CN103097543A - 逆转朗格汉斯细胞免疫抑制的方法 - Google Patents
逆转朗格汉斯细胞免疫抑制的方法 Download PDFInfo
- Publication number
- CN103097543A CN103097543A CN2010800633076A CN201080063307A CN103097543A CN 103097543 A CN103097543 A CN 103097543A CN 2010800633076 A CN2010800633076 A CN 2010800633076A CN 201080063307 A CN201080063307 A CN 201080063307A CN 103097543 A CN103097543 A CN 103097543A
- Authority
- CN
- China
- Prior art keywords
- hpv
- cell
- primary cell
- derive
- biological products
- 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
- 210000001821 langerhans cell Anatomy 0.000 title claims abstract description 157
- 238000000034 method Methods 0.000 title claims abstract description 70
- 230000008629 immune suppression Effects 0.000 title abstract 2
- 241000701806 Human papillomavirus Species 0.000 claims abstract description 151
- 210000004027 cell Anatomy 0.000 claims abstract description 79
- 230000036039 immunity Effects 0.000 claims abstract description 23
- 230000005012 migration Effects 0.000 claims abstract description 21
- 238000013508 migration Methods 0.000 claims abstract description 21
- 230000001939 inductive effect Effects 0.000 claims abstract description 19
- 230000003213 activating effect Effects 0.000 claims abstract description 6
- 210000001744 T-lymphocyte Anatomy 0.000 claims description 53
- 102000004127 Cytokines Human genes 0.000 claims description 46
- 108090000695 Cytokines Proteins 0.000 claims description 46
- 230000004913 activation Effects 0.000 claims description 42
- 230000004044 response Effects 0.000 claims description 32
- 230000008569 process Effects 0.000 claims description 20
- 208000015181 infectious disease Diseases 0.000 claims description 19
- 230000007170 pathology Effects 0.000 claims description 14
- 102000004890 Interleukin-8 Human genes 0.000 claims description 13
- 108090001007 Interleukin-8 Proteins 0.000 claims description 13
- 230000001506 immunosuppresive effect Effects 0.000 claims description 12
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical group CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 claims description 12
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 claims description 12
- 206010062016 Immunosuppression Diseases 0.000 claims description 11
- 108010074328 Interferon-gamma Proteins 0.000 claims description 11
- 108060008682 Tumor Necrosis Factor Proteins 0.000 claims description 11
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 claims description 11
- 230000001225 therapeutic effect Effects 0.000 claims description 11
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 claims description 10
- 102100037850 Interferon gamma Human genes 0.000 claims description 10
- 102000004889 Interleukin-6 Human genes 0.000 claims description 10
- 108090001005 Interleukin-6 Proteins 0.000 claims description 10
- 239000013000 chemical inhibitor Substances 0.000 claims description 10
- 230000003053 immunization Effects 0.000 claims description 10
- 229960003444 immunosuppressant agent Drugs 0.000 claims description 9
- 230000001861 immunosuppressant effect Effects 0.000 claims description 9
- 239000003018 immunosuppressive agent Substances 0.000 claims description 9
- 230000028327 secretion Effects 0.000 claims description 9
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 8
- 210000000981 epithelium Anatomy 0.000 claims description 8
- 239000011701 zinc Substances 0.000 claims description 8
- 229910052725 zinc Inorganic materials 0.000 claims description 8
- 230000002441 reversible effect Effects 0.000 claims description 7
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical group ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 claims description 6
- 229960000905 indomethacin Drugs 0.000 claims description 6
- 102100035793 CD83 antigen Human genes 0.000 claims description 5
- 101000946856 Homo sapiens CD83 antigen Proteins 0.000 claims description 5
- 101000914484 Homo sapiens T-lymphocyte activation antigen CD80 Proteins 0.000 claims description 5
- 102000000589 Interleukin-1 Human genes 0.000 claims description 5
- 108010002352 Interleukin-1 Proteins 0.000 claims description 5
- 102100027222 T-lymphocyte activation antigen CD80 Human genes 0.000 claims description 5
- 101150013553 CD40 gene Proteins 0.000 claims description 4
- 102000003777 Interleukin-1 beta Human genes 0.000 claims description 4
- 108090000193 Interleukin-1 beta Proteins 0.000 claims description 4
- 102100040245 Tumor necrosis factor receptor superfamily member 5 Human genes 0.000 claims description 4
- 229940100198 alkylating agent Drugs 0.000 claims description 4
- 239000002168 alkylating agent Substances 0.000 claims description 4
- 229960000590 celecoxib Drugs 0.000 claims description 4
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 claims description 4
- 229960000371 rofecoxib Drugs 0.000 claims description 4
- RZJQGNCSTQAWON-UHFFFAOYSA-N rofecoxib Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C1=C(C=2C=CC=CC=2)C(=O)OC1 RZJQGNCSTQAWON-UHFFFAOYSA-N 0.000 claims description 4
- 102100036301 C-C chemokine receptor type 7 Human genes 0.000 claims description 3
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 claims description 3
- 101000716065 Homo sapiens C-C chemokine receptor type 7 Proteins 0.000 claims description 3
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 claims description 3
- 230000006044 T cell activation Effects 0.000 claims description 3
- 229960001680 ibuprofen Drugs 0.000 claims description 3
- 239000002955 immunomodulating agent Substances 0.000 claims description 3
- 229940121354 immunomodulator Drugs 0.000 claims description 3
- 230000002584 immunomodulator Effects 0.000 claims description 3
- 108010017080 Granulocyte Colony-Stimulating Factor Proteins 0.000 claims description 2
- 102000013462 Interleukin-12 Human genes 0.000 claims description 2
- 108010065805 Interleukin-12 Proteins 0.000 claims description 2
- 102000003812 Interleukin-15 Human genes 0.000 claims description 2
- 108090000172 Interleukin-15 Proteins 0.000 claims description 2
- 108010002586 Interleukin-7 Proteins 0.000 claims description 2
- 102000000704 Interleukin-7 Human genes 0.000 claims description 2
- 229940124614 TLR 8 agonist Drugs 0.000 claims description 2
- 239000005557 antagonist Substances 0.000 claims description 2
- 230000003915 cell function Effects 0.000 claims description 2
- 230000002503 metabolic effect Effects 0.000 claims description 2
- 230000035764 nutrition Effects 0.000 claims description 2
- 235000016709 nutrition Nutrition 0.000 claims description 2
- 150000003180 prostaglandins Chemical class 0.000 claims description 2
- 210000003289 regulatory T cell Anatomy 0.000 claims description 2
- 108010002350 Interleukin-2 Proteins 0.000 claims 5
- 102000000588 Interleukin-2 Human genes 0.000 claims 5
- 102000004269 Granulocyte Colony-Stimulating Factor Human genes 0.000 claims 1
- 102000004457 Granulocyte-Macrophage Colony-Stimulating Factor Human genes 0.000 claims 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 claims 1
- 210000001165 lymph node Anatomy 0.000 abstract description 6
- 230000028993 immune response Effects 0.000 abstract description 3
- 230000003902 lesion Effects 0.000 abstract description 3
- 108010043766 IRX 2 Proteins 0.000 description 77
- 239000000203 mixture Substances 0.000 description 35
- 206010028980 Neoplasm Diseases 0.000 description 25
- 239000000427 antigen Substances 0.000 description 23
- 102000036639 antigens Human genes 0.000 description 23
- 108091007433 antigens Proteins 0.000 description 23
- 239000000047 product Substances 0.000 description 22
- 230000000694 effects Effects 0.000 description 17
- 241000341655 Human papillomavirus type 16 Species 0.000 description 15
- 238000011282 treatment Methods 0.000 description 14
- 102000019034 Chemokines Human genes 0.000 description 13
- 108010012236 Chemokines Proteins 0.000 description 13
- 201000011510 cancer Diseases 0.000 description 13
- 201000010099 disease Diseases 0.000 description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 12
- 230000006907 apoptotic process Effects 0.000 description 10
- 229960005486 vaccine Drugs 0.000 description 9
- 210000003679 cervix uteri Anatomy 0.000 description 8
- 210000004443 dendritic cell Anatomy 0.000 description 8
- 238000002347 injection Methods 0.000 description 8
- 239000007924 injection Substances 0.000 description 8
- 210000001616 monocyte Anatomy 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 7
- 229940096397 interleukin-8 Drugs 0.000 description 7
- 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 7
- 108090000765 processed proteins & peptides Proteins 0.000 description 7
- 206010008342 Cervix carcinoma Diseases 0.000 description 6
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 6
- 241000700605 Viruses Species 0.000 description 6
- 201000010881 cervical cancer Diseases 0.000 description 6
- 230000000139 costimulatory effect Effects 0.000 description 6
- 230000006870 function Effects 0.000 description 6
- 230000004083 survival effect Effects 0.000 description 6
- 208000009608 Papillomavirus Infections Diseases 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 229940100601 interleukin-6 Drugs 0.000 description 5
- 230000035800 maturation Effects 0.000 description 5
- 230000008093 supporting effect Effects 0.000 description 5
- 102100036846 C-C motif chemokine 21 Human genes 0.000 description 4
- 101000713085 Homo sapiens C-C motif chemokine 21 Proteins 0.000 description 4
- 102100030703 Interleukin-22 Human genes 0.000 description 4
- 102000038030 PI3Ks Human genes 0.000 description 4
- 108091007960 PI3Ks Proteins 0.000 description 4
- 239000002671 adjuvant Substances 0.000 description 4
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 description 4
- 229960004397 cyclophosphamide Drugs 0.000 description 4
- 210000002615 epidermis Anatomy 0.000 description 4
- 230000003308 immunostimulating effect Effects 0.000 description 4
- 239000003112 inhibitor Substances 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 108010074109 interleukin-22 Proteins 0.000 description 4
- 210000002540 macrophage Anatomy 0.000 description 4
- 230000007246 mechanism Effects 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- 235000019198 oils Nutrition 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 230000000638 stimulation Effects 0.000 description 4
- 239000006228 supernatant Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- 206010059313 Anogenital warts Diseases 0.000 description 3
- 206010008263 Cervical dysplasia Diseases 0.000 description 3
- 102000009410 Chemokine receptor Human genes 0.000 description 3
- 108050000299 Chemokine receptor Proteins 0.000 description 3
- 108020004414 DNA Proteins 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 206010061218 Inflammation Diseases 0.000 description 3
- 108091054455 MAP kinase family Proteins 0.000 description 3
- 102000043136 MAP kinase family Human genes 0.000 description 3
- 101150021539 MT-CO2 gene Proteins 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 108091008611 Protein Kinase B Proteins 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 230000000735 allogeneic effect Effects 0.000 description 3
- 238000013459 approach Methods 0.000 description 3
- 230000001413 cellular effect Effects 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- 230000004069 differentiation Effects 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- 238000000684 flow cytometry Methods 0.000 description 3
- 238000013467 fragmentation Methods 0.000 description 3
- 238000006062 fragmentation reaction Methods 0.000 description 3
- 229960002751 imiquimod Drugs 0.000 description 3
- DOUYETYNHWVLEO-UHFFFAOYSA-N imiquimod Chemical compound C1=CC=CC2=C3N(CC(C)C)C=NC3=C(N)N=C21 DOUYETYNHWVLEO-UHFFFAOYSA-N 0.000 description 3
- 230000001900 immune effect Effects 0.000 description 3
- 230000002757 inflammatory effect Effects 0.000 description 3
- 230000004054 inflammatory process Effects 0.000 description 3
- 210000001365 lymphatic vessel Anatomy 0.000 description 3
- 210000004698 lymphocyte Anatomy 0.000 description 3
- 239000003550 marker Substances 0.000 description 3
- 239000003226 mitogen Substances 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 230000001717 pathogenic effect Effects 0.000 description 3
- 230000006320 pegylation Effects 0.000 description 3
- 210000005105 peripheral blood lymphocyte Anatomy 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 238000012545 processing Methods 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 210000003491 skin Anatomy 0.000 description 3
- 230000004936 stimulating effect Effects 0.000 description 3
- 239000000277 virosome Substances 0.000 description 3
- UEJJHQNACJXSKW-UHFFFAOYSA-N 2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1C1CCC(=O)NC1=O UEJJHQNACJXSKW-UHFFFAOYSA-N 0.000 description 2
- ZOOGRGPOEVQQDX-UUOKFMHZSA-N 3',5'-cyclic GMP Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-UUOKFMHZSA-N 0.000 description 2
- -1 4-aminoquinolone (4-aminoquinolone) Chemical compound 0.000 description 2
- 102100028681 C-type lectin domain family 4 member K Human genes 0.000 description 2
- 101710183165 C-type lectin domain family 4 member K Proteins 0.000 description 2
- 108090000397 Caspase 3 Proteins 0.000 description 2
- 102100029855 Caspase-3 Human genes 0.000 description 2
- 102000011727 Caspases Human genes 0.000 description 2
- 108010076667 Caspases Proteins 0.000 description 2
- 208000000907 Condylomata Acuminata Diseases 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 2
- 102100022297 Integrin alpha-X Human genes 0.000 description 2
- 102000009571 Macrophage Inflammatory Proteins Human genes 0.000 description 2
- 108010009474 Macrophage Inflammatory Proteins Proteins 0.000 description 2
- 108090000430 Phosphatidylinositol 3-kinases Proteins 0.000 description 2
- 102000001708 Protein Isoforms Human genes 0.000 description 2
- 108010029485 Protein Isoforms Proteins 0.000 description 2
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 2
- 208000032124 Squamous Intraepithelial Lesions Diseases 0.000 description 2
- 230000006052 T cell proliferation Effects 0.000 description 2
- 102100025387 Tyrosine-protein kinase JAK3 Human genes 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 239000012190 activator Substances 0.000 description 2
- 230000000996 additive effect Effects 0.000 description 2
- 230000000240 adjuvant effect Effects 0.000 description 2
- 208000025009 anogenital human papillomavirus infection Diseases 0.000 description 2
- 201000004201 anogenital venereal wart Diseases 0.000 description 2
- 230000030741 antigen processing and presentation Effects 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 229940022399 cancer vaccine Drugs 0.000 description 2
- 238000009566 cancer vaccine Methods 0.000 description 2
- 238000010523 cascade reaction Methods 0.000 description 2
- 208000026735 cervix disease Diseases 0.000 description 2
- 229960003405 ciprofloxacin Drugs 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- XEYBRNLFEZDVAW-ARSRFYASSA-N dinoprostone Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O XEYBRNLFEZDVAW-ARSRFYASSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000012377 drug delivery Methods 0.000 description 2
- 230000008030 elimination Effects 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- HKSZLNNOFSGOKW-UHFFFAOYSA-N ent-staurosporine Natural products C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1C1CC(NC)C(OC)C4(C)O1 HKSZLNNOFSGOKW-UHFFFAOYSA-N 0.000 description 2
- 238000013401 experimental design Methods 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 210000000987 immune system Anatomy 0.000 description 2
- 238000002649 immunization Methods 0.000 description 2
- 238000009169 immunotherapy Methods 0.000 description 2
- 239000007943 implant Substances 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 230000008595 infiltration Effects 0.000 description 2
- 238000001764 infiltration Methods 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- 230000002045 lasting effect Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 230000005923 long-lasting effect Effects 0.000 description 2
- 238000002826 magnetic-activated cell sorting Methods 0.000 description 2
- 230000010534 mechanism of action Effects 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- 210000004400 mucous membrane Anatomy 0.000 description 2
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 2
- 230000002688 persistence Effects 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 235000019633 pungent taste Nutrition 0.000 description 2
- 229950010550 resiquimod Drugs 0.000 description 2
- BXNMTOQRYBFHNZ-UHFFFAOYSA-N resiquimod Chemical compound C1=CC=CC2=C(N(C(COCC)=N3)CC(C)(C)O)C3=C(N)N=C21 BXNMTOQRYBFHNZ-UHFFFAOYSA-N 0.000 description 2
- HKSZLNNOFSGOKW-FYTWVXJKSA-N staurosporine Chemical compound C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1[C@H]1C[C@@H](NC)[C@@H](OC)[C@]4(C)O1 HKSZLNNOFSGOKW-FYTWVXJKSA-N 0.000 description 2
- CGPUWJWCVCFERF-UHFFFAOYSA-N staurosporine Natural products C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1C1CC(NC)C(OC)C4(OC)O1 CGPUWJWCVCFERF-UHFFFAOYSA-N 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 229960003433 thalidomide Drugs 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- 230000009385 viral infection Effects 0.000 description 2
- 229940088594 vitamin Drugs 0.000 description 2
- 239000011782 vitamin Substances 0.000 description 2
- 229930003231 vitamin Natural products 0.000 description 2
- 235000013343 vitamin Nutrition 0.000 description 2
- 150000003722 vitamin derivatives Chemical class 0.000 description 2
- FBFJOZZTIXSPPR-UHFFFAOYSA-N 1-(4-aminobutyl)-2-(ethoxymethyl)imidazo[4,5-c]quinolin-4-amine Chemical compound C1=CC=CC2=C(N(C(COCC)=N3)CCCCN)C3=C(N)N=C21 FBFJOZZTIXSPPR-UHFFFAOYSA-N 0.000 description 1
- VNBFUGOVQMFIRN-UHFFFAOYSA-N 1-chlorobutan-2-ol Chemical compound CCC(O)CCl VNBFUGOVQMFIRN-UHFFFAOYSA-N 0.000 description 1
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-M 4-hydroxybenzoate Chemical compound OC1=CC=C(C([O-])=O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-M 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 102100032814 ATP-dependent zinc metalloprotease YME1L1 Human genes 0.000 description 1
- 102100021569 Apoptosis regulator Bcl-2 Human genes 0.000 description 1
- 102100032367 C-C motif chemokine 5 Human genes 0.000 description 1
- 102100025752 CASP8 and FADD-like apoptosis regulator Human genes 0.000 description 1
- 102000000905 Cadherin Human genes 0.000 description 1
- 108050007957 Cadherin Proteins 0.000 description 1
- 102100025805 Cadherin-1 Human genes 0.000 description 1
- 101100322915 Caenorhabditis elegans akt-1 gene Proteins 0.000 description 1
- 108090000565 Capsid Proteins Proteins 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- 108090000567 Caspase 7 Proteins 0.000 description 1
- 102100038902 Caspase-7 Human genes 0.000 description 1
- 102100023321 Ceruloplasmin Human genes 0.000 description 1
- 108010055166 Chemokine CCL5 Proteins 0.000 description 1
- 108091026890 Coding region Proteins 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- 108010039471 Fas Ligand Protein Proteins 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 102100039619 Granulocyte colony-stimulating factor Human genes 0.000 description 1
- 108010088729 HLA-A*02:01 antigen Proteins 0.000 description 1
- 102000015789 HLA-DP Antigens Human genes 0.000 description 1
- 108010010378 HLA-DP Antigens Proteins 0.000 description 1
- 101000971171 Homo sapiens Apoptosis regulator Bcl-2 Proteins 0.000 description 1
- 101000914211 Homo sapiens CASP8 and FADD-like apoptosis regulator Proteins 0.000 description 1
- 101000984015 Homo sapiens Cadherin-1 Proteins 0.000 description 1
- 101001056180 Homo sapiens Induced myeloid leukemia cell differentiation protein Mcl-1 Proteins 0.000 description 1
- 101000800483 Homo sapiens Toll-like receptor 8 Proteins 0.000 description 1
- 101000934996 Homo sapiens Tyrosine-protein kinase JAK3 Proteins 0.000 description 1
- 101000767631 Human papillomavirus type 16 Protein E7 Proteins 0.000 description 1
- 102100026539 Induced myeloid leukemia cell differentiation protein Mcl-1 Human genes 0.000 description 1
- 102000008070 Interferon-gamma Human genes 0.000 description 1
- 108090000177 Interleukin-11 Proteins 0.000 description 1
- 102000003815 Interleukin-11 Human genes 0.000 description 1
- 108090000978 Interleukin-4 Proteins 0.000 description 1
- 206010062049 Lymphocytic infiltration Diseases 0.000 description 1
- 101150079116 MT-CO1 gene Proteins 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 206010027336 Menstruation delayed Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 101710151805 Mitochondrial intermediate peptidase 1 Proteins 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 101800000795 Proadrenomedullin N-20 terminal peptide Proteins 0.000 description 1
- 108010029477 STAT5 Transcription Factor Proteins 0.000 description 1
- BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical compound [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 description 1
- 102100024481 Signal transducer and activator of transcription 5A Human genes 0.000 description 1
- 102100024784 Suppressor of cytokine signaling 2 Human genes 0.000 description 1
- 101710137422 Suppressor of cytokine signaling 2 Proteins 0.000 description 1
- 230000005867 T cell response Effects 0.000 description 1
- 229940124613 TLR 7/8 agonist Drugs 0.000 description 1
- 102000002689 Toll-like receptor Human genes 0.000 description 1
- 108020000411 Toll-like receptor Proteins 0.000 description 1
- 102100033110 Toll-like receptor 8 Human genes 0.000 description 1
- 102100031988 Tumor necrosis factor ligand superfamily member 6 Human genes 0.000 description 1
- 101710112792 Tyrosine-protein kinase JAK3 Proteins 0.000 description 1
- 208000018079 Uterine Cervical disease Diseases 0.000 description 1
- 208000000260 Warts Diseases 0.000 description 1
- DPDMMXDBJGCCQC-UHFFFAOYSA-N [Na].[Cl] Chemical compound [Na].[Cl] DPDMMXDBJGCCQC-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000000961 alloantigen Effects 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 239000012491 analyte Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000006909 anti-apoptosis Effects 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000002155 anti-virotic effect Effects 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 229940034982 antineoplastic agent Drugs 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 210000000436 anus Anatomy 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000005441 aurora Substances 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 210000000270 basal cell Anatomy 0.000 description 1
- 239000000227 bioadhesive Substances 0.000 description 1
- 238000001574 biopsy Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 230000005907 cancer growth Effects 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 230000020411 cell activation Effects 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 208000007951 cervical intraepithelial neoplasia Diseases 0.000 description 1
- 230000003399 chemotactic effect Effects 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 238000003501 co-culture Methods 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 239000003636 conditioned culture medium Substances 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 239000002385 cottonseed oil Substances 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 238000005336 cracking Methods 0.000 description 1
- 239000012228 culture supernatant Substances 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000030609 dephosphorylation Effects 0.000 description 1
- 238000006209 dephosphorylation reaction Methods 0.000 description 1
- UGMCXQCYOVCMTB-UHFFFAOYSA-K dihydroxy(stearato)aluminium Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[Al](O)O UGMCXQCYOVCMTB-UHFFFAOYSA-K 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 229960002986 dinoprostone Drugs 0.000 description 1
- 239000002612 dispersion medium Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000004043 dyeing Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000012645 endogenous antigen Substances 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 230000017188 evasion or tolerance of host immune response Effects 0.000 description 1
- 230000000763 evoking effect Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 229940044627 gamma-interferon Drugs 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 230000012447 hatching Effects 0.000 description 1
- 208000013210 hematogenous Diseases 0.000 description 1
- 230000002519 immonomodulatory effect Effects 0.000 description 1
- 230000006054 immunological memory Effects 0.000 description 1
- 230000007365 immunoregulation Effects 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 230000001976 improved effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 229940074383 interleukin-11 Drugs 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 230000001926 lymphatic effect Effects 0.000 description 1
- 230000000527 lymphocytic effect Effects 0.000 description 1
- ADKOXSOCTOWDOP-UHFFFAOYSA-L magnesium;aluminum;dihydroxide;trihydrate Chemical compound O.O.O.[OH-].[OH-].[Mg+2].[Al] ADKOXSOCTOWDOP-UHFFFAOYSA-L 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 210000001700 mitochondrial membrane Anatomy 0.000 description 1
- 238000007799 mixed lymphocyte reaction assay Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 210000005087 mononuclear cell Anatomy 0.000 description 1
- 210000000822 natural killer cell Anatomy 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 244000309711 non-enveloped viruses Species 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- PIRWNASAJNPKHT-SHZATDIYSA-N pamp Chemical compound C([C@@H](C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](C)N)C(C)C)C1=CC=CC=C1 PIRWNASAJNPKHT-SHZATDIYSA-N 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 239000013612 plasmid Substances 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004417 polycarbonate Substances 0.000 description 1
- 229920000515 polycarbonate Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- XEYBRNLFEZDVAW-UHFFFAOYSA-N prostaglandin E2 Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CC=CCCCC(O)=O XEYBRNLFEZDVAW-UHFFFAOYSA-N 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000009711 regulatory function Effects 0.000 description 1
- 210000005000 reproductive tract Anatomy 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004043 responsiveness Effects 0.000 description 1
- 230000005070 ripening Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 238000005204 segregation Methods 0.000 description 1
- 239000011669 selenium Substances 0.000 description 1
- 229910052711 selenium Inorganic materials 0.000 description 1
- 238000001338 self-assembly Methods 0.000 description 1
- 210000000582 semen Anatomy 0.000 description 1
- 239000003352 sequestering agent Substances 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 201000010153 skin papilloma Diseases 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 238000011272 standard treatment Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 235000020238 sunflower seed Nutrition 0.000 description 1
- 238000011477 surgical intervention Methods 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 1
- 229940021747 therapeutic vaccine Drugs 0.000 description 1
- 210000001541 thymus gland Anatomy 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 229940044616 toll-like receptor 7 agonist Drugs 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/21—Interferons [IFN]
- A61K38/217—IFN-gamma
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
- A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
-
- 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
- A61K31/66—Phosphorus compounds
- A61K31/664—Amides of phosphorus 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
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/191—Tumor necrosis factors [TNF], e.g. lymphotoxin [LT], i.e. TNF-beta
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/193—Colony stimulating factors [CSF]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/20—Interleukins [IL]
- A61K38/2006—IL-1
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/20—Interleukins [IL]
- A61K38/2013—IL-2
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/20—Interleukins [IL]
- A61K38/204—IL-6
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/20—Interleukins [IL]
- A61K38/2046—IL-7
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/20—Interleukins [IL]
- A61K38/2053—IL-8
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/20—Interleukins [IL]
- A61K38/208—IL-12
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/20—Interleukins [IL]
- A61K38/2086—IL-13 to IL-16
-
- 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
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
-
- 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
-
- 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
Abstract
通过向感染有HPV的患者施用治疗有效量的来源于原代细胞之生物制品以及诱导针对HPV的免疫应答来治疗人***瘤病毒(HPV)的方法。通过向感染有HPV的患者施用治疗有效量的来源于原代细胞之生物制品以及使朗格汉斯细胞(LC)活化来克服HPV诱导之LC免疫抑制的方法。通过向感染有HPV的患者施用治疗有效量的来源于原代细胞之生物制品、使LC活化以及诱导LC向***迁移来提高LC向***迁移的方法。通过向感染有HPV的患者施用有效量的来源于原代细胞之生物制品、产生针对HPV的免疫力以及防止新病变发生来产生针对HPV的免疫力的方法。
Description
技术领域
本发明涉及逆转免疫抑制的方法。特别地，本发明涉及逆转人***瘤病毒(human papillomavirus，HPV)的免疫抑制以及治疗HPV感染。
背景技术
人***瘤病毒(HPV)是性传播的DNA病毒家族，其具有超过100种不同的基因型。基于它们所引发的病变谱，所述基因型分为低风险型和高风险型。低风险型主要诱导良性生殖道湿疣和低级别鳞状上皮内病变(low-grade squamous intraepithelial lesion)，而高风险型与***生殖器癌的发生有关并且可以在＞99％的子***中检测到(其中在约50％的病例中发现HPV16)。在美国，估计有75％的性活跃人群在其一生中染上至少一种生殖器HPV类型。
尽管通过有效的帕帕尼古拉乌(Papanicolaou，Pap))涂片筛查、早期检测和治疗可以使由子***导致的发病率和死亡率降低，然而在美国很多移民所来源的发展中国家中，这些措施均不易获得。在发展中国家中，子***仍是妇女中癌症相关死亡的第二大原因。重要的是，由于不断变化的人口特征，预计该疾病所造成的负担在接下来的几十年间将显著增加。即使在美国，其筛查计划已使侵袭性癌症的整体比率降低，但是在白种非西班牙裔妇女、黑人妇女、西班牙裔妇女和经济上处于劣势的妇女之间，癌症的发生率仍存在不同。在美国，目前FDA批准之HPV预防性疫苗((Merck))的外显率令人失望。在2007年，该疫苗仅施用给年龄为13-17岁女孩中的25％、年龄为18-26岁的所有女性中的10％，并且仅给与西班牙裔妇女中的1.1％。此外，该疫苗对已感染所述病毒的妇女(无论其是否已发生(前)癌性子宫颈病变)无效。考虑到感染HPV的终生风险以及疫苗覆盖率严重不足的人群将很可能继续以惊人速度发生子宫颈疾病和其它HPV相关疾病的事实，显然非常需要减轻病毒感染发生后产生之致癌作用的治疗方法。
HPV是非裂解性、非包膜病毒。其“早期”和“晚期”蛋白的基因组编码区被命名为“E”和“L”。E蛋白执行对于基因组复制来说关键的调节功能，其中的两种蛋白(E6和E7)在肿瘤发生中发挥重要作用，而两种L蛋白(L1和L2)是自组装的衣壳蛋白，其负责DNA包装和病毒体组装。***瘤病毒感染的独特之处在于：其生成周期与增殖中的宿主表皮或粘膜基底上皮细胞的细胞分化相关联。HPV在其生命周期中保持在上基部(suprabasal)，因此其仅与表皮中的细胞(例如基底细胞和朗格汉斯细胞(Langerhans cells，LC)相接触。由于其生成周期与细胞分化相关联，因此很难在体外产生HPV病毒体。作为HPV病毒体的替代物，已开发了能够携带报告质粒的HPV病毒样颗粒(virus-like particle，VLP)和HPV假病毒体(二者均是在本申请人实验室中建立的技术)。
高风险HPV的持久感染是发生子***的主要风险因素。虽然大多数感染HPV的妇女清除了病毒，但是所花费的时间可能在数月至数年的范围内。约15％的已感染高风险HPV的妇女不能引发针对HPV的有效免疫应答，这使得病毒持续存在数十年。清除速率慢和缺乏有效免疫表明，HPV以某种方式逃脱了免疫应答。
HPV已发展出逃避立即清除的多种逃脱机制，使病毒得以在宿主中复制和持续存在。本申请人已显示HPV利用LC作为免疫逃脱的一种机制，显示于图4中。LC位于皮肤和粘膜的上皮层中，其是与HPV接触的第一个并且是关键性的APC。因此，LC负责起始针对HPV感染的有效免疫应答。一旦识别外来抗原，LC经历包括表型和功能变化的成熟过程，包括共刺激分子CD80和CD86、I类和II类MHC、趋化因子受体(例如CCR7)的上调，细胞因子和趋化因子的分泌以及向局部***的迁移。本申请人已确定，暴露于HPV16 L1L2 VLP的LC不上调共刺激分子和趋化因子受体，不分泌细胞因子和趋化因子，并且不起始针对HPV16 VLP来源之抗原的表位特异性免疫应答。相反，髓样DC被HPV16L1L2 VLP活化，并且一经活化即刺激HPV特异性T细胞。摄入HPV16L1L2 VLP后，DC和LC中起始不同的胞内信号级联反应。当用HPV16L1L2 VLP刺激时，在DC中，有丝***原活化的蛋白激酶(mitogen-activated protein kinase，MAPK)途径被活化，而其在LC中不活化。然而，在LC中，磷脂酰肌醇3-激酶(phosphoinositide 3-kinase，PI3K)途径被活化，引发导致Akt失活的信号级联反应。HPV16 E7特异性T细胞能够识别并杀死暴露于HPV16 L1L2-E7嵌合型VLP(chimeric VLP，cVLP)的LC，表明cVLP内化后，HPV肽由LC呈递，但是HPV16 L1L2 VLP抑制LC引发免疫应答。综上，这些数据揭示，在不存在共刺激时，LC呈递HPV来源的肽，因而发生耐受和免疫抑制。这继而可以导致HPV持久感染以及发生癌症的可能性增加。
HPV的预防性疫苗诱导产生高效价的HPV中和抗体，并且已显示在长达6.5年的随访中具有高效力以及稳定水平的抗体。然而，在感染HPV的妇女中，一项3期试验未发现经接种组与对照组相比病毒清除加速的证据，确定性地表明基于VLP的预防性疫苗缺乏治疗效力。此外，由于HPV培养时间长、存在几种免疫逃避机制以及仅进行了几年的观察，因此预防性疫苗对癌症预防的持续效力仍有待确定。事实上，约三分之一的子***是由除目前疫苗中存在之HPV以外的HPV类型引起的，这增加了难题的范围。因此，需要花费数十年才能够测出针对子***率的可计量效果。同时，对于全世界数以亿计的、目前感染了高风险HPV或者在未来几年内会感染的妇女来说，仍然需要治疗HPV感染和相关病变的疗法。
手术是对患有子宫颈上皮内肿瘤(cervical intraepithelial neoplasia，CIN)病变之患者的标准疗法，其通常据称在一年随访时去除CIN病变的有效率高达90％。然而，当监测妇女的整个生存期时，其有效率较低。多于80％的经历过手术过程的妇女在如下情形下将随后再次需要进行第二次相关过程：手术未去除HPV感染，或者对一种HPV类型的清除激发了继发性HPV感染的再活化。开发中的治疗性疫苗旨在通过活化患者自身的细胞免疫应答来控制恶变，以及靶向(前)癌细胞中存在的抗原。在过去的十五年中，已开发了数种候选疫苗，然而迄今为止还没有一种癌症疫苗得到美国食品药品监督管理局的批准。
需要防止HPV感染到达诱导癌症发生阶段的干预手段。这样的干预是可行的，因为利用市售的HPV检测试剂盒(Digene Corp.)可以在早期检测到HPV感染。
几条证据证实了细胞免疫***在控制HPV和相关子宫颈病变的发病机制中的重要性。首先，25～40％的HPV阳性、轻微发育异常的病变自发地或者在局部活检不久之后消退，这表明衰退可能涉及局部炎症的诱导。其次，免疫缺陷与HPV感染的发生率增加有关。衰退中的HPV相关之皮肤疣和生殖器疣常常在病变处存在T淋巴细胞，这表明活跃的针对HPV的细胞介导之免疫应答可能是疾病衰退的要件之一。综上所述，这些研究表明，对HPV感染及其相关疾病的治疗方案应当旨在诱导感染部位的强的细胞免疫。
因此，需要在妇女的整个生存期间针对HPV的有效免疫治疗，以及克服HPV诱导之LC免疫抑制(其阻止有效治疗)的方法。
发明概要
本发明提供了治疗人***瘤病毒(HPV)的方法，其包括向感染有HPV的患者施用治疗有效量的来源于原代细胞之生物制品以及诱导针对HPV感染之免疫应答的步骤。
本发明还提供了克服HPV诱导之朗格汉斯细胞(LC)免疫抑制的方法，其包括向感染有HPV的患者施用治疗有效量的来源于原代细胞之生物制品以及使LC活化的步骤。
本发明提供了提高LC向***迁移的方法，其包括向感染有HPV的患者施用治疗有效量的来源于原代细胞之生物制品、使LC活化以及诱导LC向***迁移的步骤。
本发明还提供了产生针对HPV之免疫力的方法，其包括向感染有HPV的患者施用有效量的来源于原代细胞之生物制品、产生针对HPV的免疫力以及防止新病变发生的步骤。
附图说明
通过参考以下详细描述并结合附图，本发明的其它优点会很容易理解。
图1是朗格汉斯细胞(LC)中表达的表型标志物的直方图(现有技术)；
图2是显示LC之CD86表达的图(现有技术)；
图3是未活化LC与活化LC的示意图；
图4是HPV诱导LC耐受的示意图；
图5是LC活化实验的实验设计的示意图；
图6是暴露于HPV16和IRX-2的人LC上的表面活化标志物上调的图。
图7是显示在不存在和存在HPV16时IRX-2诱导人LC迁移的图。
图8是显示暴露于IRX-2的人朗格汉斯细胞在HPV存在下较好地刺激同种异体T细胞的图。
图9是显示暴露于HPV之后经IRX-2处理的人朗格汉斯细胞分泌高水平之IL-8和IP-10的图。
发明详述
本发明一般性地提供了通过施用来源于原代细胞的生物制品(IRX-2)来治疗HPV以及克服HPV诱导之LC免疫抑制的方法。本发明的疗法有效地用于治疗具有持久性HPV以及免疫***不能产生针对HPV之有效应答的患者。
本文中使用的“有效量”是指实现本发明期望结果(即，在感染HPV的患者中产生LC免疫抑制的逆转)所需的来源于原代细胞之生物制品的量。本领域技术人员能够确定应给予特定患者的来源于原代细胞之生物制品的量。
“IRX-2”也称为“citoplurikin”，其是来源于白细胞、来源于天然原代细胞的生物制品，其在cGMP标准下由经植物血凝素(PHA)和环丙沙星(ciprofloxacin)刺激的纯化人白细胞(单个核细胞(mononuclear))产生。主要的活性组分有白介素1β(IL-1β，本文中也称为IL-1)、白介素2(IL-2)、白介素6(IL-6)、白介素8(IL-8)、肿瘤坏死因子α(TNF-α)和γ-干扰素(IFN-γ)。优选地，本发明中使用的IRX-2包括这6种关键性细胞因子，并且可以仅含有这6种关键性细胞因子。IRX-2先前还被称为“NCM”——天然细胞因子混合物，其在美国专利No.6,977,072和7,153,499中定义和列出。术语“IRX-2”、“来源于原代细胞的生物制品”和“NCM”在本文中可互换使用。
简言之，在4-氨基喹诺酮(4-aminoquinolone)抗生素持续存在下以及有丝***原(在优选的实施方案中为PHA)持续或间断存在下制备IRX-2。然而，也可以使用其它有丝***原。所生产的用于向患者施用的IRX-2含有浓度为60～6,000pcg/mL(更优选150～1,800pcg/mL)的IL-1β、浓度为600～60,000pcg/mL(更优选3,000～12,000pcg/mL)的IL-2以及浓度为200～20,000pcg/mL(更优选1,000～4,000pcg/mL)的IFN-γ和TNF-α。
IRX-2还可包含浓度为60～6,000pcg/mL(更优选300～2,000pcg/mL)的IL-6、浓度为6000～600,000pcg/mL(更优选20,000～180,000pcg/mL)的IL-8、浓度为200～20,000pcg/mL(更优选1,000～4,000pcg/mL)的TNF-α。可以使用重组、天然或聚乙二醇化的细胞因子，或者IRX-2可包括重组、天然或聚乙二醇化细胞因子的混合物。IRX-2可以仅包含上述细胞因子，然而也可以包含其它细胞因子。本发明的IRX-2还可包含其它重组、天然或聚乙二醇化的细胞因子，例如IL-7、IL-12、IL-15、GM-CSF(浓度为100～10,000pcg/mL，更优选500～2,000pcg/mL)以及G-CSF。制备IRX-2的方法公开于上文引用的专利文献以及美国专利申请No.12/423,601中。
本发明还包括与本文公开之细胞因子相关的衍生物、片段和肽，其中所述衍生物、片段和肽保留其相应细胞因子的生物学活性。
IRX-2的多种活性细胞因子组分作用于免疫***的多种细胞类型，包括T细胞和树突状细胞。在H&NSCC患者的临床试验中，IRX-2显示是安全、可耐受并具有生物学活性的，其导致明显的无疾病存活和总体存活。IRX-2中生理量的细胞因子可以局部施用(例如表面施用)，提供改变LC“遭遇”HPV处微环境的机会。传统上，已使用来自单核细胞条件化培养基的天然细胞因子混合物或者含TNF-α、IL-1β、IL-6和PGE2之重组炎性细胞因子的混合物使DC成熟，以离体制备基于DC的癌症疫苗。IRX-2中的生理细胞因子水平远远低于离体DC成熟中或高剂量全身性细胞因子疗法中所使用的重组细胞因子的浓度。IRX-2中低水平的细胞因子使其能够直接注射入患者中而无显著毒性。
IRX-2还含有作为T细胞活化和增殖之关键介导物的几种细胞因子。IRX-2同时活化DC和T细胞的能力使其尤其具有吸引力，这是因为正是这种免疫细胞亚组的组合协调针对感染病毒之细胞的免疫应答。
还可以将另一些化合物与IRX-2一起施用，例如化学抑制剂、非甾体类抗炎药(NSAID)、锌及其组合。
所述化学抑制剂可以是不具有免疫抑制性(优选以低剂量使用)而具有免疫调节作用从而提高免疫力和/或免疫应答(例如通过抑制体内的免疫抑制或抑制物机制来实现)的任何化疗剂。根据一个优选的实施方案，所述化学抑制剂是抗肿瘤剂，包括但不限于烷化剂、抗代谢物和抗生素。所述化学抑制剂还可以是免疫调节剂，例如萨立多胺(thalidomide)。所述化学抑制剂还可以采用盐或其它复合物形式。优选地，所述化学抑制剂是烷化剂环磷酰胺(cyclophosphamide，CY)。
优选地，所述NSAID是吲哚美辛(indomethacin，INDO)，其是CoxI和CoxII二者的抑制剂。所述NSAID还可以是布洛芬或CoxII抑制剂(例如塞来昔布(celecoxib)和罗非昔布(rofecoxib))或其组合。
联合使用所述四种组分(即化学抑制剂、NSAID、来源于原代细胞的生物制品和锌)能够应对由免疫靶标所产生的抑制性环境并恢复患者的细胞免疫应答。更具体地，化学抑制剂抑制调节性T细胞；NSAID逆转***素的局部免疫抑制，来源于原代细胞的生物制品使树突状细胞活化、刺激T细胞并保护T细胞免于凋亡；锌提供对于T细胞功能来说关键的营养物。这一组合作用激发了针对内源和外源抗原的免疫应答。
更具体地，本发明提供了通过向感染有HPV的患者施用治疗有效量的IRX-2以及诱导针对HPV的免疫应答来治疗HPV的方法。优选地，IRX-2包含如上所述的6种关键性细胞因子——IL-1、IL-2、IL-6、IL-8、TNF-α和IFN-γ。如上所述，还可包含额外的细胞因子。如上所述，还可以施用额外的化合物，例如化学抑制剂、NSAID和锌。优选地，通过注射将IRX-2施用至上皮中存在HPV感染处以及诱导免疫应答所需的LC位置处。还优选表面应用至子宫颈。表面应用的方法包括但不限于将IRX-2分散于脂质体制剂BiphasixTM(Helix Biopharma Corp.，Aurora，Ontario，CA)中，随后应用至子宫颈上皮；使用子宫颈药物递送***TM(Cervical Drug Delivery SystemTM)(Inc.Chicago，IL)，其中IRX-2吸收进生物粘附聚合物贴剂中，然后将其粘贴至子宫颈上皮；以及通过子宫颈分离和递送设备(例如公开于Tracy等人的美国专利No.7,165,550中的设备)将IRX-2溶液注入子宫颈中。
一般来讲，IRX-2通过使未成熟的树突状细胞成熟从而有效地“启动”免疫***，刺激幼稚(
)T细胞的产生，并有效地将抗原呈递至幼稚T细胞。IRX-2通过诱导针对HPV的免疫应答从而能够有效地治疗HPV(由于HPV对LC的免疫抑制作用，HPV患者中缺乏所述免疫应答)。
针对HPV的免疫应答通过活化LC来诱导。活化与未活化的LC显示于图3中。基本上，IRX-2能够克服HPV对LC的免疫抑制。然后，活化的LC分泌活化T细胞和调节免疫的细胞因子，以诱导针对HPV的免疫应答，从而由于免疫***能够有效地攻击HPV而消除所有存在的病变以及抗御未来病变发作。例如，IRX-2增加LC的IL-8分泌和ILIP-10产生。LC能够活化HPV特异性CD8+T细胞。如以下实施例中所述，LC的活化由CD1a、MHC I类分子、MHC II类分子、CD40、CD80、CD83、CD86和CCR7的上调证实。
本发明还提供了通过向感染有HPV的患者施用治疗有效量的IRX-2以及使LC活化从而克服HPV诱导的LC免疫抑制的方法。IRX-2如上所述。通过活化LC，IRX-2能够克服由HPV所致的LC免疫抑制。因此，这样的LC可以有效地诱导T细胞活化，以攻击患者中存在的HPV。
本发明提供了通过施用治疗有效量的IRX-2、使LC活化以及诱导LC向***迁移从而提高LC向***迁移的方法。IRX-2如上所述。在IRX-2处理后，活性LC可有效地向患者的***迁移，并在感染HPV的患者中产生免疫应答。由于HPV的免疫抑制，正常情况下LC不能迁移至***。然而，使用IRX-2进行处理逆转了该免疫抑制，使得LC能够有效地在免疫***中起作用。
本发明提供了通过向感染有HPV的患者施用有效量的IRX-2、产生针对HPV的免疫力以及防止新病变发生从而产生针对HPV之免疫力的方法。IRX-2能够使已被HPV抑制的LC活化。活化的LC能够产生针对HPV的免疫应答。具有活跃地识别并能够攻击HPV的免疫***使得能够预防任何新病变的发生。活化的免疫***能够有效地治疗HPV以及预防未来的疾病发生。
本发明具有几个益处。由于病变主要由HPV的持久存在引起，因此诱导感染之免疫清除以及防止HPV传播的干预行为对于公共卫生来说具有重大影响。消除HPV持久存在有助于降低针对每种HPV相关癌症所发生的卫生保健费用。该方法是反复筛查或昂贵手术干预的低成本替代方法，并且其成功性具有高的合理预期，这是因为其靶向了HPV诱导之病变发生的原因(即，HPV持久存在及其相关的免疫逃脱)。
对于任何上述实施方案，使用如下治疗施用细节和/或步骤：
优选地，通过注射将所述细胞因子组合物局部应用至被HPV感染的上皮。或者，可以将本发明的细胞因子组合物注射至如下***周围，所述***流入所治疗之病变或其它病毒感染区区域的***中。更具体地，施用本领域技术人员已知的局部***外周注射或其它注射，以提供免疫治疗制备物的充分定位。
在使用外源性抗原的实施方案中，外源提供的合成或提取的抗原(例如肿瘤抗原和肽(参见Bellone，1998))可以以单独的制备物或者作为本发明细胞因子组合物的一部分施用至预先激发(pre-primed)或共激发(co-primed)的区域或远端***中。
可由例如癌症或其它免疫抑制疾病引起的T细胞内源性抑制可以通过低剂量环磷酰胺(CY)和非甾体类抗炎药(NSAID)的共施用(即与本发明的细胞因子组合物联用)而阻断。NSAID优选是吲哚美辛(INDO)，但也可以使用布洛芬或CoxII抑制剂(例如塞来昔布
或罗非昔布
)或其组合。NSAID的副作用可以用质子抑制剂和***素E类似物主动地进行治疗。还可以加入锌和复合维生素(可包括加入硒)作为帮助恢复T细胞免疫的试剂。优选地，锌的剂量是15～75mg。可以施用标准的复合维生素。锌可以是可获得的葡糖酸盐。
本发明的细胞因子组合物可以在手术、放疗、化疗或其组合之前或之后施用。本发明的组合物可以在肿瘤复发期间施用，即在认为肿瘤已经消失或者减轻的时期后再次发生肿瘤生长的期间。
IRX-2的作用机制
如上文所定义，本发明的来源于原代细胞之生物制品作为佐剂起作用，即刺激或增强患者针对特定抗原的免疫应答。此外，本发明的IRX-2组合物和方法特别适用于刺激T细胞介导的免疫应答。由本发明的组合物和方法引发的免疫应答包括诱导或产生幼稚T细胞、使树突状细胞分化和成熟、使抗原正确地呈递至T细胞(例如在***中)以及使单核细胞和巨噬细胞活化。具体地，在癌症患者中，由本发明的组合物和方法引发的免疫应答包括淋巴细胞对肿瘤的浸润、肿瘤破碎和消退以及窦组织细胞增生(存在时)降低。基本上，来源于原代细胞的生物制品诱导免疫产生，并阻断免疫破坏。来源于原代细胞之生物制品的作用机制进一步描述于本申请人的美国专利申请No.12/323,595中。
更具体地，本发明的组合物和方法通过诱导产生幼稚T细胞从而有助于克服患者的免疫阻遏/抑制。如本文所定义地，术语“幼稚”T细胞是指新产生的T细胞，该T细胞尚未暴露于抗原。因此，本发明的组合物和方法补充或产生新的T细胞。
由于已知树突状细胞在体内产生适当免疫应答的抗原呈递中发挥重要作用，因此对树突状细胞成熟具有刺激性作用的试剂将作为激发针对抗原之良好免疫应答的佐剂起作用。本发明的细胞因子组合物促进树突状细胞的成熟。本发明的细胞因子组合物还通过作为单核细胞/巨噬细胞的强效活化剂而提供进一步的佐剂作用。单核细胞是体内DC和巨噬细胞的前体，因而促进单核细胞/巨噬细胞活化的试剂对体内免疫应答具有佐剂作用。
来源于原代细胞的生物制品还通过保护活化的T细胞免于凋亡从而阻断免疫破坏。临床和实验数据显示，某些细胞因子(特别是利用共同的受体γ链的存活性细胞因子(survival cytokine))能够保护活化的T细胞免于肿瘤诱导的死亡并增强其抗肿瘤活性。
更具体地，有几种方式使来源于原代细胞的生物制品保护T细胞免于凋亡。使抗凋亡信号分子(即JAK-3和磷酸化的Akt)的表达上调以及使促凋亡分子(即SOCS-2)的表达下调。使CD8+和CD4+T淋巴细胞中胱天蛋白酶(caspase)的活化降低以及使cFLIP的表达增加。IRX-2对抗了PI3K/Akt存活途径的抑制。T细胞受到保护免于外在凋亡(MV诱导的和FasL诱导的凋亡)和内在线粒体凋亡。
通过阻止JAK3、CD3-ζ和STAT5下调，抑制Akt-1/2去磷酸化以及维持Bax/Bcl-2、Bax-Bcl-xL和Bim/Mcl-1的平衡比率，从而进一步保护免于MV诱导的外在调亡。还通过阻止胱天蛋白酶-3和胱天蛋白酶-7活性的诱导来保护免于MV诱导的调亡。更具体地，阻断胱天蛋白酶-3之经切割活性形式的诱导，以及线粒体膜电势的损失。抑制核DNA片段化。来源于原代细胞的生物制品保护免于内在凋亡表现为其保护活化的T细胞免于星孢菌素(staurosporine)诱导的凋亡。
重要的是，来源于原代细胞之生物制品的细胞因子以协同方式保护活化的T细胞免于凋亡。换言之，来源于原代细胞之生物制品中的细胞因子组合物产生的作用比单独施用各细胞因子时的更强。
鉴于以上方面，本发明的组合物和方法通过多种作用方式刺激免疫***，包括使树突状细胞体内成熟(导致肽抗原有效呈递)以及使单核细胞和巨噬细胞活化和产生幼稚未定向T细胞。抗原的正确呈递导致T和B细胞克隆扩增，使患者体内产生免疫力。在癌症患者的情形中，上述作用导致例如淋巴细胞浸润入肿瘤中(例如通过血行播散来实现)以及肿瘤减小和/或破坏。结果是由于免疫记忆而使得存活率提高。
使本发明细胞因子组合物的给药和剂量促进对外源或内源抗原的最佳免疫，其中需考虑个体患者的临床病症、施用位点和方法、施用方案、患者年龄、性别和体重。因此，出于本文目的的药学“有效量”如本领域已知地通过考虑这些因素来确定。所述量必须有效地促进免疫，导致例如肿瘤减小、肿瘤破碎和白细胞浸润、复发延迟或存活率提高或者症状改善或消除(包括T细胞数增加)。
在本发明的方法中，本发明的组合物可采用多种方式施用。应当注意，本发明组合物中使用的细胞因子或外源抗原可以其标准形式或者作为可药用衍生物来施用，并且可以单独施用或者作为活性成分与可药用载体、稀释剂、佐剂和载剂联用。此外，本发明的组合物可以皮内或皮下、或者***外周或***内、淋巴节内或脾内或肌内、腹膜内和胸内施用。本发明的组合物还可以表面应用至HPV感染的上皮，例如通过注入患者的子宫颈中来实现。接受治疗的患者是温血动物，特别是哺乳动物(包括人)。可药用的载体、稀释剂、佐剂和载剂以及植入载体一般是指惰性、非毒性的固体或液体填充剂、稀释剂或包封材料，其不与本发明的活性成分发生反应。
剂量可以是单次剂量或数天期间内的多次剂量。当施用本发明的组合物时，一般将其制备为单位剂量的注射用形式(例如溶液、混悬液或乳液)。适于注射的药物制剂包括无菌水溶液或分散体系，以及用于重溶形成无菌注射用溶液或分散体系的无菌粉末。载体可以是含有例如水、乙醇、多元醇(例如甘油、丙二醇、液态聚乙二醇等)、其合适混合物或植物油的溶剂或分散介质。
可例如通过使用包衣(例如卵磷脂)、通过在分散体系的情形中维持所需颗粒大小以及通过使用表面活性剂来维持适当的流动性。还可以使用非水性载剂(例如棉花籽油、芝麻油、橄榄油、大豆油、玉米油、葵花籽油或者花生油以及酯(例如肉豆蔻酸异丙酯))作为本发明组合物的溶剂***。此外，可以添加增强组合物稳定性、无菌性和等渗性的多种添加剂，包括抗微生物防腐剂、抗氧化剂、螯合剂和缓冲剂。可以通过不同的抗细菌剂和抗真菌剂(例如对羟基苯甲酸酯(paraben)、氯丁醇、苯酚、山梨酸等)来确保抑制微生物的作用。在很多情况下，包含等渗剂(例如糖、氯化钠等)是理想的。可以通过使用延迟吸收的试剂(例如单硬脂酸铝和明胶)来延长注射用药物形式的吸收。然而，根据本发明，所使用的任何载剂、稀释剂或添加剂需要与本发明的细胞因子或外源抗原相容。
可以通过将实施本发明时使用的细胞因子或外源抗原掺入所需量的合适溶剂中来制备无菌注射用溶液，其中所述溶剂含有所期望的几种其它成分。
本发明的药物制剂可以以含有任何相容载体(例如多种载剂、添加剂和稀释剂)的注射用制剂向患者施用，或者，本发明中使用的细胞因子和/或外源抗原可以以缓慢释放皮下植入物或靶向递送***(例如单克隆抗体、运载体递送、离子电渗入疗法、聚合物基质、脂质体和微球)的形式向患者进行肠胃外施用。可用于本发明的递送***的实例包括公开于美国专利No.5,225,182、5,169,383、5,167,616、4,959,217、4,925,678、4,487,603、4,486,194、4,447,233、4,447,224、4,439,196和4,475,196中的那些。很多其它的这种植入物、递送***和组件是本领域技术人员公知的。
应当理解，如上所讨论地，本发明的组合物和方法可用于治疗抗原引发的疾病，例如癌症、感染性疾病或持久性病变。所述组合物和方法通过刺激患者体内的免疫应答从而促进针对产生这些疾病之抗原的免疫，该免疫应答有助于减轻或消除患者之疾病的症状和效应。
本发明通过参考以下实验例而进一步详细描述。除非另有指明，否则这些实施例仅出于举例说明的目的而提供，而非旨在用于限定。因此，本发明不应以任何方式解释为限制于以下实施例，而应视为包括根据本文教导显见的任何及所有变化形式。
实施例1
产生人LC
由于HPV仅感染人类，因此使用人免疫细胞来研究HPV与LC的相互作用。从人皮肤中分离的原代LC通过迁移过程而活化，并表达高水平的MHC和共刺激分子。因此，从人供体分离原代未活化的皮肤来源之LC以进行有意义的体外长期和可重复性功能研究是不可行的。对于本实验而言，利用分化细胞因子从分离自健康供体的外周血单核细胞离体产生原代LC。循环单核细胞是体内表皮LC的直接前体。本申请人等已显示离体产生的LC表达与表皮LC同样的表面标志物(Langerin、E-钙粘素、CD11c、CD1a、高的MHC II类分子和胞内Birbeck颗粒)(图1)，并且可以在体外LC研究中一致地使用。
图1显示人单核细胞来源的朗格汉斯细胞表达与表皮来源之朗格汉斯细胞类似的表型标志物。未成熟的朗格汉斯细胞由粘附单核细胞在1000IU/mL GM-CSF、1000IU/mL IL-4和10ng/mL TGFβ中7天分化得到。通过流式细胞术分析细胞中MHC II类分子(HLA-DP、DQ、DR)、CD1a、CD11c、Langerin或E-钙粘蛋白的表达(灰色阴影直方图)。同工型对照显示为黑色无阴影的直方图。该数据代表获自数个健康供体的LC。
逆转HPV免疫逃脱
本申请人先前已着手研究通过靶向LC来逆转HPV免疫逃脱的策略。LC表达多种TLR，包括TLR3、7、8和9，其识别病原体相关分子模式(pathogen-associated molecular pattern，PAMP)并且一经与其配体结合即使细胞活化。出人意料的是，通过测量CD86的表达，发现FDA批准用于外部生殖器疣的TLR7激动剂
(咪喹莫特(Imiquimod)，Graceway Pharmaceuticals，LLC)对LC活化完全没有作用(图2)。这可以解释尚未发表的观察结果，即使用咪喹莫特治疗子宫颈病变没有效果。令人感兴趣的是，TLR8活化剂(3M-002)和TLR7/8激动剂(雷西莫特(Resiquimod))使感染HPV的LC完全活化，从而它们开始体外诱导HPV特异性T细胞应答。这些数据表明，可以通过使某些“危险信号”途径活化来逆转HPV对LC功能的抑制。
用IRX-2使人朗格汉斯细胞活化
暴露于病原体或其它“危险信号”后，LC从表皮迁移至引流***(draining lymph node)后能够有效地刺激T细胞，这种能力需要其细胞表面上共刺激分子和趋化因子受体的表达。研究了IRX-2在体外对人单核细胞来源之LC的表型成熟的作用。发现IRX-2处理诱导MHC I类分子和MHC II类分子以及共刺激分子CD40、CD80和CD86、成熟标志物CD83的上调。如先前所述进行LC的活化。简单地讲，收获LC，清洗，对其不处理或者用HPV16L1L2VLP以10μg/106个细胞的浓度于37℃处理1小时。孵育后，将细胞于37℃置于完全培养基中6小时。接着，不对细胞进行处理，或者用IRX-2(1∶2稀释)处理，或者用1μg/mL LPS处理作为阳性对照。IRX-2处理后，细胞再孵育48小时。收获细胞，清洗，染色以进行流式细胞分析，其中对CD1a、MHC I类分子、MHC II类分子、CD40、CD80、CD83、CD86或同工型对照进行染色。由MFI值计算处理组之间表面标志物的变化倍数。MFI提高表明标志物上调和LC活化。数据代表3个个体供体。
IRX-2的来源是从经植物血凝素(PHA)刺激24小时的人外周血单个核细胞中收集的上清液。利用QC试验测定混合物中细胞因子的水平，并根据4种关键细胞因子的水平将其标准化。cGMP生产过程得到高度一致的产物，各批次之间具有非常近似的细胞因子浓度。为了确保IRX-2对LC活化的一致性，使用两个不同批次的IRX-2对LC进行活化。
如图6所示，IRX-2处理使全部6种LC标志物的表达均显著增加，而与LC是否已暴露于HPV16 L1L2 VLP无关。令人感兴趣的是，与对照相比，暴露于HPV16 L1L2 VLP的LC中共刺激分子CD86的增加甚至更有效。多于95％的细胞表达CD86，多于80％的LC表达成熟标志物CD83(未显示)。
结果表明，IRX-2是LC活化和成熟的强效诱导物，并且其有效性不受LC先前暴露于HPV的影响。
实施例2
确定目前临床上可用的IRX-2是否能够使先前暴露于HPV16的LC活化是必要的。IRX-2对LC活化标志物表达的作用报道于实施例1中。在接下来的实验中，通过测定细胞因子分泌、迁移和同种异体抗原(alloantigen)特异性T细胞的活化来测试IRX-2的效力。
与LC类似地，APC的活化对于原代T淋巴细胞的成功相互作用和活化是必需的。炎性细胞因子能够使APC活化，导致其成熟以及抗原呈递功能的提高。IRX-2是有前景的免疫调节剂，当局部应用至感染HPV的上皮时，其能够影响LC的免疫刺激能力。为了确定IRX-2是否在表型上和功能上使暴露于HPV的LC活化，对细胞因子/趋化因子分泌、迁移以及刺激同种异体抗原特异性T细胞应答的能力进行测定。这些研究确定，与TLR8激动剂类似，IRX-2亦能够逆转HPV导致的免疫抑制。
实验设计：
当使LC暴露于HPV16并接着暴露于IRX-2时，测定LC的T细胞共刺激标志物的表达水平。LC由分离自健康供体的外周血单核细胞分化得到。如图5所示，将LC暴露于HPV16病毒样颗粒(VLP)6小时，然后加入IRX-2额外48小时。利用荧光抗体通过流式细胞术对细胞表面分子进行测定。测定细胞培养上清液中免疫刺激性细胞因子和趋化因子的存在情况，以确定LC是否已活化以及是否分泌活化T细胞的细胞因子或其它免疫调节细胞因子。通过体外迁移穿过transwell膜，测定暴露于HPVVLP和IRX-2后的LC迁移。通过在混合淋巴细胞反应(mixed lymphocytereaction，MLR)中将LC与同种异体T细胞一起培养，评估刺激T细胞的能力。每个实验中利用未经处理的LC、仅暴露于HPV VLP的LC以及仅用IRX-2处理的LC作为对照。每个实验利用来源于个体健康供体的LC重复至少3次。选择HLA-A＊0201阳性的受试者，以使能够针对已知的HPV来源之肽抗原对已明确的T细胞免疫应答进行测定。这些数据显示，IRX-2能够使暴露于HPV的LC重新获得刺激T细胞和迁移的能力，这两种功能对于产生抗病毒免疫应答来说是必需的。
产生人朗格汉斯细胞：
利用分化细胞因子由通过匿名健康供体的白细胞采集而分离的市售外周血单核细胞离体产生原代LC。首先使冻存的PBMC粘附至塑料培养瓶来产生单核细胞来源的LC。贴壁细胞在含有1000U/mL重组人(recombinant human，rhu)-GM-CSF、1000U/mL rhu-IL-4和10ng/mLrhu-TGF-β1的培养基中培养7天，培养期间添料两次。
LC迁移：
利用具有5μm孔径聚碳酸酯滤膜的24孔Transwell板(CorningCostar)进行趋化因子引导的LC迁移。将培养基(含有250ng/ml rhuCCL21(R&D Systems)，或者仅为培养基以作为自发迁移的对照)加入下部腔室中。将未经处理或经上述处理的LC加入上部腔室中，并于37℃孵育4小时。利用血细胞计数器或自动细胞计数器对迁移至下部腔室中的细胞进行计数，CCL21依赖性迁移计算为：CCL21存在时迁移细胞与无CCL21时迁移细胞的比率，称为“迁移指数”。迁移指数提高表明LC功能性活化，从组织向引流***移动(图7)。
IRX-2处理使得对照和HVP L1L2VLP中迁移提高了3至4倍。结果说明，IRX-2可以促进LC向区域***迁移，甚至当LC已暴露于HVP时。
混合淋巴细胞反应测定：
如上所述用HPV16 L1L2 VLP和IRX-2对LC进行处理。将LC与未经接触的(untouched)同种异体T细胞共培养，所述T细胞利用MACS阴性选择人泛T细胞分离试剂盒(MACS negative selection human pan Tcell isolation kit)分离。应答性T细胞(responder T cell)和刺激性LC(stimulator LC)以10∶1和5∶1的R∶S比率培养5天。单独培养的T细胞、单独培养的LC、与自体PBMC一起培养的T细胞以及与T细胞有丝***原PHA一起培养的T细胞用作测定对照。收获经放射性3H-胸腺嘧啶脉冲处理的细胞，并利用闪烁板计数器对放射性进行计数。确定放射性cpm，并在处理组间进行比较。增加的胸腺嘧啶掺入指示更多的T细胞增殖。暴露于HPV16 L1L2 VLP并用IRX-2刺激后T细胞增殖增加，这证实了暴露于HPV16 L1L2 VLP的LC在HPV存在下重新获得其免疫刺激能力(图8)。
细胞因子和趋化因子分析：
从用IRX-2刺激的LC中收集上清液，并对所分泌的细胞因子和趋化因子进行测试。如上所述对LC进行处理。IRX-2处理后36小时，清洗LC，并在收集上清液前培养额外的36小时。这免除了对IRX-2混合物中存在之细胞因子的测定。利用使得能够对数种炎症和T细胞刺激和趋化分析物同时进行测定的Bio-Plex Suspension Assay System完成该测定。所测定的细胞因子和趋化因子包括IL-8、IFN-γ可诱导蛋白10(IFN-γInducible Protein 10，IP-10)、单核细胞趋化蛋白(MCP)-1、巨噬细胞炎性蛋白(MIP)-1α、MIP-1β和RANTES。通过比较处理组上清液中细胞因子和趋化因子的浓度，对数据进行分析。Th1相关细胞因子和趋化因子的分泌增加，表示LC功能性活化，这支持了CD8+T细胞应答的诱导，而抑制性细胞因子的增加表明LC的耐受或功能抑制。
用IRX-2处理LC使得两种Th1相关趋化因子IP-10和IP10的分泌显著增加(图9)。这两种趋化因子均是促炎的，已知IP-10吸引T细胞、NK细胞和单核细胞至炎症部位。结果显示，在IRX-2刺激下，暴露于L1L2 VLP的LC在HPV存在下重新获得其免疫刺激能力。
结论：
IRX-2在表型上和功能上使来自健康供体的人LC活化，即使在其暴露于HPV L1L2 VLP之后也是如此。HPV和IRX-2处理后MHC和表面活化分子的水平增加，炎性和活化T细胞之细胞因子和趋化因子的分泌增加，进行趋化因子引导之迁移的能力增强(图6-9)。所有这些结果均支持本发明在克服HPV诱导之LC耐受以及提供HPV感染治疗中的有效性。已经以举例说明的方式对本发明进行了描述，应理解，所使用的术语旨在描述词语的本义而非限制性的。
显然，根据上述教导，本发明可具有多种修改和变化形式。因此，应理解，在所附权利要求的范围内，可以以除具体描述之外的方式实践本发明。
Claims (23)
1.治疗人***瘤病毒(HPV)感染的方法，其包括如下步骤：
向感染有HPV的患者施用治疗有效量的来源于原代细胞之生物制品；以及
诱导针对HPV的免疫应答。
2.权利要求1的方法，其中所述来源于原代细胞的生物制品包括IL-1、IL-2、IL-6、IL-8、TNF-α和IFN-γ。
3.权利要求2的方法，其中所述来源于原代细胞的生物制品包括浓度为60～6,000pcg/mL的IL-1β、浓度为600～60,000pcg/mL的IL-2、浓度为60～6,000pcg/mL的IL-6、浓度为6000～600,000pcg/mL的IL-8、浓度为200～20,000pcg/mL的TNF-α以及浓度为200～20,000pcg/mL的IFN-γ。
4.权利要求2的方法，其中所述来源于原代细胞的生物制品还包括IL-7、IL-12、IL-15、GM-CSF和G-CSF。
5.权利要求1的方法，其中所述施用步骤还包括施用选自烷化剂、抗代谢物、抗生素和免疫调节剂的化学抑制剂，以及抑制调节性T细胞。
6.权利要求5的方法，其中所述烷化剂是环磷酰胺。
7.权利要求5的方法，其中所述施用步骤还包括施用选自吲哚美辛、布洛芬、塞来昔布、罗非昔布及其组合的NSAID，以及逆转***素所致的局部免疫抑制。
8.权利要求7的方法，其中所述施用步骤还包括施用锌，以及提供T细胞功能的营养物。
9.权利要求1的方法，其中所述施用步骤进一步限定为将所述来源于原代细胞的生物制品注射入所述患者的上皮中。
10.权利要求1的方法，其中所述施用步骤进一步限定为将所述来源于原代细胞的生物制品表面应用至所述患者的上皮。
11.权利要求1的方法，其中所述诱导步骤还包括使朗格汉斯细胞(LC)活化的步骤。
12.权利要求11的方法，其还包括所述LC分泌活化T细胞和调节免疫的细胞因子以及诱导针对HPV之免疫应答的步骤。
13.权利要求12的方法，其还包括使HPV特异性CD8+T细胞活化的步骤。
14.权利要求12的方法，其还包括提高LC的IL-8分泌和ILIP-10产生的步骤。
15.权利要求11的方法，其还包括检测CD1a、MHC I类分子、MHCII类分子、CD40、CD80、CD83、CD86和CCR7的上调以及证实LC已被活化的步骤。
16.克服人***瘤病毒(HPV)诱导的朗格汉斯细胞(LC)免疫抑制的方法，其包括如下步骤：
向感染有HPV的患者施用治疗有效量的来源于原代细胞之生物制品；以及
使LC活化。
17.权利要求16的方法，其中所述来源于原代细胞的生物制品包括IL-1、IL-2、IL-6、IL-8、TNF-α和IFN-γ。
18.提高朗格汉斯细胞(LC)向***迁移的方法，其包括如下步骤：
向感染有人***瘤病毒(HPV)的患者施用治疗有效量的来源于原代细胞之生物制品；
使LC活化；以及
诱导LC向***迁移。
19.权利要求18的方法，其中所述来源于原代细胞的生物制品包括IL-1、IL-2、IL-6、IL-8、TNF-α和IFN-γ。
20.产生针对人***瘤病毒(HPV)之免疫力的方法，其包括如下步骤：
向感染有HPV的患者施用有效量的来源于原代细胞之生物制品；
产生针对HPV的免疫力；以及
防止新病变发生。
21.权利要求20的方法，其中所述来源于原代细胞的生物制品包括IL-1、IL-2、IL-6、IL-8、TNF-α和IFN-γ。
22.与TLR8激动剂类似地逆转人***瘤病毒(HPV)诱导之朗格汉斯细胞(LC)免疫抑制的方法，其包括如下步骤：
向感染有HPV的患者施用治疗有效量的来源于原代细胞之生物制品；以及
使LC活化。
23.使暴露于人***瘤病毒(HPV)的朗格汉斯细胞(LC)重新获得其刺激T细胞和迁移的能力的方法，其包括如下步骤：
向感染有HPV的患者施用治疗有效量的来源于原代细胞之生物制品；以及
使LC活化。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710091427.0A CN107050430B (zh) | 2009-12-08 | 2010-12-08 | 逆转朗格汉斯细胞免疫抑制的方法 |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US26759009P | 2009-12-08 | 2009-12-08 | |
| US61/267,590 | 2009-12-08 | ||
| PCT/US2010/059450 WO2011072006A1 (en) | 2009-12-08 | 2010-12-08 | Method of reversing immune suppression of langerhans cells |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710091427.0A Division CN107050430B (zh) | 2009-12-08 | 2010-12-08 | 逆转朗格汉斯细胞免疫抑制的方法 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103097543A true CN103097543A (zh) | 2013-05-08 |
Family
ID=44145893
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2010800633076A Pending CN103097543A (zh) | 2009-12-08 | 2010-12-08 | 逆转朗格汉斯细胞免疫抑制的方法 |
| CN201710091427.0A Active CN107050430B (zh) | 2009-12-08 | 2010-12-08 | 逆转朗格汉斯细胞免疫抑制的方法 |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710091427.0A Active CN107050430B (zh) | 2009-12-08 | 2010-12-08 | 逆转朗格汉斯细胞免疫抑制的方法 |
Country Status (9)
| Country | Link |
|---|---|
| US (2) | US9333238B2 (zh) |
| EP (1) | EP2510106B1 (zh) |
| JP (2) | JP5889797B2 (zh) |
| CN (2) | CN103097543A (zh) |
| AU (1) | AU2010328197B2 (zh) |
| CA (1) | CA2820202C (zh) |
| DK (1) | DK2510106T3 (zh) |
| ES (1) | ES2667476T3 (zh) |
| WO (1) | WO2011072006A1 (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110317786A (zh) * | 2019-07-12 | 2019-10-11 | 赛德特生物科技开发有限公司 | 一种可以预防肿瘤发生的免疫细胞及其制备方法与应用 |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070025958A1 (en) | 2000-10-27 | 2007-02-01 | Hadden John W | Vaccine immunotherapy |
| US6977072B2 (en) * | 2000-10-27 | 2005-12-20 | Irx Therapeutics, Inc. | Vaccine immunotherapy for immune suppressed patients |
| US20070154399A1 (en) * | 2000-10-27 | 2007-07-05 | Hadden John W | Immunotherapy for immune suppressed patients |
| AU2008329741B2 (en) | 2007-11-28 | 2013-09-12 | Irx Therapeutics, Inc. | Method of increasing immunological effect |
| ES2679043T3 (es) | 2009-05-15 | 2018-08-21 | Irx Therapeutics, Inc. | Inmunoterapia de vacuna |
| US9333238B2 (en) | 2009-12-08 | 2016-05-10 | Irx Therapeutics, Inc. | Method of immunotherapy for treament of human papillomavirus infection |
| ITRM20110654A1 (it) * | 2011-12-07 | 2013-06-08 | Ist Superiore Sanita | Combinazione di ciclofosfamide e cellule dendritiche per lo uso nel trattamento del carcinoma alla cervice uterina . |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050008614A1 (en) * | 2001-11-07 | 2005-01-13 | John Nieland | Topical use of cytokines and chemokines for the treatment of viral or mykotic skin diseases or tumoral diseases |
| US20060194242A1 (en) * | 2000-10-27 | 2006-08-31 | Hadden John W | Immunotherapy for immune suppressed patients |
Family Cites Families (83)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4079127A (en) | 1976-10-28 | 1978-03-14 | Board Of Regents Of The University Of Texas | Thymosin alpha 1 |
| US4116951A (en) | 1977-04-22 | 1978-09-26 | Hoffmann-La Roche Inc. | [Asn2 ]-thymosin α1 and analogs thereof |
| US4148788A (en) | 1978-01-23 | 1979-04-10 | Hoffmann-La Roche Inc. | Synthesis of thymosin α1 |
| DE2919592A1 (de) | 1979-05-15 | 1981-01-15 | Max Planck Gesellschaft | Verfahren zur herstellung von thymosin- alpha 1 und derivaten davon |
| US4470926A (en) | 1980-01-18 | 1984-09-11 | Max-Planck-Gesellschaft zur F/o/ rderung der Wissenschaften e.V. | Medicaments containing thymosin alpha 1 fragments and having an immunostimulant action, and fragments of thymosin alpha 1 |
| DE3100974A1 (de) | 1980-01-18 | 1982-01-21 | Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V., 3400 Göttingen | Thymosin(alpha)(pfeil abwaerts)1(pfeil abwaerts)-fragmente enthaltende arzneimittel mit immunregulierender wirkung, und thymosin(alpha)(pfeil abwaerts)1(pfeil abwaerts)-fragmente |
| US4612365A (en) | 1980-03-25 | 1986-09-16 | Max-Planck-Gesellschaft Zur Foederung Der Wissenschaften | Medicaments containing alpha 1-thymosin and having an immuno regulatory action and alpha 1-thymosin fragments |
| US4293455A (en) | 1980-04-07 | 1981-10-06 | Rockefeller University | N.sup.α -Desacetylthymosinα1 and process |
| GR74132B (zh) | 1980-05-22 | 1984-06-06 | Deutsches Krebsforsch | |
| US4390623A (en) | 1980-10-02 | 1983-06-28 | Hooper Trading Company | Serum-free and mitogen-free T-cell growth factor and process for making same |
| US4448879A (en) | 1981-03-26 | 1984-05-15 | Hooper Trading Company | High yield process for in vitro production of serum-free and mitogen-free interleukin-2 |
| US4464355A (en) | 1981-03-26 | 1984-08-07 | Hooper Trading Co. | Serum-free and mitogen-free T-cell growth factor and process for making same |
| US4406830A (en) | 1981-04-17 | 1983-09-27 | Shanksville Corporation, N.V. | Regulatory glycoprotein for immune response and the use thereof in the production of T-cell growth factor |
| US4504415A (en) | 1983-04-04 | 1985-03-12 | Hoffman-La Roche Inc. | Synthesis of thymosin α1 and desacetyl thymosin α1 |
| US4614731A (en) | 1983-09-15 | 1986-09-30 | Hoffmann-La Roche Inc. | Peptide having immunopotentiating activity similar to thymosin alpha1 |
| US4659694A (en) | 1983-10-27 | 1987-04-21 | Hoffmann-La Roche Inc. | Prothymosin alpha |
| US4716148A (en) | 1984-08-13 | 1987-12-29 | Hoffman-La Roche Inc. | Prothymosin alpha |
| US5643565A (en) | 1985-09-20 | 1997-07-01 | Chiron Corporation | Human IL-2 as a vaccine adjuvant |
| US5503841A (en) | 1985-09-20 | 1996-04-02 | Cetus Oncology Corporation | Human IL-2 as a vaccine adjuvant |
| US5100664A (en) | 1985-09-20 | 1992-03-31 | Cetus Corporation | Human IL-2 as a vaccine adjuvant |
| US5098702A (en) | 1986-04-09 | 1992-03-24 | Cetus Corporation | Combination therapy using interleukin-2 and tumor necrosis factor |
| EP0271521A4 (en) | 1986-05-09 | 1989-11-14 | Sloan Kettering Inst Cancer | PREPARATIONS OF LIPOPOLYSACCHARIDES AND NATURAL FACTOR FOR ANTITURAL THERAPY AND METHOD FOR TREATING. |
| SE8801426D0 (sv) | 1988-04-15 | 1988-04-15 | Ulf Rothman | Forfarande och medel for blodbehandling |
| CA2003455C (en) | 1988-11-23 | 2000-02-22 | Craig B. Thompson | Immunotherapy involving cd28 stimulation |
| US6534055B1 (en) | 1988-11-23 | 2003-03-18 | Genetics Institute, Inc. | Methods for selectively stimulating proliferation of T cells |
| IT1238231B (it) | 1989-12-18 | 1993-07-12 | Consiglio Nazionale Ricerche | Impiego di immunomodulanti come agenti sinergici di chemioterapici nella terapia dei tumori |
| JPH07503851A (ja) | 1992-02-10 | 1995-04-27 | インターフェロン・サイエンシズ、インコーポレイテッド | 改良インターフェロン及びヒトの末梢血液白血球からのその製造方法 |
| EP0651656A1 (en) | 1992-07-08 | 1995-05-10 | Schering Corporation | Use of gm-csf as a vaccine adjuvant |
| CN1094310A (zh) | 1992-12-15 | 1994-11-02 | 托马斯·C·梅里根 | 人体免疫缺陷性病毒感染用组合式化学疗法 |
| US5747024A (en) | 1993-03-08 | 1998-05-05 | Immunex Corporation | Vaccine adjuvant comprising interleukin-15 |
| ATE293686T1 (de) | 1993-06-04 | 2005-05-15 | Us Navy | Verfahren zur selektiven stimulierung der t- zellproliferation. |
| US5925362A (en) | 1993-08-11 | 1999-07-20 | Jenner Technologies | Method to elicit an antitumor response with human prostate-specific antigen |
| CN1044781C (zh) | 1994-02-05 | 1999-08-25 | 丹东市生物制品免疫技术应用研究中心 | 复方免疫抗生素 |
| DE4412794A1 (de) | 1994-04-14 | 1995-12-14 | Univ Ludwigs Albert | Verfahren zur Herstellung von dendritischen Zellen, so erhaltene Zellen und Behälter zur Durchführung dieses Verfahrens |
| AU694304B2 (en) | 1994-11-17 | 1998-07-16 | University Of South Florida | Method for making a medicament for treating secondary immunodeficiency |
| US5632983A (en) | 1994-11-17 | 1997-05-27 | University Of South Florida | Method for treating secondary immunodeficiency |
| EP0826043B1 (en) | 1995-05-04 | 2003-07-02 | THE GOVERNMENT OF THE UNITED STATES OF AMERICA as represented by THE SECRETARY OF THE NAVY | Methods for modulating t cell survival by modulating bcl-xl protein level |
| US5788963A (en) | 1995-07-31 | 1998-08-04 | Pacific Northwest Cancer Foundation | Isolation and/or preservation of dendritic cells for prostate cancer immunotherapy |
| JP2000517290A (ja) * | 1996-02-21 | 2000-12-26 | リスジーウィックス，ジュリアナ | 保護的及び治療的な遺伝子免疫化のための方法及び組成物 |
| US5849589A (en) | 1996-03-11 | 1998-12-15 | Duke University | Culturing monocytes with IL-4, TNF-α and GM-CSF TO induce differentiation to dendric cells |
| US6017527A (en) | 1996-07-10 | 2000-01-25 | Immunex Corporation | Activated dendritic cells and methods for their activation |
| US5849307A (en) | 1997-03-26 | 1998-12-15 | The Picower Institute For Medical Research | Vaccine adjuvant |
| CA2307345A1 (en) | 1997-10-17 | 1999-04-29 | University Of South Florida | Method to diagnose and monitor cellular immune deficiencies |
| ATE428769T1 (de) | 1997-10-27 | 2009-05-15 | Univ Rockefeller | Methode und zusammensetzung zur herstellung von reifen dendritischen zellen |
| US6488936B1 (en) | 1998-02-12 | 2002-12-03 | Wyeth | Immunogenic composition of interleukin-12 (IL-12), alum, herpes simplex viral (HSV) antigen, and method thereof |
| US20050124645A1 (en) | 1998-04-20 | 2005-06-09 | Finkel Terri H. | Methods and compositions for increasing CD4lymphocyte immune responsiveness |
| EP0974357A1 (en) | 1998-07-16 | 2000-01-26 | Schering-Plough | Chemokines as adjuvants of immune response |
| IL125608A0 (en) | 1998-07-30 | 1999-03-12 | Yeda Res & Dev | Tumor associated antigen peptides and use of same as anti-tumor vaccines |
| GB9827103D0 (en) | 1998-12-10 | 1999-02-03 | Onyvax Ltd | New cancer treatments |
| US6350589B1 (en) | 1998-12-31 | 2002-02-26 | Viragen, Inc. | Compositions of highly-purified natural mixtures of type I interferon derived from leukocytes and methods |
| US6667175B1 (en) | 1999-06-15 | 2003-12-23 | The Trustees Of Columbia University | Generation of antigen specific T suppressor cells for treatment of rejection |
| US7056503B2 (en) | 1999-08-19 | 2006-06-06 | Regents Of The University Of Michigan | Enclosures housing cell-coated supports for treating tumors |
| US6406699B1 (en) | 1999-10-05 | 2002-06-18 | Gary W. Wood | Composition and method of cancer antigen immunotherapy |
| JP2004500095A (ja) | 2000-02-24 | 2004-01-08 | エクサイト セラピーズ， インコーポレイテッド | 細胞の同時の刺激および濃縮 |
| IL153133A0 (en) | 2000-06-22 | 2003-06-24 | American Cyanamid Co | Qs-21 and il-12 as an adjuvant combination |
| US20070025958A1 (en) | 2000-10-27 | 2007-02-01 | Hadden John W | Vaccine immunotherapy |
| US6977072B2 (en) | 2000-10-27 | 2005-12-20 | Irx Therapeutics, Inc. | Vaccine immunotherapy for immune suppressed patients |
| US20070031372A1 (en) | 2004-08-05 | 2007-02-08 | Hadden John W | Vaccine immunotherapy for immune suppressed patients |
| US7182942B2 (en) | 2000-10-27 | 2007-02-27 | Irx Therapeutics, Inc. | Vaccine immunotherapy for immune suppressed patients |
| US20070154399A1 (en) | 2000-10-27 | 2007-07-05 | Hadden John W | Immunotherapy for immune suppressed patients |
| EP1810691A3 (en) | 2001-10-26 | 2008-03-26 | IRX Therapeutics, Inc. | Immunotherapy for reversing immune suppression |
| JP4502641B2 (ja) | 2002-01-24 | 2010-07-14 | ティルタン ファーマ リミテッド | 抗癌組み合わせおよびその使用方法 |
| RS20050501A (en) | 2002-12-26 | 2007-08-03 | Mountain View Pharmaceuticals Inc., | Polymer conjugates of cytokines,chemokines,growth factors, polypeptide hormones and antagonists thereof with preserved receptor-binding activity |
| AU2004230328A1 (en) | 2003-04-15 | 2004-10-28 | Sanofi Pasteur Limited | Tumor antigens BFA5 for prevention and/or treatment of cancer |
| US6896879B2 (en) | 2003-07-03 | 2005-05-24 | Cel-Sci Corporation | Method of pre-sensitizing cancer prior to treatment with radiation and/or chemotherapy and a novel cytokine mixture |
| WO2005077048A2 (en) | 2004-02-09 | 2005-08-25 | The Johns Hopkins University | Immune modulation by regulating expression of the “minor” gene in immune dendritic cells |
| GB0409799D0 (en) | 2004-04-30 | 2004-06-09 | Isis Innovation | Method of generating improved immune response |
| CA2568295A1 (en) | 2004-06-04 | 2005-12-22 | Cel-Sci Corporation | A method for altering the cd4/cd8 ratio and the mononuclear cellular infiltrate into a tumor |
| JP2008502605A (ja) | 2004-06-16 | 2008-01-31 | スマート ドラッグ システムズ インコーポレイティド | 徐放性ワクチン組成物 |
| JP5623004B2 (ja) | 2004-10-25 | 2014-11-12 | ベイラー リサーチ インスティテュートＢａｙｌｏｒ Ｒｅｓｅａｒｃｈ Ｉｎｓｔｉｔｕｔｅ | 熱ショックをかけたメラノーマ細胞体が装填された樹状細胞 |
| US20070065415A1 (en) | 2005-09-16 | 2007-03-22 | Kleinsek Donald A | Compositions and methods for the augmentation and repair of defects in tissue |
| US20070128174A1 (en) | 2005-09-21 | 2007-06-07 | Kleinsek Donald A | Methods and compositions for organ and tissue functionality |
| TW200800252A (en) | 2005-12-08 | 2008-01-01 | Northwest Biotherapeutics Inc | Compositions and methods for inducing the activation of immature monocytic dendritic cells |
| US20070259330A1 (en) | 2006-05-04 | 2007-11-08 | Ge Healthcare Bio-Sciences Ab | Separation of cells |
| US20090181078A1 (en) | 2006-09-26 | 2009-07-16 | Infectious Disease Research Institute | Vaccine composition containing synthetic adjuvant |
| KR20100025514A (ko) | 2007-04-25 | 2010-03-09 | 임뮤룩스, 인코포레이티드 | Ｎｋｔ 활성화제，ｃｄ40 효능제 및 임의의 항원의 애주번트 조합물 및 상승적인 세포 면역성의 유도에 의한 용도 |
| JP2010530895A (ja) | 2007-06-21 | 2010-09-16 | アンジェリカ セラピューティックス，インク． | 修飾毒素 |
| AU2008329741B2 (en) | 2007-11-28 | 2013-09-12 | Irx Therapeutics, Inc. | Method of increasing immunological effect |
| EP2276850B9 (en) | 2008-04-14 | 2013-10-30 | IRX Therapeutics, Inc. | Irx-2 modified manufacturing process |
| EP2296704A4 (en) | 2008-05-29 | 2012-03-07 | Irx Therapeutics Inc | ACTION MECHANISM OF BIOLOGICAL MEANS FROM PRIMARY CELLS |
| ES2679043T3 (es) | 2009-05-15 | 2018-08-21 | Irx Therapeutics, Inc. | Inmunoterapia de vacuna |
| US9333238B2 (en) | 2009-12-08 | 2016-05-10 | Irx Therapeutics, Inc. | Method of immunotherapy for treament of human papillomavirus infection |
| WO2012037551A2 (en) | 2010-09-17 | 2012-03-22 | Irx Therapeutics, Inc. | Primary cell-derived biologic and wt1 synthetic long peptide vaccine |
-
2010
- 2010-12-08 US US13/514,688 patent/US9333238B2/en active Active
- 2010-12-08 CA CA2820202A patent/CA2820202C/en active Active
- 2010-12-08 JP JP2012543241A patent/JP5889797B2/ja active Active
- 2010-12-08 CN CN2010800633076A patent/CN103097543A/zh active Pending
- 2010-12-08 DK DK10836605.5T patent/DK2510106T3/en active
- 2010-12-08 AU AU2010328197A patent/AU2010328197B2/en active Active
- 2010-12-08 EP EP10836605.5A patent/EP2510106B1/en active Active
- 2010-12-08 WO PCT/US2010/059450 patent/WO2011072006A1/en active Application Filing
- 2010-12-08 CN CN201710091427.0A patent/CN107050430B/zh active Active
- 2010-12-08 ES ES10836605.5T patent/ES2667476T3/es active Active
-
2015
- 2015-10-22 JP JP2015207657A patent/JP2016014071A/ja not_active Withdrawn
-
2016
- 2016-04-13 US US15/097,693 patent/US9931378B2/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060194242A1 (en) * | 2000-10-27 | 2006-08-31 | Hadden John W | Immunotherapy for immune suppressed patients |
| US20050008614A1 (en) * | 2001-11-07 | 2005-01-13 | John Nieland | Topical use of cytokines and chemokines for the treatment of viral or mykotic skin diseases or tumoral diseases |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110317786A (zh) * | 2019-07-12 | 2019-10-11 | 赛德特生物科技开发有限公司 | 一种可以预防肿瘤发生的免疫细胞及其制备方法与应用 |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2013512967A (ja) | 2013-04-18 |
| AU2010328197B2 (en) | 2015-07-16 |
| CN107050430A (zh) | 2017-08-18 |
| CA2820202C (en) | 2018-06-12 |
| US9333238B2 (en) | 2016-05-10 |
| CA2820202A1 (en) | 2011-06-16 |
| EP2510106A1 (en) | 2012-10-17 |
| EP2510106B1 (en) | 2018-02-14 |
| CN107050430B (zh) | 2021-10-15 |
| US20120244117A1 (en) | 2012-09-27 |
| ES2667476T3 (es) | 2018-05-11 |
| US20160303198A1 (en) | 2016-10-20 |
| JP2016014071A (ja) | 2016-01-28 |
| WO2011072006A1 (en) | 2011-06-16 |
| AU2010328197A1 (en) | 2012-07-26 |
| EP2510106A4 (en) | 2013-06-05 |
| US9931378B2 (en) | 2018-04-03 |
| DK2510106T3 (en) | 2018-05-28 |
| JP5889797B2 (ja) | 2016-03-22 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103097543A (zh) | 逆转朗格汉斯细胞免疫抑制的方法 | |
| Salem et al. | The adjuvant effects of the toll-like receptor 3 ligand polyinosinic-cytidylic acid poly (I: C) on antigen-specific CD8+ T cell responses are partially dependent on NK cells with the induction of a beneficial cytokine milieu | |
| Jafarzadeh et al. | Immunomodulatory properties of cimetidine: Its therapeutic potentials for treatment of immune-related diseases | |
| Wu et al. | In vivo vaccination with tumor cell lysate plus CpG oligodeoxynucleotides eradicates murine glioblastoma | |
| Obermajer et al. | Promoting the accumulation of tumor-specific T cells in tumor tissues by dendritic cell vaccines and chemokine-modulating agents | |
| Ghiringhelli et al. | Links between innate and cognate tumor immunity | |
| Noori et al. | Antitumor and immunomodulatory effects of salvigenin on tumor bearing mice | |
| CN110575537A (zh) | Dc疫苗和nkg2a拮抗剂的组合物及在抗乳腺癌或肝癌中的应用 | |
| JP2006507262A (ja) | 癌治療における免疫療法 | |
| EP3350318B1 (en) | Methods relating to activated dendritic cell compositions for subjects with advanced cancers | |
| Da Silva et al. | Immunostimulatory activity of the cytokine-based biologic, IRX-2, on human papillomavirus-exposed Langerhans cells | |
| CN106075432A (zh) | 皮卡钙联合佐剂及含有皮卡钙联合佐剂的疫苗 | |
| Huang et al. | Natural blood plasma-based hydrogels as tumor vaccines delivery systems to enhance biomimetic recruitment of antigen presenting cells for tumor immunotherapy | |
| CN1201817C (zh) | 一种治疗肝癌的肿瘤ct抗原免疫诱导剂及其制备方法 | |
| EP1959007A1 (en) | Method for providing mature dendritic cells | |
| Wurzenberger et al. | Short-term activation induces multifunctional dendritic cells that generate potent antitumor T-cell responses in vivo | |
| KR101117186B1 (ko) | 수지상세포의 이동성 증진 및 수지상세포에 의해 제조된 세포독성 ｔ 세포의 세포살상능 증진방법 | |
| KR101083404B1 (ko) | 수지상세포의 이동성 증진 및 수지상세포에 의해 제조된 세포독성 т 세포의 세포살상능 증진방법 | |
| WO2009086694A1 (zh) | 卡介菌多糖核酸提取物在制备治疗病毒性皮肤病的药物中的应用及其注射剂和制备方法 | |
| US20210153848A1 (en) | Skin cancer treatment | |
| CN115120714A (zh) | 免疫制剂、包含免疫制剂的组合物及其用途、制备方法 | |
| CN114949189A (zh) | 纳米肿瘤特异抗原与发生icd的肿瘤细胞联合作为制备治疗性肿瘤疫苗的应用 | |
| Werthmöller | Immunogenicity of B16 melanoma cells after radiochemoimmunotherapy and cell death modulation by zVAD-fmk | |
| Ershler et al. | Biological therapies in geriatric populations | |
| Hengge | Topical immunotherapy |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| ASS | Succession or assignment of patent right |
Free format text: FORMER OWNER: EGAN JAMES KAST MARTIN DA SILVA DIANE BRANDWEIN HARVEY Effective date: 20131017 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20131017 Address after: American New York Applicant after: IRX Therapeutics Inc. Address before: American New York Applicant before: IRX Therapeutics Inc. Applicant before: Egan James Applicant before: Kast Martin Applicant before: Da Silva Diane Applicant before: Brandwein Harvey |
|
| C53 | Correction of patent of invention or patent application | ||
| CB03 | Change of inventor or designer information |
Inventor after: Egan James Inventor after: Kast Martin Inventor after: Brandwein Harvey Inventor before: Egan James Inventor before: Kast Martin Inventor before: Da Silva Diane Inventor before: Brandwein Harvey |
|
| COR | Change of bibliographic data |
Free format text: CORRECT: INVENTOR; FROM: EGAN JAMES KAST MARTIN DA SILVA DIANE BRANDWEIN HARVEY TO: EGAN JAMES KAST MARTIN BRANDWEIN HARVEY |
|
| REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 1185103 Country of ref document: HK |
|
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20130508 |
|
| RJ01 | Rejection of invention patent application after publication | ||
| REG | Reference to a national code |
Ref country code: HK Ref legal event code: WD Ref document number: 1185103 Country of ref document: HK |