen-binding fragment thereof that binds at least one S. aureus leukotoxin comprises an Fc region having a YTE mutation. , compositions, antibodies or antigen-binding fragments thereof or uses.
[Section 88]
88. The method of any one of the preceding paragraphs 1-87, wherein the antibody or antigen-binding fragment thereof that binds at least one S. aureus leukotoxin is a monoclonal antibody or antigen-binding fragment thereof. , compositions, antibodies or antigen-binding fragments thereof or uses.
[Section 89]
89. The method, composition of any one of the preceding paragraphs 1-88, wherein said antibody or antigen-binding fragment thereof that binds at least one S. aureus leukotoxin is a full-length antibody; Antibodies or antigen-binding fragments thereof or uses.
[Item 90]
89. The method, composition of any one of the preceding paragraphs 1-88, wherein the antibody or antigen-binding fragment thereof that binds to at least one S. aureus leukotoxin is an antigen-binding fragment; Antibodies or antigen-binding fragments thereof or uses.
[Item 91]
Said antibodies or antigen-binding fragments thereof that bind S. aureus AT include Fab, Fab', F(ab') ₂ , single chain Fv (scFv), disulfide-linked Fv, intrabody, IgGΔCH2, mini 91. The method, composition, antibody of paragraph 90, comprising a body, F(ab') ₃ , tetrabody, triabody, diabodies, DVD-Ig, Fcab, mAb ² , (scFv) ₂ or scFv-Fc or an antigen-binding fragment or use thereof.
[Item 92]
said antibody or antigen-binding fragment thereof that binds to at least one S. aureus leukotoxin has an affinity of less than 75 pM for S. aureus LukF, LukD and H1gB; 92. The method, composition, antibody or antigen-binding fragment thereof, or use of any one of paragraphs 1-91 above.
[Item 93]
93. Any one of paragraphs 1 to 92 above, wherein said antibody or antigen-binding fragment thereof that binds to at least one S. aureus leukotoxin has similar affinities for LukF, LukD and HIgB. The method, composition, antibody or antigen-binding fragment thereof, or use according to the clause.
[Item 94]
94. The method, composition, antibody or antigen-binding fragment thereof or use of any one of paragraphs 1, 2 and 5-93 above, wherein said S. aureus infection is sepsis.
[Item 95]
94. The method, composition, antibody or antigen-binding fragment thereof or use of any one of paragraphs 1, 2 and 5-93, wherein said S. aureus infection is bacteremia.
[Item 96]
94. The method, composition, antibody or antigen-binding fragment thereof or use of any one of paragraphs 1, 2 and 5-93 above, wherein said S. aureus infection is pneumonia.
[Item 97]
94. The method, composition, antibody or antigen-binding fragment thereof or use of any one of paragraphs 1, 2 and 5-93 above, wherein said S. aureus infection is ICU pneumonia.
[Item 98]
94. The method, composition, antibody or antigen thereof according to any one of the above items 1, 2 and 5-93, wherein the S. aureus infection is a skin or soft tissue infection (SSTI) binding fragment or use.
[Item 99]
94. The method, composition, antibody or antigen-binding fragment thereof according to any one of Items 1, 2 and 5 to 93 above, wherein the S. aureus infection is a diabetic infection of the lower extremities. or use.
[Item 100]
94. The method, composition, antibody or antigen thereof according to any one of the above items 1, 2 and 5 to 93, wherein the S. aureus infection is diabetic foot ulcer (DFU) binding fragment or use.
[Item 101]
101. The method, composition, antibody or antigen-binding fragment thereof or use of paragraph 100, wherein said DFU is non-infectious.
[Item 102]
101. The method, composition, antibody or antigen-binding fragment thereof or use of paragraph 100, wherein said DFU is infectious.
[Item 103]
101. The method, composition, antibody or antigen-binding fragment thereof, or use of paragraph 100, wherein said DFU is Grade 1, 2 or 3 DFU.
[Item 104]
94. The method, composition, antibody or antigen-binding fragment thereof of any one of 1, 2 and 5 to 93 above, or use.
[Item 105]
94. Any one of paragraphs 1, 2 and 5-93 above, wherein the S. aureus infection is a joint infection, device-associated infection, wound infection, surgical site infection or osteomyelitis. A method, composition, antibody or antigen-binding fragment thereof or use as described in .
[Item 106]
106. The method, composition, antibody or antigen-binding fragment thereof or use of any one of paragraphs 1, 2 and 5-105 above, wherein said subject is a surgical patient.
[Item 107]
107. The method, composition, antibody of any one of items 1, 2 and 5 to 106 above, wherein the S. aureus infection comprises antibiotic-resistant S. aureus. or an antigen-binding fragment or use thereof.
[Item 108]
108. The method, composition, antibody or antigen-binding fragment thereof or use of any one of paragraphs 1, 2 and 5-107 above, wherein said subject has diabetes.
[Item 109]
109. The method, composition, antibody or antigen-binding fragment thereof, or use according to any one of Items 1, 2 and 5-108 above, wherein said subject is a human.
[Item 110]
Said treating or preventing S. aureus infection comprises inhibiting aggregation of S. aureus, neutralizing toxins, inducing opsonic erosion, S. aureus ( inhibiting fibrinogen binding of S. aureus, inhibiting aggregation of S. aureus, inhibiting thromboembolic lesion formation, inhibiting S. aureus-associated sepsis or any combination of the above.
[Item 111]
said antibody or antigen-binding fragment thereof that binds S. aureus AT and said antibody or antigen-binding fragment thereof that binds S. aureus ClfA are administered in said same pharmaceutical composition; The method, composition, antibody or antigen-binding fragment thereof, or use of any one of Items 1, 2, 6-8 and 10-110 above.
[Item 112]
said antibody or antigen-binding fragment thereof that binds S. aureus AT and said antibody or antigen-binding fragment thereof that binds S. aureus ClfA are administered in said separate pharmaceutical compositions The method, composition, antibody or antigen-binding fragment thereof or use of any one of paragraphs 1, 2, 6-8 and 10-110 above.
[Item 113]
Said antibody or antigen-binding fragment thereof that binds to S. aureus AT and said antibody or antigen-binding fragment thereof that binds to at least one S. aureus leukotoxin are combined in said same pharmaceutical composition 111. The method, composition, antibody or antigen-binding fragment thereof or use of any one of paragraphs 1, 2, 6-8 and 10-110 above administered in a body.
[Item 114]
Said antibody or antigen-binding fragment thereof that binds to S. aureus AT and at least one said antibody or antigen-binding fragment thereof that binds to S. aureus leukotoxin are combined with said separate medicament The method, composition, antibody or antigen-binding fragment thereof or use of any one of paragraphs 1, 2, 6-8 and 10-110 above administered in a composition.
[Item 115]
Said antibody or antigen-binding fragment thereof that binds to S. aureus ClfA and at least one said antibody or antigen-binding fragment thereof that binds to S. aureus leukotoxin are combined in said same pharmaceutical composition 111. The method, composition, antibody or antigen-binding fragment thereof or use of any one of paragraphs 1, 2, 6-8 and 10-110 above administered in a body.
[Item 116]
Said antibody or antigen-binding fragment thereof that binds to S. aureus ClfA and at least one said antibody or antigen-binding fragment thereof that binds to S. aureus leukotoxin are combined with said separate medicament The method, composition, antibody or antigen-binding fragment thereof or use of any one of paragraphs 1, 2, 6-8 and 10-110 above administered in a composition.
[Item 117]
117. The method, composition, antibody or antigen-binding fragment thereof or use of any one of Clauses 112, 114 and 116 above, wherein said separate pharmaceutical compositions are administered simultaneously.
[Item 118]
117. The method, composition, antibody or antigen-binding fragment thereof or use of any one of Clauses 112, 114 and 116 above, wherein said separate pharmaceutical compositions are administered sequentially.
[Item 119]
Said antibody or antigen-binding fragment thereof that binds to S. aureus AT, said antibody or antigen-binding fragment thereof that binds to S. aureus ClfA and at least one S. aureus (S. aureus) aureus), wherein said antibody or antigen-binding fragment thereof that binds to leukotoxin is administered in said same pharmaceutical composition; Compositions, antibodies or antigen-binding fragments thereof or uses.
[Item 120]
A method of treating or preventing S. aureus infection in a subject with diabetes, comprising administering to said subject an antibody or antigen-binding fragment thereof that binds to S. aureus AT. method including.
[Item 121]
An antibody or antigen-binding fragment thereof that binds S. aureus AT for use in treating or preventing S. aureus infection in a subject with diabetes.
[Item 122]
Use of an antibody that binds S. aureus AT or an antigen-binding fragment thereof in said preparation of a medicament for treating or preventing S. aureus infection in a subject with diabetes.
[Item 123]
The antibody or antigen-binding fragment thereof that binds to S. aureus AT is the same S. aureus antibody as the 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. 123. The method, antibody or antigen-binding fragment thereof or use of any one of paragraphs 120-122, which binds to a S. aureus AT epitope.
[Item 124]
The antibody or antigen-binding fragment thereof that binds to S. aureus AT is a S. aureus antibody comprising a VH comprising said amino acid sequence of SEQ ID NO: 19 and a VL comprising said amino acid sequence of SEQ ID NO: 33 ( 124. The method, antibody or antigen-binding fragment thereof or use of any one of paragraphs 120-123, which competitively inhibits binding to S. aureus AT.
[Item 125]
Said antibody or antigen-binding fragment that binds to S. aureus AT has a VH CDR1 comprising said amino acid sequence of SEQ ID NO:1, a VH CDR2 comprising said amino acid sequence of SEQ ID NO:2, said amino acid sequence of SEQ ID NO:3 125, comprising a VH CDR3 comprising a sequence, a VL CDR1 comprising said amino acid sequence of SEQ ID NO: 10, a VL CDR2 comprising said amino acid sequence of SEQ ID NO: 11, and a VL CDR3 comprising said amino acid sequence of SEQ ID NO: 12. The method, antibody or antigen-binding fragment thereof, or use of any one.
[Item 126]
126. The method, antibody of any one of paragraphs 120-125, wherein said antibody or antigen-binding fragment thereof that binds to S. aureus AT comprises a VH comprising said amino acid sequence of SEQ ID NO: 19. or an antigen-binding fragment or use thereof.
[Item 127]
127. The method, antibody of any one of paragraphs 120-126, wherein said antibody or antigen-binding fragment thereof that binds to S. aureus AT comprises a VL comprising said amino acid sequence of SEQ ID NO:33. or an antigen-binding fragment or use thereof.
[Item 128]
128. The method of any one of paragraphs 120-127, wherein said antibody or antigen-binding fragment thereof that binds S. aureus AT comprises a heavy chain comprising said amino acid sequence of SEQ ID NO:47. Antibodies or antigen-binding fragments thereof or uses.
[Item 129]
129. The method of any one of paragraphs 120-128, wherein said antibody or antigen-binding fragment thereof that binds S. aureus AT comprises a light chain comprising said amino acid sequence of SEQ ID NO:52. Antibodies or antigen-binding fragments thereof or uses.
[Item 130]
125. Any of the above paragraphs 120-124, wherein said antibody or antigen-binding fragment thereof that binds to S. aureus AT comprises VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VL CDR3 of MEDI4893. The method, antibody or antigen-binding fragment thereof, or use according to any one of claims 1 to 3.
[Item 131]
131. The method, antibody or antigen-binding fragment thereof or use of paragraph 130, wherein said CDRs are Kabat defined CDRs, Chothia defined CDRs or AbM defined CDRs.
[Item 132]
The method, antibody or antibody of any one of paragraphs 120-127 and 129-131 above, wherein said antibody or antigen-binding fragment thereof that binds to S. aureus AT further comprises a heavy chain constant region. Antigen-binding fragments or uses thereof.
[Item 133]
_{133. The method , antibody or} Antigen-binding fragments or uses.
[Item 134]
133. The method, antibody or antigen-binding fragment thereof or use of Paragraph 132, wherein said heavy chain constant region is a human IgG ₁ constant region.
[Item 135]
The method, antibody or antibody of any one of paragraphs 120-128 and 130-134 above, wherein said antibody or antigen-binding fragment thereof that binds to S. aureus AT further comprises a light chain constant region. Antigen-binding fragments or uses thereof.
[Item 136]
136. The method, antibody or antigen-binding fragment thereof or use of Paragraph 135, wherein said light chain constant region is selected from the group consisting of human immunoglobulin IgGκ and IgGλ light chain constant regions.
[Section 137]
136. The method, antibody or antigen-binding fragment thereof or use of Paragraph 135, wherein said light chain constant region is a human IgG kappa light chain constant region.
[Item 138]
138. The method, antibody or antigen thereof according to any one of paragraphs 120 to 137, wherein said antibody or antigen-binding fragment thereof that binds to S. aureus AT is an IgG antibody or antigen-binding fragment thereof. binding fragment or use.
[Item 139]
139. Any one of paragraphs 120 to 138, wherein said antibody or antigen-binding fragment thereof that binds S. aureus AT comprises an Fc region that has been genetically engineered for improved half-life. method, antibody or antigen-binding fragment thereof or use of.
[Item 140]
140. The method, antibody or antigen thereof of any one of paragraphs 120-139, wherein said antibody or antigen-binding fragment thereof that binds S. aureus AT comprises an Fc region having a YTE mutation. binding fragment or use.
[Item 141]
141. The method, antibody or antigen binding thereof according to any one of paragraphs 120 to 140, wherein said antibody or antigen binding fragment thereof that binds S. aureus AT is a monoclonal antibody or antigen binding fragment thereof. fragment or use.
[Item 142]
142. The method, antibody or antigen-binding fragment thereof, or use of any one of paragraphs 120 to 141, wherein said antibody or antigen-binding fragment thereof that binds to S. aureus AT is a full-length antibody. .
[Item 143]
142. The method, antibody or antigen-binding fragment thereof, or use according to any one of paragraphs 120 to 141, wherein said antibody or antigen-binding fragment thereof that binds to S. aureus AT is an antigen-binding fragment. .
[Item 144]
Said antibodies or antigen-binding fragments thereof that bind S. aureus AT include Fab, Fab', F(ab') ₂ , single chain Fv (scFv), disulfide-linked Fv, intrabody, IgGΔCH2, mini 144. The method, antibody or antigen thereof according to paragraph 143, comprising a body, F(ab') ₃ , tetrabody, triabody, diabody, DVD-Ig, Fcab, mAb ² , (scFv) ₂ or scFv-Fc binding fragment or use.
[Item 145]
145. Any of paragraphs 120-144 above, wherein said antibody or antigen-binding fragment thereof that binds S. aureus AT has an affinity for S. aureus AT of 80-100 pM. The method, antibody or antigen-binding fragment thereof, or use of any one of claims 1 to 3.
[Item 146]
146. The method, antibody or antigen-binding fragment thereof or use of any one of paragraphs 120-145, wherein said S. aureus infection is sepsis.
[Section 147]
146. The method, antibody or antigen-binding fragment thereof or use of any one of paragraphs 120-145, wherein said S. aureus infection is bacteremia.
[Item 148]
146. The method, antibody or antigen-binding fragment thereof or use of any one of paragraphs 120-145, wherein said S. aureus infection is pneumonia.
[Item 149]
146. The method, antibody or antigen-binding fragment thereof or use of any one of paragraphs 120-145, wherein said S. aureus infection is ICU pneumonia.
[Item 150]
146. The method, antibody or antigen-binding fragment thereof or use of any one of paragraphs 120-145, wherein said S. aureus infection is SSTI.
[Item 151]
146. The method, antibody or antigen-binding fragment thereof or use of any one of paragraphs 120 to 145, wherein said S. aureus infection is a diabetic infection of the lower extremities.
[Item 152]
146. The method, antibody or antigen-binding fragment thereof or use of any one of paragraphs 120-145, wherein said S. aureus infection is DFU.
[Item 153]
153. The method, antibody or antigen-binding fragment thereof or use of Paragraph 152, wherein said DFU is non-infectious.
[Item 154]
153. The method, antibody or antigen-binding fragment thereof or use of paragraph 152, wherein said DFU is infectious.
[Item 155]
155. The method, antibody or antigen-binding fragment thereof or use of Paragraph 154, wherein said DFU is Grade 1, 2 or 3 DFU.
[Item 156]
146. The method, antibody or antigen-binding fragment thereof or use of any one of the preceding paragraphs and paragraphs 120-145, wherein said S. aureus infection is a bone or joint infection.
[Item 157]
146. The method of any one of paragraphs 120-145, wherein the S. aureus infection is a joint infection, device-associated infection, wound infection, surgical site infection, or osteomyelitis. , antibodies or antigen-binding fragments thereof or uses.
[Item 158]
158. The method, antibody or antigen-binding fragment thereof or use of any one of paragraphs 120-157 above, wherein said subject is a surgical patient.
[Item 159]
159. The method, antibody or antigen-binding fragment thereof or use of any one of paragraphs 120 to 158, wherein said S. aureus infection comprises antibiotic-resistant S. aureus. .
[Item 160]
160. The method, antibody or antigen-binding fragment thereof or use of any one of paragraphs 120-159, wherein said subject is a human.
The following examples further illustrate the invention but, of course, should not be construed as limiting its scope in any way.

Claims (31)

1. A pharmaceutical composition for treating or preventing a Staphylococcus aureus (S. aureus) infection in a subject, comprising an antibody or antigen-binding fragment thereof,
(a) the antibody or antigen-binding fragment thereof is an antibody or antigen-binding fragment thereof that binds to S. aureus alpha-toxin (AT), and the pharmaceutical composition comprises
(i) an antibody or antigen-binding fragment thereof that binds to S. aureus clumping factor A (ClfA) and (ii) at least one antibody that binds to S. aureus leukotoxin or further comprising an antigen-binding fragment thereof,
in combination with (i) an antibody or antigen-binding fragment thereof that binds to S. aureus ClfA and (ii) at least one antibody or antigen-binding fragment thereof that binds to S. aureus leukotoxin or (i) an antibody or antigen-binding fragment thereof that binds S. aureus ClfA and (ii) at least one antibody that binds S. aureus leukotoxin or further comprising one of its antigen-binding fragments, administered in combination with the other;
(b) the antibody or antigen-binding fragment thereof is an antibody or antigen-binding fragment thereof that binds to S. aureus ClfA, and the pharmaceutical composition comprises
(i) an antibody or antigen-binding fragment thereof that binds to S. aureus AT and (ii) at least one antibody or antigen-binding fragment thereof that binds to S. aureus leukotoxin include,
in combination with (i) an antibody or antigen-binding fragment thereof that binds to S. aureus AT and (ii) at least one antibody or antigen-binding fragment thereof that binds to S. aureus leukotoxin (i) an antibody or antigen-binding fragment thereof that binds S. aureus AT and (ii) at least one antibody that binds S. aureus leukotoxin or or (c) wherein said antibody or antigen-binding fragment thereof binds at least one S. aureus leukotoxin or antibody thereof which binds to S. aureus leukotoxin an antigen-binding fragment, wherein the pharmaceutical composition comprises
(i) an antibody or antigen-binding fragment thereof that binds to S. aureus AT and/or (ii) an antibody or antigen-binding fragment thereof that binds to S. aureus ClfA,
administered in combination with (i) an antibody or antigen-binding fragment thereof that binds to S. aureus AT and/or (ii) an antibody or antigen-binding fragment thereof that binds to S. aureus ClfA or (i) an antibody or antigen-binding fragment thereof that binds to S. aureus AT and (ii) an antibody or antigen-binding fragment thereof that binds to S. aureus ClfA administered in combination with the other,
pharmaceutical composition. said pharmaceutical composition comprises at least one antibody or antigen-binding fragment thereof that binds to S. aureus leukotoxin;
(i) an antibody or antigen-binding fragment thereof that binds to S. aureus AT and (ii) an antibody or antigen-binding fragment thereof that binds to S. aureus ClfA,
administered in combination with (i) an antibody or antigen-binding fragment thereof that binds to S. aureus AT and (ii) an antibody or antigen-binding fragment thereof that binds to S. aureus ClfA; or further comprising one of (i) an antibody or antigen-binding fragment thereof that binds to S. aureus AT and (ii) an antibody or antigen-binding fragment thereof that binds to S. aureus ClfA, administered in combination with another,
A pharmaceutical composition according to claim 1 . The antibody or antigen-binding fragment thereof that binds to S. aureus AT comprises
(i) variable heavy chain (VH) complementarity determining region (CDR) 1 comprising the amino acid sequence of SEQ ID NO: 1, VH CDR2 comprising the amino acid sequence of SEQ ID NO: 2, VH CDR3 comprising the amino acid sequence of SEQ ID NO: 3, SEQ ID NO: a variable light chain (VL) CDR1 comprising a ten amino acid sequence, 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; or (ii) comprising the amino acid sequence of SEQ ID NO:19 comprising a VH and a VL comprising the amino acid sequence of SEQ ID NO:33;
may be a monoclonal antibody or an antigen-binding fragment thereof;
3. The pharmaceutical composition according to claim 1 or 2. Claims 1-3, wherein said antibody or antigen-binding fragment thereof that binds to S. aureus AT comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:47 and a light chain comprising the amino acid sequence of SEQ ID NO:52. The pharmaceutical composition according to any one of . The antibody or antigen-binding fragment that binds to S. aureus ClfA comprises
(i) VH CDR1 comprising the amino acid sequence of SEQ ID NO:4, VH CDR2 comprising the amino acid sequence of SEQ ID NO:5, VH CDR3 comprising the amino acid sequence of SEQ ID NO:6, VL CDR1 comprising the amino acid sequence of SEQ ID NO:13, SEQ ID NO:14 or (ii) 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;
may be a monoclonal antibody or an antigen-binding fragment thereof;
The pharmaceutical composition according to any one of claims 1-4. The antibody or antigen-binding fragment thereof that binds to S. aureus ClfA has a heavy chain constant domain comprising the amino acid sequence of CSYHLC (SEQ ID NO:55) or a heavy chain constant domain comprising the amino acid sequence of MHEACSYHLCQKSLSLS (SEQ ID NO:56). A pharmaceutical composition according to any one of claims 1 to 5, comprising a normal domain. Claims 1-6, wherein said antibody or antigen-binding fragment thereof that binds to S. aureus ClfA comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:49 and a light chain comprising the amino acid sequence of SEQ ID NO:53. The pharmaceutical composition according to any one of . said antibody or antigen-binding fragment thereof that binds to at least one S. aureus leukotoxin binds to LukF, LukD and/or HlgB and/or neutralizes LukF, LukD and/or HlgB The pharmaceutical composition according to any one of claims 1 to 7. said antibody or antigen-binding fragment that binds to at least one S. aureus leukotoxin,
(i) VHCDR1 comprising the amino acid sequence of SEQ ID NO: 7, VH CDR2 comprising the amino acid sequence of SEQ ID NO: 8, VH CDR3 comprising the amino acid sequence of SEQ ID NO: 9, VL CDR1 comprising the amino acid sequence of SEQ ID NO: 16, SEQ ID NO: 17 or (ii) 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;
may be a monoclonal antibody or an antigen-binding fragment thereof;
The pharmaceutical composition according to any one of claims 1-8. said antibody or antigen-binding fragment thereof that binds to at least one S. aureus leukotoxin comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:50 and a light chain comprising the amino acid sequence of SEQ ID NO:54; A pharmaceutical composition according to any one of claims 1-9. (a) said 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/or (c) ) said antibody or antigen-binding fragment thereof that binds at least one S. aureus leukotoxin comprising (i) human immunoglobulins IgG ₁ , IgG ₂ , IgG ₃ , IgG ₄ , IgA ₁ and IgA ₂ ; 1. The light chain constant region of claim 1, further comprising a heavy chain constant region selected from the group consisting of heavy chain constant regions and/or (ii) a light chain constant region selected from the group consisting of human immunoglobulin IgGκ and IgGλ light chain constant regions. The pharmaceutical composition according to any one of -3, 5, 6, 8 and 9. (a) said 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/or (c) ) said antibody or antigen-binding fragment thereof that binds at least one S. aureus leukotoxin comprises an Fc region that has been genetically modified for improved half-life or has a YTE mutation; 10. The pharmaceutical composition of any one of claims 1-3, 5, 6, 8 and 9, comprising an Fc region. (a) said 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/or (c) ) said antibody or antigen-binding fragment thereof that binds at least one S. aureus leukotoxin is a full-length antibody, claims 1-3, 5, 6, 8, 9, 11 and 12; The pharmaceutical composition according to any one of . (a) said 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/or (c) ) said antibody or antigen-binding fragment thereof that binds to at least one S. aureus leukotoxin is an antigen-binding fragment, said antigen-binding fragment being Fab, Fab', F(ab') ₂ , single-chain Fv (scFv), disulfide-linked Fv, intrabody, IgGΔCH2, minibody, F(ab′) ₃ , tetrabody, triabody, diabodies, DVD-Ig, Fcab, mAb ² , (scFv) ₂ or Pharmaceutical composition according to any one of claims 1 to 3, 5, 6, 8, 9, 11 and 12, which may comprise scFv-Fc. The S. aureus infections include sepsis, bacteremia, pneumonia, ICU pneumonia, skin or soft tissue infections (SSTI), diabetic infections of the lower extremities, diabetic foot ulcers (DFU), bone or joint infection, device-related infection, wound infection, surgical site infection, osteomyelitis, or any combination of the above, and/or said S. aureus infection is antibiotic-resistant yellow A pharmaceutical composition according to any one of claims 1 to 14, comprising S. aureus. 16. The pharmaceutical composition of claim 15, wherein the DFU is non-infectious, infectious, or grade 1, 2 or 3 DFU. The pharmaceutical composition according to any one of claims 1 to 16, wherein said subject is a surgical patient and/or a diabetic patient. The pharmaceutical composition according to any one of claims 1-17, wherein the subject is a human. Treatment or prevention of S. aureus infection includes inhibiting S. aureus aggregation, toxin neutralization, inducing opsonic erosion, S. aureus ), inhibiting aggregation of S. aureus, inhibiting thromboembolic lesion formation, inhibiting S. aureus-associated sepsis, or A pharmaceutical composition according to any one of claims 1 to 18, in any combination of the above. Said antibody or antigen-binding fragment thereof that binds to S. aureus AT, said antibody or antigen-binding fragment thereof that binds to S. aureus ClfA and at least one S. aureus (S. aureus) aureus). The pharmaceutical composition of any one of claims 1 to 19, comprising said antibody or antigen-binding fragment thereof that binds to leukotoxin. (i) said antibody or antigen-binding fragment thereof that binds to S. aureus AT, (ii) said antibody or antigen-binding fragment thereof that binds to S. aureus ClfA, and (iii) Antibodies or antigen-binding fragments thereof that bind to at least one S. aureus leukotoxin. or the pharmaceutical composition according to claim 1. (i) said antibody or antigen-binding fragment thereof that binds to S. aureus AT; (ii) said antibody or antigen-binding fragment thereof that binds to S. aureus ClfA; and (iii) at least one S. aureus leukotoxin-binding antibody or antigen-binding fragment thereof is administered simultaneously or sequentially. A pharmaceutical composition according to any one of claims. 1. A pharmaceutical composition for treating or preventing S. aureus infection in a subject with diabetes, comprising an antibody or antigen-binding fragment thereof that binds S. aureus AT pharmaceutical composition. The antibody or antigen-binding fragment that binds to S. aureus AT comprising:
(i) VH CDR1 comprising the amino acid sequence of SEQ ID NO: 1, VH CDR2 comprising the amino acid sequence of SEQ ID NO: 2, VH CDR3 comprising the amino acid sequence of SEQ ID NO: 3, VL CDR1 comprising the amino acid sequence of SEQ ID NO: 10, SEQ ID NO: 11 or (ii) 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;
may be a monoclonal antibody or an antigen-binding fragment thereof;
24. A pharmaceutical composition according to claim 23. 25. The antibody or antigen-binding fragment thereof that binds to S. aureus AT comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:47 and a light chain comprising the amino acid sequence of SEQ ID NO:52. The pharmaceutical composition according to . Said antibody or antigen-binding fragment thereof that binds S. aureus AT consists of (i) human immunoglobulin IgG ₁ , IgG ₂ , IgG ₃ , IgG ₄ , IgA ₁ and IgA ₂ heavy chain constant regions 25. A medicament according to claim 23 or 24, further comprising a heavy chain constant region selected from the group and/or (ii) a light chain constant region selected from the group consisting of human immunoglobulin IgGκ and IgGλ light chain constant regions. Composition. wherein said antibody or antigen-binding fragment thereof that binds S. aureus AT comprises an Fc region that has been genetically engineered for improved half-life or comprises an Fc region with a YTE mutation. 27. The pharmaceutical composition according to Item 23, 24 or 26. 28. The pharmaceutical composition of claim 23, 24, 26 or 27, wherein said antibody or antigen-binding fragment thereof that binds S. aureus AT is a full-length antibody. Said antibody or antigen-binding fragment thereof that binds to S. aureus AT is an antigen-binding fragment, said antigen-binding fragment being Fab, Fab', F(ab') ₂ , single-chain Fv (scFv ), disulfide-linked Fv, intrabody, IgGΔCH2, minibody, F(ab′) ₃ , tetrabody, triabody, diabody, DVD-Ig, Fcab, mAb ² , (scFv) ₂ or scFv-Fc 28. The pharmaceutical composition of claim 23, 24, 26 or 27. The S. aureus infections include sepsis, bacteremia, pneumonia, ICU pneumonia, skin or soft tissue infections (SSTI), diabetic infections of the lower extremities, diabetic foot ulcers (DFU), bone or joint infection, joint infection, device-related infection, wound infection, surgical site infection, osteomyelitis, or any combination of the above, and/or said S. aureus infection is A pharmaceutical composition according to any one of claims 23 to 29, comprising antibiotic-resistant S. aureus. 31. The pharmaceutical composition of claim 30, wherein the DFU is non-infectious, infectious, or grade 1, 2 or 3 DFU.