Oligosaccharide-protein conjugates

Patent metadata

Field	Value
Publication number	US-9493498-B2
Application number	US-201414445941-A
Country	US
Kind code	B2
Filing date	Jul 29, 2014
Priority date	Dec 16, 2008
Publication date	Nov 15, 2016
Grant date	Nov 15, 2016

Abstract

Provided herein are conjugates comprising a protein and an oligosaccharide of one of Formulae I-VI. Also provided herein are pharmaceutical compositions comprising such conjugates. Further provided herein are methods of treating a lysosomal storage disorder in a mammal by administration of an oligosaccharide-glycoprotein conjugate.

First claim

The invention claimed is:

1. A method of preparing an oligosaccharide comprising a linker comprising an aminooxy group, the method comprising:
a) treating a compound having the Formula VIII:

wherein:
R 1 is selected from the group consisting of hydrogen, hydroxyl, optionally substituted lower alkyl, phosphate, sulfate, —OR 7 , and a protecting group;
R 2 , R 3 , R 4 , and R 5 are each independently selected from the group consisting of hydrogen, sulfate, hydroxyl, —OR 8 , and a protecting group;
R 7 and R 8 are each independently selected from the group consisting of acetyl and optionally substituted lower alkyl; and
R 9 and R 10 are selected from the group consisting of hydrogen and hydroxyl, such that when one of R 9 and R 10 is hydroxyl, the other is hydrogen;
with a compound having the Formula R 11 R 12 (Sn═O) to form a compound having the Formula IX:

wherein:
R 1 is selected from the group consisting of hydrogen, hydroxyl, optionally substituted lower alkyl, phosphate, sulfate, —OR 7 , and a protecting group;
R 2 , R 3 , R 4 , and R 5 are each independently selected from the group consisting of hydrogen, sulfate, hydroxyl, —OR 8 , and a protecting group;
R 7 and R 8 are each independently selected from the group consisting of acetyl and optionally substituted lower alkyl; and
R 11 and R 12 are each independently an unsubstituted alkyl, or R 11 and R 12 , taken together, are unsubstituted alkylene; and
b) treating the compound of Formula IX, optionally in the presence of a metal halide, with a compound having the Formula R 6 —(CH 2 ) n -L,

wherein:
R 6 is selected from the group consisting of hydroxyl, carboxyl, alkoxycarbonyl, amino, amide, alkylamino, aminoalkyl, aminoxy, hydrazide, hydrazine, optionally substituted alkenyl, and optionally substituted C 2 -C 6 alkyl;
n is an integer from 1 to 10; and
L is a halogen; to form the compound of Formula VII:

wherein:
R 1 is selected from the group consisting of hydrogen, hydroxyl, optionally substituted lower alkyl, phosphate, sulfate, —OR 7 , and a protecting group;
R 2 , R 3 , R 4 , and R 5 are each independently selected from the group consisting of hydrogen, sulfate, hydroxyl, —OR 8 , and a protecting group;
R 6 is selected from the group consisting of hydroxyl, carboxyl, alkoxycarbonyl, amino, amide, alkylamino, aminoalkyl, aminoxy, hydrazide, hydrazine, optionally substituted alkenyl, and optionally substituted C 2 -C 6 alkyl;
R 7 and R 8 are each independently selected from the group consisting of acetyl and optionally substituted lower alkyl; and
n is an integer from 1 to 10;
c) treating the compound of Formula VII with at least one optionally protected monosaccharide to form an oligosaccharide, wherein the monosaccharide is added to any of R 1 , R 2 , R 3 , R 4 , or R 5 ; and
d) attaching a linker comprising an aminooxy group to the oligosaccharide, wherein the linker comprising an aminooxy group is attached to R 6 .

2. The method of claim 1 , wherein the compound of Formula R 6 —(CH 2 ) n -L is methyl 4-bromobutyrate.

3. The method of claim 2 , wherein the compound of Formula VIII is selected from optionally protected mannose, rhamnose, idose, talose and altrose.

4. The method of claim 3 , wherein the compound of Formula VIII is optionally protected mannose.

5. The method of claim 1 , wherein the metal halide is selected from cesium fluoride, sodium fluoride, calcium fluoride, magnesium fluoride, lithium fluoride, and potassium fluoride.

6. The method of claim 1 , wherein step b further comprises reacting the compound of Formula IX in the presence of a tetraalkylammonium halide.

7. The method of claim 6 , wherein the tetraalkylammonium halide is tetrabutylammonium iodide.

8. The method of claim 1 , wherein R 11 and R 12 are each butyl, R 11 and R 12 are each hexyl, or R 11 and R 12 , taken together, form hexamethylene.

9. The method of claim 1 , wherein the compound of Formula VIII is optionally protected mannose, and the compound of Formula R 6 —(CH 2 ) n -L is methyl 4-bromobutyrate.

10. The method of claim 9 , wherein the compound of Formula VIII is selected from 3,4,6-tri-O-benzyl-α-D-mannose and 3-O-allyl-6-O-trityl-α-D-mannose.

11. The method of claim 10 , wherein the compound of Formula VIII is 3-O-allyl-6-O-trityl-α-D-mannose.

12. The method of claim 1 , wherein the oligosaccharide is a hexasaccharide.

13. The method of claim 12 , wherein the hexasaccharide is

14. The method of claim 1 , wherein the oligosaccharide comprising a linker comprising an aminooxy group is

Assignees

• Genzyme Corp

Inventors

• Avila Luis Z
• Pan Clark Q
• Finn Patrick
• Harrahy John
• Zhou Qun
• Zhu Yunxiang
• Konowicz Paul A
• Paterson Duncan E
• Peer Andreas
• Kutzko Joseph P
• Reardon Michael R
• Stefano James E
• Zheng Xiaoyang
• Miller Robert J
• Young Lauren

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P3/00

  Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) · CPC title

• C07H15/04 Primary

  attached to an oxygen atom of the saccharide radical · CPC title

• A61K38/46 Primary

  Hydrolases (3) · CPC title

• A61K47/61

  the organic macromolecular compound being a polysaccharide or a derivative thereof · CPC title