Use of fluorinated cyclic dinucleotides as oral vaccine adjuvants

Patent metadata

Field	Value
Publication number	US-2016287698-A1
Application number	US-201415038229-A
Country	US
Kind code	A1
Filing date	Nov 18, 2014
Priority date	Nov 22, 2013
Publication date	Oct 6, 2016
Grant date	—

Abstract

Disclosed is the use of fluorinated cyclic dinucleotides and pharmaceutically acceptable salts thereof as an adjuvant for the preparation of an oral vaccine. Further disclosed is the use of fluorinated cyclic dinucleotides and pharmaceutically acceptable salts thereof for enhancing the immune response to an orally administered vaccine.

First claim

1 - 5 . (canceled)

6 . A method for preparing an oral vaccine, comprising admixing one or more non-replicating antigens with an adjuvant, wherein said adjuvant is a fluorinated cyclic dinucleotide having the following structure:
wherein A, C, A′ and C′ are independently selected from NH, O or S; X, Y, X′, and Y′ are independently selected from O or S; Z and Z′ are independently selected from O, S, NH or CH 2 ; and B 1 and B 2 are independently a purine selected from:

wherein Q is hydrogen or NH 2 ; nitrogen is optionally substituted with C 1 -C 6 alkyl or C 1 -C 6 acyl group; and R is O or S.

7 . The method according to claim 6 , wherein the fluorinated cyclic dinucleotide is 2′-F-c-di-GMP having the following structure:

8 . The method according to claim 6 , wherein said oral vaccine is an oral vaccine for the prevention or treatment of a bacterial infection.

9 . The method according to claim 8 , wherein the bacterial infection is a gastrointestinal bacterial infection.

10 . The method according to claim 9 , wherein the gastrointestinal bacterial infection is a H. pylori infection, a C. difficile infection or a Listeria infection.

11 . A method for enhancing an immune response to an orally administered vaccine, comprising:
administering an oral vaccine with an effective amount of an adjuvant comprising a fluorinated cyclic dinucleotide or a pharmaceutically acceptable salt thereof, wherein the fluorinated cyclic dinucleotide has the following structure: wherein A, C, A′ and C′ are independently selected from NH, O or S; X, Y, X′, and Y′ are independently selected from O or S; Z and Z′ are independently selected from O, S, NH or CH 2 ; and B 1 and B 2 are independently a purine selected from:

wherein Q is hydrogen or NH 2 ; nitrogen is optionally substituted with C 1 -C 6 alkyl or C 1 -C 6 acyl group; and R is O or S.

12 . The method according to claim 11 , wherein the fluorinated cyclic dinucleotide is 2′-F-c-di-GMP having the following structure:

13 . The method according to claim 11 , wherein said oral vaccine is an oral vaccine for the prevention or treatment of an infection comprising one or more non-replicating antigens.

14 . The method of according to claim 13 , wherein the infection is a gastrointestinal infection.

15 . The method according to claim 14 , wherein the gastrointestinal infection is a H. pylori infection, a C. difficile infection or a Listeria infection.

16 . The method according to claim 11 , wherein said vaccine and said adjuvant are administered as separate dosage forms.

17 . The method according to claim 11 , wherein said vaccine and said adjuvant are administered as an admixture.

18 . The method according to claim 11 , wherein said immune response comprises an antigen-specific mucosal immune response.

19 . The method of claim 18 , wherein said immune response is characterized by an antigen-specific secretive IgA antibody response at mucosal sites.

20 . The method according to claim 11 , wherein said immune response further comprises an antigen-specific humoral immune response.

21 . The method according to claim 11 , wherein said immune response further comprises an antigen-specific cellular immune response.

22 - 30 . (canceled)

31 . An oral vaccine comprising a fluorinated cyclic dinucleotide or a pharmaceutically acceptable salt thereof and a composition comprising H. pylori antigen, wherein said fluorinated cyclic dinucleotide has the following structure:
wherein A, C, A′ and C′ are independently selected from NH, O or S; X, Y, X′, and Y′ are independently selected from O or S; Z and Z′ are independently selected from O, S, NH or CH 2 ; and B 1 and B 2 are independently a purine selected from:

wherein Q is hydrogen or NH 2 ; nitrogen is optionally substituted with C 1 -C 6 alkyl or C 1 -C 6 acyl group; and R is O or S.

32 . The oral vaccine according to claim 31 , wherein the fluorinated cyclic dinucleotide is 2′-F-c-di-GMP having the following structure:

33 . The oral vaccine according to claim 31 , wherein the composition comprising H. pylori antigen comprises H. pylori cell free extract or one or more H. pylori specific peptides and/or proteins.

Assignees

• Brock Univ
• Nat Res Council Canada

Inventors

• Yan Hongbin
• Chen Wangxue
• Kuo Lee Rhonda

Classifications

• A61P31/04

  Antibacterial agents · CPC title

• A61K2039/6037

  Bacterial toxins, e.g. diphteria toxoid [DT], tetanus toxoid [TT] · CPC title

• A61K39/39 Primary

  characterised by the immunostimulating additives, e.g. chemical adjuvants · CPC title

• A61K2039/542

  oral/gastrointestinal · CPC title

• A61K2039/543

  intranasal · CPC title