Methods of treating S. aureus-associated diseases

Patent metadata

Field	Value
Publication number	US-9845348-B2
Application number	US-201314440749-A
Country	US
Kind code	B2
Filing date	Nov 5, 2013
Priority date	Nov 6, 2012
Publication date	Dec 19, 2017
Grant date	Dec 19, 2017

Abstract

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.

First claim

What is claimed is:

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.

Assignees

• Medimmune Llc

Inventors

• Sellman Brett
• Tkaczyk Christine
• Hamilton Melissa
• Hua Lei

Classifications

• A61P31/04

  Antibacterial agents · CPC title

• C07K2317/52

  Constant or Fc region; Isotype · CPC title

• A61K2039/505

  comprising antibodies · CPC title

• C07K16/1271 Primary

  Micrococcaceae (F); Staphylococcaceae (F), e.g. Staphylococcus (G) · CPC title

• A61K39/085 Primary

  Staphylococcus · CPC title