Carbohydrate ligands that bind to IgM antibodies against myelin-associated glycoprotein

Patent metadata

Field	Value
Publication number	US-11220523-B2
Application number	US-202016848268-A
Country	US
Kind code	B2
Filing date	Apr 14, 2020
Priority date	Mar 13, 2014
Publication date	Jan 11, 2022
Grant date	Jan 11, 2022

Abstract

The invention relates to carbohydrate ligands presenting the minimal Human Natural Killer-1 (HNK-1) epitope that bind to anti-MAG (myelin-associated glycoprotein) IgM antibodies, and their use in diagnosis as well as for the treatment of anti-MAG neuropathy. In particular, the invention relates to disaccharides of formula (I) and (II) wherein Z is optionally substituted phenyl, heteroaryl, arylcarbonyl, or heteroarylmethyl, and to therapeutically acceptable polymers comprising a multitude of substituents of formula (I) and/or formula (II), wherein Z is a bifunctional linker connecting the disaccharides to the polymer backbone.

First claim

The invention claimed is:

1. A method of preparing a HNK-1 polymer comprising a multitude of disaccharide substituents of formula (I):

or a salt thereof, wherein:
the polymer backbone is polylysine having a molecular weight of 30,000 D to 70,000 D;
Z is a linker that is phenyl substituted by —(CH 2 ) 2 NH(C═O)(CH 2 ) 3 S—CH 2 —(C═)—connecting said substituent to lysine sidechains of the polylysine polymer backbone at the C═O function; and
10% to 80% of the lysine sidechains in the polylysine polymer are linked to the disaccharide substituents of formula (I) or a salt thereof and the remaining lysine sidechains in the polylysine polymer are capped with 2,3-dihydroxypropylthioacetyl;

the method comprising:
coupling a sub-stochiometric amount of a compound of formula (Ib):

or a salt thereof, with chloroacetamide groups of a chloroacetylated polylysine polymer under conditions sufficient to produce a coupled polylysine polymer; and
contacting the coupled polylysine polymer with an excess of thioglycerol under conditions sufficient to substantially cap the remaining chloroacetamide groups and produce the HNK-1 polymer.

2. The method of claim 1 , wherein the polylysine polymer is poly-L-lysine polymer.

3. The method of claim 1 , further comprising contacting polylysine with chloroacetic anhydride to prepare the chloroacetylated polylysine polymer.

4. The method of claim 1 , further comprising contacting a compound of formula:

with thiobutyrolactone under conditions sufficient to produce the compound of formula (Ib).

5. The method of claim 1 , wherein the compound of formula (Ib) is of the formula:

6. The method of claim 1 , wherein 30% to 60% of the lysine sidechains in the polylysine polymer are linked to the disaccharide substituents of formula (I) or a salt thereof.

7. The method of claim 1 , wherein the method further comprises isolating and purifying the HNK-1 polymer.

8. A method of preparing a HNK-1 linker compound, the method comprising:
contacting a compound of formula (Ic):

or a salt thereof, with a compound of formula:

under reaction conditions sufficient to produce a compound of formula (Ib):

or a salt thereof.

9. The method of claim 8 , wherein the compound of formula (Ib) is of the formula:

10. The method of claim 8 , wherein the compound of formula (Ic) is of the formula:

11. The method of claim 9 , wherein the contacting step is performed in DMF solvent in the presence of triethylamine.

Assignees

• Univ Basel

Inventors

• Ernst Beat
• Herrendorff Ruben
• Steck Andreas
• Yang Fan

Classifications

• C07H15/207 Primary

  Cyclohexane rings not substituted by nitrogen atoms, e.g. kasugamycins · CPC title

• C08G69/48

  Polymers modified by chemical after-treatment · CPC title

• C08G69/10

  Alpha-amino-carboxylic acids {(polysuccinimides C08G73/1092)} · CPC title

• G01N33/6896

  Neurological disorders, e.g. Alzheimer's disease · CPC title

• A61P25/02

  for peripheral neuropathies · CPC title