Potent mucosal immune response induced by modified immunomodulatory oligonucleotides
The invention relates to the therapeutic use of immunostimulatory oligonucleotides and/or immunomers on mucosal innate immunity as well as adjuvant activity using ovalbumin (OVA) as an antigen through administration to the mucosal lining.
1 . A method for generating a mucosal immune response in a vertebrate, the method comprising administering an immunomer to the mucosal lining of the vertebrate.
2 . The method according to claim 1 , wherein the immunomer is administered orally.
3 . The method according to claim 1 , wherein the route of administration is selected from the group consisting of intranasal, intratracheal, intrarectal, intravaginal and intragastric administration.
4 . The method according to claim 1 , wherein the vertebrate is selected from the group consisting of fish, birds, and mammals.
5 . The method according to claim 4 , wherein the mammal is selected from the group consisting of rats, mice, cats, dogs, horses, cattle, cows, pigs, rabbits, non-human primates, and humans.
6 . The method according to claim 1 , wherein the immunomer comprises at least two oligonucleotides linked by a non-nucleotidic linker and having more than one 5′ end, wherein at least one of the oligonucleotides is an immunostimulatory oligonucleotide having an accessible 5′ end and comprises an immunostimulatory dinucleotide.
7 . The method according to claim 1 , wherein the immunostimulatory dinucleotide is selected from the group consisting of CpG, C*pG, CpG*, and C*pG*, wherein C is cytidine or 2′-deoxycytidine, C* is 2′-deoxythymidine, arabinocytidine, 1-(2′-deoxy-β-D-ribofuranosyl)-2-oxo-7-deaza-8-methyl-purine, 2′-deoxy-2′-substituted-arabinocytidine, 2′-O-substituted-arabinocytidine, 2′-deoxy-5-hydroxycytidine, 2′-deoxy-N4-alkyl-cytidine, 2′-deoxy-4-thiouridine or other non-natural pyrimidine nucleoside, G is guanosine or 2′-deoxyguanosine, G* is 2′-deoxy-7-deazaguanosine, 2′-deoxy-6-thioguanosine, arabinoguanosine, 2′-deoxyinosine, 2′-deoxy-2′substituted-arabinoguanosine, 2′-O-substituted-arabinoguanosine.
8 . A method for therapeutically treating a vertebrate having a disease or disorder, the method comprising administering an immunomer to the mucosal lining of the vertebrate.
9 . The method according to claim 8 , wherein the immunomer is administered orally.
10 . The method according to claim 8 , wherein the route of administration is selected from the group consisting of intranasal, intratracheal, intrarectal, intravaginal and intragastric administration.
11 . The method according to claim 8 , wherein the vertebrate is selected from the group consisting of fish, birds, and mammals.
12 . The method according to claim 11 , wherein the mammal is selected from the group consisting of rats, mice, cats, dogs, horses, cattle, cows, pigs, rabbits, non-human primates, and humans.
13 . The method according to claim 8 , wherein the immunomer comprises at least two oligonucleotides linked by a non-nucleotidic linker and having more than one 5′ end, wherein at least one of the oligonucleotides is an immunostimulatory oligonucleotide having an accessible 5′ end and comprises an immunostimulatory dinucleotide.
14 . The method according to claim 8 , wherein the immunostimulatory dinucleotide is selected from the group consisting of CpG, C*pG, CpG*, and C*pG*, wherein C is cytidine or 2′-deoxycytidine, C* is 2′-deoxythymidine, arabinocytidine, 1-(2′-deoxy-β-D-ribofuranosyl)-2-oxo-7-deaza-8-methyl- purine, 2′-deoxy-2′-substituted-arabinocytidine, 2′-O-substituted-arabinocytidine, 2′-deoxy-5-hydroxycytidine, 2′-deoxy-N4-alkyl-cytidine, 2′-deoxy-4-thiouridine or other non-natural pyrimidine nucleoside, G is guanosine or 2′-deoxyguanosine, G* is 2′-deoxy-7-deazaguanosine, 2′-deoxy-6-thioguanosine, arabinoguanosine, 2′-deoxyinosine, 2′-deoxy-2′substituted-arabinoguanosine, 2′-O-substituted-arabinoguanosine.
15 . The method according to claim 8 , wherein the disease or disorder is selected from the group consisting of cancer, inflammatory disorders, inflammatory bowel syndrome, ulcerated colitis, Crohn's disease, airway inflammation, asthma and allergy.
16 . The method according to claim 8 , further comprising administering an agent selected from the group consisting of vaccines, allergens, antigens, antibodies, monoclonal antibodies, chemotherapeutic drugs, antibiotics, lipids, DNA vaccines and other adjuvants such as alum.
17 . The method according to claim 16 , further comprising administering an antigen associated with said disease or disorder.
18 . The method according to claim 17 , wherein the immunomer or the antigen, or both, are linked to an immunogenic protein or non-immunogenic protein.
19 . The method according to claim 8 , further comprising administering an adjuvant.
20 . A method for modulating a mucosal immune response in a vertebrate, the method comprising administering an immunomer to the mucosal lining of the vertebrate.
21 . The method according to claim 20 , wherein the immune response is a Th1 immune response.
22 . The method according to claim 20 , wherein the immune response is a Th2 immune response.
23 . The method according to claim 20 , wherein the immunomer is administered orally.
24 . The method according to claim 20 , wherein the route of administration is selected from the group consisting of intranasal, intratracheal, intrarectal, intravaginal and intragastric administration.
25 . The method according to claim 20 , wherein the vertebrate is selected from the group consisting of fish, birds, and mammals.
26 . The method according to claim 25 , wherein the mammal is selected from the group consisting of rats, mice, cats, dogs, horses, cattle, cows, pigs, rabbits, non-human primates, and humans.
27 . The method according to claim 20 , wherein the immunomer comprises at least two oligonucleotides linked by a non-nucleotidic linker and having more than one 5′ end, wherein at least one of the oligonucleotides is an immunostimulatory oligonucleotide having an accessible 5′ end and comprises an immunostimulatory dinucleotide.
30 . The method according to claim 22 , wherein the immunostimulatory dinucleotide is selected from the group consisting of CpG, C*pG, CpG*, and C*pG*, wherein C is cytidine or 2′-deoxycytidine, C* is 2′-deoxythymidine, arabinocytidine, 1-(2′-deoxy-β-D-ribofuranosyl)-2-oxo-7-deaza-8-methyl-purine, 2′-deoxy-2′-substituted-arabinocytidine, 2′-O-substituted-arabinocytidine, 2′-deoxy-5-hydroxycytidine 2′-deoxy-N4-alkyl-cytidine, 2′-deoxy-4-thiouridine or other non-natural pyrimidine nucleoside, G is guanosine or 2′-deoxyguanosine, G* is 2′-deoxy-7-deazaguanosine, 2′-deoxy-6-thioguanosine, arabinoguanosine, 2′-deoxyinosine, 2′-deoxy-2′substituted-arabinoguanosine, 2′-0-substituted-arabinoguanosine.