Modified saccharides, conjugates thereof, and their manufacture
AssigneeNovartis AG
InventorsAldo Giannozzi, Giovanni Averani, Francesco Norelli, Paolo Costantino
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Abstract
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(R1)-L-M wherein: A is a bond, —C(O)— or —OC(O)—; R1 is selected from H or C1-C6 alkyl; L is a C1-C12 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.
Claims29
A saccharide of the formula:
- wherein:
- T is of the formula (A) or (B):
- n is integer from 1 to 100;
- each Z group is independently selected from —OH, —OAc, —OC(O)N(R1)-L-M or —OC(O)N(R1)-L-C(O)H;
- each Q group is independently selected from —OH, —OAc, —OC(O)N(R1)-L-M or —OC(O)N(R1)-L-C(O)H;
- W is selected from —OH, —OAc, —OC(O)N(R1)-L-M or —OC(O)N(R1)-L-C(O)H;
- V is —N(R1)-L-M or —N(R1)-L-C(O)H;
- wherein R1 is selected from H or C1-C6 alkyl, L is a C1-C12 alkylene group and M is a masked aldehyde group, and provided that the saccharide comprises at least one moiety of the formula —N(R1)-L-M, —N(R1)-L-C(O)H, —OC(O)N(R1)-L-M or —OC(O)N(R1)-L-C(O)H.
A process for modifying a capsular saccharide comprising the steps of:
- (a) providing a capsular saccharide having a hydroxyl group;
- (b) reacting the hydroxyl group with a bifunctional reagent in an organic solvent;
- (c) reacting the product of step (b) with an amino compound of formula (III):
- HN(R1)-L-M (III)
- wherein R1 is selected from H or C1-C6 alkyl, L is a C1-C12 alkylene group and M is a masked aldehyde group.
A process for modifying a Neisseria meningitidis serogroup A saccharide comprising the steps of:
- (a) providing a Neisseria meningitidis serogroup A saccharide;
- (b) reacting a hydroxyl group on the saccharide with CDI in DMSO solvent;
- (c) reacting the product of step (b) with H2N(CH2)3CH(OH)CH2OH;
- (d) cleaving the product of step (c) with periodate, thereby providing an aldehyde compound;
- and
- (e) linking the aldehyde compound of step (d) to a protein by a reductive amination reaction using NaBH3CN.
A saccharide-protein conjugate wherein the saccharide and protein moieties are linked via a group of formula (IV):
- A-N(R1)-L-NH— (IV)
- wherein A is a bond, —C(O)— or —OC(O)—;
- R1 is selected from H or C1-C6 alkyl;
- and L is a C1-C12 alkylene group.
Dependencies are inferred from the claim text.