Methods of treating
The present invention provides for methods of preventing and/or treating S. aureus -associated bacteremia and sepsis, and methods for preventing and/or treating S. aureus -associated pneumonia in immunocompromised patients using anti- S. aureus alpha-toxin (anti-AT) antibodies. Also provided are methods of reducing S. aureus bacterial load in the bloodstream or heart of a mammalian subject comprising administering to the subject an effective amount of an isolated anti- S. aureus alpha toxin (anti-AT) antibody or antigen-binding fragment thereof. Methods of reducing S. aureus bacterial agglutination and/or thromboembolic lesion formation in a mammalian subject comprising administering to the subject an effective amount of an isolated anti- S. aureus alpha toxin (anti-AT) antibody or antigen-binding fragment thereof, are also provided. Also provided are methods of preventing or reducing the severity of S. aureus associated pneumonia in an immunocompromised mammalian subject.
1. A method of preventing or reducing the severity of S. aureus -associated pneumonia in an immunocompromised mammalian subject, comprising administering to said subject an effective amount of an isolated anti- S. aureus alpha toxin (anti-AT) antibody or antigen-binding fragment thereof, wherein the isolated antibody or antigen-binding fragment thereof immunospecifically binds to a Staphylococcus aureus alpha toxin polypeptide and includes:
(a) a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 7, 10, 13 or 69;
(b) a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 8, 11, 14, 17, 70 or 75;
(c) a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 9, 12, 15, 18, 16, 65, 66, 67, 71, 72, 76 or 78;
(d) a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 1 or 4;
(e) a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 2, 5, 73 or 77; and
(f) a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 3, 6, 64, 68 or 74.
2. The method of claim 1 , wherein said mammalian subject is human.
3. The method of claim 1 , wherein said isolated anti-AT antibody or antigen-binding fragment thereof is selected from the group consisting of Fv, Fab, Fab′, and F(ab′)2.
4. The method of claim 1 , wherein said antibody is a full-length antibody.
5. The method of claim 4 , wherein said antibody comprises an Fc variant region.
6. The method of claim 1 , wherein the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VL CDR3 correspond to the amino acid sequences of (a) SEQ ID NOs: 7, 8, 9, 1, 2 and 3; (b) SEQ ID NOs: 10, 11, 12, 1, 2 and 3; (c) SEQ ID NOs: 13, 14, 15, 4, 5 and 6; (d) SEQ ID NOs: 7, 17, 18, 1, 2 and 3; (e) SEQ ID NOs: 7, 8, 16, 1, 2 and 64; (f) SEQ ID NOs: 7, 8, 65, 1, 2 and 64; (g) SEQ ID NOs; 7, 8, 66, 1, 2 and 64; (h) SEQ ID NOs: 7, 8, 67, 1, 2 and 68; (i) SEQ ID NOs: 7, 8, 67, 1, 2 and 64; (j) SEQ ID NOs: 7, 8, 78, 1, 2 and 64; (k) SEQ ID NOs: 7, 8, 65, 1, 2 and 68; (l) SEQ ID NOs: 69, 70, 71, 1, 2 and 68; (m) SEQ ID NOs: 7, 8, 72, 1, 73 and 74; (n) SEQ ID NOs: 69, 75, 71, 1, 2 and 68; (o) SEQ ID NOs: 69, 75, 76, 1, 2 and 68; (p) SEQ ID NOs: 69, 75, 76, 1, 77 and 74; or (q) SEQ ID NOs: 69, 70, 71, 1, 77 and 74, respectively.
7. The method of claim 6 , wherein the isolated antibody or antigen-binding fragment thereof comprises (i) a heavy chain variable domain having at least 90% identity to the amino acid sequence of SEQ ID NO: 20, 22, 24, 26, 28, 41, 43, 45, 47, 49, 51, 53, 55, 57, 79, 59, 61, or 62; and (ii) comprises a light chain variable domain having at least 90% identity to the amino acid sequence of SEQ ID NO: 19, 21, 23, 25, 27, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60 or 63.
8. The method of claim 6 , wherein the isolated antibody or antigen-binding fragment thereof comprises a heavy chain variable domain of SEQ ID NO 20, 22, 24, 26, 28, 41, 43, 45, 47, 49, 51, 53, 55, 57, 79, 59, 61, or 62 and a light chain variable domain of SEQ ID NO: 19, 21, 23, 25, 27, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60 or 63.
9. The method of claim 6 , wherein the VH and VL correspond to the amino acid sequences of (a) SEQ ID NOs: 20 and 19; (b) SEQ ID NOs; 22 and 21; (c) SEQ ID NOs: 24 and 23; (d) SEQ ID NOs: 26 and 25; (e) SEQ ID NOs: 28 and 27; (f) SEQ ID NOs: 41 and 42; (g) SEQ ID NOs: 43 and 44; (h) SEQ ID NOs: 45 and 46; (i) SEQ ID NOs: 47 and 48; (j) SEQ ID NOs: 47 and 48; (k) SEQ ID NOs: 49 and 50; (l) SEQ ID NOs: 51 and 52; (m) SEQ ID NOs: 51 and 52; (n) SEQ ID NOs: 53 and 54; (o) SEQ ID NOs: 55 and 56; (p) SEQ ID NOs: 57 and 58; (q) SEQ ID NOs: 59 and 60; (r) SEQ ID NOs: 61 and 58; (s) SEQ ID NOs: 62 and 58; (t) SEQ ID NOs: 62 and 63; or (u) SEQ ID NOs: 79 and 63.
10. The method of claim 6 , wherein the isolated antibody further comprises an Fc variant domain, wherein the antibody comprises a VH-IgG1-YTE corresponding to SEQ ID NO: 80 and/or a VL-Kappa corresponding to SEQ ID NO: 81.