CN103285392A - 用于癌症免疫疗法的组合物和其用途 - Google Patents
用于癌症免疫疗法的组合物和其用途 Download PDFInfo
- Publication number
- CN103285392A CN103285392A CN2013101300117A CN201310130011A CN103285392A CN 103285392 A CN103285392 A CN 103285392A CN 2013101300117 A CN2013101300117 A CN 2013101300117A CN 201310130011 A CN201310130011 A CN 201310130011A CN 103285392 A CN103285392 A CN 103285392A
- Authority
- CN
- China
- Prior art keywords
- cancer
- antigen
- chemical compound
- peptide
- alkyl
- 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
- 239000000203 mixture Substances 0.000 title claims abstract description 62
- 238000002619 cancer immunotherapy Methods 0.000 title abstract description 3
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 182
- 201000011510 cancer Diseases 0.000 claims abstract description 148
- 150000001875 compounds Chemical class 0.000 claims abstract description 87
- 238000011282 treatment Methods 0.000 claims abstract description 39
- 230000004936 stimulating effect Effects 0.000 claims abstract description 10
- 238000011161 development Methods 0.000 claims abstract description 8
- 239000000427 antigen Substances 0.000 claims description 186
- 108091007433 antigens Proteins 0.000 claims description 186
- 102000036639 antigens Human genes 0.000 claims description 186
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 64
- 210000004027 cell Anatomy 0.000 claims description 45
- 150000003839 salts Chemical class 0.000 claims description 33
- 125000000217 alkyl group Chemical group 0.000 claims description 31
- 239000002955 immunomodulating agent Substances 0.000 claims description 28
- 229910052760 oxygen Inorganic materials 0.000 claims description 28
- 238000000034 method Methods 0.000 claims description 27
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 26
- 239000001301 oxygen Substances 0.000 claims description 26
- -1 alkyl sulfonate esters Chemical class 0.000 claims description 25
- 230000003302 anti-idiotype Effects 0.000 claims description 21
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 21
- 239000002158 endotoxin Substances 0.000 claims description 20
- 241000700605 Viruses Species 0.000 claims description 18
- 125000003545 alkoxy group Chemical group 0.000 claims description 18
- 239000003814 drug Substances 0.000 claims description 18
- 229920006008 lipopolysaccharide Polymers 0.000 claims description 18
- 230000001225 therapeutic effect Effects 0.000 claims description 18
- 229910052736 halogen Inorganic materials 0.000 claims description 16
- 150000002367 halogens Chemical class 0.000 claims description 16
- 238000007689 inspection Methods 0.000 claims description 14
- 239000003795 chemical substances by application Substances 0.000 claims description 12
- 238000002560 therapeutic procedure Methods 0.000 claims description 12
- 239000000556 agonist Substances 0.000 claims description 11
- 210000004443 dendritic cell Anatomy 0.000 claims description 11
- 239000007787 solid Substances 0.000 claims description 9
- 239000012453 solvate Substances 0.000 claims description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 claims description 8
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 claims description 8
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 8
- 230000036039 immunity Effects 0.000 claims description 8
- WYWHKKSPHMUBEB-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 claims description 8
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 claims description 7
- 102000014150 Interferons Human genes 0.000 claims description 7
- 108010050904 Interferons Proteins 0.000 claims description 7
- 229960004397 cyclophosphamide Drugs 0.000 claims description 7
- 229940079322 interferon Drugs 0.000 claims description 7
- QWPXBEHQFHACTK-KZVYIGENSA-N (10e,12e)-86-chloro-12,14,4-trihydroxy-85,14-dimethoxy-33,2,7,10-tetramethyl-15,16-dihydro-14h-7-aza-1(6,4)-oxazina-3(2,3)-oxirana-8(1,3)-benzenacyclotetradecaphane-10,12-dien-6-one Chemical compound CN1C(=O)CC(O)C2(C)OC2C(C)C(OC(=O)N2)CC2(O)C(OC)\C=C\C=C(C)\CC2=CC(OC)=C(Cl)C1=C2 QWPXBEHQFHACTK-KZVYIGENSA-N 0.000 claims description 6
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 claims description 6
- 108010017080 Granulocyte Colony-Stimulating Factor Proteins 0.000 claims description 6
- 102000004269 Granulocyte Colony-Stimulating Factor Human genes 0.000 claims description 6
- QWPXBEHQFHACTK-UHFFFAOYSA-N Maytansinol Natural products CN1C(=O)CC(O)C2(C)OC2C(C)C(OC(=O)N2)CC2(O)C(OC)C=CC=C(C)CC2=CC(OC)=C(Cl)C1=C2 QWPXBEHQFHACTK-UHFFFAOYSA-N 0.000 claims description 6
- RHJPBGWFGOAEID-UHFFFAOYSA-N aplysiatoxin Natural products O1C2(OC(O)(CC(=O)OC(CC(=O)O3)C(C)O)C(C)CC2(C)C)CC3C(C)C1C(C)CCC(OC)C1=CC(O)=CC=C1Br RHJPBGWFGOAEID-UHFFFAOYSA-N 0.000 claims description 6
- 239000011324 bead Substances 0.000 claims description 6
- 150000001768 cations Chemical class 0.000 claims description 6
- RHJPBGWFGOAEID-BEDNPZBZSA-N chembl1256416 Chemical compound C1([C@H](CC[C@H](C)[C@@H]2[C@H]([C@@H]3C[C@@]4(O[C@@](O)(CC(=O)O[C@H](CC(=O)O3)[C@@H](C)O)[C@H](C)CC4(C)C)O2)C)OC)=CC(O)=CC=C1Br RHJPBGWFGOAEID-BEDNPZBZSA-N 0.000 claims description 6
- 238000009792 diffusion process Methods 0.000 claims description 6
- QZGIWPZCWHMVQL-UIYAJPBUSA-N neocarzinostatin chromophore Chemical compound O1[C@H](C)[C@H](O)[C@H](O)[C@@H](NC)[C@H]1O[C@@H]1C/2=C/C#C[C@H]3O[C@@]3([C@@H]3OC(=O)OC3)C#CC\2=C[C@H]1OC(=O)C1=C(O)C=CC2=C(C)C=C(OC)C=C12 QZGIWPZCWHMVQL-UIYAJPBUSA-N 0.000 claims description 6
- 102000004127 Cytokines Human genes 0.000 claims description 5
- 108090000695 Cytokines Proteins 0.000 claims description 5
- 101000669447 Homo sapiens Toll-like receptor 4 Proteins 0.000 claims description 5
- 102100039360 Toll-like receptor 4 Human genes 0.000 claims description 5
- 230000000903 blocking effect Effects 0.000 claims description 5
- 229960001924 melphalan Drugs 0.000 claims description 5
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- 229960004641 rituximab Drugs 0.000 claims description 5
- DIWRORZWFLOCLC-HNNXBMFYSA-N (3s)-7-chloro-5-(2-chlorophenyl)-3-hydroxy-1,3-dihydro-1,4-benzodiazepin-2-one Chemical compound N([C@H](C(NC1=CC=C(Cl)C=C11)=O)O)=C1C1=CC=CC=C1Cl DIWRORZWFLOCLC-HNNXBMFYSA-N 0.000 claims description 4
- FPVKHBSQESCIEP-UHFFFAOYSA-N (8S)-3-(2-deoxy-beta-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol Natural products C1C(O)C(CO)OC1N1C(NC=NCC2O)=C2N=C1 FPVKHBSQESCIEP-UHFFFAOYSA-N 0.000 claims description 4
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 claims description 4
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 claims description 4
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 claims description 4
- 108010006654 Bleomycin Proteins 0.000 claims description 4
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 claims description 4
- GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 claims description 4
- GAGWJHPBXLXJQN-UHFFFAOYSA-N Capecitabine Natural products C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1C1C(O)C(O)C(C)O1 GAGWJHPBXLXJQN-UHFFFAOYSA-N 0.000 claims description 4
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 claims description 4
- PTOAARAWEBMLNO-KVQBGUIXSA-N Cladribine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)O1 PTOAARAWEBMLNO-KVQBGUIXSA-N 0.000 claims description 4
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 claims description 4
- DBVJJBKOTRCVKF-UHFFFAOYSA-N Etidronic acid Chemical compound OP(=O)(O)C(O)(C)P(O)(O)=O DBVJJBKOTRCVKF-UHFFFAOYSA-N 0.000 claims description 4
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 claims description 4
- MPBVHIBUJCELCL-UHFFFAOYSA-N Ibandronate Chemical compound CCCCCN(C)CCC(O)(P(O)(O)=O)P(O)(O)=O MPBVHIBUJCELCL-UHFFFAOYSA-N 0.000 claims description 4
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 claims description 4
- XDXDZDZNSLXDNA-UHFFFAOYSA-N Idarubicin Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XDXDZDZNSLXDNA-UHFFFAOYSA-N 0.000 claims description 4
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 claims description 4
- 229930192392 Mitomycin Natural products 0.000 claims description 4
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 claims description 4
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 claims description 4
- 101710204212 Neocarzinostatin Proteins 0.000 claims description 4
- 229930012538 Paclitaxel Natural products 0.000 claims description 4
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 claims description 4
- 102000013394 Troponin I Human genes 0.000 claims description 4
- 108010065729 Troponin I Proteins 0.000 claims description 4
- 108060008682 Tumor Necrosis Factor Proteins 0.000 claims description 4
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 claims description 4
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 claims description 4
- OFCNXPDARWKPPY-UHFFFAOYSA-N allopurinol Chemical compound OC1=NC=NC2=C1C=NN2 OFCNXPDARWKPPY-UHFFFAOYSA-N 0.000 claims description 4
- 229960003459 allopurinol Drugs 0.000 claims description 4
- 229960000473 altretamine Drugs 0.000 claims description 4
- JKOQGQFVAUAYPM-UHFFFAOYSA-N amifostine Chemical compound NCCCNCCSP(O)(O)=O JKOQGQFVAUAYPM-UHFFFAOYSA-N 0.000 claims description 4
- 229960001097 amifostine Drugs 0.000 claims description 4
- 230000000259 anti-tumor effect Effects 0.000 claims description 4
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 claims description 4
- 229960000397 bevacizumab Drugs 0.000 claims description 4
- 229960001561 bleomycin Drugs 0.000 claims description 4
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 claims description 4
- 229960002092 busulfan Drugs 0.000 claims description 4
- 229960004117 capecitabine Drugs 0.000 claims description 4
- 239000004202 carbamide Substances 0.000 claims description 4
- 235000013877 carbamide Nutrition 0.000 claims description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 4
- 229960004562 carboplatin Drugs 0.000 claims description 4
- 229960005243 carmustine Drugs 0.000 claims description 4
- 229960005395 cetuximab Drugs 0.000 claims description 4
- 229960004630 chlorambucil Drugs 0.000 claims description 4
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 claims description 4
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 claims description 4
- 229960004316 cisplatin Drugs 0.000 claims description 4
- 229960002436 cladribine Drugs 0.000 claims description 4
- 229960003901 dacarbazine Drugs 0.000 claims description 4
- 229960000975 daunorubicin Drugs 0.000 claims description 4
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 claims description 4
- 229960003668 docetaxel Drugs 0.000 claims description 4
- FGXWKSZFVQUSTL-UHFFFAOYSA-N domperidone Chemical compound C12=CC=CC=C2NC(=O)N1CCCN(CC1)CCC1N1C2=CC=C(Cl)C=C2NC1=O FGXWKSZFVQUSTL-UHFFFAOYSA-N 0.000 claims description 4
- 229960001253 domperidone Drugs 0.000 claims description 4
- BZEWSEKUUPWQDQ-UHFFFAOYSA-N dyclonine Chemical compound C1=CC(OCCCC)=CC=C1C(=O)CCN1CCCCC1 BZEWSEKUUPWQDQ-UHFFFAOYSA-N 0.000 claims description 4
- 229960000385 dyclonine Drugs 0.000 claims description 4
- 229960001904 epirubicin Drugs 0.000 claims description 4
- 229960001842 estramustine Drugs 0.000 claims description 4
- FRPJXPJMRWBBIH-RBRWEJTLSA-N estramustine Chemical compound ClCCN(CCCl)C(=O)OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 FRPJXPJMRWBBIH-RBRWEJTLSA-N 0.000 claims description 4
- 229940009626 etidronate Drugs 0.000 claims description 4
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 claims description 4
- 229960005420 etoposide Drugs 0.000 claims description 4
- 229960000390 fludarabine Drugs 0.000 claims description 4
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 claims description 4
- 229960002949 fluorouracil Drugs 0.000 claims description 4
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 claims description 4
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 claims description 4
- 229960002584 gefitinib Drugs 0.000 claims description 4
- 229960005277 gemcitabine Drugs 0.000 claims description 4
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 claims description 4
- 239000003102 growth factor Substances 0.000 claims description 4
- UUVWYPNAQBNQJQ-UHFFFAOYSA-N hexamethylmelamine Chemical compound CN(C)C1=NC(N(C)C)=NC(N(C)C)=N1 UUVWYPNAQBNQJQ-UHFFFAOYSA-N 0.000 claims description 4
- 229940015872 ibandronate Drugs 0.000 claims description 4
- 229960000908 idarubicin Drugs 0.000 claims description 4
- 229960001101 ifosfamide Drugs 0.000 claims description 4
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 claims description 4
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 claims description 4
- 229960004768 irinotecan Drugs 0.000 claims description 4
- 229960004194 lidocaine Drugs 0.000 claims description 4
- 229960004391 lorazepam Drugs 0.000 claims description 4
- 229960004961 mechlorethamine Drugs 0.000 claims description 4
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical compound ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 claims description 4
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 claims description 4
- 229960001428 mercaptopurine Drugs 0.000 claims description 4
- 229960004857 mitomycin Drugs 0.000 claims description 4
- 229960001156 mitoxantrone Drugs 0.000 claims description 4
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 238000011275 oncology therapy Methods 0.000 claims description 4
- 229960001592 paclitaxel Drugs 0.000 claims description 4
- 229960002340 pentostatin Drugs 0.000 claims description 4
- FPVKHBSQESCIEP-JQCXWYLXSA-N pentostatin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(N=CNC[C@H]2O)=C2N=C1 FPVKHBSQESCIEP-JQCXWYLXSA-N 0.000 claims description 4
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 4
- CPTBDICYNRMXFX-UHFFFAOYSA-N procarbazine Chemical compound CNNCC1=CC=C(C(=O)NC(C)C)C=C1 CPTBDICYNRMXFX-UHFFFAOYSA-N 0.000 claims description 4
- 229960000624 procarbazine Drugs 0.000 claims description 4
- 102000005962 receptors Human genes 0.000 claims description 4
- 108020003175 receptors Proteins 0.000 claims description 4
- 229960001603 tamoxifen Drugs 0.000 claims description 4
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 claims description 4
- 229960004964 temozolomide Drugs 0.000 claims description 4
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 claims description 4
- 229960001278 teniposide Drugs 0.000 claims description 4
- 229960003087 tioguanine Drugs 0.000 claims description 4
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 claims description 4
- 229960000303 topotecan Drugs 0.000 claims description 4
- 229960000575 trastuzumab Drugs 0.000 claims description 4
- 229960003048 vinblastine Drugs 0.000 claims description 4
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 claims description 4
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 claims description 4
- 229960004528 vincristine Drugs 0.000 claims description 4
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 claims description 4
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 claims description 4
- 229960002066 vinorelbine Drugs 0.000 claims description 4
- 229950009268 zinostatin Drugs 0.000 claims description 4
- ZADWXFSZEAPBJS-SNVBAGLBSA-N (2r)-2-amino-3-(1-methylindol-3-yl)propanoic acid Chemical compound C1=CC=C2N(C)C=C(C[C@@H](N)C(O)=O)C2=C1 ZADWXFSZEAPBJS-SNVBAGLBSA-N 0.000 claims description 3
- NWXMGUDVXFXRIG-WESIUVDSSA-N (4s,4as,5as,6s,12ar)-4-(dimethylamino)-1,6,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4,4a,5,5a-tetrahydrotetracene-2-carboxamide Chemical compound C1=CC=C2[C@](O)(C)[C@H]3C[C@H]4[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]4(O)C(=O)C3=C(O)C2=C1O NWXMGUDVXFXRIG-WESIUVDSSA-N 0.000 claims description 3
- 229930195573 Amycin Natural products 0.000 claims description 3
- 229940080328 Arginase inhibitor Drugs 0.000 claims description 3
- 108010071942 Colony-Stimulating Factors Proteins 0.000 claims description 3
- 102000007644 Colony-Stimulating Factors Human genes 0.000 claims description 3
- 229920001503 Glucan Polymers 0.000 claims description 3
- 101000669402 Homo sapiens Toll-like receptor 7 Proteins 0.000 claims description 3
- 102000026633 IL6 Human genes 0.000 claims description 3
- 102000008070 Interferon-gamma Human genes 0.000 claims description 3
- 108010074328 Interferon-gamma Proteins 0.000 claims description 3
- 108010002350 Interleukin-2 Proteins 0.000 claims description 3
- 108010002386 Interleukin-3 Proteins 0.000 claims description 3
- 108010002586 Interleukin-7 Proteins 0.000 claims description 3
- 102000015696 Interleukins Human genes 0.000 claims description 3
- 108010063738 Interleukins Proteins 0.000 claims description 3
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 claims description 3
- 108010046938 Macrophage Colony-Stimulating Factor Proteins 0.000 claims description 3
- 102000007651 Macrophage Colony-Stimulating Factor Human genes 0.000 claims description 3
- 125000003047 N-acetyl group Chemical group 0.000 claims description 3
- 108010060818 Toll-Like Receptor 9 Proteins 0.000 claims description 3
- 102100039390 Toll-like receptor 7 Human genes 0.000 claims description 3
- 102100033117 Toll-like receptor 9 Human genes 0.000 claims description 3
- 238000002659 cell therapy Methods 0.000 claims description 3
- 229960004679 doxorubicin Drugs 0.000 claims description 3
- 239000012634 fragment Substances 0.000 claims description 3
- 229940044627 gamma-interferon Drugs 0.000 claims description 3
- 238000012239 gene modification Methods 0.000 claims description 3
- 230000005017 genetic modification Effects 0.000 claims description 3
- 235000013617 genetically modified food Nutrition 0.000 claims description 3
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 claims description 3
- 239000003112 inhibitor Substances 0.000 claims description 3
- TWNIBLMWSKIRAT-VFUOTHLCSA-N levoglucosan Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@H]2CO[C@@H]1O2 TWNIBLMWSKIRAT-VFUOTHLCSA-N 0.000 claims description 3
- 229960000485 methotrexate Drugs 0.000 claims description 3
- 239000001397 quillaja saponaria molina bark Substances 0.000 claims description 3
- ZADWXFSZEAPBJS-UHFFFAOYSA-N racemic N-methyl tryptophan Natural products C1=CC=C2N(C)C=C(CC(N)C(O)=O)C2=C1 ZADWXFSZEAPBJS-UHFFFAOYSA-N 0.000 claims description 3
- 229930182490 saponin Natural products 0.000 claims description 3
- 150000007949 saponins Chemical class 0.000 claims description 3
- 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 2
- YJGVMLPVUAXIQN-LGWHJFRWSA-N (5s,5ar,8ar,9r)-5-hydroxy-9-(3,4,5-trimethoxyphenyl)-5a,6,8a,9-tetrahydro-5h-[2]benzofuro[5,6-f][1,3]benzodioxol-8-one Chemical compound COC1=C(OC)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O)[C@@H]3[C@@H]2C(OC3)=O)=C1 YJGVMLPVUAXIQN-LGWHJFRWSA-N 0.000 claims description 2
- WYXSYVWAUAUWLD-SHUUEZRQSA-N 6-azauridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=N1 WYXSYVWAUAUWLD-SHUUEZRQSA-N 0.000 claims description 2
- 102400000068 Angiostatin Human genes 0.000 claims description 2
- 108010079709 Angiostatins Proteins 0.000 claims description 2
- MBUVEWMHONZEQD-UHFFFAOYSA-N Azeptin Chemical compound C1CN(C)CCCC1N1C(=O)C2=CC=CC=C2C(CC=2C=CC(Cl)=CC=2)=N1 MBUVEWMHONZEQD-UHFFFAOYSA-N 0.000 claims description 2
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 claims description 2
- 208000010392 Bone Fractures Diseases 0.000 claims description 2
- DGGZCXUXASNDAC-QQNGCVSVSA-N C-1027 chromophore Chemical compound COc1cc2OC(=C)C(=O)Nc2c(c1)C(=O)O[C@H]3COC(=O)C[C@H](N)c4cc(O)c(O[C@@H]5C#C\C=C\3/C#CC6=CC=C[C@]56O[C@@H]7OC(C)(C)[C@H]([C@@H](O)[C@H]7O)N(C)C)c(Cl)c4 DGGZCXUXASNDAC-QQNGCVSVSA-N 0.000 claims description 2
- OBMZMSLWNNWEJA-XNCRXQDQSA-N C1=CC=2C(C[C@@H]3NC(=O)[C@@H](NC(=O)[C@H](NC(=O)N(CC#CCN(CCCC[C@H](NC(=O)[C@@H](CC4=CC=CC=C4)NC3=O)C(=O)N)CC=C)NC(=O)[C@@H](N)C)CC3=CNC4=C3C=CC=C4)C)=CNC=2C=C1 Chemical compound C1=CC=2C(C[C@@H]3NC(=O)[C@@H](NC(=O)[C@H](NC(=O)N(CC#CCN(CCCC[C@H](NC(=O)[C@@H](CC4=CC=CC=C4)NC3=O)C(=O)N)CC=C)NC(=O)[C@@H](N)C)CC3=CNC4=C3C=CC=C4)C)=CNC=2C=C1 OBMZMSLWNNWEJA-XNCRXQDQSA-N 0.000 claims description 2
- 102400000730 Canstatin Human genes 0.000 claims description 2
- 101800000626 Canstatin Proteins 0.000 claims description 2
- 229930188224 Cryptophycin Natural products 0.000 claims description 2
- 229930193152 Dynemicin Natural products 0.000 claims description 2
- 229930189413 Esperamicin Natural products 0.000 claims description 2
- 101000904173 Homo sapiens Progonadoliberin-1 Proteins 0.000 claims description 2
- VSNHCAURESNICA-UHFFFAOYSA-N Hydroxyurea Chemical compound NC(=O)NO VSNHCAURESNICA-UHFFFAOYSA-N 0.000 claims description 2
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical class OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 claims description 2
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Lomustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 0.000 claims description 2
- 102000029749 Microtubule Human genes 0.000 claims description 2
- 108091022875 Microtubule Proteins 0.000 claims description 2
- 229930182507 Neplanocin Natural products 0.000 claims description 2
- 102000008108 Osteoprotegerin Human genes 0.000 claims description 2
- 108010035042 Osteoprotegerin Proteins 0.000 claims description 2
- 101710176384 Peptide 1 Proteins 0.000 claims description 2
- 239000010103 Podophyllin Substances 0.000 claims description 2
- 102100024028 Progonadoliberin-1 Human genes 0.000 claims description 2
- 101000996723 Sus scrofa Gonadotropin-releasing hormone receptor Proteins 0.000 claims description 2
- FOCVUCIESVLUNU-UHFFFAOYSA-N Thiotepa Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 claims description 2
- HVYLDJKDVOOTHV-UHFFFAOYSA-N acetic acid;2-iminoethanethiol Chemical compound CC(O)=O.CC(O)=O.SCC=N HVYLDJKDVOOTHV-UHFFFAOYSA-N 0.000 claims description 2
- RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin D Chemical compound CC1OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)NC4C(=O)NC(C(N5CCCC5C(=O)N(C)CC(=O)N(C)C(C(C)C)C(=O)OC4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-UHFFFAOYSA-N 0.000 claims description 2
- 239000003470 adrenal cortex hormone Substances 0.000 claims description 2
- 229940100198 alkylating agent Drugs 0.000 claims description 2
- 239000002168 alkylating agent Substances 0.000 claims description 2
- YBBLVLTVTVSKRW-UHFFFAOYSA-N anastrozole Chemical compound N#CC(C)(C)C1=CC(C(C)(C#N)C)=CC(CN2N=CN=C2)=C1 YBBLVLTVTVSKRW-UHFFFAOYSA-N 0.000 claims description 2
- 229960002932 anastrozole Drugs 0.000 claims description 2
- 239000004037 angiogenesis inhibitor Substances 0.000 claims description 2
- 239000003242 anti bacterial agent Substances 0.000 claims description 2
- 239000000051 antiandrogen Substances 0.000 claims description 2
- 229940088710 antibiotic agent Drugs 0.000 claims description 2
- 239000003005 anticarcinogenic agent Substances 0.000 claims description 2
- 229940045719 antineoplastic alkylating agent nitrosoureas Drugs 0.000 claims description 2
- FZCSTZYAHCUGEM-UHFFFAOYSA-N aspergillomarasmine B Natural products OC(=O)CNC(C(O)=O)CNC(C(O)=O)CC(O)=O FZCSTZYAHCUGEM-UHFFFAOYSA-N 0.000 claims description 2
- 229960004574 azelastine Drugs 0.000 claims description 2
- 239000003124 biologic agent Substances 0.000 claims description 2
- 229960000455 brentuximab vedotin Drugs 0.000 claims description 2
- 229940126608 cBR96-doxorubicin immunoconjugate Drugs 0.000 claims description 2
- HXCHCVDVKSCDHU-LULTVBGHSA-N calicheamicin Chemical compound C1[C@H](OC)[C@@H](NCC)CO[C@H]1O[C@H]1[C@H](O[C@@H]2C\3=C(NC(=O)OC)C(=O)C[C@](C/3=C/CSSSC)(O)C#C\C=C/C#C2)O[C@H](C)[C@@H](NO[C@@H]2O[C@H](C)[C@@H](SC(=O)C=3C(=C(OC)C(O[C@H]4[C@@H]([C@H](OC)[C@@H](O)[C@H](C)O4)O)=C(I)C=3C)OC)[C@@H](O)C2)[C@@H]1O HXCHCVDVKSCDHU-LULTVBGHSA-N 0.000 claims description 2
- 229930195731 calicheamicin Natural products 0.000 claims description 2
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical class C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 claims description 2
- 239000005482 chemotactic factor Substances 0.000 claims description 2
- 108010006226 cryptophycin Proteins 0.000 claims description 2
- PSNOPSMXOBPNNV-VVCTWANISA-N cryptophycin 1 Chemical compound C1=C(Cl)C(OC)=CC=C1C[C@@H]1C(=O)NC[C@@H](C)C(=O)O[C@@H](CC(C)C)C(=O)O[C@H]([C@H](C)[C@@H]2[C@H](O2)C=2C=CC=CC=2)C/C=C/C(=O)N1 PSNOPSMXOBPNNV-VVCTWANISA-N 0.000 claims description 2
- PSNOPSMXOBPNNV-UHFFFAOYSA-N cryptophycin-327 Natural products C1=C(Cl)C(OC)=CC=C1CC1C(=O)NCC(C)C(=O)OC(CC(C)C)C(=O)OC(C(C)C2C(O2)C=2C=CC=CC=2)CC=CC(=O)N1 PSNOPSMXOBPNNV-UHFFFAOYSA-N 0.000 claims description 2
- 229960000684 cytarabine Drugs 0.000 claims description 2
- 229940070968 depocyt Drugs 0.000 claims description 2
- 238000000151 deposition Methods 0.000 claims description 2
- XQRLCLUYWUNEEH-UHFFFAOYSA-L diphosphonate(2-) Chemical compound [O-]P(=O)OP([O-])=O XQRLCLUYWUNEEH-UHFFFAOYSA-L 0.000 claims description 2
- AMRJKAQTDDKMCE-UHFFFAOYSA-N dolastatin Chemical compound CC(C)C(N(C)C)C(=O)NC(C(C)C)C(=O)N(C)C(C(C)C)C(OC)CC(=O)N1CCCC1C(OC)C(C)C(=O)NC(C=1SC=CN=1)CC1=CC=CC=C1 AMRJKAQTDDKMCE-UHFFFAOYSA-N 0.000 claims description 2
- 229930188854 dolastatin Natural products 0.000 claims description 2
- 229950007432 endomycin Drugs 0.000 claims description 2
- YJGVMLPVUAXIQN-UHFFFAOYSA-N epipodophyllotoxin Natural products COC1=C(OC)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(O)C3C2C(OC3)=O)=C1 YJGVMLPVUAXIQN-UHFFFAOYSA-N 0.000 claims description 2
- 210000000981 epithelium Anatomy 0.000 claims description 2
- LJQQFQHBKUKHIS-WJHRIEJJSA-N esperamicin Chemical compound O1CC(NC(C)C)C(OC)CC1OC1C(O)C(NOC2OC(C)C(SC)C(O)C2)C(C)OC1OC1C(\C2=C/CSSSC)=C(NC(=O)OC)C(=O)C(OC3OC(C)C(O)C(OC(=O)C=4C(=CC(OC)=C(OC)C=4)NC(=O)C(=C)OC)C3)C2(O)C#C\C=C/C#C1 LJQQFQHBKUKHIS-WJHRIEJJSA-N 0.000 claims description 2
- 229960000961 floxuridine Drugs 0.000 claims description 2
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N floxuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 claims description 2
- 229940064302 folacin Drugs 0.000 claims description 2
- 235000019152 folic acid Nutrition 0.000 claims description 2
- 239000011724 folic acid Substances 0.000 claims description 2
- 238000005194 fractionation Methods 0.000 claims description 2
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 claims description 2
- 239000010931 gold Substances 0.000 claims description 2
- 229910052737 gold Inorganic materials 0.000 claims description 2
- XLXSAKCOAKORKW-UHFFFAOYSA-N gonadorelin Chemical compound C1CCC(C(=O)NCC(N)=O)N1C(=O)C(CCCN=C(N)N)NC(=O)C(CC(C)C)NC(=O)CNC(=O)C(NC(=O)C(CO)NC(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C(CC=1NC=NC=1)NC(=O)C1NC(=O)CC1)CC1=CC=C(O)C=C1 XLXSAKCOAKORKW-UHFFFAOYSA-N 0.000 claims description 2
- 230000002607 hemopoietic effect Effects 0.000 claims description 2
- 229940022353 herceptin Drugs 0.000 claims description 2
- 239000005556 hormone Substances 0.000 claims description 2
- 229940088597 hormone Drugs 0.000 claims description 2
- 229960001330 hydroxycarbamide Drugs 0.000 claims description 2
- RSXFZXJOBQZOOM-WXIIGEIKSA-N kedarcidin Chemical compound O([C@@H]\1COC(=O)C[C@H](C2=CC=C(C(=N2)Cl)O[C@@H]2[C@H](O[C@@H]3O[C@@H](C)[C@H](O)[C@](C)(O)C3)[C@]34O[C@H]3C#C/C=C/1C#CC4=C2)NC(=O)C=1C(O)=CC2=CC(OC(C)C)=C(C(=C2C=1)OC)OC)[C@H]1C[C@H](O)[C@H](N(C)C)[C@H](C)O1 RSXFZXJOBQZOOM-WXIIGEIKSA-N 0.000 claims description 2
- 229960005535 lidamycin Drugs 0.000 claims description 2
- 239000002502 liposome Substances 0.000 claims description 2
- 229960002247 lomustine Drugs 0.000 claims description 2
- TTWJBBZEZQICBI-UHFFFAOYSA-N metoclopramide Chemical compound CCN(CC)CCNC(=O)C1=CC(Cl)=C(N)C=C1OC TTWJBBZEZQICBI-UHFFFAOYSA-N 0.000 claims description 2
- 229960004503 metoclopramide Drugs 0.000 claims description 2
- 210000004688 microtubule Anatomy 0.000 claims description 2
- XXUPLYBCNPLTIW-UHFFFAOYSA-N octadec-7-ynoic acid Chemical compound CCCCCCCCCCC#CCCCCCC(O)=O XXUPLYBCNPLTIW-UHFFFAOYSA-N 0.000 claims description 2
- WRUUGTRCQOWXEG-UHFFFAOYSA-N pamidronate Chemical compound NCCC(O)(P(O)(O)=O)P(O)(O)=O WRUUGTRCQOWXEG-UHFFFAOYSA-N 0.000 claims description 2
- 229940046231 pamidronate Drugs 0.000 claims description 2
- 229960002087 pertuzumab Drugs 0.000 claims description 2
- 229910052697 platinum Inorganic materials 0.000 claims description 2
- 229940068582 podophyllin Drugs 0.000 claims description 2
- 150000003212 purines Chemical class 0.000 claims description 2
- ZUFQODAHGAHPFQ-UHFFFAOYSA-N pyridoxine hydrochloride Chemical compound Cl.CC1=NC=C(CO)C(CO)=C1O ZUFQODAHGAHPFQ-UHFFFAOYSA-N 0.000 claims description 2
- 150000003230 pyrimidines Chemical class 0.000 claims description 2
- 229960001196 thiotepa Drugs 0.000 claims description 2
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 claims 1
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 claims 1
- 230000028993 immune response Effects 0.000 abstract description 12
- 230000001093 anti-cancer Effects 0.000 abstract 1
- 125000001424 substituent group Chemical group 0.000 description 21
- 229960005486 vaccine Drugs 0.000 description 21
- 206010009944 Colon cancer Diseases 0.000 description 19
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 17
- 239000002671 adjuvant Substances 0.000 description 16
- 125000003118 aryl group Chemical group 0.000 description 16
- 239000002585 base Substances 0.000 description 16
- 241000699670 Mus sp. Species 0.000 description 15
- 108091008605 VEGF receptors Proteins 0.000 description 15
- 150000001413 amino acids Chemical class 0.000 description 13
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 13
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 12
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 description 12
- 239000002773 nucleotide Substances 0.000 description 12
- 125000003729 nucleotide group Chemical group 0.000 description 12
- 159000000000 sodium salts Chemical class 0.000 description 12
- 102100025475 Carcinoembryonic antigen-related cell adhesion molecule 5 Human genes 0.000 description 11
- 241001465754 Metazoa Species 0.000 description 11
- 235000001014 amino acid Nutrition 0.000 description 11
- 229940024606 amino acid Drugs 0.000 description 11
- 230000000694 effects Effects 0.000 description 11
- 201000001441 melanoma Diseases 0.000 description 11
- 239000011734 sodium Substances 0.000 description 11
- 229910052708 sodium Inorganic materials 0.000 description 11
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 10
- 241001502974 Human gammaherpesvirus 8 Species 0.000 description 10
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 10
- 125000003342 alkenyl group Chemical group 0.000 description 10
- 208000029742 colonic neoplasm Diseases 0.000 description 10
- 201000010989 colorectal carcinoma Diseases 0.000 description 10
- 238000005516 engineering process Methods 0.000 description 10
- 125000002769 thiazolinyl group Chemical group 0.000 description 10
- 206010006187 Breast cancer Diseases 0.000 description 9
- 208000026310 Breast neoplasm Diseases 0.000 description 9
- 230000008685 targeting Effects 0.000 description 9
- 241000701806 Human papillomavirus Species 0.000 description 8
- 125000000304 alkynyl group Chemical group 0.000 description 8
- 201000008275 breast carcinoma Diseases 0.000 description 8
- 210000000987 immune system Anatomy 0.000 description 8
- 208000015181 infectious disease Diseases 0.000 description 8
- 238000011081 inoculation Methods 0.000 description 8
- 125000005647 linker group Chemical group 0.000 description 8
- 206010005003 Bladder cancer Diseases 0.000 description 7
- 241000341655 Human papillomavirus type 16 Species 0.000 description 7
- 206010033128 Ovarian cancer Diseases 0.000 description 7
- 206010061535 Ovarian neoplasm Diseases 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 7
- 238000009169 immunotherapy Methods 0.000 description 7
- 238000007912 intraperitoneal administration Methods 0.000 description 7
- 201000001514 prostate carcinoma Diseases 0.000 description 7
- 108090000623 proteins and genes Proteins 0.000 description 7
- 201000005112 urinary bladder cancer Diseases 0.000 description 7
- 201000009030 Carcinoma Diseases 0.000 description 6
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 101800001271 Surface protein Proteins 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 230000004913 activation Effects 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 6
- 230000000844 anti-bacterial effect Effects 0.000 description 6
- 238000009566 cancer vaccine Methods 0.000 description 6
- 229940022399 cancer vaccine Drugs 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 108010087914 epidermal growth factor receptor VIII Proteins 0.000 description 6
- 229910052731 fluorine Inorganic materials 0.000 description 6
- 239000011737 fluorine Substances 0.000 description 6
- 208000032839 leukemia Diseases 0.000 description 6
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 6
- 108020004999 messenger RNA Proteins 0.000 description 6
- 238000007920 subcutaneous administration Methods 0.000 description 6
- 231100000419 toxicity Toxicity 0.000 description 6
- 230000001988 toxicity Effects 0.000 description 6
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 description 5
- 102100041003 Glutamate carboxypeptidase 2 Human genes 0.000 description 5
- 102000002812 Heat-Shock Proteins Human genes 0.000 description 5
- 108010004889 Heat-Shock Proteins Proteins 0.000 description 5
- 101000892862 Homo sapiens Glutamate carboxypeptidase 2 Proteins 0.000 description 5
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 5
- 241000699666 Mus <mouse, genus> Species 0.000 description 5
- 206010035226 Plasma cell myeloma Diseases 0.000 description 5
- 208000006265 Renal cell carcinoma Diseases 0.000 description 5
- 239000002131 composite material Substances 0.000 description 5
- 239000006185 dispersion Substances 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 230000004927 fusion Effects 0.000 description 5
- 230000001900 immune effect Effects 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 108010014186 ras Proteins Proteins 0.000 description 5
- 210000002966 serum Anatomy 0.000 description 5
- 230000035939 shock Effects 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 210000004881 tumor cell Anatomy 0.000 description 5
- KKVYYGGCHJGEFJ-UHFFFAOYSA-N 1-n-(4-chlorophenyl)-6-methyl-5-n-[3-(7h-purin-6-yl)pyridin-2-yl]isoquinoline-1,5-diamine Chemical compound N=1C=CC2=C(NC=3C(=CC=CN=3)C=3C=4N=CNC=4N=CN=3)C(C)=CC=C2C=1NC1=CC=C(Cl)C=C1 KKVYYGGCHJGEFJ-UHFFFAOYSA-N 0.000 description 4
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
- 0 CCC(*C(N)=O)N Chemical compound CCC(*C(N)=O)N 0.000 description 4
- 206010008342 Cervix carcinoma Diseases 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 238000002965 ELISA Methods 0.000 description 4
- 208000017604 Hodgkin disease Diseases 0.000 description 4
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 4
- 208000034578 Multiple myelomas Diseases 0.000 description 4
- 241001529936 Murinae Species 0.000 description 4
- 101100381978 Mus musculus Braf gene Proteins 0.000 description 4
- 208000005718 Stomach Neoplasms Diseases 0.000 description 4
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 4
- 201000010881 cervical cancer Diseases 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 206010017758 gastric cancer Diseases 0.000 description 4
- 150000002632 lipids Chemical class 0.000 description 4
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 4
- 230000002018 overexpression Effects 0.000 description 4
- 235000018102 proteins Nutrition 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- 201000011549 stomach cancer Diseases 0.000 description 4
- 230000004083 survival effect Effects 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 239000003053 toxin Substances 0.000 description 4
- 231100000765 toxin Toxicity 0.000 description 4
- 108700012359 toxins Proteins 0.000 description 4
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 4
- 230000009385 viral infection Effects 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- 208000003174 Brain Neoplasms Diseases 0.000 description 3
- 101150065749 Churc1 gene 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
- 108700024394 Exon Proteins 0.000 description 3
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 3
- 108010075704 HLA-A Antigens Proteins 0.000 description 3
- 102000011786 HLA-A Antigens Human genes 0.000 description 3
- 208000021519 Hodgkin lymphoma Diseases 0.000 description 3
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 206010025323 Lymphomas Diseases 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 3
- 108010081690 Pertussis Toxin Proteins 0.000 description 3
- 102100038239 Protein Churchill Human genes 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- 102000009484 Vascular Endothelial Growth Factor Receptors Human genes 0.000 description 3
- 230000000843 anti-fungal effect Effects 0.000 description 3
- 229940121375 antifungal agent Drugs 0.000 description 3
- 230000000890 antigenic effect Effects 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000014509 gene expression Effects 0.000 description 3
- 229940102223 injectable solution Drugs 0.000 description 3
- 230000000968 intestinal effect Effects 0.000 description 3
- 108010045069 keyhole-limpet hemocyanin Proteins 0.000 description 3
- 210000004072 lung Anatomy 0.000 description 3
- 238000012544 monitoring process Methods 0.000 description 3
- 229940035032 monophosphoryl lipid a Drugs 0.000 description 3
- 230000002974 pharmacogenomic effect Effects 0.000 description 3
- 239000010452 phosphate Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 102000004196 processed proteins & peptides Human genes 0.000 description 3
- 230000028327 secretion Effects 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 230000000638 stimulation Effects 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 229910052717 sulfur Chemical group 0.000 description 3
- 239000011593 sulfur Chemical group 0.000 description 3
- 229940124597 therapeutic agent Drugs 0.000 description 3
- 229960005267 tositumomab Drugs 0.000 description 3
- 230000007704 transition Effects 0.000 description 3
- 238000002255 vaccination Methods 0.000 description 3
- 235000014393 valine Nutrition 0.000 description 3
- 125000002987 valine group Chemical class [H]N([H])C([H])(C(*)=O)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 229940124676 vascular endothelial growth factor receptor Drugs 0.000 description 3
- VDCRFBBZFHHYGT-IOSLPCCCSA-N 2-amino-9-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-enyl-3h-purine-6,8-dione Chemical compound O=C1N(CC=C)C=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O VDCRFBBZFHHYGT-IOSLPCCCSA-N 0.000 description 2
- 206010001167 Adenocarcinoma of colon Diseases 0.000 description 2
- 108010088751 Albumins Proteins 0.000 description 2
- 102000009027 Albumins Human genes 0.000 description 2
- 208000003950 B-cell lymphoma Diseases 0.000 description 2
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 2
- 241000193738 Bacillus anthracis Species 0.000 description 2
- 108030001720 Bontoxilysin Proteins 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- 206010055113 Breast cancer metastatic Diseases 0.000 description 2
- 208000011691 Burkitt lymphomas Diseases 0.000 description 2
- 101100381481 Caenorhabditis elegans baz-2 gene Proteins 0.000 description 2
- 208000017897 Carcinoma of esophagus Diseases 0.000 description 2
- 102100025064 Cellular tumor antigen p53 Human genes 0.000 description 2
- 108010049048 Cholera Toxin Proteins 0.000 description 2
- 102000009016 Cholera Toxin Human genes 0.000 description 2
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 2
- 206010052358 Colorectal cancer metastatic Diseases 0.000 description 2
- 208000011231 Crohn disease Diseases 0.000 description 2
- 241000790917 Dioxys <bee> Species 0.000 description 2
- 108010053187 Diphtheria Toxin Proteins 0.000 description 2
- 102000016607 Diphtheria Toxin Human genes 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 241000588724 Escherichia coli Species 0.000 description 2
- 102000009109 Fc receptors Human genes 0.000 description 2
- 108010087819 Fc receptors Proteins 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 108700039691 Genetic Promoter Regions Proteins 0.000 description 2
- 108010074032 HLA-A2 Antigen Proteins 0.000 description 2
- 102000025850 HLA-A2 Antigen Human genes 0.000 description 2
- 108010088652 Histocompatibility Antigens Class I Proteins 0.000 description 2
- 102000008949 Histocompatibility Antigens Class I Human genes 0.000 description 2
- 101000578784 Homo sapiens Melanoma antigen recognized by T-cells 1 Proteins 0.000 description 2
- 208000007766 Kaposi sarcoma Diseases 0.000 description 2
- 108010044023 Ki-1 Antigen Proteins 0.000 description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 2
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 2
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 2
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 2
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 2
- 102100028389 Melanoma antigen recognized by T-cells 1 Human genes 0.000 description 2
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 2
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 2
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- 101800004196 Peptide P4 Proteins 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 108091000080 Phosphotransferase Proteins 0.000 description 2
- 241000605862 Porphyromonas gingivalis Species 0.000 description 2
- 102000007066 Prostate-Specific Antigen Human genes 0.000 description 2
- 108010072866 Prostate-Specific Antigen Proteins 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 101100372762 Rattus norvegicus Flt1 gene Proteins 0.000 description 2
- 108010055044 Tetanus Toxin Proteins 0.000 description 2
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Chemical group CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 2
- 102000016549 Vascular Endothelial Growth Factor Receptor-2 Human genes 0.000 description 2
- 108010053099 Vascular Endothelial Growth Factor Receptor-2 Proteins 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 235000010323 ascorbic acid Nutrition 0.000 description 2
- 239000011668 ascorbic acid Substances 0.000 description 2
- 229960005070 ascorbic acid Drugs 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 229940053031 botulinum toxin Drugs 0.000 description 2
- 229940098773 bovine serum albumin Drugs 0.000 description 2
- 150000001720 carbohydrates Chemical class 0.000 description 2
- 235000014633 carbohydrates Nutrition 0.000 description 2
- 229940030156 cell vaccine Drugs 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 201000010897 colon adenocarcinoma Diseases 0.000 description 2
- 231100000433 cytotoxic Toxicity 0.000 description 2
- 230000001472 cytotoxic effect Effects 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 230000002708 enhancing effect Effects 0.000 description 2
- 201000005619 esophageal carcinoma Diseases 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 235000013922 glutamic acid Nutrition 0.000 description 2
- 239000004220 glutamic acid Substances 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 235000011167 hydrochloric acid Nutrition 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 description 2
- 229960002411 imatinib Drugs 0.000 description 2
- 229960002751 imiquimod Drugs 0.000 description 2
- 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 2
- 230000005847 immunogenicity Effects 0.000 description 2
- 230000003308 immunostimulating effect Effects 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 208000037903 inflammatory enteropathy Diseases 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 239000007951 isotonicity adjuster Substances 0.000 description 2
- 210000002540 macrophage Anatomy 0.000 description 2
- 230000003211 malignant effect Effects 0.000 description 2
- 210000001161 mammalian embryo Anatomy 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 210000004303 peritoneum Anatomy 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 102000020233 phosphotransferase Human genes 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 230000003449 preventive effect Effects 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 102000016914 ras Proteins Human genes 0.000 description 2
- 230000000306 recurrent effect Effects 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 201000000849 skin cancer Diseases 0.000 description 2
- 201000008261 skin carcinoma Diseases 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 150000005846 sugar alcohols Polymers 0.000 description 2
- 229940118376 tetanus toxin Drugs 0.000 description 2
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 2
- 229940033663 thimerosal Drugs 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 239000004474 valine Chemical group 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- WOWDZACBATWTAU-FEFUEGSOSA-N (2s)-2-[[(2s)-2-(dimethylamino)-3-methylbutanoyl]amino]-n-[(3r,4s,5s)-1-[(2s)-2-[(1r,2r)-3-[[(1s,2r)-1-hydroxy-1-phenylpropan-2-yl]amino]-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl]-3-methoxy-5-methyl-1-oxoheptan-4-yl]-n,3-dimethylbutanamide Chemical compound CC(C)[C@H](N(C)C)C(=O)N[C@@H](C(C)C)C(=O)N(C)[C@@H]([C@@H](C)CC)[C@H](OC)CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C)[C@@H](O)C1=CC=CC=C1 WOWDZACBATWTAU-FEFUEGSOSA-N 0.000 description 1
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- WEYNBWVKOYCCQT-UHFFFAOYSA-N 1-(3-chloro-4-methylphenyl)-3-{2-[({5-[(dimethylamino)methyl]-2-furyl}methyl)thio]ethyl}urea Chemical compound O1C(CN(C)C)=CC=C1CSCCNC(=O)NC1=CC=C(C)C(Cl)=C1 WEYNBWVKOYCCQT-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- SNKUSVNHTCUELQ-UHFFFAOYSA-N 2-[[4-amino-2-[[2-[[2-[2-[[2-[[2-[[2-[[2-amino-3-(4-hydroxyphenyl)propanoyl]amino]-4-methylpentanoyl]amino]-3-hydroxypropanoyl]amino]acetyl]amino]propanoylamino]-3-carboxypropanoyl]amino]-4-methylpentanoyl]amino]-4-oxobutanoyl]amino]-4-methylpentanoic aci Chemical compound CC(C)CC(C(O)=O)NC(=O)C(CC(N)=O)NC(=O)C(CC(C)C)NC(=O)C(CC(O)=O)NC(=O)C(C)NC(=O)CNC(=O)C(CO)NC(=O)C(CC(C)C)NC(=O)C(N)CC1=CC=C(O)C=C1 SNKUSVNHTCUELQ-UHFFFAOYSA-N 0.000 description 1
- QUTGXAIWZAMYEM-UHFFFAOYSA-N 2-cyclopentyloxyethanamine Chemical compound NCCOC1CCCC1 QUTGXAIWZAMYEM-UHFFFAOYSA-N 0.000 description 1
- LKKMLIBUAXYLOY-UHFFFAOYSA-N 3-Amino-1-methyl-5H-pyrido[4,3-b]indole Chemical compound N1C2=CC=CC=C2C2=C1C=C(N)N=C2C LKKMLIBUAXYLOY-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-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
- 102100030310 5,6-dihydroxyindole-2-carboxylic acid oxidase Human genes 0.000 description 1
- 101710163881 5,6-dihydroxyindole-2-carboxylic acid oxidase Proteins 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 206010000830 Acute leukaemia Diseases 0.000 description 1
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 1
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 1
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 1
- 101710137115 Adenylyl cyclase-associated protein 1 Proteins 0.000 description 1
- 101710137132 Adenylyl cyclase-associated protein 2 Proteins 0.000 description 1
- 102100021879 Adenylyl cyclase-associated protein 2 Human genes 0.000 description 1
- 101710145634 Antigen 1 Proteins 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 241000271566 Aves Species 0.000 description 1
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 1
- 208000028564 B-cell non-Hodgkin lymphoma Diseases 0.000 description 1
- 230000003844 B-cell-activation Effects 0.000 description 1
- 102100022005 B-lymphocyte antigen CD20 Human genes 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 102000015735 Beta-catenin Human genes 0.000 description 1
- 108060000903 Beta-catenin Proteins 0.000 description 1
- 125000001433 C-terminal amino-acid group Chemical group 0.000 description 1
- 238000011740 C57BL/6 mouse Methods 0.000 description 1
- 101800004711 CAP-3 Proteins 0.000 description 1
- 108010077333 CAP1-6D Proteins 0.000 description 1
- 108010063916 CD40 Antigens Proteins 0.000 description 1
- 102100025570 Cancer/testis antigen 1 Human genes 0.000 description 1
- 102000014914 Carrier Proteins Human genes 0.000 description 1
- 108010078791 Carrier Proteins Proteins 0.000 description 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 241001112696 Clostridia Species 0.000 description 1
- 241000193155 Clostridium botulinum Species 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 241000759568 Corixa 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
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 208000030453 Drug-Related Side Effects and Adverse reaction Diseases 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 102000001301 EGF receptor Human genes 0.000 description 1
- 108060006698 EGF receptor Proteins 0.000 description 1
- 208000004232 Enteritis Diseases 0.000 description 1
- 101710181478 Envelope glycoprotein GP350 Proteins 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 101710113436 GTPase KRas Proteins 0.000 description 1
- 206010017993 Gastrointestinal neoplasms Diseases 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
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 102000009465 Growth Factor Receptors Human genes 0.000 description 1
- 108010009202 Growth Factor Receptors Proteins 0.000 description 1
- 108010088729 HLA-A*02:01 antigen Proteins 0.000 description 1
- 102220372951 HLA-A*3101 Human genes 0.000 description 1
- 108010013476 HLA-A24 Antigen Proteins 0.000 description 1
- 108010086377 HLA-A3 Antigen Proteins 0.000 description 1
- 102000018713 Histocompatibility Antigens Class II Human genes 0.000 description 1
- 108010027412 Histocompatibility Antigens Class II Proteins 0.000 description 1
- 101000897405 Homo sapiens B-lymphocyte antigen CD20 Proteins 0.000 description 1
- 101000856237 Homo sapiens Cancer/testis antigen 1 Proteins 0.000 description 1
- 101500025419 Homo sapiens Epidermal growth factor Proteins 0.000 description 1
- 101000744505 Homo sapiens GTPase NRas Proteins 0.000 description 1
- 101100346929 Homo sapiens MUC1 gene Proteins 0.000 description 1
- 101000851007 Homo sapiens Vascular endothelial growth factor receptor 2 Proteins 0.000 description 1
- 241000714259 Human T-lymphotropic virus 2 Species 0.000 description 1
- 241000701044 Human gammaherpesvirus 4 Species 0.000 description 1
- 206010021432 Immunisation reaction Diseases 0.000 description 1
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 description 1
- 208000005016 Intestinal Neoplasms Diseases 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical group NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical group OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 1
- 102100031413 L-dopachrome tautomerase Human genes 0.000 description 1
- 101710093778 L-dopachrome tautomerase Proteins 0.000 description 1
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 1
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 1
- 108090001030 Lipoproteins Proteins 0.000 description 1
- 102000004895 Lipoproteins Human genes 0.000 description 1
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 1
- 208000028018 Lymphocytic leukaemia Diseases 0.000 description 1
- PEEHTFAAVSWFBL-UHFFFAOYSA-N Maleimide Chemical compound O=C1NC(=O)C=C1 PEEHTFAAVSWFBL-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 206010027480 Metastatic malignant melanoma Diseases 0.000 description 1
- 102000007298 Mucin-1 Human genes 0.000 description 1
- 108010008707 Mucin-1 Proteins 0.000 description 1
- 201000003793 Myelodysplastic syndrome Diseases 0.000 description 1
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 1
- 125000000729 N-terminal amino-acid group Chemical group 0.000 description 1
- 208000002454 Nasopharyngeal Carcinoma Diseases 0.000 description 1
- 206010061306 Nasopharyngeal cancer Diseases 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 108091028043 Nucleic acid sequence Proteins 0.000 description 1
- 101710160107 Outer membrane protein A Proteins 0.000 description 1
- 108010058846 Ovalbumin Proteins 0.000 description 1
- 108010089430 Phosphoproteins Proteins 0.000 description 1
- 102000007982 Phosphoproteins Human genes 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229920002685 Polyoxyl 35CastorOil Polymers 0.000 description 1
- 102100025067 Potassium voltage-gated channel subfamily H member 4 Human genes 0.000 description 1
- 101710163352 Potassium voltage-gated channel subfamily H member 4 Proteins 0.000 description 1
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 102100025517 Serpin B9 Human genes 0.000 description 1
- 101710173693 Short transient receptor potential channel 1 Proteins 0.000 description 1
- 101710173694 Short transient receptor potential channel 2 Proteins 0.000 description 1
- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- 102000013275 Somatomedins Human genes 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 241000282898 Sus scrofa Species 0.000 description 1
- 208000000389 T-cell leukemia Diseases 0.000 description 1
- 208000028530 T-cell lymphoblastic leukemia/lymphoma Diseases 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 102100033082 TNF receptor-associated factor 3 Human genes 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- 208000033781 Thyroid carcinoma Diseases 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- 206010070863 Toxicity to various agents Diseases 0.000 description 1
- 102100023935 Transmembrane glycoprotein NMB Human genes 0.000 description 1
- LVTKHGUGBGNBPL-UHFFFAOYSA-N Trp-P-1 Chemical compound N1C2=CC=CC=C2C2=C1C(C)=C(N)N=C2C LVTKHGUGBGNBPL-UHFFFAOYSA-N 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 125000004442 acylamino group Chemical group 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical group [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 239000003098 androgen Substances 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 230000005875 antibody response Effects 0.000 description 1
- 230000010056 antibody-dependent cellular cytotoxicity Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 229960000190 bacillus calmette–guérin vaccine Drugs 0.000 description 1
- 230000003385 bacteriostatic effect Effects 0.000 description 1
- 210000000270 basal cell Anatomy 0.000 description 1
- 238000005284 basis set Methods 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 229960004217 benzyl alcohol Drugs 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
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 238000003763 carbonization Methods 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 231100000315 carcinogenic Toxicity 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- 125000003636 chemical group Chemical group 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 1
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 231100001102 clostridial toxin Toxicity 0.000 description 1
- 238000011284 combination treatment Methods 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 230000002380 cytological effect Effects 0.000 description 1
- 210000001151 cytotoxic T lymphocyte Anatomy 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 238000010195 expression analysis Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 201000003444 follicular lymphoma Diseases 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 230000013595 glycosylation Effects 0.000 description 1
- 238000006206 glycosylation reaction Methods 0.000 description 1
- 210000002149 gonad Anatomy 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 208000002672 hepatitis B Diseases 0.000 description 1
- 210000003494 hepatocyte Anatomy 0.000 description 1
- 102000055590 human KDR Human genes 0.000 description 1
- 102000057860 human MUC1 Human genes 0.000 description 1
- 229940116978 human epidermal growth factor Drugs 0.000 description 1
- 230000008348 humoral response Effects 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 150000001261 hydroxy acids Chemical group 0.000 description 1
- 230000008105 immune reaction Effects 0.000 description 1
- 230000000899 immune system response Effects 0.000 description 1
- 229960001438 immunostimulant agent Drugs 0.000 description 1
- 239000003022 immunostimulating agent Substances 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 201000002313 intestinal cancer Diseases 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229960000310 isoleucine Drugs 0.000 description 1
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 1
- 238000002647 laser therapy Methods 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- UTEFBSAVJNEPTR-RGEXLXHISA-N loprazolam Chemical compound C1CN(C)CCN1\C=C/1C(=O)N2C3=CC=C([N+]([O-])=O)C=C3C(C=3C(=CC=CC=3)Cl)=NCC2=N\1 UTEFBSAVJNEPTR-RGEXLXHISA-N 0.000 description 1
- 229960003019 loprazolam Drugs 0.000 description 1
- 229950005634 loxoribine Drugs 0.000 description 1
- 208000003747 lymphoid leukemia Diseases 0.000 description 1
- 230000002101 lytic effect Effects 0.000 description 1
- 229960003511 macrogol Drugs 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 210000005075 mammary gland Anatomy 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 208000021039 metastatic melanoma Diseases 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 229950003063 mitumomab Drugs 0.000 description 1
- 210000005087 mononuclear cell Anatomy 0.000 description 1
- 230000002969 morbid Effects 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 210000003887 myelocyte Anatomy 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 description 1
- 201000011216 nasopharynx carcinoma Diseases 0.000 description 1
- 210000000822 natural killer cell Anatomy 0.000 description 1
- 238000011328 necessary treatment Methods 0.000 description 1
- GVUGOAYIVIDWIO-UFWWTJHBSA-N nepidermin Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)NC(=O)CNC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H](CS)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CS)NC(=O)[C@H](C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C(C)C)C(C)C)C1=CC=C(O)C=C1 GVUGOAYIVIDWIO-UFWWTJHBSA-N 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 231100001223 noncarcinogenic Toxicity 0.000 description 1
- 229920001542 oligosaccharide Polymers 0.000 description 1
- 150000002482 oligosaccharides Chemical class 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 229940092253 ovalbumin Drugs 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- QUANRIQJNFHVEU-UHFFFAOYSA-N oxirane;propane-1,2,3-triol Chemical compound C1CO1.OCC(O)CO QUANRIQJNFHVEU-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 229960003742 phenol Drugs 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 239000008389 polyethoxylated castor oil Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 230000002787 reinforcement Effects 0.000 description 1
- 201000010174 renal carcinoma Diseases 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 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 1
- 229950010550 resiquimod Drugs 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 201000000306 sarcoidosis Diseases 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 238000012163 sequencing technique Methods 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000005728 strengthening Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- LZOZLBFZGFLFBV-UHFFFAOYSA-N sulfene Chemical compound C=S(=O)=O LZOZLBFZGFLFBV-UHFFFAOYSA-N 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 229940021747 therapeutic vaccine Drugs 0.000 description 1
- 150000003573 thiols Chemical group 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 208000013077 thyroid gland carcinoma Diseases 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 229940044616 toll-like receptor 7 agonist Drugs 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000009261 transgenic effect Effects 0.000 description 1
- 108091007466 transmembrane glycoproteins Proteins 0.000 description 1
- 231100000402 unacceptable toxicity Toxicity 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
Images
Classifications
-
- 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
-
- 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
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
-
- 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
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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
- A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
- A61K2039/55511—Organic adjuvants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K39/46
- A61K2239/46—Indexing codes associated with cellular immunotherapy of group A61K39/46 characterised by the cancer treated
- A61K2239/57—Skin; melanoma
Abstract
本发明涉及用于癌症免疫疗法的组合物和其用途。本发明的组合物包含一种或一种以上抗癌抗体;和一种或一种以上式(I)的化合物。该组合物可用于用于刺激受检者个体的免疫反应,以通过阻止或减缓即存癌症的生长而稳定肿瘤,阻止肿瘤扩散或转移扩散,减小肿瘤尺寸,阻止所治疗癌症的复发,消除早期治疗未杀死的癌细胞,或阻止或延缓癌症的发展。
Description
本申请是申请日为2006年4月26日,申请号为200680014380.8、发明名称为“用于癌症免疫疗法的组合物和方法”的发明专利申请的分案申请。
技术领域
本发明提供用于癌症免疫疗法的组合物和方法。
背景技术
癌症免疫疗法涉及使用组合物和方法来引发和增强个体自身抵抗癌细胞或倾向于癌症的感染的免疫系统。癌症疫苗通过引起免疫系统对以非致癌形式引入体内并引起身体赋予免疫性或获得长久“记忆”免疫反应的抗原(例如,通常为蛋白、肽或糖)产生反应而起作用。例如参看Kast,Peptide-Based Cancer Vaccines,Landes Bioscience(2000);Stern等人,Cancer Vaccines and Immunotherapy,Cambridge University Press(2000)。一旦建立免疫系统反应,那么免疫系统暴露于所述抗原(例如呈癌性肿瘤的形式)就产生快速且加强的免疫反应。
经常有必要增强对疫苗中存在抗原的免疫反应,从而来将免疫系统刺激到足以使得疫苗有效的程度,即赋予免疫性。许多单独投予的蛋白、肽和糖抗原并不产生足以赋予免疫性的反应。此情况的原因可能是癌症反应性免疫反应所识别的抗原来源于在与癌症相同的组织类型的正常组织中表达的蛋白,以致免疫耐受性可能阻止对抗原的有效免疫反应。所述抗原需要以其将产生免疫反应的方式提供给免疫系统。为此目的,已设计出固定抗原并增强免疫反应的佐剂。众所周知的佐剂,即弗氏完全佐剂(Freund′s completeadjuvant)由分枝杆菌(mycobacteria)在油/水乳液中的混合物组成。弗氏佐剂(Freund′sadjuvant)(i)通过增强细胞和体液介导性免疫和(ii)通过阻断抗原激发的快速分散(储积效应)来起作用。弗氏佐剂主要用于实验疗法以帮助刺激动物的免疫系统,而且在人类中,分枝杆菌制剂卡介苗(Bacille Calmette-Guerin,BCG)是一种批准作为膀胱癌治疗的免疫疗法。
已显示具有免疫刺激或佐剂活性的另一种分子是内毒素,也称为脂多糖(LPS)。LPS也是一种可克服对自体抗原的耐受性的典型佐剂。Waldner,等人,JClin.Invest,(2004);113 990-997。虽然LPS毒性太大而不能成为可行的佐剂,但结构上与内毒素相关的分子,诸如单磷酰脂质A(“MPL”)在临床试验中正作为佐测进行测试。FDA唯一批准用于人类的佐剂是铝盐,明矾。
此项技术中需要可作为癌症免疫治疗剂刺激免疫系统的安全且有效的组合物。本发明针对此目的,以及其它重要目的。
发明内容
本发明涉及一种组合物,其具有(i)至少一种免疫治疗剂,其可为一种或一种以上癌抗原、一种或一种以上源自与癌症相关的病毒的抗原、一种或一种以上抗癌抗体和抗癌抗体的抗独特型抗体;和(ii)一种或一种以上式(I)、(II)、(III)、(IV)和(V)的化合物和/或其医药学上可接受的盐、水合物、溶剂合物、立体异构体、非晶形固体,或其任何组合。
本发明的化合物可投予存在发展癌症的风险、经诊断患有癌症、处于癌症治疗期间或处于癌症治疗后恢复期间的受检者个体,或本发明的化合物可作为预防剂投予受检者个体以阻止或延缓癌症的发展。
本发明还涉及用于通过以下步骤刺激受检者个体的免疫反应的方法:(a)向个体投予至少一种选自以下各物的免疫治疗剂:一种或一种以上癌抗原;一种或一种以上源自与癌症相关的病毒的抗原;一种或一种以上抗癌抗体;和抗癌抗体的一种或一种以上抗独特型抗体;和(b)向个体投予一种或一种以上选自式(I)、(II)、(III)、(IV)和(V)的化合物和/或其医药学上可接受的盐、水合物、溶剂合物、立体异构体、非晶形固体,或其任何组合。
本发明的这些和其它方面在本文中更详细描述。
附图说明
图1显示了腹膜内(i.p.)TLR激动剂增强B16-GM-CSF疫苗的治疗功效。其描述在用皮下B16GM-CSF(R)细胞、E6020或B16GM-CSF(r)细胞和E6020治疗后或未经治疗而存活的荷瘤小鼠百分比的图表。
图2显示了局部TLR激动剂增强B16-GM-CSF疫苗的治疗功效。其描述用B16GM-CSF(R)细胞或B16GM-CSF(r)细胞和E6020肿瘤内治疗后或未经治疗而存活的荷瘤小鼠百分比的图表。
图3为描述未经治疗或用疫苗和E6020治疗后无疾病征兆的动物百分比的图表。
图4为描述未经治疗、用疫苗治疗或用E6020治疗后存活动物百分比的图表。
具体实施方式
本发明提供组合物,其包含(i)至少一种免疫治疗剂,其选自一种或一种以上癌抗原、一种或一种以上源自与癌症相关的病毒的抗原、一种或一种以上抗癌抗体和抗癌抗体的一种或一种以上抗独特型抗体;和(ii)一种或一种以上选自式(I)、(II)、(III)、(IV)和(V)的化合物和/或其医药学上可接受的盐、水合物、溶剂合物、立体异构体、非晶形固体,或其任何组合。所述化合物在下文详细描述。所述组合物可为治疗剂,即,投予化合物来治疗即存的癌症,或阻止癌症的复发;或所述组合物可为预防剂,即,投予化合物以阻止或延缓癌症的发展。当治疗性地使用组合物时,将其投予癌症患者并用于引发免疫反应,从而通过阻止或减缓即存癌症的生长来稳定肿瘤,阻止肿瘤扩散或转移扩散,减小肿瘤尺寸,阻止所治疗癌症的复发,或消除早期治疗未杀死的癌细胞。将用作预防性治疗的组合物投予不患有癌症的个体,并用于引发免疫反应以靶向潜在癌细胞或靶向源自与癌症相关的病毒的抗原。
本发明的组合物可包括多于一种免疫治疗剂以及另一种免疫治疗剂,例如,癌抗原与一种或一种以上源自与癌症相关的病毒的抗原、一种或一种以上抗癌抗体和抗癌抗体的一种或一种以上抗独特型抗体组合。组合物的另一实施例可包括一种或一种以上癌抗原和抗癌抗体和/或抗癌抗体的抗独特型抗体。组合物的其它实施例可包括抗癌抗体和抗癌抗体的抗独特型抗体。另一实施例可包括一种或一种以上源自与癌症相关的病毒的抗原和抗癌抗体和/或抗癌抗体的抗独特型抗体。
4.1癌抗原
医药组合物的免疫治疗剂之一可为一种或一种以上癌抗原。癌抗原是(a)可在恶性细胞上发现的细胞表面抗原,(b)可在恶性细胞内部发现的抗原或(c)肿瘤细胞生长的介体。
术语“癌抗原”指的是(i)肿瘤特异性抗原、(ii)肿瘤相关抗原、(iii)表达肿瘤特异性抗原的细胞、(iv)表达肿瘤相关抗原的细胞、(v)肿瘤上的胚胎抗原、(vi)自体性肿瘤细胞、(vii)肿瘤特异性膜抗原、(viii)肿瘤相关膜抗原、(ix)生长因子受体、(x)生长因子配位体和(xi)任何其它类型的抗原或提供抗原的细胞或与癌症相关的物质。
癌抗原可为此项技术中已知的任何类型的癌抗原。癌抗原可为上皮癌抗原(例如,乳腺、胃肠、肺)、前列腺特异性癌抗原(PSA)或前列腺特异性膜抗原(PSMA)、膀胱癌抗原、肺(例如,小细胞肺)癌抗原、结肠癌抗原、卵巢癌抗原、脑癌抗原、胃癌抗原、肾细胞癌抗原、胰腺癌抗原、肝癌抗原、食道癌抗原、头颈部癌抗原或结肠直肠癌抗原。
在另一实施例中,癌抗原为淋巴瘤抗原(例如,非霍奇金氏淋巴瘤(non-Hodgkin′slymphoma)或霍奇金氏淋巴瘤(Hodgkin′s lymphoma))、B细胞淋巴瘤癌抗原、白血病抗原、骨髓瘤(即,多发性骨髓瘤或浆细胞骨髓瘤)抗原、急性淋巴母细胞性白血病抗原、慢性髓细胞白血病抗原或急性骨髓性白血病抗原。
在另一实施例中,癌抗原为在所有人类腺癌上发现的粘蛋白-1蛋白或肽(MUC-1):胰腺癌、结肠癌、乳腺癌、卵巢癌、肺癌、前列腺癌、头颈部癌,包括多发性骨髓瘤和一些B细胞淋巴瘤。患有发炎性肠病(克罗恩氏病(Crohn′s disease)或溃疡性结肠炎)的患者发展结肠直肠癌的风险增多。MUC-1是I型跨膜糖蛋白。MUC-1的主要胞外部分具有许多由包含免疫原性表位的20种氨基酸组成的串联重复。在一些癌症中,其以由免疫系统识别的未糖基化形式暴露。参看Gendler,S.J.,等人,JBiol.Chem.265:15286-15293(1990)。
在另一实施例中,癌抗原为突变B-Raf抗原,其与黑素瘤和结肠癌有关。绝大多数这些突变都代表在核苷酸1796处的T-A的单核苷酸变化,从而导致在B-Raf的活化区段内的残基599处缬氨酸变成谷氨酸。Raf蛋白作为活化Ras蛋白的效应物也间接地与癌症有关,致癌形式的Raf蛋白存在于所有人类癌症的约三分之一中。正常非突变B-Raf与细胞信号转导、从细胞膜转播信号到核有关。所述蛋白通常只在需要转播信号时具有活性。相反,已报导突变体B-Raf始终有活性,从而中断信号转播。Mercer和Pritchard,Biochim BiophysActa.(2003);1653(l):25-40;Sharkey,等人,Cancer Res.(2004);64(5):1595-9。
在一实施例中,癌抗原为人类表皮生长因子受体-2(HER-2/neu)抗原。具有过度表达HER-2/neu的细胞的癌症被称为HER-2/neu+癌症。示范性的HER-2/neu+癌症包括前列腺癌、肺癌、乳腺癌、卵巢癌、胰腺癌、皮肤癌、肝癌(例如,肝细胞性腺癌)、肠癌和膀胱癌。
HER-2/neu具有与表皮生长因子受体(epidermal growth factor receptor,EGFR)具40%同源性的约645aa的胞外结合域(extracellular binding domain,ECD)、高度疏水性跨膜锚定域(transmembrane anchor domain,TMD)和与EGFR具80%同源性的约580aa的羧基末端胞内域(intracellular domain,ICD)。HER-2/neu的核苷酸序列可以下列名称得到:登录号AH002823(人类HER-2基因,启动子区和外显子1);M16792(人类HER-2基因,外显子4);M16791(人类HER-2基因,外显子3);M16790(人类HER-2基因,外显子2);和M16789(人类HER-2基因,启动子区和外显子1)。HER-2/neu蛋白的氨基酸序列可以登录号AAA58637得到。基于这些序列,所属领域的技术人员可使用已知分析来开发HER-2/neu抗原,从而发现产生有效免疫反应的适当表位。示范性的HER-2/neu抗原包括p369-377(HER-2/neu衍生的HLA-A2肽);dHER2(Co rixa Corporation);li-Key MHC II型表位杂合体(Generex Biotechnology Corporation);肽P4(氨基酸378-398);肽P7(氨基酸610-623);肽P6(氨基酸544-560)和P7的混合物;肽P4、P6和P7的混合物;HER2[9754];和类似物。
在一实施例中,癌抗原为表皮生长因子受体(EGFR)抗原。EGFR抗原可为EGFR变异体1抗原、EGFR变异体2抗原、EGFR变异体3抗原和/或EGFR变异体4抗原。具有过度表达EGFR的细胞的癌症被称为EGFR+癌症。示范性的EGFR+癌症包括肺癌、头颈部癌、结肠癌、结肠直肠癌、乳腺癌、前列腺癌、胃癌、卵巢癌、脑癌和膀胱癌。
EGFR变异体1的核苷酸序列(mRNA)可由登录号NM_005228得到。EGFR变异体2的核苷酸序列(mRNA)可由登录号NM_201282得到。EGFR变异体3的核苷酸序列(mRNA)可由登录号NM_201283得到。EGFR变异体4的核苷酸序列(mRNA)可由登录号NM_201284得到。示范性的EGFR抗原包括GI-3001;肽aa1168-1181;和类似物。
在一实施例中,癌抗原为血管内皮生长因子受体(vascular endothelial growth factorreceptor,VEGFR)抗原。VEGFR抗原可为VEGFR变异体1抗原或VEGFR变异体2抗原。VEGFR变异体1与Flt-1同义。VEGFR变异体2与Flk-1和Kdr(即,插入域蛋白受体的激酶)同义。VEGFR被认为是癌症诱发的血管生成的调节物。具有过度表达VEGFR的细胞的癌症被称为VEGFR+癌症。示范性的VEGFR+癌症包括乳腺癌、肺癌、小细胞肺癌、结肠癌、结肠直肠癌、肾癌、白血病和淋巴细胞白血症。
VEGFR变异体1(Flt-1)的核苷酸序列(DNA)可由登录号D64016(血管内皮生长因子受体的人类基因,启动子和外显子1)得到。VEGFR变异体2(Flk-1或Kdr)的核苷酸序列(mRNA)可由登录号AF063658(人类血管内皮生长因子受体2)得到。
在一实施例中,癌抗原为在雄激素非依赖性前列腺癌中普遍表达的前列腺特异性抗原(prostate-specific antigen,PSA)和/或前列腺特异性膜抗原(prostate-specific membraneantigen,PSMA)。
在另一实施例中,癌抗原为Gp-100。糖蛋白100(gp100)是一种与黑素瘤相关的肿瘤特异性抗原。
在一实施例中,癌抗原为癌胚(carcinoembryonic,CEA)抗原。具有过度表达CEA的细胞的癌症被称为CEA+癌症。示范性的CEA+癌症包括结肠直肠癌、胃癌和胰腺癌。人类癌胚样抗原1的核苷酸序列(mRNA)可由登录号NM_020219得到。示范性的CEA抗原包括CAP-1(即,CEA aa571-579)、CAP1-6D、CAP-2(即,CEA aa555-579)、CAP-3(即,CEA aa87-89)、CAP-4(CEA aa1-11)、CAP-5(即,CEA aa345-354)、CAP-6(即,CEA aa19-28)和CAP-7。
在一实施例中,癌抗原为糖抗原10.9(CA19.9)。CA19.9是一种与路易斯A血型物质(Lewis Ablood group substance)有关的寡糖并且与结肠直肠癌有关。
在另一实施例中,癌抗原为黑素瘤癌抗原。黑素瘤癌抗原适用于治疗黑素瘤。示范性的黑素瘤癌抗原包括MART-1(例如,MART-126-35肽、MART-127-35肽);MART-1/Melan A;pMe117;pMe117/gp100;gp100(例如,gp100肽280-288、gp100肽154-162、gp100肽457-467);TRP-1;TRP-2;NY-ESO-1;p16;β-索烃素(beta-catenin);mum-1;和类似物。
在一实施例中,癌抗原为突变体或野生型ras肽。突变体ras肽可为突变体K-ras肽、突变体N-ras肽和/或突变体H-ras肽。ras蛋白中的突变通常发生在位置12(例如,精氨酸或缬氨酸取代甘氨酸)、13(例如,天冬酰胺取代甘氨酸)、61(例如,谷氨酰胺取代亮氨酸)和/或59。突变体ras肽可用作肺癌抗原、胃肠癌抗原、肝癌抗原、髓细胞癌抗原(例如,急性白血病、骨髓发育不良)、皮肤癌抗原(例如,黑素瘤、基底细胞、鳞状细胞)、膀胱癌抗原、结肠癌抗原、结肠直肠癌抗原和肾细胞癌抗原。
在本发明的另一实施例中,癌抗原为突变体和/或野生型p53肽。p53肽可用作结肠癌抗原、肺癌抗原、乳腺癌抗原、肝细胞癌癌抗原、淋巴瘤癌抗原、前列腺癌抗原、甲状腺癌抗原、膀胱癌抗原、胰腺癌抗原和卵巢癌抗原。
癌抗原可为细胞、蛋白、肽、融合蛋白、编码肽或蛋白的DNA、编码肽或蛋白的RNA、糖蛋白、脂蛋白、磷蛋白、糖、脂多糖、脂质、其两种或两种以上的化学连接组合、其两种或两种以上的融合或其两种或两种以上的混合物。在另一实施例中,癌抗原为包含约6到约24个氨基酸;约8到约20个氨基酸;约8到约12个氨基酸;约8到约10个氨基酸;或约12到约20个氨基酸的肽。在一实施例中,癌抗原为具有MHC I型结合基元或MHC II型结合基元的肽。在另一实施例中,癌抗原包含对应于一种或一种以上细胞毒性T淋巴细胞(cytotoxic Tlymphocyte,CTL)表位的肽。
在另一实施例中,癌抗原为外来同源癌抗原的形式。外来同源癌抗原和其制造方法在美国专利第6,942,862号中有所描述。因为许多人类癌抗原自身是蛋白(即,通常由个体产生而非必定只有癌症才产生的蛋白),所以可能存在免疫耐受性,而且免疫耐受性代表对抵抗人类癌抗原的有效疫苗接种的障碍。本发明的此方面通过用外来(即,与个体内的蛋白或肽不一致)但却与个体自身的癌抗原或其部分同源的蛋白或肽使患者免疫来克服免疫耐受性。“外来”癌抗原可例如由兔子、大鼠、小鼠和猪产生。通常,外来癌抗原(例如,蛋白或肽)将与靶向的癌抗原具有至少约75%的序列同源性。序列同源性的意思是在序列中相同位置处的一致氨基酸(即,序列一致性),或在序列中相同位置处氨基酸的保守取代。保守取代在此项技术中众所周知。实例是异亮氨酸取代亮氨酸、缬氨酸取代丙氨酸、谷氨酸取代天冬氨酸、苏氨酸取代丝氨酸等。通常,外来癌抗原(例如,蛋白或肽)将具有约80%、85%、90%、95%或99%的序列同源性。优选的外来癌抗原(例如,蛋白或肽)是高度同源的那些癌抗原,例如具有约(但小于)100%的序列同源性。尤其优选的外来癌抗原(例如,蛋白或肽)是上述序列同源性百分比各自表示序列一致性百分比的那些癌抗原。
4.2源自与癌症相关的病毒的病毒抗原
医药组合物的免疫治疗剂之一可为一种或一种以上源自与癌症相关的病毒的抗原。已知某些病毒的感染导致不同类型癌症的发展,例如,人类乳头瘤病毒(human papillomavirus,HPV)、肝炎病毒感染、伊波病毒(Epstein-Barr virus,EBV)、人类疱疹病毒8(human herpes virus8,HHV-8)、人类T细胞白血病病毒-1(human T-cell leukemia viras-1,HTLV-1)和人类T细胞白血病病毒-2(human T-cell leukemia virus-2,HTLV-2)。
已感染人类乳头瘤病毒(HPV)或存在感染风险的患者比HPV阴性患者发展子宫颈癌的风险更高。具有HPV-16、HPV-18、HPV-31、HPV-33和/或HPV-35感染的患者罹患子宫颈癌的风险尤其高。可用于本发明的医药组合物和方法中的HPV抗原可为HPV-16抗原、HPV-18抗原、HPV-31抗原、HPV-33抗原和/或HPV-35抗原;并且优选为HPV-16抗原和/或HPV-18抗原。HPV-16的基因组在Virology,145:181-185(1985)中有所描述,而编码HPV-18的DNA序列在美国专利第5,840,306号中有所描述,所述文献的公开内容以全文引用的方式并入本文中。HPV-16抗原(例如,HPV-16的E1和/或E2蛋白的血清活性区)在美国专利第6,531,127号中有所描述,而HPV-18抗原(例如,HPV-18的L1和/或L2蛋白的血清活性区)在美国专利第5,840,306号中有所描述,所述专利的公开内容以引用的方式并入本文中。基于这些参考文献中所述的HPV-16和HPV-18的序列和抗原,所属领域的技术人员可使用已知分析来开发其它HPV抗原,从而发现产生有效免疫反应的适当表位。
已感染肝炎病毒感染(诸如B型肝炎(HBV)和/或C型肝炎(HCV)病毒感染)或存在感染风险的患者比不具有肝炎病毒感染的患者发展肝癌的风险更高。HBV抗原和HCV抗原可用于本发明的医药组合物和方法中。HBV的完整基因组可由登录号NC_003977得到,其公开内容并入本文中。HCV的基因组在欧洲专利申请案第318216号中有所描述,所述专利申请案的公开内容并入本文中。以引用的方式并入本文中的PCT/US90/01348公开HCV基因组的克隆体的序列信息、HCV病毒蛋白的氨基酸序列和对于包含HCV蛋白和其所衍生的肽的HCV疫苗制造和使用所述组合物的方法。基于这些参考文献中所述的HBV和HCV的序列和抗原,所属领域的技术人员可使用已知分析来开发其它HBV和/或HCV抗原,从而发现产生有效免疫反应的适当表位。
已感染伊波病毒(EBV)或存在感染风险的患者比EBV阴性患者发展伯基特氏淋巴瘤(Burkitt′s lymphoma)、鼻咽癌和霍奇金氏病的风险更高。EBV抗原可用于本发明的医药组合物和方法中。EBV DNA的核苷酸序列例如在美国专利第4,707,358号中有所描述。基于EBV的这些序列,所属领域的技术人员可使用已知分析来开发EBV抗原,从而发现产生有效免疫反应的适当表位。本发明的化合物、EBV抗原和免疫刺激化合物可单独投予或以组合物的形式投予。组合物可呈预防性疫苗(即,用于EBV阴性患者)或治疗性疫苗(即,用于EBV阳性患者)的形式。
已感染人类疱疹病毒8(HHV-8)或存在感染风险的患者比HHV-8阴性患者发展卡波西氏肉瘤(Kaposi′s sarcoma)的风险更高。HHV-8抗原可用于本发明的医药组合物和方法中。HHV-8的核苷酸序列例如由Russo等人的“Nucleotide sequence of the Kaposisarcoma-associated herpes virus(HHV8),”Proc.Natl.Acad.Sci USA,93:14862-14867(1996)加以描述。基于HHV-8的已知序列,所属领域的技术人员可使用已知分析来开发HHV-8抗原,从而发现产生有效免疫反应的适当表位。
已感染人类T细胞白血病病毒-1(HTLV-1)或人类T细胞白血病病毒-2(HTLV-2)或存在感染风险的患者比HTLV-1或HTLV-2阴性患者发展T细胞白血病的风险更高。HTLV-1和HTLV-2的序列在此项技术中众所周知并在Wong-StaalF,Gallo RC.HumanT-lymphotropic retroviruses.Nature 317:395-403,1985中有所描述。
4.3抗癌抗体
医药组合物的免疫治疗剂之一可为一种或一种以上抗癌抗体,即,一种或一种以上癌抗原的已产生抗体。示范性的抗癌抗体包括以下抗体:
贝伐单抗(bevacizumab)(Genentech的),其用于治疗结肠直肠癌、转移性结肠直肠癌、乳腺癌、转移性乳腺癌、非小细胞肺癌或肾细胞癌;
西妥昔单抗(cetuximab)(ImClone Systems Incorporated的),其可用于治疗结肠直肠癌、转移性结肠直肠癌、肺癌、头颈部癌、结肠癌、乳腺癌、前列腺癌、胃癌、卵巢癌、脑癌、胰腺癌、食道癌、肾细胞癌、前列腺癌、子宫颈癌或膀胱癌;
IMC-1C11(ImClone Systems Incorporated),其用于治疗结肠直肠癌、头颈部癌,以及其它潜在癌症目标;
托西莫单抗(tositumomab)和托西莫单抗和碘I131(Corixa Corporation的),其用于治疗可为CD20阳性、滤泡性的非霍奇金氏淋巴瘤,已转型或未转型的非霍奇金氏淋巴瘤,所述疾病用利妥昔单抗难以治愈而且在化疗后会复发;
In111替伊莫单抗(ibirtumomab tiuxetan);Y90替伊莫单抗;In111替伊莫单抗和Y90替伊莫单抗(Biogen Idec的),其用于治疗淋巴瘤或非霍奇金氏淋巴瘤,其可包括复发性滤泡性淋巴瘤;复发性或难治性、低级或滤泡性非霍奇金氏淋巴瘤;或已转型B细胞非霍奇金氏淋巴瘤;
EMD7200(EMD Pharmaceuticals),其用于治疗非小细胞肺癌或子宫颈癌的癌症;
SGN-30(Seattle Genetics的靶向CD30抗原的遗传工程化单克隆抗体)(霍奇金氏淋巴瘤或非霍奇金氏淋巴瘤);SGN-15(Seattle Genetics的靶向与阿霉素(doxorubicin)结合的路易斯γ相关抗原的遗传工程化单克隆抗体)(非小细胞肺癌);SGN-40(SeattleGenetics的靶向CD40抗原的人化单克隆抗体)(多发性骨髓瘤或非霍奇金氏淋巴瘤);SGN-35(Seattle Genetics的靶向与奥瑞他汀E(Auristatin E)结合的CD30抗原的遗传工程化单克隆抗体)(非霍奇金氏淋巴瘤);SGN-17/19(Seattle Genetics的含有与美法仑(melphalan)前药结合的抗体和酶的融合蛋白)(黑素瘤或转移性黑素瘤)。
抗癌抗体可为抗体的片段;包含抗体的复合物;或包含抗体的结合物。抗体可视情况为嵌合的或人化的。
这些抗体中许多抗体的作用机制尚不完全清楚,但经常相信诸如抗体依赖性细胞介导的细胞毒性(ADCC)的免疫反应的产生是治疗作用的一部分。由具有Fc受体的细胞上的TLR4连接活化ADCC可增强抗体的抗肿瘤功效。使用抗癌抗体与一种或一种以上选自式(I)、(II)、(III)、(IV)和(V)的化合物的组合将增加免疫反应。
4.4抗独特型抗体
抗原的抗体在抗原结合部位处具有血清学独特结构,称为独特型。可产生原始抗体的抗体,从而导致产生抗独特型抗体。原始抗体称为Ab1,而抗独特型抗体称为Ab2。Ab2抗体识别Ab1的抗原结合部位,且因此与原始抗原共享基元或结构类似性。发展到Ab2上的结合部位的抗体可因此与原始抗原反应。如果原始抗原是癌抗原,那么抗Ab2抗体可具有治疗作用。
当单独投予时,抗独特型抗体不能对癌抗原产生足够的免疫反应。然而,当抗独特型抗体与一种或一种以上选自式(I)、(II)、(III)、(IV)和(V)的化合物组合用作本发明的医药组合物或用于本发明的投药方法中时,产生免疫反应。式(I)、(II)、(III)、(IV)和(V)的佐剂化合物可改善抗独特型抗体的免疫原性或通过中断免疫耐受性为抗独特型抗体提供产生免疫反应的能力。另外,本发明的医药组合物也可以减少诱发免疫反应所必需的抗独特型抗体的量和/或减少诱发所需免疫反应所必需的投药次数。
抗独特型抗体在此项技术中已知。抗独特型抗体可为对上文所述癌抗原作出反应而产生的抗体或抗癌抗体的抗体。示范性的抗独特型抗体包括105AD7(在美国专利第6,042,827号中有所描述,所述专利的公开内容以全文引用的方式并入本文中);BEC2(ImClone Systems Incorporated);IGN301(Igeneon,Aphton Corporation的子公司);和类似物。抗独特型抗体的产生在此项技术中众所周知且例如在美国专利第6,926,893号中有所描述,所述专利的公开内容以全文引用的方式并入本文中。
4.5医药组合物的投药方式
医药组合物的投药可通过适合于传递的几种途径来完成。示范性的传递方式包括非经肠投药,例如皮下注射、经皮、静脉内、肿瘤内、肿瘤周围、鼻内、眼部、肌肉内、皮内、腹膜内、肺部;和经肠投药,例如经粘膜、透皮、吸入、阴道内、直肠或口服投药。
4.6治疗方法
医药组合物提供一种用于刺激或引发或增强受检者个体的免疫反应的方法。尽管本发明可应用于包括哺乳动物或鸟类物种的动物物种的兽医应用,但受检者个体优选为人类。
受检者个体可能存在发展癌症的风险、经诊断患有癌症、处于癌症治疗期间或处于癌症治疗后恢复期间。
术语“免疫反应”包括细胞和体液免疫反应,包括刺激细胞因子的产生、刺激免疫细胞的增殖、刺激免疫细胞的活化或刺激免疫细胞的溶解活性。通过本发明的方法刺激的免疫反应的实例是细胞因子的分泌,NK细胞的活化,B细胞、T细胞、巨噬细胞、单核细胞和其它免疫细胞的增殖,以及其它免疫反应。举例来说,为了检测细胞免疫反应,可使用标准分析来检测抵抗表达抗原的细胞的T细胞效应物活性,例如靶细胞杀死、巨噬细胞活化、B细胞活化或淋巴因子产生。可以通过使用诸如ELISA的常规方法检测例如抗原特异性抗体的出现或其效价的增加来测量体液反应。可以通过测量级别转变(诸如从早期IgM反应转变成后期IgG反应)来确定抗体反应的进展。
如本文中所使用,术语“刺激免疫反应”包括刺激、引发、增加、增强、持续和/或改善新免疫反应或先前存在的免疫反应的刺激。因此,“刺激免疫反应”作为免疫疗法指的是增强治疗功效,增加存活时间,减缓癌性肿瘤的发展或缩小癌性肿瘤的尺寸,阻止肿瘤扩散或转移扩散,阻止或减缓所治疗癌症的复发,消除早期治疗未杀死的癌细胞,靶向潜在癌细胞或靶向源自与癌症相关的病毒的抗原。在本发明的方法中,以有效刺激受检者个体的免疫反应的量,以足以产生有效免疫反应而无不可接受的毒性的剂量投予免疫治疗剂和选自式(I)、(II)、(III)、(IV)和(V)的化合物。如所属领域的技术人员将了解,免疫反应的量值和反应的维持可具有不同的程度,这将通过具有潜在治疗性或预防性益处来识别。
为刺激免疫反应,向受检者个体投予(i)至少一种免疫治疗剂,其选自一种或一种以上癌抗原、一种或一种以上源自与癌症相关的病毒的抗原、抗癌抗体和抗癌抗体的抗独特型抗体;和(ii)一种或一种以上选自式(I)、(II)、(III)、(IV)和(V)的化合物和/或其医药学上可接受的盐、水合物、溶剂合物、立体异构体、非晶形固体,或其任何组合。通常,免疫治疗剂和选自式(I)、(II)、(III)、(IV)和(V)的化合物的投予将呈疫苗的形式或以疫苗方案投予。治疗剂和选自式(I)、(II)、(III)、(IV)和(V)的化合物可大约同时投予受检者个体,或可分开和/或依次投予。“大约同时”包括同时投予,同时但通过不同投药方式或在身体的不同部位投予,在同一天的不同时间投予,或在不同日期投予一种或一种以上免疫治疗剂和一种或一种以上选自式(I)、(II)、(III)、(IV)和(V)的化合物,但是其都是作为整体给药治疗方案的一部分投予。当分开或依次投予时,所述一种或一种以上免疫治疗剂和一种或一种以上选自式(I)、(II)、(III)、(IV)和(V)的化合物是整体治疗方案(诸如治疗性混合物或组合疗法)的一部分。给药进程常规上可由所属领域的技术人员来确定,而且可根据用于受检者个体的适当治疗而变化或修改。举例来说,免疫治疗剂和式(I)、(II)、(III)、(IV)和(V)的化合物可以单一剂量形式,或以一剂量治疗剂与一剂量式(I)、(II)、(III)、(IV)和(V)化合物的形式大约同时投予。给药进程可以诸如1到4周时期的规律时间间隔持续,接着以例如1到3个月的规律时间间隔给药。在另一实施例中,给药进程可以基于“初免”和“加强”治疗,其中投予免疫治疗剂来初免或刺激CTL的产生,且接着投予另一剂量的免疫治疗剂与一种或一种以上选自式(I)、(II)、(III)、(IV)和(V)的化合物的组合来加强中和抗体的产生和抗体依赖性细胞细胞毒性。可以通过已知方法评估和监控受检者个体的免疫反应。
在某些情况下,这些治疗可与适用于治疗癌症或传染性疾病的常规癌症疗法或医药配方组合使用。这些治疗可以包括外科手术、放射疗法和/或切除疗法(例如,激光疗法、红外线疗法和类似疗法)。
癌症疗法包括树突状细胞疗法、趋化因子、细胞因子、肿瘤坏死因子(例如,TNF-α)、化疗剂(例如,腺苷类似物(例如,克拉屈滨(cladribine)、喷司他丁(pentostatin))、磺酸烷基酯(例如,白消安(busulfan)))、抗肿瘤抗生素(例如,博莱霉素(bleomycin)、放线菌素D(dactinomycin)、柔红霉素(daunorubicin)、阿霉素(doxorubicin)、表柔比星(epirubicin)、伊达比星(idarubicin)、米托蒽醌(mitoxantrone)、丝裂霉素(mitomycin))、氮丙啶(例如,塞替派(thiotepa))、喜树碱类似物(例如,伊立替康(irinotecan)、拓朴替康(topotecan))、自念珠藻环肽(cryptophycin)(例如,自念珠藻环肽52、自念珠藻环肽1)、海兔毒素(dolastatin)(例如,海兔毒素10、海兔毒素15)、烯二炔抗癌药(例如,埃斯培拉霉素(esperamicin)、刺孢霉素(calicheamicin)、达内霉素(dynemicin)、新制癌菌素(neocarzinostatin)、新制癌菌素发色团、可达霉素(kedarcidin)、可达霉素发色团、C-1027发色团和类似物)、表鬼臼素(epipodophyllotoxin)(例如,依托泊苷(etoposide)、替尼泊苷(teniposide))、叶酸类似物(例如,甲氨喋呤)、美登素类(maytansinoids)(例如,美登醇(maytansinol)和美登醇类似物)、微管剂(例如,多烯紫杉醇(docetaxel)、太平洋紫杉醇(paclitaxel)、长春碱(vinblastine)、长春新碱(vincristine)、长春瑞宾(vinorelbine))、氮芥类(例如,苯丁酸氮芥(chlorambucil)、环磷酰胺(cyclophosphamide)、雌氮芥(estramustine)、异环磷酰胺(ifosfamide)、氮芥(mechlorethamine)、美法仑)、亚硝基脲(例如,卡莫司汀(carmustine)、洛莫司汀(lamustine)、鏈脲佐菌素(streptoxacin))、非典型烷基化剂(例如,六甲密胺(altretamine)、达卡巴嗪(dacarbazine)、丙卡巴肼(procarbazine)、替莫唑胺(temozolamide))、铂络合物(例如,卡铂(carboplatin)、顺铂(cisplatin))、嘌呤类似物(例如,氟达拉滨(fludarabine)、巯嘌呤(mercaptopurine)、硫鸟嘌呤(thioguanine))、嘧啶类似物(例如,卡培他滨(capecitabine)、阿糖胞苷(cytarabine)、脂质体阿糖胞苷(depocyt)、氮尿苷(floxuridine)、氟尿嘧啶(fluorouracil)、吉西他滨(gemcitabine))、经取代的尿素(例如,羟基脲)];抗血管生成剂(例如,血管生成抑制素(canstatin)、肌钙蛋白I(troponinI))、生物药剂(例如,ZD1839、维如利金(virulizin)和干扰素(interferon))、抗体和其片段(例如,抗EGFR、抗HER-2/neu、抗KDR、IMC-C225)、止吐药(例如,劳拉西泮(lorazepam)、甲氧氯普胺(metroclopramide)和多潘立酮(domperidone))、上皮生长因子抑制剂(例如,转化生长因子β1)、抗粘剂(例如,达克罗宁(dyclonine)、利多卡因(lignocaine)、氮拉斯汀(azelastine)、谷氨酰胺、类皮质激素甾类和别嘌呤醇(allopurinol))、抗破骨剂(例如,双膦酸盐{例如,依替膦酸盐(etidronate)、帕米膦酸盐(pamidronate)、伊班膦酸盐(ibandronate)和护骨素(osteoprotegerin)})、激素调节剂(例如,抗雄激素、LHRH激动剂、安美达锭(anastrozole)、他莫昔芬(tamoxifen))、造血生长因子、抗毒性剂(例如,氨磷汀(amifostine))、激酶抑制剂(吉非替尼(gefitinib)、伊马替尼(imatinib))和其两种或两种以上的混合物。
阻断免疫抑制功能的抗体,例如阻断T细胞上切断活化的受体的抗CTLA4抗体也可以与免疫治疗剂和式(I)、(II)、(III)、(IV)和(V)的化合物组合使用。因此,投予免疫治疗剂和式(I)、(II)、(III)、(IV)和(V)的化合物以及抗CTLA4抗体将增加受检者个体的免疫反应。
关于治疗的预防性和治疗性方法,基于从药物基因组学领域获得的认识,可特别制定或修改所述治疗。如本文中所使用,“药物基因组学”指的是将诸如基因测序、统计遗传学和基因表达分析的基因组学技术应用于临床开发和出售的药物。更确切地说,所述术语指的是研究患者的基因如何决定他或她对药物的反应(例如,患者的“药物反应表型”或“药物反应基因型”)。因此,本发明的另一方面提供用于根据个体的药物反应基因型来制定个体的预防性或治疗性治疗的方法。药物基因组学使得临床医师或内科医师可以把将最得益于所述治疗的患者作为预防性或治疗性治疗的目标,而且可以避免治疗将经历毒性药物相关副作用的患者。临床医师或内科医师进而可以制定可能为特定患者所必需的治疗类型。
4.7可选免疫刺激化合物
在免疫疗法的方法的一实施例中,通过投予可充当免疫刺激化合物的化合物来进一步扩大免疫反应。示范性的免疫刺激化合物包括toll样受体(TLR)激动剂(例如,TLR4、TLR7、TLR9)、N-乙酰基胞壁酰基-L-丙氨酸-D-异谷氨酰胺(MDP)、脂多糖(LPS)、遗传修饰和/或降解的LPS、明矾、葡聚糖、集落刺激因子(例如,EPO、GM-CSF、G-CSF、M-CSF、聚乙二醇化G-CSF、SCF、IL-3、IL6、PIXY321)、干扰素(例如,γ-干扰素、α-干扰素)、白细胞介素(例如,IL-2、IL-7、IL-12、IL-15、IL-18)、MHC II型结合肽、皂苷(例如,QS21)、未甲基化的CpG序列、1-甲基色氨酸、精氨酸酶抑制剂、环磷酰胺或阻断免疫抑制功能的抗体(例如,抗CTLA4抗体)或其两种或两种以上的混合物。示范性的TLR4激动剂包括脂多糖(LPS);大肠杆菌(E.coli)LPS;和牙龈卟啉单胞菌(P.gingivalis)LPS。示范性的TLR7激动剂包括咪唑并喹啉化合物(例如,咪喹莫特(imiquimod)、雷西喹莫特(resiquimod)和类似物);和洛索立宾(loxoribine)。
4.8医药配方
将医药组合物调配成与其既定投药途径相容,且通常将包括医药学上可接受的载剂。如本文中所使用,术语“医药学上可接受的载剂”包括与医药投药相容的溶剂、分散介质、涂层、抗菌剂和抗真菌剂、等张剂和吸收延迟剂和类似物。也可以向组合物中并入补充活性化合物。可根据常规医药规范来调配医药组合物(例如参看Remington:TheScience and Practice of Pharmacy(第20版),编辑A.R.Gennaro,Lippincott Williams &Wilkins,2000和Encyclopedia of Pharmaceutical Technology,(编辑J.Swarbrick和J.C.Boylan),1988-1999,Marcel Dekker,New York)。
用于非经肠、皮内或皮下应用的溶液或悬浮液可包括以下组分:无菌稀释剂,诸如注射用水、生理食盐水溶液、不挥发性油类、聚乙二醇、甘油、丙二醇或其它合成溶剂;抗菌剂,诸如苄醇或对羟基苯甲酸甲酯;抗氧化剂,诸如抗坏血酸或亚硫酸氢钠;螯合剂,诸如乙二胺四乙酸;缓冲剂,诸如乙酸盐、柠檬酸盐或磷酸盐;和用于调节张力的药剂,诸如氯化钠或右旋糖。可以用诸如盐酸或氢氧化钠的酸或碱来调节pH值。可将非经肠制剂封装到由玻璃或塑料制成的安瓿、一次性注射器或多剂量小瓶中。
适合于可注射使用的医药组合物包括无菌水性溶液(当为水溶性时)或分散液和用于临时制备无菌可注射溶液或分散液的无菌粉末。对于静脉内投药来说,合适的载剂包括生理盐水、抑菌水、Cremophor ELTM(BASF,Parsippany,NJ)或磷酸盐缓冲生理食盐水(PBS)。在所有情况下,组合物必须是无菌的,而且应为达到存在易注射性程度的流体。它在制造和储存条件下应该是稳定的,而且必须防止诸如细菌和真菌的微生物的污染作用。载剂可为含有例如水、乙醇、多元醇(例如,甘油、丙二醇和液体聚乙二醇和类似物)和其合适混合物的溶剂或分散介质。例如可以通过使用诸如卵磷酯的涂层,通过维持所选择的粒度(就分散液来说)和通过使用表面活性剂来维持适当的流动性。可以通过各种抗菌剂和抗真菌剂来实现防御微生物的作用,所述抗菌剂和抗真菌剂例如对羟基苯甲酸酯、氯丁醇、苯酚、抗坏血酸、硫柳汞(thimerosal)和类似物。在多数情况下,组合物中包括等张剂,例如糖、多元醇(诸如甘露糖醇、山梨糖醇)和氯化钠。可以通过在组合物中包括延缓吸收的药剂(例如,单硬脂酸铝和明胶)来使可注射组合物的吸收延长。
可以通过将选自式(I)、(II)、(III)、(IV)和(V)的化合物以及上文列举成分中的一种或其组合以规定量并入适当溶剂中,视需要接着进行过滤灭菌来制备无菌可注射溶液。一般通过将活性化合物并入无菌媒剂中来制备分散液,所述无菌媒剂含有碱性分散介质和其它选自上文例举成分或此项技术中已知的其它成分的成分。在用于制备无菌可注射溶液的无菌粉末的情况下,制备方法可为真空干燥和冷冻干燥,从而产生活性成份加上来自其预先经无菌过滤的溶液的任何其它所需成分的粉末。
4.9共价键结、复合物和结合物
在一实施例中,一种或一种以上免疫治疗剂和选自式(I)、(II)、(III)、(IV)和(V)的化合物可以通过选自式(I)、(II)、(III)、(IV)和(V)的化合物的烷基、氨基、羰基、醚、羟基、磷酸酯、膦酰基、磺酰基、硫酸酯、硫醇醚或硫醇部分而共价键结在一起。举例来说,一种或一种以上免疫治疗剂可以与选自式(I)、(II)、(III)、(IV)和(V)的化合物中的R1、X1和/或Y1取代基共价键结。举例来说,免疫治疗剂可以与本发明的一种或一种以上化合物中的-C(O)-基团的羰基部分(例如,C1羰基)或与其中R1取代基的-C(O)-C1-4烷基-C(O)-基团共价键结。再举例来说,免疫治疗剂可以通过选自式(I)、(II)、(III)、(IV)和(V)的化合物中的X1和/或Y1取代基中的氮原子共价键结。所属领域的技术人员将能够按照例如由以下文献所述的方法将一种或一种以上免疫治疗剂与选自式(I)、(II)、(III)、(IV)和(V)的化合物连接在一起:Hoffman等人,Biol.Chem.Hoppe-Sayler,370:575-582(1989);Wiesmuller等人,Vaccine,7:29-33(1989);Wiesmuller等人,Int.JPeptide Protein Res.,40:255-260(1992);Defourt等人,Proc.Natl.Acad.Sci.,89:3879-3883(1992);Tohokuni等人,J.Am.Chem.Soc.,116:395-396(1994);Reichel,Chem.Commun.,2087-2088(1997);Kamitakahara,Agnew.Chem.Int.编辑37:1524-1528(1998);Dullenkopf等人,Chem.Eur.J.,5:2432-2438(1999);所述文献的公开内容以全文引用的方式并入本文中。
在一实施例中,免疫治疗剂可呈复合物的形式。所述复合物可包含至少一种癌抗原(视情况与选自式(I)、(II)、(III)、(IV)和(V)的化合物键结)和一种或一种以上蛋白、肽、免疫刺激化合物和/或细胞。示范性的蛋白和肽包括热休克蛋白、热休克肽、MHC I型蛋白质、MHC I型肽、MHC II型蛋白、MHC II型肽和类似物。
示范性的细胞包括树突状细胞、自体性树突状细胞、受癌抗原冲击的树突状细胞、受癌抗原冲击的自体性树突状细胞和类似细胞。示范性的免疫刺激化合物包括TLR激动剂(例如,TLR4、TLR7、TLR9)、N-乙酰基胞壁酰基-L-丙氨酸-D-异谷氨酰胺(MDP)、脂多糖(LPS)、遗传修饰和/或降解的LPS、明矾、葡聚糖、集落刺激因子(例如,EPO、GM-CSF、G-CSF、M-CSF、聚乙二醇化G-CSF、SCF、IL-3、IL6、PIXY321)、干扰素(例如,γ-干扰素、α-干扰素)、白细胞介素(例如,IL-2、IL-7、IL-12、IL-15、IL-18)、皂苷(例如,QS21)、单磷酰脂质A、3De-O-酰化单磷酰脂质A(3D-MPL)、未甲基化的CpG序列、1-甲基色氨酸、精氨酸酶抑制剂、环磷酰胺、阻断免疫抑制功能的抗体(例如,抗CTLA4抗体)和类似物。与至少一种癌抗原(视情况与选自式(I)、(II)、(III)、(IV)和(V)的化合物键结)和蛋白、肽、免疫刺激化合物和/或细胞的复合物可为非共价键结、离子键结、共价键结、范德瓦尔斯力(van der Waals′forces)键结、氢键结和类似键结。
在另一实施例中,癌抗原(视情况与选自式(I)、(II)、(III)、(IV)和(V)的化合物键结)呈包含热休克蛋白或热休克肽(HSP),尤其gp96的复合物形式。在一实施例中,通过活体外肽冲击热休克蛋白和/或热休克肽来形成复合物。复合物可为共价或非共价的。在另一实施例中,癌抗原(视情况与选自式(I)、(II)、(III)、(IV)和(V)的化合物键结)呈包含肽、至少一种热休克蛋白和/或热休克肽和至少一种MHC I型和/或II型蛋白或肽的复合物形式。
在另一实施例中,癌抗原(视情况与选自式(I)、(II)、(III)、(IV)和(V)的化合物键结)呈包含肽和树突状细胞的复合物形式。在一实施例中,通过活体外肽冲击树突状细胞以形成载有癌抗原的树突状细胞来形成复合物。可以用癌抗原和/或表达癌抗原的有机体(例如,重组病毒或细菌)来冲击树突状细胞。树突状细胞可为自体性的。
在另一实施例中,癌抗原(视情况与选自式(I)、(II)、(III)、(IV)和(V)的化合物键结)呈包含肽和MHC I型蛋白或肽;和/或包含肽和MHC II型蛋白或肽的复合物形式。在一实施例中,MHC I型蛋白或肽是HLA(例如,HLA-A*0201、HLA-A2、HLA-A3、HLA-A*1101、HLA-A*3101、HLA-A*3301、HLA-A*6801、HLA-A24)。复合物可为共价或非共价的。在另一实施例中,癌抗原(视情况与选自式(I)、(II)、(III)、(IV)和(V)的化合物键结)呈包含肽、MHC I型和/或II型蛋白或肽和至少一种热休克蛋白和/或热休克肽的复合物形式。
在另一实施例中,癌抗原呈结合物的形式。举例来说,一种或一种以上癌抗原可与一种或一种以上蛋白、肽、糖、聚合物、脂质和/或毒性部分化学连接。结合物可具有下式:A-L-X,其中“A”为如本文中所述的一种或一种以上癌抗原,“L”为一种或一种以上连接基团,且“X”为一种或一种以上蛋白、肽、糖、聚合物、脂质和/或毒性部分。示范性的连接基团包括化学连接基团和肽连接基团。连接“A”和“X”的最常见方法依赖于游离氨基(α-氨基或Lys)、巯基(Cys)或羧酸基团(Asp、Glu或α-羧基)的存在。应该使用通过羧基-末端残基或氨基-末端残基将肽与载体蛋白、肽、糖、脂质和/或毒性部分连接在一起的连接方法。其它常见的连接方法包括马来酰亚胺和碳化二酰亚胺偶合化学。可以选择如此的连接基团以使得酶对连接基团起作用,从而使得“A”和“X”在活体内相互分开。或者,可以选择如此的连接基团以使得“A”和“X”在活体内仍通过连接基团共价键结。在其它实施例中,“L”可简单地是“A”与“X”之间的共价键。“X”可为肽、蛋白(诸如MHC I型蛋白或MHC II型蛋白);钥孔嘁血蓝蛋白;白蛋白;牛血清白蛋白;卵清蛋白;兔血清白蛋白、抗体和类似物。“X”可为肽。所述肽可以是与“A”相同或不同的癌抗原。所述结合物可以称作多抗原肽(MAP),而且肽在存在或不存在连接基团“L”的情况下都可以形成融合蛋白。肽可以是可有助于产生免疫反应的I型和/或II型肽。所属领域的技术人员将了解,当两个肽连接在一起时,可使用术语“融合蛋白”,在这种情况下,“L”基团可以离开结构。在其它实施例中,“X”可以是毒性部分。示范性的毒性部分包括病毒毒素、细菌毒素(例如,白喉毒素(diphtheriatoxin)、破伤风毒素(tetanus toxin)、梭状芽孢杆菌毒素(clostridia toxin)、霍乱毒素(choleratoxin)、炭疽毒素(anthrax toxin)、肉毒梭菌毒素(botulinum toxin)、百日咳毒素(pertussistoxin)、气管毒素(trachealtoxin),
5.式(I)、(II)、(III)、(IV)和(V)的化合物
医药组合物包括上文所述的免疫治疗剂和选自式(I)、(II)、(III)、(IV)和(V)的化合物和/或其医药学上可接受的盐、水合物、溶剂合物、立体异构体、非晶固体,或其任何组合。所述式(I)、(II)、(III)、(IV)和(V)的化合物可充当佐剂和/或免疫刺激化合物,这取决于使用其的应用。
其中:
R1为:(a)-C(O)-;
(b)-C(O)-C1-14烷基-C(O)-或-C(O)-C1-14烯基-C(O)-;
其中-C1-14烷基-或-C1-14烯基-视情况经一个或一个以上选自以下各基的取代基取代:羟基、C1-6烷基、C1-6烷氧基、C1-6烷基二氧基、C1-5烷基氨基、羧基、C1-6烷氧羰基、C1-6氨甲酰基、C1-6酰基氨基和/或(芳基)C1-6烷基;且
其中(芳基)C1-6烷基的芳基部分视情况经一个或一个以上选自以下各基的取代基取代:C1-6烷基、C1-6烷氧基、C1-6烷基氨基、C1-6烷氧基氨基、C1-6烷基氨基-C1-6烷氧基、-O-C1-6烷基氨基-C1-6烷氧基、-O-C1-6烷基氨基-C(O)-C1-6烷基-C(O)OH、-O-C1-6烷基氨基-C(O)-C1-6烷基-C(O)-C1-6烷基、-O-C1-6烷基-NH-C1-6烷基-O-C1-6烷基、-O-C1-6烷基-NH-C(O)-C1-6烷基-C(O)OH和/或-O-C1-6烷基-NH-C(O)-C1-6烷基-C(O)-C1-6烷基;
(c)C2到C15直链或支链烷基,其视情况经一个或一个以上羟基和/或烷氧基取代;或
(d)-C(O)-C6-12芳基-C(O)-,其中芳基视情况经一个或一个以上羟基、卤素(例如,氟)、硝基、氨基、C1-6烷基和/或C1-6烷氧基取代;
a和b各自独立地为0、1、2、3或4;(优选为2);
a′和b′独立地为2、3、4、5、6、7或8;(优选为2);
d和e各自独立地为1、2、3、4、5或6;
d′和e′各自独立地为0、1、2、3或4;(优选为0、1或2);
d″和e″各自独立地为0、1、2、3或4;(优选为1、2、3或4);
T为氧或硫;
X1、X2、Y1和Y2各自独立地为空、氧、NH、-N(C(O)C1-4烷基)-或-N(C1-4烷基)-;
W1和W2各自独立地为羰基、亚甲基、砜或亚砜;
R2、R3、R4、R5、R6和R7各自独立地为:
(a)C2到C20直链或支链烷基,其视情况经一个或一个以上氧基、卤素(优选为氟)、羟基和/或烷氧基取代;
(b)C2到C20直链或支链烯基,其视情况经氧基、卤素(优选为氟)、羟基和/或烷氧基中的一个或一个以上取代;
(c)C2到C20直链或支链烷氧基,其视情况经一个或一个以上氧基、卤素(例如,氟)、羟基和/或烷氧基取代;
(d)-NH-C2-20直链或支链烷基,其中烷基视情况经一个或一个以上氧基、卤素(例如,氟)、羟基和/或烷氧基取代;
(e)-C(O)-C2-20直链或支链烷基或烯基,其中烷基或烯基视情况经一个或一个以上氧基、卤素(例如,氟)、羟基和/或烷氧基取代;
(f)
Z为O或NH;且M和N各自独立地为C2到C20直链或支链烷基、烯基、烷氧基、酰氧基、烷基氨基或酰基氨基;
(g)
R8为C1-6直链或支链烷基或C2-6直链或支链烯基或炔基;
R9和R10独立地选自由以下各基组成的群组:
(i)C1到C20直链或支链烷基,其视情况经一个或一个以上卤素、氧基、羟基和/或烷氧基取代;和
(ii)C2到C20直链或支链烯基或炔基,其视情况经一个或一个以上卤素、氧基、羟基和/或烷氧基取代;
G1、G2、G3、G4和G5各自独立地为氧、亚甲基、-NH-、硫醇、-N(C1-4烷基)-、-N[C(O)-C1-4烷基]-、-NH-C(O)-、-NH-SO2-、-C(O)-O-、-C(O)-NH-、-O-C(O)-、-O-C(O)-NH-、-O-C(O)-O-、-NH-C(O)-NH-、-C(O)NH-、-C(O)N(C1-4烷基)、芳基和-S(O)n-,其中n为0、1或2;
或G1R2、G2R4、G3R5和/或G4R7可一起为氢原子或羟基;
Z1和Z2各自独立地选自-OP(O)(OH)2、-P(O)(OH)2、-OP(O)(OR8)(OH){其中R8为C1-4烷基}、-OS(O)2OH、-S(O)2OH-、-CO2H、-OB(OH)2、-OH、-CH3、-NH2和-N(R9)2{其中R9为C1-4烷基};
R12为H或C1-4直链或支链烷基;且
M独立地选自氢原子和医药学上可接受的阳离子{一价阳离子将代替一个M,而二价阳离子将代替两个M变量}。
在一实施例中,式(I)-(V)的化合物中的R1为-C(O)-或-C(O)-C1-4烷基-C(O)-。在另一实施例中,式(I)-(V)的化合物中的R1为-C(O)-。
在本发明的一个实施例中,在式(I)-(V)的化合物中,T为氧。
在另一实施例中,式(I)-(V)的化合物中的G1、G2、G3和G4各自独立地为氧、-NH-、-NH-C(O)-、-C(O)-O-、-C(O)-NH-、-O-C(O)-、-O-C(O)-NH-、-O-C(O)-O-、-NH-C(O)-NH-或-C(O)NH-。在另一实施例中,式(I)-(V)的化合物中的G1、G2、G3和G4各自独立地为氧、-C(O)-O-或-O-C(O)-。在另一实施例中,式(I)-(V)的化合物中的G1和G3为-O-C(O)-。
在式(I)-(V)化合物{优选为式(I)-(III)的化合物}的一个实施例中,R2和R5各自独立地为选自本文R2和R5定义中的(a)、(b)、(c)、(d)和(f)的取代基;R3和R6各自独立地为选自本文R3和R6定义中的(a)和(b)的取代基;且R4和R7各自独立地为选自本文R4和R7定义中的(a)、(b)、(c)和(e)的取代基。
在式(I)-(V)的化合物{优选式(IV)或(V)的化合物}的其它实施例中,R2、R3、R4、R5、R6和R7各自独立地为选自本文R2、R3、R4、R5、R6和R7定义中的(a)、(b)、(g)和(h)的取代基。
在式(I)-(III)的化合物的其它实施例中,存在下列中的一项或一项以上:a和b各为2;X1和Y1各为NH;R1为-C(O)-或-C(O)-C1-4烷基-C(O)-;d′和e′各为1;d″和e″各为1;X为O或NH,更优选为NH;且W为C(O);或d′和e′各为2。
在式(I)-(III)的其它实施例中,R1为-C(O)C1-4烷基-C(O)-,其中C1-14烷基例如经C1-5烷氧基取代。
在一实施例中,式(I)-(III)的化合物是“类型1”,其中a和b的值相同;d和e的值相同;d′和e′的值相同;d″和e″的值相同;X1和Y1相同;X2和Y2相同;W1和W2相同;R2和R5相同;G1和G3相同;R3和R6相同;G2和G4相同;且R4和R7相同。
在另一实施例中,式(I)-(III)的化合物是“类型2”,其中a和b的值不同、d和e的值相同、d′和e′的值不同;d″和e″的值相同;X1和Y1不同;X2和Y2不同;W1和W2不同;R2和R5不同;G1和G3不同;R3和R6不同;G2和G4不同;或R4和R7不同。
在另一实施例中,式(I)-(III)的化合物是“类型3”,其中a和b的值不同、d和e的值不同、d′和e′的值不同;d″和e″的值不同;X1和Y1不同;X2和Y2不同;W1和W2不同;R2和R5不同;G1和G3不同;R3和R6不同;G2和G4不同;或R4和R7不同。
在其它实施例中,式(I)、(II)和/或(III)的化合物优选为:
ER 803022;其医药学上可接受的盐,如下所示的钠盐除外;和/或如下所示的一个或一个以上钠阳离子可由氢原子置换:
ER 803058;其医药学上可接受的盐,如下所示的钠盐除外;和/或如下所示的一个或一个以上钠阳离子可由氢原子置换:
ER 803732;其医药学上可接受的盐,如下所示的钠盐除外;和/或如下所示的一个或一个以上钠阳离子可由氢原子置换:
ER 804053;其医药学上可接受的盐,如下所示的钠盐除外;和/或如下所示的一个或一个以上钠阳离子可由氢原子置换:
ER 804058;其医药学上可接受的盐,如下所示的钠盐除外;和/或如下所示的一个或一个以上钠阳离子可由氢原子置换:
ER 804059;其医药学上可接受的盐,如下所示的钠盐除外;和/或如下所示的一个或一个以上钠阳离子可由氢原子置换:
ER 804442;其医药学上可接受的盐,如下所示的钠盐除外;和/或如下所示的一个或一个以上钠阳离子可由氢原子置换:
ER 804680;其医药学上可接受的盐,如下所示的钠盐除外;和/或如下所示的一个或一个以上钠阳离子可由氢原子置换:
ER 804764;其医药学上可接受的盐,如下所示的钠盐除外;和/或如下所示的一个或一个以上钠阳离子可由氢原子置换:
在一实施例中,优选化合物为112066;其立体异构体;其医药学上可接受的盐,如下所示的钠盐除外;和/或如下所示的一个或一个以上钠阳离子可由氢原子置换:
在一实施例中,优选化合物为ER 804057;其医药学上可接受的盐,如下所示的钠盐除外;或如下所示的一个或一个以上钠阳离子可由氢原子置换:
在式(IV)和(V)的一些实施例中,存在以下限制中的一种或一种以上:a和b各为2;X1和Y1各为NH;d和e各为1或2;且d′和e′各为0、1或2。在特定优选实施例中,d和e各为1且d′和e′各为0。在特定其它优选实施例中,d和e各为1且d′和e′各为1或2。
在式(IV)和(V)的一些实施例中,R1为-C(O)-或-C(O)-C1-14烷基-C(O)-,其中C1-14烷基视情况经一或两个选自由羟基、C1-6烷氧基、C1-6烷基二氧基、C1-6烷基氨基或(芳基)C1-6烷基组成的群组的取代基取代,其中(芳基)C1-6烷基的芳基部分视情况经C1-6烷基、C1-6烷氧基、C1-6烷基氨基、(C1-6烷氧基)C1-6烷基氨基、(C1-6烷基氨基)C1-6烷氧基、-O-C1-6烷基-NH-C1-6烷基-O-C1-6烷基、-O-C1-6烷基-NH-C(O)-C1-6烷基-C(O)OH或-O-C1-6烷基-NH-C(O)-C1-6烷基-C(O)-C1-6烷基取代。
在式(IV)和(V)的一些实施例中,G1、G2、G3和G4各自独立地选自由-NH-C(O)-和-O-C(O)-组成的群组。
在式(IV)和(V)的一些实施例中,R2、R3、R4、R5、R6、R7、R9和R10中的至少两个是C6-20直链或支链烷基、烯基或炔基;其中任一者都可以视情况经一个或一个以上选自由卤素、氧、羟基和/或烷氧基组成的群组的取代基取代。在其它实施例中,R2、R3、R4、R5、R6、R7、R9和R10中的至少两个是C8-15直链或支链烷基、烯基或炔基;其中任一者都可以视情况经一个或一个以上选自由卤素、氧基、羟基和烷氧基组成的群组的取代基取代。
在式(IV)和(V)的一些实施例中,R2、R3、R4、R5、R6、R7、R9和R10中的至少四个是C6-20直链或支链烷基、烯基或炔基;其中任一者都可以视情况经一个或一个以上选自由卤素、氧基、羟基和烷氧基组成的群组的取代基取代。在特定优选实施例中,R2、R3、R4、R5、R6、R7、R9和R10中的至少四个是C8-15直链或支链烷基、烯基或炔基;其中任一者都可以视情况经一个或一个以上选自由卤素、氧基、羟基和烷氧基组成的群组的取代基取代。
在式(IV)和(V)的一些实施例中,R2、R3、R4、R5、R6、R7、R9和R10中的至少六个是C6-20直链或支链烷基、烯基或炔基;其中任一者都可以视情况经一个或一个以上选自由卤素、氧基、羟基和烷氧基组成的群组的取代基取代。在其它实施例中,R2、R3、R4、R5、R6、R7、R9和R10中的至少六个是C8-15直链或支链烷基、烯基或炔基;其中任一者都可以视情况经一个或一个以上选自由卤素、氧基、羟基和烷氧基组成的群组的取代基取代。
在其它实施例中,本发明提供式(I)、(II)、(III)、(IV)或(V)的化合物,其中T为硫。在其它实施例中,本发明提供式(I)、(II)、(III)、(IV)或(V)的化合物,其中T为硫;但是所述化合物不是第804678号化合物。
在本发明的另一实施例中,存在限制条件,即式(I)、(II)或(III)的化合物不是:
如本文中所使用,术语“烷基”包括经取代或未经取代之直链或支链一价或二价脂族烃基团。鉴于术语“烷基”在任何特定取代基定义中的内容,所属领域的技术人员将了解一价烷基和二价烷基之间的区别。当烷基是端基时,其将是一价的,诸如-CH3、-CH2CH3、-CH2CH2CH3、-CH2CH2CH2CH3和类似基团。当烷基在其它部分之间时,诸如R1定义中的“-C(O)-C1-14烷基-C(O)-”,烷基就将是二价的,诸如-CH2-、-CH2CH2-、-CH2CH2CH2-、-CH2CH2CH2CH2-和类似基团。
如本文中所使用,术语“烯基”包括经取代或未经取代之直链或支链不饱和一价或二价脂族烃基团。“烯基”基团可具有任何数目的碳-碳双键,优选具有一个或两个。鉴于术语“烯基”在任何特定取代基定义中的内容,所属领域的技术人员将了解一价烯基和二价烯基之间的区别。当烯基是端基时,其将是一价的,诸如-CH=CH2、-CH=CHCH3和类似基团。当烯基在其它部分之间时,诸如R1定义中的“-C(O)-C1-14烯基-C(O)-”,烯基就将是二价的,诸如-CH=CH-、-CH=CHCH2-、-CH2CH=CHCH2-和类似基团。
如本文中所使用,术语“芳基”包括经取代或未经取代的一价或二价芳族烃基团。鉴于术语“芳基”在任何特定取代基定义中的内容,所属领域的技术人员将了解一价芳基和二价芳基之间的区别。当芳基是端基时,其将是一价的。当芳基在其它部分之间时,诸如R1定义中的“-C(O)-C6-12芳基-C(O)-”,芳基就将是二价的。
Boc为叔丁基氧基羰基。
关于特定取代基的空意思是所述取代基不存在,而且取代基介于中间的化学基团通过共价键直接相互连接。
式(I)、(II)、(III)、(IV)和(V)的化合物可能具有一个或一个以上的不对称碳原子,这取决于取代基,而且可以具有立体异构体,这在本发明的范畴内。式(I)、(II)、(III)、(IV)和/或(V)的化合物可以医药学上可接受的盐(例如,其中式(I)、(II)、(III)、(IV)和/或(V)的化合物中的M是医药学上可接受的阳离子)的形式来投予。式(I)、(II)、(III)、(IV)和/或(V)的化合物可以化合物立体异构体的医药学上可接受的盐的形式来投予。“医药学上可接受的盐”指的是保留其生物有效性的盐。可由无机碱和有机碱来制备医药学上可接受的碱加成盐。衍生自无机碱的示范性医药学上可接受的盐包括钠盐、钾盐、锂盐、铵盐、钙盐和镁盐。衍生自有机碱的示范性盐包括伯胺、仲胺和叔胺的盐。可由无机酸和有机酸来制备医药学上可接受的酸加成盐。衍生自无机酸的示范性盐包括盐酸、氢溴酸、硫酸、硝酸、磷酸和类似酸的盐。衍生自有机酸的示范性盐包括乙酸、丙酸、乙醇酸、丙酮酸、草酸、苹果酸、丙二酸、丁二酸、马来酸、延胡索酸、酒石酸、柠檬酸、苯甲酸、肉桂酸、扁桃酸、甲烷磺酸、乙烷磺酸、对甲苯磺酸、水杨酸和类似酸的盐。
用于制造式(I)、(II)、(III)、(IV)和(V)的化合物的方法在美国公开案第2004/0006242号、美国公开案第2003/0153532号、美国公开案第2002/0176861号、美国公开案第2002/0049314号、美国专利第6,551,600号、美国专利第6,521,776号、美国专利第6,290,973号和WO 03/099195中有所描述,所述专利的公开内容以全文引用的方式并入本文中。一些式(I)、(II)、(III)、(IV)和(V)的化合物和其制造方法也由Hawkins等人,The Journal of Pharmacology and Experimental Therapeutics,300(2):655-661(2000);Lien等人,The Journal of Biological Chemistry,276(3):1873-1880(2001);Przetak等人,Vaccine,21:961-970(2003);和Seydel等人,Eur.J.Immunol.,33:1586-1592(2003)描述,所述文献的公开内容以全文引用的方式并入本文中。
属于式(I)-(V)的化合物范畴内的示范性化合物在下文中列出。
实例
实例1
腹膜内投予TLR激动剂增强疫苗的治疗功效
为确定E6020在与癌症疫苗(例如,分泌粒细胞-巨噬细胞集落刺激因子(GM-CSF)的肿瘤细胞)一起腹膜内投予时的作用,使用具有黑素瘤细胞的小鼠模型。E6020是TLR-4(Toll样受体-4)激动剂。用1×106个同基因B16F10鼠科动物黑素瘤细胞经皮下植入B6小鼠(C57BL/6小鼠)。在肿瘤细胞接种三天后,将小鼠:(1)经皮下(s.c)接种1×106个经过遗传改良来稳定表达和分泌鼠科动物GM-CSF的B16F10肿瘤细胞(B16-GM-CSF细胞);(2)经腹膜内(i.p.)接种E6020;或(3)用皮下GM-CSF细胞疫苗接种和腹膜內E6020的组合来治疗(GM-CSF细胞疫苗接种和E6020疫苗接种在小鼠体内的分开部位进行投予)。在这些实验中,在接种之前通过γ照射使GM-CSF细胞失活。监测动物的存活率。
这些实验证明用B16GM-CSF细胞和腹膜內E6020对动物进行疫苗接种增强了GM-CSF细胞的治疗功效(图1)。
实例2
局部投予TLR激动剂增强癌症疫苗的治疗功效
检查E6020对皮下植入1×106个同基因B16F10鼠科动物黑素瘤细胞的B6小鼠的治疗作用。当肿瘤变得可触知时,对小鼠肿瘤内单独注射GM-CSF细胞,或注射GM-CSF细胞与E6020(约3-10μg)的组合。监测动物的存活率。
发现用GM-CSF细胞与E6020的组合肿瘤内治疗的动物群体与未经治疗或单独用GM-CSF细胞治疗的动物相比存活率增加(图2)。
实例3
MUC-1/E6020疫苗治疗作用
为测试MUC-1疫苗和E6020佐剂对于治疗发炎性肠病(IBD)和随后结肠腺癌的发展的作用,使用缺乏IL-10基因并且表达转基因人类MUC1的工程化小鼠品系。所述小鼠自发地发展类似IBD的肠炎,接着发展结肠腺癌。这些数据在Beatty等人,AACRAnnual Meeting 2006,Washington D.C.,2006年4月4日中提供和公开。
在这些实验中,每个鼻孔用30mg的Tn MUC100mer(HGVTSAPDTRPAPGSTAPPA)×5、SEQ ID NO:1)和3mg的E6020经鼻内使小鼠免疫。
在实验期间,用疫苗和E6020治疗的MUC1IL-10-/-小鼠延缓了IBD的发作或不发展D3D(图3)。用疫苗和E6020治疗的小鼠改善了存活率,而且不发展结肠癌(图4和表1)。
表1
治疗/所治疗小鼠的数目 | 年龄(周) | 结肠肿瘤 |
疫苗/6只小鼠 | 14-35.5 | 0/6 |
佐剂/3只小鼠 | 12.5-18 | 3/3 |
未治疗/4只小鼠 | 8-15.5 | 4/4 |
数据证明向MUC-1疫苗中添加E6020可以减缓与IBD相关的直肠脱垂的进展,并抑制组织学检测的肿瘤的出现。
实例4
EGFRvIII治疗作用和佐剂
为确定佐剂是否可以增强肿瘤学抗原的作用(即,可用于对动物接种抵抗癌症的疫苗的抗原),经皮下用与蛋白质载体钥孔嘁血蓝蛋白(KLH)结合的肿瘤相关肽,LEEKKGNYVVTDHC(SEQ ID NO:2)(源自EGFR的突变体形式,EGFRvIII),在有或没有E6020或鼠科动物GM-CSF(一种用于癌症疫苗试验中来加强免疫反应的细胞因子)的情况下,使C57/BL6J小鼠免疫。每剂给予3μg的E6020,5μg的GM-CSF和25μg的肽-KLH结合物。以三周的时间间隔使小鼠免疫三次。在每次免疫后两周时从小鼠制备血清,并使用ELISA在涂有与牛血清白蛋白结合的EGFRvIII肽的平板上测试EGFRvIII肽特异性抗体。表2中的结果以个别动物的效价形式提供。效价定义为观察到0.25OD单位时的信号高于本底时的最终血清稀释度。
这些实验的数据证明E6020增强了抗原特异性IgG2a的平均效价,所述抗原特异性IgG2a与抗体依赖性细胞介导的细胞毒性(ADCC)中所涉及的高亲合力Fc受体相结合。IgG2a是人类IgG1同型的小鼠相关物,因为人类IgG1同型在肿瘤杀死方面最为有效,所以其用于目前销售的人类抗肿瘤单克隆抗体中。
在用EGFRvIII肽的疫苗接种中,E6020与GM-CSF的组合证明比单独任一种物质对IgG2a效价的作用都更大。这些数据证明E6020与其它免疫增强剂组合的适用性。
表2.由E6020增强EGFRvIII肽的抗体效价
等效物
所属领域的技术人员只使用常规实验就将认识到或能够确认本文所述特定物质和程序的多种等效物。所述等效物被认为在本发明的范畴内,并由随附的权利要求书所涵盖。
Claims (12)
1.一种组合物,其包含:
一种或一种以上抗癌抗体;和
一种或一种以上式(I)的化合物
其中:
R1为-C(O)-;
a和b各自独立为0、1、2、3或4;
d和e各自独立为1、2、3、4、5或6;
d′和e′各自独立为0、1、2、3或4;
d″和e″各自独立为0、1、2、3或4;
T为氧;
X1、X2、Y1和Y2各自独立为NH;
W1和W2各自独立为羰基;
R2、R3、R4、R5、R6和R7各自独立为C2到C20直链烷基,其任选经一个或一个
以上选自氧基、卤素、羟基和/或烷氧基所组成的基团取代;
G1、G2、G3和G4各自为氧;且
M为医药学上可接受的阳离子;
和/或其医药学上可接受的盐、水合物、溶剂合物、立体异构体、非晶形固体,或其任何组合。
3.根据权利要求1所述的组合物,其中所述化合物是选自ER 803022、ER 803732、ER 804053、ER 804764、ER 112066和ER 804057,和/或其医药学上可接受的盐、水合物、溶剂合物、立体异构体、非晶形固体,或其任何组合。
4.根据权利要求3所述的组合物,其中所述化合物是ER 804057和/或其医药学上可接受的盐、水合物、溶剂合物、立体异构体、非晶形固体,或其任何组合。
5.根据权利要求1所述的组合物,还包含第二免疫治疗剂,所述第二免疫治疗剂选自一种或一种以上癌抗原、一种或一种以上源自与癌症相关的病毒的抗原、和抗癌抗体的一种或一种以上抗独特型抗体。
6.一种组合物在制备药物中的用途,所述药物用于刺激受检者个体的免疫反应,以通过阻止或减缓即存癌症的生长而稳定肿瘤,阻止肿瘤扩散或转移扩散,减小肿瘤尺寸,阻止所治疗癌症的复发,消除早期治疗未杀死的癌细胞,或阻止或延缓癌症的发展;
其中所述组合物包含一种或一种以上抗癌抗体;和
一种或一种以上式(I)的化合物
其中:
R1为-C(O)-;
a和b各自独立为0、1、2、3或4;
d和e各自独立为1、2、3、4、5或6;
d′和e′各自独立为0、1、2、3或4;
d″和e″各自独立为0、1、2、3或4;
T为氧;
X1、X2、Y1和Y2各自独立为NH;
W1和W2各自独立为羰基;
R2、R3、R4、R5、R6和R7各自独立为C2到C20直链烷基,其任选经一个或一个
以上选自氧基、卤素、羟基和/或烷氧基所组成的基团取代;
G1、G2、G3和G4各自为氧;且
M为医药学上可接受的阳离子;
和/或其医药学上可接受的盐、水合物、溶剂合物、立体异构体、非晶形固体,或其任何组合。
7.根据权利要求6所述的用途,其中所述受检者个体存在发展癌症的风险、经诊断患有癌症、处于癌症治疗期间或处于癌症治疗后恢复期间。
8.根据权利要求7所述的用途,其中所述一种或一种以上抗癌抗体和一种或一种以上式(I)的化合物是与用以除去癌症肿瘤或减小癌症肿瘤尺寸的外科手术、放射疗法、化疗法和/或切除疗法组合来治疗性地投予。
9.根据权利要求6所述的用途,其中所述一种或一种以上抗癌抗体和一种或一种以上式(I)的化合物是与癌症疗法组合投予。
10.根据权利要求9所述的用途,其中所述癌症疗法是树突状细胞疗法、趋化因子、细胞因子、肿瘤坏死因子(例如,TNF-α)、化疗剂(例如,腺苷类似物(例如,克拉屈滨(cladribine)、喷司他丁(pentostatin))、磺酸烷基酯(例如,白消安(busulfan)))、抗肿瘤抗生素(例如,博莱霉素(bleomycin)、放线菌素D(dactinomycin)、柔红霉素(daunorubicin)、阿霉素(doxorubicin)、表柔比星(epirubicin)、伊达比星(idarubicin)、米托蒽醌(mitoxantrone)、丝裂霉素(mitomycin))、氮丙啶(例如,塞替派(thiotepa))、喜树碱类似物(例如,伊立替康(irinotecan)、拓朴替康(topotecan))、自念珠藻环肽(cryptophycin)(例如,自念珠藻环肽52、自念珠藻环肽1)、海兔毒素(dolastatin)(例如,海兔毒素10、海兔毒素15)、烯二炔抗癌药(例如,埃斯培拉霉素(esperamicin)、刺孢霉素(calicheamicin)、达内霉素(dynemicin)、新制癌菌素(neocarzinostatin)、新制癌菌素发色团、可达霉素(kedarcidin)、可达霉素发色团、C-1027发色团和类似物)、表鬼臼素(epipodophyllotoxin)(例如,依托泊苷(etoposide)、替尼泊苷(teniposide))、叶酸类似物(例如,甲氨喋呤(methotrexate))、美登素类(maytansinoids)(例如,美登醇(maytansinol)和美登醇类似物)、微管剂(例如,多烯紫杉醇(docetaxel)、太平洋紫杉醇(paclitaxel)、长春碱(vinblastine)、长春新碱(vincristine)、长春瑞宾(vinorelbine))、氮芥类(例如,苯丁酸氮芥(chlorambucil)、环磷酰胺(cyclophosphamide)、雌氮芥(estramustine)、异环磷酰胺(ifosfamide)、氮芥(mechlorethamine)、美法仑(melphalan))、亚硝基脲(例如,卡莫司汀(carmustine)、洛莫司汀(lamustine)、鏈脲佐菌素(streptoxacin))、非典型烷基化剂(例如,六甲密胺(altretamine)、达卡巴嗪(dacarbazine)、丙卡巴肼(procarbazine)、替莫唑胺(temozolamide))、铂络合物(例如,卡铂(carboplatin)、顺铂(cisplatin))、嘌呤类似物(例如,氟达拉滨(fludarabine)、巯嘌呤(mercaptopurine)、硫鸟嘌呤(thioguanine))、嘧啶类似物(例如,卡培他滨(capecitabine)、阿糖胞苷(cytarabine)、脂质体阿糖胞苷(depocyt)、氮尿苷(floxuridine)、氟尿嘧啶(fluorouracil)、吉西他滨(gemcitabine))、经取代的尿素(例如,羟基脲)];抗血管生成剂(例如,血管生成抑制素(canstatin)、肌钙蛋白I(troponin I))、生物药剂(例如,ZD1839、维如利金(virulizin)和干扰素(interferon))、抗体和其片段(例如,抗EGFR、抗HER-2/neu、抗KDR、IMC-C225)、止吐药(例如,劳拉西泮(lorazepam)、甲氧氯普胺(metroclopramide)和多潘立酮(domperidone))、上皮生长因子抑制剂(例如,转化生长因子β1)、抗粘剂(例如,达克罗宁(dyclonine)、利多卡因(lignocaine)、氮拉斯汀(azelastine)、谷氨酰胺、类皮质激素甾类和别嘌呤醇(allopurinol))、抗破骨剂(例如,双膦酸盐{例如,依替膦酸盐(etidronate)、帕米膦酸盐(pamidronate)、伊班膦酸盐(ibandronate)和护骨素(osteoprotegerin)})、激素调节剂(例如,抗雄激素、LHRH激动剂、安美达锭(anastrozole)、他莫昔芬(tamoxifen))、造血生长因子、抗毒性剂(例如,氨磷汀(amifostine))和其两种或两种以上的混合物。
11.根据权利要求6所述的用途,进一步包括投予免疫刺激化合物。
12.根据权利要求11所述的用途,其中所述免疫刺激化合物是toll样受体(TLR)激动剂(例如,TLR4、TLR7、TLR9)、N-乙酰基胞壁酰基-L-丙氨酸-D-异谷氨酰胺(MDP)、脂多糖(LPS)、遗传修饰和/或降解的LPS、明矾、葡聚糖、集落刺激因子(例如,EPO、GM-CSF、G-CSF、M-CSF、聚乙二醇化G-CSF、SCF、IL-3、IL6、PIXY321)、干扰素(例如,γ-干扰素、α-干扰素)、白细胞介素(例如,IL-2、IL-7、IL-12、IL-15、IL-18)、MHC II型结合肽、皂苷(例如,QS21)、未甲基化的CpG序列、1-甲基色氨酸、精氨酸酶抑制剂、环磷酰胺或阻断免疫抑制功能的抗体(例如,抗CTLA4抗体)或其两种或两种以上的混合物。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US67468005P | 2005-04-26 | 2005-04-26 | |
US60/674,680 | 2005-04-26 |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN2006800143808A Division CN101355928B (zh) | 2005-04-26 | 2006-04-26 | 用于癌症免疫疗法的组合物和方法 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN103285392A true CN103285392A (zh) | 2013-09-11 |
Family
ID=37215428
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN2006800143808A Active CN101355928B (zh) | 2005-04-26 | 2006-04-26 | 用于癌症免疫疗法的组合物和方法 |
CN2013101300117A Pending CN103285392A (zh) | 2005-04-26 | 2006-04-26 | 用于癌症免疫疗法的组合物和其用途 |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN2006800143808A Active CN101355928B (zh) | 2005-04-26 | 2006-04-26 | 用于癌症免疫疗法的组合物和方法 |
Country Status (8)
Country | Link |
---|---|
US (3) | US7976852B2 (zh) |
EP (1) | EP1874342B1 (zh) |
JP (2) | JP5185813B2 (zh) |
KR (1) | KR101205064B1 (zh) |
CN (2) | CN101355928B (zh) |
AU (1) | AU2006241206B2 (zh) |
CA (1) | CA2605749C (zh) |
WO (1) | WO2006116423A2 (zh) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107126563A (zh) * | 2016-02-26 | 2017-09-05 | 博生吉医药科技(苏州)有限公司 | 含低剂量阻断vegf信号通路的抗体的组合物及其用途 |
CN107206054A (zh) * | 2015-01-27 | 2017-09-26 | 奥斯塔拉生物医学公司 | 胚胎植入 |
Families Citing this family (91)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7915238B2 (en) * | 1999-02-01 | 2011-03-29 | Eisai R & D Management Co., Ltd. | Immunomodulatory compounds and methods of use thereof |
US6835721B2 (en) | 1999-02-01 | 2004-12-28 | Eisai Co., Ltd. | Immunomodulatory compounds and methods of use thereof |
US20040006242A1 (en) * | 1999-02-01 | 2004-01-08 | Hawkins Lynn D. | Immunomodulatory compounds and method of use thereof |
US7507724B2 (en) | 2001-01-16 | 2009-03-24 | Sloan-Kettering Institute For Cancer Research | Therapy-enhancing glucan |
US7906492B2 (en) * | 2001-01-16 | 2011-03-15 | Sloan-Kettering Institute For Cancer Research | Therapy-enhancing glucan |
AU2006241206B2 (en) | 2005-04-26 | 2011-06-09 | Eisai R&D Management Co., Ltd. | Compositions and methods for cancer immunotherapy |
US20070292418A1 (en) * | 2005-04-26 | 2007-12-20 | Eisai Co., Ltd. | Compositions and methods for immunotherapy |
CA2632630C (en) | 2005-12-13 | 2016-12-06 | President And Fellows Of Harvard College | Scaffolds for cell transplantation |
US8323644B2 (en) * | 2006-01-17 | 2012-12-04 | Sloan-Kettering Institute For Cancer Research | Therapy-enhancing glucan |
US20090053221A1 (en) * | 2006-01-17 | 2009-02-26 | Cheung Nai-Kong V | Immune response enhancing glucan |
WO2009002401A2 (en) | 2007-06-21 | 2008-12-31 | President And Fellows Of Harvard College | Scaffolds for cell collection or elimination |
WO2009003082A2 (en) * | 2007-06-26 | 2008-12-31 | Vanderbilt University | Immunological compositions as cancer biomarkers and/or therapeutics |
JP5564431B2 (ja) | 2007-10-29 | 2014-07-30 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | ゼアラレノンアナログ化合物ががんを処置する能力を予測する方法 |
EP2254602B1 (en) | 2008-02-13 | 2018-11-21 | President and Fellows of Harvard College | Continuous cell programming devices |
WO2011063336A2 (en) * | 2009-11-20 | 2011-05-26 | President And Fellows Of Harvard College | Secondary site of antigen stimulation for therapeutic vaccination |
US9370558B2 (en) | 2008-02-13 | 2016-06-21 | President And Fellows Of Harvard College | Controlled delivery of TLR agonists in structural polymeric devices |
WO2009146456A1 (en) * | 2008-05-30 | 2009-12-03 | President And Fellows Of Harvard College | Controlled release of growth factors and signaling molecules for promoting angiogenesis |
EP2310006A4 (en) | 2008-07-03 | 2012-04-25 | Mayo Foundation | TREATMENT OF CANCER |
SG174507A1 (en) * | 2009-03-24 | 2011-10-28 | Transgene Sa | Biomarker for monitoring patients |
US9297005B2 (en) | 2009-04-13 | 2016-03-29 | President And Fellows Of Harvard College | Harnessing cell dynamics to engineer materials |
US8728456B2 (en) | 2009-07-31 | 2014-05-20 | President And Fellows Of Harvard College | Programming of cells for tolerogenic therapies |
BR112012003926A2 (pt) * | 2009-08-24 | 2020-08-11 | Genentech Inc | método para identificar um paciente não responsivo ao tratamento com um inibidor de b-raf, método para determinar se um tumor irá responder ao tratamento com um inibidor de b-raf, método para predizer se um paciente será não responsivo ao tratamento com um inibidor de braf específico, kit, método para classificar um tumor de mama, pulmão, cólon, ovário, tiroide, melanoma, ou pancreático e método para identificar um tumor não responsivo ao tratamento com um inibidor de b-raf |
WO2011109834A2 (en) | 2010-03-05 | 2011-09-09 | President And Fellows Of Harvard College | Enhancement of skeletal muscle stem cell engrafment by dual delivery of vegf and igf-1 |
CA2798074A1 (en) * | 2010-04-27 | 2011-11-03 | The Johns Hopkins University | Immunogenic compositions and methods for treating neoplasia |
CN103183724B (zh) * | 2010-05-27 | 2015-01-14 | 深圳信立泰药业股份有限公司 | 多西紫杉醇共缀物的制备方法 |
WO2011163669A2 (en) | 2010-06-25 | 2011-12-29 | President And Fellows Of Harvard College | Co-delivery of stimulatory and inhibitory factors to create temporally stable and spatially restricted zones |
WO2012011100A1 (en) | 2010-07-19 | 2012-01-26 | Yeda Research And Development Co. Ltd. | Peptides based on the transmembrane domain of a toll-like receptor (tlr) for treatment of tlr-mediated diseases |
BR112013007681A2 (pt) * | 2010-10-01 | 2019-05-14 | Ventirx Pharmaceuticals, Inc. | uso terapêutico de um agonista trl e terapia de combinação |
PL2624873T3 (pl) | 2010-10-06 | 2020-12-14 | President And Fellows Of Harvard College | Nadające się do wstrzykiwania hydrożele tworzące pory do terapii komórkowych opartych na materiałach |
US9603894B2 (en) | 2010-11-08 | 2017-03-28 | President And Fellows Of Harvard College | Materials presenting notch signaling molecules to control cell behavior |
JP5990752B2 (ja) * | 2011-01-31 | 2016-09-14 | オリンパス株式会社 | 抗体療法の効果増強剤 |
US10647959B2 (en) | 2011-04-27 | 2020-05-12 | President And Fellows Of Harvard College | Cell-friendly inverse opal hydrogels for cell encapsulation, drug and protein delivery, and functional nanoparticle encapsulation |
US9675561B2 (en) | 2011-04-28 | 2017-06-13 | President And Fellows Of Harvard College | Injectable cryogel vaccine devices and methods of use thereof |
WO2012149358A1 (en) | 2011-04-28 | 2012-11-01 | President And Fellows Of Harvard College | Injectable preformed macroscopic 3-dimensional scaffolds for minimally invasive administration |
HUE048876T2 (hu) | 2011-05-09 | 2020-08-28 | Mayo Found Medical Education & Res | Rákos megbetegedések kezelése |
MX345538B (es) * | 2011-05-27 | 2017-02-03 | Ambrx Inc | Composiciones que contienen, metodos que incluyen, y usos de derivados de dolastatina enlazados a aminoacidos no naturales. |
CA2838125A1 (en) | 2011-06-03 | 2012-12-06 | President And Fellows Of Harvard College | In situ antigen-generating cancer vaccine |
WO2013019620A2 (en) * | 2011-07-29 | 2013-02-07 | Glaxosmithkline Llc | Method of treating cancer using combination of braf inhibitor, mek inhibitor, and anti-ctla-4 antibody |
CN108434440B (zh) * | 2011-09-06 | 2022-08-23 | 新加坡科技研究局 | 多肽疫苗 |
EP2766384B1 (en) | 2011-10-10 | 2016-11-23 | Yeda Research and Development Co. Ltd. | Toll-like receptor 4 (tlr-4) agonist peptides for modulating tlr-4 mediated immune response |
PT2838515T (pt) | 2012-04-16 | 2020-02-25 | Harvard College | Composições de sílica mesoporosa para modular respostas imunológicas |
NZ713941A (en) * | 2012-06-07 | 2017-02-24 | Ambrx Inc | Prostate-specific membrane antigen antibody drug conjugates |
CN112587671A (zh) | 2012-07-18 | 2021-04-02 | 博笛生物科技有限公司 | 癌症的靶向免疫治疗 |
US10413606B2 (en) | 2012-10-01 | 2019-09-17 | Mayo Foundation For Medical Education And Research | Methods for treating cancer with nanoparticle complexes of albumin-bound paclitaxel and anti-VEGF antibodies |
CN103768596B (zh) * | 2012-10-17 | 2016-06-22 | 苏州丁孚靶点生物技术有限公司 | 用于肿瘤治疗的组合产品、其用途及相关方法 |
SG11201504293WA (en) * | 2012-12-03 | 2015-06-29 | Merrimack Pharmaceuticals Inc | Combination therapy for treating her2-positive cancers |
EP3092254A4 (en) | 2014-01-10 | 2017-09-20 | Birdie Biopharmaceuticals Inc. | Compounds and compositions for treating her2 positive tumors |
WO2015168379A2 (en) | 2014-04-30 | 2015-11-05 | President And Fellows Of Harvard College | Combination vaccine devices and methods of killing cancer cells |
KR20170020371A (ko) | 2014-06-16 | 2017-02-22 | 메이오 파운데이션 포 메디칼 에쥬케이션 앤드 리써치 | 골수종의 치료 |
CA2954446A1 (en) | 2014-07-09 | 2016-01-14 | Shanghai Birdie Biotech, Inc. | Anti-pd-l1 combinations for treating tumors |
CN112546230A (zh) * | 2014-07-09 | 2021-03-26 | 博笛生物科技有限公司 | 用于治疗癌症的联合治疗组合物和联合治疗方法 |
US11219672B2 (en) | 2014-08-07 | 2022-01-11 | Haruki Okamura | Therapeutic agent for cancer which comprises combination of IL-18 and molecule-targeting antibody |
CN112587672A (zh) | 2014-09-01 | 2021-04-02 | 博笛生物科技有限公司 | 用于治疗肿瘤的抗-pd-l1结合物 |
US9446148B2 (en) | 2014-10-06 | 2016-09-20 | Mayo Foundation For Medical Education And Research | Carrier-antibody compositions and methods of making and using the same |
US11786457B2 (en) | 2015-01-30 | 2023-10-17 | President And Fellows Of Harvard College | Peritumoral and intratumoral materials for cancer therapy |
JP7094533B2 (ja) | 2015-04-10 | 2022-07-04 | プレジデント アンド フェローズ オブ ハーバード カレッジ | 免疫細胞捕捉デバイスおよびその製造および使用方法 |
CN108290827B (zh) | 2015-07-31 | 2021-01-01 | 约翰霍普金斯大学 | 谷氨酰胺类似物的前药 |
EP3328376A4 (en) | 2015-07-31 | 2019-03-13 | The Johns Hopkins University | METHODS AND COMPOSITIONS FOR THE TREATMENT OF METABOLIC REPROGRAMMING DISORDERS |
US10842763B2 (en) * | 2015-07-31 | 2020-11-24 | The Johns Hopkins University | Methods for cancer and immunotherapy using prodrugs of glutamine analogs |
TW201707725A (zh) | 2015-08-18 | 2017-03-01 | 美國馬友醫藥教育研究基金會 | 載體-抗體組合物及其製造及使用方法 |
TW201713360A (en) | 2015-10-06 | 2017-04-16 | Mayo Foundation | Methods of treating cancer using compositions of antibodies and carrier proteins |
MA44334A (fr) | 2015-10-29 | 2018-09-05 | Novartis Ag | Conjugués d'anticorps comprenant un agoniste du récepteur de type toll |
CN115554406A (zh) | 2016-01-07 | 2023-01-03 | 博笛生物科技有限公司 | 用于治疗肿瘤的抗-cd20组合 |
CN106943598A (zh) | 2016-01-07 | 2017-07-14 | 博笛生物科技(北京)有限公司 | 用于治疗肿瘤的抗-her2组合 |
CN106943597A (zh) | 2016-01-07 | 2017-07-14 | 博笛生物科技(北京)有限公司 | 用于治疗肿瘤的抗-egfr组合 |
EP3399861A4 (en) | 2016-01-07 | 2019-08-07 | Mayo Foundation for Medical Education and Research | INTERFERON CANCER TREATMENT METHODS |
JP7138864B2 (ja) | 2016-02-06 | 2022-09-20 | プレジデント アンド フェローズ オブ ハーバード カレッジ | 免疫を再構成するための造血ニッチの再現 |
AU2017217881B2 (en) | 2016-02-12 | 2022-11-17 | Mayo Foundation For Medical Education And Research | Hematologic cancer treatments |
CA3018340A1 (en) | 2016-03-21 | 2017-09-28 | Mayo Foundation For Medical Education And Research | Methods for improving the therapeutic index for a chemotherapeutic drug |
AU2017238119A1 (en) | 2016-03-21 | 2018-10-11 | Mayo Foundation For Medical Education And Research | Methods for reducing toxicity of a chemotherapeutic drug |
US10618969B2 (en) | 2016-04-06 | 2020-04-14 | Mayo Foundation For Medical Education And Research | Carrier-binding agent compositions and methods of making and using the same |
EP3484448A4 (en) | 2016-07-13 | 2020-04-01 | President and Fellows of Harvard College | MIMETIC SCAFFOLDS OF CELLS HAVING ANTIGEN AND METHODS OF PREPARING AND USING THEM |
WO2018045239A1 (en) | 2016-09-01 | 2018-03-08 | Mayo Foundation For Medical Education And Research | Carrier-pd-l1 binding agent compositions for treating cancers |
MX2019002473A (es) | 2016-09-01 | 2019-09-18 | Mayo Found Medical Education & Res | Métodos y composiciones para el direccionamiento de cánceres de células t. |
US11590098B2 (en) | 2016-09-06 | 2023-02-28 | Mayo Foundation For Medical Education And Research | Methods of treating triple-negative breast cancer using compositions of antibodies and carrier proteins |
CN109843924A (zh) | 2016-09-06 | 2019-06-04 | 梅约医学教育与研究基金会 | 治疗表达pd-l1的癌症的方法 |
KR102486055B1 (ko) | 2016-09-06 | 2023-01-09 | 메이오 파운데이션 포 메디칼 에쥬케이션 앤드 리써치 | 파클리탁셀-알부민-결합제 조성물 및 그의 사용 및 제조 방법 |
AU2018226857A1 (en) * | 2017-03-03 | 2019-09-19 | Obsidian Therapeutics, Inc. | Compositions and methods for immunotherapy |
CN108567977B (zh) * | 2017-03-13 | 2022-04-12 | 复旦大学 | 一种免疫增强剂、免疫治疗药物组合物及其制备与用途 |
WO2018166298A1 (en) * | 2017-03-13 | 2018-09-20 | Fudan University | Immunopotentiator, immunotherapeutic pharmaceutical composition and its preparation and use |
CN108794467A (zh) | 2017-04-27 | 2018-11-13 | 博笛生物科技有限公司 | 2-氨基-喹啉衍生物 |
WO2018232725A1 (en) | 2017-06-23 | 2018-12-27 | Birdie Biopharmaceuticals, Inc. | PHARMACEUTICAL COMPOSITIONS |
WO2019102265A1 (en) | 2017-11-23 | 2019-05-31 | Theraphage Inc. | Peptide displaying bacteriophage nanoparticles and related compositions and methods |
WO2019175145A1 (en) | 2018-03-12 | 2019-09-19 | Janssen Vaccines & Prevention B.V. | Vaccines against urinary tract infections |
CN112334141A (zh) | 2018-06-14 | 2021-02-05 | 株式会社明治 | 用于促进免疫检查点抑制疗法的组合物 |
WO2021050696A1 (en) * | 2019-09-10 | 2021-03-18 | The Research Foundation For The State University Of New York | Compositions and methods for improving tumor penetration of tumor specific antibodies |
KR20220107166A (ko) | 2019-10-02 | 2022-08-02 | 얀센 백신스 앤드 프리벤션 비.브이. | 스타필로코커스 펩티드 및 사용 방법 |
CN115038461A (zh) | 2020-01-16 | 2022-09-09 | 杨森制药公司 | FimH突变体、其组合物及其用途 |
AU2022207740A1 (en) | 2021-01-12 | 2023-06-29 | Janssen Pharmaceuticals, Inc. | Fimh mutants, compositions therewith and use thereof |
UY39710A (es) | 2021-04-01 | 2022-09-30 | Janssen Pharmaceuticals Inc | Producción de bioconjugados de o18 de e. coli |
WO2023168342A2 (en) * | 2022-03-02 | 2023-09-07 | Abreos Biosciences, Inc. | Methods and compositions for measuring serum analyte levels from biological matrices |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20010036459A1 (en) * | 2000-04-13 | 2001-11-01 | Ravetch Jeffrey V. | Enhancement of antibody-mediated immune responses |
CN1344167A (zh) * | 1999-01-13 | 2002-04-10 | 伊格尼昂癌症治疗研发股份公司 | 抗体用于抗癌接种的用途 |
Family Cites Families (46)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4707358A (en) | 1984-01-30 | 1987-11-17 | The University Of Chicago | Vaccine against Epstein-Barr Virus |
US5030621A (en) * | 1987-04-23 | 1991-07-09 | Bystryn Jean Claude | Shed melanoma antigen compositions |
CN1074422C (zh) | 1987-11-18 | 2001-11-07 | 希龙股份有限公司 | 制备含有hcv表位的分离多肽的方法 |
JP3095169B2 (ja) | 1988-10-17 | 2000-10-03 | キャンサー リサーチ キャンペーン テクノロジー リミティド | 抗イディオタイプ抗体による抗腫瘍応答の誘導 |
JPH06104789B2 (ja) | 1989-03-31 | 1994-12-21 | 日本ペイント株式会社 | 金属顔料組成物およびそれを含む水性塗料組成物 |
DE4123760C2 (de) | 1991-07-18 | 2000-01-20 | Dade Behring Marburg Gmbh | Seroreaktive Bereiche auf den HPV 16 Proteinen E1 und E2 |
WO1993004672A1 (en) | 1991-09-11 | 1993-03-18 | Pitman-Moore, Inc. | Method for enhancing the immune system in a host employing liposome-encapsulated polypeptides |
US5484911A (en) * | 1993-04-01 | 1996-01-16 | Health Research, Inc. | Nucleoside 5'-diphosphate conjugates of ether lipids |
US5961970A (en) * | 1993-10-29 | 1999-10-05 | Pharmos Corporation | Submicron emulsions as vaccine adjuvants |
WO1995011700A1 (en) | 1993-10-29 | 1995-05-04 | Pharmos Corp. | Submicron emulsions as vaccine adjuvants |
DK0732936T3 (da) * | 1993-12-09 | 2000-09-04 | Heinrich Exner | Adjuvans til antigener, fremgangsmåde til fremstilling og anvendelse |
GB9326253D0 (en) * | 1993-12-23 | 1994-02-23 | Smithkline Beecham Biolog | Vaccines |
US5798100A (en) | 1994-07-06 | 1998-08-25 | Immunomedics, Inc. | Multi-stage cascade boosting vaccine |
US5840306A (en) | 1995-03-22 | 1998-11-24 | Merck & Co., Inc. | DNA encoding human papillomavirus type 18 |
DE19511276C2 (de) * | 1995-03-27 | 1999-02-18 | Immuno Ag | Adjuvans auf der Basis kolloidaler Eisenverbindungen |
US6180111B1 (en) * | 1995-05-18 | 2001-01-30 | University Of Maryland | Vaccine delivery system |
US5750664A (en) * | 1995-06-05 | 1998-05-12 | Eisai Co., Ltd. | Substituted liposaccharides useful in the treatment and prevention of endotoxemia |
WO1996040725A1 (en) * | 1995-06-07 | 1996-12-19 | Genta Incorporated | Phosphonic acid-based cationic lipids |
TW343975B (en) * | 1995-12-15 | 1998-11-01 | Boehringer Mannheim Gmbh | New phospholipid derivatives of phosphonocarboxylic acids, the production thereof as well as their use as antiviral pharmaceutical agents |
US6942862B2 (en) | 1996-04-01 | 2005-09-13 | University Of Washington | Methods and compositions to generate immunity in humans against self tumor antigens by immunization with homologous foreign proteins |
US5834015A (en) * | 1996-09-11 | 1998-11-10 | Albany Medical College | Protein-lipid vesicles and autogenous vaccine comprising the same |
US6355257B1 (en) * | 1997-05-08 | 2002-03-12 | Corixa Corporation | Aminoalkyl glucosamine phosphate compounds and their use as adjuvants and immunoeffectors |
GB9712347D0 (en) | 1997-06-14 | 1997-08-13 | Smithkline Beecham Biolog | Vaccine |
EP1075276B1 (en) * | 1998-05-07 | 2007-10-17 | Corixa Corporation | Adjuvant composition and methods for its use |
US6146659A (en) * | 1998-07-01 | 2000-11-14 | Neopharm, Inc. | Method of administering liposomal encapsulated taxane |
US6306404B1 (en) * | 1998-07-14 | 2001-10-23 | American Cyanamid Company | Adjuvant and vaccine compositions containing monophosphoryl lipid A |
US20040006242A1 (en) * | 1999-02-01 | 2004-01-08 | Hawkins Lynn D. | Immunomodulatory compounds and method of use thereof |
US6835721B2 (en) * | 1999-02-01 | 2004-12-28 | Eisai Co., Ltd. | Immunomodulatory compounds and methods of use thereof |
US6551600B2 (en) | 1999-02-01 | 2003-04-22 | Eisai Co., Ltd. | Immunological adjuvant compounds compositions and methods of use thereof |
AU768574B2 (en) * | 1999-02-01 | 2003-12-18 | Eisai R&D Management Co., Ltd. | Immunological adjuvant compound |
US7915238B2 (en) * | 1999-02-01 | 2011-03-29 | Eisai R & D Management Co., Ltd. | Immunomodulatory compounds and methods of use thereof |
WO2000073263A1 (en) | 1999-05-28 | 2000-12-07 | Vical Incorporated | Cytofectin dimers and methods of use thereof |
US7189397B2 (en) * | 1999-10-08 | 2007-03-13 | Arius Research Inc. | Cytotoxicity mediation of cells evidencing surface expression of CD44 |
AU1581400A (en) | 1999-12-22 | 2001-07-03 | Om Pharma | Acyl pseudopeptides bearing a functionalised auxiliary spacer |
ES2305086T3 (es) | 2000-05-19 | 2008-11-01 | Corixa Corporation | Tratamiento profilactico y terapeutico de enfermedades alergicas, autoinmunes e infecciosas con compuestos con base de monosacaridos. |
DE60115051T2 (de) | 2000-07-31 | 2006-08-24 | Eisai Co., Ltd. | Immunologische adjuvans verbindungen |
AU2001285331B2 (en) * | 2000-08-31 | 2006-04-06 | Merck & Co., Inc. | Phosphate derivatives as immunoregulatory agents |
US7507724B2 (en) * | 2001-01-16 | 2009-03-24 | Sloan-Kettering Institute For Cancer Research | Therapy-enhancing glucan |
EP1458242A4 (en) * | 2001-07-06 | 2006-06-07 | Sloan Kettering Inst Cancer | COMPREHENSIVE CONJUGATED VACCINE AGAINST CANCER |
JP2005532296A (ja) * | 2002-04-19 | 2005-10-27 | エンドサイト,インコーポレイテッド | アジュバントにより増強される免疫療法 |
US20040197312A1 (en) * | 2003-04-02 | 2004-10-07 | Marina Moskalenko | Cytokine-expressing cellular vaccine combinations |
AU2004267506A1 (en) * | 2003-08-26 | 2005-03-03 | Board Of Regents, The University Of Texas System | Anti-cancer vaccines |
FR2863890B1 (fr) * | 2003-12-19 | 2006-03-24 | Aventis Pasteur | Composition immunostimulante |
US20070292418A1 (en) * | 2005-04-26 | 2007-12-20 | Eisai Co., Ltd. | Compositions and methods for immunotherapy |
AU2006241206B2 (en) | 2005-04-26 | 2011-06-09 | Eisai R&D Management Co., Ltd. | Compositions and methods for cancer immunotherapy |
JP6136343B2 (ja) | 2012-06-12 | 2017-05-31 | 株式会社リコー | 情報処理システム、情報処理方法、プログラム、及び記録媒体 |
-
2006
- 2006-04-26 AU AU2006241206A patent/AU2006241206B2/en active Active
- 2006-04-26 CA CA2605749A patent/CA2605749C/en active Active
- 2006-04-26 JP JP2008509049A patent/JP5185813B2/ja active Active
- 2006-04-26 CN CN2006800143808A patent/CN101355928B/zh active Active
- 2006-04-26 CN CN2013101300117A patent/CN103285392A/zh active Pending
- 2006-04-26 US US11/411,332 patent/US7976852B2/en active Active
- 2006-04-26 EP EP06751398.6A patent/EP1874342B1/en active Active
- 2006-04-26 KR KR1020077024654A patent/KR101205064B1/ko active IP Right Grant
- 2006-04-26 WO PCT/US2006/015668 patent/WO2006116423A2/en active Application Filing
-
2011
- 2011-06-13 US US13/158,786 patent/US8603482B2/en active Active
-
2012
- 2012-08-02 JP JP2012171874A patent/JP5539460B2/ja active Active
-
2013
- 2013-11-08 US US14/075,130 patent/US20140065100A1/en not_active Abandoned
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1344167A (zh) * | 1999-01-13 | 2002-04-10 | 伊格尼昂癌症治疗研发股份公司 | 抗体用于抗癌接种的用途 |
US20010036459A1 (en) * | 2000-04-13 | 2001-11-01 | Ravetch Jeffrey V. | Enhancement of antibody-mediated immune responses |
US7416726B2 (en) * | 2000-04-13 | 2008-08-26 | The Rockefeller University | Enhancement of antibody-mediated immune responses |
Non-Patent Citations (1)
Title |
---|
LYNN D. HAWKINS等: "A Novel Class of Endotoxin Receptor Agonists with Simplified Structure, Toll-Like Receptor 4-Dependent Immunostimulatory Action, and Adjuvant Activity", <THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS> * |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107206054A (zh) * | 2015-01-27 | 2017-09-26 | 奥斯塔拉生物医学公司 | 胚胎植入 |
CN107206054B (zh) * | 2015-01-27 | 2021-08-20 | 奥斯塔拉生物医学公司 | 胚胎植入 |
CN107126563A (zh) * | 2016-02-26 | 2017-09-05 | 博生吉医药科技(苏州)有限公司 | 含低剂量阻断vegf信号通路的抗体的组合物及其用途 |
CN107126563B (zh) * | 2016-02-26 | 2021-09-10 | 博生吉医药科技(苏州)有限公司 | 含低剂量阻断vegf信号通路的抗体的组合物及其用途 |
Also Published As
Publication number | Publication date |
---|---|
US20110250171A1 (en) | 2011-10-13 |
KR20070122510A (ko) | 2007-12-31 |
US8603482B2 (en) | 2013-12-10 |
US20070020232A1 (en) | 2007-01-25 |
EP1874342A4 (en) | 2012-08-08 |
CA2605749C (en) | 2015-06-30 |
WO2006116423A2 (en) | 2006-11-02 |
CN101355928B (zh) | 2013-05-22 |
EP1874342B1 (en) | 2018-06-06 |
WO2006116423A3 (en) | 2008-10-09 |
CN101355928A (zh) | 2009-01-28 |
EP1874342A2 (en) | 2008-01-09 |
CA2605749A1 (en) | 2006-11-02 |
US7976852B2 (en) | 2011-07-12 |
AU2006241206B2 (en) | 2011-06-09 |
US20140065100A1 (en) | 2014-03-06 |
JP2008539249A (ja) | 2008-11-13 |
JP5539460B2 (ja) | 2014-07-02 |
AU2006241206A1 (en) | 2006-11-02 |
JP2012211196A (ja) | 2012-11-01 |
KR101205064B1 (ko) | 2012-11-27 |
JP5185813B2 (ja) | 2013-04-17 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN101355928B (zh) | 用于癌症免疫疗法的组合物和方法 | |
US20070292418A1 (en) | Compositions and methods for immunotherapy | |
JP5674273B2 (ja) | 同時の化学療法及び免疫療法 | |
TW202118518A (zh) | 用於癌症、腫瘤及腫瘤細胞之局部及全身性治療之組合物及方法 | |
Gray et al. | Controlled clinical trial of adjuvant immunotherapy with BCG and neuraminidase‐treated autologous tumour cells in large bowel cancer | |
Prager et al. | Enhanced response to chemoimmunotherapy and immunoprophylaxis with the use of tumor-associated antigens with a lipophilic agent | |
AU2011211457B2 (en) | Compositions and methods for cancer immunotherapy | |
Slovin | Cancer Immunotherapeutics Meeting |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 1189348 Country of ref document: HK |
|
RJ01 | Rejection of invention patent application after publication | ||
RJ01 | Rejection of invention patent application after publication |
Application publication date: 20130911 |
|
REG | Reference to a national code |
Ref country code: HK Ref legal event code: WD Ref document number: 1189348 Country of ref document: HK |