Methods of inhibition of protein fucosylation in vivo using fucose analogs

Patent metadata

Field	Value
Publication number	US-11033561-B2
Application number	US-201916452160-A
Country	US
Kind code	B2
Filing date	Jun 25, 2019
Priority date	Aug 5, 2010
Publication date	Jun 15, 2021
Grant date	Jun 15, 2021

Abstract

The invention provides methods and compositions for the inhibition of fucosylation of proteins, including antibodies, in vivo by administration of a fucose analog.

First claim

What is claimed is:

1. A method for the treatment of rheumatoid arthritis in a human in need thereof, comprising administering to the human a therapeutically effective amount of a fucose analog or a biologically acceptable salt thereof, or a composition thereof,
wherein each fucose analog has formulae (III) or (IV):

wherein each fucose analog of formula (III) or (IV) can be the alpha or beta anomer or the corresponding aldose form;
wherein each of R1, R3, and R4 is independently selected from the group consisting of —OH and —OC(O)C 1 -C 10 alkyl, R 2 is F, R 2a and R 3a are each H, and R 5 is —CH 3 .

2. The method of claim 1 , wherein each of R 1 , R 3 , and R 4 is independently selected from the group consisting of —OH and —OAc, R 2 is F, R 2a and R 3a are each H, and R 5 is —CH 3 .

3. The method of claim 1 , wherein the fucose analog is 2-deoxy-2-fluorofucose.

4. The method of claim 1 , wherein the fucose analog is 2-deoxy-2-fluorofucose peracetate.

5. The method of claim 1 , further comprising administering a therapeutic agent for the treatment of rheumatoid arthritis.

6. The method of claim 5 , the therapeutic agent is cyclosporine, cyclosporine A, mycophenylate, mofetil, sirolimus, tacrolimus, enanercept, prednisone, azathioprine, methotrexate, cyclophosphamide, aminocaproic acid, chloroquine, hydroxychloroquine, hydrocortisone, dexamethasone, chlorambucil, DHEA, danazol, bromocriptine, meloxicam or infliximab.

7. The method of claim 1 , wherein administration is oral administration.

8. The method of claim 1 , wherein administration of the therapeutically effective amount is in the form of one or more dosage units.

9. The method of claim 1 , wherein protein fucosylation in the human is reduced by at least 10% relative to the amount of protein fucosylation in the absence of administration of said fucose analog.

10. The method of claim 9 , wherein protein fucosylation in the human is reduced by about 20% relative to the amount of protein fucosylation in the absence of administration of said fucose analog and wherein the mammal is a human.

11. The method of claim 9 , wherein protein fucosylation in the human is reduced by about 30% relative to the amount of protein fucosylation in the absence of administration of said fucose analog.

12. The method of claim 9 , wherein protein fucosylation in the human is reduced by about 40% relative to the amount of protein fucosylation in the absence of administration of said fucose analog.

13. The method of claim 9 , wherein protein fucosylation in the human is reduced by about 50% relative to the amount of protein fucosylation in the absence of administration of said fucose analog.

14. The method of claim 9 , wherein protein fucosylation in the human is reduced by about 60% relative to the amount of protein fucosylation in the absence of administration of said fucose analog.

15. The method of claim 1 , wherein fucosylation of white blood cells in the serum of the human is reduced by at least about 10% relative to the amount of fucosylation of white blood cells in the serum of a mammal in the absence of administration of said fucose analog.

16. The method of claim 15 , wherein fucosylation of white blood cells in the serum of the human is reduced by at least about 20% relative to the amount of fucosylation of white blood cells in the serum of a mammal in the absence of administration of said fucose analog.

17. The method of claim 15 , wherein fucosylation of white blood cells in the serum of the human is reduced by at least about 60% relative to the amount of fucosylation of white blood cells in the serum of a mammal in the absence of administration of said fucose analog.

Assignees

• Seagen Inc

Inventors

• Senter Peter
• Alley Stephen
• Benjamin Dennis

Classifications

• A61K2039/5152

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• A61K31/7024

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• Y02A50/30

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