MODIFIED SACCHARIDES, CONJUGATES THEREOF, AND THEIR MANUFACTURE
Saccharide-protein conjugates having a new type of linker are described. The conjugates comprising the new linker are prepared from modified saccharides comprising a moiety of the formula (I): -A-N(R 1 )-L-M wherein: A is a bond, —C(O)— or —OC(O)—; R 1 is selected from H or C 1 -C 6 alkyl; L is a C 1 -C 12 alkylene group; and M is a masked aldehyde group. The new linker is especially useful for preparing conjugates of Neisseria meningitidis serogroup A saccharide. Conjugates having this new linker have improved immunogenicity compared to other types of conjugates.
1 . A modified capsular saccharide comprising a moiety of the formula (I):
-A-N(R 1 )-L-M (I)
wherein:
A is a bond, —C(O)— or —OC(O)—
R 1 is selected from H or C 1 -C 6 alkyl;
L is a C 1 -C 12 alkylene group;
M is a masked aldehyde group.
2 . The modified capsular saccharide of claim 1 wherein A is —OC(O)—.
3 . The modified capsular saccharide of claim 1 wherein R 1 is H.
4 . The modified capsular saccharide of claim 1 wherein L is a C 1 -C 6 alkylene group.
5 . The modified capsular saccharide of claim 4 wherein L is —CH 2 CH 2 CH 2 —.
6 . The modified capsular saccharide of claim 1 wherein the masked aldehyde is selected from:
wherein:
R 2 is selected from H, C 1 -C 12 alkyl, C 3 -C 12 cycloalkyl, C 5 -C 12 aryl or C 5-12 aryl-C 1-6 alkyl;
X and Y are the same or different and are independently selected from O or S;
R 3 and R 4 are independently selected from C 1 -C 12 alkyl, C 3 -C 12 cycloalkyl, C 5 -C 12 aryl or C 5-12 aryl-C 1-6 alkyl; or R 3 and R 4 are joined to form a C 3 , C 4 , C 5 , C 6 , C 7 or C 8 cycloalkyl ring containing the heteroatoms X and Y;
R 5 and R 6 are independently selected from H, C 1 -C 12 alkyl, C 3 -C 12 cycloalkyl, C 5 -C 12 aryl or C 5-12 aryl-C 1-6 alkyl; or R 5 and R 6 are joined to form a C 3 or C 12 cycloalkyl ring;
R 9 and R 10 are independently selected from H, C 1 -C 12 alkyl, C 3 -C 12 cycloalkyl, C 5 -C 12 aryl or C 5-12 aryl-C 1-6 alkyl; or R 9 and R 10 are joined to form a C 3 to C 12 cycloalkyl ring; and
R 7 and R 8 are independently selected from C 1 -C 12 alkyl or C 3 -C 12 cycloalkyl groups.
7 . The modified capsular saccharide of claim 6 wherein the masked aldehyde is
—CH(OH)CH 2 OH.
8 . The modified capsular saccharide of claim 1 comprising a moiety of the formula: —NH(CH 2 ) 3 CH(OH)CH 2 OH.
9 . The modified saccharide of claim 1 comprising a moiety of the formula:
—OC(O)NH(CH 2 ) 3 CH(OH)CH 2 OH.
10 . A modified capsular saccharide comprising a moiety of the formula (II):
-A-N(R 1 )-L-C(O)H (II)
wherein A, R 1 and L are as defined in claim 1 .
11 . The modified capsular saccharide of claim 10 wherein A is —OC(O)—.
12 . The modified capsular saccharide of claim 10 comprising a moiety of the formula: —NH(CH 2 ) 3 C(O)H.
13 . The modified capsular saccharide of claim 10 comprising a moiety of the formula: —OC(O)NH(CH 2 ) 3 C(O)H
14 . The modified capsular saccharide of claim 1 wherein the capsular saccharide is Neisseria meningitidis serogroup A saccharide.
15 - 45 . (canceled)