Anti-wall teichoic antibodies and conjugates

Patent metadata

Field	Value
Publication number	US-9803002-B2
Application number	US-201414292289-A
Country	US
Kind code	B2
Filing date	May 30, 2014
Priority date	May 31, 2013
Publication date	Oct 31, 2017
Grant date	Oct 31, 2017

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-wall teichoic acid monoclonal antibody binds to Staphylococcus aureus , and covalently attached to a rifamycin-type antibiotic by a protease-cleavable, peptide linker, the antibody-antibiotic conjugate compound having Formula I:

wherein:
the dashed lines indicate an optional bond;
R is H, C 1 -C 12 alkyl, or C(O)CH 3 ;
R 1 is OH;
R 2 is CH═N-(heterocyclyl), wherein the heterocyclyl is optionally substituted with one or more groups independently selected from C(O)CH 3 , C 1 -C 12 alkyl, C 1 -C 12 heteroaryl, C 2 -C 20 heterocyclyl, C 6 -C 20 aryl, and C 3 -C 12 carbocyclyl;
or R 1 and R 2 form a five- or six-membered fused heteroaryl or heterocyclyl, and optionally forming a spiro or fused six-membered heteroaryl, heterocyclyl, aryl, or carbocyclyl ring, wherein the spiro or fused six-membered heteroaryl, heterocyclyl, aryl, or carbocyclyl ring is optionally substituted H, F, Cl, Br, I, C 1 -C 12 alkyl, or OH;
L is the peptide linker attached to R 2 or the fused heteroaryl or heterocyclyl formed by R 1 and R 2 ;
Ab is the anti-wall teichoic acid monoclonal antibody; and
p is an integer from 1 to 8.

2. The antibody-antibiotic conjugate compound of claim 1 , wherein the VL of the anti-WTA monoclonal 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).

3. The antibody-antibiotic conjugate compound of claim 2 , wherein the antibody comprises a VL comprising the amino acid sequence SEQ ID NO:119.

4. The antibody-antibiotic conjugate compound of claim 2 , wherein the antibody comprises a VH comprising the amino acid sequence of SEQ ID NO:156.

5. The antibody-antibiotic conjugate compound of claim 2 , 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.

6. The antibody-antibiotic conjugate compound of claim 2 , 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.

7. The antibody-antibiotic conjugate compound of claim 2 , wherein the antibody comprises a VH comprising the amino acid sequence of SEQ ID NO:120.

8. The antibody-antibiotic conjugate compound of claim 2 , 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:120.

9. The antibody-antibiotic conjugate compound of claim 2 , wherein the antibody comprises a light chain (LC) wherein the LC comprises the amino acid sequence of SEQ ID NO:121, and a heavy chain (HC) wherein the HC comprises the amino acid sequence of SEQ ID NO:146.

10. The antibody-antibiotic conjugate compound of claim 1 , wherein the rifamycin-type antibiotic comprises a quaternary amine attached to the peptide linker.

11. The antibody-antibiotic conjugate compound of claim 10 , wherein the peptide linker is attached to a cysteine or an engineered cysteine of the anti-WTA antibody.

12. The antibody-antibiotic conjugate compound of claim 10 , wherein the peptide linker is a S. aureus endopeptidase or cysteine protease cleavable linker.

13. The antibody-antibiotic conjugate compound of claim 12 , wherein the peptide linker is a staphopain B or a staphopain A cleavable linker.

14. The antibody-antibiotic conjugate compound of claim 12 , wherein the peptide linker is a human protease cathepsin B cleavable linker.

15. The antibody-antibiotic conjugate compound of claim 14 , wherein the peptide linker is a val-cit dipeptide linker.

16. The antibody-antibiotic conjugate compound 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.

17. The antibody-antibiotic conjugate compound of claim 16 , wherein p is 2 to 4.

18. The antibody-antibiotic conjugate compound of claim 1 wherein the formula is selected from the group consisting of:
a)

wherein
R 3 is independently selected from H and C 1 -C 12 alkyl;
n is 1 or 2;
R 4 is selected from H, F, Cl, Br, I, C 1 -C 12 alkyl, and OH; and
Z is selected from NH, N(C 1 -C 12 alkyl), O and S;
b)

wherein
R 5 is selected from H and C 1 -C 12 alkyl; and
n is 0 or 1;
c)

wherein
R 5 is selected from H and C 1 -C 12 alkyl; and
n is 0 or 1;
d)

wherein
R 5 is independently selected from H and C 1 -C 12 alkyl; and
n is 0 or 1;
e)

wherein
R 3 is independently selected from H and C 1 -C 12 alkyl; and
n is 1 or 2; and
f)

19. The antibody-antibiotic conjugate compound of claim 16 , 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)-C1-C10 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.

20. The antibody-antibiotic conjugate compound of claim 19 , wherein R 6 is —(CH 2 ) 5 —.

21. The antibody-antibiotic conjugate compound of claim 16 , wherein Pep comprises two to twelve amino acid residues independently selected from glycine, alanine, phenylalanine, lysine, arginine, valine, and citrulline.

22. The antibody-antibiotic conjugate compound of claim 21 , wherein Pep is selected from valine-citrulline (val-cit, vc); phenylalanine-lysine (fk); and valine-citrulline-phenylalanine (val-cit-phe.

23. The antibody-antibiotic conjugate compound of claim 16 , wherein Y comprises para-aminobenzyl or para-aminobenzyloxycarbonyl.

24. The antibody-antibiotic conjugate compound of claim 16 wherein L

Assignees

• Genentech Inc
• Genentench Inc

Inventors

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

Classifications

• C07K16/1271 Primary

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

• C07K2317/92

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

• C07K2317/624

  Disulfide-stabilized antibody (dsFv) · CPC title

• C07K2317/567

  Framework region [FR] · CPC title

• C07K2317/565

  Complementarity determining region [CDR] · CPC title