CN112584861A - 使用组合疗法治疗癌症的方法 - Google Patents
使用组合疗法治疗癌症的方法 Download PDFInfo
- Publication number
- CN112584861A CN112584861A CN201980042052.6A CN201980042052A CN112584861A CN 112584861 A CN112584861 A CN 112584861A CN 201980042052 A CN201980042052 A CN 201980042052A CN 112584861 A CN112584861 A CN 112584861A
- Authority
- CN
- China
- Prior art keywords
- days
- inhibitor
- seq
- vsv
- ser
- 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
- 238000000034 method Methods 0.000 title claims abstract description 60
- 206010028980 Neoplasm Diseases 0.000 title abstract description 49
- 201000011510 cancer Diseases 0.000 title abstract description 21
- 238000002648 combination therapy Methods 0.000 title description 10
- 108010074708 B7-H1 Antigen Proteins 0.000 claims abstract description 31
- 102000008096 B7-H1 Antigen Human genes 0.000 claims abstract description 31
- 239000003112 inhibitor Substances 0.000 claims abstract description 14
- 102000003996 Interferon-beta Human genes 0.000 claims abstract description 9
- 108090000467 Interferon-beta Proteins 0.000 claims abstract description 9
- 229960001388 interferon-beta Drugs 0.000 claims abstract description 9
- 239000012271 PD-L1 inhibitor Substances 0.000 claims description 63
- 229940121656 pd-l1 inhibitor Drugs 0.000 claims description 63
- 241000711975 Vesicular stomatitis virus Species 0.000 claims description 39
- 238000011282 treatment Methods 0.000 claims description 29
- 206010055114 Colon cancer metastatic Diseases 0.000 claims description 15
- 239000003814 drug Substances 0.000 claims description 15
- 108090000088 Symporters Proteins 0.000 claims description 12
- 102000003673 Symporters Human genes 0.000 claims description 12
- 238000011275 oncology therapy Methods 0.000 claims description 12
- 108010047041 Complementarity Determining Regions Proteins 0.000 claims description 11
- 229910052740 iodine Inorganic materials 0.000 claims description 11
- 239000011630 iodine Substances 0.000 claims description 11
- 239000005660 Abamectin Substances 0.000 claims description 10
- 206010061818 Disease progression Diseases 0.000 claims description 10
- 230000005750 disease progression Effects 0.000 claims description 10
- IBSREHMXUMOFBB-JFUDTMANSA-N 5u8924t11h Chemical group O1[C@@H](C)[C@H](O)[C@@H](OC)C[C@@H]1O[C@@H]1[C@@H](OC)C[C@H](O[C@@H]2C(=C/C[C@@H]3C[C@@H](C[C@@]4(O3)C=C[C@H](C)[C@@H](C(C)C)O4)OC(=O)[C@@H]3C=C(C)[C@@H](O)[C@H]4OC\C([C@@]34O)=C/C=C/[C@@H]2C)/C)O[C@H]1C.C1=C[C@H](C)[C@@H]([C@@H](C)CC)O[C@]11O[C@H](C\C=C(C)\[C@@H](O[C@@H]2O[C@@H](C)[C@H](O[C@@H]3O[C@@H](C)[C@H](O)[C@@H](OC)C3)[C@@H](OC)C2)[C@@H](C)\C=C\C=C/2[C@]3([C@H](C(=O)O4)C=C(C)[C@@H](O)[C@H]3OC\2)O)C[C@H]4C1 IBSREHMXUMOFBB-JFUDTMANSA-N 0.000 claims description 9
- 229950008167 abamectin Drugs 0.000 claims description 9
- 208000015181 infectious disease Diseases 0.000 claims description 9
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 8
- 229910052708 sodium Inorganic materials 0.000 claims description 8
- 239000011734 sodium Substances 0.000 claims description 8
- 239000002671 adjuvant Substances 0.000 claims description 6
- 230000002458 infectious effect Effects 0.000 claims description 5
- 230000010056 antibody-dependent cellular cytotoxicity Effects 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 102100040678 Programmed cell death protein 1 Human genes 0.000 claims description 3
- 101710089372 Programmed cell death protein 1 Proteins 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- 210000001744 T-lymphocyte Anatomy 0.000 claims description 2
- 125000003275 alpha amino acid group Chemical group 0.000 claims 7
- 108010021625 Immunoglobulin Fragments Proteins 0.000 claims 4
- 102000008394 Immunoglobulin Fragments Human genes 0.000 claims 4
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims 3
- 239000008194 pharmaceutical composition Substances 0.000 claims 3
- 102000037982 Immune checkpoint proteins Human genes 0.000 claims 2
- 108091008036 Immune checkpoint proteins Proteins 0.000 claims 2
- 101100510617 Caenorhabditis elegans sel-8 gene Proteins 0.000 claims 1
- 102100034458 Hepatitis A virus cellular receptor 2 Human genes 0.000 claims 1
- 101001068133 Homo sapiens Hepatitis A virus cellular receptor 2 Proteins 0.000 claims 1
- 230000000295 complement effect Effects 0.000 claims 1
- 239000002552 dosage form Substances 0.000 claims 1
- 210000002865 immune cell Anatomy 0.000 claims 1
- 230000008595 infiltration Effects 0.000 claims 1
- 238000001764 infiltration Methods 0.000 claims 1
- 210000005259 peripheral blood Anatomy 0.000 claims 1
- 239000011886 peripheral blood Substances 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 238000002203 pretreatment Methods 0.000 claims 1
- 241000700605 Viruses Species 0.000 abstract description 20
- 238000002560 therapeutic procedure Methods 0.000 abstract description 8
- 238000011285 therapeutic regimen Methods 0.000 abstract description 2
- 208000003265 stomatitis Diseases 0.000 abstract 1
- 208000005925 vesicular stomatitis Diseases 0.000 abstract 1
- 230000003902 lesion Effects 0.000 description 49
- 229920001184 polypeptide Polymers 0.000 description 32
- 102000004196 processed proteins & peptides Human genes 0.000 description 32
- 108090000765 processed proteins & peptides Proteins 0.000 description 32
- 150000007523 nucleic acids Chemical group 0.000 description 29
- 201000010099 disease Diseases 0.000 description 23
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 23
- 230000004044 response Effects 0.000 description 23
- 210000004027 cell Anatomy 0.000 description 17
- 108020004707 nucleic acids Proteins 0.000 description 17
- 102000039446 nucleic acids Human genes 0.000 description 17
- 206010009944 Colon cancer Diseases 0.000 description 16
- 238000001802 infusion Methods 0.000 description 16
- 239000000203 mixture Substances 0.000 description 16
- 208000029742 colonic neoplasm Diseases 0.000 description 15
- 238000002347 injection Methods 0.000 description 14
- 239000007924 injection Substances 0.000 description 14
- 241000282414 Homo sapiens Species 0.000 description 13
- 231100000371 dose-limiting toxicity Toxicity 0.000 description 13
- 210000001165 lymph node Anatomy 0.000 description 13
- 230000002601 intratumoral effect Effects 0.000 description 11
- 150000001875 compounds Chemical class 0.000 description 10
- 210000000056 organ Anatomy 0.000 description 10
- 229940079593 drug Drugs 0.000 description 9
- 238000001990 intravenous administration Methods 0.000 description 9
- 231100000682 maximum tolerated dose Toxicity 0.000 description 9
- 208000037821 progressive disease Diseases 0.000 description 9
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 8
- 102100040019 Interferon alpha-1/13 Human genes 0.000 description 7
- 108091028043 Nucleic acid sequence Proteins 0.000 description 7
- HTONZBWRYUKUKC-RCWTZXSCSA-N Val-Thr-Val Chemical compound CC(C)[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(O)=O HTONZBWRYUKUKC-RCWTZXSCSA-N 0.000 description 7
- 238000004458 analytical method Methods 0.000 description 7
- 238000002591 computed tomography Methods 0.000 description 7
- 238000009472 formulation Methods 0.000 description 7
- 238000005259 measurement Methods 0.000 description 7
- 108090000623 proteins and genes Proteins 0.000 description 7
- 210000001519 tissue Anatomy 0.000 description 7
- 230000003612 virological effect Effects 0.000 description 7
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 6
- 244000309459 oncolytic virus Species 0.000 description 6
- 238000009097 single-agent therapy Methods 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 101001054334 Homo sapiens Interferon beta Proteins 0.000 description 5
- 229940076838 Immune checkpoint inhibitor Drugs 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 125000002091 cationic group Chemical group 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 210000001072 colon Anatomy 0.000 description 5
- 230000034994 death Effects 0.000 description 5
- 231100000517 death Toxicity 0.000 description 5
- 239000012634 fragment Substances 0.000 description 5
- 239000012274 immune-checkpoint protein inhibitor Substances 0.000 description 5
- 150000002632 lipids Chemical class 0.000 description 5
- 230000000174 oncolytic effect Effects 0.000 description 5
- 230000001575 pathological effect Effects 0.000 description 5
- 239000000825 pharmaceutical preparation Substances 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 230000004083 survival effect Effects 0.000 description 5
- 241000880493 Leptailurus serval Species 0.000 description 4
- HYMLKESRWLZDBR-WEDXCCLWSA-N Leu-Gly-Thr Chemical compound CC(C)C[C@H](N)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(O)=O HYMLKESRWLZDBR-WEDXCCLWSA-N 0.000 description 4
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 4
- 206010037660 Pyrexia Diseases 0.000 description 4
- SGAOHNPSEPVAFP-ZDLURKLDSA-N Thr-Ser-Gly Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)NCC(O)=O SGAOHNPSEPVAFP-ZDLURKLDSA-N 0.000 description 4
- 150000001413 amino acids Chemical group 0.000 description 4
- 239000000739 antihistaminic agent Substances 0.000 description 4
- 238000011260 co-administration Methods 0.000 description 4
- 238000013461 design Methods 0.000 description 4
- 210000004072 lung Anatomy 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 208000037843 metastatic solid tumor Diseases 0.000 description 4
- 238000012544 monitoring process Methods 0.000 description 4
- 230000036961 partial effect Effects 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 108010013351 sodium-iodide symporter Proteins 0.000 description 4
- 229940124597 therapeutic agent Drugs 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- 238000011269 treatment regimen Methods 0.000 description 4
- 229960005486 vaccine Drugs 0.000 description 4
- 230000003442 weekly effect Effects 0.000 description 4
- YYSWCHMLFJLLBJ-ZLUOBGJFSA-N Ala-Ala-Ser Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O YYSWCHMLFJLLBJ-ZLUOBGJFSA-N 0.000 description 3
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 3
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 description 3
- KBBRNEDOYWMIJP-KYNKHSRBSA-N Thr-Gly-Thr Chemical compound C[C@H]([C@@H](C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(=O)O)N)O KBBRNEDOYWMIJP-KYNKHSRBSA-N 0.000 description 3
- 108700019146 Transgenes Proteins 0.000 description 3
- 108700041558 Vesicular stomatitis virus M Proteins 0.000 description 3
- 208000037844 advanced solid tumor Diseases 0.000 description 3
- 230000002411 adverse Effects 0.000 description 3
- 108010008685 alanyl-glutamyl-aspartic acid Proteins 0.000 description 3
- 230000001387 anti-histamine Effects 0.000 description 3
- 229950002916 avelumab Drugs 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 150000001720 carbohydrates Chemical class 0.000 description 3
- 235000014633 carbohydrates Nutrition 0.000 description 3
- 238000002512 chemotherapy Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 230000014509 gene expression Effects 0.000 description 3
- 108010015792 glycyllysine Proteins 0.000 description 3
- 238000003384 imaging method Methods 0.000 description 3
- 238000003780 insertion Methods 0.000 description 3
- 230000037431 insertion Effects 0.000 description 3
- 238000007918 intramuscular administration Methods 0.000 description 3
- 238000007912 intraperitoneal administration Methods 0.000 description 3
- 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 description 3
- 239000002502 liposome Substances 0.000 description 3
- 210000004185 liver Anatomy 0.000 description 3
- 201000001441 melanoma Diseases 0.000 description 3
- 239000011859 microparticle Substances 0.000 description 3
- PBAPPPCECJKMCM-IBGZPJMESA-N mirabegron Chemical compound S1C(N)=NC(CC(=O)NC=2C=CC(CCNC[C@H](O)C=3C=CC=CC=3)=CC=2)=C1 PBAPPPCECJKMCM-IBGZPJMESA-N 0.000 description 3
- 229960005489 paracetamol Drugs 0.000 description 3
- 230000002980 postoperative effect Effects 0.000 description 3
- 235000018102 proteins Nutrition 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 230000008685 targeting Effects 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- 239000000439 tumor marker Substances 0.000 description 3
- 210000002845 virion Anatomy 0.000 description 3
- OPCHFPHZPIURNA-MFERNQICSA-N (2s)-2,5-bis(3-aminopropylamino)-n-[2-(dioctadecylamino)acetyl]pentanamide Chemical compound CCCCCCCCCCCCCCCCCCN(CC(=O)NC(=O)[C@H](CCCNCCCN)NCCCN)CCCCCCCCCCCCCCCCCC OPCHFPHZPIURNA-MFERNQICSA-N 0.000 description 2
- IESDGNYHXIOKRW-YXMSTPNBSA-N (2s)-2-[[(2s)-1-[(2s)-6-amino-2-[[(2s,3r)-2-amino-3-hydroxybutanoyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-5-(diaminomethylideneamino)pentanoic acid Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(N)=N)C(O)=O IESDGNYHXIOKRW-YXMSTPNBSA-N 0.000 description 2
- DIBLBAURNYJYBF-XLXZRNDBSA-N (2s)-2-[[(2s)-2-[[2-[[(2s)-6-amino-2-[[(2s)-2-amino-3-methylbutanoyl]amino]hexanoyl]amino]acetyl]amino]-3-phenylpropanoyl]amino]-3-(4-hydroxyphenyl)propanoic acid Chemical compound C([C@H](NC(=O)CNC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)C(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C1=CC=CC=C1 DIBLBAURNYJYBF-XLXZRNDBSA-N 0.000 description 2
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 2
- BTYTYHBSJKQBQA-GCJQMDKQSA-N Ala-Asp-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](C)N)O BTYTYHBSJKQBQA-GCJQMDKQSA-N 0.000 description 2
- OYJCVIGKMXUVKB-GARJFASQSA-N Ala-Leu-Pro Chemical compound C[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N1CCC[C@@H]1C(=O)O)N OYJCVIGKMXUVKB-GARJFASQSA-N 0.000 description 2
- IORKCNUBHNIMKY-CIUDSAMLSA-N Ala-Pro-Glu Chemical compound C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O IORKCNUBHNIMKY-CIUDSAMLSA-N 0.000 description 2
- WQLDNOCHHRISMS-NAKRPEOUSA-N Ala-Pro-Ile Chemical compound [H]N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)CC)C(O)=O WQLDNOCHHRISMS-NAKRPEOUSA-N 0.000 description 2
- XWFWAXPOLRTDFZ-FXQIFTODSA-N Ala-Pro-Ser Chemical compound C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O XWFWAXPOLRTDFZ-FXQIFTODSA-N 0.000 description 2
- 108010088751 Albumins Proteins 0.000 description 2
- 102000009027 Albumins Human genes 0.000 description 2
- VKKYFICVTYKFIO-CIUDSAMLSA-N Arg-Ala-Glu Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCN=C(N)N VKKYFICVTYKFIO-CIUDSAMLSA-N 0.000 description 2
- LKDHUGLXOHYINY-XUXIUFHCSA-N Arg-Ile-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCCN=C(N)N)N LKDHUGLXOHYINY-XUXIUFHCSA-N 0.000 description 2
- SLKLLQWZQHXYSV-CIUDSAMLSA-N Asn-Ala-Lys Chemical compound NC(=O)C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(O)=O SLKLLQWZQHXYSV-CIUDSAMLSA-N 0.000 description 2
- JJGRJMKUOYXZRA-LPEHRKFASA-N Asn-Arg-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(=O)N)N)C(=O)O JJGRJMKUOYXZRA-LPEHRKFASA-N 0.000 description 2
- MKJBPDLENBUHQU-CIUDSAMLSA-N Asn-Ser-Leu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O MKJBPDLENBUHQU-CIUDSAMLSA-N 0.000 description 2
- UGXYFDQFLVCDFC-CIUDSAMLSA-N Asn-Ser-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O UGXYFDQFLVCDFC-CIUDSAMLSA-N 0.000 description 2
- JBDLMLZNDRLDIX-HJGDQZAQSA-N Asn-Thr-Leu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O JBDLMLZNDRLDIX-HJGDQZAQSA-N 0.000 description 2
- LGCVSPFCFXWUEY-IHPCNDPISA-N Asn-Trp-Tyr Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CC3=CC=C(C=C3)O)C(=O)O)NC(=O)[C@H](CC(=O)N)N LGCVSPFCFXWUEY-IHPCNDPISA-N 0.000 description 2
- PDECQIHABNQRHN-GUBZILKMSA-N Asp-Glu-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CC(O)=O PDECQIHABNQRHN-GUBZILKMSA-N 0.000 description 2
- SNDBKTFJWVEVPO-WHFBIAKZSA-N Asp-Gly-Ser Chemical compound [H]N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@@H](CO)C(O)=O SNDBKTFJWVEVPO-WHFBIAKZSA-N 0.000 description 2
- NVFSJIXJZCDICF-SRVKXCTJSA-N Asp-Lys-Lys Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC(=O)O)N NVFSJIXJZCDICF-SRVKXCTJSA-N 0.000 description 2
- AHWRSSLYSGLBGD-CIUDSAMLSA-N Asp-Pro-Glu Chemical compound OC(=O)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O AHWRSSLYSGLBGD-CIUDSAMLSA-N 0.000 description 2
- MNQMTYSEKZHIDF-GCJQMDKQSA-N Asp-Thr-Ala Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O MNQMTYSEKZHIDF-GCJQMDKQSA-N 0.000 description 2
- SQIARYGNVQWOSB-BZSNNMDCSA-N Asp-Tyr-Phe Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O SQIARYGNVQWOSB-BZSNNMDCSA-N 0.000 description 2
- QOJJMJKTMKNFEF-ZKWXMUAHSA-N Asp-Val-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CC(O)=O QOJJMJKTMKNFEF-ZKWXMUAHSA-N 0.000 description 2
- ZXCAQANTQWBICD-DCAQKATOSA-N Cys-Lys-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CS)N ZXCAQANTQWBICD-DCAQKATOSA-N 0.000 description 2
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 2
- OYTPNWYZORARHL-XHNCKOQMSA-N Gln-Ala-Pro Chemical compound C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCC(=O)N)N OYTPNWYZORARHL-XHNCKOQMSA-N 0.000 description 2
- DHNWZLGBTPUTQQ-QEJZJMRPSA-N Gln-Asp-Trp Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CCC(=O)N)N DHNWZLGBTPUTQQ-QEJZJMRPSA-N 0.000 description 2
- FQCILXROGNOZON-YUMQZZPRSA-N Gln-Pro-Gly Chemical compound NC(=O)CC[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O FQCILXROGNOZON-YUMQZZPRSA-N 0.000 description 2
- XKPACHRGOWQHFH-IRIUXVKKSA-N Gln-Thr-Tyr Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O XKPACHRGOWQHFH-IRIUXVKKSA-N 0.000 description 2
- FITIQFSXXBKFFM-NRPADANISA-N Gln-Val-Ser Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(O)=O FITIQFSXXBKFFM-NRPADANISA-N 0.000 description 2
- ITYRYNUZHPNCIK-GUBZILKMSA-N Glu-Ala-Leu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(O)=O ITYRYNUZHPNCIK-GUBZILKMSA-N 0.000 description 2
- GLWXKFRTOHKGIT-ACZMJKKPSA-N Glu-Asn-Asn Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O GLWXKFRTOHKGIT-ACZMJKKPSA-N 0.000 description 2
- HNVFSTLPVJWIDV-CIUDSAMLSA-N Glu-Glu-Gln Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O HNVFSTLPVJWIDV-CIUDSAMLSA-N 0.000 description 2
- ALMBZBOCGSVSAI-ACZMJKKPSA-N Glu-Ser-Asn Chemical compound C(CC(=O)O)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(=O)N)C(=O)O)N ALMBZBOCGSVSAI-ACZMJKKPSA-N 0.000 description 2
- MFYLRRCYBBJYPI-JYJNAYRXSA-N Glu-Tyr-Lys Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCC(=O)O)N)O MFYLRRCYBBJYPI-JYJNAYRXSA-N 0.000 description 2
- YQPFCZVKMUVZIN-AUTRQRHGSA-N Glu-Val-Gln Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O YQPFCZVKMUVZIN-AUTRQRHGSA-N 0.000 description 2
- VSVZIEVNUYDAFR-YUMQZZPRSA-N Gly-Ala-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)CN VSVZIEVNUYDAFR-YUMQZZPRSA-N 0.000 description 2
- GRIRDMVMJJDZKV-RCOVLWMOSA-N Gly-Asn-Val Chemical compound [H]NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(O)=O GRIRDMVMJJDZKV-RCOVLWMOSA-N 0.000 description 2
- PABFFPWEJMEVEC-JGVFFNPUSA-N Gly-Gln-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCC(=O)N)NC(=O)CN)C(=O)O PABFFPWEJMEVEC-JGVFFNPUSA-N 0.000 description 2
- XMPXVJIDADUOQB-RCOVLWMOSA-N Gly-Gly-Ile Chemical compound CC[C@H](C)[C@@H](C([O-])=O)NC(=O)CNC(=O)C[NH3+] XMPXVJIDADUOQB-RCOVLWMOSA-N 0.000 description 2
- MIIVFRCYJABHTQ-ONGXEEELSA-N Gly-Leu-Val Chemical compound [H]NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(O)=O MIIVFRCYJABHTQ-ONGXEEELSA-N 0.000 description 2
- PDUHNKAFQXQNLH-ZETCQYMHSA-N Gly-Lys-Gly Chemical compound NCCCC[C@H](NC(=O)CN)C(=O)NCC(O)=O PDUHNKAFQXQNLH-ZETCQYMHSA-N 0.000 description 2
- WNZOCXUOGVYYBJ-CDMKHQONSA-N Gly-Phe-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)NC(=O)CN)O WNZOCXUOGVYYBJ-CDMKHQONSA-N 0.000 description 2
- HAOUOFNNJJLVNS-BQBZGAKWSA-N Gly-Pro-Ser Chemical compound NCC(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O HAOUOFNNJJLVNS-BQBZGAKWSA-N 0.000 description 2
- FFJQHWKSGAWSTJ-BFHQHQDPSA-N Gly-Thr-Ala Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O FFJQHWKSGAWSTJ-BFHQHQDPSA-N 0.000 description 2
- ZZWUYQXMIFTIIY-WEDXCCLWSA-N Gly-Thr-Leu Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O ZZWUYQXMIFTIIY-WEDXCCLWSA-N 0.000 description 2
- 206010019233 Headaches Diseases 0.000 description 2
- WMKXFMUJRCEGRP-SRVKXCTJSA-N His-Asn-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC2=CN=CN2)C(=O)O)N WMKXFMUJRCEGRP-SRVKXCTJSA-N 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 101000746373 Homo sapiens Granulocyte-macrophage colony-stimulating factor Proteins 0.000 description 2
- 206010020751 Hypersensitivity Diseases 0.000 description 2
- MKWSZEHGHSLNPF-NAKRPEOUSA-N Ile-Ala-Val Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)O)N MKWSZEHGHSLNPF-NAKRPEOUSA-N 0.000 description 2
- FADXGVVLSPPEQY-GHCJXIJMSA-N Ile-Cys-Asn Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(=O)N)C(=O)O)N FADXGVVLSPPEQY-GHCJXIJMSA-N 0.000 description 2
- AYLAAGNJNVZDPY-CYDGBPFRSA-N Ile-Met-Met Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCSC)C(=O)O)N AYLAAGNJNVZDPY-CYDGBPFRSA-N 0.000 description 2
- 108010065920 Insulin Lispro Proteins 0.000 description 2
- PMGDADKJMCOXHX-UHFFFAOYSA-N L-Arginyl-L-glutamin-acetat Natural products NC(=N)NCCCC(N)C(=O)NC(CCC(N)=O)C(O)=O PMGDADKJMCOXHX-UHFFFAOYSA-N 0.000 description 2
- OIARJGNVARWKFP-YUMQZZPRSA-N Leu-Asn-Gly Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(O)=O OIARJGNVARWKFP-YUMQZZPRSA-N 0.000 description 2
- PVMPDMIKUVNOBD-CIUDSAMLSA-N Leu-Asp-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O PVMPDMIKUVNOBD-CIUDSAMLSA-N 0.000 description 2
- AXZGZMGRBDQTEY-SRVKXCTJSA-N Leu-Gln-Met Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCSC)C(O)=O AXZGZMGRBDQTEY-SRVKXCTJSA-N 0.000 description 2
- GPICTNQYKHHHTH-GUBZILKMSA-N Leu-Gln-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(O)=O GPICTNQYKHHHTH-GUBZILKMSA-N 0.000 description 2
- FEHQLKKBVJHSEC-SZMVWBNQSA-N Leu-Glu-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CC(C)C)C(O)=O)=CNC2=C1 FEHQLKKBVJHSEC-SZMVWBNQSA-N 0.000 description 2
- QJUWBDPGGYVRHY-YUMQZZPRSA-N Leu-Gly-Cys Chemical compound CC(C)C[C@@H](C(=O)NCC(=O)N[C@@H](CS)C(=O)O)N QJUWBDPGGYVRHY-YUMQZZPRSA-N 0.000 description 2
- QNBVTHNJGCOVFA-AVGNSLFASA-N Leu-Leu-Glu Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CCC(O)=O QNBVTHNJGCOVFA-AVGNSLFASA-N 0.000 description 2
- YOKVEHGYYQEQOP-QWRGUYRKSA-N Leu-Leu-Gly Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O YOKVEHGYYQEQOP-QWRGUYRKSA-N 0.000 description 2
- KIZIOFNVSOSKJI-CIUDSAMLSA-N Leu-Ser-Cys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)O)N KIZIOFNVSOSKJI-CIUDSAMLSA-N 0.000 description 2
- SBANPBVRHYIMRR-UHFFFAOYSA-N Leu-Ser-Pro Natural products CC(C)CC(N)C(=O)NC(CO)C(=O)N1CCCC1C(O)=O SBANPBVRHYIMRR-UHFFFAOYSA-N 0.000 description 2
- AIQWYVFNBNNOLU-RHYQMDGZSA-N Leu-Thr-Val Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(O)=O AIQWYVFNBNNOLU-RHYQMDGZSA-N 0.000 description 2
- YQFZRHYZLARWDY-IHRRRGAJSA-N Leu-Val-Lys Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CCCCN YQFZRHYZLARWDY-IHRRRGAJSA-N 0.000 description 2
- GQZMPWBZQALKJO-UWVGGRQHSA-N Lys-Gly-Arg Chemical compound [H]N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(O)=O GQZMPWBZQALKJO-UWVGGRQHSA-N 0.000 description 2
- XNKDCYABMBBEKN-IUCAKERBSA-N Lys-Gly-Gln Chemical compound NCCCC[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CCC(N)=O XNKDCYABMBBEKN-IUCAKERBSA-N 0.000 description 2
- WQDKIVRHTQYJSN-DCAQKATOSA-N Lys-Ser-Arg Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N WQDKIVRHTQYJSN-DCAQKATOSA-N 0.000 description 2
- CTJUSALVKAWFFU-CIUDSAMLSA-N Lys-Ser-Cys Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)O)N CTJUSALVKAWFFU-CIUDSAMLSA-N 0.000 description 2
- IOQWIOPSKJOEKI-SRVKXCTJSA-N Lys-Ser-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O IOQWIOPSKJOEKI-SRVKXCTJSA-N 0.000 description 2
- IEVXCWPVBYCJRZ-IXOXFDKPSA-N Lys-Thr-His Chemical compound NCCCC[C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@H](C(O)=O)CC1=CN=CN1 IEVXCWPVBYCJRZ-IXOXFDKPSA-N 0.000 description 2
- DLCAXBGXGOVUCD-PPCPHDFISA-N Lys-Thr-Ile Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O DLCAXBGXGOVUCD-PPCPHDFISA-N 0.000 description 2
- 208000002030 Merkel cell carcinoma Diseases 0.000 description 2
- 208000000112 Myalgia Diseases 0.000 description 2
- YBAFDPFAUTYYRW-UHFFFAOYSA-N N-L-alpha-glutamyl-L-leucine Natural products CC(C)CC(C(O)=O)NC(=O)C(N)CCC(O)=O YBAFDPFAUTYYRW-UHFFFAOYSA-N 0.000 description 2
- SITLTJHOQZFJGG-UHFFFAOYSA-N N-L-alpha-glutamyl-L-valine Natural products CC(C)C(C(O)=O)NC(=O)C(N)CCC(O)=O SITLTJHOQZFJGG-UHFFFAOYSA-N 0.000 description 2
- 206010028851 Necrosis Diseases 0.000 description 2
- 206010029266 Neuroendocrine carcinoma of the skin Diseases 0.000 description 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 2
- MSHZERMPZKCODG-ACRUOGEOSA-N Phe-Leu-Phe Chemical compound C([C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 MSHZERMPZKCODG-ACRUOGEOSA-N 0.000 description 2
- JDMKQHSHKJHAHR-UHFFFAOYSA-N Phe-Phe-Leu-Tyr Natural products C=1C=C(O)C=CC=1CC(C(O)=O)NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)CC1=CC=CC=C1 JDMKQHSHKJHAHR-UHFFFAOYSA-N 0.000 description 2
- JLLJTMHNXQTMCK-UBHSHLNASA-N Phe-Pro-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CC1=CC=CC=C1 JLLJTMHNXQTMCK-UBHSHLNASA-N 0.000 description 2
- WWPAHTZOWURIMR-ULQDDVLXSA-N Phe-Pro-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CC1=CC=CC=C1 WWPAHTZOWURIMR-ULQDDVLXSA-N 0.000 description 2
- IIEOLPMQYRBZCN-SRVKXCTJSA-N Phe-Ser-Cys Chemical compound N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)O IIEOLPMQYRBZCN-SRVKXCTJSA-N 0.000 description 2
- MCIXMYKSPQUMJG-SRVKXCTJSA-N Phe-Ser-Ser Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O MCIXMYKSPQUMJG-SRVKXCTJSA-N 0.000 description 2
- FGWUALWGCZJQDJ-URLPEUOOSA-N Phe-Thr-Ile Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O FGWUALWGCZJQDJ-URLPEUOOSA-N 0.000 description 2
- IHCXPSYCHXFXKT-DCAQKATOSA-N Pro-Arg-Glu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(O)=O IHCXPSYCHXFXKT-DCAQKATOSA-N 0.000 description 2
- TUYWCHPXKQTISF-LPEHRKFASA-N Pro-Cys-Pro Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CS)C(=O)N2CCC[C@@H]2C(=O)O TUYWCHPXKQTISF-LPEHRKFASA-N 0.000 description 2
- UAYHMOIGIQZLFR-NHCYSSNCSA-N Pro-Gln-Val Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(O)=O UAYHMOIGIQZLFR-NHCYSSNCSA-N 0.000 description 2
- LGSANCBHSMDFDY-GARJFASQSA-N Pro-Glu-Pro Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CCC(=O)O)C(=O)N2CCC[C@@H]2C(=O)O LGSANCBHSMDFDY-GARJFASQSA-N 0.000 description 2
- VPEVBAUSTBWQHN-NHCYSSNCSA-N Pro-Glu-Val Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O VPEVBAUSTBWQHN-NHCYSSNCSA-N 0.000 description 2
- ZLXKLMHAMDENIO-DCAQKATOSA-N Pro-Lys-Asp Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(O)=O ZLXKLMHAMDENIO-DCAQKATOSA-N 0.000 description 2
- PCWLNNZTBJTZRN-AVGNSLFASA-N Pro-Pro-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 PCWLNNZTBJTZRN-AVGNSLFASA-N 0.000 description 2
- GOMUXSCOIWIJFP-GUBZILKMSA-N Pro-Ser-Arg Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O GOMUXSCOIWIJFP-GUBZILKMSA-N 0.000 description 2
- OWQXAJQZLWHPBH-FXQIFTODSA-N Pro-Ser-Asn Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O OWQXAJQZLWHPBH-FXQIFTODSA-N 0.000 description 2
- GMJDSFYVTAMIBF-FXQIFTODSA-N Pro-Ser-Asp Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(O)=O GMJDSFYVTAMIBF-FXQIFTODSA-N 0.000 description 2
- PRKWBYCXBBSLSK-GUBZILKMSA-N Pro-Ser-Val Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O PRKWBYCXBBSLSK-GUBZILKMSA-N 0.000 description 2
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 2
- 102100024952 Protein CBFA2T1 Human genes 0.000 description 2
- 208000006265 Renal cell carcinoma Diseases 0.000 description 2
- QEDMOZUJTGEIBF-FXQIFTODSA-N Ser-Arg-Asp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(O)=O QEDMOZUJTGEIBF-FXQIFTODSA-N 0.000 description 2
- OYEDZGNMSBZCIM-XGEHTFHBSA-N Ser-Arg-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(O)=O OYEDZGNMSBZCIM-XGEHTFHBSA-N 0.000 description 2
- VGNYHOBZJKWRGI-CIUDSAMLSA-N Ser-Asn-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CO VGNYHOBZJKWRGI-CIUDSAMLSA-N 0.000 description 2
- YMTLKLXDFCSCNX-BYPYZUCNSA-N Ser-Gly-Gly Chemical compound OC[C@H](N)C(=O)NCC(=O)NCC(O)=O YMTLKLXDFCSCNX-BYPYZUCNSA-N 0.000 description 2
- GZFAWAQTEYDKII-YUMQZZPRSA-N Ser-Gly-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CO GZFAWAQTEYDKII-YUMQZZPRSA-N 0.000 description 2
- UIGMAMGZOJVTDN-WHFBIAKZSA-N Ser-Gly-Ser Chemical compound OC[C@H](N)C(=O)NCC(=O)N[C@@H](CO)C(O)=O UIGMAMGZOJVTDN-WHFBIAKZSA-N 0.000 description 2
- QYSFWUIXDFJUDW-DCAQKATOSA-N Ser-Leu-Arg Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O QYSFWUIXDFJUDW-DCAQKATOSA-N 0.000 description 2
- YUJLIIRMIAGMCQ-CIUDSAMLSA-N Ser-Leu-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O YUJLIIRMIAGMCQ-CIUDSAMLSA-N 0.000 description 2
- MUJQWSAWLLRJCE-KATARQTJSA-N Ser-Leu-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O MUJQWSAWLLRJCE-KATARQTJSA-N 0.000 description 2
- GZSZPKSBVAOGIE-CIUDSAMLSA-N Ser-Lys-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O GZSZPKSBVAOGIE-CIUDSAMLSA-N 0.000 description 2
- FPCGZYMRFFIYIH-CIUDSAMLSA-N Ser-Lys-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(O)=O FPCGZYMRFFIYIH-CIUDSAMLSA-N 0.000 description 2
- HHJFMHQYEAAOBM-ZLUOBGJFSA-N Ser-Ser-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(O)=O HHJFMHQYEAAOBM-ZLUOBGJFSA-N 0.000 description 2
- PPCZVWHJWJFTFN-ZLUOBGJFSA-N Ser-Ser-Asp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(O)=O PPCZVWHJWJFTFN-ZLUOBGJFSA-N 0.000 description 2
- JCLAFVNDBJMLBC-JBDRJPRFSA-N Ser-Ser-Ile Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O JCLAFVNDBJMLBC-JBDRJPRFSA-N 0.000 description 2
- XQJCEKXQUJQNNK-ZLUOBGJFSA-N Ser-Ser-Ser Chemical compound OC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O XQJCEKXQUJQNNK-ZLUOBGJFSA-N 0.000 description 2
- VGQVAVQWKJLIRM-FXQIFTODSA-N Ser-Ser-Val Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O VGQVAVQWKJLIRM-FXQIFTODSA-N 0.000 description 2
- RXUOAOOZIWABBW-XGEHTFHBSA-N Ser-Thr-Arg Chemical compound OC[C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@H](C(O)=O)CCCN=C(N)N RXUOAOOZIWABBW-XGEHTFHBSA-N 0.000 description 2
- PCJLFYBAQZQOFE-KATARQTJSA-N Ser-Thr-Lys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CO)N)O PCJLFYBAQZQOFE-KATARQTJSA-N 0.000 description 2
- RCOUFINCYASMDN-GUBZILKMSA-N Ser-Val-Met Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCSC)C(O)=O RCOUFINCYASMDN-GUBZILKMSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- ASJDFGOPDCVXTG-KATARQTJSA-N Thr-Cys-Leu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(C)C)C(O)=O ASJDFGOPDCVXTG-KATARQTJSA-N 0.000 description 2
- KWQBJOUOSNJDRR-XAVMHZPKSA-N Thr-Cys-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CS)C(=O)N1CCC[C@@H]1C(=O)O)N)O KWQBJOUOSNJDRR-XAVMHZPKSA-N 0.000 description 2
- DSLHSTIUAPKERR-XGEHTFHBSA-N Thr-Cys-Val Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(=O)N[C@@H](C(C)C)C(O)=O DSLHSTIUAPKERR-XGEHTFHBSA-N 0.000 description 2
- FIFDDJFLNVAVMS-RHYQMDGZSA-N Thr-Leu-Met Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(O)=O FIFDDJFLNVAVMS-RHYQMDGZSA-N 0.000 description 2
- NCXVJIQMWSGRHY-KXNHARMFSA-N Thr-Leu-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N1CCC[C@@H]1C(=O)O)N)O NCXVJIQMWSGRHY-KXNHARMFSA-N 0.000 description 2
- BDGBHYCAZJPLHX-HJGDQZAQSA-N Thr-Lys-Asn Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(O)=O BDGBHYCAZJPLHX-HJGDQZAQSA-N 0.000 description 2
- DXPURPNJDFCKKO-RHYQMDGZSA-N Thr-Lys-Val Chemical compound CC(C)[C@H](NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)[C@@H](C)O)C(O)=O DXPURPNJDFCKKO-RHYQMDGZSA-N 0.000 description 2
- MEBDIIKMUUNBSB-RPTUDFQQSA-N Thr-Phe-Tyr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O MEBDIIKMUUNBSB-RPTUDFQQSA-N 0.000 description 2
- MROIJTGJGIDEEJ-RCWTZXSCSA-N Thr-Pro-Pro Chemical compound C[C@@H](O)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 MROIJTGJGIDEEJ-RCWTZXSCSA-N 0.000 description 2
- BEZTUFWTPVOROW-KJEVXHAQSA-N Thr-Tyr-Arg Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N)O BEZTUFWTPVOROW-KJEVXHAQSA-N 0.000 description 2
- UKINEYBQXPMOJO-UBHSHLNASA-N Trp-Asn-Ser Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CO)C(=O)O)N UKINEYBQXPMOJO-UBHSHLNASA-N 0.000 description 2
- DQDXHYIEITXNJY-BPUTZDHNSA-N Trp-Gln-Gln Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N DQDXHYIEITXNJY-BPUTZDHNSA-N 0.000 description 2
- SVGAWGVHFIYAEE-JSGCOSHPSA-N Trp-Gly-Gln Chemical compound C1=CC=C2C(C[C@H](N)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(O)=O)=CNC2=C1 SVGAWGVHFIYAEE-JSGCOSHPSA-N 0.000 description 2
- MBLJBGZWLHTJBH-SZMVWBNQSA-N Trp-Val-Arg Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O)=CNC2=C1 MBLJBGZWLHTJBH-SZMVWBNQSA-N 0.000 description 2
- 206010054094 Tumour necrosis Diseases 0.000 description 2
- SCCKSNREWHMKOJ-SRVKXCTJSA-N Tyr-Asn-Ser Chemical compound N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(O)=O SCCKSNREWHMKOJ-SRVKXCTJSA-N 0.000 description 2
- SINRIKQYQJRGDQ-MEYUZBJRSA-N Tyr-Lys-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 SINRIKQYQJRGDQ-MEYUZBJRSA-N 0.000 description 2
- YYLHVUCSTXXKBS-IHRRRGAJSA-N Tyr-Pro-Ser Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O YYLHVUCSTXXKBS-IHRRRGAJSA-N 0.000 description 2
- MQGGXGKQSVEQHR-KKUMJFAQSA-N Tyr-Ser-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 MQGGXGKQSVEQHR-KKUMJFAQSA-N 0.000 description 2
- NHOVZGFNTGMYMI-KKUMJFAQSA-N Tyr-Ser-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 NHOVZGFNTGMYMI-KKUMJFAQSA-N 0.000 description 2
- RIVVDNTUSRVTQT-IRIUXVKKSA-N Tyr-Thr-Gln Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)N)O RIVVDNTUSRVTQT-IRIUXVKKSA-N 0.000 description 2
- 241000700618 Vaccinia virus Species 0.000 description 2
- GNWUWQAVVJQREM-NHCYSSNCSA-N Val-Asn-His Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N GNWUWQAVVJQREM-NHCYSSNCSA-N 0.000 description 2
- QHDXUYOYTPWCSK-RCOVLWMOSA-N Val-Asp-Gly Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)NCC(=O)O)N QHDXUYOYTPWCSK-RCOVLWMOSA-N 0.000 description 2
- COSLEEOIYRPTHD-YDHLFZDLSA-N Val-Asp-Tyr Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 COSLEEOIYRPTHD-YDHLFZDLSA-N 0.000 description 2
- WDIGUPHXPBMODF-UMNHJUIQSA-N Val-Glu-Pro Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N1CCC[C@@H]1C(=O)O)N WDIGUPHXPBMODF-UMNHJUIQSA-N 0.000 description 2
- UEHRGZCNLSWGHK-DLOVCJGASA-N Val-Glu-Val Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O UEHRGZCNLSWGHK-DLOVCJGASA-N 0.000 description 2
- PIFJAFRUVWZRKR-QMMMGPOBSA-N Val-Gly-Gly Chemical compound CC(C)[C@H]([NH3+])C(=O)NCC(=O)NCC([O-])=O PIFJAFRUVWZRKR-QMMMGPOBSA-N 0.000 description 2
- ZIGZPYJXIWLQFC-QTKMDUPCSA-N Val-His-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CN=CN1)NC(=O)[C@H](C(C)C)N)O ZIGZPYJXIWLQFC-QTKMDUPCSA-N 0.000 description 2
- XTDDIVQWDXMRJL-IHRRRGAJSA-N Val-Leu-His Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](C(C)C)N XTDDIVQWDXMRJL-IHRRRGAJSA-N 0.000 description 2
- SYSWVVCYSXBVJG-RHYQMDGZSA-N Val-Leu-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C(C)C)N)O SYSWVVCYSXBVJG-RHYQMDGZSA-N 0.000 description 2
- HPANGHISDXDUQY-ULQDDVLXSA-N Val-Lys-Phe Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)N HPANGHISDXDUQY-ULQDDVLXSA-N 0.000 description 2
- KRAHMIJVUPUOTQ-DCAQKATOSA-N Val-Ser-His Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N KRAHMIJVUPUOTQ-DCAQKATOSA-N 0.000 description 2
- JAIZPWVHPQRYOU-ZJDVBMNYSA-N Val-Thr-Thr Chemical compound C[C@H]([C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)O)NC(=O)[C@H](C(C)C)N)O JAIZPWVHPQRYOU-ZJDVBMNYSA-N 0.000 description 2
- OWFGFHQMSBTKLX-UFYCRDLUSA-N Val-Tyr-Tyr Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CC2=CC=C(C=C2)O)C(=O)O)N OWFGFHQMSBTKLX-UFYCRDLUSA-N 0.000 description 2
- ZLNYBMWGPOKSLW-LSJOCFKGSA-N Val-Val-Asp Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O ZLNYBMWGPOKSLW-LSJOCFKGSA-N 0.000 description 2
- LLJLBRRXKZTTRD-GUBZILKMSA-N Val-Val-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(=O)O)N LLJLBRRXKZTTRD-GUBZILKMSA-N 0.000 description 2
- 230000002745 absorbent Effects 0.000 description 2
- 239000002250 absorbent Substances 0.000 description 2
- 108010081667 aflibercept Proteins 0.000 description 2
- 108010069020 alanyl-prolyl-glycine Proteins 0.000 description 2
- 108010086434 alanyl-seryl-glycine Proteins 0.000 description 2
- -1 alkaline earth metal carbonates Chemical class 0.000 description 2
- 108010050025 alpha-glutamyltryptophan Proteins 0.000 description 2
- 108010008355 arginyl-glutamine Proteins 0.000 description 2
- 108010052670 arginyl-glutamyl-glutamic acid Proteins 0.000 description 2
- 239000011324 bead Substances 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 229960005395 cetuximab Drugs 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 208000017763 cutaneous neuroendocrine carcinoma Diseases 0.000 description 2
- 230000009089 cytolysis Effects 0.000 description 2
- 230000006866 deterioration Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- MWRBNPKJOOWZPW-CLFAGFIQSA-N dioleoyl phosphatidylethanolamine Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(COP(O)(=O)OCCN)OC(=O)CCCCCCC\C=C/CCCCCCCC MWRBNPKJOOWZPW-CLFAGFIQSA-N 0.000 description 2
- 229960002949 fluorouracil Drugs 0.000 description 2
- 108010078144 glutaminyl-glycine Proteins 0.000 description 2
- 108010000434 glycyl-alanyl-leucine Proteins 0.000 description 2
- 108010067216 glycyl-glycyl-glycine Proteins 0.000 description 2
- XKUKSGPZAADMRA-UHFFFAOYSA-N glycyl-glycyl-glycine Natural products NCC(=O)NCC(=O)NCC(O)=O XKUKSGPZAADMRA-UHFFFAOYSA-N 0.000 description 2
- 108010010096 glycyl-glycyl-tyrosine Proteins 0.000 description 2
- 108010050475 glycyl-leucyl-tyrosine Proteins 0.000 description 2
- 108010050848 glycylleucine Proteins 0.000 description 2
- 108010037850 glycylvaline Proteins 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 201000010536 head and neck cancer Diseases 0.000 description 2
- 208000014829 head and neck neoplasm Diseases 0.000 description 2
- 231100000869 headache Toxicity 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 2
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 239000002050 international nonproprietary name Substances 0.000 description 2
- XMBWDFGMSWQBCA-RNFDNDRNSA-M iodine-131(1-) Chemical compound [131I-] XMBWDFGMSWQBCA-RNFDNDRNSA-M 0.000 description 2
- 229960005386 ipilimumab Drugs 0.000 description 2
- 229960004768 irinotecan Drugs 0.000 description 2
- 108010044374 isoleucyl-tyrosine Proteins 0.000 description 2
- 108010044311 leucyl-glycyl-glycine Proteins 0.000 description 2
- 108010073472 leucyl-prolyl-proline Proteins 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000003589 local anesthetic agent Substances 0.000 description 2
- 108010064235 lysylglycine Proteins 0.000 description 2
- 108010017391 lysylvaline Proteins 0.000 description 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 210000004379 membrane Anatomy 0.000 description 2
- 230000001394 metastastic effect Effects 0.000 description 2
- 239000000693 micelle Substances 0.000 description 2
- 239000004005 microsphere Substances 0.000 description 2
- 230000017074 necrotic cell death Effects 0.000 description 2
- 229960003301 nivolumab Drugs 0.000 description 2
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 2
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 2
- 229960001756 oxaliplatin Drugs 0.000 description 2
- 201000002528 pancreatic cancer Diseases 0.000 description 2
- 208000008443 pancreatic carcinoma Diseases 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 229960002621 pembrolizumab Drugs 0.000 description 2
- 108010024654 phenylalanyl-prolyl-alanine Proteins 0.000 description 2
- 239000013612 plasmid Substances 0.000 description 2
- 108010020755 prolyl-glycyl-glycine Proteins 0.000 description 2
- 108010070643 prolylglutamic acid Proteins 0.000 description 2
- 108010053725 prolylvaline Proteins 0.000 description 2
- 230000000069 prophylactic effect Effects 0.000 description 2
- 229960002633 ramucirumab Drugs 0.000 description 2
- FNHKPVJBJVTLMP-UHFFFAOYSA-N regorafenib Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=C(F)C(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 FNHKPVJBJVTLMP-UHFFFAOYSA-N 0.000 description 2
- 230000010076 replication Effects 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 108010048397 seryl-lysyl-leucine Proteins 0.000 description 2
- 210000003491 skin Anatomy 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 238000010561 standard procedure Methods 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 206010044412 transitional cell carcinoma Diseases 0.000 description 2
- 230000032258 transport Effects 0.000 description 2
- 229960003962 trifluridine Drugs 0.000 description 2
- VSQQQLOSPVPRAZ-RRKCRQDMSA-N trifluridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(C(F)(F)F)=C1 VSQQQLOSPVPRAZ-RRKCRQDMSA-N 0.000 description 2
- 108010080629 tryptophan-leucine Proteins 0.000 description 2
- 230000004614 tumor growth Effects 0.000 description 2
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 2
- 108010052774 valyl-lysyl-glycyl-phenylalanyl-tyrosine Proteins 0.000 description 2
- 108010073969 valyllysine Proteins 0.000 description 2
- 108010027345 wheylin-1 peptide Proteins 0.000 description 2
- UCTWMZQNUQWSLP-VIFPVBQESA-N (R)-adrenaline Chemical compound CNC[C@H](O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-VIFPVBQESA-N 0.000 description 1
- 229930182837 (R)-adrenaline Natural products 0.000 description 1
- LEBVLXFERQHONN-UHFFFAOYSA-N 1-butyl-N-(2,6-dimethylphenyl)piperidine-2-carboxamide Chemical compound CCCCN1CCCCC1C(=O)NC1=C(C)C=CC=C1C LEBVLXFERQHONN-UHFFFAOYSA-N 0.000 description 1
- CPKVUHPKYQGHMW-UHFFFAOYSA-N 1-ethenylpyrrolidin-2-one;molecular iodine Chemical compound II.C=CN1CCCC1=O CPKVUHPKYQGHMW-UHFFFAOYSA-N 0.000 description 1
- LDGWQMRUWMSZIU-LQDDAWAPSA-M 2,3-bis[(z)-octadec-9-enoxy]propyl-trimethylazanium;chloride Chemical compound [Cl-].CCCCCCCC\C=C/CCCCCCCCOCC(C[N+](C)(C)C)OCCCCCCCC\C=C/CCCCCCCC LDGWQMRUWMSZIU-LQDDAWAPSA-M 0.000 description 1
- KSXTUUUQYQYKCR-LQDDAWAPSA-M 2,3-bis[[(z)-octadec-9-enoyl]oxy]propyl-trimethylazanium;chloride Chemical compound [Cl-].CCCCCCCC\C=C/CCCCCCCC(=O)OCC(C[N+](C)(C)C)OC(=O)CCCCCCC\C=C/CCCCCCCC KSXTUUUQYQYKCR-LQDDAWAPSA-M 0.000 description 1
- PLIXOHWIPDGJEI-OJSHLMAWSA-N 5-chloro-6-[(2-iminopyrrolidin-1-yl)methyl]-1h-pyrimidine-2,4-dione;1-[(2r,4s,5r)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-5-(trifluoromethyl)pyrimidine-2,4-dione;hydrochloride Chemical compound Cl.N1C(=O)NC(=O)C(Cl)=C1CN1C(=N)CCC1.C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(C(F)(F)F)=C1 PLIXOHWIPDGJEI-OJSHLMAWSA-N 0.000 description 1
- 206010000077 Abdominal mass Diseases 0.000 description 1
- 206010001367 Adrenal insufficiency Diseases 0.000 description 1
- KIUYPHAMDKDICO-WHFBIAKZSA-N Ala-Asp-Gly Chemical compound C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(O)=O KIUYPHAMDKDICO-WHFBIAKZSA-N 0.000 description 1
- SMCGQGDVTPFXKB-XPUUQOCRSA-N Ala-Gly-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)CNC(=O)[C@H](C)N SMCGQGDVTPFXKB-XPUUQOCRSA-N 0.000 description 1
- BTRULDJUUVGRNE-DCAQKATOSA-N Ala-Pro-Lys Chemical compound C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(O)=O BTRULDJUUVGRNE-DCAQKATOSA-N 0.000 description 1
- ARHJJAAWNWOACN-FXQIFTODSA-N Ala-Ser-Val Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O ARHJJAAWNWOACN-FXQIFTODSA-N 0.000 description 1
- PHQXWZGXKAFWAZ-ZLIFDBKOSA-N Ala-Trp-Lys Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@@H](N)C)C(=O)N[C@@H](CCCCN)C(O)=O)=CNC2=C1 PHQXWZGXKAFWAZ-ZLIFDBKOSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 108020005544 Antisense RNA Proteins 0.000 description 1
- BECXEHHOZNFFFX-IHRRRGAJSA-N Arg-Ser-Tyr Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O BECXEHHOZNFFFX-IHRRRGAJSA-N 0.000 description 1
- 206010003445 Ascites Diseases 0.000 description 1
- APHUDFFMXFYRKP-CIUDSAMLSA-N Asn-Asn-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CC(=O)N)N APHUDFFMXFYRKP-CIUDSAMLSA-N 0.000 description 1
- RCFGLXMZDYNRSC-CIUDSAMLSA-N Asn-Lys-Ala Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O RCFGLXMZDYNRSC-CIUDSAMLSA-N 0.000 description 1
- IDUUACUJKUXKKD-VEVYYDQMSA-N Asn-Pro-Thr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)O)C(O)=O IDUUACUJKUXKKD-VEVYYDQMSA-N 0.000 description 1
- WLVLIYYBPPONRJ-GCJQMDKQSA-N Asn-Thr-Ala Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O WLVLIYYBPPONRJ-GCJQMDKQSA-N 0.000 description 1
- DPSUVAPLRQDWAO-YDHLFZDLSA-N Asn-Tyr-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)NC(=O)[C@H](CC(=O)N)N DPSUVAPLRQDWAO-YDHLFZDLSA-N 0.000 description 1
- VAWNQIGQPUOPQW-ACZMJKKPSA-N Asp-Glu-Ala Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(O)=O VAWNQIGQPUOPQW-ACZMJKKPSA-N 0.000 description 1
- ITGFVUYOLWBPQW-KKHAAJSZSA-N Asp-Thr-Val Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(O)=O ITGFVUYOLWBPQW-KKHAAJSZSA-N 0.000 description 1
- ALMIMUZAWTUNIO-BZSNNMDCSA-N Asp-Tyr-Tyr Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O ALMIMUZAWTUNIO-BZSNNMDCSA-N 0.000 description 1
- 231100000699 Bacterial toxin Toxicity 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 101100263837 Bovine ephemeral fever virus (strain BB7721) beta gene Proteins 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 101100454807 Caenorhabditis elegans lgg-1 gene Proteins 0.000 description 1
- 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 description 1
- 206010008479 Chest Pain Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 206010052358 Colorectal cancer metastatic Diseases 0.000 description 1
- 206010010741 Conjunctivitis Diseases 0.000 description 1
- VPQZSNQICFCCSO-BJDJZHNGSA-N Cys-Leu-Ile Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O VPQZSNQICFCCSO-BJDJZHNGSA-N 0.000 description 1
- YNJBLTDKTMKEET-ZLUOBGJFSA-N Cys-Ser-Ser Chemical compound SC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O YNJBLTDKTMKEET-ZLUOBGJFSA-N 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
- 229920002307 Dextran Polymers 0.000 description 1
- 201000011001 Ebola Hemorrhagic Fever Diseases 0.000 description 1
- 101100316840 Enterobacteria phage P4 Beta gene Proteins 0.000 description 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 208000010201 Exanthema Diseases 0.000 description 1
- 108091006027 G proteins Proteins 0.000 description 1
- 108091000058 GTP-Binding Proteins 0.000 description 1
- 102100039556 Galectin-4 Human genes 0.000 description 1
- RZSLYUUFFVHFRQ-FXQIFTODSA-N Gln-Ala-Glu Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(O)=O RZSLYUUFFVHFRQ-FXQIFTODSA-N 0.000 description 1
- GPISLLFQNHELLK-DCAQKATOSA-N Gln-Gln-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CCC(=O)N)N GPISLLFQNHELLK-DCAQKATOSA-N 0.000 description 1
- KUBFPYIMAGXGBT-ACZMJKKPSA-N Gln-Ser-Ala Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(O)=O KUBFPYIMAGXGBT-ACZMJKKPSA-N 0.000 description 1
- RAUDKMVXNOWDLS-WDSKDSINSA-N Glu-Gly-Ser Chemical compound OC(=O)CC[C@H](N)C(=O)NCC(=O)N[C@@H](CO)C(O)=O RAUDKMVXNOWDLS-WDSKDSINSA-N 0.000 description 1
- CAQXJMUDOLSBPF-SUSMZKCASA-N Glu-Thr-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O CAQXJMUDOLSBPF-SUSMZKCASA-N 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
- SCWYHUQOOFRVHP-MBLNEYKQSA-N Gly-Ile-Thr Chemical compound NCC(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(O)=O SCWYHUQOOFRVHP-MBLNEYKQSA-N 0.000 description 1
- IKAIKUBBJHFNBZ-LURJTMIESA-N Gly-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)CN IKAIKUBBJHFNBZ-LURJTMIESA-N 0.000 description 1
- CUVBTVWFVIIDOC-YEPSODPASA-N Gly-Thr-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)CN CUVBTVWFVIIDOC-YEPSODPASA-N 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 1
- 101000608765 Homo sapiens Galectin-4 Proteins 0.000 description 1
- 241000700588 Human alphaherpesvirus 1 Species 0.000 description 1
- 206010020850 Hyperthyroidism Diseases 0.000 description 1
- YSGBJIQXTIVBHZ-AJNGGQMLSA-N Ile-Lys-Leu Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(O)=O YSGBJIQXTIVBHZ-AJNGGQMLSA-N 0.000 description 1
- FBGXMKUWQFPHFB-JBDRJPRFSA-N Ile-Ser-Cys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)O)N FBGXMKUWQFPHFB-JBDRJPRFSA-N 0.000 description 1
- ZLFNNVATRMCAKN-ZKWXMUAHSA-N Ile-Ser-Gly Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)NCC(=O)O)N ZLFNNVATRMCAKN-ZKWXMUAHSA-N 0.000 description 1
- 206010022004 Influenza like illness Diseases 0.000 description 1
- 206010051792 Infusion related reaction Diseases 0.000 description 1
- 108091008026 Inhibitory immune checkpoint proteins Proteins 0.000 description 1
- 102000037984 Inhibitory immune checkpoint proteins Human genes 0.000 description 1
- 102000004310 Ion Channels Human genes 0.000 description 1
- 239000002138 L01XE21 - Regorafenib Substances 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- VQPPIMUZCZCOIL-GUBZILKMSA-N Leu-Gln-Ala Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(O)=O VQPPIMUZCZCOIL-GUBZILKMSA-N 0.000 description 1
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 description 1
- NNCDAORZCMPZPX-GUBZILKMSA-N Lys-Gln-Ser Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CO)C(=O)O)N NNCDAORZCMPZPX-GUBZILKMSA-N 0.000 description 1
- YTJFXEDRUOQGSP-DCAQKATOSA-N Lys-Pro-Ser Chemical compound [H]N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O YTJFXEDRUOQGSP-DCAQKATOSA-N 0.000 description 1
- SBQDRNOLGSYHQA-YUMQZZPRSA-N Lys-Ser-Gly Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)NCC(O)=O SBQDRNOLGSYHQA-YUMQZZPRSA-N 0.000 description 1
- RIPJMCFGQHGHNP-RHYQMDGZSA-N Lys-Val-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CCCCN)N)O RIPJMCFGQHGHNP-RHYQMDGZSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- AFVOKRHYSSFPHC-STECZYCISA-N Met-Ile-Tyr Chemical compound CSCC[C@H](N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 AFVOKRHYSSFPHC-STECZYCISA-N 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 206010051696 Metastases to meninges Diseases 0.000 description 1
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 1
- 101100407308 Mus musculus Pdcd1lg2 gene Proteins 0.000 description 1
- 208000009525 Myocarditis Diseases 0.000 description 1
- 201000002481 Myositis Diseases 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 241000845082 Panama Species 0.000 description 1
- 208000005228 Pericardial Effusion Diseases 0.000 description 1
- 201000007100 Pharyngitis Diseases 0.000 description 1
- ZJPGOXWRFNKIQL-JYJNAYRXSA-N Phe-Pro-Pro Chemical compound C([C@H](N)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(O)=O)C1=CC=CC=C1 ZJPGOXWRFNKIQL-JYJNAYRXSA-N 0.000 description 1
- QTDBZORPVYTRJU-KKXDTOCCSA-N Phe-Tyr-Ala Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](C)C(O)=O QTDBZORPVYTRJU-KKXDTOCCSA-N 0.000 description 1
- 108010089430 Phosphoproteins Proteins 0.000 description 1
- 102000007982 Phosphoproteins Human genes 0.000 description 1
- 208000002151 Pleural effusion Diseases 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- VDGTVWFMRXVQCT-GUBZILKMSA-N Pro-Glu-Gln Chemical compound NC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H]1CCCN1 VDGTVWFMRXVQCT-GUBZILKMSA-N 0.000 description 1
- CLNJSLSHKJECME-BQBZGAKWSA-N Pro-Gly-Ala Chemical compound OC(=O)[C@H](C)NC(=O)CNC(=O)[C@@H]1CCCN1 CLNJSLSHKJECME-BQBZGAKWSA-N 0.000 description 1
- JMVQDLDPDBXAAX-YUMQZZPRSA-N Pro-Gly-Gln Chemical compound NC(=O)CC[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H]1CCCN1 JMVQDLDPDBXAAX-YUMQZZPRSA-N 0.000 description 1
- UIMCLYYSUCIUJM-UWVGGRQHSA-N Pro-Gly-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H]1CCCN1 UIMCLYYSUCIUJM-UWVGGRQHSA-N 0.000 description 1
- OFGUOWQVEGTVNU-DCAQKATOSA-N Pro-Lys-Ala Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O OFGUOWQVEGTVNU-DCAQKATOSA-N 0.000 description 1
- BGWKULMLUIUPKY-BQBZGAKWSA-N Pro-Ser-Gly Chemical compound OC(=O)CNC(=O)[C@H](CO)NC(=O)[C@@H]1CCCN1 BGWKULMLUIUPKY-BQBZGAKWSA-N 0.000 description 1
- IURWWZYKYPEANQ-HJGDQZAQSA-N Pro-Thr-Glu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(O)=O)C(O)=O IURWWZYKYPEANQ-HJGDQZAQSA-N 0.000 description 1
- 108700030875 Programmed Cell Death 1 Ligand 2 Proteins 0.000 description 1
- 102100024213 Programmed cell death 1 ligand 2 Human genes 0.000 description 1
- 108010029485 Protein Isoforms Proteins 0.000 description 1
- 102000001708 Protein Isoforms Human genes 0.000 description 1
- 208000037323 Rare tumor Diseases 0.000 description 1
- 241000702263 Reovirus sp. Species 0.000 description 1
- 241000711931 Rhabdoviridae Species 0.000 description 1
- 239000012891 Ringer solution Substances 0.000 description 1
- 206010039897 Sedation Diseases 0.000 description 1
- OBXVZEAMXFSGPU-FXQIFTODSA-N Ser-Asn-Arg Chemical compound C(C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CO)N)CN=C(N)N OBXVZEAMXFSGPU-FXQIFTODSA-N 0.000 description 1
- OLIJLNWFEQEFDM-SRVKXCTJSA-N Ser-Asp-Phe Chemical compound OC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 OLIJLNWFEQEFDM-SRVKXCTJSA-N 0.000 description 1
- TUYBIWUZWJUZDD-ACZMJKKPSA-N Ser-Cys-Gln Chemical compound OC[C@H](N)C(=O)N[C@@H](CS)C(=O)N[C@H](C(O)=O)CCC(N)=O TUYBIWUZWJUZDD-ACZMJKKPSA-N 0.000 description 1
- XXXAXOWMBOKTRN-XPUUQOCRSA-N Ser-Gly-Val Chemical compound [H]N[C@@H](CO)C(=O)NCC(=O)N[C@@H](C(C)C)C(O)=O XXXAXOWMBOKTRN-XPUUQOCRSA-N 0.000 description 1
- ZOPISOXXPQNOCO-SVSWQMSJSA-N Ser-Ile-Thr Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)O)NC(=O)[C@H](CO)N ZOPISOXXPQNOCO-SVSWQMSJSA-N 0.000 description 1
- MQQBBLVOUUJKLH-HJPIBITLSA-N Ser-Ile-Tyr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O MQQBBLVOUUJKLH-HJPIBITLSA-N 0.000 description 1
- CKDXFSPMIDSMGV-GUBZILKMSA-N Ser-Pro-Val Chemical compound [H]N[C@@H](CO)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(O)=O CKDXFSPMIDSMGV-GUBZILKMSA-N 0.000 description 1
- GYDFRTRSSXOZCR-ACZMJKKPSA-N Ser-Ser-Glu Chemical compound OC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CCC(O)=O GYDFRTRSSXOZCR-ACZMJKKPSA-N 0.000 description 1
- OLKICIBQRVSQMA-SRVKXCTJSA-N Ser-Ser-Tyr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O OLKICIBQRVSQMA-SRVKXCTJSA-N 0.000 description 1
- RTXKJFWHEBTABY-IHPCNDPISA-N Ser-Trp-Tyr Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CC3=CC=C(C=C3)O)C(=O)O)NC(=O)[C@H](CO)N RTXKJFWHEBTABY-IHPCNDPISA-N 0.000 description 1
- UBTNVMGPMYDYIU-HJPIBITLSA-N Ser-Tyr-Ile Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O UBTNVMGPMYDYIU-HJPIBITLSA-N 0.000 description 1
- PLQWGQUNUPMNOD-KKUMJFAQSA-N Ser-Tyr-Leu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(C)C)C(O)=O PLQWGQUNUPMNOD-KKUMJFAQSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- DIPIPFHFLPTCLK-LOKLDPHHSA-N Thr-Gln-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N1CCC[C@@H]1C(=O)O)N)O DIPIPFHFLPTCLK-LOKLDPHHSA-N 0.000 description 1
- KZSYAEWQMJEGRZ-RHYQMDGZSA-N Thr-Leu-Val Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(O)=O KZSYAEWQMJEGRZ-RHYQMDGZSA-N 0.000 description 1
- WPSKTVVMQCXPRO-BWBBJGPYSA-N Thr-Ser-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O WPSKTVVMQCXPRO-BWBBJGPYSA-N 0.000 description 1
- LECUEEHKUFYOOV-ZJDVBMNYSA-N Thr-Thr-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@@H](N)[C@@H](C)O LECUEEHKUFYOOV-ZJDVBMNYSA-N 0.000 description 1
- OGOYMQWIWHGTGH-KZVJFYERSA-N Thr-Val-Ala Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C)C(O)=O OGOYMQWIWHGTGH-KZVJFYERSA-N 0.000 description 1
- KPMIQCXJDVKWKO-IFFSRLJSSA-N Thr-Val-Glu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O KPMIQCXJDVKWKO-IFFSRLJSSA-N 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- ULHASJWZGUEUNN-XIRDDKMYSA-N Trp-Lys-Ser Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(O)=O ULHASJWZGUEUNN-XIRDDKMYSA-N 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- NSTPFWRAIDTNGH-BZSNNMDCSA-N Tyr-Asn-Tyr Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O NSTPFWRAIDTNGH-BZSNNMDCSA-N 0.000 description 1
- WQOHKVRQDLNDIL-YJRXYDGGSA-N Tyr-Thr-Ser Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(O)=O WQOHKVRQDLNDIL-YJRXYDGGSA-N 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- ZLFHAAGHGQBQQN-GUBZILKMSA-N Val-Ala-Pro Natural products CC(C)[C@H](N)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O ZLFHAAGHGQBQQN-GUBZILKMSA-N 0.000 description 1
- UMPVMAYCLYMYGA-ONGXEEELSA-N Val-Leu-Gly Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O UMPVMAYCLYMYGA-ONGXEEELSA-N 0.000 description 1
- CKTMJBPRVQWPHU-JSGCOSHPSA-N Val-Phe-Gly Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)NCC(=O)O)N CKTMJBPRVQWPHU-JSGCOSHPSA-N 0.000 description 1
- TVGWMCTYUFBXAP-QTKMDUPCSA-N Val-Thr-His Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](C(C)C)N)O TVGWMCTYUFBXAP-QTKMDUPCSA-N 0.000 description 1
- LCHZBEUVGAVMKS-RHYQMDGZSA-N Val-Thr-Leu Chemical compound CC(C)C[C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)C(C)C)[C@@H](C)O)C(O)=O LCHZBEUVGAVMKS-RHYQMDGZSA-N 0.000 description 1
- 108010067390 Viral Proteins Proteins 0.000 description 1
- 229930003779 Vitamin B12 Natural products 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- HIHOWBSBBDRPDW-PTHRTHQKSA-N [(3s,8s,9s,10r,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1h-cyclopenta[a]phenanthren-3-yl] n-[2-(dimethylamino)ethyl]carbamate Chemical compound C1C=C2C[C@@H](OC(=O)NCCN(C)C)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HIHOWBSBBDRPDW-PTHRTHQKSA-N 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- 238000002679 ablation Methods 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 210000004100 adrenal gland Anatomy 0.000 description 1
- 208000017515 adrenocortical insufficiency Diseases 0.000 description 1
- 229960002833 aflibercept Drugs 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 229910000318 alkali metal phosphate Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 208000030961 allergic reaction Diseases 0.000 description 1
- KOSRFJWDECSPRO-UHFFFAOYSA-N alpha-L-glutamyl-L-glutamic acid Natural products OC(=O)CCC(N)C(=O)NC(CCC(O)=O)C(O)=O KOSRFJWDECSPRO-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 230000036592 analgesia Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 229940125715 antihistaminic agent Drugs 0.000 description 1
- 230000005975 antitumor immune response Effects 0.000 description 1
- 230000009118 appropriate response Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 108010068265 aspartyltyrosine Proteins 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 229960003852 atezolizumab Drugs 0.000 description 1
- 230000002238 attenuated effect Effects 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 229940120638 avastin Drugs 0.000 description 1
- RRZXIRBKKLTSOM-XPNPUAGNSA-N avermectin B1a Chemical compound C1=C[C@H](C)[C@@H]([C@@H](C)CC)O[C@]11O[C@H](C\C=C(C)\[C@@H](O[C@@H]2O[C@@H](C)[C@H](O[C@@H]3O[C@@H](C)[C@H](O)[C@@H](OC)C3)[C@@H](OC)C2)[C@@H](C)\C=C\C=C/2[C@]3([C@H](C(=O)O4)C=C(C)[C@@H](O)[C@H]3OC\2)O)C[C@H]4C1 RRZXIRBKKLTSOM-XPNPUAGNSA-N 0.000 description 1
- 239000000688 bacterial toxin Substances 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
- 229940064804 betadine Drugs 0.000 description 1
- 229960000397 bevacizumab Drugs 0.000 description 1
- 239000003833 bile salt Substances 0.000 description 1
- 229940093761 bile salts Drugs 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 239000000090 biomarker Substances 0.000 description 1
- 230000002051 biphasic effect Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000007975 buffered saline Substances 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 229960003150 bupivacaine Drugs 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 229940088954 camptosar Drugs 0.000 description 1
- 238000002619 cancer immunotherapy Methods 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000005018 casein Substances 0.000 description 1
- BECPQYXYKAMYBN-UHFFFAOYSA-N casein, tech. Chemical compound NCCCCC(C(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(CC(C)C)N=C(O)C(CCC(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(C(C)O)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(COP(O)(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(N)CC1=CC=CC=C1 BECPQYXYKAMYBN-UHFFFAOYSA-N 0.000 description 1
- 235000021240 caseins Nutrition 0.000 description 1
- 230000004700 cellular uptake Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000013043 chemical agent Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000011976 chest X-ray Methods 0.000 description 1
- 229960003333 chlorhexidine gluconate Drugs 0.000 description 1
- YZIYKJHYYHPJIB-UUPCJSQJSA-N chlorhexidine gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O.C1=CC(Cl)=CC=C1NC(=N)NC(=N)NCCCCCCNC(=N)NC(=N)NC1=CC=C(Cl)C=C1 YZIYKJHYYHPJIB-UUPCJSQJSA-N 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 150000001841 cholesterols Chemical class 0.000 description 1
- AGVAZMGAQJOSFJ-WZHZPDAFSA-M cobalt(2+);[(2r,3s,4r,5s)-5-(5,6-dimethylbenzimidazol-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] [(2r)-1-[3-[(1r,2r,3r,4z,7s,9z,12s,13s,14z,17s,18s,19r)-2,13,18-tris(2-amino-2-oxoethyl)-7,12,17-tris(3-amino-3-oxopropyl)-3,5,8,8,13,15,18,19-octamethyl-2 Chemical compound [Co+2].N#[C-].[N-]([C@@H]1[C@H](CC(N)=O)[C@@]2(C)CCC(=O)NC[C@@H](C)OP(O)(=O)O[C@H]3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)\C2=C(C)/C([C@H](C\2(C)C)CCC(N)=O)=N/C/2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O AGVAZMGAQJOSFJ-WZHZPDAFSA-M 0.000 description 1
- 206010009887 colitis Diseases 0.000 description 1
- 238000001246 colloidal dispersion Methods 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 239000003184 complementary RNA Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000011970 concomitant therapy Methods 0.000 description 1
- 229940124301 concurrent medication Drugs 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 229960001334 corticosteroids Drugs 0.000 description 1
- 230000000120 cytopathologic effect Effects 0.000 description 1
- 230000005860 defense response to virus Effects 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- UMGXUWVIJIQANV-UHFFFAOYSA-M didecyl(dimethyl)azanium;bromide Chemical compound [Br-].CCCCCCCCCC[N+](C)(C)CCCCCCCCCC UMGXUWVIJIQANV-UHFFFAOYSA-M 0.000 description 1
- PSLWZOIUBRXAQW-UHFFFAOYSA-M dimethyl(dioctadecyl)azanium;bromide Chemical compound [Br-].CCCCCCCCCCCCCCCCCC[N+](C)(C)CCCCCCCCCCCCCCCCCC PSLWZOIUBRXAQW-UHFFFAOYSA-M 0.000 description 1
- FSXRLASFHBWESK-UHFFFAOYSA-N dipeptide phenylalanyl-tyrosine Natural products C=1C=C(O)C=CC=1CC(C(O)=O)NC(=O)C(N)CC1=CC=CC=C1 FSXRLASFHBWESK-UHFFFAOYSA-N 0.000 description 1
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical compound C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 1
- 229960000520 diphenhydramine Drugs 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 229940126534 drug product Drugs 0.000 description 1
- 229950009791 durvalumab Drugs 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 229940120655 eloxatin Drugs 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 206010014599 encephalitis Diseases 0.000 description 1
- 208000030172 endocrine system disease Diseases 0.000 description 1
- 239000002158 endotoxin Substances 0.000 description 1
- 229960005139 epinephrine Drugs 0.000 description 1
- 229940082789 erbitux Drugs 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 201000005884 exanthem Diseases 0.000 description 1
- 230000027950 fever generation Effects 0.000 description 1
- 238000009093 first-line therapy Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 108010055341 glutamyl-glutamic acid Proteins 0.000 description 1
- 230000013595 glycosylation Effects 0.000 description 1
- 238000006206 glycosylation reaction Methods 0.000 description 1
- 108010089804 glycyl-threonine Proteins 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 230000005484 gravity Effects 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 108010085325 histidylproline Proteins 0.000 description 1
- 208000003532 hypothyroidism Diseases 0.000 description 1
- 230000002989 hypothyroidism Effects 0.000 description 1
- 229940091204 imlygic Drugs 0.000 description 1
- 230000002163 immunogen Effects 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011503 in vivo imaging Methods 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000002697 interventional radiology Methods 0.000 description 1
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 238000009533 lab test Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 229960004194 lidocaine Drugs 0.000 description 1
- 229920006008 lipopolysaccharide Polymers 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 238000002690 local anesthesia Methods 0.000 description 1
- 229960005015 local anesthetics Drugs 0.000 description 1
- 229940024740 lonsurf Drugs 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 201000003265 lymphadenitis Diseases 0.000 description 1
- 230000001926 lymphatic effect Effects 0.000 description 1
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 206010025482 malaise Diseases 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 238000007726 management method Methods 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 208000004396 mastitis Diseases 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 201000011475 meningoencephalitis Diseases 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 208000037819 metastatic cancer Diseases 0.000 description 1
- 208000011575 metastatic malignant neoplasm Diseases 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 108010085203 methionylmethionine Proteins 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 239000002088 nanocapsule Substances 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 210000000633 nuclear envelope Anatomy 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 239000006179 pH buffering agent Substances 0.000 description 1
- 229960001972 panitumumab Drugs 0.000 description 1
- 229960005547 pelareorep Drugs 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 210000004303 peritoneum Anatomy 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 230000000644 propagated effect Effects 0.000 description 1
- 230000001902 propagating effect Effects 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 206010037844 rash Diseases 0.000 description 1
- 230000007115 recruitment Effects 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 229960004836 regorafenib Drugs 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 208000011727 retrobulbar pain Diseases 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 230000036280 sedation Effects 0.000 description 1
- 108010048818 seryl-histidine Proteins 0.000 description 1
- 108010026333 seryl-proline Proteins 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 238000002603 single-photon emission computed tomography Methods 0.000 description 1
- 206010040882 skin lesion Diseases 0.000 description 1
- 231100000444 skin lesion Toxicity 0.000 description 1
- 239000008354 sodium chloride injection Substances 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- PFNFFQXMRSDOHW-UHFFFAOYSA-N spermine Chemical class NCCCNCCCCNCCCN PFNFFQXMRSDOHW-UHFFFAOYSA-N 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 238000011272 standard treatment Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 229940090374 stivarga Drugs 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000003319 supportive effect Effects 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 229950008461 talimogene laherparepvec Drugs 0.000 description 1
- 230000002123 temporal effect Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 108010071097 threonyl-lysyl-proline Proteins 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 230000036962 time dependent Effects 0.000 description 1
- QQHMKNYGKVVGCZ-UHFFFAOYSA-N tipiracil Chemical compound N1C(=O)NC(=O)C(Cl)=C1CN1C(=N)CCC1 QQHMKNYGKVVGCZ-UHFFFAOYSA-N 0.000 description 1
- 229960002952 tipiracil Drugs 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 230000014599 transmission of virus Effects 0.000 description 1
- WFKWXMTUELFFGS-UHFFFAOYSA-N tungsten Chemical compound [W] WFKWXMTUELFFGS-UHFFFAOYSA-N 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
- 239000010937 tungsten Substances 0.000 description 1
- 239000011123 type I (borosilicate glass) Substances 0.000 description 1
- 241000701161 unidentified adenovirus Species 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 230000017613 viral reproduction Effects 0.000 description 1
- 235000019163 vitamin B12 Nutrition 0.000 description 1
- 239000011715 vitamin B12 Substances 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229940036061 zaltrap Drugs 0.000 description 1
Images
Classifications
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
- C07K16/2827—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against B7 molecules, e.g. CD80, CD86
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/66—Microorganisms or materials therefrom
- A61K35/76—Viruses; Subviral particles; Bacteriophages
- A61K35/766—Rhabdovirus, e.g. vesicular stomatitis virus
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/21—Interferons [IFN]
- A61K38/215—IFN-beta
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2760/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses negative-sense
- C12N2760/00011—Details
- C12N2760/20011—Rhabdoviridae
- C12N2760/20211—Vesiculovirus, e.g. vesicular stomatitis Indiana virus
- C12N2760/20241—Use of virus, viral particle or viral elements as a vector
- C12N2760/20243—Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Immunology (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Chemistry (AREA)
- Epidemiology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Gastroenterology & Hepatology (AREA)
- Mycology (AREA)
- Microbiology (AREA)
- Zoology (AREA)
- Virology (AREA)
- Molecular Biology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biochemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Marine Sciences & Fisheries (AREA)
- Dermatology (AREA)
- Endocrinology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Peptides Or Proteins (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
Abstract
本申请涉及治疗癌症的治疗方案和方法,其中所述方案和方法包括向对象施用程序性死亡‑配体1(PD‑L1)抑制剂和经工程化以表达干扰素β的重组水泡性口炎病毒(VSV‑IFNβ‑NIS)。
Description
在ASCII文本文件上提交序列表
以下提交的ASCII文本文件的内容通过引用全文并入本文中:序列表的计算机可读形式(CRF)(文件名:56187-501001WO Sequence Listing_ST25.txt,创建日期:2019年4月8日;大小:11030字节)。
发明背景
发明领域
本申请涉及治疗癌症的治疗方案和方法,其中所述方案和方法包括向对象施用程序性死亡-配体1(PD-L1)抑制剂和经工程化以表达干扰素β和钠/碘同向转运体的重组水泡性口炎病毒(rVSV)(VSV-IFNβ-NIS)。
发明背景
2015年,据估计美国诊断出1658370例新的癌症病例,并发生589430例癌症死亡。2004至2010年所有癌症诊断的5年相对存活率仅为68%。此外,一些癌症的预后非常悲观,其中胰腺癌的5年相对存活率为7%,肝癌、肺癌和食道癌的5年相对存活率低于20%;具有远处转移的晚期恶性肿瘤的5年相对存活率在2%(对于胰腺癌)至55%(对于甲状腺癌)的范围内。
对于大多数患有转移性和/或晚期癌症的患者,化疗仍然是标准的治疗选择。但不幸的是,对于许多患者,化疗并没有疗效,并且他们的疾病将变成难治性的。患有难治性、转移性实体瘤的患者的治疗选择很少。一旦患者在标准的一线疗法中发生进展,则二线选择取决于癌症类型而在其疗效中具有显著差异。对于一些癌症(例如,乳腺癌),有很多二线选择,并且允许对于一段时间有合理的临床益处。其他癌症,诸如头颈癌,缺乏有效的二线选择。患有罕见肿瘤的患者通常选择更少。因此,许多患有晚期、无法治愈的癌症的患者会寻求癌症临床试验,希望接受可提供临床益处的新型治疗剂。
癌症免疫疗法是一种迅速兴起的治疗类别,其中当化疗变得无效时,其提供潜在的临床益处。在过去的十年中,已经批准免疫检查点抑制剂,例如,伊匹单抗(ipilimumab)、派姆单抗(pembrolizumab)、阿特朱单抗(atezolizumab)和纳武利尤单抗(nivolumab)。这些批准最初是针对黑色素瘤的,但近来已扩展到其他疾病类型,并且最近批准了额外的药剂,包括阿维单抗(avelumab)和度伐单抗(durvalumab)。这些药剂刺激了免疫疗法在临床管道(clinical pipeline)中的复兴。许多药物正在开发当中,包括溶瘤病毒疗法。
2015年,首个溶瘤病毒疗法Imlygic(talimogene Laherparepvec)被批准用在患有局部晚期黑色素瘤的患者中。为了进一步了解其安全性和疗效,必须在患有难治性实体瘤的患者中评估溶瘤病毒。目前,T-Vec(一种编码粒细胞-巨噬细胞集落刺激因子的溶瘤性单纯疱疹病毒1型)已被FDA批准用于治疗无法手术切除的黑色素瘤,这使其成为在美国的该类别中首例获批的(Andtbacka 2015)。另外三项研究溶瘤病毒疗法的III期试验正在进行中:瘤内施用编码GMCSF的溶瘤痘苗病毒(Pexa-Vec)用于治疗肝细胞癌、膀胱内施用同样编码GMCSF的腺病毒(CG0070)用于治疗膀胱癌,以及用于头颈癌的IV呼肠孤病毒(Reolysin)治疗。在其他溶瘤病毒临床试验中,一项使用瘤内施用表达IFNβ(并且不表达同向转运体)的溶瘤VSV用于治疗肝细胞癌的1期研究已公开并开始招募。
最新的数据显示,将检查点抑制剂与溶瘤病毒组合使用可通过释放新抗原(neoantigen)来增强抗肿瘤免疫应答,这导致有持久客观应答(objective response)的患者比例高于单用检查点抑制剂所预期的。尽管一些研究表明,检查点抑制剂和溶瘤病毒的组合可能是有用的,迄今为止还没有检查由检查点抑制剂和溶瘤病毒组成的组合疗法在人类中用于转移性结肠癌的研究。
发明内容
本申请涉及治疗转移性结肠癌的方法,其中所述方法包括向对象施用程序性死亡-配体1(PD-L1)抑制剂和经工程化以表达干扰素β和钠/碘同向转运体的重组水泡性口炎病毒(VSV-IFNβ-NIS)。
本申请还涉及用于治疗转移性结肠癌的后续治疗方案,所述治疗方案包括PD-L1抑制剂和经工程化以表达干扰素β和钠/碘同向转运体的重组水泡性口炎病毒(VSV-IFNβ-NIS)。
本申请还涉及试剂盒,所述试剂盒包含PD-L1抑制剂、VSV-IFNβ-NIS,以及包装说明书,所述包装说明书包括使用PD-L1抑制剂和VSV-IFNβ-NIS来在对象中治疗转移性结肠癌或延迟转移性结肠癌的进展的说明。
附图说明
图1示出了阿维单抗抗体的序列。互补决定区(CDR)带有下划线,并且无下划线的中间区表示框架区。阿维单抗的重链(SEQ ID NO:7)的带下划线的部分依次分别是重链的CRD 1-3,并且在本文中也是SEQ ID No:1-3。阿维单抗的轻链(SEQ ID NO:9)的带下划线的部分依次分别是轻链的CRD 1-3,并且在本文中也是SEQ ID No:4-6。
图2示出了用于转移性结肠癌的组合疗法的研究设计。
发明详述
本申请涉及治疗转移性结肠癌的方法,其中所述方法包括向对象施用程序性死亡-配体1(PD-L1)抑制剂和经工程化以表达干扰素β和钠/碘同向转运体的重组水泡性口炎病毒(VSV-IFNβ-NIS)。在本发明中,术语对象和患者可互换使用。
本申请还涉及用于治疗转移性结肠癌的后续治疗方案,所述治疗方案包括PD-L1抑制剂和经工程化以表达干扰素β和钠/碘同向转运体的重组水泡性口炎病毒(VSV-IFNβ-NIS)。
人感染野生型VSV通常是无症状的,但会引起急性、发热、流感样疾病,持续3-6天,特征是发烧(fever)、发冷、恶心、呕吐、头痛、球后痛、肌痛、胸骨下疼痛、不适、咽炎、结膜炎和淋巴结炎。虽然已公布的3岁巴拿马儿童患非致命性脑膜脑炎的病例归因于VSV感染,但在感染野生型VSV的人中通常没有发现并发症且没有死亡的记录。改良的印第安纳株VSV已在埃博拉疫苗接种计划中用于17000多名健康志愿者,使得研究人员得出结论,认为安全特性在健康成年人中是可接受的。基于VSV的疫苗通常被良好地耐受,并且很少有疫苗相关不良事件的报道。常见的不良事件包括头痛、发热(pyrexia)、疲劳和肌痛,其中大多数为轻度至中度,并且通常持续时间短。既没有看到活病毒脱落,也没有发现人与人之间的传播。
水泡性口炎病毒是弹状病毒科的成员。VSV基因组是编码以下五个主要多肽的反义RNA的单分子:核衣壳(N)多肽、磷蛋白(P)多肽、基质(M)多肽、糖蛋白(G)多肽和病毒聚合酶(L)多肽。本文提供的编码VSV N多肽、VSV P多肽、VSV M多肽、VSV G多肽和VSV L多肽的水泡性口炎病毒的核酸序列可来自于GenBank登录号NC_001560(GI No.9627229)所示的VSV印第安纳株,或可来自于VSV新泽西株。
在一个实施方案中,本发明的方法和方案包括施用VSV-IFNβ-NIS。VSV-IFNβ-NIS是一种经工程化以表达人干扰素β(hIFNβ)基因和甲状腺钠碘同向转运体(NIS)的活病毒。该病毒通过向印第安纳株水泡性口炎病毒(VSV)的全长感染性分子克隆中在M基因下游插入hIFNβ基因和在G蛋白基因下游插入NIS基因(cDNA)来进行构建。PCT/US2011/050227中描述了VSV-IFNβ-NIS,其通过引用并入本文。VSV-IFNβ-NIS是包含RNA分子的病毒。编码VSV-IFNβ-NIS的RNA在3'至5'的方向上包含以下各项或基本由以下各项组成:作为编码VSV N多肽的正义转录本的模板的核酸序列、作为编码VSV P多肽的正义转录本的模板的核酸序列、作为编码VSV M多肽的正义转录本的模板的核酸序列、作为编码人IFNβ多肽的正义转录本的模板的核酸序列、作为编码VSV G多肽的正义转录本的模板的核酸序列、作为编码人NIS多肽的正义转录本的模板的核酸序列,以及作为编码VSV L多肽的正义转录本的模板的核酸序列。当病毒感染哺乳动物细胞时,病毒可表达IFNβ多肽和NIS多肽。但是,这种病毒不被视为疫苗。
编码VSV-IFNβ-NIS的人NIS多肽的核酸序列如GenBank登录号NM_000453.2(GINo.164663746)、BC105049.1(GI No.85397913)或BC105047.1(GI No.85397519)所示,它们全部通过引用并入本文。编码VSV-IFNβ-NIS的人IFNβ多肽的核酸如GenBank登录号NM_002176.2(GI No.50593016)所示。
VSV-IFNβ-NIS在BHK细胞上繁殖(其动力学与病毒的亲代菌株相似),并且可以生长至高滴度。它在人癌细胞中选择性繁殖,因为它们中的许多细胞无法引起通过IFN途径介导的有效抗病毒应答。但是,感染的细胞中产生的IFN可以保护非癌细胞免受病毒的影响。因此,病毒直接对肿瘤细胞具有细胞病变效应,导致随着病毒的扩增而迅速溶胞(lysis)。被VSV-IFNβ-NIS感染的肿瘤细胞也表达NIS(主动将碘转运到细胞中的膜离子通道)。表达NIS的细胞对放射性碘的摄取为99mTc高锝酸盐或放射性碘I-123的体内成像提供了基础,该成像可以揭示病毒传播和消除过程中VSV-IFNβ-NIS基因表达的时间依赖特性和VSV-IFNβ-NIS感染细胞的位置。
已经工程化了另一种VSV,以仅表达人干扰素β(hIFNβ)基因而不表达同向转运体(VSV-IFNβ)。该VSV-IFNβ完全是不同的载体,并且本领域技术人员应当理解,VSV-IFNβ和VSV-IFNβ-NIS之间的差异不仅仅是简单地是否包含同向转运体。例如,在VSV-IFNβ-NIS和VSV-IFNβ之间,IFNβ转基因位置不同,并且这种位置影响病毒的生命周期。事实上,VSV-IFNβ-NIS的复制要比VSV-IFNβ慢得多,并且复制上的这种差异可以直接影响VSV介导治疗的安全性和疗效。因此,本发明的方法和方案不包括使用VSV-IFNβ,而是包括使用VSV-IFNβ-NIS。
在本发明的方法和方案的某些实施方案中,PD-L1抑制剂包含特异性结合PD-L1的抗体或其抗原结合片段。在具体实施方案中,抗PD-L1抗体或其片段包含重链和轻链,其中所述重链包含分别具有SEQ ID NO:1、SEQ ID NO:2和SEQ ID NO:3的氨基酸序列的三个互补决定区(CDR),并且所述轻链包含分别具有SEQ ID NO:4、SEQ ID NO:5和SEQ ID NO:6的氨基酸序列的三个CDR。
阿维单抗的重链CDR序列
CDR1-SYIMM(SEQ ID NO:1)
CDR2-SIYPSGGITF YADTVKG(SEQ ID NO:2)
CDR3-IKLGTVTTVDY(SEQ ID NO:3)
阿维单抗的轻链CDR序列
CDR1-TGTSSDVGGYNYVS(SEQ ID NO:4)
CDR2-DVSNRPS(SEQ ID NO:5)
CDR3-SSYTSSSTRV(SEQ ID NO:6)
在本发明的方法和方案的另一个具体实施方案中,抗PD-L1抗体或其片段包含重链和轻链,其中,所述重链包含SEQ ID NO:7或8的氨基酸序列,并且所述轻链包含SEQ IDNO:9的氨基酸序列。
在具体实施方案中,PD-L1抑制剂是介导抗体依赖性细胞介导细胞毒性(ADCC)的抗体或其片段。在更具体的实施方案中,所述抗PD-L1抑制剂是阿维单抗,其选择性结合PD-L1,并竞争性阻断其与PD-1的相互作用。与靶向T细胞的抗PD-1抗体相比,阿维单抗靶向肿瘤细胞,并因此自身免疫相关的安全性问题的风险可以更低,因为阻断PD-L1可使PD-L2/PD-1途径完整,以促进外周自身耐受性。
阿维单抗(BAVENCIOTM)是特异性靶向和阻断PD-L1的lgG1同种型的完全人类单克隆抗体(mAb)。阿维单抗是抗PD-L1单克隆抗体MSB0010718C的国际非专利药品名称(INN),并且已在PCT公开No.WO 2013/079174中通过其全长重链和轻链序列进行了描述,在该公开中将其称为A09-246-2,并且该公开的全部内容通过引用并入本文中。阿维单抗重链中C端赖氨酸的糖基化和截短在PCT公开No.WO 2017/097407中也进行了描述,该公开的全部内容通过引用并入本文。阿维单抗已经在临床开发中用于治疗梅克尔细胞癌(Merkel CellCarcinoma,MCC)、非小细胞肺癌(NSCLC)、尿路上皮癌(UC)、肾细胞癌(RCC)和许多其他癌症病况。
术语“结肠癌”在本文中可与“结肠直肠癌”互换使用。在本发明的方法和方案的某些实施方案中,对象已诊断出患有结肠癌。结肠癌可以处于任何阶段。在所选实施方案中,对象诊断出患有0期、1期、2期(及2A、2B、2C期)、3期(3A、3B、3C期中的任何)或4期(4A、4B期中的任何)结肠癌。在具体实施方案中,对象诊断出患有转移性结肠癌。术语“转移性”包括扩散到一个或多个淋巴结以及扩散到一个或多个器官或组织的癌症。在一个具体实施方案中,使用本文所公开的方法和方案治疗的转移性结肠癌是已经扩散到不在结肠附近的一个或多个器官或组织或扩散到一个或多个远处淋巴结的转移性结肠癌。在其他具体实施方案中,使用本文所公开的方法和方案治疗的转移性结肠癌已经扩散到选自肺、肾、肝、卵巢、脑、腹膜、骨、肾上腺和肌肉的至少一个器官或组织。
本文所使用的术语治疗是指本文所述的方法的执行或方案的施用以减轻任何症状(例如但不限于肿瘤生长或扩散),或防止出现额外的症状。术语“延迟进展”用于表示,症状(例如,肿瘤生长或扩散)没有随时间而增加。
本发明的方法和方案还包括在对象接受至少一线、二线或三线结肠癌疗法后,在疾病进展后向对象施用PD-L1抑制剂和VSV-IFNβ-NIS。换言之,还预期在一线结肠癌疗法已经失败并且疾病已经进展之后,应用所述方法和方案。还预期在一线和二线结肠癌疗法已经失败并且疾病已经进展之后,应用所述方法和方案。还预期在一线、二线和三线结肠癌疗法已经失败并且疾病已经进展之后,应用所述方法和方案。
如本文所用,术语“疾病进展”是指,在对象已经接受至少一线、二线或三线结肠癌疗法后,癌症继续生长或扩散。疾病进展还可以包括在对象已经接受至少一线、二线或三线结肠癌疗法后,癌症肿瘤没有收缩或变小(即,生长静止)的情况。疾病进展还可包括在对象已经接受至少一线、二线或三线结肠癌疗法后,对象中可检测肿瘤的数量增加的情况。疾病进展还包括对象从先前的疗法的线中得到缓解,并且癌症,甚至是单个生长物或肿瘤,再次变得可检测的情况。在缓解期后可检测到的癌症并不一定可在结肠或周围组织或淋巴结内检测到,因为通常在缓解期后变得可检测的癌症可能返回到与结肠不同的器官或组织。本发明的方法和方案包括在对象接受至少一线、二线或三线结肠癌疗法后,在疾病进展后向对象施用PD-L1抑制剂和VSV-IFNβ-NIS,其中疾病进展使得癌症已经返回到结肠和/或紧邻的淋巴结以外的身体的不同器官或组织。当然,本发明的方法和方案包括在对象接受至少一线、二线或三线结肠癌疗法后,在疾病进展后向对象施用PD-L1抑制剂和VSV-IFNβ-NIS,其中疾病进展使得癌症返回到结肠和/或紧邻的淋巴结。
在所选实施方案中,在应用本文所述的方法和方案之前施用的这些一线、二线或三线结肠癌疗法包括施用选自由以下组成的组的至少一种治疗化合物:5-氟尿嘧啶(5-FU)、卡培他滨(Capecitabine,XELODATM)、伊立替康(Irinotecan,CAMPTOSARTM)、奥沙利铂(Oxaliplatin,ELOXATINTM)、三氟尿苷(Trifluridine)、Tipiracil(LONSURFTM)、帕尼单抗(Panitumumab,VECTIBIXTM)、西妥昔单抗(Cetuximab,ERBITUXTM)、贝伐单抗(Bevacizumab,AVASTINTM)、雷莫芦单抗(Ramucirumab,CYRAMZATM)、阿柏西普(Aflibercept,ZALTRAPTM)、瑞格非尼(Regorafenib,STIVARGATM)和阿维单抗(BAVENCIOTM)。
在所选实施方案中,在应用本文所述的方法和方案之前施用的这些一线、二线或三线结肠癌疗法包括放疗。
如本文所用,术语“施用”是指在对象内或对象上引入治疗剂。VSV-IFNβ-NIS和PD-L1抑制剂各自的施用途径可以相同或彼此不同。VSV-IFNβ-NIS和/或PD-L1抑制剂的施用途径包括但不限于静脉内(IV)、瘤内(IT)、腹膜内(IP)、肌内(IM)、皮下、口服、经鼻或直肠。
在具体实施方案中,将PD-L1抑制剂(例如,阿维单抗)以静脉内(IV)或瘤内(IT)或两者施用于对象。在一个具体实施方案中,将PD-L1抑制剂(例如,阿维单抗)静脉内施用于对象。PD-L1抑制剂(例如,阿维单抗)的总剂量可以以每次施用至少约200mg、300mg、400mg、600mg、800mg、1000mg、1200mg、1400mg、1600mg、1800mg或2000mg的量施用。当然,临床医生可以将阿维单抗(一般来说是在盐水溶液中)的浓度调节在约5mg/kg至约20mg/kg的范围内。在具体实施方案中,可以以至少约5mg/kg、至少约6mg/kg、至少约7mg/kg、至少约8mg/kg、至少约9mg/kg、至少约10mg/kg、至少约11mg/kg、至少约12mg/kg、至少约13mg/kg、至少约14mg/kg、至少约15mg/kg、至少约16mg/kg、至少约17mg/kg、至少约18mg/kg、至少约19mg/kg或至少约20mg/kg的浓度向对象施用阿维单抗。在更具体的实施方案中,可以以至少约5mg/kg、至少约6mg/kg、至少约7mg/kg、至少约8mg/kg、至少约9mg/kg、至少约10mg/kg、至少约11mg/kg、至少约12mg/kg、至少约13mg/kg、至少约14mg/kg、至少约15mg/kg、至少约16mg/kg、至少约17mg/kg、至少约18mg/kg、至少约19mg/kg或至少约20mg/kg的浓度向对象静脉内施用阿维单抗。
在一个具体实施方案中,将PD-L1抑制剂(例如,阿维单抗)通过输注静脉内施用于对象。通常,通过泵施用或“滴注”(利用重力)进行输注,并且本文所述的方法和方案考虑了PD-L1抑制剂(例如,阿维单抗)的泵输注或滴注输注两者。本文所述的方法和方案还考虑到了VSV-IFNβ-NIS的泵输注或滴注输注两者。
在所选实施方案中,本文所述的方法和方案包括在一段时间内通过输注施用PD-L1抑制剂(例如,阿维单抗)。例如,PD-L1抑制剂(例如,阿维单抗)的输注可以持续约10分钟至约180分钟、约20分钟至约150分钟、约30分钟至约120分钟、约40分钟至约90分钟、约50分钟至约80分钟、约45分钟至约75分钟,以及约50分钟至约70分钟。
在所选实施方案中,本文所述的方法和方案包括以静脉内、瘤内或两者施用VSV-IFNβ-NIS。在一个具体实施方案中,VSV-IFNβ-NIS通过瘤内施用。在更具体的实施方案中,VSV-IFNβ-NIS以至少约3×106 50%组织培养感染剂量(TCID50)、1×107TCID50、3×107TCID50、1×108TCID50、3×108TCID50、1×109TCID50或3×109TCID50的剂量向对象施用。在甚至更具体的实施方案中,VSV-IFNβ-NIS以至少约3×106TCID50、1×107TCID50、3×107TCID50、1×108TCID50、3×108TCID50、1×109TCID50或3×109TCID50的剂量瘤内施用于对象。
在本发明的方法和方案的一个实施方案中,VSV-IFNβ-NIS和PD-L1抑制剂是依次施用的。在一个具体实施方案中,在施用PD-L1抑制剂(例如,阿维单抗)之前,向对象施用VSV-IFNβ-NIS。在一个具体实施方案中,在施用PD-L1抑制剂(例如,阿维单抗)之后,向对象施用VSV-IFNβ-NIS。当在施用VSV-IFNβ-NIS之后施用PD-L1抑制剂(例如,阿维单抗)时,可以在VSV-IFNβ-NIS初次施用的至少半天、1天、2天、3天、4天、5天、6天、7天、8天、9天、10天、11天、12天、13天、14天、15天、16天、17天、18天、19天、20天、21天、22天、23天、24天、25天、26天、27天、28天、29天或30天之后,施用PD-L1抑制剂(例如,阿维单抗)。
当依次施用时,本发明的方法和方案包括在主治医师的指导、控制或监督下施用PD-L1和VSV-IFNβ-NIS两者的情形。本发明的方法和方案还包括医师开具了在首次施用PD-L1抑制剂之前,不在主治医师指导、控制或监督下施用(例如但不限于,自身施用、门诊施用、非现场施用)VSV-IFNβ-NIS的处方的情形。
在另一个实施方案中,VSV-IFNβ-NIS和PD-L1抑制剂(例如,阿维单抗)彼此共同施用。如本文所用,术语共同施用用于表示,两种或更多种化合物或药剂的施用在时间上彼此接近。尽管共同施用可以包括两种或更多种化合物的“同时”施用,术语共同施用在本文中用于包括这样的时间范围,其为非同时的而是考虑到两种或更多种化合物施用之间的时间间隔小。例如,如果两种化合物的施用间隔时间少于12小时,例如但不限于约15分钟或更少、约30分钟或更少、约45分钟或更少、约60分钟或更少、约1.5小时或更少、约2小时或更少、约2.5小时或更少、约3小时或更少、约3.5小时或更少、约4小时或更少、约4.5小时或更少、约5小时或更少、约5.5小时或更少、约6小时或更少、约6.5小时或更少、约7小时或更少、约7.5小时或更少、约8小时或更少、约8.5小时或更少、约9小时或更少、约9.5小时或更少、约10小时或更好、约10.5小时或更少、约11小时或更少、约11.5小时或更少、或小于约12小时,则将VSV-IFNβ-NIS和PD-L1抑制剂(例如,阿维单抗)视为“共同施用”。在PD-L1抑制剂的施用是通过IV滴注或输注施用(例如,阿维单抗)的情况下,考虑何时共同施用一种化合物的时间窗是从第一个化合物完全施用到下一个化合物开始施用的时间。
在其他实施方案中,本发明的方法和方案包括向对象施用VSV-IFNβ-NIS多于一次。在一个具体实施方案中,在施用PD-L1抑制剂(例如,阿维单抗)之前以及还有之后施用VSV-IFNβ-NIS。在另一个具体实施方案中,在初次施用PD-L1抑制剂(例如,阿维单抗)之后,施用VSV-IFNβ-NIS多于一次。
在其他实施方案中,本发明的方法和方案包括将PD-L1抑制剂和/或VSV-IFNβ-NIS与药学上可接受的载体一起施用。本发明的PD-L1抑制剂和/或VSV-IFNβ-NIS组合物可以通过本领域技术人员已知的技术制备,并且包含例如治疗有效量的本文所公开的PD-L1抑制剂和/或VSV-IFNβ-NIS,任选地与以下组合或融合或缀合:一种或多种其他免疫原(包括脂质、磷脂、碳水化合物、脂多糖、灭活或减毒的完整生物和其他蛋白质)、药学上可接受的载体、任选地合适的佐剂及任选地本领域传统使用的其他材料。
PD-L1抑制剂和/或VSV-IFNβ-NIS和药学上可接受的载体可以制备成水溶液、乳液或悬浮液,或者可以是干燥的制备物。以下将这些制备物称为本发明的药物制备物。合适的载体是本领域技术人员已知的,并且包括稳定剂、稀释剂和缓冲剂。合适的稳定剂包括诸如山梨糖醇、乳糖、甘露糖醇、淀粉、蔗糖、葡聚糖和葡萄糖的碳水化合物,以及诸如白蛋白或酪蛋白的蛋白质。合适的稀释剂包括盐水、Hanks平衡盐(Hanks Balanced Salts)和林格氏液(Ringers solution)。合适的缓冲剂包括碱金属磷酸盐、碱金属碳酸盐或碱土金属碳酸盐。在所选实施方案中,本发明的组合物配制用于施用于人。
鉴于本文所包含的教导,可以通过本领域技术人员已知的技术来制备本发明的药物制备物。通常,将诸如PD-L1抑制剂和/或VSV-IFNβ-NIS的治疗剂与载体混合,以形成溶液、悬浮液或乳液。可以将本文所述的一种或多种添加剂添加到载体中,或者可以依次添加。本文所公开的制备物可以例如通过冷冻干燥或喷雾干燥而变干或冻干,以用于储存或配制目的。随后可以通过添加适当的液体载体将它们重构为液体疫苗,或者使用本领域技术人员已知的方法将它们以干燥制剂(特别是以胶囊或片剂形式)施用。
应施用有效量的本发明的药物制备物,其中“有效量”定义为足以在对象中产生所需的预防、治疗或改善应答(包括但不限于表明病毒正在有效繁殖的应答)的量。所需的量取决于所使用的治疗剂以及待被施用的对象的物种与体重而变化,但是可以使用标准技术来确定。
本发明的药物制备物还可包含一种或多种辅助物质,例如润湿剂或乳化剂、pH缓冲剂或佐剂,以增强其效力。给药方案的各个组分可以通过多种施用途径施用于对象,包括肠胃外、皮内、腹膜内、皮下或肌内。给药方案的各个组分,例如PD-L1抑制剂和VSV-IFNβ-NIS,的施用途径不必相同。
PD-L1抑制剂和/或VSV-IFNβ-NIS组合物可以以在粘膜表面引起适当应答的方式配制和递送。因此,可以通过例如经鼻、口服(胃内)或直肠内等途径将PD-L1抑制剂和VSV-IFNβ-NIS组合物施用于粘膜表面。其他施用方式包括但不限于口服制剂。口服制剂可包括通常使用的辅料,例如药品级糖精、纤维素和碳酸镁。这些组合物可以采取微球、溶液、悬浮液、片剂、丸剂、胶囊、缓释制剂或粉剂的形式。PD-L1抑制剂和/或VSV-IFNβ-NIS组合物可以以与剂量制剂相容的方式,且以将是治疗有效的、保护性的或免疫原性的量施用。PD-L1抑制剂和/或VSV-IFNβ-NIS组合物可以任选地包含佐剂。
在一些实施方案中,PD-L1抑制剂和/或VSV-IFNβ-NIS组合物可以与一种或多种靶向分子组合或缀合而使用,以递送至对象的特定细胞。一些实例包括但不限于维生素B12、细菌毒素或其片段、单克隆抗体,以及其他特异性靶向性脂质、蛋白质、核酸或碳水化合物。
在其他实施方案中,本发明的PD-L1抑制剂和/或VSV-IFNβ-NIS组合物可以与以下一起施用:无菌盐水或无菌缓冲盐水胶体分散系统,诸如大分子复合物、纳米胶囊、二氧化硅微粒、钨微粒、金微粒、微球、珠粒和基于脂质的系统(包括水包油乳液、微胶粒(micelles)、混合微胶粒和脂质体)。体外和体内用作递送载体的一种胶体系统是脂质体(即,人工囊泡)。通过将核酸分子掺入可生物降解珠粒之中和/或掺入可生物降解珠粒之上,可以提高裸核酸分子(例如,编码VSV-IFNβ-NIS的核酸)的摄取,所述可生物降解珠粒可被有效地转运到细胞中。这种系统的制备和使用是本领域众所周知的。
在其他实施方案中,核酸分子(例如,编码VSV-IFNβ-NIS的核酸)可以与有助于细胞摄取的试剂缔合。其可以与改变细胞通透性的化学试剂(例如,布比卡因)配制(参见,例如,WO 94/16737)。阳离子脂质在本领域中也是已知的,并且通常用于核酸分子递送。此类脂质包括LIPOFECTINTM,也称为DOTMA(N-[1-(2,3-二油氧基)丙基]-N,N,N-三甲基氯化铵)、DOTAP(1,2-二(油氧基)-3-(三甲氨基)丙烷)、DDAB(双十八烷基二甲基溴化铵)、DOGS(双十八烷基酰氨基甘氨酰精胺(dioctadecylamidologlycy spermine)),以及胆固醇衍生物诸如DC-Chol(3β-(N--(N',N'-二甲基氨基甲烷)-氨甲酰基)胆固醇)(3beta-(N--(N',N'-dimethyl aminomethane)-carbamoyl)cholesterol)。这些阳离子脂质的描述可以在EP187,702、WO 90/11092、美国专利No.5,283,185、WO 91/15501、WO 95/26356和美国专利No.5,527,928中找到。可以将用于核酸分子递送的阳离子脂质与诸如DOPE(二油酰基磷脂酰乙醇胺)的中性脂质结合使用,如例如WO 90/11092中所述。可以将其他转染促进化合物添加到含有阳离子脂质体的制剂中。它们包括例如,用于促进核酸分子通过核膜转运的精胺衍生物(参见,例如,WO 93/18759)以及诸如GAL4、Gramicidine S和阳离子胆盐的膜通透性化合物(参见,例如,WO 93/19768)。
在其他实施方案中,本发明的方法和方案包括向对象施用PD-L1抑制剂(例如,阿维单抗)多于一次。在一个具体实施方案中,PD-L1抑制剂(例如,阿维单抗)在施用VSV-IFNβ-NIS之前以及还有之后施用。在另一个具体实施方案中,在首次施用VSV-IFNβ-NIS之后,施用PD-L1抑制剂(例如,阿维单抗)多于一次。
当向对象施用多剂量PD-L1抑制剂(例如,阿维单抗)的情况下,可以在PD-L1抑制剂(例如,阿维单抗)初次施用或先前施用的至少约1天、2天、3天、4天、5天、6天、7天、8天、9天、10天、11天、12天、13天、14天、15天、16天、17天、18天、19天、20天、21天、22天、23天、24天、25天、26天、27天、28天、29天或30天之后,施用第二剂量及后续剂量。
多剂量的PD-L1抑制剂(例如,阿维单抗)可在预定或规定的时间段出现。例如,PD-L1抑制剂(例如,阿维单抗)可以以每周一次施用数周。在其他实例中,PD-L1抑制剂(例如,阿维单抗)可以以每周多于一次(例如每周两次、三次、四次、五次、六次或七次)施用数周。在具体实施方案中,PD-L1抑制剂(例如,阿维单抗)以每周两次施用至少1周、2周、3周、4周、5周、6周、7周、8周、9周、10周、11周、12周、13周、14周、15周、16周、17周、18周、19周或20周。在一个具体实施方案中,PD-L1抑制剂(例如,阿维单抗)以约10mg/kg的剂量(对于每次施用)以每周两次施用至少1周、2周、3周、4周、5周、6周、7周、8周、9周、10周、11周、12周、13周、14周、15周、16周、17周、18周、19周或20周。
在向对象施用多剂量VSV-IFNβ-NIS的情况下,可以在VSV-IFNβ-NIS初次施用或先前施用的至少约1天、2天、3天、4天、5天、6天、7天、8天、9天、10天、11天、12天、13天、14天、15天、16天、17天、18天、19天、20天、21天、22天、23天、24天、25天、26天、27天、28天、29天或30天之后,施用第二剂量及后续剂量。
多剂量的VSV-IFNβ-NIS可以在预定或规定的时间段发生。例如,VSV-IFNβ-NIS可以以每周一次施用数周。在其他实例中,VSV-IFNβ-NIS可以以每周多于一次(例如每周两次、三次、四次、五次、六次或七次)施用数周。在具体实施方案中,VSV-IFNβ-NIS以每周两次施用至少1周、2周、3周、4周、5周、6周、7周、8周、9周、10周、11周、12周、13周、14周、15周、16周、17周、18周、19周或20周。在一个具体实施方案中,VSV-IFNβ-NIS以至少约3x106 TCID50的剂量(对于每次施用)以每周两次施用至少1周、2周、3周、4周、5周、6周、7周、8周、9周、10周、11周、12周、13周、14周、15周、16周、17周、18周、19周或20周。
在其他实施方案中,所述方法和方案还包括在施用PD-L1抑制剂(例如,阿维单抗)之前,向对象施用抗组胺剂和/或扑热息痛(paracetamol)。如果所述方法和方案包括多剂量的PD-L1抑制剂(例如,阿维单抗),则PD-L1抑制剂的每次施用可包括或不包括预施用抗组胺药和/或扑热息痛。
本发明还涉及试剂盒,其中试剂盒包括至少两个容器,其中第一容器包含至少一剂量的VSV-IFNβ-NIS,且第二容器包含至少一剂量的PD-L1抑制剂(例如,阿维单抗)。
实施例
实施例1—产生VSV-IFNβ-NIS
简而言之,使用PCR利用特异性限制位点生成期望转基因的核酸序列。将转基因在特异性插入位点沿5'至3'方向插入编码VSV基因组正链的质粒中。扩增经修饰的质粒,并通过用编码所需T7聚合酶的痘苗病毒感染和VSV病毒蛋白N、P和L的转染来回收感染性病毒。这允许产生所需的病毒多肽,使得生成组装成感染性病毒体的负义病毒基因组。扩增回收的病毒,并在培养物(例如,BHK-21细胞)中的合适细胞系上测量感染量。用于制备这些水泡性口炎病毒的人IFN-β多肽的核酸序列如GenBank登录号NM_002176.2(GI No.50593016)所示。用于制备这些水泡性口炎病毒的人NIS多肽的核酸序列如GenBank登录号NM_000453.2(GI No.164663746)示出。
当将编码人NIS多肽的核酸插入编码VSV G多肽的核酸上游时,不会生成功能性病毒体,因为NIS表达水平似乎对于细胞而言太高而无法保持活力和无法允许病毒繁殖。将编码NIS多肽的核酸插入编码VSV G多肽的核酸下游导致生成功能性表达NIS的病毒体,这是因为产生的NIS多肽数量较少,从而不仅使得病毒高效繁殖,还使得在感染细胞中有足够数量的用于功能性摄取碘的NIS多肽。
将编码IFNβ多肽的核酸插入编码VSV M多肽的核酸和编码VSV G多肽的核酸之间会产生病毒,其感染细胞并产生在感染的细胞的上清液中观察到明显升高的IFNβ多肽表达水平。VSV-IFNβ-NIS病毒能够在感染的细胞中体外高效复制,并且还能表达高水平的功能性NIS。
实施例2—研究设计
这是一项两部分的开放标签I期研究,旨在确定每两周一次向患有难治性晚期/转移性实体瘤的患者瘤内(IT)施用单剂量VSV-IFNβ-NIS、静脉内(IV)施用阿维单抗后的安全特性、最大耐受剂量(MTD)、药代动力学(PK)以及肿瘤和生物标记物应答。该研究包括在患有难治性晚期/转移性实体瘤的患者中与阿维单抗的组合疗法,之后为单一疗法,以及在患有转移性结肠癌的患者中VSV-IFNβ-NIS MTD或RP2D的组合疗法剂量扩大。
对于剂量上升(dose escalation),根据RECIST 1.1,患者需要具有至少一个可测量病变,用于一次性IT注射VSV-IFNβ-NIS。根据RECIST 1.1,每群组中至少一名患者需要具有至少2个可测量病变,1个用于一次性IT注射VSV-IFNβ-NIS,且另一个用作对照。根据RECIST 1.1,具有2个可测量病变的患者将获得优先招募。每个剂量水平应有至少一名患者患有转移性结肠癌。为了满足这些要求,每个剂量群组将需要3或4位患者。
将通过使用改良的斐波那契(Fibonacci)群组3+3设计来定义和确定最大耐受剂量(MTD)。治疗将从剂量水平1(DL1)开始。直到对当前剂量水平中的患者观察至少3周(21天),剂量才会上升至DL2和后续剂量。如果到该时间点未发生剂量限制性毒性(DLT),则在这3名参与者中,可以发生剂量上升至下一个水平。在任何时候,如果一个剂量水平中的3名参与者中有1名在这3周的时间段内经历DLT,则在该剂量水平中必须招募额外3名患者。每个群组中的前3名参与者必须每次参与一人,从一名参与者到另一名参与者的治疗间隔至少7天。如果在该剂量水平下观察3周后,6名参与者中只有1名经历了DLT,则如前所述,可以发生3名参与者上升到下一个剂量水平。如果一个剂量水平的6名参与者中有2名发生DLT,则将确定已经超出MTD。在这种情况下,如果尚未完成这一点,则先前的剂量水平将被扩大到共6名患者,以确认6名患者中只有1名患有DLT。然后这将是最终推荐的2期剂量(RP2D)。
如果有2名或更多名患者在起始剂量DL1经历DLT,然后将修改或终止该研究。一旦使用VSV-IFNβ-NIS探索了单一疗法的剂量水平3,并且上升进行至剂量水平4,则将开始使用VSV-IFNβ-NIS和阿维单抗的组合进行剂量上升。组合上升将从VSV-IFNβ-NIS剂量水平3开始,并且直到在特定剂量水平完成单一疗法上升后才可以进行更高的上升。
如果发生可疑的DLT,则将尽快召开数据安全监查委员会(DSMB)会议。同时,将继续对该群组中正在进行的患者进行给药,除非基于观察到的DLT的性质和/或严重性有理由怀疑有不可接受的安全风险。如果单个患者经历DLT,则该患者将中断研究药物。
一旦确定了剂量上升中的MTD和/或RP2D,则将开放两个分两阶段的扩大群组(一个用于单一疗法,且一个用于组合疗法),并且两者都将招募患有转移性结肠直肠癌的患者,以进一步表征与或不与阿维单抗一起的VSV-IFNβ-NIS的安全性、耐受性、药代动力学(PK)、药效学(PD)和抗肿瘤活性。扩大群组将使用Simon两阶段设计。在扩大研究阶段1中,将获得12名患者并评估疗效。如果这12名患者为0应答,则该群组将停止。否则,将获得额外9名患者,并按照研究时间表对总共21名患者进行评估。该研究不会在阶段1和阶段2之间停止。根据RECIST 1.1,每个群组中至少6名患者需要具有2个可测量病变,其中一个用于IT注射VSV-IFNβ-NIS,且另一个用作对照。每个群组中至少六名患者还需要进行SPECT/CT成像。
扩大群组中的患者将按照与该研究的剂量上升部分相同的研究程序进行治疗和监测。
实施例3—给药
将由经过适当培训的外科和介入放射学辅助研究者用VSV-IFNβ-NIS进行试验治疗。将按照主要研究者和施用辅助研究者所同意的,使用TB注射器(或等效物)和20至23号针头或用于较大肿瘤的多管针头,在一个单个肿瘤位置IT施用VSV-IFNβ-NIS。允许向包括皮肤、软组织、结节、肺或肝病变的部位施用。施用标准如下:
表1:注射部位大小和图像指导标准
1沿最长尺寸测量的
2图像应包括记录最长可测量尺寸的测尺
3所测量的结节的最短尺寸为1.5cm
一旦分配给参与者VSV-IFNβ-NIS剂量后,将按照药房手册操作方案将病毒解冻并制备,并在施用前立即进行白蛋白稀释(理想地是大约30分钟,但最多6个小时)。最终体积取决于肿瘤病变大小,并根据以下公式进行估算:
注射体积(Vi)=(a^2)(b)(0.5)
可注射产品的[a=较短直径,且b=较长直径]。
递送至肿瘤的体积将取决于肿瘤结节的大小,并将根据以下算法确定:
对于最长尺寸为1.0-1.5cm的肿瘤,多达0.5mL。
对于最长尺寸为1.5-2.5cm的肿瘤,多达1.0mL。
对于最长尺寸为2.5-5cm的肿瘤,多达2.0mL。
对于最长直径>5cm的肿瘤,多达4.0mL。
注意,仅对于DL 7(3x109 TCID50),由于体积的限制,具有最大病变直径<1.5cm的患者不能包括在内。
一旦解冻并稀释试验治疗,将按以下进行施用:
注射部位将使用适当的试剂进行清洁,例如,双氯苯双胍己烷葡糖酸盐(chlorhexadine)或必妥碘(betadine)。
该区域将以无菌方式覆盖。
如果施用辅助研究者认为有必要,则按照常规护理标准为研究参与者提供轻微镇静。
根据常规护理标准如果施用辅助研究者认为有必要,则可以在注射部位使用用1%利多卡因进行的局部麻醉。但是,不应将其直接注射到病变上。如果在病变周围注射局部麻醉药,应达到足够的镇痛。
使用根据下表中概述的适当图像指导,施用辅助研究者或指定人员将从药房提供的小瓶中吸取研究药物溶液至TB注射器(或等效物)中,并通过20-23号针头,或用于较大肿瘤的多管头针,将VSV-IFNβ-NIS施用至预先确定的肿瘤部位。
对于可见病变,可以使用局部麻醉剂对注射部位预处理。VSV-IFNβ-NIS应沿着病变内的多个不同轨道注射,以获得尽可能宽的分散。
病毒产品的注射应缓慢进行。如果肿瘤部位的直径>2cm,则由于溶解的病毒产品量,可能需要多次注射。如果需要多次注射,则应在距先前注射约2cm进行施用。该手术总时间预计将花费30-60分钟。
手术后应在治疗室或麻醉后监护室(PACU)进行约2小时的术后监测,其中每15分钟检查一次生命体征。
术后监测结束后,研究参与者将在手术后入住医院病房,以门诊病床状态监测至多23小时。在病房的头4个小时,每小时将记录生命体征,然后在23小时停留的其他时间,每4个小时将记录生命体征。如9.4节所述,将提供支持性护理。
一旦23小时结束,并经由主要研究者或辅助研究者批准后,参与者将被解除监测。根据个体毒性,可能需要进行额外的监测。
阿维单抗药物产品是一种用于IV输注的无菌溶液,是在由橡胶塞封闭并由铝Flip卷边密封闭合件密封的欧洲药典(Ph.Eur.)和美国药典(USP)I型玻璃瓶中的浓度为20mg/mL的透明、无色溶液浓缩液。
每2周一次,在1小时(-10分钟/+20分钟)内将以800mg的剂量以IV输注施用阿维单抗。将在第1天VSV后施用阿维单抗。
阿维单抗药物产品必须用输液袋中提供的0.9%盐水溶液(氯化钠注射液)进行稀释;或者,如果需要,也可以使用0.45%盐水溶液。有关剂量制备物的说明,请参阅获批的美国处方信息。
在所有需要用阿维单抗治疗的对象中,要求前4剂使用抗组胺药和扑热息痛(对乙酰氨基酚)进行强制性术前用药。为了减轻与输注相关的反应,在前4剂阿维单抗之前约30-60分钟,强制用抗组胺药和扑热息痛(对乙酰氨基酚)(例如,iv施用25-50mg苯海拉明和500-650mg扑热息痛[对乙酰氨基酚],或口服施用等效物)进行术前用药。应根据临床判断和先前输注反应的存在/严重程度,针对随后的阿维单抗剂量来施用术前用药。该方案可根据当地治疗标准及指南进行适当修改。但是,预防性使用全身性皮质类固醇是不允许的。
作为常规预防措施,对于前4次输注,在输注后必须在有复苏设备和急救人员的区域内对本试验中招募的对象观察1小时。在阿维单抗治疗期间的任何时候,必须确保根据制度性规范立即紧急治疗输注相关反应或严重过敏性反应。例如,为了治疗可能的过敏性反应,应始终提供10mg地塞米松和1:1000稀释的肾上腺素或等效物,以及呼吸辅助设备。
研究者还应密切监测对象的潜在免疫相关AE(irAE),这些AE可能在治疗期间的任何时间表现出来。此类事件包括但不限于,肺炎、肝炎、结肠炎、内分泌病(甲状腺功能减退、甲状腺功能亢进、肾上腺功能不全、1型糖尿病)、心肌炎、肌炎、皮疹。有关irAE管理的详细信息,参见9.1.10.2节。
实施例4—疗效评估
RECIST 1.1版将在本研究中用于评估肿瘤应答。虽然根据RECIST 1.1可以使用CT或MRI,CT是本研究中优选的成像技术。
在IT注射研究药物后6周(就诊43天)将进行肿瘤测量以评估疗效。对CR或PR的放射学评估要求在初步评估所观察到的应答后至少4周进行确认性成像。
可测量疾病:肿瘤病变:必须在至少一维(要记录测量平面上的最大直径)尺寸上进行准确测量,其中最小尺寸为:
由计算机断层扫描(CT)为10mm(CT扫描切片的厚度不大于5mm)。
由临床检查为10mm卡尺测量(使用卡尺无法准确测量的病变应记录为不可测量)。
由胸部X光为20mm。
皮肤病变:建议通过彩色摄像术包括尺子进行记录来估计病变的大小。
恶性淋巴结:为了被认为在病理上是扩大和可测量的,通过CT扫描评估时,淋巴结的短轴必须>15mm。在基线和随访中,将仅测量和跟踪短轴。
不可测量疾病:所有其他病变,包括小病变(最长直径<10mm,或病理性淋巴结短轴≥10mm至<15mm)以及真正的不可测量病变。被认为是真正不可测量的病变包括:柔脑膜疾病、腹水、胸腔或心包积液、炎性乳腺疾病,以及皮肤或肺的淋巴管性损害、腹部包块、腹部器官肿大,这是无法通过可再现成像技术进行测量的而通过体格检查鉴定的。
靶病变:可再现性最高的可测量病变,每个器官多达最多2个病变,且总共5个病变,应将所有涉及的器官的代表鉴定为靶病变,并在基线时记录和测量。
靶病变应根据其大小(具有最长直径的病变)进行选择,应为所有涉及的器官的代表,此外,应是那些适于可再现重复测量的病变。被定义为可测量且可能被识别为靶病变的病理性结节必须满足短轴≥15mm的标准。将计算所有的靶病变,并记录为基线总直径。如果总和中包括淋巴结,则如上所述,仅将短轴添加到总和中。基线总直径将用作进一步表征任何客观肿瘤应答的参考。
非靶病变:将所有其他病变(或疾病部位)鉴定为非靶病变(根据所涉及器官的代表和在重复测量中再现能力而选择的),并应记录为基线。不需要对这些病变进行测量,但是在整个随访过程中应记录每个存在与否。短轴≥10mm但<15mm的淋巴结应视为非靶病变。具有短轴<10mm的淋巴结被认为是非病理性的,并且不会进行记录或跟踪。
靶病变评估
完全应答(CR):所有靶病变均消失。任何病理性淋巴结(无论是靶还是非靶)都必须将短轴缩小至<10mm。肿瘤标记物结果必须正常化。
部分应答(PR):参考基线总直径,靶病变直径的总和减少至少30%。
病情稳定(SD):参考从治疗开始以来的最小(最低点)直径总和,既没有足够的收缩率来达到PR,也没有足够的增加来达到PD。
进行性疾病(PD):参考从治疗开始以来的最小(最低点)总和,靶病变直径的总和增加至少20%,或出现一个或多个新病变。总和不仅需要增加20%,而且需要绝对增加至少5mm。
非靶病变评估
完全应答(CR):所有非靶病变均消失,且肿瘤标记物正常化。所有淋巴结的大小均必须是非病理性的(短轴<10mm)。
病情稳定(SD):一种或多种非靶病变持续存在,和/或肿瘤标记物水平持续超过正常范围。
进行性疾病(PD):出现一种或多种新病变,和/或现有非靶病变有明确进展。当患者也患有可检测疾病时,非靶标疾病的总体水平必须实质性恶化,即使在靶疾病中存在SD或PR,肿瘤总体负荷已充分增加以值得中止治疗。
表2:最佳总体应答评估
当结节疾病包括在靶病变的总和中,并且结节缩小至“正常”大小(<10mm)时,扫描时可能仍有测量值被报告。即使结节正常,也应记录此测量值,以避免夸大进展,其应当是基于节点大小的增加。如前所述,这意味着CR患者在病例报告表(CRF)上的总和可以不为“零”。
如果在计划的评估前根据临床或实验室发现怀疑有疾病进展,则应进行计划外评估。患者的健康状况出现整体恶化,需要中止治疗,而此时没有疾病进展的客观证据,则应报告为“症状性恶化”。即使在中止治疗后,应尽一切努力记录客观进展。
实施例5—统计学考量
安全人群:安全人群由接受至少一个剂量的研究药物的所有患者组成。所有安全性和耐受性评估将基于该分析组。
PK/PD人群:PK/PD人群包括没有影响PK和/或PD的可解释性的方案偏差的所有患者。
疗效人群:主要疗效分析将利用与安全人群相同的受治疗人群。
所有分析将在预先指定的分析组中按剂量和总体(即总体剂量水平)进行(将分开分析单一疗法和组合疗法)。扩大群组将按疗法(单一疗法组/组合疗法组)进行分析。
将显示筛选的、招募的患者数量和百分比、筛选失败的主要原因以及中止的主要原因。人口统计学变量、基线特征、主要和次要诊断以及既往和伴随疗法将通过描述性统计或分类表按治疗进行总结。
VSV-IFNβ-NIS和阿维单抗的暴露数据将报告为每名患者的总施用剂量和按剂量群组和总体来汇总的相对剂量强度(实际剂量/计划剂量)。
伴随药物将使用目前的世界卫生组织药物字典进行编码,且数据将汇总并示于表格和列表中。
由于这些端点的探索性,将只使用描述性统计。结果将按剂量群组和总体来呈现。
总体应答率(ORR):分析人群中在第43天根据RECIST 1.1成像具有完全应答(CR)或部分应答(PR)的患者比例。对于每一个将计算频率和相对频率(总体、按剂量水平和按疾病类型)。
疾病控制率(DCR):各个分析人群中在第43天根据RECIST 1.1成像具有完全应答(CR)、部分应答(PR)或病情稳定(SD)的患者比例。对于每一个将计算频率和相对频率(总体、按剂量水平和按疾病类型)。
被注射的病变(TNi)和远处病变(TNd)的肿瘤应答率:分析人群中TNi和TNd在第43天根据RECIST 1.1成像具有完全应答(CR)或部分应答(PR)的患者比例。对于每一个将计算频率和相对频率(总体、按剂量水平和按疾病类型)。
无进展存活期(PFS):从第1天治疗施用到第一次记录的疾病进展或死亡(以先发生者为准)的时间。
应答持续时间(DOR):从第一次观察到应答到第一次记录的疾病进展或死亡(以先发生者为准)的时间。
总体存活期(OS):从第1天治疗施用到因任何原因而死亡的时间。
肿瘤坏死(TN):被注射的病变(TNi)和远处病变(TNd)的坏死率将分别定义为坏死比基线增加30%以上的TNi和TNd。对于每一个将计算频率和相对频率(总体、按剂量水平和按疾病类型)。
表3:关键疗效端点的统计方法
本试验的主要安全性目标是表征VSV-IFNβ-NIS(与或不与阿维单抗一起)在患有难治性晚期/转移性实体瘤的患者中的安全性。主要安全性分析将基于VSV-IFNβ-NIS的MTD。MTD将由剂量限制性毒性(DLT)的发生来确定。安全性将通过使用CTCAE 4.03版和CRS分级系统所报告的副作用来评估。治疗的归因、发病时间、不良事件持续时间、其解决方案,以及施用的任何伴随药物将被记录。将分析AE,包括但不限于所有AE、SAE、致命AE和实验室变化。
安全性和耐受性将通过分析所有相关参数来评估,包括DLT、不良事件(AE)、实验室试验、ECG和生命体征。将提供AE的计数和等级百分比。根据二项式分布,利用精确的方法,来估计临床关注的AE比例的Clopper-Pearson 95%置信区间。所有安全性参数将按剂量群组和总体以及按与研究药物的关系来表示。
序列表
<110> 维里亚德公司
默克专利股份有限公司
辉瑞公司
妙佑医学教育研究基金会
<120> 使用组合疗法治疗癌症的方法
<130> 056187-501001WO
<150> 62/688,563
<151> 2018-06-22
<160> 9
<170> PatentIn version 3.5
<210> 1
<211> 5
<212> PRT
<213> Homo sapiens
<400> 1
Ser Tyr Ile Met Met
1 5
<210> 2
<211> 17
<212> PRT
<213> Homo sapiens
<400> 2
Ser Ile Tyr Pro Ser Gly Gly Ile Thr Phe Tyr Ala Asp Thr Val Lys
1 5 10 15
Gly
<210> 3
<211> 11
<212> PRT
<213> Homo sapiens
<400> 3
Ile Lys Leu Gly Thr Val Thr Thr Val Asp Tyr
1 5 10
<210> 4
<211> 14
<212> PRT
<213> Homo sapiens
<400> 4
Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr Asn Tyr Val Ser
1 5 10
<210> 5
<211> 7
<212> PRT
<213> Homo sapiens
<400> 5
Asp Val Ser Asn Arg Pro Ser
1 5
<210> 6
<211> 10
<212> PRT
<213> Homo sapiens
<400> 6
Ser Ser Tyr Thr Ser Ser Ser Thr Arg Val
1 5 10
<210> 7
<211> 450
<212> PRT
<213> Homo sapiens
<400> 7
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ile Met Met Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Tyr Pro Ser Gly Gly Ile Thr Phe Tyr Ala Asp Thr Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ile Lys Leu Gly Thr Val Thr Thr Val Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly Lys
450
<210> 8
<211> 449
<212> PRT
<213> Homo sapiens
<400> 8
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ile Met Met Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Tyr Pro Ser Gly Gly Ile Thr Phe Tyr Ala Asp Thr Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ile Lys Leu Gly Thr Val Thr Thr Val Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly
<210> 9
<211> 216
<212> PRT
<213> Homo sapiens
<400> 9
Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15
Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr
20 25 30
Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu
35 40 45
Met Ile Tyr Asp Val Ser Asn Arg Pro Ser Gly Val Ser Asn Arg Phe
50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu
65 70 75 80
Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Ser Ser
85 90 95
Ser Thr Arg Val Phe Gly Thr Gly Thr Lys Val Thr Val Leu Gly Gln
100 105 110
Pro Lys Ala Asn Pro Thr Val Thr Leu Phe Pro Pro Ser Ser Glu Glu
115 120 125
Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr
130 135 140
Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Gly Ser Pro Val Lys
145 150 155 160
Ala Gly Val Glu Thr Thr Lys Pro Ser Lys Gln Ser Asn Asn Lys Tyr
165 170 175
Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His
180 185 190
Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys
195 200 205
Thr Val Ala Pro Thr Glu Cys Ser
210 215
Claims (19)
1.一种在需要此治疗的对象中治疗转移性结肠癌的方法,所述方法包括向所述对象施用程序性死亡-配体1(PD-L1)抑制剂和向所述对象施用经工程化以表达干扰素β和钠/碘同向转运体的重组水泡性口炎病毒(rVSV),其中,所述PD-L1抑制剂是特异性结合PD-L1并包含重链和轻链的抗PD-L1抗体或其抗PD-L1抗体片段,其中所述重链包含分别具有SEQ IDNO:1、SEQ ID NO:2和SEQ ID NO:3的氨基酸序列的三个互补决定区(CDR),并且所述轻链包含分别具有SEQ ID NO:4、SEQ ID NO:5和SEQ ID NO:6的氨基酸序列的三个CDR。
2.根据权利要求1所述的方法,其中所述抗PD-L1抗体或其抗PD-L1抗体片段介导抗体依赖性细胞介导的细胞毒性(ADCC)。
3.根据权利要求1或2所述的方法,其中所述PD-L1抗体包含重链和轻链,其中所述重链包含SEQ ID NO:7或8的氨基酸序列,并且所述轻链包含SEQ ID NO:9的氨基酸序列。
4.根据权利要求1-3中任一项所述的方法,其中所述PD-L1抑制剂是阿维单抗。
5.根据权利要求1-4中任一项所述的方法,其中在所述对象已经接受至少一线、二线或三线癌症疗法后,将所述PD-L1抑制剂和所述rVSV在疾病进展之后施用于所述对象。
6.根据权利要求1-5中任一项所述的方法,其中所述rVSV和所述PD-L1抑制剂以任一次序依次施用。
7.根据权利要求1-6中任一项所述的方法,其中所述rVSV在所述PD-L1抑制剂之前施用。
8.根据权利要求7所述的方法,所述方法包括:(a)在医师的指导或控制下,所述对象在首次接受所述PD-L1抑制剂之前接受所述rVSV;以及(b)在医师的指导或控制下,所述对象接受所述PD-L1抑制剂。
9.根据权利要求7所述的方法,其中所述PD-L1抑制剂在所述rVSV初次施用的至少半天、1天、2天、3天、4天、5天、6天、7天、8天、9天、10天、11天、12天、13天、14天、15天、16天、17天、18天、19天、20天、21天、22天、23天、24天、25天、26天、27天、28天、29天或30天之后施用。
10.根据权利要求1-9中任一项所述的方法,其中所述PD-L1抑制剂被施用多于一次,其中任选地多剂量的PD-L1抑制剂在PD-L1初次施用的至少半天、1天、2天、3天、4天、5天、6天、7天、8天、9天、10天、11天、12天、13天、14天、15天、16天、17天、18天、19天、20天、21天、22天、23天、24天、25天、26天、27天、28天、29天或30天之后施用。
11.根据权利要求1-10中任一项所述的方法,其中所述rVSV在瘤内施用。
12.根据权利要求1-11中任一项所述的方法,其中所述rVSV的剂量为每次施用至少约3×106 50%组织培养感染剂量(TCID50)、1×107TCID50、3×107TCID50、1×108TCID50、3×108TCID50、1×109TCID50或3×109TCID50。
13.根据权利要求1-12中任一项所述的方法,其中所施用的所述PD-L1抑制剂的总剂量为每次施用至少约200mg、300mg、400mg、600mg、800mg、1000mg、1200mg、1400mg、1600mg、1800mg或2000mg。
14.根据权利要求1-13中任一项所述的方法,其中通过测量外周血T细胞群体上的免疫检查点和共刺激分子而监测所述对象,其中任选地所述免疫检查点和共刺激分子包括PD-1、TIM3和LAG3。
15.根据权利要求1-14中任一项所述的方法,其中通过比较治疗前和治疗后免疫细胞浸润而监测所述对象。
16.一种包含程序性死亡-配体1(PD-L1)抑制剂和经工程化以表达干扰素β和钠/碘同向转运体的重组水泡性口炎病毒(rVSV)的组合,其中所述PD-L1抑制剂是特异性结合PD-L1并包含重链和轻链的抗PD-L1抗体或其抗PD-L1抗体片段,其中所述重链包含分别具有SEQID NO:1、SEQ ID NO:2和SEQ ID NO:3的氨基酸序列的三个互补决定区(CDR),并且所述轻链包含分别具有SEQ ID NO:4、SEQ ID NO:5和SEQ ID NO:6的氨基酸序列的三个CDR。
17.一种包含程序性死亡-配体1(PD-L1)抑制剂、经工程化以表达干扰素β和钠/碘同向转运体的重组水泡性口炎病毒(rVSV)和药学上可接受的载体、稀释剂、赋形剂和/或佐剂的药物组合物,其中所述PD-L1抑制剂是特异性结合PD-L1并包含重链和轻链的抗PD-L1抗体或其抗PD-L1抗体片段,其中所述重链包含具有SEQ ID NO:1、SEQ ID NO:2和SEQ ID NO:3的氨基酸序列的三个互补决定区(CDR),并且所述轻链包含具有SEQ ID NO:4、SEQ ID NO:5和SEQ ID NO:6的氨基酸序列的三个CDR。
18.权利要求16所述的组合或权利要求17所述的药物组合物,其用作药物。
19.权利要求16所述的组合或权利要求17所述的药物组合物,其用于治疗转移性结肠癌;并且其中任选地所述PD-L1抑制剂和所述rVSV以单一或分开的单位剂型提供。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201862688563P | 2018-06-22 | 2018-06-22 | |
US62/688,563 | 2018-06-22 | ||
PCT/US2019/038480 WO2019246528A1 (en) | 2018-06-22 | 2019-06-21 | Methods of treating cancer using combination therapy |
Publications (1)
Publication Number | Publication Date |
---|---|
CN112584861A true CN112584861A (zh) | 2021-03-30 |
Family
ID=68983064
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201980042052.6A Pending CN112584861A (zh) | 2018-06-22 | 2019-06-21 | 使用组合疗法治疗癌症的方法 |
Country Status (8)
Country | Link |
---|---|
US (1) | US20210252143A1 (zh) |
EP (1) | EP3810192A1 (zh) |
JP (1) | JP2021531330A (zh) |
CN (1) | CN112584861A (zh) |
AU (1) | AU2019290212A1 (zh) |
CA (1) | CA3104509A1 (zh) |
IL (1) | IL279591A (zh) |
WO (1) | WO2019246528A1 (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111494432A (zh) * | 2019-01-31 | 2020-08-07 | 惠君生物医药科技(杭州)有限公司 | 一种用于治疗肿瘤或癌症的药物组合物及其应用 |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2597623A (en) | 2017-08-07 | 2022-02-02 | Univ California | Platform for generating safe cell therapeutics |
WO2022066877A1 (en) * | 2020-09-23 | 2022-03-31 | Mayo Foundation For Medical Education And Research | Methods and materials for treating cancer |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3763741A1 (en) * | 2011-11-28 | 2021-01-13 | Merck Patent GmbH | Anti-pd-l1 antibodies and uses thereof |
NL2020422B1 (en) * | 2018-02-12 | 2019-08-19 | Stichting Het Nederlands Kanker Inst Antoni Van Leeuwenhoek Ziekenhuis | Methods for Predicting Treatment Outcome and/or for Selecting a Subject Suitable for Immune Checkpoint Therapy. |
-
2019
- 2019-06-21 AU AU2019290212A patent/AU2019290212A1/en not_active Abandoned
- 2019-06-21 CN CN201980042052.6A patent/CN112584861A/zh active Pending
- 2019-06-21 EP EP19822128.5A patent/EP3810192A1/en not_active Withdrawn
- 2019-06-21 WO PCT/US2019/038480 patent/WO2019246528A1/en active Application Filing
- 2019-06-21 CA CA3104509A patent/CA3104509A1/en not_active Abandoned
- 2019-06-21 JP JP2021520284A patent/JP2021531330A/ja active Pending
- 2019-06-21 US US17/253,175 patent/US20210252143A1/en not_active Abandoned
-
2020
- 2020-12-20 IL IL279591A patent/IL279591A/en unknown
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111494432A (zh) * | 2019-01-31 | 2020-08-07 | 惠君生物医药科技(杭州)有限公司 | 一种用于治疗肿瘤或癌症的药物组合物及其应用 |
Also Published As
Publication number | Publication date |
---|---|
US20210252143A1 (en) | 2021-08-19 |
WO2019246528A1 (en) | 2019-12-26 |
IL279591A (en) | 2021-03-01 |
JP2021531330A (ja) | 2021-11-18 |
EP3810192A1 (en) | 2021-04-28 |
CA3104509A1 (en) | 2019-12-26 |
AU2019290212A1 (en) | 2021-02-04 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20230115328A1 (en) | Anti-B7-H1 and Anti-CTLA-4 Antibodies for Treating Non-Small Cell Lung Cancer | |
EP3043816B1 (en) | Anti-b7-h1 antibodies for treating tumors | |
JP7316120B2 (ja) | 腫瘍性疾患のための治療 | |
JP6695003B2 (ja) | 癌のための併用療法 | |
JP7113619B2 (ja) | リポソーマルイリノテカンによる乳がんの治療 | |
CN112584861A (zh) | 使用组合疗法治疗癌症的方法 | |
TWI817958B (zh) | 用於治療肝癌之組合物及方法 | |
US20240101666A1 (en) | Lag-3 antagonist therapy for lung cancer | |
CN119997973A (zh) | 使用间充质上皮转化因子(met)靶向剂治疗非小细胞肺癌的方法 | |
RU2802962C2 (ru) | Композиции и способы лечения рака печени | |
EP4494654A1 (en) | Pharmaceutical composition of anti-tim-3 antibody and hypomethylating agent | |
WO2025141589A1 (en) | Treatment of cancer with anti-ilt3 antibodies | |
WO2024137776A1 (en) | Combination therapy for lung cancer | |
WO2024223299A2 (en) | Methods of treating cancer by administering immunogenic compositions and a pd-1 inhibitor | |
EP4548929A1 (en) | Pharmaceutical composition comprising mixed antibody of anti-ctla4 and anti-pd1 and therapeutic use thereof | |
WO2024216238A2 (en) | Use of beta-catenin antagonist and immunomodulator | |
EP4469477A1 (en) | Combination therapy for hepatocellular carcinoma | |
Headquarters | RADIATION THERAPY ONCOLOGY GROUP RTOG 0324 A PHASE II STUDY OF CETUXIMAB (C225) IN COMBINATION WITH CHEMORADIATION IN PATIENTS WITH STAGE IIIA/B NON-SMALL CELL LUNG CANCER (NSCLC) |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20210330 |
|
WD01 | Invention patent application deemed withdrawn after publication |