Anti-wall teichoic antibodies and conjugates

Patent metadata

Field	Value
Publication number	US-9884126-B2
Application number	US-201414284619-A
Country	US
Kind code	B2
Filing date	May 22, 2014
Priority date	May 31, 2013
Publication date	Feb 6, 2018
Grant date	Feb 6, 2018

Abstract

The invention provides anti-wall teichoic acid antibodies and antibiotic conjugates thereof, and methods of using the same.

First claim

We claim:

1. An antibody-antibiotic conjugate compound comprising an anti-wall teichoic acid (WTA) monoclonal antibody, wherein the anti-WTA antibody binds to Staphylococcus aureus , and covalently attached by a protease-cleavable, peptide linker (L) to an antibiotic moiety selected from clindamycin, novobiocin, retapamulin, daptomycin, GSK-2140944 (gepotidacin) having the structure:

CG-400549 having the structure:

sitafloxacin, teicoplanin, triclosan, napthyridone, radezolid, doxorubicin, ampicillin, vancomycin, imipenem, doripenem, gemcitabine, dalbavancin, and azithromycin; and wherein the anti-WTA antibody comprises: CDR L1 comprising the sequence of KSSQSIFRTSRNKNLLN (SEQ ID NO:99), CDR L2 comprising the sequence of WASTRKS (SEQ ID NO:100), and CDR L3 comprising the sequence of QQYFSPPYT (SEQ ID NO:101); and the VH of the anti-WTA monoclonal antibody comprises CDR H1 comprising the sequence of SFWMH (SEQ ID NO:102), CDR H2 comprising the sequence of FTNNEGTTTAYADSVRG (SEQ ID NO:103), and CDR H3 comprising the sequence of GEGGLDD (SEQ ID NO:118) or GDGGLDD (SEQ ID NO:104).

2. The antibody-antibiotic conjugate compound of claim 1 wherein the anti-wall teichoic acid (WTA) antibody binds to methicillin-resistant Staphylococcus aureus (MRSA).

3. The antibody-antibiotic conjugate of claim 1 wherein the antibiotic moiety comprises a quaternary amine attached to the peptide linker.

4. The antibody-antibiotic conjugate of claim 1 wherein:
L is the peptide linker having the formula:
-Str-Pep-Y-

where Str is a stretcher unit; Pep is a peptide of two to twelve amino acid residues, and Y is a spacer unit.

5. The antibody-antibiotic conjugate of claim 4 wherein Str has the formula:

wherein R 6 is selected from the group consisting of C 1 -C 10 alkylene-, —C 3 -C 8 carbocyclo, —O—(C 1 -C 8 alkyl)-, -arylene-, —C 1 -C 10 alkylene-arylene-, -arylene-C 1 -C 10 alkylene-, —C 1 -C 10 alkylene-(C 3 -C 8 carbocyclo)-, —(C 3 -C 8 carbocyclo)-C 1 -C 10 alkylene-, —C 3 -C 8 heterocyclo-, —C 1 -C 10 alkylene-(C 3 -C 8 heterocyclo)-, —(C 3 -C 8 heterocyclo)-C 1 -C 10 alkylene-, —(CH 2 CH 2 O) r —, and —(CH 2 CH 2 O) r —CH 2 —; and r is an integer ranging from 1 to 10.

6. The antibody-antibiotic conjugate of claim 5 wherein R 6 is —(CH 2 ) 5 —.

7. The antibody-antibiotic conjugate of claim 4 wherein Pep comprises two to twelve amino acid residues independently selected from glycine, alanine, phenylalanine, lysine, arginine, valine, and citrulline.

8. The antibody-antibiotic conjugate of claim 7 wherein Pep is valine-citrulline.

9. The antibody-antibiotic conjugate of claim 4 wherein Y comprises para-aminobenzyl or para-aminobenzyloxycarbonyl.

10. The antibody-antibiotic conjugate of claim 1 wherein L is the peptide linker having the formula:

where AA1 and AA2 are independently selected from an amino acid side chain.

11. The antibody-antibiotic conjugate of claim 10 wherein the amino acid side chain is independently selected from H, —CH 3 , —CH 2 (C 6 H 5 ), —CH 2 CH 2 CH 2 CH 2 NH 2 , —CH 2 CH 2 CH 2 NHC(NH)NH 2 , —CHCH(CH 3 )CH 3 , and —CH 2 CH 2 CH 2 NHC(O)NH 2 .

12. The antibody-antibiotic conjugate of claim 10 wherein L is the peptide linker having the formula:

13. The antibody-antibiotic conjugate of claim 10 wherein L is the peptide linker having the formula:

14. The antibody-antibiotic conjugate of claim 13 wherein L is the peptide linker having the formula:

15. The antibody-antibiotic conjugate of claim 13 wherein L is the peptide linker having the formula:

16. The antibody-antibiotic conjugate of claim 13 wherein L is the peptide linker having the formula:

17. The antibody-antibiotic conjugate of claim 13 wherein L is the peptide linker having the formula:

18. The antibody-antibiotic conjugate of claim 13 wherein L is the peptide linker having the formula:

19. The antibody-antibiotic conjugate of claim 13 wherein L is the peptide linker having the formula:

where R 7 is independently selected from H and C 1 -C 12 alkyl.

20. A pharmaceutical composition comprising the antibody-antibiotic conjugate compound of claim 1 , and a pharmaceutically acceptable carrier, glidant, diluent, or excipient.

21. A process for making the antibody-antibiotic conjugate compound of claim 1 comprising the steps of:
a) preparing the anti-wall teichoic acid monoclonal antibody by reduction with DTT (dithiothreitol) or tricarbonylethylphosphine (TCEP); and
b) conjugating an anti-wall teichoic acid (WTA) antibody to an antibiotic moiety selected from clindamycin, novobiocin, retapamulin, daptomycin, GSK-2140944, CG-400549, sitafloxacin, teicoplanin, triclosan, napthyridone, radezolid, doxorubicin, ampicillin, vancomycin, imipenem, doripenem, gemcitabine, dalbavancin, and azithromycin;
whereby the antibody-antibiotic conjugate compound is formed.

22. A kit for treating a bacterial infection, comprising:
a) the pharmaceutical composition of claim 20 ; and
b) instructions for use.

23. The antibody-antibiotic conjugate compound of claim 1 , wherein the antibody comprises a VL comprising the amino acid sequence SEQ ID NO:119.

24. The antibody-antibiotic conjugate compound of claim 1 , wherein the antibody comprises a VH comprising the amino acid sequence of SEQ ID NO:156.

25. The antibody-antibiotic conjugate compound of claim 1 , wherein the antibody comprises a VL and a VH, wherein the VL comprises the sequence of SEQ ID NO:119 and the VH comprises the sequence SEQ ID NO:156.

26. The antibody-antibiotic conjugate compound of claim 1 , wherein the antibody comprises a light chain and a heavy chain sequence of
(a) SEQ ID NO:123 and SEQ ID NO:147, or
(b) SEQ ID NO:145 and SEQ ID NO:147.

Assignees

• Genentech Inc

Inventors

• Brown Eric J
• Flygare John
• Hazenbos Wouter
• Lehar Sophie M
• Mariathasan Sanjeev
• Morisaki John Hiroshi
• Pillow Thomas H
• Staben Leanna
• Vandlen Richard
• Koefoed Klaus
• Strandh Magnus
• Andersen Peter S

Classifications

• A61P31/04

  Antibacterial agents · CPC title

• C07K2317/522

  CH1 domain · CPC title

• C07K2317/92

  Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value · CPC title

• A61K47/6851

  the antibody targeting a determinant of a tumour cell · CPC title

• C07K2317/55

  Fab or Fab' · CPC title