Modulation of immunostimulatory properties of oligonucleotide-based compounds by utilizing modified immunostimulatory dinucleotides
원문보기
IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
C07H-021/02
C07H-021/04
A01N-043/04
A61K-031/70
출원번호
UP-0757345
(2004-01-14)
등록번호
US-7851453
(2011-02-10)
발명자
/ 주소
Agrawal, Sudhir
Bhagat, Lakshmi
Yu, Dong
Kandimalla, Ekambar R.
출원인 / 주소
Idera Pharmaceuticals, Inc.
대리인 / 주소
Wood, Phillips, Katz, Clark & Mortimer
인용정보
피인용 횟수 :
5인용 특허 :
14
초록▼
The invention relates to the therapeutic use of oligonucleotides as immunostimulatory agents in immunotherapy applications. More particularly, the invention provides immunomers and an immunostimulatory oligonucleotides for use in methods for generating an immune response or for treating a patient in
The invention relates to the therapeutic use of oligonucleotides as immunostimulatory agents in immunotherapy applications. More particularly, the invention provides immunomers and an immunostimulatory oligonucleotides for use in methods for generating an immune response or for treating a patient in need of immunostimulation. The immunomers and an immunostimulatory oligonucleotides of the invention preferably comprise novel purines. The immunomers according to the invention further comprise at least two oligonucleotides linked at their 3′ ends, internucleoside linkages or functionalized nucleobase or sugar to a non-nucleotidic linker, at least one of the oligonucleotides being an immunomodulatory oligonucleotide and having an accessible 5′ end.
대표청구항▼
What is claimed is: 1. An immunomer compound, comprising at least two oligonucleotides linked at their 3′ ends, internucleoside linkages, functionalized nucleobase or sugar to a non-nucleotidic linker, wherein at least one of the oligonucleotides is an oligonucleotide having an accessible 5&
What is claimed is: 1. An immunomer compound, comprising at least two oligonucleotides linked at their 3′ ends, internucleoside linkages, functionalized nucleobase or sugar to a non-nucleotidic linker, wherein at least one of the oligonucleotides is an oligonucleotide having an accessible 5′ end and comprising an immunostimulatory dinucleotide having the structure RpG, wherein R is a nucleotide having 2-oxo-7-deaza-8-methyl-purine as a base and G is a nucleotide having a base selected from the group consisting of guanine, 2-amino-6-oxo-7-deazapurine, 2-amino-6-thiopurine, 6-oxo-purine or other non-natural purine. 2. The immunomer according to claim 1 wherein at least one of the oligonucleotides has structure 5′-Nn-N1-Y—Z—N1-Nn-3′ (III) wherein: Y is 1-(2′-deoxy-β-D-ribofuranosyl)-2-oxo-7-deaza-8-methylpurine; Z is guanosine, 2′-deoxyguanosine, 2′-deoxy-7-deazaguanosine, 2′-deoxy-6-thioguanosine, arabinoguanosine, 2′-deoxy-2′-substituted-arabinoguanosine, 2′-O-substituted-arabino guanosine or other non-natural purine nucleotide, N1 and Nn at each occurrence, is independently a naturally occurring or a synthetic nucleoside or an immunostimulatory moiety selected from the group consisting of abasic nucleotides, arabinonucleotides, 2′-deoxyuridine, α-deoxyribonucleotides, β-L-deoxyribonucleotides, nucleotides linked by a modified internucleotide linkage to the adjacent nucleotide on the 3′ side, nucleotides having 2′-substituted pentose sugar modifications; nucleotides having 3′-substituted pentose sugar modifications; 1′,2′-dideoxyribose; arabinose; substituted arabinose sugars, hexose sugars, and alpha-anomers, peptide nucleic acids (PNA), peptide nucleic acids with phosphate groups (PHONA), locked nucleic acids (LNA), morpholinonucleic acids, oligonucleotides having backbone linker sections having a length of from about 2 angstroms to about 200 angstroms, alkyl linkers or amino linkers, DNA isoforms, β-L-deoxyribonucleotides, α-deoxyribonucleotides, nucleotides having unnatural internucleotide linkage positions, and nucleotides having modified heterocyclic bases; wherein the recited oligonucleotide is directly or indirectly linked to another oligonucleotide, and wherein n is a number from 0-30. 3. The immunomer according to claim 2 wherein the immunostimulatory moiety at each occurrence, is independently selected from the group consisting of abasic nucleotides, arabinonucleotides, 2′-deoxyuridine, α-deoxyribonucleotides, β-L-deoxyribonucleotides, and nucleotides linked by a phosphodiester or modified internucleotide linkage to the adjacent nucleotide on the 3′ side, oligonucleotides having backbone linker sections having a length of from about 2 angstroms to about 200 angstroms. 4. The immunomer according to claim 2 wherein the 2′-substituted pentose sugar is selected from the group consisting of 2′-O-methylribose, 2′-O-methoxyethyl-ribose, 2′-O-propargylribose, and 2′-deoxy-2′-fluororibose. 5. The immunomer according to claim 2 wherein the 3′-substituted pentose sugar is selected from the group consisting of 3′-O-methylribose. 6. The immunomer according to claim 2 wherein the modified internucleotide linkage is selected from the group consisting of C2-C18 alkyl linker, poly(ethylene glycol) linkage, 2-aminobutyl-1,3-propanediol linker, 2′-5′ internucleotide linkage, methylphosphonate internucleotide linkage; methylphosphonothioates, phosphotriesters, phosphothiotriesters, phosphorothioates, phosphorodithioates, triester prodrugs, sulfones, sulfonamides, sulfamates, formacetal, N-methylhydroxylamine, carbonate, carbamate, morpholino, boranophosphonate, phosphoramidates, and stereospecific linkages. 7. The immunomer according to claim 6 wherein the phosphoramidate is selected from the group consisting of primary amino-phosphoramidate, N3 phosphoramidate and N5 phosphoramidate. 8. The immunomer according to claim 1 wherein the G base in the immunostimulatory dinucleotide has the structure (II): wherein: D is a hydrogen bond donor; D′ is selected from the group consisting of hydrogen, hydrogen bond donor, and hydrophilic group; A is a hydrogen bond acceptor or a hydrophilic group; X is carbon or nitrogen; each L is independently an atom selected from the group consisting of C, O, N and S; and S′ is a pentose or hexose sugar ring, or a non-naturally occurring sugar. 9. The immunomer according to claim 8 wherein the sugar ring is derivatized with a phosphate moiety, modified phosphate moiety, or other linker moiety suitable for linking the purine nucleoside to another nucleoside or nucleoside analog. 10. The immunomer according to claim 8 wherein the hydrogen bond donors are selected from the group consisting of —NH—, —NH2, —SH and —OH. 11. The immunomer according to claim 8 wherein the hydrogen bond acceptors are selected from the group consisting of C═O, C═S, —N═ and the ring nitrogen atoms of an aromatic heterocycle. 12. The immunomer according to claim 8 wherein the non-naturally occurring purine is 2-amino-6-thiopurine, 6-oxopurine or 2-amino-6-oxo-7-deazapurine. 13. The immunomer according to claim 1, wherein the non-nucleotidic linker is selected from the group consisting of a linker from about 2 angstroms to about 200 angstroms in length, a metal, a soluble or insoluble biodegradable polymer bead, an organic moiety having functional groups that permit attachment to the 3′-terminal nucleoside of the oligonucleotide, a biomolecule, a cyclic or acyclic small molecule, an aliphatic or aromatic hydrocarbon, either of which optionally can include, either in the linear chain connecting the oligonucleotides or appended to it, one or more functional groups selected from the group consisting of hydroxy, amino, thiol, thioether, ether, amide, thioamide, ester, urea, and thiourea; amino acids, carbohydrates, cyclodextrins, adamantane, cholesterol, haptens antibiotics, glycerol or a glycerol homolog of the formula HO—(CH2)o—CH(OH)—(CH2)p—OH, wherein o and p independently are integers from 1 to about 6, and a derivative of 1,3-diamino-2-hydroxypropane. 14. The immunomer according to claim 1, wherein G is arabinoguanosine or 2′-deoxy-2′-substituted arabinguanosine, 2′-deoxy-7-deazaguanosine or 2′-deoxy-6-thioguanosine, or 2′-deoxyinosine. 15. The immunomer according to claim 1 having the structure 5′-CTGTC1GTTCTC-X-CTCTTGC1TGTC-5′ (5′-SEQ ID NO 177-X-SEQ ID NO 177-5′); wherein X is a glycerol linker and C1 is 1-(2′-deoxy-β-D-ribofuranosyl)-2-oxo-7-deaza-8-methylpurine. 16. The immunomer according to claim 1 having the structure 5′-TC1GTC1GTTCTG-X-GTCTTGC1TGC1T-5′ (SEQ ID NO 181-X-SEQ ID NO 181-5′); wherein X is a glycerol linker and C1 is 1-(2′-deoxy-β-D-ribofuranosyl)-2-oxo-7-deaza-8-methylpurine. 17. The immunomer according to claim 1, wherein the internucleoside linkages comprise phosphorothioate linkages. 18. A composition comprising an immunomer according to claim 1 and a physiologically acceptable carrier. 19. A method for generating an immune response in a vertebrate, the method comprising administering to the vertebrate an immunomer according to claim 1. 20. The method of claim 19 further comprising administering a vaccine. 21. The method of claim 20 further comprising administering an adjuvant. 22. The method of claim 19 further comprising administering an adjuvant.
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이 특허에 인용된 특허 (14)
Agrawal Sudhir ; Habus Ivan ; Kandimalla Ekambar R., Affinity-based purification of oligonucleotides using soluble multimeric oligonucleotides.
Adrian Christopher Simmonds GB; Alan Hamilton GB; Clifford Smith GB; David Loakes GB; Daniel Brown GB; Fergal Hill GB; Shiv Kumar ; Satyam Nampalli ; Mark McDougall, Base analogues.
Froehler Brian (Belmont CA) Matteucci Mark (Burlingame CA), Enhanced triple-helix and double-helix formation with oligomers containing modified purines.
Pederson Thoru (Worcester MA) Agrawal Sudhir (Shrewsbury MA) Mayrand Sandra (Shrewsbury MA) Zamecnik Paul C. (Shrewsbury MA), Method of site-specific alteration of RNA and production of encoded polypeptides.
Pederson Thoru (Worcester MA) Agrawal Sudhir (Shrewsbury MA) Mayrand Sandra (Shrewsbury MA) Zamecnik Paul C. (Shrewsbury MA), Method of site-specific alteration of RNA and production of encoded polypeptides.
Agrawal Sudhir (Shrewsbury MA) Zamecnik Paul C. (Shrewsbury MA), Process for synthesizing oligonucleotides and their analogs adaptable to large scale syntheses.
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