Enhancement of natural killer (NK) cell proliferation and activity
원문보기
IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
A01N-063/00
C12N-005/0783
A61K-035/17
C12N-015/85
출원번호
US-0946266
(2013-07-19)
등록번호
US-9175266
(2015-11-03)
발명자
/ 주소
Peled, Tony
Frei, Gabi M.
출원인 / 주소
Gamida Cell Ltd.
대리인 / 주소
Cooley LLP
인용정보
피인용 횟수 :
1인용 특허 :
175
초록▼
Methods of ex-vivo culture of natural killer (NK) cells are provided and, more particularly, methods for enhancing propagation and/or functionality of NK cells by treating the cells with an aryl hydrocarbon antagonist in combination with cytokines driving NK cell proliferation. Also envisioned are c
Methods of ex-vivo culture of natural killer (NK) cells are provided and, more particularly, methods for enhancing propagation and/or functionality of NK cells by treating the cells with an aryl hydrocarbon antagonist in combination with cytokines driving NK cell proliferation. Also envisioned are compositions comprising cultured NK cells and therapeutic uses thereof.
대표청구항▼
1. A method of ex-vivo culturing natural killer (NK) cells, the method comprising culturing a population of cells comprising NK cells with an aryl hydrocarbon receptor (AHR) antagonist, wherein said AHR antagonist is represented by Formula I: wherein:G1 is selected from N and CR3;R3 is selected from
1. A method of ex-vivo culturing natural killer (NK) cells, the method comprising culturing a population of cells comprising NK cells with an aryl hydrocarbon receptor (AHR) antagonist, wherein said AHR antagonist is represented by Formula I: wherein:G1 is selected from N and CR3;R3 is selected from hydrogen, C1-4alkyl and biphenyl;G2, G3 and G4 are each independently selected from —CH— and N; with the proviso that at least one of G3 and G4 is N; and with the proviso that G1 and G2 are not both N;L is selected from a substituted or unsubstituted alkylamino, a substituted or unsubstituted amino or a substituted or unsubstituted alkyl;R1 is selected from hydrogen, a substituted or unsubstituted aryl and a substituted or unsubstituted heteroaryl; with the proviso that R1 and R3 are not both hydrogen;R2 is selected from —S(O)2NR6aR6b, —NR9aC(O)R9b, —NR6aC(O)NR6bR6c, a substituted or unsubstituted aryl and a substituted or unsubstituted heteroaryl; andR4 is selected from a substituted or unsubstituted C1-10alkyl, a substituted or unsubstituted C1-10alkenyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted alkaryl, a substituted or unsubstituted heteroalicyclic and a substituted or unsubstituted heteroaryl. 2. The method of claim 1, wherein said culturing is of said population of cells with said AHR antagonist and at least one growth factor. 3. The method of claim 1, wherein a concentration of said AHR antagonist ranges from 1 to 100000 nM. 4. The method of claim 1, wherein said culturing is effected for a time period that ranges from 3 days to 6 weeks. 5. The method of claim 1, wherein culturing said NK cells with said AHR antagonist results in at least one of the following: (a) elevated expression of CD62L as compared to NK cells cultured under otherwise identical culturing conditions without added AHR antagonist;(b) reduced expression of CD200R or PD-1 or both as compared to NK cells cultured under otherwise identical culturing conditions without added AHR antagonist;(c) elevated homing and in-vivo retention as compared to NK cells cultured under otherwise identical culturing conditions without added AHR antagonist; and(d) greater proliferation as compared to NK cells cultured under otherwise identical culturing conditions without added AHR antagonist. 6. The method of claim 2, wherein said at least one growth factor is IL-2, said exposure time is from seeding of said population of cells comprising NK cells, said exposure duration is from 2 to 3 weeks and said concentration of said AHR antagonist is 250 to 1000 nM. 7. The method of claim 1, wherein said population of cells comprising said NK cells is obtained from a source selected from the group consisting of cord blood, bone marrow and peripheral blood. 8. The method of claim 1, wherein said population of cells comprising said NK cells is a heterogenous cell population which comprises an NK cell fraction and a CD3+ cell fraction. 9. The method of claim 8, wherein said population of cells comprising said NK cells is a mononuclear or total nuclear cell population depleted of CD3+ cells. 10. The method of claim 1, wherein said population of cells comprising said NK cells is an unselected NK cell population. 11. The method of claim 1, wherein said culturing said population of cells comprising said NK cells is effected without a feeder layer or feeder cells. 12. The method of claim 2, wherein said at least one growth factor comprises a growth factor selected from the group consisting of SCF, FLT3, IL-2, IL-7, IL-15, IL-12 and IL-21. 13. The method of claim 1, wherein said AHR antagonist is 4-(2-(2-(benzo[b]thiophen-3-yl)-9-isopropyl-9H-purin-6-ylamino)ethyl) phenol (Stem Reginin 1). 14. The method of claim 1, wherein said AHR antagonist is selected from: 4-(2-(2-(benzo[b]thiophen-3-yl)-9-isopropyl-9H-purin-6-ylamino)ethyl)phenol;4-(2-(2-(benzo[b]thiophen-3-yl)-9-sec-butyl-9H-purin-6-ylamino)ethyl)phenol;4-(2-(9-benzhydryl-2-(benzo[b]thiophen-3-yl)-9H-purin-6-ylamino)ethyl)phenol;4-(2-(2-(benzo[b]thiophen-3-yl)-9-(tetrahydro-2H-pyran-3-yl)-9H-purin-6-ylamino)ethyl)phenol;4-(2-(9-isopropyl-2-(thiophen-2-yl)-9H-purin-6-ylamino)ethyl)phenol;4-(2-(2-(benzo[b]thiophen-3-yl)-9-(4-(trifluoromethyl)benzyl)-9H-purin-6-ylamino)ethyl)phenol;4-(2-(2-(benzo[b]thiophen-3-yl)-9-isobutyl-9H-purin-6-ylamino)ethyl)phenol;4-(2-(2-(benzo[b]thiophen-3-yl)-9-methyl-9H-purin-6-ylamino)ethyl)phenol;4-(2-(2-(benzo[b]thiophen-3-yl)-9-(4-methylbenzyl)-9H-purin-6-ylamino)ethyl)phenol;N-(2-(1H-indol-3-yl)ethyl)-2-(benzo[b]thiophen-3-yl)-9-isopropyl-9H-purin-6-amine;2-(benzo[b]thiophen-3-yl)-9-isopropyl-N-(2-(thiophen-3-yl)ethyl)-9H-purin-6-amine;3-(2-(2-(benzo[1)]thiophen-3-yl)-9-isopropyl-9H-purin-6-ylamino)ethyl)phenol;2-(benzo[b]thiophen-3-yl)-N-(4-fluorophenethyl)-9-isopropyl-9H-purin-6-amine;N-(4-aminophenethyl)-2-(benzo[b]thiophen-3-yl)-9-isopropyl-9H-purin-6-amine;4-(2-(9-isopropyl-2-(pyrimidin-5-yl)-9H-purin-6-ylamino)ethyl)phenol;4-(2-(9-isopropyl-2-(pyridin-3-yl)-9H-purin-6-ylamino)ethyl)phenol;4-(2-(9-isopropyl-2-phenyl-9H-purin-6-ylamino)ethyl)phenol;4-(2-(9-isopropyl-2-(thiophen-3-yl)-9H-purin-6-ylamino)ethyl)phenol;4-(2-(2-(furan-3-yl)-9-isopropyl-9H-purin-6-ylamino)ethyl)phenol;2-(benzo[b]thiophen-3-yl)-N-(4-fluorophenethyl)-9-phenyl-9H-purin-6-amine;N-benzyl-8-(biphenyl-4-yl)-9-isopropyl-9H-purin-6-amine;4-(2-(2-(benzo[b]thiophen-3-yl)-9-(nonan-2-yl)-9H-purin-6-ylamino)ethyl)phenol;N-(2-(1H-indol-3-yl)ethyl)-2-(benzo[b]thiophen-3-yl)-9-sec-butyl-9H-purin-6-amine;3-(2-(2-(benzo[b]thiophen-3-yl)-9-isopropyl-9H-purin-6-ylamino)ethyl)-1H-indol-5-yl, 5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanoate;N-(2-(2-(2-(2-(4-(1-(2-(benzo[b]thiophen-3-yl)-6-(4-hydroxyphenethylamino)-9H-purin-9-yl)ethyl)-1H-1,2,3-triazol-1-yl)ethoxy)ethoxy)ethoxy)ethyl)acetamide;4-(2-(9-isopropyl-2-(pyridin-4-yl)-9H-purin-6-ylamino)ethyl)phenol;ethyl 5-(6-(4-hydroxyphenethylamino)-9-isopropyl-9H-purin-2-yl)nicotinate;ethyl 5-(6-(4-hydroxyphenethylamino)-9-isopropyl-9H-purin-2-yl)nicotinate;4-(2-(2-(6-fluoropyridin-3-yl)-9-isopropyl-9H-purin-6-ylamino)ethyl)phenol;4-(2-(9-isopropyl-2-(4-methylpyridin-3-yl)-9H-purin-6-ylamino)ethyl)phenol;5-(6-(4-hydroxyphenethylamino)-9-isopropyl-9H-purin-2-yl)nicotinonitrile;4-(2-(9-isopropyl-2-(pyrrolidin-1-yl)-9H-purin-6-ylamino)ethyl)phenol;4-(2-(2-(1H-imidazol-1-yl)-9-isopropyl-9H-purin-6-ylamino)ethyl)phenol;4-(2-(9-isopropyl-2-(pyridazin-4-yl)-9H-purin-6-ylamino)ethyl)phenol;4-(2-(9-isopropyl-2-(pyrazin-2-yl)-9H-purin-6-ylamino)ethyl)phenol;4-(2-(9-isopropyl-2-(pyridin-2-yl)-9H-purin-6-ylamino)ethyl)phenol;4-(2-(9-isopropyl-2-(5-(methylsulfonyl)pyridin-3-yl)-9H-purin-6-ylamino)ethyl)phenol;4-(2-(9-isopropyl-2-(5-methylpyridin-3-yl)-9H-purin-6-ylamino)ethyl)phenol;4-(2-(2-(4-chloropyridin-3-yl)-9-isopropyl-9H-purin-6-ylamino)ethyl)phenol;4-(2-(2-(5-fluoropyridin-3-yl)-9-isopropyl-9H-purin-6-ylamino)ethyl)phenol;4-(2-(9-isopropyl-2-(1-methyl-1H-pyrazol-4-yl)-9H-purin-6-ylamino)ethyl)phenol;4-(2-(9-isopropyl-2-(pyridin-3-yl)-9H-purin-6-ylamino)ethyl)-2-methoxy phenol;4-(2-(9-isopropyl-2-(pyridin-3-yl)-9H-purin-6-ylamino)ethyl)-2-methoxy phenol;N-[2-(6-methoxy-1H-indol-3-yl)ethyl]-9-(propan-2-yl)-2-(pyridin-3-yl)-9H-purin-6-amine;N-[2-(5-methyl-1H-indol-3-yl)ethyl]-9-(propan-2-yl)-2-(pyridin-3-yl)-9H-purin-6-amine;1-(2-{[9-(propan-2-yl)-2-(pyridin-3-yl)-9H-purin-6-yl]amino}ethyl)imidazolidin-2-one;N-(2-{[9-(propan-2-yl)-2-(pyridin-3-yl)-9H-purin-6-yl]amino}ethyl)pyridin-2-amine;9-(propan-2-yl)-N-[3-(1H-pyrazol-4-yl)propyl]-2-(pyridin-3-yl)-9-H-purin-6-amine;N-{2-[(3-methyl-1H-1,2,4-triazol-5-yl)sulfanyl]ethyl}-9-(propan-2-yl)-2-(pyridin-3-yl)-9H-purin-6-amine;1-(2-{[2-(1-benzothiophen-3-yl)-9-(propan-2-yl)-9H-purin-6-yl]amino}ethyl)imidazolidin-2-one;N-[2-(5-amino-1H-1,2,4-triazol-3-yl)ethyl]-2-(1-benzothiophen-3-yl)-9-(propan-2-yl)-9H-purin-6-amine;N-(2-{[2-(1-benzothiophen-3-yl)-9-(propan-2-yl)-9H-purin-6-yl]amino}ethyl)pyridin-2-amine;2-(1-benzothiophen-3-yl)-9-(propan-2-yl)-N-[3-(1H-pyrazol-4-yl)propyl]-9H-purin-6-amine;2-(1-benzothiophen-3-yl)-N-[3-(3,5-dimethyl-1H-pyrazol-4-yl)propyl]-9-(propan-2-yl)-9H-purin-6-amine;(2-{[2-(1-benzothiophen-3-yl)-9-(propan-2-yl)-9H-purin-6-yl]amino}ethyl)urea;5-({[2-(1-benzothiophen-3-yl)-9-(propan-2-yl)-9H-purin-6-yl]amino}methyl)-2,3-dihydro-1H-1,3-benzodiazol-2-one;N-[2-(1H-indol-3-yl)ethyl]-9-(propan-2-yl)-2-(pyridin-3-yl)-9H-purin-6-amine;N-(4-(2-(9-isopropyl-2-(pyridin-3-yl)-9H-purin-6-ylamino)ethyl)phenyl)methane-sulfonamide;4-(2-(2-(pyridin-3-yl)-9-(tetrahydrofuran-3-yl)-9H-purin-6-ylamino)ethyl)-phenol;4-(2-(9-isopropyl-2-(pyridin-3-yl)-9H-purin-6-ylamino)propyl)phenol;4-(2-(9-(oxetan-3-yl)-2-(pyridin-3-yl)-9H-purin-6-ylamino)ethyl)phenol;5-(6-(4-hydroxyphenethylamino)-9-isopropyl-9H-purin-2-yl)-N-methylnicotin-amide;4-(2-(9-(1-hydroxypropan-2-yl)-2-(pyridin-3-yl)-9H-purin-6-ylamino)-ethyl)phenol;4-(2-(9-isopropyl-2-(pyridin-3-yl)-9H-purin-6-ylamino)ethyl)phenyl sulfamate;4-(2-(2-(2-fluoropyridin-3-yl)-9-isopropyl-9H-purin-6-ylamino)ethyl)phenol;4-(2-(9-isopropyl-2-(1-methyl-1H-pyrrol-2-yl)-9H-purin-6-ylamino)ethyl)-phenol;4-(2-(9-isopropyl-2-(thiazol-5-yl)-9H-purin-6-ylamino)ethyl)phenol;4-(2-(2-(1H-benzo[d]imidazol-1-yl)-9-isopropyl-9H-purin-6-ylamino)ethyl)-phenol;4-(2-(2-(2,4-dimethyl-1H-imidazol-1-yl)-9-isopropyl-9H-purin-6-ylamino)ethyl)phenol;4-(2-(9-isopropyl-2-(2-methyl-1H-imidazol-1-yl)-9H-purin-6-ylamino)ethyl)-phenol;5-(9-sec-butyl-6-(4-hydroxy-3-methylphenethylamino)-9H-purin-2-yl)-nicotinonitrile;N-(2-(1H-pyrrolo[2,3-b]pyridin-5-yl)ethyl)-9-isopropyl-2-(pyridin-3-yl)-9-H-purin-6-amine;9-isopropyl-N-(2-(5-methyl-1H-pyrazol-3-yl)ethyl)-2-(pyridin-3-yl)-9H-purin-6-amine;4-(2-(2-(5-fluoropyridin-3-yl)-9-(oxetan-3-yl)-9H-purin-6-ylamino)ethyl)phenol;4-(2-(2-(5-chloropyridin-3-yl)-9-isopropyl-9H-purin-6-ylamino)ethyl)phenol;4-(2-(9-isopropyl-2-(5-(trifluoromethyl)pyridin-3-yl)-9H-purin-6-ylamino)ethyl)phenol;5-(6-(2-(1H-indol-3-yl)ethylamino)-9-sec-butyl-9H-purin-2-yl)nicotinonitrile;N-(2-(1H-indol-3-yl)ethyl)-9-sec-butyl-2-(5-methylpyridin-3-yl)-9H-purin-6-amine;(R)—N-(2-(1H-indol-3-yl)ethyl)-9-sec-butyl-2-(5-fluoropyridin-3-yl)-9H-purin-6-amine;(S)—N-(2-(1H-indol-3-yl)ethyl)-9-sec-butyl-2-(5-fluoropyridin-3-yl)-9H-purin-6-amine;N-(2-(1H-indol-3-yl)ethyl)-9-sec-butyl-2-(5-fluoropyridin-3-yl)-9H-purin-6-amine;(R)—N-(2-(1H-indol-3-yl)ethyl)-9-sec-butyl-2-(5-methylpyridin-3-yl)-9H-purin-6-amine;(S)—N-(2-(1H-indol-3-yl)ethyl)-9-sec-butyl-2-(5-methylpyridin-3-yl)-9H-purin-6-amine;5-(6-(4-hydroxyphenethylamino)-9-(oxetan-3-yl)-9H-purin-2-yl)nicotinonitrile;4-(2-(6-(5-fluoropyridin-3-yl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)ethyl)phenol;4-(2-(6-(benzo[b]thiophen-3-yl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)ethyl)phenol;(R)-4-(2-(2-(5-fluoropyridin-3-yl)-9-(tetrahydrofuran-3-yl)-9H-purin-6-yl-amino)ethyl)phenol;4-(2-(9-isopropyl-2-(pyridin-3-yl)-9H-purin-6-ylamino)ethyl)-3-methylphenol;5-(6-(4-hydroxyphenethylamino)-9-isopropyl-9H-purin-2-yl)picolinonitrile;3-(6-(4-hydroxyphenethylamino)-9-isopropyl-9H-purin-2-yl)isonicotinonitrile;4-(2-(2-(5-fluoropyridin-3-yl)-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)ethyl)phenol;3-(6-(4-hydroxyphenethylamino)-9-isopropyl-9H-purin-2-yl)picolinonitrile;4-(2-(9-isopropyl-2-(6-methylpyridin-3-yl)-9H-purin-6-ylamino)ethyl)phenol;4-(2-(9-isopropyl-2-(isoquinolin-4-yl)-9H-purin-6-ylamino)ethyl)phenol;2-chloro-4-(2-(9-isopropyl-2-(pyridin-3-yl)-9H-purin-6-ylamino)ethyl)phenol;3-fluoro-4-(2-(9-isopropyl-2-(pyridin-3-yl)-9H-purin-6-ylamino)ethyl)phenol;N-(2-(5-chloro-1H-indol-3-yl)ethyl)-9-isopropyl-2-(pyridin-3-yl)-9H-purin-6-amine;N-(2-(5-fluoro-1H-indol-3-yl)ethyl)-9-isopropyl-2-(pyridin-3-yl)-9H-purin-6-amine;4-(2-(9-isopropyl-2-(pyridin-3-yl)-9H-purin-6-ylamino)ethyl)-2-methylphenol;4-(2-(2-(benzo[b]thiophen-3-yl)-9-(oxetan-3-yl)-9H-purin-6-ylamino)ethyl)-phenol;(S)-4-(2-(2-(benzo[b]thiophen-3-yl)-9-(tetrahydrofuran-3-yl)-9H-purin-6-ylamino)ethyl)phenol;(R)-4-(2-(2-(benzo[b]thiophen-3-yl)-9-(tetrahydrofuran-3-yl)-9H-purin-6-ylamino)ethyl)phenol;2-(6-(2-(1H-indol-3-yl)ethylamino)-2-(5-fluoropyridin-3-yl)-9H-purin-9-yl)propan-1-ol;(R)-2-(6-(2-(1H-indol-3-yl)ethylamino)-2-(5-fluoropyridin-3-yl)-9H-purin-9-yl)propan-1-ol;(S)-2-(6-(2-(1H-indol-3-yl)ethylamino)-2-(5-fluoropyridin-3-yl)-9H-purin-9-yl)propan-1-ol;(R)—N-(2-(1H-indol-3-yl)ethyl)-2-(5-fluoropyridin-3-yl)-9-(tetrahydrofuran-3-yl)-9H-purin-6-amine;4-(2-(2-(3H-imidazo[4,5-b]pyridin-3-yl)-9-isopropyl-9H-purin-6-ylamino)ethyl)phenol;4-(2-(2-(1H-imidazo[4,5-b]pyridin-1-yl)-9-isopropyl-9H-purin-6-ylamino)ethyl)phenol;4-(2-(6-(5-fluoropyridin-3-yl)-1-isopropyl-1H-imidazo[4,5-c]pyridin-4-ylamino)ethyl)phenol;4-(2-(2-(4,5-dimethyl-1H-imidazol-1-yl)-9-isopropyl-9H-purin-6-ylamino)ethyl)phenol;2-(5-fluoropyridin-3-yl)-9-isopropyl-N-(2-(pyridin-3-yl)ethyl)-9H-purin-6-amine;4-(2-(2-(5-fluoropyridin-3-yl)-9-isopropyl-9H-purin-6-ylamino)-1-hydroxyethyl)phenol;2-(5-fluoropyridin-3-yl)-9-isopropyl-N-(2-(6-methoxy-1H-indol-3-yl)ethyl)-9H-purin-6-amine;N-(2-(1H-indol-3-yl)ethyl)-2-(5-fluoropyridin-3-yl)-9-isopropyl-9H-purin-6-amine;2-(5-fluoropyridin-3-yl)-9-isopropyl-N-(2-(5-methoxy-1H-indol-3-yl)ethyl)-9H-purin-6-amine;N-(2-(1H-indol-3-yl)ethyl)-2-(5-fluoropyridin-3-yl)-9-(prop-1-en-2-yl)-9H-purin-6-amine;5-(2-(2-(5-fluoropyridin-3-yl)-9-isopropyl-9H-purin-6-ylamino)ethyl)pyridin-2-ol;N-(2-(1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl)-2-(5-fluoropyridin-3-yl)-9-isopropyl-9H-purin-6-amine;N-(2-(6-(2-(diethylamino)ethoxy)-1H-indol-3-yl)ethyl)-2-(5-fluoropyridin-3-yl)-9-isopropyl-9H-purin-6-amine;4-(2-(5-(5-fluoropyridin-3-yl)-3-isopropyl-3H-imidazo[4,5-b]pyridin-7-ylamino)ethyl)phenol;N-(2-(1H-indol-3-yl)ethyl)-9-sec-butyl-2-(2-methyl-1H-imidazol-1-yl)-9H-purin-6-amine;4-(2-(2-(2-ethyl-1H-imidazol-1-yl)-9-isopropyl-9H-purin-6-ylamino)ethyl)phenol;4-(2-(9-isopropyl-2-(2-propyl-1H-imidazol-1-yl)-9H-purin-6-ylamino)-ethyl)phenol;3-(2-(2-(5-fluoropyridin-3-yl)-9-isopropyl-9H-purin-6-ylamino)ethyl)-1H-indol-6-ol;N-(2-(1H-indol-3-yl)ethyl)-9-isopropyl-2-(5-methylpyridin-3-yl)-9H-purin-6-amine;N-(2-(1H-indol-3-yl)ethyl)-9-isopropyl-2-(2-methyl-1H-imidazol-1-yl)-9H-purin-6-amine;2-(5-fluoropyridin-3-yl)-9-isopropyl-N-(2-(7-methyl-1H-indol-3-yl)ethyl)-9H-purin-6-amine;N-(2-(1H-indol-3-yl)ethyl)-2-(5-fluoropyridin-3-yl)-9-(oxetan-3-yl)-9H-purin-6-amine;N-(2-(1H-indol-3-yl)ethyl)-2-(5-methylpyridin-3-yl)-9-(oxetan-3-yl)-9H-purin-6-amine;N-(2-(6-fluoro-1H-indol-3-yl)ethyl)-2-(5-fluoropyridin-3-yl)-9-isopropyl-9H-purin-6-amine;2-(5-fluoropyridin-3-yl)-9-isopropyl-N-(2-(6-methyl-1H-indol-3-yl)ethyl)-9H-purin-6-amine;2-(5-fluoropyridin-3-yl)-9-isopropyl-N-(2-(2-methyl-1H-indol-3-yl)ethyl)-9H-purin-6-amine;N-(2-(4-fluoro-1H-indol-3-yl)ethyl)-2-(5-fluoropyridin-3-yl)-9-isopropyl-9H-purin-6-amine;N-(2-(7-fluoro-1H-indol-3-yl)ethyl)-2-(5-fluoropyridin-3-yl)-9-isopropyl-9H-purin-6-amine;2-(5-fluoropyridin-3-yl)-9-isopropyl-N-(2-(4-methyl-1H-indol-3-yl)ethyl)-9H-purin-6-amine;4-(2-(2-(benzo[b]thiophen-3-yl)-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)ethyl)phenol;9-isopropyl-2-(pyridin-3-yl)-N-(2-(pyridin-4-yl)ethyl)-9H-purin-6-amine;N-(2-(1H-pyrrolo[2,3-b]pyridin-5-yl)ethyl)-9-isopropyl-2-(pyridin-3-yl)-9H-purin-6-amine;4-(2-(2-(5-fluoropyridin-3-yl)-9-(1-hydroxypropan-2-yl)-9H-purin-6-ylamino)ethyl)-2-methylphenol;4-(2-(2-(benzo[b]thiophen-3-yl)-9-cyclohexyl-9H-purin-6-ylamino)ethyl)phenol;4-(2-(9-isopropyl-2-(thiophen-3-yl)-9H-purin-6-ylamino)ethyl)phenol; and1-(2-(2-(benzo[b]thiophen-3-yl)-6-(4-hydroxyphenethylamino)-9H-purin-9-yl)ethyl)pyrrolidin-2-one. 15. The method of claim 1, wherein said population of cells comprising said NK cells is a cell population a CD34+ depleted cell population.
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Cook Phillip D. (Carlsbad CA) Sanghvi Yogesh S. (San Marcos CA) Vasseur Jean J. (San Marcos CA) Debart Francoise (Montpellier FRX), Backbone modified oligonucleotide analogues.
Sanghvi Yogesh S. (San Marcos CA) Cook Phillip D. (Vista CA), Backbone-modified oligonucleotide analogs and preparation thereof through radical coupling.
Capon Daniel J. ; Tian Huan ; Smith Douglas H. ; Winslow Genine A. ; Siekevitz Miriam, Chimeric receptors comprising janus kinase for regulating cellular pro liferation.
Ohtsuka Eiko (Sappro JPX) Inoue Hideo (Sappro JPX) Morisawa Hirokazu (Kawasaki JPX) Shibahara Susumu (Kawasaki JPX) Mukai Sachiko (Kawasaki JPX) Nishihara Tohru (Kurashiki JPX), Compounds for the cleavage at a specific position of RNA, oligomers employed for the formation of said compounds, and st.
Capon Daniel J. ; Tian Huan ; Smith Douglas H. ; Winslow Genine A. ; Siekevitz Miriam, DNA encoding an intracellular chimeric receptor comprising Janus kinase.
Baxter Anthony D. (Northwich GB2) Baylis Eric K. (Stockport GB2) Collingwood Stephen P. (Westhoughton GB2) Taylor Roger J. (Stretford GB2) De Mesmaeker Alain (Kanerkinden CHX) Schmit Chantal (Basel C, Dinucleoside phosphinates and their pharmaceutical compositions.
Wands Jack R. (Waban MA) Zurawski ; Jr. Vincent R. (West Chester PA) Schoemaker ; Hubert J. P. (Newton MA), Immunoassay utilizing monoclonal high affinity IgM antibodies.
Weiss Samuel,CAX ; Reynolds Brent,CAX ; Hammang Joseph P. ; Baetge E. Edward, In vitro growth and proliferation of multipotent neural stem cells and their progeny.
Morgan Jeffrey R. (Brighton MA) Mulligan Richard C. (Cambridge MA), In vivo introduction and expression of foreign genetic material in epithelial cells.
Bonjouklian Rosanne (Zionsville IN) Dodge Jeffrey A. (Indianapolis IN) Vlahos Chris J. (Carmel IN), Inhibition of phosphatidylinositol 3-kinase with 17 b
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Bonjouklian Rosanne (Zionsville IN) Vlahos Chris J. (Carmel IN) Powis Garth (Tucson AZ), Inhibition of phosphatidylinositol 3-kinase with wortmannin and analogs thereof.
Cohen Jack S. (Bethesda MD) Neckers Len (Bethesda MD) Stein Cy (Gaithersburg MD) Loke She L. (Wheaton MD) Shinozuka Kazuo (Kazo JPX), Inhibitors for replication of retroviruses and for the expression of oncogene products.
Cohen Jack S. (Bethesda MD) Neckers Len (Bethesda MD) Stein Cy (Gaithersburg MD) Loke She L. (Wheaton MD) Shinozuka Kazuo (Kazo JPX), Inhibitors for replication of retroviruses and for the expression of oncogene products.
Cohen Jack S. (Bethesda MD) Neckers Len (Bethesda MD) Stein Cy (Gaithersburg MD) Loke Shee L. (Wheaton MD) Shinozuka Kazuo (Kazo JPX), Inhibitors for replication of retroviruses and for the expression of oncogene products.
Prockop Darwin J. ; Pereira Ruth F. ; Leeper Dennis B. ; O'Hara Michael D., Isolated stromal cells for treating diseases, disorders or conditions characterized by bone defects.
Dubensky ; Jr. Thomas W. ; Polo John M. ; Chang Steven M.W. ; Jolly Douglas J., Method for stimulating an immune response utilizing recombinant alphavirus particles.
Emerson Stephen G. (Ann Arbor MI) Clarke Michael F. (Ann Arbor MI) Palsson Bernhard O. (Ann Arbor MI), Method for the ex vivo replication of stem cells, for the optimization of hematopoietic progenitor cell cultur.
Smulson Mark E. (Washington DC) Bhatia Kishor (Arbutus MD) Huppi Konrad (Reston VA), Method of detecting a predisposition to cancer by the use of restriction fragment length polymorphism of the gene for hu.
Capon Daniel J. ; Tian Huan ; Smith Douglas H. ; Winslow Genine A. ; Siekevitz Miriam, Method of inducing a cell to proliferate using a chimeric receptor comprising janus kinase.
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.
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.
Orgill Dennis P. ; Butler Charles E. ; Barlow Mark ; Ritterbush Scott ; Yannas Ioannis V. ; Compton Carolyn C., Method of skin regeneration using a collagen-glycosaminoglycan matrix and cultured epithelial autograft.
Emerson Stephen G. ; Clarke Michael F. ; Palsson Bernhard O., Methods and compositions for the ex vivo replication of stem cells, for the optimization of hematopoietic progenitor cell cultures, and for increasing the metabolism, GM-CSF secretion and/or IL-6 sec.
Walder Joseph A. (Iowa City IA) Walder Roxanne Y. (Iowa City IA) Eder Paul S. (Iowa City IA) Dagle John M. (Iowa City IA), Methods for blocking the expression of specifically targeted genes.
Klein Elliott S. ; Nagpal Sunil ; Chandraratna Roshantha A., Methods of identifying compounds having nuclear receptor negative hormone and/or antagonist activities.
Matteucci Mark (Burlingame CA) Jones Robert J. (Daly City CA) Munger John (San Francisco CA), Modified internucleoside linkages having one nitrogen and two carbon atoms.
Ts\o Paul O. P. (2117 Folkstone Rd. Lutherville MD 21093) Miller Paul S. (225 Hopkins Rd. Baltimore MD 21212), Nonionic nucleic acid alkyl and aryl phosphonates and processes for manufacture and use thereof.
Walder Joseph A. (Iowa City IA) Walder Roxanne Y. (Iowa City IA), Nucleic acid hybridization and amplification method for detection of specific sequences in which a complementary labeled.
Meyer ; Jr. Rich B. (Woodinville WA) Adams A. David (Snohomish WA) Petrie Charles R. (Woodinville WA), Oligo (aa
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Letsinger Robert L. (Wilmette IL) Gryaznov Sergei M. (San Mateo CA), Oligodeoxyribonucleotides including 3′-aminonucleoside-phosphoramidate linkages and terminal 3′-amino groups.
Bischofberger Norbert (San Carlos CA) Kent Ken (Mountain View CA) Wagner Rick (Burlingame CA) Buhr Chris (Daly City CA) Lin Kuei-Ying (Fremont CA), Oligonucleotide analogs capable of passive cell membrane permeation.
Weis Alexander Ludvik (Berwyn PA) Hausheer Frederick Herman (San Antonio TX) Chaturvedula Prasad Venkata Chala (Exton PA) Delecki Daniel Joseph (Radnor PA) Cavanaugh ; Jr. Paul Francis (West Chester , Oligonucleotide analogues containing phosphate diester linkage substitutes, compositions thereof, and precursor dinucleo.
Imbach Jean-Louis (Montpellier FRX) Gosselin Gilles J. M. (Montpellier FRX), Oligonucleotides, a process for preparing the same and their application as mediators of the action of interferon.
Spielvogel Bernard F. (Raleigh NC) Sood Anup (Durham NC) Hall Iris H. (Chapel Hill NC) Shaw Barbara R. (Durham NC), Oligoribonucleoside and oligodeoxyribonucleoside boranophosphates.
Maddry Joseph A. (Birmingham AL) Reynolds Robert C. (Birmingham AL) Secrist John A. (Birmingham AL) Montgomery John A. (Birmingham AL) Crooks Peter A. (Lexington KY), Polynucleotide analogs containing sulfonate and sulfonamide internucleoside linkages.
Caruthers Marvin H. (Boulder CO) Marshall William S. (Boulder CO) Brill Wolfgang (Freiburg DEX) Nielsen John (Horsholm DKX), Polynucleotide phosphorodithioate.
Surani Azim M. (Cambridge GB3) Neuberger Michael S. (Cambridge GB3) Bruggemann Marianne (Cambridge GB3), Production of antibodies from transgenic animals.
Michnick Stephen William Watson,CAX ; Pelletier Joelle Nina,CAX ; Remy Ingrid,CAX, Protein fragment complementation assays for the detection of biological or drug interactions.
Cabilly Shmuel (Monrovia CA) Heyneker Herbert L. (Burlingame CA) Holmes William E. (Pacifica CA) Riggs Arthur D. (La Verne CA) Wetzel Ronald B. (San Francisco CA), Recombinant immunoglobin preparations.
Wilson Elaine L. (New York NY) Gabrilove Janice (New York NY), Stimulation, production and culturing of hematopoietic progenitor cells by fibroblast growth factors.
Klein Elliot S. ; Johnson Alan T. ; Standeven Andrew M. ; Beard Richard L. ; Gillett Samuel J. ; Duong Tien T. ; Nagpal Sunil ; Vuligonda Vidyasagar ; Teng Min ; Chandraratna Roshantha A., Synthesis and use of retinoid compounds having negative hormone and/or antagonist activities.
Klein Elliott S. ; Johnson Alan T. ; Standeven Andrew M. ; Beard Richard L. ; Gillett Samuel J. ; Duong Tien T. ; Nagpal Sunil ; Vuligonda Vidyasagar ; Teng Min ; Chandraratna Roshantha A., Synthesis and use of retinoid compounds having negative hormone and/or antagonist activities.
Klein Elliott S. ; Johnson Alan T. ; Standeven Andrew M. ; Beard Richard L. ; Gillett Samuel J. ; Duong Tien T. ; Nagpal Sunil ; Vuligonda Vidyasagar ; Teng Min ; Chandraratna Roshantha A., Synthesis and use of retinoid compounds having negative hormone and/or antagonist activities.
Klein Elliott S. ; Johnson Alan T. ; Standeven Andrew M. ; Beard Richard L. ; Gillett Samuel J. ; Duong Tien T. ; Nagpal Sunil ; Vuligonda Vidyasagar ; Teng Min ; Chandraratna Roshantha A., Synthesis and use of retinoid compounds having negative hormone and/or antagonist activities.
Klein Elliott S. ; Johnson Alan T. ; Standeven Andrew M. ; Beard Richard L. ; Gillett Samuel J. ; Duong Tien T. ; Nagpal Sunil ; Vuligonda Vidyasagar ; Teng Min ; Chandraratna Roshantha A., Synthesis and use of retinoid compounds having negative hormone and/or antagonist activities.
Klein Elliott S. ; Johnson Alan T. ; Standeven Andrew M. ; Beard Richard L. ; Gillett Samuel J. ; Duong Tien T. ; Nagpal Sunil ; Vuligonda Vidyasagar ; Teng Min ; Chandraratna Roshantha A., Synthesis and use of retinoid compounds having negative hormone and/or antagonist activities.
Chambon Pierre,FRX ; Gronemeyer Hinrich,DEX ; Reczek Peter R. ; Ostrowski Jacek, Therapeutic combinations of RAR antagonists and RXR agonists and use thereof.
Lonberg Nils (San Francisco CA) Kay Robert M. (San Francisco CA), Transgenic non-human animals capable of producing heterologous antibodies of various isotypes.
Lonberg Nils (San Francisco CA) Kay Robert M. (San Francisco CA), Transgenic non-human animals capable of producing heterologous antibodies of various isotypes.
Hwang Chan Kou ; White Steven K. ; Bennani Youssef L. ; Canan Koch Stacie S. ; Badea Beth Ann ; Hebert Jonathan J. ; Nadzan Alex M., Tricyclic retinoids, methods for their production and use.
Goldenberg Milton D. (11837 Gainsborough Rd. Potomac MD 20854), Tumor localization and therapy with labeled antibody fragments specific to tumor-associated markers.
Summerton James E. (Corvallis OR) Weller Dwight D. (Corvallis OR), Uncharged morpolino-based polymers having phosphorous containing chiral intersubunit linkages.
Anderson, Charles Daniel; Dodd, Charlie W.; Anderson, Mark Stuart, Vessel, preferably spherical or oblate spherical for growing or culturing cells, cellular aggregates, tissues and organoids and methods for using same.
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