VACCINE AGAINST KLEBSIELLA PNEUMONIAE
The present invention relates to novel immunogenic compounds comprising at least one antigen of Formula (I), in particular immunogenic compounds of Formula (II), and their use as pharmaceuticals, in particular as vaccines. The invention also concerns related aspects including intermediates, as well as processes for the preparation of the immunogenic compounds. Furthermore, the invention relates to pharmaceutical compositions comprising the immunogenic compounds, as well as the use of the antigen of Formula (I) in biological assays.
1 . An immunogenic compound comprising at least one oligosaccharide hybrid antigen having the structure of formula (I)
wherein
R is OH, or
m is 3, 4, 5, 6, 7 or 8; and
n is 1, 2, 3, 4, 5 or 6;
or a pharmaceutically acceptable salt thereof.
2 . The immunogenic compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein
m is 4, n is 2 and R is OH;
m is 4, n is 2 and R is
or;
m is 4, n is 3 and R is OH.
3 . The immunogenic compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein m is 4, n is 2 and R is OH.
4 . An immunogenic compound of formula (II)
wherein
R is OH, or
m is 3, 4, 5, 6, 7 or 8;
n is 1, 2, 3, 4, 5 or 6;
i is from 1 to 28; and
-L-T- represents a linker L and a spacer T which together form a bridge having a backbone with a length of 5 to 25 atoms covalently linked together that forms the shortest distance between the oxygen at C1 of the reducing end of the oligosaccharide and the nitrogen of the amino group of a lysine residue at the carrier protein CRM 197 , wherein the atoms of the backbone are selected from the group consisting of carbon, nitrogen, oxygen and sulphur;
or a pharmaceutically acceptable salt thereof.
5 . The immunogenic compound according to claim 4 , or a pharmaceutically acceptable salt thereof, wherein
m is 4, n is 2 and R is OH;
m is 4, n is 2 and R is
or;
m is 4, n is 3 and R is OH.
6 . The immunogenic compound according to claim 4 , or a pharmaceutically acceptable salt thereof, wherein m is 4, n is 2 and R is OH.
7 . The immunogenic compound according to claim 4 , or a pharmaceutically acceptable salt thereof, wherein
-L-T- represents a linker L and a spacer T which together form a bridge having a backbone with a length of 5 to 25 atoms covalently linked together that forms the shortest distance between the oxygen at C1 of the reducing end of the oligosaccharide and the nitrogen of the amino group of a lysine residue at the carrier protein CRM 197 , bearing at most one double bond,
wherein the atoms of the backbone are selected from the group consisting of carbon, nitrogen, oxygen and sulphur, and
wherein the backbone may be substituted with one or more substituents independently selected from oxo, (C 1-4 )alkyl, fluoro, and (C 1-2 )alkoxy, and
wherein a part of the backbone optionally may be part of a 4-, 5- or 6-membered ring selected from:
8 . The immunogenic compound according to claim 4 , or a pharmaceutically acceptable salt thereof, wherein the backbone of the bridge has a length of 8 to 20, atoms covalently linked together that forms the shortest distance between the oxygen at C1 of the reducing end of the oligosaccharide and the nitrogen of the amino group of a lysine residue at the carrier protein CRM 197 .
9 . The immunogenic compound according to claim 4 , or a pharmaceutically acceptable salt thereof, wherein
L represents
*—(CH 2 ) a —NH—; wherein a is from 2 to 10;
*—(CH 2 CH 2 O) b —CH 2 CH 2 NH—, wherein b is 1, 2 or 3;
*—CH 2 CH 2 S—CH 2 CH 2 NH—;
*—(C 2-10 )fluoroalkylene-NH— with fluoroalkylene being a saturated straight chain;
*—(CH 2 ) c NHC(O)(CH 2 ) c′ —NH—, wherein c and c′ are independently from each other from 2 to 6;
*—(CH 2 ) d NHC(O)NH(CH 2 ) d′ —NH—, wherein d and d′ are independently from each other from 2 to 6;
*—(CH 2 ) e —C(O)—NH—(CH 2 ) e′ —NH—; wherein e is from 1 to 10 and e′ is from 2 to 10; or
*—(CH 2 ) f —O—NH—, wherein f is from 2 to 10; or
L-T represents
*—(CH 2 ) g —S—R 1 , wherein g is from 2 to 10; and
T represents
—C(O)—(CH 2 ) h —C(O)—, wherein h is from 0 to 10;
—C(O)—CH 2 CH 2 —(OCH 2 CH 2 ) j —C(O)—, wherein j is from 1 to 5;
—C(O)—CH 2 (CH 2 ) k —(SCH 2 (CH 2 ) k′ ) k″ —C(O)—, wherein k is 0 or 1, k′ is 0 or 1, and k″ is 1, 2, or 3;
wherein l is 1 or 2; or
wherein p is from 1 to 4, and p′ is 1 or 2; and
R 1 represents
wherein q is 2 or 3;
wherein r is 2 or 3; or
10 . The immunogenic compound according to claim 4 , or a pharmaceutically acceptable salt thereof, wherein
L represents
and
T represents
11 . The immunogenic compound according to claim 4 , or a pharmaceutically acceptable salt thereof, wherein i is from 6 to 15.
12 . The immunogenic compound according to claim 4 , or a pharmaceutically acceptable salt thereof, selected from the group consisting of the structures of formula (IIa), (IIb) and (IIc):
wherein i is from 1 to 28.
13 . A pharmaceutical composition comprising, as active principle, an immunogenic compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and at least one therapeutically inert excipient.
14 . The pharmaceutical composition according to claim 13 , further comprising an adjuvant.
15 . (canceled)
16 . A method for the prevention and/or treatment of a K. pneumoniae infection in a human and/or animal, wherein the method comprises administering to the human and/or animal an effective amount of an immunogenic compound according to claim 1 .
17 . A multivalent vaccine comprising the immunogenic compound according to claim 1 , or a pharmaceutically acceptable salt thereof.
18 . A compound having the structure of formula (III):
wherein
R is OH, or
m is 3, 4, 5, 6, 7 or 8; preferably 3, 4, 5 or 6;
n is 1, 2, 3, 4, 5 or 6; preferably 2, 3, or 4;
L 1 represents
*—(C 2-10 )alkylene-NH 2 , preferably *—(CH 2 ) a —NH 2 ; wherein a is from 2 to 10, more preferably l is 5;
*—(CH 2 CH 2 O) b —CH 2 CH 2 NH 2 , wherein b is 1, 2 or 3;
*—CH 2 CH 2 S—CH 2 CH 2 NH 2 ;
*—(C 2-10 )fluoroalkylene-NH 2 ;
*—(CH 2 ) c NHC(O)(CH 2 ) c′ —NH 2 , wherein c and c′ are independently from each other from 2 to 6;
*—(CH 2 ) d NHC(O)NH(CH 2 ) d′ —NH 2 , wherein d and d′ are independently from each other from 2 to 6;
*—(C 1-10 )alkylene-C(O)—NH—(C 2-10 )alkylene-NH 2 ;
—(C 2-10 )alkylene-O—NH 2 ; or
*—(C 2-10 )alkylene-SH;
or a pharmaceutically acceptable salt thereof.
19 . A compound having the structure of formula (IV):
wherein
R is OH, or
m is 3, 4, 5, 6, 7 or 8; preferably 3, 4, 5 or 6;
n is 1, 2, 3, 4, 5 or 6; preferably 2, 3, or 4;
L represents
*—(C 2-10 )alkylene-NH—, preferably *—(CH 2 ) a —NH— wherein a is from 2 to 10, more preferably 5;
*—(CH 2 CH 2 O) b —CH 2 CH 2 NH—, wherein b is 1, 2 or 3;
*—CH 2 CH 2 S—CH 2 CH 2 NH—;
*—(C 2-10 )fluoroalkylene-NH—;
*—(CH 2 ) c NHC(O)(CH 2 ) c′ —NH—, wherein c and c′ are independently from each other from 2 to 6;
*—(CH 2 ) d NHC(O)NH(CH 2 ) d′ —NH—, wherein d and d′ are independently from each other from 2 to 6;
*—(C 1-10 )alkylene-C(O)—NH—(C 2-10 )alkylene-NH—; or
*—(C 2-10 )alkylene-O—NH—;
T 1 represents
—C(O)—(C 0-10 )alkylene-C(O)X;
—C(O)—CH 2 CH 2 —(OCH 2 CH 2 ) j —C(O)X, wherein j is from 1 to 5;
—C(O)—CH 2 (CH 2 ) k —(SCH 2 (CH 2 ) k′ ) k″ —C(O)X, wherein k is 0 or 1, k′ is 0 or 1, and k″ is 1, 2, or 3;
wherein l is 1 or 2; or
wherein p is from 1 to 4, preferably 1, and
p′ is 1 or 2;
—C(O)X represents —C(O)OH or an activated ester, wherein preferably
X represents
and
Y represents Me, Et, Bu or —(CH 2 CH 2 O) 3 CH 3 .
20 . The immunogenic compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein
m is 3, 4, 5 or 6; and
n is 2, 3, or 4.
21 . The immunogenic compound according to claim 4 , or a pharmaceutically acceptable salt thereof, wherein
m is 3, 4, 5 or 6; and
n is 2, 3, or 4.
22 . The immunogenic compound according to claim 4 , or a pharmaceutically acceptable salt thereof, wherein the backbone of the bridge has a length of 8 to 16 atoms covalently linked together that forms the shortest distance between the oxygen at C1 of the reducing end of the oligosaccharide and the nitrogen of the amino group of a lysine residue at the carrier protein CRM 197 .
23 . The immunogenic compound according to claim 4 , or a pharmaceutically acceptable salt thereof, wherein
L represents *—(CH 2 ) 5 —NH—; and
T represents —C(O)—(CH 2 ) 4 —C(O)—.
24 . The immunogenic compound according to claim 4 , or a pharmaceutically acceptable salt thereof, wherein i is from 6 to 15.
25 . A pharmaceutical composition comprising, as active principle, an immunogenic compound according to claim 4 , or a pharmaceutically acceptable salt thereof, and at least one therapeutically inert excipient.
26 . A pharmaceutical composition comprising, as active principle, an immunogenic compound according to claim 12 , or a pharmaceutically acceptable salt thereof, and at least one therapeutically inert excipient.
27 . A method for the prevention and/or treatment of a K. pneumoniae infection in a human and/or animal, wherein the method comprises administering to the human and/or animal an effective amount of an immunogenic compound according to claim 4 .
28 . A method for the prevention and/or treatment of a K. pneumoniae infection in a human and/or animal, wherein the method comprises administering to the human and/or animal an effective amount of an immunogenic compound according to claim 12 .
29 . A multivalent vaccine comprising the immunogenic compound according to claim 4 , or a pharmaceutically acceptable salt thereof.
30 . A multivalent vaccine comprising the immunogenic compound according to claim 12 , or a pharmaceutically acceptable salt thereof.