Vaccines against carbapenem-resistant Klebsiella pneumoniae

Patent metadata

Field	Value
Publication number	US-10688169-B2
Application number	US-201615560719-A
Country	US
Kind code	B2
Filing date	Mar 29, 2016
Priority date	Mar 27, 2015
Publication date	Jun 23, 2020
Grant date	Jun 23, 2020

Abstract

The present invention relates to synthetic saccharides of general formula (I): V*—[Ux+2—Ux+1—Ux]n—V—O-L-NH2 that are related to carbapenem-resistant Klebsiella pneumoniae capsular polysaccharide and conjugates thereof. Said conjugates and pharmaceutical composition containing said conjugates are useful for prevention and/or treatment of diseases associated with carbapenem-resistant Klebsiella pneumoniae. Furthermore, the synthetic saccharides of general formula (I): V*—[Ux+2—Ux+1—Ux]n—V—O-L-NH2 are useful as marker in immunological assays for detection of antibodies against carbapenem-resistant Klebsiella pneumoniae bacteria.

First claim

The invention claimed is:

1. A synthetic saccharide of general formula (II)

wherein

represents a bond,

and
L represents a linker;
or a diastereoisomer or a pharmaceutically acceptable salt thereof.

2. The synthetic saccharide according to claim 1 , wherein
L- is selected from: -L a -, -L a -L e -, -L a -L b -L e -, -L a -L d -L e -;
L a - is selected from: —(CH 2 ) o —, —(CH 2 —CH 2 —O) o —C 2 H 4 —, —(CH 2 —CH 2 —O) o —CH 2 ;
L b - represents —O—;
L d - is selected from: —(CH 2 ) q —, —(CF 2 ) q —, —(CH 2 —CH 2 —O) q —C 2 H 4 —, and —(CH 2 —CH 2 —O) q —CH 2 —;
L e - is selected from: —(CH 2 ) p1 —, —(CF 2 ) p1 —, —C 2 H 4 —(O—CH 2 —CH 2 ) p1 —, —CH 2 —(O—CH 2 —CH 2 ) p1 — and —(CH 2 ) p1 —O—(CH 2 ) p2 —;
and o, q, p1 and p2 are independently of each other an integer selected from 1, 2, 3, 4, 5, and 6.

3. A conjugate comprising the saccharide according to claim 1 .

4. The conjugate according to claim 3 of general formula (X)

wherein

represents a bond,

L represents a linker;
m is comprised between 2 and 18;
-T- is selected from:

a represents an integer from 1 to 10; and
b represents an integer from 1 to 4.

5. The conjugate according to claim 4 , wherein -T-represents

and a is an integer selected from 2, 3, 4, 5 and 6.

6. The conjugate according to claim 4 , wherein -L- is selected from: -L a -, -L a -L e -, -L a -L b -L e -, -L a -L d -L e -;
L a - is selected from: —(CH 2 ) o —, —(CH 2 —CH 2 —O) o —C 2 H 4 —, —(CH 2 —CH 2 —O) o —CH 2 ;
L b - represents —O—;
L d - is selected from: —(CH 2 ) q —, —(CF 2 ) q —, —(CH 2 —CH 2 —O) q —C 2 H 4 —, and —(CH 2 —CH 2 —O) q —CH 2 —;
L e - is selected from: —(CH 2 ) p1 —, —(CF 2 ) p1 —, —C 2 H 4 —(O—CH 2 —CH 2 ) p1 —, —CH 2 —(O—CH 2 —CH 2 ) p1 — and —(CH 2 ) p1 —O—(CH 2 ) p2 —;
and o, q, p1 and p2 are independently of each other an integer selected from 1, 2, 3, 4, 5, and 6.

7. A method for raising a protective immune response in a human or animal host comprising administering to the human or animal host a saccharide according to claim 1 , or a conjugate comprising the saccharide.

8. A method for increasing immunogenicity against or treating a disease associated with carbapenem-resistant Klebsiella pneumoniae comprising administering to a patient a saccharide according to claim 1 .

9. A pharmaceutical composition comprising the saccharide according to claim 1 and/or a conjugate comprising the saccharide together with at least one pharmaceutically acceptable adjuvant or excipient.

10. A method comprising the use of the saccharide according to claim 1 as marker in immunological assays for detection of antibodies against carbapenem-resistant Klebsiella pneumoniae.

11. A method of synthesis of a saccharide of general formula (II)

wherein

represents a bond,

L represents a linker;
comprising the following steps:
A) reacting a compound 1 of the formula:

wherein P 1 -P 3 represent protecting groups and P 4 is selected from:

with a compound 2 of the formula:

wherein P 5 -P 7 represent protecting groups and LG 1 represents a leaving group selected from:

to provide a compound 3 of formula:

wherein P 1 -P 3 , P 5 -P 7 represent protecting groups and P 4 is selected from:

and
performing selective removal of protective group P 2 on compound 3 to obtain compound 4 of formula:

wherein P 1 , P 3 , P 5 -P 7 represent protecting groups and P 4 is selected from:

and
reacting compound 4 with compound 5 of formula:

wherein P 8 -P 11 represent protecting groups and LG 2 represents a leaving group selected from:

to obtain compound 6 of formula:

wherein P 1 , P 3 , P 5 -P 11 represent protecting groups and P 4 is selected from:

and
converting compound 6 to compound 7 of formula:

wherein P 1 , P 3 , P 5 -P 11 represent protecting groups and LG 3 represents a leaving group selected from:

and
B1) reacting compound 2 with compound 8 of formula:

wherein P 12 and P 13 represent protecting groups to provide compound 9 of formula:

wherein P 5 -P 7 , P 12 and P 13 represent protecting groups;
and
performing selective removal of protective group P 5 on compound 9 to provide compound 10 of formula:

wherein P 6 , P 7 , P 12 and P 13 represent protecting groups;
and
B2) reacting compound 2 with compound 10 to obtain compound 11 of formula:

wherein P 5 -P 7 , P 12 and P 13 represent protecting groups;
and

Assignees

• Max Planck Gesellschaft

Inventors

• Seeberger Peter H
• Pereira Claney Lebev
• Xiao Guozhi
• Khan Naeem
• Anish Chakkumkal

Classifications

• A61P31/04

  Antibacterial agents · CPC title

• C07H15/04

  attached to an oxygen atom of the saccharide radical · CPC title

• A61K39/0266 Primary

  Klebsiella · CPC title

• A61K2039/55566

  Emulsions, e.g. Freund's adjuvant, MF59 · CPC title

• A61K2039/6037

  Bacterial toxins, e.g. diphteria toxoid [DT], tetanus toxoid [TT] · CPC title