Conjugates of a polypeptide and a pentasaccharide
View Patent ↗The present invention relates to conjugates of a polypeptide and an oligosaccharide, wherein the polypeptide is conjugated to at least one oligosaccharide-spacer residue, the oligosaccharide being a synthetic sulfated oligosaccharide comprising 4-18 monosaccharide units and per se having affinity to antithrombin III and the spacer being a bond or an essentially pharmacologically inactive flexible linking residue, or a pharmaceutically acceptable salt thereof. The conjugates of the invention have improved pharmacokinetic properties when compared to the original polypeptides (i.e. the corresponding non-conjugated polypeptides per se).
1. A conjugate of insulin and an oligosaccharide, wherein the insulin is conjugated to at least one oligosaccharide-spacer residue having the structure (II)
wherein R is independently OSO 3 − or (1-8C)alkoxy, or a pharmacologically inactive flexible linking residue, the charge of OSO 3 − and COO − being compensated by positively charged counter ions, and wherein one pharmacologically inactive flexible linking residue is present, or a pharmaceutically acceptable salt thereof.
2. The conjugate of claim 1 , having a circulating plasma level of ≦50 nM.
3. The conjugate of claim 1 , wherein the oligosaccharide per se has an anticoagulant activity which is of subtherapeutic level when compared to the pharmacological activity of the insulin per se.
4. The conjugate of claim 1 , wherein the oligosaccharide residue has the structure (III)
wherein R is independently OSO 3 − or (1-8C)alkoxy, the charge of OSO 3 − and COO − being compensated by positively charged counterions.
5. The conjugate of claim 4 , wherein the oligosaccharide residue has the structure (IV)
wherein R is independently OCH 3 or OSO 3 − .
6. The conjugate of claim 5 , wherein both R groups in (IV) are OSO 3 − .
7. The conjugate of claim 1 , wherein the insulin is monosubstituted with an oligosaccharide-spacer residue.
8. The conjugate of claim 1 , wherein the pharmacologically inactive flexible linking residue has a length of 10-50 atoms.
9. The conjugate of claim 1 , wherein the pharmacologically inactive flexible linking residue comprises at least one
—(CH 2 CH 2 O)— element.
10. The conjugate of claim 1 , selected from the structures
and wherein Y is selected from structures A, B, C and D
11. The conjugate of claim 10 , wherein Y is selected from structures A and B.
12. A pharmaceutical composition comprising the conjugate of claim 1 and pharmaceutically suitable auxiliaries.
13. The conjugate of claim 1 for use as an anti-diabetic agent.