Human iNKT cell activation using glycolipids with altered glycosyl groups
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IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
A61K-039/39
C07H-015/18
A61K-039/00
출원번호
US-0689165
(2017-08-29)
등록번호
US-10111951
(2018-10-30)
발명자
/ 주소
Wong, Chi-Huey
Yu, Alice L.
Lin, Kun-Hsien
Wu, Tai-Na
출원인 / 주소
ACADEMIA SINICA
대리인 / 주소
Duane Morris LLP
인용정보
피인용 횟수 :
0인용 특허 :
194
초록▼
Glycosphingolipids (GSLs) bearing α-glucose (α-Glc) that preferentially stimulate human invariant NKT (iNKT) cells are provided. GSLs with α-glucose (α-Glc) that exhibit stronger induction in humans (but weaker in mice) of cytokines and chemokines and expansion and/or activation of immune cells than
Glycosphingolipids (GSLs) bearing α-glucose (α-Glc) that preferentially stimulate human invariant NKT (iNKT) cells are provided. GSLs with α-glucose (α-Glc) that exhibit stronger induction in humans (but weaker in mice) of cytokines and chemokines and expansion and/or activation of immune cells than those with α-galactose (α-Gal) are disclosed. GSLs bearing α-glucose (α-Glc) and derivatives of α-Glc with F at the 4 and/or 6 positions are provided. Methods for iNKT-independent induction of chemokines by the GSL with α-Glc and derivatives thereof are disclosed. Methods for immune stimulation in humans using GSLs with α-Glc and derivatives thereof are provided.
대표청구항▼
1. A method for augmenting an immunogenicity of an antigen in a subject in need thereof, comprising co-administering said antigen with an adjuvant composition comprising a compound having a structure of Formula (I): or a pharmaceutically acceptable salt thereof;wherein: R1 is —OH or halogen;R2 is —O
1. A method for augmenting an immunogenicity of an antigen in a subject in need thereof, comprising co-administering said antigen with an adjuvant composition comprising a compound having a structure of Formula (I): or a pharmaceutically acceptable salt thereof;wherein: R1 is —OH or halogen;R2 is —OH or halogen;R3 is hydrogen;R4 is selected from the group consisting of optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted alkoxy, an optionally substituted amino group, and optionally substituted acyl;R5 is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted alkoxy, an optionally substituted amino group, and optionally substituted acyl;n is an integer of 1 to 15, inclusive; andm is an integer of 1 to 20, inclusive. 2. The method of claim 1, wherein the adjuvant composition is a vaccine adjuvant. 3. The method of claim 1, wherein the adjuvant composition is administered in an amount capable of elevating the level of invariant Natural Killer T (iNKT) cells in humans. 4. The method of claim 3, wherein administration of the adjuvant composition increases production of one or more cytokines and/or one or more chemokines in humans. 5. The method of claim 4, wherein the cytokine production is sufficient to transactivate downstream immune cells. 6. The method of claim 5, wherein the downstream immune cells comprise one or more of dendritic cells (DC), natural killer cells (NK), B cells, CD4+ T and CD8+ T cells. 7. The method of claim 4, wherein the cytokines comprise Th1 cytokines. 8. The method of claim 7, wherein the Th1 cytokine is selected from at least one of the group consisting of interferon-gamma (IFN-γ), GM-CSF, TNFα, interleukin 2, interleukin 12 and interleukin10. 9. The method of claim 4, wherein the chemokine is selected from at least one of the group consisting of RANTES, MIP-1α, KC, MCP-1, IP-10 and MIG. 10. The method of claim 1, wherein administration of the composition results in an anti-cancer effect. 11. The method of claim 10, wherein the cancer is selected from the group consisting of lung cancer, breast cancer, hepatoma, leukemia, solid tumor and carcinoma. 12. The method of claim 1, wherein R4 in the compound of Formula I is selected from substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, and wherein increase in Th1 cytokines in humans exceeds any increase in Th2 cytokines. 13. The method of claim 1, wherein R4 in the compound is selected from substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, and wherein the compound is capable of increasing Th1 cytokines in humans with minimum accompanying increase in Th2 cytokines. 14. A method for stimulating an immune response in a human subject in need thereof, the method comprising: administering to the subject a therapeutically effective amount of an immune adjuvant composition in a pharmaceutically acceptable carrier, wherein the composition comprises (i) a pharmaceutically acceptable excipient and (ii) a compound having a structure of Formula (I) or a pharmaceutically acceptable salt thereof;wherein: R1 is —OH or halogen;R2 is —OH or halogen;R3 is hydrogen;R4 is selected from the group consisting of optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted alkoxy, an optionally substituted amino group, and optionally substituted acyl;R5 is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted alkoxy, an optionally substituted amino group, and optionally substituted acyl;n is an integer of 1 to 15, inclusive; andm is an integer of 1 to 20, inclusive. 15. A method for elevating the level of invariant Natural Killer T (iNKT) cells production in a human subject in need thereof, the method comprising: administering to the subject a therapeutically effective amount of a pharmaceutical composition, wherein the composition comprises (i) a pharmaceutically acceptable excipient, and (ii) a compound having a structure of formula (I) or a pharmaceutically acceptable salt thereof;wherein: R1 is —OH or halogen;R2 is —OH or halogen;R3 is hydrogen;R4 is selected from the group consisting of optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted alkoxy, an optionally substituted amino group, and optionally substituted acyl;R5 is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted alkoxy, an optionally substituted amino group, and optionally substituted acyl;n is an integer of 1 to 15, inclusive; andm is an integer of 1 to 20, inclusive. 16. The method of claim 15, wherein the elevation of iNKT levels is greater when compared to the elevation resulting from administration of an equivalent amount of a glycolipid analogue comprising alpha-galactose (αGal) as the glycosyl head group. 17. A method for stimulating production of one or more cytokines and/or one or more chemokines in a human subject in need thereof, the method comprising: administering to the subject a therapeutically effective amount of a pharmaceutical composition, wherein the composition comprises a compound having a structure of Formula (I) in an amount sufficient to increase cytokine and/or chemokine production, wherein Formula (I) has the structure of: or a pharmaceutically acceptable salt thereof;wherein: R1 is —OH or halogen;R2 is —OH or halogen;R3 is hydrogen;R4 is selected from the group consisting of optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted alkoxy, an optionally substituted amino group, and optionally substituted acyl;R5 is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted alkoxy, an optionally substituted amino group, and optionally substituted acyl;n is an integer of 1 to 15, inclusive; andm is an integer of 1 to 20, inclusive. 18. The method of claim 17, wherein the cytokine production is sufficient to transactivate downstream immune cells. 19. The method of claim 18, wherein the downstream immune cells comprise one or more of dendritic cells (DC), natural killer cells (NK), B cells, CD4+ T and CD8+ T cells. 20. The method of claim 17, wherein the cytokines comprise Th1 cytokines. 21. The method of claim 20, wherein the one or more cytokines are selected from the group consisting of interferon-gamma (IFN-γ), GM-CSF, TNFα, interleukin 2, interleukin 12 and interleukin10. 22. The method of claim 17, wherein the one or more chemokines are selected from the group consisting of RANTES, MIP-1α, KC, MCP-1, IP-10 and MIG. 23. A method for augmenting the immune response by an antigen in a subject, the method comprising administering to the subject an effective amount of a vaccine comprising one or more antigens and an immunogenic amount of an adjuvant composition comprising (i) a pharmaceutically acceptable excipient, and (ii) a compound having a structure of Formula (I) or a pharmaceutically acceptable salt thereof,wherein: R1 is —OH or halogen;R2 is —OH or halogen;R3 is hydrogen;R4 is selected from the group consisting of optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted alkoxy, an optionally substituted amino group, and optionally substituted acyl;R5 is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted alkoxy, an optionally substituted amino group, and optionally substituted acyl;n is an integer of 1 to 15, inclusive; andm is an integer of 1 to 20, inclusive. 24. The method of claim 23, wherein the one or more antigens are selected from the group consisting of bacterial antigen, viral antigen, fungal antigen, protozoal antigen, prion antigen, neoantigen, tumor antigen and self-antigen. 25. The method of claim 23, wherein the vaccine is in a form selected from the group consisting of a nucleic acid, protein, peptide, glycoprotein, carbohydrate, fusion protein, lipid, glycolipid, carbohydrate-protein conjugate; cells or extracts thereof; dead or attenuated cells, or extracts thereof; tumor cells or extracts thereof; viral particles; and allergens or mixtures thereof. 26. The method of claim 23, wherein the antigen administered is a tumor antigen. 27. The method of claim 23, wherein said amount of vaccine is administered in the range of 0.1 μg-100 mg per kg of body weight. 28. The method of claim 23, wherein said amount of the adjuvant is in the range of 10-100 μg per kg of body weight. 29. The method of claim 23, wherein the composition co-administered is a co-formulated pharmaceutically acceptable adjuvant composition comprising the compound having Formula (I) and a pharmaceutically acceptable carrier.
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이 특허에 인용된 특허 (194)
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