CN114599390A - 抗体-白介素融合蛋白以及使用方法 - Google Patents
抗体-白介素融合蛋白以及使用方法 Download PDFInfo
- Publication number
- CN114599390A CN114599390A CN202080055588.4A CN202080055588A CN114599390A CN 114599390 A CN114599390 A CN 114599390A CN 202080055588 A CN202080055588 A CN 202080055588A CN 114599390 A CN114599390 A CN 114599390A
- Authority
- CN
- China
- Prior art keywords
- antibody
- protein
- antigen
- disease
- cancer
- 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 description 31
- 102000037865 fusion proteins Human genes 0.000 title description 103
- 108020001507 fusion proteins Proteins 0.000 title description 103
- 239000000427 antigen Substances 0.000 claims abstract description 94
- 102000036639 antigens Human genes 0.000 claims abstract description 93
- 108091007433 antigens Proteins 0.000 claims abstract description 93
- 230000027455 binding Effects 0.000 claims abstract description 77
- 239000012634 fragment Substances 0.000 claims abstract description 65
- 108090000623 proteins and genes Proteins 0.000 claims abstract description 56
- 102000004169 proteins and genes Human genes 0.000 claims abstract description 50
- 102000003814 Interleukin-10 Human genes 0.000 claims abstract description 30
- 108090000174 Interleukin-10 Proteins 0.000 claims abstract description 30
- 102000015696 Interleukins Human genes 0.000 claims abstract description 28
- 108010063738 Interleukins Proteins 0.000 claims abstract description 28
- 102000037982 Immune checkpoint proteins Human genes 0.000 claims abstract description 11
- 108091008036 Immune checkpoint proteins Proteins 0.000 claims abstract description 11
- 206010028980 Neoplasm Diseases 0.000 claims description 61
- 210000004027 cell Anatomy 0.000 claims description 56
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 40
- 201000010099 disease Diseases 0.000 claims description 33
- 201000011510 cancer Diseases 0.000 claims description 20
- 102000008096 B7-H1 Antigen Human genes 0.000 claims description 17
- 108010074708 B7-H1 Antigen Proteins 0.000 claims description 16
- 102000040430 polynucleotide Human genes 0.000 claims description 10
- 108091033319 polynucleotide Proteins 0.000 claims description 10
- 239000002157 polynucleotide Substances 0.000 claims description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims description 9
- 239000013598 vector Substances 0.000 claims description 9
- 201000001441 melanoma Diseases 0.000 claims description 8
- 102100040678 Programmed cell death protein 1 Human genes 0.000 claims description 7
- 101710089372 Programmed cell death protein 1 Proteins 0.000 claims description 7
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 claims description 7
- 208000035475 disorder Diseases 0.000 claims description 7
- 229940076144 interleukin-10 Drugs 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 230000001225 therapeutic effect Effects 0.000 claims description 7
- 239000003937 drug carrier Substances 0.000 claims description 6
- 208000032839 leukemia Diseases 0.000 claims description 6
- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 5
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 claims description 5
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 5
- 208000026310 Breast neoplasm Diseases 0.000 claims description 4
- 208000009329 Graft vs Host Disease Diseases 0.000 claims description 4
- 206010038389 Renal cancer Diseases 0.000 claims description 4
- 210000004978 chinese hamster ovary cell Anatomy 0.000 claims description 4
- 208000024908 graft versus host disease Diseases 0.000 claims description 4
- 201000010982 kidney cancer Diseases 0.000 claims description 4
- 201000000596 systemic lupus erythematosus Diseases 0.000 claims description 4
- 208000009137 Behcet syndrome Diseases 0.000 claims description 3
- 206010006187 Breast cancer Diseases 0.000 claims description 3
- 206010009900 Colitis ulcerative Diseases 0.000 claims description 3
- 206010009944 Colon cancer Diseases 0.000 claims description 3
- 208000011231 Crohn disease Diseases 0.000 claims description 3
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 3
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 3
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 3
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 3
- 206010060862 Prostate cancer Diseases 0.000 claims description 3
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 3
- 201000004681 Psoriasis Diseases 0.000 claims description 3
- 208000024770 Thyroid neoplasm Diseases 0.000 claims description 3
- 201000006704 Ulcerative Colitis Diseases 0.000 claims description 3
- 206010046851 Uveitis Diseases 0.000 claims description 3
- 206010047642 Vitiligo Diseases 0.000 claims description 3
- 208000004631 alopecia areata Diseases 0.000 claims description 3
- 201000007270 liver cancer Diseases 0.000 claims description 3
- 208000014018 liver neoplasm Diseases 0.000 claims description 3
- 201000005202 lung cancer Diseases 0.000 claims description 3
- 208000020816 lung neoplasm Diseases 0.000 claims description 3
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 3
- 210000004962 mammalian cell Anatomy 0.000 claims description 3
- 201000002528 pancreatic cancer Diseases 0.000 claims description 3
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 3
- 201000000306 sarcoidosis Diseases 0.000 claims description 3
- 201000002510 thyroid cancer Diseases 0.000 claims description 3
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 2
- 206010033645 Pancreatitis Diseases 0.000 claims description 2
- 206010033647 Pancreatitis acute Diseases 0.000 claims description 2
- 201000009594 Systemic Scleroderma Diseases 0.000 claims description 2
- 206010042953 Systemic sclerosis Diseases 0.000 claims description 2
- 206010047115 Vasculitis Diseases 0.000 claims description 2
- 206010048222 Xerosis Diseases 0.000 claims description 2
- 208000024340 acute graft versus host disease Diseases 0.000 claims description 2
- 201000003229 acute pancreatitis Diseases 0.000 claims description 2
- 230000001684 chronic effect Effects 0.000 claims description 2
- 230000002489 hematologic effect Effects 0.000 claims description 2
- 201000000050 myeloid neoplasm Diseases 0.000 claims description 2
- 208000012934 primary antiphospholipid syndrome Diseases 0.000 claims description 2
- 230000000069 prophylactic effect Effects 0.000 claims description 2
- 125000003275 alpha amino acid group Chemical group 0.000 claims 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 39
- 235000018102 proteins Nutrition 0.000 description 34
- 150000001413 amino acids Chemical group 0.000 description 33
- 230000003211 malignant effect Effects 0.000 description 30
- 102000004196 processed proteins & peptides Human genes 0.000 description 30
- 239000000203 mixture Substances 0.000 description 28
- 229920001184 polypeptide Polymers 0.000 description 27
- 125000005647 linker group Chemical group 0.000 description 25
- -1 IL-IL-9 Proteins 0.000 description 16
- 239000003814 drug Substances 0.000 description 15
- 150000007523 nucleic acids Chemical group 0.000 description 13
- 241000699666 Mus <mouse, genus> Species 0.000 description 12
- 235000001014 amino acid Nutrition 0.000 description 12
- 210000000987 immune system Anatomy 0.000 description 12
- 239000003795 chemical substances by application Substances 0.000 description 11
- 239000000463 material Substances 0.000 description 11
- 102000039446 nucleic acids Human genes 0.000 description 11
- 108020004707 nucleic acids Proteins 0.000 description 11
- 238000011282 treatment Methods 0.000 description 11
- 208000023275 Autoimmune disease Diseases 0.000 description 10
- 108010047041 Complementarity Determining Regions Proteins 0.000 description 9
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 9
- 239000012636 effector Substances 0.000 description 9
- 230000006870 function Effects 0.000 description 9
- 229940124597 therapeutic agent Drugs 0.000 description 9
- 230000000694 effects Effects 0.000 description 8
- 208000024891 symptom Diseases 0.000 description 8
- 201000009030 Carcinoma Diseases 0.000 description 7
- 238000012217 deletion Methods 0.000 description 7
- 230000037430 deletion Effects 0.000 description 7
- 230000007246 mechanism Effects 0.000 description 7
- 230000004048 modification Effects 0.000 description 7
- 238000012986 modification Methods 0.000 description 7
- 210000001519 tissue Anatomy 0.000 description 7
- 210000004881 tumor cell Anatomy 0.000 description 7
- 102000004127 Cytokines Human genes 0.000 description 6
- 108090000695 Cytokines Proteins 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 101001033233 Homo sapiens Interleukin-10 Proteins 0.000 description 6
- 108010065637 Interleukin-23 Proteins 0.000 description 6
- 102000013264 Interleukin-23 Human genes 0.000 description 6
- 108010002586 Interleukin-7 Proteins 0.000 description 6
- 102000000704 Interleukin-7 Human genes 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 208000009956 adenocarcinoma Diseases 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- 230000004044 response Effects 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 108091026890 Coding region Proteins 0.000 description 5
- 206010061218 Inflammation Diseases 0.000 description 5
- 210000001744 T-lymphocyte Anatomy 0.000 description 5
- 210000003719 b-lymphocyte Anatomy 0.000 description 5
- 230000004663 cell proliferation Effects 0.000 description 5
- 239000000539 dimer Substances 0.000 description 5
- 230000002068 genetic effect Effects 0.000 description 5
- 102000052620 human IL10 Human genes 0.000 description 5
- 230000004054 inflammatory process Effects 0.000 description 5
- 210000000056 organ Anatomy 0.000 description 5
- 150000003839 salts Chemical class 0.000 description 5
- 206010003571 Astrocytoma Diseases 0.000 description 4
- 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 4
- 208000015023 Graves' disease Diseases 0.000 description 4
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 4
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 4
- 102000004551 Interleukin-10 Receptors Human genes 0.000 description 4
- 108010017550 Interleukin-10 Receptors Proteins 0.000 description 4
- 102100030703 Interleukin-22 Human genes 0.000 description 4
- 206010025323 Lymphomas Diseases 0.000 description 4
- 102100031789 Myeloid-derived growth factor Human genes 0.000 description 4
- 206010029260 Neuroblastoma Diseases 0.000 description 4
- 239000004698 Polyethylene Substances 0.000 description 4
- 206010039491 Sarcoma Diseases 0.000 description 4
- 208000031981 Thrombocytopenic Idiopathic Purpura Diseases 0.000 description 4
- 238000007792 addition Methods 0.000 description 4
- 201000003710 autoimmune thrombocytopenic purpura Diseases 0.000 description 4
- 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 4
- 238000002512 chemotherapy Methods 0.000 description 4
- 230000006378 damage Effects 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 210000002865 immune cell Anatomy 0.000 description 4
- 208000026278 immune system disease Diseases 0.000 description 4
- 230000001965 increasing effect Effects 0.000 description 4
- 238000001802 infusion Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 4
- 238000001990 intravenous administration Methods 0.000 description 4
- 206010025135 lupus erythematosus Diseases 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 238000010186 staining Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 239000003981 vehicle Substances 0.000 description 4
- 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 3
- 201000003076 Angiosarcoma Diseases 0.000 description 3
- 208000023328 Basedow disease Diseases 0.000 description 3
- 241000282836 Camelus dromedarius Species 0.000 description 3
- 102100039498 Cytotoxic T-lymphocyte protein 4 Human genes 0.000 description 3
- 208000006168 Ewing Sarcoma Diseases 0.000 description 3
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 3
- 208000001258 Hemangiosarcoma Diseases 0.000 description 3
- 108060003951 Immunoglobulin Proteins 0.000 description 3
- 102000013691 Interleukin-17 Human genes 0.000 description 3
- 108050003558 Interleukin-17 Proteins 0.000 description 3
- 108010002350 Interleukin-2 Proteins 0.000 description 3
- 102000000588 Interleukin-2 Human genes 0.000 description 3
- 108010002386 Interleukin-3 Proteins 0.000 description 3
- 102100039064 Interleukin-3 Human genes 0.000 description 3
- 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 3
- 241000699670 Mus sp. Species 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 108010003723 Single-Domain Antibodies Proteins 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 206010052779 Transplant rejections Diseases 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000033289 adaptive immune response Effects 0.000 description 3
- 239000002246 antineoplastic agent Substances 0.000 description 3
- 108010068265 aspartyltyrosine Proteins 0.000 description 3
- 210000004556 brain Anatomy 0.000 description 3
- 230000021615 conjugation Effects 0.000 description 3
- 229940127089 cytotoxic agent Drugs 0.000 description 3
- 238000010494 dissociation reaction Methods 0.000 description 3
- 230000005593 dissociations Effects 0.000 description 3
- 231100000673 dose–response relationship Toxicity 0.000 description 3
- 230000007613 environmental effect Effects 0.000 description 3
- 206010016256 fatigue Diseases 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 102000018358 immunoglobulin Human genes 0.000 description 3
- 238000009169 immunotherapy Methods 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 230000003993 interaction Effects 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 230000000670 limiting effect Effects 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 210000004698 lymphocyte Anatomy 0.000 description 3
- 108010064235 lysylglycine Proteins 0.000 description 3
- 201000006417 multiple sclerosis Diseases 0.000 description 3
- 239000002773 nucleotide Substances 0.000 description 3
- 125000003729 nucleotide group Chemical group 0.000 description 3
- 201000008968 osteosarcoma Diseases 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 230000004614 tumor growth Effects 0.000 description 3
- HKZAAJSTFUZYTO-LURJTMIESA-N (2s)-2-[[2-[[2-[[2-[(2-aminoacetyl)amino]acetyl]amino]acetyl]amino]acetyl]amino]-3-hydroxypropanoic acid Chemical compound NCC(=O)NCC(=O)NCC(=O)NCC(=O)N[C@@H](CO)C(O)=O HKZAAJSTFUZYTO-LURJTMIESA-N 0.000 description 2
- JPSHPWJJSVEEAX-OWPBQMJCSA-N (2s)-2-amino-4-fluoranylpentanedioic acid Chemical compound OC(=O)[C@@H](N)CC([18F])C(O)=O JPSHPWJJSVEEAX-OWPBQMJCSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- MIJDSYMOBYNHOT-UHFFFAOYSA-N 2-(ethylamino)ethanol Chemical compound CCNCCO MIJDSYMOBYNHOT-UHFFFAOYSA-N 0.000 description 2
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 2
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- GIVATXIGCXFQQA-FXQIFTODSA-N Arg-Ala-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCN=C(N)N GIVATXIGCXFQQA-FXQIFTODSA-N 0.000 description 2
- ORJQQZIXTOYGGH-SRVKXCTJSA-N Asn-Lys-Leu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(O)=O ORJQQZIXTOYGGH-SRVKXCTJSA-N 0.000 description 2
- COWITDLVHMZSIW-CIUDSAMLSA-N Asn-Lys-Ser Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(O)=O COWITDLVHMZSIW-CIUDSAMLSA-N 0.000 description 2
- JUWISGAGWSDGDH-KKUMJFAQSA-N Asp-Phe-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC(O)=O)CC1=CC=CC=C1 JUWISGAGWSDGDH-KKUMJFAQSA-N 0.000 description 2
- 208000000659 Autoimmune lymphoproliferative syndrome Diseases 0.000 description 2
- 102100029822 B- and T-lymphocyte attenuator Human genes 0.000 description 2
- 206010004146 Basal cell carcinoma Diseases 0.000 description 2
- 102100038078 CD276 antigen Human genes 0.000 description 2
- 102100036008 CD48 antigen Human genes 0.000 description 2
- 108010021064 CTLA-4 Antigen Proteins 0.000 description 2
- 229940045513 CTLA4 antagonist Drugs 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- 201000000274 Carcinosarcoma Diseases 0.000 description 2
- 208000005243 Chondrosarcoma Diseases 0.000 description 2
- 208000015943 Coeliac disease Diseases 0.000 description 2
- 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 2
- 206010014733 Endometrial cancer Diseases 0.000 description 2
- 206010014759 Endometrial neoplasm Diseases 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 206010014967 Ependymoma Diseases 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 208000001640 Fibromyalgia Diseases 0.000 description 2
- 201000008808 Fibrosarcoma Diseases 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 208000007465 Giant cell arteritis Diseases 0.000 description 2
- 208000032612 Glial tumor Diseases 0.000 description 2
- 206010018338 Glioma Diseases 0.000 description 2
- QBLMTCRYYTVUQY-GUBZILKMSA-N Gln-Leu-Asp Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O QBLMTCRYYTVUQY-GUBZILKMSA-N 0.000 description 2
- KBKGRMNVKPSQIF-XDTLVQLUSA-N Glu-Ala-Tyr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O KBKGRMNVKPSQIF-XDTLVQLUSA-N 0.000 description 2
- HTTSBEBKVNEDFE-AUTRQRHGSA-N Glu-Gln-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CCC(=O)O)N HTTSBEBKVNEDFE-AUTRQRHGSA-N 0.000 description 2
- MQVNVZUEPUIAFA-WDSKDSINSA-N Gly-Cys-Gln Chemical compound C(CC(=O)N)[C@@H](C(=O)O)NC(=O)[C@H](CS)NC(=O)CN MQVNVZUEPUIAFA-WDSKDSINSA-N 0.000 description 2
- RIYIFUFFFBIOEU-KBPBESRZSA-N Gly-Tyr-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)CN)CC1=CC=C(O)C=C1 RIYIFUFFFBIOEU-KBPBESRZSA-N 0.000 description 2
- 208000035186 Hemolytic Autoimmune Anemia Diseases 0.000 description 2
- 108010007712 Hepatitis A Virus Cellular Receptor 1 Proteins 0.000 description 2
- 102100034459 Hepatitis A virus cellular receptor 1 Human genes 0.000 description 2
- 102100034458 Hepatitis A virus cellular receptor 2 Human genes 0.000 description 2
- 101710083479 Hepatitis A virus cellular receptor 2 homolog Proteins 0.000 description 2
- 208000017604 Hodgkin disease Diseases 0.000 description 2
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 101000864344 Homo sapiens B- and T-lymphocyte attenuator Proteins 0.000 description 2
- 101000716130 Homo sapiens CD48 antigen Proteins 0.000 description 2
- 101001002470 Homo sapiens Interferon lambda-1 Proteins 0.000 description 2
- 101001010591 Homo sapiens Interleukin-20 Proteins 0.000 description 2
- 101000853002 Homo sapiens Interleukin-25 Proteins 0.000 description 2
- 101000853000 Homo sapiens Interleukin-26 Proteins 0.000 description 2
- 101000998139 Homo sapiens Interleukin-32 Proteins 0.000 description 2
- 101000984189 Homo sapiens Leukocyte immunoglobulin-like receptor subfamily B member 2 Proteins 0.000 description 2
- 101000984186 Homo sapiens Leukocyte immunoglobulin-like receptor subfamily B member 4 Proteins 0.000 description 2
- 101000868279 Homo sapiens Leukocyte surface antigen CD47 Proteins 0.000 description 2
- 101001128431 Homo sapiens Myeloid-derived growth factor Proteins 0.000 description 2
- 101000831007 Homo sapiens T-cell immunoreceptor with Ig and ITIM domains Proteins 0.000 description 2
- 101000666896 Homo sapiens V-type immunoglobulin domain-containing suppressor of T-cell activation Proteins 0.000 description 2
- 102100034980 ICOS ligand Human genes 0.000 description 2
- 206010021245 Idiopathic thrombocytopenic purpura Diseases 0.000 description 2
- WYUHAXJAMDTOAU-IAVJCBSLSA-N Ile-Phe-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)CC)C(=O)O)N WYUHAXJAMDTOAU-IAVJCBSLSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 108010067060 Immunoglobulin Variable Region Proteins 0.000 description 2
- 102000017727 Immunoglobulin Variable Region Human genes 0.000 description 2
- 102000004877 Insulin Human genes 0.000 description 2
- 108090001061 Insulin Proteins 0.000 description 2
- 102000000589 Interleukin-1 Human genes 0.000 description 2
- 108010002352 Interleukin-1 Proteins 0.000 description 2
- 108090000177 Interleukin-11 Proteins 0.000 description 2
- 102000003815 Interleukin-11 Human genes 0.000 description 2
- 108010065805 Interleukin-12 Proteins 0.000 description 2
- 102000013462 Interleukin-12 Human genes 0.000 description 2
- 108090000176 Interleukin-13 Proteins 0.000 description 2
- 102000003816 Interleukin-13 Human genes 0.000 description 2
- 108090000172 Interleukin-15 Proteins 0.000 description 2
- 102000003812 Interleukin-15 Human genes 0.000 description 2
- 101800003050 Interleukin-16 Proteins 0.000 description 2
- 102000049772 Interleukin-16 Human genes 0.000 description 2
- 102000003810 Interleukin-18 Human genes 0.000 description 2
- 108090000171 Interleukin-18 Proteins 0.000 description 2
- 102100039879 Interleukin-19 Human genes 0.000 description 2
- 108050009288 Interleukin-19 Proteins 0.000 description 2
- 102100030692 Interleukin-20 Human genes 0.000 description 2
- 102100036679 Interleukin-26 Human genes 0.000 description 2
- 108010066979 Interleukin-27 Proteins 0.000 description 2
- 101710181613 Interleukin-31 Proteins 0.000 description 2
- 108010067003 Interleukin-33 Proteins 0.000 description 2
- 108091007973 Interleukin-36 Proteins 0.000 description 2
- 108090000978 Interleukin-4 Proteins 0.000 description 2
- 102000004388 Interleukin-4 Human genes 0.000 description 2
- 108010002616 Interleukin-5 Proteins 0.000 description 2
- 102000000743 Interleukin-5 Human genes 0.000 description 2
- 108090001005 Interleukin-6 Proteins 0.000 description 2
- 102000004889 Interleukin-6 Human genes 0.000 description 2
- 108090001007 Interleukin-8 Proteins 0.000 description 2
- 102000004890 Interleukin-8 Human genes 0.000 description 2
- 208000007766 Kaposi sarcoma Diseases 0.000 description 2
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 2
- 102000017578 LAG3 Human genes 0.000 description 2
- 101150030213 Lag3 gene Proteins 0.000 description 2
- 208000018142 Leiomyosarcoma Diseases 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
- JIHDFWWRYHSAQB-GUBZILKMSA-N Leu-Ser-Glu Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CCC(O)=O JIHDFWWRYHSAQB-GUBZILKMSA-N 0.000 description 2
- 108010017736 Leukocyte Immunoglobulin-like Receptor B1 Proteins 0.000 description 2
- 102100025584 Leukocyte immunoglobulin-like receptor subfamily B member 1 Human genes 0.000 description 2
- 102100025583 Leukocyte immunoglobulin-like receptor subfamily B member 2 Human genes 0.000 description 2
- 102100025578 Leukocyte immunoglobulin-like receptor subfamily B member 4 Human genes 0.000 description 2
- 102100032913 Leukocyte surface antigen CD47 Human genes 0.000 description 2
- WQWZXKWOEVSGQM-DCAQKATOSA-N Lys-Ala-Met Chemical compound CSCC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCCN WQWZXKWOEVSGQM-DCAQKATOSA-N 0.000 description 2
- IRNSXVOWSXSULE-DCAQKATOSA-N Lys-Ala-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCCN IRNSXVOWSXSULE-DCAQKATOSA-N 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- RVYDCISQIGHAFC-ZPFDUUQYSA-N Met-Ile-Gln Chemical compound CSCC[C@H](N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(N)=O)C(O)=O RVYDCISQIGHAFC-ZPFDUUQYSA-N 0.000 description 2
- QEDGNYFHLXXIDC-DCAQKATOSA-N Met-Pro-Gln Chemical compound CSCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(O)=O QEDGNYFHLXXIDC-DCAQKATOSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 101100407308 Mus musculus Pdcd1lg2 gene Proteins 0.000 description 2
- GXCLVBGFBYZDAG-UHFFFAOYSA-N N-[2-(1H-indol-3-yl)ethyl]-N-methylprop-2-en-1-amine Chemical compound CN(CCC1=CNC2=C1C=CC=C2)CC=C GXCLVBGFBYZDAG-UHFFFAOYSA-N 0.000 description 2
- 102100029527 Natural cytotoxicity triggering receptor 3 ligand 1 Human genes 0.000 description 2
- 108091005461 Nucleic proteins Proteins 0.000 description 2
- 201000010133 Oligodendroglioma Diseases 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- 206010061332 Paraganglion neoplasm Diseases 0.000 description 2
- 235000019483 Peanut oil Nutrition 0.000 description 2
- 241001494479 Pecora Species 0.000 description 2
- 206010034277 Pemphigoid Diseases 0.000 description 2
- ROOQMPCUFLDOSB-FHWLQOOXSA-N Phe-Phe-Gln Chemical compound C([C@H](N)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCC(N)=O)C(O)=O)C1=CC=CC=C1 ROOQMPCUFLDOSB-FHWLQOOXSA-N 0.000 description 2
- ZYNBEWGJFXTBDU-ACRUOGEOSA-N Phe-Tyr-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)NC(=O)[C@H](CC2=CC=CC=C2)N ZYNBEWGJFXTBDU-ACRUOGEOSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 2
- LCWXSALTPTZKNM-CIUDSAMLSA-N Pro-Cys-Glu Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(=O)O)C(=O)O LCWXSALTPTZKNM-CIUDSAMLSA-N 0.000 description 2
- 108700030875 Programmed Cell Death 1 Ligand 2 Proteins 0.000 description 2
- 102100024213 Programmed cell death 1 ligand 2 Human genes 0.000 description 2
- 206010037660 Pyrexia Diseases 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 102100037422 Receptor-type tyrosine-protein phosphatase C Human genes 0.000 description 2
- 208000006265 Renal cell carcinoma Diseases 0.000 description 2
- 201000000582 Retinoblastoma Diseases 0.000 description 2
- 101150036449 SIRPA gene Proteins 0.000 description 2
- XNCUYZKGQOCOQH-YUMQZZPRSA-N Ser-Leu-Gly Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O XNCUYZKGQOCOQH-YUMQZZPRSA-N 0.000 description 2
- 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 2
- 229930006000 Sucrose Natural products 0.000 description 2
- 102100039367 T-cell immunoglobulin and mucin domain-containing protein 4 Human genes 0.000 description 2
- 101710174757 T-cell immunoglobulin and mucin domain-containing protein 4 Proteins 0.000 description 2
- 229940126547 T-cell immunoglobulin mucin-3 Drugs 0.000 description 2
- 102100024834 T-cell immunoreceptor with Ig and ITIM domains Human genes 0.000 description 2
- UDNVOQMPQBEITB-MEYUZBJRSA-N Thr-His-Phe Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O UDNVOQMPQBEITB-MEYUZBJRSA-N 0.000 description 2
- 101710165473 Tumor necrosis factor receptor superfamily member 4 Proteins 0.000 description 2
- 102100022153 Tumor necrosis factor receptor superfamily member 4 Human genes 0.000 description 2
- 102100038929 V-set domain-containing T-cell activation inhibitor 1 Human genes 0.000 description 2
- 102100038282 V-type immunoglobulin domain-containing suppressor of T-cell activation Human genes 0.000 description 2
- XPKCFQZDQGVJCX-RHYQMDGZSA-N Val-Lys-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C(C)C)N)O XPKCFQZDQGVJCX-RHYQMDGZSA-N 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 208000020990 adrenal cortex carcinoma Diseases 0.000 description 2
- 208000007128 adrenocortical carcinoma Diseases 0.000 description 2
- 125000000539 amino acid group Chemical group 0.000 description 2
- 239000003708 ampul Substances 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000033115 angiogenesis Effects 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 230000010056 antibody-dependent cellular cytotoxicity Effects 0.000 description 2
- 102000025171 antigen binding proteins Human genes 0.000 description 2
- 108091000831 antigen binding proteins Proteins 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000001185 bone marrow Anatomy 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 230000010261 cell growth Effects 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 239000002738 chelating agent Substances 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 208000006990 cholangiocarcinoma Diseases 0.000 description 2
- 230000000295 complement effect Effects 0.000 description 2
- 230000004540 complement-dependent cytotoxicity Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000013270 controlled release Methods 0.000 description 2
- 239000007822 coupling agent Substances 0.000 description 2
- 208000035250 cutaneous malignant susceptibility to 1 melanoma Diseases 0.000 description 2
- 230000016396 cytokine production Effects 0.000 description 2
- 201000001981 dermatomyositis Diseases 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 238000012377 drug delivery Methods 0.000 description 2
- 230000002327 eosinophilic effect Effects 0.000 description 2
- MMXKVMNBHPAILY-UHFFFAOYSA-N ethyl laurate Chemical compound CCCCCCCCCCCC(=O)OCC MMXKVMNBHPAILY-UHFFFAOYSA-N 0.000 description 2
- 230000001747 exhibiting effect Effects 0.000 description 2
- IJJVMEJXYNJXOJ-UHFFFAOYSA-N fluquinconazole Chemical compound C=1C=C(Cl)C=C(Cl)C=1N1C(=O)C2=CC(F)=CC=C2N=C1N1C=NC=N1 IJJVMEJXYNJXOJ-UHFFFAOYSA-N 0.000 description 2
- 230000004927 fusion Effects 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 208000005017 glioblastoma Diseases 0.000 description 2
- 108010079547 glutamylmethionine Proteins 0.000 description 2
- 108010010147 glycylglutamine Proteins 0.000 description 2
- 108010050848 glycylleucine Proteins 0.000 description 2
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 2
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 2
- 150000004679 hydroxides Chemical class 0.000 description 2
- 238000003384 imaging method Methods 0.000 description 2
- 230000028993 immune response Effects 0.000 description 2
- 230000006058 immune tolerance Effects 0.000 description 2
- 230000002998 immunogenetic effect Effects 0.000 description 2
- 239000003018 immunosuppressive agent Substances 0.000 description 2
- 229940124589 immunosuppressive drug Drugs 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 229940125396 insulin Drugs 0.000 description 2
- 108010074108 interleukin-21 Proteins 0.000 description 2
- 108010074109 interleukin-22 Proteins 0.000 description 2
- 108090000237 interleukin-24 Proteins 0.000 description 2
- 102000003898 interleukin-24 Human genes 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 2
- 210000004072 lung Anatomy 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 210000005075 mammary gland Anatomy 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 239000003550 marker Substances 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- 208000025113 myeloid leukemia Diseases 0.000 description 2
- 210000000822 natural killer cell Anatomy 0.000 description 2
- 210000002569 neuron Anatomy 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 230000002611 ovarian Effects 0.000 description 2
- 210000000496 pancreas Anatomy 0.000 description 2
- 208000007312 paraganglioma Diseases 0.000 description 2
- 239000000312 peanut oil Substances 0.000 description 2
- PTMHPRAIXMAOOB-UHFFFAOYSA-N phosphoramidic acid Chemical compound NP(O)(O)=O PTMHPRAIXMAOOB-UHFFFAOYSA-N 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 2
- 229960004919 procaine Drugs 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 201000009410 rhabdomyosarcoma Diseases 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 230000035945 sensitivity Effects 0.000 description 2
- 239000008159 sesame oil Substances 0.000 description 2
- 235000011803 sesame oil Nutrition 0.000 description 2
- 210000003491 skin Anatomy 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000003549 soybean oil Substances 0.000 description 2
- 235000012424 soybean oil Nutrition 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 210000000130 stem cell Anatomy 0.000 description 2
- 210000002784 stomach Anatomy 0.000 description 2
- 210000002536 stromal cell Anatomy 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 230000008961 swelling Effects 0.000 description 2
- 208000011580 syndromic disease Diseases 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 206010043207 temporal arteritis Diseases 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- 239000003053 toxin Substances 0.000 description 2
- 231100000765 toxin Toxicity 0.000 description 2
- 108700012359 toxins Proteins 0.000 description 2
- 238000003146 transient transfection Methods 0.000 description 2
- 238000012384 transportation and delivery Methods 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 108010073969 valyllysine Proteins 0.000 description 2
- 230000004580 weight loss Effects 0.000 description 2
- KYRUKRFVOACELK-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 3-(4-hydroxyphenyl)propanoate Chemical compound C1=CC(O)=CC=C1CCC(=O)ON1C(=O)CCC1=O KYRUKRFVOACELK-UHFFFAOYSA-N 0.000 description 1
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 1
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- NFGXHKASABOEEW-UHFFFAOYSA-N 1-methylethyl 11-methoxy-3,7,11-trimethyl-2,4-dodecadienoate Chemical compound COC(C)(C)CCCC(C)CC=CC(C)=CC(=O)OC(C)C NFGXHKASABOEEW-UHFFFAOYSA-N 0.000 description 1
- AGFIRQJZCNVMCW-UAKXSSHOSA-N 5-bromouridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(Br)=C1 AGFIRQJZCNVMCW-UAKXSSHOSA-N 0.000 description 1
- BDDLHHRCDSJVKV-UHFFFAOYSA-N 7028-40-2 Chemical compound CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O BDDLHHRCDSJVKV-UHFFFAOYSA-N 0.000 description 1
- 208000016557 Acute basophilic leukemia Diseases 0.000 description 1
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 1
- 208000004804 Adenomatous Polyps Diseases 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- MKZCBYZBCINNJN-DLOVCJGASA-N Ala-Asp-Phe Chemical compound C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 MKZCBYZBCINNJN-DLOVCJGASA-N 0.000 description 1
- RNHKOQHGYMTHFR-UBHSHLNASA-N Ala-Phe-Met Chemical compound CSCC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@H](C)N)CC1=CC=CC=C1 RNHKOQHGYMTHFR-UBHSHLNASA-N 0.000 description 1
- YCRAFFCYWOUEOF-DLOVCJGASA-N Ala-Phe-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)C)CC1=CC=CC=C1 YCRAFFCYWOUEOF-DLOVCJGASA-N 0.000 description 1
- 201000004384 Alopecia Diseases 0.000 description 1
- 206010061424 Anal cancer Diseases 0.000 description 1
- 206010002556 Ankylosing Spondylitis Diseases 0.000 description 1
- 244000303258 Annona diversifolia Species 0.000 description 1
- 235000002198 Annona diversifolia Nutrition 0.000 description 1
- 208000003343 Antiphospholipid Syndrome Diseases 0.000 description 1
- KJGNDQCYBNBXDA-GUBZILKMSA-N Arg-Arg-Cys Chemical compound C(C[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CS)C(=O)O)N)CN=C(N)N KJGNDQCYBNBXDA-GUBZILKMSA-N 0.000 description 1
- XLWSGICNBZGYTA-CIUDSAMLSA-N Arg-Glu-Asp Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O XLWSGICNBZGYTA-CIUDSAMLSA-N 0.000 description 1
- HPSVTWMFWCHKFN-GARJFASQSA-N Arg-Glu-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CCCN=C(N)N)N)C(=O)O HPSVTWMFWCHKFN-GARJFASQSA-N 0.000 description 1
- NKNILFJYKKHBKE-WPRPVWTQSA-N Arg-Gly-Val Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](C(C)C)C(O)=O NKNILFJYKKHBKE-WPRPVWTQSA-N 0.000 description 1
- 208000006820 Arthralgia Diseases 0.000 description 1
- RZVVKNIACROXRM-ZLUOBGJFSA-N Asn-Ala-Asp Chemical compound C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)O)NC(=O)[C@H](CC(=O)N)N RZVVKNIACROXRM-ZLUOBGJFSA-N 0.000 description 1
- YNSCBOUZTAGIGO-ZLUOBGJFSA-N Asn-Asn-Cys Chemical compound C([C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CS)C(=O)O)N)C(=O)N YNSCBOUZTAGIGO-ZLUOBGJFSA-N 0.000 description 1
- ZMWDUIIACVLIHK-GHCJXIJMSA-N Asn-Cys-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CS)NC(=O)[C@H](CC(=O)N)N ZMWDUIIACVLIHK-GHCJXIJMSA-N 0.000 description 1
- COUZKSSMBFADSB-AVGNSLFASA-N Asn-Glu-Phe Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CC(=O)N)N COUZKSSMBFADSB-AVGNSLFASA-N 0.000 description 1
- GQRDIVQPSMPQME-ZPFDUUQYSA-N Asn-Ile-Leu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(O)=O GQRDIVQPSMPQME-ZPFDUUQYSA-N 0.000 description 1
- HDHZCEDPLTVHFZ-GUBZILKMSA-N Asn-Leu-Glu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O HDHZCEDPLTVHFZ-GUBZILKMSA-N 0.000 description 1
- GLWFAWNYGWBMOC-SRVKXCTJSA-N Asn-Leu-Leu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O GLWFAWNYGWBMOC-SRVKXCTJSA-N 0.000 description 1
- PPCORQFLAZWUNO-QWRGUYRKSA-N Asn-Phe-Gly Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)NCC(=O)O)NC(=O)[C@H](CC(=O)N)N PPCORQFLAZWUNO-QWRGUYRKSA-N 0.000 description 1
- KYQJHBWHRASMKG-ZLUOBGJFSA-N Asn-Ser-Cys Chemical compound NC(=O)C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(O)=O KYQJHBWHRASMKG-ZLUOBGJFSA-N 0.000 description 1
- BEHQTVDBCLSCBY-CFMVVWHZSA-N Asn-Tyr-Ile Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O BEHQTVDBCLSCBY-CFMVVWHZSA-N 0.000 description 1
- RYEWQKQXRJCHIO-SRVKXCTJSA-N Asp-Asn-Tyr Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 RYEWQKQXRJCHIO-SRVKXCTJSA-N 0.000 description 1
- KESWRFKUZRUTAH-FXQIFTODSA-N Asp-Pro-Asp Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(O)=O)C(O)=O KESWRFKUZRUTAH-FXQIFTODSA-N 0.000 description 1
- SFJUYBCDQBAYAJ-YDHLFZDLSA-N Asp-Val-Phe Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 SFJUYBCDQBAYAJ-YDHLFZDLSA-N 0.000 description 1
- 206010003591 Ataxia Diseases 0.000 description 1
- 206010003827 Autoimmune hepatitis Diseases 0.000 description 1
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 1
- 238000011725 BALB/c mouse Methods 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 208000009299 Benign Mucous Membrane Pemphigoid Diseases 0.000 description 1
- 206010004593 Bile duct cancer Diseases 0.000 description 1
- 208000008439 Biliary Liver Cirrhosis Diseases 0.000 description 1
- 208000033222 Biliary cirrhosis primary Diseases 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 201000004569 Blindness Diseases 0.000 description 1
- 208000018084 Bone neoplasm Diseases 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 208000007690 Brenner tumor Diseases 0.000 description 1
- 206010073258 Brenner tumour Diseases 0.000 description 1
- 208000003170 Bronchiolo-Alveolar Adenocarcinoma Diseases 0.000 description 1
- 208000011691 Burkitt lymphomas Diseases 0.000 description 1
- 210000001239 CD8-positive, alpha-beta cytotoxic T lymphocyte Anatomy 0.000 description 1
- 241000282832 Camelidae Species 0.000 description 1
- 240000001548 Camellia japonica Species 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 208000031229 Cardiomyopathies Diseases 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- 206010008479 Chest Pain Diseases 0.000 description 1
- 206010008583 Chloroma Diseases 0.000 description 1
- 201000009047 Chordoma Diseases 0.000 description 1
- 208000006332 Choriocarcinoma Diseases 0.000 description 1
- 208000030939 Chronic inflammatory demyelinating polyneuropathy Diseases 0.000 description 1
- 208000011038 Cold agglutinin disease Diseases 0.000 description 1
- 206010009868 Cold type haemolytic anaemia Diseases 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 241000699800 Cricetinae Species 0.000 description 1
- 208000019707 Cryoglobulinemic vasculitis Diseases 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-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
- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 description 1
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 1
- 208000003164 Diplopia Diseases 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 206010014561 Emphysema Diseases 0.000 description 1
- 206010014958 Eosinophilic leukaemia Diseases 0.000 description 1
- 241000283073 Equus caballus Species 0.000 description 1
- 208000031637 Erythroblastic Acute Leukemia Diseases 0.000 description 1
- 208000036566 Erythroleukaemia Diseases 0.000 description 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- 244000239659 Eucalyptus pulverulenta Species 0.000 description 1
- 208000010201 Exanthema Diseases 0.000 description 1
- 108091092566 Extrachromosomal DNA Proteins 0.000 description 1
- 201000006107 Familial adenomatous polyposis Diseases 0.000 description 1
- 108010087819 Fc receptors Proteins 0.000 description 1
- 102000009109 Fc receptors Human genes 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 241000724791 Filamentous phage Species 0.000 description 1
- 208000004463 Follicular Adenocarcinoma Diseases 0.000 description 1
- 208000008999 Giant Cell Carcinoma Diseases 0.000 description 1
- 208000002966 Giant Cell Tumor of Bone Diseases 0.000 description 1
- RKAQZCDMSUQTSS-FXQIFTODSA-N Gln-Asp-Gln Chemical compound C(CC(=O)N)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N RKAQZCDMSUQTSS-FXQIFTODSA-N 0.000 description 1
- QYKBTDOAMKORGL-FXQIFTODSA-N Gln-Gln-Asp Chemical compound C(CC(=O)N)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CC(=O)O)C(=O)O)N QYKBTDOAMKORGL-FXQIFTODSA-N 0.000 description 1
- RBWKVOSARCFSQQ-FXQIFTODSA-N Gln-Gln-Ser Chemical compound NC(=O)CC[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(O)=O RBWKVOSARCFSQQ-FXQIFTODSA-N 0.000 description 1
- MAGNEQBFSBREJL-DCAQKATOSA-N Gln-Glu-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CCC(=O)N)N MAGNEQBFSBREJL-DCAQKATOSA-N 0.000 description 1
- JXFLPKSDLDEOQK-JHEQGTHGSA-N Gln-Gly-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CCC(N)=O JXFLPKSDLDEOQK-JHEQGTHGSA-N 0.000 description 1
- RWQCWSGOOOEGPB-FXQIFTODSA-N Gln-Ser-Glu Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(O)=O RWQCWSGOOOEGPB-FXQIFTODSA-N 0.000 description 1
- OTQSTOXRUBVWAP-NRPADANISA-N Gln-Ser-Val Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O OTQSTOXRUBVWAP-NRPADANISA-N 0.000 description 1
- UBRQJXFDVZNYJP-AVGNSLFASA-N Gln-Tyr-Ser Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CCC(=O)N)N)O UBRQJXFDVZNYJP-AVGNSLFASA-N 0.000 description 1
- MLCPTRRNICEKIS-FXQIFTODSA-N Glu-Asn-Gln Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O MLCPTRRNICEKIS-FXQIFTODSA-N 0.000 description 1
- QJCKNLPMTPXXEM-AUTRQRHGSA-N Glu-Glu-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CCC(O)=O QJCKNLPMTPXXEM-AUTRQRHGSA-N 0.000 description 1
- YGLCLCMAYUYZSG-AVGNSLFASA-N Glu-Lys-His Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(O)=O)CC1=CN=CN1 YGLCLCMAYUYZSG-AVGNSLFASA-N 0.000 description 1
- DMYACXMQUABZIQ-NRPADANISA-N Glu-Ser-Val Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O DMYACXMQUABZIQ-NRPADANISA-N 0.000 description 1
- SXRSQZLOMIGNAQ-UHFFFAOYSA-N Glutaraldehyde Chemical compound O=CCCCC=O SXRSQZLOMIGNAQ-UHFFFAOYSA-N 0.000 description 1
- XVYKMNXXJXQKME-XEGUGMAKSA-N Gly-Ile-Tyr Chemical compound NCC(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 XVYKMNXXJXQKME-XEGUGMAKSA-N 0.000 description 1
- JJGBXTYGTKWGAT-YUMQZZPRSA-N Gly-Pro-Glu Chemical compound NCC(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O JJGBXTYGTKWGAT-YUMQZZPRSA-N 0.000 description 1
- DNAZKGFYFRGZIH-QWRGUYRKSA-N Gly-Tyr-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)CN)CC1=CC=C(O)C=C1 DNAZKGFYFRGZIH-QWRGUYRKSA-N 0.000 description 1
- GBYYQVBXFVDJPJ-WLTAIBSBSA-N Gly-Tyr-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)NC(=O)CN)O GBYYQVBXFVDJPJ-WLTAIBSBSA-N 0.000 description 1
- IZVICCORZOSGPT-JSGCOSHPSA-N Gly-Val-Tyr Chemical compound [H]NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O IZVICCORZOSGPT-JSGCOSHPSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 206010018498 Goitre Diseases 0.000 description 1
- 206010018691 Granuloma Diseases 0.000 description 1
- 206010072579 Granulomatosis with polyangiitis Diseases 0.000 description 1
- 208000003807 Graves Disease Diseases 0.000 description 1
- 102100031547 HLA class II histocompatibility antigen, DO alpha chain Human genes 0.000 description 1
- 208000030836 Hashimoto thyroiditis Diseases 0.000 description 1
- 208000002125 Hemangioendothelioma Diseases 0.000 description 1
- 206010020112 Hirsutism Diseases 0.000 description 1
- CJGDTAHEMXLRMB-ULQDDVLXSA-N His-Arg-Phe Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O CJGDTAHEMXLRMB-ULQDDVLXSA-N 0.000 description 1
- JENKOCSDMSVWPY-SRVKXCTJSA-N His-Leu-Asn Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O JENKOCSDMSVWPY-SRVKXCTJSA-N 0.000 description 1
- GYXDQXPCPASCNR-NHCYSSNCSA-N His-Val-Asn Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CC1=CN=CN1)N GYXDQXPCPASCNR-NHCYSSNCSA-N 0.000 description 1
- 208000002291 Histiocytic Sarcoma Diseases 0.000 description 1
- 208000021519 Hodgkin lymphoma Diseases 0.000 description 1
- 101000889276 Homo sapiens Cytotoxic T-lymphocyte protein 4 Proteins 0.000 description 1
- 101000866278 Homo sapiens HLA class II histocompatibility antigen, DO alpha chain Proteins 0.000 description 1
- 101000852992 Homo sapiens Interleukin-12 subunit beta Proteins 0.000 description 1
- 101000852980 Homo sapiens Interleukin-23 subunit alpha Proteins 0.000 description 1
- 101001043807 Homo sapiens Interleukin-7 Proteins 0.000 description 1
- 101001138062 Homo sapiens Leukocyte-associated immunoglobulin-like receptor 1 Proteins 0.000 description 1
- 101001117317 Homo sapiens Programmed cell death 1 ligand 1 Proteins 0.000 description 1
- 101000611936 Homo sapiens Programmed cell death protein 1 Proteins 0.000 description 1
- 101000738771 Homo sapiens Receptor-type tyrosine-protein phosphatase C Proteins 0.000 description 1
- 101000997835 Homo sapiens Tyrosine-protein kinase JAK1 Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010048643 Hypereosinophilic syndrome Diseases 0.000 description 1
- 208000008454 Hyperhidrosis Diseases 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 description 1
- 208000010159 IgA glomerulonephritis Diseases 0.000 description 1
- 206010021263 IgA nephropathy Diseases 0.000 description 1
- UIEZQYNXCYHMQS-BJDJZHNGSA-N Ile-Lys-Ala Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)O)N UIEZQYNXCYHMQS-BJDJZHNGSA-N 0.000 description 1
- ADDYYRVQQZFIMW-MNXVOIDGSA-N Ile-Lys-Glu Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N ADDYYRVQQZFIMW-MNXVOIDGSA-N 0.000 description 1
- 229940076838 Immune checkpoint inhibitor Drugs 0.000 description 1
- 108010054477 Immunoglobulin Fab Fragments Proteins 0.000 description 1
- 102000001706 Immunoglobulin Fab Fragments Human genes 0.000 description 1
- 206010062016 Immunosuppression 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
- UGQMRVRMYYASKQ-KQYNXXCUSA-N Inosine Chemical class O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C2=NC=NC(O)=C2N=C1 UGQMRVRMYYASKQ-KQYNXXCUSA-N 0.000 description 1
- 102100036701 Interleukin-12 subunit beta Human genes 0.000 description 1
- 102100036705 Interleukin-23 subunit alpha Human genes 0.000 description 1
- 206010023232 Joint swelling Diseases 0.000 description 1
- 208000003456 Juvenile Arthritis Diseases 0.000 description 1
- 206010059176 Juvenile idiopathic arthritis Diseases 0.000 description 1
- 241000588748 Klebsiella Species 0.000 description 1
- FADYJNXDPBKVCA-UHFFFAOYSA-N L-Phenylalanyl-L-lysin Natural products NCCCCC(C(O)=O)NC(=O)C(N)CC1=CC=CC=C1 FADYJNXDPBKVCA-UHFFFAOYSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- SENJXOPIZNYLHU-UHFFFAOYSA-N L-leucyl-L-arginine Natural products CC(C)CC(N)C(=O)NC(C(O)=O)CCCN=C(N)N SENJXOPIZNYLHU-UHFFFAOYSA-N 0.000 description 1
- 206010023825 Laryngeal cancer Diseases 0.000 description 1
- STAVRDQLZOTNKJ-RHYQMDGZSA-N Leu-Arg-Thr Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(O)=O STAVRDQLZOTNKJ-RHYQMDGZSA-N 0.000 description 1
- KEVYYIMVELOXCT-KBPBESRZSA-N Leu-Gly-Phe Chemical compound CC(C)C[C@H]([NH3+])C(=O)NCC(=O)N[C@H](C([O-])=O)CC1=CC=CC=C1 KEVYYIMVELOXCT-KBPBESRZSA-N 0.000 description 1
- KXCMQWMNYQOAKA-SRVKXCTJSA-N Leu-Met-Gln Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N KXCMQWMNYQOAKA-SRVKXCTJSA-N 0.000 description 1
- 206010024305 Leukaemia monocytic Diseases 0.000 description 1
- 102100020943 Leukocyte-associated immunoglobulin-like receptor 1 Human genes 0.000 description 1
- 208000000265 Lobular Carcinoma Diseases 0.000 description 1
- 208000008771 Lymphadenopathy Diseases 0.000 description 1
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 1
- 208000028018 Lymphocytic leukaemia Diseases 0.000 description 1
- UWKNTTJNVSYXPC-CIUDSAMLSA-N Lys-Ala-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCCN UWKNTTJNVSYXPC-CIUDSAMLSA-N 0.000 description 1
- DGAAQRAUOFHBFJ-CIUDSAMLSA-N Lys-Asn-Ala Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(O)=O DGAAQRAUOFHBFJ-CIUDSAMLSA-N 0.000 description 1
- VEGLGAOVLFODGC-GUBZILKMSA-N Lys-Glu-Ser Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(O)=O VEGLGAOVLFODGC-GUBZILKMSA-N 0.000 description 1
- RBEATVHTWHTHTJ-KKUMJFAQSA-N Lys-Leu-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(O)=O RBEATVHTWHTHTJ-KKUMJFAQSA-N 0.000 description 1
- MTBLFIQZECOEBY-IHRRRGAJSA-N Lys-Met-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCCN)C(O)=O MTBLFIQZECOEBY-IHRRRGAJSA-N 0.000 description 1
- MGKFCQFVPKOWOL-CIUDSAMLSA-N Lys-Ser-Asp Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(=O)O)C(=O)O)N MGKFCQFVPKOWOL-CIUDSAMLSA-N 0.000 description 1
- 102000043131 MHC class II family Human genes 0.000 description 1
- 108091054438 MHC class II family Proteins 0.000 description 1
- 206010064281 Malignant atrophic papulosis Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 208000007054 Medullary Carcinoma Diseases 0.000 description 1
- 208000000172 Medulloblastoma Diseases 0.000 description 1
- 208000035490 Megakaryoblastic Acute Leukemia Diseases 0.000 description 1
- 206010027145 Melanocytic naevus Diseases 0.000 description 1
- 208000027530 Meniere disease Diseases 0.000 description 1
- 208000002030 Merkel cell carcinoma Diseases 0.000 description 1
- 201000009574 Mesenchymal Chondrosarcoma Diseases 0.000 description 1
- 206010027406 Mesothelioma Diseases 0.000 description 1
- WDTLNWHPIPCMMP-AVGNSLFASA-N Met-Arg-Leu Chemical compound [H]N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(O)=O WDTLNWHPIPCMMP-AVGNSLFASA-N 0.000 description 1
- YYEIFXZOBZVDPH-DCAQKATOSA-N Met-Lys-Asp Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(O)=O YYEIFXZOBZVDPH-DCAQKATOSA-N 0.000 description 1
- LLKWSEXLNFBKIF-CYDGBPFRSA-N Met-Met-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@H](CCSC)NC(=O)[C@@H](N)CCSC LLKWSEXLNFBKIF-CYDGBPFRSA-N 0.000 description 1
- 208000003250 Mixed connective tissue disease Diseases 0.000 description 1
- 206010057269 Mucoepidermoid carcinoma Diseases 0.000 description 1
- 208000012192 Mucous membrane pemphigoid Diseases 0.000 description 1
- 208000010357 Mullerian Mixed Tumor Diseases 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- 101001033265 Mus musculus Interleukin-10 Proteins 0.000 description 1
- 208000010428 Muscle Weakness Diseases 0.000 description 1
- 206010028372 Muscular weakness Diseases 0.000 description 1
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 1
- 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 1
- NXTVQNIVUKXOIL-UHFFFAOYSA-N N-chlorotoluene-p-sulfonamide Chemical compound CC1=CC=C(S(=O)(=O)NCl)C=C1 NXTVQNIVUKXOIL-UHFFFAOYSA-N 0.000 description 1
- 108091028043 Nucleic acid sequence Proteins 0.000 description 1
- 208000007871 Odontogenic Tumors Diseases 0.000 description 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 1
- 108091034117 Oligonucleotide Proteins 0.000 description 1
- 208000007117 Oral Ulcer Diseases 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 208000010191 Osteitis Deformans Diseases 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 208000027868 Paget disease Diseases 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 201000011152 Pemphigus Diseases 0.000 description 1
- 208000031845 Pernicious anaemia Diseases 0.000 description 1
- 241000009328 Perro Species 0.000 description 1
- 208000009565 Pharyngeal Neoplasms Diseases 0.000 description 1
- 206010034811 Pharyngeal cancer Diseases 0.000 description 1
- YOFKMVUAZGPFCF-IHRRRGAJSA-N Phe-Met-Asn Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(O)=O YOFKMVUAZGPFCF-IHRRRGAJSA-N 0.000 description 1
- 208000009077 Pigmented Nevus Diseases 0.000 description 1
- 208000007641 Pinealoma Diseases 0.000 description 1
- 206010036018 Pollakiuria Diseases 0.000 description 1
- 229920002732 Polyanhydride Polymers 0.000 description 1
- 206010065159 Polychondritis Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 208000007048 Polymyalgia Rheumatica Diseases 0.000 description 1
- 208000012654 Primary biliary cholangitis Diseases 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- QKWYXRPICJEQAJ-KJEVXHAQSA-N Pro-Tyr-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)NC(=O)[C@@H]2CCCN2)O QKWYXRPICJEQAJ-KJEVXHAQSA-N 0.000 description 1
- 108010076504 Protein Sorting Signals Proteins 0.000 description 1
- 101710138747 Receptor-type tyrosine-protein phosphatase C Proteins 0.000 description 1
- 208000015634 Rectal Neoplasms Diseases 0.000 description 1
- 208000033464 Reiter syndrome Diseases 0.000 description 1
- 108091028664 Ribonucleotide Proteins 0.000 description 1
- PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Natural products OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 description 1
- 108010017324 STAT3 Transcription Factor Proteins 0.000 description 1
- 235000019485 Safflower oil Nutrition 0.000 description 1
- 206010039710 Scleroderma Diseases 0.000 description 1
- 208000020764 Sensation disease Diseases 0.000 description 1
- HQTKVSCNCDLXSX-BQBZGAKWSA-N Ser-Arg-Gly Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O HQTKVSCNCDLXSX-BQBZGAKWSA-N 0.000 description 1
- UBRXAVQWXOWRSJ-ZLUOBGJFSA-N Ser-Asn-Asp Chemical compound C([C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)O)NC(=O)[C@H](CO)N)C(=O)N UBRXAVQWXOWRSJ-ZLUOBGJFSA-N 0.000 description 1
- DSGYZICNAMEJOC-AVGNSLFASA-N Ser-Glu-Phe Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O DSGYZICNAMEJOC-AVGNSLFASA-N 0.000 description 1
- HZNFKPJCGZXKIC-DCAQKATOSA-N Ser-His-Met Chemical compound CSCC[C@@H](C(=O)O)NC(=O)[C@H](CC1=CN=CN1)NC(=O)[C@H](CO)N HZNFKPJCGZXKIC-DCAQKATOSA-N 0.000 description 1
- RHAPJNVNWDBFQI-BQBZGAKWSA-N Ser-Pro-Gly Chemical compound OC[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O RHAPJNVNWDBFQI-BQBZGAKWSA-N 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 102100024040 Signal transducer and activator of transcription 3 Human genes 0.000 description 1
- 208000003252 Signet Ring Cell Carcinoma Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 208000021386 Sjogren Syndrome Diseases 0.000 description 1
- 208000000453 Skin Neoplasms Diseases 0.000 description 1
- 206010072148 Stiff-Person syndrome Diseases 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- 241000282898 Sus scrofa Species 0.000 description 1
- 208000001106 Takayasu Arteritis Diseases 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric Acid Chemical class [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 206010043276 Teratoma Diseases 0.000 description 1
- 208000024313 Testicular Neoplasms Diseases 0.000 description 1
- 206010057644 Testis cancer Diseases 0.000 description 1
- 206010043458 Thirst Diseases 0.000 description 1
- OHAJHDJOCKKJLV-LKXGYXEUSA-N Thr-Asp-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O OHAJHDJOCKKJLV-LKXGYXEUSA-N 0.000 description 1
- AMXMBCAXAZUCFA-RHYQMDGZSA-N Thr-Leu-Arg Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O AMXMBCAXAZUCFA-RHYQMDGZSA-N 0.000 description 1
- ZSPQUTWLWGWTPS-HJGDQZAQSA-N Thr-Lys-Asp Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(O)=O ZSPQUTWLWGWTPS-HJGDQZAQSA-N 0.000 description 1
- YRJOLUDFVAUXLI-GSSVUCPTSA-N Thr-Thr-Asp Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@H](C(O)=O)CC(O)=O YRJOLUDFVAUXLI-GSSVUCPTSA-N 0.000 description 1
- LXXCHJKHJYRMIY-FQPOAREZSA-N Thr-Tyr-Ala Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](C)C(O)=O LXXCHJKHJYRMIY-FQPOAREZSA-N 0.000 description 1
- PELIQFPESHBTMA-WLTAIBSBSA-N Thr-Tyr-Gly Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@H](C(=O)NCC(O)=O)CC1=CC=C(O)C=C1 PELIQFPESHBTMA-WLTAIBSBSA-N 0.000 description 1
- 201000009365 Thymic carcinoma Diseases 0.000 description 1
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- SAKLWFSRZTZQAJ-GQGQLFGLSA-N Trp-Ile-Ser Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)N SAKLWFSRZTZQAJ-GQGQLFGLSA-N 0.000 description 1
- CDRYEAWHKJSGAF-BPNCWPANSA-N Tyr-Ala-Met Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](C)C(=O)N[C@@H](CCSC)C(O)=O CDRYEAWHKJSGAF-BPNCWPANSA-N 0.000 description 1
- DKKHULUSOSWGHS-UWJYBYFXSA-N Tyr-Asn-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CC1=CC=C(C=C1)O)N DKKHULUSOSWGHS-UWJYBYFXSA-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
- 102100033438 Tyrosine-protein kinase JAK1 Human genes 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 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 1
- BEGDZYNDCNEGJZ-XVKPBYJWSA-N Val-Gly-Gln Chemical compound CC(C)[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CCC(N)=O BEGDZYNDCNEGJZ-XVKPBYJWSA-N 0.000 description 1
- MYLNLEIZWHVENT-VKOGCVSHSA-N Val-Ile-Trp Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)NC(=O)[C@H](C(C)C)N MYLNLEIZWHVENT-VKOGCVSHSA-N 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 206010047513 Vision blurred Diseases 0.000 description 1
- 208000008383 Wilms tumor Diseases 0.000 description 1
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 208000006336 acinar cell carcinoma Diseases 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 208000021841 acute erythroid leukemia Diseases 0.000 description 1
- 208000020700 acute megakaryocytic leukemia Diseases 0.000 description 1
- 210000005006 adaptive immune system Anatomy 0.000 description 1
- 208000002517 adenoid cystic carcinoma Diseases 0.000 description 1
- 201000000452 adenoid squamous cell carcinoma Diseases 0.000 description 1
- 201000008395 adenosquamous carcinoma Diseases 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000009824 affinity maturation Effects 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 108010070944 alanylhistidine Proteins 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
- 206010065867 alveolar rhabdomyosarcoma Diseases 0.000 description 1
- 208000010029 ameloblastoma Diseases 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 201000007538 anal carcinoma Diseases 0.000 description 1
- 239000004037 angiogenesis inhibitor Substances 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000003460 anti-nuclear Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000002111 antiemetic agent Substances 0.000 description 1
- 229940125683 antiemetic agent Drugs 0.000 description 1
- 239000003972 antineoplastic antibiotic Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 230000001640 apoptogenic effect Effects 0.000 description 1
- 108010069205 aspartyl-phenylalanine Proteins 0.000 description 1
- 108010093581 aspartyl-proline Proteins 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 201000000448 autoimmune hemolytic anemia Diseases 0.000 description 1
- 208000027625 autoimmune inner ear disease Diseases 0.000 description 1
- 208000036923 autoimmune primary adrenal insufficiency Diseases 0.000 description 1
- 210000000227 basophil cell of anterior lobe of hypophysis Anatomy 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 208000026900 bile duct neoplasm Diseases 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 201000001531 bladder carcinoma Diseases 0.000 description 1
- 201000000053 blastoma Diseases 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 238000004820 blood count Methods 0.000 description 1
- 208000007047 blue nevus Diseases 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 201000011143 bone giant cell tumor Diseases 0.000 description 1
- 208000030224 brain astrocytoma Diseases 0.000 description 1
- 208000024055 brain glioblastoma Diseases 0.000 description 1
- 201000011609 brain glioblastoma multiforme Diseases 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 201000003714 breast lobular carcinoma Diseases 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 208000000594 bullous pemphigoid Diseases 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 229940046731 calcineurin inhibitors Drugs 0.000 description 1
- 150000001720 carbohydrates Chemical group 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 208000002458 carcinoid tumor Diseases 0.000 description 1
- 210000000845 cartilage Anatomy 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 210000002421 cell wall Anatomy 0.000 description 1
- 230000005889 cellular cytotoxicity Effects 0.000 description 1
- 230000007969 cellular immunity Effects 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- 201000007335 cerebellar astrocytoma Diseases 0.000 description 1
- 210000001638 cerebellum Anatomy 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 210000002939 cerumen Anatomy 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 210000003679 cervix uteri Anatomy 0.000 description 1
- 239000013522 chelant Substances 0.000 description 1
- 201000005217 chondroblastoma Diseases 0.000 description 1
- 230000002759 chromosomal effect Effects 0.000 description 1
- 208000021668 chronic eosinophilic leukemia Diseases 0.000 description 1
- 201000005795 chronic inflammatory demyelinating polyneuritis Diseases 0.000 description 1
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 1
- 201000010002 cicatricial pemphigoid Diseases 0.000 description 1
- 208000029664 classic familial adenomatous polyposis Diseases 0.000 description 1
- 208000009060 clear cell adenocarcinoma Diseases 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 208000011588 combined hepatocellular carcinoma and cholangiocarcinoma Diseases 0.000 description 1
- 235000018597 common camellia Nutrition 0.000 description 1
- 238000004891 communication Methods 0.000 description 1
- 230000009137 competitive binding Effects 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 230000001268 conjugating effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 229960001334 corticosteroids Drugs 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000002385 cottonseed oil Substances 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 230000037029 cross reaction Effects 0.000 description 1
- 201000003278 cryoglobulinemia Diseases 0.000 description 1
- WZHCOOQXZCIUNC-UHFFFAOYSA-N cyclandelate Chemical compound C1C(C)(C)CC(C)CC1OC(=O)C(O)C1=CC=CC=C1 WZHCOOQXZCIUNC-UHFFFAOYSA-N 0.000 description 1
- 210000005220 cytoplasmic tail Anatomy 0.000 description 1
- 239000002254 cytotoxic agent Substances 0.000 description 1
- 231100000599 cytotoxic agent Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 229920006237 degradable polymer Polymers 0.000 description 1
- 210000004443 dendritic cell Anatomy 0.000 description 1
- 239000005547 deoxyribonucleotide Substances 0.000 description 1
- 125000002637 deoxyribonucleotide group Chemical group 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- PGUYAANYCROBRT-UHFFFAOYSA-N dihydroxy-selanyl-selanylidene-lambda5-phosphane Chemical compound OP(O)([SeH])=[Se] PGUYAANYCROBRT-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- NAGJZTKCGNOGPW-UHFFFAOYSA-K dioxido-sulfanylidene-sulfido-$l^{5}-phosphane Chemical compound [O-]P([O-])([S-])=S NAGJZTKCGNOGPW-UHFFFAOYSA-K 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 230000002900 effect on cell Effects 0.000 description 1
- 210000003162 effector t lymphocyte Anatomy 0.000 description 1
- 201000008184 embryoma Diseases 0.000 description 1
- 201000009409 embryonal rhabdomyosarcoma Diseases 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 201000003914 endometrial carcinoma Diseases 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 201000004101 esophageal cancer Diseases 0.000 description 1
- 210000003238 esophagus Anatomy 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 201000005884 exanthem Diseases 0.000 description 1
- 239000013604 expression vector Substances 0.000 description 1
- 201000008825 fibrosarcoma of bone Diseases 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 210000003495 flagella Anatomy 0.000 description 1
- 235000013312 flour Nutrition 0.000 description 1
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 1
- 230000003325 follicular Effects 0.000 description 1
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 1
- 108010063718 gamma-glutamylaspartic acid Proteins 0.000 description 1
- 230000000574 ganglionic effect Effects 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 201000000052 gastrinoma Diseases 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 238000001415 gene therapy Methods 0.000 description 1
- 108010078144 glutaminyl-glycine Proteins 0.000 description 1
- YQEMORVAKMFKLG-UHFFFAOYSA-N glycerine monostearate Natural products CCCCCCCCCCCCCCCCCC(=O)OC(CO)CO YQEMORVAKMFKLG-UHFFFAOYSA-N 0.000 description 1
- SVUQHVRAGMNPLW-UHFFFAOYSA-N glycerol monostearate Natural products CCCCCCCCCCCCCCCCC(=O)OCC(O)CO SVUQHVRAGMNPLW-UHFFFAOYSA-N 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 230000013595 glycosylation Effects 0.000 description 1
- 238000006206 glycosylation reaction Methods 0.000 description 1
- 108010037850 glycylvaline Proteins 0.000 description 1
- 201000003872 goiter Diseases 0.000 description 1
- 201000007574 granular cell carcinoma Diseases 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 208000024963 hair loss Diseases 0.000 description 1
- 230000003676 hair loss Effects 0.000 description 1
- 201000009277 hairy cell leukemia Diseases 0.000 description 1
- 210000003128 head Anatomy 0.000 description 1
- 201000010536 head and neck cancer Diseases 0.000 description 1
- 208000014829 head and neck neoplasm Diseases 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 1
- 208000006359 hepatoblastoma Diseases 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- 210000003494 hepatocyte Anatomy 0.000 description 1
- 208000029824 high grade glioma Diseases 0.000 description 1
- 108010036413 histidylglycine Proteins 0.000 description 1
- 239000000710 homodimer Substances 0.000 description 1
- 238000001794 hormone therapy Methods 0.000 description 1
- 102000052622 human IL7 Human genes 0.000 description 1
- 102000048362 human PDCD1 Human genes 0.000 description 1
- 230000004727 humoral immunity Effects 0.000 description 1
- 235000003642 hunger Nutrition 0.000 description 1
- 235000011167 hydrochloric acid Nutrition 0.000 description 1
- 229960000890 hydrocortisone Drugs 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 230000037315 hyperhidrosis Effects 0.000 description 1
- 230000003463 hyperproliferative effect Effects 0.000 description 1
- 230000002267 hypothalamic effect Effects 0.000 description 1
- 230000002519 immonomodulatory effect Effects 0.000 description 1
- 239000012274 immune-checkpoint protein inhibitor Substances 0.000 description 1
- 229940127121 immunoconjugate Drugs 0.000 description 1
- 230000016784 immunoglobulin production Effects 0.000 description 1
- 238000003364 immunohistochemistry Methods 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 238000002650 immunosuppressive therapy Methods 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 208000033065 inborn errors of immunity Diseases 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 210000004969 inflammatory cell Anatomy 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000000266 injurious effect Effects 0.000 description 1
- 230000015788 innate immune response Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229940124829 interleukin-23 Drugs 0.000 description 1
- 229940100994 interleukin-7 Drugs 0.000 description 1
- 230000009878 intermolecular interaction Effects 0.000 description 1
- 208000036971 interstitial lung disease 2 Diseases 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 230000002601 intratumoral effect Effects 0.000 description 1
- 206010073095 invasive ductal breast carcinoma Diseases 0.000 description 1
- 201000010985 invasive ductal carcinoma Diseases 0.000 description 1
- 206010073096 invasive lobular breast carcinoma Diseases 0.000 description 1
- 210000004153 islets of langerhan Anatomy 0.000 description 1
- 150000002540 isothiocyanates Chemical class 0.000 description 1
- 210000000281 joint capsule Anatomy 0.000 description 1
- 210000002510 keratinocyte Anatomy 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 208000022013 kidney Wilms tumor Diseases 0.000 description 1
- 201000005264 laryngeal carcinoma Diseases 0.000 description 1
- 206010023841 laryngeal neoplasm Diseases 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 108010051673 leucyl-glycyl-phenylalanine Proteins 0.000 description 1
- 108010000761 leucylarginine Proteins 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 206010024627 liposarcoma Diseases 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 201000000014 lung giant cell carcinoma Diseases 0.000 description 1
- 230000001926 lymphatic effect Effects 0.000 description 1
- 208000003747 lymphoid leukemia Diseases 0.000 description 1
- 210000003738 lymphoid progenitor cell Anatomy 0.000 description 1
- 208000025036 lymphosarcoma Diseases 0.000 description 1
- 239000008176 lyophilized powder Substances 0.000 description 1
- 229940124302 mTOR inhibitor Drugs 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 210000002540 macrophage Anatomy 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
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 201000006812 malignant histiocytosis Diseases 0.000 description 1
- 201000009020 malignant peripheral nerve sheath tumor Diseases 0.000 description 1
- 239000003628 mammalian target of rapamycin inhibitor Substances 0.000 description 1
- 208000027202 mammary Paget disease Diseases 0.000 description 1
- 208000000516 mast-cell leukemia Diseases 0.000 description 1
- 201000008749 mast-cell sarcoma Diseases 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 208000023356 medullary thyroid gland carcinoma Diseases 0.000 description 1
- 206010027191 meningioma Diseases 0.000 description 1
- 201000008806 mesenchymal cell neoplasm Diseases 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 208000037819 metastatic cancer Diseases 0.000 description 1
- 208000011575 metastatic malignant neoplasm Diseases 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 239000011859 microparticle Substances 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 201000010225 mixed cell type cancer Diseases 0.000 description 1
- 208000029638 mixed neoplasm Diseases 0.000 description 1
- 201000006894 monocytic leukemia Diseases 0.000 description 1
- 201000010879 mucinous adenocarcinoma Diseases 0.000 description 1
- 208000010492 mucinous cystadenocarcinoma Diseases 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 206010028417 myasthenia gravis Diseases 0.000 description 1
- 201000005962 mycosis fungoides Diseases 0.000 description 1
- 201000005987 myeloid sarcoma Diseases 0.000 description 1
- 208000001611 myxosarcoma Diseases 0.000 description 1
- 239000002088 nanocapsule Substances 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 239000002077 nanosphere Substances 0.000 description 1
- 239000007923 nasal drop Substances 0.000 description 1
- 229940100662 nasal drops Drugs 0.000 description 1
- 210000001989 nasopharynx Anatomy 0.000 description 1
- 210000003739 neck Anatomy 0.000 description 1
- 230000001613 neoplastic effect Effects 0.000 description 1
- 201000008026 nephroblastoma Diseases 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 210000001020 neural plate Anatomy 0.000 description 1
- 208000007538 neurilemmoma Diseases 0.000 description 1
- 208000029974 neurofibrosarcoma Diseases 0.000 description 1
- 230000001272 neurogenic effect Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 230000021368 organ growth Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 239000006179 pH buffering agent Substances 0.000 description 1
- 238000009116 palliative therapy Methods 0.000 description 1
- 201000002530 pancreatic endocrine carcinoma Diseases 0.000 description 1
- 208000004019 papillary adenocarcinoma Diseases 0.000 description 1
- 201000010198 papillary carcinoma Diseases 0.000 description 1
- 201000010210 papillary cystadenocarcinoma Diseases 0.000 description 1
- 208000024641 papillary serous cystadenocarcinoma Diseases 0.000 description 1
- 201000001494 papillary transitional carcinoma Diseases 0.000 description 1
- 208000031101 papillary transitional cell carcinoma Diseases 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 201000001976 pemphigus vulgaris Diseases 0.000 description 1
- KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical compound OI(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-N 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 238000002823 phage display Methods 0.000 description 1
- 210000001539 phagocyte Anatomy 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 208000028591 pheochromocytoma Diseases 0.000 description 1
- SXADIBFZNXBEGI-UHFFFAOYSA-N phosphoramidous acid Chemical compound NP(O)O SXADIBFZNXBEGI-UHFFFAOYSA-N 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 230000000865 phosphorylative effect Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 208000024724 pineal body neoplasm Diseases 0.000 description 1
- 208000031223 plasma cell leukemia Diseases 0.000 description 1
- 230000004983 pleiotropic effect Effects 0.000 description 1
- 201000006292 polyarteritis nodosa Diseases 0.000 description 1
- 229920000515 polycarbonate Polymers 0.000 description 1
- 239000004417 polycarbonate Substances 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 208000005987 polymyositis Diseases 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 150000004804 polysaccharides Chemical class 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 229960005205 prednisolone Drugs 0.000 description 1
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 208000028529 primary immunodeficiency disease Diseases 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 208000013368 pseudoglandular squamous cell carcinoma Diseases 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 206010037844 rash Diseases 0.000 description 1
- 208000002574 reactive arthritis Diseases 0.000 description 1
- 238000003259 recombinant expression Methods 0.000 description 1
- 206010038038 rectal cancer Diseases 0.000 description 1
- 201000001275 rectum cancer Diseases 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 238000002271 resection Methods 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 201000003068 rheumatic fever Diseases 0.000 description 1
- 239000002336 ribonucleotide Substances 0.000 description 1
- 125000002652 ribonucleotide group Chemical group 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 239000012146 running buffer Substances 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
- 235000005713 safflower oil Nutrition 0.000 description 1
- 239000003813 safflower oil Substances 0.000 description 1
- 201000007416 salivary gland adenoid cystic carcinoma Diseases 0.000 description 1
- 208000014212 sarcomatoid carcinoma Diseases 0.000 description 1
- 206010039667 schwannoma Diseases 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 208000018964 sebaceous gland cancer Diseases 0.000 description 1
- JRPHGDYSKGJTKZ-UHFFFAOYSA-K selenophosphate Chemical compound [O-]P([O-])([O-])=[Se] JRPHGDYSKGJTKZ-UHFFFAOYSA-K 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 108010026333 seryl-proline Proteins 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 201000008123 signet ring cell adenocarcinoma Diseases 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 235000020183 skimmed milk Nutrition 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 208000000649 small cell carcinoma Diseases 0.000 description 1
- 239000007974 sodium acetate buffer Substances 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008227 sterile water for injection Substances 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 201000008205 supratentorial primitive neuroectodermal tumor Diseases 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000725 suspension Substances 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
- 206010042863 synovial sarcoma Diseases 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 231100000057 systemic toxicity Toxicity 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 201000003120 testicular cancer Diseases 0.000 description 1
- 210000001550 testis Anatomy 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- RYYWUUFWQRZTIU-UHFFFAOYSA-K thiophosphate Chemical compound [O-]P([O-])([O-])=S RYYWUUFWQRZTIU-UHFFFAOYSA-K 0.000 description 1
- 108010033670 threonyl-aspartyl-tyrosine Proteins 0.000 description 1
- 210000001541 thymus gland Anatomy 0.000 description 1
- 208000030901 thyroid gland follicular carcinoma Diseases 0.000 description 1
- 208000015191 thyroid gland papillary and follicular carcinoma Diseases 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
- 210000002105 tongue Anatomy 0.000 description 1
- 208000029335 trabecular adenocarcinoma Diseases 0.000 description 1
- 206010044412 transitional cell carcinoma Diseases 0.000 description 1
- 208000035408 type 1 diabetes mellitus 1 Diseases 0.000 description 1
- 108010051110 tyrosyl-lysine Proteins 0.000 description 1
- 210000003932 urinary bladder Anatomy 0.000 description 1
- 208000010570 urinary bladder carcinoma Diseases 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 206010046885 vaginal cancer Diseases 0.000 description 1
- 208000013139 vaginal neoplasm Diseases 0.000 description 1
- 210000003556 vascular endothelial cell Anatomy 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 230000004400 visual pathway Effects 0.000 description 1
- 210000000239 visual pathway Anatomy 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/52—Cytokines; Lymphokines; Interferons
- C07K14/54—Interleukins [IL]
- C07K14/5428—IL-10
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
- C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
-
- 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
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/54—F(ab')2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
- C07K2317/62—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising only variable region components
- C07K2317/622—Single chain antibody (scFv)
-
- 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
-
- 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
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
- C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/30—Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Immunology (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Gastroenterology & Hepatology (AREA)
- Zoology (AREA)
- Toxicology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Peptides Or Proteins (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
本公开内容提供了一种蛋白,其包含抗体或抗原结合片段;以及与所述抗体或抗原结合片段可操作地连接的白介素分子。在某些实施方式中,所述抗体或抗原结合片段特异性结合至免疫检查点蛋白。在某些实施方式中,所述白介素分子是IL‑10。
Description
相关申请的交叉引用
本申请要求2019年06月10日提交的PCT/CN2019/090494的优先权,其公开的内容通过引用并入本文。
发明领域
本公开内容一般涉及生物学、治疗学和诊断学领域。特别地,本公开内容涉及抗体-白介素融合蛋白及其用途。
背景技术
近年来,随着对潜在生物学过程的了解增加,癌症治疗取得了重大进展。例如,诱导患者自身免疫系统对抗肿瘤的免疫疗法的发展突显了促进对癌症相关基因改变表达的肿瘤抗原的免疫耐受的机制的重要性。这些以针对PD-1、PD-L1或CTLA4的单克隆抗体为代表的免疫检查点抑制剂已经对一些癌症类型越来越广泛的患者产生了显著且持久的应答。然而,目前的免疫疗法(如PD-1或PD-L1阻断剂)仅在癌症患者中表现出有限的应答(参见,例如,P Sharma and JP Allison,Cell(2015)161:205-214),并且化疗耐药性仍然是癌症治疗中最紧迫的主要困境之一。因而,持续需要开发新的组合物和方法来调节免疫系统和消除肿瘤免疫抑制作用,以解决肿瘤免疫耐受性和化疗耐药性。
发明内容
在一个方面中,本公开内容提供了一种融合蛋白。在一个实施方式中,所述蛋白包含:抗体或抗原结合片段,其包含重链可变结构域和轻链可变结构域;和可操作地连接至所述抗体或抗原结合片段的白介素分子。
在某些实施方式中,所述抗体或抗原结合片段特异性结合至免疫检查点蛋白。在某些实施方式中,所述免疫检查点蛋白选自下组:A2AR、B7.1、B7.2、B7-H2、B7-H3、B7-H4、B7-H6、BTLA、CD48、CD120b、CD160、CD244、CTLA-4、ICOS、LAG-3、LILRB1、LILRB2、LILRB4、OX40、PD-1、PD-L1、PD-L2、SIRPα(CD47)、TIGIT、TIM-3、TIM-1、TIM-4和VISTA。在某些实施方式中,所述免疫检查点是PD-1或PD-L1。
在某些实施方式中,抗体包含Fc区。在某些实施方式中,抗原结合片段是F(ab’)2片段。在某些实施方式中,抗原结合片段是单链可变片段(scFv)。
在某些实施方式中,所述白介素分子选自下组:IL-1、IL-2、IL-3、IL-4、IL-5、IL-6、IL-7、IL-8、IL-IL-9、IL-10、IL-11、IL-12、IL-13、IL-14、IL-15、IL-16、IL-17、IL-18、IL-19、IL20、IL-21、IL-22、IL-23、IL-24、IL-25、IL-26、IL-27、IL-28、IL-29、IL-30、IL-31、IL-32、IL-33、IL-35和IL-36。在某些实施方式中,白介素分子是IL-10。
在某些实施方式中,白介素分子连接至重链可变结构域。在某些实施方式中,白介素分子连接至重链可变结构域的N末端。在某些实施方式中,白介素分子连接至重链可变结构域的C末端。在某些实施方式中,白介素分子连接至轻链可变结构域。在某些实施方式中,白介素分子连接至轻链可变结构域的N末端。在某些实施方式中,白介素分子连接至轻链可变结构域的C末端。
在某个实施方式中,所述蛋白还包含接头,其连接抗体或其抗原结合片段和白介素分子。在某些实施方式中,接头包含氨基酸序列(GGGGS)n(n=2-5)。
在另一个方面中,本公开内容提供了一种分离的多核苷酸,其编码本文所述的蛋白。
在另一个方面中,本公开内容提供了一种能够表达蛋白的载体,其包含本文所述的分离的多核苷酸。
在另一个方面中,本公开内容提供了一种适于生产蛋白的重组宿主细胞,其包含本文所述的载体。在某些实施方式中,重组宿主细胞是哺乳动物细胞系。在某些实施方式中,哺乳动物细胞系是CHO细胞系。
在另一个方面中,本公开内容提供了一种药物组合物,其包含本文所述的蛋白和药学上可接受的载体。
在另一个方面中,本公开内容提供了一种在有需要的对象中治疗疾病的方法,其包括向所述对象施用治疗有效量的本文所述的药物组合物。在某些实施方式中,所述疾病是肿瘤。在某些实施方式中,所述肿瘤选自下组:肺癌、黑色素瘤、肾癌、肝癌、骨髓瘤、前列腺癌、乳腺癌、结直肠癌、胰腺癌、甲状腺癌、血液系统癌症、白血病和非霍奇金氏淋巴瘤。
在某些实施方式中,所述疾病是免疫相关病证。在某些实施方式中,所述免疫相关病证选自下组:炎性肠病、克罗恩病、溃疡性结肠炎、类风湿性关节炎、银屑病、I型糖尿病、急性胰腺炎、葡萄膜炎、干燥病、白塞氏病、结节病、移植物抗宿主病(GVHD)、系统性红斑狼疮、白癜风、慢性预防性急性移植物抗宿主病(pGvHD)、HIV诱发的血管炎、斑秃、系统性硬化症和原发性抗磷脂综合征。
单词“一个(a)”或“一种(an)”当与术语“包含(comprising)”在权利要求书和/或说明书中一起使用时,可能表示“一个”,但也可能与“一个或多个”、“至少一个”和“一个或多于一个”的含义一致。
预期本文描述的任何方法或组合物可以相对于本文描述的任何其他方法或组合物实施。本公开内容的其他目的、特征和优点将从以下具体描述中变得显而易见。然而,应当理解的是,具体描述和特定实施例虽然指示了本发明的具体实施方式,但仅作为说明给出,因为从该具体实施方式中,本公开内容的精神和范围的各种改变和修改对于本领域技术人员而言将变得显而易见。
附图说明
以下附图构成本说明书的一部分并且被包括以进一步展示本公开内容的某些方面。通过参考这些附图中的一幅或多幅并结合在此呈现的具体实施方式的详细描述,可以更好地理解本公开内容。
图1显示了本发明融合蛋白的示例性实施方式。
图2显示了本发明融合蛋白的示例性实施方式。
图3显示了本发明融合蛋白的示例性实施方式。
图4显示了本发明融合蛋白的示例性实施方式。
图5显示了本发明融合蛋白的示例性实施方式。
图6显示了本发明融合蛋白的示例性实施方式。
图7显示了本发明融合蛋白的示例性实施方式。
图8显示了本发明融合蛋白的示例性实施方式。
图9A和图9B显示了在由抗PD-1(7A4D)、抗PD-L1(5G11)单克隆抗体和衍生的抗体-IL-10融合蛋白引发的混合淋巴细胞反应(MLR)中细胞因子产生的诱导。LC,IL-10连接在Ig轻链C末端;HC,IL-10连接在Ig重链C末端。
图10显示了由基于抗PD-1(7A4D)和抗PD-L1(5G11)单克隆抗体的抗体-IL-10融合蛋白激发的MC/9细胞增殖。
图11显示了抗PD-L1(10F.9G2)抗体和抗PD-L1(10F.9G2)抗体-HC-mIL-10融合蛋白与表达PD-L1的小鼠肿瘤细胞的结合特征。小鼠肿瘤细胞系A20和CT26分别以非常高的水平和低水平在表面上表达PD-L1。抗PD-L1(10F.9G2)抗体和抗PD-L1(10F.9G2)抗体-HC-mIL-10融合蛋白分别使用R-藻红蛋白缀合试剂盒(Abcam)用PE标记。在染色之前,使用1μg/mL小鼠BD Fc封闭(BD Biosciences)在4℃下处理A20和CT26细胞5min。使用指定的各种量的PE标记蛋白对总体积为100μl的处理过的细胞进行染色。在LSRFortessa X-20流式细胞仪上对染色细胞进行分析。左图和右图分别显示了来自CT26和A20细胞的数据。
图12显示了抗PD-L1抗体-HC-mIL-10融合蛋白对同源CT26小鼠肿瘤模型的影响。
具体实施方式
在更详细地描述本公开内容之前,应当理解,本公开内容不限于所描述的特定实施方式,并且因此当然可以变化。还应理解,本文所用的术语仅用于描述特定实施方式的目的,并不旨在限制,因为本公开内容的范围将仅由所附权利要求限制。
除非另有定义,否则本文使用的所有技术和科学术语与本公开内容所属领域的普通技术人员通常理解的含义相同。尽管在本公开内容的实施或测试中也可以使用与本文所述的那些相似或等效的任何方法和材料,但是现在描述优选的方法和材料。
在本说明书中引用的所有出版物和专利均通过引用并入本文,就如同每个单独的出版物或专利都被明确地和单独地指示为通过引用并入本文并且通过引用并入本文以公开和描述与引用出版物相关的方法和/或材料。任何出版物的引用是针对其在申请日之前的公开内容,不应被解释为承认本公开内容无权因在先公开内容而早于此类出版物。此外,所提供的出版日期可能与实际出版日期不同,可能需要单独确认。
本领域技术人员在阅读本公开内容后将意识到,本文描述和说明的各个实施方式中的每一个都具有分立的组分和特征,在不脱离本公开内容的范围或精神的情况下,其可以容易地与其他几个实施方式中的任一个的特征分离或组合。任何叙述的方法都可以按照所叙述的事件的顺序或以逻辑上可能的任何其他顺序来执行。
I.定义
应当理解,前面的一般描述和下面的详细描述都只是示例性和解释性的,而不是对所要求保护的本发明的限制。在本申请中,除非另有说明,否则单数的使用包括复数。在本公开内容中,术语“或”用于表示“和/或”,除非明确指出仅指替代方案或替代方案是互斥的。如本文所用,“另一个”可以指至少第二个或更多。此外,术语“包括(including)”以及诸如“包括(includes)”和“包括(included)”的其他形式的使用不是限制性的。此外,诸如“元件”或“组分”之类的术语包括包含一个单元的元件和组分以及包含多于一个子单元的元件和组分,除非另有明确说明。此外,术语“部分”的使用可以包括部分的一部分或整个部分。
如本文所用,除非上下文另有明确规定,否则单数形式的“一个(a)”、“一种(an)”和“所述(the)”包括复数引用。
如本文所用,术语“施用”指向对象提供药剂或组合物,并且包括但不限于由医学专业人员施用和自我施用。
如本文所用,术语“抗体”包括与特定抗原结合的任何免疫球蛋白、单克隆抗体、多克隆抗体、多价抗体、二价抗体、单价抗体、多特异性抗体、双特异性抗体及其抗原结合片段。天然完整抗体包含两条重(H)链和两条轻(L)链。哺乳动物重链分为α、δ、ε、γ和μ,每条重链由可变结构域(VH)和恒定区组成,所述恒定区包含第一、第二和第三恒定结构域(分别为CH1、CH2、CH3);哺乳动物轻链分为λ或κ,轻链由可变结构域(VL)和恒定结构域(CL)组成。抗体呈“Y”形,Y的主干由通过二硫键结合在一起的两条重链的第二和第三恒定结构域组成。Y的每个臂包含与单个轻链的可变和恒定结构域结合的单个重链的可变结构域和第一恒定结构域。轻链和重链的可变结构域负责抗原结合。重链和轻链两者的每个可变结构域均通常包含三个高变环,称为互补性决定区(CDR)(轻链CDR包含LCDR1、LCDR2和LCDR3,重链CDR包含HCDR1、HCDR2、HCDR3)。本文公开的抗体的CDR边界可由Kabat、IMGT、Chothia或Al-Lazikani的约定定义或鉴定(Al-Lazikani,B.,Chothia,C.,Lesk,A.M.,J.Mol.Biol.,273(4),927(1997);Chothia,C.等,J Mol Biol.Dec 5;186(3):651-63(1985);Chothia,C.和Lesk,A.M.,J.Mol.Biol.,196,901(1987);Chothia,C.等,Nature.Dec 21-28;342(6252):877-83(1989);Kabat E.A.等,National Institutes of Health,Bethesda,Md.(1991);Marie-Paule Lefranc等,Developmental and Comparative Immunology,27:55-77(2003);Marie-Paule Lefranc等,Immunome Research,1(3),(2005);Marie-PauleLefranc,Molecular Biology of B cells(第二版),第26章,481-514,(2015))。重链或轻链可变结构域的三个CDR插入称为框架区(FR)的侧翼片段之间,其比CDR更高度保守并形成支架以支持高变环。重链和轻链的恒定结构域不参与抗原结合,但显示出各种效应功能。抗体根据其重链恒定区的氨基酸序列进行分类。抗体的五个主要类别或同种型是IgA、IgD、IgE、IgG和IgM,其特征在于分别存在α、δ、ε、γ和μ重链。几个主要抗体类别分成诸如IgG1(γ1重链)、IgG2(γ2重链)、IgG3(γ3重链)、IgG4(γ4重链)、IgA1(α1重链)或IgA2(α2重链)的几个亚类。
术语“抗原”指能够诱导适应性免疫应答的物质。具体而言,抗原是与抗体或T淋巴细胞抗原受体特异性结合的物质。抗原通常是蛋白和多糖,不太常见是脂质。适宜的抗原包括但不限于细菌的部分(外壳、荚膜、细胞壁、鞭毛、菌毛和毒素)、病毒和其他微生物。抗原还包括肿瘤抗原,例如,由肿瘤突变产生的抗原。如本文所用,抗原还包括免疫原和半抗原。
如本文所用,术语“抗原结合片段”指蛋白能够特异性结合抗原的部分。在某个实施方式中,抗原结合片段衍生自包含一个或多个CDR的抗体,或任何其他与抗原结合但不包含完整天然抗体结构的抗体片段。抗原结合片段的实例包括但不限于双体Fab、Fab'、F(ab')2、Fv片段、二硫键稳定化的Fv片段(dsFv)、(dsFv)2、双特异性dsFv(dsFv-dsFv')、二硫键稳定化的双体(ds双体)、单链抗体分子(scFv)、scFv二聚体(二价双体)、多特异性抗体、单域抗体(sdAb)、骆驼抗体或纳米抗体、域抗体和二价域抗体。在某些实施方式中,抗原结合片段能够结合与亲本抗体结合的相同抗原。
“Fab片段”包含一条轻链以及一条重链的CH1和可变结构域。Fab分子的重链不能与另一个重链分子形成二硫键。
“Fab’片段”包含一条轻链和一条重链的一部分,其包含VH结构域和CH1结构域以及CH1和CH2结构域之间的区域,以使得可以在两个Fab’片段的两条重链之间形成链间二硫键以形成F(ab')2分子。
“F(ab')2片段”包含两条轻链和两条重链,其在CH1和CH2结构域之间含有恒定区的一部分,以使得在两条重链之间形成链间二硫键。因此,F(ab')2片段由两个Fab’片段组成,其通过两条重链之间的二硫键结合在一起。
“Fc”区包含两个重链片段,其含有抗体的CH2和CH3结构域。两个重链片段通过两个或更多个二硫键和通过CH3结构域的疏水相互作用保持在一起。抗体的Fc区负责各种效应功能,如抗体依赖性细胞介导的细胞毒性(ADCC)和补体依赖性细胞毒性(CDC),但在抗原结合中不起作用。
“Fv区”包含来自重链和轻链的可变结构域,但缺乏恒定结构域。
“单链抗体”或“单链Fvs”或“scFv”是其中重链和轻链可变结构域已通过柔性接头连接以形成单个多肽链的Fv分子,该多肽链形成抗原结合区。在国际专利申请号WO88/01649以及美国专利号4,946,778和5,260,203中详细讨论了单链抗体,其公开内容通过引用并入本文。
“单链Fv-Fc抗体”或“scFv-Fc”指由与抗体的Fc区连接的scFv组成的工程化抗体。
“dsFv”是指单轻链的可变结构域与单重链的可变结构域之间的连接为二硫键的二硫键稳定的Fv片段。在一些实施方式中,“(dsFv)2”或“(dsFv-dsFv')”包含三条肽链:两个VH结构域通过肽接头(例如,长的柔性接头)连接,并分别通过二硫键桥与两个VL结构域结合。在一些实施方式中,dsFv-dsFv'是双特异性的,其中每个二硫键配对的重链和轻链具有不同的抗原特异性。
“骆驼单域抗体”、“重链抗体”或“HCAb”指包含两个VH结构域,并且无轻链的抗体(Riechmann L.和Muyldermans S.,J Immunol Methods.Dec 10;231(1-2):25-38(1999);Muyldermans S.,J Biotechnol.Jun;74(4):277-302(2001);WO94/04678;WO94/25591;美国专利号6,005,079)。重链抗体最初来源于骆驼科(骆驼、单峰骆驼和美洲驼)。尽管没有轻链,但是骆驼化抗体具有真正的抗原结合库(Hamers-Casterman C.等,Nature.Jun 3;363(6428):446-8(1993);Nguyen VK.等,“Heavy-chain antibodies in Camelidae;a caseof evolutionary innovation,”Immunogenetics.Apr;54(1):39-47(2002);Nguyen VK.等,Immunology.May;109(1):93-101(2003))。重链抗体的可变结构域(“VHH结构域”)代表由适应性免疫应答产生的最小已知抗原结合单位(Koch-Nolte F.等,FASEB J.Nov;21(13):3490-8.Epub 2007Jun 15(2007))。
“纳米抗体”指由来自传统IgG的重链抗体的一个VH结构域和两个重链恒定结构域(例如,CH2和CH3)组成的抗体片段。
“双体”或“dAb”包括具有两个抗原结合位点的小抗体片段,其中这些片段包含与同一多肽链中的VL结构域连接的VH结构域(VH-VL或VL-VH)(参见,例如,Holliger P.等,ProcNatl Acad Sci U S A.Jul 15;90(14):6444-8(1993);EP404097;WO93/11161)。通过使用过短而无法在同一链上的两个结构域之间配对的接头,这些结构域被迫与另一条链的互补结构域配对,从而产生两个抗原结合位点。抗原结合位点可以靶向相同或不同抗原(或表位)。在某些实施方式中,“双特异性ds双体”是靶向两个不同抗原(或表位)的双体。
在某些实施方式中,“scFv二聚体”是包含与另一个VH-VL部分二聚化的VH-VL(通过肽接头连接)的二价双体或二价ScFv(BsFv),以使得一部分的VH与另一部分的VL配位并形成两个可以靶向相同抗原(或表位)或不同抗原(或表位)的结合位点。在其他实施方式中,“scFv二聚体”是包含VH1-VL2(通过肽接头连接)与VL1-VH2(也通过肽接头连接)结合的双特异性双抗体,以使得VH1和VL1配位以及VH2和VL2配位,并且每个配位对具有不同抗原特异性。
“域抗体”是仅包含重链可变结构域或轻链可变结构域的免疫功能性免疫球蛋白片段。在一些情况下,两个或更多个VH结构域与肽接头共价连接以产生二价域抗体。二价域抗体的两个VH结构域可以靶向相同或不同抗原。
如本文所用,术语“嵌合的”指抗体或抗原结合片段,其重链和/或轻链的一部分来源于一个物种,而重链和/或轻链的其余部分来源于不同物种。在说明性实例中,嵌合抗体可以包含源自人的恒定区和源自非人动物如小鼠的可变区。在一些实施方式中,非人动物是哺乳动物,例如,小鼠、大鼠、家兔、山羊、绵羊、豚鼠或仓鼠。
如本文所用,术语“人源化”指抗体或抗原结合片段包含来源于非人动物的CDR,来源于人的FR区,并且当适用时,恒定区来源于人。
“结合亲和力”通常是指分子(例如,抗体)的单个结合位点与其结合伴侣(例如,抗原)之间的非共价相互作用总和的强度。除非另有说明,否则如本文所用,“结合亲和力”是指反映结合对成员(例如,抗体和抗原)之间1:1相互作用的内在结合亲和力。分子X对其伴侣Y的亲和力通常可以用解离常数(Kd)表示。亲合力可以通过本领域公知的常用方法测量,包括本文所述的那些。低亲和力抗体通常与抗原结合较慢且易于解离,而高亲和力抗体通常与抗原结合较快且结合时间较长。测量结合亲和力的多种方法在本领域中是公知的,其中任何一种都可以用于本发明的目的。下文描述了用于测量结合亲和力的具体说明性和示例性实施方式。
“特异结合”或“特异于”特定多肽或特定多肽上的表位的蛋白或抗体是与该特定多肽或特定多肽上的表位结合而基本上不与任何其他多肽或多肽表位结合的蛋白或抗体。例如,本文所述的抗体可以与免疫检查点蛋白特异性结合。在一些实施方式中,与免疫检查点蛋白结合的抗体的解离常数(Kd)≦100nM、≦10nM、≦1nM、≦0.1nM、≦0.01nM或≦0.001nM(例如,10-8M或更低,例如,从10-8M至10-13M,例如,从10-9M至10-13M)。
如本文所用,术语“癌症”和“肿瘤”可互换使用,指任何涉及异常细胞生长的疾病,包括影响身体任何组织、器官或细胞的所有阶段和所有形式的疾病。该术语包括所有已知的肿瘤和赘生物病况,无论其特征为恶性、良性、软组织还是实体,以及所有阶段和分级的癌症,包括转移前和转移后的癌症。一般来说,可以根据肿瘤所在或起源的组织或器官以及癌组织和细胞的形态对肿瘤进行分类。如本文所用,肿瘤类型包括急性淋巴细胞白血病(ALL)、急性髓性白血病、肾上腺皮质癌、肛门癌、星形细胞瘤、儿童小脑或脑、基底细胞癌、胆管癌、膀胱癌、骨肿瘤、脑癌、乳腺癌、伯基特氏淋巴瘤、小脑星形细胞瘤、脑星形细胞瘤/恶性胶质瘤、宫颈癌、慢性淋巴细胞白血病、粒细胞性白血病、结肠癌、肺气肿、子宫内膜癌、室管膜瘤、食道癌、尤文家族肿瘤、尤文氏肉瘤、胃(胃)癌、神经胶质瘤、头颈癌、心脏病、霍奇金淋巴瘤、胰岛细胞癌(内分泌胰腺)、卡波西肉瘤、肾癌(肾细胞癌)、喉癌、白血病、肝癌、肺癌、髓母细胞瘤、黑色素瘤、神经母细胞瘤、非霍奇金淋巴瘤、卵巢癌、胰腺癌、咽癌、前列腺癌、直肠癌、肾细胞癌(肾癌)、视网膜母细胞瘤、皮肤癌、胃癌、幕上原始神经外胚层肿瘤、睾丸癌、喉癌、甲状腺癌、阴道癌、视觉通路和下丘脑胶质瘤。
如本文所用,术语“有效量”或“治疗有效量”是指足以预防、治疗、减轻和/或改善任何病症或疾病的症状和/或根本病因的药剂的量,或者足以对细胞产生所需效果的药剂的量。在一个实施方式中,“治疗有效量”是足以减轻或消除疾病的症状的量。在另一个实施方式中,治疗有效量是足以克服疾病本身的量。
如本文所用,术语“表位”指抗原上与抗原结合多肽结合的特定原子或氨基酸基团。表位可以是线形表位或构象表位。线形表位由来自抗原的连续氨基酸序列形成,并根据其一级结构与抗体相互作用。另一方面,构象表位由抗原氨基酸序列的不连续部分组成,并根据抗原的3D结构与抗体相互作用。在通常情况下,表位的长度约为五个或六个氨基酸。如果两种抗体表现出对抗原的竞争性结合,则其可以结合抗原内的相同表位。
术语“宿主细胞”是指已经用核酸序列转化或能够转化并由此表达目的基因的细胞。该术语包括亲本细胞的后代,无论后代在形态或遗传组成上是否与原始亲本细胞相同,只要存在目标基因即可。
如本文所用,“分离的”生物组分(如核酸、肽或细胞)已与该组分天然存在的生物体的其他生物组分或细胞(即,其他染色体和染色体外DNA和RNA、细胞和蛋白)基本上分离,分离生产或从其中纯化。因此,已“分离”的核酸、肽和蛋白包括通过标准纯化方法纯化的核酸和蛋白。该术语还包括通过在宿主细胞中重组表达制备的核酸、肽和蛋白以及化学合成的核酸。
如本文所用,术语“连接”是指通过分子内相互作用(例如,共价键、金属键和/或离子键)或分子间相互作用(例如,氢键或非共价键)的缔合。
术语“可操作地连接”指元件的排布,其中这样描述的组件被配置为执行其的通常功能。这样,与多肽有效连接的给定信号肽指导多肽从细胞中分泌。在启动子的情况下,与编码序列有效连接的启动子将指导编码序列的表达。启动子或其他控制元件不必与编码序列连续,只要其起指导其表达的作用即可。例如,在启动子序列和编码序列之间可以存在插入的未翻译但转录的序列,并且仍然可以认为启动子序列与编码序列“可操作地连接”。
术语“多核苷酸”或“核酸”包括单链和双链核苷酸聚合物。构成多核苷酸的核苷酸可以是核糖核苷酸或脱氧核糖核苷酸或任一类型核苷酸的修饰形式。所述修饰包括碱基修饰如溴尿苷和肌苷衍生物,核糖修饰如2’,3’-二脱氧核糖,以及核苷酸间连接修饰如硫代磷酸酯、二硫代磷酸酯、硒代磷酸酯、二硒酸磷酸酯、苯氨基硫代磷酸酯、苯胺磷酸酯和氨基磷酸酯。
术语“多肽”或“蛋白”是指具有天然蛋白氨基酸序列的大分子,即由天然存在的非重组细胞产生的蛋白;或者其由基因工程或重组细胞产生,并且包含具有天然蛋白的氨基酸序列的分子,或具有天然序列的一个或多个氨基酸的缺失、添加和/或取代的分子。该术语还包括氨基酸聚合物,其中一种或多种氨基酸是相应天然存在的氨基酸的化学类似物和聚合物。术语“多肽”和“蛋白”具体包括LAIR1抗原结合蛋白、抗体或具有抗原结合蛋白的一个或多个氨基酸的缺失、添加和/或取代的序列。术语“多肽片段”是指与全长天然蛋白相比具有氨基末端缺失、羧基末端缺失和/或内部缺失的多肽。与天然蛋白相比,此类片段还可以含有修饰的氨基酸。在某些实施方式中,片段约5至500个氨基酸长。例如,片段可以是至少5、6、8、10、14、20、50、70、100、110、150、200、250、300、350、400或450个氨基酸长。有用的多肽片段包括抗体的免疫功能片段,包括结合结构域。在抗体的情况下,有用的片段包括但不限于CDR区、重链和/或轻链可变区、抗体链的一部分或仅包含两个CDR的其可变区等。
如本文所用,短语“药学上可接受的载体”是指药学上可接受的材料、组合物或载剂,如液体或固体填充剂、稀释剂、赋形剂或溶剂包封材料,其参与将主题化合物从一个器官或身体的一部分运送或运输到另一个器官或身体的一部分。在与制剂的其他成分相容且对患者无害的意义上,每种载体必须是“可接受的”。可以用作药学上可接受的载体的材料的一些实例包括:糖,如乳糖、葡萄糖和蔗糖;淀粉,如玉米淀粉和马铃薯淀粉;纤维素及其衍生物,如羧甲基纤维素钠、乙基纤维素和醋酸纤维素;粉状黄蓍胶;麦芽;明胶;滑石;赋形剂,如可可脂和栓剂蜡;油类,如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油和大豆油;二醇类,如丙二醇;多元醇,如甘油、山梨糖醇、甘露醇和聚乙二醇;酯类,如油酸乙酯和月桂酸乙酯;琼脂;缓冲剂,如氢氧化镁和氢氧化铝;海藻酸;无热原水;等渗盐水;林格氏液;乙醇;pH缓冲溶液;聚酯、聚碳酸酯和/或聚酐;和其他用于药物制剂的无毒相容性物质。
如本文所用,术语“对象”指人或任何非人动物(例如,小鼠、大鼠、家兔、犬、猫、牛、猪、羊、马或灵长类动物)。人包括产前和产后形式。在很多实施方式中,对象是人类。对象可以是患者,其指向医疗提供者提供以诊断或治疗疾病的人。术语“对象”在本文中可与“个体”或“患者”互换使用。对象可能患有或易患疾病或病症,但可能会或可能不会表现出疾病或病症的症状。
如本文所用,病况的“治疗”(“treating/treatment”)包括预防或减轻病况、减缓病况的发作或发展速度、降低发展成病况的风险、预防或延迟与病况相关的症状的发展、减少或结束与病况相关的症状,产生病况的完全或部分消退,治愈病况,或者其的某种组合。
如本文所用,“载体”指引入宿主细胞中的核酸分子,从而产生转化的宿主细胞。载体可以包含允许其在宿主细胞中复制的核酸序列,如复制原点。载体还可以包含一种或多种治疗基因和/或选择标记基因和本领域公知的其他遗传元件。载体可以转导、转化或感染细胞,从而使细胞表达不同于细胞天然的核酸和/或蛋白。载体任选地包括有助于实现核酸进入细胞的材料,如病毒颗粒、脂质体、蛋白涂层等。
II.融合蛋白及其生产
A.融合蛋白
本公开内容的一个方面提供了一种融合蛋白,其包含:包含重链可变结构域和轻链可变结构域的抗体或其抗原结合片段;和可操作地连接至抗原或抗原结合片段的白介素分子。应当意识到的是,本公开内容的融合蛋白可以具有多种形式和结构。本公开内容的融合蛋白可以通过图1-8中所示的示例性实施方式来理解。
参见图1,在本发明的一个示例性实施方式中,融合蛋白包含常规Y形抗体,该抗体包含两对重链和轻链。每条重链由可变结构域(VH)和恒定区组成,恒定区包含第一、第二和第三恒定结构域(分别为CH1、CH2、CH3)。每条轻链由可变结构域(VL)和恒定结构域(CL)组成。Y形抗体的茎由通过二硫键结合在一起的两条重链的第二和第三恒定结构域组成。Y形抗体的每个臂包含与单个轻链的可变结构域和恒定结构域结合的单个重链的可变结构域和第一恒定结构域。在每条重链的C末端,白介素(IL)分子通过接头与重链的第三个恒定结构域连接。
参见图2,在本发明的另一个示例性实施方式中,融合蛋白包含具有与图1中所示相同结构的常规Y形抗体。与图1不同的是,在图2中所示的融合蛋白中,不是与重链连接,IL分子通过接头与轻链恒定结构域连接。
参见图3,在本发明的另一个示例性实施方式中,融合蛋白包含具有与图1中所示相同结构的常规Y形抗体。在图3中所示的融合蛋白中,IL分子通过接头连接至重链可变结构域。
参见图4,在本发明的另一个示例性实施方式中,融合蛋白包含具有与图1中所示相同结构的常规Y形抗体。在图4中所示的融合蛋白中,IL分子通过接头连接至轻链可变结构域。
在某些实施方式中,如图5-8中所示,融合蛋白包含抗原结合片段。参见图5,在本发明的另一个示例性实施方式中,融合蛋白包含由两对轻链和重链片段组成的抗原结合片段F(ab’)2。每个重链片段在CH1和CH2结构域之间包含一部分恒定区,从而在两个重链片段之间形成链间二硫键。在每条重链的C末端,IL分子通过接头与重链片段连接。
参见图6,在本发明的另一个示例性实施方式中,融合蛋白包含具有与图5中所示相同结构的F(ab’)2片段。与图5不同的是,在图6中所示的融合蛋白中,不是与重链片段连接,IL分子通过接头与轻链恒定结构域连接。
参见图7,在本发明的另一个示例性实施方式中,融合蛋白包含一对单链可变片段(scFv)。scFv是一种分子,其中重链和轻链可变结构域已通过柔性接头连接以形成单个多肽链,该多肽链形成抗原结合区。在国际专利申请号WO 88/01649以及美国专利号4,946,778和5,260,203中详细讨论了单链可变片段,其公开内容通过引用并入本文。参见图7,重链可变结构域与CH1和CH2结构域之间的部分重链恒定区连接,从而在两个单链可变片段之间形成链间二硫键。在每个scFv的C末端,IL分子通过接头连接至scFv。
参见图8,在本发明的另一个示例性实施方式中,融合蛋白包含一对scFv,每个scFv从多肽的N端到C端包含一个重链可变结构域和一个轻链可变结构域。轻链可变结构域与CH1和CH2结构域之间的部分重链恒定区连接,从而在两个单链可变片段之间形成链间二硫键。在每个scFv的C末端,IL分子通过接头连接至scFv。
在某些实施方式中,抗体或抗原结合片段特异性结合至免疫检查点蛋白。在某些实施方式中,免疫检查点蛋白选自下组:A2AR、B7.1、B7.2、B7-H2、B7-H3、B7-H4、B7-H6、BTLA、CD48、CD120b、CD160、CD244、CTLA-4、ICOS、LAG-3、LILRB1、LILRB2、LILRB4、OX40、PD-1、PD-L1、PD-L2、SIRPα(CD47)、TIGIT、TIM-3、TIM-1、TIM-4和VISTA。
在某些实施方式中,融合蛋白包含选自在Qui等的US10,428,146中公开的那些抗PD-1抗体,其公开内容整体通过引用并入本文。在某些实施方式中,抗PD-1抗体是在US10,428,146中公开的7A4D。在某些实施方式中,融合蛋白包含来源于在US10,428,146中公开的抗PD-1抗体的抗原结合片段。在某些实施方式中,抗PD-1抗体或抗原结合片段包含(i)具有HCDR1、HCDR2和HCDR3的重链可变区,所述HCDR1具有SEQ ID NO:1的氨基酸序列,HCDR2具有SEQ ID NO:2的氨基酸序列,HCDR3具有SEQ ID NO:3的氨基酸序列;以及(ii)具有LCDR1、LCDR2和LCDR3的轻链可变区,所述LCDR1具有SEQ ID NO:4的氨基酸序列,LCDR2具有SEQ IDNO:5的氨基酸序列,LCDR3具有SEQ ID NO:6的氨基酸序列。
在某些实施方式中,融合蛋白包含选自在Zha等的US 10,435,470中公开的那些抗PD-L1抗体,其公开内容整体通过引用并入本文。在某些实施方式中,抗PD-L1抗体是在US10,435,470中公开的5G11。在某些实施方式中,融合蛋白包含来源于在US 10,435,470中公开的抗PD-L1抗体的抗原结合片段。在某些实施方式中,抗PD-L1抗体或抗原结合片段包含(i)具有HCDR1、HCDR2和HCDR3的重链可变区,所述HCDR1具有SEQ ID NO:7的氨基酸序列,HCDR2具有SEQ ID NO:8的氨基酸序列,HCDR3具有SEQ ID NO:9的氨基酸序列;以及(ii)具有LCDR1、LCDR2和LCDR3的轻链可变区,所述LCDR1具有SEQ ID NO:10的氨基酸序列,LCDR2具有SEQ ID NO:511的氨基酸序列,LCDR3具有SEQ ID NO:12的氨基酸序列。
在某些实施方式中,白介素分子选自下组:IL-1、IL-2、IL-3、IL-4、IL-5、IL-6、、IL-7、IL-8、IL-IL-9、IL-10、IL-11、IL-12、IL-13、IL-14、IL-15、IL-16、IL-17,IL-18、IL-19、IL20、IL-21、IL-22、IL-23、IL-24、IL-25、IL-26、IL-27、IL-28、IL-29、IL-30、IL-31、IL-32、IL-33、IL-35和IL-36。在某些实施方式中,白介素分子是IL-7、IL10或IL-23。在某些实施方式中,白介素分子是人白介素。
白介素7(IL-7)是一种由骨髓和胸腺中的基质细胞分泌的造血生长因子。其也由角质形成细胞、树突细胞、肝细胞、神经元和上皮细胞产生,但不是由正常淋巴细胞产生。人IL-7mRNA具有GenBank登录号NM_000880、NM_001199886、NM_001199887和NM_001199888的序列。人IL-7蛋白具有GenBank登录号NP_000871、NP_001186815、NP_001186816和NP_001186817的序列。IL-7刺激多能(专能)造血干细胞分化为淋巴祖细胞。其还刺激淋巴谱系中所有细胞的增殖,包括B细胞、T细胞和NK细胞。
白细胞介素10(IL-10),也称为人细胞因子合成抑制因子(CSIF),通常被认为是一种抗炎细胞因子。人IL-10蛋白是同型二聚体,每个亚基长178个氨基酸。人IL-10mRNA具有GenBank登录号NM_000572的序列。人IL-10蛋白具有GenBank登录号NP_000563的序列。在某些实施方式中,在融合蛋白中包含的IL-10分子具有SEQ ID NO:13的氨基酸序列,或与其具有至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%同一性的序列。在某些实施方式中,在融合蛋白中包含的IL-10分子具有SEQ ID NO:14的氨基酸序列,或与其具有至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%同一性的序列。
在多肽或多核苷酸的上下文中,“同一性百分比”通过在比较窗口中比较两个最佳比对的序列来确定,其中与参考序列(其不包含添加或缺失)相比,比较窗口中的多核苷酸或多肽序列的部分可以包含添加或缺失(即,空位)用于两条序列的最佳比对。百分比通过确定两个序列中出现相同核酸碱基或氨基酸残基的位置数来计算以产生匹配位置的数量,将匹配位置的数量除以比较窗口中的位置总数,然后将结果乘以100,得到序列同一性百分比。
IL-10通过由两个IL-10受体1和两个IL-10受体2蛋白组成的受体复合物发出信号。IL-10结合通过JAK1和Tyk2磷酸化IL-10受体1和IL-10受体2的胞质尾部来诱导STAT3信号转导。IL-10是一种细胞因子,在免疫调节和炎症中具有多种多效性。其下调巨噬细胞上Th1细胞因子、MHC II类抗原和共刺激分子的表达。其还增强了B细胞的存活、增殖和抗体产生。
白介素23(IL-23)是一种异二聚体细胞因子,由IL12B亚基和IL23A亚基组成。IL-23维持产生IL-17的细胞,增加血管生成并减少CD8 T细胞浸润。
在某些实施方式中,融合蛋白含有将白介素分子与抗体或抗原结合片段连接的接头。在某个实施方式中,接头通常由促进螺旋和转角的氨基酸残基组成,如丙氨酸、丝氨酸和甘氨酸。然而,其他残基也可能是功能性的。在某些实施方式中,接头包含氨基酸序列(GGGGS)n(n=2-5)。
B.生产方法
根据本公开内容的融合蛋白可以重组制备,通过例如从编码融合蛋白的核酸构建体表达,例如,如在Antibody Engineering:Methods and Protocols,第2版(HumanaPress,2012),第40章:Production of Bispecific Antibodies:Diabodies and TandemscFv(Hornig and Farber-Schwarz)中所描述的。
在某些实施方式中,融合蛋白可以基于针对靶抗原的单克隆抗体制备,例如,免疫检查点蛋白,其可以使用标准方法制备,然后进行筛选、表征和功能评估。可以对单克隆抗体的可变区进行测序,然后将其亚克隆到表达载体中以产生编码融合蛋白的基因,然后对其进行表达和纯化。
融合蛋白可以进一步通过亲和力成熟过程进行工程改造,其中产生修饰的抗体或抗原结合片段,与未修饰的亲本抗体或抗原结合片段相比,修饰的抗体或抗原结合片段与抗原结合的亲和力有所提高。亲和力成熟的抗体或抗原结合片段可通过本领域公知的程序产生,例如,Marks等,Rio/Technology 10:779-783(1992);Barbas等,ProcNat.Acad.Sci.USA 91:3809-3813(1994);Schier等,Gene 169:147-155(1995);Yelton等,J.Immunol.155:1994-2004(1995);Jackson等,J.Immunol.154(7):331 0-15 9(1995);和Hawkins等,J.Mol.Biol.226:889-896(1992)。
包含如本文所公开的常规Y形抗体的融合蛋白也可被工程化以包含在Fc区内的修饰,通常以改变抗体的一种或多种功能特性,如血清半衰期、补体固定、Fc受体结合和/或效应功能(例如,抗原依赖性细胞毒性)。此外,本文公开的抗原结合多肽可以被化学修饰(例如,一种或多种化学部分可以连接至抗体)或被修饰以改变其糖基化,再次改变抗原结合多肽的一种或多种功能特性。本文公开的抗体还包括具有修饰的(或封闭的)Fc区以提供改变的效应功能的抗原结合多肽。参见,例如,美国专利号5,624,821;WO2003/086310;WO2005/120571;WO2006/0057702。这种修饰可用于增强或抑制免疫系统的各种反应,可能对诊断和治疗产生有益的影响。
在某些实施方式中,融合蛋白中包含的scFv可以通过噬菌体展示产生,其中非常方便地将抗原结合结构域表达为单个肽。通常,可以构建随机接头文库,其中重链和轻链可变结构域的基因通过编码可变组成的18个氨基酸多肽的区段连接。scFv库(约5×106个不同成员)展示在丝状噬菌体上,并与靶抗原(例如,IL-10)进行亲和选择。
或者,可以从单克隆抗体衍生的亚克隆重链和轻链直接产生scFv。
在某些实施方式中,可以对本公开内容的融合蛋白进行纯化。如本文所用,术语“纯化的”旨在指可与其他组分分离的组合物,其中蛋白相对于其天然可获得状态被纯化至任何程度。因此,纯化的蛋白也指一种蛋白,其不受其可能天然存在的环境的影响。当使用术语“基本上纯化的”时,该名称将指一种组合物,其中蛋白或肽形成该组合物的主要成分,如构成组合物中蛋白的约50%、约60%、约70%、约80%、约90%、约95%或更多(例如,以重量计)。
III.组合物和缀合物
A.制剂
本公开内容提供了一种药物组合物,其包含本文所述的融合蛋白。此类组合物包含预防或治疗有效量的抗原结合多肽和药学上可接受的载体。在一个具体实施方式中,术语“药学上可接受的”指由联邦或州政府的监管机构批准或在美国药典或其他公认的药典中列出的用于动物,更具体地用于人类。此类药物载体可以是无菌液体,如水和油,包括石油、动物、植物或合成来源的那些,如花生油、大豆油、矿物油、芝麻油等。当药物组合物是静脉内施用时,水是一种特殊的载体。盐水溶液和右旋糖和甘油水溶液也可以用作液体载体,特别是用于可注射溶液。其他适宜的药物赋形剂包括淀粉、葡萄糖、乳糖、蔗糖、明胶、麦芽、大米、面粉、白垩、硅胶、硬脂酸钠、单硬脂酸甘油酯、滑石粉、氯化钠、脱脂奶粉、甘油、丙烯、乙二醇、水、乙醇等。
如有需要,该组合物还可以含有少量润湿剂或乳化剂,或pH缓冲剂。这些组合物可以采用溶液、混悬液、乳剂、片剂、丸剂、胶囊、粉末、缓释剂型等形式。口服制剂可以包括标准载体,如药物级甘露醇、乳糖、淀粉、硬脂酸镁、糖精钠、纤维素、碳酸镁等。适宜药剂的实例参见“Remington's Pharmaceutical Sciences”。这样的组合物将含有预防或治疗有效量的抗原结合多肽,优选纯化形式,连同合适量的载体,以便为患者提供适合施用的形式。制剂应适合施用模式,可以是口服、静脉内、动脉内、颊内、鼻内、雾化、支气管吸入或机械通气递送。
如本文所述,本公开内容的融合蛋白可以配制用于胃肠外施用,例如,配制用于通过皮内、静脉内、肌内、皮下、瘤内或甚至腹腔途径注射。或者,抗原结合多肽可以通过局部途径直接施用于粘膜,例如通过滴鼻剂、吸入或通过喷雾器。药学上可接受的盐包括酸式盐和与无机酸例如盐酸或磷酸或有机酸例如乙酸、草酸、酒石酸、扁桃酸等形成的那些。与游离羧基形成的盐也可以衍生自无机碱,例如氢氧化钠、氢氧化钾、氢氧化铵、氢氧化钙或氢氧化铁,以及如有机碱,如异丙胺、三甲胺、2-乙基氨基乙醇、组氨酸、普鲁卡因等。
通常,本公开内容的组合物的成分单独提供或以单位剂型混合在一起提供,例如,作为干燥的冻干粉末或无水浓缩物,在密封容器中,如安瓿或小袋,指示活性剂的量。当组合物通过输注施用时,其可以用装有无菌药用级水或盐水的输液瓶分配。在通过注射施用组合物的情况下,可以提供无菌注射用水或盐水的安瓿,从而可以在施用前混合成分。
可以将本公开内容的组合物配制成中性或盐形式。药学上可接受的盐包括与阴离子形成的盐,如衍生自盐酸、磷酸、乙酸、草酸、酒石酸等的盐,以及与阳离子形成的盐,如衍生自钠、钾、铵、钙、氢氧化铁、异丙胺、三乙胺、2-乙氨基乙醇、组氨酸、普鲁卡因等的盐。
B.缀合物
本公开内容的融合蛋白可以与至少一种药剂连接以形成缀合物。为了增加融合蛋白作为治疗剂的有效性,通常连接或共价结合或复合至少一种所需分子或部分。此类分子或部分可以是但不限于至少一种效应分子或报告分子。效应分子包括具有所需活性的分子,例如,细胞毒活性。已连接至抗体的效应分子的非限制性实例包括毒素、抗肿瘤、治疗性酶、放射性核素、抗病毒剂、螯合剂、细胞因子、生长因子和寡核苷酸或多核苷酸。
在某些实施方式中,本公开内容的缀合物包括药物缀合物,其包含与药物共价连接的融合蛋白。在某些实施方式中,将缀合物用于治疗疾病,例如,通过向患有疾病的对象施用缀合物。适宜药物的实例包括抗肿瘤药物、抗生素和免疫抑制药物。
本领域公知几种用于将抗体附着或缀合至其缀合部分的方法。一些附接方法包括使用金属螯合络合物,例如,附接至抗体的有机螯合剂如二亚乙基三胺五乙酸酐(DTPA);乙三胺四乙酸;N-氯对甲苯磺酰胺;和/或四氯-3α-6α-二苯基甘脲-3(美国专利4,472,509和4,938,948)。单克隆抗体也可以在偶联剂如戊二醛或高碘酸盐的存在下与酶反应。在这些偶联剂存在下或通过与异硫氰酸酯反应制备具有荧光素标记的缀合物。在美国专利4,938,948中,乳腺肿瘤的成像是使用单克隆抗体实现的,并且可检测的成像部分使用接头如对羟基苯甲酸甲酯或N-琥珀酰亚胺基-3-(4-羟基苯基)丙酸酯与抗体结合。
在其他实施方式中,考虑使用不改变抗体结合位点的反应条件,通过在免疫球蛋白的Fc区选择性地引入巯基来衍生免疫球蛋白。公开了根据该方法产生的抗体缀合物显示出改进的寿命、特异性和敏感性(美国专利5,196,066,通过引用并入本文)。效应分子或报告分子的位点特异性连接,其中效应分子与Fc区中的碳水化合物残基缀合,也已在文献中公开(O’Shannessy等,1987)。
IV.由融合蛋白治疗的疾病
在一个方面中,本公开内容提供了使用本文公开的融合蛋白治疗疾病的方法,所述疾病包括但不限于肿瘤和免疫病症。
A.肿瘤
虽然过度增殖性疾病可能与导致细胞开始不受控制地繁殖的任何疾病有关,但典型的实例是肿瘤。肿瘤的关键要素之一是细胞的正常凋亡周期被中断,因此中断细胞生长的药物作为治疗这些疾病的治疗剂很重要。在此,可以针对肿瘤细胞表面上的抗原产生感兴趣的融合蛋白,特别是在癌症干细胞的表面上,或在被这种抗原的存在抑制的免疫细胞的存在下。
根据本公开内容可以治疗的肿瘤细胞包括但不限于来自膀胱、血液、骨、骨髓、脑、乳房、结肠、食道、胃肠道、牙龈、头、肾、肝、肺、鼻咽、颈部、卵巢、前列腺、皮肤、胃、胰腺、睾丸、舌、宫颈或子宫的细胞。此外,肿瘤可能特别具有以下组织学类型,但不限于这些:肿瘤,恶性;癌;癌、未分化的;巨细胞癌和梭形细胞癌;小细胞癌;乳头状癌;鳞状细胞癌;淋巴上皮癌;基底细胞癌;毛母细胞癌;移行细胞癌;乳头状移行细胞癌;腺癌;胃泌素瘤,恶性;胆管癌;肝细胞癌;合并肝细胞癌和胆管癌;小梁腺癌;腺样囊性癌;腺瘤性息肉中的腺癌;腺癌,家族性结肠息肉病;实体癌;类癌,恶性;细支气管肺泡腺癌;乳头状腺癌;嫌色细胞癌;嗜酸性细胞癌;嗜酸性腺癌;嗜碱性粒细胞癌;透明细胞腺癌;颗粒细胞癌;滤泡性腺癌;乳头状和滤泡状腺癌;非包膜硬化性癌;肾上腺皮质癌;子宫内膜癌;皮肤附件癌;大汗腺癌;皮脂腺癌;耵聍腺癌;粘液表皮样癌;囊腺癌;乳头状囊腺癌;乳头状浆液性囊腺癌;粘液性囊腺癌;粘液性腺癌;印戒细胞癌;浸润性导管癌;髓样癌;小叶癌;炎性癌;佩吉特病,乳腺;腺泡细胞癌;腺鳞癌;腺癌伴鳞状化生;胸腺瘤,恶性;卵巢间质瘤,恶性;泡膜细胞瘤,恶性;颗粒细胞瘤,恶性;男性母细胞瘤,恶性;支持细胞癌;间质细胞瘤,恶性;脂质细胞瘤,恶性;副神经节瘤,恶性;乳腺外副神经节瘤,恶性;嗜铬细胞瘤;血管肉瘤;恶性黑色素瘤;无色素性黑色素瘤;浅表扩散黑色素瘤;巨大色素痣中的恶性黑色素瘤;上皮样细胞黑色素瘤;蓝色痣,恶性;肉瘤;纤维肉瘤;纤维组织细胞瘤,恶性;粘液肉瘤;脂肪肉瘤;平滑肌肉瘤;横纹肌肉瘤;胚胎性横纹肌肉瘤;肺泡横纹肌肉瘤;间质肉瘤;混合瘤,恶性;苗勒管混合瘤;肾母细胞瘤;肝母细胞瘤;癌肉瘤;间充质瘤,恶性的;布伦纳肿瘤,恶性;叶状肿瘤,恶性;滑膜肉瘤;间皮瘤,恶性;无性细胞瘤;胚胎癌;畸胎瘤,恶性;卵巢甲状腺肿,恶性;绒毛膜癌;中肾瘤,恶性;血管肉瘤;血管内皮瘤,恶性;卡波西氏肉瘤;恶性血管外皮细胞瘤;淋巴管肉瘤;骨肉瘤;皮质旁骨肉瘤;软骨肉瘤;恶性软骨母细胞瘤;间充质软骨肉瘤;骨巨细胞瘤;尤因氏肉瘤;牙源性肿瘤,恶性;成釉细胞牙肉瘤;成釉细胞瘤,恶性;成釉细胞纤维肉瘤;松果体瘤,恶性;脊索瘤;胶质瘤,恶性;室管膜瘤;星形细胞瘤;原生质星形细胞瘤;纤维星形细胞瘤;星形母细胞瘤;胶质母细胞瘤;少突胶质细胞瘤;少突胶质母细胞瘤;原始神经外胚层;小脑肉瘤;神经节神经母细胞瘤;神经母细胞瘤;视网膜母细胞瘤;嗅觉神经源性肿瘤;脑膜瘤,恶性;神经纤维肉瘤;神经鞘瘤,恶性;颗粒细胞瘤,恶性;恶性淋巴瘤;霍奇金氏病;副肉芽肿;恶性淋巴瘤,小淋巴细胞;恶性淋巴瘤,大细胞,弥漫性;恶性淋巴瘤,滤泡性;蕈样肉芽肿;其他特定的非霍奇金氏淋巴瘤;恶性组织细胞增多症;多发性骨髓瘤;肥大细胞肉瘤;免疫增殖性小肠疾病;白血病;淋巴样白血病;浆细胞白血病;红白血病;淋巴肉瘤细胞白血病;髓性白血病;嗜碱性白血病;嗜酸性粒细胞白血病;单核细胞白血病;肥大细胞白血病;巨核细胞白血病;骨髓肉瘤;和毛细胞白血病。在某些方案中,肿瘤可以包括骨肉瘤、血管肉瘤、横纹肌肉瘤、平滑肌肉瘤、尤因肉瘤、胶质母细胞瘤、神经母细胞瘤或白血病。
B.免疫病症
免疫病症是由免疫系统功能障碍引起的。针对调控免疫细胞(如B细胞、T细胞、NK细胞等)的抗原的融合蛋白可用于调节免疫细胞,从而治疗免疫病症,如炎症、自身免疫性疾病和移植排斥。
如本文所用,自身免疫性疾病是指由对正常身体部位的异常免疫应答引起的病况。由自身免疫性疾病引起的疾病有80多种。几乎可以涉及任何身体部位。自身免疫性疾病具有多种不同影响,包括组织损伤或破坏、器官生长改变和器官功能改变。美国约有2400万人(7%)受到自身免疫性疾病的影响。
一些认为是自身免疫性疾病的常见疾病包括斑秃、强直性脊柱炎、抗磷脂综合征、自身免疫性艾迪生病、自身免疫性溶血性贫血、自身免疫性肝炎、自身免疫性内耳病、自身免疫性淋巴组织增生综合征(ALPS)、自身免疫性血小板减少性紫癜(ATP)、白塞氏病、大疱性类天疱疮、心肌病、乳糜泻、乳糜泻口炎、慢性疲劳免疫缺陷综合征(CFIDS)、慢性炎症性脱髓鞘性多发性神经病、瘢痕性类天疱疮、冷凝集素病、克雷斯特综合征、克罗恩病、德戈病、皮肌炎、皮肌炎-青少年、盘状狼疮、原发性混合冷球蛋白血症、纤维肌痛-纤维肌炎、格雷夫病、格林巴利病、桥本氏甲状腺炎、特发性肺纤维化、特发性血小板减少性紫癜(ITP)、IgA肾病、炎症性肠病、胰岛素依赖型糖尿病(I型)、幼年关节炎、梅尼埃氏病、混合结缔组织病、多发性硬化症、重症肌无力、寻常型天疱疮、恶性贫血、结节性多动脉炎、多软骨炎、多毛综合征、风湿性多肌痛、多肌炎和皮肌炎、原发性胆汁性肝硬化、银屑病、雷蒙德氏现象、赖特氏综合征、风湿热、类风湿性关节炎、结节病、硬皮病、干燥综合征、僵人综合征、系统性红斑狼疮、大动脉炎、颞动脉炎/巨细胞动脉炎、1型糖尿病、溃疡性结肠炎、葡萄膜炎、白癜风和韦格纳氏肉芽肿。
1型糖尿病是一种糖尿病,其没有足够的胰岛素产生,导致体内血糖水平升高。1型糖尿病的症状包括尿频、口渴增加、饥饿感增加、体重减轻、视力模糊、感觉疲倦和愈合不良。虽然1型糖尿病的病因尚不清楚,但其潜在机制涉及胰腺中产生胰岛素的β细胞的自身免疫性破坏。
系统性红斑狼疮,也称为狼疮,是一种身体免疫系统错误地攻击身体很多部位的健康组织的疾病。常见症状包括关节疼痛和肿胀、发烧、胸痛、脱发、口腔溃疡、淋巴结肿大、感觉疲倦和最常见在面部的红疹。虽然狼疮的病因尚不清楚,但其可能涉及遗传和环境因素。狼疮的机制涉及自身抗体对人自身组织的免疫应答,最常见的是导致炎症的抗核抗体。
类风湿性关节炎是一种长期的自身免疫性疾病,主要影响关节,通常会导致关节发热、肿胀和疼痛。其他症状包括低红细胞计数、肺部和心脏周围的炎症、发烧和低能量。虽然类风湿性关节炎的病因尚不清楚,但据信其涉及遗传和环境因素的组合。潜在机制涉及身体的免疫系统错误地攻击关节,导致关节囊发炎和增厚,并影响下面的骨骼和软骨。
多发性硬化症是一种自身免疫性疾病,其中大脑和脊髓中神经细胞的绝缘覆盖物被人自身的免疫系统破坏。这种损伤会破坏神经系统的交流能力,导致一系列症状,包括复视、单眼失明、肌肉无力、感觉障碍或协调障碍。虽然原因尚不清楚,但认为多发性硬化症的潜在机制是免疫系统的破坏。提出的原因包括遗传和环境因素。
尽管自身免疫性疾病普遍存在,但其原因通常尚不清楚。包括T细胞和B细胞在内的人类适应性免疫系统能够与自身抗原发生反应。但是这些自我反应的T细胞和B系统通常要么在免疫系统内变得活跃之前被杀死,要么进入无反应状态,要么被调控细胞从免疫系统内的角色中除去。当这些机制中的任何一种失败时,一些自我反应细胞可能会在免疫系统中发挥作用并导致自身免疫性疾病。
当移植组织被受体的免疫系统排斥时,就会发生移植排斥,这会破坏移植组织。排斥的潜在机制涉及通过由杀伤性T细胞介导的细胞免疫和由活化的B细胞介导的体液免疫的适应性免疫应答的组合。某些先天免疫应答的组分(如吞噬细胞和可溶性免疫蛋白)也可能参与其中。
急性移植排斥反应可用免疫抑制疗法治疗。免疫抑制药物包括皮质类固醇,如泼尼松龙和氢化可的松、钙调神经磷酸酶抑制剂和mTOR抑制剂。
C.融合蛋白的施用
在一些实施方式中,本公开内容提供了一种在对象中治疗疾病的方法,包括向所述对象施用治疗有效量的本文提供的融合蛋白或药物组合物。
本文提供的融合蛋白的治疗有效量(当单独使用或与其他药剂如化疗剂组合使用时)将取决于本领域公知的各种因素,例如待治疗的疾病类型、体重、年龄、过去的病史、目前的药物治疗、对象的健康状况、免疫状况和潜在的交叉反应、过敏、敏感性和不良副作用,以及施用途径和疾病的类型、严重程度和发展以及主治医师或兽医师的判断。在某些实施方式中,可以以约0.001mg/kg至约100mg/kg每天一次或多次(例如,约0.001mg/kg、约0.3mg/kg、约0.5mg/kg、约1mg/kg、约3mg/kg、约5mg/kg、约10mg/kg、约15mg/kg、约20mg/kg、约25mg/kg、约30mg/kg、约35mg/kg、约40mg/kg、约45mg/kg、约50mg/kg、约55mg/kg、约60mg/kg、约65mg/kg、约70mg/kg、约75mg/kg、约80mg/kg、约85mg/kg、约90mg/kg、约95mg/kg或约100mg/kg每天一次或多次)的治疗有效量施用本文提供的融合蛋白。在某些实施方式中,以约50mg/kg或更低的剂量施用融合蛋白,以及在某些实施方式中,剂量是20mg/kg或更低、10mg/kg或更低、3mg/kg或更低、1mg/kg或更低、0.3mg/kg或更低、0.1mg/kg或更低、或0.01mg/kg或更低、或0.001mg/kg更低。在某些实施方式中,施用剂量可以在治疗过程中改变。例如,在某些实施方式中,初始施用剂量可以高于随后的施用剂量。在某些实施方式中,根据对象的反应,可以在治疗过程中改变施用剂量。
可以调整剂量方案以提供最佳所需应答(例如,治疗应答)。在某些实施方式中,将本文提供的融合蛋白一次性或在一系列治疗中施用于对象。在某些实施方式中,根据疾病的类型和严重程度,通过一次或多次单独施用或通过连续输注将本文提供的融合蛋白施用于对象。
本文提供的融合蛋白可以通过本领域公知的任何途径施用,例如胃肠外(例如,皮下、覆膜内、静脉内,包括静脉内输注、肌内或皮内注射)或非胃肠外(例如,口服、鼻内、眼内、舌下、直肠或局部)途径。
在某些实施方式中,本文提供的其融合蛋白可以以控释方式施用。可以将控释胃肠外制剂制成植入剂,油性注射剂或微粒系统(例如,微球、微粒、微囊、纳米胶囊、纳米球和纳米粒子)(参见Banga,A.J.,Therapeutic Peptides and Proteins:Formulation,Processing,and Delivery Systems,Technomic Publishing Company,Inc.,Lancaster,Pa.,(1995);Kreuter,J.,Colloidal Drug Delivery Systems,J.Kreuter编著,MarcelDekker,Inc.,New York,N.Y.,pp.219-342(1994);Tice&Tabibi,Treatise on ControlledDrug Delivery,A.Kydonieus编著,Marcel Dekker,Inc.New York,N.Y.,pp.315-339,(1992))。在某些实施方式中,本文公开的融合蛋白可以在可降解或不可降解的聚合物基质中施用(参见Langer,Accounts Chem.Res.26:537-542,1993)。
在一些实施方式中,本文提供的融合蛋白可以单独施用或与一种或多种其他治疗剂或手段组合施用。例如,本文提供的融合蛋白可以与第二疗法组合施用,如放疗、化疗、靶向疗法、基因疗法、免疫疗法、激素疗法、血管生成抑制、姑息治疗、用于治疗肿瘤的手术(例如,肿瘤切除术)、一种或多种止吐剂或用于化疗引起的并发症的其他治疗或者用于治疗肿瘤或任何医学病症的第二治疗剂,例如,另一种抗体、治疗性多核苷酸、一种或多种化疗剂、抗血管生成剂、细胞因子、一种或多种其他细胞毒剂、一种或多种生长抑制剂。在这些实施方式的某些中,本文提供的融合蛋白可以与一种或多种另外的治疗剂同时施用,并且在这些实施方式的某些中,融合蛋白和一种或多种另外的治疗剂可以作为同一药物组合物的一部分施用。然而,与另一种治疗剂“组合”施用的融合蛋白不必与该药剂同时施用或在与该药剂的组合物中施用。如本文所用的短语,在另一种药剂之前或之后施用的融合蛋白被视为与该药剂“组合”施用,即使融合蛋白和第二药剂通过不同途径施用。在可能的情况下,与本文提供的融合蛋白组合施用的另外的治疗剂根据在另外的治疗剂中提供的产品信息表,或根据Physicians'Desk Reference 2003(Physicians'Desk Reference,第57版;MedicalEconomics Company;ISBN:1563634457;第57版(2002年11月))或本领域众所周知的方案施用。
提供以下实施例以更好地说明所要求保护的发明并且不应被解释为限制本发明的范围。下面描述的所有具体化合物、材料和方法,全部或部分地落入本发明的范围内。这些特定的组合物、材料和方法并非旨在限制本发明,而仅仅是为了说明落入本发明范围内的特定实施方式。本领域技术人员可以在不行使创造性能力和不脱离本发明范围的情况下开发等效的组合物、材料和方法。应当理解的是,可以在本文描述的程序中进行多种变化,同时仍保持在本发明的范围内。本发明的意图是这些变化包括在本发明的范围内。
实施例1
本实施例显示了抗体-IL-10融合蛋白的产生及其体外功能测试。
分别根据抗人PD-1 7A4D(参见Qui等的US10,428,146)和抗人PD-L1抗体5G11(参见Zha等的US 10,435,470)设计抗体-IL-10融合蛋白列表。抗体-IL-10融合蛋白通过瞬时转染在CHO细胞中表达,并进行亲和纯化。IL-10部分通过(GGGGSGGGGS(SEQ ID NO:15))的接头连接到相应抗体的重链或轻链的C末端。如表1中所示,每种抗IL-10融合蛋白的表达产量与相应抗体相似。
此外,通过Biacore分析测量每种抗体-IL-10融合蛋白与相应靶点的结合动力学和结合亲和力。无论融合形式如何,抗体和抗体-IL-10融合蛋白之间的Ka、Kd和KD值相似。
表1:基于抗人PD-1抗体7A4D和抗人PD-L1抗体5G11的抗体-IL-10融合蛋白的结合动力学的表征
对于Biacore分析,抗人IgG Fc二抗用pH 5.0的醋酸钠缓冲液稀释至25μg/mL,并使用胺偶联试剂盒固定在CM5芯片上的参考通道和测试通道上。每种抗体或抗体-IL-10融合蛋白用运行缓冲液稀释至1-3μg/mL,并以10μl/min的流速在预固定CM5芯片的不同通道上捕获60秒。通过将重组人PD-1或PD-L1抗原以3.125和100nM之间的浓度在HBS EP缓冲液中以30μl/min的流速进行2倍连续稀释来测量结合。结合时间和解离时间分别设置为90s和400s。使用Biacore T200评价软件3.1将测得的亲和力数据拟合到1:1Langmuir结合模型。
如图9A和图9B所示,7A4D和5G11抗体均阻断PD-L1-PD-1通路并诱导CD4+效应T细胞分泌IFN-γ和IL-2。基于任一抗体的抗体-IL-10融合蛋白引发了相同的效果,其中IL-10部分连接到Ig重链或轻链C末端。每种抗体和相应的抗体-IL-10融合蛋白都以类似的方式显示细胞因子产生的剂量依赖性诱导,表明IL-10与抗体的连接对7A4D和5G11抗体的功能影响最小。
发明人进一步测试了抗体-IL-10融合蛋白是否保留了诱导免疫细胞增殖的IL-10活性。向MC/9细胞施用IL-10导致以剂量依赖性方式的细胞增殖。在96孔微量滴定板上,将100μl培养基中的2.5x104个MC/9细胞置于每个孔中,所述培养基添加有到指定终浓度的重组人IL-10(rIL-10)或每种抗体-IL-10融合蛋白。rIL-10或融合蛋白的最大浓度是5,260pmol/L。在37℃、5%CO2下48小时,将CellTiterAQueous One Solution(Promega)添加到每个测定孔中,并在490nm吸光度处测量细胞数。EC50由补充剂浓度与OD 490nm的拟合曲线计算得出。
如图10中所示,IL-10与抗PD-1抗体7A4D的Ig重链C末端连接,而不是轻链,强烈诱导MC/9细胞增殖,表现出与人IL-10相似的EC50。类似地,与抗PD-L1抗体5G11的重链或轻链C末端连接的IL-10强烈诱导MC/9细胞增殖,表现出与人IL-10相似的EC50。
实施例2
本实施例在同基因小鼠肿瘤模型中评价了抗体-IL-10融合蛋白的体内治疗有效性。设计了一种基于大鼠抗小鼠PD-L1单克隆抗体10F.9G2的融合蛋白,其通过瞬时转染在CHO细胞中表达并进行亲和纯化。抗体10F.9G2是IgG2a,κ-同种型,融合蛋白含有融合在Ig重链C末端的小鼠IL-10部分。与10F.9G2抗体相比,抗体-IL-10融合蛋白的表达产量列于表2。
表2:抗小鼠PD-L1抗体-IL-10融合蛋白的表达产量
小鼠肿瘤细胞系A20和CT26在表面分别以非常高和低水平表达PD-L1。使用R-藻红蛋白缀合试剂盒(Abcam)分别用PE标记抗PD-L1(10F.9G2)抗体和抗PD-L1(10F.9G2)抗体-HC-mIL-10融合蛋白。染色前,在4℃下将A20和CT26细胞用1μg/mL小鼠BD Fc Block(BDBiosciences)处理5min。使用规定的各种量的PE标记的蛋白对总体积为100μl的处理过的细胞进行染色。在LSRFortessa X-20流式细胞仪上分析染色的细胞。
如图11中所示,与抗PD-L1(10F.9G2)类似,抗PD-L1(10F.9G2)抗体HC-mIL-10融合蛋白显示出剂量依赖性的A20细胞染色,该细胞具有高表达的PD-L1。对于PD-L1表达较弱的CT26细胞,当使用大量标记蛋白(2.5μg)时,抗PD-L1(10F.9G2)抗体和抗PD-L1(10F.9G2)抗体-HC-mIL-10融合蛋白均显示出适度的细胞染色。这些数据表明IL-10的融合对抗小鼠PD-L1抗体与其靶点的结合几乎没有影响。
很多同基因小鼠肿瘤模型可用于评价与未缀合的抗PD-L1(10F.9G2)抗体和载剂对照相比抗PD-L1(10F.9G2)抗体-HC-mIL-10融合蛋白的治疗有效性。此类模型包括使用CT26、A20、Hepa1-6、MBT-2、B16-F10肿瘤细胞系建立的那些。
对于CT26同基因肿瘤模型,在雌性BALB/c小鼠的右后腹区域皮下注射5x 105个CT26肿瘤细胞。在开始治疗之前,允许肿瘤达到100–250mm3的尺寸。对于每个治疗组,使用了8只小鼠,不同组中个体小鼠的肿瘤体积变化保持非常相似。对于治疗,以每周两次的频率在远离肿瘤的部位腹腔内施用抗PD-L1(10F.9G2)抗体(6mg/kg,10ul/g)、抗PD-L1(10F.9G2)抗体-HC-mIL-10融合蛋白(7mg/kg,10ul/g)或仅载剂(PBS缓冲剂,10ul/g)对照,持续两周。每次施用后,使用电子卡尺每周监测肿瘤生长2-3次。此外,在指定的实验终点收集肿瘤组织,用于对包括CD45、CD4、CD8和F4/80在内的几种炎症细胞标志物进行免疫组织化学。
如图12中所示,全身性治疗后,抗PD-L1(10F.9G2)抗体-HC-mIL-10融合蛋白比抗PD-L1(10F.9G2)抗体具有更明显的肿瘤生长抑制作用,后者仅显示出适度的抗肿瘤作用,而在载剂对照组中观察到持续肿瘤生长。此外,在治疗组的所有小鼠中没有观察到明显的体重减轻,表明单独使用抗体或抗体-IL-10融合蛋白引起的全身毒性很小。
序列表
<110> 浙江冠科美博生物科技有限公司
<120> 抗体-白介素融合蛋白以及使用方法
<130> 071017-8008WO02
<160> 15
<170> PatentIn 3.5版
<210> 1
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 1
Asn Phe Gly Met Asn
1 5
<210> 2
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 2
Trp Ile Ser Gly Tyr Thr Arg Glu Pro Thr Tyr Ala Ala Asp Phe Lys
1 5 10 15
Gly
<210> 3
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 3
Asp Val Phe Asp Tyr
1 5
<210> 4
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 4
Arg Ala Ser Glu Ser Val Asp Asn Tyr Gly Tyr Ser Phe Met Asn
1 5 10 15
<210> 5
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 5
Arg Ala Ser Asn Leu Glu Ser
1 5
<210> 6
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 6
Gln Gln Ser Asn Ala Asp Pro Thr
1 5
<210> 7
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 7
Thr Tyr Gly Val His
1 5
<210> 8
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 8
Val Ile Trp Arg Gly Val Thr Thr Asp Tyr Asn Ala Ala Phe Met Ser
1 5 10 15
<210> 9
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 9
Leu Gly Phe Tyr Ala Met Asp Tyr
1 5
<210> 10
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 10
Lys Ala Ser Gln Ser Val Ser Asn Asp Val Ala
1 5 10
<210> 11
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 11
Tyr Ala Ala Asn Arg Tyr Thr
1 5
<210> 12
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 12
Gln Gln Asp Tyr Thr Ser Pro Tyr Thr
1 5
<210> 13
<211> 160
<212> PRT
<213> 小家鼠
<400> 13
Ser Arg Gly Gln Tyr Ser Arg Glu Asp Asn Asn Cys Thr His Phe Pro
1 5 10 15
Val Gly Gln Ser His Met Leu Leu Glu Leu Arg Thr Ala Phe Ser Gln
20 25 30
Val Lys Thr Phe Phe Gln Thr Lys Asp Gln Leu Asp Asn Ile Leu Leu
35 40 45
Thr Asp Ser Leu Met Gln Asp Phe Lys Gly Tyr Leu Gly Cys Gln Ala
50 55 60
Leu Ser Glu Met Ile Gln Phe Tyr Leu Val Glu Val Met Pro Gln Ala
65 70 75 80
Glu Lys His Gly Pro Glu Ile Lys Glu His Leu Asn Ser Leu Gly Glu
85 90 95
Lys Leu Lys Thr Leu Arg Met Arg Leu Arg Arg Cys His Arg Phe Leu
100 105 110
Pro Cys Glu Asn Lys Ser Lys Ala Val Glu Gln Val Lys Ser Asp Phe
115 120 125
Asn Lys Leu Gln Asp Gln Gly Val Tyr Lys Ala Met Asn Glu Phe Asp
130 135 140
Ile Phe Ile Asn Cys Ile Glu Ala Tyr Met Met Ile Lys Met Lys Ser
145 150 155 160
<210> 14
<211> 160
<212> PRT
<213> 智人
<400> 14
Ser Pro Gly Gln Gly Thr Gln Ser Glu Asn Ser Cys Thr His Phe Pro
1 5 10 15
Gly Asn Leu Pro Asn Met Leu Arg Asp Leu Arg Asp Ala Phe Ser Arg
20 25 30
Val Lys Thr Phe Phe Gln Met Lys Asp Gln Leu Asp Asn Leu Leu Leu
35 40 45
Lys Glu Ser Leu Leu Glu Asp Phe Lys Gly Tyr Leu Gly Cys Gln Ala
50 55 60
Leu Ser Glu Met Ile Gln Phe Tyr Leu Glu Glu Val Met Pro Gln Ala
65 70 75 80
Glu Asn Gln Asp Pro Asp Ile Lys Ala His Val Asn Ser Leu Gly Glu
85 90 95
Asn Leu Lys Thr Leu Arg Leu Arg Leu Arg Arg Cys His Arg Phe Leu
100 105 110
Pro Cys Glu Asn Lys Ser Lys Ala Val Glu Gln Val Lys Asn Ala Phe
115 120 125
Asn Lys Leu Gln Glu Lys Gly Ile Tyr Lys Ala Met Ser Glu Phe Asp
130 135 140
Ile Phe Ile Asn Tyr Ile Glu Ala Tyr Met Thr Met Lys Ile Arg Asn
145 150 155 160
<210> 15
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 合成的
<400> 15
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10
Claims (22)
1.一种蛋白,其包含:
(a)特异性结合至免疫检查点蛋白的抗体或抗原结合片段,所述抗体或抗原结合片段包含
(1)重链可变结构域,和
(2)轻链可变结构域;和
(b)可操作地连接至所述抗体或抗原结合片段的白介素-10(IL-10)分子。
2.根据权利要求1所述的蛋白,其中所述免疫检查点蛋白是PD-1或PD-L1。
3.根据权利要求1所述的蛋白,其中所述抗体包含Fc区。
4.根据权利要求1所述的蛋白,其中所述抗原结合片段是F(ab’)2片段或单链可变片段(scFv)。
5.根据权利要求1所述的蛋白,其中所述抗体或抗原结合片段包含(1)重链和(2)轻链,所述重链包含所述重链可变结构域,所述轻链包含所述轻链可变结构域。
6.根据权利要求5所述的蛋白,其中所述IL-10分子连接至所述重链。
7.根据权利要求6所述的蛋白,其中所述IL-10分子连接至所述重链的C末端。
8.根据权利要求5所述的蛋白,其中所述IL-10分子连接至所述轻链。
9.根据权利要求8所述的蛋白,其中所述IL-10分子连接至所述轻链的C末端。
10.根据权利要求1所述的蛋白,其还包含接头,所述接头连接所述抗体或其抗原结合片段和所述白介素分子。
11.根据权利要求10所述的蛋白,其中所述接头包含氨基酸序列(GGGGS)n(n=2-5)。
12.一种分离的多核苷酸,其编码权利要求1-11中任一项所述的蛋白。
13.一种能够表达蛋白的载体,其包含权利要求12所述的分离的多核苷酸。
14.一种适于生产蛋白的重组宿主细胞,其包含权利要求13所述的载体。
15.根据权利要求14所述的重组宿主细胞,其是哺乳动物细胞系。
16.根据权利要求15所述的重组宿主细胞,其是CHO细胞系。
17.一种药物组合物,其包含权利要求1-11中任一项所述的蛋白和药学上可接受的载体。
18.一种在有需要的对象中治疗疾病的方法,其包括:
向所述对象施用治疗量的权利要求17所述的药物组合物。
19.根据权利要求18所述的方法,其中所述疾病是肿瘤。
20.根据权利要求19所述的方法,其中所述肿瘤选自以下:肺癌、黑色素瘤、肾癌、肝癌、骨髓瘤、前列腺癌、乳腺癌、结直肠癌、胰腺癌、甲状腺癌、血液系统癌症、白血病和非霍奇金氏淋巴瘤。
21.根据权利要求20所述的方法,其中所述疾病是免疫相关病症。
22.根据权利要求21所述的方法,其中所述免疫相关病症选自以下:炎性肠病、克罗恩病、溃疡性结肠炎、类风湿性关节炎、银屑病、I型糖尿病、急性胰腺炎、葡萄膜炎、干燥病、白塞氏病、结节病、移植物抗宿主病(GVHD)、系统性红斑狼疮、白癜风、慢性预防性急性移植物抗宿主病(pGvHD)、HIV诱发的血管炎、斑秃、系统性硬化症和原发性抗磷脂综合征。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2019090494 | 2019-06-10 | ||
CNPCT/CN2019/090494 | 2019-06-10 | ||
PCT/CN2020/095354 WO2020249003A1 (en) | 2019-06-10 | 2020-06-10 | Antibody-interleukin fusion protein and methods of use |
Publications (1)
Publication Number | Publication Date |
---|---|
CN114599390A true CN114599390A (zh) | 2022-06-07 |
Family
ID=73781610
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202080055588.4A Pending CN114599390A (zh) | 2019-06-10 | 2020-06-10 | 抗体-白介素融合蛋白以及使用方法 |
Country Status (6)
Country | Link |
---|---|
US (1) | US20220306713A1 (zh) |
EP (1) | EP3980067A4 (zh) |
JP (1) | JP2022537515A (zh) |
CN (1) | CN114599390A (zh) |
CA (1) | CA3143218A1 (zh) |
WO (1) | WO2020249003A1 (zh) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2024518013A (ja) * | 2021-03-10 | 2024-04-24 | イミュノウェイク インコーポレイテッド | 免疫調節分子及びその使用 |
CN115838424A (zh) * | 2021-09-22 | 2023-03-24 | 上海康岱生物医药技术股份有限公司 | 靶向tigit的单克隆抗体 |
AU2022358772A1 (en) * | 2021-10-10 | 2024-05-02 | Elixiron Immunotherapeutics (hong Kong) Limited | Method of treating diseases with anti-pd-l1/il-10 fusion proteins |
TW202325746A (zh) * | 2021-11-02 | 2023-07-01 | 大陸商廣東菲鵬製藥股份有限公司 中國廣東省東莞市松山湖園區桃園路1號10棟301室 郵編:523808 | Il10單體融合蛋白及其應用 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2010040105A2 (en) * | 2008-10-02 | 2010-04-08 | Trubion Pharmaceuticals, Inc. | Cd86 antagonist multi-target binding proteins |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR20160079114A (ko) * | 2013-11-11 | 2016-07-05 | 아르모 바이오사이언시스 인코포레이티드 | 질환 및 장애를 치료하기 위한 인터류킨-10을 사용하는 방법 |
MX2016010174A (es) * | 2014-02-06 | 2016-11-15 | Hoffmann La Roche | Proteinas de fusion de interleucina-10 y usos de las mismas. |
EP3171892B1 (en) * | 2014-07-22 | 2021-11-24 | Apollomics Inc. | Anti-pd-1 antibodies |
WO2017134305A1 (en) * | 2016-02-05 | 2017-08-10 | Orionis Biosciences Nv | Bispecific signaling agents and uses thereof |
CN111315398A (zh) * | 2017-11-10 | 2020-06-19 | 阿尔莫生物科技股份有限公司 | 白介素-10与免疫检查点途径抑制剂的组合的组合物和使用方法 |
-
2020
- 2020-06-10 CA CA3143218A patent/CA3143218A1/en active Pending
- 2020-06-10 JP JP2021573591A patent/JP2022537515A/ja active Pending
- 2020-06-10 WO PCT/CN2020/095354 patent/WO2020249003A1/en unknown
- 2020-06-10 CN CN202080055588.4A patent/CN114599390A/zh active Pending
- 2020-06-10 EP EP20822767.8A patent/EP3980067A4/en active Pending
- 2020-06-10 US US17/617,945 patent/US20220306713A1/en active Pending
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2010040105A2 (en) * | 2008-10-02 | 2010-04-08 | Trubion Pharmaceuticals, Inc. | Cd86 antagonist multi-target binding proteins |
Non-Patent Citations (3)
Title |
---|
PELLERIN,L. 等: "APVO210: A Bispecific Anti-CD86-IL-10 Fusion Protein (ADAPTIR™) to Induce Antigen-Specific T Regulatory Type 1 Cells" * |
WANG,Y. 等: "Autocrine Complement Inhibits IL10-Dependent T-cell-Mediated Antitumor Immunity to Promote Tumor Progression" * |
ZHANG,H 等: "Interleukin-10: An Immune-Activating Cytokine in Cancer Immunotherapy" * |
Also Published As
Publication number | Publication date |
---|---|
EP3980067A4 (en) | 2023-08-02 |
EP3980067A1 (en) | 2022-04-13 |
CA3143218A1 (en) | 2020-12-17 |
WO2020249003A1 (en) | 2020-12-17 |
JP2022537515A (ja) | 2022-08-26 |
US20220306713A1 (en) | 2022-09-29 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN110050000B (zh) | 含有TGF-β受体的融合蛋白及其医药用途 | |
CN109762067B (zh) | 结合人Claudin 18.2的抗体及其用途 | |
JP6432121B2 (ja) | Pdl−1抗体、その医薬組成物及びその使用 | |
AU2010303142B2 (en) | Bispecific death receptor agonistic antibodies | |
WO2020143836A1 (zh) | Cd73抗体及其制备方法和应用 | |
US20200362047A1 (en) | Single domain antibodies that bind to cd137 | |
WO2018228442A1 (en) | Proteinaceous heterodimer and use thereof | |
CN114599390A (zh) | 抗体-白介素融合蛋白以及使用方法 | |
AU2016329197A1 (en) | Binding molecules with modified J-chain | |
TWI821699B (zh) | 抗b7h4抗體及其雙抗和應用 | |
EP3904381A1 (en) | Antibody fusion protein, preparation method therefor and application thereof | |
EP4389770A1 (en) | Bispecific antibody and use thereof | |
CN116891530A (zh) | 双特异性抗体及其应用 | |
EP4155318A1 (en) | Bispecific antibody and use thereof | |
WO2021244553A1 (zh) | 一种抗pd-l1和egfr的四价双特异性抗体 | |
CA3160436A1 (en) | Bispecific antibodies with alternatively matched interchain cysteines and uses thereof | |
JP7510209B2 (ja) | ヘルパーT細胞TGF-βシグナルを特異的に中和する二重特異性抗体、その薬物組成物およびその使用 | |
US20240026004A1 (en) | ANTI-PD-L1/TGF-ß BIFUNCTIONAL ANTIBODY AND USE THEREOF | |
WO2022247826A1 (zh) | 靶向pd-l1和cd73的特异性结合蛋白 | |
CN117177999B (zh) | 一种靶向IL-18Rβ的抗体及其应用 | |
CN117024592B (zh) | 抗b7h3抗体及其用途 | |
TWI840433B (zh) | 新穎合理設計的蛋白質組合物 | |
WO2023143535A1 (zh) | 一种靶向il-18bp的抗体及其应用 | |
WO2023133842A1 (zh) | 一种靶向IL-18Rβ的抗体及其应用 | |
CN117355540A (zh) | 抗cd137抗体和使用方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
WD01 | Invention patent application deemed withdrawn after publication | ||
WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20220607 |