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

Patent metadata

Field	Value
Publication number	US-9994605-B2
Application number	US-201515124913-A
Country	US
Kind code	B2
Filing date	Mar 12, 2015
Priority date	Mar 13, 2014
Publication date	Jun 12, 2018
Grant date	Jun 12, 2018

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 compound of formula (I)

or of formula (II)

wherein Z is optionally substituted phenyl, heteroaryl, arylcarbonyl, or heteroarylmethyl.

2. The compound of claim 1 of formula (I) or (II) wherein Z is unsubstituted or substituted phenyl.

3. The compound of claim 2 of formula (I) or (II) wherein Z is p-methoxyphenyl.

4. The compound of claim 2 of formula (I) wherein Z is p-methoxyphenyl.

5. The compound of claim 2 of formula (II) wherein Z is p-methoxyphenyl.

6. A polymer comprising a multitude of substituents of formula (I) and/or formula (II),

wherein Z is a linker connecting said substituent to the polymer backbone.

7. The polymer according to claim 6 wherein the polymer backbone is an α-amino acid polymer, an acrylic acid or methacrylic acid polymer or copolymer, or a N-vinyl-2-pyrrolidone-vinyl alcohol copolymer.

8. The polymer according to claim 6 wherein the polymer backbone is an α-amino acid polymer, wherein the α-amino acid is lysine, glutamic acid or aspartic acid.

9. The polymer according to claim 6 wherein the polymer backbone is poly-lysine.

10. The polymer according to claim 7 wherein the molecular weight of the polymer backbone is 1,000 D to 300,000 D.

11. The polymer according to claim 6 , wherein the linker Z is aryl, heteroaryl, aryl-lower alkyl, arylcarbonyl, or heteroarylmethyl, wherein aryl or heteroaryl is substituted by alkylene with 3 to 25 carbon atoms connecting to the polymer wherein optionally
(a) one or more carbon atoms of alkylene are replaced by nitrogen carrying a hydrogen atom, and one of the adjacent carbon atoms is substituted by oxo, representing an amide function —NH—CO—; and/or
(b) one or more carbon atoms of alkylene are replaced by oxygen;
(c) one or more carbon atoms of alkylene are replaced by sulphur; and/or
(d1) the terminal carbon atom connecting to the polymer is substituted by oxo; or
(d2) the terminal carbon atom connecting to the polymer is replaced —NH—.

12. The polymer according to claim 6 , wherein the relative molecular weight of polymer backbone to disaccharide of formula (I) and/or (II) is between 10:1 and 1:1.5.

13. A pharmaceutical composition comprising a compound of formula (I) or (II) according to claim 1 .

14. A diagnostic kit comprising a compound of formula (I) or (II) according to claim 1 .

15. A method of treatment of anti-MAG neuropathy, which comprises administering a compound of formula (I) or (II) according to claim 1 in a quantity effective against said disease, to a warm-blooded animal requiring such treatment.

16. A method of detecting an autoantibody against the Human Natural Killer-1 (HNK-1) epitope in a sample, comprising
(i) contacting a compound of formula (I) or (II) according to claim 1 with said sample, wherein said sample is a body fluid; and
(ii) detecting binding of said autoantibody and said compound of formula (I) or (II).

17. A method of diagnosis of anti-MAG neuropathy of a patient, which comprises
(i) providing a body fluid sample of said patient;
(ii) subjecting a compound of formula (I) or (II) according to claim 1 to said body fluid sample for binding of said compound to IgM autoantibodies against the Human Natural Killer-1 (HNK-1) epitope comprised in said body fluid sample; and
(iii) determining said binding.

18. A pharmaceutical composition comprising a polymer according to claim 6 .

19. A diagnostic kit comprising a polymer according to claim 6 .

20. A method of detecting an autoantibody against the Human Natural Killer-1 (HNK-1) epitope in a sample, comprising
(i) contacting a polymer according to claim 6 with said sample, wherein said sample is a body fluid; and
(ii) detecting binding of autoantibody with said polymer of claim 6 .

21. A method of diagnosis of anti-MAG neuropathy of a patient, which comprises
(i) providing a body fluid sample of said patient;
(ii) subjecting a polymer according to claim 6 to said body fluid sample for binding of said polymer to IgM autoantibodies against the Human Natural Killer-1 (HNK-1) epitope comprised in said body fluid sample; and
(iii) determining said binding.

22. A method of treatment of anti-MAG neuropathy, which comprises administering a polymer according to claim 6 in a quantity effective against said disease, to a warm-blooded animal requiring such treatment.

23. The polymer according to claim 9 , wherein said linker Z is phenyl substituted by —(CH 2 ) 2 NH(C═O)(CH 2 ) 3 S—CH 2 —(C═O)— connecting at the C═O function said substituent to the aminoalkyl side chains of said poly-lysine.

24. The polymer according to claim 23 , wherein said polymer is poly-L-lysine.

25. The polymer according to claim 24 , wherein said substituents are substituents of formula (I).

Assignees

• Univ Basel

Inventors

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

Classifications

• A61P37/02

  Immunomodulators · CPC title

• A61P25/02

  for peripheral neuropathies · CPC title

• C08G69/10

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

• C08F2/00

  Processes of polymerisation · CPC title

• C08G69/48

  Polymers modified by chemical after-treatment · CPC title