CN111971049A - 促进免疫应答 - Google Patents
促进免疫应答 Download PDFInfo
- Publication number
- CN111971049A CN111971049A CN201980025130.1A CN201980025130A CN111971049A CN 111971049 A CN111971049 A CN 111971049A CN 201980025130 A CN201980025130 A CN 201980025130A CN 111971049 A CN111971049 A CN 111971049A
- Authority
- CN
- China
- Prior art keywords
- adp
- heptose
- glycerol
- beta
- mannoheptose
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 230000028993 immune response Effects 0.000 title claims abstract description 14
- 230000001737 promoting effect Effects 0.000 title claims abstract description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 17
- 230000002163 immunogen Effects 0.000 claims abstract description 15
- 229940076838 Immune checkpoint inhibitor Drugs 0.000 claims abstract description 8
- 239000012274 immune-checkpoint protein inhibitor Substances 0.000 claims abstract description 8
- 102000037984 Inhibitory immune checkpoint proteins Human genes 0.000 claims abstract description 7
- 108091008026 Inhibitory immune checkpoint proteins Proteins 0.000 claims abstract description 7
- 239000000203 mixture Substances 0.000 claims description 29
- 238000000034 method Methods 0.000 claims description 23
- 239000002552 dosage form Substances 0.000 claims description 19
- 210000004027 cell Anatomy 0.000 claims description 17
- 206010028980 Neoplasm Diseases 0.000 claims description 16
- 239000000427 antigen Substances 0.000 claims description 10
- 108091007433 antigens Proteins 0.000 claims description 10
- 102000036639 antigens Human genes 0.000 claims description 10
- 150000002386 heptoses Chemical class 0.000 claims description 10
- 230000001225 therapeutic effect Effects 0.000 claims description 10
- 229910019142 PO4 Inorganic materials 0.000 claims description 7
- 239000010452 phosphate Substances 0.000 claims description 7
- YPZMPEPLWKRVLD-PAMBMQIZSA-N (2r,3s,4s,5r,6s)-2,3,4,5,6,7-hexahydroxyheptanal Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)[C@@H](O)C=O YPZMPEPLWKRVLD-PAMBMQIZSA-N 0.000 claims description 6
- YPZMPEPLWKRVLD-UHFFFAOYSA-N L-glycero-D-manno-heptose Natural products OCC(O)C(O)C(O)C(O)C(O)C=O YPZMPEPLWKRVLD-UHFFFAOYSA-N 0.000 claims description 6
- 241000700605 Viruses Species 0.000 claims description 6
- 229940045513 CTLA4 antagonist Drugs 0.000 claims description 5
- 201000011510 cancer Diseases 0.000 claims description 5
- 108010074708 B7-H1 Antigen Proteins 0.000 claims description 4
- 102100039498 Cytotoxic T-lymphocyte protein 4 Human genes 0.000 claims description 4
- YPZMPEPLWKRVLD-PJEQPVAWSA-N D-Glycero-D-gulo-Heptose Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O)C=O YPZMPEPLWKRVLD-PJEQPVAWSA-N 0.000 claims description 4
- 102000002698 KIR Receptors Human genes 0.000 claims description 4
- 108010043610 KIR Receptors Proteins 0.000 claims description 4
- 108700030875 Programmed Cell Death 1 Ligand 2 Proteins 0.000 claims description 4
- 102100024216 Programmed cell death 1 ligand 1 Human genes 0.000 claims description 4
- 102100024213 Programmed cell death 1 ligand 2 Human genes 0.000 claims description 4
- 229940126547 T-cell immunoglobulin mucin-3 Drugs 0.000 claims description 4
- 102000006639 indoleamine 2,3-dioxygenase Human genes 0.000 claims description 4
- 108020004201 indoleamine 2,3-dioxygenase Proteins 0.000 claims description 4
- 239000003112 inhibitor Substances 0.000 claims description 4
- 241000894006 Bacteria Species 0.000 claims description 3
- 101000889276 Homo sapiens Cytotoxic T-lymphocyte protein 4 Proteins 0.000 claims description 3
- YPZMPEPLWKRVLD-ULQPCXBYSA-N (2s,3r,4s,5s,6r)-2,3,4,5,6,7-hexahydroxyheptanal Chemical compound OC[C@@H](O)[C@H](O)[C@H](O)[C@@H](O)[C@H](O)C=O YPZMPEPLWKRVLD-ULQPCXBYSA-N 0.000 claims description 2
- 102000007471 Adenosine A2A receptor Human genes 0.000 claims description 2
- 108010085277 Adenosine A2A receptor Proteins 0.000 claims description 2
- 102100029822 B- and T-lymphocyte attenuator Human genes 0.000 claims description 2
- 101000864344 Homo sapiens B- and T-lymphocyte attenuator Proteins 0.000 claims description 2
- 101001137987 Homo sapiens Lymphocyte activation gene 3 protein Proteins 0.000 claims description 2
- 101000666896 Homo sapiens V-type immunoglobulin domain-containing suppressor of T-cell activation Proteins 0.000 claims description 2
- 102000017578 LAG3 Human genes 0.000 claims description 2
- 101150030213 Lag3 gene Proteins 0.000 claims description 2
- 102100020862 Lymphocyte activation gene 3 protein Human genes 0.000 claims description 2
- 101100407308 Mus musculus Pdcd1lg2 gene Proteins 0.000 claims description 2
- 230000006044 T cell activation Effects 0.000 claims description 2
- 210000001744 T-lymphocyte Anatomy 0.000 claims description 2
- 102100038282 V-type immunoglobulin domain-containing suppressor of T-cell activation Human genes 0.000 claims description 2
- 210000003719 b-lymphocyte Anatomy 0.000 claims description 2
- 230000004069 differentiation Effects 0.000 claims description 2
- IJJVMEJXYNJXOJ-UHFFFAOYSA-N fluquinconazole Chemical compound C=1C=C(Cl)C=C(Cl)C=1N1C(=O)C2=CC(F)=CC=C2N=C1N1C=NC=N1 IJJVMEJXYNJXOJ-UHFFFAOYSA-N 0.000 claims description 2
- 244000045947 parasite Species 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 description 63
- 239000000546 pharmaceutical excipient Substances 0.000 description 28
- 150000003839 salts Chemical class 0.000 description 16
- 239000000651 prodrug Substances 0.000 description 11
- 229940002612 prodrug Drugs 0.000 description 11
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 10
- 239000003814 drug Substances 0.000 description 9
- 239000007924 injection Substances 0.000 description 9
- 238000002347 injection Methods 0.000 description 9
- 102100030009 Azurocidin Human genes 0.000 description 8
- 102100025248 C-X-C motif chemokine 10 Human genes 0.000 description 8
- -1 ADP heptose Chemical class 0.000 description 7
- 102000004127 Cytokines Human genes 0.000 description 7
- 108090000695 Cytokines Proteins 0.000 description 7
- 241000699666 Mus <mouse, genus> Species 0.000 description 7
- 241000699670 Mus sp. Species 0.000 description 7
- 210000004712 air sac Anatomy 0.000 description 7
- 201000010099 disease Diseases 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 210000002966 serum Anatomy 0.000 description 7
- 102100033805 Alpha-protein kinase 1 Human genes 0.000 description 6
- 101710098275 C-X-C motif chemokine 10 Proteins 0.000 description 6
- 102000019034 Chemokines Human genes 0.000 description 6
- 108010012236 Chemokines Proteins 0.000 description 6
- 101000779568 Homo sapiens Alpha-protein kinase 1 Proteins 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- 208000015181 infectious disease Diseases 0.000 description 6
- 229940124597 therapeutic agent Drugs 0.000 description 6
- 238000011282 treatment Methods 0.000 description 6
- 238000001727 in vivo Methods 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 230000001717 pathogenic effect Effects 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- 102100021943 C-C motif chemokine 2 Human genes 0.000 description 4
- 101710155857 C-C motif chemokine 2 Proteins 0.000 description 4
- 108010058846 Ovalbumin Proteins 0.000 description 4
- 230000004913 activation Effects 0.000 description 4
- 239000013543 active substance Substances 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 210000000440 neutrophil Anatomy 0.000 description 4
- 229940092253 ovalbumin Drugs 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 229950007217 tremelimumab Drugs 0.000 description 4
- 229960005486 vaccine Drugs 0.000 description 4
- 238000011814 C57BL/6N mouse Methods 0.000 description 3
- 101000651298 Homo sapiens TRAF-interacting protein with FHA domain-containing protein A Proteins 0.000 description 3
- 102100027651 TRAF-interacting protein with FHA domain-containing protein A Human genes 0.000 description 3
- 239000002671 adjuvant Substances 0.000 description 3
- 230000001580 bacterial effect Effects 0.000 description 3
- 244000052616 bacterial pathogen Species 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 230000001419 dependent effect Effects 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 239000007884 disintegrant Substances 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000000945 filler Substances 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- 125000000524 functional group Chemical group 0.000 description 3
- 239000012678 infectious agent Substances 0.000 description 3
- 230000015788 innate immune response Effects 0.000 description 3
- 230000002601 intratumoral effect Effects 0.000 description 3
- 239000000314 lubricant Substances 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
- 239000008184 oral solid dosage form Substances 0.000 description 3
- 238000007911 parenteral administration Methods 0.000 description 3
- 244000052769 pathogen Species 0.000 description 3
- 229940124531 pharmaceutical excipient Drugs 0.000 description 3
- 230000000770 proinflammatory effect Effects 0.000 description 3
- 230000007115 recruitment Effects 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 230000000699 topical effect Effects 0.000 description 3
- 208000035143 Bacterial infection Diseases 0.000 description 2
- 241001453380 Burkholderia Species 0.000 description 2
- 102100032367 C-C motif chemokine 5 Human genes 0.000 description 2
- 108091033409 CRISPR Proteins 0.000 description 2
- 108010055166 Chemokine CCL5 Proteins 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- 229920002785 Croscarmellose sodium Polymers 0.000 description 2
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 2
- 102000004457 Granulocyte-Macrophage Colony-Stimulating Factor Human genes 0.000 description 2
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 2
- 241000700739 Hepadnaviridae Species 0.000 description 2
- 101000858088 Homo sapiens C-X-C motif chemokine 10 Proteins 0.000 description 2
- 108090001005 Interleukin-6 Proteins 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 241000712079 Measles morbillivirus Species 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- 101710151805 Mitochondrial intermediate peptidase 1 Proteins 0.000 description 2
- 229920000881 Modified starch Polymers 0.000 description 2
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 2
- 102000003945 NF-kappa B Human genes 0.000 description 2
- 108010057466 NF-kappa B Proteins 0.000 description 2
- 241001631646 Papillomaviridae Species 0.000 description 2
- 241000606701 Rickettsia Species 0.000 description 2
- 241000607768 Shigella Species 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 108010069584 Type III Secretion Systems Proteins 0.000 description 2
- 241000607734 Yersinia <bacteria> Species 0.000 description 2
- VJHCJDRQFCCTHL-UHFFFAOYSA-N acetic acid 2,3,4,5,6-pentahydroxyhexanal Chemical compound CC(O)=O.OCC(O)C(O)C(O)C(O)C=O VJHCJDRQFCCTHL-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 208000038016 acute inflammation Diseases 0.000 description 2
- 230000006022 acute inflammation Effects 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 239000000783 alginic acid Substances 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 229960001126 alginic acid Drugs 0.000 description 2
- 150000004781 alginic acids Chemical class 0.000 description 2
- 208000022362 bacterial infectious disease Diseases 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 229960005168 croscarmellose Drugs 0.000 description 2
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 238000003018 immunoassay Methods 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 230000002458 infectious effect Effects 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 238000011081 inoculation Methods 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 108010060077 keratinocyte-derived chemokines Proteins 0.000 description 2
- 239000007937 lozenge Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 210000001616 monocyte Anatomy 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 230000003071 parasitic effect Effects 0.000 description 2
- 230000026731 phosphorylation Effects 0.000 description 2
- 238000006366 phosphorylation reaction Methods 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 230000034190 positive regulation of NF-kappaB transcription factor activity Effects 0.000 description 2
- 229920001592 potato starch Polymers 0.000 description 2
- 230000000069 prophylactic effect Effects 0.000 description 2
- 230000011664 signaling Effects 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 238000007910 systemic administration Methods 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 238000011200 topical administration Methods 0.000 description 2
- 230000004614 tumor growth Effects 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 108010039224 Amidophosphoribosyltransferase Proteins 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 241000712892 Arenaviridae Species 0.000 description 1
- 241000228212 Aspergillus Species 0.000 description 1
- 241001533362 Astroviridae Species 0.000 description 1
- 241000588807 Bordetella Species 0.000 description 1
- 241000588832 Bordetella pertussis Species 0.000 description 1
- 241000589968 Borrelia Species 0.000 description 1
- 241000589969 Borreliella burgdorferi Species 0.000 description 1
- 241000589562 Brucella Species 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- 238000010354 CRISPR gene editing Methods 0.000 description 1
- 108010021064 CTLA-4 Antigen Proteins 0.000 description 1
- 239000012275 CTLA-4 inhibitor Substances 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000714198 Caliciviridae Species 0.000 description 1
- 241000589876 Campylobacter Species 0.000 description 1
- 241000589875 Campylobacter jejuni Species 0.000 description 1
- 241000222120 Candida <Saccharomycetales> Species 0.000 description 1
- 241000606161 Chlamydia Species 0.000 description 1
- 241001647372 Chlamydia pneumoniae Species 0.000 description 1
- 241000606153 Chlamydia trachomatis Species 0.000 description 1
- 241000193403 Clostridium Species 0.000 description 1
- 241000223205 Coccidioides immitis Species 0.000 description 1
- 206010052360 Colorectal adenocarcinoma Diseases 0.000 description 1
- 241000711573 Coronaviridae Species 0.000 description 1
- 241000186227 Corynebacterium diphtheriae Species 0.000 description 1
- 241000709687 Coxsackievirus Species 0.000 description 1
- 241001337994 Cryptococcus <scale insect> Species 0.000 description 1
- 241000701022 Cytomegalovirus Species 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 241000725619 Dengue virus Species 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 239000001692 EU approved anti-caking agent Substances 0.000 description 1
- 241000194032 Enterococcus faecalis Species 0.000 description 1
- 241000991587 Enterovirus C Species 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 241000588722 Escherichia Species 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 241000711950 Filoviridae Species 0.000 description 1
- 241000710781 Flaviviridae Species 0.000 description 1
- 241000589601 Francisella Species 0.000 description 1
- 241000589602 Francisella tularensis Species 0.000 description 1
- 206010017533 Fungal infection Diseases 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 229920002907 Guar gum Polymers 0.000 description 1
- 241000606790 Haemophilus Species 0.000 description 1
- 241000606768 Haemophilus influenzae Species 0.000 description 1
- 241000589989 Helicobacter Species 0.000 description 1
- 241000590002 Helicobacter pylori Species 0.000 description 1
- 241000711549 Hepacivirus C Species 0.000 description 1
- 241000700721 Hepatitis B virus Species 0.000 description 1
- 241000709721 Hepatovirus A Species 0.000 description 1
- 241000700586 Herpesviridae Species 0.000 description 1
- 241000228402 Histoplasma Species 0.000 description 1
- 241000701085 Human alphaherpesvirus 3 Species 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 208000029462 Immunodeficiency disease Diseases 0.000 description 1
- 102100026236 Interleukin-8 Human genes 0.000 description 1
- 108090001007 Interleukin-8 Proteins 0.000 description 1
- 241000588748 Klebsiella Species 0.000 description 1
- 241000588747 Klebsiella pneumoniae Species 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 241000589248 Legionella Species 0.000 description 1
- 241000589242 Legionella pneumophila Species 0.000 description 1
- 208000007764 Legionnaires' Disease Diseases 0.000 description 1
- 241000222722 Leishmania <genus> Species 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 241000186781 Listeria Species 0.000 description 1
- 241000186779 Listeria monocytogenes Species 0.000 description 1
- 108060001084 Luciferase Proteins 0.000 description 1
- 239000005089 Luciferase Substances 0.000 description 1
- 208000016604 Lyme disease Diseases 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000711386 Mumps virus Species 0.000 description 1
- 241000186367 Mycobacterium avium Species 0.000 description 1
- 241000186362 Mycobacterium leprae Species 0.000 description 1
- 241000187479 Mycobacterium tuberculosis Species 0.000 description 1
- 208000031888 Mycoses Diseases 0.000 description 1
- 241000588653 Neisseria Species 0.000 description 1
- 241000588652 Neisseria gonorrhoeae Species 0.000 description 1
- 241000588650 Neisseria meningitidis Species 0.000 description 1
- 239000006057 Non-nutritive feed additive Substances 0.000 description 1
- 241000712464 Orthomyxoviridae Species 0.000 description 1
- 239000012271 PD-L1 inhibitor Substances 0.000 description 1
- 241000711504 Paramyxoviridae Species 0.000 description 1
- 208000002606 Paramyxoviridae Infections Diseases 0.000 description 1
- 241000701945 Parvoviridae Species 0.000 description 1
- 241000606856 Pasteurella multocida Species 0.000 description 1
- 241001668579 Pasteuria Species 0.000 description 1
- 241000150350 Peribunyaviridae Species 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 241000709664 Picornaviridae Species 0.000 description 1
- 241000224016 Plasmodium Species 0.000 description 1
- 241000233870 Pneumocystis Species 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 241000700625 Poxviridae Species 0.000 description 1
- 241000589516 Pseudomonas Species 0.000 description 1
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 1
- 241000711798 Rabies lyssavirus Species 0.000 description 1
- 241000702247 Reoviridae Species 0.000 description 1
- 108700008625 Reporter Genes Proteins 0.000 description 1
- 241000725643 Respiratory syncytial virus Species 0.000 description 1
- 241000712907 Retroviridae Species 0.000 description 1
- 241000711931 Rhabdoviridae Species 0.000 description 1
- 241000710799 Rubella virus Species 0.000 description 1
- 241000607142 Salmonella Species 0.000 description 1
- 241000293869 Salmonella enterica subsp. enterica serovar Typhimurium Species 0.000 description 1
- 241000242678 Schistosoma Species 0.000 description 1
- 241000607764 Shigella dysenteriae Species 0.000 description 1
- 241000607762 Shigella flexneri Species 0.000 description 1
- 241000607760 Shigella sonnei Species 0.000 description 1
- 241000700584 Simplexvirus Species 0.000 description 1
- 241000295644 Staphylococcaceae Species 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 241000193998 Streptococcus pneumoniae Species 0.000 description 1
- 241000193996 Streptococcus pyogenes Species 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 241000710924 Togaviridae Species 0.000 description 1
- 241000223996 Toxoplasma Species 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 241000589886 Treponema Species 0.000 description 1
- 241000589884 Treponema pallidum Species 0.000 description 1
- 241000607598 Vibrio Species 0.000 description 1
- 241000607626 Vibrio cholerae Species 0.000 description 1
- 241000607447 Yersinia enterocolitica Species 0.000 description 1
- 241000607479 Yersinia pestis Species 0.000 description 1
- 241000607477 Yersinia pseudotuberculosis Species 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000011149 active material Substances 0.000 description 1
- IAJILQKETJEXLJ-RSJOWCBRSA-N aldehydo-D-galacturonic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-RSJOWCBRSA-N 0.000 description 1
- IAJILQKETJEXLJ-QTBDOELSSA-N aldehydo-D-glucuronic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-QTBDOELSSA-N 0.000 description 1
- 229940037003 alum Drugs 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 150000001483 arginine derivatives Chemical class 0.000 description 1
- 239000000305 astragalus gummifer gum Substances 0.000 description 1
- 229960003852 atezolizumab Drugs 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 229950002916 avelumab Drugs 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 229960000397 bevacizumab Drugs 0.000 description 1
- 238000010256 biochemical assay Methods 0.000 description 1
- 238000002306 biochemical method Methods 0.000 description 1
- 230000001851 biosynthetic effect Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000007894 caplet Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 239000013043 chemical agent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 229940038705 chlamydia trachomatis Drugs 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 201000003486 coccidioidomycosis Diseases 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 230000001010 compromised effect Effects 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 229960000913 crospovidone Drugs 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- WZHCOOQXZCIUNC-UHFFFAOYSA-N cyclandelate Chemical compound C1C(C)(C)CC(C)CC1OC(=O)C(O)C1=CC=CC=C1 WZHCOOQXZCIUNC-UHFFFAOYSA-N 0.000 description 1
- 230000016396 cytokine production Effects 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 230000012969 defense response to bacterium Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 235000019700 dicalcium phosphate Nutrition 0.000 description 1
- 229940095079 dicalcium phosphate anhydrous Drugs 0.000 description 1
- 239000001177 diphosphate Substances 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 229950009791 durvalumab Drugs 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 229940032049 enterococcus faecalis Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 229940118764 francisella tularensis Drugs 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 229940097043 glucuronic acid Drugs 0.000 description 1
- 239000003979 granulating agent Substances 0.000 description 1
- 239000000665 guar gum Substances 0.000 description 1
- 235000010417 guar gum Nutrition 0.000 description 1
- 229960002154 guar gum Drugs 0.000 description 1
- 229940047650 haemophilus influenzae Drugs 0.000 description 1
- 229940037467 helicobacter pylori Drugs 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 230000005934 immune activation Effects 0.000 description 1
- 230000005746 immune checkpoint blockade Effects 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 208000026278 immune system disease Diseases 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 238000003119 immunoblot Methods 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 108091005434 innate immune receptors Proteins 0.000 description 1
- XKTZWUACRZHVAN-VADRZIEHSA-N interleukin-8 Chemical compound C([C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@@H](NC(C)=O)CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CCSC)C(=O)N1[C@H](CCC1)C(=O)N1[C@H](CCC1)C(=O)N[C@@H](C)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC=1C=CC(O)=CC=1)C(=O)N[C@H](CO)C(=O)N1[C@H](CCC1)C(N)=O)C1=CC=CC=C1 XKTZWUACRZHVAN-VADRZIEHSA-N 0.000 description 1
- 229940096397 interleukin-8 Drugs 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229940115932 legionella pneumophila Drugs 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 238000006384 oligomerization reaction Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 229940051027 pasteurella multocida Drugs 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 238000003909 pattern recognition Methods 0.000 description 1
- 108010089193 pattern recognition receptors Proteins 0.000 description 1
- 102000007863 pattern recognition receptors Human genes 0.000 description 1
- 229940121656 pd-l1 inhibitor Drugs 0.000 description 1
- 125000001151 peptidyl group Chemical group 0.000 description 1
- 239000008196 pharmacological composition Substances 0.000 description 1
- OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical class OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 201000000317 pneumocystosis Diseases 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 108091033319 polynucleotide Proteins 0.000 description 1
- 102000040430 polynucleotide Human genes 0.000 description 1
- 239000002157 polynucleotide Substances 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 230000004043 responsiveness Effects 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 229940007046 shigella dysenteriae Drugs 0.000 description 1
- 229940115939 shigella sonnei Drugs 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 229940031000 streptococcus pneumoniae Drugs 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 239000006068 taste-masking agent Substances 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 239000006211 transdermal dosage form Substances 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 241000701161 unidentified adenovirus Species 0.000 description 1
- 241000712461 unidentified influenza virus Species 0.000 description 1
- 229940118696 vibrio cholerae Drugs 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229940098232 yersinia enterocolitica Drugs 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/549—Sugars, nucleosides, nucleotides or nucleic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/61—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule the organic macromolecular compound being a polysaccharide or a derivative thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
- C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Immunology (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Mycology (AREA)
- Microbiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Endocrinology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
药物组合物,其包含1‑ADP‑庚糖缀合物,并且可以包含免疫原或免疫检查点抑制剂,并用于促进免疫应答。
Description
简介
许多疾病和病理学与受损的免疫系统和对感染物的提高的易感性有关。经受手术、放射或化学疗法的患者以及那些患有自身免疫性疾病或其他免疫缺陷疾病的患者具有升高的因感染而发展病理状况的风险。免疫激活策略可用于诱导免疫应答,以预防或抵抗感染。
疫苗被广泛用于预防或治疗许多感染性生物体引起的感染,所述感染性生物体包括细菌、病毒和真菌,并且已开发出多种疫苗和免疫疗法来治疗癌症,并且许多策略和佐剂已被用于增强其功效。
持续需要开发进一步的治疗和预防选择,以应对由感染物、癌细胞和免疫或炎性疾病引起的感染。
相关文献包括WO2016054745和Gaudet等人.Science 348,1251-1255(2015)。
发明概述
本发明提供了促进免疫应答的方法和相应的药物组合物。
一方面,本发明提供了一种促进免疫应答的方法,所述方法包括向有其需要的人给予包含1-ADP-庚糖缀合物的组合物。
在实施方案中
-所述庚糖的构型为:L/D-甘油-α/β-L/D-甘露庚糖/葡萄庚糖/半乳庚糖。
-所述庚糖的构型为:L/D-甘油-α/β-L/D-甘露庚糖。
-所述庚糖的构型为:L/D-甘油-α/β-D-甘露庚糖。
-所述庚糖的构型为:L/D-甘油-β-D-甘露庚糖。
-所述庚糖的构型为:
-所述缀合物为1-ADP-庚糖-7-磷酸酯。
-所述方法还包括向所述人给予免疫原,所述免疫原优选地包含细菌、病毒、寄生虫或癌细胞的抗原。
-所述方法还包括向所述人给予免疫检查点抑制剂,所述免疫检查点抑制剂优选地包含对以下具有特异性的治疗性抗体:
腺苷A2A受体(A2AR);
分化簇276(CD276;B7-H3);
B和T淋巴细胞衰减因子(BTLA;CD272);
细胞毒性T淋巴细胞相关蛋白4(CTLA-4)
吲哚胺2,3-双加氧酶(IDO);
杀伤细胞免疫球蛋白样受体(KIR);
淋巴细胞激活基因3(LAG-3;CD223);
PD-1/程序性死亡配体1或2(PD-L1或PD-L2);
T细胞免疫球蛋白粘蛋白-3(TIM-3);或
T细胞激活的V结构域Ig抑制剂(VISTA);
-所述检查点抑制剂是治疗性抗体,其是PD-L1抑制剂,如度伐单抗(durvalumab)、阿特珠单抗(atezolizumab)或阿维单抗(avelumab);或CTLA-4抑制剂,如替西木单抗(tremelimumab)或替西木单抗(tremelimumab);
-所述方法还包括向所述人给予所述免疫原或免疫检查点抑制剂,其中所述组合物包含所述免疫原或所述抑制剂。
一方面,本发明提供了包含1-ADP-庚糖缀合物的促进免疫应答的药物组合物。
在实施方案中:
-所述组合物还包含免疫原或免疫检查点抑制剂。
-所述组合物为单位剂型。
本发明包括本文叙述的具体实施方案的所有组合。
附图简述
图1A.ADP-庚糖及其类似物(UDP-庚糖、CDP-庚糖、dCDP-庚糖、dADP-庚糖、dGDP-庚糖、GDP-庚糖和dTDP-庚糖)以剂量依赖的方式激活293T细胞中的NF-κB。NF-κB激活通过荧光素酶报告基因活性来测量。
图1B.ADP-庚糖及其类似物在293T细胞中诱导TIFA磷酸化。将稳定表达EGFP-TIFA的293T细胞用ADP-庚糖类似物(5μM)处理5小时,并通过抗pT9-TIFA免疫印迹分析。
图1C.ADP庚糖在体内显示佐剂活性,以提高血清卵清蛋白(OVA)特异性IgG的产生。用与PBS、明矾(2mg/小鼠)或ADP-庚糖(0.5mg/小鼠)混合的10μg OVA肌内免疫C57BL/6N小鼠(每组8只小鼠)。21天后,通过ELISA测量OVA特异性IgG的血清滴度。
图1D和图1E.通过用ADP-庚糖进行肿瘤后治疗来抑制B16-OVA肿瘤的生长。在第0天,对C57BL/6N小鼠(每组n=6只小鼠)皮下注射2×105个B16-OVA黑色素瘤细胞。在肿瘤接种后的第8、11、14和17天通过肿瘤内注射给予ADP-庚糖(0.5mg/小鼠)。肿瘤体积(D)和肿瘤重量(E)。
图1F.通过用ADP-庚糖和检查点阻断进行肿瘤后治疗来抑制MC38肿瘤生长。在第0天,对C57BL/6N小鼠(每组n=6只小鼠)皮下注射2×105个MC38结直肠腺癌细胞。在肿瘤接种后第13、16、19、22、25和28天给予ADP庚糖(0.5mg/小鼠,肿瘤内注射)和抗PD-1抗体(40μg/小鼠,腹膜内注射)。
本发明的具体实施方案的描述
以下具体实施方案和实例的描述通过说明而非限制的方式提供。本领域技术人员将容易地识别可以改变或修饰以产生基本相同结果的各种非关键参数。本发明提供了多种实施方案。
除非有相反指明或另外说明,在这些描述和整个说明书中,术语“一种(a)”和“一种(an)”表示一种或多种,术语“或”表示和/或,多核苷酸序列理解为包括相反的链以及本文描述的供选择的骨架。
免疫原可以是感染物的抗原,所述感染物例如感染性细菌、病毒或寄生虫病原体,包括属于以下菌属的革兰氏阴性细菌病原体:奈瑟氏球菌属(包括脑膜炎奈瑟氏球菌、淋病奈瑟氏球菌)、埃希氏菌属(包括大肠杆菌)、克雷伯氏菌属(包括肺炎克雷伯菌)、沙门氏菌属(包括鼠伤寒沙门氏菌)、志贺氏菌属(包括痢疾志贺氏菌、福氏志贺氏菌、宋内氏志贺氏菌)、弧菌属(包括霍乱弧菌)、螺杆菌属(包括幽门螺杆菌)、假单胞菌属(包括铜绿假单胞菌)、伯克霍尔德菌属(包括多噬伯克霍尔德菌(Burkhoideria multivorans))、嗜血杆菌属(包括流感嗜血杆菌)、莫拉氏菌属(包括卡他莫拉氏菌)、博德特氏菌属(包括百日咳博德特氏菌)、弗朗西斯菌属(包括土拉弗朗西斯菌)、巴斯德氏菌属(包括多杀性巴斯德氏菌)、军团菌属(包括嗜肺军团菌)、疏螺旋体属(包括伯氏疏螺旋体)、弯曲菌属(包括空肠弯曲菌)、耶尔森氏菌属(包括鼠疫耶尔森菌和小肠结肠炎耶尔森氏菌)、立克次体(包括立氏立克次体)、密螺旋体属(包括梅毒螺旋体)、衣原体(包括沙眼衣原体,肺炎衣原体)和布鲁氏菌属;以及包括属于以下菌属的革兰氏阳性细菌病原体:葡萄球菌属(包括金黄色葡萄球菌)、链球菌属(包括肺炎链球菌、化脓性链球菌)、李斯特菌属(包括单核细胞增多性李斯特菌)、棒状杆菌属(包括白喉棒状杆菌)、肠球菌属(包括粪肠球菌)、梭状芽孢杆菌属和分枝杆菌属(包括结核分枝杆菌、麻风分枝杆菌、鸟分枝杆菌)。
免疫原或抗原也可以来自病原性病毒,包括腺病毒科(包括腺病毒)、疱疹病毒科(包括EB病毒、单纯疱疹病毒、巨细胞病毒、水痘带状疱疹病毒)、乳头瘤病毒科(Papillomviridae)、痘病毒科(包括乳头瘤病毒)、嗜肝病毒科(包括乙型肝炎病毒)、细小病毒科、星状病毒科、杯状病毒科、小RNA病毒科(包括柯萨奇病毒、甲型肝炎病毒、脊髓灰质炎病毒)、冠状病毒科、黄病毒科(包括丙型肝炎病毒、登革热病毒)、披膜病毒科(包括风疹病毒)、肝炎病毒科、逆转录病毒科(包括艾滋病病毒)、正粘病毒科(包括流感病毒)、砂粒病毒科、布尼亚病毒科、丝状病毒科、副粘液病毒科(包括麻疹病毒、腮腺炎病毒、副流感病毒、呼吸道合胞病毒)、弹状病毒科(包括狂犬病病毒)或呼肠孤病毒科。
免疫原或抗原也可以来自病原性真菌感染,包括由念珠菌、曲霉菌、隐球菌、组织胞浆菌、肺囊虫或球孢子菌引起的那些。疫苗也可以针对寄生性病原体,包括利什曼原虫、疟原虫、弓形虫、锥虫和血吸虫。
免疫原或抗原可以来自在受试者自身细胞上表达的蛋白质或其他抗原,如肿瘤抗原或癌抗原,以激发针对病原性细胞或组织的免疫应答。在一个实施方案中,可将组合物直接引入肿瘤中以提高针对肿瘤的免疫应答。免疫原可以作为疫苗制剂的一部分给予。
所述方法和组合物可以采用任何合适的形式和剂量单位的化合物,包括盐、前药、立体异构体、无定形形式等。
术语“药学上可接受的盐”是指包括活性化合物的盐,所述活性化合物的盐是用相对无毒的酸或碱制备的,其取决于本文描述的化合物上存在的特定取代基。当本发明的化合物含有相对酸性的官能团时,可以通过使这样的化合物的中性形式与足够量的纯净或在合适的惰性溶剂中的期望的碱接触而获得碱加成盐。药学上可接受的碱加成盐的实例包括钠、钾、钙、铵、有机胺或镁盐,或类似的盐。当本发明的化合物含有相对碱性的官能团时,可以通过使这样的化合物的中性形式与足够量的纯净或在合适的惰性溶剂中的期望的酸接触来获得酸加成盐。药学上可接受的酸加成盐的实例包括衍生自无机酸的那些,所述无机酸如盐酸、氢溴酸、硝酸、碳酸、一氢碳酸、磷酸、一氢磷酸、二氢磷酸、硫酸、一氢硫酸、氢碘酸或亚磷酸等,以及衍生自相对无毒的有机酸的盐,所述有机酸如乙酸、丙酸、异丁酸、草酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、富马酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸(p-tolylsulfonic)、柠檬酸、酒石酸、甲磺酸等。还包括氨基酸的盐,如精氨酸盐等,以及有机酸的盐,所述有机酸如葡糖醛酸或半乳糖醛酸等。本发明的某些特定化合物同时含有使得该化合物可以转化为碱或酸加成盐的碱性和酸性官能团。
可以通过使盐与碱或酸接触并以常规方式分离母体化合物来使化合物的中性形式再生。化合物的母体形式在某些物理性质,如在极性溶剂中的溶解度方面与各种盐形式不同,但是出于本发明的目的,这些盐在其他方面与化合物的母体形式相当。
除了盐形式以外,本发明提供了前药形式的化合物。本文描述的化合物的前药是那些在生理条件下经历化学变化以提供本发明化合物的化合物。另外,可以在离体环境中通过化学或生化方法将前药转化为本发明的化合物。例如,当将前药与合适的酶或化学试剂一起置于透皮贴剂储库中时,前药可以缓慢转化为本发明的化合物。前药通常是有用的,因为在一些情况下,它们可能比母体药物更容易给药。例如,与母体药物相比,它们通过口服给药可能具有更高的生物利用度。与母体药物相比,前药在药理学组合物中也可以具有提高的溶解度。多种前药衍生物在本领域中是已知的,例如依赖于前药的水解裂解或氧化激活的那些。前药的一个非限制性实例是,本发明的化合物以酯(“前药”)的形式给药,但是随后被代谢水解为羧酸,即活性实体。另外的实例包括本发明化合物的肽基衍生物。
本发明的某些化合物可以以非溶剂化形式以及溶剂化形式,包括水合形式存在。通常,溶剂化形式等同于非溶剂化形式,并且意在包括在本发明的范围内。本发明的某些化合物可以多种结晶或无定形形式存在。通常,所有物理形式对于本发明预期的用途是等同的,并且意在落入本发明的范围内。
本发明的某些化合物具有不对称碳原子(光学中心)或双键;外消旋体,非对映异构体,几何异构体和单个异构体均意图包括在本发明的范围内。
术语“治疗有效量”是指研究人员、兽医、医生或其他临床医生所寻求的将在某种明显的程度上引起组织、系统、动物或人类的生物学或医学反应的主题化合物的量,例如当给予时,足以预防所治疗的疾病或病症的一种或多种症状的发展,或在某种程度上减轻所治疗的疾病或病症的一种或多种症状。治疗有效量将根据化合物,疾病及其严重程度,以及所治疗哺乳动物的年龄、体重等变化。
本发明还提供了包含主题化合物和药学上可接受的赋形剂的药物组合物,特别是包含单位剂量的主题化合物的这样的组合物,尤其是与描述该组合物用于治疗(本文)可适用的疾病或状况的说明书共同包装的这样的组合物。
用于给药的组合物可以采取散装液体溶液或悬浮液或散装粉末的形式。然而,更通常地,所述组合物以单位剂型提供以有助于精确给药。术语“单位剂型”是指适合作为人受试者和其他哺乳动物的单位剂量的物理上离散的单位,每个单位含有预定量的经计算产生期望治疗效果的活性物质,以及合适的药物赋形剂。典型的单位剂型形式包括液体组合物的预填充的、预先测量的安瓿或注射器,或者在固体组合物的情况下为丸剂、片剂、胶囊、锭剂(losenge)等。在这样的组合物中,化合物通常是次要组分(按重量计约0.1%至约50%,或优选按重量计约1%至约40%),其余是各种媒介物或载体,和有助于形成期望的剂量形式的加工助剂。
合适的赋形剂或载体以及用于制备可给药组合物的方法对于本领域技术人员而言是已知的或显而易见的,并且更详细地描述在诸如Remington's PharmaceuticalScience,Mack Publishing Co,NJ(1991)的出版物中。另外,所述化合物可有利地与本文描述的或本领域已知的其他治疗剂,特别是其他抗坏死剂联合使用。因此,所述组合物可以单独、联合或以单一剂量单位组合给药。
给药的量取决于化合物制剂、给药途径等,并且通常在常规试验中根据经验确定,并且必然会根据靶标、宿主和给药途径等发生变化。通常,根据具体应用,单位剂量制剂中活性化合物的量可以在约1、3、10或30至约30、100、300或1000mg之间变化或调节。在一个具体的实施方案中,单位剂型包装在适于顺序使用的多包装中,如泡罩包装,其包括至少6、9或12个单位剂型的片。所使用的实际剂量可以取决于患者的需求和所治疗病症的严重性而变化。确定用于特定情况的合适剂量在本领域技术范围内。通常,以小于化合物最佳剂量的较小剂量开始治疗。此后,以少量增加剂量,直到在这种情况下达到最佳效果。为了方便起见,如果需要,可以将每日总剂量分开并在一天中分批给药。
所述化合物可以通过多种方法给药,包括但不限于肠胃外、局部(topical)、口服或局部(local)给药,如通过气雾剂或透皮给药,以用于预防性和/或治疗性的治疗。而且,根据熟练的临床医生的知识,鉴于所观察到的给予的治疗剂对患者的作用以及鉴于所观察到的疾病对所给予的治疗剂的反应,可以改变治疗方案(例如,剂量和给药时间)。
本发明的治疗剂可以在用于治疗患者的治疗有效方案的过程中以治疗有效的剂量和量给药。对于更有效的化合物,每千克患者微克(ug)量可能就足够了,例如在约1、10或100ug/kg到约0.01、0.1、1、10或100mg/kg的范围内,但是最佳剂量是化合物特异性的,并且通常针对每种化合物根据经验确定。
一般而言,临床试验中的常规实验将确定对于每种治疗剂的最佳治疗效果的特定范围,每种给药方案以及对特定患者的给药也将根据患者的状况和对初次给药的反应性而调整到有效和安全的范围内。但是,考虑到诸如年龄、状况和患者大小以及化合物效力、所治疗疾病的严重性等因素,最终的给药方案将根据主治医生的判断进行调整。例如,化合物的剂量方案可以是以2至4个(优选2个)分开的剂量口服给药10mg至2000mg/天,优选10至1000mg/天,更优选50至600mg/天。也可以使用间歇治疗(例如,三周中的一周或四周中的三周)。
主题化合物可以单独使用或与其他治疗剂组合使用。因此,组合治疗包括给予化合物的至少一种药学上可接受的结晶或无定形形式以及至少一种其他治疗活性剂。主题化合物和其他治疗活性剂(多种活性剂)可以在单一药物组合物中一起或分开给药,并且当分开给药时,这可以同时或以任何顺序依次进行。将选择主题化合物和其他治疗活性剂(多种活性剂)的量以及给药的相对时机,以便实现期望的联合治疗效果。因此,在另一方面,提供了包含药学上可接受的结晶或无定形形式的化合物以及一种或多种其他治疗活性剂的组合。
本发明的化合物可以通过任何合适的给药途径给药,包括全身给药和局部给药。全身给药包括口服给药、肠胃外给药、透皮给药、直肠给药和通过吸入给药。肠胃外给药是指除肠内、透皮或通过吸入以外的给药途径,并且通常是通过注射或输注。肠胃外给药包括静脉内、肌内和皮下注射或输注。吸入是指通过口腔或通过鼻腔通道吸入给药到患者的肺部。局部给药包括施用于皮肤。
本发明的化合物可以一次给药或根据给药方案给药,其中在给定的时间段内以不同的时间间隔给予许多剂量。例如,可以每天一次、两次、三次或四次给予剂量。可以给予剂量直至实现期望的治疗效果或无限期地维持期望的治疗效果。用于本发明的化合物的合适的给药方案取决于该化合物的药代动力学性质,如吸收、分布和半衰期,其可以由技术人员确定。另外,对于本发明的化合物,合适的给药方案,包括这种方案的给药持续时间,取决于所治疗的疾病或障碍、所治疗的疾病或障碍的严重程度、所治疗患者的年龄和身体状况、待治疗患者的病史、同时进行的治疗的性质、期望的治疗效果以及技术人员的知识和专长内的类似因素。这些技术人员将进一步理解,鉴于个体患者对给药方案的反应或个体患者需求随着时间推移的变化,可能需要调整合适的给药方案。每日总剂量为1mg至2000mg。
为了用于治疗,在向患者给药之前,通常但并非必须将本发明化合物配制成药物组合物或给药单位。因此,本发明还涉及包含本发明化合物和一种或多种药学上可接受的赋形剂的药物组合物。本发明还涉及包含本发明化合物和一种或多种药学上可接受的赋形剂的给药单位。
本发明的药物组合物或给药单位可以以散装形式制备和包装,其中可以提取有效量的本发明化合物,然后例如与粉末、糖浆和注射用溶液一起给予患者。供选择地,可以制备本发明的药物组合物或给药单位并包装成单位剂型。例如,对于口服施用,可以给予一种或多种片剂或胶囊剂。药物组合物的剂量含有至少治疗有效量的本发明化合物。当以单位剂型制备时,药物组合物或给药单位可含有1mg至1000mg的主题化合物。
如本文所提供,可以每天一次、两次、三次或四次,优选每天一次、两次或三次,更优选每天一次或两次给予含有1mg至1000mg化合物的单位剂型(药物组合物或给药单位)。
如本文所用,“药学上可接受的赋形剂”是指涉及赋予组合物形状或稠度的材料、组合物或媒介物。每种赋形剂在混合时必须与药物组合物的其他成分相容,以避免当给予患者时会实质上降低本发明化合物的功效的相互作用和会导致药物组合物不是药学上可接受的相互作用。另外,每种赋形剂当然必须具有足够高的纯度以使其是药学上可接受的。
通常将本发明的化合物和药学上可接受的赋形剂或多种赋形剂配制成适合通过期望的给药途径给予患者的剂型。常规剂型包括适于(1)口服给药的剂型,如片剂、胶囊剂、囊片、丸剂、锭剂、散剂、糖浆剂、酏剂、混悬剂、溶液剂、乳剂、囊剂(sachet)和扁囊剂;(2)肠胃外给药的剂型,如无菌溶液、混悬剂和用于重构的粉剂;(3)透皮给药的剂型,如透皮贴剂;(4)直肠给药的剂型,如栓剂;(5)吸入的剂型,如气雾剂和溶液剂;和(6)局部给药的剂型,如乳膏剂、软膏剂、洗剂、溶液剂、糊剂、喷雾剂、泡沫剂和凝胶剂。
合适的药学上可接受的赋形剂将取决于所选的特定剂型而变化。另外,可以选择合适的药学上可接受的赋形剂以实现它们在组合物中的特定功能。例如,可以选择某些药学上可接受的赋形剂,因为它们具有促进产生均匀剂型的能力。可以选择某些药学上可接受的赋形剂,因为它们具有促进产生稳定剂型的能力。可以选择某些药学上可接受的赋形剂,因为它们具有促进本发明的一种或多种化合物在给予患者后从一个器官或身体的一部分携带或运输到另一个器官或身体的一部分的能力。可以选择某些药学上可接受的赋形剂,因为它们具有增强患者依从性的能力。
合适的药学上可接受的赋形剂包括以下类型的赋形剂:稀释剂、填充剂、粘合剂、崩解剂、润滑剂、助流剂、制粒剂、包衣剂、润湿剂、溶剂、助溶剂、助悬剂、乳化剂、甜味剂、矫味剂、掩味剂、着色剂、抗结块剂、保湿剂、螯合剂、增塑剂、增粘剂、抗氧化剂、防腐剂、稳定剂、表面活性剂和缓冲剂。技术人员将理解,某些药学上可接受的赋形剂可以起到一种以上的功能,并且可以起到替代功能的作用,这取决于制剂中存在多少赋形剂以及制剂中存在什么其他成分。技术人员具有本领域的知识和技能,以使他们能够选择合适量的合适的药学上可接受的赋形剂用于本发明。另外,技术人员可获得许多描述药学上可接受的赋形剂的资源,这些资源可用于选择合适的药学上可接受的赋形剂。实例包括Remington'sPharmaceutical Sciences(Mack Publishing Company),药物添加剂手册(The Handbookof Pharmaceutical Additives,Gower Publishing Limited)和药物赋形剂手册(TheHandbook of Pharmaceutical Excipients,the American Pharmaceutical Associationand the Pharmaceutical Press)。
使用本领域技术人员已知的技术和方法制备本发明的药物组合物。Remington'sPharmaceutical Sciences(同上)中描述了本领域中常用的一些方法。因此,本发明的另一个实施方案是制备药物组合物或给药单位的方法,其包括将主题化合物的药学上可接受的结晶形式与一种或多种药学上可接受的赋形剂混合的步骤。
一方面,本发明涉及固体口服剂型,如片剂或胶囊,其包含有效量的本发明化合物和稀释剂或填充剂。合适的稀释剂和填充剂包括乳糖、蔗糖、右旋糖、甘露醇、山梨糖醇、淀粉(例如玉米淀粉、马铃薯淀粉和预糊化淀粉)、纤维素及其衍生物(例如微晶纤维素)、硫酸钙和磷酸氢钙。口服固体剂型还可以包含粘合剂。合适的粘合剂包括淀粉(例如玉米淀粉、马铃薯淀粉和预糊化淀粉)、明胶、阿拉伯胶、海藻酸钠、海藻酸、黄蓍胶、瓜尔豆胶、聚维酮和纤维素及其衍生物(例如微晶纤维素)。口服固体剂型还可以包含崩解剂。合适的崩解剂包括交聚维酮、羟乙酸淀粉钠、交联羧甲基纤维素(croscarmelose)、海藻酸和羧甲基纤维素钠。口服固体剂型还可以包含润滑剂。合适的润滑剂包括硬脂酸、硬脂酸镁、硬脂酸钙和滑石。
应当理解,本文描述的实施例和实施方案仅用于说明目的,并且鉴于其的各种修改或改变将被暗示给本领域技术人员,并且将被包括在本申请的精神和范围以及本发明所附权利要求的范围之内。本文引用的所有出版物、专利和专利申请,包括其中的引文,出于所有目的在此通过引用整体并入。
实施例
α-激酶1是细菌1-ADP-庚糖的胞质先天免疫受体
模式识别受体对病原体相关分子模式(PAMP)的免疫检测通常激活促炎性NF-κB信号传导,从而决定抗菌防御。已知的细菌PAMP限于几种类型的结构分子或核苷酸第二信使。先前的研究表明,耶尔森氏菌属和其他细菌病原体中的III型分泌系统(T3SS)可以激活宿主NF-κB信号传导。在这里,我们在假结核耶尔森氏菌和生化分析中结合了转座子筛选,并确定了介导T3SS依赖性NF-κB激活和炎性细胞因子产生的糖代谢物1-ADP-β-D-甘露庚糖(ADP-Hep)。ADP-Hep但不是其生物合成前体D-甘油-β-D-甘露庚糖1,7-二磷酸(HBP)可以自行进入宿主细胞质,导致在THP-1和293T细胞中的NF-kB激活以及细胞因子诱导(如白介素-8)。这允许我们进行全基因组CRISPR/Cas9筛选,以确定ADP-Hep诱导的NF-κB激活所需的α-激酶1(ALPK1)-TIFA轴。ALPK1 N末端结构域(NTD)直接与ADP-Hep结合,刺激NTD结合的C末端激酶结构域以使TIFA磷酸化并诱导其寡聚。ALPK1-NTD/ADP-Hep络合物的晶体结构揭示了这种配体/受体识别的原子机制。HBP可以通过宿主来源的腺苷基转移酶转化为具有ALPK1激活能力的ADP-庚糖7-P,解释了HBP转染到宿主细胞后观察到的NF-κB激活。ADP-Hep(但不是细胞不可渗透的HBP)的注射或细菌感染以Alpk1依赖的方式在小鼠中诱导强烈的炎症反应。ADP-Hep和ALPK1是抗菌免疫中一种新的通用模式识别途径。
单独的或在细菌感染过程中的ADP-Hep以Alpk1依赖的方式诱导强烈的免疫反应
为了研究单独的ADP-Hep是否可以刺激体内先天免疫应答,采用了建立的小鼠背部气囊模型来评估急性炎症(Gaudet等人Science 348,1251-1255(2015))。
将化学合成的ADP-LD-Hep注入气囊中诱导大量嗜中性粒细胞募集到气囊中。相反,相同量的化学合成的HBP无法增加气囊嗜中性粒细胞的数量,这与HBP无法进入哺乳动物细胞相符。然后,我们对气囊清洗液和接受注射的小鼠的血清中的36种细胞因子进行了多重免疫分析。与盐水对照组相比,注射ADP-LD-Hep的气囊中的一系列促炎细胞因子和趋化因子,包括IL-6、TNFα、C-X-C基序趋化因子10(IP-10/CXCL10)、单核细胞趋化因子蛋白1和3(MCP-1/3)、IFNγ、GM-CSF、MIP-1α和β以及RANTES大幅升高。ADP-LD-Hep还使血清中角化细胞源性趋化因子(GRO-α/KC/CXCL1)、IP-10和MCP-1的水平升高。与ADP-LD-Hep相比,将HBP注入气囊不影响这些炎性细胞因子和趋化因子的局部和全身生成,这些因子已知是NF-κB介导的转录的靶标。因此,ADP-Hep而不是单独HBP可以有效地激活小鼠的先天免疫应答。
1-ADP-L/D-甘油-α/β-L/D-甘露庚糖/葡萄庚糖/半乳庚糖缀合物促进强烈的免疫应答
为了确认1-ADP-庚糖和1-ADP-庚糖-7-磷酸酯可以在体内刺激先天性免疫应答,采用了建立的小鼠背部气囊模型用于评估急性炎症(Gaudet等人Science 348,1251-1255(2015))。
将1-ADP-庚糖和1-ADP-庚糖-7-磷酸注入气囊诱导嗜中性粒细胞募集到气囊中。对气囊清洗液和接受注射的小鼠的血清中的36种细胞因子进行相同的多重免疫分析,与盐水对照组相比,注射1-ADP-庚糖和1-ADP-庚糖-7-磷酸的气囊中的一系列促炎细胞因子和趋化因子,包括IL-6,TNFα、C-X-C基序趋化因子10(IP-10/CXCL10)、单核细胞趋化因子蛋白1和3(MCP-1/3)、IFNγ、GM-CSF、MIP-1α和β以及RANTES大幅升高。1-ADP-庚糖和1-ADP-庚糖-7-磷酸还使血清中角化细胞源性趋化因子(GRO-α/KC/CXCL1)、IP-10和MCP-1的水平升高。化合物1-24(表1)和化合物25-38(表2)各自显示出增强的嗜中性粒细胞募集和细胞因子/趋化因子诱导,其范围为ADP-LD-Hep的约30-200%。因此,这些1-ADP-L/D-甘油-α/β-L/D-甘露庚糖/葡萄庚糖/半乳庚糖缀合物在体内促进强烈的免疫应答。
我们的结果尤其证明,我们已经确定可以激活NF-kB并在293T细胞中诱导TIFA磷酸化的ADP-庚糖类似物(包括UDP-庚糖、CDP-庚糖、dCDP-庚糖、dADP-庚糖、dGDP-庚糖、GDP-庚糖和dTDP-庚糖);ADP-庚糖在体内表现出佐剂活性,以提高血清抗原特异性IgG产生;ADP-庚糖肿瘤内注射可抑制B16-OVA肿瘤生长;并且ADP-庚糖联合抗PD-1抗体可抑制MC38肿瘤的生长;见图1A-1F。
表1.活性1-ADP-庚糖
1 | 1-ADP-L-甘油-β-D-葡萄庚糖 | 13 | 1-ADP-L-甘油-β-L-半乳庚糖 |
2 | 1-ADP-D-甘油-β-D-葡萄庚糖 | 14 | 1-ADP-D-甘油-β-L-半乳庚糖 |
3 | 1-ADP-L-甘油-α-D-葡萄庚糖 | 15 | 1-ADP-L-甘油-α-L-半乳庚糖 |
4 | 1-ADP-D-甘油-α-D-葡萄庚糖 | 16 | 1-ADP-D-甘油-α-L-半乳庚糖 |
5 | 1-ADP-L-甘油-β-L-葡萄庚糖 | 17 | 1-ADP-L-甘油-β-D-甘露庚糖 |
6 | 1-ADP-D-甘油-β-L-葡萄庚糖 | 18 | 1-ADP-D-甘油-β-D-甘露庚糖 |
7 | 1-ADP-L-甘油-α-L-葡萄庚糖 | 19 | 1-ADP-L-甘油-α-D-甘露庚糖 |
8 | 1-ADP-D-甘油-α-L-葡萄庚糖 | 20 | 1-ADP-D-甘油-α-D-甘露庚糖 |
9 | 1-ADP-L-甘油-β-D-半乳庚糖 | 21 | 1-ADP-L-甘油-β-L-甘露庚糖 |
10 | 1-ADP-D-甘油-β-D-半乳庚糖 | 22 | 1-ADP-D-甘油-β-L-甘露庚糖 |
11 | 1-ADP-L-甘油-α-D-半乳庚糖 | 23 | 1-ADP-L-甘油-α-L-甘露庚糖 |
12 | 1-ADP-D-甘油-α-D-半乳庚糖 | 24 | 1-ADP-D-甘油-α-L-甘露庚糖 |
表2.活性1-ADP-庚糖-7-磷酸酯
25 | 1-ADP-L-甘油-β-D-葡萄庚糖-7P | 37 | 1-ADP-L-甘油-β-L-半乳庚糖-7P |
26 | 1-ADP-D-甘油-β-D-葡萄庚糖-7P | 38 | 1-ADP-D-甘油-β-L-半乳庚糖-7P |
27 | 1-ADP-L-甘油-α-D-葡萄庚糖-7P | 39 | 1-ADP-L-甘油-α-L-半乳庚糖-7P |
28 | 1-ADP-D-甘油-α-D-葡萄庚糖-7P | 40 | 1-ADP-D-甘油-α-L-半乳庚糖-7P |
29 | 1-ADP-L-甘油-β-L-葡萄庚糖-7P | 41 | 1-ADP-L-甘油-β-D-甘露庚糖-7P |
30 | 1-ADP-D-甘油-β-L-葡萄庚糖-7P | 42 | 1-ADP-D-甘油-β-D-甘露庚糖-7P |
31 | 1-ADP-L-甘油-α-L-葡萄庚糖-7P | 43 | 1-ADP-L-甘油-α-D-甘露庚糖-7P |
32 | 1-ADP-D-甘油-α-L-葡萄庚糖-7P | 44 | 1-ADP-D-甘油-α-D-甘露庚糖-7P |
33 | 1-ADP-L-甘油-β-D-半乳庚糖-7P | 45 | 1-ADP-L-甘油-β-L-甘露庚糖-7P |
34 | 1-ADP-D-甘油-β-D-半乳庚糖-7P | 46 | 1-ADP-D-甘油-β-L-甘露庚糖-7P |
35 | 1-ADP-L-甘油-α-D-半乳庚糖-7P | 47 | 1-ADP-L-甘油-α-L-甘露庚糖-7P |
36 | 1-ADP-D-甘油-α-D-半乳庚糖-7P | 48 | 1-ADP-D-甘油-α-L-甘露庚糖-7P |
Claims (15)
1.一种促进免疫应答的方法,所述方法包括向有其需要的人给予包含1-ADP-庚糖缀合物的组合物。
2.权利要求1所述的方法,其中所述庚糖的构型为:
L/D-甘油-α/β-L/D-甘露庚糖/葡萄庚糖/半乳庚糖。
3.权利要求1所述的方法,其中所述庚糖的构型为:
L/D-甘油-α/β-L/D-甘露庚糖。
4.权利要求1所述的方法,其中所述庚糖的构型为:
L/D-甘油-α/β-D-甘露庚糖。
5.权利要求1所述的方法,其中所述庚糖的构型为:
L/D-甘油-β-D-甘露庚糖。
6.权利要求1、2、3、4或5所述的方法,其中所述缀合物为1-ADP-庚糖-7-磷酸酯。
7.权利要求1所述的方法,其还包括向所述人给予免疫原。
8.权利要求1所述的方法,其还包括向所述人给予包含细菌、病毒、寄生虫或癌细胞的抗原的免疫原。
9.权利要求1所述的方法,其还包括向所述人给予免疫检查点抑制剂。
10.权利要求1所述的方法,其还包括向所述人给予免疫检查点抑制剂,所述免疫检查点抑制剂包含对以下具有特异性的治疗性抗体:
腺苷A2A受体(A2AR);
分化簇276(CD276;B7-H3);
B和T淋巴细胞衰减因子(BTLA;CD272);
细胞毒性T淋巴细胞相关蛋白4(CTLA-4);
吲哚胺2,3-双加氧酶(IDO);
杀伤细胞免疫球蛋白样受体(KIR);
淋巴细胞激活基因3(LAG-3;CD223);
PD-1/程序性死亡配体1或2(PD-L1或PD-L2);
T细胞免疫球蛋白粘蛋白-3(TIM-3);或
T细胞激活的V结构域Ig抑制剂(VISTA)。
11.权利要求7、8、9或10所述的方法,其中所述组合物包含所述免疫原或所述抑制剂。
12.一种促进免疫应答的药物组合物,其包含1-ADP-庚糖缀合物。
13.权利要求12所述的组合物,其还包含免疫原。
14.权利要求12所述的组合物,其还包含免疫检查点抑制剂。
15.权利要求12、13或14所述的组合物,其为单位剂型。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CNPCT/CN2018/091177 | 2018-06-14 | ||
CN2018091177 | 2018-06-14 | ||
PCT/CN2019/090647 WO2019238024A1 (en) | 2018-06-14 | 2019-06-11 | Promoting immune responses |
Publications (1)
Publication Number | Publication Date |
---|---|
CN111971049A true CN111971049A (zh) | 2020-11-20 |
Family
ID=68842704
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201980025130.1A Pending CN111971049A (zh) | 2018-06-14 | 2019-06-11 | 促进免疫应答 |
Country Status (9)
Country | Link |
---|---|
US (1) | US11229707B2 (zh) |
EP (1) | EP3752163A4 (zh) |
JP (1) | JP2021527133A (zh) |
KR (1) | KR20210020104A (zh) |
CN (1) | CN111971049A (zh) |
AU (1) | AU2019284192A1 (zh) |
CA (1) | CA3103724A1 (zh) |
SG (1) | SG11202012496XA (zh) |
WO (1) | WO2019238024A1 (zh) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2022127914A1 (en) | 2020-12-18 | 2022-06-23 | Pyrotech (Beijing) Biotechnology Co., Ltd. | Nucleoside-thiodiphosphate-heptose compounds for treating conditions associated with alpk1 activity |
EP4392431A1 (en) | 2021-09-30 | 2024-07-03 | Pyrotech (Beijing) Biotechnology Co., Ltd. | Nucleoside-diphosphate-heptose compounds for treating conditions associated with alpk1 activity |
CN117517657B (zh) * | 2024-01-08 | 2024-04-09 | 中国农业科学院北京畜牧兽医研究所 | Lnx1基因或蛋白在调控禽类先天免疫应答反应中的应用 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000018950A2 (en) * | 1998-09-25 | 2000-04-06 | Bioqual Inc. | Assay method for ntp hydrolising enzymes |
EP2017281A1 (en) * | 2006-04-14 | 2009-01-21 | Kyowa Hakko Kirin Co., Ltd. | Toll-like receptor 9 agonists |
WO2016054745A1 (en) * | 2014-10-10 | 2016-04-14 | The Governing Council Of The University Of Toronto | Methods of modulating immune system responses |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3582793A4 (en) * | 2017-02-17 | 2020-12-16 | Aivita Biomedical, Inc. | METHOD OF INCREASING TUMOR IMMUNOGENITY AND COMPOSITIONS FOR AUTOLOGOUS CANCER IMMUNOTHERAPEUTIC PRODUCTS USING MODIFIED TUMOR CELLS AND MODIFIED DENDRITIC CELLS |
AU2018355487B2 (en) * | 2017-10-27 | 2023-09-21 | Shanghai Yao Yuan Biotechnology Co., Ltd. | Compositions and methods of modulating the immune response by activating alpha protein kinase 1 |
-
2019
- 2019-06-11 KR KR1020217000953A patent/KR20210020104A/ko unknown
- 2019-06-11 SG SG11202012496XA patent/SG11202012496XA/en unknown
- 2019-06-11 CN CN201980025130.1A patent/CN111971049A/zh active Pending
- 2019-06-11 CA CA3103724A patent/CA3103724A1/en not_active Abandoned
- 2019-06-11 EP EP19818829.4A patent/EP3752163A4/en not_active Withdrawn
- 2019-06-11 JP JP2021518839A patent/JP2021527133A/ja active Pending
- 2019-06-11 WO PCT/CN2019/090647 patent/WO2019238024A1/en unknown
- 2019-06-11 AU AU2019284192A patent/AU2019284192A1/en not_active Abandoned
-
2020
- 2020-09-15 US US17/022,073 patent/US11229707B2/en active Active
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000018950A2 (en) * | 1998-09-25 | 2000-04-06 | Bioqual Inc. | Assay method for ntp hydrolising enzymes |
EP2017281A1 (en) * | 2006-04-14 | 2009-01-21 | Kyowa Hakko Kirin Co., Ltd. | Toll-like receptor 9 agonists |
WO2016054745A1 (en) * | 2014-10-10 | 2016-04-14 | The Governing Council Of The University Of Toronto | Methods of modulating immune system responses |
Non-Patent Citations (8)
Also Published As
Publication number | Publication date |
---|---|
WO2019238024A1 (en) | 2019-12-19 |
EP3752163A4 (en) | 2021-04-07 |
SG11202012496XA (en) | 2021-01-28 |
JP2021527133A (ja) | 2021-10-11 |
EP3752163A1 (en) | 2020-12-23 |
AU2019284192A1 (en) | 2021-01-28 |
CA3103724A1 (en) | 2019-12-19 |
KR20210020104A (ko) | 2021-02-23 |
US20200405869A1 (en) | 2020-12-31 |
US11229707B2 (en) | 2022-01-25 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US11229707B2 (en) | Promoting immune responses | |
JP7330312B2 (ja) | Hivを治療するためのトール様受容体の調節因子 | |
US8604184B2 (en) | Chemically programmable immunity | |
JP2020503303A (ja) | がんの処置のための環状ジヌクレオチドstingアゴニスト | |
JP5117660B2 (ja) | 癌疾患治療剤 | |
US20190031708A1 (en) | Cyclic dinucleotides for treating conditions associated with sting activity such as cancer | |
US20200330427A1 (en) | Benzo[b]thiophene STING Agonists for Cancer Treatment | |
US20110262442A1 (en) | Compositions for treating cns disorders | |
AU2016229146A1 (en) | Compositions and methods for activating "stimulator of interferon gene" -dependent signalling | |
RU2006120950A (ru) | Антитело к cd40: препарат и способы | |
TWI820984B (zh) | 替諾福韋埃拉酚胺(tenofovir alafenamide)之晶型 | |
US20230321074A1 (en) | Use of chiauranib in combination with immune checkpoint inhibitor in antitumor therapy | |
JP2007527419A (ja) | 化学的にプログラム可能な免疫 | |
JP2015172060A5 (zh) | ||
US20210315991A1 (en) | Combination including a cpg-c type oligonucleotide and a pd-1 antagonist for treating breast cancer | |
ES2935265T3 (es) | Método para tratar acontecimientos adversos inducidos por inhibidores de punto de control | |
CN110573620A (zh) | 血癌治疗剂 | |
TW200306185A (en) | Combinations comprising EPOTHILONES and anti-metabolites | |
KR20210142614A (ko) | 암 치료를 위한 이아다뎀스타트 조합물 | |
Kalinova et al. | Rheumatological aspects of pathogenesis and treatment of COVID-19 infection | |
US11648252B2 (en) | Methotrexate for use as a medicament | |
EP3939987A1 (en) | Oligonucleotide having anti-inflammatory activity | |
WO2020091052A1 (ja) | 関節炎治療剤 | |
WO2013027063A1 (en) | Chemically programmable immunity | |
CN117083083A (zh) | Toll样受体7激动剂和抗PD-L1抗体的药物联合 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
TA01 | Transfer of patent application right |
Effective date of registration: 20220325 Address after: 102206 Room 101, 7 / F, building 1, courtyard 9, Yiyi Road, Changping District, Beijing Applicant after: Beijing Yanming Biotechnology Co.,Ltd. Address before: 102206, 7 science Road, Zhongguancun Life Science Park, Changping District, Beijing Applicant before: NATIONAL INSTITUTE OF BIOLOGICAL SCIENCES, BEIJING |
|
TA01 | Transfer of patent application right |