IP Library Granted Patent US 10,864,261
Granted Patent B2
US 10,864,261 · App. 16/061,478 · Granted Dec 15, 2020

Synthetic vaccines against

Inventors: Peter H. Seeberger (Kleinmachnow, DE); Claney Lebev Pereira (Berlin, DE); Chakkumkal Anish (The Hague, NL); Naeem Khan (Berlin, DE); Madhu Emmadi (Berlin, DE)
Assignee: Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V.
A61K39/092A61K31/7028A61K31/715A61K47/36C07H1/00C07H15/00C07H15/04A61K2039/55505A61K2039/6037A61K2039/627
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Quick Facts
Patent No.
US 10,864,261
App. No.
16/061,478
Granted
Dec 15, 2020
Kind
B2
Abstract

The present invention relates to a synthetic saccharide of general formula (I) that is related to Streptococcus pneumoniae serotype 2 capsular polysaccharide, a conjugate thereof and the use of said saccharide and conjugate for raising a protective immune response in a human and/or animal host. Furthermore, the synthetic saccharide of general formula (I) is useful as marker in immunological assays for detection of antibodies against Streptococcus pneumoniae type 2 bacteria.

Claims (54)

1. A saccharide of general formula (I)

V*-U x+3 -U x+2 -U x+1 -U x -O-L-NH 2    (I)

wherein

x is an integer selected from 1, 2, 3 and 4;

V*- represents H-, H-U x -, H-U x+1 -U x -, H-U x+2 -U x+1 -U x - or H-U x+3 -U x+2 -U x+1 -U x -;

L is selected from

—CH 2 —, —(CH 2 ) 2 —, —(CH 2 ) 3 —, —(CH 2 ) 4 —, —(CH 2 ) 5 —, —(CH 2 ) 6 —, —(CH 2 ) 7 —, —(CH 2 ) 8 —, —(CH 2 ) 9 —, —(CH 2 ) 10 —, —CF 2 —, —(CF 2 ) 2 —, —(CF 2 ) 3 —, —(CF 2 ) 4 —, —(CF 2 ) 5 —, —(CF 2 ) 6 —, —(CF 2 ) 7 —, —(CF 2 ) 8 —, —(CF 2 ) 9 —, —(CF 2 ) 10 —, —(CH 2 ) 2 —O—(CH 2 ) 2 —, —CH 2 —O—(CH 2 ) 3 —, —(CH 2 ) 3 O—CH 2 —, —CH 2 —O—(CH 2 ) 2 —, —(CH 2 ) 2 O—CH 2 —, —(CH 2 ) 3 —O—(CH 2 ) 2 —, —(CH 2 ) 2 —O—(CH 2 ) 3 —, —(CH 2 ) 4 —O—CH 2 —, —CH 2 —O—(CH 2 ) 4 —, -L a -, -L a -L e -, -L a -L b -L e -, -L a -L b -L d -L c -L e -, and -L a -L d -L e -;

wherein

-L a - is selected from: —(CH 2 ) o —, —(CF 2 ) o —, —(CH 2 —CH 2 —O) o —C 2 H 4 —, —(CH 2 —CH 2 —O) o —CH 2 —, —(CR 10 R 11 ) o —,

-L b - and -L c - are independently of each other selected from: —O—, —NH—C(O)—NH—, —NH—C(S)—NH—, —NH—C(O)—, —C(O)—NH—, —NH—C(O)—O—, —NR 9 —, —NR 18 —, —SO 2 —,

-L d - represents —(CH 2 ) q —, —(CF 2 ) q —, —(CR 12 R 13 ) q —, —(CH 2 —CH 2 —O) q —C 2 H 4 —, —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 —, —(CH 2 ) p1 —O—(CH 2 ) p2 —, —(CR 14 R 15 ) p1 —, —(CR 14 R 15 ) p1 —O—(CR 21 R 22 ) q2 —,

R 9 and R 18 are independently of each other selected from: —CH 3 , —C 2 H 5 , —C 3 H 7 , and —C(O)CH 3 ;

R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 19 , R 20 , R 21 and R 22 are independently of each other selected from: —H, —F, —Cl, —CH 3 , —C 2 H 5 , —C 3 H 7 , —C 5 H 9 , —C 6 H 13 , —OCH 3 , —OC 2 H 5 , —CH 2 F, —CHF 2 , —CF 3 , —C(O)—NH 2 , —SCH 3 , —SC 2 H 5 , —NHC(O)CH 3 , —N(CH 3 ) 2 and —N(C 2 H 5 ) 2 ;

o, q, p1 and p2 are independently of each other an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

or a pharmaceutically acceptable salt thereof.

2. The saccharide according to claim 1 , wherein x represents 1, or a pharmaceutically acceptable salt thereof.

3. The saccharide according to claim 1 , wherein

or a pharmaceutically acceptable salt thereof.

4. The saccharide according to claim 1 , wherein

or a pharmaceutically acceptable salt thereof.

5. A method of synthesis of a saccharide of general formula (I) according to claim 1 , wherein x represents 1, V*- represents H- and

comprising the following steps:

A) reacting a disaccharide of general formula (II)

wherein P 1 -P 3 represent protecting groups, and LG 1 represents a leaving group, with a disaccharide of general formula (III)

wherein P 4 -P 8 represent protecting groups and L has the meaning as defined in claim 1 , to obtain a tetrasaccharide of general formula (IV)

wherein P 1 -P 8 represent protecting groups;

and

B) subjecting the tetrasaccharide of general formula (IV) to selective deprotection to obtain a tetrasaccharide of general formula (V)

wherein P 1 -P 4 , P 6 -P 8 represent protecting groups and L has the meaning defined in claim 1 ; and

C) reacting the tetrasaccharide of general formula (V) with a disaccharide of general formula (VI)

wherein P 9 and P 10 represent protecting groups and LG 2 represents a leaving group to obtain a hexasaccharide of general formula (VII)

wherein P 1 -P 4 , P 6 -P 10 represent protecting groups and L has the meaning defined in claim 1 ;

and

D) performing the removal of protecting groups P 1 -P 4 , P 6 -P 10 on the compound of general formula (VII).

6. An intermediate of general formula (V)

wherein P 1 - P 4 , P 6 -P 8 represent protecting groups and L has the meaning defined in claim 1 .

7. The intermediate of general formula (V) according to claim 6 , wherein P 1 , P 6 and P 7 represent a benzyl group, P 2 , P 3 and P 4 are independently of each other selected from benzoyl and acetyl group, and P 8 represents a benzyloxy carbonyl group.

8. A conjugate of general formula (X)

[V*-U x+3 -U x+2 -U x+1 -U x -O-L-NH-W] m -CRM 197    (X)

wherein m is comprised between about 2 and about 18;

-W- is selected from:

a represents an integer from 1 to 10;

b represents an integer from 1 to 4; and

V*, U x+3 , U x+2 , U x+1 , U x , x and L have the meanings as defined in claim 1 .

9. A saccharide according to claim 1 for use in raising a protective immune response in a human and/or animal host.

10. A saccharide according to claim 1 for use in the prevention and/or treatment of a disease caused by Streptococcus pneumoniae type 2.

11. A vaccine comprising the saccharide and/or the pharmaceutically acceptable salt thereof according to claim 1 together with at least one pharmaceutically acceptable adjuvant and/or excipient.

12. The vaccine composition according to claim 11 , further comprising at least a capsular polysaccharide of Streptococcus pneumoniae and/or a fragment of a capsular polysaccharide of Streptococcus pneumoniae and/or a conjugate of a carrier protein and a capsular polysaccharide of Streptococcus pneumoniae or a fragment of a capsular polysaccharide of Streptococcus pneumoniae , wherein Streptococcus pneumoniae is selected from the group comprising Streptococcus pneumoniae type 1, 3, 4, 5, 6A, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19F, 19A, 20, 22F, 23F and 33F.

13. A saccharide according to claim 1 for use as marker in immunological assays for detection of antibodies against Streptococcus pneumoniae type 2.

14. A conjugate according to claim 8 for use in raising a protective immune response in a human and/or animal host.

15. A conjugate according to claim 8 for use in the prevention and/or treatment of a disease caused by Streptococcus pneumoniae type 2.

16. A vaccine comprising the conjugate according to claim 8 together with at least one pharmaceutically acceptable adjuvant and/or excipient.

17. The vaccine composition according to claim 16 , further comprising at least a capsular polysaccharide of Streptococcus pneumoniae and/or a fragment of a capsular polysaccharide of Streptococcus pneumoniae and/or a conjugate of a carrier protein and a capsular polysaccharide of Streptococcus pneumoniae or a fragment of a capsular polysaccharide of Streptococcus pneumoniae , wherein Streptococcus pneumoniae is selected from the group comprising Streptococcus pneumoniae type 1, 3, 4, 5, 6A, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19F, 19A, 20, 22F, 23F and 33F.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 26, 2018
From: SEEBERGER, PETER H.; PEREIRA, CLANEY LEBEV; ANISH, CHAKKUMKAL; KHAN, NAEEM; EMMADI, MADHU
To: MAX-PLANCK-GESELLSCHAFT ZUR FÖRDERUNG DER WISSENSCHAFFEN E.V.
Reel/Frame 046474/0762 →
Priority Claims (2)
EP 15200729 · Dec 17, 2015 · regional
EP 16167505 · Apr 28, 2016 · regional
Continuity (1)
Related Publication 20200016257A1 · Jan 16, 2020
Cited By (1)
US 12,251,438