TW202214846A - 用於治療egfr陽性癌症之組合物及方法 - Google Patents
用於治療egfr陽性癌症之組合物及方法 Download PDFInfo
- Publication number
- TW202214846A TW202214846A TW110130697A TW110130697A TW202214846A TW 202214846 A TW202214846 A TW 202214846A TW 110130697 A TW110130697 A TW 110130697A TW 110130697 A TW110130697 A TW 110130697A TW 202214846 A TW202214846 A TW 202214846A
- Authority
- TW
- Taiwan
- Prior art keywords
- seq
- cells
- receptor
- hla
- sequence
- Prior art date
Links
- 206010028980 Neoplasm Diseases 0.000 title claims abstract description 164
- 238000000034 method Methods 0.000 title claims abstract description 91
- 108060006698 EGF receptor Proteins 0.000 title claims description 181
- 239000000203 mixture Substances 0.000 title description 18
- 108020003175 receptors Proteins 0.000 claims abstract description 327
- 210000002865 immune cell Anatomy 0.000 claims abstract description 269
- 201000011510 cancer Diseases 0.000 claims abstract description 134
- 108091008042 inhibitory receptors Proteins 0.000 claims abstract description 126
- 239000012190 activator Substances 0.000 claims abstract description 100
- 238000011282 treatment Methods 0.000 claims abstract description 7
- 210000004027 cell Anatomy 0.000 claims description 481
- 102000005962 receptors Human genes 0.000 claims description 326
- 239000000427 antigen Substances 0.000 claims description 242
- 108091007433 antigens Proteins 0.000 claims description 242
- 102000036639 antigens Human genes 0.000 claims description 242
- 102100028972 HLA class I histocompatibility antigen, A alpha chain Human genes 0.000 claims description 213
- 108090000623 proteins and genes Proteins 0.000 claims description 189
- 102000001301 EGF receptor Human genes 0.000 claims description 179
- 108020001756 ligand binding domains Proteins 0.000 claims description 148
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 139
- 230000003834 intracellular effect Effects 0.000 claims description 131
- 108010017736 Leukocyte Immunoglobulin-like Receptor B1 Proteins 0.000 claims description 98
- 108010047041 Complementarity Determining Regions Proteins 0.000 claims description 86
- 210000001744 T-lymphocyte Anatomy 0.000 claims description 79
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 73
- 108091054437 MHC class I family Proteins 0.000 claims description 69
- 229920001184 polypeptide Polymers 0.000 claims description 67
- 230000014509 gene expression Effects 0.000 claims description 65
- 102000043129 MHC class I family Human genes 0.000 claims description 63
- 108010019670 Chimeric Antigen Receptors Proteins 0.000 claims description 62
- 239000013598 vector Substances 0.000 claims description 56
- 239000008194 pharmaceutical composition Substances 0.000 claims description 49
- 102000040430 polynucleotide Human genes 0.000 claims description 48
- 108091033319 polynucleotide Proteins 0.000 claims description 48
- 239000002157 polynucleotide Substances 0.000 claims description 48
- 150000007523 nucleic acids Chemical class 0.000 claims description 44
- 102100028971 HLA class I histocompatibility antigen, C alpha chain Human genes 0.000 claims description 42
- 102000039446 nucleic acids Human genes 0.000 claims description 37
- 108020004707 nucleic acids Proteins 0.000 claims description 37
- 108091032973 (ribonucleotides)n+m Proteins 0.000 claims description 36
- 102000015736 beta 2-Microglobulin Human genes 0.000 claims description 31
- 108010081355 beta 2-Microglobulin Proteins 0.000 claims description 31
- 108010052199 HLA-C Antigens Proteins 0.000 claims description 29
- 230000000295 complement effect Effects 0.000 claims description 23
- 230000035772 mutation Effects 0.000 claims description 23
- 238000012217 deletion Methods 0.000 claims description 22
- 230000037430 deletion Effects 0.000 claims description 22
- 230000000694 effects Effects 0.000 claims description 21
- 230000002452 interceptive effect Effects 0.000 claims description 21
- 102000054767 gene variant Human genes 0.000 claims description 19
- 238000006467 substitution reaction Methods 0.000 claims description 19
- 108010008553 HLA-B*07 antigen Proteins 0.000 claims description 18
- 230000004048 modification Effects 0.000 claims description 17
- 238000012986 modification Methods 0.000 claims description 17
- 108091027967 Small hairpin RNA Proteins 0.000 claims description 16
- 238000003780 insertion Methods 0.000 claims description 16
- 230000037431 insertion Effects 0.000 claims description 16
- 108020004999 messenger RNA Proteins 0.000 claims description 16
- 239000004055 small Interfering RNA Substances 0.000 claims description 16
- 230000002829 reductive effect Effects 0.000 claims description 15
- 108010042407 Endonucleases Proteins 0.000 claims description 14
- 230000002147 killing effect Effects 0.000 claims description 12
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 10
- 206010038389 Renal cancer Diseases 0.000 claims description 10
- 230000000415 inactivating effect Effects 0.000 claims description 10
- 201000005202 lung cancer Diseases 0.000 claims description 10
- 208000020816 lung neoplasm Diseases 0.000 claims description 10
- 230000001939 inductive effect Effects 0.000 claims description 9
- 206010009944 Colon cancer Diseases 0.000 claims description 8
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 8
- 208000006265 Renal cell carcinoma Diseases 0.000 claims description 8
- 201000010174 renal carcinoma Diseases 0.000 claims description 8
- 206010006187 Breast cancer Diseases 0.000 claims description 7
- 208000026310 Breast neoplasm Diseases 0.000 claims description 7
- 238000012228 RNA interference-mediated gene silencing Methods 0.000 claims description 7
- 230000009368 gene silencing by RNA Effects 0.000 claims description 7
- 208000005017 glioblastoma Diseases 0.000 claims description 7
- 201000010536 head and neck cancer Diseases 0.000 claims description 7
- 208000014829 head and neck neoplasm Diseases 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 230000001404 mediated effect Effects 0.000 claims description 7
- 108010058607 HLA-B Antigens Proteins 0.000 claims description 6
- 206010039491 Sarcoma Diseases 0.000 claims description 6
- 230000000735 allogeneic effect Effects 0.000 claims description 6
- 206010005003 Bladder cancer Diseases 0.000 claims description 5
- 206010033128 Ovarian cancer Diseases 0.000 claims description 5
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 5
- 208000008900 Pancreatic Ductal Carcinoma Diseases 0.000 claims description 5
- 206010060862 Prostate cancer Diseases 0.000 claims description 5
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 5
- 206010041067 Small cell lung cancer Diseases 0.000 claims description 5
- 208000034254 Squamous cell carcinoma of the cervix uteri Diseases 0.000 claims description 5
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 5
- 208000000728 Thymus Neoplasms Diseases 0.000 claims description 5
- 208000024770 Thyroid neoplasm Diseases 0.000 claims description 5
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 5
- 208000002495 Uterine Neoplasms Diseases 0.000 claims description 5
- 201000006612 cervical squamous cell carcinoma Diseases 0.000 claims description 5
- 208000006990 cholangiocarcinoma Diseases 0.000 claims description 5
- 208000028653 esophageal adenocarcinoma Diseases 0.000 claims description 5
- 201000006585 gastric adenocarcinoma Diseases 0.000 claims description 5
- 206010017758 gastric cancer Diseases 0.000 claims description 5
- 201000007270 liver cancer Diseases 0.000 claims description 5
- 208000014018 liver neoplasm Diseases 0.000 claims description 5
- 230000003211 malignant effect Effects 0.000 claims description 5
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 5
- 201000008129 pancreatic ductal adenocarcinoma Diseases 0.000 claims description 5
- 208000000587 small cell lung carcinoma Diseases 0.000 claims description 5
- 201000011549 stomach cancer Diseases 0.000 claims description 5
- 201000002510 thyroid cancer Diseases 0.000 claims description 5
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 5
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 5
- 206010046766 uterine cancer Diseases 0.000 claims description 5
- 208000036764 Adenocarcinoma of the esophagus Diseases 0.000 claims description 4
- 208000030808 Clear cell renal carcinoma Diseases 0.000 claims description 4
- 206010030137 Oesophageal adenocarcinoma Diseases 0.000 claims description 4
- 230000015556 catabolic process Effects 0.000 claims description 4
- 206010073251 clear cell renal cell carcinoma Diseases 0.000 claims description 4
- 238000006731 degradation reaction Methods 0.000 claims description 4
- 231100000221 frame shift mutation induction Toxicity 0.000 claims description 4
- 230000037433 frameshift Effects 0.000 claims description 4
- 210000002540 macrophage Anatomy 0.000 claims description 4
- 210000000581 natural killer T-cell Anatomy 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 3
- 102000009484 Vascular Endothelial Growth Factor Receptors Human genes 0.000 claims description 2
- 108010034265 Vascular Endothelial Growth Factor Receptors Proteins 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 230000036210 malignancy Effects 0.000 claims description 2
- 208000037843 metastatic solid tumor Diseases 0.000 claims description 2
- 210000000822 natural killer cell Anatomy 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 230000000306 recurrent effect Effects 0.000 claims description 2
- 230000001131 transforming effect Effects 0.000 claims description 2
- 230000004614 tumor growth Effects 0.000 claims description 2
- 108010075704 HLA-A Antigens Proteins 0.000 claims 36
- 102000004569 Leukocyte Immunoglobulin-like Receptor B1 Human genes 0.000 claims 11
- 102100024952 Protein CBFA2T1 Human genes 0.000 claims 5
- 102100031780 Endonuclease Human genes 0.000 claims 2
- 201000010915 Glioblastoma multiforme Diseases 0.000 claims 2
- 208000008839 Kidney Neoplasms Diseases 0.000 claims 2
- 201000010982 kidney cancer Diseases 0.000 claims 2
- 102100028976 HLA class I histocompatibility antigen, B alpha chain Human genes 0.000 claims 1
- 108700005089 MHC Class I Genes Proteins 0.000 claims 1
- 230000008030 elimination Effects 0.000 claims 1
- 238000003379 elimination reaction Methods 0.000 claims 1
- 210000003238 esophagus Anatomy 0.000 claims 1
- 201000007550 esophagus adenocarcinoma Diseases 0.000 claims 1
- 210000003734 kidney Anatomy 0.000 claims 1
- 101000986086 Homo sapiens HLA class I histocompatibility antigen, A alpha chain Proteins 0.000 description 178
- 239000003446 ligand Substances 0.000 description 119
- 108091008874 T cell receptors Proteins 0.000 description 111
- 102000016266 T-Cell Antigen Receptors Human genes 0.000 description 111
- 102100025584 Leukocyte immunoglobulin-like receptor subfamily B member 1 Human genes 0.000 description 95
- 230000027455 binding Effects 0.000 description 77
- 230000002401 inhibitory effect Effects 0.000 description 75
- 102000017420 CD3 protein, epsilon/gamma/delta subunit Human genes 0.000 description 62
- 108050005493 CD3 protein, epsilon/gamma/delta subunit Proteins 0.000 description 61
- 102000004169 proteins and genes Human genes 0.000 description 48
- 230000008685 targeting Effects 0.000 description 48
- 229940024606 amino acid Drugs 0.000 description 45
- 150000001413 amino acids Chemical class 0.000 description 44
- 230000004913 activation Effects 0.000 description 42
- 101000914514 Homo sapiens T-cell-specific surface glycoprotein CD28 Proteins 0.000 description 41
- 102100027213 T-cell-specific surface glycoprotein CD28 Human genes 0.000 description 41
- 230000000139 costimulatory effect Effects 0.000 description 38
- 108020005004 Guide RNA Proteins 0.000 description 36
- 108091033409 CRISPR Proteins 0.000 description 35
- 125000003275 alpha amino acid group Chemical group 0.000 description 35
- 239000002773 nucleotide Substances 0.000 description 35
- 230000009977 dual effect Effects 0.000 description 34
- 125000003729 nucleotide group Chemical group 0.000 description 34
- 101000889133 Homo sapiens C-X-C motif chemokine 16 Proteins 0.000 description 32
- 101000684673 Homo sapiens Protein APCDD1 Proteins 0.000 description 32
- 102100039396 C-X-C motif chemokine 16 Human genes 0.000 description 31
- 230000006870 function Effects 0.000 description 30
- 102100023735 Protein APCDD1 Human genes 0.000 description 29
- 230000001086 cytosolic effect Effects 0.000 description 26
- 239000011324 bead Substances 0.000 description 24
- 230000011664 signaling Effects 0.000 description 22
- 230000004068 intracellular signaling Effects 0.000 description 21
- -1 linear antibodies Proteins 0.000 description 20
- 238000010354 CRISPR gene editing Methods 0.000 description 19
- 102000006390 HLA-B Antigens Human genes 0.000 description 19
- 101000851370 Homo sapiens Tumor necrosis factor receptor superfamily member 9 Proteins 0.000 description 19
- 102100036856 Tumor necrosis factor receptor superfamily member 9 Human genes 0.000 description 19
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 17
- 108091028043 Nucleic acid sequence Proteins 0.000 description 17
- 230000004936 stimulating effect Effects 0.000 description 17
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 17
- 241000282414 Homo sapiens Species 0.000 description 16
- 239000012634 fragment Substances 0.000 description 16
- 108010041397 CD4 Antigens Proteins 0.000 description 15
- 102100036011 T-cell surface glycoprotein CD4 Human genes 0.000 description 15
- 238000010453 CRISPR/Cas method Methods 0.000 description 14
- 101000986087 Homo sapiens HLA class I histocompatibility antigen, B alpha chain Proteins 0.000 description 14
- 101000986084 Homo sapiens HLA class I histocompatibility antigen, C alpha chain Proteins 0.000 description 13
- 101000946843 Homo sapiens T-cell surface glycoprotein CD8 alpha chain Proteins 0.000 description 13
- 108700018351 Major Histocompatibility Complex Proteins 0.000 description 13
- 102100034922 T-cell surface glycoprotein CD8 alpha chain Human genes 0.000 description 13
- 239000003153 chemical reaction reagent Substances 0.000 description 13
- 238000010362 genome editing Methods 0.000 description 13
- 102000004533 Endonucleases Human genes 0.000 description 12
- 102210042925 HLA-A*02:01 Human genes 0.000 description 12
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 12
- 239000002245 particle Substances 0.000 description 12
- 210000001519 tissue Anatomy 0.000 description 12
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 11
- 102100039087 Peptidyl-alpha-hydroxyglycine alpha-amidating lyase Human genes 0.000 description 11
- 108700008625 Reporter Genes Proteins 0.000 description 11
- 238000010459 TALEN Methods 0.000 description 11
- 108010043645 Transcription Activator-Like Effector Nucleases Proteins 0.000 description 11
- 238000011467 adoptive cell therapy Methods 0.000 description 11
- 238000003556 assay Methods 0.000 description 11
- 239000003112 inhibitor Substances 0.000 description 11
- 101150076800 B2M gene Proteins 0.000 description 10
- 239000005089 Luciferase Substances 0.000 description 10
- 108010029485 Protein Isoforms Proteins 0.000 description 10
- 102000001708 Protein Isoforms Human genes 0.000 description 10
- 108091028113 Trans-activating crRNA Proteins 0.000 description 10
- 241000700605 Viruses Species 0.000 description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 10
- 230000004044 response Effects 0.000 description 10
- 230000020382 suppression by virus of host antigen processing and presentation of peptide antigen via MHC class I Effects 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 108060001084 Luciferase Proteins 0.000 description 9
- 239000012636 effector Substances 0.000 description 9
- 102000040650 (ribonucleotides)n+m Human genes 0.000 description 8
- 108060003951 Immunoglobulin Proteins 0.000 description 8
- 102100022153 Tumor necrosis factor receptor superfamily member 4 Human genes 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 8
- 201000010099 disease Diseases 0.000 description 8
- 102000018358 immunoglobulin Human genes 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 230000035899 viability Effects 0.000 description 8
- 108020004414 DNA Proteins 0.000 description 7
- 101710089372 Programmed cell death protein 1 Proteins 0.000 description 7
- 102100040678 Programmed cell death protein 1 Human genes 0.000 description 7
- 230000000890 antigenic effect Effects 0.000 description 7
- 239000013604 expression vector Substances 0.000 description 7
- 239000012528 membrane Substances 0.000 description 7
- 239000013603 viral vector Substances 0.000 description 7
- 102100038080 B-cell receptor CD22 Human genes 0.000 description 6
- 101000884305 Homo sapiens B-cell receptor CD22 Proteins 0.000 description 6
- 101000934341 Homo sapiens T-cell surface glycoprotein CD5 Proteins 0.000 description 6
- 102100025244 T-cell surface glycoprotein CD5 Human genes 0.000 description 6
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 6
- 230000003213 activating effect Effects 0.000 description 6
- 238000013459 approach Methods 0.000 description 6
- 210000003719 b-lymphocyte Anatomy 0.000 description 6
- 230000010261 cell growth Effects 0.000 description 6
- 230000002068 genetic effect Effects 0.000 description 6
- 230000003993 interaction Effects 0.000 description 6
- 210000004698 lymphocyte Anatomy 0.000 description 6
- 230000007246 mechanism Effects 0.000 description 6
- 239000002609 medium Substances 0.000 description 6
- 210000001616 monocyte Anatomy 0.000 description 6
- 102000054765 polymorphisms of proteins Human genes 0.000 description 6
- 125000006850 spacer group Chemical group 0.000 description 6
- 230000000638 stimulation Effects 0.000 description 6
- 239000011701 zinc Substances 0.000 description 6
- 229910052725 zinc Inorganic materials 0.000 description 6
- 102100027207 CD27 antigen Human genes 0.000 description 5
- 230000004568 DNA-binding Effects 0.000 description 5
- BCCRXDTUTZHDEU-VKHMYHEASA-N Gly-Ser Chemical compound NCC(=O)N[C@@H](CO)C(O)=O BCCRXDTUTZHDEU-VKHMYHEASA-N 0.000 description 5
- 101000914511 Homo sapiens CD27 antigen Proteins 0.000 description 5
- 101000984190 Homo sapiens Leukocyte immunoglobulin-like receptor subfamily B member 1 Proteins 0.000 description 5
- 108010002350 Interleukin-2 Proteins 0.000 description 5
- 102000000588 Interleukin-2 Human genes 0.000 description 5
- 108010064548 Lymphocyte Function-Associated Antigen-1 Proteins 0.000 description 5
- 108010052285 Membrane Proteins Proteins 0.000 description 5
- 241000699666 Mus <mouse, genus> Species 0.000 description 5
- 101710163270 Nuclease Proteins 0.000 description 5
- 108010038807 Oligopeptides Proteins 0.000 description 5
- 102000015636 Oligopeptides Human genes 0.000 description 5
- 230000007423 decrease Effects 0.000 description 5
- 230000008014 freezing Effects 0.000 description 5
- 238000007710 freezing Methods 0.000 description 5
- 238000010363 gene targeting Methods 0.000 description 5
- 239000000833 heterodimer Substances 0.000 description 5
- 230000005931 immune cell recruitment Effects 0.000 description 5
- 230000001965 increasing effect Effects 0.000 description 5
- 230000001105 regulatory effect Effects 0.000 description 5
- 210000002966 serum Anatomy 0.000 description 5
- 208000024891 symptom Diseases 0.000 description 5
- 102000035160 transmembrane proteins Human genes 0.000 description 5
- 108091005703 transmembrane proteins Proteins 0.000 description 5
- 210000004881 tumor cell Anatomy 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 108010021064 CTLA-4 Antigen Proteins 0.000 description 4
- 229940045513 CTLA4 antagonist Drugs 0.000 description 4
- 108091026890 Coding region Proteins 0.000 description 4
- 102000004127 Cytokines Human genes 0.000 description 4
- 108090000695 Cytokines Proteins 0.000 description 4
- 102100039498 Cytotoxic T-lymphocyte protein 4 Human genes 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
- 108010022070 HLA-A*02 antigen Proteins 0.000 description 4
- 101000934346 Homo sapiens T-cell surface antigen CD2 Proteins 0.000 description 4
- 101000679851 Homo sapiens Tumor necrosis factor receptor superfamily member 4 Proteins 0.000 description 4
- 101000851376 Homo sapiens Tumor necrosis factor receptor superfamily member 8 Proteins 0.000 description 4
- 101000818543 Homo sapiens Tyrosine-protein kinase ZAP-70 Proteins 0.000 description 4
- 102000003839 Human Proteins Human genes 0.000 description 4
- 108090000144 Human Proteins Proteins 0.000 description 4
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 108010003723 Single-Domain Antibodies Proteins 0.000 description 4
- 230000006044 T cell activation Effects 0.000 description 4
- 102100025237 T-cell surface antigen CD2 Human genes 0.000 description 4
- 108010073062 Transcription Activator-Like Effectors Proteins 0.000 description 4
- 101710165473 Tumor necrosis factor receptor superfamily member 4 Proteins 0.000 description 4
- 102100036857 Tumor necrosis factor receptor superfamily member 8 Human genes 0.000 description 4
- 102100021125 Tyrosine-protein kinase ZAP-70 Human genes 0.000 description 4
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 238000002659 cell therapy Methods 0.000 description 4
- 230000001413 cellular effect Effects 0.000 description 4
- 238000004590 computer program Methods 0.000 description 4
- 238000012258 culturing Methods 0.000 description 4
- 230000001419 dependent effect Effects 0.000 description 4
- 239000008121 dextrose Substances 0.000 description 4
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 4
- 230000028993 immune response Effects 0.000 description 4
- 210000000987 immune system Anatomy 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 208000015181 infectious disease Diseases 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 239000003550 marker Substances 0.000 description 4
- 230000006780 non-homologous end joining Effects 0.000 description 4
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 4
- 239000002953 phosphate buffered saline Substances 0.000 description 4
- 230000002441 reversible effect Effects 0.000 description 4
- 241001430294 unidentified retrovirus Species 0.000 description 4
- 239000004474 valine Substances 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- 102000006306 Antigen Receptors Human genes 0.000 description 3
- 108010083359 Antigen Receptors Proteins 0.000 description 3
- 102100027205 B-cell antigen receptor complex-associated protein alpha chain Human genes 0.000 description 3
- 102100027203 B-cell antigen receptor complex-associated protein beta chain Human genes 0.000 description 3
- 102100038078 CD276 antigen Human genes 0.000 description 3
- 102100032937 CD40 ligand Human genes 0.000 description 3
- 102100037904 CD9 antigen Human genes 0.000 description 3
- 108010087819 Fc receptors Proteins 0.000 description 3
- 102000009109 Fc receptors Human genes 0.000 description 3
- 101150000578 HLA-B gene Proteins 0.000 description 3
- 102100026122 High affinity immunoglobulin gamma Fc receptor I Human genes 0.000 description 3
- 101000914489 Homo sapiens B-cell antigen receptor complex-associated protein alpha chain Proteins 0.000 description 3
- 101000914491 Homo sapiens B-cell antigen receptor complex-associated protein beta chain Proteins 0.000 description 3
- 101000738354 Homo sapiens CD9 antigen Proteins 0.000 description 3
- 101000913074 Homo sapiens High affinity immunoglobulin gamma Fc receptor I Proteins 0.000 description 3
- 101000777628 Homo sapiens Leukocyte antigen CD37 Proteins 0.000 description 3
- 101000917858 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor III-A Proteins 0.000 description 3
- 101000917839 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor III-B Proteins 0.000 description 3
- 101000934338 Homo sapiens Myeloid cell surface antigen CD33 Proteins 0.000 description 3
- 101000738771 Homo sapiens Receptor-type tyrosine-protein phosphatase C Proteins 0.000 description 3
- 101000914496 Homo sapiens T-cell antigen CD7 Proteins 0.000 description 3
- 101000914484 Homo sapiens T-lymphocyte activation antigen CD80 Proteins 0.000 description 3
- 101000801234 Homo sapiens Tumor necrosis factor receptor superfamily member 18 Proteins 0.000 description 3
- 108091006905 Human Serum Albumin Proteins 0.000 description 3
- 102000008100 Human Serum Albumin Human genes 0.000 description 3
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 3
- 108090001090 Lectins Proteins 0.000 description 3
- 102000004856 Lectins Human genes 0.000 description 3
- 241000713666 Lentivirus Species 0.000 description 3
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 3
- 102100031586 Leukocyte antigen CD37 Human genes 0.000 description 3
- 102100029185 Low affinity immunoglobulin gamma Fc region receptor III-B Human genes 0.000 description 3
- 102100025243 Myeloid cell surface antigen CD33 Human genes 0.000 description 3
- 108010076504 Protein Sorting Signals Proteins 0.000 description 3
- 102100037422 Receptor-type tyrosine-protein phosphatase C Human genes 0.000 description 3
- 108020004511 Recombinant DNA Proteins 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 102100027208 T-cell antigen CD7 Human genes 0.000 description 3
- 102100027222 T-lymphocyte activation antigen CD80 Human genes 0.000 description 3
- 102100033728 Tumor necrosis factor receptor superfamily member 18 Human genes 0.000 description 3
- 102100040245 Tumor necrosis factor receptor superfamily member 5 Human genes 0.000 description 3
- 238000004873 anchoring Methods 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 210000004899 c-terminal region Anatomy 0.000 description 3
- 230000003833 cell viability Effects 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 238000003776 cleavage reaction Methods 0.000 description 3
- 210000005220 cytoplasmic tail Anatomy 0.000 description 3
- 230000002950 deficient Effects 0.000 description 3
- 108010087914 epidermal growth factor receptor VIII Proteins 0.000 description 3
- 102000054430 human APCDD1 Human genes 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 230000000977 initiatory effect Effects 0.000 description 3
- 239000002523 lectin Substances 0.000 description 3
- 210000000265 leukocyte Anatomy 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 210000000440 neutrophil Anatomy 0.000 description 3
- 230000006461 physiological response Effects 0.000 description 3
- 210000002381 plasma Anatomy 0.000 description 3
- 210000002706 plastid Anatomy 0.000 description 3
- 230000035755 proliferation Effects 0.000 description 3
- 230000009257 reactivity Effects 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 230000010076 replication Effects 0.000 description 3
- 230000001177 retroviral effect Effects 0.000 description 3
- 230000007017 scission Effects 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 210000001541 thymus gland Anatomy 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- 238000013518 transcription Methods 0.000 description 3
- 230000035897 transcription Effects 0.000 description 3
- 101710185679 CD276 antigen Proteins 0.000 description 2
- 210000001266 CD8-positive T-lymphocyte Anatomy 0.000 description 2
- 102100029382 CMRF35-like molecule 6 Human genes 0.000 description 2
- 101150069031 CSN2 gene Proteins 0.000 description 2
- 108700004991 Cas12a Proteins 0.000 description 2
- 102000008186 Collagen Human genes 0.000 description 2
- 108010035532 Collagen Proteins 0.000 description 2
- 241000701022 Cytomegalovirus Species 0.000 description 2
- 102000053602 DNA Human genes 0.000 description 2
- 230000007018 DNA scission Effects 0.000 description 2
- 241000702421 Dependoparvovirus Species 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 108010043121 Green Fluorescent Proteins Proteins 0.000 description 2
- 102100028970 HLA class I histocompatibility antigen, alpha chain E Human genes 0.000 description 2
- 101150118346 HLA-A gene Proteins 0.000 description 2
- 101150035071 HLA-C gene Proteins 0.000 description 2
- 102000006354 HLA-DR Antigens Human genes 0.000 description 2
- 108010058597 HLA-DR Antigens Proteins 0.000 description 2
- 102100029360 Hematopoietic cell signal transducer Human genes 0.000 description 2
- 101000990034 Homo sapiens CMRF35-like molecule 6 Proteins 0.000 description 2
- 101000986085 Homo sapiens HLA class I histocompatibility antigen, alpha chain E Proteins 0.000 description 2
- 101000990188 Homo sapiens Hematopoietic cell signal transducer Proteins 0.000 description 2
- 101001109503 Homo sapiens NKG2-C type II integral membrane protein Proteins 0.000 description 2
- 101000946860 Homo sapiens T-cell surface glycoprotein CD3 epsilon chain Proteins 0.000 description 2
- 241000725303 Human immunodeficiency virus Species 0.000 description 2
- 108010067060 Immunoglobulin Variable Region Proteins 0.000 description 2
- 102000017727 Immunoglobulin Variable Region Human genes 0.000 description 2
- 108010002586 Interleukin-7 Proteins 0.000 description 2
- 102100021592 Interleukin-7 Human genes 0.000 description 2
- 108020004684 Internal Ribosome Entry Sites Proteins 0.000 description 2
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 2
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 2
- 241000829100 Macaca mulatta polyomavirus 1 Species 0.000 description 2
- 102000018697 Membrane Proteins Human genes 0.000 description 2
- 108091092878 Microsatellite Proteins 0.000 description 2
- 108010085220 Multiprotein Complexes Proteins 0.000 description 2
- 102000007474 Multiprotein Complexes Human genes 0.000 description 2
- 102100022683 NKG2-C type II integral membrane protein Human genes 0.000 description 2
- 108091008606 PDGF receptors Proteins 0.000 description 2
- 102000011653 Platelet-Derived Growth Factor Receptors Human genes 0.000 description 2
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 description 2
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 2
- 102100035794 T-cell surface glycoprotein CD3 epsilon chain Human genes 0.000 description 2
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 2
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 2
- 108010017070 Zinc Finger Nucleases Proteins 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 210000000612 antigen-presenting cell Anatomy 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000001772 blood platelet Anatomy 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- 229910000389 calcium phosphate Inorganic materials 0.000 description 2
- 235000011010 calcium phosphates Nutrition 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 230000024245 cell differentiation Effects 0.000 description 2
- 230000022534 cell killing Effects 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 230000005754 cellular signaling Effects 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 229920001436 collagen Polymers 0.000 description 2
- 101150055601 cops2 gene Proteins 0.000 description 2
- 230000016396 cytokine production Effects 0.000 description 2
- 102000003675 cytokine receptors Human genes 0.000 description 2
- 108010057085 cytokine receptors Proteins 0.000 description 2
- 230000001461 cytolytic effect Effects 0.000 description 2
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 230000005782 double-strand break Effects 0.000 description 2
- 239000003623 enhancer Substances 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- 230000008995 epigenetic change Effects 0.000 description 2
- 210000000981 epithelium Anatomy 0.000 description 2
- 210000003743 erythrocyte Anatomy 0.000 description 2
- 210000003527 eukaryotic cell Anatomy 0.000 description 2
- 238000000684 flow cytometry Methods 0.000 description 2
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 2
- 238000012239 gene modification Methods 0.000 description 2
- 230000030279 gene silencing Effects 0.000 description 2
- 230000005017 genetic modification Effects 0.000 description 2
- 235000013617 genetically modified food Nutrition 0.000 description 2
- 229930004094 glycosylphosphatidylinositol Natural products 0.000 description 2
- 210000003714 granulocyte Anatomy 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 125000001165 hydrophobic group Chemical group 0.000 description 2
- 238000003384 imaging method Methods 0.000 description 2
- 239000012642 immune effector Substances 0.000 description 2
- 230000036039 immunity Effects 0.000 description 2
- 229940121354 immunomodulator Drugs 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 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 2
- 230000010354 integration Effects 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 230000000503 lectinlike effect Effects 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- FVVLHONNBARESJ-NTOWJWGLSA-H magnesium;potassium;trisodium;(2r,3s,4r,5r)-2,3,4,5,6-pentahydroxyhexanoate;acetate;tetrachloride;nonahydrate Chemical compound O.O.O.O.O.O.O.O.O.[Na+].[Na+].[Na+].[Mg+2].[Cl-].[Cl-].[Cl-].[Cl-].[K+].CC([O-])=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O FVVLHONNBARESJ-NTOWJWGLSA-H 0.000 description 2
- 230000005291 magnetic effect Effects 0.000 description 2
- 210000004962 mammalian cell Anatomy 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 210000003071 memory t lymphocyte Anatomy 0.000 description 2
- 239000000693 micelle Substances 0.000 description 2
- 238000010369 molecular cloning Methods 0.000 description 2
- 230000001537 neural effect Effects 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 230000005298 paramagnetic effect Effects 0.000 description 2
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 108091008146 restriction endonucleases Proteins 0.000 description 2
- 238000003757 reverse transcription PCR Methods 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- 230000035945 sensitivity Effects 0.000 description 2
- 238000012163 sequencing technique Methods 0.000 description 2
- 230000019491 signal transduction Effects 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- DAEPDZWVDSPTHF-UHFFFAOYSA-M sodium pyruvate Chemical compound [Na+].CC(=O)C([O-])=O DAEPDZWVDSPTHF-UHFFFAOYSA-M 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical compound CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 description 2
- 230000002103 transcriptional effect Effects 0.000 description 2
- 230000002463 transducing effect Effects 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- 230000009261 transgenic effect Effects 0.000 description 2
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 2
- 241000701161 unidentified adenovirus Species 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 2
- DIGQNXIGRZPYDK-WKSCXVIASA-N (2R)-6-amino-2-[[2-[[(2S)-2-[[2-[[(2R)-2-[[(2S)-2-[[(2R,3S)-2-[[2-[[(2S)-2-[[2-[[(2S)-2-[[(2S)-2-[[(2R)-2-[[(2S,3S)-2-[[(2R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S)-2-[[(2R)-2-[[2-[[2-[[2-[(2-amino-1-hydroxyethylidene)amino]-3-carboxy-1-hydroxypropylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1-hydroxyethylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1,3-dihydroxypropylidene]amino]-1-hydroxyethylidene]amino]-1-hydroxypropylidene]amino]-1,3-dihydroxypropylidene]amino]-1,3-dihydroxypropylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1,3-dihydroxybutylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1-hydroxypropylidene]amino]-1,3-dihydroxypropylidene]amino]-1-hydroxyethylidene]amino]-1,5-dihydroxy-5-iminopentylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1,3-dihydroxybutylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1,3-dihydroxypropylidene]amino]-1-hydroxyethylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1-hydroxyethylidene]amino]hexanoic acid Chemical compound C[C@@H]([C@@H](C(=N[C@@H](CS)C(=N[C@@H](C)C(=N[C@@H](CO)C(=NCC(=N[C@@H](CCC(=N)O)C(=NC(CS)C(=N[C@H]([C@H](C)O)C(=N[C@H](CS)C(=N[C@H](CO)C(=NCC(=N[C@H](CS)C(=NCC(=N[C@H](CCCCN)C(=O)O)O)O)O)O)O)O)O)O)O)O)O)O)O)N=C([C@H](CS)N=C([C@H](CO)N=C([C@H](CO)N=C([C@H](C)N=C(CN=C([C@H](CO)N=C([C@H](CS)N=C(CN=C(C(CS)N=C(C(CC(=O)O)N=C(CN)O)O)O)O)O)O)O)O)O)O)O)O DIGQNXIGRZPYDK-WKSCXVIASA-N 0.000 description 1
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 1
- 108020005029 5' Flanking Region Proteins 0.000 description 1
- 102000007469 Actins Human genes 0.000 description 1
- 108010085238 Actins Proteins 0.000 description 1
- 229930024421 Adenine Natural products 0.000 description 1
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 1
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 1
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 1
- 108010031480 Artificial Receptors Proteins 0.000 description 1
- 206010003445 Ascites Diseases 0.000 description 1
- 241000714230 Avian leukemia virus Species 0.000 description 1
- 102100029822 B- and T-lymphocyte attenuator Human genes 0.000 description 1
- 102100022005 B-lymphocyte antigen CD20 Human genes 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 102100026189 Beta-galactosidase Human genes 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 102100024217 CAMPATH-1 antigen Human genes 0.000 description 1
- 102100024263 CD160 antigen Human genes 0.000 description 1
- 108010065524 CD52 Antigen Proteins 0.000 description 1
- 102100035793 CD83 antigen Human genes 0.000 description 1
- 108010040467 CRISPR-Associated Proteins Proteins 0.000 description 1
- 238000010443 CRISPR/Cpf1 gene editing Methods 0.000 description 1
- 101150018129 CSF2 gene Proteins 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 108010067225 Cell Adhesion Molecules Proteins 0.000 description 1
- 102000016289 Cell Adhesion Molecules Human genes 0.000 description 1
- 102100024046 Cell adhesion molecule 3 Human genes 0.000 description 1
- 101710197433 Cell adhesion molecule 3 Proteins 0.000 description 1
- 102100021396 Cell surface glycoprotein CD200 receptor 1 Human genes 0.000 description 1
- 108010012236 Chemokines Proteins 0.000 description 1
- 102000019034 Chemokines Human genes 0.000 description 1
- 108091007741 Chimeric antigen receptor T cells Proteins 0.000 description 1
- 108010035563 Chloramphenicol O-acetyltransferase Proteins 0.000 description 1
- 108010077544 Chromatin Proteins 0.000 description 1
- 108091035707 Consensus sequence Proteins 0.000 description 1
- 102000004420 Creatine Kinase Human genes 0.000 description 1
- 108010042126 Creatine kinase Proteins 0.000 description 1
- 101150074775 Csf1 gene Proteins 0.000 description 1
- IGXWBGJHJZYPQS-SSDOTTSWSA-N D-Luciferin Chemical compound OC(=O)[C@H]1CSC(C=2SC3=CC=C(O)C=C3N=2)=N1 IGXWBGJHJZYPQS-SSDOTTSWSA-N 0.000 description 1
- 102000004163 DNA-directed RNA polymerases Human genes 0.000 description 1
- 108090000626 DNA-directed RNA polymerases Proteins 0.000 description 1
- CYCGRDQQIOGCKX-UHFFFAOYSA-N Dehydro-luciferin Natural products OC(=O)C1=CSC(C=2SC3=CC(O)=CC=C3N=2)=N1 CYCGRDQQIOGCKX-UHFFFAOYSA-N 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 102100025137 Early activation antigen CD69 Human genes 0.000 description 1
- 101150039808 Egfr gene Proteins 0.000 description 1
- 108700024394 Exon Proteins 0.000 description 1
- 108050001049 Extracellular proteins Proteins 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- BJGNCJDXODQBOB-UHFFFAOYSA-N Fivefly Luciferin Natural products OC(=O)C1CSC(C=2SC3=CC(O)=CC=C3N=2)=N1 BJGNCJDXODQBOB-UHFFFAOYSA-N 0.000 description 1
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 1
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 1
- 206010059024 Gastrointestinal toxicity Diseases 0.000 description 1
- 108700039691 Genetic Promoter Regions Proteins 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 1
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 1
- 102000004144 Green Fluorescent Proteins Human genes 0.000 description 1
- 102100028966 HLA class I histocompatibility antigen, alpha chain F Human genes 0.000 description 1
- 102100028967 HLA class I histocompatibility antigen, alpha chain G Human genes 0.000 description 1
- 102000012153 HLA-B27 Antigen Human genes 0.000 description 1
- 108010061486 HLA-B27 Antigen Proteins 0.000 description 1
- 108010024164 HLA-G Antigens Proteins 0.000 description 1
- 102000001554 Hemoglobins Human genes 0.000 description 1
- 108010054147 Hemoglobins Proteins 0.000 description 1
- 108010034791 Heterochromatin Proteins 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- 101000777636 Homo sapiens ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1 Proteins 0.000 description 1
- 101000864344 Homo sapiens B- and T-lymphocyte attenuator Proteins 0.000 description 1
- 101000897405 Homo sapiens B-lymphocyte antigen CD20 Proteins 0.000 description 1
- 101000761938 Homo sapiens CD160 antigen Proteins 0.000 description 1
- 101000884279 Homo sapiens CD276 antigen Proteins 0.000 description 1
- 101000946856 Homo sapiens CD83 antigen Proteins 0.000 description 1
- 101000969553 Homo sapiens Cell surface glycoprotein CD200 receptor 1 Proteins 0.000 description 1
- 101000909528 Homo sapiens Collectin-12 Proteins 0.000 description 1
- 101000934374 Homo sapiens Early activation antigen CD69 Proteins 0.000 description 1
- 101000986080 Homo sapiens HLA class I histocompatibility antigen, alpha chain F Proteins 0.000 description 1
- 101000935040 Homo sapiens Integrin beta-2 Proteins 0.000 description 1
- 101001057504 Homo sapiens Interferon-stimulated gene 20 kDa protein Proteins 0.000 description 1
- 101001055144 Homo sapiens Interleukin-2 receptor subunit alpha Proteins 0.000 description 1
- 101000945339 Homo sapiens Killer cell immunoglobulin-like receptor 2DS2 Proteins 0.000 description 1
- 101000945490 Homo sapiens Killer cell immunoglobulin-like receptor 3DL2 Proteins 0.000 description 1
- 101000945493 Homo sapiens Killer cell immunoglobulin-like receptor 3DL3 Proteins 0.000 description 1
- 101000971538 Homo sapiens Killer cell lectin-like receptor subfamily F member 1 Proteins 0.000 description 1
- 101100128412 Homo sapiens LILRB1 gene Proteins 0.000 description 1
- 101000984192 Homo sapiens Leukocyte immunoglobulin-like receptor subfamily B member 3 Proteins 0.000 description 1
- 101001109501 Homo sapiens NKG2-D type II integral membrane protein Proteins 0.000 description 1
- 101000633784 Homo sapiens SLAM family member 7 Proteins 0.000 description 1
- 101000738413 Homo sapiens T-cell surface glycoprotein CD3 gamma chain Proteins 0.000 description 1
- 101000738335 Homo sapiens T-cell surface glycoprotein CD3 zeta chain Proteins 0.000 description 1
- 101000835093 Homo sapiens Transferrin receptor protein 1 Proteins 0.000 description 1
- 101000611183 Homo sapiens Tumor necrosis factor Proteins 0.000 description 1
- 101000830565 Homo sapiens Tumor necrosis factor ligand superfamily member 10 Proteins 0.000 description 1
- 101000830594 Homo sapiens Tumor necrosis factor ligand superfamily member 14 Proteins 0.000 description 1
- 101000795169 Homo sapiens Tumor necrosis factor receptor superfamily member 13C Proteins 0.000 description 1
- 101001022129 Homo sapiens Tyrosine-protein kinase Fyn Proteins 0.000 description 1
- 101001047681 Homo sapiens Tyrosine-protein kinase Lck Proteins 0.000 description 1
- 241000701044 Human gammaherpesvirus 4 Species 0.000 description 1
- 229920001612 Hydroxyethyl starch Polymers 0.000 description 1
- 108010073807 IgG Receptors Proteins 0.000 description 1
- 102000009490 IgG Receptors Human genes 0.000 description 1
- 229940076838 Immune checkpoint inhibitor Drugs 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
- 108090001061 Insulin Proteins 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 102100025390 Integrin beta-2 Human genes 0.000 description 1
- 108010064593 Intercellular Adhesion Molecule-1 Proteins 0.000 description 1
- 102100037877 Intercellular adhesion molecule 1 Human genes 0.000 description 1
- 102100037850 Interferon gamma Human genes 0.000 description 1
- 108010074328 Interferon-gamma Proteins 0.000 description 1
- 102000003814 Interleukin-10 Human genes 0.000 description 1
- 108090000174 Interleukin-10 Proteins 0.000 description 1
- 102000013462 Interleukin-12 Human genes 0.000 description 1
- 108010065805 Interleukin-12 Proteins 0.000 description 1
- 102000003812 Interleukin-15 Human genes 0.000 description 1
- 108090000172 Interleukin-15 Proteins 0.000 description 1
- 102100026878 Interleukin-2 receptor subunit alpha Human genes 0.000 description 1
- 102000004388 Interleukin-4 Human genes 0.000 description 1
- 108090000978 Interleukin-4 Proteins 0.000 description 1
- 108091092195 Intron Proteins 0.000 description 1
- 102100033630 Killer cell immunoglobulin-like receptor 2DS2 Human genes 0.000 description 1
- 102100034840 Killer cell immunoglobulin-like receptor 3DL2 Human genes 0.000 description 1
- 102100034834 Killer cell immunoglobulin-like receptor 3DL3 Human genes 0.000 description 1
- 102100021458 Killer cell lectin-like receptor subfamily F member 1 Human genes 0.000 description 1
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 description 1
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 1
- 101710145789 Leukocyte immunoglobulin-like receptor subfamily B member 1 Proteins 0.000 description 1
- 101710145805 Leukocyte immunoglobulin-like receptor subfamily B member 3 Proteins 0.000 description 1
- DDWFXDSYGUXRAY-UHFFFAOYSA-N Luciferin Natural products CCc1c(C)c(CC2NC(=O)C(=C2C=C)C)[nH]c1Cc3[nH]c4C(=C5/NC(CC(=O)O)C(C)C5CC(=O)O)CC(=O)c4c3C DDWFXDSYGUXRAY-UHFFFAOYSA-N 0.000 description 1
- 102100034709 Lymphocyte cytosolic protein 2 Human genes 0.000 description 1
- 101710195102 Lymphocyte cytosolic protein 2 Proteins 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 108010061593 Member 14 Tumor Necrosis Factor Receptors Proteins 0.000 description 1
- 102000003792 Metallothionein Human genes 0.000 description 1
- 108090000157 Metallothionein Proteins 0.000 description 1
- 241000713333 Mouse mammary tumor virus Species 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- 241000714177 Murine leukemia virus Species 0.000 description 1
- 101500027988 Mus musculus ADGRV1 subunit beta Proteins 0.000 description 1
- 101100219625 Mus musculus Casd1 gene Proteins 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 102000003505 Myosin Human genes 0.000 description 1
- 108060008487 Myosin Proteins 0.000 description 1
- 108091008877 NK cell receptors Proteins 0.000 description 1
- 102100022680 NKG2-D type II integral membrane protein Human genes 0.000 description 1
- 102000010648 Natural Killer Cell Receptors Human genes 0.000 description 1
- 206010061309 Neoplasm progression Diseases 0.000 description 1
- 101100385413 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) csm-3 gene Proteins 0.000 description 1
- 108090000590 Neurotransmitter Receptors Proteins 0.000 description 1
- 102000004108 Neurotransmitter Receptors Human genes 0.000 description 1
- 102000007607 Non-Receptor Type 11 Protein Tyrosine Phosphatase Human genes 0.000 description 1
- 108010032107 Non-Receptor Type 11 Protein Tyrosine Phosphatase Proteins 0.000 description 1
- 238000000636 Northern blotting Methods 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 102000010292 Peptide Elongation Factor 1 Human genes 0.000 description 1
- 108010077524 Peptide Elongation Factor 1 Proteins 0.000 description 1
- 108010089430 Phosphoproteins Proteins 0.000 description 1
- 102000007982 Phosphoproteins Human genes 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 102220547352 Protein APCDD1_V150I_mutation Human genes 0.000 description 1
- 102000001253 Protein Kinase Human genes 0.000 description 1
- 230000026279 RNA modification Effects 0.000 description 1
- 239000012979 RPMI medium Substances 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 101100047461 Rattus norvegicus Trpm8 gene Proteins 0.000 description 1
- 102000004389 Ribonucleoproteins Human genes 0.000 description 1
- 108010081734 Ribonucleoproteins Proteins 0.000 description 1
- 102000014400 SH2 domains Human genes 0.000 description 1
- 108050003452 SH2 domains Proteins 0.000 description 1
- 102100029198 SLAM family member 7 Human genes 0.000 description 1
- XZKQVQKUZMAADP-IMJSIDKUSA-N Ser-Ser Chemical compound OC[C@H](N)C(=O)N[C@@H](CO)C(O)=O XZKQVQKUZMAADP-IMJSIDKUSA-N 0.000 description 1
- 108010074687 Signaling Lymphocytic Activation Molecule Family Member 1 Proteins 0.000 description 1
- 102000008115 Signaling Lymphocytic Activation Molecule Family Member 1 Human genes 0.000 description 1
- 241000700584 Simplexvirus Species 0.000 description 1
- 206010059516 Skin toxicity Diseases 0.000 description 1
- 238000002105 Southern blotting Methods 0.000 description 1
- 241000193996 Streptococcus pyogenes Species 0.000 description 1
- 230000020385 T cell costimulation Effects 0.000 description 1
- 230000006052 T cell proliferation Effects 0.000 description 1
- 230000005867 T cell response Effects 0.000 description 1
- 102100037911 T-cell surface glycoprotein CD3 gamma chain Human genes 0.000 description 1
- 102100037906 T-cell surface glycoprotein CD3 zeta chain Human genes 0.000 description 1
- 102000002259 TNF-Related Apoptosis-Inducing Ligand Receptors Human genes 0.000 description 1
- 108010000449 TNF-Related Apoptosis-Inducing Ligand Receptors Proteins 0.000 description 1
- 108700012411 TNFSF10 Proteins 0.000 description 1
- 239000004098 Tetracycline Substances 0.000 description 1
- 102000006601 Thymidine Kinase Human genes 0.000 description 1
- 108020004440 Thymidine kinase Proteins 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 102100026144 Transferrin receptor protein 1 Human genes 0.000 description 1
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 1
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 1
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 1
- 108060008683 Tumor Necrosis Factor Receptor Proteins 0.000 description 1
- 102100040247 Tumor necrosis factor Human genes 0.000 description 1
- 102100024586 Tumor necrosis factor ligand superfamily member 14 Human genes 0.000 description 1
- 102100029690 Tumor necrosis factor receptor superfamily member 13C Human genes 0.000 description 1
- 102100028785 Tumor necrosis factor receptor superfamily member 14 Human genes 0.000 description 1
- 102100035221 Tyrosine-protein kinase Fyn Human genes 0.000 description 1
- 102100024036 Tyrosine-protein kinase Lck Human genes 0.000 description 1
- 102100021657 Tyrosine-protein phosphatase non-receptor type 6 Human genes 0.000 description 1
- 101710128901 Tyrosine-protein phosphatase non-receptor type 6 Proteins 0.000 description 1
- 108091023045 Untranslated Region Proteins 0.000 description 1
- 241000589634 Xanthomonas Species 0.000 description 1
- PTFCDOFLOPIGGS-UHFFFAOYSA-N Zinc dication Chemical compound [Zn+2] PTFCDOFLOPIGGS-UHFFFAOYSA-N 0.000 description 1
- 229960004308 acetylcysteine Drugs 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000003044 adaptive effect Effects 0.000 description 1
- 210000005006 adaptive immune system Anatomy 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 229960000643 adenine Drugs 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000030741 antigen processing and presentation Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 239000000823 artificial membrane Substances 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 230000008267 autocrine signaling Effects 0.000 description 1
- 210000003651 basophil Anatomy 0.000 description 1
- 108010005774 beta-Galactosidase Proteins 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 238000010170 biological method Methods 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 210000000746 body region Anatomy 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 101150055766 cat gene Proteins 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 230000020411 cell activation Effects 0.000 description 1
- 230000011712 cell development Effects 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 230000023549 cell-cell signaling Effects 0.000 description 1
- 230000007248 cellular mechanism Effects 0.000 description 1
- 230000033077 cellular process Effects 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 230000035605 chemotaxis Effects 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 210000003483 chromatin Anatomy 0.000 description 1
- 230000002759 chromosomal effect Effects 0.000 description 1
- 238000010367 cloning Methods 0.000 description 1
- 238000003501 co-culture Methods 0.000 description 1
- 238000012761 co-transfection Methods 0.000 description 1
- 238000001246 colloidal dispersion Methods 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 108091036078 conserved sequence Proteins 0.000 description 1
- 230000004940 costimulation Effects 0.000 description 1
- 229940104302 cytosine Drugs 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 238000002784 cytotoxicity assay Methods 0.000 description 1
- 231100000263 cytotoxicity test Toxicity 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 230000000779 depleting effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 231100000371 dose-limiting toxicity Toxicity 0.000 description 1
- 238000003182 dose-response assay Methods 0.000 description 1
- 230000034431 double-strand break repair via homologous recombination Effects 0.000 description 1
- 238000004520 electroporation Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 210000003979 eosinophil Anatomy 0.000 description 1
- 230000001973 epigenetic effect Effects 0.000 description 1
- 230000004049 epigenetic modification Effects 0.000 description 1
- 230000008029 eradication Effects 0.000 description 1
- 108700021358 erbB-1 Genes Proteins 0.000 description 1
- 210000004700 fetal blood Anatomy 0.000 description 1
- 230000001605 fetal effect Effects 0.000 description 1
- 108091006047 fluorescent proteins Proteins 0.000 description 1
- 102000034287 fluorescent proteins Human genes 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000012595 freezing medium Substances 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 108020001507 fusion proteins Proteins 0.000 description 1
- 102000037865 fusion proteins Human genes 0.000 description 1
- 231100000414 gastrointestinal toxicity Toxicity 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 238000001476 gene delivery Methods 0.000 description 1
- 238000012226 gene silencing method Methods 0.000 description 1
- 238000010353 genetic engineering Methods 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 150000002339 glycosphingolipids Chemical class 0.000 description 1
- 210000000224 granular leucocyte Anatomy 0.000 description 1
- 239000005090 green fluorescent protein Substances 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 210000003494 hepatocyte Anatomy 0.000 description 1
- 229940064366 hespan Drugs 0.000 description 1
- 210000004458 heterochromatin Anatomy 0.000 description 1
- 210000003630 histaminocyte Anatomy 0.000 description 1
- 239000000710 homodimer Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 108091008039 hormone receptors Proteins 0.000 description 1
- 102000044811 human COLEC12 Human genes 0.000 description 1
- 102000056727 human CXCL16 Human genes 0.000 description 1
- 102000057041 human TNF Human genes 0.000 description 1
- 102000044949 human TNFSF10 Human genes 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 238000009396 hybridization Methods 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 230000005965 immune activity Effects 0.000 description 1
- 230000006450 immune cell response Effects 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 239000012274 immune-checkpoint protein inhibitor Substances 0.000 description 1
- 230000003053 immunization Effects 0.000 description 1
- 238000002649 immunization Methods 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 229940072221 immunoglobulins Drugs 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 230000015788 innate immune response Effects 0.000 description 1
- 102000006029 inositol monophosphatase Human genes 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 108010044426 integrins Proteins 0.000 description 1
- 102000006495 integrins Human genes 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 229960000310 isoleucine Drugs 0.000 description 1
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 1
- 238000005304 joining Methods 0.000 description 1
- 238000001638 lipofection Methods 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 210000001165 lymph node Anatomy 0.000 description 1
- 230000002934 lysing effect Effects 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 238000000520 microinjection Methods 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 230000002438 mitochondrial effect Effects 0.000 description 1
- 230000004898 mitochondrial function Effects 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 108700003805 myo-inositol-1 (or 4)-monophosphatase Proteins 0.000 description 1
- 239000002088 nanocapsule Substances 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 238000012259 partial gene deletion Methods 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 210000005105 peripheral blood lymphocyte Anatomy 0.000 description 1
- 230000002688 persistence Effects 0.000 description 1
- 210000001539 phagocyte Anatomy 0.000 description 1
- 238000000053 physical method Methods 0.000 description 1
- 108010058237 plasma protein fraction Proteins 0.000 description 1
- 229940081858 plasmalyte a Drugs 0.000 description 1
- 229940002993 plasmanate Drugs 0.000 description 1
- 238000010837 poor prognosis Methods 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000002028 premature Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 210000004990 primary immune cell Anatomy 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 239000000186 progesterone Substances 0.000 description 1
- 229960003387 progesterone Drugs 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 108010054624 red fluorescent protein Proteins 0.000 description 1
- 230000008263 repair mechanism Effects 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000002864 sequence alignment Methods 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 231100000438 skin toxicity Toxicity 0.000 description 1
- 229940054269 sodium pyruvate Drugs 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 238000010257 thawing Methods 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 229940113082 thymine Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000005026 transcription initiation Effects 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- 230000026683 transduction Effects 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 230000005909 tumor killing Effects 0.000 description 1
- 102000003298 tumor necrosis factor receptor Human genes 0.000 description 1
- 230000005751 tumor progression Effects 0.000 description 1
- 241001529453 unidentified herpesvirus Species 0.000 description 1
- 241001515965 unidentified phage Species 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 1
- 239000012808 vapor phase Substances 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/06—Animal cells or tissues; Human cells or tissues
- C12N5/0602—Vertebrate cells
- C12N5/0634—Cells from the blood or the immune system
- C12N5/0636—T lymphocytes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/14—Blood; Artificial blood
- A61K35/17—Lymphocytes; B-cells; T-cells; Natural killer cells; Interferon-activated or cytokine-activated lymphocytes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/14—Blood; Artificial blood
- A61K35/15—Cells of the myeloid line, e.g. granulocytes, basophils, eosinophils, neutrophils, leucocytes, monocytes, macrophages or mast cells; Myeloid precursor cells; Antigen-presenting cells, e.g. dendritic cells
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/46—Cellular immunotherapy
- A61K39/461—Cellular immunotherapy characterised by the cell type used
- A61K39/4611—T-cells, e.g. tumor infiltrating lymphocytes [TIL], lymphokine-activated killer cells [LAK] or regulatory T cells [Treg]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/46—Cellular immunotherapy
- A61K39/463—Cellular immunotherapy characterised by recombinant expression
- A61K39/4631—Chimeric Antigen Receptors [CAR]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/46—Cellular immunotherapy
- A61K39/464—Cellular immunotherapy characterised by the antigen targeted or presented
- A61K39/4643—Vertebrate antigens
- A61K39/4644—Cancer antigens
- A61K39/464402—Receptors, cell surface antigens or cell surface determinants
- A61K39/464403—Receptors for growth factors
- A61K39/464404—Epidermal growth factor receptors [EGFR]
-
- 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
- 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
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
-
- 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
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
- C07K14/70503—Immunoglobulin superfamily
-
- 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
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
- C07K14/70503—Immunoglobulin superfamily
- C07K14/7051—T-cell receptor (TcR)-CD3 complex
-
- 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
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
- C07K14/70503—Immunoglobulin superfamily
- C07K14/70539—MHC-molecules, e.g. HLA-molecules
-
- 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
-
- 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
- C07K16/2833—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 MHC-molecules, e.g. HLA-molecules
-
- 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
- C07K16/2863—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for growth factors, growth regulators
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/06—Animal cells or tissues; Human cells or tissues
- C12N5/0602—Vertebrate cells
- C12N5/0693—Tumour cells; Cancer cells
-
- 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
- C07K2319/00—Fusion polypeptide
- C07K2319/01—Fusion polypeptide containing a localisation/targetting motif
- C07K2319/02—Fusion polypeptide containing a localisation/targetting motif containing a signal sequence
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/01—Fusion polypeptide containing a localisation/targetting motif
- C07K2319/03—Fusion polypeptide containing a localisation/targetting motif containing a transmembrane segment
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2501/00—Active agents used in cell culture processes, e.g. differentation
- C12N2501/10—Growth factors
- C12N2501/11—Epidermal growth factor [EGF]
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2501/00—Active agents used in cell culture processes, e.g. differentation
- C12N2501/50—Cell markers; Cell surface determinants
- C12N2501/515—CD3, T-cell receptor complex
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2510/00—Genetically modified cells
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Immunology (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Genetics & Genomics (AREA)
- Cell Biology (AREA)
- Biochemistry (AREA)
- Engineering & Computer Science (AREA)
- Zoology (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Biomedical Technology (AREA)
- Microbiology (AREA)
- Epidemiology (AREA)
- Biotechnology (AREA)
- Mycology (AREA)
- Wood Science & Technology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Toxicology (AREA)
- Gastroenterology & Hepatology (AREA)
- Oncology (AREA)
- Hematology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- General Engineering & Computer Science (AREA)
- Dermatology (AREA)
- Virology (AREA)
- Developmental Biology & Embryology (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
Abstract
本揭示案提供包含第一活化劑受體及第二抑制性受體之免疫細胞,以及製造及使用該等免疫細胞以供治療癌症之方法。
Description
本申請案大體上係關於用於細胞療法應用中之工程改造之受體及包含該等受體之免疫細胞組合物。
細胞療法為用於治療各種疾病,尤其癌症之有力工具。在常規過繼細胞療法中,免疫細胞經工程改造以表現特異性受體,例如嵌合抗原受體(CAR)或T細胞受體(TCR),該等受體經由受體與由靶細胞表現之配位體的相互作用將免疫細胞之活性導向細胞標靶。適合之靶分子的鑑定仍具有挑戰性,此係因為許多標靶在正常組織中表現。當移植之細胞靶向表現靶分子之正常組織時,此表現可導致毒性。因此,此項技術中需要適用於藉由過繼細胞療法治療疾病,尤其癌症之組合物及方法。
本揭示案提供用於增加過繼細胞療法中所用之免疫細胞之特異性的組合物及方法。本揭示案提供包含雙受體系統之免疫細胞,該系統增加免疫細胞對表現靶抗原之靶細胞的特異性。免疫細胞包含第一活化劑受體,其對第一受體由靶抗原結合作出反應而活化免疫細胞。免疫細胞進一步包含對非靶抗原具有特異性之第二抑制性受體。當第二受體由非靶抗原結合時,即使當第一受體由靶抗原結合時,此第二受體會抑制免疫細胞之活化。
在一個態樣中,本揭示案提供一種免疫細胞,該免疫細胞包含:a.)第一受體,其包含對表皮生長因子受體(EGFR)具有特異性之細胞外配位體結合結構域;及b.)第二受體,其包含對由於雜合性損失而在EGFR+癌症中損失之非靶抗原具有特異性之細胞外配位體結合結構域,其中第一受體為對EGFR有反應之活化劑受體;且其中第二受體為對非靶抗原有反應之抑制性受體。
在一些實施例中,第二受體之細胞外配位體結合結構域特異性結合MHC蛋白之對偶基因變異體。在一些實施例中,第二受體之細胞外配位體結合結構域特異性結合HLA-A、HLA-B或HLA-C蛋白之對偶基因變異體。在一些實施例中,第二受體之細胞外配位體結合結構域特異性結合HLA-A*02。在一些實施例中,第二受體之細胞外配位體結合結構域特異性結合 HLA-A*01、HLA-A*03、HLA-A*11、HLA-C*07或HLA-B*07。
在一些實施例中,第二受體之細胞外配位體結合結構域包含如表5所揭示之互補決定區(CDR) CDR-L1、CDR-L2、CDR-L3、CDR-H1、CDR-H2、CDR-H3;或相對於表5之CDR具有至多1個、2個或3個取代、缺失或插入之CDR序列。
在一些實施例中,第二受體之細胞外配位體結合結構域包含SEQ ID NO: 101-106或SEQ ID NO: 106-112之互補決定區(CDR) CDR-L1、CDR-L2、CDR-L3、CDR-H1、CDR-H2、CDR-H3;或相對於表5之CDR具有至多1個、2個或3個取代、缺失或插入之CDR序列。
在一些實施例中,第二受體之細胞外配位體結合結構域包含選自表4中所揭示之多肽序列的多肽序列;或與其具有至少85%、至少90%、至少95%、至少97%或至少99%一致性之序列。在一些實施例中,第二受體之細胞外配位體結合結構域包含SEQ ID NO: 89-100中之任一者;或與其具有至少85%、至少90%、至少95%、至少97%或至少99%一致性之序列。
在一些實施例中,第一受體為嵌合抗原受體(CAR)。
在一些實施例中,第一受體之細胞外配位體結合結構域包含可變重(VH)部分,其包含選自表3所列之序列之群的一組重鏈互補決定區(HC-CDR);及/或可變輕(VL)部分,其包含來自表3中所列之序列之群的一組輕鏈互補決定區(LC-CDR);或在各CDR中具有至多1個、2個、3個、4個取代、插入或缺失之CDR序列。
在一些實施例中,第一受體之細胞外配位體結合結構域包含具有選自表2中所列之VH序列之序列的可變重(VH)部分;及/或包含表2中所列之序列的可變輕(VL)部分;或與其具有至少70%、至少85%、至少90%或至少95%一致性之序列。
在一些實施例中,第一受體之細胞外配位體結合結構域包含選自表1中所列之序列之群的序列;或與其具有至少85%、至少90%、至少95%、至少97%或至少99%一致性之序列。
在一些實施例中,第一受體之細胞外配位體結合結構域包含選自由SEQ ID NO: 9-18組成之群的scFv序列;或與其具有至少85%、至少90%、至少95%、至少97%或至少99%一致性之序列。
在一些實施例中,第二受體包含LILRB1細胞內結構域或其功能變異體。在一些實施例中,LILRB1細胞內結構域包含與SEQ ID NO: 129至少90%、至少95%、至少97%、至少99%或一致之序列。
在一些實施例中,第二受體包含LILRB1跨膜結構域或其功能變異體。在一些實施例中,LILRB1跨膜結構域或其功能變異體包含與SEQ ID NO: 133至少90%、至少95%、至少97%、至少99%或一致之序列。
在一些實施例中,第二受體包含LILRB1鉸鏈結構域或其功能變異體。在一些實施例中,LILRB1鉸鏈結構域包含與SEQ ID NO: 132、SEQ ID NO: 125、SEQ ID NO: 126至少90%、至少95%、至少97%、至少99%或一致之序列。
在一些實施例中,第二受體包含LILRB1細胞內結構域、LILRB1跨膜結構域、LILRB1鉸鏈結構域、此等中之任一者之功能變異體,或其組合。在一些實施例中,LILRB1細胞內結構域及LILRB1跨膜結構域包含SEQ ID NO: 128或與SEQ ID NO: 128至少95%一致之序列。
在一些實施例中,EGFR+癌細胞為肺癌細胞、小細胞肺癌細胞、非小細胞肺癌細胞、胰管癌細胞、結腸直腸癌細胞、頭頸癌細胞、食道及胃腺癌細胞、卵巢癌細胞、多形性神經膠質母細胞瘤細胞、子宮頸鱗狀細胞癌細胞、腎癌細胞、乳頭狀腎癌細胞、腎臟腎透明細胞癌細胞、膀胱癌細胞、乳癌細胞、膽管癌細胞、肝癌細胞、前列腺癌細胞、肉瘤細胞、甲狀腺癌細胞、胸腺癌細胞、胃癌細胞或子宮癌細胞。
在一些實施例中,EGFR+癌細胞為不表現HLA-A*02之EGFR+/HLA-A*02-癌細胞;或不表現HLA-A*02之來源於HLA-A*02+個體之癌細胞。在一些實施例中,EGFR+/HLA-A*02-癌細胞藉由在HLA-A處雜合性損失,導致HLA-A*02損失而來源於EGFR+/HLA-A*02+細胞。
在一些實施例中,第一受體及第二受體在具有雜合性損失之EGFR/HLA-A*02-癌細胞存在下一起特異性活化免疫細胞。
在一些實施例中,第一受體及第二受體在未因雜合性損失而損失HLA-A*02之EGFR+細胞存在下一起不特異性活化免疫細胞。
在一些實施例中,免疫細胞為T細胞、巨噬細胞、NK細胞、iNKT細胞或γδ T細胞。在一些實施例中,T細胞為CD8+ CD4- T細胞。
在一些實施例中,免疫細胞進一步包含減少或消除之MHC I類基因表現及/或功能。
在一些實施例中,MHC I類基因為β-2-微球蛋白(B2M)。
在一些實施例中,免疫細胞進一步包含含有干擾RNA之多核苷酸,該干擾RNA包含與B2M mRNA (SEQ ID NO: 172)之序列互補之序列。在一些實施例中,干擾RNA能夠誘導RNAi介導之B2M mRNA之降解。在一些實施例中,干擾RNA為短髮夾RNA (shRNA)。在一些實施例中,shRNA包含:a.)第一序列,其自5'末端至3'末端具有與B2M mRNA之序列互補之序列;及b.)第二序列,其自5'末端至3'末端具有與第一序列互補之序列,其中第一序列及第二序列形成shRNA。
在一些實施例中,免疫細胞包含對編碼B2M之序列(SEQ ID NO: 170)的一或多個修飾,其中該一或多個修飾降低B2M之表現及/或消除B2M之功能。在一些實施例中,一或多個修飾包括編碼B2M之內源基因的一或多個失活突變。在一些實施例中,一或多個失活突變包括缺失、插入、取代或框移突變。在一些實施例中,用核酸引導之核酸內切酶與特異性靶向編碼B2M之內源基因之序列(SEQ ID NO: 170)的至少一個嚮導核酸(gNA)復合來引入一或多個失活突變。
在一些實施例中,MHC I類基因為HLA-A*02。
在一些實施例中,免疫細胞進一步包含含有干擾RNA之多核苷酸,該干擾RNA包含與HLA-A*02 mRNA (SEQ ID NO: 171)之序列互補之序列。在一些實施例中,干擾RNA能夠誘導RNA干擾(RNAi)介導之HLA-A*02 mRNA之降解。在一些實施例中,干擾RNA為包含以下之短髮夾RNA (shRNA):a.)第一序列,其自5'末端至3'末端具有與HLA-A*02 mRNA之序列互補之序列;及b.)第二序列,其自5'末端至3'末端具有與第一序列互補之序列,其中第一序列及第二序列形成shRNA。
在一些實施例中,免疫細胞包含對編碼HLA-A*02之內源基因之序列(SEQ ID NO: 169)的一或多個修飾,其中該一或多個修飾降低HLA-A*02之表現及/或消除HLA-A*02之功能。在一些實施例中,一或多個修飾包括編碼HLA-A*02之內源基因的一或多個失活突變。在一些實施例中,一或多個失活突變包括缺失、插入、取代或框移突變。在一些實施例中,用核酸引導之核酸內切酶與特異性靶向編碼HLA-A*02之內源基因之序列的至少一個嚮導核酸(gNA)復合來引入一或多個失活突變。
在一些實施例中,第一受體包含SEQ ID NO: 177,或與其共享至少75%、至少80%、至少85%、至少90%、至少95%或至少98%一致性之序列;且第二受體包含SEQ ID NO: 174,或與其共享至少75%、至少80%、至少85%、至少90%、至少95%或至少98%一致性之序列。
在一些實施例中,第一受體包含SEQ ID NO: 177,或與其共享至少75%、至少80%、至少85%、至少90%、至少95%或至少98%一致性之序列;且第二受體包含SEQ ID NO: 173,或與其共享至少75%、至少80%、至少85%、至少90%、至少95%或至少98%一致性之序列。
在一些實施例中,第一受體包含SEQ ID NO: 175,或與其共享至少75%、至少80%、至少85%、至少90%、至少95%或至少98%一致性之序列;且第二受體包含SEQ ID NO: 174,或與其共享至少75%、至少80%、至少85%、至少90%、至少95%或至少98%一致性之序列。
在一些實施例中,第一受體包含SEQ ID NO: 175,或與其共享至少75%、至少80%、至少85%、至少90%、至少95%或至少98%一致性之序列;且第二受體包含SEQ ID NO: 173,或與其共享至少75%、至少80%、至少85%、至少90%、至少95%或至少98%一致性之序列。
在一些實施例中,第一受體包含SEQ ID NO: 176,或與其共享至少75%、至少80%、至少85%、至少90%、至少95%或至少98%一致性之序列;且第二受體包含SEQ ID NO: 173,或與其共享至少75%、至少80%、至少85%、至少90%、至少95%或至少98%一致性之序列。
在一些實施例中,第一受體包含SEQ ID NO: 176,或與其共享至少75%、至少80%、至少85%、至少90%、至少95%或至少98%一致性之序列;且第二受體包含SEQ ID NO: 173,或與其共享至少75%、至少80%、至少85%、至少90%、至少95%或至少98%一致性之序列。
在一些實施例中,免疫細胞進一步包含T2A自裂解肽,其中T2A自裂解肽包含SEQ ID NO: 178,或與其共享至少75%、至少80%、至少85%、至少90%、至少95%或至少98%一致性之序列。
在一些實施例中,免疫細胞進一步包含干擾RNA,其中干擾RNA包含SEQ ID NO: 179,或與其共享至少75%、至少80%、至少85%、至少90%、至少95%或至少98%一致性之序列。
在一些實施例中,免疫細胞為自體的。在一些實施例中,免疫細胞為同種異體的。
在一個態樣中,本揭示案提供一種醫藥組合物,該醫藥組合物包含治療有效量之本文所述之免疫細胞。在一些實施例中,免疫細胞表現第一受體及第二受體兩者。在一些實施例中,至少約50%、約55%、約60%、約65%、約70%、約75%、約80%、約85%、約90%或約95%之免疫細胞表現第一受體及第二受體兩者。在一些實施例中,至少90%之免疫細胞表現第一受體及第二受體兩者。在一些實施例中,醫藥組合物進一步包含醫藥學上可接受之載劑、稀釋劑或賦形劑。在一些實施例中,本文所述之醫藥組合物用作治療EGFR+癌症之藥劑。
在一個態樣中,本揭示案提供一種多核苷酸或多核苷酸系統,該多核苷酸或多核苷酸系統包含含有編碼以下之多核苷酸序列之一或多個多核苷酸:a.)第一受體,其包含對內皮生長因子受體(EGFR)具有特異性之細胞外配位體結合結構域;及b.)第二受體,其包含對由於雜合性損失而在EGFR+癌細胞中已損失之非靶抗原具有特異性之細胞外配位體結合結構域,其中第一受體為對EGFR+癌細胞上之EGFR有反應之活化劑受體;且其中第二受體為對非靶抗原有反應之抑制性受體。
在一個態樣中,本揭示案提供一種多核苷酸或多核苷酸系統,該多核苷酸或多核苷酸系統包含含有編碼第一受體及第二受體之多核苷酸序列之一或多個多核苷酸,用於產生本文所述之免疫細胞。
在本揭示案之多核苷酸或多核苷酸系統之一些實施例中,多核苷酸或多核苷酸系統包含編碼對B2M具有特異性之shRNA的序列。在一些實施例中,編碼第一受體、第二受體及對B2M具有特異性之shRNA的序列由相同多核苷酸編碼。
在一個態樣中,本揭示案提供一種載體,該載體包含本文所述之一或多個多核苷酸。
在一個態樣中,本揭示案提供一種殺死在MHC I類基因座處具有雜合性損失之EGFR+癌細胞的方法,該方法包括向個體投與有效量之本文所述之免疫細胞或本文所述之醫藥組合物。
在一些實施例中,EGFR+癌細胞為肺癌細胞、小細胞肺癌細胞、非小細胞肺癌細胞、胰管癌細胞、結腸直腸癌細胞、頭頸癌細胞、食道及胃腺癌細胞、卵巢癌細胞、多形性神經膠質母細胞瘤細胞、子宮頸鱗狀細胞癌細胞、腎癌細胞、乳頭狀腎癌細胞、腎臟腎透明細胞癌細胞、膀胱癌細胞、乳癌細胞、膽管癌細胞、肝癌細胞、前列腺癌細胞、肉瘤細胞、甲狀腺癌細胞、胸腺癌細胞、胃癌細胞或子宮癌細胞。在一些實施例中,EGFR+癌細胞為肺癌細胞。
在一些實施例中,EGFR+癌細胞為不表現HLA-A*02之EGFR+/HLA-A*02-癌細胞;或不表現HLA-A*02之來源於HLA-A*02+個體之癌細胞。在一些實施例中,EGFR+/HLA-A*02-癌細胞藉由在HLA-A處雜合性損失,導致HLA-A*02損失而來源於EGFR+/HLA-A*02+細胞。
在一個態樣中,本揭示案提供一種治療患有在編碼非靶抗原之基因座處具有雜合性損失之EGFR+腫瘤之個體之EGFR+癌症的方法,該方法包括向個體投與有效量之本文所述之免疫細胞或本文所述之醫藥組合物。
在一些實施例中,個體為患有表現EGFR且已損失HLA-A*02表現之惡性病的雜合HLA-A*02患者。
在一些實施例中,個體為患有表現EGFR且已損失HLA-A*02表現之復發性不可切除性或轉移性實體腫瘤的雜合HLA-A*02患者。
在一個態樣中,本揭示案提供一種治療個體之癌症的方法,該方法包括:a.)確定個體之非惡性細胞及癌細胞中非靶抗原之基因型或表現水準;b.)確定個體之癌細胞中EGFR之表現水準;及c.)若非惡性細胞表現非靶抗原且癌細胞不表現非靶抗原,且癌細胞為EGFR陽性的,則向個體投與有效量之本文所述之免疫細胞或本文所述之醫藥組合物。
在一些實施例中,本文所述之免疫細胞或本文所述之醫藥組合物的投與減小個體中之腫瘤的大小。
在一些實施例中,腫瘤減小約5%、約10%、約15%、約20%、約25%、約30%、約35%、約40%、約45%、約50%、約55%、約60%、約65%、約70%、約75%、約80%、約85%、約90%、約95%或約100%。在一些實施例中,腫瘤得以消除。
在一些實施例中,免疫細胞或醫藥組合物之投與阻止個體中之腫瘤的生長。在一些實施例中,本文所述之免疫細胞或本文所述之醫藥組合物的投與減少個體中之腫瘤的數目。
在一些實施例中,免疫細胞或醫藥組合物之投與選擇性殺死個體中之癌細胞而非正常細胞。在一些實施例中,所殺死之至少約60%之細胞為癌細胞,所殺死之至少約65%之細胞為癌細胞,所殺死之至少約70%之細胞為癌細胞,所殺死之至少約75%之細胞為癌細胞,所殺死之至少約80%之細胞為癌細胞,所殺死之至少約85%之細胞為癌細胞,所殺死之至少約90%之細胞為癌細胞,所殺死之至少約95%之細胞為癌細胞,或所殺死之約100%之細胞為癌細胞。
在一些實施例中,免疫細胞或醫藥組合物之投與殺死個體之約40%、約50%、約60%、約70%、約80%、約90%或所有癌細胞。在一些實施例中,癌細胞包括肺癌細胞、小細胞肺癌細胞、非小細胞肺癌細胞、胰管癌細胞、結腸直腸癌細胞、頭頸癌細胞、食道及胃腺癌細胞、卵巢癌細胞、多形性神經膠質母細胞瘤細胞、子宮頸鱗狀細胞癌細胞、腎癌細胞、乳頭狀腎癌細胞、腎臟腎透明細胞癌細胞、膀胱癌細胞、乳癌細胞、膽管癌細胞、肝癌細胞、前列腺癌細胞、肉瘤細胞、甲狀腺癌細胞、胸腺癌細胞、胃癌細胞或子宮癌細胞。在一些實施例中,與包含第一活化劑受體但不含第二抑制性受體之其他方面等效之免疫細胞的投與相比,免疫細胞或醫藥組合物之投與對個體產生較少副作用。
在一個態樣中,本揭示案提供一種製造複數個免疫細胞之方法,該方法包括:a.)提供複數個免疫細胞,及b.)用本文所述之多核苷酸系統或本文所述之載體將該複數個免疫細胞轉型。
在一個態樣中,本揭示案提供一種套組,該套組包含本文所述之免疫細胞或本文所述之醫藥組合物。在一些實施例中,套組進一步包括使用說明書。
相關申請案
本申請案主張2020年8月20日申請之美國臨時專利申請案63/068,249及2020年10月26日申請之美國臨時專利申請案63/105,639之優先權,各專利申請案之內容以全文引用之方式併入本文中。
序列表參考
序列表段落申請案含有序列表,該序列表已經由EFS-WEB以ASCII格式提交且藉此以全文引用之方式併入。2021年8月17日創建之該ASCII複本命名為A2BI_021_01WO_SeqList_ST25.txt且大小為675 KB。
本文提供使用包含對癌症與正常細胞之間的配位體之基因表現差異有反應之雙受體系統之免疫細胞治療癌症的組合物及方法。此等表現差異可歸因於癌細胞中之雜合性損失。或者,表現差異可能係因為基因表現不在癌細胞中表現,或者在癌細胞中以低於正常細胞之水準表現。雙受體系統在免疫細胞,例如用於過繼細胞療法之免疫細胞中表現,且將此等免疫細胞之活性靶向展現雜合性損失或表現差異之癌細胞。在此雙受體系統中,第一受體(活化劑受體,在本文中有時稱作A模組)活化免疫細胞或促進免疫細胞之活化,而第二受體(抑制性受體,在本文中有時稱作阻斷劑,或抑制劑受體,或B模組)用來抑制第一受體對免疫細胞之活化。各受體含有結合特異性配位體之配位體結合結構域(LBD)。在配位體結合後來自兩種受體之信號由免疫細胞整合。癌症及正常細胞中第一受體及第二受體之配位體之差異表現,例如經由癌細胞中編碼抑制性配位體之基因座之雜合性損失或轉錄水準之差異,介導表現第一活化劑配位體而非第二抑制性配位體之靶癌細胞對免疫細胞之活化。
在本文所提供之組合物及方法之特定實施例中,包含本文所述之雙受體系統之免疫細胞用於治療表皮生長因子受體(EGFR)陽性癌症。此包括肺癌、神經膠質母細胞瘤、乳癌、頭頸癌及結腸直腸癌。在EGFR陽性癌症之情況下,活化劑受體之靶抗原為EGFR或與主要組織相容性複合物I類(MHC-I)複合之其肽抗原。EGFR在多種正常組織,諸如上皮、間葉及神經元組織中表現,且在正常細胞過程,諸如細胞增殖及分化以及發育中起主要作用。由於其在某些腫瘤中之表現,EGFR為有吸引力之腫瘤特異性抗原,若可用適當治療劑特異性靶向此等癌細胞,則EGFR可介導對EGFR+腫瘤之選擇性殺死。然而,非癌(非靶)細胞中之正常EGFR表現已阻止EGFR有效用於靶向療法,諸如過繼細胞療法。皮膚及胃腸毒性已阻止EGFR陽性癌症中EGFR之有效靶向。藉由將EGFR活化劑受體與抑制性受體配對,本文所提供之方法增加EGFR靶向之過繼細胞療法之特異性且減少與此等療法相關之有害作用,諸如劑量限制性毒性。
在一些實施例中,活化劑之配位體為與MHC I類複合之EGFR肽。在本文所述之方法中,此EGFR靶向之活化劑受體與抑制性受體配對,從而藉由阻斷活化劑對正常EGFR陽性組織之細胞溶解作用來增加活化劑之安全窗口。然而,由於腫瘤細胞不表現抑制劑或阻斷劑受體之配位體,因此活化劑受體仍指導包含雙受體系統之免疫細胞對腫瘤細胞之靶向殺死。第二抑制性受體之標靶由諸如上皮組織之EGFR陽性組織表現,但不在癌細胞中表現,且抑制性受體將此「非靶抗原」識別為抑制性刺激物。第二抑制性受體之示例性標靶由肺上皮組織表現,且由於雜合性(LOH)而自EGFR陽性癌細胞中損失,從而在癌細胞中留下單一對偶基因形式,該形式可經由抑制性受體上之對偶基因特異性配位體結合結構域與其他對偶基因相區分。抑制性受體之示例性標靶包括但不限於主要組織相容性複合物(MHC)蛋白,諸如人類白血球抗原A (HLA-A)。HLA-B、HLA-C及其他HLA。HLA由變異基因編碼,諸如HLA-A*01、HLA-A*02、HLA*A03、HLA-C*07及其他,其可經由雜合性損失而自EGFR陽性癌細胞中損失。或者,抑制性受體之其他示例性標靶包括膠原凝集素亞家族成員12 COLEC12、APC下調1 (APCDD1)及C-X-C基元趨化激素配位體16 (CXCL16)。此等標靶中之每一者具有常見非同義變異形式,在其細胞外結構域中之胺基酸改變可由抗體所用,該變異形式可用作細胞整合器之B模組標靶,該細胞整合器經設計以用由活化劑受體,諸如EGFR或EGFR pMHC反應性活化劑受體活化之工程改造之T細胞安全治療患有EGFR陽性癌症之患者。本揭示案之組合物及方法可減少或消除由正常組織對EGFR之表現引起之DLT。本揭示案提供靶向癌細胞中之EGFR以使用過繼細胞療法治療EGFR陽性癌症之方法,該等方法係藉由添加在第二配位體(除EGFR以外之配位體,稱為「非靶抗原」)存在下阻斷過繼免疫細胞之活化的第二抑制性受體。使用本文所述之組合物及方法,表現EGFR之腫瘤細胞受表現兩種受體之過繼免疫細胞攻擊,此係因為此等腫瘤細胞僅表現活化劑配位體EGFR。相比之下,表現EGFR加上非靶抗原(或稱為「阻斷劑抗原」)之正常細胞受到保護而免於過繼免疫細胞攻擊。對正常細胞上之非靶抗原之抑制性受體反應,且從而阻止EGFR靶向之活化劑受體對免疫細胞之活化。此雙重靶向方法創造將允許EGFR導向之細胞療法在EGFR陽性癌症患者中安全且有效地給藥之治療窗口。
本揭示案提供允許使用誘導中靶毒性之強效EGFR CAR及TCR之方法及組合物,且藉由減輕其毒性促使此等EGFR靶向之受體適用作治療劑。
在變型中,本文所述之組合物及方法可用於殺死靶細胞及/或治療其中非靶抗原之表現由於除雜合性損失以外之原因而部分或完全降低之個體,該等原因包括但不限於部分基因缺失、表觀遺傳靜默、點突變、截短。
定義
在更詳細地闡述本揭示案之前,提供將在本文中使用之某些術語之定義可有助於對本揭示案之理解。
除非另有定義,否則本文所用之所有技術及科學術語皆具有與一般熟習本揭露案所屬技術者通常所理解之含義相同的含義。儘管在特定實施例之實踐或測試中可使用與本文所述之彼等類似或等效之任何方法及材料,但本文描述組合物、方法及材料之較佳實施例。出於本揭示案之目的,下文定義以下術語。額外定義在本揭示案通篇闡述。
如本文所用,術語「約」或「大約」係指相對於參考數量、水準、值、數目、頻率、百分比、尺寸、大小、量、重量或長度變化至多15%、10%、9%、8%、7%、6%、5%、4%、3%、2%或1%之數量、水準、值、數目、頻率、百分比、尺寸、大小、量、重量或長度。在一個實施例中,術語「約」或「大約」係指參考數量、水準、值、數目、頻率、百分比、尺寸、大小、量、重量或長度 ± 15%、± 10%、± 9%、± 8%、± 7%、± 6%、± 5%、± 4%、± 3%、± 2%或± 1%之數量、水準、值、數目、頻率、百分比、尺寸、大小、量、重量或長度範圍。
如本文所用,術語「經分離」意指實質上或基本上不含在其天然狀態中通常伴隨出現之組分的材料。在特定實施例中,術語「獲得」或「衍生」與經分離同義使用。
術語「個體」、「患者」及「個人」在本文中可互換使用以指脊椎動物,較佳為哺乳動物,更佳為人類。亦涵蓋活體內獲得或活體外培養之生物實體之組織、細胞及其子代。如本文所用,「個體」、「患者」或「個人」包括展現可用本文所涵蓋之載體、組合物及方法治療之疼痛的任何動物。適合之個體(例如,患者)包括實驗室動物(諸如小鼠、大鼠、兔或天竺鼠)、農場動物及家畜或寵物(諸如貓或犬)。包括非人類靈長類動物,且較佳包括人類患者。
如本文所用,「治療(treatment)」或「治療(treating)」包括任何有益或期望之作用,且甚至可包括症狀之最小改善。「治療」不一定指示疾病或疾患或其相關症狀之完全根除或治癒。
如本文所用,「預防(prevent)」及諸如「預防(prevented)」、「預防(preventing)」等類似詞語指示用於預防、抑制疾病症狀或降低疾病症狀之可能性的方法。其亦指延遲疾病或疾患之發作或複發或延遲疾病症狀之發生或複發。如本文所用,「預防」及類似詞語亦包括降低在發作或復發前疾病之強度、影響、症狀及/或負擔。
如本文所用,術語「量」係指達成有益或所需之預防或治療結果(包括臨床結果)之病毒的「有效用量」或「有效量」。
病毒或細胞之「治療有效量」可根據如下因素而變化:個體之疾病狀態、年齡、性別及體重以及病毒或細胞在個體中引發所需反應之能力。治療有效量亦為其中治療有益作用超過病毒或細胞之任何毒性或有害作用之量。術語「治療有效量」包括有效「治療」個體(例如,患者)之量。
生理反應,例如電生理活性或細胞活性之「增加」或「提高」量典型地為「統計上顯著」之量,且可包括未處理細胞中之活性水準之1.1、1.2、1.5、2、3、4、5、6、7、8、9、10、15、20、30倍或更多倍(例如,500、1000倍) (包括在其之間且大於1之所有整數及小數點,例如,1.5、1.6、1.7、1.8等)的增加。
生理反應,例如電生理活性或細胞活性之「減少」或「降低」量典型地為「統計上顯著」之量,且可包括未處理細胞中之活性水準之1.1、1.2、1.5、2、3、4、5、6、7、8、9、10、15、20、30倍或更多倍(例如,500、1000倍) (包括在其之間且大於1之所有整數及小數點,例如,1.5、1.6、1.7、1.8等)的減少。
「維持」或「保留」或「保持」或「無變化」或「無實質性變化」或「無實質性減少」一般係指與由任一媒劑或對照分子/組合物引起之反應可比之生理反應。可比之反應為與參考反應無顯著差異或可量測差異之反應。
一般而言,「序列一致性」或「序列同源性」分別係指兩個多核苷酸或多肽序列之準確核苷酸對核苷酸或胺基酸對胺基酸對應性。典型地,用於確定序列一致性之技術包括確定多核苷酸之核苷酸序列及/或確定由此編碼之胺基酸序列,及將此等序列與第二核苷酸或胺基酸序列進行比較。兩個或更多個序列(多核苷酸或胺基酸)可藉由確定其「一致性百分比」來進行比較。兩個序列(無論為核酸抑或胺基酸序列)之一致性百分比為兩個比對序列之間準確匹配之數目除以較短序列之長度且乘以100。舉例而言,亦可藉由使用自國立衛生研究所可得之高級BLAST電腦程式(包括2.2.9版)比較序列資訊來確定一致性百分比。BLAST程式係基於Karlin及Altschul, Proc. Natl. Acad. Sci. USA 87:2264-2268 (1990)之比對方法且如Altschul等人, J. Mol. Biol. 215:403-410 (1990);Karlin及Altschul, Proc. Natl. Acad. Sci. USA 90:5873-5877 (1993);及Altschul等人, Nucleic Acids Res. 25:3389-3402 (1997)中所論述。簡言之,BLAST程式將一致性定義為一致比對符號(一般為核苷酸或胺基酸)之數目除以兩個序列中之較短序列中的符號總數。該程式可用於確定所比較之蛋白質全長之一致性百分比。提供預設參數以最佳化使用短查詢序列之搜索,例如,使用blastp程式。該程式亦允許使用SEG過濾器來屏蔽由Wootton及Federhen, Computers and Chemistry 17:149-163 (1993)之SEG程式確定之查詢序列的區段。所需序列一致性程度之範圍約為80%至100%及其之間的整數值。典型地,所揭示之序列與所主張之序列之間的一致性百分比為至少80%、至少85%、至少90%、至少95%或至少98%。
術語「MOI」在本文中用於指感染複數,其為試劑(例如,病毒粒子)與感染標靶(例如,細胞)之比率。
在本說明書中,除非另有指示,否則任何濃度範圍、百分比範圍、比率範圍或整數範圍應理解為包括所敘述之範圍內的任何整數值且在適當時包括其分數(諸如整數之十分之一及百分之一)。
如本文所用,「靶細胞」係指過繼細胞療法靶向之細胞。舉例而言,靶細胞可為癌細胞,其可由過繼細胞療法之移植T細胞殺死。本揭示案之靶細胞表現如本文所述之靶抗原,且不表現非靶抗原。
如本文所用,「非靶細胞」係指過繼細胞療法不靶向之細胞。舉例而言,在靶向癌細胞之過繼細胞中,正常、健康、非癌細胞為非靶細胞。個體中之一些或所有非靶細胞可表現靶抗原及非靶抗原兩者。個體中之非靶細胞可表現非靶抗原,而不管此等細胞是否亦表現靶抗原。
如本文所用,「靶抗原」,無論使用術語抗原抑或特異性抗原之名稱來提及,係指由諸如癌細胞之靶細胞表現之抗原。靶抗原之表現不限於靶細胞。靶抗原可由個體中之癌細胞及正常非癌細胞兩者表現。
如本文所用,「非靶抗原」 (或「阻斷劑抗原」),無論使用術語抗原抑或特異性抗原之名稱來提及,係指由正常非癌細胞表現且在癌細胞中不表現之抗原。此種表現差異允許抑制性受體在非靶細胞存在下抑制免疫細胞活化,但在靶細胞存在下不抑制免疫細胞活化。
多態性係指群體中核苷酸序列之兩個或更多個變異體之存在。多態性可包括一或多個鹼基變化、插入、重複或缺失。多態性包括例如簡單序列重複(SSR)及單核苷酸多態性(SNP),此為當腺嘌呤(A)、胸腺嘧啶(T)、胞嘧啶(C)或鳥嘌呤(G)之單個核苷酸改變時發生之變異。
如本文所用,「親和力」係指配位體與受體上之單個配位體結合位點,例如抗原對本文所述之受體中之任一者之抗原結合結構域的結合強度。配位體結合結構域與其配位體可具有較弱相互作用(低親和力),或較強相互作用(高親和力)。
Kd或解離常數為一種類型之平衡常數,該常數量測較大物體可逆分離成較小組分之傾向,例如,當包含受體及其同源配位體之大分子復合物分離成配位體及受體時。當Kd高時,意謂需要高濃度之配位體佔據受體,且受體對配位體之親和力低。反之,低Kd意謂配位體對受體具有高親和力。
如本文所用,「有反應」或「對……有反應」之受體係指包含細胞內結構域之受體,當由配位體(亦即,抗原)結合時產生對應於細胞內結構域之已知功能的信號。結合至靶抗原之活化劑受體可產生引起表現活化劑受體之免疫細胞活化的信號。結合至非靶抗原之抑制性受體可產生阻止或減少表現活化劑受體之免疫細胞活化的抑制性信號。受體之反應性及其活化或抑制表現受體之免疫細胞的能力可藉由此項技術中已知及本文所述之任何方式來檢定,包括但不限於報告體檢定及細胞毒性檢定。
如本文所用,免疫細胞之「活化」或「經活化」之免疫細胞為可執行免疫反應之一或多種特徵性功能的免疫細胞。此等功能包括增殖、細胞激素釋放及細胞毒性,亦即,殺死靶細胞。經活化之免疫細胞表現將為熟習此項技術者顯而易見之標誌。舉例而言,經活化之T細胞可表現CD69、CD71、CD25及HLA-DR中之一或多者。當活化劑受體變得對靶抗原(例如,EGFR)之結合有反應時,表現活化劑受體(例如,EGFR CAR)之免疫細胞可由活化劑受體活化。。「靶抗原」亦可稱作「活化劑抗原」且可由靶細胞分離或表現。當抑制性受體變得對非靶抗原(例如,HLA-A*02)之結合有反應時,甚至當活化劑受體結合至標靶活化劑配位體時,可減少或阻止表現抑制性受體之免疫細胞的活化。「非靶抗原」亦可稱作「抑制性配位體」或「阻斷劑」,且可由靶細胞分離或表現。
免疫細胞上之受體表現可藉由報告本文所述之活化劑受體及抑制性受體之存在的檢定來驗證。舉例而言,可用經標記之分子(例如,螢光團標記之受體特異性抗體或螢光團標記之受體特異性配位體)將免疫細胞群體染色,且使用螢光活化細胞分選(FACS)流式細胞術進行定量。此方法允許將免疫細胞群體中一定百分比之免疫細胞表徵為表現活化劑受體、抑制性受體或兩種受體。由本文所述之免疫細胞表現之活化劑受體與抑制性受體之比率可藉由例如數位液滴PCR來確定。此等方法可用於表徵用於生產及製造本文所述之免疫細胞、醫藥組合物及套組之細胞群體。對於本文所述之免疫細胞、醫藥組合物及套組,應了解,表現活化劑受體及抑制性受體兩者之免疫細胞的適合百分比係針對本文所述之方法專門確定。舉例而言,表現活化劑受體及抑制性受體兩者之免疫細胞的適合百分比可為至少50%、至少55%、至少60%、至少65%、至少70%、至少75%、至少80%、至少85%、至少90%或至少95%。舉例而言,表現活化劑受體及抑制性受體兩者之免疫細胞的適合百分比可為至多50%、至多55%、至多60%、至多65%、至多70%、至多75%、至多80%、至多85%、至多90%或至多95%。舉例而言,免疫細胞中活化劑受體與抑制性受體之適合比率可為約5:1、約4:1、約3:1、約2:1、約1:1、約1:2、約1:3、約1:4或約1:5。應了解,純化、富集及/或消耗步驟可用於免疫細胞群體以滿足本文所述之免疫細胞、醫藥組合物及套組之適合值。
由本文所述之免疫細胞表現之反應性受體可藉由量測預期由受體之細胞內結構域產生之信號產生的檢定來驗證。報告細胞株,諸如Jurkat-螢光素酶NFAT細胞(Jurkat細胞),可用於表徵反應性受體。Jurkat細胞來源於T細胞且包含穩定整合之活化T細胞核因子(NFAT)可誘導性螢光素酶報告系統。NFAT為免疫細胞活化所需之轉錄因子家族,其活化可用作T細胞活化之信號傳導標誌。可用本文所述之活化劑受體及/或抑制性受體轉導或轉染Jurkat細胞。若Jurkat細胞表現螢光素酶報告基因,則活化劑受體對配位體之結合有反應,且反應性水準可由報告基因表現之水準決定。螢光素酶之存在可使用任何已知螢光素酶偵測試劑,諸如螢光素來確定。若當抑制性受體與活化劑受體在Jurkat細胞中共表現時,該抑制性受體阻止正常反應性免疫細胞對活化劑受體作出反應而表現螢光素酶,則抑制性受體對配位體之結合有反應。舉例而言,在表現活化劑及抑制劑兩者之Jurkat細胞中抑制性受體之反應性可藉由觀測到以下情況來確定及定量:1)在存在活化劑受體配位體及不存在抑制性受體配位體之情況下,Jurkat細胞表現螢光素酶;及2)在存在活化劑受體配位體及抑制性受體配位體兩者之情況下,Jurkat細胞中之螢光素酶表現降低或消除。此方法可用於確定活化劑受體及活化劑受體與抑制性受體之特定對的敏感性、效力及選擇性。可使用劑量-反應實驗由EC50或IC50值來定量敏感性、效力及選擇性,其中將活化劑受體配位體及/或抑制性受體配位體滴定至表現活化劑受體或活化劑與抑制性受體之特定對的Jurkat細胞之培養物中。或者,可在表現活化劑受體或活化劑與抑制性受體之特定對的免疫細胞(例如,Jurkat細胞或初級免疫細胞)與表現增加量之活化劑配位體或抑制劑配位體之靶細胞的共培養物中確定EC50及IC50值。藉由例如將編碼mRNA之活化劑配位體或抑制劑配位體滴定至靶細胞中,或使用天然表現不同水準之靶配位體的靶細胞,可在靶細胞中實現增加量之活化劑配位體或抑制劑配位體。如使用表現不同量之靶配位體及非靶配位體之靶細胞確定之活化劑及抑制性受體之示例性適合之EC50及IC50值包括對於活化劑受體為260個轉錄物/百萬(TPM)或更小之EC50,例如介於10與260 TPM之間的EC50,及對於抑制性受體為10 TPM或更小之IC50,例如1-5 TPM之IC50。
表現活化劑受體或活化劑與抑制性受體之特定對的本文所述之免疫細胞之活化可藉由量測在與該等免疫細胞一起共培育之後靶細胞之生存力的檢定來進一步確定。將免疫細胞(有時稱作效應細胞)與表現活化劑受體配位體、抑制性受體配位體或活化劑及抑制性受體配位體兩者之靶細胞一起共培育。共培育之後,使用任何方法量測靶細胞之生存力以量測細胞培養物中之生存力。舉例而言,可使用線粒體功能檢定來確定生存力,該檢定使用四唑鎓鹽受質以量測活性粒線體酶。亦可使用基於成像之方法來確定生存力。靶細胞可表現螢光蛋白,諸如綠色螢光蛋白或紅色螢光蛋白。總細胞螢光之降低指示靶細胞之生存力降低。與表現活化劑受體或活化劑與抑制性受體之特定對的免疫細胞一起培育之後靶細胞之生存力降低應解釋為靶細胞介導之免疫細胞活化。亦可使用此方法來確定免疫細胞之選擇性的量度。若觀測到以下情況,則表現一對活化劑與抑制性受體之免疫細胞為選擇性的:1)表現活化劑受體配位體而非抑制性受體配位體之靶細胞的生存力降低;2)表現活化劑受體配位體及抑制性受體配位體兩者之靶細胞的生存力未降低。自此等量測可得出「特異性殺死」值,該值基於靶細胞生存力之降低將免疫細胞活化之百分比定量為陰性對照(不表現活化劑受體之免疫細胞)之百分比。此外,自此等量測可得出「選擇性比率」值,該值代表在不存在抑制性受體配位體之情況下表現活化劑受體配位體之靶細胞中所觀測之特異性殺死與表現活化劑受體配位體及抑制性受體配位體兩者之靶細胞中所觀測之特異性殺死的比率。此方法可用於表徵用於生產及製造本文所述之免疫細胞、醫藥組合物及套組之細胞群體。對於免疫細胞、醫藥組合物及套組之適合特異性殺死值可為例如以下準則:1)在不存在抑制性受體配位體之情況下免疫細胞與表現活化劑受體配位體之靶細胞共培育48小時後至少50%之特異性殺死;2)表現活化劑受體配位體及抑制性受體配位體兩者之靶細胞的特異性殺死小於或等於20%。作為另一個實例,免疫細胞能夠在6小時、12小時、18小時、24小時、30小時、36小時、42小時、48小時、54小時或60小時之時段內殺死至少30%、至少40%、至少50%、至少60%、至少70%、至少80%、至少90%、至少95%、至少97%或至少99%之表現活化劑配位體而非抑制劑配位體之靶細胞,而在相同時間段內殺死少於40%、少於30%、少於20%、少於10%、少於5%、少於3%或少於1%之表現活化劑及抑制劑配位體之靶細胞。
對於免疫細胞、醫藥組合物及套組,在不存在抑制性配位體值之情況下表現活化劑配位體之靶細胞的適合特異性殺死值可為例如至少約50%至至少約95%。對於免疫細胞、醫藥組合物及套組,在不存在抑制性配位體值之情況下表現活化劑配位體之靶細胞的適合特異性殺死值可為例如至少約50%、至少約55%、至少約60%、至少約65%、至少約70%、至少約75%、至少約80%、至少約85%、至少約90%或至少約95%。對於免疫細胞、醫藥組合物及套組,在不存在抑制性配位體值之情況下表現活化劑配位體之靶細胞的適合特異性殺死值可為例如至多約50%、至多約55%、至多約60%、至多約65%、至多約70%、至多約75%、至多約80%、至多約85%、至多約90%或至多約95%。對於免疫細胞、醫藥組合物及套組,表現活化劑受體配位體及抑制性受體配位體兩者之靶細胞的適合特異性殺死值可小於約50%、小於約45%、小於約40%、小於約35%、小於約30%、小於約25%、小於約20%、小於約15%、小於約10%或小於約5%。可在免疫細胞與靶細胞一起共培育約6小時、約12小時、約18小時、約24、約30小時、約36小時、約42小時、約48小時、約54小時、約60小時、約66小時或約72小時後確定對於免疫細胞、醫藥組合物及套組之適合特異性殺死值。
對於免疫細胞、醫藥組合物及套組,在不存在抑制性配位體值之情況下表現活化劑配位體之靶細胞的適合特異性殺死值可為例如至少約50%至至少約95%。對於免疫細胞、醫藥組合物及套組,在不存在抑制性配位體值之情況下表現活化劑配位體之靶細胞的適合特異性殺死值可為例如至少約50%、至少約55%、至少約60%、至少約65%、至少約70%、至少約75%、至少約80%、至少約85%、至少約90%或至少約95%。對於免疫細胞、醫藥組合物及套組,在不存在抑制性配位體值之情況下表現活化劑配位體之靶細胞的適合特異性殺死值可為例如至多約50%、至多約55%、至多約60%、至多約65%、至多約70%、至多約75%、至多約80%、至多約85%、至多約90%或至多約95%。對於免疫細胞、醫藥組合物及套組,表現活化劑受體配位體及抑制性受體配位體兩者之靶細胞的適合特異性殺死值可小於約50%、小於約45%、小於約40%、小於約35%、小於約30%、小於約25%、小於約20%、小於約15%、小於約10%或小於約5%。可在免疫細胞與靶細胞一起共培育約6小時、約12小時、約18小時、約24、約30小時、約36小時、約42小時、約48小時、約54小時、約60小時、約66小時或約72小時後確定對於免疫細胞、醫藥組合物及套組之適合特異性殺死值。
對於免疫細胞、醫藥組合物及套組,在不存在抑制性配位體值之情況下表現活化劑配位體之靶細胞的適合特異性殺死值可為例如至少約50%至至少約95%。對於免疫細胞、醫藥組合物及套組,在不存在抑制性配位體值之情況下表現活化劑配位體之靶細胞的適合特異性殺死值可為例如至少約50%、至少約55%、至少約60%、至少約65%、至少約70%、至少約75%、至少約80%、至少約85%、至少約90%或至少約95%。對於免疫細胞、醫藥組合物及套組,在不存在抑制性配位體值之情況下表現活化劑配位體之靶細胞的適合特異性殺死值可為例如至多約50%、至多約55%、至多約60%、至多約65%、至多約70%、至多約75%、至多約80%、至多約85%、至多約90%或至多約95%。對於免疫細胞、醫藥組合物及套組,表現活化劑受體配位體及抑制性受體配位體兩者之靶細胞的適合特異性殺死值可小於約50%、小於約45%、小於約40%、小於約35%、小於約30%、小於約25%、小於約20%、小於約15%、小於約10%或小於約5%。可在免疫細胞與靶細胞一起共培育約6小時、約12小時、約18小時、約24、約30小時、約36小時、約42小時、約48小時、約54小時、約60小時、約66小時或約72小時後確定對於免疫細胞、醫藥組合物及套組之適合特異性殺死值。
如本文所用,術語「功能變異體」係指與親本蛋白質相比具有一或多個胺基酸取代、插入或缺失且保留親本蛋白質之一或多種所需活性的蛋白質。功能變異體可為保留親本蛋白質之一或多種所需活性的蛋白質片段(亦即,具有N端及/或C端缺失之變異體)。
如本文所用,「非靶對偶基因變異體」係指其產物由非靶細胞表現但不由靶細胞表現之基因的對偶基因。舉例而言,非靶對偶基因變異體為由個體之正常非癌細胞表現但不由個體之癌細胞表現之基因的對偶基因。非靶對偶基因變異體之表現可藉由任何機制在癌細胞中損失,包括但不限於編碼非靶對偶基因變異體之基因的雜合性損失、突變或表觀遺傳修飾。
如本文所用,當關於配位體結合結構域,諸如抗原結合結構域使用時,「對……具有特異性」或「特異性結合至」係指對指定標靶具有高特異性之配位體結合結構域。抗體特異性可視為配位體結合結構域與相應配位體之間的擬合優度之量度,或配位體結合結構域區分相似或甚至不相似配位體之能力。與特異性相比,親和力為配位體結合結構域與配位體之間的結合強度之量度,使得低親和力配位體結合結構域結合較弱且高親和力配位體結合結構域結合牢固。對靶對偶基因具有特異性之配位體結合結構域為可區分基因之不同對偶基因的結構域。舉例而言,對HLA-A*02具有特異性之配位體結合結構域不結合或僅弱結合至其他HLA-A對偶基因,諸如HLA-A*01或HLA-A*03。在本文所述之活化劑及抑制性受體之情形中,配位體結合結構域介導免疫細胞反應之特異性活化或抑制。熟習此項技術者將了解,配位體結合結構域可據稱對特定標靶具有特異性,且仍與一或多個額外標靶具有低結合水準,此不會影響其在本文所述之受體系統中之功能。
本文所提及之所有公開案及專利藉此以全文引用之方式併入,如同各個別公開案或專利特定及個別地指示以引用之方式併入一般。在衝突之情況下,將以本申請案(包括本文中之任何定義)為準。然而,本文所引用之任何參考文獻、文章、公開案、專利、專利公開案及專利申請案之提及不為且不應視為承認或以任何形式建議其構成有效之先前技術或形成全世界任何國家之公知常識的一部分。
活化劑受體
本揭示案提供第一受體,該第一受體包含對靶抗原具有特異性之第一細胞外配位體結合結構域,該靶抗原包括癌細胞特異性抗原或與主要組織相容性複合物I類(MHC-I)複合之其肽抗原。第一受體為活化劑受體,且在靶抗原由第一受體之細胞外配位體結合結構域結合後介導表現第一受體之免疫細胞的活化。第一受體對靶抗原(亦即,活化劑配位體)有反應。舉例而言,當靶抗原結合至或接觸第一受體時,在靶抗原由第一受體之細胞外配位體結合結構域結合後第一受體有反應且活化表現第一受體之免疫細胞。在一些實施例中,第一受體為嵌合抗原受體(CAR)。在一些實施例中,第一受體為T細胞受體(TCR)。
在一些實施例中,第一受體為人源化的。如本文所用,「人源化」係指用同源或功能等效之人類序列置換已自非人類物種分離或衍生之轉殖基因中之序列或子序列。舉例而言,可藉由將小鼠CDR移植至人類框架序列中,繼而用某些人類框架殘基反向取代來自源抗體之相應小鼠殘基來創造人源化抗體。
活化劑標靶
根據本揭示案,第一受體之靶抗原為表皮生長因子受體(EGFR)或與主要組織相容性複合物I類(MHC-I)複合之EGFR之肽抗原。
主要組織相容性複合物I類(MHC-I)為可向免疫系統之細胞展示抗原,從而觸發免疫反應之蛋白質複合物。對應於MHC-I之人類白血球抗原(HLA)為HLA-A、HLA-B及HLA-C。
設想包含HLA-A、HLA-B、HLA-C、HLA-E、HLA-F或HLA-G中之任一者之癌細胞特異性pMHC抗原在本揭示案之範疇內。在一些實施例中,癌細胞特異性抗原包含HLA-A。HLA-A受體為包含重α鏈及較小β鏈之異二聚體。α鏈由HLA-A之變異體編碼,而β鏈(β2-微球蛋白)為非變異體。存在數千個變異體HLA-A基因,所有此等皆處於本揭示案之範疇內。在一些實施例中,MHC-I包含人類白血球抗原A*02對偶基因(HLA-A*02)。
在一些實施例中,癌細胞特異性抗原包含HLA-B。HLA-B基因之數百個型式(對偶基因)為已知的,給予各型式以特定編號(諸如HLA-B27)。
在一些實施例中,癌細胞特異性抗原包含HLA-C。HLA-C屬於HLA I類重鏈旁系同源物。此I類分子為由重鏈及輕鏈組成之異二聚體(β-2微球蛋白)。超過一百種HLA-C對偶基因在此項技術中為已知的。
在一些實施例中,癌細胞特異性抗原為肺癌抗原、神經膠質母細胞瘤抗原、乳癌抗原、頭頸癌抗原或結腸直腸癌抗原。在一些實施例中,癌細胞特異性抗原為結腸直腸癌抗原。在一些實施例中,癌細胞特異性抗原為EGFR或其肽抗原。
在一些實施例中,癌細胞特異性抗原為EGFR或與主要組織相容性複合物I類(MHC-I)複合之其肽抗原。EGFR為跨膜蛋白,其作為細胞外蛋白配位體之表皮生長因子(EGF)家族的受體形式成員。EGFR在正常組織,諸如間葉、上皮及神經元組織中廣泛表現,且在細胞增殖、分化及發育中起重要作用。EGFR亦在多種實體腫瘤中高度表現,且EGFR表現與腫瘤進展、對化學療法之抗性及不良預後相關聯。
設想EGFR之所有同種型及EGFR之臨床相關突變(例如,EGFRvIII、S468/492R)為本揭示案之癌細胞特異性抗原。EGFR同種型a在NCBI記錄號NP_005219.2中描述,其內容以引用之方式併入本文中。在一些實施例中,EGFR包含以下胺基酸序列:
在一些實施例中,癌細胞特異性抗原為來源於EGFR之肽抗原。在一些實施例中,肽抗原包含與SEQ ID NO: 1-8中之任一者之序列或子序列具有至少80%、至少85%、至少90%、至少95%、至少96%、至少97%、至少98%或至少99%一致性之序列。在一些實施例中,肽抗原包含與SEQ ID NO: 1-8或SEQ ID NO: 918-919中之任一者之子序列一致的序列。
細胞外配位體結合結構域
本揭示案提供第一受體,該第一受體包含對靶抗原具有特異性之第一細胞外配位體結合結構域。在一些實施例中,靶抗原包括癌細胞特異性抗原。
在一些實施例中,癌細胞特異性抗原為與MHC-I複合之EGFR或EGFR源性肽抗原,且第一受體之配位體結合結構域識別並結合至EGFR抗原。在一些實施例中,癌細胞特異性抗原為EGFR之臨床相關突變體。舉例而言,EGFR之突變變異體可為針對EGFR基因之取代突變(例如,外顯子21中之L858R)、缺失突變(例如,EGFRvIII,或外顯子19或外顯子23中之缺失)或擴增突變。
設想可依配位體依賴性方式調控受體活性之任何類型之配位體結合結構域在本揭示案之範疇內。在一些實施例中,配位體結合結構域為抗原結合結構域。示例性抗原結合結構域尤其包括scFv、SdAb、僅Vβ結構域及來源於TCR α及β鏈可變結構域之TCR抗原結合結構域。
設想任何類型之抗原結合結構域在本揭示案之範疇內。
舉例而言,第一細胞外配位體結合結構域可為連續多肽鏈之一部分,包括例如僅Vβ結構域、單結構域抗體片段(sdAb)或重鏈抗體HCAb、來源於鼠類、人源化或人類抗體之單鏈抗體(scFv) (Harlow等人, 1999, Using Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, N.Y.;Harlow等人, 1989, Antibodies: A Laboratory Manual, Cold Spring Harbor, N.Y.;Houston等人, 1988, Proc. Natl. Acad. Sci. USA 85:5879-5883;Bird等人, 1988, Science 242:423-426)。在一些態樣中,第一細胞外配位體結合結構域包含含有抗體片段之抗原結合結構域。在其他態樣中,第一細胞外配位體結合結構域包含含有scFv或sdAb之抗體片段。
如本文所用,術語「抗體」係指來源於免疫球蛋白分子之蛋白質或多肽序列,該抗體特異性結合至抗原。抗體可為多株或單株來源之完整免疫球蛋白或其片段,且可來源於天然或重組來源。
術語「抗體片段」或「抗體結合結構域」係指抗體或其重組變異體之至少一部分,其含有足以賦予抗體片段對標靶(諸如抗原及其確定之抗原決定基)之識別及特異性結合的抗原結合結構域,亦即,完整抗體之抗原決定可變區。抗體片段之實例包括但不限於Fab、Fab'、F(ab')2及Fv片段、單鏈(sc)Fv (「scFv」)抗體片段、線性抗體、單結構域抗體(縮寫為「sdAb」) (VL或VH)、駱駝科VHH結構域及由抗體片段形成之多特異性抗體。
術語「scFv」係指包含至少一個包含輕鏈可變區之抗體片段及至少一個包含重鏈可變區之抗體片段的融合蛋白,其中輕鏈及重鏈可變區經由短可撓性多肽連接子連續連接,且能夠表現為單個多肽鏈,且其中scFv保留其所來源之完整抗體的特異性。
關於抗體之「重鏈可變區」或「VH」 (或者,在單結構域抗體之情況下,例如,奈米抗體,「VHH」)係指含有穿插於稱為框架區之側翼段之間的三個CDR之重鏈片段,此等框架區一般比CDR更高度保守且形成支架以支持CDR。
除非指定,否則如本文所用,scFv可具有任一次序之VL及VH可變區,例如,相對於多肽之N端及C端末端,scFv可包含VL-連接子-VH或可包含VH-連接子-VL。
在一些實施例中,活化劑及/或抑制性受體之抗原結合結構域包含scFv。在一些實施例中,scFv包含由連接子連接之VL及VH區。在一些實施例中,連接子包含甘胺酸絲胺酸連接子,例如,GGGGSGGGGSGGGGSGG (SEQ ID NO: 136)。在一些實施例中,scFv進一步包含在scFv之N端的信號序列。示例性信號序列包括MDMRVPAQLLGLLLLWLRGARC (SEQ ID NO: 137),其由ATGGACATGAGGGTCCCCGCTCAGCTCCTGGGGCTCCTGCTACTCTGGCTCCGAGGTGCCAGATGT (SEQ ID NO: 138)或ATGGATATGAGAGTGCCTGCCCAGCTGCTCGGACTGCTCCTTCTGTGGTTGAGAGGAGCTCGGTGC (SEQ ID NO: 917)編碼。
術語「抗體輕鏈」係指以天然存在之構形存在於抗體分子中之兩種類型之多肽鏈中的較小者。Kappa (「Κ」)及lambda (「λ」)輕鏈係指兩種主要抗體輕鏈同種型。
術語「重組抗體」係指使用重組DNA技術產生之抗體,諸如由噬菌體或酵母表現系統表現之抗體。該術語亦應解釋為意指已藉由合成編碼抗體之DNA分子產生且其DNA分子表現抗體蛋白之抗體或指定該抗體之胺基酸序列,其中DNA或胺基酸序列已使用此項技術中可用且熟知之重組DNA或胺基酸序列技術獲得。
術語「Vβ結構域」、「僅Vβ結構域」、「β鏈可變結構域」或「單可變結構域TCR (svd-TCR)」係指基本上由單個T細胞受體(TCR) β可變結構域組成之抗原結合結構域,該結構域在不存在第二TCR可變結構域之情況下特異性結合至抗原。僅Vβ結構域使用互補決定區(CDR)嚙合抗原。各僅Vβ結構域含有三個補體決定區(CDR1、CDR2及CDR3)。可組合額外元件,前提條件為Vβ結構域經配置以在不存在第二TCR可變結構域之情況下結合抗原決定基。
在一些實施例中,第一受體之細胞外配位體結合結構域包含抗體片段、單鏈Fv抗體片段(scFv)或β鏈可變結構域(Vβ)。
在一些實施例中,第一受體之細胞外配位體結合結構域包含TCR α鏈可變結構域及TCR β鏈可變結構域。
在一些實施例中,第一受體之細胞外配位體結合結構域包含scFv抗原結合結構域。示例性EGFR scFv示於下表1中。
表1. EGFR scFv結構域
胺基酸序列 | DNA序列 |
CT-478 EGFR (VH-VL scFv格式): QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWDDGSYKYYGDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGITMVRGVMKDYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGAIQLTQSPSSLSASVGDRVTITCRASQDISSALVWYQQKPGKAPKLLIYDASSLESGVPSRFSGSESGTDFTLTISSLQPEDFATYYCQQFNSYPLTFGGGTKVEIK (SEQ ID NO: 9) | CT-478 EGFR: CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGCGTCTGGATTCACCTTCAGTACCTATGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATGGGATGATGGAAGTTATAAATACTATGGAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGATGGTATTACTATGGTTCGGGGAGTTATGAAGGACTACTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGGCGGAGGTGGAAGCGGAGGGGGAGGATCTGGCGGCGGAGGAAGCGGAGGCGCCATCCAGTTGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGGACATTAGCAGTGCTTTAGTCTGGTATCAGCAGAAACCAGGGAAAGCTCCTAAGCTCCTGATCTATGATGCCTCCAGTTTGGAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGAATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTATTACTGTCAACAGTTTAATAGTTACCCGCTCACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA (SEQ ID NO: 139) |
CT-479 EGFR (VL-VH scFv格式): AIQLTQSPSSLSASVGDRVTITCRASQDISSALVWYQQKPGKAPKLLIYDASSLESGVPSRFSGSESGTDFTLTISSLQPEDFATYYCQQFNSYPLTFGGGTKVEIKGGGGSGGGGSGGGGSGGQVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWDDGSYKYYGDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGITMVRGVMKDYFDYWGQGTLVTVSS (SEQ ID NO: 10) | CT-479 EGFR: GCCATCCAGTTGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGGACATTAGCAGTGCTTTAGTCTGGTATCAGCAGAAACCAGGGAAAGCTCCTAAGCTCCTGATCTATGATGCCTCCAGTTTGGAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGAATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTATTACTGTCAACAGTTTAATAGTTACCCGCTCACTTTCGGCGGAGGGACCAAGGTGGAGATCAAAGGCGGAGGTGGAAGCGGAGGGGGAGGATCTGGCGGCGGAGGAAGCGGAGGCCAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGCGTCTGGATTCACCTTCAGTACCTATGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATGGGATGATGGAAGTTATAAATACTATGGAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGATGGTATTACTATGGTTCGGGGAGTTATGAAGGACTACTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA (SEQ ID NO: 140) |
CT-480 EGFR (VH-VL scFv格式): QIQLVQSGPELKKPGETVKISCKASGYTFTEYPIHWVKQAPGKGFKWMGMIYTDIGKPTYAEEFKGRFAFSLETSASTAYLQINNLKNEDTATYFCVRDRYDSLFDYWGQGTTLTVSSGGGGSGGGGSGGGGSGGDVVMTQTPLSLPVSLGDQASISCRSSQSLVHSNGNTYLHWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPWTFGGGTKLEIK (SEQ ID NO: 11) | CT-480 EGFR: CAGATCCAGTTGGTGCAGTCTGGACCTGAGCTGAAGAAGCCTGGAGAGACAGTCAAGATCTCCTGCAAGGCCTCTGGGTATACCTTCACAGAATATCCAATACACTGGGTGAAGCAGGCTCCAGGAAAGGGTTTCAAGTGGATGGGCATGATATACACCGACATTGGAAAGCCAACATATGCTGAAGAGTTCAAGGGACGGTTTGCCTTCTCTTTGGAGACCTCTGCCAGCACTGCCTATTTGCAGATCAACAACCTCAAGAATGAGGACACGGCTACATATTTCTGTGTAAGAGATCGATATGATTCCCTCTTTGACTACTGGGGCCAAGGCACCACTCTCACAGTCTCCTCAGGCGGAGGTGGAAGCGGAGGGGGAGGATCTGGCGGCGGAGGAAGCGGAGGCGATGTTGTGATGACCCAAACTCCACTCTCCCTGCCTGTCAGTCTTGGAGATCAAGCCTCCATCTCTTGCAGATCTAGTCAGAGCCTTGTACACAGTAATGGAAACACCTATTTACATTGGTACCTGCAGAAGCCAGGCCAGTCTCCAAAGCTCCTGATCTACAAAGTTTCCAACCGATTTTCTGGGGTCCCAGACAGGTTCAGTGGCAGTGGATCAGGGACAGATTTCACACTCAAGATCAGCAGAGTGGAGGCTGAGGATCTGGGAGTTTATTTCTGCTCTCAAAGTACACATGTTCCGTGGACGTTCGGTGGAGGCACCAAGCTGGAAATCAAA (SEQ ID NO: 141) |
CT-481 EGFR (VL-VH scFv格式): DVVMTQTPLSLPVSLGDQASISCRSSQSLVHSNGNTYLHWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPWTFGGGTKLEIKGGGGSGGGGSGGGGSGGQIQLVQSGPELKKPGETVKISCKASGYTFTEYPIHWVKQAPGKGFKWMGMIYTDIGKPTYAEEFKGRFAFSLETSASTAYLQINNLKNEDTATYFCVRDRYDSLFDYWGQGTTLTVSS (SEQ ID NO: 12) | CT-481 EGFR: GATGTTGTGATGACCCAAACTCCACTCTCCCTGCCTGTCAGTCTTGGAGATCAAGCCTCCATCTCTTGCAGATCTAGTCAGAGCCTTGTACACAGTAATGGAAACACCTATTTACATTGGTACCTGCAGAAGCCAGGCCAGTCTCCAAAGCTCCTGATCTACAAAGTTTCCAACCGATTTTCTGGGGTCCCAGACAGGTTCAGTGGCAGTGGATCAGGGACAGATTTCACACTCAAGATCAGCAGAGTGGAGGCTGAGGATCTGGGAGTTTATTTCTGCTCTCAAAGTACACATGTTCCGTGGACGTTCGGTGGAGGCACCAAGCTGGAAATCAAAGGCGGAGGTGGAAGCGGAGGGGGAGGATCTGGCGGCGGAGGAAGCGGAGGCCAGATCCAGTTGGTGCAGTCTGGACCTGAGCTGAAGAAGCCTGGAGAGACAGTCAAGATCTCCTGCAAGGCCTCTGGGTATACCTTCACAGAATATCCAATACACTGGGTGAAGCAGGCTCCAGGAAAGGGTTTCAAGTGGATGGGCATGATATACACCGACATTGGAAAGCCAACATATGCTGAAGAGTTCAAGGGACGGTTTGCCTTCTCTTTGGAGACCTCTGCCAGCACTGCCTATTTGCAGATCAACAACCTCAAGAATGAGGACACGGCTACATATTTCTGTGTAAGAGATCGATATGATTCCCTCTTTGACTACTGGGGCCAAGGCACCACTCTCACAGTCTCCTCA (SEQ ID NO: 142) |
CT-482 EGFR (VH-VL scFv格式): EMQLVESGGGFVKPGGSLKLSCAASGFAFSHYDMSWVRQTPKQRLEWVAYIASGGDITYYADTVKGRFTISRDNAQNTLYLQMSSLKSEDTAMFYCSRSSYGNNGDALDFWGQGTSVTVSSGGGGSGGGGSGGGGSGGDVVMTQTPLSLPVSLGDQASISCRSSQSLVHSNGNTYLHWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVLTFGSGTKLEIK (SEQ ID NO: 13) | CT-482 EGFR: GAAATGCAGCTGGTGGAGTCTGGGGGAGGCTTCGTGAAGCCTGGAGGGTCCCTGAAACTCTCATGTGCAGCCTCTGGATTCGCTTTCAGTCACTATGACATGTCTTGGGTTCGCCAGACTCCGAAGCAGAGGCTGGAGTGGGTCGCATACATTGCTAGTGGTGGTGATATCACCTACTATGCAGACACTGTGAAGGGCCGATTCACCATCTCCAGAGACAATGCCCAGAACACCCTGTACCTGCAAATGAGCAGTCTGAAGTCTGAGGACACAGCCATGTTTTACTGTTCACGATCCTCCTATGGTAACAACGGAGATGCCCTGGACTTCTGGGGTCAAGGTACCTCAGTCACCGTCTCCTCAGGCGGAGGTGGAAGCGGAGGGGGAGGATCTGGCGGCGGAGGAAGCGGAGGCGATGTTGTGATGACCCAAACTCCACTCTCCCTGCCTGTCAGTCTTGGAGATCAAGCCTCCATCTCTTGCAGATCTAGTCAGAGCCTTGTTCACAGTAATGGAAACACCTATTTACATTGGTACCTGCAGAAGCCAGGCCAGTCTCCAAAGCTCCTGATCTACAAAGTTTCCAACCGATTTTCTGGGGTCCCAGACAGGTTCAGTGGCAGTGGATCAGGGACAGATTTCACACTCAAGATCAGCAGAGTGGAGGCTGAGGATCTGGGAGTTTATTTCTGCTCTCAAAGTACACATGTTCTCACGTTCGGCTCGGGGACAAAGTTGGAAATAAAA (SEQ ID NO: 143) |
CT-483 EGFR (VL-VH scFv格式): DVVMTQTPLSLPVSLGDQASISCRSSQSLVHSNGNTYLHWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVLTFGSGTKLEIKGGGGSGGGGSGGGGSGGEMQLVESGGGFVKPGGSLKLSCAASGFAFSHYDMSWVRQTPKQRLEWVAYIASGGDITYYADTVKGRFTISRDNAQNTLYLQMSSLKSEDTAMFYCSRSSYGNNGDALDFWGQGTSVTVSS (SEQ ID NO: 14) | CT-483 EGFR: GATGTTGTGATGACCCAAACTCCACTCTCCCTGCCTGTCAGTCTTGGAGATCAAGCCTCCATCTCTTGCAGATCTAGTCAGAGCCTTGTTCACAGTAATGGAAACACCTATTTACATTGGTACCTGCAGAAGCCAGGCCAGTCTCCAAAGCTCCTGATCTACAAAGTTTCCAACCGATTTTCTGGGGTCCCAGACAGGTTCAGTGGCAGTGGATCAGGGACAGATTTCACACTCAAGATCAGCAGAGTGGAGGCTGAGGATCTGGGAGTTTATTTCTGCTCTCAAAGTACACATGTTCTCACGTTCGGCTCGGGGACAAAGTTGGAAATAAAAGGCGGAGGTGGAAGCGGAGGGGGAGGATCTGGCGGCGGAGGAAGCGGAGGCGAAATGCAGCTGGTGGAGTCTGGGGGAGGCTTCGTGAAGCCTGGAGGGTCCCTGAAACTCTCATGTGCAGCCTCTGGATTCGCTTTCAGTCACTATGACATGTCTTGGGTTCGCCAGACTCCGAAGCAGAGGCTGGAGTGGGTCGCATACATTGCTAGTGGTGGTGATATCACCTACTATGCAGACACTGTGAAGGGCCGATTCACCATCTCCAGAGACAATGCCCAGAACACCCTGTACCTGCAAATGAGCAGTCTGAAGTCTGAGGACACAGCCATGTTTTACTGTTCACGATCCTCCTATGGTAACAACGGAGATGCCCTGGACTTCTGGGGTCAAGGTACCTCAGTCACCGTCTCCTCA (SEQ ID NO: 144) |
CT-486 EGFR (VH-VL scFv格式): QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYEFAYWGQGTLVTVSAGGGGSGGGGSGGGGSGGDILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLELK (SEQ ID NO: 15) | CT-486 EGFR: CAGGTGCAGCTGAAGCAGTCCGGCCCCGGCCTGGTGCAGCCCTCCCAGTCCCTGTCCATCACCTGCACCGTGTCCGGCTTCTCCCTGACCAACTACGGCGTGCACTGGGTGCGGCAGTCCCCCGGCAAGGGCCTGGAGTGGCTGGGCGTGATCTGGTCCGGCGGCAACACCGACTACAACACCCCCTTCACCTCCCGGCTGTCCATCAACAAGGACAACTCCAAGTCCCAGGTGTTCTTCAAGATGAACTCCCTGCAGTCCAACGACACCGCCATCTACTACTGCGCCCGGGCCCTGACCTACTACGACTACGAGTTCGCCTACTGGGGCCAGGGCACCCTGGTGACCGTGTCCGCCGGCGGAGGTGGAAGCGGAGGGGGAGGATCTGGCGGCGGAGGAAGCGGAGGCGACATCCTGCTGACCCAGTCCCCCGTGATCCTGTCCGTGTCCCCCGGCGAGCGGGTGTCCTTCTCCTGCCGGGCCTCCCAGTCCATCGGCACCAACATCCACTGGTACCAGCAGCGGACCAACGGCTCCCCCCGGCTGCTGATCAAGTACGCCTCCGAGTCCATCTCCGGCATCCCCTCCCGGTTCTCCGGCTCCGGCTCCGGCACCGACTTCACCCTGTCCATCAACTCCGTGGAGTCCGAGGACATCGCCGACTACTACTGCCAGCAGAACAACAACTGGCCCACCACCTTCGGCGCCGGCACCAAGCTGGAGCTGAAG (SEQ ID NO: 145) |
CT-487 EGFR (VH-VL scFv格式): QVQLVQSGAEVKKPGASVKVSCKASGYTFTSHWMHWVRQAPGQGLEWIGEFNPSNGRTNYNEKFKSKATMTVDTSTNTAYMELSSLRSEDTAVYYCASRDYDYDGRYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGDIQMTQSPSSLSASVGDRVTITCSASSSVTYMYWYQQKPGKAPKLLIYDTSNLASGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQQWSSHIFTFGQGTKVEIK (SEQ ID NO: 16) | CT-487 EGFR: CAGGTGCAGCTGGTGCAGTCCGGCGCCGAGGTGAAGAAGCCCGGCGCCTCCGTGAAGGTGTCCTGCAAGGCCTCCGGCTACACCTTCACCTCCCACTGGATGCACTGGGTGCGGCAGGCCCCCGGCCAGGGCCTGGAGTGGATCGGCGAGTTCAACCCCTCCAACGGCCGGACCAACTACAACGAGAAGTTCAAGTCCAAGGCCACCATGACCGTGGACACCTCCACCAACACCGCCTACATGGAGCTGTCCTCCCTGCGGTCCGAGGACACCGCCGTGTACTACTGCGCCTCCCGGGACTACGACTACGACGGCCGGTACTTCGACTACTGGGGCCAGGGCACCCTGGTGACCGTGTCCTCCGGCGGAGGTGGAAGCGGAGGGGGAGGATCTGGCGGCGGAGGAAGCGGAGGCGACATCCAGATGACCCAGTCCCCCTCCTCCCTGTCCGCCTCCGTGGGCGACCGGGTGACCATCACCTGCTCCGCCTCCTCCTCCGTGACCTACATGTACTGGTACCAGCAGAAGCCCGGCAAGGCCCCCAAGCTGCTGATCTACGACACCTCCAACCTGGCCTCCGGCGTGCCCTCCCGGTTCTCCGGCTCCGGCTCCGGCACCGACTACACCTTCACCATCTCCTCCCTGCAGCCCGAGGACATCGCCACCTACTACTGCCAGCAGTGGTCCTCCCACATCTTCACCTTCGGCCAGGGCACCAAGGTGGAGATCAAG (SEQ ID NO: 146) |
CT-488 EGFR (VH-VL scFv格式): QVQLQESGPGLVKPSETLSLTCTVSGGSVSSGDYYWTWIRQSPGKGLEWIGHIYYSGNTNYNPSLKSRLTISIDTSKTQFSLKLSSVTAADTAIYYCVRDRVTGAFDIWGQGTMVTVSSGGGGSGGGGSGGGGSGGDIQMTQSPSSLSASVGDRVTITCQASQDISNYLNWYQQKPGKAPKLLIYDASNLETGVPSRFSGSGSGTDFTFTISSLQPEDIATYFCQHFDHLPLAFGGGTKVEIK (SEQ ID NO: 17) | CT-488 EGFR: CAGGTGCAGCTGCAGGAGTCCGGCCCCGGCCTGGTGAAGCCCTCCGAGACCCTGTCCCTGACCTGCACCGTGTCCGGCGGCTCCGTGTCCTCCGGCGACTACTACTGGACCTGGATCCGGCAGTCCCCCGGCAAGGGCCTGGAGTGGATCGGCCACATCTACTACTCCGGCAACACCAACTACAACCCCTCCCTGAAGTCCCGGCTGACCATCTCCATCGACACCTCCAAGACCCAGTTCTCCCTGAAGCTGTCCTCCGTGACCGCCGCCGACACCGCCATCTACTACTGCGTGCGGGACCGGGTGACCGGCGCCTTCGACATCTGGGGCCAGGGCACCATGGTGACCGTGTCCTCCGGCGGAGGTGGAAGCGGAGGGGGAGGATCTGGCGGCGGAGGAAGCGGAGGCGACATCCAGATGACCCAGTCCCCCTCCTCCCTGTCCGCCTCCGTGGGCGACCGGGTGACCATCACCTGCCAGGCCTCCCAGGACATCTCCAACTACCTGAACTGGTACCAGCAGAAGCCCGGCAAGGCCCCCAAGCTGCTGATCTACGACGCCTCCAACCTGGAGACCGGCGTGCCCTCCCGGTTCTCCGGCTCCGGCTCCGGCACCGACTTCACCTTCACCATCTCCTCCCTGCAGCCCGAGGACATCGCCACCTACTTCTGCCAGCACTTCGACCACCTGCCCCTGGCCTTCGGCGGCGGCACCAAGGTGGAGATCAAG (SEQ ID NO: 147) |
CT-489 EGFR scFv: QVQLQESGPGLVKPSQTLSLTCTVSGGSISSGDYYWSWIRQPPGKGLEWIGYIYYSGSTDYNPSLKSRVTMSVDTSKNQFSLKVNSVTAADTAVYYCARVSIFGVGTFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGEIVMTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCHQYGSTPLTFGGGTKAEIK (SEQ ID NO: 18) | CAGGTCCAGCTCCAAGAGTCAGGACCAGGTCTGGTCAAACCCTCACAGACGCTCTCTCTTACTTGCACAGTATCAGGCGGATCCATTAGTTCCGGTGATTATTACTGGTCTTGGATCCGCCAGCCTCCTGGTAAGGGGCTGGAGTGGATCGGATACATATACTACAGTGGTTCCACTGATTATAATCCGTCACTCAAGTCCCGAGTAACTATGTCCGTGGATACTAGCAAAAATCAGTTCAGCCTCAAAGTCAATTCCGTAACTGCCGCCGACACCGCGGTCTATTATTGTGCGCGGGTGAGCATCTTCGGCGTCGGTACGTTCGATTACTGGGGACAAGGAACTCTCGTAACAGTAAGCTCTGGCGGAGGTGGAAGCGGAGGGGGAGGATCTGGCGGCGGAGGAAGCGGAGGCGAGATTGTAATGACCCAAAGCCCTGCCACTCTTTCTCTGTCTCCGGGGGAACGAGCGACTCTGTCATGTAGGGCGTCCCAGAGTGTCTCTAGCTACCTCGCATGGTATCAGCAGAAACCCGGACAAGCCCCTCGGCTCTTGATTTACGATGCCTCAAACAGAGCAACGGGGATTCCGGCACGGTTCAGCGGGTCTGGTAGCGGGACAGACTTCACACTGACGATCTCTTCACTCGAACCAGAAGATTTTGCAGTCTACTATTGCCATCAGTATGGTTCTACGCCACTTACATTTGGCGGGGGCACCAAGGCGGAGATAAAA (SEQ ID NO: 148) |
在一些實施例中,活化劑配位體為EGFR或其肽抗原,且活化劑配位體結合結構域包含EGFR結合結構域。在一些實施例中,EGFR配位體結合結構域包含scFv結構域。在一些實施例中,EGFR配位體結合結構域包含SEQ ID NO: 9-18中之任一者之序列。在一些實施例中,EGFR配位體結合結構域包含與SEQ ID NO: 9-18中之任一者至少90%、至少95%或至少99%一致之序列。在一些實施例中,EGFR配位體結合結構域由選自表1中之序列之群的序列編碼。在一些實施例中,EGFR配位體結合結構域由與來自表1之序列具有至少80%一致性、至少85%一致性、至少90%一致性、至少95%一致性或至少99%一致性之序列編碼。應了解,結合EGFR之本揭示案之scFv結構域可與EGFR之一或多個變異體交叉反應。舉例而言,scFv可結合正常EGFR、EGFR變異體或突變EGFR (例如,EGFRvIII)中之至少一者。
在一些實施例中,第一受體之細胞外配位體結合結構域包含與SEQ ID NO: 9-18中之任一者具有至少80%一致性、至少85%一致性、至少90%一致性、至少95%一致性、至少97%一致性或至少99%一致性之scFv抗原結合結構域。在一些實施例中,第一受體之細胞外配位體結合結構域包含含有SEQ ID NO: 9-18中之任一者之序列的ScFv抗原結合結構域。在一些實施例中,第一受體之細胞外配位體結合結構域基本上由選自由SEQ ID NO: 9-18組成之群的序列組成。
表2. EGFR可變重(VH)及可變輕(VL)結構域
EGFR VH | EGFR VL |
CT478、CT479: QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWDDGSYKYYGDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGITMVRGVMKDYFDYWGQGTLVTVSS (SEQ ID NO: 19) | CT478、CT479: AIQLTQSPSSLSASVGDRVTITCRASQDISSALVWYQQKPGKAPKLLIYDASSLESGVPSRFSGSESGTDFTLTISSLQPEDFATYYCQQFNSYPLTFGGGTKVEIK (SEQ ID NO: 25) |
CT480、CT481: QIQLVQSGPELKKPGETVKISCKASGYTFTEYPIHWVKQAPGKGFKWMGMIYTDIGKPTYAEEFKGRFAFSLETSASTAYLQINNLKNEDTATYFCVRDRYDSLFDYWGQGTTLTVSS (SEQ ID NO: 20) | CT480、CT481: DVVMTQTPLSLPVSLGDQASISCRSSQSLVHSNGNTYLHWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPWTFGGGTKLEIK (SEQ ID NO: 26) |
CT482、CT483: EMQLVESGGGFVKPGGSLKLSCAASGFAFSHYDMSWVRQTPKQRLEWVAYIASGGDITYYADTVKGRFTISRDNAQNTLYLQMSSLKSEDTAMFYCSRSSYGNNGDALDFWGQGTSVTVSS (SEQ ID NO: 21) | CT482、CT483: DVVMTQTPLSLPVSLGDQASISCRSSQSLVHSNGNTYLHWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVLTFGSGTKLEIK (SEQ ID NO: 27) |
CT486: QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYEFAYWGQGTLVTVSA (SEQ ID NO: 22) | CT486: DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLELK (SEQ ID NO: 28) |
CT487: QVQLVQSGAEVKKPGASVKVSCKASGYTFTSHWMHWVRQAPGQGLEWIGEFNPSNGRTNYNEKFKSKATMTVDTSTNTAYMELSSLRSEDTAVYYCASRDYDYDGRYFDYWGQGTLVTVSS (SEQ ID NO: 23) | CT487: DIQMTQSPSSLSASVGDRVTITCSASSSVTYMYWYQQKPGKAPKLLIYDTSNLASGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQQWSSHIFTFGQGTKVEIK (SEQ ID NO: 29) |
CT488: QVQLQESGPGLVKPSETLSLTCTVSGGSVSSGDYYWTWIRQSPGKGLEWIGHIYYSGNTNYNPSLKSRLTISIDTSKTQFSLKLSSVTAADTAIYYCVRDRVTGAFDIWGQGTMVTVSS (SEQ ID NO: 24) | CT488: DIQMTQSPSSLSASVGDRVTITCQASQDISNYLNWYQQKPGKAPKLLIYDASNLETGVPSRFSGSGSGTDFTFTISSLQPEDIATYFCQHFDHLPLAFGGGTKVEIK (SEQ ID NO: 30) |
CT489: QVQLQESGPGLVKPSQTLSLTCTVSGGSISSGDYYWSWIRQPPGKGLEWIGYIYYSGSTDYNPSLKSRVTMSVDTSKNQFSLKVNSVTAADTAVYYCARVSIFGVGTFDYWGQGTLVTVSS (SEQ ID NO: 149) | CT: 489: EIVMTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCHQYGSTPLTFGGGTKAEIK (SEQ ID NO: 150) |
在一些實施例中,活化劑配位體為EGFR或其肽抗原,且活化劑配位體結合結構域包含EGFR配位體結合結構域。在一些實施例中,EGFR結合結構域包含選自表2中所揭示之群的VH及/或VL結構域或與其具有至少90%一致性、至少95%一致性、至少97%一致性或至少99%一致性之序列。在一些實施例中,EGFR配位體結合結構域包含選自由SEQ ID NO: 19-24組成之群的VH結構域。在一些實施例中,EGFR配位體結合結構域包含選自由SEQ ID NO: 19-24組成之群的VH或與其具有至少90%、至少95%或至少99%一致性之序列。在一些實施例中,EGFR配位體結合結構域包含選自由SEQ ID NO: 25-30組成之群的VL結構域。在一些實施例中,EGFR配位體結合結構域包含選自由SEQ ID NO: 25-30組成之群的VL或與其具有至少90%、至少95%或至少99%一致性之序列。
表3. EGFR抗原結合結構域CDR.
CDR H1 | CDR H2 | CDR H3 | CDR L1 | CDR L2 | CDR L3 |
TYGMH (SEQ ID NO: 31) | VIWDDGSYKYYGDSVKG (SEQ ID NO: 37) | DGITMVRGVMKDYFDY (SEQ ID NO: 43) | RASQDISSALV (SEQ ID NO: 49) | DASSLES (SEQ ID NO: 55) | QQFNSYPLT (SEQ ID NO: 60) |
EYPIH (SEQ ID NO: 32) | MIYTDIGKPTYAEEFKG (SEQ ID NO: 38) | DRYDSLFDY (SEQ ID NO: 44) | RSSQSLVHSNGNTYLH (SEQ ID NO: 50) | KVSNRFS (SEQ ID NO: 56) | SQSTHVPWT (SEQ ID NO: 61) |
HYDMS (SEQ ID NO: 33) | YIASGGDITYYADTVKG (SEQ ID NO: 39) | SSYGNNGDALDF (SEQ ID NO: 45) | RSSQSLVHSNGNTYLH (SEQ ID NO: 51) | KVSNRFS (SEQ ID NO: 56) | SQSTHVLT (SEQ ID NO: 62) |
NYGVH (SEQ ID NO: 34) | VIWSGGNTDYNTPFTS (SEQ ID NO: 40) | ALTYYDYEFAY (SEQ ID NO: 46) | RASQSIGTNIH (SEQ ID NO: 52) | YASESIS (SEQ ID NO: 57) | QQNNNWPTT (SEQ ID NO: 63) |
SHWMH (SEQ ID NO: 35) | EFNPSNGRTNYNEKFKS (SEQ ID NO: 41) | RDYDYDGRYFDY (SEQ ID NO: 47) | SASSSVTYMY (SEQ ID NO: 53) | DTSNLAS (SEQ ID NO: 58) | QQWSSHIFT (SEQ ID NO: 64) |
SGDYYWT (SEQ ID NO: 36) | HIYYSGNTNYNPSLKS (SEQ ID NO: 42) | DRVTGAFDI (SEQ ID NO: 48) | QASQDISNYLN (SEQ ID NO: 54) | DASNLET (SEQ ID NO: 59) | QHFDHLPLA (SEQ ID NO: 65) |
SGDYYWS (SEQ ID NO: 151) | YIYYSGSTDYNPSLKS (SEQ ID NO: 152) | VSIFGVGTFDY (SEQ ID NO: 153) | RASQSVSSYLA (SEQ ID NO: 154) | DASNRAT (SEQ ID NO: 155) | HQYGSTPLTSEQ ID NO: 156) |
在一些實施例中,活化劑配位體為EGFR或其肽抗原,且活化劑配位體結合結構域為EGFR配位體結合結構域。在一些實施例中,EGFR結合結構域包含選自表3中所揭示之CDR之群的互補決定區(CDR)。在一些實施例中,EGFR配位體結合結構域包含與表3中所揭示之CDR具有至少95%序列一致性之CDR。在一些實施例中,EGFR配位體結合結構域包含選自SEQ ID NO: 31-65之CDR。在一些實施例中,EGFR配位體結合結構域包含選自由SEQ ID NO: 31-36組成之群的重鏈CDR 1 (CDR H1)。在一些實施例中,EGFR配位體結合結構域包含選自由SEQ ID NO: 37-42組成之群的重鏈CDR 2 (CDR H2)。在一些實施例中,EGFR配位體結合結構域包含選自由SEQ ID NO: 43-48組成之群的重鏈CDR 3 (CDR H3)。在一些實施例中,EGFR配位體結合結構域包含選自由SEQ ID NO: 49-54組成之群的輕鏈CDR 1 (CDR L1)。在一些實施例中,EGFR配位體結合結構域包含選自由SEQ ID NO: 55-59組成之群的輕鏈CDR 2 (CDR L2)。在一些實施例中,EGFR配位體結合結構域包含選自由SEQ ID NO: 60-65組成之群的輕鏈CDR 3 (CDR L3)。在一些實施例中,EGFR配位體結合結構域包含選自SEQ ID NO: 31-36之CDR H1、選自SEQ ID NO: 37-42之CDR H2、選自SEQ ID NO: 43-48之CDR H3、選自SEQ ID NO: 49-54之CDR L1、選自SEQ ID NO: 55-59之CDR L2及選自SEQ ID NO: 60-65之CDR L3。
嵌合抗原受體(CAR)
本揭示案提供第一活化劑受體及包含其之免疫細胞。在一些實施例中,第一受體為嵌合抗原受體。
在一些實施例中,第一受體包含SEQ ID NO: 175,或與其共享至少75%、至少80%、至少85%、至少90%、至少95%或至少98%一致性之序列。在一些實施例中,第一受體包含SEQ ID NO: 176,或與其共享至少75%、至少80%、至少85%、至少90%、至少95%或至少98%一致性之序列。在一些實施例中,第一受體包含SEQ ID NO: 177,或與其共享至少75%、至少80%、至少85%、至少90%、至少95%或至少98%一致性之序列。
如本文所用,術語「嵌合抗原受體(CAR)」可指來源於T細胞受體之人工受體且涵蓋將人工特異性移植至特定免疫效應細胞上之工程改造之受體。可採用CAR以將單株抗體之特異性賦予T細胞上,從而允許產生大量特異性T細胞,例如,用於在過繼細胞療法中使用。在特定實施例中,例如,CAR將細胞之特異性導向腫瘤相關抗原。示例性CAR包含細胞內活化結構域、跨膜結構域及包含腫瘤相關抗原結合區之細胞外結構域。在一些實施例中,CAR進一步包含鉸鏈結構域。在特定態樣中,CAR包含來源於單株抗體之單鏈可變片段(scFv)融合至CD3跨膜結構域及內結構域之融合體。其他CAR設計之特異性可來源於受體(例如,肽)之配位體。在某些情況下,CAR包含用於額外共刺激信號傳導之結構域,諸如CD3、4-1BB、FcR、CD27、CD28、CD137、DAP10及/或OX40。在一些情況下,分子可與CAR共表現,該CAR包括共刺激分子、用於成像之報告基因、在添加前藥後有條件地消融T細胞之基因產物、歸巢受體、細胞激素及細胞激素受體。
在一些實施例中,第一受體之細胞外配位體結合結構域融合至CAR之細胞外結構域。
在一些實施例中,本揭示案之CAR包含細胞外鉸鏈區。鉸鏈區之併入可影響自CAR-T細胞之細胞激素產生,且改善活體內CAR-T細胞之擴增。示例性鉸鏈可分離自或來源於IgD及CD8結構域,例如,IgG1。在一些實施例中,鉸鏈分離自或來源於CD8α或CD28。
在一些實施例中,鉸鏈分離自或來源於CD8α或CD28。在一些實施例中,CD8α鉸鏈包含與TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACD (SEQ ID NO: 66)之序列具有至少80%一致性、至少90%一致性、至少95%一致性、至少99%一致性或一致之胺基酸序列。在一些實施例中,CD8α鉸鏈包含SEQ ID NO: 66。在一些實施例中,CD8α鉸鏈基本上由SEQ ID NO: 66組成。在一些實施例中,CD8α鉸鏈由與以下序列具有至少80%一致性、至少90%一致性、至少95%一致性、至少99%一致性或一致之核苷酸序列編碼:
ACCACGACGCCAGCGCCGCGACCACCAACACCGGCGCCCACCATCGCGTCGCAGCCCCTGTCCCTGCGCCCAGAGGCGTGCCGGCCAGCGGCGGGGGGCGCAGTGCACACGAGGGGGCTGGACTTCGCCTGTGAT (SEQ ID NO: 67)。在一些實施例中,CD8α鉸鏈由SEQ ID NO: 67編碼。
在一些實施例中,CD28鉸鏈包含與CTIEVMYPPPYLDNEKSNGTIIHVKGKHLCPSPLFPGPSKP (SEQ ID NO: 68)之序列具有至少80%一致性、至少90%一致性、至少95%一致性、至少99%一致性或一致之胺基酸序列。在一些實施例中,CD28鉸鏈包含或基本上由SEQ ID NO: 68組成。在一些實施例中,CD28鉸鏈由與以下序列具有至少80%一致性、至少90%一致性、至少95%一致性、至少99%一致性或一致之核苷酸序列編碼:TGTACCATTGAAGTTATGTATCCTCCTCCTTACCTAGACAATGAGAAGAGCAATGGAACCATTATCCATGTGAAAGGGAAACACCTTTGTCCAAGTCCCCTATTTCCCGGACCTTCTAAGCCC (SEQ ID NO: 69)。在一些實施例中,CD28鉸鏈由SEQ ID NO: 69編碼。
本揭示案之CAR可經設計以包含融合至CAR之細胞外結構域的跨膜結構域。在一些實施例中,使用與CAR中之結構域中之一者天然相關之跨膜結構域。舉例而言,包含CD28共刺激結構域之CAR可能亦使用CD28跨膜結構域。在一些情況下,跨膜結構域可藉由胺基酸取代來選擇或修飾以避免此類結構域結合至相同或不同表面膜蛋白之跨膜結構域,從而使得與受體複合物之其他成員之相互作用最小化。
跨膜結構域可來源於天然或合成來源。若來源為天然的,則結構域可來源於任何膜結合蛋白或跨膜蛋白。跨膜區可分離自或來源於T細胞受體α、β或ζ鏈、CD28、CD3 ε、CD45、CD4、CD5、CD8、CD9、CD16、CD22、CD33、CD37、CD64、CD80、CD86、CD134、CD137、CD154 (亦即,至少包含其跨膜區),或來自免疫球蛋白,諸如IgG4。或者,跨膜結構域可為合成的,在此種情況下,其將主要包含疏水性殘基,諸如白胺酸及纈胺酸。在一些實施例中,在合成跨膜結構域之各末端將發現苯丙胺酸、色胺酸及纈胺酸之三聯體。視情況,長度較佳在2個與10個胺基酸之間的短寡肽或多肽連接子可形成CAR之跨膜結構域與細胞質信號傳導結構域之間的連接。甘胺酸-絲胺酸雙聯體提供尤其適合之連接子。
在本揭示案之CAR之一些實施例中,CAR包含CD28跨膜結構域。在一些實施例中,CD28跨膜結構域包含與FWVLVVVGGVLACYSLLVTVAFIIFWV (SEQ ID NO: 70)之序列具有至少80%一致性、至少90%一致性、至少95%一致性、至少99%一致性或一致之胺基酸序列。在一些實施例中,CD28跨膜結構域包含或基本上由SEQ ID NO:70組成。在一些實施例中,CD28跨膜結構域由與以下序列具有至少80%一致性、至少90%一致性、至少95%一致性、至少99%一致性或一致之核苷酸序列編碼:
TTCTGGGTGCTGGTCGTTGTGGGCGGCGTGCTGGCCTGCTACAGCCTGCTGGTGACAGTGGCCTTCATCATCTTTTGGGTG (SEQ ID NO: 71)。在一些實施例中,CD28跨膜結構域由SEQ ID NO:71編碼。
在本揭示案之CAR之一些實施例中,CAR包含IL-2Rβ跨膜結構域。在一些實施例中,IL-2Rβ跨膜結構域包含與IPWLGHLLVGLSGAFGFIILVYLLI (SEQ ID NO: 72)之序列具有至少80%一致性、至少90%一致性、至少95%一致性、至少99%一致性或一致之胺基酸序列。在一些實施例中,IL-2Rβ跨膜結構域包含或基本上由SEQ ID NO: 72組成。在一些實施例中,IL-2Rβ跨膜結構域由與以下序列具有至少80%一致性、至少90%一致性、至少95%一致性、至少99%一致性或一致之核苷酸序列編碼:
ATTCCGTGGC TCGGCCACCT CCTCGTGGGC CTCAGCGGGG CTTTTGGCTT CATCATCTTA GTGTACTTGC TGATC (SEQ ID NO: 73)。在一些實施例中,IL-2Rβ跨膜結構域由SEQ ID NO: 73編碼。
本揭示案之CAR之細胞質結構域或其他細胞內信號傳導結構域負責活化CAR已置於其中之免疫細胞之正常效應功能中之至少一者。術語「效應功能」係指細胞之特殊化功能。因此,術語「細胞內信號傳導結構域」係指轉導效應功能信號且指導細胞執行特殊化功能之蛋白質部分。儘管通常可採用整個細胞內信號傳導結構域,但在許多情況下不必要使用整個結構域。就使用細胞內信號傳導結構域之截短部分而言,此種截短部分可用於替代完整鏈,只要其轉導效應功能信號即可。在一些情況下,可組合多個細胞內結構域以達成本揭示案之CAR-T細胞之所需功能。因此,術語細胞內信號傳導結構域意在包括足以轉導效應功能信號之一或多個細胞內信號傳導結構域之任何截短部分。
用於本揭示案之CAR之細胞內信號傳導結構域的實例包括T細胞受體(TCR)之細胞質序列及協同作用以在抗原受體嚙合後啟動信號轉導之共受體,以及此等序列之任何衍生物或變異體及具有相同功能能力之任何合成序列。
因此,本揭示案之CAR之細胞內結構域包含至少一個細胞質活化結構域。在一些實施例中,細胞內活化結構域確保存在活化CAR T細胞之效應功能所必需之T細胞受體(TCR)信號傳導。在一些實施例中,至少一種細胞質活化為CD247分子(CD3ζ)活化結構域、刺激性殺死免疫球蛋白樣受體(KIR) KIR2DS2活化結構域或12 kDa DNAX活化蛋白(DAP12)活化結構域。
在一些實施例中,CD3ζ活化結構域包含與RVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR (SEQ ID NO: 74)之序列具有至少80%一致性、至少90%一致性、至少95%一致性、至少99%一致性或一致之胺基酸序列。在一些實施例中,CD3ζ活化結構域包含或基本上由SEQ ID NO: 74組成。在一些實施例中,CD3ζ活化結構域由與以下序列具有至少80%一致性、至少90%一致性、至少95%一致性、至少99%一致性或一致之核苷酸序列編碼:
AGAGTGAAGTTCAGCAGGAGCGCAGACGCCCCCGCGTACAAGCAGGGCCAGAACCAGCTCTATAACGAGCTCAATCTAGGACGAAGAGAGGAGTACGATGTTTTGGACAAGCGTAGAGGCCGGGACCCTGAGATGGGGGGAAAGCCGAGAAGGAAGAACCCTCAGGAAGGCCTGTACAATGAACTGCAGAAAGATAAGATGGCGGAGGCCTACAGTGAGATTGGGATGAAAGGCGAGCGCCGGAGGGGCAAGGGGCACGATGGCCTTTACCAGGGACTCAGTACAGCCACCAAGGACACCTACGACGCCCTTCACATGCAGGCCCTGCCCCCTCGC (SEQ ID NO: 75)。在一些實施例中,CD3ζ活化結構域由SEQ ID NO: 75編碼。
已知經由單獨TCR產生之信號常常不足以完全活化T細胞且亦需要次級或共刺激信號。因此,T細胞活化可據稱由以下兩類不同之細胞質信號傳導序列介導:經由TCR (初級細胞質信號傳導序列)啟動抗原依賴性初級活化之彼等及以抗原非依賴性方式起作用以提供次級或共刺激信號(次級細胞質信號傳導序列)之彼等。
初級細胞質信號傳導序列以刺激方式或抑制方式調控TCR複合物之初級活化。以刺激方式起作用之初級細胞質信號傳導序列可含有信號傳導基元,稱為基於免疫受體酪胺酸之活化基元或ITAM。在一些實施例中,ITAM含有與白胺酸或異白胺酸由任何兩個其他胺基酸隔開之酪胺酸(YxxL/I) (SEQ ID NO: 157)。在一些實施例中,細胞質結構域含有1、2、3、4或5個ITAM。含有細胞質結構域之示例性ITAM為CD3ζ活化結構域。可用於本揭示案之CAR的含有初級細胞質信號傳導序列之ITAM之其他實例包括來源於TCRζ、FcRγ、FcRβ、CD3γ、CD3δ、CD3ε、CD3ζ、CD5、CD22、CD79a、CD79b及CD66d之彼等。
在一些實施例中,包含單個ITAM之CD3ζ活化結構域包含與RVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLHMQALPPR (SEQ ID NO: 76)之序列具有至少80%一致性、至少90%一致性、至少95%一致性、至少99%一致性或一致之胺基酸序列。在一些實施例中,CD3ζ活化結構域包含SEQ ID NO: 76。在一些實施例中,包含單個ITAM之CD3ζ活化結構域基本上由RVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLHMQALPPR (SEQ ID NO: 76)之胺基酸序列組成。在一些實施例中,包含單個ITAM之CD3ζ活化結構域由與以下序列具有至少80%一致性、至少90%一致性、至少95%一致性、至少99%一致性或一致之核苷酸序列編碼:
CCCCCTCGC (SEQ ID NO: 77)。在一些實施例中,CD3ζ活化結構域由SEQ ID NO: 77編碼。
在一些實施例中,CAR之細胞質結構域可經設計以包含CD3ζ信號傳導結構域本身或與在本揭示案之CAR之情形中適用之任何其他所需細胞質結構域組合。舉例而言,CAR之細胞質結構域可包含CD3ζ鏈部分及共刺激結構域。共刺激結構域係指包含共刺激分子之細胞內結構域之CAR的一部分。共刺激分子為淋巴細胞對抗原之有效反應所需之抗原受體或其配位體以外之細胞表面分子。此類分子之實例包括選自由以下組成之群的共刺激結構域:IL-2Rβ、Fc受體γ (FcRγ)、Fc受體β (FcRβ)、CD3g分子γ (CD3γ)、CD3δ、CD3ε、CD5分子(CD5)、CD22分子(CD22)、CD79a分子(CD79a)、CD79b分子(CD79b)、癌胚抗原相關細胞黏附分子3 (CD66d)、CD27分子(CD27)、CD28分子(CD28)、TNF受體超家族成員9 (4-1BB)、TNF受體超家族成員4 (OX40)、TNF受體超家族成員8 (CD30)、CD40分子(CD40)、程式性細胞死亡1 (PD-1)、可誘導性T細胞共刺激(ICOS)、淋巴細胞功能相關抗原1 (LFA-1)、CD2分子(CD2)、CD7分子(CD7)、TNF超家族成員14 (LIGHT)、殺死細胞凝集素樣受體C2 (NKG2C)及CD276分子(B7-H3)共刺激結構域,或其功能片段。在一些實施例中,本揭示案之CAR之細胞內結構域包含至少一個共刺激結構域。在一些實施例中,共刺激結構域分離自或來源於CD28。
在一些實施例中,本揭示案之CAR之細胞內結構域包含至少一個共刺激結構域。在一些實施例中,共刺激結構域分離自或來源於CD28。在一些實施例中,CD28共刺激結構域包含與以下序列具有至少80%一致性、至少90%一致性、至少95%一致性、至少99%一致性或一致之胺基酸序列:
RSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS (SEQ ID NO: 78)。在一些實施例中,CD28共刺激結構域包含或基本上由SEQ ID NO: 78組成。在一些實施例中,CD28共刺激結構域由與以下序列具有至少80%一致性、至少90%一致性、至少95%一致性、至少99%一致性或一致之核苷酸序列編碼:
AGGAGCAAGCGGAGCAGACTGCTGCACAGCGACTACATGAACATGACCCCCCGGAGGCCTGGCCCCACCCGGAAGCACTACCAGCCCTACGCCCCTCCCAGGGATTTCGCCGCCTACCGGAGC (SEQ ID NO: 79)。在一些實施例中,CD28共刺激結構域由SEQ ID NO:79編碼。本揭示案之CAR之細胞質信號傳導部分內之細胞質結構域可依隨機或指定次序彼此連接。視情況,長度例如在2個與10個胺基酸之間的短寡肽或多肽連接子可形成連接。甘胺酸-絲胺酸雙聯體提供適合連接子之實例。
在一些實施例中,共刺激結構域分離自或來源於4-1BB。在一些實施例中,4-1BB共刺激結構域包含與KRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL (SEQ ID NO: 159)之序列具有至少80%一致性、至少90%一致性、至少95%一致性、至少99%一致性或一致之胺基酸序列。在一些實施例中,4-1BB共刺激結構域包含或基本上由KRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL (SEQ ID NO: 159)組成。在一些實施例中,4-1BB共刺激結構域由與aaacggggcagaaagaaactcctgtatatattcaaacaaccatttatgaggccagtacaaactactcaagaggaagatggctgtagctgccgatttccagaagaagaagaaggaggatgtgaactg (SEQ ID NO: 160)具有至少80%一致性、至少90%一致性、至少95%一致性、至少99%一致性或一致之核苷酸序列編碼。
在一些實施例中,CAR之細胞內結構域包含CD28共刺激結構域、4-1BB共刺激結構域及CD3ζ活化結構域。在一些實施例中,CAR之細胞內結構域包含RSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR (SEQ ID NO: 158)之序列,或與其具有至少80%一致性、至少90%一致性、至少95%一致性、至少99%一致性之序列。
本揭示案之CAR之細胞質信號傳導部分內之細胞質結構域可依隨機或指定次序彼此連接。視情況,長度例如在2個與10個胺基酸之間的短寡肽或多肽連接子可形成連接。甘胺酸-絲胺酸雙聯體提供適合連接子之實例。示例性連接子包含GGGGSGGGGSGGGGSGG (SEQ ID NO: 136)之序列。
本揭示案之CAR之細胞質信號傳導部分內之細胞質結構域可依隨機或指定次序彼此連接。視情況,長度例如在2個與10個胺基酸之間的短寡肽或多肽連接子可形成連接。甘胺酸-絲胺酸雙聯體提供適合連接子之實例。
T細胞受體(TCR)
本揭示案提供第一活化劑受體及包含其之免疫細胞。在一些實施例中,第一受體為T細胞受體(TCR)。
用於本揭示案之包含細胞內結構域之示例性TCR描述於2020年9月6日申請之PCT/US2020/045250中,其內容以引用之方式併入本文中。
如本文所用,「TCR」,有時亦稱為「TCR複合物」或 「TCR/CD3複合物」係指包含TCR α鏈、TCR β鏈、及非變異CD3鏈(ζ、γ、δ及ε)中之一或多者,有時稱作次單元的蛋白質複合物。TCR α及β鏈可經二硫鍵連接以充當異二聚體結合至肽-MHC複合物。一旦TCR α/β異二聚體嚙合肽-MHC,即誘導相關非變異CD3次單元中之TCR複合物的構形變化,促使其磷酸化且與下游蛋白質相關,從而轉導初級刺激信號。在示例性TCR複合物中,TCR α及TCR β多肽形成異二聚體,CD3 ε及CD3 δ形成異二聚體,CD3 ε及CD3 γ形成異二聚體,且兩個CD3 ζ形成同二聚體。
任何適合之配位體結合結構域可融合至本文所述之TCR之細胞外結構域、鉸鏈結構域或跨膜。舉例而言,配位體結合結構域可為抗體或TCR之抗原結合結構域,或包含抗體片段、僅Vβ結構域、線性抗體、單鏈可變片段(scFv)或單結構域抗體(sdAb)。
在一些實施例中,配位體結合結構域融合至一或多個TCR次單元之一或多個細胞外結構域或跨膜結構域。TCR次單元可為TCR α、TCR β、CD3 δ、CD3 ε、CD3 γ或CD3 ζ。舉例而言,配位體結合結構域可融合至TCR α或TCR β,或配位體結合之部分可融合至兩個次單元,例如,配位體結合結構域之部分可融合至TCR α及TCR β兩者。
TCR次單元包括TCR α、TCR β、CD3 ζ、CD3 δ、CD3 γ及CD3 ε。TCR α、TCR β鏈、CD3 γ、CD3 δ、CD3 ε或CD3 ζ或其片段或衍生物中之任何一或多者可融合至一或多個能夠提供本揭示案之刺激信號的結構域,從而增強TCR功能及活性。
設想分離自或來源於任何來源之TCR跨膜結構域在本揭示案之範疇內。跨膜結構域可來源於天然或重組來源。若來源為天然的,則結構域可來源於任何膜結合蛋白或跨膜蛋白。
在一些實施例中,每當TCR複合物已結合至標靶時,跨膜結構域能夠向細胞內結構域傳導信號。在本揭示案中特定使用之跨膜結構域可至少包括例如TCR α、β或ζ鏈、CD3 δ、CD3 ε或CD3 γ、CD28、CD3 ε、CD45、CD4、CD5、CD8、CD9、CD16、CD22、CD33、CD37、CD64、CD80、CD86、CD134、CD137、CD154之跨膜區。
在一些實施例中,跨膜結構域可經由鉸鏈,例如來自人類蛋白質之鉸鏈附接至TCR多肽之細胞外區,例如TCR α或β鏈之抗原結合結構域。舉例而言,鉸鏈可為人類免疫球蛋白(Ig)鉸鏈,例如,IgG4鉸鏈或CD8a鉸鏈。在一些實施例中,鉸鏈分離自或來源於CD8α或CD28。
在一些實施例中,細胞外配位體結合結構域附接至TCR之一或多個跨膜結構域。在一些實施例中,跨膜結構域包括TCR α跨膜結構域、TCR β跨膜結構域或兩者。在一些實施例中,跨膜包括CD3 ζ跨膜結構域。
跨膜結構域可包括與跨膜區相鄰之一或多個額外胺基酸,例如,與跨膜所來源之蛋白質之細胞外區相關的一或多個胺基酸(例如,細胞外區之1、2、3、4、5、6、7、8、9、10個或至多15個胺基酸)及/或與跨膜蛋白所來源之蛋白質之細胞內區相關的一或多個額外胺基酸(例如,細胞內區之1、2、3、4、5、6、7、8、9、10個或至多15個胺基酸)。
在一些實施例下,跨膜結構域可藉由胺基酸取代來選擇或修飾以避免此類結構域結合至相同或不同表面膜蛋白之跨膜結構域,例如,從而使得與受體複合物之其他成員之相互作用最小化。
當存在時,跨膜結構域可為天然TCR跨膜結構域、來自異源膜蛋白之天然跨膜結構域、或人工跨膜結構域。跨膜結構域可為膜錨定結構域。非限制性地,天然或人工跨膜結構域可包含約20個胺基酸之疏水a-螺旋,常常在跨膜區段側翼帶有正電荷。跨膜結構域可具有一個跨膜片段或多於一個跨膜片段。可使用公開可用之預測工具(例如TMHMM,Krogh等人 Journal of Molecular Biology 2001; 305(3):567-580;或TMpred, Hofmann及Stoffel Biol. Chem. Hoppe-Seyler 1993; 347: 166)作出跨膜結構域/區段之預測。膜錨定系統之非限制性實例包括血小板源性生長因子受體(PDGFR)跨膜結構域、糖基磷脂醯肌醇(GPI)錨定(轉譯後添加至信號序列)及類似物。
在一些實施例中,跨膜結構域包括TCR α跨膜結構域。在一些實施例中,TCR α跨膜結構域包含與以下序列具有至少85%一致性、至少90%一致性、至少95%一致性、至少96%一致性、至少97%一致性、至少98%一致性、至少99%一致性或一致之胺基酸序列:VIGFRILLLKVAGFNLLMTLRLW (SEQ ID NO: 80)。在一些實施例中,TCR α跨膜結構域包含或基本上由SEQ ID NO: 80組成。在一些實施例中,TCR α跨膜結構域由以下序列編碼:
GTGATTGGGTTCCGAATCCTCCTCCTGAAAGTGGCCGGGTTTAATCTGCTCATGACGCTGCGGCTGTGG (SEQ ID NO: 81)。
在一些實施例中,跨膜結構域包括TCR β跨膜結構域。在一些實施例中,TCR β跨膜結構域包含與以下序列具有至少85%一致性、至少90%一致性、至少95%一致性、至少96%一致性、至少97%一致性、至少98%一致性、至少99%一致性或一致之胺基酸序列:TILYEILLGKATLYAVLVSALVL (SEQ ID NO: 82)。在一些實施例中,TCR β跨膜結構域包含或基本上由SEQ ID NO: 82組成。在一些實施例中,TCR β跨膜結構域由以下序列編碼:
ACCATCCTCTATGAGATCTTGCTAGGGAAGGCCACCTTGTATGCCGTGCTGGTCAGTGCCCTCGTGCTG (SEQ ID NO: 83)。
本揭示案之TCR可包含一或多個細胞內結構域。在一些實施例中,細胞內結構域包含一或多個能夠向跨膜結構域提供刺激信號之結構域。在一些實施例中,細胞內結構域包含能夠提供刺激信號之第一細胞內結構域及能夠提供刺激信號之第二細胞內結構域。在其他實施例中,細胞內結構域包含能夠提供刺激信號之第一、第二及第三細胞內結構域。能夠提供刺激信號之細胞內結構域係選自由以下組成之群:CD28分子(CD28)結構域、LCK原癌基因、Src家族酪胺酸激酶(Lck)結構域、TNF受體超家族成員9 (4-1BB)結構域、TNF受體超家族成員18 (GITR)結構域、CD4分子(CD4)結構域、CD8a分子(CD8a)結構域、FYN原癌基因、Src家族酪胺酸激酶(Fyn)結構域、T細胞受體相關蛋白激酶70 ζ鏈(ZAP70)結構域、T細胞活化連接子(LAT)結構域、淋巴細胞胞質蛋白 2 (SLP76)結構域、(TCR) α、TCR β、CD3 δ、CD3 γ及CD3 ε細胞內結構域。
在一些實施例中,細胞內結構域包含至少一個細胞內信號傳導結構域。細胞內信號傳導結構域產生促進細胞功能之信號,例如,含有TCR之細胞,例如表現TCR之T細胞的免疫效應功能。在一些實施例中,本揭示案之第一受體之細胞內結構域包括至少一個細胞內信號傳導結構域。舉例而言,CD3 γ、δ或ε之細胞內結構域包含信號傳導結構域。
在一些實施例中,細胞外結構域、跨膜結構域及細胞內結構域分離自或來源於相同蛋白質,例如,T細胞受體(TCR) α、TCR β、CD3 δ、CD3 γ、CD3 ε或CD3 ζ。
用於本揭示案之活化劑受體之細胞內結構域的實例包括TCR α、TCR β、CD3 ζ及4-1BB之細胞質序列及協同作用以在抗原受體嚙合後啟動信號轉導之細胞內信號傳導共受體,以及此等序列之任何衍生物或變異體及具有相同功能能力之任何重組序列。
在一些實施例中,細胞內信號傳導結構域包括初級細胞內信號傳導結構域。示例性初級細胞內信號傳導結構域包括來源於負責初級刺激或抗原依賴性刺激之蛋白質的彼等。
在一些實施例中,細胞內結構域包括CD3 δ細胞內結構域、CD3 ε細胞內結構域、CD3 γ細胞內結構域、CD3 ζ細胞內結構域、TCR α細胞內結構域或TCR β細胞內結構域。
在一些實施例中,細胞內結構域包括TCR α細胞內結構域。在一些實施例中,TCR α細胞內結構域包含Ser-Ser。在一些實施例中,TCR α細胞內結構域由TCCAGC之序列編碼。
在一些實施例中,細胞內結構域包括TCR β細胞內結構域。在一些實施例中,TCR β細胞內結構域包含與以下序列具有至少80%一致性、至少90%一致性或一致之胺基酸序列:MAMVKRKDSR (SEQ ID NO: 84)。在一些實施例中,TCR β細胞內結構域包含或基本上由SEQ ID NO: 84組成。在一些實施例中,TCR β細胞內結構域由以下序列編碼:
ATGGCCATGGTCAAGAGAAAGGATTCCAGA (SEQ ID NO: 85)。
在一些實施例中,細胞內信號傳導結構域包括至少一個刺激性細胞內結構域。在一些實施例中,細胞內信號傳導結構域包括初級細胞內信號傳導結構域,諸如CD3 δ、CD3 γ及CD3 ε細胞內結構域,及一個額外刺激性細胞內結構域,例如共刺激結構域。在一些實施例中,細胞內信號傳導結構域包括初級細胞內信號傳導結構域,諸如CD3 δ、CD3 γ及CD3 ε細胞內結構域,及兩個額外刺激性細胞內結構域。
示例性共刺激細胞內信號傳導結構域包括來源於負責共刺激信號或抗原非依賴性刺激之蛋白質的彼等。共刺激分子包括但不限於MHC I類分子、BTLA、Toll配位體受體,以及DAP10、DAP12、CD30、LIGHT、OX40、CD2、CD27、CDS、ICAM-1、LFA-1 (CD11a/CD18) 4-1BB (CD137,TNF受體超家族成員9)及CD28分子(CD28)。共刺激蛋白可在以下蛋白質家族中代表:TNF受體蛋白、免疫球蛋白樣蛋白、細胞激素受體、整聯蛋白、信號傳導淋巴細胞活化分子(SLAM蛋白)及活化NK細胞受體。此類分子之實例包括CD27、CD28、4-1BB (CD137)、OX40、GITR、CD30、CD40、ICOS、BAFFR、HVEM、淋巴細胞功能相關抗原1 (LFA-1)、CD2、CD7、LIGHT、NKG2C、SLAMF7、NKp80、CD160、B7-H3、與CD83、CD4及類似物特異性結合之配位體。共刺激結構域可包含其所來源之分子之整個細胞內部分或整個原生細胞內信號傳導結構域,或其功能片段。
在一些實施例中,刺激結構域包括共刺激結構域。在一些實施例中,共刺激結構域包括CD28或4-1BB共刺激結構域。CD28及4-1BB為完全T細胞活化所需且已知增強T細胞效應功能之充分表徵之共刺激分子。舉例而言,CD28及4-1BB已用於嵌合抗原受體(CAR)中,以加強細胞激素釋放、細胞溶解功能及僅含有CD3 ζ信號傳導結構域之第一代CAR的持久性。同樣地,在TCR中包括共刺激結構域,例如CD28及4-1BB結構域可增加T細胞效應功能,且特定地允許在不存在共刺激配位體之情況下進行共刺激,該共刺激配位體在腫瘤細胞表面上典型地下調。在一些實施例中,刺激結構域包括CD28細胞內結構域或4-1BB細胞內結構域。
抑制性受體
本揭示案提供第二受體,該第二受體包含對癌細胞中已損失之非靶抗原(諸如基因之對偶基因變異體)具有特異性之細胞外配位體結合結構域。非靶對偶基因變異體可經由任何機制在癌細胞中損失,諸如但不限於影響非靶對偶基因變異體表現之表觀遺傳變化、編碼非靶對偶基因變異體之基因的突變、調控非靶對偶基因變異體表現之細胞信號傳導的破壞、染色體損失、基因體基因座之部分或完全缺失、經由核酸或異染色質修飾引起之基因靜默,或經由其他機制引起之表現損失。在本文所揭示之組合物及方法之變型中,所治療之細胞或個體可能由於非遺傳變化而展現非靶對偶基因變異體之表現損失。因此,本揭示案提供用於殺死細胞及/或治療因任何原因缺乏非靶抗原表現之個體的組合物及方法 ,該原因包括但不限於雜合性損失。
非靶抗原可為蛋白質或與主要組織相容性複合物I類(MHC-I)複合之其抗原肽,其中非靶抗原包含多態性。由於非靶抗原為多態的,因此可能經由癌細胞中之雜合性損失而發生之編碼非靶抗原之基因之單個複本損失會產生保留基因之其他多態變異體,但已損失非靶抗原之癌細胞。舉例而言,在HLA基因座處具有HLA-A*02及HLA-A*01對偶基因之個體可能患有僅損失HLA-A*02對偶基因之癌症。在此種個體中,HLA-A*01蛋白質仍存在,但不由遭遇癌細胞之免疫細胞之抑制性受體識別,此係因為抑制性受體經設計以對HLA-A*02 (或其他非靶抗原)具有特異性。在正常非惡性細胞中,HLA-A*02 (或其他非靶抗原)存在且抑制工程改造之免疫細胞之活化。在雜合性損失之癌細胞中,HLA-A*02對偶基因變異體(或其他非靶抗原)損失。經工程改造以表現抑制性受體之免疫細胞不會自抑制性受體接收抑制性信號,此係因為抑制性受體僅對癌細胞上不存在之HLA-A*02 (或其他非靶抗原)作出反應。藉由此種機制,免疫細胞經選擇性活化,且選擇性殺死表現EGFR但由於雜合性損失已損失HLA-A*02 (或其他非靶抗原)之癌細胞。此處以HLA-A為例。類似多態變異在群體中其他MHC基因處以及其他非MHC基因中發生。因此,在一些實施例中,非靶抗原包含COLEC12、APCDD1或CXCL16之多態變異體,或HLA-A*02。在一些實施例中,非靶抗原為HLA I類對偶基因或次要組織相容性抗原(MiHA)。在一些實施例中,HLA I類對偶基因包括HLA-A、HLA-B、HLA-C或HLA-E。在一些實施例中,HLA I類對偶基因為HLA-A*02。在一些實施例中,HLA-A*02非靶抗原由個體之健康細胞表現。在一些實施例中,非靶抗原為非靶對偶基因變異體。在一些實施例中,非靶抗原不在個體之癌細胞中表現。在一些實施例中,非靶抗原不在個體腫瘤中之一部分細胞中表現。在一些實施例中,個體中之癌細胞已損失非靶抗原之表現。細胞中非靶抗原之表現損失或表現缺乏可由任何機制所致,諸如但不限於影響非靶基因表現之表觀遺傳變化、編碼非靶抗原之基因的突變,或調控非靶基因表現之細胞信號傳導的破壞。
在一些實施例中,第二受體為抑制性嵌合抗原受體(亦即,抑制性受體)。在一些實施例中,第二受體為抑制性受體。在一些實施例中,第二受體為人源化的。
在一些實施例中,第二受體包含SEQ ID NO: 173,或與其共享至少75%、至少80%、至少85%、至少90%、至少95%或至少98%一致性之序列。在一些實施例中,174或與其共享至少75%、至少80%、至少85%、至少90%、至少95%或至少98%一致性之序列。
本揭示案提供第二受體,該第二受體為抑制性受體,其包含可區分非靶抗原之單個胺基酸變異體對偶基因之細胞外配位體結合。區分非靶抗原之對偶基因變異體之此種能力允許第二受體在表現由配位體結合結構域識別之對偶基因之非靶細胞存在下抑制包含第二受體之免疫細胞的活化。然而,在已損失對偶基因之靶細胞,例如經由雜合性損失已損失基因之一個對偶基因的癌細胞存在下,免疫細胞之活化不受抑制。
本揭示案提供第二受體,該第二受體為抑制性受體,其包含可區分非靶抗原之不同表現水準之細胞外配位體結合。此允許第二受體在表現第二受體之配位體之非靶細胞存在下抑制包含第二受體之免疫細胞的活化,但允許在表現低水準或不表現第二受體之配位體的癌細胞存在下活化免疫細胞。
抑制劑配位體
在一些實施例中,非靶抗原不由靶細胞表現,且由非靶細胞表現。在一些實施例中,非靶抗原由健康細胞,亦即,並非癌細胞之細胞表現。在一些實施例中,靶細胞為經由雜合性損失(LOH)已損失非靶抗原表現之複數個癌細胞。在一些實施例中,非靶細胞為表現靶抗原及非靶抗原兩者之複數個健康細胞(亦即,非癌細胞)。
由非靶細胞表現但不由靶細胞表現之任何細胞表面分子可為第二受體細胞外配位體結合結構域之適合非靶抗原。舉例而言,細胞黏附分子、細胞-細胞信號傳導分子、細胞外結構域、參與趨化性之分子、醣蛋白、G蛋白偶聯受體、跨膜、神經傳遞質受體或電位閘控離子通道可用作非靶抗原。
在一些實施例中,靶抗原為與主要組織相容性複合物I類(MHC-I)複合之癌細胞特異性抗原之肽抗原。
在一些實施例中,由於雜合性損失,在癌細胞中損失非靶抗原。由於雜合性損失而在癌細胞中損失之示例性非靶抗原包括COLEC12、APCDD1、CXCL16及HLA-A*02。在一些實施例中,非靶抗原係選自由以下組成之群:COLEC12、APCDD1及CXCL166之多態變異體,或與主要組織相容性複合物I類(MHC-I)複合之其肽抗原,或HLA-A*02。在一些實施例中,非靶抗原為與主要組織相容性複合物I類(MHC-I)複合之包含COLEC12、APCDD1及CXCL16之多態殘基的抗原肽。
設想包含HLA-A、HLA-B或HLA-C中之任一者的非靶MHC-1 (MHC)抗原在本揭示案之範疇內。在一些實施例中,非靶抗原包括HLA-A。在一些實施例中,非靶抗原包括人類白血球抗原A*02對偶基因產物(HLA-A*02)。在一些實施例中,非靶抗原包括人類白血球抗原A*69。在一些實施例中,非靶抗原包括HLA-B。在一些實施例中,非靶抗原包括HLA-C。
在一些實施例中,非靶抗原包括HLA-A*02。
在一些實施例中,非靶抗原包含C-X-C基元趨化激素配位體16 (CXCL16)或與MHC-I複合之其抗原肽。人類CXCL16前體描述於NCBI記錄號NP_001094282.1中,其內容以全文引用之方式併入本文中。在一些實施例中,CXCL16包含以下胺基酸序列:
在一些實施例中,非靶抗原包含CXCL16之多態性。舉例而言,非靶抗原包含來源於CXCL16之肽,該肽包含CXCL16之多態殘基。CXCL16之多態殘基包括SEQ ID NO: 86之位置142及200。在一些實施例中,非靶抗原包含含有SEQ ID NO: 86之胺基酸142或200的CXCL16之肽。在一些實施例中,非靶抗原包含含有SEQ ID NO: 86之胺基酸200處之A的CXCL16之肽。在一些實施例中,非靶抗原包含含有SEQ ID NO: 86之胺基酸200處之V的CXCL16之肽。在一些實施例中,非靶抗原包含含有SEQ ID NO: 86之胺基酸142處之I的CXCL16之肽。在一些實施例中,非靶抗原包含含有SEQ ID NO: 86之胺基酸142處之T的CXCL16之肽。
在一些實施例中,非靶抗原包含CXCL16之多態性。在一些實施例中,非靶抗原包含在SEQ ID NO: 86之胺基酸200處包含A的CXCL16之肽,且第二受體包含對在SEQ ID NO: 86之位置200處具有A之CXCL16配位體具有比在SEQ ID NO: 86之位置200處具有V之CXCL16配位體更高之親和力的配位體結合結構域。在一些實施例中,非靶抗原包含在SEQ ID NO: 86之胺基酸200處包含V的CXCL16之肽,且第二受體包含對在SEQ ID NO: 86之位置200處具有V之CXCL16配位體具有比在SEQ ID NO: 86之位置200處具有A之CXCL16配位體更高之親和力的配位體結合結構域。在一些實施例中,非靶抗原包含在SEQ ID NO: 86之胺基酸142處包含I的CXCL16之肽,且第二受體包含對在SEQ ID NO: 86之位置142處具有I之CXCL16配位體具有比在SEQ ID NO: 86之位置142處具有T之CXCL16配位體更高之親和力的配位體結合結構域。在一些實施例中,非靶抗原包含在SEQ ID NO: 86之胺基酸142處包含T的CXCL16之肽,且第二受體包含對在SEQ ID NO: 86之位置142處具有T之CXCL16配位體具有比在SEQ ID NO: 86之位置142處具有I之CXCL16配位體更高之親和力的配位體結合結構域。
在一些實施例中,非靶抗原包含膠原凝集素亞家族成員12 (COLEC12)或與MHC-I複合之其抗原肽。人類COLEC12描述於NCBI記錄號NP_569057.2中,其內容以全文引用之方式併入本文中。在一些實施例中,COLEC12包含以下胺基酸序列:
在一些實施例中,非靶抗原包含COLEC12之多態性。舉例而言,非靶抗原包含來源於COLEC12之肽,該肽包含COLEC12之多態殘基。COLEC12之多態殘基包括SEQ ID NO: 87之位置522。在一些實施例中,非靶抗原包含含有SEQ ID NO: 87之胺基酸522的COLEC12之肽。在一些實施例中,非靶抗原包含含有SEQ ID NO: 87之胺基酸522處之S的COLEC12之肽。在一些實施例中,非靶抗原包含含有SEQ ID NO: 87之胺基酸522處之P的COLEC12之肽。
在一些實施例中,非靶抗原包含APC下調1 (APCDD1)或與MHC-I複合之其抗原肽。示例性人類APCDD1描述於UniProtKB記錄號Q8J025中,其內容以全文引用之方式併入本文中。在一些實施例中,APCDD1包含以下胺基酸序列:
在一些實施例中,非靶抗原包含APCDD1之多態性。APCDD1之示例性多態性包括rs3748415,其可為SEQ ID NO: 88之位置150處之V、I或L。在一些實施例中,非靶抗原包含含有SEQ ID NO: 88之胺基酸150的APCDD1之肽。在一些實施例中,非靶抗原包含含有SEQ ID NO: 88之胺基酸150處之V的APCDD1之肽。在一些實施例中,非靶抗原包含含有SEQ ID NO: 88之胺基酸150處之I的APCDD1之肽。在一些實施例中,非靶抗原包含含有SEQ ID NO: 88之胺基酸150處之L的APCDD1之肽。
APCDD1之示例性多態性包括rs1786683,其可為SEQ ID NO: 133之位置165處之Y或S。在一些實施例中,非靶抗原包含含有SEQ ID NO: 134之胺基酸165的APCDD1之肽。在一些實施例中,非靶抗原包含含有SEQ ID NO: 134之胺基酸165處之Y的APCDD1之肽。在一些實施例中,非靶抗原包含含有SEQ ID NO: 134之胺基酸165處之S的APCDD1之肽。
APCDD1之示例性多態性包括rs9952598,其可為SEQ ID NO: 135之位置28處之Q或R。在一些實施例中,非靶抗原包含含有SEQ ID NO: 135之胺基酸28的APCDD1之肽。在一些實施例中,非靶抗原包含含有SEQ ID NO: 135之胺基酸28處之Q的APCDD1之肽。在一些實施例中,非靶抗原包含含有SEQ ID NO: 135之胺基酸28處之R的APCDD1之肽。
在一些實施例中,APCDD1包含與SEQ ID NO: 88或134-135中之任一者共享至少80%、至少85%、至少90%、至少95%、至少94%、至少97%、至少98%或至少99%一致性之序列。APCDD1之多態殘基在SEQ ID NO: 88或134-135中標記為粗體且加下劃線。
在一些實施例中,非靶抗原包括HLA-A*02。結合至並識別HLA-A*02的此項技術中已知或本文所揭示之各種單可變結構域適合用於實施例中。
在一些實施例中,非靶抗原包括HLA-B*07。結合至並識別HLA-B*07的此項技術中已知或本文所揭示之各種單可變結構域適合用於實施例中。
在一些實施例中,非靶抗原包括HLA-A*11。結合至並識別HLA-A*11的此項技術中已知或本文所揭示之各種單可變結構域適合用於實施例中。
在一些實施例中,非靶抗原包括HLA-A*01。結合至並識別HLA-A*01的此項技術中已知或本文所揭示之各種單可變結構域適合用於實施例中。
在一些實施例中,非靶抗原包括HLA-A*03。結合至並識別HLA-A*03的此項技術中已知或本文所揭示之各種單可變結構域適合用於實施例中。
在一些實施例中,非靶抗原包括HLA-C*07。結合至並識別HLA-C*07的此項技術中已知或本文所揭示之各種單可變結構域適合用於實施例中。
此類scFv包括例如且不限於以肽非依賴性方式結合非靶抗原(例如,HLA-A*02、HLA-A*01、HLA-A*03、HLA-A*11、HLA-B*07或HLA-C*07)之以下小鼠及人源化scFv抗體,如下表4中所示(在指示之處,互補決定區加下劃線):
表4. scFv結合結構域
HLA-A*02 抗原結合結構域 | |
C-001765 PA2.1 scFv (小鼠) | DVLMTQTPLSLPVSLGDQASISC RSSQSIVHSNGNTYLEWYLQKPGQSPKLLIY KVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYYC FQGSHVPRTSGGGTKLEIKGGGGSGGGGSGGGGSGGQVQLQQSGPELVKPGASVRISCK ASGYTFTSYHIHWVKQRPGQGLEWIG WIYPGNVNTEYNEKFKGKATLTADKSSSTAYMHLSSLTSEDSAVYFCAR EEITYAMDYWGQGTSVTVSS (SEQ ID NO: 89) |
C-002159 PA2.1.8 scFv (人源化) | QVQLVQSGAEVKKPGSSVKVSCK ASGYTFTSYHIHWVRQAPGQGLEWMG WIYPGNVNTEYNEKFKGKATITADKSTSTAYMELSSLRSEDTAVYYCAR EEITYAMDYWGQGTTVTVSSGGGGSGGGGSGGGGSGGEIVLTQSPGTLSLSPGERATLSC RSSQSIVHSNGNTYLEWYQQKPGQAPRLLIY KVSNRFSGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYC FQGSHVPRTFGGGTKVEIK (SEQ ID NO: 90) |
C-002160 PA2.1.9 scFv (人源化) | C-002160 PA2.1.9 scFv (人源化): QVQLVQSGAEVKKPGSSVKVSCK ASGYTFTSYHIHWVRQAPGQGLEWMG WIYPGNVNTEYNEKFKGKATITADKSTSTAYMELSSLRSEDTAVYYCAR EEITYAMDYWGQGTTVTVSSGGGGSGGGGSGGGGSGGDIVMTQTPLSLPVTPGEPASISC RSSQSIVHSNGNTYLEWYLQKPGQSPQLLIY KVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYC FQGSHVPRTFGGGTKVEIK (SEQ ID NO: 91) |
C-002161 PA2.1.10 scFv (人源化) | EVQLVESGGGLVKPGGSLRLSCA ASGYTFTSYHIHWVRQAPGKGLEWVG WIYPGNVNTEYNEKFKGRFTISRDDSKNTLYLQMNSLKTEDTAVYYCAR EEITYAMDYWGQGTTVTVSSGGGGSGGGGSGGGGSGGDIQMTQSPSSLSASVGDRVTITC RSSQSIVHSNGNTYLEWYQQKPGKAPKLLIY KVSNRFSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYC FQGSHVPRTFGGGTKVEIK (SEQ ID NO: 92) |
C-002162 PA2.1.14 scFv (人源化) | QVQLVQSGAEVKKPGSSVKVSCK ASGYTFTSYHIHWVRQAPGQGLEWIG WIYPGNVNTEYNEKFKGKATITADESTNTAYMELSSLRSEDTAVYYCAR EEITYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGDIQMTQSPSTLSASVGDRVTITC RSSQSIVHSNGNTYLEWYQQKPGKAPKLLIY KVSNRFSGVPARFSGSGSGTEFTLTISSLQPDDFATYYC FQGSHVPRTFGQGTKVEVK (SEQ ID NO: 93) |
C-002163 PA2.1.18 scFv (人源化) | QVQLVQSGAEVKKPGSSVKVSCKA SGYTFTSYHMHWVRQAPGQGLEWIG YIYPGNVNTEYNEKFKGKATLTADKSTNTAYMELSSLRSEDTAVYFCAR EEITYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGDVQMTQSPSTLSASVGDRVTITC SSSQSIVHSNGNTYMEWYQQKPGKAPKLLIY KVSNRFSGVPDRFSGSGSGTEFTLTISSLQPDDFATYYC HQGSHVPRTFGQGTKVEVK (SEQ ID NO: 94) |
來源於 BB7.2 mAb 之 HLA-A*02 抗原結合結構域 | |
C-002164 BB7.2 scFv (小鼠): | QVQLQQSGPELVKPGASVKMSCKA SGYTFTSYHIQWVKQRPGQGLEWIG WIYPGDGSTQYNEKFKGKTTLTADKSSSTAYMLLSSLTSEDSAIYFCAR EGTYYAMDYWGQGTSVTVSSGGGGSGGGGSGGGGSGGDVLMTQTPLSLPVSLGDQVSISC RSSQSIVHSNGNTYLEWYLQKPGQSPKLLIY KVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYYC FQGSHVPRTFGGGTKLEIK (SEQ ID NO: 95) |
C-002165 BB7.2.1 scFv (人源化) | QLQLQESGPGLVKPSETLSLTCTV SGYTFTSYHIQWIRQPPGKGLEWIG WIYPGDGSTQYNEKFKGRATISVDTSKNQFSLNLDSVSAADTAIYYCAR EGTYYAMDYWGKGSTVTVSSGGGGSGGGGSGGGGSGGDIQMTQSPSSLSASVGDRVTITC RSSQSIVHSNGNTYLEWYQQKPGKAPKLLIY KVSNRFSGVPSRFSGSGSGTDFTFTISSLQPEDIATYYC FQGSHVPRTFGPGTKVDIK (SEQ ID NO: 96) |
C-002166 BB7.2.2 scFv (人源化) | EVQLVQSGAELKKPGSSVKVSCKA SGYTFTSYHIQWVKQAPGQGLEWIG WIYPGDGSTQYNEKFKGKATLTVDKSTNTAYMELSSLRSEDTAVYYCAR EGTYYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGDIQMTQSPSTLSASVGDRVTITC RSSQSIVHSNGNTYLEWYQQKPGKAPKLLIY KVSNRFSGVPSRFSGSGSGTDFTLTISSLQPDDFATYYC FQGSHVPRTFGQGTKVEVK (SEQ ID NO: 97) |
C-002167 BB7.2.3 scFv (人源化): | QVQLVQSGAEVKKPGSSVKVSCKA SGYTFTSYHIQWVRQAPGQGLEWMG WIYPGDGSTQYNEKFKGRVTITADKSTSTAYMELSSLRSEDTAVYYCAR EGTYYAMDYWGQGTTVTVSSGGGGSGGGGSGGGGSGGEIVLTQSPGTLSLSPGERATLSC RSSQSIVHSNGNTYLEWYQQKPGQAPRLLIY KVSNRFSGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYC FQGSHVPRTFGGGTKVEIK (SEQ ID NO: 98) |
C-002168 BB7.2.5 scFv (人源化) | QVTLKQSGAEVKKPGSSVKVSCTA SGYTFTSYHVSWVRQAPGQGLEWLG RIYPGDGSTQYNEKFKGKVTITADKSMDTSFMELTSLTSEDTAVYYCAR EGTYYAMDLWGQGTLVTVSSGGGGSGGGGSGGGGSGGEIVLTQSPGTLSLSPGERATLSC RSSQSIVHSNGNTYLAWYQQKPGQAPRLLIS KVSNRFSGVPDRFSGSGSGTDFTLTISRLEPEDFAVYYC QQGSHVPRTFGGGTKVEIK (SEQ ID NO: 99) |
C-002169 BB7.2.6 scFv (人源化) | QVQLVQSGAEVKKPGASVKVSCKA SGYTFTSYHMHWVRQAPGQRLEWMG WIYPGDGSTQYNEKFKGKVTITRDTSASTAYMELSSLRSEDTAVYYCAR EGTYYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGDIVMTQTPLSLPVTPGEPASISC RSSQSIVHSNGNTYLDWYLQKPGQSPQLLIY KVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYC MQGSHVPRTFGGGTKVEIK (SEQ ID NO: 100) |
HLA-B*07 抗原結合結構域 | |
BB7.1.10_scFv | QVQLQESGPGLVKPSQTLSLTCTVSGYSITSGYSWHWIRQPPGKGLEWIGYIHFSGSTHYHPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARGGVVSHYAMDCWGQGTTVTVSSGGGGSGGGGSGGGGSGGDIQMTQSPSSLSASVGDRVTITCRASENIYSNLAWYQQKPGKAPKLLIYAATYLPDGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQHFWVTPYTFGGGTKVEIK (SEQ ID NO: 199) |
BB7.1.9_scFv | EVQLVESGGGLVKPGGSLRLSCAASGYSITSGYSWHWVRQAPGKGLEWVSYIHFSGSTHYHPSLKSRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARGGVVSHYAMDCWGQGTTVTVSSGGGGSGGGGSGGGGSGGDIQMTQSPSSVSASVGDRVTITCRASENIYSNLAWYQQKPGKAPKLLIYAATYLPDGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQHFWVTPYTFGGGTKVEIK (SEQ ID NO: 200) |
BB7.1.8_scFv | EVQLVESGGGLVKPGGSLRLSCAASGYSITSGYSWHWVRQAPGKGLEWVGYIHFSGSTHYHPSLKSRFTISRDDSKNTLYLQMNSLKTEDTAVYYCARGGVVSHYAMDCWGQGTTVTVSSGGGGSGGGGSGGGGSGGEIVLTQSPATLSLSPGERATLSCRASENIYSNLAWYQQKPGQAPRLLIYAATYLPDGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQHFWVTPYTFGGGTKVEIK(SEQ ID NO: 201) |
BB7.1.7_scFv | QVQLQQSGPGLVKPSQTLSLTCAISGYSITSGYSWHWIRQSPSRGLEWLGYIHFSGSTHYHPSLKSRITINPDTSKNQFSLQLNSVTPEDTAVYYCARGGVVSHYAMDCWGQGTTVTVSSGGGGSGGGGSGGGGSGGEIVLTQSPATLSLSPGERATLSCRASENIYSNLAWYQQKPGQAPRLLIYAATYLPDGIPARFSGSGSGTDFTLTISRLEPEDFAVYYCQHFWVTPYTFGGGTKVEIK(SEQ ID NO: 202) |
BB7.1.6_scFv | EVQLVESGGGLVKPGGSLRLSCAASGYSITSGYSWHWVRQAPGKGLEWVGYIHFSGSTHYHPSLKSRFTISRDDSKNTLYLQMNSLKTEDTAVYYCARGGVVSHYAMDCWGQGTTVTVSSGGGGSGGGGSGGGGSGGDIQMTQSPSSVSASVGDRVTITCRASENIYSNLAWYQQKPGKAPKLLIYAATYLPDGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQHFWVTPYTFGGGTKVEIK(SEQ ID NO: 203) |
BB7.1.5_scFv | EVQLVESGGGLVQPGGSLRLSCAASGYSITSGYSWHWVRQAPGKGLEWVSYIHFSGSTHYHPSLKSRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGGVVSHYAMDCWGQGTTVTVSSGGGGSGGGGSGGGGSGGDIQMTQSPSSLSASVGDRVTITCRASENIYSNLAWYQQKPGKAPKLLIYAATYLPDGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQHFWVTPYTFGGGTKVEIK(SEQ ID NO: 204) |
BB7.1.4_scFv | EVQLVESGGGLVKPGGSLRLSCAASGYSITSGYSWHWVRQAPGKGLEWVGYIHFSGSTHYHPSLKSRFTISRDDSKNTLYLQMNSLKTEDTAVYYCARGGVVSHYAMDCWGQGTTVTVSSGGGGSGGGGSGGGGSGGDIQMTQSPSSLSASVGDRVTITCRASENIYSNLAWYQQKPGKAPKLLIYAATYLPDGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQHFWVTPYTFGGGTKVEIK(SEQ ID NO: 205) |
BB7.1.3_scFv | QVQLQQWGAGLLKPSETLSLTCAVYGYSITSGYSWHWIRQPPGKGLEWIGYIHFSGSTHYHPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARGGVVSHYAMDCWGQGTTVTVSSGGGGSGGGGSGGGGSGGDIQMTQSPSSLSASVGDRVTITCRASENIYSNLAWYQQKPGKAPKLLIYAATYLPDGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQHFWVTPYTFGGGTKVEIK(SEQ ID NO: 206) |
BB7.1.2_scFv | QVQLQESGPGLVKPSQTLSLTCTVSGYSITSGYSWHWIRQHPGKGLEWIGYIHFSGSTHYHPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARGGVVSHYAMDCWGQGTTVTVSSGGGGSGGGGSGGGGSGGDIQMTQSPSSLSASVGDRVTITCRASENIYSNLAWYQQKPGKAPKLLIYAATYLPDGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQHFWVTPYTFGGGTKVEIK(SEQ ID NO: 207) |
BB7.1.1_scFv | QVQLQQSGPGLVKPSQTLSLTCAISGYSITSGYSWHWIRQSPSRGLEWLGYIHFSGSTHYHPSLKSRITINPDTSKNQFSLQLNSVTPEDTAVYYCARGGVVSHYAMDCWGQGTTVTVSSGGGGSGGGGSGGGGSGGDIQMTQSPSSLSASVGDRVTITCRASENIYSNLAWYQQKPGKAPKLLIYAATYLPDGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQHFWVTPYTFGGGTKVEIK(SEQ ID NO: 208) |
HLA-A*11 抗原結合結構域 | |
9 | QVQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQPPGKGLEWIGYIYYSGSTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARHYYYYSMDVWGKGTTVTVSSGGGGSGGGGSGGGGSGGDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKVEIK (SEQ ID NO: 209) |
8 | QITLKESGPTLVKPTQTLTLTCTFSGFSLSTSGVGVGWIRQPPGKALEWLALIYWNDDKRYSPSLKSRLTITKDTSKNQVVLTMTNMDPVDTATYYCAHRHMRLSCFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKVEIK (SEQ ID NO: 210) |
7 | QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYAMHWVRQAPGQRLEWMGWINAGNGNTKYSQKFQGRVTITRDTSASTAYMELSSLRSEDTAVYYCAREGNGANPDAFDIWGQGTMVTVSSGGGGSGGGGSGGGGSGGDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKVEIK (SEQ ID NO: 211) |
6 | EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYDMHWVRQATGKGLEWVSAIGTAGDTYYPGSVKGRFTISRENAKNSLYLQMNSLRAGDTAVYYCARDLPGSYWYFDLWGRGTLVTVSSGGGGSGGGGSGGGGSGGDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKVEIK (SEQ ID NO: 212) |
5 | QVQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQPPGKGLEWIGYIYYSGSTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARHYYYYYLDVWGKGTTVTVSSGGGGSGGGGSGGGGSGGDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKVEIK (SEQ ID NO: 213) |
4 | EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMHWVRQAPGKGLVWVSRINSDGSSTSYADSVKGRFTISRDNAKNTLYLQMNSLRAEDTAVYYCCLGVLLYNWFDPWGQGTLVTVSSGGGGSGGGGSGGGGSGGDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKVEIK (SEQ ID NO: 214) |
3 | QVQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQPPGKGLEWIGYIYYSGSTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARHYYYYMDVWGKGTTVTVSSGGGGSGGGGSGGGGSGGDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKVEIK (SEQ ID NO: 215) |
2 | QITLKESGPTLVKPTQTLTLTCTFSGFSLSTSGVGVGWIRQPPGKALEWLALIYWNDDKRYSPSLKSRLTITKDTSKNQVVLTMTNMDPVDTATYYCAHKTTSFYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKVEIK (SEQ ID NO: 216) |
1 | QVQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQPPGKGLEWIGYIYYSGSTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARHYYYYYMDVWGKGTTVTVSSGGGGSGGGGSGGGGSGGDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKVEIK (SEQ ID NO: 217) |
HLA-C*07 抗原結合結構域 | |
C7-45 | EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAVSFDWFDPWGQGTLVTVSSGGGGSGGGGSGGGGSGGDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKVEIK (SEQ ID NO: 218) |
C7-44 | QVQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQPPGKGLEWIGYIYYSGSTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARERSISPYYYYYMDVWGKGTTVTVSSGGGGSGGGGSGGGGSGGDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKVEIK (SEQ ID NO: 219) |
C7-43 | QLQLQESGPGLVKPSETLSLTCTVSGGSISSSSYYWGWIRQPPGKGLEWIGSIYYSGSTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARDSVIWYWFDPWGQGTLVTVSSGGGGSGGGGSGGGGSGGQSVLTQPPSASGTPGQRVTISCSGSSSNIGSNTVNWYQQLPGTAPKLLIYSNNQRPSGVPDRFSGSKSGTSASLAISGLQSEDEADYYCAAWDDSLNGWVFGGGTKLTVL (SEQ ID NO: 220) |
C7-42 | QVQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQPPGKGLEWIGYIYYSGSTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCAREEILPRLSYYYYMDVWGKGTTVTVSSGGGGSGGGGSGGGGSGGDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKVEIK (SEQ ID NO: 221) |
C7-41 | QVQLVQSGSELKKPGASVKVSCKASGYTFTSYAMNWVRQAPGQGLEWMGWINTNTGNPTYAQGFTGRFVFSFDTSVSTAYLQICSLKAEDTAVYYCARGGRAHSSWYFDLWGRGTLVTVSSGGGGSGGGGSGGGGSGGDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKVEIK (SEQ ID NO: 222) |
C7-40 | QVQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQPPGKGLEWIGYIYYSGSTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARDRIKILPRLGYYYYMDVWGKGTTVTVSSGGGGSGGGGSGGGGSGGDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKVEIK (SEQ ID NO: 223) |
C7-39 | QVQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQPPGKGLEWIGYIYYSGSTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARDTVIHYYYYMDVWGKGTTVTVSSGGGGSGGGGSGGGGSGGDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKVEIK (SEQ ID NO: 224) |
C7-38 | QVQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQPPGKGLEWIGYIYYSGSTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARDVIVEVFLSYYYYMDVWGKGTTVTVSSGGGGSGGGGSGGGGSGGDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKVEIK (SEQ ID NO: 225) |
C7-37 | QVQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQPPGKGLEWIGYIYYSGSTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARDIFIHYYYYMDVWGKGTTVTVSSGGGGSGGGGSGGGGSGGDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKVEIK (SEQ ID NO: 226) |
C7-36 | EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYSMNWVRQAPGKGLEWVSYISSSSSTIYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDGTFYSYSPYYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKVEIK (SEQ ID NO: 227) |
C7-35 | QVQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQPPGKGLEWIGYIYYSGSTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCAREWIKILPRLGYYYYMDVWGKGTTVTVSSGGGGSGGGGSGGGGSGGDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKVEIK (SEQ ID NO: 228) |
C7-34 | QVQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQPPGKGLEWIGYIYYSGSTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARDRSLYYYYYMDVWGKGTTVTVSSGGGGSGGGGSGGGGSGGDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKVEIK (SEQ ID NO: 229) |
C7-33 | QVQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQPPGKGLEWIGYIYYSGSTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARDKILAPNYYYYMDVWGKGTTVTVSSGGGGSGGGGSGGGGSGGDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKVEIK (SEQ ID NO: 230) |
C7-32 | QVQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQPPGKGLEWIGYIYYSGSTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCAREKSWKYFYYYYYYMDVWGKGTTVTVSSGGGGSGGGGSGGGGSGGDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKVEIK (SEQ ID NO: 231) |
C7-31 | QVQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQPPGKGLEWIGYIYYSGSTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARENTSTIPYYYYYMDVWGKGTTVTVSSGGGGSGGGGSGGGGSGGDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKVEIK (SEQ ID NO: 232) |
C7-30 | QVQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQPPGKGLEWIGYIYYSGSTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCAREDVDKNTSTIYYYYYYMDVWGKGTTVTVSSGGGGSGGGGSGGGGSGGDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKVEIK (SEQ ID NO: 233) |
C7-29 | QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSYISSSGSTIYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDGGDIVSSSAIYWYFDLWGRGTLVTVSSGGGGSGGGGSGGGGSGGAIQLTQSPSSLSASVGDRVTITCRASQGISSALAWYQQKPGKAPKLLIYDASSLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQFNSYPLTFGGGTKVEIK (SEQ ID NO: 234) |
C7-28 | QVQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQPPGKGLEWIGYIYYSGSTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARDLILPPYYYYYMDVWGKGTTVTVSSGGGGSGGGGSGGGGSGGDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKVEIK (SEQ ID NO: 235) |
C7-27 | QVQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQPPGKGLEWIGYIYYSGSTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARETWIKILPRYYYYYYYMDVWGKGTTVTVSSGGGGSGGGGSGGGGSGGDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKVEIK (SEQ ID NO: 236) |
C7-26 | QVQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQPPGKGLEWIGYIYYSGSTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARDLSRYYYYYMDVWGKGTTVTVSSGGGGSGGGGSGGGGSGGDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKVEIK (SEQ ID NO: 237) |
C7-25 | EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYSMNWVRQAPGKGLEWVSYISSSSSTIYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAREHIVLCFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGDIQMTQSPSSLSASVGDRVTITCRASQGISSWLAWYQQKPEKAPKSLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYNSYPLTFGGGTKVEIK (SEQ ID NO: 238) |
C7-24 | QVQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQPPGKGLEWIGYIYYSGSTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARDKILPRPYYYYYMDVWGKGTTVTVSSGGGGSGGGGSGGGGSGGDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKVEIK (SEQ ID NO: 239) |
C7-23 | QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYGISWVRQAPGQGLEWMGWISAYNGNTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARGSNEYFQHWGQGTLVTVSSGGGGSGGGGSGGGGSGGQSALTQPPSASGSPGQSVTISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYEVSKRPSGVPDRFSGSKSGNTASLTVSGLQAEDEADYYCSSYAGSNNWVFGGGTKLTVL (SEQ ID NO: 240) |
C7-22 | QVQLVQSGSELKKPGASVKVSCKASGYTFTSYAMNWVRQAPGQGLEWMGWINTNTGNPTYAQGFTGRFVFSFDTSVSTAYLQICSLKAEDTAVYYCARGTSYWYFDLWGRGTLVTVSSGGGGSGGGGSGGGGSGGDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKVEIK (SEQ ID NO: 241) |
C7-21 | QVQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQPPGKGLEWIGYIYYSGSTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCAREEIVEVFYYYYMDVWGKGTTVTVSSGGGGSGGGGSGGGGSGGDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKVEIK (SEQ ID NO: 242) |
C7-20 | EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKVDDYYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKVEIK (SEQ ID NO: 243) |
C7-19 | EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMHWVRQAPGKGLVWVSRINSDGSSTSYADSVKGRFTISRDNAKNTLYLQMNSLRAEDTAVYYCAWSTNILLSYTKAFDIWGQGTMVTVSSGGGGSGGGGSGGGGSGGDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKVEIK (SEQ ID NO: 244) |
C7-18 | QVQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQPPGKGLEWIGYIYYSGSTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARDKTYYYYYYMDVWGKGTTVTVSSGGGGSGGGGSGGGGSGGDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKVEIK (SEQ ID NO: 245) |
C7-17 | QVQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQPPGKGLEWIGYIYYSGSTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCAREKYFHDKYFHDYYYYYMDVWGKGTTVTVSSGGGGSGGGGSGGGGSGGDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKVEIK (SEQ ID NO: 246) |
C7-16 | QVQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQPPGKGLEWIGYIYYSGSTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARDTSVYYYYYMDVWGKGTTVTVSSGGGGSGGGGSGGGGSGGDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKVEIK (SEQ ID NO: 247) |
C7-15 | QVQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQPPGKGLEWIGYIYYSGSTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCAREKILPYYYYYYMDVWGKGTTVTVSSGGGGSGGGGSGGGGSGGDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKVEIK (SEQ ID NO: 248) |
C7-14 | EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYSMNWVRQAPGKGLEWVSYISSSSSTIYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAIQWIYIYINPRGFIFLHDAFDIWGQGTMVTVSSGGGGSGGGGSGGGGSGGQSVLTQPPSASGTPGQRVTISCSGSSSNIGSNTVNWYQQLPGTAPKLLIYSNNQRPSGVPDRFSGSKSGTSASLAISGLQSEDEADYYCAAWDDSLNGWVFGGGTKLTVL (SEQ ID NO: 249) |
C7-13 | QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSRGLEWLGRTYYRSKWYNDYAVSVKSRITINPDTSKNQFSLQLNSVTPEDTAVYYCAKEDVDFHHDAFDIWGQGTMVTVSSGGGGSGGGGSGGGGSGGDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKVEIK (SEQ ID NO: 250) |
C7-12 | QVQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQPPGKGLEWIGYIYYSGSTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCAREGVDKNTSTIYYYYYYMDVWGKGTTVTVSSGGGGSGGGGSGGGGSGGDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKVEIK (SEQ ID NO: 251) |
C7-11 | EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYSMNWVRQAPGKGLEWVSYISSSSSTIYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDRRGYFDLWGRGTLVTVSSGGGGSGGGGSGGGGSGGDIQMTQSPSSLSASVGDRVTITCRASQGISSWLAWYQQKPEKAPKSLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYNSYPLTFGGGTKVEIK (SEQ ID NO: 252) |
C7-10 | EVQLVQSGAEVKKPGATVKISCKVSGYTFTDYYMHWVQQAPGKGLEWMGLVDPEDGETIYAEKFQGRVTITADTSTDTAYMELSSLRSEDTAVYYCATGIHVDIRSMEDWFDPWGQGTLVTVSSGGGGSGGGGSGGGGSGGDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKVEIK (SEQ ID NO: 253) |
C7-9 | QVQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQPPGKGLEWIGYIYYSGSTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARDIGTSYYYYMDVWGKGTTVTVSSGGGGSGGGGSGGGGSGGDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKVEIK (SEQ ID NO: 254) |
C7-8 | QVQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQPPGKGLEWIGYIYYSGSTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCAREVVEVFLYYYYYMDVWGKGTTVTVSSGGGGSGGGGSGGGGSGGDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKVEIK (SEQ ID NO: 255) |
C7-7 | QVQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQPPGKGLEWIGYIYYSGSTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARDLYYYYYYYMDVWGKGTTVTVSSGGGGSGGGGSGGGGSGGDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKVEIK (SEQ ID NO: 256) |
C7-6 | QVQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQPPGKGLEWIGYIYYSGSTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARESWKYFYPRGSIFIHYYYYMDVWGKGTTVTVSSGGGGSGGGGSGGGGSGGDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKVEIK (SEQ ID NO: 257) |
C7-5 | QVQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQPPGKGLEWIGYIYYSGSTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARDRIVEVFYYYYMDVWGKGTTVTVSSGGGGSGGGGSGGGGSGGDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKVEIK (SEQ ID NO: 258) |
C7-4 | QVQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQPPGKGLEWIGYIYYSGSTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCAREKYFHDWLYYYYYMDVWGKGTTVTVSSGGGGSGGGGSGGGGSGGDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKVEIK (SEQ ID NO: 259) |
C7-3 | QVQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQPPGKGLEWIGYIYYSGSTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARDLVDKNTSYYYYYMDVWGKGTTVTVSSGGGGSGGGGSGGGGSGGDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKVEIK (SEQ ID NO: 260) |
C7-2 | QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYGISWVRQAPGQGLEWMGWISAYNGNTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARVQNEYFQHWGQGTLVTVSSGGGGSGGGGSGGGGSGGQSALTQPPSASGSPGQSVTISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYEVSKRPSGVPDRFSGSKSGNTASLTVSGLQAEDEADYYCSSYAGSNNWVFGGGTKLTVL (SEQ ID NO: 261) |
C7-1 | QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSYISSSGSTIYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCATANWFDPWGQGTLVTVSSGGGGSGGGGSGGGGSGGDIQMTQSPSSVSASVGDRVTITCRASQGISSWLAWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANSFPLTFGGGTKVEIK (SEQ ID NO: 262) |
HLA-A*03 scFv 序列 | |
15 | QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYGISWVRQAPGQGLEWMGWISAYNGNTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARERVSQRGAFDIWGQGTMVTVSSGGGGSGGGGSGGGGSGGDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKVEIK (SEQ ID NO: 263) |
16 | EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYSMNWVRQAPGKGLEWVSYISSSSSTIYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARGNPDKDPFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKVEIK (SEQ ID NO: 264) |
17 | QVQLQESGPGLVKPSETLSLTCTVSGGSVSSGSYYWSWIRQPPGKGLEWIGYIYYSGSTNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARDFYCTNWYFDLWGRGTLVTVSSGGGGSGGGGSGGGGSGGDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKVEIK (SEQ ID NO: 265) |
18 | QVQLQESGPGLVKPSETLSLTCTVSGGSISSYYWSWIRQPPGKGLEWIGYIYYSGSTNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARESSSGSYWYFDLWGRGTLVTVSSGGGGSGGGGSGGGGSGGDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKVEIK (SEQ ID NO: 266) |
19 | EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGIIYPGDSDTRYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCARDSGYKYNLYYYYYYMDVWGKGTTVTVSSGGGGSGGGGSGGGGSGGDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKVEIK (SEQ ID NO: 267) |
20 | QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYGISWVRQAPGQGLEWMGWISAYNGNTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARGGDLSHYYYYMDVWGKGTTVTVSSGGGGSGGGGSGGGGSGGQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGYYPNWFQQKPGQAPRALIYSTSNKHSWTPARFSGSLLGGKAALTLSGVQPEDEAEYYCLLYYGGAQWVFGGGTKLTVL (SEQ ID NO: 268) |
21 | QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYGISWVRQAPGQGLEWMGWISAYNGNTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARENRRYNSCYYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKVEIK (SEQ ID NO: 269) |
22 | QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYGISWVRQAPGQGLEWMGWISAYNGNTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARGGDLSHYYYYLDVWGKGTTVTVSSGGGGSGGGGSGGGGSGGQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGYYPNWFQQKPGQAPRALIYSTSNKHSWTPARFSGSLLGGKAALTLSGVQPEDEAEYYCLLYYGGAQWVFGGGTKLTVL (SEQ ID NO: 270) |
23 | EVQLVESGGGLVQPGGSLRLSCAASGFTVSSNYMSWVRQAPGKGLEWVSVIYSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARATLLSLSYDAFDIWGQGTMVTVSSGGGGSGGGGSGGGGSGGDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKVEIK (SEQ ID NO: 271) |
24 | QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYGISWVRQAPGQGLEWMGWISAYNGNTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARGGDLSHYYYMDVWGKGTTVTVSSGGGGSGGGGSGGGGSGGQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGYYPNWFQQKPGQAPRALIYSTSNKHSWTPARFSGSLLGGKAALTLSGVQPEDEAEYYCLLYYGGAQWVFGGGTKLTVL (SEQ ID NO: 272) |
25 | EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGIIYPGDSDTRYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCARERDRWFDPWGQGTLVTVSSGGGGSGGGGSGGGGSGGDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKVEIK (SEQ ID NO: 273) |
26 | QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYGISWVRQAPGQGLEWMGWISAYNGNTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARETPPSLGAFDIWGQGTMVTVSSGGGGSGGGGSGGGGSGGQSALTQPPSASGSPGQSVTISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYEVSKRPSGVPDRFSGSKSGNTASLTVSGLQAEDEADYYCSSYAGSNNWVFGGGTKLTVL (SEQ ID NO: 274) |
27 | QLQLQESGPGLVKPSETLSLTCTVSGGSISSSSYYWGWIRQPPGKGLEWIGSIYYSGSTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCAREAYCLSDSYWYFDLWGRGTLVTVSSGGGGSGGGGSGGGGSGGQSVLTQPPSASGTPGQRVTISCSGSSSNIGSNTVNWYQQLPGTAPKLLIYSNNQRPSGVPDRFSGSKSGTSASLAISGLQSEDEADYYCAAWDDSLNGWVFGGGTKLTVL(SEQ ID NO:275) |
28 | QVQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQPPGKGLEWIGYIYYSGSTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARESWKYFYPRGYMDVWGKGTTVTVSSGGGGSGGGGSGGGGSGGDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKVEIK (SEQ ID NO: 276) |
HLA-A*01 scFv 序列 | |
A1-9 | QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYGISWVRQAPGQGLEWMGWISAYNGNTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARGGWTAWYYYMDVWGKGTTVTVSSGGGGSGGGGSGGGGSGGQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGYYPNWFQQKPGQAPRALIYSTSNKHSWTPARFSGSLLGGKAALTLSGVQPEDEAEYYCLLYYGGAQWVFGGGTKLTVL (SEQ ID NO: 277) |
A1-8 | EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYSMNWVRQAPGKGLEWVSYISSSSSTIYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARAKYYYMDVWGKGTTVTVSSGGGGSGGGGSGGGGSGGQSVLTQPPSASGTPGQRVTISCSGSSSNIGSNTVNWYQQLPGTAPKLLIYSNNQRPSGVPDRFSGSKSGTSASLAISGLQSEDEADYYCAAWDDSLNGWVFGGGTKLTVL (SEQ ID NO: 278) |
A1-7 | QVQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQPPGKGLEWIGYIYYSGSTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARDQVDKNTYYYYMDVWGKGTTVTVSSGGGGSGGGGSGGGGSGGDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKVEIK (SEQ ID NO: 279) |
A1-6 | QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSYISSSGSTIYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARACQLAEYFQHWGQGTLVTVSSGGGGSGGGGSGGGGSGGDIQMTQSPSSVSASVGDRVTITCRASQGISSWLAWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANSFPLTFGGGTKVEIK (SEQ ID NO: 280) |
A1-5 | QVQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQPPGKGLEWIGYIYYSGSTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARDRVDKNTSYYYMDVWGKGTTVTVSSGGGGSGGGGSGGGGSGGDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKVEIK (SEQ ID NO: 281) |
A1-4 | QVQLQESGPGLVKPSDTLSLTCAVSGYSISSSNWWGWIRQPPGKGLEWIGYIYYSGSTYYNPSLKSRVTMSVDTSKNQFSLKLSSVTAVDTAVYYCARRVQLKLVHWFDPWGQGTLVTVSSGGGGSGGGGSGGGGSGGDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKVEIK (SEQ ID NO: 282) |
A1-3 | QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDINWVRQATGQGLEWMGWMNPNSGNTGYAQKFQGRVTMTRNTSISTAYMELSSLRSEDTAVYYCATYYDYVTVFYFQHWGQGTLVTVSSGGGGSGGGGSGGGGSGGDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKVEIK (SEQ ID NO: 283) |
A1-2 | QLQLQESGSGLVKPSQTLSLTCAVSGGSISSGGYSWSWIRQPPGKGLEWIGYIYHSGSTYYNPSLKSRVTISVDRSKNQFSLKLSSVTAADTAVYYCARESYPSFYAFDIWGQGTMVTVSSGGGGSGGGGSGGGGSGGDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKVEIK (SEQ ID NO: 284) |
A1-1 | QITLKESGPTLVKPTQTLTLTCTFSGFSLSTSGVGVGWIRQPPGKALEWLALIYWNDDKRYSPSLKSRLTITKDTSKNQVVLTMTNMDPVDTATYYCAHSNMWSYSLNDYYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKVEIK (SEQ ID NO: 285) |
非靶配位體結合結構域之示例性重鏈及輕鏈CDR (分別為CDR-H1、CDR-H2及CDR-H3,或CDR-L1、CDR-L2及CDR-L3)示於下表5中。
表5. 對應於抗原結合結構域之CDR
CDR-L1 | CDR-L2 | CDR-L3 | CDR-H1 | CDR-H2 | CDR-H3 |
HLA-A*02 CDR | |||||
RSSQSIVHSNGNTYLE (SEQ ID NO: 101) | KVSNRFSGVPDR (SEQ ID NO: 102) | FQGSHVPRT (SEQ ID NO: 103) | ASGYTFTSYHIH (SEQ ID NO: 104) | WIYPGNVNTEYNEKFKGK (SEQ ID NO: 105) | EEITYAMDY (SEQ ID NO: 106) |
RSSQSIVHSNGNTYLD (SEQ ID NO: 107) | KVSNRFSGVPDR (SEQ ID NO: 108) | MQGSHVPRT (SEQ ID NO: 109) | SGYTFTSYHMH (SEQ ID NO: 110) | WIYPGDGSTQYNEKFKG (SEQ ID NO: 111) | EGTYYAMDY (SEQ ID NO: 112) |
HLA-A*03 CDR | |||||
RASQSISSYLN (SEQ ID NO: 286) | AASSLQS (SEQ ID NO: 293) | QQSYSTPLT (SEQ ID NO: 298) | SYGIS (SEQ ID NO: 305) | WISAYNGNTNYAQKLQG (SEQ ID NO: 326) | ERVSQRGAFDI (SEQ ID NO: 345) |
RASQSISSYLN (SEQ ID NO: 286) | AASSLQS (SEQ ID NO: 293) | QQSYSTPLT (SEQ ID NO: 298) | SYSMN (SEQ ID NO: 306) | YISSSSSTIYYADSVKG (SEQ ID NO: 327) | GNPDKDPFDY (SEQ ID NO: 346) |
RASQSISSYLN (SEQ ID NO: 286) | AASSLQS (SEQ ID NO: 293) | QQSYSTPLT (SEQ ID NO: 298) | SGSYYWS (SEQ ID NO: 307) | YIYYSGSTNYNPSLKS (SEQ ID NO: 328) | DFYCTNWYFDL (SEQ ID NO: 347) |
RASQSISSYLN (SEQ ID NO: 286) | AASSLQS (SEQ ID NO: 293) | QQSYSTPLT (SEQ ID NO: 298) | SYYWS (SEQ ID NO: 308) | YIYYSGSTNYNPSLKS (SEQ ID NO: 328) | ESSSGSYWYFDL (SEQ ID NO: 348) |
RASQSISSYLN (SEQ ID NO: 286) | AASSLQS (SEQ ID NO: 293) | QQSYSTPLT (SEQ ID NO: 298) | SYWIG (SEQ ID NO: 309) | IIYPGDSDTRYSPSFQG (SEQ ID NO: 329) | DSGYKYNLYYYYYYMDV (SEQ ID NO: 349) |
ASSTGAVTSGYYPN (SEQ ID NO: 287) | STSNKHS (SEQ ID NO: 294) | LLYYGGAQWV (SEQ ID NO: 299) | SYGIS (SEQ ID NO: 305) | WISAYNGNTNYAQKLQG (SEQ ID NO: 326) | GGDLSHYYYYMDV (SEQ ID NO: 350) |
RASQSISSYLN (SEQ ID NO: 286) | AASSLQS (SEQ ID NO: 293) | QQSYSTPLT (SEQ ID NO: 298) | SYGIS (SEQ ID NO: 305) | WISAYNGNTNYAQKLQG (SEQ ID NO: 326) | ENRRYNSCYYFDY (SEQ ID NO: 351) |
ASSTGAVTSGYYPN (SEQ ID NO: 287) | STSNKHS (SEQ ID NO: 294) | LLYYGGAQWV (SEQ ID NO: 299) | SYGIS (SEQ ID NO: 305) | WISAYNGNTNYAQKLQG (SEQ ID NO: 326) | GGDLSHYYYYLDV (SEQ ID NO: 352) |
RASQSISSYLN (SEQ ID NO: 286) | AASSLQS (SEQ ID NO: 293) | QQSYSTPLT (SEQ ID NO: 298) | SNYMS (SEQ ID NO: 310) | VIYSGGSTYYADSVKG (SEQ ID NO: 330) | ATLLSLSYDAFDI (SEQ ID NO: 353) |
ASSTGAVTSGYYPN (SEQ ID NO: 287) | STSNKHS (SEQ ID NO: 294) | LLYYGGAQWV (SEQ ID NO: 299) | SYGIS (SEQ ID NO: 305) | WISAYNGNTNYAQKLQG (SEQ ID NO: 326) | GGDLSHYYYMDV (SEQ ID NO: 354) |
RASQSISSYLN (SEQ ID NO: 286) | AASSLQS (SEQ ID NO: 293) | QQSYSTPLT (SEQ ID NO: 298) | SYWIG (SEQ ID NO: 309) | IIYPGDSDTRYSPSFQG (SEQ ID NO: 329) | ERDRWFDP (SEQ ID NO: 355) |
TGTSSDVGGYNYVS (SEQ ID NO: 288) | EVSKRPS (SEQ ID NO: 295) | SSYAGSNNWV (SEQ ID NO: 300) | SYGIS (SEQ ID NO: 305) | WISAYNGNTNYAQKLQG (SEQ ID NO: 326) | ETPPSLGAFDI (SEQ ID NO: 356) |
SGSSSNIGSNTVN (SEQ ID NO: 289) | SNNQRPS (SEQ ID NO: 296) | AAWDDSLNGWV (SEQ ID NO: 301) | SSSYYWG (SEQ ID NO: 311) | SIYYSGSTYYNPSLKS (SEQ ID NO: 331) | EAYCLSDSYWYFDL (SEQ ID NO: 357) |
RASQSISSYLN (SEQ ID NO: 286) | AASSLQS (SEQ ID NO: 293) | QQSYSTPLT (SEQ ID NO: 298) | SGGYYWS (SEQ ID NO: 312) | YIYYSGSTYYNPSLKS (SEQ ID NO: 332) | ESWKYFYPRGYMDV (SEQ ID NO: 358) |
HLA-B*07 CDR | |||||
RASENIYSNLA (SEQ ID NO: 290) | AATYLPD (SEQ ID NO: 297) | QHFWVTPYT (SEQ ID NO: 302) | SGYSWH (SEQ ID NO: 313) | YIHFSGSTHYHPSLKS (SEQ ID NO: 333) | GGVVSHYAMDC (SEQ ID NO: 359) |
HLA-A*11 CDR | |||||
RASQSISSYLN (SEQ ID NO: 286) | AASSLQS (SEQ ID NO: 293) | QQSYSTPLT (SEQ ID NO: 298) | SGGYYWS (SEQ ID NO: 312) | YIYYSGSTYYNPSLKS (SEQ ID NO: 332) | HYYYYYMDV (SEQ ID NO: 360) |
RASQSISSYLN (SEQ ID NO: 286) | AASSLQS (SEQ ID NO: 293) | QQSYSTPLT (SEQ ID NO: 298) | TSGVGVG (SEQ ID NO: 314) | LIYWNDDKRYSPSLKS (SEQ ID NO: 334) | KTTSFYFDY (SEQ ID NO: 361) |
RASQSISSYLN (SEQ ID NO: 286) | AASSLQS (SEQ ID NO: 293) | QQSYSTPLT (SEQ ID NO: 298) | SGGYYWS (SEQ ID NO: 312) | YIYYSGSTYYNPSLKS (SEQ ID NO: 332) | HYYYYMDV (SEQ ID NO: 362) |
RASQSISSYLN (SEQ ID NO: 286) | AASSLQS (SEQ ID NO: 293) | QQSYSTPLT (SEQ ID NO: 298) | SYWMH (SEQ ID NO: 315) | RINSDGSSTSYADSVKG (SEQ ID NO: 335) | GVLLYNWFDP (SEQ ID NO: 363) |
RASQSISSYLN (SEQ ID NO: 286) | AASSLQS (SEQ ID NO: 293) | QQSYSTPLT (SEQ ID NO: 298) | SGGYYWS (SEQ ID NO: 312) | YIYYSGSTYYNPSLKS (SEQ ID NO: 332) | HYYYYYLDV (SEQ ID NO: 364) |
RASQSISSYLN (SEQ ID NO: 286) | AASSLQS (SEQ ID NO: 293) | QQSYSTPLT (SEQ ID NO: 298) | SYDMH (SEQ ID NO: 316) | AIGTAGDTYYPGSVKG (SEQ ID NO: 336) | DLPGSYWYFDL (SEQ ID NO: 365) |
RASQSISSYLN (SEQ ID NO: 286) | AASSLQS (SEQ ID NO: 293) | QQSYSTPLT (SEQ ID NO: 298) | SYAMH (SEQ ID NO: 317) | WINAGNGNTKYSQKFQG (SEQ ID NO: 337) | EGNGANPDAFDI (SEQ ID NO: 366) |
RASQSISSYLN (SEQ ID NO: 286) | AASSLQS (SEQ ID NO: 293) | QQSYSTPLT (SEQ ID NO: 298) | TSGVGVG (SEQ ID NO: 314) | LIYWNDDKRYSPSLKS (SEQ ID NO: 334) | RHMRLSCFDY (SEQ ID NO: 367) |
RASQSISSYLN (SEQ ID NO: 286) | AASSLQS (SEQ ID NO: 293) | QQSYSTPLT (SEQ ID NO: 298) | SGGYYWS (SEQ ID NO: 312) | YIYYSGSTYYNPSLKS (SEQ ID NO: 332) | HYYYYSMDV (SEQ ID NO: 368) |
HLA-C*07 CDR | |||||
RASQSISSYLN (SEQ ID NO: 286) | AASSLQS (SEQ ID NO: 293) | QQSYSTPLT (SEQ ID NO: 298) | SYAMS (SEQ ID NO: 318) | AISGSGGSTYYADSVKG (SEQ ID NO: 338) | SFDWFDP (SEQ ID NO: 369) |
RASQSISSYLN (SEQ ID NO: 286) | AASSLQS (SEQ ID NO: 293) | QQSYSTPLT (SEQ ID NO: 298) | SGGYYWS (SEQ ID NO: 312) | YIYYSGSTYYNPSLKS (SEQ ID NO: 332) | ERSISPYYYYYMDV (SEQ ID NO: 370) |
SGSSSNIGSNTVN (SEQ ID NO: 289) | SNNQRPS (SEQ ID NO: 296) | AAWDDSLNGWV (SEQ ID NO: 301) | SSSYYWG (SEQ ID NO: 311) | SIYYSGSTYYNPSLKS (SEQ ID NO: 331) | DSVIWYWFDP (SEQ ID NO: 371) |
RASQSISSYLN (SEQ ID NO: 286) | AASSLQS (SEQ ID NO: 293) | QQSYSTPLT (SEQ ID NO: 298) | SGGYYWS (SEQ ID NO: 312) | YIYYSGSTYYNPSLKS (SEQ ID NO: 332) | EEILPRLSYYYYMDV (SEQ ID NO: 372) |
RASQSISSYLN (SEQ ID NO: 286) | AASSLQS (SEQ ID NO: 293) | QQSYSTPLT (SEQ ID NO: 298) | SYAMN (SEQ ID NO: 319) | WINTNTGNPTYAQGFTG (SEQ ID NO: 339) | GGRAHSSWYFDL (SEQ ID NO: 373) |
RASQSISSYLN (SEQ ID NO: 286) | AASSLQS (SEQ ID NO: 293) | QQSYSTPLT (SEQ ID NO: 298) | SGGYYWS (SEQ ID NO: 312) | YIYYSGSTYYNPSLKS (SEQ ID NO: 332) | DRIKILPRLGYYYYMDV (SEQ ID NO: 374) |
RASQSISSYLN (SEQ ID NO: 286) | AASSLQS (SEQ ID NO: 293) | QQSYSTPLT (SEQ ID NO: 298) | SGGYYWS (SEQ ID NO: 312) | YIYYSGSTYYNPSLKS (SEQ ID NO: 332) | DTVIHYYYYMDV (SEQ ID NO: 375) |
RASQSISSYLN (SEQ ID NO: 286) | AASSLQS (SEQ ID NO: 293) | QQSYSTPLT (SEQ ID NO: 298) | SGGYYWS (SEQ ID NO: 312) | YIYYSGSTYYNPSLKS (SEQ ID NO: 332) | DVIVEVFLSYYYYMDV (SEQ ID NO: 376) |
RASQSISSYLN (SEQ ID NO: 286) | AASSLQS (SEQ ID NO: 293) | QQSYSTPLT (SEQ ID NO: 298) | SGGYYWS (SEQ ID NO: 312) | YIYYSGSTYYNPSLKS (SEQ ID NO: 332) | DIFIHYYYYMDV (SEQ ID NO: 377) |
RASQSISSYLN (SEQ ID NO: 286) | AASSLQS (SEQ ID NO: 293) | QQSYSTPLT (SEQ ID NO: 298) | SYSMN (SEQ ID NO: 306) | YISSSSSTIYYADSVKG (SEQ ID NO: 327) | DGTFYSYSPYYFDY (SEQ ID NO: 378) |
RASQSISSYLN (SEQ ID NO: 286) | AASSLQS (SEQ ID NO: 293) | QQSYSTPLT (SEQ ID NO: 298) | SGGYYWS (SEQ ID NO: 312) | YIYYSGSTYYNPSLKS (SEQ ID NO: 332) | EWIKILPRLGYYYYMDV (SEQ ID NO: 379) |
RASQSISSYLN (SEQ ID NO: 286) | AASSLQS (SEQ ID NO: 293) | QQSYSTPLT (SEQ ID NO: 298) | SGGYYWS (SEQ ID NO: 312) | YIYYSGSTYYNPSLKS (SEQ ID NO: 332) | DRSLYYYYYMDV (SEQ ID NO: 380) |
RASQSISSYLN (SEQ ID NO: 286) | AASSLQS (SEQ ID NO: 293) | QQSYSTPLT (SEQ ID NO: 298) | SGGYYWS (SEQ ID NO: 312) | YIYYSGSTYYNPSLKS (SEQ ID NO: 332) | DKILAPNYYYYMDV (SEQ ID NO: 381) |
RASQSISSYLN (SEQ ID NO: 286) | AASSLQS (SEQ ID NO: 293) | QQSYSTPLT (SEQ ID NO: 298) | SGGYYWS (SEQ ID NO: 312) | YIYYSGSTYYNPSLKS (SEQ ID NO: 332) | EKSWKYFYYYYYYMDV (SEQ ID NO: 382) |
RASQSISSYLN (SEQ ID NO: 286) | AASSLQS (SEQ ID NO: 293) | QQSYSTPLT (SEQ ID NO: 298) | SGGYYWS (SEQ ID NO: 312) | YIYYSGSTYYNPSLKS (SEQ ID NO: 332) | ENTSTIPYYYYYMDV (SEQ ID NO: 383) |
RASQSISSYLN (SEQ ID NO: 286) | AASSLQS (SEQ ID NO: 293) | QQSYSTPLT (SEQ ID NO: 298) | SGGYYWS (SEQ ID NO: 312) | YIYYSGSTYYNPSLKS (SEQ ID NO: 332) | EDVDKNTSTIYYYYYYMDV (SEQ ID NO: 384) |
RASQGISSALA (SEQ ID NO: 291) | DASSLES (SEQ ID NO: 55) | QQFNSYPLT (SEQ ID NO: 60) | DYYMS (SEQ ID NO: 320) | YISSSGSTIYYADSVKG (SEQ ID NO: 340) | DGGDIVSSSAIYWYFDL (SEQ ID NO: 385) |
RASQSISSYLN (SEQ ID NO: 286) | AASSLQS (SEQ ID NO: 293) | QQSYSTPLT (SEQ ID NO: 298) | SGGYYWS (SEQ ID NO: 312) | YIYYSGSTYYNPSLKS (SEQ ID NO: 332) | DLILPPYYYYYMDV (SEQ ID NO: 386) |
RASQSISSYLN (SEQ ID NO: 286) | AASSLQS (SEQ ID NO: 293) | QQSYSTPLT (SEQ ID NO: 298) | SGGYYWS (SEQ ID NO: 312) | YIYYSGSTYYNPSLKS (SEQ ID NO: 332) | ETWIKILPRYYYYYYYMDV (SEQ ID NO: 387) |
RASQSISSYLN (SEQ ID NO: 286) | AASSLQS (SEQ ID NO: 293) | QQSYSTPLT (SEQ ID NO: 298) | SGGYYWS (SEQ ID NO: 312) | YIYYSGSTYYNPSLKS (SEQ ID NO: 332) | DLSRYYYYYMDV (SEQ ID NO: 388) |
RASQGISSWLA (SEQ ID NO: 292) | AASSLQS (SEQ ID NO: 293) | QQYNSYPLT (SEQ ID NO: 303) | SYSMN (SEQ ID NO: 306) | YISSSSSTIYYADSVKG (SEQ ID NO: 327) | EHIVLCFDY (SEQ ID NO: 389) |
RASQSISSYLN (SEQ ID NO: 286) | AASSLQS (SEQ ID NO: 293) | QQSYSTPLT (SEQ ID NO: 298) | SGGYYWS (SEQ ID NO: 312) | YIYYSGSTYYNPSLKS (SEQ ID NO: 332) | DKILPRPYYYYYMDV (SEQ ID NO: 390) |
TGTSSDVGGYNYVS (SEQ ID NO: 288) | EVSKRPS (SEQ ID NO: 295) | SSYAGSNNWV (SEQ ID NO: 300) | SYGIS (SEQ ID NO: 305) | WISAYNGNTNYAQKLQG (SEQ ID NO: 326) | GSNEYFQH (SEQ ID NO: 391) |
RASQSISSYLN (SEQ ID NO: 286) | AASSLQS (SEQ ID NO: 293) | QQSYSTPLT (SEQ ID NO: 298) | SYAMN (SEQ ID NO: 319) | WINTNTGNPTYAQGFTG (SEQ ID NO: 339) | GTSYWYFDL (SEQ ID NO: 392) |
RASQSISSYLN (SEQ ID NO: 286) | AASSLQS (SEQ ID NO: 293) | QQSYSTPLT (SEQ ID NO: 298) | SGGYYWS (SEQ ID NO: 312) | YIYYSGSTYYNPSLKS (SEQ ID NO: 332) | EEIVEVFYYYYMDV (SEQ ID NO: 393) |
RASQSISSYLN (SEQ ID NO: 286) | AASSLQS (SEQ ID NO: 293) | QQSYSTPLT (SEQ ID NO: 298) | SYAMS (SEQ ID NO: 318) | AISGSGGSTYYADSVKG (SEQ ID NO: 338) | VDDYYFDY (SEQ ID NO: 394) |
RASQSISSYLN (SEQ ID NO: 286) | AASSLQS (SEQ ID NO: 293) | QQSYSTPLT (SEQ ID NO: 298) | SYWMH (SEQ ID NO: 315) | RINSDGSSTSYADSVKG (SEQ ID NO: 335) | STNILLSYTKAFDI (SEQ ID NO: 395) |
RASQSISSYLN (SEQ ID NO: 286) | AASSLQS (SEQ ID NO: 293) | QQSYSTPLT (SEQ ID NO: 298) | SGGYYWS (SEQ ID NO: 312) | YIYYSGSTYYNPSLKS (SEQ ID NO: 332) | DKTYYYYYYMDV (SEQ ID NO: 396) |
RASQSISSYLN (SEQ ID NO: 286) | AASSLQS (SEQ ID NO: 293) | QQSYSTPLT (SEQ ID NO: 298) | SGGYYWS (SEQ ID NO: 312) | YIYYSGSTYYNPSLKS (SEQ ID NO: 332) | EKYFHDKYFHDYYYYYMDV (SEQ ID NO: 397) |
RASQSISSYLN (SEQ ID NO: 286) | AASSLQS (SEQ ID NO: 293) | QQSYSTPLT (SEQ ID NO: 298) | SGGYYWS (SEQ ID NO: 312) | YIYYSGSTYYNPSLKS (SEQ ID NO: 332) | DTSVYYYYYMDV (SEQ ID NO: 398) |
RASQSISSYLN (SEQ ID NO: 286) | AASSLQS (SEQ ID NO: 293) | QQSYSTPLT (SEQ ID NO: 298) | SGGYYWS (SEQ ID NO: 312) | YIYYSGSTYYNPSLKS (SEQ ID NO: 332) | EKILPYYYYYYMDV (SEQ ID NO: 399) |
SGSSSNIGSNTVN (SEQ ID NO: 289) | SNNQRPS (SEQ ID NO: 296) | AAWDDSLNGWV (SEQ ID NO: 301) | SYSMN (SEQ ID NO: 306) | YISSSSSTIYYADSVKG (SEQ ID NO: 327) | QWIYIYINPRGFIFLHDAFDI (SEQ ID NO: 400) |
RASQSISSYLN (SEQ ID NO: 286) | AASSLQS (SEQ ID NO: 293) | QQSYSTPLT (SEQ ID NO: 298) | SNSAAWN (SEQ ID NO: 321) | RTYYRSKWYNDYAVSVKS (SEQ ID NO: 341) | EDVDFHHDAFDI (SEQ ID NO: 401) |
RASQSISSYLN (SEQ ID NO: 286) | AASSLQS (SEQ ID NO: 293) | QQSYSTPLT (SEQ ID NO: 298) | SGGYYWS (SEQ ID NO: 312) | YIYYSGSTYYNPSLKS (SEQ ID NO: 332) | EGVDKNTSTIYYYYYYMDV (SEQ ID NO: 402) |
RASQGISSWLA (SEQ ID NO: 292) | AASSLQS (SEQ ID NO: 293) | QQYNSYPLT (SEQ ID NO: 303) | SYSMN (SEQ ID NO: 306) | YISSSSSTIYYADSVKG (SEQ ID NO: 327) | DRRGYFDL (SEQ ID NO: 403) |
RASQSISSYLN (SEQ ID NO: 286) | AASSLQS (SEQ ID NO: 293) | QQSYSTPLT (SEQ ID NO: 298) | DYYMH (SEQ ID NO: 322) | LVDPEDGETIYAEKFQG (SEQ ID NO: 342) | GIHVDIRSMEDWFDP (SEQ ID NO: 404) |
RASQSISSYLN (SEQ ID NO: 286) | AASSLQS (SEQ ID NO: 293) | QQSYSTPLT (SEQ ID NO: 298) | SGGYYWS (SEQ ID NO: 312) | YIYYSGSTYYNPSLKS (SEQ ID NO: 332) | DIGTSYYYYMDV (SEQ ID NO: 405) |
RASQSISSYLN (SEQ ID NO: 286) | AASSLQS (SEQ ID NO: 293) | QQSYSTPLT (SEQ ID NO: 298) | SGGYYWS (SEQ ID NO: 312) | YIYYSGSTYYNPSLKS (SEQ ID NO: 332) | EVVEVFLYYYYYMDV (SEQ ID NO: 406) |
RASQSISSYLN (SEQ ID NO: 286) | AASSLQS (SEQ ID NO: 293) | QQSYSTPLT (SEQ ID NO: 298) | SGGYYWS (SEQ ID NO: 312) | YIYYSGSTYYNPSLKS (SEQ ID NO: 332) | DLYYYYYYYMDV (SEQ ID NO: 407) |
RASQSISSYLN (SEQ ID NO: 286) | AASSLQS (SEQ ID NO: 293) | QQSYSTPLT (SEQ ID NO: 298) | SGGYYWS (SEQ ID NO: 312) | YIYYSGSTYYNPSLKS (SEQ ID NO: 332) | ESWKYFYPRGSIFIHYYYYMDV (SEQ ID NO: 408) |
RASQSISSYLN (SEQ ID NO: 286) | AASSLQS (SEQ ID NO: 293) | QQSYSTPLT (SEQ ID NO: 298) | SGGYYWS (SEQ ID NO: 312) | YIYYSGSTYYNPSLKS (SEQ ID NO: 332) | DRIVEVFYYYYMDV (SEQ ID NO: 409) |
RASQSISSYLN (SEQ ID NO: 286) | AASSLQS (SEQ ID NO: 293) | QQSYSTPLT (SEQ ID NO: 298) | SGGYYWS (SEQ ID NO: 312) | YIYYSGSTYYNPSLKS (SEQ ID NO: 332) | EKYFHDWLYYYYYMDV (SEQ ID NO: 410) |
RASQSISSYLN (SEQ ID NO: 286) | AASSLQS (SEQ ID NO: 293) | QQSYSTPLT (SEQ ID NO: 298) | SGGYYWS (SEQ ID NO: 312) | YIYYSGSTYYNPSLKS (SEQ ID NO: 332) | DLVDKNTSYYYYYMDV (SEQ ID NO: 411) |
TGTSSDVGGYNYVS (SEQ ID NO: 288) | EVSKRPS (SEQ ID NO: 295) | SSYAGSNNWV (SEQ ID NO: 300) | SYGIS (SEQ ID NO: 305) | WISAYNGNTNYAQKLQG (SEQ ID NO: 326) | VQNEYFQH (SEQ ID NO: 412) |
RASQGISSWLA (SEQ ID NO: 292) | AASSLQS (SEQ ID NO: 293) | QQANSFPLT (SEQ ID NO: 304) | DYYMS (SEQ ID NO: 320) | YISSSGSTIYYADSVKG (SEQ ID NO: 340) | ANWFDP (SEQ ID NO: 413) |
HLA-A*01 CDR | |||||
ASSTGAVTSGYYPN (SEQ ID NO: 287) | STSNKHS (SEQ ID NO: 294) | LLYYGGAQWV (SEQ ID NO: 299) | SYGIS (SEQ ID NO: 305) | WISAYNGNTNYAQKLQG (SEQ ID NO: 326) | GGWTAWYYYMDV (SEQ ID NO: 414) |
SGSSSNIGSNTVN (SEQ ID NO: 289) | SNNQRPS (SEQ ID NO: 296) | AAWDDSLNGWV (SEQ ID NO: 301) | SYSMN (SEQ ID NO: 306) | YISSSSSTIYYADSVKG (SEQ ID NO: 327) | AKYYYMDV (SEQ ID NO: 415) |
RASQSISSYLN (SEQ ID NO: 286) | AASSLQS (SEQ ID NO: 293) | QQSYSTPLT (SEQ ID NO: 298) | SGGYYWS (SEQ ID NO: 312) | YIYYSGSTYYNPSLKS (SEQ ID NO: 332) | DQVDKNTYYYYMDV (SEQ ID NO: 416) |
RASQGISSWLA (SEQ ID NO: 292) | AASSLQS (SEQ ID NO: 293) | QQANSFPLT (SEQ ID NO: 304) | DYYMS (SEQ ID NO: 320) | YISSSGSTIYYADSVKG (SEQ ID NO: 340) | ACQLAEYFQH (SEQ ID NO: 417) |
RASQSISSYLN (SEQ ID NO: 286) | AASSLQS (SEQ ID NO: 293) | QQSYSTPLT (SEQ ID NO: 298) | SGGYYWS (SEQ ID NO: 312) | YIYYSGSTYYNPSLKS (SEQ ID NO: 332) | DRVDKNTSYYYMDV (SEQ ID NO: 418) |
RASQSISSYLN (SEQ ID NO: 286) | AASSLQS (SEQ ID NO: 293) | QQSYSTPLT (SEQ ID NO: 298) | SSNWWG (SEQ ID NO: 323) | YIYYSGSTYYNPSLKS (SEQ ID NO: 332) | RVQLKLVHWFDP (SEQ ID NO: 419) |
RASQSISSYLN (SEQ ID NO: 286) | AASSLQS (SEQ ID NO: 293) | QQSYSTPLT (SEQ ID NO: 298) | SYDIN (SEQ ID NO: 324) | WMNPNSGNTGYAQKFQG (SEQ ID NO: 343) | YYDYVTVFYFQH (SEQ ID NO: 420) |
RASQSISSYLN (SEQ ID NO: 286) | AASSLQS (SEQ ID NO: 293) | QQSYSTPLT (SEQ ID NO: 298) | SGGYSWS (SEQ ID NO: 325) | YIYHSGSTYYNPSLKS (SEQ ID NO: 344) | ESYPSFYAFDI (SEQ ID NO: 421) |
RASQSISSYLN (SEQ ID NO: 286) | AASSLQS (SEQ ID NO: 293) | QQSYSTPLT (SEQ ID NO: 298) | TSGVGVG (SEQ ID NO: 314) | LIYWNDDKRYSPSLKS (SEQ ID NO: 334) | SNMWSYSLNDYYFDY (SEQ ID NO: 422) |
在一些實施例中,非靶抗原包含HLA-A*02,且第二受體之配位體結合結構域包含HLA-A*02配位體結合結構域。在一些實施例中,配位體結合結構域結合HLA-A*02而不依賴於包含HLA-A*02之pMHC複合物中之肽。在一些實施例中,HLA-A*02配位體結合結構域包含scFv結構域。在一些實施例中,HLA-A*02配位體結合結構域包含SEQ ID NO: 89-100中之任一者之序列。在一些實施例中,HLA-A*02配位體結合結構域包含與SEQ ID NO: 89-100中之任一者之序列至少90%、至少95%或至少99%一致之序列。
在一些實施例中,HLA-A*02 scFv包含SEQ ID NO: 101-112中之任一者之互補決定區(CDR)。在一些實施例中,scFv包含與SEQ ID NO: 101-112中之任一者至少95%一致之序列。在一些實施例中,scFv包含與SEQ ID NO: 101-112中之任一者一致之序列。在一些實施例中,抗原結合結構域之重鏈包含SEQ ID NO: 101-112中之任一者之重鏈CDR,且其中抗原結合結構域之輕鏈包含SEQ ID NO: 101-112中之任一者之輕鏈CDR。在一些實施例中,HLA-A*02抗原結合結構域包含重鏈及輕鏈,且重鏈包含選自SEQ ID NO: 104-106及110-112之CDR,且輕鏈包含選自SEQ ID NO: 101-103及107-109之CDR。在配位體結合結構域中之任一者之其他實施例中,各CDR序列可具有1、2、3個或更多個取代、插入或缺失。CDR序列可容許取代、缺失或插入。使用序列比對工具、常規實驗及已知檢定,熟習此項技術者無需過度實驗即可生成及測試在CDR序列中具有1、2、3個或更多個取代、插入或缺失之變異序列。
在一些實施例中,HLA-A*02抗原結合結構域包含重鏈及輕鏈,且重鏈包含與SEQ ID NO: 89-100中之任一者之重鏈部分至少95%一致之序列,且輕鏈包含與SEQ ID NO: 89-100中之任一者之輕鏈部分至少95%一致之序列。
在一些實施例中,重鏈包含與SEQ ID NO: 89-100中之任一者之重鏈部分一致之序列,且其中輕鏈包含與SEQ ID NO: 89-100中之任一者之輕鏈部分一致之序列。
在一些實施例中,非靶抗原包含HLA-B*07,且第二受體之配位體結合結構域包含HLA-B*07配位體結合結構域。在一些實施例中,配位體結合結構域結合HLA-B*07而不依賴於包含HLA-B*07之pMHC複合物中之肽。在一些實施例中,HLA-B*07配位體結合結構域包含scFv結構域。在一些實施例中,HLA-B*07配位體結合結構域包含表4中所指示之B7結合結構域中之任一者之序列。在一些實施例中,HLA-B*07配位體結合結構域包含與表4中所指示之HLA-B*07結合結構域中之任一者之序列至少90%、至少95%或至少99%一致之序列。在一些實施例中,HLA-B*07 scFv包含表5中所指示之HLA-B*07互補決定區(CDR)中之任一者。在一些實施例中,scFv包含與表4中所指示之HLA-B*07 scFv序列中之任一者至少95%一致之序列。在一些實施例中,scFv包含與表4中所指示之HLA-B*07 scFv序列中之任一者一致之序列。
在一些實施例中,非靶抗原包含HLA-A*11,且第二受體之配位體結合結構域包含HLA-A*11配位體結合結構域。在一些實施例中,配位體結合結構域結合HLA-A*11而不依賴於包含HLA-A*11之pMHC複合物中之肽。在一些實施例中,HLA-A*11配位體結合結構域包含scFv結構域。在一些實施例中,HLA-A*11配位體結合結構域包含表4中所指示之HLA-A*11結合結構域中之任一者之序列。在一些實施例中,HLA-A*11配位體結合結構域包含與表4中所指示之HLA-A*11結合結構域中之任一者之序列至少90%、至少95%或至少99%一致之序列。在一些實施例中,HLA-A*11 scFv包含表5中所指示之HLA-A*11互補決定區(CDR)中之任一者。在一些實施例中,scFv包含與表4中所指示之HLA-A*11 scFv序列中之任一者至少95%一致之序列。在一些實施例中,scFv包含與表4中所指示之HLA-A*11 scFv序列中之任一者一致之序列。
在一些實施例中,非靶抗原包含HLA-A*01,且第二受體之配位體結合結構域包含HLA-A*01配位體結合結構域。在一些實施例中,配位體結合結構域結合HLA-A*01而不依賴於包含HLA-A*01之pMHC複合物中之肽。在一些實施例中,HLA-A*01配位體結合結構域包含scFv結構域。在一些實施例中,HLA-A*01配位體結合結構域包含表4中所指示之HLA-A*01結合結構域中之任一者之序列。在一些實施例中,HLA-A*01配位體結合結構域包含與表4中所指示之HLA-A*01結合結構域中之任一者之序列至少90%、至少95%或至少99%一致之序列。在一些實施例中,HLA-A*01 scFv包含表5中所指示之HLA-A*01互補決定區(CDR)中之任一者。在一些實施例中,scFv包含與表4中所指示之HLA-A*01 scFv序列中之任一者至少95%一致之序列。在一些實施例中,scFv包含與表4中所指示之HLA-A*01 scFv序列中之任一者一致之序列。
在一些實施例中,非靶抗原包含HLA-A*03,且第二受體之配位體結合結構域包含HLA-A*03配位體結合結構域。在一些實施例中,配位體結合結構域結合HLA-A*03而不依賴於包含HLA-A*03之pMHC複合物中之肽。在一些實施例中,HLA-A*03配位體結合結構域包含scFv結構域。在一些實施例中,HLA-A*03配位體結合結構域包含表4中所指示之HLA-A*03結合結構域中之任一者之序列。在一些實施例中,HLA-A*03配位體結合結構域包含與表4中所指示之HLA-A*03結合結構域中之任一者之序列至少90%、至少95%或至少99%一致之序列。在一些實施例中,HLA-A*03 scFv包含表5中所指示之HLA-A*03互補決定區(CDR)中之任一者。在一些實施例中,scFv包含與表4中所指示之HLA-A*03 scFv序列中之任一者至少95%一致之序列。在一些實施例中,scFv包含與表4中所指示之HLA-A*03 scFv序列中之任一者一致之序列。
在一些實施例中,非靶抗原包含HLA-C*07,且第二受體之配位體結合結構域包含HLA-C*07配位體結合結構域。在一些實施例中,配位體結合結構域結合HLA-C*07而不依賴於包含HLA-C*07之pMHC複合物中之肽。在一些實施例中,HLA-C*07配位體結合結構域包含scFv結構域。在一些實施例中,HLA-C*07配位體結合結構域包含表4中所指示之HLA-C*07結合結構域中之任一者之序列。在一些實施例中,HLA-C*07配位體結合結構域包含與表4中所指示之HLA-C*07結合結構域中之任一者之序列至少90%、至少95%或至少99%一致之序列。在一些實施例中,HLA-C*07 scFv包含表5中所指示之HLA-C*07互補決定區(CDR)中之任一者。在一些實施例中,scFv包含與表4中所指示之HLA-C*07 scFv序列中之任一者至少95%一致之序列。在一些實施例中,scFv包含與表4中所指示之HLA-C*07 scFv序列中之任一者一致之序列。
抑制性嵌合抗原受體
本揭示案提供第二受體,該第二受體為抑制性嵌合抗原受體(亦即,抑制性受體)。抑制性受體可包含結合至並識別MHC-I複合物中之非靶抗原或其肽衍生物之細胞外配位體結合結構域。
示例性抑制性受體描述於2020年9月6日申請之PCT/US2020/045228、2020年12月11日申請之PCT/US2020/064607、2021年4月29日申請之PCT/US2021/029907及2020年11月10日申請之PCT/US2020/059856中,各文獻之內容以引用之方式併入本文中。
非靶抗原可為非靶對偶基因變異體。如本文所用,「非靶對偶基因變異體」係指對偶基因(例如,MHC I類基因之對偶基因變異體),其在靶細胞(例如,癌細胞)中之表現由於雜合性損失或另一種表現損失機制而降低或消除,但在正常或健康細胞中表現或可偵測地表現。
如本文所用,術語「抑制性嵌合抗原受體」或「抑制性受體」係指融合至細胞內信號傳導結構域之抗原結合結構域,該細胞內信號傳導結構域能夠轉導抑制或阻抑免疫細胞之免疫活性的抑制性信號。抑制性受體具有免疫細胞抑制潛力且與CAR截然不同且可區分,該等CAR為具有免疫細胞活化潛力之受體。舉例而言,CAR為活化受體,此係因為其包括細胞內刺激及/或共刺激結構域。抑制性受體為含有細胞內抑制性結構域之抑制性受體。
如本文所用,「抑制性信號」係指信號轉導或免疫細胞中蛋白質表現之變化,從而阻抑免疫反應(例如,細胞激素產生減少或免疫細胞活化降低)。免疫細胞之抑制或阻抑可為選擇性的及/或可逆的,或非選擇性的及/或可逆的。抑制性受體對非靶抗原(例如,HLA-A*02)有反應。舉例而言,當非靶抗原(例如,HLA-A*02)結合至或接觸抑制性受體時,抑制性受體有反應且在非靶抗原由抑制性受體之細胞外配位體結合結構域結合後在表現抑制性受體之免疫細胞中活化抑制性信號。
本揭示案之抑制性受體可包含細胞外配位體結合結構域。設想可依配位體依賴性方式調控受體活性之任何類型之配位體結合結構域在本揭示案之範疇內。
在一些實施例中,配位體結合結構域為抗原結合結構域。示例性抗原結合結構域尤其包括scFv、SdAb、僅Vβ結構域及來源於TCR α及β鏈可變結構域之TCR抗原結合結構域。
設想任何類型之抗原結合結構域在本揭示案之範疇內。
在一些實施例中,第二受體之細胞外配位體結合結構域結合至並識別COLEC12、APCDD1、CXCL16之多態變異體,或與主要組織相容性複合物I類(MHC-I)複合之其抗原肽,或HLA-A*02。在一些實施例中,第二受體之細胞外配位體結合結構域為scFv。
在一些實施例中,第二受體之細胞外配位體結合結構域融合至抑制性受體之細胞外結構域。
在一些實施例中,本揭示案之抑制性受體包含細胞外鉸鏈區。示例性鉸鏈可分離自或來源於IgD及CD8結構域,例如,IgG1。在一些實施例中,鉸鏈分離自或來源於CD8α或CD28。
本揭示案之抑制性受體可經設計以包含融合至抑制性受體之細胞外結構域的跨膜結構域。在一些情況下,跨膜結構域可藉由胺基酸取代來選擇或修飾以避免此類結構域結合至相同或不同表面膜蛋白之跨膜結構域,從而使得與受體複合物之其他成員之相互作用最小化。
跨膜結構域可來源於天然或合成來源。若來源為天然的,則結構域可來源於任何膜結合蛋白或跨膜蛋白。跨膜區可分離自或來源於T細胞受體α、β或ζ鏈、CD28、CD3 ε、CD45、CD4、CD5、CD8、CD9、CD16、CD22、CD33、CD37、CD64、CD80、CD86、CD134、CD137、CD154 (亦即,至少包含其跨膜區),或來自免疫球蛋白,諸如IgG4。或者,跨膜結構域可為合成的,在此種情況下,其將主要包含疏水性殘基,諸如白胺酸及纈胺酸。在一些實施例中,在合成跨膜結構域之各末端將發現苯丙胺酸、色胺酸及纈胺酸之三聯體。視情況,長度較佳在2個與10個胺基酸之間的短寡肽或多肽連接子可形成抑制性受體之跨膜結構域與細胞內結構域之間的連接。甘胺酸-絲胺酸雙聯體提供尤其適合之連接子。
本揭示案提供包含細胞內結構域之抑制性受體。本揭示案之抑制性受體之細胞內結構域負責抑制包含抑制性受體之免疫細胞的活化,否則免疫細胞將對活化信號作出反應而由第一受體活化。在一些實施例中,抑制性細胞內結構域包含基於免疫受體酪胺酸之抑制性基元(ITIM)。在一些實施例中,包含ITIM之抑制性細胞內結構域可分離自或來源於免疫檢查點抑制劑,諸如CTLA-4及PD-1。CTLA-4及PD-1為在T細胞表面上表現之免疫抑制性受體,且在減弱或終止T細胞反應中起關鍵作用。
在一些實施例中,抑制性細胞內結構域自人類腫瘤壞死因子相關凋亡誘導配位體(TRAIL)受體及CD200受體1分離。在一些實施例中,TRAIL受體包括TR10A、TR10B或TR10D。
在一些實施例中,抑制性細胞內結構域自具有醣神經鞘脂質微結構域1 (PAG1)之磷蛋白膜錨分離。在一些實施例中,抑制性細胞內結構域自白血球免疫球蛋白樣受體B1 (LILRB1)分離。
在一些實施例中,抑制性結構域分離自或來源於人類蛋白質,例如,人類TRAIL受體、CTLA-4、PD-1、PAG1或LILRB1蛋白質。
在一些實施例中,抑制性結構域包括細胞內結構域、跨膜或其組合。在一些實施例中,抑制性結構域包括細胞內結構域、跨膜結構域、鉸鏈區或其組合。
在一些實施例中,抑制性結構域分離自或來源於殺死細胞免疫球蛋白樣受體、三個Ig結構域及長胞質尾2 (KIR3DL2)、殺死細胞免疫球蛋白樣受體、三個Ig結構域及長胞質尾3 (KIR3DL3)、白血球免疫球蛋白樣受體B1 (LIR1,亦稱為LIR-1及LILRB1)、程式性細胞死亡1 (PD-1)、Fc γ受體IIB (FcgRIIB)、殺死細胞凝集素樣受體K1 (NKG2D)、CTLA-4、含合成共通ITIM結構域、ZAP70 SH2結構域(例如,N端及C端SH2結構域中之一或兩者)或ZAP70 KI_K369A (激酶失活ZAP70)。
在一些實施例中,抑制性結構域分離自或來源於人類蛋白質。
在一些實施例中,第二抑制性受體包含抑制性結構域。在一些實施例中,第二抑制性受體包含抑制性細胞內結構域及/或抑制性跨膜結構域。在一些實施例中,抑制性細胞內結構域融合至抑制性受體之細胞內結構域。在一些實施例中,抑制性細胞內結構域融合至抑制性受體之跨膜結構域。
在一些實施例中,第二抑制性受體包含分離自或來源於相同蛋白質(例如,含ITIM蛋白質)之細胞質結構域、跨膜結構域及細胞外結構域或其一部分。在一些實施例中,第二抑制性受體包含與細胞內結構域及/或跨膜結構域分離自或來源於相同蛋白質(例如,含ITIM蛋白質)之鉸鏈區。
在一些實施例中,第二受體為包含抑制性結構域之TCR (抑制性TCR)。在一些實施例中,抑制性TCR包含抑制性細胞內結構域及/或抑制性跨膜結構域。在一些實施例中,抑制性細胞內結構域融合至TCR之TCR α、TCR β、CD3 δ、CD3 γ或CD3 ε或其一部分之細胞內結構域。在一些實施例中,抑制性細胞內結構域融合至TCR α、TCR β、CD3 δ、CD3 γ或CD3 ε之跨膜結構域。
在一些實施例中,第二受體為包含抑制性結構域之TCR (抑制性TCR)。在一些實施例中,抑制性結構域分離自或來源於LILRB1。
LILRB1抑制性受體
本揭示案提供包含LILRB1抑制性結構域及視情況存在之LILRB1跨膜及/或鉸鏈結構域之第二抑制性受體或其功能變異體。與具有其他跨膜結構域或其他鉸鏈結構域之參考抑制性受體相比,抑制性受體中包含LILRB1跨膜結構域及/或LILRB1鉸鏈結構域可增加由抑制性受體產生之抑制性信號。如本文所述,包含LILRB1抑制性結構域之第二抑制性受體可為CAR或TCR。如本文所述,任何適合之配位體結合結構域可融合至基於LILRB1之第二抑制性受體。
白血球免疫球蛋白樣受體亞家族B成員1 (LILRB1),亦稱為白血球免疫球蛋白樣受體B1,以及ILT2、LIR1、MIR7、PIRB、CD85J、ILT-2 LIR-1、MIR-7及PIR-B,為白血球免疫球蛋白樣受體(LIR)家族之成員。LILRB1蛋白屬於LIR受體之亞家族B類。此等受體含有兩個至四個細胞外免疫球蛋白結構域、跨膜結構域及兩個至四個基於細胞質免疫受體酪胺酸之抑制基元(ITIM)。LILRB1受體在免疫細胞上表現,在此處該受體結合至抗原呈現細胞上之 MHC I類分子且轉導抑制免疫反應刺激之負信號。據信LILRB1調控發炎反應以及細胞毒性,且在限制自體反應性中起作用。存在編碼LILRB1之不同同種型的多種轉錄變異體,預期所有此等變異體皆在本揭示案之範疇內。
在本文所述之抑制性受體之一些實施例中,抑制性受體包含一或多個分離自或來源於LILRB1之結構域。在具有一或多個分離自或來源於LILRB1之結構域的受體之一些實施例中,LILRB1之一或多個結構域包含與SEQ ID NO: 113之序列或子序列至少80%、至少90%、至少95%、至少96%、至少97%、至少98%、至少99%或一致之胺基酸序列。在一些實施例中,LILRB1之一或多個結構域包含與SEQ ID NO: 113之序列或子序列一致之胺基酸序列。在一些實施例中,LILRB1之一或多個結構域由與SEQ ID NO: 113之序列或子序列至少80%、至少90%、至少95%、至少96%、至少97%、至少98%、至少99%或一致之胺基酸序列組成。在一些實施例中,LILRB1之一或多個結構域由與SEQ ID NO: 113之序列或子序列一致之胺基酸序列組成。
在具有一或多個分離自或來源於LILRB1之結構域的受體之一些實施例中,LILRB1之一或多個結構域由與以下序列或子序列至少80%、至少90%、至少95%、至少96%、至少97%、至少98%、至少99%或一致之多核苷酸序列編碼:
在具有LILRB1之一或多個結構域的受體之一些實施例中,LILRB1之一或多個結構域由與SEQ ID NO: 114之序列或子序列一致之多核苷酸序列編碼。
在各種實施例中,提供包含多肽之抑制性受體,其中該多肽包含以下一或多者:LILRB1鉸鏈結構域或其功能片段或變異體;LILRB1跨膜結構域或其功能變異體;及LILRB1細胞內結構域或包含至少一個或至少兩個基於免疫受體酪胺酸之抑制基元(ITIM)之細胞內結構域,其中各ITIM獨立地選自NLYAAV (SEQ ID NO: 115)、VTYAEV (SEQ ID NO: 116)、VTYAQL (SEQ ID NO: 117)及SIYATL (SEQ ID NO: 118)。
如本文所用,「基於免疫受體酪胺酸之抑制基元」或「ITIM」係指具有S/I/V/LxYxxI/V/L (SEQ ID NO: 423)之共通序列或類似序列之胺基酸的保守序列,該序列在免疫系統之許多抑制性受體之胞質尾中發現。在具有ITIM之抑制性受體與其配位體相互作用之後,ITIM基元經磷酸化,從而允許抑制性受體募集其他酶,諸如磷酸酪胺酸磷酸酶SHP-1及SHP-2,或稱為SHIP之肌醇磷酸酶。
在一些實施例中,多肽包含含有至少一個基於免疫受體酪胺酸之抑制基元(ITIM)、至少兩個ITIM、至少3個ITIM、至少4個ITIM、至少5個ITIM或至少6個ITIM之細胞內結構域。在一些實施例中,細胞內結構域具有1、2、3、4、5或6個ITIM。
在一些實施例中,多肽包含含有至少一個ITIM之細胞內結構域,該ITIM係選自由NLYAAV (SEQ ID NO: 115)、VTYAEV (SEQ ID NO: 116)、VTYAQL (SEQ ID NO: 117)及SIYATL (SEQ ID NO: 118)組成之群。
在其他特定實施例中,多肽包含含有至少兩個基於免疫受體酪胺酸之抑制基元(ITIM)之細胞內結構域,其中各ITIM獨立地選自NLYAAV (SEQ ID NO: 115)、VTYAEV (SEQ ID NO: 116)、VTYAQL (SEQ ID NO: 117)及SIYATL (SEQ ID NO: 118)。
在一些實施例中,細胞內結構域包含兩個ITIM NLYAAV (SEQ ID NO: 115)及VTYAEV (SEQ ID NO: 116)。在一些實施例中,細胞內結構域包含與SEQ ID NO: 119至少95%一致之序列。在一些實施例中,細胞內結構域包含或基本上由與SEQ ID NO: 119一致之序列組成。
在一些實施例中,細胞內結構域包含兩個ITIM VTYAEV (SEQ ID NO: 116)及VTYAQL (SEQ ID NO: 117)。在一些實施例中,細胞內結構域包含與SEQ ID NO: 120至少95%一致之序列。在一些實施例中,細胞內結構域包含或基本上由與SEQ ID NO: 120一致之序列組成。
在一些實施例中,細胞內結構域包含兩個ITIM VTYAQL (SEQ ID NO: 117)及SIYATL (SEQ ID NO: 118)。在一些實施例中,細胞內結構域包含與SEQ ID NO: 121至少95%一致之序列。在一些實施例中,細胞內結構域包含或基本上由與SEQ ID NO: 121一致之序列組成。
在一些實施例中,細胞內結構域包含ITIM NLYAAV (SEQ ID NO: 115)、VTYAEV (SEQ ID NO: 116)及VTYAQL (SEQ ID NO: 117)。在一些實施例中,細胞內結構域包含與SEQ ID NO: 122至少95%一致之序列。在一些實施例中,細胞內結構域包含或基本上由與SEQ ID NO: 122一致之序列組成。
在一些實施例中,細胞內結構域包含ITIM VTYAEV (SEQ ID NO: 116)、VTYAQL (SEQ ID NO: 117)及SIYATL (SEQ ID NO: 118)。在一些實施例中,細胞內結構域包含與SEQ ID NO: 123至少95%一致之序列。在一些實施例中,細胞內結構域包含或基本上由與SEQ ID NO: 123一致之序列組成。
在一些實施例中,細胞內結構域包含ITIM NLYAAV (SEQ ID NO: 115)、VTYAEV (SEQ ID NO: 116)、VTYAQL (SEQ ID NO: 117)及SIYATL (SEQ ID NO: 118)。在實施例中,細胞內結構域包含與SEQ ID NO: 124至少95%一致之序列。在一些實施例中,細胞內結構域包含或基本上由與SEQ ID NO: 124一致之序列組成。
在一些實施例中,細胞內結構域包含與LILRB1細胞內結構域(SEQ ID NO: 129)至少95%一致之序列。在一些實施例中,細胞內結構域包含或基本上由與LILRB1細胞內結構域(SEQ ID NO: 129)一致之序列組成。
本揭示案之LILRB1細胞內結構域或其功能變異體可具有至少1個、至少2個、至少4個、至少4個、至少5個、至少6個、至少7個或至少8個ITIM。在一些實施例中,LILRB1細胞內結構域或其功能變異體具有2、3、4、5或6個ITIM。
在特定實施例中,細胞內結構域包含兩個、三個、四個、五個或六個基於免疫受體酪胺酸之抑制基元(ITIM),其中各ITIM獨立地選自NLYAAV (SEQ ID NO: 115)、VTYAEV (SEQ ID NO: 116)、VTYAQL (SEQ ID NO: 117)及SIYATL (SEQ ID NO: 118)。
在特定實施例中,細胞內結構域包含至少三個基於免疫受體酪胺酸之抑制基元(ITIM),其中各ITIM獨立地選自NLYAAV (SEQ ID NO: 115)、VTYAEV (SEQ ID NO: 116)、VTYAQL (SEQ ID NO: 117)及SIYATL (SEQ ID NO: 118)。
在特定實施例中,細胞內結構域包含三個基於免疫受體酪胺酸之抑制基元(ITIM),其中各ITIM獨立地選自NLYAAV (SEQ ID NO: 115)、VTYAEV (SEQ ID NO: 116)、VTYAQL (SEQ ID NO: 117)及SIYATL (SEQ ID NO: 118)。
在特定實施例中,細胞內結構域包含四個基於免疫受體酪胺酸之抑制基元(ITIM),其中各ITIM獨立地選自NLYAAV (SEQ ID NO: 115)、VTYAEV (SEQ ID NO: 116)、VTYAQL (SEQ ID NO: 117)及SIYATL (SEQ ID NO: 118)。
在特定實施例中,細胞內結構域包含五個基於免疫受體酪胺酸之抑制基元(ITIM),其中各ITIM獨立地選自NLYAAV (SEQ ID NO: 115)、VTYAEV (SEQ ID NO: 116)、VTYAQL (SEQ ID NO: 117)及SIYATL (SEQ ID NO: 118)。
在特定實施例中,細胞內結構域包含六個基於免疫受體酪胺酸之抑制基元(ITIM),其中各ITIM獨立地選自NLYAAV (SEQ ID NO: 115)、VTYAEV (SEQ ID NO: 116)、VTYAQL (SEQ ID NO: 117)及SIYATL (SEQ ID NO: 118)。
在特定實施例中,細胞內結構域包含至少七個基於免疫受體酪胺酸之抑制基元(ITIM),其中各ITIM獨立地選自NLYAAV (SEQ ID NO: 115)、VTYAEV (SEQ ID NO: 116)、VTYAQL (SEQ ID NO: 117)及SIYATL (SEQ ID NO: 118)。
LILRB1蛋白具有四個免疫球蛋白(Ig)樣結構域,稱為D1、D2、D3及D4。在一些實施例中,LILRB1鉸鏈結構域包含LILRB1 D3D4結構域或其功能變異體。在一些實施例中,LILRB1 D3D4結構域包含與SEQ ID NO: 125至少95%、至少96%、至少97%、至少98%、至少99%或一致之序列。在一些實施例中,LILRB1 D3D4結構域包含或基本上由SEQ ID NO: 125組成。
在一些實施例中,多肽包含LILRB1鉸鏈結構域或其功能片段或變異體。在實施例中,LILRB1鉸鏈結構域或其功能片段或變異體包含與SEQ ID NO: 132、SEQ ID NO: 125或SEQ ID NO: 126至少95%、至少96%、至少97%、至少98%、至少99%一致或一致之序列。在實施例中,LILRB1鉸鏈結構域或其功能片段或變異體包含與SEQ ID NO: 132、SEQ ID NO: 125或SEQ ID NO: 126至少95%一致之序列。
在一些實施例中,LILRB1鉸鏈結構域包含與SEQ ID NO: 132、SEQ ID NO: 125或SEQ ID NO: 126一致之序列。
在一些實施例中,LILRB1鉸鏈結構域基本上由與SEQ ID NO: 132、SEQ ID NO: 125或SEQ ID NO: 126一致之序列組成。
在一些實施例中,跨膜結構域為LILRB1跨膜結構域或其功能變異體。在一些實施例中,LILRB1跨膜結構域或其功能變異體包含與SEQ ID NO: 133至少95%一致、至少96%一致、至少97%一致、至少98%一致或至少99%之序列。在一些實施例中,LILRB1跨膜結構域或其功能變異體包含與SEQ ID NO: 133至少95%一致之序列。在一些實施例中,LILRB1跨膜結構域包含與SEQ ID NO: 133一致之序列。在實施例中,LILRB1跨膜結構域基本上由與SEQ ID NO: 133一致之序列組成。
在一些實施例中,跨膜結構域可經由鉸鏈,例如來自人類蛋白質之鉸鏈附接至第二抑制性受體之細胞外區,例如,抗原結合結構域或配位體結合結構域。舉例而言,在一些實施例中,鉸鏈可為人類免疫球蛋白(Ig)鉸鏈,例如,IgG4鉸鏈、CD8a鉸鏈或LILRB1鉸鏈。
在一些實施例中,第二抑制性受體包含抑制性結構域。在一些實施例中,第二抑制性受體包含抑制性細胞內結構域及/或抑制性跨膜結構域。在一些實施例中,抑制性結構域分離自或來源於LILR1B。
包含LILRB1結構域之組合的抑制性受體
在一些實施例中,本揭示案之基於LILRB1之抑制性受體包含多於一個LILRB1結構域或其功能等效物。舉例而言,在一些實施例中,抑制性受體包含LILRB1跨膜結構域及細胞內結構域,或LILRB1鉸鏈結構域、跨膜結構域及細胞內結構域。
在特定實施例中,抑制性受體包含LILRB1鉸鏈結構域或其功能片段或變異體,及LILRB1跨膜結構域或其功能變異體。在一些實施例中,多肽包含與SEQ ID NO: 127至少95%一致、至少96%一致、至少97%一致、至少98%一致、至少99%一致或一致之序列。在一些實施例中,多肽包含與SEQ ID NO: 127至少95%一致之序列。在一些實施例中,多肽包含與SEQ ID NO: 127一致之序列。
在其他實施例中,抑制性受體包含:LILRB1跨膜結構域或其功能變異體,及LILRB1細胞內結構域及/或包含至少一個基於免疫受體酪胺酸之抑制基元(ITIM)之細胞內結構域,其中ITIM係選自NLYAAV (SEQ ID NO: 115)、VTYAEV (SEQ ID NO: 116)、VTYAQL (SEQ ID NO: 117)及SIYATL (SEQ ID NO: 118)。在一些實施例中,多肽包含LILRB1跨膜結構域或其功能變異體,及LILRB1細胞內結構域及/或包含至少兩個ITIM之細胞內結構域,其中各ITIM獨立地選自NLYAAV (SEQ ID NO: 115)、VTYAEV (SEQ ID NO: 116)、VTYAQL (SEQ ID NO: 117)及SIYATL (SEQ ID NO: 118)。
在一些實施例中,抑制性受體包含LILRB1跨膜結構域及細胞內結構域。在一些實施例中,多肽包含與SEQ ID NO: 128至少95%一致、至少96%一致、至少97%一致、至少98%一致、至少99%一致或一致之序列。在一些實施例中,多肽包含與SEQ ID NO: 128至少95%一致之序列。在一些實施例中,多肽包含與SEQ ID NO: 128一致之序列。
在較佳實施例中,抑制性受體包含:LILRB1鉸鏈結構域或其功能片段或變異體;LILRB1跨膜結構域或其功能變異體;及LILRB1細胞內結構域及/或包含至少兩個基於免疫受體酪胺酸之抑制基元(ITIM)之細胞內結構域,其中各ITIM獨立地選自LYAAV (SEQ ID NO: 115)、VTYAE (SEQ ID NO: 116)、VTYAQL (SEQ ID NO: 117)及SIYATL (SEQ ID NO: 118)。
在一些實施例中,抑制性受體包含與SEQ ID NO: 130或SEQ ID NO: 131至少95%一致,或與SEQ ID NO: 130或SEQ ID NO: 131至少99%一致,或與SEQ ID NO: 130或SEQ ID NO: 131一致之序列。
在一些實施例中,多肽包含與SEQ ID NO: 127至少99%一致,或與SEQ ID NO: 127至少99%一致,或與SEQ ID NO: 127一致之序列。
在一些實施例中,多肽包含與SEQ ID NO: 128至少99%一致,或與SEQ ID NO: 128至少99%一致,或與SEQ ID NO: 128一致之序列。
表6. 說明性的基於LILRB1之抑制性受體之多肽序列
多核苷酸及載體
名稱 | 序列 |
LILRB1 | MTPILTVLICLGLSLGPRTHVQAGHLPKPTLWAEPGSVITQGSPVTLRCQGGQETQEYRLYREKKTALWITRIPQELVKKGQFPIPSITWEHAGRYRCYYGSDTAGRSESSDPLELVVTGAYIKPTLSAQPSPVVNSGGNVILQCDSQVAFDGFSLCKEGEDEHPQCLNSQPHARGSSRAIFSVGPVSPSRRWWYRCYAYDSNSPYEWSLPSDLLELLVLGVSKKPSLSVQPGPIVAPEETLTLQCGSDAGYNRFVLYKDGERDFLQLAGAQPQAGLSQANFTLGPVSRSYGGQYRCYGAHNLSSEWSAPSDPLDILIAGQFYDRVSLSVQPGPTVASGENVTLLCQSQGWMQTFLLTKEGAADDPWRLRSTYQSQKYQAEFPMGPVTSAHAGTYRC YGSQSSKPYLLTHPSDPLEL VVSGPSGGPSSPTTGPTSTSGPEDQPLTPTGSDPQSGLGRHLGVVIGILVAVILLLLLLLLLFLILRHRRQGKHWTSTQRKADFQHPAGAVGPEPTDRGLQWRSSPAADAQEEN LYAAV KHTQPEDGVEMDTRSPHDEDPQA VTYAEV KHSRPRREMASPPSPLSGEFLDTKDRQAEEDRQMDTEAAASEAPQD VTYAQ LHSLTLRREATEPPPSQEGPSPAVP SIYAT LAIHPSQEGPSPAVPSIYATLAIH SEQ ID NO: 113 |
LILRB1鉸鏈-跨膜-細胞內結構域 | YGSQSSKPYLLTHPSDPLEL VVSGPSGGPSSPTTGPTSTSGPEDQPLTPTGSDPQSGLGRHLG VVIGILVAVILLLLLLLLLFLILRHRRQGKHWTSTQRKADFQHPAGAVGPEPTDRGLQWRSSPAADAQEENLYAAVKHTQPEDGVEMDTRSPHDEDPQAVTYAEVKHSRPRREMASPPSPLSGEFLDTKDRQAEEDRQMDTEAAASEAPQDVTYAQLHSLTLRREATEPPPSQEGPSPAVPSIYATLAIH SEQ ID NO: 130 |
LILRB1鉸鏈-跨膜-細胞內結構域(w/o YGSQSSKPYLLTHPSDPLEL) | VVSGPSGGPSSPTTGPTSTSGPEDQPLTPTGSDPQSGLGRHLG VVIGILVAVILLLLLLLLLFLILRHRRQGKHWTSTQRKADFQHPAGAVGPEPTDRGLQWRSSPAADAQEENLYAAVKHTQPEDGVEMDTRSPHDEDPQAVTYAEVKHSRPRREMASPPSPLSGEFLDTKDRQAEEDRQMDTEAAASEAPQDVTYAQLHSLTLRREATEPPPSQEGPSPAVPSIYATLAIH SEQ ID NO: 131 |
LILRB1鉸鏈結構域 | YGSQSSKPYLLTHPSDPLEL VVSGPSGGPSSPTTGPTSTSGPEDQPLTPTGSDPQSGLGRHLG SEQ ID NO: 132 |
LILRB1跨膜結構域 | VVIGILVAVILLLLLLLLLFLILSEQ ID NO: 133 |
LILRB1細胞內結構域 | RHRRQGKHWTSTQRKADFQHPAGAVGPEPTDRGLQWRSSPAADAQEENLYAAVKHTQPEDGVEMDTRSPHDEDPQAVTYAEVKHSRPRREMASPPSPLSGEFLDTKDRQAEEDRQMDTEAAASEAPQDVTYAQLHSLTLRREATEPPPSQEGPSPAVPSIYATLAIH SEQ ID NO: 129 |
ITIM1 | NLYAAV SEQ ID NO: 115 |
ITIM2 | VTYAEV SEQ ID NO: 116 |
ITIM3 | VTYAQL SEQ ID NO: 117 |
ITIM4 | SIYATL SEQ ID NO: 118 |
ITIM1-2 | NLYAAV KHTQPEDGVEMDTRSPHDEDPQA VTYAEV SEQ ID NO: 119 |
ITIM2-3 | VTYAEV KHSRPRREMASPPSPLSGEFLDTKDRQAEEDRQMDTEAAASEAPQD VTYAQL SEQ ID NO: 120 |
ITIM3-4 | VTYAQL HSLTLRREATEPPPSQEGPSPAVP SIYATL SEQ ID NO: 121 |
ITIM1-3 | NLYAAV KHTQPEDGVEMDTRSPHDEDPQA VTYAEV KHSRPRREMASPPSPLSGEFLDTKDRQAEEDRQMDTEAAASEAPQD VTYAQL SEQ ID NO: 122 |
ITIM2-4 | VTYAEV KHSRPRREMASPPSPLSGEFLDTKDRQAEEDRQMDTEAAASEAPQD VTYAQL HSLTLRREATEPPPSQEGPSPAVP SIYATL SEQ ID NO: 123 |
ITIM1-4 | NLYAAV KHTQPEDGVEMDTRSPHDEDPQA VTYAEV KHSRPRREMASPPSPLSGEFLDTKDRQAEEDRQMDTEAAASEAPQD VTYAQL HSLTLRREATEPPPSQEGPSPAVP SIYATL SEQ ID NO: 124 |
D3D4結構域 | YGSQSSKPYLLTHPSDPLEL SEQ ID NO: 125 |
短鉸鏈 | VVSGPSGGPSSPTTGPTSTSGPEDQPLTPTGSDPQSGLGRHLG SEQ ID NO: 126 |
鉸鏈(iTIM鉸鏈) | YGSQSSKPYLLTHPSDPLELVVSGPSGGPSSPTTGPTSTSGPEDQPLTPTGSDPQSGLGRHLGV (SEQ ID NO: 424) |
短鉸鏈2 | VVSGPSGGPSSPTTGPTSTSGPEDQPLTPTGSDPQSGLGRHLGV (SEQ ID NO: 425) |
長鉸鏈1 | AGSGGSGGSGGSPVPSTPPTPSPSTPPTPSPSGGSGNSSGSGGSPVPSTPPTPSPSTPPTPSPSASV (SEQ ID NO: 426) |
長鉸鏈2 | AGSGGSGGSGGSPVPSTPPTNSSSTPPTPSPSPVPSTPPTNSSSTPPTPSPSPVPSTPPTNSSSTPPTPSPSASV (SEQ ID NO: 427) |
2x短鉸鏈 | VVSGPSGGPSSPTTGPTSTSGPEDQPLTPTGSDPQSGLGRHVVSGPSGGPSSPTTGPTSTSGPEDQPLTPTGSDPQSGLGRHLGV (SEQ ID NO: 428) |
鉸鏈(截短) | TTGPTSTSGPEDQPLTPTGSDPQSGLGRHLGV (SEQ ID NO: 429) |
鉸鏈-跨膜 | YGSQSSKPYLLTHPSDPLEL VVSGPSGGPSSPTTGPTSTSGPEDQPLTPTGSDPQSGLGRHLG VVIGILVAVILLLLLLLLLFLILSEQ ID NO: 127 |
跨膜-細胞內結構域 | VVIGILVAVILLLLLLLLLFLILRHRRQGKHWTSTQRKADFQHPAGAVGPEPTDRGLQWRSSPAADAQEENLYAAVKHTQPEDGVEMDTRSPHDEDPQAVTYAEVKHSRPRREMASPPSPLSGEFLDTKDRQAEEDRQMDTEAAASEAPQDVTYAQLHSLTLRREATEPPPSQEGPSPAVPSIYATLAIH SEQ ID NO: 128 |
本揭示案提供編碼本揭示案之第一受體及第二受體之序列的多核苷酸。本揭示案提供包含本文所述之多核苷酸及載體之免疫細胞。
在一些實施例中,第一受體及/或第二受體之序列可操作地連接至啟動子。在一些實施例中,編碼第一受體之序列可操作地連接至第一啟動子,且編碼第二受體之序列可操作地連接至第二啟動子。
本揭示案提供包含本文所述之多核苷酸之載體。
在一些實施例中,第一受體由第一載體編碼且第二受體由第二載體編碼。在一些實施例中,兩個受體均由單個載體編碼。
在一些實施例中,第一受體及第二受體由單個載體編碼。使用單個載體編碼多個多肽之方法將為一般熟習此項技術者所知,且尤其包括在不同啟動子控制下編碼多個多肽,或者若單個啟動子用於控制多個多肽之轉錄,則使用編碼內部核糖體進入位點(IRES)及/或自裂解肽之序列。示例性自裂解肽包括T2A、P2A、E2A及F2A自裂解肽。在一些實施例中,T2A自裂解肽包含EGRGSLLTCGDVEENPGP (SEQ ID NO: 430)之序列。在一些實施例中,P2A自裂解肽包含ATNFSLLKQAGDVEENPGP (SEQ ID NO: 431)之序列。在一些實施例中,E2A自裂解肽包含QCTNYALLKLAGDVESNPGP (SEQ ID NO: 432)之序列。在一些實施例中,F2A自裂解肽包含VKQTLNFDLLKLAGDVESNPGP (SEQ ID NO: 433)之序列。在一些實施例中,T2A自裂解肽包含EGRGSLLTCGDVEENPGP (SEQ ID NO: 430)之序列。前述任一者亦可包括N端GSG連接子。舉例而言,T2A自裂解肽亦可包含GSGEGRGSLLTCGDVEENPGP (SEQ ID NO: 178)之序列,其可由GGATCCGGAGAGGGCAGAGGCAGCCTGCTGACATGTGGCGACGTGGAAGAGAACCCTGGCCCC (SEQ ID NO: 434)之序列編碼。
在一些實施例中,載體包含SEQ ID NO: 180,或與其共享至少80%、至少85%、至少90%、至少95%或至少98%一致性之序列。在一些實施例中,載體包含SEQ ID NO: 181,或與其共享至少80%、至少85%、至少90%、至少95%或至少98%一致性之序列。在一些實施例中,載體包含SEQ ID NO: 182,或與其共享至少80%、至少85%、至少90%、至少95%或至少98%一致性之序列。在一些實施例中,載體包含SEQ ID NO: 183,或與其共享至少80%、至少85%、至少90%、至少95%或至少98%一致性之序列。在一些實施例中,載體包含SEQ ID NO: 184,或與其共享至少80%、至少85%、至少90%、至少95%或至少98%一致性之序列。
在一些實施例中,載體包含SEQ ID NO: 185,或與其共享至少80%、至少85%、至少90%、至少95%或至少98%一致性之序列。在一些實施例中,載體包含SEQ ID NO: 187,或與其共享至少80%、至少85%、至少90%、至少95%或至少98%一致性之序列。在一些實施例中,載體包含SEQ ID NO: 189,或與其共享至少80%、至少85%、至少90%、至少95%或至少98%一致性之序列。在一些實施例中,載體包含SEQ ID NO: 191,或與其共享至少80%、至少85%、至少90%、至少95%或至少98%一致性之序列。在一些實施例中,載體包含SEQ ID NO: 193,或與其共享至少80%、至少85%、至少90%、至少95%或至少98%一致性之序列。
在一些實施例中,載體編碼包含SEQ ID NO: 186之多肽序列,或與其共享至少80%、至少85%、至少90%、至少95%或至少98%一致性之序列。在一些實施例中,載體編碼包含SEQ ID NO: 188之多肽序列,或與其共享至少80%、至少85%、至少90%、至少95%或至少98%一致性之序列。在一些實施例中,載體編碼包含SEQ ID NO: 190之多肽序列,或與其共享至少80%、至少85%、至少90%、至少95%或至少98%一致性之序列。在一些實施例中,載體編碼包含SEQ ID NO: 192之多肽序列,或與其共享至少80%、至少85%、至少90%、至少95%或至少98%一致性之序列。在一些實施例中,載體編碼包含SEQ ID NO: 194之多肽序列,或與其共享至少80%、至少85%、至少90%、至少95%或至少98%一致性之序列。
在一些實施例中,載體為表現載體,亦即,用於在適合之細胞中表現第一受體及/或第二受體。
來源於諸如慢病毒之反轉錄病毒的載體為達成長期基因轉移之適合工具,此係因為該等載體允許轉殖基因之長期穩定整合及在子細胞中之繁殖。慢病毒載體比來源於癌反轉錄病毒(諸如鼠類白血病病毒)之載體具有附加優勢,此係因為該等慢病毒載體可轉導非增殖細胞,諸如肝細胞。該等慢病毒載體亦具有低免疫原性之附加優勢。
編碼受體之天然或合成核酸之表現典型地藉由使編碼受體或其部分之核酸可操作地連接至啟動子且將構築體併入表現載體中來達成。載體可適用於復制及整合真核細胞。典型選殖載體含有轉錄及轉譯終止子、起始序列及适用於調控所需核酸序列之表現的啟動子。
可將編碼受體之多核苷酸選殖至許多類型之載體中。舉例而言,可將多核苷酸選殖至載體中,包括但不限於質體、噬菌粒、噬菌體衍生物、動物病毒及黏粒。尤其關注之載體包括表現載體、複製載體、探針生成載體及定序載體。
此外,可將表現載體以病毒載體之形式提供給細胞,諸如免疫細胞。病毒載體技術在此項技術中為熟知的,且描述於例如Sambrook等人(2001, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory, New York)中以及其他病毒學及分子生物學手冊中。適用作載體之病毒包括但不限於反轉錄病毒、腺病毒、腺相關病毒、疱疹病毒及慢病毒。一般而言,適合之載體含有在至少一種生物體中有功能之複制起點、啟動子序列、適宜之限制性核酸內切酶位點及一或多個可選擇標誌(例如,WO 01/96584;WO 01/29058;及美國專利第6,326,193號)。
已開發許多基於病毒之系統用於將基因轉移至哺乳動物細胞中。舉例而言,反轉錄病毒為基因遞送系統提供適宜之平台。可使用此項技術中已知之技術將所選基因插入載體中且封裝於反轉錄病毒粒子中。接著可在活體內或離體分離重組病毒且將其遞送至個體之細胞。許多反轉錄病毒系統在此項技術中為已知的。在一些實施例中,使用腺病毒載體。許多腺病毒載體在此項技術中為已知的。在一個實施例中,使用慢病毒載體。
額外啟動子元件,例如增強子調控轉錄起始之頻率。典型地,此等元件位於起始位點上游30-110個鹼基對(bp)之區域中,不過最近已顯示許多啟動子亦含有起始位點下游之功能元件。啟動子元件之間的間距通常為可撓的,因此當元件相對於彼此倒置或移動時,啟動子功能得以保留。在胸苷激酶(tk)啟動子中,在活性開始下降之前,啟動子元件之間的間距可增至相隔50 bp。視啟動子而定,個別元件似乎可協同或獨立地發揮功能以活化轉錄。
適合啟動子之一個實例為立即早期巨細胞病毒(CMV)啟動子序列。此啟動子序列為強組成型啟動子序列,能夠驅動與其可操作連接之任何多核苷酸序列的高水準表現。適合啟動子之另一個實例為延伸生長因子1α (EF-1α)。然而,亦可使用其他組成型啟動子序列,包括但不限於猿猴病毒40 (SV40)早期啟動子、小鼠乳腺腫瘤病毒(MMTV)、人類免疫缺陷病毒(HIV)長末端重複(LTR)啟動子、MoMuLV啟動子、禽類白血病病毒啟動子、愛潑斯坦-巴爾病毒立即早期啟動子、勞斯肉瘤病毒啟動子,以及人類基因啟動子,諸如但不限於肌動蛋白啟動子、肌球蛋白啟動子、血紅蛋白啟動子及肌酸激酶啟動子。此外,本揭示案不應限於使用組成型啟動子。亦預期誘導型啟動子作為本揭示案之一部分。誘導型啟動子之使用提供一種分子開關,當需要表現時能夠開啟與其可操作連接之多核苷酸序列的此種表現,或者當不需要表現時關閉表現。誘導型啟動子之實例包括但不限於金屬硫蛋白啟動子、糖皮質激素啟動子、孕酮啟動子及四環素啟動子。
為評估受體之表現,有待引入細胞中之表現載體亦可含有可選擇標誌基因或報告基因或兩者,以促進自試圖經病毒載體轉染或感染之細胞群體中鑑定及選擇表現細胞。在其他態樣中,可在單獨DNA段上攜帶可選擇標誌且用於共轉染程序中。可選擇標誌及報告基因兩者可側接有適當調控序列以能夠在宿主細胞中表現。適用之可選擇標誌包括例如抗生素抗性基因,諸如neo及類似基因。
報告基因用於鑑定潛在轉染或轉導之細胞且用於評價調控序列之功能性。一般而言,報告基因為不存在於接受體生物體或組織中或不由接受體生物體或組織表現且編碼多肽之基因,該多肽之表現由一些易於偵測之特性,例如酶促活性來體現。已將DNA引入接受體細胞中之後,在適合之時間檢定報告基因之表現。適合之報告基因可包括編碼螢光素酶、β-半乳糖苷酶、氯黴素乙醯轉移酶、分泌性鹼性磷酸酶或綠色螢光蛋白基因之基因(例如,Ui-Tei等人, 2000 FEBS Letters 479: 79-82)。適合之表現系統為熟知的且可使用已知技術製備或商業獲得。一般而言,具有顯示報告基因之最高表現水準之最小5'側翼區域的構築體鑑定為啟動子。此類啟動子區域可連接至報告基因且用於評價試劑調節啟動子驅動之轉錄的能力。
將基因引入細胞中及在細胞中表現之方法在此項技術中為已知的。在表現載體之情形中,可藉由此項技術中之任何方法將載體容易地引入宿主細胞,例如哺乳動物、細菌、酵母或昆蟲細胞中。舉例而言,可藉由物理、化學或生物方式將表現載體轉移至宿主細胞中。
將多核苷酸引入宿主細胞中之物理方法包括磷酸鈣沈澱、脂質轉染、粒子轟擊、顯微注射、電穿孔及類似方法。產生包含載體及/或外源核酸之細胞的方法在此項技術中為熟知的。參見例如Sambrook等人(2001, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory, New York)。一種將多核苷酸引入宿主細胞中之方法為磷酸鈣轉染。
將所關注之多核苷酸引入宿主細胞中之生物方法包括使用DNA及RNA載體。病毒載體及尤其反轉錄病毒載體已成為將基因插入哺乳動物,例如人類細胞中的最廣泛使用之方法。其他病毒載體可來源於慢病毒、痘病毒、單純疱疹病毒I、腺病毒及腺相關病毒,及類似病毒。參見例如美國專利第5,350,674號及第5,585,362號。
將多核苷酸引入宿主細胞中之化學方式包括膠體分散系統,諸如大分子復合物、奈米膠囊、微球、珠粒及基於脂質之系統,包括水中油乳液、膠束、混合膠束及脂質體。用作活體外及活體內遞送運載體之示例性膠體系統為脂質體(例如,人工膜囊泡)。
無論用於將外源核酸引入宿主細胞中或以其他方式使細胞暴露於本揭示案之抑制劑的方法如何,為確認宿主細胞中重組DNA序列之存在,可進行多種檢定。此類檢定包括例如熟習此項技術者熟知之「分子生物學」檢定,諸如南方及北方墨點法、RT-PCR及PCR;「生物化學」檢定,諸如偵測特定肽之存在或不存在,例如,藉由免疫學方式(ELISA及西方墨點法)或藉由本文所述之檢定以鑑定處於本揭示案之範疇內的試劑。
免疫細胞
本揭示案提供包含本文所述之受體、載體及多核苷酸之免疫細胞。
在一些實施例中,免疫細胞包含:(a)第一受體,包含對選自以下之靶抗原具有特異性之第一細胞外配位體結合結構域:(i)癌細胞特異性抗原或與主要組織相容性複合物I類(MHC-I)復合之其肽抗原;或(ii) EGFR或與主要組織相容性複合物I類(MHC-I)複合之其肽抗原;及(b)第二受體,包含特異性結合至由於雜合性損失已自癌細胞中損失之非靶抗原的第二細胞外配位體。在一些實施例中,非靶抗原係選自CXCL16、COLEC12及APCDD1,或與主要組織相容性複合物I類(MHC-I)複合之其抗原肽,或HLA-A*02。在一些實施例中,第一受體為CAR或TCR。在一些實施例中,第二受體為抑制性受體。
如本文所用,術語「免疫細胞」係指參與先天或適應性(後天)免疫系統之細胞。示例性先天免疫細胞包括吞噬細胞,諸如嗜中性粒細胞、單核細胞及巨噬細胞;自然殺手(NK)細胞;多形核白血球,諸如嗜中性粒細胞、嗜酸性粒細胞及嗜鹼性粒細胞;及單核細胞,諸如單核細胞、巨噬細胞及肥大細胞。在後天免疫中起作用之免疫細胞包括淋巴細胞,諸如T細胞及B細胞。
在一些實施例中,第一受體包含SEQ ID NO: 177,或與其共享至少75%、至少80%、至少85%、至少90%、至少95%或至少98%一致性之序列;且第二受體包含SEQ ID NO: 174,或與其共享至少75%、至少80%、至少85%、至少90%、至少95%或至少98%一致性之序列。在一些實施例中,第一受體包含SEQ ID NO: 177,或與其共享至少75%、至少80%、至少85%、至少90%、至少95%或至少98%一致性之序列;且第二受體包含SEQ ID NO: 173,或與其共享至少75%、至少80%、至少85%、至少90%、至少95%或至少98%一致性之序列。在一些實施例中,第一受體包含SEQ ID NO: 175,或與其共享至少75%、至少80%、至少85%、至少90%、至少95%或至少98%一致性之序列;且第二受體包含SEQ ID NO: 174,或與其共享至少75%、至少80%、至少85%、至少90%、至少95%或至少98%一致性之序列。在一些實施例中,第一受體包含SEQ ID NO: 175,或與其共享至少75%、至少80%、至少85%、至少90%、至少95%或至少98%一致性之序列;且第二受體包含SEQ ID NO: 173,或與其共享至少75%、至少80%、至少85%、至少90%、至少95%或至少98%一致性之序列。在一些實施例中,第一受體包含SEQ ID NO: 176,或與其共享至少75%、至少80%、至少85%、至少90%、至少95%或至少98%一致性之序列;且第二受體包含SEQ ID NO: 173,或與其共享至少75%、至少80%、至少85%、至少90%、至少95%或至少98%一致性之序列。在一些實施例中,第一受體包含SEQ ID NO: 176,或與其共享至少75%、至少80%、至少85%、至少90%、至少95%或至少98%一致性之序列;且第二受體包含SEQ ID NO: 174,或與其共享至少75%、至少80%、至少85%、至少90%、至少95%或至少98%一致性之序列。
在一些實施例中,免疫細胞進一步包含T2A自裂解肽,其中T2A自裂解肽包含SEQ ID NO: 178,或與其共享至少75%、至少80%、至少85%、至少90%、至少95%或至少98%一致性之序列。
在一些實施例中,免疫細胞進一步包含干擾RNA,其中干擾RNA包含SEQ ID NO: 179,或與其共享至少75%、至少80%、至少85%、至少90%、至少95%或至少98%一致性之序列。
如本文所用,「T細胞」係指起源於在胸腺中發育之骨髓前體的一類淋巴細胞。若干不同類型之T細胞在遷移至胸腺後發育,包括輔助CD4+ T細胞、細胞毒性CD8+ T細胞、記憶T細胞、調控性CD4+ T細胞、NK T細胞、γδ T細胞、黏膜相關非變異T (MAIT)細胞及幹記憶T細胞。一般技術人員可基於標誌之表現來區分不同類型之T細胞。區分T細胞類型之方法將為一般技術人員顯而易見。
在一些實施例中,免疫細胞係選自由T細胞、B細胞及自然殺手(NK)細胞組成之群。在一些實施例中,免疫細胞為T細胞。在一些實施例中,免疫細胞為B細胞。在一些實施例中,免疫細胞為自然殺手(NK)細胞。在一些實施例中,免疫細胞為CD8-。在一些實施例中,免疫細胞為CD8+。在一些實施例中,免疫細胞為CD4+。在一些實施例中,免疫細胞為CD4-。在一些實施例中,免疫細胞為CD8-/CD4+。在一些實施例中,免疫細胞為CD8+ CD4- T細胞。
在一些實施例中,免疫細胞為γδ T細胞。在一些實施例中,免疫細胞為非變異T細胞。在一些實施例中,免疫細胞為非變異自然殺手T細胞(iNKT細胞)。
在一些實施例中,第一受體及第二受體在靶細胞存在下一起特異性活化免疫細胞。
在一些實施例中,免疫細胞為非天然的。在一些實施例中,免疫細胞經分離。
用本揭示案之載體將免疫細胞(諸如T細胞)群體轉型之方法將為一般熟習此項技術者顯而易見。舉例而言,根據製造商之說明書,可使用CD3+ T細胞陰性分離套組(Miltenyi)自PBMC中分離CD3+ T細胞。可將T細胞以1 x 10^6個細胞/毫升之密度在補充有5%人類A/B血清及1% Pen/strep之X-Vivo 15培養基中在CD3/28 Dynabeads (1:1細胞與珠粒比)及300個單位/毫升IL-2 (Miltenyi)存在下培養。2天后,可使用此項技術中已知之方法用諸如慢病毒載體之病毒載體轉導T細胞。在一些實施例中,以5之感染複數(MOI)轉導病毒載體。接著可將細胞在IL-2或其他細胞激素,諸如IL-7/15/21之組合中再培養5天,隨後進行富集。分離及培養其他免疫細胞(諸如B細胞)群體或其他T細胞群體之方法將為一般熟習此項技術者顯而易見。儘管此方法概述潛在方法,但應注意,此等方法處於迅速演變中。舉例而言,在生長5天后可達成外周血單核細胞之極佳病毒轉導,以產生 >99% CD3+高度轉導之細胞群體。
活化及培養包含TCR、CAR、抑制性受體、受體或編碼其之載體之T細胞群體的方法將為一般熟習此項技術者顯而易見。
無論在對T細胞進行遺傳修飾以表現TCR之前抑或之後,T細胞一般可使用以下文獻中所述之方法活化及擴增:例如,美國專利第6,352,694號;第6,534,055號;第6,905,680號;第6,692,964號;第5,858,358號;第6,887,466號;第6,905,681號;第7,144,575號;第7,067,318號;第7,172,869號;第7,232,566號;第7,175,843號;第5,883,223號;第6,905,874號;第6,797,514號;第6,867,041號;第10040846號;及美國專利申請公開案第2006/0121005號。
在一些實施例中,本揭示案之T細胞在活體外擴增及活化。一般而言,本揭示案之T細胞在活體外藉由與表面接觸而擴增,該表面附著有刺激CD3/TCR複合物相關信號之試劑及刺激T細胞表面上之共刺激分子之配位體。詳言之,可如本文所述,諸如藉由與抗CD3抗體接觸來刺激T細胞群體。為共刺激T細胞表面上之輔助分子,使用結合輔助分子之配位體。舉例而言,在適於刺激T細胞增殖之條件下,可將T細胞群體與抗CD3抗體及抗CD28抗體接觸。為刺激CD4+ T細胞或CD8+ T細胞之增殖,可使用抗CD3抗體及抗CD28抗體。抗CD28抗體之實例包括9.3、B-T3、XR-CD28 (Diaclone, Besançon, France),亦可使用此項技術中通常已知之其他方法(Berg等人, Transplant Proc. 30(8):3975-3977, 1998;Haanen等人, J. Exp. Med. 190(9):13191328, 1999;Garland等人, J. Immunol Meth. 227(1-2):53-63, 1999)。
在一些實施例中,T細胞之初級刺激信號及共刺激信號可由不同方案提供。舉例而言,提供各信號之試劑可在溶液中或偶聯至表面。當偶聯至表面時,試劑可偶聯至相同表面(亦即,以「順式」形式)或偶聯至獨立表面(亦即,以「反式」形式)。或者,一種試劑可偶聯至表面且另一種試劑在溶液中。在一些實施例中,提供共刺激信號之試劑結合至細胞表面且提供初級活化信號之試劑在溶液中或偶聯至表面。在某些實施例中,兩種試劑均可在溶液中。在另一個實施例中,試劑可呈可溶形式,接著交聯至表面,諸如表現Fc受體之細胞或將結合至試劑之抗體或其他結合劑。就此而言,對於預期用於在本揭示案中活化及擴增T細胞之人工抗原呈現細胞(aAPC),參見例如美國專利申請公開案第20040101519號及第20060034810號。
在一些實施例中,將兩種試劑固定於珠粒上,在相同珠粒上,亦即「順式」,或固定至獨立珠粒,亦即「反式」。舉例而言,提供初級活化信號之試劑為抗CD3抗體或其抗原結合片段,且提供共刺激信號之試劑為抗CD28抗體或其抗原結合片段;且兩種試劑以當量分子量共固定至相同珠粒。在一個實施例中,使用1:1比率之結合至珠粒之各抗體用於CD4+ T細胞擴增及T細胞生長。在一些實施例中,結合至珠粒之CD3:CD28抗體之比率在100:1至1:100及其之間的所有整數值之範圍內。在本揭示案之一個態樣中,與抗CD3抗體相比,更多抗CD28抗體結合至粒子,亦即,CD3:CD28之比率小於1。在本揭示案之某些實施例中,結合至珠粒之抗CD28抗體與抗CD3抗體之比率大於2:1。
1:500至500:1及其之間的任何整數值之粒子與細胞比率可用於刺激T細胞或其他靶細胞。一般熟習此項技術者可易於了解,粒子與細胞之比率可視相對於靶細胞之粒子大小而定。舉例而言,小尺寸之珠粒僅可結合少數細胞,而較大珠粒可結合許多細胞。在某些實施例中,細胞與粒子之比率在1:100至100:1及其之間的任何整數值之範圍內,且在其他實施例中,比率包括1:9至9:1及其之間的任何整數值,亦可用於刺激T細胞。在一些實施例中,使用1:1比率之細胞與珠粒。熟習此項技術者將了解,多種其他比率可適用於本揭示案。詳言之,比率將視粒子大小及細胞大小及類型而變化。
在本揭示案之其他實施例中,將諸如T細胞之細胞與試劑包覆之珠粒組合,隨後分離珠粒與細胞,接著培養細胞。在替代性實施例中,在培養之前,不分離試劑包覆之珠粒與細胞但一起培養。在另一個實施例中,首先藉由施加力,諸如磁力而集中珠粒及細胞,使得細胞表面標誌之接合增加,從而誘導細胞刺激。
舉例而言,可藉由使抗CD3及抗CD28所附著之順磁珠粒接觸T細胞來接合細胞表面蛋白。在一個實施例中,在緩衝液中組合細胞(例如,CD4+ T細胞)及珠粒(例如,1:1比率之DYNABEADS CD3/CD28 T順磁珠粒)。再次,一般熟習此項技術者可易於了解可使用任何細胞濃度。在某些實施例中,可能需要顯著減少粒子與細胞混合在一起之體積(亦即,增加細胞濃度),以確保細胞與粒子之最大接觸。舉例而言,在一個實施例中,使用約20億個細胞/毫升之濃度。在另一個實施例中,使用大於1億個細胞/毫升。在另一個實施例中,使用1000、1500、2000、2500、3000、3500、4000、4500或5000萬個細胞/毫升之細胞濃度。在又一個實施例中,使用7500、8000、8500、9000、9500或10000萬個細胞/毫升之細胞濃度。在其他實施例中,可使用12500或15000萬個細胞/毫升之濃度。在一些實施例中,使用以1x10
6個細胞/毫升之密度培養之細胞。
在一些實施例中,可將混合物培養數小時(約3小時)至約14天或其之間的任何小時整數值。在另一個實施例中,將珠粒與T細胞一起培養2-3天。適於T細胞培養之條件包括適當培養基(例如,最低必需培養基或RPMI培養基1640或X-vivo 15 (Lonza)),其可含有增殖及生存力所必需之因子,包括血清(例如,胎牛或人血清)、介白素2 (IL-2)、胰島素、IFN-γ、IL-4、IL-7、GM-CSF、IL-10、IL-12、IL-15、TGFβ及TNF-α或技術人員已知的用於細胞生長之任何其他添加劑。用於細胞生長之其他添加劑包括但不限於表面活性劑、人血漿蛋白粉(plasmanate)及還原劑,諸如N-乙醯基-半胱胺酸及2-巰基乙醇。培養基可包括RPMI 1640、AIM-V、DMEM、MEM、α-MEM、F-12、X-Vivo 15及X-Vivo 20、Optimizer,添加有胺基酸、丙酮酸鈉及維生素,無血清或補充有適量血清(或血漿)或一組規定之激素,及/或足以用於T細胞生長及擴增之量的細胞激素。在一些實施例中,培養基包括補充有5%人類A/B血清、1%青黴素/鏈黴素(pen/strep)及300個單位/毫升IL-2 (Miltenyi)之X-VIVO-15培養基。
將T細胞維持於支持生長所必需之條件下,例如,適當溫度(例如,37℃)及氣氛(例如,空氣加上5% CO2)。
在一些實施例中,包含本揭示案之TCR、CAR及抑制性受體之T細胞為自體的。在擴增及遺傳修飾之前,自個體獲得T細胞來源。諸如T細胞之免疫細胞可獲自許多來源,包括外周血單核細胞、骨髓、淋巴結組織、臍帶血、胸腺組織、來自感染部位之組織、腹水、胸膜積水、脾組織及腫瘤。在本揭示案之某些實施例中,可使用此項技術中可用之許多T細胞株。在本揭示案之某些實施例中,可使用技術人員已知之許多技術,諸如Ficoll™分離,自個體所收集之血液單位中獲得T細胞。
在一些實施例中,藉由血球分離術自個體循環血液中獲得細胞。血球分離術之產物典型地含有淋巴細胞,包括T細胞、單核細胞、粒細胞、B細胞、其他有核白血球、紅血球及血小板。在一些實施例中,可洗滌藉由血球分離術收集之細胞以移除血漿部分且將細胞置於適當緩衝液或培養基中以用於後續處理步驟。在一些實施例中,用磷酸鹽緩衝鹽水(PBS)洗滌細胞。在替代性實施例中,洗滌溶液缺乏鈣且可能缺乏鎂或可能缺乏許多(若非全部)二價陽離子。一般熟習此項技術者將易於了解,洗滌步驟可藉由熟習此項技術者已知之方法完成,諸如根據製造商之說明書藉由使用半自動「流通」離心機(例如,Cobe 2991細胞處理器、Baxter CytoMate或Haemonetics Cell Saver 5)。洗滌後,可將細胞再懸浮於多種生物相容性緩衝液中,諸如無Ca2+、無Mg2+ PBS、PlasmaLyte A或含或不含緩衝液之其他鹽水溶液。或者,可移除血球分離術樣品中不需要之組分,且將細胞直接再懸浮於培養基中。
在一些實施例中,藉由使紅血球溶解且消耗單核細胞,例如藉由PERCOLL™梯度離心或藉由逆流離心淘洗,自外周血淋巴細胞中分離免疫細胞,諸如T細胞。可藉由陽性或陰性選擇技術進一步分離免疫細胞之特定亞群,諸如T細胞、B細胞或CD4+ T細胞。舉例而言,在一個實施例中,藉由與抗CD4結合之珠粒一起培育足以陽性選擇所需T細胞之時間段來分離T細胞。
藉由陰性選擇富集免疫細胞群體,諸如T細胞群體,可用針對陰性選擇之細胞所特有之表面標誌的抗體組合來完成。一種方法為細胞分選及/或經由陰性磁性免疫黏附或流式細胞術進行選擇,該技術使用針對陰性選擇之細胞上存在之細胞表面標誌的單株抗體混合液。舉例而言,為藉由陰性選擇富集CD4+細胞,單株抗體混合液典型地包括針對CD 14、CD20、CD 11b、CD 16、HLA-DR及CD8之抗體。
為藉由陽性或陰性選擇分離所需之免疫細胞群體,可改變細胞及表面(例如粒子,諸如珠粒)之濃度。在某些實施例中,可能需要顯著減少珠粒與細胞混合在一起之體積(亦即,增加細胞濃度),以確保細胞與珠粒之最大接觸。
在一些實施例中,可在旋轉器上以不同速度在2-10℃下或室溫下培育細胞不同時長。
亦可在洗滌步驟之後冷凍用於刺激之T細胞或自其中分離免疫細胞(諸如T細胞)之PBMC。不希望受理論約束,冷凍及後續解凍步驟藉由移除細胞群體中之粒細胞且在一定程度上移除單核細胞來提供更均勻之產物。在移除血漿及血小板之洗滌步驟之後,可將細胞懸浮於冷凍溶液中。儘管許多冷凍溶液及參數在此項技術中為已知的且將在此情形中適用,但一種方法涉及使用含有20% DMSO及8%人血清白蛋白之PBS,或含有10%右旋糖聚糖40及5%右旋糖、20%人血清白蛋白及7.5% DMSO,或31.25%勃脈力A (Plasmalyte-A)、31.25%右旋糖5%、0.45% NaCl、10%右旋糖聚糖40及5%右旋糖、20%人血清白蛋白及7.5% DMSO之培養基,或含有例如羥乙基澱粉(Hespan)及勃脈力A之其他適合細胞冷凍培養基,接著將細胞以每分鐘1°之速率冷凍至-80℃並儲存於液氮儲罐之蒸氣相中。可使用受控冷凍之其他方法以及立即在-20℃下或液氮中進行非受控冷凍。
本揭示案提供表現本文所述之活化劑及/或抑制性受體之免疫細胞,其中該免疫細胞具有降低之主要組織相容性(MHC) I類複合物表現及/或功能。
在一些實施例中,免疫細胞為自體的。舉例而言,免疫細胞分離自或來源於將接受細胞作為治療方案之一部分的同一個體。修飾自體免疫細胞以具有降低之MHC I 類表現及/或功能可為有利的,其中抑制性受體對MHC I類抗原具有特異性。不希望受理論約束,修飾自體免疫細胞以具有降低之MHC I類表現及/或功能會降低免疫細胞表現之MHC I類對抑制性受體之結合,無論呈順式抑或反式。
在一些實施例中,免疫細胞全部為同種異體的。同種異體免疫細胞可來源於除免疫細胞將投與之個體以外的供體。同種異體免疫細胞通常已在細胞療法中稱作「現成的」或「通用的」,此係因為有可能製備及儲存同種異體細胞以用於多種基因型之個體。
設想降低MHC I類複合物之表現及/或功能之任何適合方法在本揭示案之範疇內,且尤其包括敲低編碼MHC I類組分之一或多個RNA之干擾RNA的表現,或編碼MHC I類組分之基因的修飾。
主要組織相容性複合物(MHC)為編碼適應性免疫系統所需之一組多肽之脊椎動物基因體上的基因座。其中有包括HLA-A、HLA-B及HLA-C及其對偶基因之MHC I類多肽。MHC I類對偶基因具有高度多態性且在所有有核細胞中表現。由HLA-A、HLA-B及HLA-C及其對偶基因編碼之MHC I類多肽與β2微球蛋白(B2M)形成異二聚體,且與細胞表面上之抗原呈現為複合物。如本文所提及,MHC I類基因或多肽可指在MHC中發現之任何多肽或編碼該多肽之相應基因。在一些實施例中,本揭示案之免疫細胞由包含MHC I類多肽,例如HLA-A、HLA-B及HLA-C及其對偶基因之抑制劑配位體滅活。HLA-A對偶基因可為例如且不限於HLA-A*02、HLA-A*02:01、HLA-A*02:01:01、HLA-A*02:01:01:01及/或編碼與HLA-A*02蛋白相同或相似之蛋白質的任何基因。因此,為防止如本文所述之自分泌信號傳導/結合,需要消除或降低免疫細胞中由HLA-A、HLA-B及HLA-C及其對偶基因編碼之多肽的表現。
具有降低之 MHC I 類多肽表現之免疫細胞
在一些實施例中,本文所述之免疫細胞經修飾以滅活或者降低或消除編碼內源MHC I類多肽之對偶基因之內源基因的表現或功能。在一些實施例中,編碼MHC I類多肽之基因為HLA-A、HLA-B及/或HLA-C。HLA-A、HLA-B及HLA-C由HLA-A、HLA-B及HLA-C基因座編碼。HLA-A、HLA-B及HLA-C中之每一者包括許多變異體對偶基因,設想所有此等對偶基因在本揭示案之範疇內。在一些實施例中,編碼MHC I類多肽之基因為HLA-A。在一些實施例中,編碼MHC I類多肽之基因為HLA-A*02。在一些實施例中,編碼MHC I類多肽之基因為HLA-A*02:01。在一些實施例中,編碼MHC I類多肽之基因為HLA-A*02:01:01。在一些實施例中,編碼MHC I類多肽之基因為HLA-A*02:01:01:01。
在一些實施例中,本文所述之遺傳工程改造之免疫細胞經修飾以降低或消除B2M基因產物之表現。β-2微球蛋白(B2M)基因編碼與主要組織相容性複合物(MHC) I類(亦即,MHC-I複合物)相關之蛋白質。MHC-I複合物為在細胞表面上呈現抗原所需的。當B2M缺失時,MHC-I複合物遭破壞且無功能(Wang D等人 Stem Cells Transl Med. 4:1234‐1245 (2015))。此外,可使用此項技術中已知之基因編輯技術高效地破壞B2M基因(Ren等人 Clin. Cancer Res. 23:2255-2266 (2017))。減少或消除B2M可減少或消除免疫細胞表面上之功能性MHC I。
本揭示案提供用於編輯免疫細胞中之內源靶基因的基因編輯系統。本揭示案提供對靶基因序列具有特異性之干擾RNA。基因編輯系統,諸如CRISPR/Cas系統、TALEN及鋅指可用於產生雙鏈斷裂,此經由諸如同源定向修復或非同源末端連接(NHEJ)之基因修復機制,可用於引入突變。NHEJ在切除斷裂末端或不當末端連接之後,可用於引入缺失。在一些實施例中,靶基因包括編碼MHC-I複合物次單元之基因。
靶基因序列包括但不限於啟動子、增強子、內含子、外顯子、內含子/外顯子連接點、轉錄產物(前mRNA、mRNA及剪接變異體)及/或3'及5'非轉譯區(UTR)。可靶向任何基因元件或基因元件之組合用於本文所述之免疫細胞中之基因編輯目的。可使用此項技術中已知的編輯靶基因之任何方法來完成對靶基因之修飾,從而改變或破壞靶基因或基因產物之表現或功能。
在一些實施例中,修飾編碼MHC I類多肽之基因包括使該基因之全部或一部分缺失。在一些實施例中,修飾編碼MHC I類多肽之基因包括在基因中引入突變。在一些實施例中,突變包括缺失、插入、取代或框移突變。在一些實施例中,對基因進行修飾包括使用核酸引導之核酸內切酶。
本文所述之靶基因的基因序列在此項技術中為已知的。序列可在公共資料庫,諸如NCBI GenBank或NCBI核苷酸資料庫中找到。序列可使用基因標識符找到,例如,HLA-A基因具有NCBI基因ID:3105,HLA-B基因具有NCBI基因ID:3106,HLA-C基因具有NCBI基因ID:3107,且
B2M基因具有NCBI基因ID:567及NCBI參考序列:NC_000015.10。基因序列亦可藉由使用關鍵字搜索公共資料庫找到。舉例而言,HLA-A對偶基因可在NCBI核苷酸資料庫中藉由搜索關鍵字「HLA-A*02」、「HLA-A*02:01」、「HLA-A*02:01:01」或「HLA-A*02:01:01:01」找到。此等序列可在此項技術中已知之各種基因編輯技術中用於靶向。表7提供針對如本文所述之修飾所靶向之HLA-A對偶基因及B2M基因序列的非限制性說明性序列。
表7. 示例性靶基因序列
B2MmRNA | AUUCCUGAAGCUGACAGCAUUCGGGCCGAGAUGUCUCGCUCCGUGGCCUUAGCUGUGCUCGCGCUACUCUCUCUUUCUGGCCUGGAGGCUAUCCAGCGUACUCCAAAGAUUCAGGUUUACUCACGUCAUCCAGCAGAGAAUGGAAAGUCAAAUUUCCUGAAUUGCUAUGUGUCUGGGUUUCAUCCAUCCGACAUUGAAGUUGACUUACUGAAGAAUGGAGAGAGAAUUGAAAAAGUGGAGCAUUCAGACUUGUCUUUCAGCAAGGACUGGUCUUUCUAUCUCUUGUACUACACUGAAUUCACCCCCACUGAAAAAGAUGAGUAUGCCUGCCGUGUGAACCAUGUGACUUUGUCACAGCCCAAGAUAGUUAAGUGGGAUCGAGACAUGUAAGCAGCAUCAUGGAGGUUUGAAGAUGCCGCAUUUGGAUUGGAUGAAUUCCAAAUUCUGCUUGCUUGCUUUUUAAUAUUGAUAUGCUUAUACACUUACACUUUAUGCACAAAAUGUAGGGUUAUAAUAAUGUUAACAUGGACAUGAUCUUCUUUAUAAUUCUACUUUGAGUGCUGUCUCCAUGUUUGAUGUAUCUGAGCAGGUUGCUCCACAGGUAGCUCUAGGAGGGCUGGCAACUUAGAGGUGGGGAGCAGAGAAUUCUCUUAUCCAACAUCAACAUCUUGGUCAGAUUUGAACUCUUCAAUCUCUUGCACUCAAAGCUUGUUAAGAUAGUUAAGCGUGCAUAAGUUAACUUCCAAUUUACAUACUCUGCUUAGAAUUUGGGGGAAAAUUUAGAAAUAUAAUUGACAGGAUUAUUGGAAAUUUGUUAUAAUGAAUGAAACAUUUUGUCAUAUAAGAUUCAUAUUUACUUCUUAUACAUUUGAUAAAGUAAGGCAUGGUUGUGGUUAAUCUGGUUUAUUUUUGUUCCACAAGUUAAAUAAAUCAUAAAACUUGA (SEQ ID NO: 172) |
B2M基因(GenBank: 567) | AAGTGGAGGCGTCGCGCTGGCGGGCATTCCTGAAGCTGACAGCATTCGGGCCGAGATGTCTCGCTCCGTGGCCTTAGCTGTGCTCGCGCTACTCTCTCTTTCTGGCCTGGAGGCTATCCAGCGTGAGTCTCTCCTACCCTCCCGCTCTGGTCCTTCCTCTCCCGCTCTGCACCCTCTGTGGCCCTCGCTGTGCTCTCTCGCTCCGTGACTTCCCTTCTCCAAGTTCTCCTTGGTGGCCCGCCGTGGGGCTAGTCCAGGGCTGGATCTCGGGGAAGCGGCGGGGTGGCCTGGGAGTGGGGAAGGGGGTGCGCACCCGGGACGCGCGCTACTTGCCCCTTTCGGCGGGGAGCAGGGGAGACCTTTGGCCTACGGCGACGGGAGGGTCGGGACAAAGTTTAGGGCGTCGATAAGCGTCAGAGCGCCGAGGTTGGGGGAGGGTTTCTCTTCCGCTCTTTCGCGGGGCCTCTGGCTCCCCCAGCGCAGCTGGAGTGGGGGACGGGTAGGCTCGTCCCAAAGGCGCGGCGCTGAGGTTTGTGAACGCGTGGAGGGGCGCTTGGGGTCTGGGGGAGGCGTCGCCCGGGTAAGCCTGTCTGCTGCGGCTCTGCTTCCCTTAGACTGGAGAGCTGTGGACTTCGTCTAGGCGCCCGCTAAGTTCGCATGTCCTAGCACCTCTGGGTCTATGTGGGGCCACACCGTGGGGAGGAAACAGCACGCGACGTTTGTAGAATGCTTGGCTGTGATACAAAGCGGTTTCGAATAATTAACTTATTTGTTCCCATCACATGTCACTTTTAAAAAATTATAAGAACTACCCGTTATTGACATCTTTCTGTGTGCCAAGGACTTTATGTGCTTTGCGTCATTTAATTTTGAAAACAGTTATCTTCCGCCATAGATAACTACTATGGTTATCTTCTGCCTCTCACAGATGAAGAAACTAAGGCACCGAGATTTTAAGAAACTTAATTACACAGGGGATAAATGGCAGCAATCGAGATTGAAGTCAAGCCTAACCAGGGCTTTTGCGGGAGCGCATGCCTTTTGGCTGTAATTCGTGCATTTTTTTTTAAGAAAAACGCCTGCCTTCTGCGTGAGATTCTCCAGAGCAAACTGGGCGGCATGGGCCCTGTGGTCTTTTCGTACAGAGGGCTTCCTCTTTGGCTCTTTGCCTGGTTGTTTCCAAGATGTACTGTGCCTCTTACTTTCGGTTTTGAAAACATGAGGGGGTTGGGCGTGGTAGCTTACGCCTGTAATCCCAGCACTTAGGGAGGCCGAGGCGGGAGGATGGCTTGAGGTCCGTAGTTGAGACCAGCCTGGCCAACATGGTGAAGCCTGGTCTCTACAAAAAATAATAACAAAAATTAGCCGGGTGTGGTGGCTCGTGCCTGTGGTCCCAGCTGCTCCGGTGGCTGAGGCGGGAGGATCTCTTGAGCTTAGGCTTTTGAGCTATCATGGCGCCAGTGCACTCCAGCGTGGGCAACAGAGCGAGACCCTGTCTCTCAAAAAAGAAAAAAAAAAAAAAAGAAAGAGAAAAGAAAAGAAAGAAAGAAGTGAAGGTTTGTCAGTCAGGGGAGCTGTAAAACCATTAATAAAGATAATCCAAGATGGTTACCAAGACTGTTGAGGACGCCAGAGATCTTGAGCACTTTCTAAGTACCTGGCAATACACTAAGCGCGCTCACCTTTTCCTCTGGCAAAACATGATCGAAAGCAGAATGTTTTGATCATGAGAAAATTGCATTTAATTTGAATACAATTTATTTACAACATAAAGGATAATGTATATATCACCACCATTACTGGTATTTGCTGGTTATGTTAGATGTCATTTTAAAAAATAACAATCTGATATTTAAAAAAAAATCTTATTTTGAAAATTTCCAAAGTAATACATGCCATGCATAGACCATTTCTGGAAGATACCACAAGAAACATGTAATGATGATTGCCTCTGAAGGTCTATTTTCCTCCTCTGACCTGTGTGTGGGTTTTGTTTTTGTTTTACTGTGGGCATAAATTAATTTTTCAGTTAAGTTTTGGAAGCTTAAATAACTCTCCAAAAGTCATAAAGCCAGTAACTGGTTGAGCCCAAATTCAAACCCAGCCTGTCTGATACTTGTCCTCTTCTTAGAAAAGATTACAGTGATGCTCTCACAAAATCTTGCCGCCTTCCCTCAAACAGAGAGTTCCAGGCAGGATGAATCTGTGCTCTGATCCCTGAGGCATTTAATATGTTCTTATTATTAGAAGCTCAGATGCAAAGAGCTCTCTTAGCTTTTAATGTTATGAAAAAAATCAGGTCTTCATTAGATTCCCCAATCCACCTCTTGATGGGGCTAGTAGCCTTTCCTTAATGATAGGGTGTTTCTAGAGAGATATATCTGGTCAAGGTGGCCTGGTACTCCTCCTTCTCCCCACAGCCTCCCAGACAAGGAGGAGTAGCTGCCTTTTAGTGATCATGTACCCTGAATATAAGTGTATTTAAAAGAATTTTATACACATATATTTAGTGTCAATCTGTATATTTAGTAGCACTAACACTTCTCTTCATTTTCAATGAAAAATATAGAGTTTATAATATTTTCTTCCCACTTCCCCATGGATGGTCTAGTCATGCCTCTCATTTTGGAAAGTACTGTTTCTGAAACATTAGGCAATATATTCCCAACCTGGCTAGTTTACAGCAATCACCTGTGGATGCTAATTAAAACGCAAATCCCACTGTCACATGCATTACTCCATTTGATCATAATGGAAAGTATGTTCTGTCCCATTTGCCATAGTCCTCACCTATCCCTGTTGTATTTTATCGGGTCCAACTCAACCATTTAAGGTATTTGCCAGCTCTTGTATGCATTTAGGTTTTGTTTCTTTGTTTTTTAGCTCATGAAATTAGGTACAAAGTCAGAGAGGGGTCTGGCATATAAAACCTCAGCAGAAATAAAGAGGTTTTGTTGTTTGGTAAGAACATACCTTGGGTTGGTTGGGCACGGTGGCTCGTGCCTGTAATCCCAACACTTTGGGAGGCCAAGGCAGGCTGATCACTTGAAGTTGGGAGTTCAAGACCAGCCTGGCCAACATGGTGAAATCCCGTCTCTACTGAAAATACAAAAATTAACCAGGCATGGTGGTGTGTGCCTGTAGTCCCAGGAATCACTTGAACCCAGGAGGCGGAGGTTGCAGTGAGCTGAGATCTCACCACTGCACACTGCACTCCAGCCTGGGCAATGGAATGAGATTCCATCCCAAAAAATAAAAAAATAAAAAAATAAAGAACATACCTTGGGTTGATCCACTTAGGAACCTCAGATAATAACATCTGCCACGTATAGAGCAATTGCTATGTCCCAGGCACTCTACTAGACACTTCATACAGTTTAGAAAATCAGATGGGTGTAGATCAAGGCAGGAGCAGGAACCAAAAAGAAAGGCATAAACATAAGAAAAAAAATGGAAGGGGTGGAAACAGAGTACAATAACATGAGTAATTTGATGGGGGCTATTATGAACTGAGAAATGAACTTTGAAAAGTATCTTGGGGCCAAATCATGTAGACTCTTGAGTGATGTGTTAAGGAATGCTATGAGTGCTGAGAGGGCATCAGAAGTCCTTGAGAGCCTCCAGAGAAAGGCTCTTAAAAATGCAGCGCAATCTCCAGTGACAGAAGATACTGCTAGAAATCTGCTAGAAAAAAAACAAAAAAGGCATGTATAGAGGAATTATGAGGGAAAGATACCAAGTCACGGTTTATTCTTCAAAATGGAGGTGGCTTGTTGGGAAGGTGGAAGCTCATTTGGCCAGAGTGGAAATGGAATTGGGAGAAATCGATGACCAAATGTAAACACTTGGTGCCTGATATAGCTTGACACCAAGTTAGCCCCAAGTGAAATACCCTGGCAATATTAATGTGTCTTTTCCCGATATTCCTCAGGTACTCCAAAGATTCAGGTTTACTCACGTCATCCAGCAGAGAATGGAAAGTCAAATTTCCTGAATTGCTATGTGTCTGGGTTTCATCCATCCGACATTGAAGTTGACTTACTGAAGAATGGAGAGAGAATTGAAAAAGTGGAGCATTCAGACTTGTCTTTCAGCAAGGACTGGTCTTTCTATCTCTTGTACTACACTGAATTCACCCCCACTGAAAAAGATGAGTATGCCTGCCGTGTGAACCATGTGACTTTGTCACAGCCCAAGATAGTTAAGTGGGGTAAGTCTTACATTCTTTTGTAAGCTGCTGAAAGTTGTGTATGAGTAGTCATATCATAAAGCTGCTTTGATATAAAAAAGGTCTATGGCCATACTACCCTGAATGAGTCCCATCCCATCTGATATAAACAATCTGCATATTGGGATTGTCAGGGAATGTTCTTAAAGATCAGATTAGTGGCACCTGCTGAGATACTGATGCACAGCATGGTTTCTGAACCAGTAGTTTCCCTGCAGTTGAGCAGGGAGCAGCAGCAGCACTTGCACAAATACATATACACTCTTAACACTTCTTACCTACTGGCTTCCTCTAGCTTTTGTGGCAGCTTCAGGTATATTTAGCACTGAACGAACATCTCAAGAAGGTATAGGCCTTTGTTTGTAAGTCCTGCTGTCCTAGCATCCTATAATCCTGGACTTCTCCAGTACTTTCTGGCTGGATTGGTATCTGAGGCTAGTAGGAAGGGCTTGTTCCTGCTGGGTAGCTCTAAACAATGTATTCATGGGTAGGAACAGCAGCCTATTCTGCCAGCCTTATTTCTAACCATTTTAGACATTTGTTAGTACATGGTATTTTAAAAGTAAAACTTAATGTCTTCCTTTTTTTTCTCCACTGTCTTTTTCATAGATCGAGACATGTAAGCAGCATCATGGAGGTAAGTTTTTGACCTTGAGAAAATGTTTTTGTTTCACTGTCCTGAGGACTATTTATAGACAGCTCTAACATGATAACCCTCACTATGTGGAGAACATTGACAGAGTAACATTTTAGCAGGGAAAGAAGAATCCTACAGGGTCATGTTCCCTTCTCCTGTGGAGTGGCATGAAGAAGGTGTATGGCCCCAGGTATGGCCATATTACTGACCCTCTACAGAGAGGGCAAAGGAACTGCCAGTATGGTATTGCAGGATAAAGGCAGGTGGTTACCCACATTACCTGCAAGGCTTTGATCTTTCTTCTGCCATTTCCACATTGGACATCTCTGCTGAGGAGAGAAAATGAACCACTCTTTTCCTTTGTATAATGTTGTTTTATTCTTCAGACAGAAGAGAGGAGTTATACAGCTCTGCAGACATCCCATTCCTGTATGGGGACTGTGTTTGCCTCTTAGAGGTTCCCAGGCCACTAGAGGAGATAAAGGGAAACAGATTGTTATAACTTGATATAATGATACTATAATAGATGTAACTACAAGGAGCTCCAGAAGCAAGAGAGAGGGAGGAACTTGGACTTCTCTGCATCTTTAGTTGGAGTCCAAAGGCTTTTCAATGAAATTCTACTGCCCAGGGTACATTGATGCTGAAACCCCATTCAAATCTCCTGTTATATTCTAGAACAGGGAATTGATTTGGGAGAGCATCAGGAAGGTGGATGATCTGCCCAGTCACACTGTTAGTAAATTGTAGAGCCAGGACCTGAACTCTAATATAGTCATGTGTTACTTAATGACGGGGACATGTTCTGAGAAATGCTTACACAAACCTAGGTGTTGTAGCCTACTACACGCATAGGCTACATGGTATAGCCTATTGCTCCTAGACTACAAACCTGTACAGCCTGTTACTGTACTGAATACTGTGGGCAGTTGTAACACAATGGTAAGTATTTGTGTATCTAAACATAGAAGTTGCAGTAAAAATATGCTATTTTAATCTTATGAGACCACTGTCATATATACAGTCCATCATTGACCAAAACATCATATCAGCATTTTTTCTTCTAAGATTTTGGGAGCACCAAAGGGATACACTAACAGGATATACTCTTTATAATGGGTTTGGAGAACTGTCTGCAGCTACTTCTTTTAAAAAGGTGATCTACACAGTAGAAATTAGACAAGTTTGGTAATGAGATCTGCAATCCAAATAAAATAAATTCATTGCTAACCTTTTTCTTTTCTTTTCAGGTTTGAAGATGCCGCATTTGGATTGGATGAATTCCAAATTCTGCTTGCTTGCTTTTTAATATTGATATGCTTATACACTTACACTTTATGCACAAAATGTAGGGTTATAATAATGTTAACATGGACATGATCTTCTTTATAATTCTACTTTGAGTGCTGTCTCCATGTTTGATGTATCTGAGCAGGTTGCTCCACAGGTAGCTCTAGGAGGGCTGGCAACTTAGAGGTGGGGAGCAGAGAATTCTCTTATCCAACATCAACATCTTGGTCAGATTTGAACTCTTCAATCTCTTGCACTCAAAGCTTGTTAAGATAGTTAAGCGTGCATAAGTTAACTTCCAATTTACATACTCTGCTTAGAATTTGGGGGAAAATTTAGAAATATAATTGACAGGATTATTGGAAATTTGTTATAATGAATGAAACATTTTGTCATATAAGATTCATATTTACTTCTTATACATTTGATAAAGTAAGGCATGGTTGTGGTTAATCTGGTTTATTTTTGTTCCACAAGTTAAATAAATCATAAAACTTGA (SEQ ID NO: 170) |
編碼mRNA之HLA-A*02:01:01:01序列 | CAGAAGCAGAGGGGTCAGGGCGAAGTCCCAGGGCCCCAGGCGTGGCTCTCAGGGTCTCAGGCCCCGAAGGCGGTGTATGGATTGGGGAGTCCCAGCCTTGGGGATTCCCCAACTCCGCAGTTTCTTTTCTCCCTCTCCCAACCTATGTAGGGTCCTTCTTCCTGGATACTCACGACGCGGACCCAGTTCTCACTCCCATTGGGTGTCGGGTTTCCAGAGAAGCCAATCAGTGTCGTCGCGGTCGCGGTTCTAAAGTCCGCACGCACCCACCGGGACTCAGATTCTCCCCAGACGCCGAGGATGGCCGTCATGGCGCCCCGAACCCTCGTCCTGCTACTCTCGGGGGCTCTGGCCCTGACCCAGACCTGGGCGGGCTCTCACTCCATGAGGTATTTCTTCACATCCGTGTCCCGGCCCGGCCGCGGGGAGCCCCGCTTCATCGCAGTGGGCTACGTGGACGACACGCAGTTCGTGCGGTTCGACAGCGACGCCGCGAGCCAGAGGATGGAGCCGCGGGCGCCGTGGATAGAGCAGGAGGGTCCGGAGTATTGGGACGGGGAGACACGGAAAGTGAAGGCCCACTCACAGACTCACCGAGTGGACCTGGGGACCCTGCGCGGCTACTACAACCAGAGCGAGGCCGGTTCTCACACCGTCCAGAGGATGTATGGCTGCGACGTGGGGTCGGACTGGCGCTTCCTCCGCGGGTACCACCAGTACGCCTACGACGGCAAGGATTACATCGCCCTGAAAGAGGACCTGCGCTCTTGGACCGCGGCGGACATGGCAGCTCAGACCACCAAGCACAAGTGGGAGGCGGCCCATGTGGCGGAGCAGTTGAGAGCCTACCTGGAGGGCACGTGCGTGGAGTGGCTCCGCAGATACCTGGAGAACGGGAAGGAGACGCTGCAGCGCACGGACGCCCCCAAAACGCATATGACTCACCACGCTGTCTCTGACCATGAAGCCACCCTGAGGTGCTGGGCCCTGAGCTTCTACCCTGCGGAGATCACACTGACCTGGCAGCGGGATGGGGAGGACCAGACCCAGGACACGGAGCTCGTGGAGACCAGGCCTGCAGGGGATGGAACCTTCCAGAAGTGGGCGGCTGTGGTGGTGCCTTCTGGACAGGAGCAGAGATACACCTGCCATGTGCAGCATGAGGGTTTGCCCAAGCCCCTCACCCTGAGATGGGAGCCGTCTTCCCAGCCCACCATCCCCATCGTGGGCATCATTGCTGGCCTGGTTCTCTTTGGAGCTGTGATCACTGGAGCTGTGGTCGCTGCTGTGATGTGGAGGAGGAAGAGCTCAGATAGAAAAGGAGGGAGCTACTCTCAGGCTGCAAGCAGTGACAGTGCCCAGGGCTCTGATGTGTCTCTCACAGCTTGTAAAGTGTGAGACAGCTGCCTTGTGTGGGACTGAGAGGCAAGAGTTGTTCCTGCCCTTCCCTTTGTGACTTGAAGAACCCTGACTTTGTTTCTGCAAAGGCACCTGCATGTGTCTGTGTTCGTGTAGGCATAATGTGAGGAGGTGGGGAGACCACCCCACCCCCATGTCCACCATGACCCTCTTCCCACGCTGACCTGTGCTCCCTCCCCAATCATCTTTCCTGTTCCAGAGAGGTGGGGCTGAGGTGTCTCCATCTCTGTCTCAACTTCATGGTGCACTGAGCTGTAACTTCTTCCTTCCCTATTAAAA (SEQ ID NO: 171) |
HLA-A*02 (GenBank: LK021978.1) | ATGGCCGTCATGGCGCCCCGAACCCTCGTCCTGCTACTCTCGGGGGCTCTGGCCCTGACCCAGACCTGGGCGGGTGAGTGCGGGGTCGGGAGGGAAACGGCCTCTGTGGGGAGAAGCAACGGGCCCGCCTGGCGGGGGCGCAGGACCCGGGAAGCCGCGCCGGGAGGAGGGTCGGGCGGGTCTCAGCCACTCCTCGTCCCCAGGCTCTCACTCCATGAGGTATTTCTTCACATCCGTGTCCCGGCCCGGCCGCGGGGAGCCCCGCTTCATCGCAGTGGGCTACGTGGACGACACGCAGTTCGTGCGGTTCGACAGCGACGCCGCGAGCCAGAGGATGGAGCCGCGGGCGCCGTGGATAGAGCAGGAGGGTCCGGAGTATTGGGACGGGGAGACACGGAAAGTGAAGGCCCACTCACAGACTCACCGAGTGGACCTGGGGACCCTGCGCGGCTACTACAACCAGAGCGAGGCCGGTGAGTGACCCCGGCCCGGGGCGCAGGTCACGACCTCTCATCCCCCACGGACGGGCCAGGTCGCCCACAGTCTCCGGGTCCGAGATCCGCCCCGAAGCCGCGGGACCCCGAGACCCTTGCCCCGGGAGAGGCCCAGGCGCCTTTACCCGGTTTCATTTTCAGTTTAGGCCAAAAATCCCCCCAGGTTGGTCGGGGCGGGGCGGGGCTCGGGGGACCGGGCTGACCGCGGGGTCCGGGCCAGGTTCTCACACCGTCCAGAGGATGTATGGCTGCGACGTGGGGTCGGACTGGCGCTTCCTCCGCGGGTACCACCAGTACGCCTACGACGGCAAGGATTACATCGCCCTGAAAGAGGACCTGCGCTCTTTGACCGCGGCGGACATGGCAGCTCAGACCACCAAGCACAAGTGGGAGGCGGCCCATGTGGCGGAGCAGTTGAGAGCCTACCTGGAGGGCACGTGCGTGGAGTGGCTCCGCAGATACCTGGAGAACGGGAAGGAGACGCTGCAGCGCACGGGTACCAGGGGCCACGGGGCGCCTCCCTGATCGCCTGTAGATCTCCCGGGCTGGCCTCCCACAAGGAGGGGAGACAATTGGGACCAACACTAGAATATCGCCCTCCCTCTGGTCCTGAGGGAGAGGAATCCTCCTGGGTTTCCAGATCCTGTACCAGAGAGTGACTCTGAGGTTCCGCCCTGCTCTCTGACACAATTAAGGGATAAAATCTCTGAAGGAATGACGGGAAGACGATCCCTCGAATACTGATGAGTGGTTCCCTTTGACACACACAGGCAGCAGCCTTGGGCCCGTGACTTTTCCTCTCAGGCCTTGTTCTCTGCTTCACACTCAATGTGTGTGGGGGTCTGAGTCCAGCACTTCTGAGTCCTTCAGCCTCCACTCAGGTCAGGACCAGAAGTCGCTGTTCCCTCTTCAGGGACTAGAATTTTCCACGGAATAGGAGATTATCCCAGGTGCCTGTGTCCAGGCTGGTGTCTGGGTTCTGTGCTCCCTTCCCCATCCCAGGTGTCCTGTCCATTCTCAAGATAGCCACATGTGTGCTGGAGGAGTGTCCCATGACAGATGCAAAATGCCTGAATGATCTGACTCTTCCTGACAGACGCCCCCAAAACGCATATGACTCACCACGCTGTCTCTGACCATGAAGCCACCCTGAGGTGCTGGGCCCTGAGCTTCTACCCTGCGGAGATCACACTGACCTGGCAGCGGGATGGGGAGGACCAGACCCAGGACACGGAGCTCGTGGAGACCAGGCCTGCAGGGGATGGAACCTTCCAGAAGTGGGCGGCTGTGGTGGTGCCTTCTGGACAGGAGCAGAGATACACCTGCCATGTGCAGCATGAGGGTTTGCCCAAGCCCCTCACCCTGAGATGGGGTAAGGAGGGAGACGGGGGTGTCATGTCTTTTAGGGAAAGCAGGAGCCTCTCTGACCTTTAGCAGGGTCAGGGCCCCTCACCTTCCCCTCTTTTCCCAGAGCCGTCTTCCCAGCCCACCATCCCCATCGTGGGCATCATTGCTGGCCTGGTTCTCTTTGGAGCTGTGATCACTGGAGCTGTGGTCGCTGCTGTGATGTGGAGGAGGAAGAGCTCAGGTGGGGAAGGGGTGAAGGGTGGGTCTGAGATTTCTTGTCTCACTGAGGGTTCCAAGACCCAGGTAGAAGTGTGCCCTGCCTCGTTACTGGGAAGCACCACCCACAATTATGGGCCTACCCAGCCTGGGCCCTGTGTGCCAGCACTTACTCTTTTGTAAAGCACCTGTTAAAATGAAGGACAGATTTATCACCTTGATTACAGCGGTGATGGGACCTGATCCCAGCAGTCACAAGTCACAGGGGAAGGTCCCTGAGGACCTTCAGGAGGGCGGTTGGTCCAGGACCCACACCTGCTTTCTTCATGTTTCCTGATCCCGCCCTGGGTCTGCAGTCACACATTTCTGGAAACTTCTCTGAGGTCCAAGACTTGGAGGTTCCTCTAGGACCTTAAGGCCCTGACTCCTTTCTGGTATCTCACAGGACATTTTCTTCCCACAGATAGAAAAGGAGGGAGCTACTCTCAGGCTGCAAGTAAGTATGAAGGAGGCTGATGCCTGAGGTCCTTGGGATATTGTGTTTGGGAGCCCATGGGGGAGCTCACCCACCCCACAATTCCTCCTCTAGCCACATCTTCTGTGGGATCTGACCAGGTTCTGTTTTTGTTCTACCCCAGGCAGTGACAGTGCCCAGGGCTCTGATGTGTCTCTCACAGCTTGTAAAGGTGAGAGCCTGGAGGGCCTGATGTGTGTTGGGTGTTGGGCGGAACAGTGGACACAGCTGTGCTATGGGGTTTCTTTCCATTGGATGTATTGAGCATGCGATGGGCTGTTTAAAGTGTGACCCCTCACTGTGACAGATACGAATTTGTTCATGAATATTTTTTTCTATAGTGTGAGACAGCTGCCTTGTGTGGGACTGAGAGGCAAGAGTTGTTCCTGCCCTTCCCTTTGTGACTTGAAGAACCCTGACTTTGTTTCTGCAAAGGCACCTGCATGTGTCTGTGTTCGTGTAGGCATAATGTGAGGAGGTGGGGAGACCACCCCACCCCCATGTCCACCATGACCCTCTTCCCACGCTGACCTGTGCTCCCTCCCCAATCATCTTTCCTGTTCCAGAGAGGTGGGGCTGAGGTGTCTCCATCTCTGTCTCAACTTCATGGTGCACTGAGCTGTAACTTCTTCCTTCCCTATTAAAA (SEQ ID NO: 169) |
一般熟習此項技術者將了解,T可取代U以將RNA序列轉化為DNA序列,反之亦然,且設想兩者為本揭示案之靶基因序列。
在一些實施例中,使用核酸引導之核酸內切酶在本文所述之免疫細胞中編輯靶基因。示例性核酸引導之核酸內切酶包括II類核酸內切酶,諸如CRISPR/Cas9。
如本文所用,「CRISPR」或「CRISPR基因編輯」係指一組成簇規則間隔之短迴文重複,或包含一組此類重複之系統。如本文所用,「Cas」係指CRISPR相關蛋白。「CRISPR/Cas」 系統係指可用於使靶基因靜默、敲除或突變之來源於CRISPR及Cas之系統。此系統為一種類型之原核免疫系統,該系統賦予對諸如質體及噬菌體之外來遺傳元件的抗性且提供一種形式之後天免疫。已修飾CRISPR/Cas系統以用於基因編輯。此係藉由將一或多種專門設計之嚮導核酸(gNA),典型地為嚮導RNA (gRNA),以及與gNA形成核糖核蛋白複合物之適當Cas核酸內切酶引入真核細胞中來完成。gNA將gNA-核酸內切酶蛋白複合物引導至靶基因體位置,且核酸內切酶在靶基因體位置處引入鏈斷裂。此種雙鏈斷裂可藉由細胞機制修復,諸如非同源末端連接(引起缺失)或同源修復(可產生插入),從而將遺傳修飾引入宿主細胞基因體中。
CRISPR/Cas系統按類別及類型分類。2類系統當前代表歸類為三種不同類型(II型、V型及VI型)之單一干擾蛋白。設想適合於基因編輯之任何2類CRISPR/Cas系統,例如II型、V型或VI型系統在本揭示案之範疇內。示例性2類II型CRISPR系統包括Cas9、Csn2及Cas4。示例性2類V型CRISPR系統包括Cas12、Cas12a (Cpf1)、Cas12b (C2c1)、Cas12c (C2c3)、Cas12d (CasY)、Cas12e (CasX)、Cas12f、Cas12g、Cas12h、Cas12i及Cas12k (C2c5)。示例性2類VI型系統包括Cas13、Cas13a (C2c2) Cas13b、Cas13c及Cas13d。
CRISPR序列,有時稱為CRISPR基因座,包含交替重複及間隔子。在天然存在之CRISPR中,間隔子通常包含細菌之外來序列,諸如質體或噬菌體序列。如本文所述,間隔子序列亦可稱作「靶向序列」。在用於遺傳工程改造之CRISPR/Cas系統中,間隔子來源於靶基因序列(gNA)。
示例性2類II型CRISPR系統依賴於蛋白質Cas9,此為具有兩個活性切割位點之核酸酶,一個位點用於雙螺旋之各鏈。組合Cas9與經修飾之CRISPR基因座RNA可用於基因編輯系統。Pennisi (2013) Science 341: 833-836。在一些實施例中,用於修飾免疫細胞之Cas蛋白為Cas9。
因此,藉由添加或缺失鹼基對,或引入過早終止,由此降低標靶表現,CRISPR/Cas系統可用於編輯靶基因,諸如針對在本文所述之免疫細胞中編輯所靶向之基因。或者,可如同RNA干擾一般使用CRISPR/Cas系統,以可逆方式關閉靶基因。舉例而言,在哺乳動物細胞中,RNA可將Cas蛋白引導至靶基因啟動子,從而空間上阻斷RNA聚合酶。
Cas蛋白可來源於任何細菌或古菌Cas蛋白。設想任何適合之CRISPR/Cas系統在本揭示案之範疇內。在其他態樣中,Cas蛋白包含以下一或多者:Cas1、Cas1B、Cas2、Cas3、Cas4、Cas5、Cas6、Cas7、Cas8、Cas9、Cas10、Cas12a (Cpf1)、Cas13、Csy1、Csy2、Csy3、Cse1、Cse2、Csc1、Csc2、Csa5、Csn2、Csm2、Csm3、Csm4、Csm5、Csm6、Cmr1、Cmr3、Cmr4、Cmr5、Cmr6、Csb1、Csb2、Csb3、Csx17、Csx14、Csx10、Csx16、CsaX、Csx3、Csx1、Csx15、Csf1、Csf2、Csf3、Csf4、CasX、CasY、其同源物或其經修飾型式。在一些實施例中,Cas蛋白為Cas9蛋白、Cpf1蛋白、C2c1蛋白、C2c2蛋白、C2c3蛋白、Cas3、Cas3-HD、Cas 5、Cas7、Cas8、Cas10,或此等之組合或複合物。在一些實施例中,Cas蛋白為Cas9蛋白。
使用此項技術中已知之技術可產生抑制靶基因之人工CRISPR/Cas系統,例如,美國公開案第20140068797號及Cong (2013) Science 339: 819-823中所述。亦可產生抑制靶基因之此項技術中已知之其他人工CRISPR/Cas系統,例如,Tsai (2014) Nature Biotechnol., 32:6 569-576;美國專利第8,871,445號;第8,865,406號;第8,795,965號;第8,771,945號;及第8,697,359號中所述。設計適合於特定Cas蛋白之gNA的方法將為一般熟習此項技術者所知。
本揭示案提供基因靶向嚮導核酸(gNA),其可將相關多肽(例如,核酸引導之核酸內切酶)之活性導向靶核酸基因體內之特異性靶基因序列。基因體靶向核酸可為RNA。基因體靶向RNA在本文中稱作「嚮導RNA」或「gRNA」。嚮導RNA可至少包含與所關注之靶核酸序列雜交的靶向序列及CRISPR重複序列。在一些II型系統中,gRNA亦包含稱為tracrRNA序列之第二RNA,本文亦稱作「支架」序列。在II型嚮導RNA (gRNA)中,CRISPR重複序列及支架序列彼此雜交以形成雙鏈體。在V型嚮導RNA (gRNA)中,crRNA形成雙鏈體。在兩個系統中,雙鏈體可結合定點多肽,使得嚮導RNA與定點多肽形成複合物。基因靶向核酸可藉助於其與定點多肽之關聯而提供對複合物之標靶特異性。因此,基因靶向核酸可指導定點多肽之活性。
在一些實施例中,本揭示案提供包含靶向序列及嚮導RNA支架序列之嚮導RNA,其中靶向序列與靶基因之序列互補。
示例性嚮導RNA包括約15-20個鹼基之靶向序列。如一般熟習此項技術者所了解,各gRNA可經設計以包括與其基因體靶序列互補之靶向序列。舉例而言,靶向序列中之每一者,例如表8中呈現之DNA序列之RNA型式,減去代表彼PAM位點之三個3'核苷酸,可放入單個RNA嵌合體或crRNA中。
基因靶向核酸可為雙分子嚮導RNA。基因靶向核酸可為單分子嚮導RNA。基因靶向核酸可為此項技術中已知的嚮導RNA之任何已知構型,諸如包括成對gRNA,或在單個步驟中使用之多個gRNA。儘管自基因體序列明確編碼序列及剪接點之位置,但基因表現所需之其他特徵可為特殊的及不明確的。
雙分子嚮導RNA可包含兩條RNA鏈。第一鏈包含5'至3'方向之序列、視情況存在之間隔子延伸序列、靶向序列及最小CRISPR重複序列。第二鏈可包含最小tracrRNA序列(與最小CRISPR重複序列互補)、3' tracrRNA序列及視情況存在之tracrRNA延伸序列。
II型系統中之單分子嚮導RNA (sgRNA)可在5'至3'方向上包含視情況存在之間隔子延伸序列、靶向序列、最小CRISPR重複序列、單分子嚮導連接子、最小tracrRNA序列、3' tracrRNA序列及視情況存在之tracrRNA延伸序列。視情況存在之tracrRNA延伸可包含對嚮導RNA貢獻額外功能性(例如,穩定性)之元件。單分子嚮導連接子可將最小CRISPR重複與最小tracrRNA序列連接以形成髮夾結構。視情況存在之tracrRNA延伸可包含一或多個髮夾。
在一些實施例中,嚮導RNA或單分子嚮導RNA (sgRNA)可包含靶向序列及支架序列。在一些實施例中,支架序列為Cas9 gRNA序列。在一些實施例中,支架序列由DNA序列編碼,該DNA序列包含與GTTTTAGAGCTAGAAATAGCAAGTTAAAATAAGGCTAGTCCGTTATCAACTTGAAAAAGTGGCACCGAGTCGGTGCTTTTTTT (SEQ ID NO: 435)共享至少90%、至少95%、至少96%、至少97%、至少98%或至少99%一致性之序列。在一些實施例中,支架序列由包含GTTTTAGAGCTAGAAATAGCAAGTTAAAATAAGGCTAGTCCGTTATCAACTTGAAAAAGTGGCACCGAGTCGGTGCTTTTTTT (SEQ ID NO: 435)之DNA序列編碼。
在一些實施例中,例如其中CRISPR/Cas系統為Cas9系統之彼等實施例中,sgRNA可在sgRNA序列之5'末端包含20個核苷酸之靶向序列。sgRNA可在sgRNA序列之5'末端包含少於20個核苷酸之靶向序列。sgRNA可在sgRNA序列之5'末端包含多於20個核苷酸之靶向序列。sgRNA可在sgRNA序列之5'末端包含具有17-30個核苷酸之可變長度靶向序列。
適合之支架序列及支架靶向序列之排列將視核酸內切酶之選擇而定,且將為熟習此項技術者所知。
II型系統中之單分子嚮導RNA (sgRNA),例如Cas9,可在5'至3'方向上包含最小CRISPR重複序列及靶向序列。
作為說明,CRISPR/Cas9或CRISPR/Cpf1系統中所用之嚮導RNA或其他較小RNA可易於藉由化學方式合成,如下文所說明及此項技術中所述。儘管化學合成程序不斷擴大,但由於多核苷酸長度顯著增加超過約一百個核苷酸,因此藉由諸如高效液相層析(HPLC,避免使用諸如PAGE之凝膠)之程序純化此類RNA往往變得更具挑戰性。用於產生更大長度之RNA的一種方法為產生兩個或更多個接合在一起之分子。更長之RNA,諸如編碼Cas9或Cpf1核酸內切酶之彼等RNA,更容易酶促產生。可在RNA之化學合成及/或酶促產生期間或之後引入各種類型之RNA修飾,例如,增強穩定性、降低先天免疫反應之可能性或程度及/或增強其他屬性之修飾,如此項技術中所述。
gRNA之靶向序列與所關注之靶核酸中之序列雜交。基因體靶向核酸之靶向序列可經由雜交(亦即,鹼基配對)以序列特異性方式與靶核酸相互作用。靶向序列之核苷酸序列可視所關注之靶核酸的序列而變化。
在本文所述之Cas9系統中,靶向序列可經設計以與位於系統中所用之Cas9酶之PAM之反向補體之5'的靶核酸雜交。靶向序列可與靶序列完美匹配或可具有錯配。各CRISPR/Cas系統蛋白可具有其在靶DNA中所識別之特定取向及位置之特定PAM序列。舉例而言,釀膿鏈球菌(S. pyogenes) Cas9在靶核酸中識別包含序列5'-NRG-3'之PAM,其中R包含A或G,其中N為任何核苷酸且N緊鄰由靶向序列靶向之靶核酸序列的3'。適當PAM序列之選擇將為一般熟習此項技術者顯而易見。
靶序列與gRNA之靶向序列互補及雜交。靶核酸序列可包含20個核苷酸。靶核酸可包含少於20個核苷酸。靶核酸可包含多於20個核苷酸。靶核酸可至少包含:5、10、15、16、17、18、19、20、21、22、23、24、25、30個或更多個核苷酸。在一些實施例中,例如其中CRISPR/Cas系統為Cas9系統之彼等實施例中,靶核酸序列可包含緊鄰PAM序列之反向補體之第一個核苷酸之5'的20個核苷酸。此靶核酸序列常常稱作PAM鏈或靶鏈,且互補核酸序列常常稱作非PAM鏈或非靶鏈。熟習此項技術者將認識到靶向序列與靶核酸之非PAM鏈雜交,參見例如US20190185849A1。
在一些實例中,靶向序列與靶核酸之間的互補性百分比為至少約30%、至少約40%、至少約50%、至少約60%、至少約65%、至少約70%、至少約75%、至少約80%、至少約85%、至少約90%、至少約95%、至少約97%、至少約98%、至少約99%或100%。在一些實例中,靶向序列與靶核酸之間的互補性百分比為至多約30%、至多約40%、至多約50%、至多約60%、至多約65%、至多約70%、至多約75%、至多約80%、至多約85%、至多約90%、至多約95%、至多約97%、至多約98%、至多約99%或100%。在一些實例中,靶向序列與靶核酸之間的互補性百分比在靶核酸之互補鏈之靶序列之六個連續5'-最末核苷酸上為100%。靶向序列與靶核酸之間的互補性百分比在約20個連續核苷酸上可為至少60%。靶向序列及靶核酸之長度可相差1至6個核苷酸,此可視為一或多個凸出。
可使用一般熟習此項技術者已知之電腦程式設計或選擇靶向序列。電腦程式可使用變數,諸如預測解鏈溫度、二級結構形成、預測黏接溫度、序列一致性、基因體背景、染色質可及性、% GC、基因體出現頻率(例如,一致或相似但由於錯配、插入或缺失而在一或多個點上不同之序列)、甲基化狀態、SNP之存在及類似變數。可用之電腦程式可將NCBI基因ID、官方基因符號、Ensembl基因ID、基因體坐標或DNA序列作為輸入,且創建含有靶向指定為輸入之適當基因體區域之sgRNA的輸出檔案。電腦程式亦可提供統計及分數之匯總,指示sgRNA對靶基因之中靶及脫靶結合(Doench等人
Nat Biotechnol.34:184-191 (2016))。本揭示案提供包含靶向序列之嚮導RNA。在一些實施例中,嚮導RNA進一步包含嚮導RNA支架序列。在一些實施例中,靶向序列與選自由HLA-A、HLA-B、HLA-C、B2M或其對偶基因組成之群的靶基因之序列互補。在一些實施例中,靶基因為HLA-A基因。在一些實施例中,靶基因為HLA-B基因。在一些實施例中,靶基因為HLA-C基因。在一些實施例中,靶基因為HLA-A、HLA-B、HLA-C或其組合。在一些實施例中,靶向序列包含與表7中所揭示之序列共享約90%、約95%、約96%、約97%、約98%、約99%一致性或一致之序列。
在一些實施例中,gNA特異性靶向內源HLA-A基因座之序列。在一些實施例中,特異性靶向HLA-A基因座之序列的gNA包含與選自表8中所揭示之序列的序列共享約90%、約95%、約96%、約97%、約98%或約99%一致性之序列。在一些實施例中,特異性靶向HLA-A基因座之序列的gNA包含選自表8中所揭示之序列的序列。
在一些實施例中,gNA特異性靶向HLA-A*02對偶基因之序列。舉例而言,gRNA特異性靶向由所有HLA-A*02對偶基因共享,但不由HLA-A*02及HLA-A*03對偶基因共享之序列且與其雜交。在一些實施例中,gNA特異性靶向HLA-A*02:01對偶基因之序列。在一些實施例中,gNA特異性靶向HLA-A*02:01:01對偶基因之序列。在一些實施例中,gNA特異性靶向HLA-A*02:01:01:01對偶基因之序列。在一些實施例中,gNA特異性靶向HLA-A*02:01:01:01對偶基因之序列。
在一些實施例中,gNA特異性靶向HLA-A*02之編碼DNA序列。
在一些實施例中,gNA特異性靶向由超過1000個HLA-A*02對偶基因共享之編碼DNA序列。在一些實施例中,特異性靶向大於1000個HLA-A*02對偶基因中之編碼DNA序列的gNA包含與選自SEQ ID NO: 400-465之序列共享約90%、約95%、約96%、約97%、約98%、約99%一致性或一致之序列。
表8. 靶向HLA-A及HLA-A對偶基因之說明性序列
表8中所揭示之序列包括相應基因體序列,PAM序列包括在內。技術人員將了解,gRNA之靶向序列不包括表8中之序列之三個3'端核苷酸,其代表gRNA之相應PAM位點。
本揭示案提供包含對
B2M基因具有特異性之靶向序列的gNA。在一些實施例中,gNA特異性靶向B2M基因之編碼序列(CDS)序列。在一些實施例中,gNA包含靶向
B2M基因啟動子序列之序列。
在一些實施例中,gNA包含靶向序列及gNA支架序列。在一些實施例中,靶向序列包含表9中所列之序列,或與其共享約90%、約95%、約96%、約97%、約98%、約99%一致性之序列。
在一些實施例中,靶向序列與
B2M基因之序列互補。在一些實施例中,
B2M基因包含與表7中所列之B2M序列共享約90%、約95%、約96%、約97%、約98%、約99%一致性之序列。
表9. 靶向
B2M之說明性序列
在一些實施例中,使用TALEN基因編輯來編輯本文所述之免疫細胞。
「TALEN」或「TALEN基因編輯」係指轉錄活化因子樣效應核酸酶,其為用於編輯靶基因之人工核酸酶。
藉由將TAL效應子DNA結合結構域融合至DNA裂解結構域來人工產生TALEN。來源於黃單胞菌屬細菌之轉錄活化因子樣效應子(TALE)可經工程改造以結合任何所需之DNA序列,包括靶基因之一部分,諸如TCR次單元、MHC I類複合物組分或CD52。藉由將工程改造之TALE與DNA裂解結構域組合,可產生對任何所需之DNA序列(包括靶基因序列)具有特異性之限制酶。接著可將此等引入細胞中,在細胞中其可用於基因體編輯。
為產生TALEN,將TALE蛋白融合至核酸酶(N),該核酸酶為野生型或突變型折疊核酸內切酶。已對FokI進行若干突變以用於TALEN;例如,此等會改善裂解特異性或活性。
FokI結構域作為二聚體發揮功能,需要兩個具有獨特DNA結合結構域之構築體,用於靶基因體中具有適當取向及間距之位點。TALE DNA結合結構域與FokI裂解結構域之間的胺基酸殘基數目及兩個個別TALEN結合位點之間的鹼基數目兩者似乎為達成高活性水準之重要參數。
可使用此項技術中已知之任何方法構築對靶基因中之序列具有特異性之TALEN,包括使用模組化組件之各種方案。
在一些實施例中,使用ZFN基因編輯在本文所述之免疫細胞中編輯靶基因。
「ZFN」或「鋅指核酸酶」或「ZFN基因編輯」係指鋅指核酸酶,一種可用於編輯靶基因之人工核酸酶。
如同TALEN一般,ZFN包含融合至DNA結合結構域之折疊核酸酶結構域(或其衍生物)。在ZFN之情況下,DNA結合結構域包含一或多個鋅指。
鋅指為由一或多個鋅離子穩定之小蛋白質結構基元。鋅指可包含例如Cys2His2,且可識別約3-bp序列。已知特異性之各種鋅指可組合以產生識別約6、9、12、15或18-bp序列之多指多肽。各種選擇及模組化組裝技術可用於產生識別特異性序列之鋅指(及其組合),包括噬菌體展示、酵母單雜交系統、細菌單雜交及雙雜交系統以及哺乳動物細胞。
如同TALEN一般,ZFN必須二聚化以使DNA裂解。因此,需要一對ZFN以靶向非迴文DNA位點。兩個個別ZFN必須結合DNA之相反鏈,其核酸酶適當間隔。
亦如同TALEN一般,ZFN可在DNA中產生雙鏈斷裂,若修復不當,則可能造成框移突變,導致細胞中靶基因或基因產物之表現及量減少。ZFN亦可與同源重組一起用於在靶基因中發生突變。
可使用此項技術中已知之任何方法來構築對靶基因中之序列具有特異性之ZFN。
在一些實施例中,使用RNA干擾來降低一或多種MCH-1組分之表現及功能。「RNAi」或「RNA干擾」係指由雙鏈RNA (dsRNA)介導之序列特異性轉錄後基因靜默過程。雙鏈RNA,諸如siRNA (小干擾RNA)、miRNA (微小RNA)、shRNA (短髮夾RNA)、ddRNA (DNA定向RNA)、piRNA (Piwi相互作用RNA)或rasiRNA (重複相關siRNA)及其經修飾形式全部能夠介導RNA干擾。此等dsRNA分子可為市售的或者可基於已知之序列資訊進行設計及製備。此等分子之反義鏈可包括RNA、DNA、PNA或其組合。DNA/RNA嵌合多核苷酸包括但不限於抑制靶基因表現的由DNA及RNA組成之雙鏈多核苷酸。dsRNA分子亦可包括一或多個經修飾之核苷酸,如本文所述,其可併入任一條或兩條鏈上。
在RNAi基因靜默或敲低中,將包含與靶基因之一部分互補之第一條(反義)鏈及與第一條反義鏈完全或部分互補之第二條(有義)鏈的dsRNA引入生物體中。引入生物體中之後,將靶基因特異性dsRNA加工成相對小之片段(siRNA),隨後可分佈於整個生物體中,減少靶基因之信使RNA, 使得表型可極其類似於由靶基因完全或部分缺失產生之表型。
細胞中之某些dsRNA可經歷Dicer酶(一種核糖核酸酶III酶)之作用。Dicer可將dsRNA加工成更短之dsRNA段,亦即,siRNA。RNAi亦涉及核酸內切酶複合物,稱為RNA誘導之靜默複合物(RISC)。由Dicer裂解之後,siRNA進入RISC複合物且指導具有與siRNA雙鏈體之反義鏈互補之序列的單鏈RNA標靶裂解。siRNA之另一條鏈為過客鏈。標靶RNA之裂解在與siRNA雙鏈體之反義鏈互補之區域中間發生。因此,siRNA可藉由以序列特異性方式介導RNA干擾來下調或敲低基因表現。
如本文關於RNA干擾所用,「靶基因」或「靶序列」係指靶向其相應RNA以用於使用如本文所述之dsRNA或siRNA經RNAi路徑降解之基因或基因序列。示例性靶基因序列示於表7中。為例如使用siRNA靶向基因,siRNA包含與靶基因或序列之至少一部分互補或實質上互補之反義區,及與反義鏈互補之有義鏈。一旦引入細胞中,siRNA指導RISC複合物使包含靶序列之RNA裂解,從而降解RNA。本揭示案提供干擾RNA。本揭示案之雙鏈RNA分子可呈此項技術中已知之任何類型之RNA干擾分子的形式。在一些實施例中,雙鏈RNA分子為小干擾RNA (siRNA)。在其他實施例中,雙鏈RNA分子為短髮夾RNA (shRNA)分子。在其他實施例中,雙鏈RNA分子為在細胞中加工以產生siRNA之Dicer受質。在其他實施例中,雙鏈RNA分子為微小RNA前體分子之一部分。
在一些實施例中,shRNA之長度適合作為Dicer受質,可對其進行加工以產生RISC活性siRNA分子。參見例如Rossi等人, US2005/0244858。
Dicer受質雙鏈RNA (例如,shRNA)可具有足以由Dicer加工以產生活性siRNA之長度,且可進一步包括以下一或多種特性:(i) Dicer受質shRNA可為不對稱的,例如,在反義鏈上具有3'突出端;(ii) Dicer受質shRNA可在有義鏈上具有經修飾之3'末端以指導Dicer結合之取向及dsRNA加工成活性siRNA,例如,併入一或多個DNA核苷酸;及(iii) Dicer受質dsRNA之第一條及第二條鏈之長度可為21-30 bp。
在一些實施例中,干擾RNA包含與B2M mRNA之序列互補之序列。在一些實施例中,干擾RNA能夠誘導RNAi介導之B2M mRNA之降解。在一些實施例中,B2M mRNA序列包含編碼序列。在一些實施例中,B2M mRNA序列包含非轉譯區。
在一些實施例中,干擾RNA包含與HLA-A*02 mRNA之序列互補之序列。在一些實施例中,干擾RNA能夠誘導RNAi介導之HLA-A*02 mRNA之降解。在一些實施例中,HLA-A*02 mRNA序列包含編碼序列。在一些實施例中,HLA-A*02 mRNA序列包含非轉譯區。
在一些實施例中,干擾RNA為短髮夾RNA (shRNA)。在一些實施例中,shRNA包含第一序列,其自5'至3'末端具有與B2M mRNA互補之序列;及第二序列,其自5'至3'末端具有與第一序列互補之序列,其中第一序列及第二序列形成shRNA。
在一些實施例中,第一序列為18、19、20、21或22個核苷酸。在一些實施例中,第一序列與選自表10及11中所列之序列的序列互補。在一些實施例中,第一序列之GC含量大於或等於25%且小於60%。在一些實施例中,第一序列與選自表10及11中所列之序列的序列互補。在一些實施例中,第一序列不包含相同鹼基之四個核苷酸或一連串之七個C或G核苷酸鹼基。在一些實施例中,第一序列為21個核苷酸。
與第一序列互補之說明性B2M靶序列示於表10中。
在一些情況下,第一序列可與靶核酸序列具有100%一致性,亦即,完全一致性、同源性、互補性。在其他情況下,第一序列與靶核酸序列之間可能存在一或多個錯配。舉例而言,有義區與靶核酸序列之間可能存在1、2、3、4、5、6或7個錯配。
在一些實施例中,干擾RNA包含與HLA-A*02 mRNA之序列互補之序列。在一些實施例中,干擾RNA能夠誘導RNAi介導之HLA-A*02 mRNA之降解。在一些實施例中,HLA-A*02 mRNA序列包含編碼序列。在一些實施例中,HLA-A*02 mRNA序列包含非轉譯區。
編碼B2M shRNA之示例性序列包含GCACTCAAAGCTTGTTAAGATCGAAATCTTAACAAGCTTTGAGTGC (SEQ ID NO: 179)之序列,或與其具有至少90%、至少95%、至少97%或至少99%一致性之序列。編碼B2M shRNA之另一示例性序列包含GTTAACTTCCAATTTACATACCGAAGTATGTAAATTGGAAGTTAAC (SEQ ID NO: 808)之序列,或與其具有至少90%、至少95%、至少97%或至少99%一致性之序列。
在一些實施例中,干擾RNA為短髮夾RNA (shRNA)。在一些實施例中,shRNA包含第一序列,其自5'至3'末端具有與HLA-A*02 mRNA互補之序列;及第二序列,其自5'至3'末端具有與第一序列互補之序列,其中第一序列及第二序列形成shRNA。
在一些實施例中,第一序列及第二序列由連接子(有時稱作環)隔開。在一些實施例中,第一序列及第二序列兩者均由一個單鏈RNA或DNA載體編碼。在一些實施例中,環在第一序列與第二序列之間。
在此等實施例中,且第一序列及第二序列雜交形成雙鏈體區域。第一序列及第二個序列由連接子序列連接,形成「髮夾」或「莖環」結構。shRNA可在單鏈分子之相對末端具有互補之第一序列及第二序列,使得分子可與互補序列部分形成雙鏈體區域,且該等鏈在雙鏈體區域之一個末端由連接子(亦即,環序列)連接。連接子或環序列可為核苷酸或非核苷酸連接子。連接子可經由共價鍵或非共價相互作用與第一序列相互作用,且視情況與第二序列相互作用。
設想任何適合之核苷酸環序列在本揭示案之範疇內。本揭示案之shRNA可包括將shRNA之第一序列連接至shRNA之第二序列的核苷酸、非核苷酸或混合之核苷酸/非核苷酸連接子。核苷酸環序列之長度可≥ 2個核苷酸,例如,長度為約4、5、6、7、8、9、10、11、12、13、14或15個核苷酸。表12中揭示說明性環序列。
在一些實施例中,shRNA進一步包含5'側翼序列及3'側翼序列。在一些實施例中,其中5'側翼序列連接至第一序列之5'末端,且其中3'側翼序列連接至第二序列之3'末端。
不希望受理論約束,據信具有與微小RNA中發現之序列相似之5'及3'序列的側翼shRNA莖環序列可靶向shRNA以供內源微小RNA加工機械進行加工,從而提高shRNA加工之有效性。或者或另外,側翼序列可增加shRNA與聚合酶II或聚合酶III啟動子之相容性,從而更有效地調控shRNA表現。
在一些實施例中,5'側翼序列係選自表12中所列之序列。說明性側翼序列示於表12中。
表12. 說明性側翼序列
SEQ ID NO | 5' 側翼序列 |
895 | GG |
896 | ACACCAUGUUGCCAGUCUCUAGG |
897 | UGAUAGCAAUGUCAGCAGUGCCU |
898 | UAUUGCUGUUGACAGUGAGCGAC |
SEQ ID NO | 3' 側翼序列 |
899 | UGGCGUCUGGCCCAACCACAC |
900 | GUAAGGUUGACCAUACUCUAC |
在一些實施例中,第一序列及第二序列存在於單鏈多核苷酸上,其中第一序列及第二序列由4、5、6、7、8、9、10、11、12、13、14或15個核苷酸隔開,其中4、5、6、7、8、9、10、11、12、13、14或15個核苷酸在shRNA中形成環區。在一些實施例中,環區包含選自表13中所列之序列的序列。
表13. 說明性環區序列
SEQ ID NO | 環區序列 |
901 | CGAA |
902 | UUCAAGA |
903 | AUAUUCA |
904 | UGUGCUGUC |
905 | CUCGAG |
906 | CUUCCUGUCAGA |
907 | CUUCCCUUUGUCAGA |
908 | GUGUUAUUCUUG |
909 | GUGUCUUAAUUG |
910 | GUGUUAGUCUUG |
911 | UCAAGAG |
912 | GGACAUCCAGGG |
913 | GUGAAGCCACAGAUG |
914 | GAUUCUAAAA |
本揭示案之shRNA可藉由化學合成、藉由活體外轉錄或藉由用Dicer或具有類似活性之另一種適當核酸酶使更長之雙鏈RNA裂解而外源產生。使用常規DNA/RNA合成器自經保護之核糖核苷亞磷醯胺產生之化學合成之siRNA可獲自商業供應商,諸如Millipore Sigma (Houston, Tex.)、Ambion Inc. (Austin, Tex.)、Invitrogen (Carlsbad, Calif.)或Dharmacon (Lafayette, Colo.)。舉例而言,可藉由用溶劑或樹脂萃取、沈澱、電泳、層析或其組合來純化siRNA。或者,可在極少(若存在)純化之情況下使用siRNA,以避免由於樣品處理所致之損失。
在一些實施例中,可使用表現載體產生本揭示案之shRNA,編碼雙鏈RNA之核酸已選殖至該表現載體中,例如,在適合啟動子之控制下。
在一些實施例中,免疫細胞包含
醫藥組合物
本揭示案提供醫藥組合物,該等醫藥組合物包含含有本揭示案之第一受體及第二受體之免疫細胞及醫藥學上可接受之稀釋劑、載劑或賦形劑。
此類組合物可包含緩沖劑,諸如中性緩衝鹽水、磷酸鹽緩衝鹽水及類似物;碳水化合物,諸如葡萄糖、甘露糖、蔗糖或右旋糖聚糖、甘露糖醇;蛋白質;多肽或胺基酸,諸如甘胺酸;抗氧化劑;螯合劑,諸如EDTA或麩胱甘肽;及防腐劑。
在一些實施例中,免疫細胞表現第一受體及第二受體兩者。在一些實施例中,至少約50%、約55%、約60%、約65%、約70%、約75%、約80%、約85%、約90%或約95%之免疫細胞表現第一受體及第二受體兩者。在一些實施例中,至少90%之免疫細胞表現第一受體及第二受體兩者。
治療癌症
本文提供在個體中殺死複數個癌細胞或治療癌症之方法,該方法包括向個體投與治療有效量之包含免疫細胞之組合物,該等免疫細胞包含本揭示案之第一受體及第二受體。免疫細胞在同一細胞中表現兩種受體。
癌症為異常細胞不受控制地分裂且擴散至附近組織之疾病。在一些實施例中,癌症包括液體腫瘤或實體腫瘤。癌症實際上可在身體之器官,包括上皮組織中發生。設想複數個癌細胞表現第一活化劑配位體且不表現第二抑制劑配位體之任何癌症在本揭示案之範疇內。舉例而言,可使用本文所述之方法治療之EGFR陽性癌症包括肺癌、小細胞肺癌、非小細胞肺癌、胰管癌、結腸直腸癌、頭頸癌、食道及胃腺癌、卵巢癌、多形性神經膠質母細胞瘤、子宮頸鱗狀細胞癌、腎癌、乳頭狀腎癌、腎臟腎透明細胞癌、膀胱癌、乳癌、膽管癌、肝癌、前列腺癌、肉瘤、甲狀腺癌、胸腺癌、胃癌或子宮癌,及所有其他表現EGFR標靶之腫瘤。本文所揭示之組合物及方法可用於治療復發性、難治性及/或轉移性EGFR陽性癌症。
在一些實施例中,複數個癌細胞表現靶抗原。在一些實施例中,個體之複數個癌細胞表現EGFR。EGFR陽性癌症包括但不限於肺癌、小細胞肺癌、非小細胞肺癌、胰管癌、結腸直腸癌、頭頸癌、食道及胃腺癌、卵巢癌、多形性神經膠質母細胞瘤、子宮頸鱗狀細胞癌、腎癌、乳頭狀腎癌、腎臟腎透明細胞癌、膀胱癌、乳癌、膽管癌、肝癌、前列腺癌、肉瘤、甲狀腺癌、胸腺癌、胃癌或子宮癌。
在一些實施例中,複數個癌細胞不表現COLEC12、APCDD1或CXCL16之多態對偶基因。在一些實施例中,複數個癌細胞不表現非靶抗原。在一些實施例中,複數個癌細胞不表現HLA-A*02。在一些實施例中,複數個癌細胞不表現HLA-A*02之對偶基因變異體。在一些實施例中,複數個癌細胞不表現HLA-A*01。在一些實施例中,複數個癌細胞不表現HLA-A*03。在一些實施例中,複數個癌細胞不表現HLA-A*11。在一些實施例中,複數個癌細胞不表現HLA-B*07。在一些實施例中,複數個癌細胞不表現HLA-C*07。舉例而言,癌細胞經由在彼基因座處之雜合性損失已損失COLEC12、APCDD1或CXCL16之對偶基因,或HLA-A*02。
投與本文所述之免疫細胞或醫藥組合物可減小個體中之腫瘤的大小。在一些實施例中,相對於投與免疫細胞或醫藥組合物之前的腫瘤大小,腫瘤大小減小約5%、約10%、約15%、約20%、約25%、約30%、約35%、約40%、約45%、約50%、約55%、約60%、約65%、約70%、約75%、約80%、約85%、約90%、約95%或約100%。在一些實施例中,腫瘤得以消除。
本文所述之免疫細胞或醫藥組合物之投與可阻止個體中之腫瘤的生長。舉例而言,免疫細胞或醫藥組合物可殺死腫瘤細胞,使得腫瘤停止生長或大小減小。在一些情況下,免疫細胞或醫藥組合物可防止形成額外腫瘤,或減少個體中之腫瘤的總數。
本文所述之免疫細胞或醫藥組合物之投與可選擇性殺死個體中之癌細胞而非正常細胞。在一些實施例中,所殺死之約60%之細胞為癌細胞,所殺死之約65%之細胞為癌細胞,所殺死之約70%之細胞為癌細胞,所殺死之約75%之細胞為癌細胞,所殺死之約80%之細胞為癌細胞,所殺死之約85%之細胞為癌細胞,所殺死之約90%之細胞為癌細胞,所殺死之約95%之細胞為癌細胞,或所殺死之約100%之細胞為癌細胞。
本文所述之免疫細胞或醫藥組合物之投與可殺死個體之約40%、約50%、約60%、約70%、約80%、約90%或所有癌細胞。
與包含第一活化劑受體但不含第二抑制性受體之其他方面等效之免疫細胞的投與相比,本文所述之免疫細胞或醫藥組合物之投與可對個體產生較少副作用。舉例而言,相對於EGFR CAR或在無第二抑制性受體之情況下投與之EGFR TCR,投與本文所述之免疫細胞或醫藥組合物可降低劑量限制毒性。
本揭示案提供治療個體之癌症的方法,該方法包括:(a)在選自由COLEC12之多態基因座、APCDD1之多態基因座及CXCL16之多態基因座或HLA-A*02基因座組成之群的多態基因座處確定個體之正常細胞及複數個癌細胞的基因型;(b)確定複數個癌細胞中EGFR之表現;及(c)若正常細胞對於多態基因座為雜合的且複數個癌細胞對於多態基因座為半合的或已損失HLA-A*02,且複數個癌細胞為EGFR陽性的,則向個體投與複數個免疫細胞,其中該複數個免疫細胞包含:(i)第一受體,視情況為嵌合抗原受體(CAR)或T細胞受體(TCR),該第一受體包含對EGFR具有特異性之細胞外配位體結合結構域或與主要組織相容性複合物I類(MHC-I)複合之其肽抗原;及(ii)第二受體,視情況為抑制性嵌合抗原受體(亦即,抑制性受體),該第二受體包含特異性結合至選自COLEC12、APCDD1及CXCL16或與主要組織相容性複合物I類(MHC-I)復合之其抗原肽或HLA-A*02之非靶抗原的細胞外配位體,其中該非靶抗原包含多態性。
對來自個體之癌細胞及正常細胞針對SNP之存在或不存在進行基因分型之方法將為一般熟習此項技術者顯而易見。SNP基因分型方法尤其包括基於PCR之方法,諸如雙探針TaqMan檢定、基於陣列之雜交方法及定序。
量測來自個體之癌細胞或正常細胞中靶抗原之表現的方法將為一般熟習此項技術者顯而易見。此等尤其包括量測RNA表現之方法,諸如RNA定序及反轉錄聚合酶鏈反應(RT-PCR),以及量測蛋白質表現之方法,諸如基於免疫組織化學之方法。量測複數個癌細胞中雜合性損失之方法尤其包括使用此項技術中已知之方法對自癌細胞中提取之基因體DNA進行高通量定序。
量測來自個體之癌細胞或正常細胞中靶抗原之表現的方法將為一般熟習此項技術者顯而易見。此等尤其包括量測RNA表現之方法,諸如RNA定序及反轉錄聚合酶鏈反應(RT-PCR),以及量測蛋白質表現之方法,諸如基於免疫組織化學之方法。
在一些實施例中,免疫細胞為T細胞。
在一些實施例中,免疫細胞為同種異體的或自體的。
在一些實施例中,與表現第一受體但不表現第二受體之免疫細胞相比,第二受體提高免疫細胞對EGFR陽性癌細胞之特異性。在一些實施例中,與表現第一受體但不表現第二受體之免疫細胞相比,免疫細胞具有降低之副作用。
治療癌症可使腫瘤大小減小。腫瘤大小減小亦可稱作「腫瘤消退」。較佳地,相對於治療之前的大小,在治療之後腫瘤大小減小5%或更大;更佳地,腫瘤大小減小10%或更大;更佳地,減小20%或更大;更佳地,減小30%或更大;更佳地,減小40%或更大;甚至更佳地,減小50%或更大;且最佳地,減小大於75%或更大。腫瘤大小可藉由任何再現性量測方式來量測。腫瘤大小可量測為腫瘤直徑。
治療癌症可使腫瘤體積減小。較佳地,相對於治療之前的大小,在治療之後,腫瘤體積減小5%或更大;更佳地,腫瘤體積減小10%或更大;更佳地,減小20%或更大;更佳地,減小30%或更大;更佳地,減小40%或更大;甚至更佳地,減小50%或更大;且最佳地,減小大於75%或更大。腫瘤體積可藉由任何再現性量測方式來量測。
治療癌症使得腫瘤數目減少。較佳地,相對於治療之前的數目,在治療之後,腫瘤數目減少5%或更大;更佳地,腫瘤數目減少10%或更大;更佳地,減少20%或更大;更佳地,減少30%或更大;更佳地,減少40%或更大;甚至更佳地,減少50%或更大;且最佳地,減少大於75%。腫瘤數目可藉由任何再現性量測方式來量測。腫瘤數目可藉由對肉眼或在指定放大率下可見之腫瘤進行計數來量測。較佳地,指定放大率為2x、3x、4x、5x、10x或50x。
治療癌症可減少遠離原發性腫瘤部位之其他組織或器官中之轉移性病變數目。較佳地,相對於治療之前的數目,在治療之後,轉移性病變數目減少5%或更大;更佳地,轉移性病變數目減少10%或更大;更佳地,減少20%或更大;更佳地,減少30%或更大;更佳地,減少40%或更大;甚至更佳地,減少50%或更大;且最佳地,減少大於75%。轉移性病變數目可藉由任何再現性量測方式來量測。轉移性病變數目可藉由對肉眼或在指定放大率下可見之轉移性病變進行計數來量測。較佳地,指定放大率為2x、3x、4x、5x、10x或50x。
與接受單獨載劑之群體相比,治療癌症可增加經治療之個體之群體的平均存活時間。較佳地,平均存活時間增加多於30天;更佳地,多於60天;更佳地,多於90天;且最佳地,多於120天。群體之平均存活時間增加可藉由任何再現性方式來量測。群體之平均存活時間增加可例如藉由在開始活性化合物治療之後計算群體之平均存活長度來量測。群體之平均存活時間增加亦可例如藉由在完成第一輪活性化合物治療之後計算群體之平均存活長度來量測。
與未經治療之個體之群體相比,治療癌症可增加經治療之個體之群體的平均存活時間。較佳地,平均存活時間增加多於30天;更佳地,多於60天;更佳地,多於90天;且最佳地,多於120天。群體之平均存活時間增加可藉由任何再現性方式來量測。群體之平均存活時間增加可例如藉由在開始活性化合物治療之後計算群體之平均存活長度來量測。群體之平均存活時間增加亦可例如藉由在完成第一輪活性化合物治療之後計算群體之平均存活長度來量測。
與接受不為本揭示案之化合物或其醫藥學上可接受之鹽、前藥、代謝物、類似物或衍生物之藥物之單一療法的群體相比,治療癌症可增加經治療之個體之群體的平均存活時間。較佳地,平均存活時間增加多於30天;更佳地,多於60天;更佳地,多於90天;且最佳地,多於120天。群體之平均存活時間增加可藉由任何再現性方式來量測。群體之平均存活時間增加可例如藉由在開始活性化合物治療之後計算群體之平均存活長度來量測。群體之平均存活時間增加亦可例如藉由在完成第一輪活性化合物治療之後計算群體之平均存活長度來量測。
與接受單獨載劑之群體相比,治療癌症可降低經治療之個體之群體的死亡率。與未經治療之群體相比,治療癌症可降低經治療之個體之群體的死亡率。與接受不為本揭示案之化合物或其醫藥學上可接受之鹽、前藥、代謝物、類似物或衍生物之藥物之單一療法的群體相比,治療癌症可降低經治療之個體之群體的死亡率。較佳地,死亡率降低超過2%;更佳地,超過5%;更佳地,超過10%;且最佳地,超過25%。經治療之個體之群體的死亡率降低可藉由任何再現性方式來量測。舉例而言,群體之死亡率降低可藉由計算群體在開始活性化合物治療之後每單位時間之疾病相關死亡的平均數目來量測。舉例而言,群體之死亡率降低亦可藉由計算群體在完成第一輪活性化合物治療之後每單位時間之疾病相關死亡的平均數目來量測。
治療癌症可降低腫瘤生長速率。較佳地,相對於治療之前的數目,在治療之後,腫瘤生長速率降低至少5%;更佳地,腫瘤生長速率降低至少10%;更佳地,降低至少20%;更佳地,降低至少30%;更佳地,降低至少40%;更佳地,降低至少50%;甚至更佳地,降低至少50%;且最佳地,降低至少75%。腫瘤生長速率可藉由任何再現性量測方式來量測。腫瘤生長速率可根據每單位時間之腫瘤直徑變化來量測。
治療癌症可減少腫瘤再生長。較佳地,在治療之後,腫瘤再生長少於5%;更佳地,腫瘤再生長少於10%;更佳地,少於20%;更佳地,少於30%;更佳地,少於40%;更佳地,少於50%;甚至更佳地,少於50%;且最佳地,少於75%。腫瘤再生長可藉由任何再現性量測方式來量測。舉例而言,腫瘤再生長係藉由量測治療後續之先前腫瘤收縮之後腫瘤直徑的增加來量測。腫瘤再生長之減少由停止治療之後腫瘤不再發生來指示。
治療或預防癌症可降低細胞增殖速率。較佳地,在治療之後,細胞增殖速率降低至少5%;更佳地,至少10%;更佳地,至少20%;更佳地,至少30%;更佳地,至少40%;更佳地,至少50%;甚至更佳地,至少50%;且最佳地,至少75%。細胞增殖速率可藉由任何再現性量測方式來量測。舉例而言,細胞增殖速率係藉由量測每單位時間之組織樣品中之分裂細胞的數目來量測。
治療或預防癌症可降低增殖細胞比例。較佳地,在治療之後,增殖細胞比例降低至少5%;更佳地,至少10%;更佳地,至少20%;更佳地,至少30%;更佳地,至少40%;更佳地,至少50%;甚至更佳地,至少50%;且最佳地,至少75%。增殖細胞比例可藉由任何再現性量測方式來量測。較佳地,舉例而言,增殖細胞比例係藉由定量組織樣品中分裂細胞之數目相對於非分裂細胞之數目來量測。增殖細胞比例可等效於有絲分裂指數。
治療或預防癌症可減小細胞增殖區域或區之大小。較佳地,相對於治療之前的大小,在治療之後,細胞增殖區域或區之大小減小至少5%;更佳地,減小至少10%;更佳地,減小至少20%;更佳地,減小至少30%;更佳地,減小至少40%;更佳地,減小至少50%;甚至更佳地,減小至少50%;且最佳地,減小至少75%。細胞增殖區域或區之大小可藉由任何再現性量測方式來量測。細胞增殖區域或區之大小可量測為細胞增殖區域或區之直徑或寬度。
治療或預防癌症可減少具有異常外觀或形態之細胞的數目或比例。較佳地,相對於治療之前的大小,在治療之後,具有異常形態之細胞數目減少至少5%;更佳地,減少至少10%;更佳地,減少至少20%;更佳地,減少至少30%;更佳地,減少至少40%;更佳地,減少至少50%;甚至更佳地,減少至少50%;且最佳地,減少至少75%。異常細胞外觀或形態可藉由任何再現性量測方式來量測。異常細胞形態可藉由顯微術,例如使用倒置組織培養顯微鏡來量測。異常細胞形態可採取核多形性之形式。
劑量及投藥
本揭示案之免疫細胞可視需要局部抑或全身治療而定以許多方式投與。
一般而言,投藥可為非經腸的。
用於過繼細胞療法之細胞投與方法為已知的且可與所提供之方法及組合物相結合使用。舉例而言,過繼T細胞治療方法描述於例如Gruenberg等人之美國專利申請公開案第2003/0170238號及Rosenberg之美國專利第4,690,915號中。
本揭示案之組合物適合於非經腸投藥。如本文所用,醫藥組合物之「非經腸投藥」包括以物理破壞個體之組織為特徵之任何投藥途徑及經由組織中之破口投與醫藥組合物,由此一般直接投與至血液中、肌肉中或內部器官中。因此,非經腸投藥包括但不限於藉由注射組合物、藉由經手術切口施用組合物、藉由經組織穿透性非手術創口施用組合物及類似方式來投與醫藥組合物。詳言之,預期非經腸投藥包括但不限於皮下、腹膜內、肌肉內、胸骨內、靜脈內、動脈內、鞘內、心室內、尿道內、顱內、瘤內、滑膜內注射或輸注;及腎透析輸注技術。在一些實施例中,本揭示案之組合物的非經腸投藥包括靜脈內或動脈內投藥。
本揭示案提供醫藥組合物,該等醫藥組合物包含本揭示案之複數個免疫細胞及醫藥學上可接受之載劑、稀釋劑或賦形劑。
適合於非經腸投藥之醫藥組合物之調配物典型地一般包含與醫藥學上可接受之載劑,諸如無菌水或無菌等張鹽水組合的免疫細胞。此類調配物可依適合於推注投藥或連續投藥之形式製備、封裝或銷售。可注射調配物可依單位劑型製備、封裝或銷售,諸如在安瓿中或容納防腐劑之多劑量容器中。用於非經腸投藥之調配物包括但不限於懸浮液、溶液、油性或水性媒劑中之乳液、糊劑及其類似物。此類調配物可進一步包含一或多種額外成分,包括但不限於懸浮劑、穩定劑或分散劑。非經腸調配物亦包括可含有賦形劑,諸如鹽、碳水化合物及緩沖劑之水溶液。示例性非經腸投藥形式包括無菌水溶液,例如丙二醇或右旋糖水溶液中之溶液或懸浮液。若需要,此類劑型可經適當地緩衝。用於非經腸投藥之調配物可經調配以供立即及/或修飾釋放。修飾釋放調配物包括延遲釋放、持續釋放、脈衝釋放、控制釋放、靶向釋放及程式化釋放。
在一些實施例中,包含免疫細胞之經調配組合物適合於經由注射投藥。在一些實施例中,包含免疫細胞之經調配組合物適合於經由輸注投藥。
可方便地以單位劑型呈現之本揭示案之醫藥組合物可根據醫藥工業中熟知之常規技術製備。此類技術包括使免疫細胞與醫藥載劑或賦形劑,諸如液體載劑相結合之步驟。
水性懸浮液可進一步含有增加懸浮液黏度之物質,包括例如羧甲基纖維素鈉、山梨糖醇及/或右旋糖聚糖。懸浮液亦可含有穩定劑。
本揭示案之組合物可另外含有在醫藥組合物中常規發現之其他輔助組分。因此,舉例而言,組合物可含有額外相容性醫藥活性材料,諸如止癢劑、收斂劑、局部麻醉劑或消炎劑,或可含有適用於物理調配本揭示案之組合物之各種劑型的額外材料,諸如染料、防腐劑、抗氧化劑、遮光劑、增稠劑及穩定劑。然而,此類材料在添加時不應過度干擾本揭示案之組合物之免疫細胞的生物活性。
調配物或組合物亦可含有適用於免疫細胞所治療之特定適應症、疾病或疾患的多於一種活性成分,其中各別之活性不會彼此不利地影響。此類活性成分以對預期目的有效之量適當地組合存在。因此,在一些實施例中,醫藥組合物進一步包含其他醫藥活性劑或藥物,諸如化學治療劑。
在一些態樣中,醫藥組合物可採用延時釋放、延遲釋放及持續釋放遞送系統,使得組合物之遞送在待治療部位致敏之前且以足以引起待治療部位致敏之時間發生。許多類型之釋放遞送系統為可用的且已知的。此類系統可避免組合物之重複投藥,從而增加個體及醫師之便利性。
在整個治療過程中,可單劑、連續或間斷地完成投藥。可使用由治療醫師選擇之劑量水準及模式進行單次或多次投藥。
在一些實施例中,醫藥組合物含有有效治療或預防癌症之量,諸如治療有效量或預防有效量的免疫細胞。在一些實施例中,藉由對治療個體之定期評估來監測治療或預防功效。對於數天、數週或數月之重複投藥,視狀況而定,可重複治療直至出現對癌症徵兆或症狀之所需阻抑。然而,其他劑量方案可適用且可確定。所需劑量可藉由組合物之單次推注投藥或輸注或藉由組合物之多次推注投藥或輸注來遞送。
細胞或細胞群體可依一或多個劑量投與。在一些實施例中,有效量之細胞可作為單個劑量投與。在一些實施例中,有效量之細胞可在一段時間內作為一個以上劑量投與。投藥時間在主治醫師之判斷內且視患者之臨床狀況而定。
細胞或細胞群體可獲自任何來源,諸如血庫或供體,或患者本身。
有效量意指提供治療或預防效益之量。所投與之劑量將視接受者之年齡、健康及體重、同時治療之種類(若有)、治療頻率及所需作用之性質而定。在一些實施例中,非經腸投與有效量之細胞或包含彼等細胞之組合物。在一些實施例中,投藥可為靜脈內投藥。在一些實施例中,投藥可藉由腫瘤內注射直接進行。
出於本揭示案之目的,在一組各自給予不同劑量之免疫細胞之哺乳動物當中,包括例如在向哺乳動物投與給定劑量之此類免疫細胞後比較靶細胞溶解或一或多種細胞激素由表現受體之免疫細胞分泌之程度的檢定可用於確定向哺乳動物投與之起始劑量。
在一些實施例中,細胞作為組合治療之一部分投與,諸如與另一種治療干預,諸如抗體或工程改造之細胞或受體或試劑,諸如細胞毒性劑或治療劑同時或依序以任何次序投與。在一些實施例中,本揭示案之免疫細胞與一或多種額外治療劑共同投與,或與另一種治療干預相結合同時或依序以任何次序投與。在一些情形中,免疫細胞與時間上足夠接近之另一種療法共同投與,使得免疫細胞群體增強一或多種額外治療劑之作用,反之亦然。在一些實施例中,免疫細胞在一或多種額外治療劑之前投與。在一些實施例中,免疫細胞在一或多種額外治療劑之後投與。
在實施例中,在投與(例如,輸注)過繼免疫細胞之前、同時或之後向個體投與淋巴細胞清除化學療法。在一個實例中,在投與免疫細胞之前向個體投與淋巴細胞清除化學療法。舉例而言,淋巴細胞清除化學療法在過繼細胞輸注前1-4天(例如,1、2、3或4天)結束。在實施例中,投與多個劑量之過繼細胞,例如,如本文所述。在實施例中,在投與(例如,輸注)本文所述之免疫細胞之前、同時或之後向個體投與淋巴細胞清除化學療法。淋巴細胞清除之實例包括但不限於非清髓性淋巴細胞清除化學療法、清髓性淋巴細胞清除化學療法、全身照射等。淋巴細胞清除劑之實例包括但不限於抗胸腺細胞球蛋白、抗CD3抗體、抗CD4抗體、抗CD8抗體、抗CD52抗體、抗CD2抗體、TCRαβ阻斷劑、抗CD20抗體、抗CD19抗體、硼替佐米(Bortezomib)、利妥昔單抗(rituximab)、抗CD154抗體、雷帕黴素(rapamycin)、CD3免疫毒素、氟達拉濱(fludarabine)、環磷醯胺、白消安(busulfan)、美法崙(melphalan)、美羅華(Mabthera)、他克莫司(Tacrolimus)、阿法西普(alefacept)、阿崙單抗(alemtuzumab)、OKT3、OKT4、OKT8、OKT11、芬戈莫德(fingolimod)、抗CD40抗體、抗BR3抗體、坎帕斯1H (Campath-1H)、抗CD25抗體、鈣調神經磷酸酶抑制劑、黴酚酸酯及類固醇,其可單獨或組合使用。作為另一個實例,淋巴細胞清除方案可包括投與阿崙單抗、環磷醯胺、苯妥莫司汀(benduamustin)、利妥昔單抗、噴司他丁(pentostatin)及/或氟達拉濱。淋巴細胞清除方案可在一或多個週期中投與,直至達到減少循環免疫細胞之所需結果。在一些實施例中,淋巴細胞清除包括投與特異性靶向並減少或消除個體中之CD52+細胞的試劑,且修飾免疫細胞以減少或消除CD52表現。
在一些實施例中,在投與(例如,輸注)過繼免疫細胞之前、同時或之後向個體投與免疫刺激療法。在一些實施例中,免疫刺激療法包括穩態細胞激素。在一些實施例中,免疫刺激療法包括免疫刺激分子。在一些實施例中,免疫刺激療法包括IL-2、IL-7、IL-12、IL-15、IL-21、IL-9或其功能片段。在一些實施例中,免疫刺激療法包括IL-2、IL-7、IL-12、IL-15、IL-21、IL-9或其組合。在一些實施例中,免疫刺激療法包括IL-2或其功能片段。
使用自體細胞進行過繼細胞療法之方法包括自患者血液中分離免疫細胞,對經分離之細胞進行一系列修飾,包括用一或多種編碼本文所述之雙受體系統之載體轉導細胞,及向患者投與細胞。提供來自罹患或有癌症或血液惡性病風險之個體的免疫細胞需要自患者之血液中分離免疫細胞,且可經由此項技術中已知之方法,例如藉由白血球去除術來實現。在白血球去除術期間,提取個體之血液且分離外周血單核細胞(PBMC),且使剩餘之血液返回個體之循環中。將PBMC冷凍儲存或冷凍保存作為免疫細胞之樣品,且提供用於進一步處理步驟,諸如本文所述之修飾。
在一些實施例中,本文所述之治療個體之方法包括對來自個體之免疫細胞進行修飾,包括一系列修飾,包括富集及/或消耗、活化、遺傳修飾、擴增、調配及冷凍保存。
本揭示案提供富集或消耗步驟,其可為例如此項技術中已知的用於製備用於下游程序(例如,本文所述之修飾)之主題PBMC的洗滌及分級方法。方法可包括例如但不限於移除大量紅血球及血小板污染物之裝置,用於消耗單核細胞及分離淋巴細胞的基於大小之細胞分級系統,及/或允許富集或消耗特定T細胞子組之系統,該等T細胞諸如CD4+、CD8+、CD25+或CD62L+ T細胞。在富集步驟之後,將自主題PMBC中分離靶免疫細胞亞群以供進一步處理。熟習此項技術者將了解,如本文所提供之富集步驟亦可涵蓋任何新發現之方法、裝置、試劑或其組合。
本揭示案提供之活化步驟可為此項技術中已知的用於誘導免疫細胞(例如,T細胞)活化之任何方法,該方法為免疫細胞之離體擴增所需。可例如藉由在樹突細胞存在下培養主題免疫細胞、在人工抗原呈現細胞(AAPC)存在下培養主題免疫細胞或在經照射之K562源性AAPC存在下培養免疫細胞來達成免疫細胞活化。用於活化主題免疫細胞之其他方法可為例如在經分離之活化因子及組合物存在下培養免疫細胞,該等組合物例如經活化因子功能化之珠粒、表面或粒子。活化因子可包括例如抗體,例如,抗CD3及/或抗CD28抗體。活化因子亦可為例如細胞激素,例如,介白素(IL)-2或IL-21。活化因子亦可為共刺激分子,諸如CD40、CD40L、CD70、CD80、CD83、CD86、CD137L、ICOSL、GITRL及CD134L。熟習此項技術者將了解,如本文所提供之活化因子亦可涵蓋任何新發現之可活化免疫細胞之活化因子、試劑、組合物或其組合。
本揭示案提供用於修飾主題免疫細胞之遺傳修飾步驟。在一些實施例中,遺傳修飾包括用包含本文所述之與B2M或HLA-A互補之shRNA的載體轉導免疫細胞。在一些實施例中,遺傳修飾包括使用CRISPR/Cas介導之基因體工程改造修飾免疫細胞之基因體以誘導B2M或HLA-A中之突變。在一些實施例中,該方法包括用一或多種編碼活化劑及抑制性受體之載體轉導免疫細胞,從而產生表現活化劑及抑制性受體之免疫細胞。
本揭示案提供經遺傳修飾之主題免疫細胞的擴增步驟。可在此項技術中已知之任何免疫細胞擴增系統中擴增經遺傳修飾之主題免疫細胞以產生治療劑量之免疫細胞以供投藥。舉例而言,用於包括控制器泵之系統中之生物反應器袋及允許自動進料及廢料移除之探針可用於免疫細胞擴增。底部帶有透氣膜之細胞培養瓶可用於免疫細胞擴增。此項技術中已知的能夠擴增用於臨床使用之免疫細胞的任何此種系統由本文所提供之擴增步驟涵蓋。在培養系統中在專門調配用於擴增之培養基中擴增免疫細胞。亦可藉由在如本文所述之活化因子存在下培養本揭示案之免疫細胞來促進擴增。熟習此項技術者將了解,如本文所提供之擴增步驟亦可涵蓋任何新發現的可用於擴增免疫細胞之培養系統、培養基或活化因子。
本揭示案提供用於擴增之經遺傳修飾之主題免疫細胞的調配及冷凍保存步驟。所提供之調配步驟包括例如洗去本文所述之治療方法之免疫細胞的製備及擴增中使用之過量組分。可使用此項技術中已知的與免疫細胞相容之任何醫藥學上可接受之調配介質或洗滌緩衝液來洗滌、稀釋/濃縮免疫細胞,且準備投藥劑量。調配介質對於免疫細胞之投與為可接受的,例如,用於靜脈內輸注之晶體溶液。
冷凍保存可視情況用於長期儲存免疫細胞。可使用此項技術中之已知方法達成冷凍保存,包括例如將細胞儲存於含有冷凍保存組分之冷凍保存介質中。冷凍保存組分可包括例如二甲亞砜或甘油。儲存於冷凍保存介質中之免疫細胞可藉由將儲存溫度降至-80℃至-196℃進行冷凍保存。
在一些實施例中,治療方法包括確定個體之HLA種系類型。在一些實施例中,在骨髓中確定HLA種系類型。
在一些實施例中,治療方法包括確定EGFR之表現水準。在一些實施例中,在來自個體之腫瘤組織樣品中確定EGFR之表現水準。在一些實施例中,使用下一代定序來確定EGFR之表現水準。在一些實施例中,使用RNA定序來確定EGFR之表現水準。在一些實施例中,使用免疫組織化學來確定EGFR水準。
在一些實施例中,治療方法包括向有需要之個體投與治療有效劑量之包含HLA-A*02抑制性受體之免疫細胞,其中該個體經確定為HLA種系HLA-A*02雜合的且具有HLA-A*02損失之癌細胞。在一些實施例中,治療方法包括向有需要之個體投與治療有效劑量之包含HLA-A*01抑制性受體之免疫細胞,其中該個體經確定為HLA種系HLA-A*01雜合的且具有HLA-A*01損失之癌細胞。在一些實施例中,治療方法包括向有需要之個體投與治療有效劑量之包含HLA-A*03之免疫細胞,其中該個體經確定為HLA種系HLA-A*03雜合的且具有HLA-A*03損失之癌細胞。在一些實施例中,治療方法包括向有需要之個體投與治療有效劑量之包含HLA-A*07抑制性受體之免疫細胞,其中該個體經確定為HLA種系HLA-A*07雜合的且具有HLA-A*07損失之癌細胞。在一些實施例中,治療方法包括向有需要之個體投與治療有效劑量之包含HLA-C*07抑制性受體之免疫細胞,其中該個體經確定為HLA種系HLA-C*07雜合的且具有HLA-C*07損失之癌細胞。在一些實施例中,治療方法包括向有需要之個體投與治療有效劑量之包含HLA-B*07抑制性受體之免疫細胞,其中該個體經確定為HLA種系HLA-B*07雜合的且具有HLA-B*07損失之癌細胞。
在各種實施例中,本揭示案提供治療表現EGFR且已損失HLA-A*02表現之惡性病之雜合HLA-A*02患者的方法;及/或治療患有表現EGFR且已損失HLA-A*02表現之復發性不可切除性或轉移性實體腫瘤之雜合HLA-A*02成年患者的方法。
在一些實施例中,投與治療有效劑量之本文所述之免疫細胞。在一些實施例中,藉由靜脈內注射投與本揭示案之免疫細胞。在一些實施例中,藉由腹膜內注射投與本揭示案之免疫細胞。在一些實施例中,治療有效劑量包含約0.5×10
6個細胞、約1×10
6個細胞、約2×10
6個細胞、約3×10
6個細胞、4×10
6個細胞、約5×10
6個細胞、約6×10
6個細胞、約7×10
6個細胞、約8×10
6個細胞、約9×10
6個細胞、約1×10
7、約2×10
7、約3×10
7、約4×10
7、約5×10
7、約6×10
7、約7×10
7、約8×10
7、約9×10
7、約1×10
8個細胞、約2×10
8個細胞、約3×10
8個細胞、約4×10
8個細胞、約5×10
8個細胞、約6×10
8個細胞、約7×10
8個細胞、約8×10
8個細胞、約9×10
8個細胞、約1×10
9個細胞、約2×10
9個細胞、約3×10
9個細胞、約3×10
9個細胞、約4×10
9個細胞、約5×10
9個細胞、約5×10
9個細胞、約6×10
9個細胞、約7×10
9個細胞、約8×10
9個細胞、約9×10
9個細胞、約1×10
10個細胞、約2×10
10個細胞、約3×10
10個細胞、約4×10
10個細胞、約5×10
10個細胞、約6×10
10個細胞、約7×10
10個細胞、約8×10
10個細胞或約9×10
10個細胞。
在一些實施例中,治療有效劑量包含約0.5×10
6個細胞至約9×10
10個細胞、約1×10
6個細胞至約5×10
10個細胞、約2×10
6個細胞至約5×10
9個細胞、約3×10
6個細胞至約5×10
9個細胞、約4×10
6個細胞至約3×10
9個細胞、約5×10
6個細胞至約2×10
9個細胞、約6×10
6個細胞至約1×10
9個細胞、0.5×10
6個細胞至約6×10
9個細胞、約1×10
6個細胞至約5×10
9個細胞、約2×10
6個細胞至約5×10
9個細胞、約3×10
6個細胞至約4×10
9個細胞、約4×10
6個細胞至約3×10
9個細胞、約5×10
6個細胞至約2×10
9個細胞、約6×10
6個細胞至約1×10
9個細胞、0.5×10
6個細胞至約6×10
8個細胞、約1×10
6個細胞至約5×10
8個細胞、約2×10
6個細胞至約5×10
8個細胞、約3×10
6個細胞至約4×10
8個細胞、約4×10
6個細胞至約3×10
8個細胞、約5×10
6個細胞至約2×10
8個細胞、約6×10
6個細胞至約1×10
8個細胞、約7×10
6個細胞至約9×10
8個細胞、約8×10
6個細胞至約8×10
8個細胞、約9×10
6個細胞至約 7×10
8個細胞、約1×10
7個細胞至約6×10
8個細胞、約2×10
7個細胞至約5×10
8個細胞、約7×10
6個細胞至約9×10
7個細胞、約8×10
6個細胞至約8×10
7個細胞、約9×10
6個細胞至約 7×10
7個細胞、約1×10
7個細胞至約6×10
7個細胞或約2×10
7個細胞至約5×10
7個細胞。
在一些實施例中,治療有效劑量包含約0.5×10
5個細胞至約9×10
10個細胞。在一些實施例中,治療有效劑量包含約0.5×10
6個細胞至約1×10
10個細胞。在一些實施例中,治療有效劑量包含約0.5×10
6個細胞至約5×10
9個細胞。在一些實施例中,治療有效劑量包含約0.5×10
6個細胞至約1×10
9個細胞。在一些實施例中,治療有效劑量包含約0.5×10
6個細胞至約6×10
8個細胞。在一些實施例中,治療有效劑量包含約0.5×10
6個細胞至約9×10
10個細胞。在一些實施例中,治療有效劑量包含約0.5×10
7個細胞至約1×10
10個細胞。在一些實施例中,治療有效劑量包含約0.5×10
7個細胞至約5×10
9個細胞。在一些實施例中,治療有效劑量包含約0.5×10
7個細胞至約1×10
9個細胞。在一些實施例中,治療有效劑量包含約0.5×10
7個細胞至約6×10
8個細胞。在一些實施例中,治療有效劑量包含約0.5×10
8個細胞至約9×10
10個細胞。在一些實施例中,治療有效劑量包含約0.5×10
8個細胞至約1×10
10個細胞。在一些實施例中,治療有效劑量包含約0.5×10
8個細胞至約5×10
9個細胞。在一些實施例中,治療有效劑量包含約0.5×10
8個細胞至約1×10
9個細胞。在治療劑量中提及之術語「約」可為例如± 0.5×10
6個細胞、± 0.5×10
7個細胞或± 0.5×10
8個細胞。
套組及製品
本揭示案提供包含編碼本文所述受體之多核苷酸及載體以及包含本文所述受體之免疫細胞的套組及製品。在一些實施例中,套組包括諸如小瓶、注射器及使用說明書之物品。
在一些實施例中,套組包含含有編碼本揭示案之一或多種受體之序列的多核苷酸或載體。
在一些實施例中,套組包含含有本文所述之第一受體及第二受體的複數個免疫細胞。在一些實施例中,複數個免疫細胞包括複數個T細胞。
在一些實施例中,套組進一步包括使用說明書。
列舉之實施例
實施例1. 一種免疫細胞,該免疫細胞包含:
a.) 第一受體,其包含對表皮生長因子受體(EGFR)具有特異性之細胞外配位體結合結構域;及
b.) 第二受體,其包含對由於雜合性損失而在EGFR+癌症中損失之非靶抗原具有特異性之細胞外配位體結合結構域,
其中該第一受體為對EGFR有反應之活化劑受體;且其中該第二受體為對該非靶抗原有反應之抑制性受體。
實施例2. 實施例1之免疫細胞,其中該第二受體之該細胞外配位體結合結構域特異性結合MHC蛋白之對偶基因變異體。
實施例3. 實施例1之免疫細胞,其中該第二受體之該細胞外配位體結合結構域特異性結合HLA-A、HLA-B或HLA-C蛋白之對偶基因變異體。
實施例4. 實施例1之免疫細胞,其中該第二受體之該細胞外配位體結合結構域特異性結合HLA-A*02。
實施例5. 實施例1之免疫細胞,其中該第二受體之該細胞外配位體結合結構域特異性結合HLA-A*01、HLA-A*03、HLA-A*11、HLA-C*07或HLA-B*07。
實施例6. 實施例3-5中任一項之免疫細胞,其中該第二受體之該細胞外配位體結合結構域包含如表5所揭示之互補決定區(CDR) CDR-L1、CDR-L2、CDR-L3、CDR-H1、CDR-H2、CDR-H3;或相對於表5之該等CDR具有至多1個、2個或3個取代、缺失或插入之CDR序列。
實施例7. 實施例3-5中任一項之免疫細胞,其中該第二受體之該細胞外配位體結合結構域包含SEQ ID NO: 101-106或SEQ ID NO: 106-112之互補決定區(CDR) CDR-L1、CDR-L2、CDR-L3、CDR-H1、CDR-H2、CDR-H3;或相對於表5之該等CDR具有至多1個、2個或3個取代、缺失或插入之CDR序列。
實施例8. 實施例3-5中任一項之免疫細胞,其中該第二受體之該細胞外配位體結合結構域包含選自表4中所揭示之多肽序列的多肽序列;或與其具有至少85%、至少90%、至少95%、至少97%或至少99%一致性之序列。
實施例9. 實施例4之免疫細胞,其中該第二受體之該細胞外配位體結合結構域包含SEQ ID NO: 89-100中之任一者;或與其具有至少85%、至少90%、至少95%、至少97%或至少99%一致性之序列。
實施例10. 實施例1-9中任一項之免疫細胞,其中該第一受體為嵌合抗原受體(CAR)。
實施例11. 實施例1-10中任一項之免疫細胞,其中該第一受體之該細胞外配位體結合結構域包含可變重(VH)部分,其包含選自表3所列之序列之群的一組重鏈互補決定區(HC-CDR);及/或可變輕(VL)部分,其包含來自表3中所列之序列之群的一組輕鏈互補決定區(LC-CDR);或在各CDR中具有至多1個、2個、3個、4個取代、插入或缺失之CDR序列。
實施例12. 實施例1-11中任一項之免疫細胞,其中該第一受體之該細胞外配位體結合結構域包含具有選自表2中所列之VH序列之序列的可變重(VH)部分;及/或包含表2中所列之序列的可變輕(VL)部分;或與其具有至少70%、至少85%、至少90%或至少95%一致性之序列。
實施例13. 實施例1-12中任一項之免疫細胞,其中該第一受體之該細胞外配位體結合結構域包含選自表1中所列之序列之群的序列;或與其具有至少85%、至少90%、至少95%、至少97%或至少99%一致性之序列。
實施例14. 實施例1-13中任一項之免疫細胞,其中該第一受體之該細胞外配位體結合結構域包含選自由SEQ ID NO: 9-18組成之群的scFv序列;或與其具有至少85%、至少90%、至少95%、至少97%或至少99%一致性之序列。
實施例15. 實施例1-14中任一項之免疫細胞,其中該第二受體包含LILRB1細胞內結構域或其功能變異體。
實施例16. 實施例15之免疫細胞,其中該LILRB1細胞內結構域包含與SEQ ID NO: 129至少90%、至少95%、至少97%、至少99%或一致之序列。
實施例17. 實施例1-16中任一項之免疫細胞,其中該第二受體包含LILRB1跨膜結構域或其功能變異體。
實施例18. 實施例17之免疫細胞,其中該LILRB1跨膜結構域或其功能變異體包含與SEQ ID NO: 133至少90%、至少95%、至少97%、至少99%或一致之序列。
實施例19. 實施例1-18中任一項之免疫細胞,其中該第二受體包含LILRB1鉸鏈結構域或其功能變異體。
實施例20. 實施例19之免疫細胞,其中該LILRB1鉸鏈結構域包含與SEQ ID NO: 132、SEQ ID NO: 125、SEQ ID NO: 126至少90%、至少95%、至少97%、至少99%或一致之序列。
實施例21. 實施例1-20中任一項之免疫細胞,其中該第二受體包含LILRB1細胞內結構域、LILRB1跨膜結構域、LILRB1鉸鏈結構域、此等中之任一者之功能變異體,或其組合。
實施例22. 實施例21之免疫細胞,其中該LILRB1細胞內結構域及該LILRB1跨膜結構域包含SEQ ID NO: 128或與SEQ ID NO: 128至少95%一致之序列。
實施例23. 實施例1-22中任一項之免疫細胞,其中該EGFR+癌細胞為肺癌細胞、小細胞肺癌細胞、非小細胞肺癌細胞、胰管癌細胞、結腸直腸癌細胞、頭頸癌細胞、食道及胃腺癌細胞、卵巢癌細胞、多形性神經膠質母細胞瘤細胞、子宮頸鱗狀細胞癌細胞、腎癌細胞、乳頭狀腎癌細胞、腎臟腎透明細胞癌細胞、膀胱癌細胞、乳癌細胞、膽管癌細胞、肝癌細胞、前列腺癌細胞、肉瘤細胞、甲狀腺癌細胞、胸腺癌細胞、胃癌細胞或子宮癌細胞。
實施例24. 實施例23之免疫細胞,其中該EGFR+癌細胞為肺癌細胞。
實施例25. 實施例1-24中任一項之免疫細胞,其中該EGFR+癌細胞為不表現HLA-A*02之EGFR+/HLA-A*02-癌細胞;或不表現HLA-A*02之來源於HLA-A*02+個體之癌細胞。
實施例26. 實施例25之免疫細胞,其中該EGFR+/HLA-A*02-癌細胞藉由在HLA-A處雜合性損失,導致HLA-A*02損失而來源於EGFR+/HLA-A*02+細胞。
實施例27. 實施例1-26中任一項之免疫細胞,其中該第一受體及該第二受體在具有雜合性損失之該EGFR/HLA-A*02-癌細胞存在下一起特異性活化該免疫細胞。
實施例28. 實施例1-27中任一項之免疫細胞,其中該第一受體及該第二受體在未因雜合性損失而損失HLA-A*02之EGFR+細胞存在下一起不特異性活化該免疫細胞。
實施例29. 實施例1-28中任一項之免疫細胞,其中該免疫細胞為T細胞、巨噬細胞、NK細胞、iNKT細胞或γδ T細胞。
實施例30. 實施例29之免疫細胞,其中該T細胞為CD8+ CD4- T細胞。
實施例31. 實施例1-30中任一項之免疫細胞,其中MHC I類基因之表現及/或功能已降低或消除。
實施例32. 實施例30之免疫細胞,其中該MHC I類基因為β-2-微球蛋白(B2M)。
實施例33. 實施例32之免疫細胞,該免疫細胞進一步包含含有干擾RNA之多核苷酸,該干擾RNA包含與B2M mRNA (SEQ ID NO: 172)之序列互補之序列。
實施例34. 實施例33之免疫細胞,其中該干擾RNA能夠誘導RNAi介導之該B2M mRNA之降解。
實施例35. 實施例33之免疫細胞,其中該干擾RNA為短髮夾RNA (shRNA)。
實施例 36. 實施例35之免疫細胞,其中該shRNA包含:
a.) 第一序列,其自5'末端至3'末端具有與該B2M mRNA之序列互補之序列;及
b.) 第二序列,其自5'末端至3'末端具有與該第一序列互補之序列,
其中該第一序列及該第二序列形成該shRNA。
實施例37. 實施例32之免疫細胞,該免疫細胞包含對編碼B2M之序列(SEQ ID NO: 170)的一或多個修飾,其中該一或多個修飾降低B2M之表現及/或消除B2M之功能。
實施例38. 實施例37之免疫細胞,其中該一或多個修飾包括編碼B2M之內源基因的一或多個失活突變。
實施例39. 實施例38之免疫細胞,其中該一或多個失活突變包括缺失、插入、取代或框移突變。
實施例40. 實施例38-39中任一項之免疫細胞,其中用核酸引導之核酸內切酶與特異性靶向編碼B2M之內源基因之序列(SEQ ID NO: 170)的至少一個嚮導核酸(gNA)復合來引入該一或多個失活突變。
實施例41. 實施例31之免疫細胞,其中該MHC I類基因為HLA-A*02。
實施例42. 實施例41之免疫細胞,該免疫細胞進一步包含含有干擾RNA之多核苷酸,該干擾RNA包含與HLA-A*02 mRNA (SEQ ID NO: 171)之序列互補之序列。
實施例43. 實施例42之免疫細胞,其中該干擾RNA能夠誘導RNA干擾(RNAi)介導之該HLA-A*02 mRNA之降解。
實施例44. 實施例43之免疫細胞,其中該干擾RNA為包含以下之短髮夾RNA (shRNA):
a.) 第一序列,其自5'末端至3'末端具有與該HLA-A*02 mRNA之序列互補之序列;及
b.) 第二序列,其自5'末端至3'末端具有與該第一序列互補之序列,
其中該第一序列及該第二序列形成該shRNA。
實施例45. 實施例41之免疫細胞,該免疫細胞包含對編碼HLA-A*02之內源基因之序列(SEQ ID NO: 169)的一或多個修飾,其中該一或多個修飾降低HLA-A*02之表現及/或消除HLA-A*02之功能。
實施例46. 實施例45之免疫細胞,其中該一或多個修飾包括該編碼HLA-A*02之內源基因的一或多個失活突變。
實施例47. 實施例45或實施例46之免疫細胞,其中用核酸引導之核酸內切酶與特異性靶向該編碼HLA-A*02之內源基因之序列的至少一個嚮導核酸(gNA)復合來引入該一或多個失活突變。
實施例48. 實施例1之免疫細胞,其中:
a.) 該第一受體包含SEQ ID NO: 177,或與其共享至少75%、至少80%、至少85%、至少90%、至少95%或至少98%一致性之序列;及
b.) 該第二受體包含SEQ ID NO: 174,或與其共享至少75%、至少80%、至少85%、至少90%、至少95%或至少98%一致性之序列。
實施例49. 實施例1之免疫細胞,其中:
a.) 該第一受體包含SEQ ID NO: 177,或與其共享至少75%、至少80%、至少85%、至少90%、至少95%或至少98%一致性之序列;及
b.) 該第二受體包含SEQ ID NO: 173,或與其共享至少75%、至少80%、至少85%、至少90%、至少95%或至少98%一致性之序列。
實施例50. 實施例1之免疫細胞,其中:
a.) 該第一受體包含SEQ ID NO: 175,或與其共享至少75%、至少80%、至少85%、至少90%、至少95%或至少98%一致性之序列;及
b.) 該第二受體包含SEQ ID NO: 174,或與其共享至少75%、至少80%、至少85%、至少90%、至少95%或至少98%一致性之序列。
實施例51. 實施例1之免疫細胞,其中:
a.) 該第一受體包含SEQ ID NO: 175,或與其共享至少75%、至少80%、至少85%、至少90%、至少95%或至少98%一致性之序列;及
b.) 該第二受體包含SEQ ID NO: 173,或與其共享至少75%、至少80%、至少85%、至少90%、至少95%或至少98%一致性之序列。
實施例52. 實施例1之免疫細胞,其中:
a.) 該第一受體包含SEQ ID NO: 176,或與其共享至少75%、至少80%、至少85%、至少90%、至少95%或至少98%一致性之序列;及
b.) 該第二受體包含SEQ ID NO: 173,或與其共享至少75%、至少80%、至少85%、至少90%、至少95%或至少98%一致性之序列。
實施例53. 實施例1之免疫細胞,其中:
a.) 該第一受體包含SEQ ID NO: 176,或與其共享至少75%、至少80%、至少85%、至少90%、至少95%或至少98%一致性之序列;及
b.) 該第二受體包含SEQ ID NO: 173,或與其共享至少75%、至少80%、至少85%、至少90%、至少95%或至少98%一致性之序列。
實施例54. 實施例48至53中任一項之免疫細胞,該免疫細胞進一步包含T2A自裂解肽,其中該T2A自裂解肽包含SEQ ID NO: 178,或與其共享至少75%、至少80%、至少85%、至少90%、至少95%或至少98%一致性之序列。
實施例55. 實施例48至54中任一項之免疫細胞,該免疫細胞進一步包含干擾RNA,其中該干擾RNA包含SEQ ID NO: 179,或與其共享至少75%、至少80%、至少85%、至少90%、至少95%或至少98%一致性之序列。
實施例56. 實施例1-55中任一項之免疫細胞,其中該免疫細胞為自體的。
實施例57. 實施例1-55中任一項之免疫細胞,其中該免疫細胞為同種異體的。
實施例58. 一種醫藥組合物,該醫藥組合物包含治療有效量之實施例1-57中任一項之免疫細胞。
實施例59. 實施例58之醫藥組合物,其中該免疫細胞表現該第一受體及該第二受體兩者。
實施例60. 實施例59之醫藥組合物,其中至少約50%、約55%、約60%、約65%、約70%、約75%、約80%、約85%、約90%或約95%之該等免疫細胞表現該第一受體及該第二受體兩者。
實施例61. 實施例59之醫藥組合物,其中至少90%之該等免疫細胞表現該第一受體及該第二受體兩者。
實施例62. 實施例58-61中任一項之醫藥組合物,該醫藥組合物進一步包含醫藥學上可接受之載劑、稀釋劑或賦形劑。
實施例63. 實施例58-62中任一項之醫藥組合物,該醫藥組合物係用作治療EGFR+癌症之藥劑。
實施例64. 一種多核苷酸或多核苷酸系統,該多核苷酸或多核苷酸系統包含含有編碼以下之多核苷酸序列之一或多個多核苷酸:
a.) 第一受體,其包含對內皮生長因子受體(EGFR)具有特異性之細胞外配位體結合結構域;及
b.) 第二受體,其包含對由於雜合性損失而在EGFR+癌細胞中已損失之非靶抗原具有特異性之細胞外配位體結合結構域,
其中該第一受體為對該EGFR+癌細胞上之EGFR有反應之活化劑受體;且其中該第二受體為對該非靶抗原有反應之抑制性受體。
實施例65. 一種多核苷酸或多核苷酸系統,該多核苷酸或多核苷酸系統包含含有編碼該第一受體及該第二受體之多核苷酸序列之一或多個多核苷酸,用於產生實施例1-57中任一項之免疫細胞。
實施例66. 一種載體,該載體包含實施例64或65之一或多個多核苷酸。
實施例67. 一種殺死在MHC I類基因座處具有雜合性損失之EGFR+癌細胞的方法,該方法包括向個體投與有效量之實施例1-57中任一項之免疫細胞或實施例58-62中任一項之醫藥組合物。
實施例68. 實施例67之方法,其中該EGFR+癌細胞為肺癌細胞、小細胞肺癌細胞、非小細胞肺癌細胞、胰管癌細胞、結腸直腸癌細胞、頭頸癌細胞、食道及胃腺癌細胞、卵巢癌細胞、多形性神經膠質母細胞瘤細胞、子宮頸鱗狀細胞癌細胞、腎癌細胞、乳頭狀腎癌細胞、腎臟腎透明細胞癌細胞、膀胱癌細胞、乳癌細胞、膽管癌細胞、肝癌細胞、前列腺癌細胞、肉瘤細胞、甲狀腺癌細胞、胸腺癌細胞、胃癌細胞或子宮癌細胞。
實施例69. 實施例67之方法,其中該EGFR+癌細胞為肺癌細胞。
實施例70. 實施例67之方法,其中該EGFR+癌細胞為不表現HLA-A*02之EGFR+/HLA-A*02-癌細胞;或不表現HLA-A*02之來源於HLA-A*02+個體之癌細胞。
實施例71. 實施例70之方法,其中該EGFR+/HLA-A*02-癌細胞藉由在HLA-A處雜合性損失,導致HLA-A*02損失而來源於EGFR+/HLA-A*02+細胞。
實施例72. 一種治療患有在編碼非靶抗原之基因座處具有雜合性損失之EGFR+腫瘤之個體之EGFR+癌症的方法,該方法包括向該個體投與有效量之實施例1-57中任一項之免疫細胞或實施例58-62中任一項之醫藥組合物。
實施例73. 實施例72之方法,其中該個體為患有表現EGFR且已損失HLA-A*02表現之惡性病的雜合HLA-A*02患者。
實施例74. 實施例72之方法,其中該個體為患有表現EGFR且已損失HLA-A*02表現之復發性不可切除性或轉移性實體腫瘤的雜合HLA-A*02患者。
實施例75. 一種治療個體之癌症的方法,該方法包括:
a.) 確定該個體之非惡性細胞及癌細胞中非靶抗原之基因型或表現水準;
b.) 確定該個體之癌細胞中EGFR之表現水準;及
c.) 若該非惡性細胞表現該非靶抗原且該癌細胞不表現該非靶抗原,且該等癌細胞為EGFR陽性的,則向該個體投與有效量之實施例1-57中任一項之免疫細胞或實施例58-62中任一項之醫藥組合物。
實施例76. 實施例67-75中任一項之方法,其中實施例1-57中任一項之免疫細胞或實施例58-62中任一項之醫藥組合物的投與減小該個體中之腫瘤的大小。
實施例77. 實施例76之方法,其中該腫瘤減小約5%、約10%、約15%、約20%、約25%、約30%、約35%、約40%、約45%、約50%、約55%、約60%、約65%、約70%、約75%、約80%、約85%、約90%、約95%或約100%。
實施例78. 實施例76之方法,其中該腫瘤得以消除。
實施例79. 實施例67-75中任一項之方法,其中該免疫細胞或該醫藥組合物之投與阻止該個體中之腫瘤的生長。
實施例80. 實施例67-75中任一項之方法,其中實施例1-57中任一項之免疫細胞或實施例58-62中任一項之醫藥組合物的投與減少該個體中之腫瘤的數目。
實施例81. 實施例67-80中任一項之方法,其中該免疫細胞或該醫藥組合物之投與選擇性殺死該個體中之癌細胞而非正常細胞。
實施例82. 實施例81之方法,其中所殺死之至少約60%之細胞為癌細胞,所殺死之至少約65%之細胞為癌細胞,所殺死之至少約70%之細胞為癌細胞,所殺死之至少約75%之細胞為癌細胞,所殺死之至少約80%之細胞為癌細胞,所殺死之至少約85%之細胞為癌細胞,所殺死之至少約90%之細胞為癌細胞,所殺死之至少約95%之細胞為癌細胞,或所殺死之約100%之細胞為癌細胞。
實施例83. 實施例81之方法,其中該免疫細胞或該醫藥組合物之投與殺死該個體之約40%、約50%、約60%、約70%、約80%、約90%或所有癌細胞。
實施例84. 實施例67-83中任一項之方法,其中與包含該第一活化劑受體但不含第二抑制性受體之其他方面等效之免疫細胞的投與相比,該免疫細胞或該醫藥組合物之投與對該個體產生較少副作用。
實施例85. 一種製造複數個免疫細胞之方法,該方法包括:
a.) 提供複數個免疫細胞,及
b.) 用實施例64或實施例65之多核苷酸系統或實施例66之載體將該複數個免疫細胞轉型。
實施例86. 一種套組,該套組包含實施例1-57中任一項之免疫細胞或實施例58-62中任一項之醫藥組合物。
實施例87. 實施例86之套組,該套組進一步包括使用說明書。
實施例88. 一種對癌細胞中之雜合性損失有反應之免疫細胞,該免疫細胞包含:
a. 第一受體,視情況為嵌合抗原受體(CAR)或T細胞受體(TCR),其包含對選自以下之靶抗原具有特異性之細胞外配位體結合結構域:
i. 癌細胞特異性抗原或與主要組織相容性複合物I類(MHC-I)複合之其肽抗原;或
ii. 表皮生長因子受體(EGFR)或與主要組織相容性複合物I類(MHC-I)複合之其肽抗原;及
b. 第二受體,視情況為抑制性受體,其包含對由於雜合性損失而在該癌細胞中已損失之非靶抗原具有特異性之細胞外配位體結合結構域。
實施例89. 實施例88之方法,其中該非靶抗原包含多態性。
實施例90. 實施例89之免疫細胞,其中該非靶抗原包含與SEQ ID NO: 87共享至少95%一致性之COLEC12抗原,且該多態性包含在SEQ ID NO: 87之位置522處之S或P。
實施例91. 實施例89之免疫細胞,其中該非靶抗原包含與SEQ ID NO: 88、SEQ ID NO: 134或SEQ ID NO: 135共享至少95%一致性之APCDD1抗原,且該多態性係選自由以下組成之群:
a. SEQ ID NO: 88之位置150處之V、I或L;
b. SEQ ID NO: 134之位置165處之Y或S;及
c. SEQ ID NO: 135之位置28處之Q或R。
實施例92. 實施例89之免疫細胞,其中該非靶抗原包含與SEQ ID NO: 86共享至少95%一致性之CXCL16抗原,且該多態性係選自由以下組成之群:
a. SEQ ID NO: 86之位置142處之I或T;及
b. SEQ ID NO: 86之位置200處之A或V。
實施例93. 實施例88或89之免疫細胞,其中該非靶抗原包含HLA-A*02。
實施例94. 實施例88-93中任一項之免疫細胞,其中該靶抗原由該癌細胞表現。
實施例95. 實施例88-94中任一項之免疫細胞,其中該非靶抗原不由該癌細胞表現。
實施例96. 實施例88-95中任一項之免疫細胞,其中該非靶抗原由非靶細胞表現。
實施例97. 實施例88-96中任一項之免疫細胞,其中該非靶細胞表現靶抗原及非靶抗原兩者。
實施例98. 實施例88-97中任一項之免疫細胞,其中該靶抗原為癌細胞特異性抗原。
實施例99. 實施例88-98中任一項之免疫細胞,其中該靶抗原為與主要組織相容性複合物I類(MHC-I)複合之癌細胞特異性抗原之肽抗原。
實施例100. 實施例88-99中任一項之免疫細胞,其中該癌細胞為肺癌細胞、神經膠質母細胞瘤細胞、乳癌細胞、頭頸癌細胞或結腸直腸癌細胞。
實施例101. 實施例88-100中任一項之免疫細胞,其中該癌細胞表現EGFR。
實施例102. 實施例88-101中任一項之免疫細胞,其中該第一受體及該第二受體在該癌細胞存在下一起特異性活化該免疫細胞。
實施例103. 實施例102之免疫細胞,其中該免疫細胞為T細胞、巨噬細胞、NK細胞、iNKT細胞或γδ T細胞。
實施例104. 實施例103之免疫細胞,其中該T細胞為CD8+ CD4- T細胞。
實施例105. 實施例88-104中任一項之免疫細胞,其中該EGFR包含與SEQ ID NO: 1-8中之任一者共享至少95%一致性之序列。
實施例106. 實施例88-105中任一項之免疫細胞,其中該第一受體為T細胞受體(TCR)。
實施例107. 實施例88-106中任一項之免疫細胞,其中該第一受體為嵌合抗原受體(CAR)。
實施例108. 實施例106或107之免疫細胞,其中該第一受體之該細胞外配位體結合結構域包含抗體片段、單鏈Fv抗體片段(scFv)、β鏈可變結構域(Vβ)或TCR α鏈可變結構域及TCR β鏈可變結構域。
實施例109. 實施例106或107之免疫細胞,其中該第一受體之該細胞外配位體結合結構域包含scFv。
實施例110. 實施例109之免疫細胞,其中該scFv包含選自由SEQ ID NO: 9-18組成之群的序列,或與其具有至少85%、至少90%、至少95%、至少97%或至少99%一致性之序列。
實施例111. 實施例109之免疫細胞,其中該scFv包含或基本上由選自由SEQ ID NO: 9-18組成之群的序列組成。
實施例112. 實施例106或107之免疫細胞,其中該第一受體之該細胞外配位體結合結構域包含VH及VL結構域。
實施例113. 實施例112之免疫細胞,其中該VH結構域包含選自由SEQ ID NO: 19-24組成之群的序列或表2中所揭示之VH序列,或與其具有至少85%、至少90%、至少95%、至少97%或至少99%一致性之序列。
實施例114. 實施例112之免疫細胞,其中該VH結構域包含或基本上由選自SEQ ID NO: 19-24組成之群的序列或表2中所揭示之VH序列組成。
實施例115. 實施例112-114中任一項之免疫細胞,其中該VL結構域包含選自由SEQ ID NO: 25-30組成之群的序列或表2中所揭示之VH序列,或與其具有至少85%、至少90%、至少95%、至少97%或至少99%一致性之序列。
實施例116. 實施例112-114中任一項之細胞,其中該VL結構域包含或基本上由選自SEQ ID NO: 25-30組成之群的序列或表2中所揭示之VL序列組成。
實施例117. 實施例105-107中任一項之免疫細胞,其中該第一受體之該細胞外配位體結合結構域包含選自由SEQ ID NO: 31-65組成之群的互補決定區(CDR)或表3中所揭示之CDR序列。
實施例118. 實施例88-117中任一項之免疫細胞,其中該第二受體之該細胞外配位體結合結構域包含抗體片段、單鏈Fv抗體片段(scFv)、β鏈可變結構域(Vβ)或TCR α鏈可變結構域及TCR β鏈可變結構域。
實施例119. 實施例88或93-118中任一項之免疫細胞,其中該第二受體之該細胞外配位體結合結構域包含scFv。
實施例120. 實施例119之免疫細胞,其中該scFv包含與SEQ ID NO: 89-100中之任一者具有至少85%、至少90%、至少95%、至少97%或至少99%一致性之序列。
實施例121. 實施例119之免疫細胞,其中該scFv包含或基本上由SEQ ID NO: 89-100中之任一者之序列組成。
實施例122. 實施例88或93-118中任一項之免疫細胞,其中該第二受體之該細胞外配位體結合結構域包含選自由SEQ ID NO: 101-112組成之群的CDR。
實施例123. 實施例88-122中任一項之免疫細胞,其中該第二受體包含LILRB1細胞內結構域或其功能變異體。
實施例124. 實施例123之免疫細胞,其中該LILRB1細胞內結構域包含與SEQ ID NO: 124至少95%一致之序列。
實施例125. 實施例88-124中任一項之免疫細胞,其中該第二受體包含LILRB1跨膜結構域或其功能變異體。
實施例126. 實施例125之免疫細胞,其中該LILRB1跨膜結構域或其功能變異體包含與SEQ ID NO: 133至少95%一致之序列。
實施例127. 實施例88-126中任一項之免疫細胞,其中該第二受體包含LILRB1鉸鏈結構域或其功能片段或變異體。
實施例128. 實施例127之免疫細胞,其中該LILRB1鉸鏈結構域包含與SEQ ID NO: 132、SEQ ID NO: 125或SEQ ID NO: 126至少95%一致之序列。
實施例129. 實施例88-128中任一項之免疫細胞,其中該第二受體包含LILRB1細胞內結構域及LILRB1跨膜結構域或其功能變異體。
實施例130. 實施例129之免疫細胞,其中該LILRB1細胞內結構域及該LILRB1跨膜結構域包含SEQ ID NO: 128或與SEQ ID NO: 128至少95%一致之序列。
實施例131. 實施例88-130中任一項之免疫細胞,其中該免疫細胞為T細胞、巨噬細胞、NK細胞、iNKT細胞或γδ T細胞。
實施例132. 實施例131之免疫細胞,其中該T細胞為CD8+ CD4- T細胞。
實施例133. 一種醫藥組合物,該醫藥組合物包含治療有效量之實施例88-132中任一項之免疫細胞。
實施例134. 實施例133之醫藥組合物,該醫藥組合物進一步包含醫藥學上可接受之載劑、稀釋劑或賦形劑。
實施例135. 實施例133或134之醫藥組合物,該醫藥組合物係用作治療癌症之藥劑。
實施例136. 一種多核苷酸系統,該多核苷酸系統包含含有編碼以下之多核苷酸序列之一或多個多核苷酸:
a. 第一受體,視情況為嵌合抗原受體(CAR)或T細胞受體(TCR),其包含對選自以下之靶抗原具有特異性之細胞外配位體結合結構域:
i. 癌細胞特異性抗原或與主要組織相容性複合物I類(MHC-I)複合之其肽抗原;或
ii. 表皮生長因子受體(EGFR)或與主要組織相容性複合物I類(MHC-I)複合之其肽抗原;及
b. 第二受體,視情況為抑制性受體,其包含對由於雜合性損失而在該癌細胞中已損失之非靶抗原具有特異性之細胞外配位體結合結構域。
實施例137. 實施例136之多核苷酸系統,其中該非靶抗原包含多態性。
實施例138. 實施例137之多核苷酸系統,其中該非靶抗原為與SEQ ID NO: 87共享至少95%一致性之COLEC12抗原,且該多態性包含在SEQ ID NO: 87之位置522處之S或P。
實施例139. 實施例137之多核苷酸系統,其中該非靶抗原為與SEQ ID NO: 88、SEQ ID NO: 134或SEQ ID NO: 135共享至少95%一致性之APCDD1抗原,且該多態性係選自由以下組成之群:
a. SEQ ID NO: 88之位置150處之V、I或L;
b. SEQ ID NO: 134之位置165處之Y或S;及
c. SEQ ID NO: 135之位置28處之Q或R。
實施例140. 實施例137之多核苷酸系統,其中該非靶抗原為與SEQ ID NO: 86共享至少95%一致性之CXCL16抗原,且該多態性係選自由以下組成之群:
a. SEQ ID NO: 86之位置142處之I或T;及
b. SEQ ID NO: 86之位置200處之A或V。
實施例141. 實施例136或137之多核苷酸系統,其中該非靶抗原為HLA-A*02。
實施例142. 一種載體,該載體包含實施例136-141中任一項之一或多個多核苷酸。
實施例143. 一種在個體中殺死複數個癌細胞及/或治療癌症之方法,該方法包括向該個體投與有效量之實施例88-132中任一項之免疫細胞或實施例46-48中任一項之醫藥組合物。
實施例144. 實施例143之方法,其中複數個癌細胞表現該靶抗原。
實施例145. 實施例143或144之方法,其中複數個癌細胞不表現該非靶抗原。
實施例146. 一種製造複數個免疫細胞之方法,該方法包括:
a. 提供複數個免疫細胞,及
b. 用實施例136-141中任一項之多核苷酸系統或實施例142之載體將該複數個免疫細胞轉型。
實施例147. 一種套組,該套組包含實施例88-132中任一項之免疫細胞或實施例133-135中任一項之醫藥組合物。
實施例148. 實施例147之套組,該套組進一步包括使用說明書。
實例
以下實例意欲僅用於說明且不限制本揭示案之範圍。在整個實例中,術語「阻斷劑抗原」用於描述非靶抗原之實施例。
實例 1 :由於雜合性損失而在癌細胞中損失之阻斷劑標靶的鑑定
使用生物資訊學線路來鑑定候選阻斷劑標靶。在人類基因之組中搜索細胞外結構域中具有常見非同義變異體之基因,該等變異體在結腸直腸癌中具有高雜合性損失(大於0.5)。在單核苷酸多態性資料庫dbSNP中搜索具有非同義變異體之基因,該資料庫亦包括小規模插入及缺失以及出版、群體頻率、分子結果及基因體作圖資訊。常見變異定義為在至少一個主要群體中具有大於或等於0.01之次要對偶基因頻率(MAF),且至少兩個無關個體在NCBI中具有次要對偶基因。大於或等於0.1之MAF作為常見變異之準則。集中關注染色體17及18,此係因為此等染色體在結腸直腸癌中具有高LOH。如上文所述,針對膜蛋白、結腸表現及細胞外結構域中常見之非同義變異體過濾基因。搜索過程之概述示於圖18中。
此分析中使用之額外資料庫包括:Uniprot (通用蛋白質資源),該資料庫為用於EMBL-EBI、SIB及PIR託管之蛋白質序列及註釋資料的資源。GTEx (基因型-組織表現)用作組織特異性基因表現及調控之公共資源。其含有來自近1000名個體之54個非患病組織部位的樣品。TCGA (癌症基因體圖集)用作涵蓋33種癌症類型之超過20,000種原發性癌症及匹配之正常樣品的資源。TCGA-COADREAD資料集為結腸腺癌及直腸腺癌資料集。CCLE (癌細胞株百科全書)含有關於57種結腸直腸癌(CRC)細胞株之資訊。
RNASeqDB為使用相同線路之來自GTEx及TCGA之處理資料的資料庫,其允許紀念斯隆凱特琳癌症中心(Memorial Sloan Kettering Cancer Center)進行比較研究。分析來自GTEx之372個TCGA-COADREAD樣品及339個正常結腸樣品。
將COLEC12、CXCL16及APCDD1鑑定為潛在阻斷劑標靶。表14匯總結腸直腸癌中此等基因之表現資料。來自UCSC Xena瀏覽器(用於TCGA)及CCLE樣品之表現資料。
表14. 表現
基因名稱 | TCGA-結腸直腸腺癌(中位數-FPKM (383個樣品) | 中位數表現_CCLE_結腸直腸_RPKM (57個細胞株) | 結腸 - 乙狀 | 結腸 - 橫向 |
CXCL16 | 5.7509 | 25.88884 | 11.51 | 15.44 |
COLEC12 | -0.6416 | 0.01964 | 27.25 | 11.24 |
APCDD1 | 4.1498 | 0.58982 | 12.26 | 11.22 |
表15匯總變異體及次要對偶基因頻率。
表15. 位置、特徵及變異
表16. 各種癌症中之LOH頻率
實例 2 :阻斷劑配位體結合結構域之鑑定
基因名稱 | 所有變異體 | TCGA-結腸直腸腺癌_雜合缺失頻率(分數=-1) | 胺基酸變化之蛋白質位置 | 胺基酸變化 | MAF |
CXCL16 | rs2277680,rs1050998 | 0.569805195 | 1. 200,2. 142 | 1. A/V,2. I/T | 1. 0.4615,2. 0.4633 |
COLEC12 | rs2305025 | 0.584415584 | 522 | S/P | 0.6252 |
APCDD1 | rs1786683 | 0.600649351 | 165 | Y/S | 0.2496 |
LOH 頻率 | |||
COLEC12 | CXCL16 | APCDD1 | |
所有癌症 | 0.23 | 0.36 | 0.23 |
CRC | 0.59 | 0.58 | 0.6 |
肺 | 0.3 | 0.58 | 0.29 |
胰 | 0.3 | 0.48 | 0.28 |
卵巢 | 0.39 | 0.74 | 0.36 |
DBCL | 0.15 | 0.23 | 0.13 |
血液 | 0.06 | 0.11 | 0.05 |
變異體 | S/P | I/T | Y/S |
MAF | 0.63 | 0.46 | 0.25 |
若CDR序列未知,則對候選阻斷劑抗原之公開可用抗體進行定序。若無針對候選阻斷劑標靶之抗體可用,則藉由用純化之蛋白質(例如,COLEC12、CXCL16及實例中所述之其他標靶)使小鼠、大鼠或兔免疫來產生此等抗體。來自經免疫動物之血清用於篩選與阻斷劑標靶結合之mAb。亦使用huTARG系統產生針對阻斷劑標靶之抗體。接著分離具有所需特異性之抗體且進行定序以確定CDR序列。
來自針對阻斷劑標靶之抗體的CDR序列用於使用標準分子生物學技術產生scFv。候選scFv融合至抑制性受體鉸鏈或跨膜結構域以使用標準分子生物學技術產生抑制性受體。候選scFv亦融合至活化劑受體鉸鏈或跨膜結構域(例如,CAR)以產生全長活化劑受體,用作scFv與靶抗原結合之陽性對照。使用NFAT-螢光素酶報告體檢定在Jurkat細胞中檢定候選scFv在抑制性受體之情形中起作用的能力。
實例 3 :用於 Jurkat 及初級 T 細胞活化實驗之方法 細胞培養
編碼NFAT螢光素酶報告體之Jurkat細胞獲自BPS Bioscience。在培養中,將Jurkat細胞維持於補充有10% FBS、1% Pen/Strep及0.4mg/mL G418/遺傳黴素(Geneticin)之RPMI培養基中。本研究中使用之所有其他細胞株獲自ATCC,且按照ATCC之建議進行維持。
Jurkat細胞轉染
經由100uL格局之Neon電穿孔系統(Lonza)根據製造商之方案使用以下設置對Jurkat細胞進行瞬時轉染:3個脈衝,1500V,10 msec。每1e6個細胞用1-3ug活化劑CAR或TCR構築體及1-3ug阻斷劑構築體或空載體進行共轉染,且在補充有20%熱滅活FBS及0.1% Pen/Strep之RPMI培養基中回收。
Jurkat-NFAT-螢光素酶活化研究
將Jurkat細胞再懸浮於補充有10%熱滅活FBS及0.1% Pen/Strep之15uL RPMI中,添加至肽負載之珠粒中且共培養6小時。一步螢光素酶檢定系統(BPS Bioscience)用於評價Jurkat發光。以技術重複進行檢定。
初級T細胞轉導、擴增及富集
將冷凍之PBMC在37℃水浴中解凍且以1e6個細胞/毫升在含1%人血清之LymphoONE (Takara)中培養,且使用補充有300 IU/ml IL-2之1:100 T細胞TransAct (Miltenyi)活化。24小時後,將慢病毒以5之MOI添加至PBMC中。將PBMC再培養2-3天,以允許細胞在TransAct刺激下擴增。擴增後,根據製造商之說明書使用抗PE微珠(Miltenyi)對活化劑及阻斷劑轉導之初級T細胞進行富集。簡言之,將初級T細胞與EGFR-Fc (R&D Systems)以1:25之稀釋度在室溫下於MACS緩衝液(含0.5% BSA + 2mM EDTA之PBS)中培育30分鐘。將細胞在MACS緩衝液中洗滌3次且在室溫下於MACS緩衝液中在二級抗體(1:1200)中培育30分鐘。接著將細胞在抗PE微珠中培育且穿過LS管柱(Miltenyi)。
初級T細胞活體外細胞毒性研究
對於使用pMHC標靶之細胞毒性研究,將富集之初級T細胞與表現GFP或RFP之HeLa或HCT116靶細胞一起培育。對於「腫瘤」細胞,使用WT HeLa或HLA-A*02敲除之HCT116,且對於「正常」細胞,使用HLA-A*02轉導之HeLa或WT HCT116。使用IncuCyte活細胞成像儀對共培養物進行成像,且使用靶細胞螢光區域來定量活靶細胞。
實例 4 : HLA-A*02 抑制性受體阻斷 EGFR 介導之 Jurkat 細胞活化
如先前所述,使用NFAT-螢光素酶報告系統來檢定具有HLA-A-A*02抗原結合結構域及LIR-1 ICD (C1765或C2162)之抑制性受體阻斷表現具有EGFR抗原結合結構域(例如,CT479、CT486或CT489)之活化劑 CAR的Jurkat細胞之活化的能力。EGFR+及HLA-A*02-之正常HeLa腫瘤細胞用作靶細胞。亦用編碼HLA-A*02+之多核苷酸轉導EGFR+/ HLA-A*02- HeLa細胞以產生EGFR+ /HLA-A*02+ HeLa細胞,用作表現活化劑及阻斷劑抗原兩者之靶細胞。
如圖1A中所示,與不表現阻斷劑之Jurkat細胞的CAR Emax相比,表現EGFR CAR (CT479)之Jurkat細胞中之HLA-A*02 LIR-1阻斷劑(C1765)的表現使CAR E
MAX偏移>5倍。
此外,觀測到較低阻斷,伴有靶細胞上較低之HLA-A2表現水準。正常HCT116細胞為EGFR+及HLA-A*02+。使用抗EGFR抗體及抗HLA-A*02抗體(BB7.2)在經編碼HLA-A*02多核苷酸之多核苷酸轉導之HCT116細胞及HeLa細胞中檢定EGFR及HLA-A*02之水準,繼而進行FACs分選。如圖2A及2B中所示,HCT116細胞相比經轉導之HeLa細胞具有較低水準之阻斷劑HLA-A*02抗原。當表現EGFR CAR及HLA-A*02 LIR-1阻斷劑之Jurkat細胞與表現EGFR及HLA-A*02抗原之HCT116靶細胞一起呈現時,HLA-A*02 LIR-1阻斷劑之存在使EGFR CAR之E
MAX偏移1.8倍(圖3B)。相比之下,表現較高水準之HLA-A*02抗原之經轉導之HeLa細胞能夠介導>5倍之EGFR CAR E
MAX偏移(圖1B、圖17B及圖3D)。作為對照,存在EGFR敲除HCT116細胞之最小活化(圖3A)。
使用基於珠粒之系統來檢定使用EGFR CAR及HLA-A*02 LIR-1阻斷劑達成50%阻斷所必需之阻斷劑與活化劑比率,如圖4A及圖4B中所示。
為確定活化劑抗原之EC50,在不同濃度下用活化劑抗原包覆活化劑珠粒以確定EC50。添加無關蛋白質至各濃度以使得總蛋白質濃度相同,且將恆定量之珠粒添加至表現EGFR CAR之Jurkat效應細胞中(圖4A)。
為確定阻斷劑抗原IC50,在EC50濃度(圖4A中確定)下用活化劑抗原包覆珠粒,且在不同濃度下用阻斷劑抗原包覆。在各濃度下添加無關蛋白質以使得總蛋白質濃度保持相同,且將恆定量之珠粒添加至表現EGFR CAR或EGFR CAR及HLA-A*02 LIR-1阻斷劑之Jurkat效應細胞中(圖4B)。
實例 5 :特異性受體對之表徵
將經EGFR scFv CAR活化劑(CT-479、CT-482、CT-486、CT-487、CT-488或CT-489,如圖5及7-9中所指示)或經EGFR scFv CAR活化劑及HLA-A*02 PA2.1 scFv LIR1抑制劑(C1765或C2162)轉染之T細胞與HeLa靶細胞一起共培養。正常HeLa細胞株表現EGFR而非HLA-A*02,進行轉導以表現HLA-A*02抑制性受體標靶。將細胞以效應子與標靶(E:T)之1:1比率共培養。在圖5之右下角,首先指示效應細胞受體表現,而HeLa細胞表現在括號中。如自圖5可見,當相同HLA-A*02 PA2.1 scFv LIR1抑制劑與不同EGFR活化劑受體一起使用時觀測到不同程度之阻斷。
亦檢定HLA-A*02 PA2.1 scFv LIR1抑制劑(C1765)阻斷與表現EGFR (標靶A)或EGFR及HLA-A*02 (標靶AB)之HCT.116細胞一起共培養之T細胞之EGFR scFv CAR活化的能力(圖10)。如同HeLa細胞一般,當相同HLA-A*02 PA2.1 scFv LIR1抑制劑與不同EGFR活化劑受體一起使用時觀測到不同程度之阻斷。
亦檢定當Jurkat細胞與HeLa靶細胞一起共培養時,HLA-A*02 PA2.1 scFv LIR1抑制劑(C1765)阻斷Jurkat細胞之EGFR scFv CAR活化的能力。結果示於圖2中。類似於初級T細胞之結果,當相同HLA-A*02 PA2.1 scFv LIR1抑制劑與不同EGFR活化劑受體一起使用時觀測到不同程度之阻斷。
在僅表現活化配位體之靶細胞或表現活化劑配位體及阻斷配位體兩者之靶細胞存在下,在表現活化劑或特異性活化劑/阻斷劑對之免疫細胞中量測免疫細胞活化(
圖 6A)。計算所測試之CAR活化劑與阻斷劑對之選擇性比率(SR)。藉由計算在僅表現活化配位體之靶細胞存在下表現活化劑/阻斷劑對之免疫細胞的活化與在表現活化劑配位體及阻斷配位體兩者之靶細胞存在下表現活化劑/阻斷劑對之免疫細胞的活化之比率來確定SR。所選之EGFR靶向CAR活化劑與人源化阻斷劑(C2162)或小鼠阻斷劑(C1765)成對表現。在與人源化阻斷劑配對之EGFR靶向CAR活化劑中,對於CT489之選擇性比率達到24.2;對於CT486之選擇性比率達到17;對於CT487之選擇性比率達到5.0;且對於CT487之選擇性比率達到5.0。在與小鼠阻斷劑配對之EGFR靶向CAR活化劑中,對於CT489之選擇性比率為21.6;對於CT486之選擇性比率為15.7;對於CT487之選擇性比率為18.4;且對於CT487之選擇性比率為21.2 (
圖 6A)。亦確定EGFR靶向活化劑與抑制性受體對中之每一者的最大特異性殺死。對於所有配對,特異性殺死超過約60%,指示阻斷劑之選擇不會顯著影響EGFR靶向活化劑受體之T細胞活化。然而,特異性活化劑與特異性阻斷劑對之配對對選擇性比率有影響,指示由所促進之特異性活化劑/抑制性受體對之脫靶殺死為不可預測的。
在表現單獨CAR活化劑或CAR活化劑及人源化阻斷劑或小鼠阻斷劑之免疫細胞中確定活化劑及阻斷劑敏感性(
圖 6B)。為確定活化劑敏感性,在EGFR陰性靶細胞存在下培育免疫細胞。在培育之前,用EGFR mRNA滴定靶細胞,使得EGFR表現水準增加(
圖 6B ,左圖)。為確定阻斷劑敏感性,在表現EGFR之HLA-A*02陰性靶細胞(每個細胞約53,000個EGFR分子)存在下培育免疫細胞。在培育之前,用HLA-A*02 mRNA滴定靶細胞,使得HLA-A*02表現水準增加(
圖 6B ,右圖)。計算各CAR活化劑及阻斷劑與不同CAR活化劑組合之EC
50值(表5.1)。結果進一步確認特異性活化劑受體對抑制性受體敏感性有影響。
表5.1
實例 6 :抑制性受體可逆地降低 T 細胞中活化劑受體之表面水準
活化劑 | 活化劑 EC 50(ng) | 小鼠阻斷劑 EC 50(ng) | 人類阻斷劑 EC 50(ng) |
CT486 | 5,300 | 4,700 | 4,000 |
CT487 | 3,500 | 3,500 | 2,900 |
CT488 | 4,700 | 4,700 | 3,500 |
CT489 | 3,100 | 4,200 | 3,200 |
用EGFR scFv CAR活化劑(CT-479、CT-482、CT-486、CT-487或CT-488)及HLA-A*02 PA2.1 scFv LIR1抑制劑(C1765)轉導來自兩個HLA-A*02陰性供體之初級T細胞。藉由對阻斷劑及活化劑受體進行FACS分選,或藉由對阻斷劑及活化劑受體進行雙管柱純化來富集經轉導之細胞。將經轉導之T細胞與HeLa靶細胞一起共培養。正常HeLa細胞株表現EGFR而非HLA-A*02,但進行轉導以表現HLA-A*02抑制性受體標靶。將細胞以效應子與標靶(E:T)之1:1比率共培養。120小時後,使用結合活化劑及抑制性受體之經標記肽以及螢光活化細胞分選來檢定EGFR CAR活化劑之表面表現。與表現活化劑及阻斷劑配位體兩者之HeLa細胞一起共培養後活化劑表面水準之變化對應於T細胞殺死靶細胞之能力(比較圖5與圖11A)。
將表現CT-482 EGFR scFv CAR活化劑及HLA-A*02 PA2.1 scFv LIR1抑制劑(C1765)組合之T細胞與表現EGFR (標靶A)、HLA-A*02 (標靶B)、同一細胞上之EGFR與HLA-A*02之組合(標靶AB)的HeLa細胞、表現不同細胞上之標靶A及標靶AB之混合HeLa細胞群體、或表現不同細胞上之標靶B及標靶AB之混合HeLa細胞群體一起共培養(圖12A-12B)。將T細胞與HeLa靶細胞以1:1效應細胞與靶細胞之比率一起培養。當T細胞與HeLa細胞之標靶A加標靶AB群體一起共培養時,活化劑水準降低,接著恢復(圖12A)。此外,活化劑及阻斷劑抗原必須一起存在於同一細胞上,以觸發效應T細胞上之活化劑表面表現損失。與活化劑成對比,阻斷劑表現基本上不變(圖12B)。
圖13顯示用於確定T細胞之細胞毒性、阻斷活性及活化劑受體表現之損失是否可逆之實驗的示意圖。將表現EGFR scFv CAR活化劑受體(CT-487)及HLA-A*02 PA2.1 scFv LIR1 (C1765)抑制性受體之T細胞與表現活化劑及抑制性受體標靶(AB)兩者之HeLa靶細胞一起共培養。共培養3天后,使用抗EGFR管柱移除HeLa細胞,接著將T細胞針對活化劑及抑制性受體進行染色,或與僅表現EGFR活化劑標靶之HeLa細胞一起再共培養3天。再共培養3天後,再次使用抗EGFR管柱移除HeLa細胞,且將T細胞針對活化劑及抑制性受體進行染色,或在染色前與僅表現EGFR活化劑標靶或活化劑及阻斷劑標靶兩者(AB)之HeLa細胞一起再共培養3天。使用經標記之EGFR及A2探針檢定T細胞之活化劑及抑制性受體的存在(染色),且使用螢光活化細胞分選來定量受體表現水準。實驗結果示於圖14A-14B中。如圖14A-14B中所示,T細胞與表現活化劑及抑制劑標靶兩者之HeLa細胞的共培養減少EGFR活化劑染色(圖14A-14B,左圖)。當在第2輪將T細胞與表現活化劑(僅標靶A)之HeLa細胞一起共培養時,EGFR活化劑之表現增加。因此,活化劑表面損失為可逆的且隨T細胞之細胞毒性而追踪。
圖15A-15B顯示額外實驗之結果,該等結果顯示活化劑受體表現之損失為快速可逆的。當將表現活化劑及抑制性受體兩者之T細胞與表現活化劑及抑制劑配位體兩者之模型「正常」細胞一起共培養時,活化劑CAR細胞表面表現在此等T細胞中減少。然而,當將T細胞切換至與僅表現活化劑配位體之模型「癌」細胞一起共培養時,T細胞能夠快速(在數小時內)恢復活化劑CAR之細胞表面表現。不存在表現活化劑及抑制劑配位體兩者之模型「正常」細胞亦可在類似時間框內恢復活化劑CAR之細胞表面表現,而與腫瘤細胞之存在無關。
實例 7 :基於 HLA-A*02 LIR-1 之抑制性受體可阻斷 EGFR CAR 活化劑之活化
使用實例3中所述之NFAT螢光素酶檢定來檢定表現EGFR CAR活化劑及基於pMHC HLA-A*02 scFv LIR-1之抑制性受體(包含LIR-1鉸鏈、跨膜及ICD)之Jurkat效應細胞的活化。
用活化劑及抑制性受體DNA轉染Jurkat細胞,且在基於無細胞珠粒之檢定中檢定活化(圖16)。珠粒負載有活化劑抗原、阻斷劑抗原或活化劑及抑制劑抗原,且改變珠粒與Jurkat細胞之比率。在基於無細胞珠粒之檢定中,當使細胞與攜帶呈順式之HLA-A*02阻斷劑及EGFR活化劑之珠粒接觸時,而非當HLA-A*02阻斷劑及EGFR活化劑呈反式(在不同珠粒上)時,基於HLA-A*02 scFv LIR-1之抑制性受體能夠阻斷Jurkat細胞之活化。珠粒上HLA-A*02阻斷劑之存在能夠使EGFR CAR之E
MAX偏移大於或等於9X (圖16)。
亦使用HeLa及SiHa細胞作為靶細胞來檢定表現EGFR CAR活化劑及基於HLA-A*02 scFv LIR-1之抑制性受體之Jurkat細胞的活化。正常HeLa及SiHa細胞株表現EGFR而非HLA-A*02 (SiHa WT及HeLa WT),但進行轉導以表現HLA-A*02抑制性受體標靶(SiHa A02及HeLa A02)。如圖17A及圖17B中可見,基於HLA-A*02 scFv LIR-1之抑制性受體能夠使用SiHa靶細胞使EGFR E
MAX偏移大於4X (圖17A)且使用HeLa靶細胞使其偏移大於5X (圖17B)。
實例 8 :表現 EGFR CAR 活化劑及抑制性受體之 T 細胞的活體內功效
在活體內環境中建立表現活化劑受體(EGFR CAR)與抑制性受體(阻斷劑)對之免疫細胞的功效及腫瘤對比正常細胞選擇性(
圖 19)。使用代表「正常」細胞之人類EGFR+/HLA-A*02+ HeLa細胞且使用同基因型EGFR+/HLA-A*02(-)敲除HeLa細胞作為「腫瘤」細胞之NSG (NOD.Cg- Prkdc
scidIl2rg
tm1Wjl/SzJ)中之鼠類異種移植模型。藉由比較對正常細胞對比腫瘤細胞上之活化劑/抑制性受體對之作用來建立活體內治療窗口。此等資料為中靶、非腫瘤治療窗口提供活體內支持。建立活化劑/抑制性受體對之最佳劑量且針對敏感性及選擇性進行最佳化。
活體內模型涉及右側「正常」細胞及左側「腫瘤」細胞之皮下異種移植物。在一系列時間點向動物投與表現活化劑受體、活化劑/抑制性受體對之免疫細胞,或未轉導之對照細胞。
經由臨床觀測及對體重之影響來監測動物之總體健康狀況。藉由測徑規及成像來評估腫瘤異種移植物之大小。在各時間點,藉由流式細胞術對人類T細胞進行計數且評估表面標誌,包括CD3、CD4、CD8、活化劑受體表現及抑制性受體表現。確定血清細胞激素水準,包括IFNγ及介白素2 (IL-2)。在死後分析中,由ACVP委員會認證之病理學家以組織學來評估方案指定之組織(包括注射部位及腫瘤)之腫瘤浸潤性T細胞及活化劑受體抗原(例如,EGFR)及阻斷劑抗原表現(例如,HLA-A*02)。
實例 9 : B7 及 HLA-A*11 為抑制性受體配位體
藉由使scFv #4 (表格)融合至來源於LIR-1之鉸鏈、TM及ICD來創造HLA-A*011抑制性受體。使用Golden Gate選殖來組合基因片段,且插入慢病毒表現質體中所含之人類EF1α啟動子下游。
如上文所述用CAR活化劑或CAR活化劑及scFv #4 HLA-A*11抑制性(阻斷劑)受體將Jurkat NFAT-螢光素酶效應細胞轉型。HLA-A*011抑制性受體之序列示於下表9.1中,且與表現活化劑配位體及HLA-A*011:01之HeLa細胞一起共培養。使用HeLa替代T2靶細胞進行NFAT-螢光素酶檢定。
結果示於圖20A及圖20B中。如圖20A中所示,scFv #4當融合至LIR-1之鉸鏈、TM及ICD結構域時,能夠抑制與表現活化劑配位體及HLA-A*011兩者之靶細胞一起共培養之Jurkat效應細胞的活化。
表9.1. HLA-A*011抑制性受體序列.
名稱 | 蛋白質序列 | DNA序列 |
HLA-A*11阻斷劑4 | MDMRVPAQLLGLLLLWLRGARC EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMHWVRQAPGKGLVWVSRINSDGSSTSYADSVKGRFTISRDNAKNTLYLQMNSLRAEDTAVYYCCLGVLLYNWFDPWGQGTLVTVSS GGGGSGGGGSGGGGSGGDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGGGTKVEIKYGSQSSKPYLLTHPSDPLELVVSGPSGGPSSPTTGPTSTSGPEDQPLTPTGSDPQSGLGRHLGVVIGILVAVILLLLLLLLLFLILRHRRQGKHWTSTQRKADFQHPAGAVGPEPTDRGLQWRSSPAADAQEENLYAAVKHTQPEDGVEMDTRSPHDEDPQAVTYAEVKHSRPRREMASPPSPLSGEFLDTKDRQAEEDRQMDTEAAASEAPQDVTYAQLHSLTLRREATEPPPSQEGPSPAVPSIYATLAIH (SEQ ID NO: 915) | ATGGACATGAGGGTCCCCGCTCAGCTCCTGGGGCTCCTGCTACTCTGGCTCCGAGGTGCCAGATGTGAAGTGCAGCTGGTGGAAAGCGGCGGAGGCCTGGTGCAGCCTGGCGGCAGCCTGAGACTGTCTTGCGCCGCCAGCGGCTTCACCTTCAGCAGCTACTGGATGCACTGGGTCCGCCAGGCCCCTGGCAAGGGACTGGTCTGGGTGTCTCGAATCAACAGCGACGGCAGCAGCACCAGCTACGCCGACAGCGTGAAGGGCCGGTTCACCATCAGCCGGGACAACGCCAAGAACACCCTGTACCTGCAGATGAACAGCCTGCGGGCCGAGGACACCGCCGTGTATTACTGTTGTTTGGGTGTTTTATTATACAACTGGTTCGACCCCTGGGGCCAGGGAACCCTGGTCACCGTGTCCTCAGGCGGAGGTGGAAGCGGAGGGGGAGGATCTGGCGGCGGAGGAAGCGGAGGCGACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCTCACTTTCGGCGGCGGAACAAAGGTGGAGATCAAGTACGGCTCACAGAGCTCCAAACCCTACCTGCTGACTCACCCCAGTGACCCCCTGGAGCTCGTGGTCTCAGGACCGTCTGGGGGCCCCAGCTCCCCGACAACAGGCCCCACCTCCACATCTGGCCCTGAGGACCAGCCCCTCACCCCCACCGGGTCGGATCCCCAGAGTGGTCTGGGAAGGCACCTGGGGGTTGTGATCGGCATCTTGGTGGCCGTCATCCTACTGCTCCTCCTCCTCCTCCTCCTCTTCCTCATCCTCCGACATCGACGTCAGGGCAAACACTGGACATCGACCCAGAGAAAGGCTGATTTCCAACATCCTGCAGGGGCTGTGGGGCCAGAGCCCACAGACAGAGGCCTGCAGTGGAGGTCCAGCCCAGCTGCCGATGCCCAGGAAGAAAACCTCTATGCTGCCGTGAAGCACACACAGCCTGAGGATGGGGTGGAGATGGACACTCGGAGCCCACACGATGAAGACCCCCAGGCAGTGACGTATGCCGAGGTGAAACACTCCAGACCTAGGAGAGAAATGGCCTCTCCTCCTTCCCCACTGTCTGGGGAATTCCTGGACACAAAGGACAGACAGGCGGAAGAGGACAGGCAGATGGACACTGAGGCTGCTGCATCTGAAGCCCCCCAGGATGTGACCTACGCCCAGCTGCACAGCTTGACCCTCAGACGGGAGGCAACTGAGCCTCCTCCATCCCAGGAAGGGCCCTCTCCAGCTGTGCCCAGCATCTACGCCACTCTGGCCATCCAC (SEQ ID NO: 916) |
在mRNA滴定檢定中使用經mRNA轉染之HeLa細胞來量測Jurkat NFAT螢光素酶(JNL)細胞活化。用連續稀釋之編碼HLA-B*07:02之mRNA轉染HeLa細胞。用EGFR活化CAR及HLA-B*07阻斷劑(圓圈)或陰性對照載體(三角形)瞬時轉染JNL細胞。共培養6小時後評估功能反應。圖21中所示之結果證明HLA-B*07阻斷劑在滴定之HLA-B*07:02存在下而並非不存在阻斷劑之情況下阻斷EGFR靶向CAR之活化。
實例 10 :初級 T 細胞中 EGFR 活化劑及 HLA-A*02 抑制性受體表現之表徵
為針對EGFR活化劑進行染色,在室溫下將初級T細胞與EGFR-Fc (R&D Systems)以1:25稀釋度在FACS緩衝液(含1% BSA之PBS)中培育30分鐘。將細胞在FACS緩衝液中洗滌2次且在室溫下在FACS緩衝液中於抗Fc (1:100)中培育30分鐘。為針對HLA-A*02抑制性受體進行染色,在室溫下將T細胞與HLA-A*02四聚體探針在FACS緩衝液中培育30分鐘。染色後藉由流式細胞術分析受體表現。
用編碼EGFR靶向活化劑受體及人類或小鼠HLA-A*02靶向抑制性受體之多核苷酸轉導初級T細胞。測試EGFR靶向活化劑與HLA-A*02靶向抑制性受體之若干特異性對。用編碼活化劑受體及抑制性受體兩者之單個載體或一者編碼活化劑受體且一者編碼抑制性受體之兩個載體進行轉導。在富集及不富集之情況下分析細胞以確定表現活化劑及抑制劑受體兩者之細胞的百分比(圖22)。
在用一者編碼活化劑受體且一者編碼抑制性受體之兩個載體轉導之初級T細胞中,在富集之前在經轉導之表現兩種受體之T細胞群體中之細胞的百分比為約22.5% (圖22A,左圖)。富集之後,經轉導之表現兩種受體之T細胞群體中之細胞的百分比增至約91.6%。
在用編碼活化劑受體及抑制性受體兩者之單個載體轉導之初級T細胞中,在富集之前在經轉導之表現兩種受體之T細胞群體中之細胞的百分比介於約6.29%與13.2%之間的範圍內。富集之後,表現兩種受體之細胞的百分比在22.6%至82.8%之範圍內。表現兩種受體之細胞的百分比視特異性活化劑與抑制性受體對而定。
實例 11 :表現活化劑及抑制性受體之初級 T 細胞中免疫細胞活化選擇性之表徵
對於選擇性細胞毒性研究,將富集之初級T細胞與表現GFP或RFP之HeLa或HCT116靶細胞一起培育。對於「腫瘤」細胞,使用WT HeLa或HLA-A*02敲除之HCT116,且對於「正常」細胞,使用HLA-A*02轉導之HeLa或WT HCT116。使用IncuCyte活細胞成像儀對共培養物進行成像,且使用靶細胞螢光區域來定量活靶細胞(圖23A)。為量測混合標靶培養物中之選擇性細胞毒性,將經HLA-A*02轉導之表現RFP之「腫瘤」WT HeLa細胞與表現GFP之「正常」HeLa 細胞以1:1比率混合。將富集之初級T細胞添加至混合標靶培養物中且使用IncuCyte活細胞成像儀進行成像,且使用靶細胞螢光區域來定量活靶細胞(圖23B)。
圖23A為顯示表現EGFR活化劑受體及HLA-A*02 scFv LIR1抑制劑受體之免疫細胞對HeLa靶細胞或HCT116靶細胞之特異性殺死之百分比的一系列圖。靶細胞表現EGFR抗原(A)、HLA-A*02非靶抗原(B)或兩者(AB)。將表現活化劑/抑制劑受體對之免疫細胞與靶細胞一起以1:1比率培育。
圖23B為顯示在癌細胞與正常細胞之混合培養物中表現EGFR活化劑受體及HLA-A*02 scFv LIR1抑制劑受體之免疫細胞對靶細胞之特異性及選擇性殺死的圖及一系列影像。UTD = 無活化劑或抑制劑受體之免疫細胞;CAR = 僅表現活化劑受體之免疫細胞;Tmod = 表現活化劑及抑制劑受體兩者之免疫細胞。
實例 12 :表現活化劑及抑制性受體之 Jurkat 細胞中免疫細胞活化選擇性之表徵
圖24為顯示表現EGFR活化劑受體(CAR)或EGFR活化劑受體及HLA-A*02抑制劑受體(Tmod)之Jurkat細胞(效應子)中之免疫細胞活化的圖表。將Jurkat細胞與一組表現HLA-A*02而無EGFR表現或表現HLA-A*02且有EGFR表現之靶細胞株一起培育。藉由使用CRISPR/Cas9敲除EGFR來產生EGFR陰性細胞株。當與EGFR陰性細胞一起共培養時,Tmod Jurkat效應細胞不顯示脫靶活化。
專利或申請案檔案含有至少一張彩色繪圖。本專利或專利申請公開案之帶有彩圖之複本將由專利局根據要求及支付必要費用而提供。
圖1A為顯示表現EGFR CAR活化劑及HLA-A*02 LIR-1阻斷劑之Jurkat細胞由EGFR+/HLA-A*02- HeLa靶細胞而非EGFR+/HLA-A*02+ HeLa靶細胞活化之圖。
圖1B為顯示Jurkat細胞上活化劑(CT479)及阻斷劑(C1765)受體之表現的一對螢光活化細胞分選(FACS)圖。
圖1C為顯示HeLa細胞上活化劑抗原(EGFR)及阻斷劑抗原(HLA-A*02)之表現的一對圖。使用BB7.2抗體偵測HLA-A*02表現。
圖2A顯示用HLA-A*02轉導之HeLa細胞、及HCT116細胞上HLA-A*02之表現。用抗HLA-A2抗體BB7.2標記HeLa及HCT1116細胞且對FAC進行分選。綠色:未標記之HeLa;橙色:未標記之HCT116;藍色:經BB7.2標記之野生型HCT116;紅色:用HLA-A*02轉導且經BB7.2標記之HeLa細胞。
圖2B顯示HeLa細胞及HCT116細胞上EGFR之表現。用抗EGFR抗體標記HeLa及HCT1116細胞。綠色:未標記之HeLa;橙色:未標記之HCT1116;藍色:經抗EGFR標記之野生型HCT116;紅色:用HLA-A*02轉導且經抗EGFR標記之HeLa細胞。
圖3A顯示當共培養HCT116靶細胞時,表現EGFR CAR之Jurkat細胞的EGFR CAR活化。
圖3B顯示Jurkat細胞之EGFR CAR活化可由HLA-A*02 LIR-1抑制性受體阻斷。當Jurkat細胞與表現EGFR及HLA-A*02之HCT116靶細胞一起呈現時,EGFR CAR及HLA-A*02 LIR-1抑制性受體由Jurkat細胞共表現使得CAR E
MAX移位約1.8x。
圖3C顯示當與HeLa靶細胞一起共培養時,表現EGFR CAR之Jurkat細胞的EGFR CAR活化。
圖3D顯示Jurkat細胞之EGFR CAR活化可由HLA-A*02 LIR-1抑制性受體阻斷。當Jurkat細胞與表現EGFR及HLA-A*02之HeLa靶細胞一起呈現時,EGFR CAR及HLA-A*02 LIR-1抑制性受體由Jurkat細胞共表現使得CAR E
MAX移位約5.4x。
圖4A顯示在基於珠粒之檢定中活化劑抗原之滴定以確定活化劑抗原之最佳量。
圖4B顯示在基於珠粒之檢定中阻斷劑抗原之滴定以確定活化劑與阻斷劑抗原之最佳比率。
圖5為顯示當HLA-A*02 scFv LIR1抑制劑與初級T細胞中之不同EGFR scFv CAR活化劑一起使用時觀測到不同程度之阻斷的一系列圖及表格。
圖6A為顯示當兩種不同HLA-A*02 scFv LIR1抑制劑與初級T細胞中之不同EGFR scFv CAR活化劑一起使用時觀測到不同程度之阻斷的一系列圖。
圖6B為顯示當不同對之活化及抑制性受體共表現時活化及抑制性受體之敏感性的一系列圖。藉由mRNA滴定,活化劑或非靶抗原之量在靶細胞上發生變化。
圖6C為顯示表現EGFR靶向活化劑受體及人源化抑制性受體或鼠類抑制性受體之細胞對靶細胞之最大特異性殺死(%)的一系列圖表。亦顯示各對活化劑及抑制性受體之靶腫瘤細胞對比正常細胞之選擇性比率。
圖7為顯示與HeLa細胞一起以1:1比率共培養之表現EGFR scFv CAR或EGFR scFv Car及HLA-A*02 scFv LIR1抑制性受體之T細胞之細胞毒性的一系列圖。A腫瘤細胞:表現EGFR而非HLA-A*02之HeLa細胞;AB正常細胞:表現EGFR及HLA-A*02之HeLa細胞;A-B-正常細胞:不表現EGFR或HLA-A*02之HeLa細胞;B正常細胞:表現HLA-A*02而非EGFR之HeLa細胞。Y軸顯示綠色區域,該區域與檢定中之健康HeLa細胞成比例。UTD:未轉導。
圖8為顯示表現阻斷劑及活化劑受體之初級T細胞之富集(頂行)以及表現EGFR scFv CAR或EGFR scFv CAR及HLA-A*02 scFv LIR1抑制性受體之此等T細胞之細胞毒性活性的一系列圖,該等T細胞與表現EGFR (標靶A)或EGFR及 HLA-A*02 (標靶AB)之HeLa細胞1:1混合。
圖9為顯示表現EGFR scFv CAR或EGFR scFv CAR及HLA-A*02 scFv LIR1抑制性受體之T細胞之細胞毒性的一系列圖,該等T細胞與表現EGFR、HLA-A*02或兩者之HeLa細胞1:1混合。A腫瘤細胞:表現EGFR而非HLA-A*02之HeLa細胞;AB正常細胞:表現EGFR及HLA-A*02之HeLa細胞;B正常細胞:表現HLA-A*02而非EGFR之HeLa細胞。Y軸顯示綠色區域,該區域與檢定中之健康HeLa細胞成比例。UTD:未轉導。
圖10為顯示表現EGFR scFv CAR或EGFR scFv CAR及HLA-A*02 scFv LIR1抑制性受體之T細胞之細胞毒性的一系列圖,該等T細胞與表現EGFR (標靶A)或EGFR及HLA-A*02 (標靶AB)之HCT.116細胞1:1混合。
圖11A為顯示在表現不同EGFR scFv CAR及HLA-A*02 scFv LIR1抑制劑之T細胞與表現單獨EGFR活化劑(標靶A)、單獨抑制劑標靶(標靶B)或活化劑及抑制劑標靶(標靶AB)之HeLa細胞一起培育之後T細胞對EGFR scFv CAR活化劑受體之表現的一系列螢光活化細胞分選(FACS)圖。
圖11B為顯示在暴露於靶細胞之前及在與表現單獨活化劑配位體(標靶A)之靶細胞或表現活化劑及阻斷劑配位體兩者(標靶AB)之靶細胞一起共培養120小時之後定量活化劑受體表現的圖。
圖12A為顯示在與表現EGFR (標靶A)、HLA-A*02 (標靶B)、同一細胞上之EGFR與HLA-A*02之組合(標靶AB)之HeLa細胞群體、表現標靶A及不同細胞上之標靶AB之HeLa細胞混合群體或表現標靶B及不同細胞上之標靶AB之HeLa細胞混合群體一起共培養之後表現EGFR scFv CAR (CT-482)活化劑及HLA-A*02 scFv LIR1抑制劑(C1765)之T細胞上之活化劑受體之細胞表面表現的圖。
圖12B為顯示在與表現EGFR (標靶A)、HLA-A*02 (標靶B)、同一細胞上之EGFR與HLA-A*02之組合(標靶AB)之HeLa細胞群體、表現標靶A及不同細胞上之標靶AB之HeLa細胞混合群體或表現標靶B及不同細胞上之標靶AB之HeLa細胞混合群體一起共培養之後表現EGFR scFv CAR (CT-482)活化劑及HLA-A*02 scFv LIR1抑制劑(C1765)之T細胞上之抑制性受體之細胞表面表現的圖。
圖13為確定T細胞之細胞毒性或阻斷活性是否可逆之實驗圖。
圖14A為顯示細胞毒性及阻斷活性為可逆的且對應於活化劑表面表現之一系列圖。在第1輪中將T細胞與EGFR+/HLA-A2+靶細胞一起共培養,接著在後續輪次中切換至替代性靶細胞。頂部:顯示T細胞對HeLa靶細胞之殺死百分比。底部:藉由FACS檢定之活化劑及抑制性受體表現。
圖14B為顯示細胞毒性及阻斷活性為可逆的且對應於活化劑表面表現之一系列圖。在第1輪中將T細胞與EGFR+/HLA-A2-靶細胞一起共培養,接著在後續輪次中切換至替代性靶細胞。頂部:顯示T細胞對HeLa靶細胞之殺死百分比。底部:藉由FACS檢定之活化劑及抑制性受體表現。
圖15A為顯示細胞表面上之EGFR活化劑CAR之表現由表現活化劑及抑制劑配位體兩者之靶細胞的存在而可逆下調之圖。
圖15B為顯示當僅存在活化劑靶細胞或不存在表現活化劑及阻斷劑標靶之靶細胞時細胞表面上之EGFR活化劑CAR表現迅速恢復的一系列圖。
圖16顯示當活化劑及抑制劑抗原以順式存在於珠粒上時,而非當活化劑及抑制劑抗原以反式存在於珠粒上時,使用基於珠粒之檢定對表現EGFR scFv CAR之Jurkat細胞之活化可由基於pMHC HLA-A*02 scFv LIR-1之抑制性受體阻斷。
圖17A顯示EGFR scFv CAR對Jurkat細胞之活化可由使用表現HLA-A*02之SiHa靶細胞(SiHa A02)而非不表現HLA-A*02之SiHa細胞(SiHa WT)之基於pMHC HLA-A*02 scFv LIR-1之抑制性受體阻斷。
圖17B顯示EGFR scFv CAR對Jurkat細胞之活化可由使用表現HLA-A*02之HeLa靶細胞(HeLa A02)而非不表現HLA-A*02之HeLa細胞(HeLa WT)之基於pMHC HLA-A*02 scFv LIR-1之抑制性受體阻斷。
圖18為顯示用於鑑定潛在非靶抗原候選基因之生物資訊學搜索過程之圖。
圖19為顯示用於確定活體內表現EGFR靶向活化劑受體及抑制性受體之免疫細胞之功效及選擇性之實驗設計的圖。
圖20A為顯示在使用經編碼HLA-A*11之mRNA轉染之HeLa細胞之mRNA滴定檢定中Jurkat NFAT螢光素酶(JNL)細胞抑制的圖。用連續稀釋之HLA-A*11 mRNA轉染HeLa細胞,且用具有scFv HLA-A*11 #4之EGFR活化CAR +/- HLA-A*11抑制性受體瞬時轉染JNL細胞。在共培養6小時後評估功能反應。
圖20B顯示具有HLA-A*11 #4之抑制性受體之分子/細胞敏感性(IC50)。
圖21為顯示HLA-B*07-scFv-LIR1抑制性受體抑制由共表現之EGFR靶向活化劑受體介導之免疫細胞活化。
圖22為顯示包含本文所揭示之載體之初級T細胞中EGFR活化劑受體(僅EGFR-CAR)及EGFR活化劑/HLA-A抑制性受體對之表現的一系列圖。在富集之前(富集前)及富集之後(富集後)顯示表現一或兩種受體之細胞的百分比,其中富集為表現受體之細胞而選擇。自兩個獨立載體(雙載體)或一個載體(單載體)表現受體對。
圖23A為顯示表現EGFR活化劑受體及HLA-A*02 scFv LIR1抑制劑受體之免疫細胞對HeLa靶細胞或HCT116靶細胞之特異性殺死之百分比的一系列圖。靶細胞表現EGFR抗原(A),或EGFR抗原及HLA-A*02非靶抗原兩者(B)。將表現活化劑/抑制劑受體對之免疫細胞與靶細胞一起以1:1比率培育。
圖23B為顯示在癌細胞與正常細胞之混合培養物中表現EGFR活化劑受體及HLA-A*02 scFv LIR1抑制劑受體之免疫細胞對靶細胞之特異性及選擇性殺死的圖及一系列影像。UTD = 無活化劑或抑制劑受體之免疫細胞;CAR = 僅表現活化劑受體之免疫細胞;Tmod = 表現活化劑及抑制劑受體兩者之免疫細胞。在右側之影像中:綠色 = 正常細胞;紅色 = 腫瘤細胞。
圖24為顯示表現EGFR活化劑受體(CAR)或EGFR活化劑受體及HLA-A*02抑制劑受體(Tmod)之Jurkat細胞(效應子)中之選擇性細胞活化的圖表。將Jurkat細胞與一組表現HLA-A*02而有或無EGFR表現之靶細胞株一起培育。當與表現HLA-A*02之細胞當中不表現EGFR之靶細胞一起共培養時,Tmod Jurkat效應細胞不顯示脫靶活化。
<![CDATA[<110> 美商A2生物治療學股份有限公司 (A2 Biotherapeutics, Inc.)]]> <![CDATA[<120> 用於治療EGFR陽性癌症之組合物及方法]]> <![CDATA[<130> A2BI-021/02WO 331656-2067]]> <![CDATA[<150> US 63/230,632]]> <![CDATA[<151> 2021-08-06]]> <![CDATA[<150> US 63/105,639]]> <![CDATA[<151> 2020-10-26]]> <![CDATA[<150> US 63/068,249]]> <![CDATA[<151> 2020-08-20]]> <![CDATA[<160> 919 ]]> <![CDATA[<170> PatentIn version 3.5]]> <![CDATA[<210> 1]]> <![CDATA[<211> 1210]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人(Homo sapiens)]]> <![CDATA[<400> 1]]> Met Arg Pro Ser Gly Thr Ala Gly Ala Ala Leu Leu Ala Leu Leu Ala 1 5 10 15 Ala Leu Cys Pro Ala Ser Arg Ala Leu Glu Glu Lys Lys Val Cys Gln 20 25 30 Gly Thr Ser Asn Lys Leu Thr Gln Leu Gly Thr Phe Glu Asp His Phe 35 40 45 Leu Ser Leu Gln Arg Met Phe Asn Asn Cys Glu Val Val Leu Gly Asn 50 55 60 Leu Glu Ile Thr Tyr Val Gln Arg Asn Tyr Asp Leu Ser Phe Leu Lys 65 70 75 80 Thr Ile Gln Glu Val Ala Gly Tyr Val Leu Ile Ala Leu Asn Thr Val 85 90 95 Glu Arg Ile Pro Leu Glu Asn Leu Gln Ile Ile Arg Gly Asn Met Tyr 100 105 110 Tyr Glu Asn Ser Tyr Ala Leu Ala Val Leu Ser Asn Tyr Asp Ala Asn 115 120 125 Lys Thr Gly Leu Lys Glu Leu Pro Met Arg Asn Leu Gln Glu Ile Leu 130 135 140 His Gly Ala Val Arg Phe Ser Asn Asn Pro Ala Leu Cys Asn Val Glu 145 150 155 160 Ser Ile Gln Trp Arg Asp Ile Val Ser Ser Asp Phe Leu Ser Asn Met 165 170 175 Ser Met Asp Phe Gln Asn His Leu Gly Ser Cys Gln Lys Cys Asp Pro 180 185 190 Ser Cys Pro Asn Gly Ser Cys Trp Gly Ala Gly Glu Glu Asn Cys Gln 195 200 205 Lys Leu Thr Lys Ile Ile Cys Ala Gln Gln Cys Ser Gly Arg Cys Arg 210 215 220 Gly Lys Ser Pro Ser Asp Cys Cys His Asn Gln Cys Ala Ala Gly Cys 225 230 235 240 Thr Gly Pro Arg Glu Ser Asp Cys Leu Val Cys Arg Lys Phe Arg Asp 245 250 255 Glu Ala Thr Cys Lys Asp Thr Cys Pro Pro Leu Met Leu Tyr Asn Pro 260 265 270 Thr Thr Tyr Gln Met Asp Val Asn Pro Glu Gly Lys Tyr Ser Phe Gly 275 280 285 Ala Thr Cys Val Lys Lys Cys Pro Arg Asn Tyr Val Val Thr Asp His 290 295 300 Gly Ser Cys Val Arg Ala Cys Gly Ala Asp Ser Tyr Glu Met Glu Glu 305 310 315 320 Asp Gly Val Arg Lys Cys Lys Lys Cys Glu Gly Pro Cys Arg Lys Val 325 330 335 Cys Asn Gly Ile Gly Ile Gly Glu Phe Lys Asp Ser Leu Ser Ile Asn 340 345 350 Ala Thr Asn Ile Lys His Phe Lys Asn Cys Thr Ser Ile Ser Gly Asp 355 360 365 Leu His Ile Leu Pro Val Ala Phe Arg Gly Asp Ser Phe Thr His Thr 370 375 380 Pro Pro Leu Asp Pro Gln Glu Leu Asp Ile Leu Lys Thr Val Lys Glu 385 390 395 400 Ile Thr Gly Phe Leu Leu Ile Gln Ala Trp Pro Glu Asn Arg Thr Asp 405 410 415 Leu His Ala Phe Glu Asn Leu Glu Ile Ile Arg Gly Arg Thr Lys Gln 420 425 430 His Gly Gln Phe Ser Leu Ala Val Val Ser Leu Asn Ile Thr Ser Leu 435 440 445 Gly Leu Arg Ser Leu Lys Glu Ile Ser Asp Gly Asp Val Ile Ile Ser 450 455 460 Gly Asn Lys Asn Leu Cys Tyr Ala Asn Thr Ile Asn Trp Lys Lys Leu 465 470 475 480 Phe Gly Thr Ser Gly Gln Lys Thr Lys Ile Ile Ser Asn Arg Gly Glu 485 490 495 Asn Ser Cys Lys Ala Thr Gly Gln Val Cys His Ala Leu Cys Ser Pro 500 505 510 Glu Gly Cys Trp Gly Pro Glu Pro Arg Asp Cys Val Ser Cys Arg Asn 515 520 525 Val Ser Arg Gly Arg Glu Cys Val Asp Lys Cys Asn Leu Leu Glu Gly 530 535 540 Glu Pro Arg Glu Phe Val Glu Asn Ser Glu Cys Ile Gln Cys His Pro 545 550 555 560 Glu Cys Leu Pro Gln Ala Met Asn Ile Thr Cys Thr Gly Arg Gly Pro 565 570 575 Asp Asn Cys Ile Gln Cys Ala His Tyr Ile Asp Gly Pro His Cys Val 580 585 590 Lys Thr Cys Pro Ala Gly Val Met Gly Glu Asn Asn Thr Leu Val Trp 595 600 605 Lys Tyr Ala Asp Ala Gly His Val Cys His Leu Cys His Pro Asn Cys 610 615 620 Thr Tyr Gly Cys Thr Gly Pro Gly Leu Glu Gly Cys Pro Thr Asn Gly 625 630 635 640 Pro Lys Ile Pro Ser Ile Ala Thr Gly Met Val Gly Ala Leu Leu Leu 645 650 655 Leu Leu Val Val Ala Leu Gly Ile Gly Leu Phe Met Arg Arg Arg His 660 665 670 Ile Val Arg Lys Arg Thr Leu Arg Arg Leu Leu Gln Glu Arg Glu Leu 675 680 685 Val Glu Pro Leu Thr Pro Ser Gly Glu Ala Pro Asn Gln Ala Leu Leu 690 695 700 Arg Ile Leu Lys Glu Thr Glu Phe Lys Lys Ile Lys Val Leu Gly Ser 705 710 715 720 Gly Ala Phe Gly Thr Val Tyr Lys Gly Leu Trp Ile Pro Glu Gly Glu 725 730 735 Lys Val Lys Ile Pro Val Ala Ile Lys Glu Leu Arg Glu Ala Thr Ser 740 745 750 Pro Lys Ala Asn Lys Glu Ile Leu Asp Glu Ala Tyr Val Met Ala Ser 755 760 765 Val Asp Asn Pro His Val Cys Arg Leu Leu Gly Ile Cys Leu Thr Ser 770 775 780 Thr Val Gln Leu Ile Thr Gln Leu Met Pro Phe Gly Cys Leu Leu Asp 785 790 795 800 Tyr Val Arg Glu His Lys Asp Asn Ile Gly Ser Gln Tyr Leu Leu Asn 805 810 815 Trp Cys Val Gln Ile Ala Lys Gly Met Asn Tyr Leu Glu Asp Arg Arg 820 825 830 Leu Val His Arg Asp Leu Ala Ala Arg Asn Val Leu Val Lys Thr Pro 835 840 845 Gln His Val Lys Ile Thr Asp Phe Gly Leu Ala Lys Leu Leu Gly Ala 850 855 860 Glu Glu Lys Glu Tyr His Ala Glu Gly Gly Lys Val Pro Ile Lys Trp 865 870 875 880 Met Ala Leu Glu Ser Ile Leu His Arg Ile Tyr Thr His Gln Ser Asp 885 890 895 Val Trp Ser Tyr Gly Val Thr Val Trp Glu Leu Met Thr Phe Gly Ser 900 905 910 Lys Pro Tyr Asp Gly Ile Pro Ala Ser Glu Ile Ser Ser Ile Leu Glu 915 920 925 Lys Gly Glu Arg Leu Pro Gln Pro Pro Ile Cys Thr Ile Asp Val Tyr 930 935 940 Met Ile Met Val Lys Cys Trp Met Ile Asp Ala Asp Ser Arg Pro Lys 945 950 955 960 Phe Arg Glu Leu Ile Ile Glu Phe Ser Lys Met Ala Arg Asp Pro Gln 965 970 975 Arg Tyr Leu Val Ile Gln Gly Asp Glu Arg Met His Leu Pro Ser Pro 980 985 990 Thr Asp Ser Asn Phe Tyr Arg Ala Leu Met Asp Glu Glu Asp Met Asp 995 1000 1005 Asp Val Val Asp Ala Asp Glu Tyr Leu Ile Pro Gln Gln Gly Phe 1010 1015 1020 Phe Ser Ser Pro Ser Thr Ser Arg Thr Pro Leu Leu Ser Ser Leu 1025 1030 1035 Ser Ala Thr Ser Asn Asn Ser Thr Val Ala Cys Ile Asp Arg Asn 1040 1045 1050 Gly Leu Gln Ser Cys Pro Ile Lys Glu Asp Ser Phe Leu Gln Arg 1055 1060 1065 Tyr Ser Ser Asp Pro Thr Gly Ala Leu Thr Glu Asp Ser Ile Asp 1070 1075 1080 Asp Thr Phe Leu Pro Val Pro Glu Tyr Ile Asn Gln Ser Val Pro 1085 1090 1095 Lys Arg Pro Ala Gly Ser Val Gln Asn Pro Val Tyr His Asn Gln 1100 1105 1110 Pro Leu Asn Pro Ala Pro Ser Arg Asp Pro His Tyr Gln Asp Pro 1115 1120 1125 His Ser Thr Ala Val Gly Asn Pro Glu Tyr Leu Asn Thr Val Gln 1130 1135 1140 Pro Thr Cys Val Asn Ser Thr Phe Asp Ser Pro Ala His Trp Ala 1145 1150 1155 Gln Lys Gly Ser His Gln Ile Ser Leu Asp Asn Pro Asp Tyr Gln 1160 1165 1170 Gln Asp Phe Phe Pro Lys Glu Ala Lys Pro Asn Gly Ile Phe Lys 1175 1180 1185 Gly Ser Thr Ala Glu Asn Ala Glu Tyr Leu Arg Val Ala Pro Gln 1190 1195 1200 Ser Ser Glu Phe Ile Gly Ala 1205 1210 <![CDATA[<210> 2]]> <![CDATA[<211> 628]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人(Homo sapiens)]]> <![CDATA[<400> 2]]> Met Arg Pro Ser Gly Thr Ala Gly Ala Ala Leu Leu Ala Leu Leu Ala 1 5 10 15 Ala Leu Cys Pro Ala Ser Arg Ala Leu Glu Glu Lys Lys Val Cys Gln 20 25 30 Gly Thr Ser Asn Lys Leu Thr Gln Leu Gly Thr Phe Glu Asp His Phe 35 40 45 Leu Ser Leu Gln Arg Met Phe Asn Asn Cys Glu Val Val Leu Gly Asn 50 55 60 Leu Glu Ile Thr Tyr Val Gln Arg Asn Tyr Asp Leu Ser Phe Leu Lys 65 70 75 80 Thr Ile Gln Glu Val Ala Gly Tyr Val Leu Ile Ala Leu Asn Thr Val 85 90 95 Glu Arg Ile Pro Leu Glu Asn Leu Gln Ile Ile Arg Gly Asn Met Tyr 100 105 110 Tyr Glu Asn Ser Tyr Ala Leu Ala Val Leu Ser Asn Tyr Asp Ala Asn 115 120 125 Lys Thr Gly Leu Lys Glu Leu Pro Met Arg Asn Leu Gln Glu Ile Leu 130 135 140 His Gly Ala Val Arg Phe Ser Asn Asn Pro Ala Leu Cys Asn Val Glu 145 150 155 160 Ser Ile Gln Trp Arg Asp Ile Val Ser Ser Asp Phe Leu Ser Asn Met 165 170 175 Ser Met Asp Phe Gln Asn His Leu Gly Ser Cys Gln Lys Cys Asp Pro 180 185 190 Ser Cys Pro Asn Gly Ser Cys Trp Gly Ala Gly Glu Glu Asn Cys Gln 195 200 205 Lys Leu Thr Lys Ile Ile Cys Ala Gln Gln Cys Ser Gly Arg Cys Arg 210 215 220 Gly Lys Ser Pro Ser Asp Cys Cys His Asn Gln Cys Ala Ala Gly Cys 225 230 235 240 Thr Gly Pro Arg Glu Ser Asp Cys Leu Val Cys Arg Lys Phe Arg Asp 245 250 255 Glu Ala Thr Cys Lys Asp Thr Cys Pro Pro Leu Met Leu Tyr Asn Pro 260 265 270 Thr Thr Tyr Gln Met Asp Val Asn Pro Glu Gly Lys Tyr Ser Phe Gly 275 280 285 Ala Thr Cys Val Lys Lys Cys Pro Arg Asn Tyr Val Val Thr Asp His 290 295 300 Gly Ser Cys Val Arg Ala Cys Gly Ala Asp Ser Tyr Glu Met Glu Glu 305 310 315 320 Asp Gly Val Arg Lys Cys Lys Lys Cys Glu Gly Pro Cys Arg Lys Val 325 330 335 Cys Asn Gly Ile Gly Ile Gly Glu Phe Lys Asp Ser Leu Ser Ile Asn 340 345 350 Ala Thr Asn Ile Lys His Phe Lys Asn Cys Thr Ser Ile Ser Gly Asp 355 360 365 Leu His Ile Leu Pro Val Ala Phe Arg Gly Asp Ser Phe Thr His Thr 370 375 380 Pro Pro Leu Asp Pro Gln Glu Leu Asp Ile Leu Lys Thr Val Lys Glu 385 390 395 400 Ile Thr Gly Phe Leu Leu Ile Gln Ala Trp Pro Glu Asn Arg Thr Asp 405 410 415 Leu His Ala Phe Glu Asn Leu Glu Ile Ile Arg Gly Arg Thr Lys Gln 420 425 430 His Gly Gln Phe Ser Leu Ala Val Val Ser Leu Asn Ile Thr Ser Leu 435 440 445 Gly Leu Arg Ser Leu Lys Glu Ile Ser Asp Gly Asp Val Ile Ile Ser 450 455 460 Gly Asn Lys Asn Leu Cys Tyr Ala Asn Thr Ile Asn Trp Lys Lys Leu 465 470 475 480 Phe Gly Thr Ser Gly Gln Lys Thr Lys Ile Ile Ser Asn Arg Gly Glu 485 490 495 Asn Ser Cys Lys Ala Thr Gly Gln Val Cys His Ala Leu Cys Ser Pro 500 505 510 Glu Gly Cys Trp Gly Pro Glu Pro Arg Asp Cys Val Ser Cys Arg Asn 515 520 525 Val Ser Arg Gly Arg Glu Cys Val Asp Lys Cys Asn Leu Leu Glu Gly 530 535 540 Glu Pro Arg Glu Phe Val Glu Asn Ser Glu Cys Ile Gln Cys His Pro 545 550 555 560 Glu Cys Leu Pro Gln Ala Met Asn Ile Thr Cys Thr Gly Arg Gly Pro 565 570 575 Asp Asn Cys Ile Gln Cys Ala His Tyr Ile Asp Gly Pro His Cys Val 580 585 590 Lys Thr Cys Pro Ala Gly Val Met Gly Glu Asn Asn Thr Leu Val Trp 595 600 605 Lys Tyr Ala Asp Ala Gly His Val Cys His Leu Cys His Pro Asn Cys 610 615 620 Thr Tyr Gly Ser 625 <![CDATA[<210> 3]]> <![CDATA[<211> 405]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人(Homo sapiens)]]> <![CDATA[<400> 3]]> Met Arg Pro Ser Gly Thr Ala Gly Ala Ala Leu Leu Ala Leu Leu Ala 1 5 10 15 Ala Leu Cys Pro Ala Ser Arg Ala Leu Glu Glu Lys Lys Val Cys Gln 20 25 30 Gly Thr Ser Asn Lys Leu Thr Gln Leu Gly Thr Phe Glu Asp His Phe 35 40 45 Leu Ser Leu Gln Arg Met Phe Asn Asn Cys Glu Val Val Leu Gly Asn 50 55 60 Leu Glu Ile Thr Tyr Val Gln Arg Asn Tyr Asp Leu Ser Phe Leu Lys 65 70 75 80 Thr Ile Gln Glu Val Ala Gly Tyr Val Leu Ile Ala Leu Asn Thr Val 85 90 95 Glu Arg Ile Pro Leu Glu Asn Leu Gln Ile Ile Arg Gly Asn Met Tyr 100 105 110 Tyr Glu Asn Ser Tyr Ala Leu Ala Val Leu Ser Asn Tyr Asp Ala Asn 115 120 125 Lys Thr Gly Leu Lys Glu Leu Pro Met Arg Asn Leu Gln Glu Ile Leu 130 135 140 His Gly Ala Val Arg Phe Ser Asn Asn Pro Ala Leu Cys Asn Val Glu 145 150 155 160 Ser Ile Gln Trp Arg Asp Ile Val Ser Ser Asp Phe Leu Ser Asn Met 165 170 175 Ser Met Asp Phe Gln Asn His Leu Gly Ser Cys Gln Lys Cys Asp Pro 180 185 190 Ser Cys Pro Asn Gly Ser Cys Trp Gly Ala Gly Glu Glu Asn Cys Gln 195 200 205 Lys Leu Thr Lys Ile Ile Cys Ala Gln Gln Cys Ser Gly Arg Cys Arg 210 215 220 Gly Lys Ser Pro Ser Asp Cys Cys His Asn Gln Cys Ala Ala Gly Cys 225 230 235 240 Thr Gly Pro Arg Glu Ser Asp Cys Leu Val Cys Arg Lys Phe Arg Asp 245 250 255 Glu Ala Thr Cys Lys Asp Thr Cys Pro Pro Leu Met Leu Tyr Asn Pro 260 265 270 Thr Thr Tyr Gln Met Asp Val Asn Pro Glu Gly Lys Tyr Ser Phe Gly 275 280 285 Ala Thr Cys Val Lys Lys Cys Pro Arg Asn Tyr Val Val Thr Asp His 290 295 300 Gly Ser Cys Val Arg Ala Cys Gly Ala Asp Ser Tyr Glu Met Glu Glu 305 310 315 320 Asp Gly Val Arg Lys Cys Lys Lys Cys Glu Gly Pro Cys Arg Lys Val 325 330 335 Cys Asn Gly Ile Gly Ile Gly Glu Phe Lys Asp Ser Leu Ser Ile Asn 340 345 350 Ala Thr Asn Ile Lys His Phe Lys Asn Cys Thr Ser Ile Ser Gly Asp 355 360 365 Leu His Ile Leu Pro Val Ala Phe Arg Gly Asp Ser Phe Thr His Thr 370 375 380 Pro Pro Leu Asp Pro Gln Glu Leu Asp Ile Leu Lys Thr Val Lys Glu 385 390 395 400 Ile Thr Gly Leu Ser 405 <![CDATA[<210> 4]]> <![CDATA[<211> 705]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人(Homo sapiens)]]> <![CDATA[<400> 4]]> Met Arg Pro Ser Gly Thr Ala Gly Ala Ala Leu Leu Ala Leu Leu Ala 1 5 10 15 Ala Leu Cys Pro Ala Ser Arg Ala Leu Glu Glu Lys Lys Val Cys Gln 20 25 30 Gly Thr Ser Asn Lys Leu Thr Gln Leu Gly Thr Phe Glu Asp His Phe 35 40 45 Leu Ser Leu Gln Arg Met Phe Asn Asn Cys Glu Val Val Leu Gly Asn 50 55 60 Leu Glu Ile Thr Tyr Val Gln Arg Asn Tyr Asp Leu Ser Phe Leu Lys 65 70 75 80 Thr Ile Gln Glu Val Ala Gly Tyr Val Leu Ile Ala Leu Asn Thr Val 85 90 95 Glu Arg Ile Pro Leu Glu Asn Leu Gln Ile Ile Arg Gly Asn Met Tyr 100 105 110 Tyr Glu Asn Ser Tyr Ala Leu Ala Val Leu Ser Asn Tyr Asp Ala Asn 115 120 125 Lys Thr Gly Leu Lys Glu Leu Pro Met Arg Asn Leu Gln Glu Ile Leu 130 135 140 His Gly Ala Val Arg Phe Ser Asn Asn Pro Ala Leu Cys Asn Val Glu 145 150 155 160 Ser Ile Gln Trp Arg Asp Ile Val Ser Ser Asp Phe Leu Ser Asn Met 165 170 175 Ser Met Asp Phe Gln Asn His Leu Gly Ser Cys Gln Lys Cys Asp Pro 180 185 190 Ser Cys Pro Asn Gly Ser Cys Trp Gly Ala Gly Glu Glu Asn Cys Gln 195 200 205 Lys Leu Thr Lys Ile Ile Cys Ala Gln Gln Cys Ser Gly Arg Cys Arg 210 215 220 Gly Lys Ser Pro Ser Asp Cys Cys His Asn Gln Cys Ala Ala Gly Cys 225 230 235 240 Thr Gly Pro Arg Glu Ser Asp Cys Leu Val Cys Arg Lys Phe Arg Asp 245 250 255 Glu Ala Thr Cys Lys Asp Thr Cys Pro Pro Leu Met Leu Tyr Asn Pro 260 265 270 Thr Thr Tyr Gln Met Asp Val Asn Pro Glu Gly Lys Tyr Ser Phe Gly 275 280 285 Ala Thr Cys Val Lys Lys Cys Pro Arg Asn Tyr Val Val Thr Asp His 290 295 300 Gly Ser Cys Val Arg Ala Cys Gly Ala Asp Ser Tyr Glu Met Glu Glu 305 310 315 320 Asp Gly Val Arg Lys Cys Lys Lys Cys Glu Gly Pro Cys Arg Lys Val 325 330 335 Cys Asn Gly Ile Gly Ile Gly Glu Phe Lys Asp Ser Leu Ser Ile Asn 340 345 350 Ala Thr Asn Ile Lys His Phe Lys Asn Cys Thr Ser Ile Ser Gly Asp 355 360 365 Leu His Ile Leu Pro Val Ala Phe Arg Gly Asp Ser Phe Thr His Thr 370 375 380 Pro Pro Leu Asp Pro Gln Glu Leu Asp Ile Leu Lys Thr Val Lys Glu 385 390 395 400 Ile Thr Gly Phe Leu Leu Ile Gln Ala Trp Pro Glu Asn Arg Thr Asp 405 410 415 Leu His Ala Phe Glu Asn Leu Glu Ile Ile Arg Gly Arg Thr Lys Gln 420 425 430 His Gly Gln Phe Ser Leu Ala Val Val Ser Leu Asn Ile Thr Ser Leu 435 440 445 Gly Leu Arg Ser Leu Lys Glu Ile Ser Asp Gly Asp Val Ile Ile Ser 450 455 460 Gly Asn Lys Asn Leu Cys Tyr Ala Asn Thr Ile Asn Trp Lys Lys Leu 465 470 475 480 Phe Gly Thr Ser Gly Gln Lys Thr Lys Ile Ile Ser Asn Arg Gly Glu 485 490 495 Asn Ser Cys Lys Ala Thr Gly Gln Val Cys His Ala Leu Cys Ser Pro 500 505 510 Glu Gly Cys Trp Gly Pro Glu Pro Arg Asp Cys Val Ser Cys Arg Asn 515 520 525 Val Ser Arg Gly Arg Glu Cys Val Asp Lys Cys Asn Leu Leu Glu Gly 530 535 540 Glu Pro Arg Glu Phe Val Glu Asn Ser Glu Cys Ile Gln Cys His Pro 545 550 555 560 Glu Cys Leu Pro Gln Ala Met Asn Ile Thr Cys Thr Gly Arg Gly Pro 565 570 575 Asp Asn Cys Ile Gln Cys Ala His Tyr Ile Asp Gly Pro His Cys Val 580 585 590 Lys Thr Cys Pro Ala Gly Val Met Gly Glu Asn Asn Thr Leu Val Trp 595 600 605 Lys Tyr Ala Asp Ala Gly His Val Cys His Leu Cys His Pro Asn Cys 610 615 620 Thr Tyr Gly Pro Gly Asn Glu Ser Leu Lys Ala Met Leu Phe Cys Leu 625 630 635 640 Phe Lys Leu Ser Ser Cys Asn Gln Ser Asn Asp Gly Ser Val Ser His 645 650 655 Gln Ser Gly Ser Pro Ala Ala Gln Glu Ser Cys Leu Gly Trp Ile Pro 660 665 670 Ser Leu Leu Pro Ser Glu Phe Gln Leu Gly Trp Gly Gly Cys Ser His 675 680 685 Leu His Ala Trp Pro Ser Ala Ser Val Ile Ile Thr Ala Ser Ser Cys 690 695 700 His 705 <![CDATA[<210> 5]]> <![CDATA[<211> 1091]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人(Homo sapiens)]]> <![CDATA[<400> 5]]> Met Arg Pro Ser Gly Thr Ala Gly Ala Ala Leu Leu Ala Leu Leu Ala 1 5 10 15 Ala Leu Cys Pro Ala Ser Arg Ala Leu Glu Glu Lys Lys Val Cys Gln 20 25 30 Gly Thr Ser Asn Lys Leu Thr Gln Leu Gly Thr Phe Glu Asp His Phe 35 40 45 Leu Ser Leu Gln Arg Met Phe Asn Asn Cys Glu Val Val Leu Gly Asn 50 55 60 Leu Glu Ile Thr Tyr Val Gln Arg Asn Tyr Asp Leu Ser Phe Leu Lys 65 70 75 80 Thr Ile Gln Glu Val Ala Gly Tyr Val Leu Ile Ala Leu Asn Thr Val 85 90 95 Glu Arg Ile Pro Leu Glu Asn Leu Gln Ile Ile Arg Gly Asn Met Tyr 100 105 110 Tyr Glu Asn Ser Tyr Ala Leu Ala Val Leu Ser Asn Tyr Asp Ala Asn 115 120 125 Lys Thr Gly Leu Lys Glu Leu Pro Met Arg Asn Leu Gln Gly Gln Lys 130 135 140 Cys Asp Pro Ser Cys Pro Asn Gly Ser Cys Trp Gly Ala Gly Glu Glu 145 150 155 160 Asn Cys Gln Lys Leu Thr Lys Ile Ile Cys Ala Gln Gln Cys Ser Gly 165 170 175 Arg Cys Arg Gly Lys Ser Pro Ser Asp Cys Cys His Asn Gln Cys Ala 180 185 190 Ala Gly Cys Thr Gly Pro Arg Glu Ser Asp Cys Leu Val Cys Arg Lys 195 200 205 Phe Arg Asp Glu Ala Thr Cys Lys Asp Thr Cys Pro Pro Leu Met Leu 210 215 220 Tyr Asn Pro Thr Thr Tyr Gln Met Asp Val Asn Pro Glu Gly Lys Tyr 225 230 235 240 Ser Phe Gly Ala Thr Cys Val Lys Lys Cys Pro Arg Asn Tyr Val Val 245 250 255 Thr Asp His Gly Ser Cys Val Arg Ala Cys Gly Ala Asp Ser Tyr Glu 260 265 270 Met Glu Glu Asp Gly Val Arg Lys Cys Lys Lys Cys Glu Gly Pro Cys 275 280 285 Arg Lys Val Cys Asn Gly Ile Gly Ile Gly Glu Phe Lys Asp Ser Leu 290 295 300 Ser Ile Asn Ala Thr Asn Ile Lys His Phe Lys Asn Cys Thr Ser Ile 305 310 315 320 Ser Gly Asp Leu His Ile Leu Pro Val Ala Phe Arg Gly Asp Ser Phe 325 330 335 Thr His Thr Pro Pro Leu Asp Pro Gln Glu Leu Asp Ile Leu Lys Thr 340 345 350 Val Lys Glu Ile Thr Gly Phe Leu Leu Ile Gln Ala Trp Pro Glu Asn 355 360 365 Arg Thr Asp Leu His Ala Phe Glu Asn Leu Glu Ile Ile Arg Gly Arg 370 375 380 Thr Lys Gln His Gly Gln Phe Ser Leu Ala Val Val Ser Leu Asn Ile 385 390 395 400 Thr Ser Leu Gly Leu Arg Ser Leu Lys Glu Ile Ser Asp Gly Asp Val 405 410 415 Ile Ile Ser Gly Asn Lys Asn Leu Cys Tyr Ala Asn Thr Ile Asn Trp 420 425 430 Lys Lys Leu Phe Gly Thr Ser Gly Gln Lys Thr Lys Ile Ile Ser Asn 435 440 445 Arg Gly Glu Asn Ser Cys Lys Ala Thr Gly Gln Val Cys His Ala Leu 450 455 460 Cys Ser Pro Glu Gly Cys Trp Gly Pro Glu Pro Arg Asp Cys Val Ser 465 470 475 480 Cys Arg Asn Val Ser Arg Gly Arg Glu Cys Val Asp Lys Cys Asn Leu 485 490 495 Leu Glu Gly Glu Pro Arg Glu Phe Val Glu Asn Ser Glu Cys Ile Gln 500 505 510 Cys His Pro Glu Cys Leu Pro Gln Ala Met Asn Ile Thr Cys Thr Gly 515 520 525 Arg Gly Pro Asp Asn Cys Ile Gln Cys Ala His Tyr Ile Asp Gly Pro 530 535 540 His Cys Val Lys Thr Cys Pro Ala Gly Val Met Gly Glu Asn Asn Thr 545 550 555 560 Leu Val Trp Lys Tyr Ala Asp Ala Gly His Val Cys His Leu Cys His 565 570 575 Pro Asn Cys Thr Tyr Gly Cys Thr Gly Pro Gly Leu Glu Gly Cys Pro 580 585 590 Thr Asn Gly Pro Lys Ile Pro Ser Ile Ala Thr Gly Met Val Gly Ala 595 600 605 Leu Leu Leu Leu Leu Val Val Ala Leu Gly Ile Gly Leu Phe Met Arg 610 615 620 Arg Arg His Ile Val Arg Lys Arg Thr Leu Arg Arg Leu Leu Gln Glu 625 630 635 640 Arg Glu Leu Val Glu Pro Leu Thr Pro Ser Gly Glu Ala Pro Asn Gln 645 650 655 Ala Leu Leu Arg Ile Leu Lys Glu Thr Glu Phe Lys Lys Ile Lys Val 660 665 670 Leu Gly Ser Gly Ala Phe Gly Thr Val Tyr Lys Gly Leu Trp Ile Pro 675 680 685 Glu Gly Glu Lys Val Lys Ile Pro Val Ala Ile Lys Glu Leu Arg Glu 690 695 700 Ala Thr Ser Pro Lys Ala Asn Lys Glu Ile Leu Asp Glu Ala Tyr Val 705 710 715 720 Met Ala Ser Val Asp Asn Pro His Val Cys Arg Leu Leu Gly Ile Cys 725 730 735 Leu Thr Ser Thr Val Gln Leu Ile Thr Gln Leu Met Pro Phe Gly Cys 740 745 750 Leu Leu Asp Tyr Val Arg Glu His Lys Asp Asn Ile Gly Ser Gln Tyr 755 760 765 Leu Leu Asn Trp Cys Val Gln Ile Ala Lys Gly Met Asn Tyr Leu Glu 770 775 780 Asp Arg Arg Leu Val His Arg Asp Leu Ala Ala Arg Asn Val Leu Val 785 790 795 800 Lys Thr Pro Gln His Val Lys Ile Thr Asp Phe Gly Leu Ala Lys Leu 805 810 815 Leu Gly Ala Glu Glu Lys Glu Tyr His Ala Glu Gly Gly Lys Val Pro 820 825 830 Ile Lys Trp Met Ala Leu Glu Ser Ile Leu His Arg Ile Tyr Thr His 835 840 845 Gln Ser Asp Val Trp Ser Tyr Gly Val Thr Val Trp Glu Leu Met Thr 850 855 860 Phe Gly Ser Lys Pro Tyr Asp Gly Ile Pro Ala Ser Glu Ile Ser Ser 865 870 875 880 Ile Leu Glu Lys Gly Glu Arg Leu Pro Gln Pro Pro Ile Cys Thr Ile 885 890 895 Asp Val Tyr Met Ile Met Val Lys Cys Trp Met Ile Asp Ala Asp Ser 900 905 910 Arg Pro Lys Phe Arg Glu Leu Ile Ile Glu Phe Ser Lys Met Ala Arg 915 920 925 Asp Pro Gln Arg Tyr Leu Val Ile Gln Gly Asp Glu Arg Met His Leu 930 935 940 Pro Ser Pro Thr Asp Ser Asn Phe Tyr Arg Ala Leu Met Asp Glu Glu 945 950 955 960 Asp Met Asp Asp Val Val Asp Ala Asp Glu Tyr Leu Ile Pro Gln Gln 965 970 975 Gly Phe Phe Ser Ser Pro Ser Thr Ser Arg Thr Pro Leu Leu Ser Ser 980 985 990 Leu Ser Ala Thr Ser Asn Asn Ser Thr Val Ala Cys Ile Asp Arg Asn 995 1000 1005 Gly Leu Gln Ser Cys Pro Ile Lys Glu Asp Ser Phe Leu Gln Arg 1010 1015 1020 Tyr Ser Ser Asp Pro Thr Gly Ala Leu Thr Glu Asp Ser Ile Asp 1025 1030 1035 Asp Thr Phe Leu Pro Val Pro Gly Glu Trp Leu Val Trp Lys Gln 1040 1045 1050 Ser Cys Ser Ser Thr Ser Ser Thr His Ser Ala Ala Ala Ser Leu 1055 1060 1065 Gln Cys Pro Ser Gln Val Leu Pro Pro Ala Ser Pro Glu Gly Glu 1070 1075 1080 Thr Val Ala Asp Leu Gln Thr Gln 1085 1090 <![CDATA[<210> 6]]> <![CDATA[<211> 1136]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人(Homo sapiens)]]> <![CDATA[<400> 6]]> Met Arg Pro Ser Gly Thr Ala Gly Ala Ala Leu Leu Ala Leu Leu Ala 1 5 10 15 Ala Leu Cys Pro Ala Ser Arg Ala Leu Glu Glu Lys Lys Val Cys Gln 20 25 30 Gly Thr Ser Asn Lys Leu Thr Gln Leu Gly Thr Phe Glu Asp His Phe 35 40 45 Leu Ser Leu Gln Arg Met Phe Asn Asn Cys Glu Val Val Leu Gly Asn 50 55 60 Leu Glu Ile Thr Tyr Val Gln Arg Asn Tyr Asp Leu Ser Phe Leu Lys 65 70 75 80 Thr Ile Gln Glu Val Ala Gly Tyr Val Leu Ile Ala Leu Asn Thr Val 85 90 95 Glu Arg Ile Pro Leu Glu Asn Leu Gln Ile Ile Arg Gly Asn Met Tyr 100 105 110 Tyr Glu Asn Ser Tyr Ala Leu Ala Val Leu Ser Asn Tyr Asp Ala Asn 115 120 125 Lys Thr Gly Leu Lys Glu Leu Pro Met Arg Asn Leu Gln Glu Ile Leu 130 135 140 His Gly Ala Val Arg Phe Ser Asn Asn Pro Ala Leu Cys Asn Val Glu 145 150 155 160 Ser Ile Gln Trp Arg Asp Ile Val Ser Ser Asp Phe Leu Ser Asn Met 165 170 175 Ser Met Asp Phe Gln Asn His Leu Gly Ser Cys Gln Lys Cys Asp Pro 180 185 190 Ser Cys Pro Asn Gly Ser Cys Trp Gly Ala Gly Glu Glu Asn Cys Gln 195 200 205 Lys Leu Thr Lys Ile Ile Cys Ala Gln Gln Cys Ser Gly Arg Cys Arg 210 215 220 Gly Lys Ser Pro Ser Asp Cys Cys His Asn Gln Cys Ala Ala Gly Cys 225 230 235 240 Thr Gly Pro Arg Glu Ser Asp Cys Leu Val Cys Arg Lys Phe Arg Asp 245 250 255 Glu Ala Thr Cys Lys Asp Thr Cys Pro Pro Leu Met Leu Tyr Asn Pro 260 265 270 Thr Thr Tyr Gln Met Asp Val Asn Pro Glu Gly Lys Tyr Ser Phe Gly 275 280 285 Ala Thr Cys Val Lys Lys Cys Pro Arg Asn Tyr Val Val Thr Asp His 290 295 300 Gly Ser Cys Val Arg Ala Cys Gly Ala Asp Ser Tyr Glu Met Glu Glu 305 310 315 320 Asp Gly Val Arg Lys Cys Lys Lys Cys Glu Gly Pro Cys Arg Lys Val 325 330 335 Cys Asn Gly Ile Gly Ile Gly Glu Phe Lys Asp Ser Leu Ser Ile Asn 340 345 350 Ala Thr Asn Ile Lys His Phe Lys Asn Cys Thr Ser Ile Ser Gly Asp 355 360 365 Leu His Ile Leu Pro Val Ala Phe Arg Gly Asp Ser Phe Thr His Thr 370 375 380 Pro Pro Leu Asp Pro Gln Glu Leu Asp Ile Leu Lys Thr Val Lys Glu 385 390 395 400 Ile Thr Gly Phe Leu Leu Ile Gln Ala Trp Pro Glu Asn Arg Thr Asp 405 410 415 Leu His Ala Phe Glu Asn Leu Glu Ile Ile Arg Gly Arg Thr Lys Gln 420 425 430 His Gly Gln Phe Ser Leu Ala Val Val Ser Leu Asn Ile Thr Ser Leu 435 440 445 Gly Leu Arg Ser Leu Lys Glu Ile Ser Asp Gly Asp Val Ile Ile Ser 450 455 460 Gly Asn Lys Asn Leu Cys Tyr Ala Asn Thr Ile Asn Trp Lys Lys Leu 465 470 475 480 Phe Gly Thr Ser Gly Gln Lys Thr Lys Ile Ile Ser Asn Arg Gly Glu 485 490 495 Asn Ser Cys Lys Ala Thr Gly Gln Val Cys His Ala Leu Cys Ser Pro 500 505 510 Glu Gly Cys Trp Gly Pro Glu Pro Arg Asp Cys Val Ser Cys Arg Asn 515 520 525 Val Ser Arg Gly Arg Glu Cys Val Asp Lys Cys Asn Leu Leu Glu Gly 530 535 540 Glu Pro Arg Glu Phe Val Glu Asn Ser Glu Cys Ile Gln Cys His Pro 545 550 555 560 Glu Cys Leu Pro Gln Ala Met Asn Ile Thr Cys Thr Gly Arg Gly Pro 565 570 575 Asp Asn Cys Ile Gln Cys Ala His Tyr Ile Asp Gly Pro His Cys Val 580 585 590 Lys Thr Cys Pro Ala Gly Val Met Gly Glu Asn Asn Thr Leu Val Trp 595 600 605 Lys Tyr Ala Asp Ala Gly His Val Cys His Leu Cys His Pro Asn Cys 610 615 620 Thr Tyr Gly Cys Thr Gly Pro Gly Leu Glu Gly Cys Pro Thr Asn Gly 625 630 635 640 Pro Lys Ile Pro Ser Ile Ala Thr Gly Met Val Gly Ala Leu Leu Leu 645 650 655 Leu Leu Val Val Ala Leu Gly Ile Gly Leu Phe Met Arg Arg Arg His 660 665 670 Ile Val Arg Lys Arg Thr Leu Arg Arg Leu Leu Gln Glu Arg Glu Leu 675 680 685 Val Glu Pro Leu Thr Pro Ser Gly Glu Ala Pro Asn Gln Ala Leu Leu 690 695 700 Arg Ile Leu Lys Glu Thr Glu Phe Lys Lys Ile Lys Val Leu Gly Ser 705 710 715 720 Gly Ala Phe Gly Thr Val Tyr Lys Gly Leu Trp Ile Pro Glu Gly Glu 725 730 735 Lys Val Lys Ile Pro Val Ala Ile Lys Glu Leu Arg Glu Ala Thr Ser 740 745 750 Pro Lys Ala Asn Lys Glu Ile Leu Asp Glu Ala Tyr Val Met Ala Ser 755 760 765 Val Asp Asn Pro His Val Cys Arg Leu Leu Gly Ile Cys Leu Thr Ser 770 775 780 Thr Val Gln Leu Ile Thr Gln Leu Met Pro Phe Gly Cys Leu Leu Asp 785 790 795 800 Tyr Val Arg Glu His Lys Asp Asn Ile Gly Ser Gln Tyr Leu Leu Asn 805 810 815 Trp Cys Val Gln Ile Ala Lys Gly Met Asn Tyr Leu Glu Asp Arg Arg 820 825 830 Leu Val His Arg Asp Leu Ala Ala Arg Asn Val Leu Val Lys Thr Pro 835 840 845 Gln His Val Lys Ile Thr Asp Phe Gly Leu Ala Lys Leu Leu Gly Ala 850 855 860 Glu Glu Lys Glu Tyr His Ala Glu Gly Gly Lys Val Pro Ile Lys Trp 865 870 875 880 Met Ala Leu Glu Ser Ile Leu His Arg Ile Tyr Thr His Gln Ser Asp 885 890 895 Val Trp Ser Tyr Gly Val Thr Val Trp Glu Leu Met Thr Phe Gly Ser 900 905 910 Lys Pro Tyr Asp Gly Ile Pro Ala Ser Glu Ile Ser Ser Ile Leu Glu 915 920 925 Lys Gly Glu Arg Leu Pro Gln Pro Pro Ile Cys Thr Ile Asp Val Tyr 930 935 940 Met Ile Met Val Lys Cys Trp Met Ile Asp Ala Asp Ser Arg Pro Lys 945 950 955 960 Phe Arg Glu Leu Ile Ile Glu Phe Ser Lys Met Ala Arg Asp Pro Gln 965 970 975 Arg Tyr Leu Val Ile Gln Gly Asp Glu Arg Met His Leu Pro Ser Pro 980 985 990 Thr Asp Ser Asn Phe Tyr Arg Ala Leu Met Asp Glu Glu Asp Met Asp 995 1000 1005 Asp Val Val Asp Ala Asp Glu Tyr Leu Ile Pro Gln Gln Gly Phe 1010 1015 1020 Phe Ser Ser Pro Ser Thr Ser Arg Thr Pro Leu Leu Ser Ser Leu 1025 1030 1035 Ser Ala Thr Ser Asn Asn Ser Thr Val Ala Cys Ile Asp Arg Asn 1040 1045 1050 Gly Leu Gln Ser Cys Pro Ile Lys Glu Asp Ser Phe Leu Gln Arg 1055 1060 1065 Tyr Ser Ser Asp Pro Thr Gly Ala Leu Thr Glu Asp Ser Ile Asp 1070 1075 1080 Asp Thr Phe Leu Pro Val Pro Gly Glu Trp Leu Val Trp Lys Gln 1085 1090 1095 Ser Cys Ser Ser Thr Ser Ser Thr His Ser Ala Ala Ala Ser Leu 1100 1105 1110 Gln Cys Pro Ser Gln Val Leu Pro Pro Ala Ser Pro Glu Gly Glu 1115 1120 1125 Thr Val Ala Asp Leu Gln Thr Gln 1130 1135 <![CDATA[<210> 7]]> <![CDATA[<211> 1157]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人(Homo sapiens)]]> <![CDATA[<400> 7]]> Met Phe Asn Asn Cys Glu Val Val Leu Gly Asn Leu Glu Ile Thr Tyr 1 5 10 15 Val Gln Arg Asn Tyr Asp Leu Ser Phe Leu Lys Thr Ile Gln Glu Val 20 25 30 Ala Gly Tyr Val Leu Ile Ala Leu Asn Thr Val Glu Arg Ile Pro Leu 35 40 45 Glu Asn Leu Gln Ile Ile Arg Gly Asn Met Tyr Tyr Glu Asn Ser Tyr 50 55 60 Ala Leu Ala Val Leu Ser Asn Tyr Asp Ala Asn Lys Thr Gly Leu Lys 65 70 75 80 Glu Leu Pro Met Arg Asn Leu Gln Glu Ile Leu His Gly Ala Val Arg 85 90 95 Phe Ser Asn Asn Pro Ala Leu Cys Asn Val Glu Ser Ile Gln Trp Arg 100 105 110 Asp Ile Val Ser Ser Asp Phe Leu Ser Asn Met Ser Met Asp Phe Gln 115 120 125 Asn His Leu Gly Ser Cys Gln Lys Cys Asp Pro Ser Cys Pro Asn Gly 130 135 140 Ser Cys Trp Gly Ala Gly Glu Glu Asn Cys Gln Lys Leu Thr Lys Ile 145 150 155 160 Ile Cys Ala Gln Gln Cys Ser Gly Arg Cys Arg Gly Lys Ser Pro Ser 165 170 175 Asp Cys Cys His Asn Gln Cys Ala Ala Gly Cys Thr Gly Pro Arg Glu 180 185 190 Ser Asp Cys Leu Val Cys Arg Lys Phe Arg Asp Glu Ala Thr Cys Lys 195 200 205 Asp Thr Cys Pro Pro Leu Met Leu Tyr Asn Pro Thr Thr Tyr Gln Met 210 215 220 Asp Val Asn Pro Glu Gly Lys Tyr Ser Phe Gly Ala Thr Cys Val Lys 225 230 235 240 Lys Cys Pro Arg Asn Tyr Val Val Thr Asp His Gly Ser Cys Val Arg 245 250 255 Ala Cys Gly Ala Asp Ser Tyr Glu Met Glu Glu Asp Gly Val Arg Lys 260 265 270 Cys Lys Lys Cys Glu Gly Pro Cys Arg Lys Val Cys Asn Gly Ile Gly 275 280 285 Ile Gly Glu Phe Lys Asp Ser Leu Ser Ile Asn Ala Thr Asn Ile Lys 290 295 300 His Phe Lys Asn Cys Thr Ser Ile Ser Gly Asp Leu His Ile Leu Pro 305 310 315 320 Val Ala Phe Arg Gly Asp Ser Phe Thr His Thr Pro Pro Leu Asp Pro 325 330 335 Gln Glu Leu Asp Ile Leu Lys Thr Val Lys Glu Ile Thr Gly Phe Leu 340 345 350 Leu Ile Gln Ala Trp Pro Glu Asn Arg Thr Asp Leu His Ala Phe Glu 355 360 365 Asn Leu Glu Ile Ile Arg Gly Arg Thr Lys Gln His Gly Gln Phe Ser 370 375 380 Leu Ala Val Val Ser Leu Asn Ile Thr Ser Leu Gly Leu Arg Ser Leu 385 390 395 400 Lys Glu Ile Ser Asp Gly Asp Val Ile Ile Ser Gly Asn Lys Asn Leu 405 410 415 Cys Tyr Ala Asn Thr Ile Asn Trp Lys Lys Leu Phe Gly Thr Ser Gly 420 425 430 Gln Lys Thr Lys Ile Ile Ser Asn Arg Gly Glu Asn Ser Cys Lys Ala 435 440 445 Thr Gly Gln Val Cys His Ala Leu Cys Ser Pro Glu Gly Cys Trp Gly 450 455 460 Pro Glu Pro Arg Asp Cys Val Ser Cys Arg Asn Val Ser Arg Gly Arg 465 470 475 480 Glu Cys Val Asp Lys Cys Asn Leu Leu Glu Gly Glu Pro Arg Glu Phe 485 490 495 Val Glu Asn Ser Glu Cys Ile Gln Cys His Pro Glu Cys Leu Pro Gln 500 505 510 Ala Met Asn Ile Thr Cys Thr Gly Arg Gly Pro Asp Asn Cys Ile Gln 515 520 525 Cys Ala His Tyr Ile Asp Gly Pro His Cys Val Lys Thr Cys Pro Ala 530 535 540 Gly Val Met Gly Glu Asn Asn Thr Leu Val Trp Lys Tyr Ala Asp Ala 545 550 555 560 Gly His Val Cys His Leu Cys His Pro Asn Cys Thr Tyr Gly Cys Thr 565 570 575 Gly Pro Gly Leu Glu Gly Cys Pro Thr Asn Gly Pro Lys Ile Pro Ser 580 585 590 Ile Ala Thr Gly Met Val Gly Ala Leu Leu Leu Leu Leu Val Val Ala 595 600 605 Leu Gly Ile Gly Leu Phe Met Arg Arg Arg His Ile Val Arg Lys Arg 610 615 620 Thr Leu Arg Arg Leu Leu Gln Glu Arg Glu Leu Val Glu Pro Leu Thr 625 630 635 640 Pro Ser Gly Glu Ala Pro Asn Gln Ala Leu Leu Arg Ile Leu Lys Glu 645 650 655 Thr Glu Phe Lys Lys Ile Lys Val Leu Gly Ser Gly Ala Phe Gly Thr 660 665 670 Val Tyr Lys Gly Leu Trp Ile Pro Glu Gly Glu Lys Val Lys Ile Pro 675 680 685 Val Ala Ile Lys Glu Leu Arg Glu Ala Thr Ser Pro Lys Ala Asn Lys 690 695 700 Glu Ile Leu Asp Glu Ala Tyr Val Met Ala Ser Val Asp Asn Pro His 705 710 715 720 Val Cys Arg Leu Leu Gly Ile Cys Leu Thr Ser Thr Val Gln Leu Ile 725 730 735 Thr Gln Leu Met Pro Phe Gly Cys Leu Leu Asp Tyr Val Arg Glu His 740 745 750 Lys Asp Asn Ile Gly Ser Gln Tyr Leu Leu Asn Trp Cys Val Gln Ile 755 760 765 Ala Lys Gly Met Asn Tyr Leu Glu Asp Arg Arg Leu Val His Arg Asp 770 775 780 Leu Ala Ala Arg Asn Val Leu Val Lys Thr Pro Gln His Val Lys Ile 785 790 795 800 Thr Asp Phe Gly Leu Ala Lys Leu Leu Gly Ala Glu Glu Lys Glu Tyr 805 810 815 His Ala Glu Gly Gly Lys Val Pro Ile Lys Trp Met Ala Leu Glu Ser 820 825 830 Ile Leu His Arg Ile Tyr Thr His Gln Ser Asp Val Trp Ser Tyr Gly 835 840 845 Val Thr Val Trp Glu Leu Met Thr Phe Gly Ser Lys Pro Tyr Asp Gly 850 855 860 Ile Pro Ala Ser Glu Ile Ser Ser Ile Leu Glu Lys Gly Glu Arg Leu 865 870 875 880 Pro Gln Pro Pro Ile Cys Thr Ile Asp Val Tyr Met Ile Met Val Lys 885 890 895 Cys Trp Met Ile Asp Ala Asp Ser Arg Pro Lys Phe Arg Glu Leu Ile 900 905 910 Ile Glu Phe Ser Lys Met Ala Arg Asp Pro Gln Arg Tyr Leu Val Ile 915 920 925 Gln Gly Asp Glu Arg Met His Leu Pro Ser Pro Thr Asp Ser Asn Phe 930 935 940 Tyr Arg Ala Leu Met Asp Glu Glu Asp Met Asp Asp Val Val Asp Ala 945 950 955 960 Asp Glu Tyr Leu Ile Pro Gln Gln Gly Phe Phe Ser Ser Pro Ser Thr 965 970 975 Ser Arg Thr Pro Leu Leu Ser Ser Leu Ser Ala Thr Ser Asn Asn Ser 980 985 990 Thr Val Ala Cys Ile Asp Arg Asn Gly Leu Gln Ser Cys Pro Ile Lys 995 1000 1005 Glu Asp Ser Phe Leu Gln Arg Tyr Ser Ser Asp Pro Thr Gly Ala 1010 1015 1020 Leu Thr Glu Asp Ser Ile Asp Asp Thr Phe Leu Pro Val Pro Glu 1025 1030 1035 Tyr Ile Asn Gln Ser Val Pro Lys Arg Pro Ala Gly Ser Val Gln 1040 1045 1050 Asn Pro Val Tyr His Asn Gln Pro Leu Asn Pro Ala Pro Ser Arg 1055 1060 1065 Asp Pro His Tyr Gln Asp Pro His Ser Thr Ala Val Gly Asn Pro 1070 1075 1080 Glu Tyr Leu Asn Thr Val Gln Pro Thr Cys Val Asn Ser Thr Phe 1085 1090 1095 Asp Ser Pro Ala His Trp Ala Gln Lys Gly Ser His Gln Ile Ser 1100 1105 1110 Leu Asp Asn Pro Asp Tyr Gln Gln Asp Phe Phe Pro Lys Glu Ala 1115 1120 1125 Lys Pro Asn Gly Ile Phe Lys Gly Ser Thr Ala Glu Asn Ala Glu 1130 1135 1140 Tyr Leu Arg Val Ala Pro Gln Ser Ser Glu Phe Ile Gly Ala 1145 1150 1155 <![CDATA[<210> 8]]> <![CDATA[<211> 943]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人(Homo sapiens)]]> <![CDATA[<400> 8]]> Met Arg Pro Ser Gly Thr Ala Gly Ala Ala Leu Leu Ala Leu Leu Ala 1 5 10 15 Ala Leu Cys Pro Ala Ser Arg Ala Leu Glu Glu Lys Lys Gly Asn Tyr 20 25 30 Val Val Thr Asp His Gly Ser Cys Val Arg Ala Cys Gly Ala Asp Ser 35 40 45 Tyr Glu Met Glu Glu Asp Gly Val Arg Lys Cys Lys Lys Cys Glu Gly 50 55 60 Pro Cys Arg Lys Val Cys Asn Gly Ile Gly Ile Gly Glu Phe Lys Asp 65 70 75 80 Ser Leu Ser Ile Asn Ala Thr Asn Ile Lys His Phe Lys Asn Cys Thr 85 90 95 Ser Ile Ser Gly Asp Leu His Ile Leu Pro Val Ala Phe Arg Gly Asp 100 105 110 Ser Phe Thr His Thr Pro Pro Leu Asp Pro Gln Glu Leu Asp Ile Leu 115 120 125 Lys Thr Val Lys Glu Ile Thr Gly Phe Leu Leu Ile Gln Ala Trp Pro 130 135 140 Glu Asn Arg Thr Asp Leu His Ala Phe Glu Asn Leu Glu Ile Ile Arg 145 150 155 160 Gly Arg Thr Lys Gln His Gly Gln Phe Ser Leu Ala Val Val Ser Leu 165 170 175 Asn Ile Thr Ser Leu Gly Leu Arg Ser Leu Lys Glu Ile Ser Asp Gly 180 185 190 Asp Val Ile Ile Ser Gly Asn Lys Asn Leu Cys Tyr Ala Asn Thr Ile 195 200 205 Asn Trp Lys Lys Leu Phe Gly Thr Ser Gly Gln Lys Thr Lys Ile Ile 210 215 220 Ser Asn Arg Gly Glu Asn Ser Cys Lys Ala Thr Gly Gln Val Cys His 225 230 235 240 Ala Leu Cys Ser Pro Glu Gly Cys Trp Gly Pro Glu Pro Arg Asp Cys 245 250 255 Val Ser Cys Arg Asn Val Ser Arg Gly Arg Glu Cys Val Asp Lys Cys 260 265 270 Asn Leu Leu Glu Gly Glu Pro Arg Glu Phe Val Glu Asn Ser Glu Cys 275 280 285 Ile Gln Cys His Pro Glu Cys Leu Pro Gln Ala Met Asn Ile Thr Cys 290 295 300 Thr Gly Arg Gly Pro Asp Asn Cys Ile Gln Cys Ala His Tyr Ile Asp 305 310 315 320 Gly Pro His Cys Val Lys Thr Cys Pro Ala Gly Val Met Gly Glu Asn 325 330 335 Asn Thr Leu Val Trp Lys Tyr Ala Asp Ala Gly His Val Cys His Leu 340 345 350 Cys His Pro Asn Cys Thr Tyr Gly Cys Thr Gly Pro Gly Leu Glu Gly 355 360 365 Cys Pro Thr Asn Gly Pro Lys Ile Pro Ser Ile Ala Thr Gly Met Val 370 375 380 Gly Ala Leu Leu Leu Leu Leu Val Val Ala Leu Gly Ile Gly Leu Phe 385 390 395 400 Met Arg Arg Arg His Ile Val Arg Lys Arg Thr Leu Arg Arg Leu Leu 405 410 415 Gln Glu Arg Glu Leu Val Glu Pro Leu Thr Pro Ser Gly Glu Ala Pro 420 425 430 Asn Gln Ala Leu Leu Arg Ile Leu Lys Glu Thr Glu Phe Lys Lys Ile 435 440 445 Lys Val Leu Gly Ser Gly Ala Phe Gly Thr Val Tyr Lys Gly Leu Trp 450 455 460 Ile Pro Glu Gly Glu Lys Val Lys Ile Pro Val Ala Ile Lys Glu Leu 465 470 475 480 Arg Glu Ala Thr Ser Pro Lys Ala Asn Lys Glu Ile Leu Asp Glu Ala 485 490 495 Tyr Val Met Ala Ser Val Asp Asn Pro His Val Cys Arg Leu Leu Gly 500 505 510 Ile Cys Leu Thr Ser Thr Val Gln Leu Ile Thr Gln Leu Met Pro Phe 515 520 525 Gly Cys Leu Leu Asp Tyr Val Arg Glu His Lys Asp Asn Ile Gly Ser 530 535 540 Gln Tyr Leu Leu Asn Trp Cys Val Gln Ile Ala Lys Gly Met Asn Tyr 545 550 555 560 Leu Glu Asp Arg Arg Leu Val His Arg Asp Leu Ala Ala Arg Asn Val 565 570 575 Leu Val Lys Thr Pro Gln His Val Lys Ile Thr Asp Phe Gly Leu Ala 580 585 590 Lys Leu Leu Gly Ala Glu Glu Lys Glu Tyr His Ala Glu Gly Gly Lys 595 600 605 Val Pro Ile Lys Trp Met Ala Leu Glu Ser Ile Leu His Arg Ile Tyr 610 615 620 Thr His Gln Ser Asp Val Trp Ser Tyr Gly Val Thr Val Trp Glu Leu 625 630 635 640 Met Thr Phe Gly Ser Lys Pro Tyr Asp Gly Ile Pro Ala Ser Glu Ile 645 650 655 Ser Ser Ile Leu Glu Lys Gly Glu Arg Leu Pro Gln Pro Pro Ile Cys 660 665 670 Thr Ile Asp Val Tyr Met Ile Met Val Lys Cys Trp Met Ile Asp Ala 675 680 685 Asp Ser Arg Pro Lys Phe Arg Glu Leu Ile Ile Glu Phe Ser Lys Met 690 695 700 Ala Arg Asp Pro Gln Arg Tyr Leu Val Ile Gln Gly Asp Glu Arg Met 705 710 715 720 His Leu Pro Ser Pro Thr Asp Ser Asn Phe Tyr Arg Ala Leu Met Asp 725 730 735 Glu Glu Asp Met Asp Asp Val Val Asp Ala Asp Glu Tyr Leu Ile Pro 740 745 750 Gln Gln Gly Phe Phe Ser Ser Pro Ser Thr Ser Arg Thr Pro Leu Leu 755 760 765 Ser Ser Leu Ser Ala Thr Ser Asn Asn Ser Thr Val Ala Cys Ile Asp 770 775 780 Arg Asn Gly Leu Gln Ser Cys Pro Ile Lys Glu Asp Ser Phe Leu Gln 785 790 795 800 Arg Tyr Ser Ser Asp Pro Thr Gly Ala Leu Thr Glu Asp Ser Ile Asp 805 810 815 Asp Thr Phe Leu Pro Val Pro Glu Tyr Ile Asn Gln Ser Val Pro Lys 820 825 830 Arg Pro Ala Gly Ser Val Gln Asn Pro Val Tyr His Asn Gln Pro Leu 835 840 845 Asn Pro Ala Pro Ser Arg Asp Pro His Tyr Gln Asp Pro His Ser Thr 850 855 860 Ala Val Gly Asn Pro Glu Tyr Leu Asn Thr Val Gln Pro Thr Cys Val 865 870 875 880 Asn Ser Thr Phe Asp Ser Pro Ala His Trp Ala Gln Lys Gly Ser His 885 890 895 Gln Ile Ser Leu Asp Asn Pro Asp Tyr Gln Gln Asp Phe Phe Pro Lys 900 905 910 Glu Ala Lys Pro Asn Gly Ile Phe Lys Gly Ser Thr Ala Glu Asn Ala 915 920 925 Glu Tyr Leu Arg Val Ala Pro Gln Ser Ser Glu Phe Ile Gly Ala 930 935 940 <![CDATA[<210> 9]]> <![CDATA[<211> 249]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CT-478 EGFR (VH-VL scFv格式)]]> <![CDATA[<400> 9]]> Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Trp Asp Asp Gly Ser Tyr Lys Tyr Tyr Gly Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Gly Ile Thr Met Val Arg Gly Val Met Lys Asp Tyr Phe 100 105 110 Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly 115 120 125 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Ala Ile 130 135 140 Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg 145 150 155 160 Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Ala Leu Val 165 170 175 Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Asp 180 185 190 Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Glu 195 200 205 Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp 210 215 220 Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Ser Tyr Pro Leu Thr Phe 225 230 235 240 Gly Gly Gly Thr Lys Val Glu Ile Lys 245 <![CDATA[<210> 10]]> <![CDATA[<211> 249]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CT-479 EGFR (VL-VH scFv格式)]]> <![CDATA[<400> 10]]> Ala Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Ala 20 25 30 Leu Val Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Glu Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Ser Tyr Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser 100 105 110 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gln Val Gln Leu 115 120 125 Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg Ser Leu Arg Leu 130 135 140 Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Tyr Gly Met His Trp 145 150 155 160 Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Val Ile Trp 165 170 175 Asp Asp Gly Ser Tyr Lys Tyr Tyr Gly Asp Ser Val Lys Gly Arg Phe 180 185 190 Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn 195 200 205 Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Gly 210 215 220 Ile Thr Met Val Arg Gly Val Met Lys Asp Tyr Phe Asp Tyr Trp Gly 225 230 235 240 Gln Gly Thr Leu Val Thr Val Ser Ser 245 <![CDATA[<210> 11]]> <![CDATA[<211> 247]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CT-480 EGFR (VH-VL scFv格式)]]> <![CDATA[<400> 11]]> Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu 1 5 10 15 Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Glu Tyr 20 25 30 Pro Ile His Trp Val Lys Gln Ala Pro Gly Lys Gly Phe Lys Trp Met 35 40 45 Gly Met Ile Tyr Thr Asp Ile Gly Lys Pro Thr Tyr Ala Glu Glu Phe 50 55 60 Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Leu Gln Ile Asn Asn Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys 85 90 95 Val Arg Asp Arg Tyr Asp Ser Leu Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Thr Leu Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 115 120 125 Gly Gly Gly Gly Ser Gly Gly Asp Val Val Met Thr Gln Thr Pro Leu 130 135 140 Ser Leu Pro Val Ser Leu Gly Asp Gln Ala Ser Ile Ser Cys Arg Ser 145 150 155 160 Ser Gln Ser Leu Val His Ser Asn Gly Asn Thr Tyr Leu His Trp Tyr 165 170 175 Leu Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile Tyr Lys Val Ser 180 185 190 Asn Arg Phe Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly 195 200 205 Thr Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Leu Gly 210 215 220 Val Tyr Phe Cys Ser Gln Ser Thr His Val Pro Trp Thr Phe Gly Gly 225 230 235 240 Gly Thr Lys Leu Glu Ile Lys 245 <![CDATA[<210> 12]]> <![CDATA[<211> 247]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CT-481 EGFR (VL-VH scFv格式)]]> <![CDATA[<400> 12]]> Asp Val Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly 1 5 10 15 Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser 20 25 30 Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Phe Cys Ser Gln Ser 85 90 95 Thr His Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 115 120 125 Gly Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly 130 135 140 Glu Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Glu 145 150 155 160 Tyr Pro Ile His Trp Val Lys Gln Ala Pro Gly Lys Gly Phe Lys Trp 165 170 175 Met Gly Met Ile Tyr Thr Asp Ile Gly Lys Pro Thr Tyr Ala Glu Glu 180 185 190 Phe Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala 195 200 205 Tyr Leu Gln Ile Asn Asn Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe 210 215 220 Cys Val Arg Asp Arg Tyr Asp Ser Leu Phe Asp Tyr Trp Gly Gln Gly 225 230 235 240 Thr Thr Leu Thr Val Ser Ser 245 <![CDATA[<210> 13]]> <![CDATA[<211> 249]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CT-482 EGFR (VH-VL scFv格式)]]> <![CDATA[<400> 13]]> Glu Met Gln Leu Val Glu Ser Gly Gly Gly Phe Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Ala Phe Ser His Tyr 20 25 30 Asp Met Ser Trp Val Arg Gln Thr Pro Lys Gln Arg Leu Glu Trp Val 35 40 45 Ala Tyr Ile Ala Ser Gly Gly Asp Ile Thr Tyr Tyr Ala Asp Thr Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Gln Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Ser Ser Leu Lys Ser Glu Asp Thr Ala Met Phe Tyr Cys 85 90 95 Ser Arg Ser Ser Tyr Gly Asn Asn Gly Asp Ala Leu Asp Phe Trp Gly 100 105 110 Gln Gly Thr Ser Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly 115 120 125 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Asp Val Val Met Thr Gln 130 135 140 Thr Pro Leu Ser Leu Pro Val Ser Leu Gly Asp Gln Ala Ser Ile Ser 145 150 155 160 Cys Arg Ser Ser Gln Ser Leu Val His Ser Asn Gly Asn Thr Tyr Leu 165 170 175 His Trp Tyr Leu Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile Tyr 180 185 190 Lys Val Ser Asn Arg Phe Ser Gly Val Pro Asp Arg Phe Ser Gly Ser 195 200 205 Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu 210 215 220 Asp Leu Gly Val Tyr Phe Cys Ser Gln Ser Thr His Val Leu Thr Phe 225 230 235 240 Gly Ser Gly Thr Lys Leu Glu Ile Lys 245 <![CDATA[<210> 14]]> <![CDATA[<211> 249]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CT-483 EGFR (VL-VH scFv格式)]]> <![CDATA[<400> 14]]> Asp Val Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly 1 5 10 15 Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser 20 25 30 Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Phe Cys Ser Gln Ser 85 90 95 Thr His Val Leu Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Gly 100 105 110 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 115 120 125 Glu Met Gln Leu Val Glu Ser Gly Gly Gly Phe Val Lys Pro Gly Gly 130 135 140 Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Ala Phe Ser His Tyr 145 150 155 160 Asp Met Ser Trp Val Arg Gln Thr Pro Lys Gln Arg Leu Glu Trp Val 165 170 175 Ala Tyr Ile Ala Ser Gly Gly Asp Ile Thr Tyr Tyr Ala Asp Thr Val 180 185 190 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Gln Asn Thr Leu Tyr 195 200 205 Leu Gln Met Ser Ser Leu Lys Ser Glu Asp Thr Ala Met Phe Tyr Cys 210 215 220 Ser Arg Ser Ser Tyr Gly Asn Asn Gly Asp Ala Leu Asp Phe Trp Gly 225 230 235 240 Gln Gly Thr Ser Val Thr Val Ser Ser 245 <![CDATA[<210> 15]]> <![CDATA[<211> 243]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CT-486 EGFR (VH-VL scFv格式)]]> <![CDATA[<400> 15]]> Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln 1 5 10 15 Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr 20 25 30 Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr 50 55 60 Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe 65 70 75 80 Lys Met Asn Ser Leu Gln Ser Asn Asp Thr Ala Ile Tyr Tyr Cys Ala 85 90 95 Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly 115 120 125 Ser Gly Gly Gly Gly Ser Gly Gly Asp Ile Leu Leu Thr Gln Ser Pro 130 135 140 Val Ile Leu Ser Val Ser Pro Gly Glu Arg Val Ser Phe Ser Cys Arg 145 150 155 160 Ala Ser Gln Ser Ile Gly Thr Asn Ile His Trp Tyr Gln Gln Arg Thr 165 170 175 Asn Gly Ser Pro Arg Leu Leu Ile Lys Tyr Ala Ser Glu Ser Ile Ser 180 185 190 Gly Ile Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 195 200 205 Leu Ser Ile Asn Ser Val Glu Ser Glu Asp Ile Ala Asp Tyr Tyr Cys 210 215 220 Gln Gln Asn Asn Asn Trp Pro Thr Thr Phe Gly Ala Gly Thr Lys Leu 225 230 235 240 Glu Leu Lys <![CDATA[<210> 16]]> <![CDATA[<211> 244]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CT-487 EGFR (VH-VL scFv格式)]]> <![CDATA[<400> 16]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser His 20 25 30 Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Glu Phe Asn Pro Ser Asn Gly Arg Thr Asn Tyr Asn Glu Lys Phe 50 55 60 Lys Ser Lys Ala Thr Met Thr Val Asp Thr Ser Thr Asn Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Ser Arg Asp Tyr Asp Tyr Asp Gly Arg Tyr Phe Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly 115 120 125 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Asp Ile Gln Met Thr Gln 130 135 140 Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr 145 150 155 160 Cys Ser Ala Ser Ser Ser Val Thr Tyr Met Tyr Trp Tyr Gln Gln Lys 165 170 175 Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Asp Thr Ser Asn Leu Ala 180 185 190 Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr 195 200 205 Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Tyr 210 215 220 Cys Gln Gln Trp Ser Ser His Ile Phe Thr Phe Gly Gln Gly Thr Lys 225 230 235 240 Val Glu Ile Lys <![CDATA[<210> 17]]> <![CDATA[<211> 243]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CT-488 EGFR (VH-VL scFv格式)]]> <![CDATA[<400> 17]]> Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Val Ser Ser Gly 20 25 30 Asp Tyr Tyr Trp Thr Trp Ile Arg Gln Ser Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly His Ile Tyr Tyr Ser Gly Asn Thr Asn Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Leu Thr Ile Ser Ile Asp Thr Ser Lys Thr Gln Phe 65 70 75 80 Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Ile Tyr Tyr 85 90 95 Cys Val Arg Asp Arg Val Thr Gly Ala Phe Asp Ile Trp Gly Gln Gly 100 105 110 Thr Met Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 115 120 125 Ser Gly Gly Gly Gly Ser Gly Gly Asp Ile Gln Met Thr Gln Ser Pro 130 135 140 Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Gln 145 150 155 160 Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro 165 170 175 Gly Lys Ala Pro Lys Leu Leu Ile Tyr Asp Ala Ser Asn Leu Glu Thr 180 185 190 Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 195 200 205 Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr Phe Cys 210 215 220 Gln His Phe Asp His Leu Pro Leu Ala Phe Gly Gly Gly Thr Lys Val 225 230 235 240 Glu Ile Lys <![CDATA[<210> 18]]> <![CDATA[<211> 245]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CT-489 EGFR scFv]]> <![CDATA[<400> 18]]> Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly 20 25 30 Asp Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Asp Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Val Thr Met Ser Val Asp Thr Ser Lys Asn Gln Phe 65 70 75 80 Ser Leu Lys Val Asn Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Val Ser Ile Phe Gly Val Gly Thr Phe Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly 115 120 125 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Glu Ile Val Met Thr Gln 130 135 140 Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser 145 150 155 160 Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr Leu Ala Trp Tyr Gln Gln 165 170 175 Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Asp Ala Ser Asn Arg 180 185 190 Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp 195 200 205 Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr 210 215 220 Tyr Cys His Gln Tyr Gly Ser Thr Pro Leu Thr Phe Gly Gly Gly Thr 225 230 235 240 Lys Ala Glu Ile Lys 245 <![CDATA[<210> 19]]> <![CDATA[<211> 125]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> EGFR VH CT478、CT479]]> <![CDATA[<400> 19]]> Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Trp Asp Asp Gly Ser Tyr Lys Tyr Tyr Gly Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Gly Ile Thr Met Val Arg Gly Val Met Lys Asp Tyr Phe 100 105 110 Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 125 <![CDATA[<210> 20]]> <![CDATA[<211> 118]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> EGFR VH CT480、CT481]]> <![CDATA[<400> 20]]> Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu 1 5 10 15 Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Glu Tyr 20 25 30 Pro Ile His Trp Val Lys Gln Ala Pro Gly Lys Gly Phe Lys Trp Met 35 40 45 Gly Met Ile Tyr Thr Asp Ile Gly Lys Pro Thr Tyr Ala Glu Glu Phe 50 55 60 Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Leu Gln Ile Asn Asn Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys 85 90 95 Val Arg Asp Arg Tyr Asp Ser Leu Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Thr Leu Thr Val Ser Ser 115 <![CDATA[<210> 21]]> <![CDATA[<211> 121]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> EGFR VH CT482、CT483]]> <![CDATA[<400> 21]]> Glu Met Gln Leu Val Glu Ser Gly Gly Gly Phe Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Ala Phe Ser His Tyr 20 25 30 Asp Met Ser Trp Val Arg Gln Thr Pro Lys Gln Arg Leu Glu Trp Val 35 40 45 Ala Tyr Ile Ala Ser Gly Gly Asp Ile Thr Tyr Tyr Ala Asp Thr Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Gln Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Ser Ser Leu Lys Ser Glu Asp Thr Ala Met Phe Tyr Cys 85 90 95 Ser Arg Ser Ser Tyr Gly Asn Asn Gly Asp Ala Leu Asp Phe Trp Gly 100 105 110 Gln Gly Thr Ser Val Thr Val Ser Ser 115 120 <![CDATA[<210> 22]]> <![CDATA[<211> 119]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> EGFR VH CT486]]> <![CDATA[<400> 22]]> Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln 1 5 10 15 Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr 20 25 30 Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr 50 55 60 Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe 65 70 75 80 Lys Met Asn Ser Leu Gln Ser Asn Asp Thr Ala Ile Tyr Tyr Cys Ala 85 90 95 Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ala 115 <![CDATA[<210> 23]]> <![CDATA[<211> 121]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> EGFR VH CT487]]> <![CDATA[<400> 23]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser His 20 25 30 Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Glu Phe Asn Pro Ser Asn Gly Arg Thr Asn Tyr Asn Glu Lys Phe 50 55 60 Lys Ser Lys Ala Thr Met Thr Val Asp Thr Ser Thr Asn Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Ser Arg Asp Tyr Asp Tyr Asp Gly Arg Tyr Phe Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <![CDATA[<210> 24]]> <![CDATA[<211> 119]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> EGFR VH CT488]]> <![CDATA[<400> 24]]> Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Val Ser Ser Gly 20 25 30 Asp Tyr Tyr Trp Thr Trp Ile Arg Gln Ser Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly His Ile Tyr Tyr Ser Gly Asn Thr Asn Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Leu Thr Ile Ser Ile Asp Thr Ser Lys Thr Gln Phe 65 70 75 80 Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Ile Tyr Tyr 85 90 95 Cys Val Arg Asp Arg Val Thr Gly Ala Phe Asp Ile Trp Gly Gln Gly 100 105 110 Thr Met Val Thr Val Ser Ser 115 <![CDATA[<210> 25]]> <![CDATA[<211> 107]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> EGFR VL CT478、CT479]]> <![CDATA[<400> 25]]> Ala Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Ala 20 25 30 Leu Val Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Glu Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Ser Tyr Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <![CDATA[<210> 26]]> <![CDATA[<211> 112]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> EGFR VL CT480、CT481]]> <![CDATA[<400> 26]]> Asp Val Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly 1 5 10 15 Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser 20 25 30 Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Phe Cys Ser Gln Ser 85 90 95 Thr His Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110 <![CDATA[<210> 27]]> <![CDATA[<211> 111]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> EGFR VL CT482、CT483]]> <![CDATA[<400> 27]]> Asp Val Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly 1 5 10 15 Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser 20 25 30 Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Phe Cys Ser Gln Ser 85 90 95 Thr His Val Leu Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys 100 105 110 <![CDATA[<210> 28]]> <![CDATA[<211> 107]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> EGFR VL CT486]]> <![CDATA[<400> 28]]> Asp Ile Leu Leu Thr Gln Ser Pro Val Ile Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn 20 25 30 Ile His Trp Tyr Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile 35 40 45 Lys Tyr Ala Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser 65 70 75 80 Glu Asp Ile Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr 85 90 95 Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys 100 105 <![CDATA[<210> 29]]> <![CDATA[<211> 106]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> EGFR VL CT487]]> <![CDATA[<400> 29]]> Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Ser Ser Val Thr Tyr Met 20 25 30 Tyr Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr 35 40 45 Asp Thr Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu 65 70 75 80 Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser His Ile Phe Thr 85 90 95 Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <![CDATA[<210> 30]]> <![CDATA[<211> 107]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> EGFR VL CT488]]> <![CDATA[<400> 30]]> Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asp Ile Ser Asn Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Ile Ala Thr Tyr Phe Cys Gln His Phe Asp His Leu Pro Leu 85 90 95 Ala Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <![CDATA[<210> 31]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> EGFR抗原結合結構域CDR H1]]> <![CDATA[<400> 31]]> Thr Tyr Gly Met His 1 5 <![CDATA[<210> 32]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> EGFR抗原結合結構域CDR H1]]> <![CDATA[<400> 32]]> Glu Tyr Pro Ile His 1 5 <![CDATA[<210> 33]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> EGFR抗原結合結構域CDR H1]]> <![CDATA[<400> 33]]> His Tyr Asp Met Ser 1 5 <![CDATA[<210> 34]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> EGFR抗原結合結構域CDR H1]]> <![CDATA[<400> 34]]> Asn Tyr Gly Val His 1 5 <![CDATA[<210> 35]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> EGFR抗原結合結構域CDR H1]]> <![CDATA[<400> 35]]> Ser His Trp Met His 1 5 <![CDATA[<210> 36]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> EGFR抗原結合結構域CDR H1]]> <![CDATA[<400> 36]]> Ser Gly Asp Tyr Tyr Trp Thr 1 5 <![CDATA[<210> 37]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> EGFR抗原結合結構域CDR H2]]> <![CDATA[<400> 37]]> Val Ile Trp Asp Asp Gly Ser Tyr Lys Tyr Tyr Gly Asp Ser Val Lys 1 5 10 15 Gly <![CDATA[<210> 38]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> EGFR抗原結合結構域CDR H2]]> <![CDATA[<400> 38]]> Met Ile Tyr Thr Asp Ile Gly Lys Pro Thr Tyr Ala Glu Glu Phe Lys 1 5 10 15 Gly <![CDATA[<210> 39]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> EGFR抗原結合結構域CDR H2]]> <![CDATA[<400> 39]]> Tyr Ile Ala Ser Gly Gly Asp Ile Thr Tyr Tyr Ala Asp Thr Val Lys 1 5 10 15 Gly <![CDATA[<210> 40]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> EGFR抗原結合結構域CDR H2]]> <![CDATA[<400> 40]]> Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr Ser 1 5 10 15 <![CDATA[<210> 41]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> EGFR抗原結合結構域CDR H2]]> <![CDATA[<400> 41]]> Glu Phe Asn Pro Ser Asn Gly Arg Thr Asn Tyr Asn Glu Lys Phe Lys 1 5 10 15 Ser <![CDATA[<210> 42]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> EGFR抗原結合結構域CDR H2]]> <![CDATA[<400> 42]]> His Ile Tyr Tyr Ser Gly Asn Thr Asn Tyr Asn Pro Ser Leu Lys Ser 1 5 10 15 <![CDATA[<210> 43]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> EGFR抗原結合結構域CDR H3]]> <![CDATA[<400> 43]]> Asp Gly Ile Thr Met Val Arg Gly Val Met Lys Asp Tyr Phe Asp Tyr 1 5 10 15 <![CDATA[<210> 44]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> EGFR抗原結合結構域CDR H3]]> <![CDATA[<400> 44]]> Asp Arg Tyr Asp Ser Leu Phe Asp Tyr 1 5 <![CDATA[<210> 45]]> <![CDATA[<211> 12]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> EGFR抗原結合結構域CDR H3]]> <![CDATA[<400> 45]]> Ser Ser Tyr Gly Asn Asn Gly Asp Ala Leu Asp Phe 1 5 10 <![CDATA[<210> 46]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> EGFR抗原結合結構域CDR H3]]> <![CDATA[<400> 46]]> Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr 1 5 10 <![CDATA[<210> 47]]> <![CDATA[<211> 12]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> EGFR抗原結合結構域CDR H3]]> <![CDATA[<400> 47]]> Arg Asp Tyr Asp Tyr Asp Gly Arg Tyr Phe Asp Tyr 1 5 10 <![CDATA[<210> 48]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> EGFR抗原結合結構域CDR H3]]> <![CDATA[<400> 48]]> Asp Arg Val Thr Gly Ala Phe Asp Ile 1 5 <![CDATA[<210> 49]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> EGFR抗原結合結構域CDR L1]]> <![CDATA[<400> 49]]> Arg Ala Ser Gln Asp Ile Ser Ser Ala Leu Val 1 5 10 <![CDATA[<210> 50]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> EGFR抗原結合結構域CDR L1]]> <![CDATA[<400> 50]]> Arg Ser Ser Gln Ser Leu Val His Ser Asn Gly Asn Thr Tyr Leu His 1 5 10 15 <![CDATA[<210> 51]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> EGFR抗原結合結構域CDR L1]]> <![CDATA[<400> 51]]> Arg Ser Ser Gln Ser Leu Val His Ser Asn Gly Asn Thr Tyr Leu His 1 5 10 15 <![CDATA[<210> 52]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> EGFR抗原結合結構域CDR L1]]> <![CDATA[<400> 52]]> Arg Ala Ser Gln Ser Ile Gly Thr Asn Ile His 1 5 10 <![CDATA[<210> 53]]> <![CDATA[<211> 10]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> EGFR抗原結合結構域CDR L1]]> <![CDATA[<400> 53]]> Ser Ala Ser Ser Ser Val Thr Tyr Met Tyr 1 5 10 <![CDATA[<210> 54]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> EGFR抗原結合結構域CDR L1]]> <![CDATA[<400> 54]]> Gln Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn 1 5 10 <![CDATA[<210> 55]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> EGFR抗原結合結構域CDR L2]]> <![CDATA[<400> 55]]> Asp Ala Ser Ser Leu Glu Ser 1 5 <![CDATA[<210> 56]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> EGFR抗原結合結構域CDR L2]]> <![CDATA[<400> 56]]> Lys Val Ser Asn Arg Phe Ser 1 5 <![CDATA[<210> 57]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> EGFR抗原結合結構域CDR L2]]> <![CDATA[<400> 57]]> Tyr Ala Ser Glu Ser Ile Ser 1 5 <![CDATA[<210> 58]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> EGFR抗原結合結構域CDR L2]]> <![CDATA[<400> 58]]> Asp Thr Ser Asn Leu Ala Ser 1 5 <![CDATA[<210> 59]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> EGFR抗原結合結構域CDR L2]]> <![CDATA[<400> 59]]> Asp Ala Ser Asn Leu Glu Thr 1 5 <![CDATA[<210> 60]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> EGFR抗原結合結構域CDR L3]]> <![CDATA[<400> 60]]> Gln Gln Phe Asn Ser Tyr Pro Leu Thr 1 5 <![CDATA[<210> 61]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> EGFR抗原結合結構域CDR L3]]> <![CDATA[<400> 61]]> Ser Gln Ser Thr His Val Pro Trp Thr 1 5 <![CDATA[<210> 62]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> EGFR抗原結合結構域CDR L3]]> <![CDATA[<400> 62]]> Ser Gln Ser Thr His Val Leu Thr 1 5 <![CDATA[<210> 63]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> EGFR抗原結合結構域CDR L3]]> <![CDATA[<400> 63]]> Gln Gln Asn Asn Asn Trp Pro Thr Thr 1 5 <![CDATA[<210> 64]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> EGFR抗原結合結構域CDR L3]]> <![CDATA[<400> 64]]> Gln Gln Trp Ser Ser His Ile Phe Thr 1 5 <![CDATA[<210> 65]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> EGFR抗原結合結構域CDR L3]]> <![CDATA[<400> 65]]> Gln His Phe Asp His Leu Pro Leu Ala 1 5 <![CDATA[<210> 66]]> <![CDATA[<211> 45]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 未知(Unknown)]]> <![CDATA[<220>]]> <![CDATA[<223> CD8α鉸鏈]]> <![CDATA[<400> 66]]> Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala 1 5 10 15 Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly 20 25 30 Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp 35 40 45 <![CDATA[<210> 67]]> <![CDATA[<211> 135]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 未知(Unknown)]]> <![CDATA[<220>]]> <![CDATA[<223> CD8α鉸鏈]]> <![CDATA[<400> 67]]> accacgacgc cagcgccgcg accaccaaca ccggcgccca ccatcgcgtc gcagcccctg 60 tccctgcgcc cagaggcgtg ccggccagcg gcggggggcg cagtgcacac gagggggctg 120 gacttcgcct gtgat 135 <![CDATA[<210> 68]]> <![CDATA[<211> 41]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 未知(Unknown)]]> <![CDATA[<220>]]> <![CDATA[<223> CD28鉸鏈]]> <![CDATA[<400> 68]]> Cys Thr Ile Glu Val Met Tyr Pro Pro Pro Tyr Leu Asp Asn Glu Lys 1 5 10 15 Ser Asn Gly Thr Ile Ile His Val Lys Gly Lys His Leu Cys Pro Ser 20 25 30 Pro Leu Phe Pro Gly Pro Ser Lys Pro 35 40 <![CDATA[<210> 69]]> <![CDATA[<211> 123]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 未知(Unknown)]]> <![CDATA[<220>]]> <![CDATA[<223> CD28鉸鏈]]> <![CDATA[<400> 69]]> tgtaccattg aagttatgta tcctcctcct tacctagaca atgagaagag caatggaacc 60 attatccatg tgaaagggaa acacctttgt ccaagtcccc tatttcccgg accttctaag 120 ccc 123 <![CDATA[<210> 70]]> <![CDATA[<211> 27]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 未知(Unknown)]]> <![CDATA[<220>]]> <![CDATA[<223> CD28跨膜結構域]]> <![CDATA[<400> 70]]> Phe Trp Val Leu Val Val Val Gly Gly Val Leu Ala Cys Tyr Ser Leu 1 5 10 15 Leu Val Thr Val Ala Phe Ile Ile Phe Trp Val 20 25 <![CDATA[<210> 71]]> <![CDATA[<211> 81]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 未知(Unknown)]]> <![CDATA[<220>]]> <![CDATA[<223> CD28跨膜結構域]]> <![CDATA[<400> 71]]> ttctgggtgc tggtcgttgt gggcggcgtg ctggcctgct acagcctgct ggtgacagtg 60 gccttcatca tcttttgggt g 81 <![CDATA[<210> 72]]> <![CDATA[<211> 25]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 未知(Unknown)]]> <![CDATA[<220>]]> <![CDATA[<223> IL-2Rβ跨膜結構域]]> <![CDATA[<400> 72]]> Ile Pro Trp Leu Gly His Leu Leu Val Gly Leu Ser Gly Ala Phe Gly 1 5 10 15 Phe Ile Ile Leu Val Tyr Leu Leu Ile 20 25 <![CDATA[<210> 73]]> <![CDATA[<211> 75]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 未知(Unknown)]]> <![CDATA[<220>]]> <![CDATA[<223> IL-2Rβ跨膜結構域]]> <![CDATA[<400> 73]]> attccgtggc tcggccacct cctcgtgggc ctcagcgggg cttttggctt catcatctta 60 gtgtacttgc tgatc 75 <![CDATA[<210> 74]]> <![CDATA[<211> 112]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 未知(Unknown)]]> <![CDATA[<220>]]> <![CDATA[<223> CD3ζ活化結構域]]> <![CDATA[<400> 74]]> Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly 1 5 10 15 Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr 20 25 30 Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys 35 40 45 Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys 50 55 60 Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg 65 70 75 80 Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala 85 90 95 Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg 100 105 110 <![CDATA[<210> 75]]> <![CDATA[<211> 336]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 未知(Unknown)]]> <![CDATA[<220>]]> <![CDATA[<223> CD3ζ活化結構域]]> <![CDATA[<400> 75]]> agagtgaagt tcagcaggag cgcagacgcc cccgcgtaca agcagggcca gaaccagctc 60 tataacgagc tcaatctagg acgaagagag gagtacgatg ttttggacaa gcgtagaggc 120 cgggaccctg agatgggggg aaagccgaga aggaagaacc ctcaggaagg cctgtacaat 180 gaactgcaga aagataagat ggcggaggcc tacagtgaga ttgggatgaa aggcgagcgc 240 cggaggggca aggggcacga tggcctttac cagggactca gtacagccac caaggacacc 300 tacgacgccc ttcacatgca ggccctgccc cctcgc 336 <![CDATA[<210> 76]]> <![CDATA[<211> 43]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 未知(Unknown)]]> <![CDATA[<220>]]> <![CDATA[<223> CD3ζ活化結構域]]> <![CDATA[<400> 76]]> Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly 1 5 10 15 Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr 20 25 30 Asp Val Leu His Met Gln Ala Leu Pro Pro Arg 35 40 <![CDATA[<210> 77]]> <![CDATA[<211> 129]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 未知(Unknown)]]> <![CDATA[<220>]]> <![CDATA[<223> CD3ζ活化結構域]]> <![CDATA[<400> 77]]> agagtgaagt tcagcaggag cgcagacgcc cccgcgtacc agcagggcca gaaccagctc 60 tataacgagc tcaatctagg acgaagagag gagtacgatg ttttgcacat gcaggccctg 120 ccccctcgc 129 <![CDATA[<210> 78]]> <![CDATA[<211> 41]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 未知(Unknown)]]> <![CDATA[<220>]]> <![CDATA[<223> CD28共刺激結構域]]> <![CDATA[<400> 78]]> Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met Asn Met Thr 1 5 10 15 Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro 20 25 30 Pro Arg Asp Phe Ala Ala Tyr Arg Ser 35 40 <![CDATA[<210> 79]]> <![CDATA[<211> 123]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 未知(Unknown)]]> <![CDATA[<220>]]> <![CDATA[<223> CD28共刺激結構域]]> <![CDATA[<400> 79]]> aggagcaagc ggagcagact gctgcacagc gactacatga acatgacccc ccggaggcct 60 ggccccaccc ggaagcacta ccagccctac gcccctccca gggatttcgc cgcctaccgg 120 agc 123 <![CDATA[<210> 80]]> <![CDATA[<211> 23]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 未知(Unknown)]]> <![CDATA[<220>]]> <![CDATA[<223> TCRα跨膜結構域]]> <![CDATA[<400> 80]]> Val Ile Gly Phe Arg Ile Leu Leu Leu Lys Val Ala Gly Phe Asn Leu 1 5 10 15 Leu Met Thr Leu Arg Leu Trp 20 <![CDATA[<210> 81]]> <![CDATA[<211> 69]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 未知(Unknown)]]> <![CDATA[<220>]]> <![CDATA[<223> TCRα跨膜結構域]]> <![CDATA[<400> 81]]> gtgattgggt tccgaatcct cctcctgaaa gtggccgggt ttaatctgct catgacgctg 60 cggctgtgg 69 <![CDATA[<210> 82]]> <![CDATA[<211> 23]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 未知(Unknown)]]> <![CDATA[<220>]]> <![CDATA[<223> TCRβ跨膜結構域]]> <![CDATA[<400> 82]]> Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr Leu Tyr Ala Val 1 5 10 15 Leu Val Ser Ala Leu Val Leu 20 <![CDATA[<210> 83]]> <![CDATA[<211> 69]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 未知(Unknown)]]> <![CDATA[<220>]]> <![CDATA[<223> TCRβ跨膜結構域]]> <![CDATA[<400> 83]]> accatcctct atgagatctt gctagggaag gccaccttgt atgccgtgct ggtcagtgcc 60 ctcgtgctg 69 <![CDATA[<210> 84]]> <![CDATA[<211> 10]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 未知(Unknown)]]> <![CDATA[<220>]]> <![CDATA[<223> TCRβ細胞內結構域]]> <![CDATA[<400> 84]]> Met Ala Met Val Lys Arg Lys Asp Ser Arg 1 5 10 <![CDATA[<210> 85]]> <![CDATA[<211> 30]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 未知(Unknown)]]> <![CDATA[<220>]]> <![CDATA[<223> TCRβ細胞內結構域]]> <![CDATA[<400> 85]]> atggccatgg tcaagagaaa ggattccaga 30 <![CDATA[<210> 86]]> <![CDATA[<211> 273]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人(Homo sapiens)]]> <![CDATA[<400> 86]]> Met Ser Gly Ser Gln Ser Glu Val Ala Pro Ser Pro Gln Ser Pro Arg 1 5 10 15 Ser Pro Glu Met Gly Arg Asp Leu Arg Pro Gly Ser Arg Val Leu Leu 20 25 30 Leu Leu Leu Leu Leu Leu Leu Val Tyr Leu Thr Gln Pro Gly Asn Gly 35 40 45 Asn Glu Gly Ser Val Thr Gly Ser Cys Tyr Cys Gly Lys Arg Ile Ser 50 55 60 Ser Asp Ser Pro Pro Ser Val Gln Phe Met Asn Arg Leu Arg Lys His 65 70 75 80 Leu Arg Ala Tyr His Arg Cys Leu Tyr Tyr Thr Arg Phe Gln Leu Leu 85 90 95 Ser Trp Ser Val Cys Gly Gly Asn Lys Asp Pro Trp Val Gln Glu Leu 100 105 110 Met Ser Cys Leu Asp Leu Lys Glu Cys Gly His Ala Tyr Ser Gly Ile 115 120 125 Val Ala His Gln Lys His Leu Leu Pro Thr Ser Pro Pro Ile Ser Gln 130 135 140 Ala Ser Glu Gly Ala Ser Ser Asp Ile His Thr Pro Ala Gln Met Leu 145 150 155 160 Leu Ser Thr Leu Gln Ser Thr Gln Arg Pro Thr Leu Pro Val Gly Ser 165 170 175 Leu Ser Ser Asp Lys Glu Leu Thr Arg Pro Asn Glu Thr Thr Ile His 180 185 190 Thr Ala Gly His Ser Leu Ala Ala Gly Pro Glu Ala Gly Glu Asn Gln 195 200 205 Lys Gln Pro Glu Lys Asn Ala Gly Pro Thr Ala Arg Thr Ser Ala Thr 210 215 220 Val Pro Val Leu Cys Leu Leu Ala Ile Ile Phe Ile Leu Thr Ala Ala 225 230 235 240 Leu Ser Tyr Val Leu Cys Lys Arg Arg Arg Gly Gln Ser Pro Gln Ser 245 250 255 Ser Pro Asp Leu Pro Val His Tyr Ile Pro Val Ala Pro Asp Ser Asn 260 265 270 Thr <![CDATA[<210> 87]]> <![CDATA[<211> 742]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人(Homo sapiens)]]> <![CDATA[<400> 87]]> Met Lys Asp Asp Phe Ala Glu Glu Glu Glu Val Gln Ser Phe Gly Tyr 1 5 10 15 Lys Arg Phe Gly Ile Gln Glu Gly Thr Gln Cys Thr Lys Cys Lys Asn 20 25 30 Asn Trp Ala Leu Lys Phe Ser Ile Ile Leu Leu Tyr Ile Leu Cys Ala 35 40 45 Leu Leu Thr Ile Thr Val Ala Ile Leu Gly Tyr Lys Val Val Glu Lys 50 55 60 Met Asp Asn Val Thr Gly Gly Met Glu Thr Ser Arg Gln Thr Tyr Asp 65 70 75 80 Asp Lys Leu Thr Ala Val Glu Ser Asp Leu Lys Lys Leu Gly Asp Gln 85 90 95 Thr Gly Lys Lys Ala Ile Ser Thr Asn Ser Glu Leu Ser Thr Phe Arg 100 105 110 Ser Asp Ile Leu Asp Leu Arg Gln Gln Leu Arg Glu Ile Thr Glu Lys 115 120 125 Thr Ser Lys Asn Lys Asp Thr Leu Glu Lys Leu Gln Ala Ser Gly Asp 130 135 140 Ala Leu Val Asp Arg Gln Ser Gln Leu Lys Glu Thr Leu Glu Asn Asn 145 150 155 160 Ser Phe Leu Ile Thr Thr Val Asn Lys Thr Leu Gln Ala Tyr Asn Gly 165 170 175 Tyr Val Thr Asn Leu Gln Gln Asp Thr Ser Val Leu Gln Gly Asn Leu 180 185 190 Gln Asn Gln Met Tyr Ser His Asn Val Val Ile Met Asn Leu Asn Asn 195 200 205 Leu Asn Leu Thr Gln Val Gln Gln Arg Asn Leu Ile Thr Asn Leu Gln 210 215 220 Arg Ser Val Asp Asp Thr Ser Gln Ala Ile Gln Arg Ile Lys Asn Asp 225 230 235 240 Phe Gln Asn Leu Gln Gln Val Phe Leu Gln Ala Lys Lys Asp Thr Asp 245 250 255 Trp Leu Lys Glu Lys Val Gln Ser Leu Gln Thr Leu Ala Ala Asn Asn 260 265 270 Ser Ala Leu Ala Lys Ala Asn Asn Asp Thr Leu Glu Asp Met Asn Ser 275 280 285 Gln Leu Asn Ser Phe Thr Gly Gln Met Glu Asn Ile Thr Thr Ile Ser 290 295 300 Gln Ala Asn Glu Gln Asn Leu Lys Asp Leu Gln Asp Leu His Lys Asp 305 310 315 320 Ala Glu Asn Arg Thr Ala Ile Lys Phe Asn Gln Leu Glu Glu Arg Phe 325 330 335 Gln Leu Phe Glu Thr Asp Ile Val Asn Ile Ile Ser Asn Ile Ser Tyr 340 345 350 Thr Ala His His Leu Arg Thr Leu Thr Ser Asn Leu Asn Glu Val Arg 355 360 365 Thr Thr Cys Thr Asp Thr Leu Thr Lys His Thr Asp Asp Leu Thr Ser 370 375 380 Leu Asn Asn Thr Leu Ala Asn Ile Arg Leu Asp Ser Val Ser Leu Arg 385 390 395 400 Met Gln Gln Asp Leu Met Arg Ser Arg Leu Asp Thr Glu Val Ala Asn 405 410 415 Leu Ser Val Ile Met Glu Glu Met Lys Leu Val Asp Ser Lys His Gly 420 425 430 Gln Leu Ile Lys Asn Phe Thr Ile Leu Gln Gly Pro Pro Gly Pro Arg 435 440 445 Gly Pro Arg Gly Asp Arg Gly Ser Gln Gly Pro Pro Gly Pro Thr Gly 450 455 460 Asn Lys Gly Gln Lys Gly Glu Lys Gly Glu Pro Gly Pro Pro Gly Pro 465 470 475 480 Ala Gly Glu Arg Gly Pro Ile Gly Pro Ala Gly Pro Pro Gly Glu Arg 485 490 495 Gly Gly Lys Gly Ser Lys Gly Ser Gln Gly Pro Lys Gly Ser Arg Gly 500 505 510 Ser Pro Gly Lys Pro Gly Pro Gln Gly Ser Ser Gly Asp Pro Gly Pro 515 520 525 Pro Gly Pro Pro Gly Lys Glu Gly Leu Pro Gly Pro Gln Gly Pro Pro 530 535 540 Gly Phe Gln Gly Leu Gln Gly Thr Val Gly Glu Pro Gly Val Pro Gly 545 550 555 560 Pro Arg Gly Leu Pro Gly Leu Pro Gly Val Pro Gly Met Pro Gly Pro 565 570 575 Lys Gly Pro Pro Gly Pro Pro Gly Pro Ser Gly Ala Val Val Pro Leu 580 585 590 Ala Leu Gln Asn Glu Pro Thr Pro Ala Pro Glu Asp Asn Gly Cys Pro 595 600 605 Pro His Trp Lys Asn Phe Thr Asp Lys Cys Tyr Tyr Phe Ser Val Glu 610 615 620 Lys Glu Ile Phe Glu Asp Ala Lys Leu Phe Cys Glu Asp Lys Ser Ser 625 630 635 640 His Leu Val Phe Ile Asn Thr Arg Glu Glu Gln Gln Trp Ile Lys Lys 645 650 655 Gln Met Val Gly Arg Glu Ser His Trp Ile Gly Leu Thr Asp Ser Glu 660 665 670 Arg Glu Asn Glu Trp Lys Trp Leu Asp Gly Thr Ser Pro Asp Tyr Lys 675 680 685 Asn Trp Lys Ala Gly Gln Pro Asp Asn Trp Gly His Gly His Gly Pro 690 695 700 Gly Glu Asp Cys Ala Gly Leu Ile Tyr Ala Gly Gln Trp Asn Asp Phe 705 710 715 720 Gln Cys Glu Asp Val Asn Asn Phe Ile Cys Glu Lys Asp Arg Glu Thr 725 730 735 Val Leu Ser Ser Ala Leu 740 <![CDATA[<210> 88]]> <![CDATA[<211> 514]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人(Homo sapiens)]]> <![CDATA[<400> 88]]> Met Ser Trp Pro Arg Arg Leu Leu Leu Arg Tyr Leu Phe Pro Ala Leu 1 5 10 15 Leu Leu His Gly Leu Gly Glu Gly Ser Ala Leu Leu His Pro Asp Ser 20 25 30 Arg Ser His Pro Arg Ser Leu Glu Lys Ser Ala Trp Arg Ala Phe Lys 35 40 45 Glu Ser Gln Cys His His Met Leu Lys His Leu His Asn Gly Ala Arg 50 55 60 Ile Thr Val Gln Met Pro Pro Thr Ile Glu Gly His Trp Val Ser Thr 65 70 75 80 Gly Cys Glu Val Arg Ser Gly Pro Glu Phe Ile Thr Arg Ser Tyr Arg 85 90 95 Phe Tyr His Asn Asn Thr Phe Lys Ala Tyr Gln Phe Tyr Tyr Gly Ser 100 105 110 Asn Arg Cys Thr Asn Pro Thr Tyr Thr Leu Ile Ile Arg Gly Lys Ile 115 120 125 Arg Leu Arg Gln Ala Ser Trp Ile Ile Arg Gly Gly Thr Glu Ala Asp 130 135 140 Tyr Gln Leu His Asn Val Gln Val Ile Cys His Thr Glu Ala Val Ala 145 150 155 160 Glu Lys Leu Gly Gln Gln Val Asn Arg Thr Cys Pro Gly Phe Leu Ala 165 170 175 Asp Gly Gly Pro Trp Val Gln Asp Val Ala Tyr Asp Leu Trp Arg Glu 180 185 190 Glu Asn Gly Cys Glu Cys Thr Lys Ala Val Asn Phe Ala Met His Glu 195 200 205 Leu Gln Leu Ile Arg Val Glu Lys Gln Tyr Leu His His Asn Leu Asp 210 215 220 His Leu Val Glu Glu Leu Phe Leu Gly Asp Ile His Thr Asp Ala Thr 225 230 235 240 Gln Arg Met Phe Tyr Arg Pro Ser Ser Tyr Gln Pro Pro Leu Gln Asn 245 250 255 Ala Lys Asn His Asp His Ala Cys Ile Ala Cys Arg Ile Ile Tyr Arg 260 265 270 Ser Asp Glu His His Pro Pro Ile Leu Pro Pro Lys Ala Asp Leu Thr 275 280 285 Ile Gly Leu His Gly Glu Trp Val Ser Gln Arg Cys Glu Val Arg Pro 290 295 300 Glu Val Leu Phe Leu Thr Arg His Phe Ile Phe His Asp Asn Asn Asn 305 310 315 320 Thr Trp Glu Gly His Tyr Tyr His Tyr Ser Asp Pro Val Cys Lys His 325 330 335 Pro Thr Phe Ser Ile Tyr Ala Arg Gly Arg Tyr Ser Arg Gly Val Leu 340 345 350 Ser Ser Arg Val Met Gly Gly Thr Glu Phe Val Phe Lys Val Asn His 355 360 365 Met Lys Val Thr Pro Met Asp Ala Ala Thr Ala Ser Leu Leu Asn Val 370 375 380 Phe Asn Gly Asn Glu Cys Gly Ala Glu Gly Ser Trp Gln Val Gly Ile 385 390 395 400 Gln Gln Asp Val Thr His Thr Asn Gly Cys Val Ala Leu Gly Ile Lys 405 410 415 Leu Pro His Thr Glu Tyr Glu Ile Phe Lys Met Glu Gln Asp Ala Arg 420 425 430 Gly Arg Tyr Leu Leu Phe Asn Gly Gln Arg Pro Ser Asp Gly Ser Ser 435 440 445 Pro Asp Arg Pro Glu Lys Arg Ala Thr Ser Tyr Gln Met Pro Leu Val 450 455 460 Gln Cys Ala Ser Ser Ser Pro Arg Ala Glu Asp Leu Ala Glu Asp Ser 465 470 475 480 Gly Ser Ser Leu Tyr Gly Arg Ala Pro Gly Arg His Thr Trp Ser Leu 485 490 495 Leu Leu Ala Ala Leu Ala Cys Leu Val Pro Leu Leu His Trp Asn Ile 500 505 510 Arg Arg <![CDATA[<210> 89]]> <![CDATA[<211> 247]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> C-001765 PA2.1 scFv (小鼠)]]> <![CDATA[<400> 89]]> Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly 1 5 10 15 Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser 20 25 30 Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Phe Gln Gly 85 90 95 Ser His Val Pro Arg Thr Ser Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 115 120 125 Gly Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly 130 135 140 Ala Ser Val Arg Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser 145 150 155 160 Tyr His Ile His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp 165 170 175 Ile Gly Trp Ile Tyr Pro Gly Asn Val Asn Thr Glu Tyr Asn Glu Lys 180 185 190 Phe Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala 195 200 205 Tyr Met His Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe 210 215 220 Cys Ala Arg Glu Glu Ile Thr Tyr Ala Met Asp Tyr Trp Gly Gln Gly 225 230 235 240 Thr Ser Val Thr Val Ser Ser 245 <![CDATA[<210> 90]]> <![CDATA[<211> 247]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> C-002159 PA2.1.8 scFv (人源化)]]> <![CDATA[<400> 90]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 His Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Tyr Pro Gly Asn Val Asn Thr Glu Tyr Asn Glu Lys Phe 50 55 60 Lys Gly Lys Ala Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Glu Ile Thr Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 115 120 125 Gly Gly Gly Gly Ser Gly Gly Glu Ile Val Leu Thr Gln Ser Pro Gly 130 135 140 Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ser 145 150 155 160 Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu Trp Tyr 165 170 175 Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Lys Val Ser 180 185 190 Asn Arg Phe Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly 195 200 205 Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala 210 215 220 Val Tyr Tyr Cys Phe Gln Gly Ser His Val Pro Arg Thr Phe Gly Gly 225 230 235 240 Gly Thr Lys Val Glu Ile Lys 245 <![CDATA[<210> 91]]> <![CDATA[<211> 247]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> C-002160 PA2.1.9 scFv (人源化)]]> <![CDATA[<400> 91]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 His Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Tyr Pro Gly Asn Val Asn Thr Glu Tyr Asn Glu Lys Phe 50 55 60 Lys Gly Lys Ala Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Glu Ile Thr Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 115 120 125 Gly Gly Gly Gly Ser Gly Gly Asp Ile Val Met Thr Gln Thr Pro Leu 130 135 140 Ser Leu Pro Val Thr Pro Gly Glu Pro Ala Ser Ile Ser Cys Arg Ser 145 150 155 160 Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu Trp Tyr 165 170 175 Leu Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Lys Val Ser 180 185 190 Asn Arg Phe Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly 195 200 205 Thr Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly 210 215 220 Val Tyr Tyr Cys Phe Gln Gly Ser His Val Pro Arg Thr Phe Gly Gly 225 230 235 240 Gly Thr Lys Val Glu Ile Lys 245 <![CDATA[<210> 92]]> <![CDATA[<211> 247]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> C-002161 PA2.1.10 scFv (人源化)]]> <![CDATA[<400> 92]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 His Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Gly Trp Ile Tyr Pro Gly Asn Val Asn Thr Glu Tyr Asn Glu Lys Phe 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Glu Ile Thr Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 115 120 125 Gly Gly Gly Gly Ser Gly Gly Asp Ile Gln Met Thr Gln Ser Pro Ser 130 135 140 Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ser 145 150 155 160 Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu Trp Tyr 165 170 175 Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Lys Val Ser 180 185 190 Asn Arg Phe Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly 195 200 205 Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala 210 215 220 Thr Tyr Tyr Cys Phe Gln Gly Ser His Val Pro Arg Thr Phe Gly Gly 225 230 235 240 Gly Thr Lys Val Glu Ile Lys 245 <![CDATA[<210> 93]]> <![CDATA[<211> 247]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> C-002162 PA2.1.14 scFv (人源化)]]> <![CDATA[<400> 93]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 His Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Trp Ile Tyr Pro Gly Asn Val Asn Thr Glu Tyr Asn Glu Lys Phe 50 55 60 Lys Gly Lys Ala Thr Ile Thr Ala Asp Glu Ser Thr Asn Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Glu Ile Thr Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 115 120 125 Gly Gly Gly Gly Ser Gly Gly Asp Ile Gln Met Thr Gln Ser Pro Ser 130 135 140 Thr Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ser 145 150 155 160 Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu Trp Tyr 165 170 175 Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Lys Val Ser 180 185 190 Asn Arg Phe Ser Gly Val Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly 195 200 205 Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Asp Asp Phe Ala 210 215 220 Thr Tyr Tyr Cys Phe Gln Gly Ser His Val Pro Arg Thr Phe Gly Gln 225 230 235 240 Gly Thr Lys Val Glu Val Lys 245 <![CDATA[<210> 94]]> <![CDATA[<211> 247]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> C-002163 PA2.1.18 scFv (人源化)]]> <![CDATA[<400> 94]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 His Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Tyr Ile Tyr Pro Gly Asn Val Asn Thr Glu Tyr Asn Glu Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Thr Asn Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Phe Cys 85 90 95 Ala Arg Glu Glu Ile Thr Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 115 120 125 Gly Gly Gly Gly Ser Gly Gly Asp Val Gln Met Thr Gln Ser Pro Ser 130 135 140 Thr Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Ser Ser 145 150 155 160 Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Met Glu Trp Tyr 165 170 175 Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Lys Val Ser 180 185 190 Asn Arg Phe Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly 195 200 205 Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Asp Asp Phe Ala 210 215 220 Thr Tyr Tyr Cys His Gln Gly Ser His Val Pro Arg Thr Phe Gly Gln 225 230 235 240 Gly Thr Lys Val Glu Val Lys 245 <![CDATA[<210> 95]]> <![CDATA[<211> 247]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> C-002164 BB7.2 scFv (小鼠)]]> <![CDATA[<400> 95]]> Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 His Ile Gln Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Trp Ile Tyr Pro Gly Asp Gly Ser Thr Gln Tyr Asn Glu Lys Phe 50 55 60 Lys Gly Lys Thr Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Leu Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Ile Tyr Phe Cys 85 90 95 Ala Arg Glu Gly Thr Tyr Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Ser Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 115 120 125 Gly Gly Gly Gly Ser Gly Gly Asp Val Leu Met Thr Gln Thr Pro Leu 130 135 140 Ser Leu Pro Val Ser Leu Gly Asp Gln Val Ser Ile Ser Cys Arg Ser 145 150 155 160 Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu Trp Tyr 165 170 175 Leu Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile Tyr Lys Val Ser 180 185 190 Asn Arg Phe Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly 195 200 205 Thr Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Leu Gly 210 215 220 Val Tyr Tyr Cys Phe Gln Gly Ser His Val Pro Arg Thr Phe Gly Gly 225 230 235 240 Gly Thr Lys Leu Glu Ile Lys 245 <![CDATA[<210> 96]]> <![CDATA[<211> 247]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> C-002165 BB7.2.1 scFv (人源化)]]> <![CDATA[<400> 96]]> Gln Leu Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 His Ile Gln Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Trp Ile Tyr Pro Gly Asp Gly Ser Thr Gln Tyr Asn Glu Lys Phe 50 55 60 Lys Gly Arg Ala Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser 65 70 75 80 Leu Asn Leu Asp Ser Val Ser Ala Ala Asp Thr Ala Ile Tyr Tyr Cys 85 90 95 Ala Arg Glu Gly Thr Tyr Tyr Ala Met Asp Tyr Trp Gly Lys Gly Ser 100 105 110 Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 115 120 125 Gly Gly Gly Gly Ser Gly Gly Asp Ile Gln Met Thr Gln Ser Pro Ser 130 135 140 Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ser 145 150 155 160 Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu Trp Tyr 165 170 175 Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Lys Val Ser 180 185 190 Asn Arg Phe Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly 195 200 205 Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala 210 215 220 Thr Tyr Tyr Cys Phe Gln Gly Ser His Val Pro Arg Thr Phe Gly Pro 225 230 235 240 Gly Thr Lys Val Asp Ile Lys 245 <![CDATA[<210> 97]]> <![CDATA[<211> 247]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> C-002166 BB7.2.2 scFv (人源化)]]> <![CDATA[<400> 97]]> Glu Val Gln Leu Val Gln Ser Gly Ala Glu Leu Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 His Ile Gln Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Trp Ile Tyr Pro Gly Asp Gly Ser Thr Gln Tyr Asn Glu Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Thr Asn Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Gly Thr Tyr Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 115 120 125 Gly Gly Gly Gly Ser Gly Gly Asp Ile Gln Met Thr Gln Ser Pro Ser 130 135 140 Thr Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ser 145 150 155 160 Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu Trp Tyr 165 170 175 Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Lys Val Ser 180 185 190 Asn Arg Phe Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly 195 200 205 Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Asp Asp Phe Ala 210 215 220 Thr Tyr Tyr Cys Phe Gln Gly Ser His Val Pro Arg Thr Phe Gly Gln 225 230 235 240 Gly Thr Lys Val Glu Val Lys 245 <![CDATA[<210> 98]]> <![CDATA[<211> 247]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> C-002167 BB7.2.3 scFv (人源化)]]> <![CDATA[<400> 98]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 His Ile Gln Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Tyr Pro Gly Asp Gly Ser Thr Gln Tyr Asn Glu Lys Phe 50 55 60 Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Gly Thr Tyr Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 115 120 125 Gly Gly Gly Gly Ser Gly Gly Glu Ile Val Leu Thr Gln Ser Pro Gly 130 135 140 Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ser 145 150 155 160 Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu Trp Tyr 165 170 175 Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Lys Val Ser 180 185 190 Asn Arg Phe Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly 195 200 205 Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala 210 215 220 Val Tyr Tyr Cys Phe Gln Gly Ser His Val Pro Arg Thr Phe Gly Gly 225 230 235 240 Gly Thr Lys Val Glu Ile Lys 245 <![CDATA[<210> 99]]> <![CDATA[<211> 247]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> C-002168 BB7.2.5 scFv (人源化)]]> <![CDATA[<400> 99]]> Gln Val Thr Leu Lys Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Thr Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 His Val Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Leu 35 40 45 Gly Arg Ile Tyr Pro Gly Asp Gly Ser Thr Gln Tyr Asn Glu Lys Phe 50 55 60 Lys Gly Lys Val Thr Ile Thr Ala Asp Lys Ser Met Asp Thr Ser Phe 65 70 75 80 Met Glu Leu Thr Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Gly Thr Tyr Tyr Ala Met Asp Leu Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 115 120 125 Gly Gly Gly Gly Ser Gly Gly Glu Ile Val Leu Thr Gln Ser Pro Gly 130 135 140 Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ser 145 150 155 160 Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Ala Trp Tyr 165 170 175 Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Ser Lys Val Ser 180 185 190 Asn Arg Phe Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly 195 200 205 Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala 210 215 220 Val Tyr Tyr Cys Gln Gln Gly Ser His Val Pro Arg Thr Phe Gly Gly 225 230 235 240 Gly Thr Lys Val Glu Ile Lys 245 <![CDATA[<210> 100]]> <![CDATA[<211> 247]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> C-002169 BB7.2.6 scFv (人源化)]]> <![CDATA[<400> 100]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 His Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met 35 40 45 Gly Trp Ile Tyr Pro Gly Asp Gly Ser Thr Gln Tyr Asn Glu Lys Phe 50 55 60 Lys Gly Lys Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Gly Thr Tyr Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 115 120 125 Gly Gly Gly Gly Ser Gly Gly Asp Ile Val Met Thr Gln Thr Pro Leu 130 135 140 Ser Leu Pro Val Thr Pro Gly Glu Pro Ala Ser Ile Ser Cys Arg Ser 145 150 155 160 Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Asp Trp Tyr 165 170 175 Leu Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Lys Val Ser 180 185 190 Asn Arg Phe Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly 195 200 205 Thr Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly 210 215 220 Val Tyr Tyr Cys Met Gln Gly Ser His Val Pro Arg Thr Phe Gly Gly 225 230 235 240 Gly Thr Lys Val Glu Ile Lys 245 <![CDATA[<210> 101]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-A*02 CDR-L1]]> <![CDATA[<400> 101]]> Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu 1 5 10 15 <![CDATA[<210> 102]]> <![CDATA[<211> 12]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-A*02 CDR-L2]]> <![CDATA[<400> 102]]> Lys Val Ser Asn Arg Phe Ser Gly Val Pro Asp Arg 1 5 10 <![CDATA[<210> 103]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-A*02 CDR-L3]]> <![CDATA[<400> 103]]> Phe Gln Gly Ser His Val Pro Arg Thr 1 5 <![CDATA[<210> 104]]> <![CDATA[<211> 12]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-A*02 CDR-H1]]> <![CDATA[<400> 104]]> Ala Ser Gly Tyr Thr Phe Thr Ser Tyr His Ile His 1 5 10 <![CDATA[<210> 105]]> <![CDATA[<211> 18]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-A*02 CDR-H2]]> <![CDATA[<400> 105]]> Trp Ile Tyr Pro Gly Asn Val Asn Thr Glu Tyr Asn Glu Lys Phe Lys 1 5 10 15 Gly Lys <![CDATA[<210> 106]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-A*02 CDR-H3]]> <![CDATA[<400> 106]]> Glu Glu Ile Thr Tyr Ala Met Asp Tyr 1 5 <![CDATA[<210> 107]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-A*02 CDR-L1]]> <![CDATA[<400> 107]]> Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Asp 1 5 10 15 <![CDATA[<210> 108]]> <![CDATA[<211> 12]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-A*02 CDR-L2]]> <![CDATA[<400> 108]]> Lys Val Ser Asn Arg Phe Ser Gly Val Pro Asp Arg 1 5 10 <![CDATA[<210> 109]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-A*02 CDR-L3]]> <![CDATA[<400> 109]]> Met Gln Gly Ser His Val Pro Arg Thr 1 5 <![CDATA[<210> 110]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-A*02 CDR-H1]]> <![CDATA[<400> 110]]> Ser Gly Tyr Thr Phe Thr Ser Tyr His Met His 1 5 10 <![CDATA[<210> 111]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-A*02 CDR-H2]]> <![CDATA[<400> 111]]> Trp Ile Tyr Pro Gly Asp Gly Ser Thr Gln Tyr Asn Glu Lys Phe Lys 1 5 10 15 Gly <![CDATA[<210> 112]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-A*02 CDR-H3]]> <![CDATA[<400> 112]]> Glu Gly Thr Tyr Tyr Ala Met Asp Tyr 1 5 <![CDATA[<210> 113]]> <![CDATA[<211> 670]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 未知(Unknown)]]> <![CDATA[<220>]]> <![CDATA[<223> LILRB1]]> <![CDATA[<400> 113]]> Met Thr Pro Ile Leu Thr Val Leu Ile Cys Leu Gly Leu Ser Leu Gly 1 5 10 15 Pro Arg Thr His Val Gln Ala Gly His Leu Pro Lys Pro Thr Leu Trp 20 25 30 Ala Glu Pro Gly Ser Val Ile Thr Gln Gly Ser Pro Val Thr Leu Arg 35 40 45 Cys Gln Gly Gly Gln Glu Thr Gln Glu Tyr Arg Leu Tyr Arg Glu Lys 50 55 60 Lys Thr Ala Leu Trp Ile Thr Arg Ile Pro Gln Glu Leu Val Lys Lys 65 70 75 80 Gly Gln Phe Pro Ile Pro Ser Ile Thr Trp Glu His Ala Gly Arg Tyr 85 90 95 Arg Cys Tyr Tyr Gly Ser Asp Thr Ala Gly Arg Ser Glu Ser Ser Asp 100 105 110 Pro Leu Glu Leu Val Val Thr Gly Ala Tyr Ile Lys Pro Thr Leu Ser 115 120 125 Ala Gln Pro Ser Pro Val Val Asn Ser Gly Gly Asn Val Ile Leu Gln 130 135 140 Cys Asp Ser Gln Val Ala Phe Asp Gly Phe Ser Leu Cys Lys Glu Gly 145 150 155 160 Glu Asp Glu His Pro Gln Cys Leu Asn Ser Gln Pro His Ala Arg Gly 165 170 175 Ser Ser Arg Ala Ile Phe Ser Val Gly Pro Val Ser Pro Ser Arg Arg 180 185 190 Trp Trp Tyr Arg Cys Tyr Ala Tyr Asp Ser Asn Ser Pro Tyr Glu Trp 195 200 205 Ser Leu Pro Ser Asp Leu Leu Glu Leu Leu Val Leu Gly Val Ser Lys 210 215 220 Lys Pro Ser Leu Ser Val Gln Pro Gly Pro Ile Val Ala Pro Glu Glu 225 230 235 240 Thr Leu Thr Leu Gln Cys Gly Ser Asp Ala Gly Tyr Asn Arg Phe Val 245 250 255 Leu Tyr Lys Asp Gly Glu Arg Asp Phe Leu Gln Leu Ala Gly Ala Gln 260 265 270 Pro Gln Ala Gly Leu Ser Gln Ala Asn Phe Thr Leu Gly Pro Val Ser 275 280 285 Arg Ser Tyr Gly Gly Gln Tyr Arg Cys Tyr Gly Ala His Asn Leu Ser 290 295 300 Ser Glu Trp Ser Ala Pro Ser Asp Pro Leu Asp Ile Leu Ile Ala Gly 305 310 315 320 Gln Phe Tyr Asp Arg Val Ser Leu Ser Val Gln Pro Gly Pro Thr Val 325 330 335 Ala Ser Gly Glu Asn Val Thr Leu Leu Cys Gln Ser Gln Gly Trp Met 340 345 350 Gln Thr Phe Leu Leu Thr Lys Glu Gly Ala Ala Asp Asp Pro Trp Arg 355 360 365 Leu Arg Ser Thr Tyr Gln Ser Gln Lys Tyr Gln Ala Glu Phe Pro Met 370 375 380 Gly Pro Val Thr Ser Ala His Ala Gly Thr Tyr Arg Cys Tyr Gly Ser 385 390 395 400 Gln Ser Ser Lys Pro Tyr Leu Leu Thr His Pro Ser Asp Pro Leu Glu 405 410 415 Leu Val Val Ser Gly Pro Ser Gly Gly Pro Ser Ser Pro Thr Thr Gly 420 425 430 Pro Thr Ser Thr Ser Gly Pro Glu Asp Gln Pro Leu Thr Pro Thr Gly 435 440 445 Ser Asp Pro Gln Ser Gly Leu Gly Arg His Leu Gly Val Val Ile Gly 450 455 460 Ile Leu Val Ala Val Ile Leu Leu Leu Leu Leu Leu Leu Leu Leu Phe 465 470 475 480 Leu Ile Leu Arg His Arg Arg Gln Gly Lys His Trp Thr Ser Thr Gln 485 490 495 Arg Lys Ala Asp Phe Gln His Pro Ala Gly Ala Val Gly Pro Glu Pro 500 505 510 Thr Asp Arg Gly Leu Gln Trp Arg Ser Ser Pro Ala Ala Asp Ala Gln 515 520 525 Glu Glu Asn Leu Tyr Ala Ala Val Lys His Thr Gln Pro Glu Asp Gly 530 535 540 Val Glu Met Asp Thr Arg Ser Pro His Asp Glu Asp Pro Gln Ala Val 545 550 555 560 Thr Tyr Ala Glu Val Lys His Ser Arg Pro Arg Arg Glu Met Ala Ser 565 570 575 Pro Pro Ser Pro Leu Ser Gly Glu Phe Leu Asp Thr Lys Asp Arg Gln 580 585 590 Ala Glu Glu Asp Arg Gln Met Asp Thr Glu Ala Ala Ala Ser Glu Ala 595 600 605 Pro Gln Asp Val Thr Tyr Ala Gln Leu His Ser Leu Thr Leu Arg Arg 610 615 620 Glu Ala Thr Glu Pro Pro Pro Ser Gln Glu Gly Pro Ser Pro Ala Val 625 630 635 640 Pro Ser Ile Tyr Ala Thr Leu Ala Ile His Pro Ser Gln Glu Gly Pro 645 650 655 Ser Pro Ala Val Pro Ser Ile Tyr Ala Thr Leu Ala Ile His 660 665 670 <![CDATA[<210> 114]]> <![CDATA[<211> 3229]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 未知(Unknown)]]> <![CDATA[<220>]]> <![CDATA[<223> LILRB1]]> <![CDATA[<400> 114]]> aaatgagttt taaaaaggct tgtccaggaa gcacatatgg gagctggtca ctctgcattt 60 tgggccctcc tggaggtgtt tagaccttcc gagagagaaa ctgagacaca tgagagggaa 120 gaaatgactc agtggtgaga ccctgtggag tcccacccac aaccagcaca ctgtgaccca 180 ctgcacaaac ctctagccca cagctcactt cctcctttaa gaagagaaga gaaaagagga 240 gaggagagga ggaacagaaa agaaaagaaa agaaaaagtg ggaaacaaat aatctaagaa 300 tgaggagaaa gcaagaagag tgaccccctt gtgggcactc cattggtttt atggcgcctc 360 tactttctgg agtttgtgta aaacaaaaat attatggtct ttgtgcacat ttacatcaag 420 ctcagcctgg gcggcacagc cagatgcgag atgcgtctct gctgatctga gtctgcctgc 480 agcatggacc tgggtcttcc ctgaagcatc tccagggctg gagggacgac tgccatgcac 540 cgagggctca tccatccaca gagcagggca gtgggaggag acgccatgac ccccatcctc 600 acggtcctga tctgtctcgg gctgagtctg ggcccccgga cccacgtgca ggcagggcac 660 ctccccaagc ccaccctctg ggctgaacca ggctctgtga tcacccaggg gagtcctgtg 720 accctcaggt gtcagggggg ccaggagacc caggagtacc gtctatatag agaaaagaaa 780 acagcaccct ggattacacg gatcccacag gagcttgtga agaagggcca gttccccatc 840 ccatccatca cctgggaaca cacagggcgg tatcgctgtt actatggtag cgacactgca 900 ggccgctcag agagcagtga ccccctggag ctggtggtga caggagccta catcaaaccc 960 accctctcag cccagcccag ccccgtggtg aactcaggag ggaatgtaac cctccagtgt 1020 gactcacagg tggcatttga tggcttcatt ctgtgtaagg aaggagaaga tgaacaccca 1080 caatgcctga actcccagcc ccatgcccgt gggtcgtccc gcgccatctt ctccgtgggc 1140 cccgtgagcc cgagtcgcag gtggtggtac aggtgctatg cttatgactc gaactctccc 1200 tatgagtggt ctctacccag tgatctcctg gagctcctgg tcctaggtgt ttctaagaag 1260 ccatcactct cagtgcagcc aggtcctatc gtggcccctg aggagaccct gactctgcag 1320 tgtggctctg atgctggcta caacagattt gttctgtata aggacgggga acgtgacttc 1380 cttcagctcg ctggcgcaca gccccaggct gggctctccc aggccaactt caccctgggc 1440 cctgtgagcc gctcctacgg gggccagtac agatgctacg gtgcacacaa cctctcctcc 1500 gagtggtcgg cccccagcga ccccctggac atcctgatcg caggacagtt ctatgacaga 1560 gtctccctct cggtgcagcc gggccccacg gtggcctcag gagagaacgt gaccctgctg 1620 tgtcagtcac agggatggat gcaaactttc cttctgacca aggagggggc agctgatgac 1680 ccatggcgtc taagatcaac gtaccaatct caaaaatacc aggctgaatt ccccatgggt 1740 cctgtgacct cagcccatgc ggggacctac aggtgctacg gctcacagag ctccaaaccc 1800 tacctgctga ctcaccccag tgaccccctg gagctcgtgg tctcaggacc gtctgggggc 1860 cccagctccc cgacaacagg ccccacctcc acatctggcc ctgaggacca gcccctcacc 1920 cccaccgggt cggatcccca gagtggtctg ggaaggcacc tgggggttgt gatcggcatc 1980 ttggtggccg tcatcctact gctcctcctc ctcctcctcc tcttcctcat cctccgacat 2040 cgacgtcagg gcaaacactg gacatcgacc cagagaaagg ctgatttcca acatcctgca 2100 ggggctgtgg ggccagagcc cacagacaga ggcctgcagt ggaggtccag cccagctgcc 2160 gatgcccagg aagaaaacct ctatgctgcc gtgaagcaca cacagcctga ggatggggtg 2220 gagatggaca ctcggagccc acacgatgaa gacccccagg cagtgacgta tgccgaggtg 2280 aaacactcca gacctaggag agaaatggcc tctcctcctt ccccactgtc tggggaattc 2340 ctggacacaa aggacagaca ggcggaagag gacaggcaga tggacactga ggctgctgca 2400 tctgaagccc cccaggatgt gacctacgcc cagctgcaca gcttgaccct cagacgggag 2460 gcaactgagc ctcctccatc ccaggaaggg ccctctccag ctgtgcccag catctacgcc 2520 actctggcca tccactagcc caggggggga cgcagacccc acactccatg gagtctggaa 2580 tgcatgggag ctgccccccc agtggacacc attggacccc acccagcctg gatctacccc 2640 aggagactct gggaactttt aggggtcact caattctgca gtataaataa ctaatgtctc 2700 tacaattttg aaataaagca acagacttct caataatcaa tgaagtagct gagaaaacta 2760 agtcagaaag tgcattaaac tgaatcacaa tgtaaatatt acacatcaag cgatgaaact 2820 ggaaaactac aagccacgaa tgaatgaatt aggaaagaaa aaaagtagga aatgaatgat 2880 cttggctttc ctataagaaa tttagggcag ggcacggtgg ctcacgcctg taattccagc 2940 actttgggag gccgaggcgg gcagatcacg agttcaggag atcgagacca tcttggccaa 3000 catggtgaaa ccctgtctct cctaaaaata caaaaattag ctggatgtgg tggcagtgcc 3060 tgtaatccca gctatttggg aggctgaggc aggagaatcg cttgaaccag ggagtcagag 3120 gtttcagtga gccaagatcg caccactgct ctccagcctg gcgacagagg gagactccat 3180 ctcaaattaa aaaaaaaaaa aaaaaagaaa gaaaaaaaaa aaaaaaaaa 3229 <![CDATA[<210> 115]]> <![CDATA[<211> 6]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 未知(Unknown)]]> <![CDATA[<220>]]> <![CDATA[<223> 基於免疫受體酪胺酸之抑制基元]]> <![CDATA[<400> 115]]> Asn Leu Tyr Ala Ala Val 1 5 <![CDATA[<210> 116]]> <![CDATA[<211> 6]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 未知(Unknown)]]> <![CDATA[<220>]]> <![CDATA[<223> 基於免疫受體酪胺酸之抑制基元]]> <![CDATA[<400> 116]]> Val Thr Tyr Ala Glu Val 1 5 <![CDATA[<210> 117]]> <![CDATA[<211> 6]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 未知(Unknown)]]> <![CDATA[<220>]]> <![CDATA[<223> 基於免疫受體酪胺酸之抑制基元]]> <![CDATA[<400> 117]]> Val Thr Tyr Ala Gln Leu 1 5 <![CDATA[<210> 118]]> <![CDATA[<211> 6]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 未知(Unknown)]]> <![CDATA[<220>]]> <![CDATA[<223> 基於免疫受體酪胺酸之抑制基元]]> <![CDATA[<400> 118]]> Ser Ile Tyr Ala Thr Leu 1 5 <![CDATA[<210> 119]]> <![CDATA[<211> 35]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 未知(Unknown)]]> <![CDATA[<220>]]> <![CDATA[<223> 細胞內結構域]]> <![CDATA[<400> 119]]> Asn Leu Tyr Ala Ala Val Lys His Thr Gln Pro Glu Asp Gly Val Glu 1 5 10 15 Met Asp Thr Arg Ser Pro His Asp Glu Asp Pro Gln Ala Val Thr Tyr 20 25 30 Ala Glu Val 35 <![CDATA[<210> 120]]> <![CDATA[<211> 58]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 未知(Unknown)]]> <![CDATA[<220>]]> <![CDATA[<223> 細胞內結構域]]> <![CDATA[<400> 120]]> Val Thr Tyr Ala Glu Val Lys His Ser Arg Pro Arg Arg Glu Met Ala 1 5 10 15 Ser Pro Pro Ser Pro Leu Ser Gly Glu Phe Leu Asp Thr Lys Asp Arg 20 25 30 Gln Ala Glu Glu Asp Arg Gln Met Asp Thr Glu Ala Ala Ala Ser Glu 35 40 45 Ala Pro Gln Asp Val Thr Tyr Ala Gln Leu 50 55 <![CDATA[<210> 121]]> <![CDATA[<211> 36]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 未知(Unknown)]]> <![CDATA[<220>]]> <![CDATA[<223> 細胞內結構域]]> <![CDATA[<400> 121]]> Val Thr Tyr Ala Gln Leu His Ser Leu Thr Leu Arg Arg Glu Ala Thr 1 5 10 15 Glu Pro Pro Pro Ser Gln Glu Gly Pro Ser Pro Ala Val Pro Ser Ile 20 25 30 Tyr Ala Thr Leu 35 <![CDATA[<210> 122]]> <![CDATA[<211> 87]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 未知(Unknown)]]> <![CDATA[<220>]]> <![CDATA[<223> 細胞內結構域]]> <![CDATA[<400> 122]]> Asn Leu Tyr Ala Ala Val Lys His Thr Gln Pro Glu Asp Gly Val Glu 1 5 10 15 Met Asp Thr Arg Ser Pro His Asp Glu Asp Pro Gln Ala Val Thr Tyr 20 25 30 Ala Glu Val Lys His Ser Arg Pro Arg Arg Glu Met Ala Ser Pro Pro 35 40 45 Ser Pro Leu Ser Gly Glu Phe Leu Asp Thr Lys Asp Arg Gln Ala Glu 50 55 60 Glu Asp Arg Gln Met Asp Thr Glu Ala Ala Ala Ser Glu Ala Pro Gln 65 70 75 80 Asp Val Thr Tyr Ala Gln Leu 85 <![CDATA[<210> 123]]> <![CDATA[<211> 88]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 未知(Unknown)]]> <![CDATA[<220>]]> <![CDATA[<223> 細胞內結構域]]> <![CDATA[<400> 123]]> Val Thr Tyr Ala Glu Val Lys His Ser Arg Pro Arg Arg Glu Met Ala 1 5 10 15 Ser Pro Pro Ser Pro Leu Ser Gly Glu Phe Leu Asp Thr Lys Asp Arg 20 25 30 Gln Ala Glu Glu Asp Arg Gln Met Asp Thr Glu Ala Ala Ala Ser Glu 35 40 45 Ala Pro Gln Asp Val Thr Tyr Ala Gln Leu His Ser Leu Thr Leu Arg 50 55 60 Arg Glu Ala Thr Glu Pro Pro Pro Ser Gln Glu Gly Pro Ser Pro Ala 65 70 75 80 Val Pro Ser Ile Tyr Ala Thr Leu 85 <![CDATA[<210> 124]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 未知(Unknown)]]> <![CDATA[<220>]]> <![CDATA[<223> 細胞內結構域]]> <![CDATA[<400> 124]]> Asn Leu Tyr Ala Ala Val Lys His Thr Gln Pro Glu Asp Gly Val Glu 1 5 10 15 Met Asp Thr Arg Ser Pro His Asp Glu Asp Pro Gln Ala Val Thr Tyr 20 25 30 Ala Glu Val Lys His Ser Arg Pro Arg Arg Glu Met Ala Ser Pro Pro 35 40 45 Ser Pro Leu Ser Gly Glu Phe Leu Asp Thr Lys Asp Arg Gln Ala Glu 50 55 60 Glu Asp Arg Gln Met Asp Thr Glu Ala Ala Ala Ser Glu Ala Pro Gln 65 70 75 80 Asp Val Thr Tyr Ala Gln Leu His Ser Leu Thr Leu Arg Arg Glu Ala 85 90 95 Thr Glu Pro Pro Pro Ser Gln Glu Gly Pro Ser Pro Ala Val Pro Ser 100 105 110 Ile Tyr Ala Thr Leu 115 <![CDATA[<210> 125]]> <![CDATA[<211> 20]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 未知(Unknown)]]> <![CDATA[<220>]]> <![CDATA[<223> LILRB1 D3D4結構域]]> <![CDATA[<400> 125]]> Tyr Gly Ser Gln Ser Ser Lys Pro Tyr Leu Leu Thr His Pro Ser Asp 1 5 10 15 Pro Leu Glu Leu 20 <![CDATA[<210> 126]]> <![CDATA[<211> 43]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 未知(Unknown)]]> <![CDATA[<220>]]> <![CDATA[<223> LILRB1鉸鏈結構域]]> <![CDATA[<400> 126]]> Val Val Ser Gly Pro Ser Gly Gly Pro Ser Ser Pro Thr Thr Gly Pro 1 5 10 15 Thr Ser Thr Ser Gly Pro Glu Asp Gln Pro Leu Thr Pro Thr Gly Ser 20 25 30 Asp Pro Gln Ser Gly Leu Gly Arg His Leu Gly 35 40 <![CDATA[<210> 127]]> <![CDATA[<211> 86]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 未知(Unknown)]]> <![CDATA[<220>]]> <![CDATA[<223> 鉸鏈-跨膜]]> <![CDATA[<400> 127]]> Tyr Gly Ser Gln Ser Ser Lys Pro Tyr Leu Leu Thr His Pro Ser Asp 1 5 10 15 Pro Leu Glu Leu Val Val Ser Gly Pro Ser Gly Gly Pro Ser Ser Pro 20 25 30 Thr Thr Gly Pro Thr Ser Thr Ser Gly Pro Glu Asp Gln Pro Leu Thr 35 40 45 Pro Thr Gly Ser Asp Pro Gln Ser Gly Leu Gly Arg His Leu Gly Val 50 55 60 Val Ile Gly Ile Leu Val Ala Val Ile Leu Leu Leu Leu Leu Leu Leu 65 70 75 80 Leu Leu Phe Leu Ile Leu 85 <![CDATA[<210> 128]]> <![CDATA[<211> 190]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 未知(Unknown)]]> <![CDATA[<220>]]> <![CDATA[<223> 跨膜-細胞內結構域]]> <![CDATA[<400> 128]]> Val Val Ile Gly Ile Leu Val Ala Val Ile Leu Leu Leu Leu Leu Leu 1 5 10 15 Leu Leu Leu Phe Leu Ile Leu Arg His Arg Arg Gln Gly Lys His Trp 20 25 30 Thr Ser Thr Gln Arg Lys Ala Asp Phe Gln His Pro Ala Gly Ala Val 35 40 45 Gly Pro Glu Pro Thr Asp Arg Gly Leu Gln Trp Arg Ser Ser Pro Ala 50 55 60 Ala Asp Ala Gln Glu Glu Asn Leu Tyr Ala Ala Val Lys His Thr Gln 65 70 75 80 Pro Glu Asp Gly Val Glu Met Asp Thr Arg Ser Pro His Asp Glu Asp 85 90 95 Pro Gln Ala Val Thr Tyr Ala Glu Val Lys His Ser Arg Pro Arg Arg 100 105 110 Glu Met Ala Ser Pro Pro Ser Pro Leu Ser Gly Glu Phe Leu Asp Thr 115 120 125 Lys Asp Arg Gln Ala Glu Glu Asp Arg Gln Met Asp Thr Glu Ala Ala 130 135 140 Ala Ser Glu Ala Pro Gln Asp Val Thr Tyr Ala Gln Leu His Ser Leu 145 150 155 160 Thr Leu Arg Arg Glu Ala Thr Glu Pro Pro Pro Ser Gln Glu Gly Pro 165 170 175 Ser Pro Ala Val Pro Ser Ile Tyr Ala Thr Leu Ala Ile His 180 185 190 <![CDATA[<210> 129]]> <![CDATA[<211> 167]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 未知(Unknown)]]> <![CDATA[<220>]]> <![CDATA[<223> LILRB1細胞內結構域]]> <![CDATA[<400> 129]]> Arg His Arg Arg Gln Gly Lys His Trp Thr Ser Thr Gln Arg Lys Ala 1 5 10 15 Asp Phe Gln His Pro Ala Gly Ala Val Gly Pro Glu Pro Thr Asp Arg 20 25 30 Gly Leu Gln Trp Arg Ser Ser Pro Ala Ala Asp Ala Gln Glu Glu Asn 35 40 45 Leu Tyr Ala Ala Val Lys His Thr Gln Pro Glu Asp Gly Val Glu Met 50 55 60 Asp Thr Arg Ser Pro His Asp Glu Asp Pro Gln Ala Val Thr Tyr Ala 65 70 75 80 Glu Val Lys His Ser Arg Pro Arg Arg Glu Met Ala Ser Pro Pro Ser 85 90 95 Pro Leu Ser Gly Glu Phe Leu Asp Thr Lys Asp Arg Gln Ala Glu Glu 100 105 110 Asp Arg Gln Met Asp Thr Glu Ala Ala Ala Ser Glu Ala Pro Gln Asp 115 120 125 Val Thr Tyr Ala Gln Leu His Ser Leu Thr Leu Arg Arg Glu Ala Thr 130 135 140 Glu Pro Pro Pro Ser Gln Glu Gly Pro Ser Pro Ala Val Pro Ser Ile 145 150 155 160 Tyr Ala Thr Leu Ala Ile His 165 <![CDATA[<210> 130]]> <![CDATA[<211> 253]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 未知(Unknown)]]> <![CDATA[<220>]]> <![CDATA[<223> LILRB1鉸鏈-跨膜-細胞內結構域]]> <![CDATA[<400> 130]]> Tyr Gly Ser Gln Ser Ser Lys Pro Tyr Leu Leu Thr His Pro Ser Asp 1 5 10 15 Pro Leu Glu Leu Val Val Ser Gly Pro Ser Gly Gly Pro Ser Ser Pro 20 25 30 Thr Thr Gly Pro Thr Ser Thr Ser Gly Pro Glu Asp Gln Pro Leu Thr 35 40 45 Pro Thr Gly Ser Asp Pro Gln Ser Gly Leu Gly Arg His Leu Gly Val 50 55 60 Val Ile Gly Ile Leu Val Ala Val Ile Leu Leu Leu Leu Leu Leu Leu 65 70 75 80 Leu Leu Phe Leu Ile Leu Arg His Arg Arg Gln Gly Lys His Trp Thr 85 90 95 Ser Thr Gln Arg Lys Ala Asp Phe Gln His Pro Ala Gly Ala Val Gly 100 105 110 Pro Glu Pro Thr Asp Arg Gly Leu Gln Trp Arg Ser Ser Pro Ala Ala 115 120 125 Asp Ala Gln Glu Glu Asn Leu Tyr Ala Ala Val Lys His Thr Gln Pro 130 135 140 Glu Asp Gly Val Glu Met Asp Thr Arg Ser Pro His Asp Glu Asp Pro 145 150 155 160 Gln Ala Val Thr Tyr Ala Glu Val Lys His Ser Arg Pro Arg Arg Glu 165 170 175 Met Ala Ser Pro Pro Ser Pro Leu Ser Gly Glu Phe Leu Asp Thr Lys 180 185 190 Asp Arg Gln Ala Glu Glu Asp Arg Gln Met Asp Thr Glu Ala Ala Ala 195 200 205 Ser Glu Ala Pro Gln Asp Val Thr Tyr Ala Gln Leu His Ser Leu Thr 210 215 220 Leu Arg Arg Glu Ala Thr Glu Pro Pro Pro Ser Gln Glu Gly Pro Ser 225 230 235 240 Pro Ala Val Pro Ser Ile Tyr Ala Thr Leu Ala Ile His 245 250 <![CDATA[<210> 131]]> <![CDATA[<211> 233]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 未知(Unknown)]]> <![CDATA[<220>]]> <![CDATA[<223> LILRB1鉸鏈-跨膜-細胞內結構域]]> <![CDATA[<400> 131]]> Val Val Ser Gly Pro Ser Gly Gly Pro Ser Ser Pro Thr Thr Gly Pro 1 5 10 15 Thr Ser Thr Ser Gly Pro Glu Asp Gln Pro Leu Thr Pro Thr Gly Ser 20 25 30 Asp Pro Gln Ser Gly Leu Gly Arg His Leu Gly Val Val Ile Gly Ile 35 40 45 Leu Val Ala Val Ile Leu Leu Leu Leu Leu Leu Leu Leu Leu Phe Leu 50 55 60 Ile Leu Arg His Arg Arg Gln Gly Lys His Trp Thr Ser Thr Gln Arg 65 70 75 80 Lys Ala Asp Phe Gln His Pro Ala Gly Ala Val Gly Pro Glu Pro Thr 85 90 95 Asp Arg Gly Leu Gln Trp Arg Ser Ser Pro Ala Ala Asp Ala Gln Glu 100 105 110 Glu Asn Leu Tyr Ala Ala Val Lys His Thr Gln Pro Glu Asp Gly Val 115 120 125 Glu Met Asp Thr Arg Ser Pro His Asp Glu Asp Pro Gln Ala Val Thr 130 135 140 Tyr Ala Glu Val Lys His Ser Arg Pro Arg Arg Glu Met Ala Ser Pro 145 150 155 160 Pro Ser Pro Leu Ser Gly Glu Phe Leu Asp Thr Lys Asp Arg Gln Ala 165 170 175 Glu Glu Asp Arg Gln Met Asp Thr Glu Ala Ala Ala Ser Glu Ala Pro 180 185 190 Gln Asp Val Thr Tyr Ala Gln Leu His Ser Leu Thr Leu Arg Arg Glu 195 200 205 Ala Thr Glu Pro Pro Pro Ser Gln Glu Gly Pro Ser Pro Ala Val Pro 210 215 220 Ser Ile Tyr Ala Thr Leu Ala Ile His 225 230 <![CDATA[<210> 132]]> <![CDATA[<211> 63]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 未知(Unknown)]]> <![CDATA[<220>]]> <![CDATA[<223> LILRB1鉸鏈結構域]]> <![CDATA[<400> 132]]> Tyr Gly Ser Gln Ser Ser Lys Pro Tyr Leu Leu Thr His Pro Ser Asp 1 5 10 15 Pro Leu Glu Leu Val Val Ser Gly Pro Ser Gly Gly Pro Ser Ser Pro 20 25 30 Thr Thr Gly Pro Thr Ser Thr Ser Gly Pro Glu Asp Gln Pro Leu Thr 35 40 45 Pro Thr Gly Ser Asp Pro Gln Ser Gly Leu Gly Arg His Leu Gly 50 55 60 <![CDATA[<210> 133]]> <![CDATA[<211> 23]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 未知(Unknown)]]> <![CDATA[<220>]]> <![CDATA[<223> LILRB1跨膜結構域]]> <![CDATA[<400> 133]]> Val Val Ile Gly Ile Leu Val Ala Val Ile Leu Leu Leu Leu Leu Leu 1 5 10 15 Leu Leu Leu Phe Leu Ile Leu 20 <![CDATA[<210> 134]]> <![CDATA[<211> 227]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人(Homo sapiens)]]> <![CDATA[<220>]]> <![CDATA[<221> 位點]]> <![CDATA[<222> (1)..(1)]]> <![CDATA[<223> Xaa可為任何天然存在之胺基酸]]> <![CDATA[<400> 134]]> Xaa Asp Val Ala Tyr Asp Leu Trp Arg Glu Glu Asn Gly Cys Glu Cys 1 5 10 15 Thr Lys Ala Val Asn Phe Ala Met His Glu Leu Gln Leu Ile Arg Val 20 25 30 Glu Lys Gln Tyr Leu His His Asn Leu Asp His Leu Val Glu Glu Leu 35 40 45 Phe Leu Gly Asp Ile His Thr Asp Ala Thr Gln Arg Met Phe Tyr Arg 50 55 60 Pro Ser Ser Tyr Gln Pro Pro Leu Gln Asn Ala Lys Cys Ala Ala Glu 65 70 75 80 Ser Ser Gly Ser Phe Gln Ile Leu Pro Gln Asp Ser Ser Glu Lys Glu 85 90 95 Gln Asn Gly Leu Ser His Trp Cys Leu Ser Arg Pro Gly His Gln Lys 100 105 110 Asp Trp Ala Leu Cys Ala His Ala Gly Pro Ala Thr Ala Gly Cys Pro 115 120 125 Ser Cys Leu Trp Pro Pro Ala Glu Thr Gly Arg Lys Ala Gly Arg Thr 130 135 140 Ser Ser Lys Thr Val His Ala Cys Pro Gly Glu Ala Gly Thr Ser Ser 145 150 155 160 Phe Glu Leu Phe Tyr Phe Pro Asn Cys Trp Ser Ile Glu Thr Lys Leu 165 170 175 Lys Ile Ser Leu Asn Ala Lys Leu Ser Phe Lys Pro Arg Ala Ser Ala 180 185 190 Pro Leu Glu Thr Gly His Arg Val Lys Ile Glu Thr Leu Ser Gln Leu 195 200 205 Val Phe Leu Ser Phe Ile Gln Leu Cys Cys Glu Val Gln Ser Pro Leu 210 215 220 Ala Asn Lys 225 <![CDATA[<210> 135]]> <![CDATA[<211> 94]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人(Homo sapiens)]]> <![CDATA[<400> 135]]> Pro Glu Asp Val Leu Pro Ala Leu Gln Leu Pro Ala Pro Ser Ala Glu 1 5 10 15 Cys Gln Val Glu Met Gly Phe His His Val Gly Gln Asp Gly Leu Gln 20 25 30 Leu Pro Thr Ser Ser Asp Pro Pro Ala Leu Ala Ser Gln Ser Ala Gly 35 40 45 Ile Thr Gly Val Ser His Arg Pro Pro Gly Arg His Leu Ser Asn Asp 50 55 60 Leu Arg Thr Thr Thr Met Pro Ala Ser Pro Val Gly Ser Ser Ile Gly 65 70 75 80 Gln Thr Ser Thr Thr Leu Pro Ser Cys Pro Gln Arg Gln Thr 85 90 <![CDATA[<210> 136]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 連接子]]> <![CDATA[<400> 136]]> Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 1 5 10 15 Gly <![CDATA[<210> 137]]> <![CDATA[<211> 22]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 信號序列]]> <![CDATA[<400> 137]]> Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp 1 5 10 15 Leu Arg Gly Ala Arg Cys 20 <![CDATA[<210> 138]]> <![CDATA[<211> 66]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 信號序列]]> <![CDATA[<400> 138]]> atggacatga gggtccccgc tcagctcctg gggctcctgc tactctggct ccgaggtgcc 60 agatgt 66 <![CDATA[<210> 139]]> <![CDATA[<211> 747]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CT-478 EGFR (VH-VL scFv格式)]]> <![CDATA[<400> 139]]> caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60 tcctgtgcag cgtctggatt caccttcagt acctatggca tgcactgggt ccgccaggct 120 ccaggcaagg ggctggagtg ggtggcagtt atatgggatg atggaagtta taaatactat 180 ggagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240 ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gagagatggt 300 attactatgg ttcggggagt tatgaaggac tactttgact actggggcca gggaaccctg 360 gtcaccgtct cctcaggcgg aggtggaagc ggagggggag gatctggcgg cggaggaagc 420 ggaggcgcca tccagttgac ccagtctcca tcctccctgt ctgcatctgt aggagacaga 480 gtcaccatca cttgccgggc aagtcaggac attagcagtg ctttagtctg gtatcagcag 540 aaaccaggga aagctcctaa gctcctgatc tatgatgcct ccagtttgga aagtggggtc 600 ccatcaaggt tcagcggcag tgaatctggg acagatttca ctctcaccat cagcagcctg 660 cagcctgaag attttgcaac ttattactgt caacagttta atagttaccc gctcactttc 720 ggcggaggga ccaaggtgga gatcaaa 747 <![CDATA[<210> 140]]> <![CDATA[<211> 747]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CT-479 EGFR (VL-VH scFv格式)]]> <![CDATA[<400> 140]]> gccatccagt tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60 atcacttgcc gggcaagtca ggacattagc agtgctttag tctggtatca gcagaaacca 120 gggaaagctc ctaagctcct gatctatgat gcctccagtt tggaaagtgg ggtcccatca 180 aggttcagcg gcagtgaatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240 gaagattttg caacttatta ctgtcaacag tttaatagtt acccgctcac tttcggcgga 300 gggaccaagg tggagatcaa aggcggaggt ggaagcggag ggggaggatc tggcggcgga 360 ggaagcggag gccaggtgca gctggtggag tctgggggag gcgtggtcca gcctgggagg 420 tccctgagac tctcctgtgc agcgtctgga ttcaccttca gtacctatgg catgcactgg 480 gtccgccagg ctccaggcaa ggggctggag tgggtggcag ttatatggga tgatggaagt 540 tataaatact atggagactc cgtgaagggc cgattcacca tctccagaga caattccaag 600 aacacgctgt atctgcaaat gaacagcctg agagccgagg acacggctgt gtattactgt 660 gcgagagatg gtattactat ggttcgggga gttatgaagg actactttga ctactggggc 720 cagggaaccc tggtcaccgt ctcctca 747 <![CDATA[<210> 141]]> <![CDATA[<211> 741]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CT-480 EGFR (VH-VL scFv格式)]]> <![CDATA[<400> 141]]> cagatccagt tggtgcagtc tggacctgag ctgaagaagc ctggagagac agtcaagatc 60 tcctgcaagg cctctgggta taccttcaca gaatatccaa tacactgggt gaagcaggct 120 ccaggaaagg gtttcaagtg gatgggcatg atatacaccg acattggaaa gccaacatat 180 gctgaagagt tcaagggacg gtttgccttc tctttggaga cctctgccag cactgcctat 240 ttgcagatca acaacctcaa gaatgaggac acggctacat atttctgtgt aagagatcga 300 tatgattccc tctttgacta ctggggccaa ggcaccactc tcacagtctc ctcaggcgga 360 ggtggaagcg gagggggagg atctggcggc ggaggaagcg gaggcgatgt tgtgatgacc 420 caaactccac tctccctgcc tgtcagtctt ggagatcaag cctccatctc ttgcagatct 480 agtcagagcc ttgtacacag taatggaaac acctatttac attggtacct gcagaagcca 540 ggccagtctc caaagctcct gatctacaaa gtttccaacc gattttctgg ggtcccagac 600 aggttcagtg gcagtggatc agggacagat ttcacactca agatcagcag agtggaggct 660 gaggatctgg gagtttattt ctgctctcaa agtacacatg ttccgtggac gttcggtgga 720 ggcaccaagc tggaaatcaa a 741 <![CDATA[<210> 142]]> <![CDATA[<211> 741]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CT-481 EGFR (VL-VH scFv格式)]]> <![CDATA[<400> 142]]> gatgttgtga tgacccaaac tccactctcc ctgcctgtca gtcttggaga tcaagcctcc 60 atctcttgca gatctagtca gagccttgta cacagtaatg gaaacaccta tttacattgg 120 tacctgcaga agccaggcca gtctccaaag ctcctgatct acaaagtttc caaccgattt 180 tctggggtcc cagacaggtt cagtggcagt ggatcaggga cagatttcac actcaagatc 240 agcagagtgg aggctgagga tctgggagtt tatttctgct ctcaaagtac acatgttccg 300 tggacgttcg gtggaggcac caagctggaa atcaaaggcg gaggtggaag cggaggggga 360 ggatctggcg gcggaggaag cggaggccag atccagttgg tgcagtctgg acctgagctg 420 aagaagcctg gagagacagt caagatctcc tgcaaggcct ctgggtatac cttcacagaa 480 tatccaatac actgggtgaa gcaggctcca ggaaagggtt tcaagtggat gggcatgata 540 tacaccgaca ttggaaagcc aacatatgct gaagagttca agggacggtt tgccttctct 600 ttggagacct ctgccagcac tgcctatttg cagatcaaca acctcaagaa tgaggacacg 660 gctacatatt tctgtgtaag agatcgatat gattccctct ttgactactg gggccaaggc 720 accactctca cagtctcctc a 741 <![CDATA[<210> 143]]> <![CDATA[<211> 747]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CT-482 EGFR (VH-VL scFv格式)]]> <![CDATA[<400> 143]]> gaaatgcagc tggtggagtc tgggggaggc ttcgtgaagc ctggagggtc cctgaaactc 60 tcatgtgcag cctctggatt cgctttcagt cactatgaca tgtcttgggt tcgccagact 120 ccgaagcaga ggctggagtg ggtcgcatac attgctagtg gtggtgatat cacctactat 180 gcagacactg tgaagggccg attcaccatc tccagagaca atgcccagaa caccctgtac 240 ctgcaaatga gcagtctgaa gtctgaggac acagccatgt tttactgttc acgatcctcc 300 tatggtaaca acggagatgc cctggacttc tggggtcaag gtacctcagt caccgtctcc 360 tcaggcggag gtggaagcgg agggggagga tctggcggcg gaggaagcgg aggcgatgtt 420 gtgatgaccc aaactccact ctccctgcct gtcagtcttg gagatcaagc ctccatctct 480 tgcagatcta gtcagagcct tgttcacagt aatggaaaca cctatttaca ttggtacctg 540 cagaagccag gccagtctcc aaagctcctg atctacaaag tttccaaccg attttctggg 600 gtcccagaca ggttcagtgg cagtggatca gggacagatt tcacactcaa gatcagcaga 660 gtggaggctg aggatctggg agtttatttc tgctctcaaa gtacacatgt tctcacgttc 720 ggctcgggga caaagttgga aataaaa 747 <![CDATA[<210> 144]]> <![CDATA[<211> 747]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CT-483 EGFR (VL-VH scFv格式)]]> <![CDATA[<400> 144]]> gatgttgtga tgacccaaac tccactctcc ctgcctgtca gtcttggaga tcaagcctcc 60 atctcttgca gatctagtca gagccttgtt cacagtaatg gaaacaccta tttacattgg 120 tacctgcaga agccaggcca gtctccaaag ctcctgatct acaaagtttc caaccgattt 180 tctggggtcc cagacaggtt cagtggcagt ggatcaggga cagatttcac actcaagatc 240 agcagagtgg aggctgagga tctgggagtt tatttctgct ctcaaagtac acatgttctc 300 acgttcggct cggggacaaa gttggaaata aaaggcggag gtggaagcgg agggggagga 360 tctggcggcg gaggaagcgg aggcgaaatg cagctggtgg agtctggggg aggcttcgtg 420 aagcctggag ggtccctgaa actctcatgt gcagcctctg gattcgcttt cagtcactat 480 gacatgtctt gggttcgcca gactccgaag cagaggctgg agtgggtcgc atacattgct 540 agtggtggtg atatcaccta ctatgcagac actgtgaagg gccgattcac catctccaga 600 gacaatgccc agaacaccct gtacctgcaa atgagcagtc tgaagtctga ggacacagcc 660 atgttttact gttcacgatc ctcctatggt aacaacggag atgccctgga cttctggggt 720 caaggtacct cagtcaccgt ctcctca 747 <![CDATA[<210> 145]]> <![CDATA[<211> 729]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CT-486 EGFR (VH-VL scFv格式)]]> <![CDATA[<400> 145]]> caggtgcagc tgaagcagtc cggccccggc ctggtgcagc cctcccagtc cctgtccatc 60 acctgcaccg tgtccggctt ctccctgacc aactacggcg tgcactgggt gcggcagtcc 120 cccggcaagg gcctggagtg gctgggcgtg atctggtccg gcggcaacac cgactacaac 180 acccccttca cctcccggct gtccatcaac aaggacaact ccaagtccca ggtgttcttc 240 aagatgaact ccctgcagtc caacgacacc gccatctact actgcgcccg ggccctgacc 300 tactacgact acgagttcgc ctactggggc cagggcaccc tggtgaccgt gtccgccggc 360 ggaggtggaa gcggaggggg aggatctggc ggcggaggaa gcggaggcga catcctgctg 420 acccagtccc ccgtgatcct gtccgtgtcc cccggcgagc gggtgtcctt ctcctgccgg 480 gcctcccagt ccatcggcac caacatccac tggtaccagc agcggaccaa cggctccccc 540 cggctgctga tcaagtacgc ctccgagtcc atctccggca tcccctcccg gttctccggc 600 tccggctccg gcaccgactt caccctgtcc atcaactccg tggagtccga ggacatcgcc 660 gactactact gccagcagaa caacaactgg cccaccacct tcggcgccgg caccaagctg 720 gagctgaag 729 <![CDATA[<210> 146]]> <![CDATA[<211> 732]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CT-487 EGFR (VH-VL scFv格式)]]> <![CDATA[<400> 146]]> caggtgcagc tggtgcagtc cggcgccgag gtgaagaagc ccggcgcctc cgtgaaggtg 60 tcctgcaagg cctccggcta caccttcacc tcccactgga tgcactgggt gcggcaggcc 120 cccggccagg gcctggagtg gatcggcgag ttcaacccct ccaacggccg gaccaactac 180 aacgagaagt tcaagtccaa ggccaccatg accgtggaca cctccaccaa caccgcctac 240 atggagctgt cctccctgcg gtccgaggac accgccgtgt actactgcgc ctcccgggac 300 tacgactacg acggccggta cttcgactac tggggccagg gcaccctggt gaccgtgtcc 360 tccggcggag gtggaagcgg agggggagga tctggcggcg gaggaagcgg aggcgacatc 420 cagatgaccc agtccccctc ctccctgtcc gcctccgtgg gcgaccgggt gaccatcacc 480 tgctccgcct cctcctccgt gacctacatg tactggtacc agcagaagcc cggcaaggcc 540 cccaagctgc tgatctacga cacctccaac ctggcctccg gcgtgccctc ccggttctcc 600 ggctccggct ccggcaccga ctacaccttc accatctcct ccctgcagcc cgaggacatc 660 gccacctact actgccagca gtggtcctcc cacatcttca ccttcggcca gggcaccaag 720 gtggagatca ag 732 <![CDATA[<210> 147]]> <![CDATA[<211> 729]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CT-488 EGFR (VH-VL scFv格式)]]> <![CDATA[<400> 147]]> caggtgcagc tgcaggagtc cggccccggc ctggtgaagc cctccgagac cctgtccctg 60 acctgcaccg tgtccggcgg ctccgtgtcc tccggcgact actactggac ctggatccgg 120 cagtcccccg gcaagggcct ggagtggatc ggccacatct actactccgg caacaccaac 180 tacaacccct ccctgaagtc ccggctgacc atctccatcg acacctccaa gacccagttc 240 tccctgaagc tgtcctccgt gaccgccgcc gacaccgcca tctactactg cgtgcgggac 300 cgggtgaccg gcgccttcga catctggggc cagggcacca tggtgaccgt gtcctccggc 360 ggaggtggaa gcggaggggg aggatctggc ggcggaggaa gcggaggcga catccagatg 420 acccagtccc cctcctccct gtccgcctcc gtgggcgacc gggtgaccat cacctgccag 480 gcctcccagg acatctccaa ctacctgaac tggtaccagc agaagcccgg caaggccccc 540 aagctgctga tctacgacgc ctccaacctg gagaccggcg tgccctcccg gttctccggc 600 tccggctccg gcaccgactt caccttcacc atctcctccc tgcagcccga ggacatcgcc 660 acctacttct gccagcactt cgaccacctg cccctggcct tcggcggcgg caccaaggtg 720 gagatcaag 729 <![CDATA[<210> 148]]> <![CDATA[<211> 735]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CT-489 EGFR scFv]]> <![CDATA[<400> 148]]> caggtccagc tccaagagtc aggaccaggt ctggtcaaac cctcacagac gctctctctt 60 acttgcacag tatcaggcgg atccattagt tccggtgatt attactggtc ttggatccgc 120 cagcctcctg gtaaggggct ggagtggatc ggatacatat actacagtgg ttccactgat 180 tataatccgt cactcaagtc ccgagtaact atgtccgtgg atactagcaa aaatcagttc 240 agcctcaaag tcaattccgt aactgccgcc gacaccgcgg tctattattg tgcgcgggtg 300 agcatcttcg gcgtcggtac gttcgattac tggggacaag gaactctcgt aacagtaagc 360 tctggcggag gtggaagcgg agggggagga tctggcggcg gaggaagcgg aggcgagatt 420 gtaatgaccc aaagccctgc cactctttct ctgtctccgg gggaacgagc gactctgtca 480 tgtagggcgt cccagagtgt ctctagctac ctcgcatggt atcagcagaa acccggacaa 540 gcccctcggc tcttgattta cgatgcctca aacagagcaa cggggattcc ggcacggttc 600 agcgggtctg gtagcgggac agacttcaca ctgacgatct cttcactcga accagaagat 660 tttgcagtct actattgcca tcagtatggt tctacgccac ttacatttgg cgggggcacc 720 aaggcggaga taaaa 735 <![CDATA[<210> 149]]> <![CDATA[<211> 121]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> EGFR VH CT489]]> <![CDATA[<400> 149]]> Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly 20 25 30 Asp Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Asp Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Val Thr Met Ser Val Asp Thr Ser Lys Asn Gln Phe 65 70 75 80 Ser Leu Lys Val Asn Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Val Ser Ile Phe Gly Val Gly Thr Phe Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <![CDATA[<210> 150]]> <![CDATA[<211> 107]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> EGFR VL CT489]]> <![CDATA[<400> 150]]> Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys His Gln Tyr Gly Ser Thr Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Ala Glu Ile Lys 100 105 <![CDATA[<210> 151]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> EGFR抗原結合結構域CDR H1]]> <![CDATA[<400> 151]]> Ser Gly Asp Tyr Tyr Trp Ser 1 5 <![CDATA[<210> 152]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> EGFR抗原結合結構域CDR H2]]> <![CDATA[<400> 152]]> Tyr Ile Tyr Tyr Ser Gly Ser Thr Asp Tyr Asn Pro Ser Leu Lys Ser 1 5 10 15 <![CDATA[<210> 153]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> EGFR抗原結合結構域CDR H3]]> <![CDATA[<400> 153]]> Val Ser Ile Phe Gly Val Gly Thr Phe Asp Tyr 1 5 10 <![CDATA[<210> 154]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> EGFR抗原結合結構域CDR L1]]> <![CDATA[<400> 154]]> Arg Ala Ser Gln Ser Val Ser Ser Tyr Leu Ala 1 5 10 <![CDATA[<210> 155]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> EGFR抗原結合結構域CDR L2]]> <![CDATA[<400> 155]]> Asp Ala Ser Asn Arg Ala Thr 1 5 <![CDATA[<210> 156]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> EGFR抗原結合結構域CDR L3]]> <![CDATA[<400> 156]]> His Gln Tyr Gly Ser Thr Pro Leu Thr 1 5 <![CDATA[<210> 157]]> <![CDATA[<211> 4]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 未知(Unknown)]]> <![CDATA[<220>]]> <![CDATA[<223> 基於免疫受體酪胺酸之活化基元]]> <![CDATA[<220>]]> <![CDATA[<221> 位點]]> <![CDATA[<222> (2)..(3)]]> <![CDATA[<223> Xaa為任何胺基酸]]> <![CDATA[<220>]]> <![CDATA[<221> 位點]]> <![CDATA[<222> (4)..(4)]]> <![CDATA[<223> Xaa為Leu或Ile]]> <![CDATA[<400> 157]]> Tyr Xaa Xaa Xaa 1 <![CDATA[<210> 158]]> <![CDATA[<211> 195]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 未知(Unknown)]]> <![CDATA[<220>]]> <![CDATA[<223> CAR細胞內結構域]]> <![CDATA[<400> 158]]> Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met Asn Met Thr 1 5 10 15 Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro 20 25 30 Pro Arg Asp Phe Ala Ala Tyr Arg Ser Lys Arg Gly Arg Lys Lys Leu 35 40 45 Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln 50 55 60 Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly 65 70 75 80 Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr 85 90 95 Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg 100 105 110 Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met 115 120 125 Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu 130 135 140 Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys 145 150 155 160 Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu 165 170 175 Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu 180 185 190 Pro Pro Arg 195 <![CDATA[<210> 159]]> <![CDATA[<211> 42]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 未知(Unknown)]]> <![CDATA[<220>]]> <![CDATA[<223> 4-1BB共刺激結構域]]> <![CDATA[<400> 159]]> Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met 1 5 10 15 Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe 20 25 30 Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu 35 40 <![CDATA[<210> 160]]> <![CDATA[<211> 126]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 未知(Unknown)]]> <![CDATA[<220>]]> <![CDATA[<223> 4-1BB共刺激結構域]]> <![CDATA[<400> 160]]> aaacggggca gaaagaaact cctgtatata ttcaaacaac catttatgag gccagtacaa 60 actactcaag aggaagatgg ctgtagctgc cgatttccag aagaagaaga aggaggatgt 120 gaactg 126 <![CDATA[<210> 161]]> <![CDATA[<211> 741]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> C-001765 PA2.1 scFv (小鼠)]]> <![CDATA[<400> 161]]> gatgttctga tgacccaaac tccactctcc ctgcctgtca gtcttggaga tcaagcctcc 60 atctcttgca gatctagtca gagcattgta catagtaatg gaaacaccta tttagaatgg 120 tacctgcaga agccaggcca gtctccaaag ctgctcatct acaaagtttc caaccgattt 180 tctggggtcc cagacagatt tagcggatct ggctctggga ccgatttcac actcaagatc 240 agtagagtgg aggctgagga tctgggagtt tattactgct ttcaaggttc acatgttcct 300 cggacgtccg gtggaggcac aaagctggaa atcaagggag gtggcggctc tggaggcgga 360 ggtagcggag gtggaggctc tggtggccag gtccagctgc agcagtctgg acctgagctg 420 gtgaagccag gggcttcagt gaggatatcc tgtaaggcct ctggctacac ctttacaagt 480 taccatatac attgggtgaa gcagaggcct ggacagggac tcgaatggat tggatggatt 540 tatcctggaa atgttaatac tgagtacaat gagaagttca agggcaaggc cacactgact 600 gcagacaaat cgtccagcac agcctacatg cacctcagca gcctgacctc tgaggactct 660 gcggtctatt tctgtgccag agaggagatt acctatgcta tggattattg gggtcaagga 720 acctcagtca ccgtgtcctc a 741 <![CDATA[<210> 162]]> <![CDATA[<211> 741]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> C-002159 PA2.1.8 scFv (人源化)]]> <![CDATA[<400> 162]]> caggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctgggtcctc agtgaaggtt 60 tcctgcaagg cttctggata caccttcact agctatcata tacattgggt gcgccaggcc 120 cccggacaag ggcttgagtg gatgggatgg atctaccctg gcaatgttaa cacagaatat 180 aatgagaagt tcaagggcaa agccaccatt accgcggaca aatccacgag cacagcctac 240 atggagctga gcagcctgag atctgaagac acggctgtgt attactgtgc gagggaggaa 300 attacctacg ctatggacta ctggggccag ggaaccacag tcaccgtgtc ctcaggcgga 360 ggtggaagcg gagggggagg atctggcggc ggaggaagcg gaggcgagat tgtattgacc 420 cagagcccag gcaccctgag cctctctcca ggagagcggg ccaccctcag ttgtagatcc 480 agtcagagta ttgtacacag taatgggaac acctatttgg aatggtatca gcagaaacca 540 ggtcaagccc caagattgct catctacaaa gtctctaaca gatttagtgg tattccagac 600 aggttcagcg gttccggaag tggtactgat ttcaccctca cgatctccag gctcgagcca 660 gaagatttcg ccgtttatta ctgttttcaa ggttcacatg tgccgcgcac attcggtggg 720 ggtactaaag tagaaatcaa a 741 <![CDATA[<210> 163]]> <![CDATA[<211> 741]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> C-002160 PA2.1.9 scFv (人源化)]]> <![CDATA[<400> 163]]> caggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctgggtcctc agtgaaggtt 60 tcctgcaagg cttctggata caccttcact agctatcata tacattgggt gcgccaggcc 120 cccggacaag ggcttgagtg gatgggatgg atctaccctg gcaatgttaa cacagaatat 180 aatgagaagt tcaagggcaa agccaccatt accgcggaca aatccacgag cacagcctac 240 atggagctga gcagcctgag atctgaagac acggctgtgt attactgtgc gagggaggaa 300 attacctacg ctatggacta ctggggccag ggaaccacag tcaccgtgtc ctcaggcgga 360 ggtggaagcg gagggggagg atctggcggc ggaggaagcg gaggcgacat tgtaatgacc 420 cagaccccac tcagcctgcc cgtcactcca ggagagccgg ccagcatcag ttgtagatcc 480 agtcagagta ttgtacacag taatgggaac acctatttgg aatggtatct gcagaaacca 540 ggtcaatccc cacaattgct catctacaaa gtctctaaca gatttagtgg tgtaccagac 600 aggttcagcg gttccggaag tggtactgat ttcaccctca agatctccag ggtcgaggca 660 gaagatgtcg gcgtttatta ctgttttcaa ggttcacatg tgccgcgcac attcggtggg 720 ggtactaaag tagaaatcaa a 741 <![CDATA[<210> 164]]> <![CDATA[<211> 741]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> C-002161 PA2.1.10 scFv (人源化)]]> <![CDATA[<400> 164]]> gaggtgcagc tggtggagtc tgggggtggg ctggtgaagc ctgggggctc actgaggctt 60 tcctgcgcgg cttctggata caccttcact agctatcata tacattgggt gcgccaggcc 120 cccggaaaag ggcttgagtg ggtgggatgg atctaccctg gcaatgttaa cacagaatat 180 aatgagaagt tcaagggcag attcaccatt agcagggacg attccaagaa cacactctac 240 ctgcagatga acagcctgaa aactgaagac acggctgtgt attactgtgc gagggaggaa 300 attacctacg ctatggacta ctggggccag ggaaccacag tcaccgtgtc ctcaggcgga 360 ggtggaagcg gagggggagg atctggcggc ggaggaagcg gaggcgacat tcaaatgacc 420 cagagcccat ccagcctgag cgcatctgta ggtgaccggg tcaccatcac ttgtagatcc 480 agtcagagta ttgtacacag taatgggaac acctatttgg aatggtatca gcagaaacca 540 ggtaaagccc caaaattgct catctacaaa gtctctaaca gatttagtgg tgtaccaagc 600 aggttcagcg gttccggaag tggtactgat ttcaccctca cgatctcctc tctccagcca 660 gaagatttcg ccacttatta ctgttttcaa ggttcacatg tgccgcgcac attcggtggg 720 ggtactaaag tagaaatcaa a 741 <![CDATA[<210> 165]]> <![CDATA[<211> 741]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> C-002162 PA2.1.14 scFv (人源化)]]> <![CDATA[<400> 165]]> caggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctgggtcctc agtgaaggtt 60 tcctgcaagg cttctggata caccttcact agctatcata tacattgggt gcgccaggcc 120 cccggacaag ggcttgagtg gatcggatgg atctaccctg gcaatgttaa cacagaatat 180 aatgagaagt tcaagggcaa agccaccatt accgcggacg aatccacgaa cacagcctac 240 atggagctga gcagcctgag atctgaagac acggctgtgt attactgtgc gagggaggaa 300 attacctacg ctatggacta ctggggccag ggaaccctgg tcaccgtgtc ctcaggaggt 360 ggcggctctg gaggcggagg tagcggaggt ggaggctctg gtggcgacat tcaaatgacc 420 cagagcccat ccaccctgag cgcatctgta ggtgaccggg tcaccatcac ttgtagatcc 480 agtcagagta ttgtacacag taatgggaac acctatttgg aatggtatca gcagaaacca 540 ggtaaagccc caaaattgct catctacaaa gtctctaaca gatttagtgg tgtaccagcc 600 aggttcagcg gttccggaag tggtactgaa ttcaccctca cgatctcctc tctccagcca 660 gatgatttcg ccacttatta ctgttttcaa ggttcacatg tgccgcgcac attcggtcag 720 ggtactaaag tagaagtcaa a 741 <![CDATA[<210> 166]]> <![CDATA[<211> 741]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> C-002163 PA2.1.18 scFv (人源化)]]> <![CDATA[<400> 166]]> caggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctgggtcctc agtgaaggtt 60 tcctgcaagg cttctggata caccttcact agctatcata tgcattgggt gcgccaggcc 120 cccggacaag ggcttgagtg gatcggatac atctaccctg gcaatgttaa cacagaatat 180 aatgagaagt tcaagggcaa agccaccctt accgcggaca aatccacgaa cacagcctac 240 atggagctga gcagcctgag atctgaagac acggctgtgt atttctgtgc gagggaggaa 300 attacctacg ctatggacta ctggggccag ggaaccctgg tcaccgtgtc ctcaggcgga 360 ggtggaagcg gagggggagg atctggcggc ggaggaagcg gaggcgacgt tcaaatgacc 420 cagagcccat ccaccctgag cgcatctgta ggtgaccggg tcaccatcac ttgtagctcc 480 agtcagagta ttgtacacag taatgggaac acctatatgg aatggtatca gcagaaacca 540 ggtaaagccc caaaattgct catctacaaa gtctctaaca gatttagtgg tgtaccagac 600 aggttcagcg gttccggaag tggtactgaa ttcaccctca cgatctcctc tctccagcca 660 gatgatttcg ccacttatta ctgtcatcaa ggttcacatg tgccgcgcac attcggtcag 720 ggtactaaag tagaagtcaa a 741 <![CDATA[<210> 167]]> <![CDATA[<211> 741]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> C-002164 BB7.2 scFv (小鼠)]]> <![CDATA[<400> 167]]> caggtgcagc tgcagcagtc tgggcctgag ctggtgaagc ctggggcctc agtgaagatg 60 tcctgcaagg cttctggata caccttcact agctatcata tccagtgggt gaagcagagg 120 cctggacaag ggcttgagtg gatcggatgg atctaccctg gcgatggtag tacacagtat 180 aatgagaagt tcaagggcaa aaccaccctt accgcggaca aatcctccag cacagcctac 240 atgttgctga gcagcctgac ctctgaagac tctgctatct atttctgtgc gagggagggg 300 acctactacg ctatggacta ctggggccag ggaacctcag tcaccgtgtc ctcaggcgga 360 ggtggaagcg gagggggagg atctggcggc ggaggaagcg gaggcgatgt tttgatgacc 420 cagactccac tctccctgcc tgtctctctt ggagaccaag tctccatctc ttgtagatcc 480 agtcagagta ttgtacacag taatgggaac acctatttag aatggtatct gcagaaacca 540 ggtcagtctc caaagttgct catctacaaa gtctctaaca gatttagtgg tgtaccagac 600 aggttcagcg gttccggaag tggtactgat ttcaccctca agatctcgag agtggaggct 660 gaggatctgg gagtttatta ctgttttcaa ggttcacatg tgccgcgcac attcggtgga 720 ggtactaaac tggaaatcaa a 741 <![CDATA[<210> 168]]> <![CDATA[<211> 741]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> C-002165 BB7.2.1 scFv (人源化)]]> <![CDATA[<400> 168]]> cagctgcagc tgcaggagtc tgggcccggg ctggtgaagc cttcggaaac gctgagcctc 60 acctgcacgg tttctggata caccttcacc agctatcata tccagtggat ccgacagccc 120 cctggaaaag ggcttgagtg gatcggatgg atctaccctg gcgatggttc aacacagtac 180 aatgagaagt tcaagggcag agccacgatt agcgtggaca catccaagaa ccaattctcc 240 ctgaacctgg acagcgtgag tgctgcggac acggccattt attactgtgc gagagaggga 300 acttactacg ctatggacta ctggggcaaa gggagcacgg tcaccgtgtc ctcaggcgga 360 ggtggaagcg gagggggagg atctggcggc ggaggaagcg gaggcgacat ccagatgacc 420 cagagcccaa gctccctgag tgcgtccgtg ggcgaccgcg tgaccatcac ttgcagatcc 480 tctcagtcca tcgtgcactc caacggcaac acgtacctcg agtggtacca gcagaagccc 540 gggaaggccc cgaaactgct catctacaag gtgagcaacc ggttctccgg cgtccccagc 600 cgcttctcag ggtccggctc ggggacggat ttcaccttca cgattagcag cttgcagccc 660 gaagacatcg ccacgtacta ctgctttcag ggaagtcacg tgccgcgtac cttcgggccg 720 ggcacgaaag tggatattaa g 741 <![CDATA[<210> 169]]> <![CDATA[<211> 3217]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 智人(Homo sapiens)]]> <![CDATA[<400> 169]]> atggccgtca tggcgccccg aaccctcgtc ctgctactct cgggggctct ggccctgacc 60 cagacctggg cgggtgagtg cggggtcggg agggaaacgg cctctgtggg gagaagcaac 120 gggcccgcct ggcgggggcg caggacccgg gaagccgcgc cgggaggagg gtcgggcggg 180 tctcagccac tcctcgtccc caggctctca ctccatgagg tatttcttca catccgtgtc 240 ccggcccggc cgcggggagc cccgcttcat cgcagtgggc tacgtggacg acacgcagtt 300 cgtgcggttc gacagcgacg ccgcgagcca gaggatggag ccgcgggcgc cgtggataga 360 gcaggagggt ccggagtatt gggacgggga gacacggaaa gtgaaggccc actcacagac 420 tcaccgagtg gacctgggga ccctgcgcgg ctactacaac cagagcgagg ccggtgagtg 480 accccggccc ggggcgcagg tcacgacctc tcatccccca cggacgggcc aggtcgccca 540 cagtctccgg gtccgagatc cgccccgaag ccgcgggacc ccgagaccct tgccccggga 600 gaggcccagg cgcctttacc cggtttcatt ttcagtttag gccaaaaatc cccccaggtt 660 ggtcggggcg gggcggggct cgggggaccg ggctgaccgc ggggtccggg ccaggttctc 720 acaccgtcca gaggatgtat ggctgcgacg tggggtcgga ctggcgcttc ctccgcgggt 780 accaccagta cgcctacgac ggcaaggatt acatcgccct gaaagaggac ctgcgctctt 840 tgaccgcggc ggacatggca gctcagacca ccaagcacaa gtgggaggcg gcccatgtgg 900 cggagcagtt gagagcctac ctggagggca cgtgcgtgga gtggctccgc agatacctgg 960 agaacgggaa ggagacgctg cagcgcacgg gtaccagggg ccacggggcg cctccctgat 1020 cgcctgtaga tctcccgggc tggcctccca caaggagggg agacaattgg gaccaacact 1080 agaatatcgc cctccctctg gtcctgaggg agaggaatcc tcctgggttt ccagatcctg 1140 taccagagag tgactctgag gttccgccct gctctctgac acaattaagg gataaaatct 1200 ctgaaggaat gacgggaaga cgatccctcg aatactgatg agtggttccc tttgacacac 1260 acaggcagca gccttgggcc cgtgactttt cctctcaggc cttgttctct gcttcacact 1320 caatgtgtgt gggggtctga gtccagcact tctgagtcct tcagcctcca ctcaggtcag 1380 gaccagaagt cgctgttccc tcttcaggga ctagaatttt ccacggaata ggagattatc 1440 ccaggtgcct gtgtccaggc tggtgtctgg gttctgtgct cccttcccca tcccaggtgt 1500 cctgtccatt ctcaagatag ccacatgtgt gctggaggag tgtcccatga cagatgcaaa 1560 atgcctgaat gatctgactc ttcctgacag acgcccccaa aacgcatatg actcaccacg 1620 ctgtctctga ccatgaagcc accctgaggt gctgggccct gagcttctac cctgcggaga 1680 tcacactgac ctggcagcgg gatggggagg accagaccca ggacacggag ctcgtggaga 1740 ccaggcctgc aggggatgga accttccaga agtgggcggc tgtggtggtg ccttctggac 1800 aggagcagag atacacctgc catgtgcagc atgagggttt gcccaagccc ctcaccctga 1860 gatggggtaa ggagggagac gggggtgtca tgtcttttag ggaaagcagg agcctctctg 1920 acctttagca gggtcagggc ccctcacctt cccctctttt cccagagccg tcttcccagc 1980 ccaccatccc catcgtgggc atcattgctg gcctggttct ctttggagct gtgatcactg 2040 gagctgtggt cgctgctgtg atgtggagga ggaagagctc aggtggggaa ggggtgaagg 2100 gtgggtctga gatttcttgt ctcactgagg gttccaagac ccaggtagaa gtgtgccctg 2160 cctcgttact gggaagcacc acccacaatt atgggcctac ccagcctggg ccctgtgtgc 2220 cagcacttac tcttttgtaa agcacctgtt aaaatgaagg acagatttat caccttgatt 2280 acagcggtga tgggacctga tcccagcagt cacaagtcac aggggaaggt ccctgaggac 2340 cttcaggagg gcggttggtc caggacccac acctgctttc ttcatgtttc ctgatcccgc 2400 cctgggtctg cagtcacaca tttctggaaa cttctctgag gtccaagact tggaggttcc 2460 tctaggacct taaggccctg actcctttct ggtatctcac aggacatttt cttcccacag 2520 atagaaaagg agggagctac tctcaggctg caagtaagta tgaaggaggc tgatgcctga 2580 ggtccttggg atattgtgtt tgggagccca tgggggagct cacccacccc acaattcctc 2640 ctctagccac atcttctgtg ggatctgacc aggttctgtt tttgttctac cccaggcagt 2700 gacagtgccc agggctctga tgtgtctctc acagcttgta aaggtgagag cctggagggc 2760 ctgatgtgtg ttgggtgttg ggcggaacag tggacacagc tgtgctatgg ggtttctttc 2820 cattggatgt attgagcatg cgatgggctg tttaaagtgt gacccctcac tgtgacagat 2880 acgaatttgt tcatgaatat ttttttctat agtgtgagac agctgccttg tgtgggactg 2940 agaggcaaga gttgttcctg cccttccctt tgtgacttga agaaccctga ctttgtttct 3000 gcaaaggcac ctgcatgtgt ctgtgttcgt gtaggcataa tgtgaggagg tggggagacc 3060 accccacccc catgtccacc atgaccctct tcccacgctg acctgtgctc cctccccaat 3120 catctttcct gttccagaga ggtggggctg aggtgtctcc atctctgtct caacttcatg 3180 gtgcactgag ctgtaacttc ttccttccct attaaaa 3217 <![CDATA[<210> 170]]> <![CDATA[<211> 6654]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 智人(Homo sapiens)]]> <![CDATA[<400> 170]]> aagtggaggc gtcgcgctgg cgggcattcc tgaagctgac agcattcggg ccgagatgtc 60 tcgctccgtg gccttagctg tgctcgcgct actctctctt tctggcctgg aggctatcca 120 gcgtgagtct ctcctaccct cccgctctgg tccttcctct cccgctctgc accctctgtg 180 gccctcgctg tgctctctcg ctccgtgact tcccttctcc aagttctcct tggtggcccg 240 ccgtggggct agtccagggc tggatctcgg ggaagcggcg gggtggcctg ggagtgggga 300 agggggtgcg cacccgggac gcgcgctact tgcccctttc ggcggggagc aggggagacc 360 tttggcctac ggcgacggga gggtcgggac aaagtttagg gcgtcgataa gcgtcagagc 420 gccgaggttg ggggagggtt tctcttccgc tctttcgcgg ggcctctggc tcccccagcg 480 cagctggagt gggggacggg taggctcgtc ccaaaggcgc ggcgctgagg tttgtgaacg 540 cgtggagggg cgcttggggt ctgggggagg cgtcgcccgg gtaagcctgt ctgctgcggc 600 tctgcttccc ttagactgga gagctgtgga cttcgtctag gcgcccgcta agttcgcatg 660 tcctagcacc tctgggtcta tgtggggcca caccgtgggg aggaaacagc acgcgacgtt 720 tgtagaatgc ttggctgtga tacaaagcgg tttcgaataa ttaacttatt tgttcccatc 780 acatgtcact tttaaaaaat tataagaact acccgttatt gacatctttc tgtgtgccaa 840 ggactttatg tgctttgcgt catttaattt tgaaaacagt tatcttccgc catagataac 900 tactatggtt atcttctgcc tctcacagat gaagaaacta aggcaccgag attttaagaa 960 acttaattac acaggggata aatggcagca atcgagattg aagtcaagcc taaccagggc 1020 ttttgcggga gcgcatgcct tttggctgta attcgtgcat ttttttttaa gaaaaacgcc 1080 tgccttctgc gtgagattct ccagagcaaa ctgggcggca tgggccctgt ggtcttttcg 1140 tacagagggc ttcctctttg gctctttgcc tggttgtttc caagatgtac tgtgcctctt 1200 actttcggtt ttgaaaacat gagggggttg ggcgtggtag cttacgcctg taatcccagc 1260 acttagggag gccgaggcgg gaggatggct tgaggtccgt agttgagacc agcctggcca 1320 acatggtgaa gcctggtctc tacaaaaaat aataacaaaa attagccggg tgtggtggct 1380 cgtgcctgtg gtcccagctg ctccggtggc tgaggcggga ggatctcttg agcttaggct 1440 tttgagctat catggcgcca gtgcactcca gcgtgggcaa cagagcgaga ccctgtctct 1500 caaaaaagaa aaaaaaaaaa aaagaaagag aaaagaaaag aaagaaagaa gtgaaggttt 1560 gtcagtcagg ggagctgtaa aaccattaat aaagataatc caagatggtt accaagactg 1620 ttgaggacgc cagagatctt gagcactttc taagtacctg gcaatacact aagcgcgctc 1680 accttttcct ctggcaaaac atgatcgaaa gcagaatgtt ttgatcatga gaaaattgca 1740 tttaatttga atacaattta tttacaacat aaaggataat gtatatatca ccaccattac 1800 tggtatttgc tggttatgtt agatgtcatt ttaaaaaata acaatctgat atttaaaaaa 1860 aaatcttatt ttgaaaattt ccaaagtaat acatgccatg catagaccat ttctggaaga 1920 taccacaaga aacatgtaat gatgattgcc tctgaaggtc tattttcctc ctctgacctg 1980 tgtgtgggtt ttgtttttgt tttactgtgg gcataaatta atttttcagt taagttttgg 2040 aagcttaaat aactctccaa aagtcataaa gccagtaact ggttgagccc aaattcaaac 2100 ccagcctgtc tgatacttgt cctcttctta gaaaagatta cagtgatgct ctcacaaaat 2160 cttgccgcct tccctcaaac agagagttcc aggcaggatg aatctgtgct ctgatccctg 2220 aggcatttaa tatgttctta ttattagaag ctcagatgca aagagctctc ttagctttta 2280 atgttatgaa aaaaatcagg tcttcattag attccccaat ccacctcttg atggggctag 2340 tagcctttcc ttaatgatag ggtgtttcta gagagatata tctggtcaag gtggcctggt 2400 actcctcctt ctccccacag cctcccagac aaggaggagt agctgccttt tagtgatcat 2460 gtaccctgaa tataagtgta tttaaaagaa ttttatacac atatatttag tgtcaatctg 2520 tatatttagt agcactaaca cttctcttca ttttcaatga aaaatataga gtttataata 2580 ttttcttccc acttccccat ggatggtcta gtcatgcctc tcattttgga aagtactgtt 2640 tctgaaacat taggcaatat attcccaacc tggctagttt acagcaatca cctgtggatg 2700 ctaattaaaa cgcaaatccc actgtcacat gcattactcc atttgatcat aatggaaagt 2760 atgttctgtc ccatttgcca tagtcctcac ctatccctgt tgtattttat cgggtccaac 2820 tcaaccattt aaggtatttg ccagctcttg tatgcattta ggttttgttt ctttgttttt 2880 tagctcatga aattaggtac aaagtcagag aggggtctgg catataaaac ctcagcagaa 2940 ataaagaggt tttgttgttt ggtaagaaca taccttgggt tggttgggca cggtggctcg 3000 tgcctgtaat cccaacactt tgggaggcca aggcaggctg atcacttgaa gttgggagtt 3060 caagaccagc ctggccaaca tggtgaaatc ccgtctctac tgaaaataca aaaattaacc 3120 aggcatggtg gtgtgtgcct gtagtcccag gaatcacttg aacccaggag gcggaggttg 3180 cagtgagctg agatctcacc actgcacact gcactccagc ctgggcaatg gaatgagatt 3240 ccatcccaaa aaataaaaaa ataaaaaaat aaagaacata ccttgggttg atccacttag 3300 gaacctcaga taataacatc tgccacgtat agagcaattg ctatgtccca ggcactctac 3360 tagacacttc atacagttta gaaaatcaga tgggtgtaga tcaaggcagg agcaggaacc 3420 aaaaagaaag gcataaacat aagaaaaaaa atggaagggg tggaaacaga gtacaataac 3480 atgagtaatt tgatgggggc tattatgaac tgagaaatga actttgaaaa gtatcttggg 3540 gccaaatcat gtagactctt gagtgatgtg ttaaggaatg ctatgagtgc tgagagggca 3600 tcagaagtcc ttgagagcct ccagagaaag gctcttaaaa atgcagcgca atctccagtg 3660 acagaagata ctgctagaaa tctgctagaa aaaaaacaaa aaaggcatgt atagaggaat 3720 tatgagggaa agataccaag tcacggttta ttcttcaaaa tggaggtggc ttgttgggaa 3780 ggtggaagct catttggcca gagtggaaat ggaattggga gaaatcgatg accaaatgta 3840 aacacttggt gcctgatata gcttgacacc aagttagccc caagtgaaat accctggcaa 3900 tattaatgtg tcttttcccg atattcctca ggtactccaa agattcaggt ttactcacgt 3960 catccagcag agaatggaaa gtcaaatttc ctgaattgct atgtgtctgg gtttcatcca 4020 tccgacattg aagttgactt actgaagaat ggagagagaa ttgaaaaagt ggagcattca 4080 gacttgtctt tcagcaagga ctggtctttc tatctcttgt actacactga attcaccccc 4140 actgaaaaag atgagtatgc ctgccgtgtg aaccatgtga ctttgtcaca gcccaagata 4200 gttaagtggg gtaagtctta cattcttttg taagctgctg aaagttgtgt atgagtagtc 4260 atatcataaa gctgctttga tataaaaaag gtctatggcc atactaccct gaatgagtcc 4320 catcccatct gatataaaca atctgcatat tgggattgtc agggaatgtt cttaaagatc 4380 agattagtgg cacctgctga gatactgatg cacagcatgg tttctgaacc agtagtttcc 4440 ctgcagttga gcagggagca gcagcagcac ttgcacaaat acatatacac tcttaacact 4500 tcttacctac tggcttcctc tagcttttgt ggcagcttca ggtatattta gcactgaacg 4560 aacatctcaa gaaggtatag gcctttgttt gtaagtcctg ctgtcctagc atcctataat 4620 cctggacttc tccagtactt tctggctgga ttggtatctg aggctagtag gaagggcttg 4680 ttcctgctgg gtagctctaa acaatgtatt catgggtagg aacagcagcc tattctgcca 4740 gccttatttc taaccatttt agacatttgt tagtacatgg tattttaaaa gtaaaactta 4800 atgtcttcct tttttttctc cactgtcttt ttcatagatc gagacatgta agcagcatca 4860 tggaggtaag tttttgacct tgagaaaatg tttttgtttc actgtcctga ggactattta 4920 tagacagctc taacatgata accctcacta tgtggagaac attgacagag taacatttta 4980 gcagggaaag aagaatccta cagggtcatg ttcccttctc ctgtggagtg gcatgaagaa 5040 ggtgtatggc cccaggtatg gccatattac tgaccctcta cagagagggc aaaggaactg 5100 ccagtatggt attgcaggat aaaggcaggt ggttacccac attacctgca aggctttgat 5160 ctttcttctg ccatttccac attggacatc tctgctgagg agagaaaatg aaccactctt 5220 ttcctttgta taatgttgtt ttattcttca gacagaagag aggagttata cagctctgca 5280 gacatcccat tcctgtatgg ggactgtgtt tgcctcttag aggttcccag gccactagag 5340 gagataaagg gaaacagatt gttataactt gatataatga tactataata gatgtaacta 5400 caaggagctc cagaagcaag agagagggag gaacttggac ttctctgcat ctttagttgg 5460 agtccaaagg cttttcaatg aaattctact gcccagggta cattgatgct gaaaccccat 5520 tcaaatctcc tgttatattc tagaacaggg aattgatttg ggagagcatc aggaaggtgg 5580 atgatctgcc cagtcacact gttagtaaat tgtagagcca ggacctgaac tctaatatag 5640 tcatgtgtta cttaatgacg gggacatgtt ctgagaaatg cttacacaaa cctaggtgtt 5700 gtagcctact acacgcatag gctacatggt atagcctatt gctcctagac tacaaacctg 5760 tacagcctgt tactgtactg aatactgtgg gcagttgtaa cacaatggta agtatttgtg 5820 tatctaaaca tagaagttgc agtaaaaata tgctatttta atcttatgag accactgtca 5880 tatatacagt ccatcattga ccaaaacatc atatcagcat tttttcttct aagattttgg 5940 gagcaccaaa gggatacact aacaggatat actctttata atgggtttgg agaactgtct 6000 gcagctactt cttttaaaaa ggtgatctac acagtagaaa ttagacaagt ttggtaatga 6060 gatctgcaat ccaaataaaa taaattcatt gctaaccttt ttcttttctt ttcaggtttg 6120 aagatgccgc atttggattg gatgaattcc aaattctgct tgcttgcttt ttaatattga 6180 tatgcttata cacttacact ttatgcacaa aatgtagggt tataataatg ttaacatgga 6240 catgatcttc tttataattc tactttgagt gctgtctcca tgtttgatgt atctgagcag 6300 gttgctccac aggtagctct aggagggctg gcaacttaga ggtggggagc agagaattct 6360 cttatccaac atcaacatct tggtcagatt tgaactcttc aatctcttgc actcaaagct 6420 tgttaagata gttaagcgtg cataagttaa cttccaattt acatactctg cttagaattt 6480 gggggaaaat ttagaaatat aattgacagg attattggaa atttgttata atgaatgaaa 6540 cattttgtca tataagattc atatttactt cttatacatt tgataaagta aggcatggtt 6600 gtggttaatc tggtttattt ttgttccaca agttaaataa atcataaaac ttga 6654 <![CDATA[<210> 171]]> <![CDATA[<211> 1698]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 智人(Homo sapiens)]]> <![CDATA[<400> 171]]> cagaagcaga ggggtcaggg cgaagtccca gggccccagg cgtggctctc agggtctcag 60 gccccgaagg cggtgtatgg attggggagt cccagccttg gggattcccc aactccgcag 120 tttcttttct ccctctccca acctatgtag ggtccttctt cctggatact cacgacgcgg 180 acccagttct cactcccatt gggtgtcggg tttccagaga agccaatcag tgtcgtcgcg 240 gtcgcggttc taaagtccgc acgcacccac cgggactcag attctcccca gacgccgagg 300 atggccgtca tggcgccccg aaccctcgtc ctgctactct cgggggctct ggccctgacc 360 cagacctggg cgggctctca ctccatgagg tatttcttca catccgtgtc ccggcccggc 420 cgcggggagc cccgcttcat cgcagtgggc tacgtggacg acacgcagtt cgtgcggttc 480 gacagcgacg ccgcgagcca gaggatggag ccgcgggcgc cgtggataga gcaggagggt 540 ccggagtatt gggacgggga gacacggaaa gtgaaggccc actcacagac tcaccgagtg 600 gacctgggga ccctgcgcgg ctactacaac cagagcgagg ccggttctca caccgtccag 660 aggatgtatg gctgcgacgt ggggtcggac tggcgcttcc tccgcgggta ccaccagtac 720 gcctacgacg gcaaggatta catcgccctg aaagaggacc tgcgctcttg gaccgcggcg 780 gacatggcag ctcagaccac caagcacaag tgggaggcgg cccatgtggc ggagcagttg 840 agagcctacc tggagggcac gtgcgtggag tggctccgca gatacctgga gaacgggaag 900 gagacgctgc agcgcacgga cgcccccaaa acgcatatga ctcaccacgc tgtctctgac 960 catgaagcca ccctgaggtg ctgggccctg agcttctacc ctgcggagat cacactgacc 1020 tggcagcggg atggggagga ccagacccag gacacggagc tcgtggagac caggcctgca 1080 ggggatggaa ccttccagaa gtgggcggct gtggtggtgc cttctggaca ggagcagaga 1140 tacacctgcc atgtgcagca tgagggtttg cccaagcccc tcaccctgag atgggagccg 1200 tcttcccagc ccaccatccc catcgtgggc atcattgctg gcctggttct ctttggagct 1260 gtgatcactg gagctgtggt cgctgctgtg atgtggagga ggaagagctc agatagaaaa 1320 ggagggagct actctcaggc tgcaagcagt gacagtgccc agggctctga tgtgtctctc 1380 acagcttgta aagtgtgaga cagctgcctt gtgtgggact gagaggcaag agttgttcct 1440 gcccttccct ttgtgacttg aagaaccctg actttgtttc tgcaaaggca cctgcatgtg 1500 tctgtgttcg tgtaggcata atgtgaggag gtggggagac caccccaccc ccatgtccac 1560 catgaccctc ttcccacgct gacctgtgct ccctccccaa tcatctttcc tgttccagag 1620 aggtggggct gaggtgtctc catctctgtc tcaacttcat ggtgcactga gctgtaactt 1680 cttccttccc tattaaaa 1698 <![CDATA[<210> 172]]> <![CDATA[<211> 943]]> <![CDATA[<212> RNA]]> <![CDATA[<213> 智人(Homo sapiens)]]> <![CDATA[<400> 172]]> auuccugaag cugacagcau ucgggccgag augucucgcu ccguggccuu agcugugcuc 60 gcgcuacucu cucuuucugg ccuggaggcu auccagcgua cuccaaagau ucagguuuac 120 ucacgucauc cagcagagaa uggaaaguca aauuuccuga auugcuaugu gucuggguuu 180 cauccauccg acauugaagu ugacuuacug aagaauggag agagaauuga aaaaguggag 240 cauucagacu ugucuuucag caaggacugg ucuuucuauc ucuuguacua cacugaauuc 300 acccccacug aaaaagauga guaugccugc cgugugaacc augugacuuu gucacagccc 360 aagauaguua agugggaucg agacauguaa gcagcaucau ggagguuuga agaugccgca 420 uuuggauugg augaauucca aauucugcuu gcuugcuuuu uaauauugau augcuuauac 480 acuuacacuu uaugcacaaa auguaggguu auaauaaugu uaacauggac augaucuucu 540 uuauaauucu acuuugagug cugucuccau guuugaugua ucugagcagg uugcuccaca 600 gguagcucua ggagggcugg caacuuagag guggggagca gagaauucuc uuauccaaca 660 ucaacaucuu ggucagauuu gaacucuuca aucucuugca cucaaagcuu guuaagauag 720 uuaagcgugc auaaguuaac uuccaauuua cauacucugc uuagaauuug ggggaaaauu 780 uagaaauaua auugacagga uuauuggaaa uuuguuauaa ugaaugaaac auuuugucau 840 auaagauuca uauuuacuuc uuauacauuu gauaaaguaa ggcaugguug ugguuaaucu 900 gguuuauuuu uguuccacaa guuaaauaaa ucauaaaacu uga 943 <![CDATA[<210> 173]]> <![CDATA[<211> 522]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> C1765 (抗HLA-A*02嵌合抗原受體)蛋白]]> <![CDATA[<400> 173]]> Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp 1 5 10 15 Leu Arg Gly Ala Arg Cys Asp Val Leu Met Thr Gln Thr Pro Leu Ser 20 25 30 Leu Pro Val Ser Leu Gly Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser 35 40 45 Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu 50 55 60 Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn 65 70 75 80 Arg Phe Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr 85 90 95 Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Leu Gly Val 100 105 110 Tyr Tyr Cys Phe Gln Gly Ser His Val Pro Arg Thr Ser Gly Gly Gly 115 120 125 Thr Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 130 135 140 Gly Gly Gly Gly Ser Gly Gly Gln Val Gln Leu Gln Gln Ser Gly Pro 145 150 155 160 Glu Leu Val Lys Pro Gly Ala Ser Val Arg Ile Ser Cys Lys Ala Ser 165 170 175 Gly Tyr Thr Phe Thr Ser Tyr His Ile His Trp Val Lys Gln Arg Pro 180 185 190 Gly Gln Gly Leu Glu Trp Ile Gly Trp Ile Tyr Pro Gly Asn Val Asn 195 200 205 Thr Glu Tyr Asn Glu Lys Phe Lys Gly Lys Ala Thr Leu Thr Ala Asp 210 215 220 Lys Ser Ser Ser Thr Ala Tyr Met His Leu Ser Ser Leu Thr Ser Glu 225 230 235 240 Asp Ser Ala Val Tyr Phe Cys Ala Arg Glu Glu Ile Thr Tyr Ala Met 245 250 255 Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Tyr Gly Ser 260 265 270 Gln Ser Ser Lys Pro Tyr Leu Leu Thr His Pro Ser Asp Pro Leu Glu 275 280 285 Leu Val Val Ser Gly Pro Ser Gly Gly Pro Ser Ser Pro Thr Thr Gly 290 295 300 Pro Thr Ser Thr Ser Gly Pro Glu Asp Gln Pro Leu Thr Pro Thr Gly 305 310 315 320 Ser Asp Pro Gln Ser Gly Leu Gly Arg His Leu Gly Val Val Ile Gly 325 330 335 Ile Leu Val Ala Val Ile Leu Leu Leu Leu Leu Leu Leu Leu Leu Phe 340 345 350 Leu Ile Leu Arg His Arg Arg Gln Gly Lys His Trp Thr Ser Thr Gln 355 360 365 Arg Lys Ala Asp Phe Gln His Pro Ala Gly Ala Val Gly Pro Glu Pro 370 375 380 Thr Asp Arg Gly Leu Gln Trp Arg Ser Ser Pro Ala Ala Asp Ala Gln 385 390 395 400 Glu Glu Asn Leu Tyr Ala Ala Val Lys His Thr Gln Pro Glu Asp Gly 405 410 415 Val Glu Met Asp Thr Arg Ser Pro His Asp Glu Asp Pro Gln Ala Val 420 425 430 Thr Tyr Ala Glu Val Lys His Ser Arg Pro Arg Arg Glu Met Ala Ser 435 440 445 Pro Pro Ser Pro Leu Ser Gly Glu Phe Leu Asp Thr Lys Asp Arg Gln 450 455 460 Ala Glu Glu Asp Arg Gln Met Asp Thr Glu Ala Ala Ala Ser Glu Ala 465 470 475 480 Pro Gln Asp Val Thr Tyr Ala Gln Leu His Ser Leu Thr Leu Arg Arg 485 490 495 Glu Ala Thr Glu Pro Pro Pro Ser Gln Glu Gly Pro Ser Pro Ala Val 500 505 510 Pro Ser Ile Tyr Ala Thr Leu Ala Ile His 515 520 <![CDATA[<210> 174]]> <![CDATA[<211> 522]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> C2162 (抗HLA-A*02嵌合抗原受體)蛋白]]> <![CDATA[<400> 174]]> Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp 1 5 10 15 Leu Arg Gly Ala Arg Cys Gln Val Gln Leu Val Gln Ser Gly Ala Glu 20 25 30 Val Lys Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly 35 40 45 Tyr Thr Phe Thr Ser Tyr His Ile His Trp Val Arg Gln Ala Pro Gly 50 55 60 Gln Gly Leu Glu Trp Ile Gly Trp Ile Tyr Pro Gly Asn Val Asn Thr 65 70 75 80 Glu Tyr Asn Glu Lys Phe Lys Gly Lys Ala Thr Ile Thr Ala Asp Glu 85 90 95 Ser Thr Asn Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp 100 105 110 Thr Ala Val Tyr Tyr Cys Ala Arg Glu Glu Ile Thr Tyr Ala Met Asp 115 120 125 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly 130 135 140 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Asp Ile Gln 145 150 155 160 Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly Asp Arg Val 165 170 175 Thr Ile Thr Cys Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn 180 185 190 Thr Tyr Leu Glu Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu 195 200 205 Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro Ala Arg Phe 210 215 220 Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu 225 230 235 240 Gln Pro Asp Asp Phe Ala Thr Tyr Tyr Cys Phe Gln Gly Ser His Val 245 250 255 Pro Arg Thr Phe Gly Gln Gly Thr Lys Val Glu Val Lys Tyr Gly Ser 260 265 270 Gln Ser Ser Lys Pro Tyr Leu Leu Thr His Pro Ser Asp Pro Leu Glu 275 280 285 Leu Val Val Ser Gly Pro Ser Gly Gly Pro Ser Ser Pro Thr Thr Gly 290 295 300 Pro Thr Ser Thr Ser Gly Pro Glu Asp Gln Pro Leu Thr Pro Thr Gly 305 310 315 320 Ser Asp Pro Gln Ser Gly Leu Gly Arg His Leu Gly Val Val Ile Gly 325 330 335 Ile Leu Val Ala Val Ile Leu Leu Leu Leu Leu Leu Leu Leu Leu Phe 340 345 350 Leu Ile Leu Arg His Arg Arg Gln Gly Lys His Trp Thr Ser Thr Gln 355 360 365 Arg Lys Ala Asp Phe Gln His Pro Ala Gly Ala Val Gly Pro Glu Pro 370 375 380 Thr Asp Arg Gly Leu Gln Trp Arg Ser Ser Pro Ala Ala Asp Ala Gln 385 390 395 400 Glu Glu Asn Leu Tyr Ala Ala Val Lys His Thr Gln Pro Glu Asp Gly 405 410 415 Val Glu Met Asp Thr Arg Ser Pro His Asp Glu Asp Pro Gln Ala Val 420 425 430 Thr Tyr Ala Glu Val Lys His Ser Arg Pro Arg Arg Glu Met Ala Ser 435 440 445 Pro Pro Ser Pro Leu Ser Gly Glu Phe Leu Asp Thr Lys Asp Arg Gln 450 455 460 Ala Glu Glu Asp Arg Gln Met Asp Thr Glu Ala Ala Ala Ser Glu Ala 465 470 475 480 Pro Gln Asp Val Thr Tyr Ala Gln Leu His Ser Leu Thr Leu Arg Arg 485 490 495 Glu Ala Thr Glu Pro Pro Pro Ser Gln Glu Gly Pro Ser Pro Ala Val 500 505 510 Pro Ser Ile Tyr Ala Thr Leu Ala Ile His 515 520 <![CDATA[<210> 175]]> <![CDATA[<211> 532]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CT486 (抗EGFR嵌合抗原受體)蛋白]]> <![CDATA[<400> 175]]> Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp 1 5 10 15 Leu Arg Gly Ala Arg Cys Gln Val Gln Leu Lys Gln Ser Gly Pro Gly 20 25 30 Leu Val Gln Pro Ser Gln Ser Leu Ser Ile Thr Cys Thr Val Ser Gly 35 40 45 Phe Ser Leu Thr Asn Tyr Gly Val His Trp Val Arg Gln Ser Pro Gly 50 55 60 Lys Gly Leu Glu Trp Leu Gly Val Ile Trp Ser Gly Gly Asn Thr Asp 65 70 75 80 Tyr Asn Thr Pro Phe Thr Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser 85 90 95 Lys Ser Gln Val Phe Phe Lys Met Asn Ser Leu Gln Ser Asn Asp Thr 100 105 110 Ala Ile Tyr Tyr Cys Ala Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe 115 120 125 Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala Gly Gly Gly 130 135 140 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Asp Ile 145 150 155 160 Leu Leu Thr Gln Ser Pro Val Ile Leu Ser Val Ser Pro Gly Glu Arg 165 170 175 Val Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn Ile His 180 185 190 Trp Tyr Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile Lys Tyr 195 200 205 Ala Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly Ser Gly 210 215 220 Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser Glu Asp 225 230 235 240 Ile Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr Thr Phe 245 250 255 Gly Ala Gly Thr Lys Leu Glu Leu Lys Thr Thr Thr Pro Ala Pro Arg 260 265 270 Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg 275 280 285 Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly 290 295 300 Leu Asp Phe Ala Cys Asp Phe Trp Val Leu Val Val Val Gly Gly Val 305 310 315 320 Leu Ala Cys Tyr Ser Leu Leu Val Thr Val Ala Phe Ile Ile Phe Trp 325 330 335 Val Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met Asn Met 340 345 350 Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala 355 360 365 Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser Lys Arg Gly Arg Lys Lys 370 375 380 Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr 385 390 395 400 Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly 405 410 415 Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala 420 425 430 Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg 435 440 445 Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu 450 455 460 Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn 465 470 475 480 Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met 485 490 495 Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly 500 505 510 Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala 515 520 525 Leu Pro Pro Arg 530 <![CDATA[<210> 176]]> <![CDATA[<211> 532]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CT488 (抗EGFR嵌合抗原受體)蛋白]]> <![CDATA[<400> 176]]> Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp 1 5 10 15 Leu Arg Gly Ala Arg Cys Gln Val Gln Leu Gln Glu Ser Gly Pro Gly 20 25 30 Leu Val Lys Pro Ser Glu Thr Leu Ser Leu Thr Cys Thr Val Ser Gly 35 40 45 Gly Ser Val Ser Ser Gly Asp Tyr Tyr Trp Thr Trp Ile Arg Gln Ser 50 55 60 Pro Gly Lys Gly Leu Glu Trp Ile Gly His Ile Tyr Tyr Ser Gly Asn 65 70 75 80 Thr Asn Tyr Asn Pro Ser Leu Lys Ser Arg Leu Thr Ile Ser Ile Asp 85 90 95 Thr Ser Lys Thr Gln Phe Ser Leu Lys Leu Ser Ser Val Thr Ala Ala 100 105 110 Asp Thr Ala Ile Tyr Tyr Cys Val Arg Asp Arg Val Thr Gly Ala Phe 115 120 125 Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser Gly Gly Gly 130 135 140 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Asp Ile 145 150 155 160 Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg 165 170 175 Val Thr Ile Thr Cys Gln Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn 180 185 190 Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Asp 195 200 205 Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly Ser Gly 210 215 220 Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp 225 230 235 240 Ile Ala Thr Tyr Phe Cys Gln His Phe Asp His Leu Pro Leu Ala Phe 245 250 255 Gly Gly Gly Thr Lys Val Glu Ile Lys Thr Thr Thr Pro Ala Pro Arg 260 265 270 Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg 275 280 285 Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly 290 295 300 Leu Asp Phe Ala Cys Asp Phe Trp Val Leu Val Val Val Gly Gly Val 305 310 315 320 Leu Ala Cys Tyr Ser Leu Leu Val Thr Val Ala Phe Ile Ile Phe Trp 325 330 335 Val Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met Asn Met 340 345 350 Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala 355 360 365 Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser Lys Arg Gly Arg Lys Lys 370 375 380 Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr 385 390 395 400 Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly 405 410 415 Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala 420 425 430 Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg 435 440 445 Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu 450 455 460 Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn 465 470 475 480 Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met 485 490 495 Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly 500 505 510 Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala 515 520 525 Leu Pro Pro Arg 530 <![CDATA[<210> 177]]> <![CDATA[<211> 534]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CT489 (抗EGFR嵌合抗原受體)蛋白]]> <![CDATA[<400> 177]]> Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp 1 5 10 15 Leu Arg Gly Ala Arg Cys Gln Val Gln Leu Gln Glu Ser Gly Pro Gly 20 25 30 Leu Val Lys Pro Ser Gln Thr Leu Ser Leu Thr Cys Thr Val Ser Gly 35 40 45 Gly Ser Ile Ser Ser Gly Asp Tyr Tyr Trp Ser Trp Ile Arg Gln Pro 50 55 60 Pro Gly Lys Gly Leu Glu Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser 65 70 75 80 Thr Asp Tyr Asn Pro Ser Leu Lys Ser Arg Val Thr Met Ser Val Asp 85 90 95 Thr Ser Lys Asn Gln Phe Ser Leu Lys Val Asn Ser Val Thr Ala Ala 100 105 110 Asp Thr Ala Val Tyr Tyr Cys Ala Arg Val Ser Ile Phe Gly Val Gly 115 120 125 Thr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly 130 135 140 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 145 150 155 160 Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly 165 170 175 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr 180 185 190 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 195 200 205 Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 210 215 220 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro 225 230 235 240 Glu Asp Phe Ala Val Tyr Tyr Cys His Gln Tyr Gly Ser Thr Pro Leu 245 250 255 Thr Phe Gly Gly Gly Thr Lys Ala Glu Ile Lys Thr Thr Thr Pro Ala 260 265 270 Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser 275 280 285 Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr 290 295 300 Arg Gly Leu Asp Phe Ala Cys Asp Phe Trp Val Leu Val Val Val Gly 305 310 315 320 Gly Val Leu Ala Cys Tyr Ser Leu Leu Val Thr Val Ala Phe Ile Ile 325 330 335 Phe Trp Val Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met 340 345 350 Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro 355 360 365 Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser Lys Arg Gly Arg 370 375 380 Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln 385 390 395 400 Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu 405 410 415 Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala 420 425 430 Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu 435 440 445 Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp 450 455 460 Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu 465 470 475 480 Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile 485 490 495 Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr 500 505 510 Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met 515 520 525 Gln Ala Leu Pro Pro Arg 530 <![CDATA[<210> 178]]> <![CDATA[<211> 21]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 未知(Unknown)]]> <![CDATA[<220>]]> <![CDATA[<223> T2A自裂解肽]]> <![CDATA[<400> 178]]> Gly Ser Gly Glu Gly Arg Gly Ser Leu Leu Thr Cys Gly Asp Val Glu 1 5 10 15 Glu Asn Pro Gly Pro 20 <![CDATA[<210> 179]]> <![CDATA[<211> 46]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> shRNA0089]]> <![CDATA[<400> 179]]> gcactcaaag cttgttaaga tcgaaatctt aacaagcttt gagtgc 46 <![CDATA[<210> 180]]> <![CDATA[<211> 1600]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CT486 (抗EGFR嵌合抗原受體) DNA]]> <![CDATA[<400> 180]]> atggacatga gggtccccgc tcagctcctg gggctcctgc tactctggct ccgaggtgcc 60 agatgtcagg tgcagctgaa gcagtccggc cccggcctgg tgcagccctc ccagtccctg 120 tccatcacct gcaccgtgtc cggcttctcc ctgaccaact acggcgtgca ctgggtgcgg 180 cagtcccccg gcaagggcct ggagtggctg ggcgtgatct ggtccggcgg caacaccgac 240 tacaacaccc ccttcacctc ccggctgtcc atcaacaagg acaactccaa gtcccaggtg 300 ttcttcaaga tgaactccct gcagtccaac gacaccgcca tctactactg cgcccgggcc 360 ctgacctact acgactacga gttcgcctac tggggccagg gcaccctggt gaccgtgtcc 420 gccggcggag gtggaagcgg agggggagga tctggcggcg gaggaagcgg aggcgacatc 480 ctgctgaccc agtcccccgt gatcctgtcc gtgtcccccg gcgagcgggt gtccttctcc 540 tgccgggcct cccagtccat cggcaccaac atccactggt accagcagcg gaccaacggc 600 tccccccggc tgctgatcaa gtacgcctcc gagtccatct ccggcatccc ctcccggttc 660 tccggctccg gctccggcac cgacttcacc ctgtccatca actccgtgga gtccgaggac 720 atcgccgact actactgcca gcagaacaac aactggccca ccaccttcgg cgccggcacc 780 aagctggagc tgaagaccac gacgccagcg ccgcgaccac caacaccggc gcccaccatc 840 gcgtcgcagc ccctgtccct gcgcccagag gcgtgccggc cagcggcggg gggcgcagtg 900 cacacgaggg ggctggactt cgcctgtgat ttctgggtgc tggtcgttgt gggcggcgtg 960 ctggcctgct acagcctgct ggtgacagtg gccttcatca tcttttgggt gaggagcaag 1020 cggagcagac tgctgcacag cgactacatg aacatgaccc cccggaggcc tggccccacc 1080 cggaagcact accagcccta cgcccctccc agggatttcg ccgcctaccg gagcaaacgg 1140 ggcagaaaga aactcctgta tatattcaaa caaccattta tgaggccagt acaaactact 1200 caagaggaag atggctgtag ctgccgattt ccagaagaag aagaaggagg atgtgaactg 1260 agagtgaagt tcagcaggag cgcagacgcc cccgcgtaca agcagggcca gaaccagctc 1320 tataacgagc tcaatctagg acgaagagag gagtacgatg ttttggacaa gcgtagaggc 1380 cgggaccctg agatgggggg aaagccgaga aggaagaacc ctcaggaagg cctgtacaat 1440 gaactgcaga aagataagat ggcggaggcc tacagtgaga ttgggatgaa aggcgagcgc 1500 cggaggggca aggggcacga tggcctttac cagggactca gtacagccac caaggacacc 1560 tacgacgccc ttcacatgca ggccctgccc cctcgctagc 1600 <![CDATA[<210> 181]]> <![CDATA[<211> 1566]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> C2162 (抗HLA-A*02嵌合抗原受體) DNA]]> <![CDATA[<400> 181]]> atggatatga gagtgcctgc ccagctgctc ggactgctcc ttctgtggtt gagaggagct 60 cggtgccagg tgcagctggt gcagtctggg gctgaggtga agaagcctgg gtcctcagtg 120 aaggtttcct gcaaggcttc tggatacacc ttcactagct atcatataca ttgggtgcgc 180 caggcccccg gacaagggct tgaatggatt ggctggatct accctggcaa tgttaacaca 240 gaatataatg agaagttcaa gggcaaagcc accattaccg cggacgaatc cacgaacaca 300 gcctacatgg agctgagcag cctgagatct gaagacacgg ctgtgtatta ctgtgcgagg 360 gaggaaatta cctacgctat ggactactgg ggccagggaa ccctggtcac cgtgtcctca 420 ggaggtggcg gctctggagg cggaggtagc ggaggtggag gctctggtgg cgacattcaa 480 atgacccaga gcccatccac cctgagcgca tctgtaggtg accgggtcac catcacttgt 540 agatccagtc agagtattgt acacagtaat gggaacacct atttggaatg gtaccagcag 600 aagccaggta aagccccaaa attgctcatc tacaaagtct ctaacagatt tagtggtgta 660 ccagccaggt tcagcggttc cggaagtggt actgaattca ccctcacgat ctcctctctc 720 cagccagatg atttcgccac ttattactgt tttcaaggtt cacatgtgcc gcgcacattc 780 ggtcagggta ctaaagtaga agtcaaatac ggctcacaga gctccaaacc ctacctgctg 840 actcacccta gtgatcctct ggagctcgtg gtctcaggac cgtctggagg cccaagctct 900 ccgacaacag gccccacctc cacatctggc cctgaggacc agcccctcac acccaccggg 960 tcggatcctc agagtggtct gggaagacac ctgggagttg tgatcggcat cttggtggcc 1020 gtcatcctac tgctcctcct cctgctcctg ctcttcctca tcctccgaca tcgacgtcag 1080 ggcaaacact ggacatcgac ccagagaaag gctgatttcc aacatcctgc aggggctgtg 1140 gggccagagc ccacagacag aggcctgcag tggaggtcca gcccagctgc cgatgcccag 1200 gaagaaaacc tctatgctgc cgtgaagcac acacagcctg aggatggggt ggagatggat 1260 actcggagcc cacacgatga agatccacag gcagtgacgt atgccgaggt gaaacactcc 1320 agacctagaa gggaaatggc ctctcctcct tccccactgt ctggagagtt cctggacaca 1380 aaggacagac aggcggaaga ggacaggcag atggacactg aggctgctgc atctgaagct 1440 cctcaggatg tgacctacgc ccagctgcac agcttgaccc tcagacggga ggcaactgag 1500 cctcctccat cccaggaagg gccctctcca gctgtgccca gcatctacgc cactctggcc 1560 atccac 1566 <![CDATA[<210> 182]]> <![CDATA[<211> 1599]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CT488 (抗EGFR嵌合抗原受體) DNA]]> <![CDATA[<400> 182]]> atggacatga gggtccccgc tcagctcctg gggctcctgc tactctggct ccgaggtgcc 60 agatgtcagg tgcagctgca ggagtccggc cccggcctgg tgaagccctc cgagaccctg 120 tccctgacct gcaccgtgtc cggcggctcc gtgtcctccg gcgactacta ctggacctgg 180 atccggcagt cccccggcaa gggcctggag tggatcggcc acatctacta ctccggcaac 240 accaactaca acccctccct gaagtcccgg ctgaccatct ccatcgacac ctccaagacc 300 cagttctccc tgaagctgtc ctccgtgacc gccgccgaca ccgccatcta ctactgcgtg 360 cgggaccggg tgaccggcgc cttcgacatc tggggccagg gcaccatggt gaccgtgtcc 420 tccggcggag gtggaagcgg agggggagga tctggcggcg gaggaagcgg aggcgacatc 480 cagatgaccc agtccccctc ctccctgtcc gcctccgtgg gcgaccgggt gaccatcacc 540 tgccaggcct cccaggacat ctccaactac ctgaactggt accagcagaa gcccggcaag 600 gcccccaagc tgctgatcta cgacgcctcc aacctggaga ccggcgtgcc ctcccggttc 660 tccggctccg gctccggcac cgacttcacc ttcaccatct cctccctgca gcccgaggac 720 atcgccacct acttctgcca gcacttcgac cacctgcccc tggccttcgg cggcggcacc 780 aaggtggaga tcaagaccac gacgccagcg ccgcgaccac caacaccggc gcccaccatc 840 gcgtcgcagc ccctgtccct gcgcccagag gcgtgccggc cagcggcggg gggcgcagtg 900 cacacgaggg ggctggactt cgcctgtgat ttctgggtgc tggtcgttgt gggcggcgtg 960 ctggcctgct acagcctgct ggtgacagtg gccttcatca tcttttgggt gaggagcaag 1020 cggagcagac tgctgcacag cgactacatg aacatgaccc cccggaggcc tggccccacc 1080 cggaagcact accagcccta cgcccctccc agggatttcg ccgcctaccg gagcaaacgg 1140 ggcagaaaga aactcctgta tatattcaaa caaccattta tgaggccagt acaaactact 1200 caagaggaag atggctgtag ctgccgattt ccagaagaag aagaaggagg atgtgaactg 1260 agagtgaagt tcagcaggag cgcagacgcc cccgcgtaca agcagggcca gaaccagctc 1320 tataacgagc tcaatctagg acgaagagag gagtacgatg ttttggacaa gcgtagaggc 1380 cgggaccctg agatgggggg aaagccgaga aggaagaacc ctcaggaagg cctgtacaat 1440 gaactgcaga aagataagat ggcggaggcc tacagtgaga ttgggatgaa aggcgagcgc 1500 cggaggggca aggggcacga tggcctttac cagggactca gtacagccac caaggacacc 1560 tacgacgccc ttcacatgca ggccctgccc cctcgctag 1599 <![CDATA[<210> 183]]> <![CDATA[<211> 1569]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> C1765 (抗HLA-A*02嵌合抗原受體) DNA]]> <![CDATA[<400> 183]]> atggacatga gggtccccgc tcagctcctg gggctcctgc tactctggct ccgaggtgcc 60 agatgtgatg ttttgatgac ccaaactcca ctctccctgc ctgtcagtct tggagatcaa 120 gcctccatct cttgcagatc tagtcagagc attgtacata gtaatggaaa cacctattta 180 gaatggtacc tgcagaaacc aggccagtct ccaaagctcc tgatctacaa agtttccaac 240 cgattttctg gggtcccaga caggttcagt ggcagtggat cagggacaga tttcacactc 300 aagatcagta gagtggaggc tgaggatctg ggagtttatt actgctttca aggttcacat 360 gttcctcgga cgtccggtgg aggcaccaag ctggaaatca aaggcggagg tggaagcgga 420 gggggaggat ctggcggcgg aggaagcgga ggccaggtcc agctgcagca gtctggacct 480 gagctggtga agcctggggc ttcagtgagg atatcctgca aggcttctgg ctacaccttc 540 acaagttacc atatacattg ggtgaagcag aggcctggac agggacttga gtggattgga 600 tggatttatc ctggaaatgt taatactgag tacaatgaga agttcaaggg caaggccaca 660 ctgactgcag acaaatcgtc cagcacagcc tacatgcacc tcagcagcct gacctctgag 720 gactctgcgg tctatttctg tgccagagag gagattacct atgctatgga ctactggggt 780 caaggaacct cagtcaccgt gtcctcatac ggctcacaga gctccaaacc ctacctgctg 840 actcacccca gtgaccccct ggagctcgtg gtctcaggac cgtctggggg ccccagctcc 900 ccgacaacag gccccacctc cacatctggc cctgaggacc agcccctcac ccccaccggg 960 tcggatcccc agagtggtct gggaaggcac ctgggggttg tgatcggcat cttggtggcc 1020 gtcatcctac tgctcctcct cctcctcctc ctcttcctca tcctccgaca tcgacgtcag 1080 ggcaaacact ggacatcgac ccagagaaag gctgatttcc aacatcctgc aggggctgtg 1140 gggccagagc ccacagacag aggcctgcag tggaggtcca gcccagctgc cgatgcccag 1200 gaagaaaacc tctatgctgc cgtgaagcac acacagcctg aggatggggt ggagatggac 1260 actcggagcc cacacgatga agacccccag gcagtgacgt atgccgaggt gaaacactcc 1320 agacctagga gagaaatggc ctctcctcct tccccactgt ctggggaatt cctggacaca 1380 aaggacagac aggcggaaga ggacaggcag atggacactg aggctgctgc atctgaagcc 1440 ccccaggatg tgacctacgc ccagctgcac agcttgaccc tcagacggga ggcaactgag 1500 cctcctccat cccaggaagg gccctctcca gctgtgccca gcatctacgc cactctggcc 1560 atccactag 1569 <![CDATA[<210> 184]]> <![CDATA[<211> 1605]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CT489 (抗EGFR嵌合抗原受體) DNA]]> <![CDATA[<400> 184]]> atggacatga gggtccccgc tcagctcctg gggctcctgc tactctggct ccgaggtgcc 60 agatgtcagg tccagctcca agagtcagga ccaggtctgg tcaaaccctc acagacgctc 120 tctcttactt gcacagtatc aggcggatcc attagttccg gtgattatta ctggtcttgg 180 atccgccagc ctcctggtaa ggggctggag tggatcggat acatatacta cagtggttcc 240 actgattata atccgtcact caagtcccga gtaactatgt ccgtggatac tagcaaaaat 300 cagttcagcc tcaaagtcaa ttccgtaact gccgccgaca ccgcggtcta ttattgtgcg 360 cgggtgagca tcttcggcgt cggtacgttc gattactggg gacaaggaac tctcgtaaca 420 gtaagctctg gcggaggtgg aagcggaggg ggaggatctg gcggcggagg aagcggaggc 480 gagattgtaa tgacccaaag ccctgccact ctttctctgt ctccggggga acgagcgact 540 ctgtcatgta gggcgtccca gagtgtctct agctacctcg catggtatca gcagaaaccc 600 ggacaagccc ctcggctctt gatttacgat gcctcaaaca gagcaacggg gattccggca 660 cggttcagcg ggtctggtag cgggacagac ttcacactga cgatctcttc actcgaacca 720 gaagattttg cagtctacta ttgccatcag tatggttcta cgccacttac atttggcggg 780 ggcaccaagg cggagataaa aaccacgacg ccagcgccgc gaccaccaac accggcgccc 840 accatcgcgt cgcagcccct gtccctgcgc ccagaggcgt gccggccagc ggcggggggc 900 gcagtgcaca cgagggggct ggacttcgcc tgtgatttct gggtgctggt cgttgtgggc 960 ggcgtgctgg cctgctacag cctgctggtg acagtggcct tcatcatctt ttgggtgagg 1020 agcaagcgga gcagactgct gcacagcgac tacatgaaca tgaccccccg gaggcctggc 1080 cccacccgga agcactacca gccctacgcc cctcccaggg atttcgccgc ctaccggagc 1140 aaacggggca gaaagaaact cctgtatata ttcaaacaac catttatgag gccagtacaa 1200 actactcaag aggaagatgg ctgtagctgc cgatttccag aagaagaaga aggaggatgt 1260 gaactgagag tgaagttcag caggagcgca gacgcccccg cgtacaagca gggccagaac 1320 cagctctata acgagctcaa tctaggacga agagaggagt acgatgtttt ggacaagcgt 1380 agaggccggg accctgagat ggggggaaag ccgagaagga agaaccctca ggaaggcctg 1440 tacaatgaac tgcagaaaga taagatggcg gaggcctaca gtgagattgg gatgaaaggc 1500 gagcgccgga ggggcaaggg gcacgatggc ctttaccagg gactcagtac agccaccaag 1560 gacacctacg acgcccttca catgcaggcc ctgccccctc gctag 1605 <![CDATA[<210> 185]]> <![CDATA[<211> 3234]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> C2162-T2A-CT489 DNA]]> <![CDATA[<400> 185]]> atggatatga gagtgcctgc ccagctgctc ggactgctcc ttctgtggtt gagaggagct 60 cggtgccagg tgcagctggt gcagtctggg gctgaggtga agaagcctgg gtcctcagtg 120 aaggtttcct gcaaggcttc tggatacacc ttcactagct atcatataca ttgggtgcgc 180 caggcccccg gacaagggct tgaatggatt ggctggatct accctggcaa tgttaacaca 240 gaatataatg agaagttcaa gggcaaagcc accattaccg cggacgaatc cacgaacaca 300 gcctacatgg agctgagcag cctgagatct gaagacacgg ctgtgtatta ctgtgcgagg 360 gaggaaatta cctacgctat ggactactgg ggccagggaa ccctggtcac cgtgtcctca 420 ggaggtggcg gctctggagg cggaggtagc ggaggtggag gctctggtgg cgacattcaa 480 atgacccaga gcccatccac cctgagcgca tctgtaggtg accgggtcac catcacttgt 540 agatccagtc agagtattgt acacagtaat gggaacacct atttggaatg gtaccagcag 600 aagccaggta aagccccaaa attgctcatc tacaaagtct ctaacagatt tagtggtgta 660 ccagccaggt tcagcggttc cggaagtggt actgaattca ccctcacgat ctcctctctc 720 cagccagatg atttcgccac ttattactgt tttcaaggtt cacatgtgcc gcgcacattc 780 ggtcagggta ctaaagtaga agtcaaatac ggctcacaga gctccaaacc ctacctgctg 840 actcacccta gtgatcctct ggagctcgtg gtctcaggac cgtctggagg cccaagctct 900 ccgacaacag gccccacctc cacatctggc cctgaggacc agcccctcac acccaccggg 960 tcggatcctc agagtggtct gggaagacac ctgggagttg tgatcggcat cttggtggcc 1020 gtcatcctac tgctcctcct cctgctcctg ctcttcctca tcctccgaca tcgacgtcag 1080 ggcaaacact ggacatcgac ccagagaaag gctgatttcc aacatcctgc aggggctgtg 1140 gggccagagc ccacagacag aggcctgcag tggaggtcca gcccagctgc cgatgcccag 1200 gaagaaaacc tctatgctgc cgtgaagcac acacagcctg aggatggggt ggagatggat 1260 actcggagcc cacacgatga agatccacag gcagtgacgt atgccgaggt gaaacactcc 1320 agacctagaa gggaaatggc ctctcctcct tccccactgt ctggagagtt cctggacaca 1380 aaggacagac aggcggaaga ggacaggcag atggacactg aggctgctgc atctgaagct 1440 cctcaggatg tgacctacgc ccagctgcac agcttgaccc tcagacggga ggcaactgag 1500 cctcctccat cccaggaagg gccctctcca gctgtgccca gcatctacgc cactctggcc 1560 atccacggat ccggagaggg cagaggcagc ctgctgacat gtggcgacgt ggaagagaac 1620 cctggcccca tggacatgag ggtccccgct cagctcctgg ggctcctgct actctggctc 1680 cgaggtgcca gatgtcaggt ccagctccaa gagtcaggac caggtctggt caaaccctca 1740 cagacgctct ctcttacttg cacagtatca ggcggatcca ttagttccgg tgattattac 1800 tggtcttgga tccgccagcc tcctggtaag gggctggagt ggatcggata catatactac 1860 agtggttcca ctgattataa tccgtcactc aagtcccgag taactatgtc cgtggatact 1920 agcaaaaatc agttcagcct caaagtcaat tccgtaactg ccgccgacac cgcggtctat 1980 tattgtgcgc gggtgagcat cttcggcgtc ggtacgttcg attactgggg acaaggaact 2040 ctcgtaacag taagctctgg cggaggtgga agcggagggg gaggatctgg cggcggagga 2100 agcggaggcg agattgtaat gacccaaagc cctgccactc tttctctgtc tccgggggaa 2160 cgagcgactc tgtcatgtag ggcgtcccag agtgtctcta gctacctcgc atggtatcag 2220 cagaaacccg gacaagcccc tcggctcttg atttacgatg cctcaaacag agcaacgggg 2280 attccggcac ggttcagcgg gtctggtagc gggacagact tcacactgac gatctcttca 2340 ctcgaaccag aagattttgc agtctactat tgccatcagt atggttctac gccacttaca 2400 tttggcgggg gcaccaaggc ggagataaaa accacgacgc cagcgccgcg accaccaaca 2460 ccggcgccca ccatcgcgtc gcagcccctg tccctgcgcc cagaggcgtg ccggccagcg 2520 gcggggggcg cagtgcacac gagggggctg gacttcgcct gtgatttctg ggtgctggtc 2580 gttgtgggcg gcgtgctggc ctgctacagc ctgctggtga cagtggcctt catcatcttt 2640 tgggtgagga gcaagcggag cagactgctg cacagcgact acatgaacat gaccccccgg 2700 aggcctggcc ccacccggaa gcactaccag ccctacgccc ctcccaggga tttcgccgcc 2760 taccggagca aacggggcag aaagaaactc ctgtatatat tcaaacaacc atttatgagg 2820 ccagtacaaa ctactcaaga ggaagatggc tgtagctgcc gatttccaga agaagaagaa 2880 ggaggatgtg aactgagagt gaagttcagc aggagcgcag acgcccccgc gtacaagcag 2940 ggccagaacc agctctataa cgagctcaat ctaggacgaa gagaggagta cgatgttttg 3000 gacaagcgta gaggccggga ccctgagatg gggggaaagc cgagaaggaa gaaccctcag 3060 gaaggcctgt acaatgaact gcagaaagat aagatggcgg aggcctacag tgagattggg 3120 atgaaaggcg agcgccggag gggcaagggg cacgatggcc tttaccaggg actcagtaca 3180 gccaccaagg acacctacga cgcccttcac atgcaggccc tgccccctcg ctag 3234 <![CDATA[<210> 186]]> <![CDATA[<211> 1077]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> C2162-T2A-CT489蛋白]]> <![CDATA[<400> 186]]> Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp 1 5 10 15 Leu Arg Gly Ala Arg Cys Gln Val Gln Leu Val Gln Ser Gly Ala Glu 20 25 30 Val Lys Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly 35 40 45 Tyr Thr Phe Thr Ser Tyr His Ile His Trp Val Arg Gln Ala Pro Gly 50 55 60 Gln Gly Leu Glu Trp Ile Gly Trp Ile Tyr Pro Gly Asn Val Asn Thr 65 70 75 80 Glu Tyr Asn Glu Lys Phe Lys Gly Lys Ala Thr Ile Thr Ala Asp Glu 85 90 95 Ser Thr Asn Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp 100 105 110 Thr Ala Val Tyr Tyr Cys Ala Arg Glu Glu Ile Thr Tyr Ala Met Asp 115 120 125 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly 130 135 140 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Asp Ile Gln 145 150 155 160 Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly Asp Arg Val 165 170 175 Thr Ile Thr Cys Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn 180 185 190 Thr Tyr Leu Glu Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu 195 200 205 Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro Ala Arg Phe 210 215 220 Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu 225 230 235 240 Gln Pro Asp Asp Phe Ala Thr Tyr Tyr Cys Phe Gln Gly Ser His Val 245 250 255 Pro Arg Thr Phe Gly Gln Gly Thr Lys Val Glu Val Lys Tyr Gly Ser 260 265 270 Gln Ser Ser Lys Pro Tyr Leu Leu Thr His Pro Ser Asp Pro Leu Glu 275 280 285 Leu Val Val Ser Gly Pro Ser Gly Gly Pro Ser Ser Pro Thr Thr Gly 290 295 300 Pro Thr Ser Thr Ser Gly Pro Glu Asp Gln Pro Leu Thr Pro Thr Gly 305 310 315 320 Ser Asp Pro Gln Ser Gly Leu Gly Arg His Leu Gly Val Val Ile Gly 325 330 335 Ile Leu Val Ala Val Ile Leu Leu Leu Leu Leu Leu Leu Leu Leu Phe 340 345 350 Leu Ile Leu Arg His Arg Arg Gln Gly Lys His Trp Thr Ser Thr Gln 355 360 365 Arg Lys Ala Asp Phe Gln His Pro Ala Gly Ala Val Gly Pro Glu Pro 370 375 380 Thr Asp Arg Gly Leu Gln Trp Arg Ser Ser Pro Ala Ala Asp Ala Gln 385 390 395 400 Glu Glu Asn Leu Tyr Ala Ala Val Lys His Thr Gln Pro Glu Asp Gly 405 410 415 Val Glu Met Asp Thr Arg Ser Pro His Asp Glu Asp Pro Gln Ala Val 420 425 430 Thr Tyr Ala Glu Val Lys His Ser Arg Pro Arg Arg Glu Met Ala Ser 435 440 445 Pro Pro Ser Pro Leu Ser Gly Glu Phe Leu Asp Thr Lys Asp Arg Gln 450 455 460 Ala Glu Glu Asp Arg Gln Met Asp Thr Glu Ala Ala Ala Ser Glu Ala 465 470 475 480 Pro Gln Asp Val Thr Tyr Ala Gln Leu His Ser Leu Thr Leu Arg Arg 485 490 495 Glu Ala Thr Glu Pro Pro Pro Ser Gln Glu Gly Pro Ser Pro Ala Val 500 505 510 Pro Ser Ile Tyr Ala Thr Leu Ala Ile His Gly Ser Gly Glu Gly Arg 515 520 525 Gly Ser Leu Leu Thr Cys Gly Asp Val Glu Glu Asn Pro Gly Pro Met 530 535 540 Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp Leu 545 550 555 560 Arg Gly Ala Arg Cys Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu 565 570 575 Val Lys Pro Ser Gln Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly 580 585 590 Ser Ile Ser Ser Gly Asp Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro 595 600 605 Gly Lys Gly Leu Glu Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr 610 615 620 Asp Tyr Asn Pro Ser Leu Lys Ser Arg Val Thr Met Ser Val Asp Thr 625 630 635 640 Ser Lys Asn Gln Phe Ser Leu Lys Val Asn Ser Val Thr Ala Ala Asp 645 650 655 Thr Ala Val Tyr Tyr Cys Ala Arg Val Ser Ile Phe Gly Val Gly Thr 660 665 670 Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly 675 680 685 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Glu 690 695 700 Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly Glu 705 710 715 720 Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr Leu 725 730 735 Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr 740 745 750 Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly Ser 755 760 765 Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu 770 775 780 Asp Phe Ala Val Tyr Tyr Cys His Gln Tyr Gly Ser Thr Pro Leu Thr 785 790 795 800 Phe Gly Gly Gly Thr Lys Ala Glu Ile Lys Thr Thr Thr Pro Ala Pro 805 810 815 Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu 820 825 830 Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg 835 840 845 Gly Leu Asp Phe Ala Cys Asp Phe Trp Val Leu Val Val Val Gly Gly 850 855 860 Val Leu Ala Cys Tyr Ser Leu Leu Val Thr Val Ala Phe Ile Ile Phe 865 870 875 880 Trp Val Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met Asn 885 890 895 Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr 900 905 910 Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser Lys Arg Gly Arg Lys 915 920 925 Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr 930 935 940 Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu 945 950 955 960 Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro 965 970 975 Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly 980 985 990 Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro 995 1000 1005 Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu 1010 1015 1020 Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu 1025 1030 1035 Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly 1040 1045 1050 Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala 1055 1060 1065 Leu His Met Gln Ala Leu Pro Pro Arg 1070 1075 <![CDATA[<210> 187]]> <![CDATA[<211> 3234]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> C1765-T2A-CT489 DNA]]> <![CDATA[<400> 187]]> atggatatga gagtgcctgc ccagctgctc ggactgctcc ttctgtggtt gagaggagct 60 cggtgcgatg ttctgatgac ccaaactcca ctctccctgc ctgtcagtct tggagatcaa 120 gcctccatct cttgcagatc tagtcagagc attgtacata gtaatggaaa cacctattta 180 gaatggtacc tgcagaagcc aggccagtct ccaaagctgc tcatctacaa agtttccaac 240 cgattttctg gggtcccaga cagatttagc ggatctggct ctgggaccga tttcacactc 300 aagatcagta gagtggaggc tgaggatctg ggagtttatt actgctttca aggttcacat 360 gttcctcgga cgtccggtgg aggcacaaag ctggaaatca agggaggtgg cggctctgga 420 ggcggaggta gcggaggtgg aggctctggt ggccaggtcc agctgcagca gtctggacct 480 gagctggtga agccaggggc ttcagtgagg atatcctgta aggcctctgg ctacaccttt 540 acaagttacc atatacattg ggtgaagcag aggcctggac agggactcga atggattgga 600 tggatttatc ctggaaatgt taatactgag tacaatgaga agttcaaggg caaggccaca 660 ctgactgcag acaaatcgtc cagcacagcc tacatgcacc tcagcagcct gacctctgag 720 gactctgcgg tctatttctg tgccagagag gagattacct atgctatgga ttattggggt 780 caaggaacct cagtcaccgt gtcctcatac ggctcacaga gctccaaacc ctacctgctg 840 actcacccta gtgatcctct ggagctcgtg gtctcaggac cgtctggagg cccaagctct 900 ccgacaacag gccccacctc cacatctggc cctgaggacc agcccctcac acccaccggg 960 tcggatcctc agagtggtct gggaagacac ctgggagttg tgatcggcat cttggtggcc 1020 gtcatcctac tgctcctcct cctgctcctg ctcttcctca tcctccgaca tcgacgtcag 1080 ggcaaacact ggacatcgac ccagagaaag gctgatttcc aacatcctgc aggggctgtg 1140 gggccagagc ccacagacag aggcctgcag tggaggtcca gcccagctgc cgatgcccag 1200 gaagaaaacc tctatgctgc cgtgaagcac acacagcctg aggatggggt ggagatggat 1260 actcggagcc cacacgatga agatccacag gcagtgacgt atgccgaggt gaaacactcc 1320 agacctagaa gggaaatggc ctctcctcct tccccactgt ctggagagtt cctggacaca 1380 aaggacagac aggcggaaga ggacaggcag atggacactg aggctgctgc atctgaagct 1440 cctcaggatg tgacctacgc ccagctgcac agcttgaccc tcagacggga ggcaactgag 1500 cctcctccat cccaggaagg gccctctcca gctgtgccca gcatctacgc cactctggcc 1560 atccacggat ccggagaggg cagaggcagc ctgctgacat gtggcgacgt ggaagagaac 1620 cctggcccca tggacatgag ggtccccgct cagctcctgg ggctcctgct actctggctc 1680 cgaggtgcca gatgtcaggt ccagctccaa gagtcaggac caggtctggt caaaccctca 1740 cagacgctct ctcttacttg cacagtatca ggcggatcca ttagttccgg tgattattac 1800 tggtcttgga tccgccagcc tcctggtaag gggctggagt ggatcggata catatactac 1860 agtggttcca ctgattataa tccgtcactc aagtcccgag taactatgtc cgtggatact 1920 agcaaaaatc agttcagcct caaagtcaat tccgtaactg ccgccgacac cgcggtctat 1980 tattgtgcgc gggtgagcat cttcggcgtc ggtacgttcg attactgggg acaaggaact 2040 ctcgtaacag taagctctgg cggaggtgga agcggagggg gaggatctgg cggcggagga 2100 agcggaggcg agattgtaat gacccaaagc cctgccactc tttctctgtc tccgggggaa 2160 cgagcgactc tgtcatgtag ggcgtcccag agtgtctcta gctacctcgc atggtatcag 2220 cagaaacccg gacaagcccc tcggctcttg atttacgatg cctcaaacag agcaacgggg 2280 attccggcac ggttcagcgg gtctggtagc gggacagact tcacactgac gatctcttca 2340 ctcgaaccag aagattttgc agtctactat tgccatcagt atggttctac gccacttaca 2400 tttggcgggg gcaccaaggc ggagataaaa accacgacgc cagcgccgcg accaccaaca 2460 ccggcgccca ccatcgcgtc gcagcccctg tccctgcgcc cagaggcgtg ccggccagcg 2520 gcggggggcg cagtgcacac gagggggctg gacttcgcct gtgatttctg ggtgctggtc 2580 gttgtgggcg gcgtgctggc ctgctacagc ctgctggtga cagtggcctt catcatcttt 2640 tgggtgagga gcaagcggag cagactgctg cacagcgact acatgaacat gaccccccgg 2700 aggcctggcc ccacccggaa gcactaccag ccctacgccc ctcccaggga tttcgccgcc 2760 taccggagca aacggggcag aaagaaactc ctgtatatat tcaaacaacc atttatgagg 2820 ccagtacaaa ctactcaaga ggaagatggc tgtagctgcc gatttccaga agaagaagaa 2880 ggaggatgtg aactgagagt gaagttcagc aggagcgcag acgcccccgc gtacaagcag 2940 ggccagaacc agctctataa cgagctcaat ctaggacgaa gagaggagta cgatgttttg 3000 gacaagcgta gaggccggga ccctgagatg gggggaaagc cgagaaggaa gaaccctcag 3060 gaaggcctgt acaatgaact gcagaaagat aagatggcgg aggcctacag tgagattggg 3120 atgaaaggcg agcgccggag gggcaagggg cacgatggcc tttaccaggg actcagtaca 3180 gccaccaagg acacctacga cgcccttcac atgcaggccc tgccccctcg ctaa 3234 <![CDATA[<210> 188]]> <![CDATA[<211> 1077]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> C1765-T2A-CT489蛋白]]> <![CDATA[<400> 188]]> Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp 1 5 10 15 Leu Arg Gly Ala Arg Cys Asp Val Leu Met Thr Gln Thr Pro Leu Ser 20 25 30 Leu Pro Val Ser Leu Gly Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser 35 40 45 Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu 50 55 60 Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn 65 70 75 80 Arg Phe Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr 85 90 95 Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Leu Gly Val 100 105 110 Tyr Tyr Cys Phe Gln Gly Ser His Val Pro Arg Thr Ser Gly Gly Gly 115 120 125 Thr Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 130 135 140 Gly Gly Gly Gly Ser Gly Gly Gln Val Gln Leu Gln Gln Ser Gly Pro 145 150 155 160 Glu Leu Val Lys Pro Gly Ala Ser Val Arg Ile Ser Cys Lys Ala Ser 165 170 175 Gly Tyr Thr Phe Thr Ser Tyr His Ile His Trp Val Lys Gln Arg Pro 180 185 190 Gly Gln Gly Leu Glu Trp Ile Gly Trp Ile Tyr Pro Gly Asn Val Asn 195 200 205 Thr Glu Tyr Asn Glu Lys Phe Lys Gly Lys Ala Thr Leu Thr Ala Asp 210 215 220 Lys Ser Ser Ser Thr Ala Tyr Met His Leu Ser Ser Leu Thr Ser Glu 225 230 235 240 Asp Ser Ala Val Tyr Phe Cys Ala Arg Glu Glu Ile Thr Tyr Ala Met 245 250 255 Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Tyr Gly Ser 260 265 270 Gln Ser Ser Lys Pro Tyr Leu Leu Thr His Pro Ser Asp Pro Leu Glu 275 280 285 Leu Val Val Ser Gly Pro Ser Gly Gly Pro Ser Ser Pro Thr Thr Gly 290 295 300 Pro Thr Ser Thr Ser Gly Pro Glu Asp Gln Pro Leu Thr Pro Thr Gly 305 310 315 320 Ser Asp Pro Gln Ser Gly Leu Gly Arg His Leu Gly Val Val Ile Gly 325 330 335 Ile Leu Val Ala Val Ile Leu Leu Leu Leu Leu Leu Leu Leu Leu Phe 340 345 350 Leu Ile Leu Arg His Arg Arg Gln Gly Lys His Trp Thr Ser Thr Gln 355 360 365 Arg Lys Ala Asp Phe Gln His Pro Ala Gly Ala Val Gly Pro Glu Pro 370 375 380 Thr Asp Arg Gly Leu Gln Trp Arg Ser Ser Pro Ala Ala Asp Ala Gln 385 390 395 400 Glu Glu Asn Leu Tyr Ala Ala Val Lys His Thr Gln Pro Glu Asp Gly 405 410 415 Val Glu Met Asp Thr Arg Ser Pro His Asp Glu Asp Pro Gln Ala Val 420 425 430 Thr Tyr Ala Glu Val Lys His Ser Arg Pro Arg Arg Glu Met Ala Ser 435 440 445 Pro Pro Ser Pro Leu Ser Gly Glu Phe Leu Asp Thr Lys Asp Arg Gln 450 455 460 Ala Glu Glu Asp Arg Gln Met Asp Thr Glu Ala Ala Ala Ser Glu Ala 465 470 475 480 Pro Gln Asp Val Thr Tyr Ala Gln Leu His Ser Leu Thr Leu Arg Arg 485 490 495 Glu Ala Thr Glu Pro Pro Pro Ser Gln Glu Gly Pro Ser Pro Ala Val 500 505 510 Pro Ser Ile Tyr Ala Thr Leu Ala Ile His Gly Ser Gly Glu Gly Arg 515 520 525 Gly Ser Leu Leu Thr Cys Gly Asp Val Glu Glu Asn Pro Gly Pro Met 530 535 540 Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp Leu 545 550 555 560 Arg Gly Ala Arg Cys Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu 565 570 575 Val Lys Pro Ser Gln Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly 580 585 590 Ser Ile Ser Ser Gly Asp Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro 595 600 605 Gly Lys Gly Leu Glu Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr 610 615 620 Asp Tyr Asn Pro Ser Leu Lys Ser Arg Val Thr Met Ser Val Asp Thr 625 630 635 640 Ser Lys Asn Gln Phe Ser Leu Lys Val Asn Ser Val Thr Ala Ala Asp 645 650 655 Thr Ala Val Tyr Tyr Cys Ala Arg Val Ser Ile Phe Gly Val Gly Thr 660 665 670 Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly 675 680 685 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Glu 690 695 700 Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly Glu 705 710 715 720 Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr Leu 725 730 735 Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr 740 745 750 Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly Ser 755 760 765 Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu 770 775 780 Asp Phe Ala Val Tyr Tyr Cys His Gln Tyr Gly Ser Thr Pro Leu Thr 785 790 795 800 Phe Gly Gly Gly Thr Lys Ala Glu Ile Lys Thr Thr Thr Pro Ala Pro 805 810 815 Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu 820 825 830 Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg 835 840 845 Gly Leu Asp Phe Ala Cys Asp Phe Trp Val Leu Val Val Val Gly Gly 850 855 860 Val Leu Ala Cys Tyr Ser Leu Leu Val Thr Val Ala Phe Ile Ile Phe 865 870 875 880 Trp Val Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met Asn 885 890 895 Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr 900 905 910 Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser Lys Arg Gly Arg Lys 915 920 925 Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr 930 935 940 Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu 945 950 955 960 Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro 965 970 975 Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly 980 985 990 Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro 995 1000 1005 Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu 1010 1015 1020 Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu 1025 1030 1035 Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly 1040 1045 1050 Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala 1055 1060 1065 Leu His Met Gln Ala Leu Pro Pro Arg 1070 1075 <![CDATA[<210> 189]]> <![CDATA[<211> 3228]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> C1765-T2A-CT486 DNA]]> <![CDATA[<400> 189]]> atggatatga gagtgcctgc ccagctgctc ggactgctcc ttctgtggtt gagaggagct 60 cggtgcgatg ttctgatgac ccaaactcca ctctccctgc ctgtcagtct tggagatcaa 120 gcctccatct cttgcagatc tagtcagagc attgtacata gtaatggaaa cacctattta 180 gaatggtacc tgcagaagcc aggccagtct ccaaagctgc tcatctacaa agtttccaac 240 cgattttctg gggtcccaga cagatttagc ggatctggct ctgggaccga tttcacactc 300 aagatcagta gagtggaggc tgaggatctg ggagtttatt actgctttca aggttcacat 360 gttcctcgga cgtccggtgg aggcacaaag ctggaaatca agggaggtgg cggctctgga 420 ggcggaggta gcggaggtgg aggctctggt ggccaggtcc agctgcagca gtctggacct 480 gagctggtga agccaggggc ttcagtgagg atatcctgta aggcctctgg ctacaccttt 540 acaagttacc atatacattg ggtgaagcag aggcctggac agggactcga atggattgga 600 tggatttatc ctggaaatgt taatactgag tacaatgaga agttcaaggg caaggccaca 660 ctgactgcag acaaatcgtc cagcacagcc tacatgcacc tcagcagcct gacctctgag 720 gactctgcgg tctatttctg tgccagagag gagattacct atgctatgga ttattggggt 780 caaggaacct cagtcaccgt gtcctcatac ggctcacaga gctccaaacc ctacctgctg 840 actcacccta gtgatcctct ggagctcgtg gtctcaggac cgtctggagg cccaagctct 900 ccgacaacag gccccacctc cacatctggc cctgaggacc agcccctcac acccaccggg 960 tcggatcctc agagtggtct gggaagacac ctgggagttg tgatcggcat cttggtggcc 1020 gtcatcctac tgctcctcct cctgctcctg ctcttcctca tcctccgaca tcgacgtcag 1080 ggcaaacact ggacatcgac ccagagaaag gctgatttcc aacatcctgc aggggctgtg 1140 gggccagagc ccacagacag aggcctgcag tggaggtcca gcccagctgc cgatgcccag 1200 gaagaaaacc tctatgctgc cgtgaagcac acacagcctg aggatggggt ggagatggat 1260 actcggagcc cacacgatga agatccacag gcagtgacgt atgccgaggt gaaacactcc 1320 agacctagaa gggaaatggc ctctcctcct tccccactgt ctggagagtt cctggacaca 1380 aaggacagac aggcggaaga ggacaggcag atggacactg aggctgctgc atctgaagct 1440 cctcaggatg tgacctacgc ccagctgcac agcttgaccc tcagacggga ggcaactgag 1500 cctcctccat cccaggaagg gccctctcca gctgtgccca gcatctacgc cactctggcc 1560 atccacggat ccggagaggg cagaggcagc ctgctgacat gtggcgacgt ggaagagaac 1620 cctggcccca tggacatgag ggtccccgct cagctcctgg ggctcctgct actctggctc 1680 cgaggtgcca gatgtcaggt gcagctgaag cagtccggcc ccggcctggt gcagccctcc 1740 cagtccctgt ccatcacctg caccgtgtcc ggcttctccc tgaccaacta cggcgtgcac 1800 tgggtgcggc agtcccccgg caagggcctg gagtggctgg gcgtgatctg gtccggcggc 1860 aacaccgact acaacacccc cttcacctcc cggctgtcca tcaacaagga caactccaag 1920 tcccaggtgt tcttcaagat gaactccctg cagtccaacg acaccgccat ctactactgc 1980 gcccgggccc tgacctacta cgactacgag ttcgcctact ggggccaggg caccctggtg 2040 accgtgtccg ccggcggagg tggaagcgga gggggaggat ctggcggcgg aggaagcgga 2100 ggcgacatcc tgctgaccca gtcccccgtg atcctgtccg tgtcccccgg cgagcgggtg 2160 tccttctcct gccgggcctc ccagtccatc ggcaccaaca tccactggta ccagcagcgg 2220 accaacggct ccccccggct gctgatcaag tacgcctccg agtccatctc cggcatcccc 2280 tcccggttct ccggctccgg ctccggcacc gacttcaccc tgtccatcaa ctccgtggag 2340 tccgaggaca tcgccgacta ctactgccag cagaacaaca actggcccac caccttcggc 2400 gccggcacca agctggagct gaagaccacg acgccagcgc cgcgaccacc aacaccggcg 2460 cccaccatcg cgtcgcagcc cctgtccctg cgcccagagg cgtgccggcc agcggcgggg 2520 ggcgcagtgc acacgagggg gctggacttc gcctgtgatt tctgggtgct ggtcgttgtg 2580 ggcggcgtgc tggcctgcta cagcctgctg gtgacagtgg ccttcatcat cttttgggtg 2640 aggagcaagc ggagcagact gctgcacagc gactacatga acatgacccc ccggaggcct 2700 ggccccaccc ggaagcacta ccagccctac gcccctccca gggatttcgc cgcctaccgg 2760 agcaaacggg gcagaaagaa actcctgtat atattcaaac aaccatttat gaggccagta 2820 caaactactc aagaggaaga tggctgtagc tgccgatttc cagaagaaga agaaggagga 2880 tgtgaactga gagtgaagtt cagcaggagc gcagacgccc ccgcgtacaa gcagggccag 2940 aaccagctct ataacgagct caatctagga cgaagagagg agtacgatgt tttggacaag 3000 cgtagaggcc gggaccctga gatgggggga aagccgagaa ggaagaaccc tcaggaaggc 3060 ctgtacaatg aactgcagaa agataagatg gcggaggcct acagtgagat tgggatgaaa 3120 ggcgagcgcc ggaggggcaa ggggcacgat ggcctttacc agggactcag tacagccacc 3180 aaggacacct acgacgccct tcacatgcag gccctgcccc ctcgctaa 3228 <![CDATA[<210> 190]]> <![CDATA[<211> 1075]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> C1765-T2A-CT486蛋白]]> <![CDATA[<400> 190]]> Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp 1 5 10 15 Leu Arg Gly Ala Arg Cys Asp Val Leu Met Thr Gln Thr Pro Leu Ser 20 25 30 Leu Pro Val Ser Leu Gly Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser 35 40 45 Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu 50 55 60 Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn 65 70 75 80 Arg Phe Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr 85 90 95 Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Leu Gly Val 100 105 110 Tyr Tyr Cys Phe Gln Gly Ser His Val Pro Arg Thr Ser Gly Gly Gly 115 120 125 Thr Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 130 135 140 Gly Gly Gly Gly Ser Gly Gly Gln Val Gln Leu Gln Gln Ser Gly Pro 145 150 155 160 Glu Leu Val Lys Pro Gly Ala Ser Val Arg Ile Ser Cys Lys Ala Ser 165 170 175 Gly Tyr Thr Phe Thr Ser Tyr His Ile His Trp Val Lys Gln Arg Pro 180 185 190 Gly Gln Gly Leu Glu Trp Ile Gly Trp Ile Tyr Pro Gly Asn Val Asn 195 200 205 Thr Glu Tyr Asn Glu Lys Phe Lys Gly Lys Ala Thr Leu Thr Ala Asp 210 215 220 Lys Ser Ser Ser Thr Ala Tyr Met His Leu Ser Ser Leu Thr Ser Glu 225 230 235 240 Asp Ser Ala Val Tyr Phe Cys Ala Arg Glu Glu Ile Thr Tyr Ala Met 245 250 255 Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Tyr Gly Ser 260 265 270 Gln Ser Ser Lys Pro Tyr Leu Leu Thr His Pro Ser Asp Pro Leu Glu 275 280 285 Leu Val Val Ser Gly Pro Ser Gly Gly Pro Ser Ser Pro Thr Thr Gly 290 295 300 Pro Thr Ser Thr Ser Gly Pro Glu Asp Gln Pro Leu Thr Pro Thr Gly 305 310 315 320 Ser Asp Pro Gln Ser Gly Leu Gly Arg His Leu Gly Val Val Ile Gly 325 330 335 Ile Leu Val Ala Val Ile Leu Leu Leu Leu Leu Leu Leu Leu Leu Phe 340 345 350 Leu Ile Leu Arg His Arg Arg Gln Gly Lys His Trp Thr Ser Thr Gln 355 360 365 Arg Lys Ala Asp Phe Gln His Pro Ala Gly Ala Val Gly Pro Glu Pro 370 375 380 Thr Asp Arg Gly Leu Gln Trp Arg Ser Ser Pro Ala Ala Asp Ala Gln 385 390 395 400 Glu Glu Asn Leu Tyr Ala Ala Val Lys His Thr Gln Pro Glu Asp Gly 405 410 415 Val Glu Met Asp Thr Arg Ser Pro His Asp Glu Asp Pro Gln Ala Val 420 425 430 Thr Tyr Ala Glu Val Lys His Ser Arg Pro Arg Arg Glu Met Ala Ser 435 440 445 Pro Pro Ser Pro Leu Ser Gly Glu Phe Leu Asp Thr Lys Asp Arg Gln 450 455 460 Ala Glu Glu Asp Arg Gln Met Asp Thr Glu Ala Ala Ala Ser Glu Ala 465 470 475 480 Pro Gln Asp Val Thr Tyr Ala Gln Leu His Ser Leu Thr Leu Arg Arg 485 490 495 Glu Ala Thr Glu Pro Pro Pro Ser Gln Glu Gly Pro Ser Pro Ala Val 500 505 510 Pro Ser Ile Tyr Ala Thr Leu Ala Ile His Gly Ser Gly Glu Gly Arg 515 520 525 Gly Ser Leu Leu Thr Cys Gly Asp Val Glu Glu Asn Pro Gly Pro Met 530 535 540 Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp Leu 545 550 555 560 Arg Gly Ala Arg Cys Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu 565 570 575 Val Gln Pro Ser Gln Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe 580 585 590 Ser Leu Thr Asn Tyr Gly Val His Trp Val Arg Gln Ser Pro Gly Lys 595 600 605 Gly Leu Glu Trp Leu Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr 610 615 620 Asn Thr Pro Phe Thr Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys 625 630 635 640 Ser Gln Val Phe Phe Lys Met Asn Ser Leu Gln Ser Asn Asp Thr Ala 645 650 655 Ile Tyr Tyr Cys Ala Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala 660 665 670 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala Gly Gly Gly Gly 675 680 685 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Asp Ile Leu 690 695 700 Leu Thr Gln Ser Pro Val Ile Leu Ser Val Ser Pro Gly Glu Arg Val 705 710 715 720 Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn Ile His Trp 725 730 735 Tyr Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile Lys Tyr Ala 740 745 750 Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly Ser Gly Ser 755 760 765 Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser Glu Asp Ile 770 775 780 Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr Thr Phe Gly 785 790 795 800 Ala Gly Thr Lys Leu Glu Leu Lys Thr Thr Thr Pro Ala Pro Arg Pro 805 810 815 Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro 820 825 830 Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu 835 840 845 Asp Phe Ala Cys Asp Phe Trp Val Leu Val Val Val Gly Gly Val Leu 850 855 860 Ala Cys Tyr Ser Leu Leu Val Thr Val Ala Phe Ile Ile Phe Trp Val 865 870 875 880 Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met Asn Met Thr 885 890 895 Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro 900 905 910 Pro Arg Asp Phe Ala Ala Tyr Arg Ser Lys Arg Gly Arg Lys Lys Leu 915 920 925 Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln 930 935 940 Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly 945 950 955 960 Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr 965 970 975 Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg 980 985 990 Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met 995 1000 1005 Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn 1010 1015 1020 Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly 1025 1030 1035 Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr 1040 1045 1050 Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His 1055 1060 1065 Met Gln Ala Leu Pro Pro Arg 1070 1075 <![CDATA[<210> 191]]> <![CDATA[<211> 3228]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> C2162-T2A-CT486 DNA]]> <![CDATA[<400> 191]]> atggatatga gagtgcctgc ccagctgctc ggactgctcc ttctgtggtt gagaggagct 60 cggtgccagg tgcagctggt gcagtctggg gctgaggtga agaagcctgg gtcctcagtg 120 aaggtttcct gcaaggcttc tggatacacc ttcactagct atcatataca ttgggtgcgc 180 caggcccccg gacaagggct tgagtggatc ggatggatct accctggcaa tgttaacaca 240 gaatataatg agaagttcaa gggcaaagcc accattaccg cggacgaatc cacgaacaca 300 gcctacatgg agctgagcag cctgagatct gaagacacgg ctgtgtatta ctgtgcgagg 360 gaggaaatta cctacgctat ggactactgg ggccagggaa ccctggtcac cgtgtcctca 420 ggaggtggcg gctctggagg cggaggtagc ggaggtggag gctctggtgg cgacattcaa 480 atgacccaga gcccatccac cctgagcgca tctgtaggtg accgggtcac catcacttgt 540 agatccagtc agagtattgt acacagtaat gggaacacct atttggaatg gtatcagcag 600 aaaccaggta aagccccaaa attgctcatc tacaaagtct ctaacagatt tagtggtgta 660 ccagccaggt tcagcggttc cggaagtggt actgaattca ccctcacgat ctcctctctc 720 cagccagatg atttcgccac ttattactgt tttcaaggtt cacatgtgcc gcgcacattc 780 ggtcagggta ctaaagtaga agtcaaatac ggctcacaga gctccaaacc ctacctgctg 840 actcacccta gtgatcctct ggagctcgtg gtctcaggac cgtctggagg cccaagctct 900 ccgacaacag gccccacctc cacatctggc cctgaggacc agcccctcac acccaccggg 960 tcggatcctc agagtggtct gggaagacac ctgggagttg tgatcggcat cttggtggcc 1020 gtcatcctac tgctcctcct cctgctcctg ctcttcctca tcctccgaca tcgacgtcag 1080 ggcaaacact ggacatcgac ccagagaaag gctgatttcc aacatcctgc aggggctgtg 1140 gggccagagc ccacagacag aggcctgcag tggaggtcca gcccagctgc cgatgcccag 1200 gaagaaaacc tctatgctgc cgtgaagcac acacagcctg aggatggggt ggagatggat 1260 actcggagcc cacacgatga agatccacag gcagtgacgt atgccgaggt gaaacactcc 1320 agacctagaa gggaaatggc ctctcctcct tccccactgt ctggagagtt cctggacaca 1380 aaggacagac aggcggaaga ggacaggcag atggacactg aggctgctgc atctgaagct 1440 cctcaggatg tgacctacgc ccagctgcac agcttgaccc tcagacggga ggcaactgag 1500 cctcctccat cccaggaagg gccctctcca gctgtgccca gcatctacgc cactctggcc 1560 atccacggat ccggagaggg cagaggcagc ctgctgacat gtggcgacgt ggaagagaac 1620 cctggcccca tggacatgag ggtccccgct cagctcctgg ggctcctgct actctggctc 1680 cgaggtgcca gatgtcaggt gcagctgaag cagtccggcc ccggcctggt gcagccctcc 1740 cagtccctgt ccatcacctg caccgtgtcc ggcttctccc tgaccaacta cggcgtgcac 1800 tgggtgcggc agtcccccgg caagggcctg gagtggctgg gcgtgatctg gtccggcggc 1860 aacaccgact acaacacccc cttcacctcc cggctgtcca tcaacaagga caactccaag 1920 tcccaggtgt tcttcaagat gaactccctg cagtccaacg acaccgccat ctactactgc 1980 gcccgggccc tgacctacta cgactacgag ttcgcctact ggggccaggg caccctggtg 2040 accgtgtccg ccggcggagg tggaagcgga gggggaggat ctggcggcgg aggaagcgga 2100 ggcgacatcc tgctgaccca gtcccccgtg atcctgtccg tgtcccccgg cgagcgggtg 2160 tccttctcct gccgggcctc ccagtccatc ggcaccaaca tccactggta ccagcagcgg 2220 accaacggct ccccccggct gctgatcaag tacgcctccg agtccatctc cggcatcccc 2280 tcccggttct ccggctccgg ctccggcacc gacttcaccc tgtccatcaa ctccgtggag 2340 tccgaggaca tcgccgacta ctactgccag cagaacaaca actggcccac caccttcggc 2400 gccggcacca agctggagct gaagaccacg acgccagcgc cgcgaccacc aacaccggcg 2460 cccaccatcg cgtcgcagcc cctgtccctg cgcccagagg cgtgccggcc agcggcgggg 2520 ggcgcagtgc acacgagggg gctggacttc gcctgtgatt tctgggtgct ggtcgttgtg 2580 ggcggcgtgc tggcctgcta cagcctgctg gtgacagtgg ccttcatcat cttttgggtg 2640 aggagcaagc ggagcagact gctgcacagc gactacatga acatgacccc ccggaggcct 2700 ggccccaccc ggaagcacta ccagccctac gcccctccca gggatttcgc cgcctaccgg 2760 agcaaacggg gcagaaagaa actcctgtat atattcaaac aaccatttat gaggccagta 2820 caaactactc aagaggaaga tggctgtagc tgccgatttc cagaagaaga agaaggagga 2880 tgtgaactga gagtgaagtt cagcaggagc gcagacgccc ccgcgtacaa gcagggccag 2940 aaccagctct ataacgagct caatctagga cgaagagagg agtacgatgt tttggacaag 3000 cgtagaggcc gggaccctga gatgggggga aagccgagaa ggaagaaccc tcaggaaggc 3060 ctgtacaatg aactgcagaa agataagatg gcggaggcct acagtgagat tgggatgaaa 3120 ggcgagcgcc ggaggggcaa ggggcacgat ggcctttacc agggactcag tacagccacc 3180 aaggacacct acgacgccct tcacatgcag gccctgcccc ctcgctag 3228 <![CDATA[<210> 192]]> <![CDATA[<211> 1075]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> C2162-T2A-CT486蛋白]]> <![CDATA[<400> 192]]> Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp 1 5 10 15 Leu Arg Gly Ala Arg Cys Gln Val Gln Leu Val Gln Ser Gly Ala Glu 20 25 30 Val Lys Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly 35 40 45 Tyr Thr Phe Thr Ser Tyr His Ile His Trp Val Arg Gln Ala Pro Gly 50 55 60 Gln Gly Leu Glu Trp Ile Gly Trp Ile Tyr Pro Gly Asn Val Asn Thr 65 70 75 80 Glu Tyr Asn Glu Lys Phe Lys Gly Lys Ala Thr Ile Thr Ala Asp Glu 85 90 95 Ser Thr Asn Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp 100 105 110 Thr Ala Val Tyr Tyr Cys Ala Arg Glu Glu Ile Thr Tyr Ala Met Asp 115 120 125 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly 130 135 140 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Asp Ile Gln 145 150 155 160 Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly Asp Arg Val 165 170 175 Thr Ile Thr Cys Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn 180 185 190 Thr Tyr Leu Glu Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu 195 200 205 Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro Ala Arg Phe 210 215 220 Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu 225 230 235 240 Gln Pro Asp Asp Phe Ala Thr Tyr Tyr Cys Phe Gln Gly Ser His Val 245 250 255 Pro Arg Thr Phe Gly Gln Gly Thr Lys Val Glu Val Lys Tyr Gly Ser 260 265 270 Gln Ser Ser Lys Pro Tyr Leu Leu Thr His Pro Ser Asp Pro Leu Glu 275 280 285 Leu Val Val Ser Gly Pro Ser Gly Gly Pro Ser Ser Pro Thr Thr Gly 290 295 300 Pro Thr Ser Thr Ser Gly Pro Glu Asp Gln Pro Leu Thr Pro Thr Gly 305 310 315 320 Ser Asp Pro Gln Ser Gly Leu Gly Arg His Leu Gly Val Val Ile Gly 325 330 335 Ile Leu Val Ala Val Ile Leu Leu Leu Leu Leu Leu Leu Leu Leu Phe 340 345 350 Leu Ile Leu Arg His Arg Arg Gln Gly Lys His Trp Thr Ser Thr Gln 355 360 365 Arg Lys Ala Asp Phe Gln His Pro Ala Gly Ala Val Gly Pro Glu Pro 370 375 380 Thr Asp Arg Gly Leu Gln Trp Arg Ser Ser Pro Ala Ala Asp Ala Gln 385 390 395 400 Glu Glu Asn Leu Tyr Ala Ala Val Lys His Thr Gln Pro Glu Asp Gly 405 410 415 Val Glu Met Asp Thr Arg Ser Pro His Asp Glu Asp Pro Gln Ala Val 420 425 430 Thr Tyr Ala Glu Val Lys His Ser Arg Pro Arg Arg Glu Met Ala Ser 435 440 445 Pro Pro Ser Pro Leu Ser Gly Glu Phe Leu Asp Thr Lys Asp Arg Gln 450 455 460 Ala Glu Glu Asp Arg Gln Met Asp Thr Glu Ala Ala Ala Ser Glu Ala 465 470 475 480 Pro Gln Asp Val Thr Tyr Ala Gln Leu His Ser Leu Thr Leu Arg Arg 485 490 495 Glu Ala Thr Glu Pro Pro Pro Ser Gln Glu Gly Pro Ser Pro Ala Val 500 505 510 Pro Ser Ile Tyr Ala Thr Leu Ala Ile His Gly Ser Gly Glu Gly Arg 515 520 525 Gly Ser Leu Leu Thr Cys Gly Asp Val Glu Glu Asn Pro Gly Pro Met 530 535 540 Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp Leu 545 550 555 560 Arg Gly Ala Arg Cys Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu 565 570 575 Val Gln Pro Ser Gln Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe 580 585 590 Ser Leu Thr Asn Tyr Gly Val His Trp Val Arg Gln Ser Pro Gly Lys 595 600 605 Gly Leu Glu Trp Leu Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr 610 615 620 Asn Thr Pro Phe Thr Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys 625 630 635 640 Ser Gln Val Phe Phe Lys Met Asn Ser Leu Gln Ser Asn Asp Thr Ala 645 650 655 Ile Tyr Tyr Cys Ala Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala 660 665 670 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala Gly Gly Gly Gly 675 680 685 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Asp Ile Leu 690 695 700 Leu Thr Gln Ser Pro Val Ile Leu Ser Val Ser Pro Gly Glu Arg Val 705 710 715 720 Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn Ile His Trp 725 730 735 Tyr Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile Lys Tyr Ala 740 745 750 Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly Ser Gly Ser 755 760 765 Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser Glu Asp Ile 770 775 780 Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr Thr Phe Gly 785 790 795 800 Ala Gly Thr Lys Leu Glu Leu Lys Thr Thr Thr Pro Ala Pro Arg Pro 805 810 815 Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro 820 825 830 Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu 835 840 845 Asp Phe Ala Cys Asp Phe Trp Val Leu Val Val Val Gly Gly Val Leu 850 855 860 Ala Cys Tyr Ser Leu Leu Val Thr Val Ala Phe Ile Ile Phe Trp Val 865 870 875 880 Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met Asn Met Thr 885 890 895 Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro 900 905 910 Pro Arg Asp Phe Ala Ala Tyr Arg Ser Lys Arg Gly Arg Lys Lys Leu 915 920 925 Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln 930 935 940 Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly 945 950 955 960 Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr 965 970 975 Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg 980 985 990 Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met 995 1000 1005 Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn 1010 1015 1020 Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly 1025 1030 1035 Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr 1040 1045 1050 Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His 1055 1060 1065 Met Gln Ala Leu Pro Pro Arg 1070 1075 <![CDATA[<210> 193]]> <![CDATA[<211> 3228]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> C1765-T2A-CT488 DNA]]> <![CDATA[<400> 193]]> atggatatga gagtgcctgc ccagctgctc ggactgctcc ttctgtggtt gagaggagct 60 cggtgcgatg ttctgatgac ccaaactcca ctctccctgc ctgtcagtct tggagatcaa 120 gcctccatct cttgcagatc tagtcagagc attgtacata gtaatggaaa cacctattta 180 gaatggtacc tgcagaagcc aggccagtct ccaaagctgc tcatctacaa agtttccaac 240 cgattttctg gggtcccaga cagatttagc ggatctggct ctgggaccga tttcacactc 300 aagatcagta gagtggaggc tgaggatctg ggagtttatt actgctttca aggttcacat 360 gttcctcgga cgtccggtgg aggcacaaag ctggaaatca agggaggtgg cggctctgga 420 ggcggaggta gcggaggtgg aggctctggt ggccaggtcc agctgcagca gtctggacct 480 gagctggtga agccaggggc ttcagtgagg atatcctgta aggcctctgg ctacaccttt 540 acaagttacc atatacattg ggtgaagcag aggcctggac agggactcga atggattgga 600 tggatttatc ctggaaatgt taatactgag tacaatgaga agttcaaggg caaggccaca 660 ctgactgcag acaaatcgtc cagcacagcc tacatgcacc tcagcagcct gacctctgag 720 gactctgcgg tctatttctg tgccagagag gagattacct atgctatgga ttattggggt 780 caaggaacct cagtcaccgt gtcctcatac ggctcacaga gctccaaacc ctacctgctg 840 actcacccta gtgatcctct ggagctcgtg gtctcaggac cgtctggagg cccaagctct 900 ccgacaacag gccccacctc cacatctggc cctgaggacc agcccctcac acccaccggg 960 tcggatcctc agagtggtct gggaagacac ctgggagttg tgatcggcat cttggtggcc 1020 gtcatcctac tgctcctcct cctgctcctg ctcttcctca tcctccgaca tcgacgtcag 1080 ggcaaacact ggacatcgac ccagagaaag gctgatttcc aacatcctgc aggggctgtg 1140 gggccagagc ccacagacag aggcctgcag tggaggtcca gcccagctgc cgatgcccag 1200 gaagaaaacc tctatgctgc cgtgaagcac acacagcctg aggatggggt ggagatggat 1260 actcggagcc cacacgatga agatccacag gcagtgacgt atgccgaggt gaaacactcc 1320 agacctagaa gggaaatggc ctctcctcct tccccactgt ctggagagtt cctggacaca 1380 aaggacagac aggcggaaga ggacaggcag atggacactg aggctgctgc atctgaagct 1440 cctcaggatg tgacctacgc ccagctgcac agcttgaccc tcagacggga ggcaactgag 1500 cctcctccat cccaggaagg gccctctcca gctgtgccca gcatctacgc cactctggcc 1560 atccacggat ccggagaggg cagaggcagc ctgctgacat gtggcgacgt ggaagagaac 1620 cctggcccca tggacatgag ggtccccgct cagctcctgg ggctcctgct actctggctc 1680 cgaggtgcca gatgtcaggt gcagctgcag gagtccggcc ccggcctggt gaagccctcc 1740 gagaccctgt ccctgacctg caccgtgtcc ggcggctccg tgtcctccgg cgactactac 1800 tggacctgga tccggcagtc ccccggcaag ggcctggagt ggatcggcca catctactac 1860 tccggcaaca ccaactacaa cccctccctg aagtcccggc tgaccatctc catcgacacc 1920 tccaagaccc agttctccct gaagctgtcc tccgtgaccg ccgccgacac cgccatctac 1980 tactgcgtgc gggaccgggt gaccggcgcc ttcgacatct ggggccaggg caccatggtg 2040 accgtgtcct ccggcggagg tggaagcgga gggggaggat ctggcggcgg aggaagcgga 2100 ggcgacatcc agatgaccca gtccccctcc tccctgtccg cctccgtggg cgaccgggtg 2160 accatcacct gccaggcctc ccaggacatc tccaactacc tgaactggta ccagcagaag 2220 cccggcaagg cccccaagct gctgatctac gacgcctcca acctggagac cggcgtgccc 2280 tcccggttct ccggctccgg ctccggcacc gacttcacct tcaccatctc ctccctgcag 2340 cccgaggaca tcgccaccta cttctgccag cacttcgacc acctgcccct ggccttcggc 2400 ggcggcacca aggtggagat caagaccacg acgccagcgc cgcgaccacc aacaccggcg 2460 cccaccatcg cgtcgcagcc cctgtccctg cgcccagagg cgtgccggcc agcggcgggg 2520 ggcgcagtgc acacgagggg gctggacttc gcctgtgatt tctgggtgct ggtcgttgtg 2580 ggcggcgtgc tggcctgcta cagcctgctg gtgacagtgg ccttcatcat cttttgggtg 2640 aggagcaagc ggagcagact gctgcacagc gactacatga acatgacccc ccggaggcct 2700 ggccccaccc ggaagcacta ccagccctac gcccctccca gggatttcgc cgcctaccgg 2760 agcaaacggg gcagaaagaa actcctgtat atattcaaac aaccatttat gaggccagta 2820 caaactactc aagaggaaga tggctgtagc tgccgatttc cagaagaaga agaaggagga 2880 tgtgaactga gagtgaagtt cagcaggagc gcagacgccc ccgcgtacaa gcagggccag 2940 aaccagctct ataacgagct caatctagga cgaagagagg agtacgatgt tttggacaag 3000 cgtagaggcc gggaccctga gatgggggga aagccgagaa ggaagaaccc tcaggaaggc 3060 ctgtacaatg aactgcagaa agataagatg gcggaggcct acagtgagat tgggatgaaa 3120 ggcgagcgcc ggaggggcaa ggggcacgat ggcctttacc agggactcag tacagccacc 3180 aaggacacct acgacgccct tcacatgcag gccctgcccc ctcgctaa 3228 <![CDATA[<210> 194]]> <![CDATA[<211> 1075]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> C1765-T2A-CT488蛋白]]> <![CDATA[<400> 194]]> Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp 1 5 10 15 Leu Arg Gly Ala Arg Cys Asp Val Leu Met Thr Gln Thr Pro Leu Ser 20 25 30 Leu Pro Val Ser Leu Gly Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser 35 40 45 Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu 50 55 60 Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn 65 70 75 80 Arg Phe Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr 85 90 95 Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Leu Gly Val 100 105 110 Tyr Tyr Cys Phe Gln Gly Ser His Val Pro Arg Thr Ser Gly Gly Gly 115 120 125 Thr Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 130 135 140 Gly Gly Gly Gly Ser Gly Gly Gln Val Gln Leu Gln Gln Ser Gly Pro 145 150 155 160 Glu Leu Val Lys Pro Gly Ala Ser Val Arg Ile Ser Cys Lys Ala Ser 165 170 175 Gly Tyr Thr Phe Thr Ser Tyr His Ile His Trp Val Lys Gln Arg Pro 180 185 190 Gly Gln Gly Leu Glu Trp Ile Gly Trp Ile Tyr Pro Gly Asn Val Asn 195 200 205 Thr Glu Tyr Asn Glu Lys Phe Lys Gly Lys Ala Thr Leu Thr Ala Asp 210 215 220 Lys Ser Ser Ser Thr Ala Tyr Met His Leu Ser Ser Leu Thr Ser Glu 225 230 235 240 Asp Ser Ala Val Tyr Phe Cys Ala Arg Glu Glu Ile Thr Tyr Ala Met 245 250 255 Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Tyr Gly Ser 260 265 270 Gln Ser Ser Lys Pro Tyr Leu Leu Thr His Pro Ser Asp Pro Leu Glu 275 280 285 Leu Val Val Ser Gly Pro Ser Gly Gly Pro Ser Ser Pro Thr Thr Gly 290 295 300 Pro Thr Ser Thr Ser Gly Pro Glu Asp Gln Pro Leu Thr Pro Thr Gly 305 310 315 320 Ser Asp Pro Gln Ser Gly Leu Gly Arg His Leu Gly Val Val Ile Gly 325 330 335 Ile Leu Val Ala Val Ile Leu Leu Leu Leu Leu Leu Leu Leu Leu Phe 340 345 350 Leu Ile Leu Arg His Arg Arg Gln Gly Lys His Trp Thr Ser Thr Gln 355 360 365 Arg Lys Ala Asp Phe Gln His Pro Ala Gly Ala Val Gly Pro Glu Pro 370 375 380 Thr Asp Arg Gly Leu Gln Trp Arg Ser Ser Pro Ala Ala Asp Ala Gln 385 390 395 400 Glu Glu Asn Leu Tyr Ala Ala Val Lys His Thr Gln Pro Glu Asp Gly 405 410 415 Val Glu Met Asp Thr Arg Ser Pro His Asp Glu Asp Pro Gln Ala Val 420 425 430 Thr Tyr Ala Glu Val Lys His Ser Arg Pro Arg Arg Glu Met Ala Ser 435 440 445 Pro Pro Ser Pro Leu Ser Gly Glu Phe Leu Asp Thr Lys Asp Arg Gln 450 455 460 Ala Glu Glu Asp Arg Gln Met Asp Thr Glu Ala Ala Ala Ser Glu Ala 465 470 475 480 Pro Gln Asp Val Thr Tyr Ala Gln Leu His Ser Leu Thr Leu Arg Arg 485 490 495 Glu Ala Thr Glu Pro Pro Pro Ser Gln Glu Gly Pro Ser Pro Ala Val 500 505 510 Pro Ser Ile Tyr Ala Thr Leu Ala Ile His Gly Ser Gly Glu Gly Arg 515 520 525 Gly Ser Leu Leu Thr Cys Gly Asp Val Glu Glu Asn Pro Gly Pro Met 530 535 540 Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp Leu 545 550 555 560 Arg Gly Ala Arg Cys Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu 565 570 575 Val Lys Pro Ser Glu Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly 580 585 590 Ser Val Ser Ser Gly Asp Tyr Tyr Trp Thr Trp Ile Arg Gln Ser Pro 595 600 605 Gly Lys Gly Leu Glu Trp Ile Gly His Ile Tyr Tyr Ser Gly Asn Thr 610 615 620 Asn Tyr Asn Pro Ser Leu Lys Ser Arg Leu Thr Ile Ser Ile Asp Thr 625 630 635 640 Ser Lys Thr Gln Phe Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp 645 650 655 Thr Ala Ile Tyr Tyr Cys Val Arg Asp Arg Val Thr Gly Ala Phe Asp 660 665 670 Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser Gly Gly Gly Gly 675 680 685 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Asp Ile Gln 690 695 700 Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val 705 710 715 720 Thr Ile Thr Cys Gln Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn Trp 725 730 735 Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Asp Ala 740 745 750 Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser 755 760 765 Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile 770 775 780 Ala Thr Tyr Phe Cys Gln His Phe Asp His Leu Pro Leu Ala Phe Gly 785 790 795 800 Gly Gly Thr Lys Val Glu Ile Lys Thr Thr Thr Pro Ala Pro Arg Pro 805 810 815 Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro 820 825 830 Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu 835 840 845 Asp Phe Ala Cys Asp Phe Trp Val Leu Val Val Val Gly Gly Val Leu 850 855 860 Ala Cys Tyr Ser Leu Leu Val Thr Val Ala Phe Ile Ile Phe Trp Val 865 870 875 880 Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met Asn Met Thr 885 890 895 Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro 900 905 910 Pro Arg Asp Phe Ala Ala Tyr Arg Ser Lys Arg Gly Arg Lys Lys Leu 915 920 925 Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln 930 935 940 Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly 945 950 955 960 Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr 965 970 975 Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg 980 985 990 Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met 995 1000 1005 Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn 1010 1015 1020 Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly 1025 1030 1035 Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr 1040 1045 1050 Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His 1055 1060 1065 Met Gln Ala Leu Pro Pro Arg 1070 1075 <![CDATA[<210> 195]]> <![CDATA[<211> 741]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> C-002166 BB7.2.2 scFv (人源化)]]> <![CDATA[<400> 195]]> gaggtgcagc tggtgcagtc tggggccgag ctgaagaagc ctgggtcctc ggtgaaggtg 60 tcctgcaagg cttctggata caccttcacc agctatcata tccagtgggt aaaacaggcc 120 cctggacaag ggcttgagtg gatcggatgg atctaccctg gcgatggttc aacacagtac 180 aatgagaagt tcaagggcaa agccacgctt accgtggaca aatccacgaa cacagcctac 240 atggagctga gcagcctgag atctgaggac acggccgtat attactgtgc gagagaggga 300 acttactacg ctatggacta ctggggccaa gggaccctgg tcaccgtgtc ctcaggcgga 360 ggtggaagcg gagggggagg atctggcggc ggaggaagcg gaggcgacat ccagatgacc 420 cagagcccat ccaccctgag tgcgtccgtg ggcgaccgcg tgaccatcac ttgcagatcc 480 tctcagtcca tcgtgcactc caacggcaac acgtacctcg agtggtacca gcagaagccc 540 gggaaggccc cgaaactgct catctacaag gtgagcaacc ggttctccgg cgtccccagc 600 cgcttctcag ggtccggctc ggggacggat ttcaccctca cgattagcag cttgcagccc 660 gatgacttcg ccacgtacta ctgctttcag ggaagtcacg tgccgcgtac cttcgggcag 720 ggcacgaaag tggaagttaa g 741 <![CDATA[<210> 196]]> <![CDATA[<211> 741]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> C-002167 BB7.2.3 scFv (人源化)]]> <![CDATA[<400> 196]]> caggtgcagc tggtgcagtc tggggccgag gtgaagaagc ctgggtcctc ggtgaaggtg 60 tcctgcaagg cttctggata caccttcacc agctatcata tccagtgggt acgacaggcc 120 cctggacaag ggcttgagtg gatgggatgg atctaccctg gcgatggttc aacacagtac 180 aatgagaagt tcaagggcag agtcacgatt accgcggaca aatccacgag cacagcctac 240 atggagctga gcagcctgag atctgaggac acggccgtat attactgtgc gagagaggga 300 acttactacg ctatggacta ctggggccaa gggaccacgg tcaccgtgtc ctcaggcgga 360 ggtggaagcg gagggggagg atctggcggc ggaggaagcg gaggcgagat cgtcctgacc 420 cagagcccag ggaccctgag tttgtccccg ggcgagcgcg cgaccctcag ttgcagatcc 480 tctcagtcca tcgtgcactc caacggcaac acgtacctcg agtggtacca gcagaagccc 540 gggcaggccc cgcgactgct catctacaag gtgagcaacc ggttctccgg catccccgac 600 cgcttctcag ggtccggctc ggggacggat ttcaccctca cgattagccg cttggagccc 660 gaagacttcg ccgtgtacta ctgctttcag ggaagtcacg tgccgcgtac cttcgggggg 720 ggcacgaaag tggaaattaa g 741 <![CDATA[<210> 197]]> <![CDATA[<211> 741]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> C-002168 BB7.2.5 scFv (人源化)]]> <![CDATA[<400> 197]]> caggtgaccc tgaagcagtc tggggccgag gtgaagaagc ctgggtcctc ggtgaaggtg 60 tcctgcacgg cttctggata caccttcacc agctatcatg tcagctgggt acgacaggcc 120 cctggacaag ggcttgagtg gttgggaagg atctaccctg gcgatggttc aacacagtac 180 aatgagaagt tcaagggcaa agtcacgatt accgcggaca aatccatgga cacatccttc 240 atggagctga ccagcctgac atctgaggac acggccgtat attactgtgc gagagaggga 300 acttactacg ctatggacct ctggggccaa gggaccctgg tcaccgtgtc ctcaggcgga 360 ggtggaagcg gagggggagg atctggcggc ggaggaagcg gaggcgagat cgtcctgacc 420 cagagcccag ggaccctgag tttgtccccg ggcgagcgcg cgaccctcag ttgcagatcc 480 tctcagtcca tcgtgcactc caacggcaac acgtacctcg cgtggtacca gcagaagccc 540 gggcaggccc cgcgactgct catctccaag gtgagcaacc ggttctccgg cgtccccgac 600 cgcttctcag ggtccggctc ggggacggat ttcaccctca cgattagccg cttggagccc 660 gaagacttcg ccgtgtacta ctgccaacag ggaagtcacg tgccgcgtac cttcgggggg 720 ggcacgaaag tggaaattaa g 741 <![CDATA[<210> 198]]> <![CDATA[<211> 741]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> C-002169 BB7.2.6 scFv (人源化)]]> <![CDATA[<400> 198]]> caggtgcagc tggtgcagtc tggggccgag gtgaagaagc ctggggcctc ggtgaaggtg 60 tcctgcaagg cttctggata caccttcacc agctatcata tgcactgggt acgacaggcc 120 cctggacaaa ggcttgagtg gatgggatgg atctaccctg gcgatggttc aacacagtac 180 aatgagaagt tcaagggcaa agtcacgatt acccgggaca catccgcgag cacagcctac 240 atggagctga gcagcctgag atctgaggac acggccgtat attactgtgc gagagaggga 300 acttactacg ctatggacta ctggggccaa gggaccctgg tcaccgtgtc ctcaggcgga 360 ggtggaagcg gagggggagg atctggcggc ggaggaagcg gaggcgacat cgtcatgacc 420 cagaccccac tgtccctgcc tgtgaccccg ggcgagcccg cgagcatcag ttgcagatcc 480 tctcagtcca tcgtgcactc caacggcaac acgtacctcg actggtacct gcagaagccc 540 gggcagtccc cgcaactgct catctacaag gtgagcaacc ggttctccgg cgtccccgac 600 cgcttctcag ggtccggctc ggggacggat ttcaccctca agattagccg cgtggaggcc 660 gaagacgtcg gcgtgtacta ctgcatgcag ggaagtcacg tgccgcgtac cttcgggggg 720 ggcacgaaag tggaaattaa g 741 <![CDATA[<210> 199]]> <![CDATA[<211> 244]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-B*07抗原結合結構域BB7.1.10_scFv]]> <![CDATA[<400> 199]]> Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Gly 20 25 30 Tyr Ser Trp His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp 35 40 45 Ile Gly Tyr Ile His Phe Ser Gly Ser Thr His Tyr His Pro Ser Leu 50 55 60 Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser 65 70 75 80 Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Gly Val Val Ser His Tyr Ala Met Asp Cys Trp Gly Gln 100 105 110 Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly 115 120 125 Gly Ser Gly Gly Gly Gly Ser Gly Gly Asp Ile Gln Met Thr Gln Ser 130 135 140 Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys 145 150 155 160 Arg Ala Ser Glu Asn Ile Tyr Ser Asn Leu Ala Trp Tyr Gln Gln Lys 165 170 175 Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Thr Tyr Leu Pro 180 185 190 Asp Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe 195 200 205 Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr 210 215 220 Cys Gln His Phe Trp Val Thr Pro Tyr Thr Phe Gly Gly Gly Thr Lys 225 230 235 240 Val Glu Ile Lys <![CDATA[<210> 200]]> <![CDATA[<211> 244]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-B*07抗原結合結構域BB7.1.9_scFv]]> <![CDATA[<400> 200]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Ser Ile Thr Ser Gly 20 25 30 Tyr Ser Trp His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp 35 40 45 Val Ser Tyr Ile His Phe Ser Gly Ser Thr His Tyr His Pro Ser Leu 50 55 60 Lys Ser Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Gly Val Val Ser His Tyr Ala Met Asp Cys Trp Gly Gln 100 105 110 Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly 115 120 125 Gly Ser Gly Gly Gly Gly Ser Gly Gly Asp Ile Gln Met Thr Gln Ser 130 135 140 Pro Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys 145 150 155 160 Arg Ala Ser Glu Asn Ile Tyr Ser Asn Leu Ala Trp Tyr Gln Gln Lys 165 170 175 Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Thr Tyr Leu Pro 180 185 190 Asp Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe 195 200 205 Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr 210 215 220 Cys Gln His Phe Trp Val Thr Pro Tyr Thr Phe Gly Gly Gly Thr Lys 225 230 235 240 Val Glu Ile Lys <![CDATA[<210> 201]]> <![CDATA[<211> 244]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-B*07抗原結合結構域BB7.1.8_scFv]]> <![CDATA[<400> 201]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Ser Ile Thr Ser Gly 20 25 30 Tyr Ser Trp His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp 35 40 45 Val Gly Tyr Ile His Phe Ser Gly Ser Thr His Tyr His Pro Ser Leu 50 55 60 Lys Ser Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Gly Val Val Ser His Tyr Ala Met Asp Cys Trp Gly Gln 100 105 110 Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly 115 120 125 Gly Ser Gly Gly Gly Gly Ser Gly Gly Glu Ile Val Leu Thr Gln Ser 130 135 140 Pro Ala Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys 145 150 155 160 Arg Ala Ser Glu Asn Ile Tyr Ser Asn Leu Ala Trp Tyr Gln Gln Lys 165 170 175 Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Ala Ala Thr Tyr Leu Pro 180 185 190 Asp Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe 195 200 205 Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr 210 215 220 Cys Gln His Phe Trp Val Thr Pro Tyr Thr Phe Gly Gly Gly Thr Lys 225 230 235 240 Val Glu Ile Lys <![CDATA[<210> 202]]> <![CDATA[<211> 244]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-B*07抗原結合結構域BB7.1.7_scFv]]> <![CDATA[<400> 202]]> Gln Val Gln Leu Gln Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Ala Ile Ser Gly Tyr Ser Ile Thr Ser Gly 20 25 30 Tyr Ser Trp His Trp Ile Arg Gln Ser Pro Ser Arg Gly Leu Glu Trp 35 40 45 Leu Gly Tyr Ile His Phe Ser Gly Ser Thr His Tyr His Pro Ser Leu 50 55 60 Lys Ser Arg Ile Thr Ile Asn Pro Asp Thr Ser Lys Asn Gln Phe Ser 65 70 75 80 Leu Gln Leu Asn Ser Val Thr Pro Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Gly Val Val Ser His Tyr Ala Met Asp Cys Trp Gly Gln 100 105 110 Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly 115 120 125 Gly Ser Gly Gly Gly Gly Ser Gly Gly Glu Ile Val Leu Thr Gln Ser 130 135 140 Pro Ala Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys 145 150 155 160 Arg Ala Ser Glu Asn Ile Tyr Ser Asn Leu Ala Trp Tyr Gln Gln Lys 165 170 175 Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Ala Ala Thr Tyr Leu Pro 180 185 190 Asp Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe 195 200 205 Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr 210 215 220 Cys Gln His Phe Trp Val Thr Pro Tyr Thr Phe Gly Gly Gly Thr Lys 225 230 235 240 Val Glu Ile Lys <![CDATA[<210> 203]]> <![CDATA[<211> 244]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-B*07抗原結合結構域BB7.1.6_scFv]]> <![CDATA[<400> 203]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Ser Ile Thr Ser Gly 20 25 30 Tyr Ser Trp His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp 35 40 45 Val Gly Tyr Ile His Phe Ser Gly Ser Thr His Tyr His Pro Ser Leu 50 55 60 Lys Ser Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Gly Val Val Ser His Tyr Ala Met Asp Cys Trp Gly Gln 100 105 110 Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly 115 120 125 Gly Ser Gly Gly Gly Gly Ser Gly Gly Asp Ile Gln Met Thr Gln Ser 130 135 140 Pro Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys 145 150 155 160 Arg Ala Ser Glu Asn Ile Tyr Ser Asn Leu Ala Trp Tyr Gln Gln Lys 165 170 175 Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Thr Tyr Leu Pro 180 185 190 Asp Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe 195 200 205 Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr 210 215 220 Cys Gln His Phe Trp Val Thr Pro Tyr Thr Phe Gly Gly Gly Thr Lys 225 230 235 240 Val Glu Ile Lys <![CDATA[<210> 204]]> <![CDATA[<211> 244]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-B*07抗原結合結構域BB7.1.5_scFv]]> <![CDATA[<400> 204]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Ser Ile Thr Ser Gly 20 25 30 Tyr Ser Trp His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp 35 40 45 Val Ser Tyr Ile His Phe Ser Gly Ser Thr His Tyr His Pro Ser Leu 50 55 60 Lys Ser Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Gly Val Val Ser His Tyr Ala Met Asp Cys Trp Gly Gln 100 105 110 Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly 115 120 125 Gly Ser Gly Gly Gly Gly Ser Gly Gly Asp Ile Gln Met Thr Gln Ser 130 135 140 Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys 145 150 155 160 Arg Ala Ser Glu Asn Ile Tyr Ser Asn Leu Ala Trp Tyr Gln Gln Lys 165 170 175 Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Thr Tyr Leu Pro 180 185 190 Asp Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe 195 200 205 Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr 210 215 220 Cys Gln His Phe Trp Val Thr Pro Tyr Thr Phe Gly Gly Gly Thr Lys 225 230 235 240 Val Glu Ile Lys <![CDATA[<210> 205]]> <![CDATA[<211> 244]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-B*07抗原結合結構域BB7.1.4_scFv]]> <![CDATA[<400> 205]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Ser Ile Thr Ser Gly 20 25 30 Tyr Ser Trp His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp 35 40 45 Val Gly Tyr Ile His Phe Ser Gly Ser Thr His Tyr His Pro Ser Leu 50 55 60 Lys Ser Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Gly Val Val Ser His Tyr Ala Met Asp Cys Trp Gly Gln 100 105 110 Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly 115 120 125 Gly Ser Gly Gly Gly Gly Ser Gly Gly Asp Ile Gln Met Thr Gln Ser 130 135 140 Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys 145 150 155 160 Arg Ala Ser Glu Asn Ile Tyr Ser Asn Leu Ala Trp Tyr Gln Gln Lys 165 170 175 Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Thr Tyr Leu Pro 180 185 190 Asp Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe 195 200 205 Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr 210 215 220 Cys Gln His Phe Trp Val Thr Pro Tyr Thr Phe Gly Gly Gly Thr Lys 225 230 235 240 Val Glu Ile Lys <![CDATA[<210> 206]]> <![CDATA[<211> 244]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-B*07抗原結合結構域BB7.1.3_scFv]]> <![CDATA[<400> 206]]> Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu 1 5 10 15 Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Tyr Ser Ile Thr Ser Gly 20 25 30 Tyr Ser Trp His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp 35 40 45 Ile Gly Tyr Ile His Phe Ser Gly Ser Thr His Tyr His Pro Ser Leu 50 55 60 Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser 65 70 75 80 Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Gly Val Val Ser His Tyr Ala Met Asp Cys Trp Gly Gln 100 105 110 Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly 115 120 125 Gly Ser Gly Gly Gly Gly Ser Gly Gly Asp Ile Gln Met Thr Gln Ser 130 135 140 Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys 145 150 155 160 Arg Ala Ser Glu Asn Ile Tyr Ser Asn Leu Ala Trp Tyr Gln Gln Lys 165 170 175 Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Thr Tyr Leu Pro 180 185 190 Asp Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe 195 200 205 Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr 210 215 220 Cys Gln His Phe Trp Val Thr Pro Tyr Thr Phe Gly Gly Gly Thr Lys 225 230 235 240 Val Glu Ile Lys <![CDATA[<210> 207]]> <![CDATA[<211> 244]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-B*07抗原結合結構域BB7.1.2_scFv]]> <![CDATA[<400> 207]]> Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Gly 20 25 30 Tyr Ser Trp His Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu Trp 35 40 45 Ile Gly Tyr Ile His Phe Ser Gly Ser Thr His Tyr His Pro Ser Leu 50 55 60 Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser 65 70 75 80 Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Gly Val Val Ser His Tyr Ala Met Asp Cys Trp Gly Gln 100 105 110 Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly 115 120 125 Gly Ser Gly Gly Gly Gly Ser Gly Gly Asp Ile Gln Met Thr Gln Ser 130 135 140 Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys 145 150 155 160 Arg Ala Ser Glu Asn Ile Tyr Ser Asn Leu Ala Trp Tyr Gln Gln Lys 165 170 175 Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Thr Tyr Leu Pro 180 185 190 Asp Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe 195 200 205 Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr 210 215 220 Cys Gln His Phe Trp Val Thr Pro Tyr Thr Phe Gly Gly Gly Thr Lys 225 230 235 240 Val Glu Ile Lys <![CDATA[<210> 208]]> <![CDATA[<211> 244]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-B*07抗原結合結構域BB7.1.1_scFv]]> <![CDATA[<400> 208]]> Gln Val Gln Leu Gln Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Ala Ile Ser Gly Tyr Ser Ile Thr Ser Gly 20 25 30 Tyr Ser Trp His Trp Ile Arg Gln Ser Pro Ser Arg Gly Leu Glu Trp 35 40 45 Leu Gly Tyr Ile His Phe Ser Gly Ser Thr His Tyr His Pro Ser Leu 50 55 60 Lys Ser Arg Ile Thr Ile Asn Pro Asp Thr Ser Lys Asn Gln Phe Ser 65 70 75 80 Leu Gln Leu Asn Ser Val Thr Pro Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Gly Val Val Ser His Tyr Ala Met Asp Cys Trp Gly Gln 100 105 110 Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly 115 120 125 Gly Ser Gly Gly Gly Gly Ser Gly Gly Asp Ile Gln Met Thr Gln Ser 130 135 140 Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys 145 150 155 160 Arg Ala Ser Glu Asn Ile Tyr Ser Asn Leu Ala Trp Tyr Gln Gln Lys 165 170 175 Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Thr Tyr Leu Pro 180 185 190 Asp Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe 195 200 205 Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr 210 215 220 Cys Gln His Phe Trp Val Thr Pro Tyr Thr Phe Gly Gly Gly Thr Lys 225 230 235 240 Val Glu Ile Lys <![CDATA[<210> 209]]> <![CDATA[<211> 243]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-A*11抗原結合結構域9]]> <![CDATA[<400> 209]]> Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly 20 25 30 Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe 65 70 75 80 Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg His Tyr Tyr Tyr Tyr Ser Met Asp Val Trp Gly Lys Gly 100 105 110 Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 115 120 125 Ser Gly Gly Gly Gly Ser Gly Gly Asp Ile Gln Met Thr Gln Ser Pro 130 135 140 Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg 145 150 155 160 Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr Gln Gln Lys Pro 165 170 175 Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ser Leu Gln Ser 180 185 190 Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 195 200 205 Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys 210 215 220 Gln Gln Ser Tyr Ser Thr Pro Leu Thr Phe Gly Gly Gly Thr Lys Val 225 230 235 240 Glu Ile Lys <![CDATA[<210> 210]]> <![CDATA[<211> 244]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-A*11抗原結合結構域8]]> <![CDATA[<400> 210]]> Gln Ile Thr Leu Lys Glu Ser Gly Pro Thr Leu Val Lys Pro Thr Gln 1 5 10 15 Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Ser Thr Ser 20 25 30 Gly Val Gly Val Gly Trp Ile Arg Gln Pro Pro Gly Lys Ala Leu Glu 35 40 45 Trp Leu Ala Leu Ile Tyr Trp Asn Asp Asp Lys Arg Tyr Ser Pro Ser 50 55 60 Leu Lys Ser Arg Leu Thr Ile Thr Lys Asp Thr Ser Lys Asn Gln Val 65 70 75 80 Val Leu Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr 85 90 95 Cys Ala His Arg His Met Arg Leu Ser Cys Phe Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly 115 120 125 Gly Ser Gly Gly Gly Gly Ser Gly Gly Asp Ile Gln Met Thr Gln Ser 130 135 140 Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys 145 150 155 160 Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr Gln Gln Lys 165 170 175 Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ser Leu Gln 180 185 190 Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe 195 200 205 Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr 210 215 220 Cys Gln Gln Ser Tyr Ser Thr Pro Leu Thr Phe Gly Gly Gly Thr Lys 225 230 235 240 Val Glu Ile Lys <![CDATA[<210> 211]]> <![CDATA[<211> 245]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-A*11抗原結合結構域7]]> <![CDATA[<400> 211]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met 35 40 45 Gly Trp Ile Asn Ala Gly Asn Gly Asn Thr Lys Tyr Ser Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Gly Asn Gly Ala Asn Pro Asp Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly 115 120 125 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Asp Ile Gln Met Thr Gln 130 135 140 Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr 145 150 155 160 Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr Gln Gln 165 170 175 Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ser Leu 180 185 190 Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp 195 200 205 Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr 210 215 220 Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Leu Thr Phe Gly Gly Gly Thr 225 230 235 240 Lys Val Glu Ile Lys 245 <![CDATA[<210> 212]]> <![CDATA[<211> 243]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-A*11抗原結合結構域6]]> <![CDATA[<400> 212]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Asp Met His Trp Val Arg Gln Ala Thr Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Gly Thr Ala Gly Asp Thr Tyr Tyr Pro Gly Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Glu Asn Ala Lys Asn Ser Leu Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Ala Gly Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Arg Asp Leu Pro Gly Ser Tyr Trp Tyr Phe Asp Leu Trp Gly Arg Gly 100 105 110 Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 115 120 125 Ser Gly Gly Gly Gly Ser Gly Gly Asp Ile Gln Met Thr Gln Ser Pro 130 135 140 Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg 145 150 155 160 Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr Gln Gln Lys Pro 165 170 175 Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ser Leu Gln Ser 180 185 190 Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 195 200 205 Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys 210 215 220 Gln Gln Ser Tyr Ser Thr Pro Leu Thr Phe Gly Gly Gly Thr Lys Val 225 230 235 240 Glu Ile Lys <![CDATA[<210> 213]]> <![CDATA[<211> 243]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-A*11抗原結合結構域5]]> <![CDATA[<400> 213]]> Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly 20 25 30 Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe 65 70 75 80 Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg His Tyr Tyr Tyr Tyr Tyr Leu Asp Val Trp Gly Lys Gly 100 105 110 Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 115 120 125 Ser Gly Gly Gly Gly Ser Gly Gly Asp Ile Gln Met Thr Gln Ser Pro 130 135 140 Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg 145 150 155 160 Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr Gln Gln Lys Pro 165 170 175 Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ser Leu Gln Ser 180 185 190 Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 195 200 205 Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys 210 215 220 Gln Gln Ser Tyr Ser Thr Pro Leu Thr Phe Gly Gly Gly Thr Lys Val 225 230 235 240 Glu Ile Lys <![CDATA[<210> 214]]> <![CDATA[<211> 243]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-A*11抗原結合結構域4]]> <![CDATA[<400> 214]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Trp Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Val Trp Val 35 40 45 Ser Arg Ile Asn Ser Asp Gly Ser Ser Thr Ser Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Cys Leu Gly Val Leu Leu Tyr Asn Trp Phe Asp Pro Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 115 120 125 Ser Gly Gly Gly Gly Ser Gly Gly Asp Ile Gln Met Thr Gln Ser Pro 130 135 140 Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg 145 150 155 160 Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr Gln Gln Lys Pro 165 170 175 Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ser Leu Gln Ser 180 185 190 Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 195 200 205 Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys 210 215 220 Gln Gln Ser Tyr Ser Thr Pro Leu Thr Phe Gly Gly Gly Thr Lys Val 225 230 235 240 Glu Ile Lys <![CDATA[<210> 215]]> <![CDATA[<211> 242]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-A*11抗原結合結構域3]]> <![CDATA[<400> 215]]> Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly 20 25 30 Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe 65 70 75 80 Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg His Tyr Tyr Tyr Tyr Met Asp Val Trp Gly Lys Gly Thr 100 105 110 Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 115 120 125 Gly Gly Gly Gly Ser Gly Gly Asp Ile Gln Met Thr Gln Ser Pro Ser 130 135 140 Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala 145 150 155 160 Ser Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly 165 170 175 Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ser Leu Gln Ser Gly 180 185 190 Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu 195 200 205 Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln 210 215 220 Gln Ser Tyr Ser Thr Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu 225 230 235 240 Ile Lys <![CDATA[<210> 216]]> <![CDATA[<211> 243]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-A*11抗原結合結構域2]]> <![CDATA[<400> 216]]> Gln Ile Thr Leu Lys Glu Ser Gly Pro Thr Leu Val Lys Pro Thr Gln 1 5 10 15 Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Ser Thr Ser 20 25 30 Gly Val Gly Val Gly Trp Ile Arg Gln Pro Pro Gly Lys Ala Leu Glu 35 40 45 Trp Leu Ala Leu Ile Tyr Trp Asn Asp Asp Lys Arg Tyr Ser Pro Ser 50 55 60 Leu Lys Ser Arg Leu Thr Ile Thr Lys Asp Thr Ser Lys Asn Gln Val 65 70 75 80 Val Leu Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr 85 90 95 Cys Ala His Lys Thr Thr Ser Phe Tyr Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 115 120 125 Ser Gly Gly Gly Gly Ser Gly Gly Asp Ile Gln Met Thr Gln Ser Pro 130 135 140 Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg 145 150 155 160 Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr Gln Gln Lys Pro 165 170 175 Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ser Leu Gln Ser 180 185 190 Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 195 200 205 Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys 210 215 220 Gln Gln Ser Tyr Ser Thr Pro Leu Thr Phe Gly Gly Gly Thr Lys Val 225 230 235 240 Glu Ile Lys <![CDATA[<210> 217]]> <![CDATA[<211> 243]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-A*11抗原結合結構域1]]> <![CDATA[<400> 217]]> Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly 20 25 30 Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe 65 70 75 80 Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg His Tyr Tyr Tyr Tyr Tyr Met Asp Val Trp Gly Lys Gly 100 105 110 Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 115 120 125 Ser Gly Gly Gly Gly Ser Gly Gly Asp Ile Gln Met Thr Gln Ser Pro 130 135 140 Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg 145 150 155 160 Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr Gln Gln Lys Pro 165 170 175 Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ser Leu Gln Ser 180 185 190 Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 195 200 205 Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys 210 215 220 Gln Gln Ser Tyr Ser Thr Pro Leu Thr Phe Gly Gly Gly Thr Lys Val 225 230 235 240 Glu Ile Lys <![CDATA[<210> 218]]> <![CDATA[<211> 240]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-C*07抗原結合結構域C7-45]]> <![CDATA[<400> 218]]> Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Val Ser Phe Asp Trp Phe Asp Pro Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 115 120 125 Gly Gly Ser Gly Gly Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu 130 135 140 Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln 145 150 155 160 Ser Ile Ser Ser Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala 165 170 175 Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro 180 185 190 Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile 195 200 205 Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser 210 215 220 Tyr Ser Thr Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 225 230 235 240 <![CDATA[<210> 219]]> <![CDATA[<211> 248]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-C*07抗原結合結構域C7-44]]> <![CDATA[<400> 219]]> Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly 20 25 30 Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe 65 70 75 80 Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Glu Arg Ser Ile Ser Pro Tyr Tyr Tyr Tyr Tyr Met Asp 100 105 110 Val Trp Gly Lys Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly 115 120 125 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Asp Ile Gln 130 135 140 Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val 145 150 155 160 Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn Trp 165 170 175 Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala 180 185 190 Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser 195 200 205 Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe 210 215 220 Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Leu Thr Phe Gly 225 230 235 240 Gly Gly Thr Lys Val Glu Ile Lys 245 <![CDATA[<210> 220]]> <![CDATA[<211> 247]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-C*07抗原結合結構域C7-43]]> <![CDATA[<400> 220]]> Gln Leu Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Ser 20 25 30 Ser Tyr Tyr Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Ser Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe 65 70 75 80 Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Asp Ser Val Ile Trp Tyr Trp Phe Asp Pro Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly 115 120 125 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gln Ser Val Leu Thr Gln Pro 130 135 140 Pro Ser Ala Ser Gly Thr Pro Gly Gln Arg Val Thr Ile Ser Cys Ser 145 150 155 160 Gly Ser Ser Ser Asn Ile Gly Ser Asn Thr Val Asn Trp Tyr Gln Gln 165 170 175 Leu Pro Gly Thr Ala Pro Lys Leu Leu Ile Tyr Ser Asn Asn Gln Arg 180 185 190 Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser 195 200 205 Ala Ser Leu Ala Ile Ser Gly Leu Gln Ser Glu Asp Glu Ala Asp Tyr 210 215 220 Tyr Cys Ala Ala Trp Asp Asp Ser Leu Asn Gly Trp Val Phe Gly Gly 225 230 235 240 Gly Thr Lys Leu Thr Val Leu 245 <![CDATA[<210> 221]]> <![CDATA[<211> 249]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-C*07抗原結合結構域C7-42]]> <![CDATA[<400> 221]]> Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly 20 25 30 Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe 65 70 75 80 Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Glu Glu Ile Leu Pro Arg Leu Ser Tyr Tyr Tyr Tyr Met 100 105 110 Asp Val Trp Gly Lys Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly 115 120 125 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Asp Ile 130 135 140 Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg 145 150 155 160 Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn 165 170 175 Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala 180 185 190 Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly 195 200 205 Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp 210 215 220 Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Leu Thr Phe 225 230 235 240 Gly Gly Gly Thr Lys Val Glu Ile Lys 245 <![CDATA[<210> 222]]> <![CDATA[<211> 245]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-C*07抗原結合結構域C7-41]]> <![CDATA[<400> 222]]> Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Asn Thr Asn Thr Gly Asn Pro Thr Tyr Ala Gln Gly Phe 50 55 60 Thr Gly Arg Phe Val Phe Ser Phe Asp Thr Ser Val Ser Thr Ala Tyr 65 70 75 80 Leu Gln Ile Cys Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Gly Arg Ala His Ser Ser Trp Tyr Phe Asp Leu Trp Gly 100 105 110 Arg Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly 115 120 125 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Asp Ile Gln Met Thr Gln 130 135 140 Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr 145 150 155 160 Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr Gln Gln 165 170 175 Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ser Leu 180 185 190 Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp 195 200 205 Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr 210 215 220 Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Leu Thr Phe Gly Gly Gly Thr 225 230 235 240 Lys Val Glu Ile Lys 245 <![CDATA[<210> 223]]> <![CDATA[<211> 251]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-C*07抗原結合結構域C7-40]]> <![CDATA[<400> 223]]> Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly 20 25 30 Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe 65 70 75 80 Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Asp Arg Ile Lys Ile Leu Pro Arg Leu Gly Tyr Tyr Tyr 100 105 110 Tyr Met Asp Val Trp Gly Lys Gly Thr Thr Val Thr Val Ser Ser Gly 115 120 125 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 130 135 140 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 145 150 155 160 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr 165 170 175 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 180 185 190 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 195 200 205 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 210 215 220 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Leu 225 230 235 240 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 245 250 <![CDATA[<210> 224]]> <![CDATA[<211> 246]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-C*07抗原結合結構域C7-39]]> <![CDATA[<400> 224]]> Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly 20 25 30 Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe 65 70 75 80 Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Asp Thr Val Ile His Tyr Tyr Tyr Tyr Met Asp Val Trp 100 105 110 Gly Lys Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly 115 120 125 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Asp Ile Gln Met Thr 130 135 140 Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile 145 150 155 160 Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr Gln 165 170 175 Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ser 180 185 190 Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr 195 200 205 Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr 210 215 220 Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Leu Thr Phe Gly Gly Gly 225 230 235 240 Thr Lys Val Glu Ile Lys 245 <![CDATA[<210> 225]]> <![CDATA[<211> 250]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-C*07抗原結合結構域C7-38]]> <![CDATA[<400> 225]]> Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly 20 25 30 Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe 65 70 75 80 Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Asp Val Ile Val Glu Val Phe Leu Ser Tyr Tyr Tyr Tyr 100 105 110 Met Asp Val Trp Gly Lys Gly Thr Thr Val Thr Val Ser Ser Gly Gly 115 120 125 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Asp 130 135 140 Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp 145 150 155 160 Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu 165 170 175 Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr 180 185 190 Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser 195 200 205 Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu 210 215 220 Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Leu Thr 225 230 235 240 Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 245 250 <![CDATA[<210> 226]]> <![CDATA[<211> 246]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-C*07抗原結合結構域C7-37]]> <![CDATA[<400> 226]]> Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly 20 25 30 Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe 65 70 75 80 Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Asp Ile Phe Ile His Tyr Tyr Tyr Tyr Met Asp Val Trp 100 105 110 Gly Lys Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly 115 120 125 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Asp Ile Gln Met Thr 130 135 140 Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile 145 150 155 160 Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr Gln 165 170 175 Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ser 180 185 190 Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr 195 200 205 Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr 210 215 220 Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Leu Thr Phe Gly Gly Gly 225 230 235 240 Thr Lys Val Glu Ile Lys 245 <![CDATA[<210> 227]]> <![CDATA[<211> 247]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-C*07抗原結合結構域C7-36]]> <![CDATA[<400> 227]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ser Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Tyr Ile Ser Ser Ser Ser Ser Thr Ile Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Gly Thr Phe Tyr Ser Tyr Ser Pro Tyr Tyr Phe Asp Tyr 100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser 115 120 125 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Asp Ile Gln Met 130 135 140 Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr 145 150 155 160 Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr 165 170 175 Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser 180 185 190 Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly 195 200 205 Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala 210 215 220 Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Leu Thr Phe Gly Gly 225 230 235 240 Gly Thr Lys Val Glu Ile Lys 245 <![CDATA[<210> 228]]> <![CDATA[<211> 251]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-C*07抗原結合結構域C7-35]]> <![CDATA[<400> 228]]> Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly 20 25 30 Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe 65 70 75 80 Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Glu Trp Ile Lys Ile Leu Pro Arg Leu Gly Tyr Tyr Tyr 100 105 110 Tyr Met Asp Val Trp Gly Lys Gly Thr Thr Val Thr Val Ser Ser Gly 115 120 125 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 130 135 140 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 145 150 155 160 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr 165 170 175 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 180 185 190 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 195 200 205 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 210 215 220 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Leu 225 230 235 240 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 245 250 <![CDATA[<210> 229]]> <![CDATA[<211> 246]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-C*07抗原結合結構域C7-34]]> <![CDATA[<400> 229]]> Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly 20 25 30 Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe 65 70 75 80 Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Asp Arg Ser Leu Tyr Tyr Tyr Tyr Tyr Met Asp Val Trp 100 105 110 Gly Lys Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly 115 120 125 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Asp Ile Gln Met Thr 130 135 140 Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile 145 150 155 160 Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr Gln 165 170 175 Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ser 180 185 190 Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr 195 200 205 Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr 210 215 220 Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Leu Thr Phe Gly Gly Gly 225 230 235 240 Thr Lys Val Glu Ile Lys 245 <![CDATA[<210> 230]]> <![CDATA[<211> 248]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-C*07抗原結合結構域C7-33]]> <![CDATA[<400> 230]]> Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly 20 25 30 Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe 65 70 75 80 Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Asp Lys Ile Leu Ala Pro Asn Tyr Tyr Tyr Tyr Met Asp 100 105 110 Val Trp Gly Lys Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly 115 120 125 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Asp Ile Gln 130 135 140 Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val 145 150 155 160 Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn Trp 165 170 175 Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala 180 185 190 Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser 195 200 205 Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe 210 215 220 Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Leu Thr Phe Gly 225 230 235 240 Gly Gly Thr Lys Val Glu Ile Lys 245 <![CDATA[<210> 231]]> <![CDATA[<211> 250]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-C*07抗原結合結構域C7-32]]> <![CDATA[<400> 231]]> Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly 20 25 30 Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe 65 70 75 80 Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Glu Lys Ser Trp Lys Tyr Phe Tyr Tyr Tyr Tyr Tyr Tyr 100 105 110 Met Asp Val Trp Gly Lys Gly Thr Thr Val Thr Val Ser Ser Gly Gly 115 120 125 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Asp 130 135 140 Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp 145 150 155 160 Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu 165 170 175 Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr 180 185 190 Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser 195 200 205 Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu 210 215 220 Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Leu Thr 225 230 235 240 Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 245 250 <![CDATA[<210> 232]]> <![CDATA[<211> 249]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-C*07抗原結合結構域C7-31]]> <![CDATA[<400> 232]]> Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly 20 25 30 Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe 65 70 75 80 Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Glu Asn Thr Ser Thr Ile Pro Tyr Tyr Tyr Tyr Tyr Met 100 105 110 Asp Val Trp Gly Lys Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly 115 120 125 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Asp Ile 130 135 140 Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg 145 150 155 160 Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn 165 170 175 Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala 180 185 190 Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly 195 200 205 Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp 210 215 220 Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Leu Thr Phe 225 230 235 240 Gly Gly Gly Thr Lys Val Glu Ile Lys 245 <![CDATA[<210> 233]]> <![CDATA[<211> 253]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-C*07抗原結合結構域C7-30]]> <![CDATA[<400> 233]]> Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly 20 25 30 Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe 65 70 75 80 Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Glu Asp Val Asp Lys Asn Thr Ser Thr Ile Tyr Tyr Tyr 100 105 110 Tyr Tyr Tyr Met Asp Val Trp Gly Lys Gly Thr Thr Val Thr Val Ser 115 120 125 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 130 135 140 Gly Gly Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser 145 150 155 160 Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser 165 170 175 Ser Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu 180 185 190 Leu Ile Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe 195 200 205 Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu 210 215 220 Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr 225 230 235 240 Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 245 250 <![CDATA[<210> 234]]> <![CDATA[<211> 250]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-C*07抗原結合結構域C7-29]]> <![CDATA[<400> 234]]> Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Tyr Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Tyr Ile Ser Ser Ser Gly Ser Thr Ile Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Gly Gly Asp Ile Val Ser Ser Ser Ala Ile Tyr Trp Tyr 100 105 110 Phe Asp Leu Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser Gly Gly 115 120 125 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Ala 130 135 140 Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp 145 150 155 160 Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Ala Leu 165 170 175 Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr 180 185 190 Asp Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly Ser 195 200 205 Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu 210 215 220 Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Ser Tyr Pro Leu Thr 225 230 235 240 Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 245 250 <![CDATA[<210> 235]]> <![CDATA[<211> 248]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-C*07抗原結合結構域C7-28]]> <![CDATA[<400> 235]]> Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly 20 25 30 Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe 65 70 75 80 Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Asp Leu Ile Leu Pro Pro Tyr Tyr Tyr Tyr Tyr Met Asp 100 105 110 Val Trp Gly Lys Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly 115 120 125 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Asp Ile Gln 130 135 140 Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val 145 150 155 160 Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn Trp 165 170 175 Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala 180 185 190 Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser 195 200 205 Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe 210 215 220 Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Leu Thr Phe Gly 225 230 235 240 Gly Gly Thr Lys Val Glu Ile Lys 245 <![CDATA[<210> 236]]> <![CDATA[<211> 253]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-C*07抗原結合結構域C7-27]]> <![CDATA[<400> 236]]> Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly 20 25 30 Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe 65 70 75 80 Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Glu Thr Trp Ile Lys Ile Leu Pro Arg Tyr Tyr Tyr Tyr 100 105 110 Tyr Tyr Tyr Met Asp Val Trp Gly Lys Gly Thr Thr Val Thr Val Ser 115 120 125 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 130 135 140 Gly Gly Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser 145 150 155 160 Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser 165 170 175 Ser Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu 180 185 190 Leu Ile Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe 195 200 205 Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu 210 215 220 Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr 225 230 235 240 Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 245 250 <![CDATA[<210> 237]]> <![CDATA[<211> 246]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-C*07抗原結合結構域C7-26]]> <![CDATA[<400> 237]]> Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly 20 25 30 Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe 65 70 75 80 Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Asp Leu Ser Arg Tyr Tyr Tyr Tyr Tyr Met Asp Val Trp 100 105 110 Gly Lys Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly 115 120 125 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Asp Ile Gln Met Thr 130 135 140 Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile 145 150 155 160 Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr Gln 165 170 175 Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ser 180 185 190 Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr 195 200 205 Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr 210 215 220 Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Leu Thr Phe Gly Gly Gly 225 230 235 240 Thr Lys Val Glu Ile Lys 245 <![CDATA[<210> 238]]> <![CDATA[<211> 242]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-C*07抗原結合結構域C7-25]]> <![CDATA[<400> 238]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ser Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Tyr Ile Ser Ser Ser Ser Ser Thr Ile Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu His Ile Val Leu Cys Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 115 120 125 Gly Gly Gly Gly Ser Gly Gly Asp Ile Gln Met Thr Gln Ser Pro Ser 130 135 140 Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala 145 150 155 160 Ser Gln Gly Ile Ser Ser Trp Leu Ala Trp Tyr Gln Gln Lys Pro Glu 165 170 175 Lys Ala Pro Lys Ser Leu Ile Tyr Ala Ala Ser Ser Leu Gln Ser Gly 180 185 190 Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu 195 200 205 Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln 210 215 220 Gln Tyr Asn Ser Tyr Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu 225 230 235 240 Ile Lys <![CDATA[<210> 239]]> <![CDATA[<211> 249]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-C*07抗原結合結構域C7-24]]> <![CDATA[<400> 239]]> Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly 20 25 30 Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe 65 70 75 80 Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Asp Lys Ile Leu Pro Arg Pro Tyr Tyr Tyr Tyr Tyr Met 100 105 110 Asp Val Trp Gly Lys Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly 115 120 125 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Asp Ile 130 135 140 Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg 145 150 155 160 Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn 165 170 175 Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala 180 185 190 Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly 195 200 205 Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp 210 215 220 Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Leu Thr Phe 225 230 235 240 Gly Gly Gly Thr Lys Val Glu Ile Lys 245 <![CDATA[<210> 240]]> <![CDATA[<211> 244]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-C*07抗原結合結構域C7-23]]> <![CDATA[<400> 240]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Ala Tyr Asn Gly Asn Thr Asn Tyr Ala Gln Lys Leu 50 55 60 Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Ser Asn Glu Tyr Phe Gln His Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 115 120 125 Gly Gly Gly Ser Gly Gly Gln Ser Ala Leu Thr Gln Pro Pro Ser Ala 130 135 140 Ser Gly Ser Pro Gly Gln Ser Val Thr Ile Ser Cys Thr Gly Thr Ser 145 150 155 160 Ser Asp Val Gly Gly Tyr Asn Tyr Val Ser Trp Tyr Gln Gln His Pro 165 170 175 Gly Lys Ala Pro Lys Leu Met Ile Tyr Glu Val Ser Lys Arg Pro Ser 180 185 190 Gly Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser 195 200 205 Leu Thr Val Ser Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys 210 215 220 Ser Ser Tyr Ala Gly Ser Asn Asn Trp Val Phe Gly Gly Gly Thr Lys 225 230 235 240 Leu Thr Val Leu <![CDATA[<210> 241]]> <![CDATA[<211> 242]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-C*07抗原結合結構域C7-22]]> <![CDATA[<400> 241]]> Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Asn Thr Asn Thr Gly Asn Pro Thr Tyr Ala Gln Gly Phe 50 55 60 Thr Gly Arg Phe Val Phe Ser Phe Asp Thr Ser Val Ser Thr Ala Tyr 65 70 75 80 Leu Gln Ile Cys Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Thr Ser Tyr Trp Tyr Phe Asp Leu Trp Gly Arg Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 115 120 125 Gly Gly Gly Gly Ser Gly Gly Asp Ile Gln Met Thr Gln Ser Pro Ser 130 135 140 Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala 145 150 155 160 Ser Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly 165 170 175 Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ser Leu Gln Ser Gly 180 185 190 Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu 195 200 205 Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln 210 215 220 Gln Ser Tyr Ser Thr Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu 225 230 235 240 Ile Lys <![CDATA[<210> 242]]> <![CDATA[<211> 248]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-C*07抗原結合結構域C7-21]]> <![CDATA[<400> 242]]> Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly 20 25 30 Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe 65 70 75 80 Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Glu Glu Ile Val Glu Val Phe Tyr Tyr Tyr Tyr Met Asp 100 105 110 Val Trp Gly Lys Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly 115 120 125 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Asp Ile Gln 130 135 140 Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val 145 150 155 160 Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn Trp 165 170 175 Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala 180 185 190 Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser 195 200 205 Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe 210 215 220 Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Leu Thr Phe Gly 225 230 235 240 Gly Gly Thr Lys Val Glu Ile Lys 245 <![CDATA[<210> 243]]> <![CDATA[<211> 241]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-C*07抗原結合結構域C7-20]]> <![CDATA[<400> 243]]> Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Val Asp Asp Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 115 120 125 Gly Gly Gly Ser Gly Gly Asp Ile Gln Met Thr Gln Ser Pro Ser Ser 130 135 140 Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser 145 150 155 160 Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys 165 170 175 Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val 180 185 190 Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 195 200 205 Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln 210 215 220 Ser Tyr Ser Thr Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile 225 230 235 240 Lys <![CDATA[<210> 244]]> <![CDATA[<211> 247]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-C*07抗原結合結構域C7-19]]> <![CDATA[<400> 244]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Trp Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Val Trp Val 35 40 45 Ser Arg Ile Asn Ser Asp Gly Ser Ser Thr Ser Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Trp Ser Thr Asn Ile Leu Leu Ser Tyr Thr Lys Ala Phe Asp Ile 100 105 110 Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser Gly Gly Gly Gly Ser 115 120 125 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Asp Ile Gln Met 130 135 140 Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr 145 150 155 160 Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr 165 170 175 Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser 180 185 190 Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly 195 200 205 Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala 210 215 220 Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Leu Thr Phe Gly Gly 225 230 235 240 Gly Thr Lys Val Glu Ile Lys 245 <![CDATA[<210> 245]]> <![CDATA[<211> 246]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-C*07抗原結合結構域C7-18]]> <![CDATA[<400> 245]]> Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly 20 25 30 Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe 65 70 75 80 Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Asp Lys Thr Tyr Tyr Tyr Tyr Tyr Tyr Met Asp Val Trp 100 105 110 Gly Lys Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly 115 120 125 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Asp Ile Gln Met Thr 130 135 140 Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile 145 150 155 160 Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr Gln 165 170 175 Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ser 180 185 190 Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr 195 200 205 Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr 210 215 220 Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Leu Thr Phe Gly Gly Gly 225 230 235 240 Thr Lys Val Glu Ile Lys 245 <![CDATA[<210> 246]]> <![CDATA[<211> 253]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-C*07抗原結合結構域C7-17]]> <![CDATA[<400> 246]]> Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly 20 25 30 Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe 65 70 75 80 Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Glu Lys Tyr Phe His Asp Lys Tyr Phe His Asp Tyr Tyr 100 105 110 Tyr Tyr Tyr Met Asp Val Trp Gly Lys Gly Thr Thr Val Thr Val Ser 115 120 125 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 130 135 140 Gly Gly Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser 145 150 155 160 Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser 165 170 175 Ser Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu 180 185 190 Leu Ile Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe 195 200 205 Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu 210 215 220 Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr 225 230 235 240 Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 245 250 <![CDATA[<210> 247]]> <![CDATA[<211> 246]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-C*07抗原結合結構域C7-16]]> <![CDATA[<400> 247]]> Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly 20 25 30 Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe 65 70 75 80 Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Asp Thr Ser Val Tyr Tyr Tyr Tyr Tyr Met Asp Val Trp 100 105 110 Gly Lys Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly 115 120 125 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Asp Ile Gln Met Thr 130 135 140 Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile 145 150 155 160 Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr Gln 165 170 175 Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ser 180 185 190 Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr 195 200 205 Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr 210 215 220 Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Leu Thr Phe Gly Gly Gly 225 230 235 240 Thr Lys Val Glu Ile Lys 245 <![CDATA[<210> 248]]> <![CDATA[<211> 248]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-C*07抗原結合結構域C7-15]]> <![CDATA[<400> 248]]> Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly 20 25 30 Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe 65 70 75 80 Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Glu Lys Ile Leu Pro Tyr Tyr Tyr Tyr Tyr Tyr Met Asp 100 105 110 Val Trp Gly Lys Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly 115 120 125 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Asp Ile Gln 130 135 140 Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val 145 150 155 160 Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn Trp 165 170 175 Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala 180 185 190 Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser 195 200 205 Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe 210 215 220 Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Leu Thr Phe Gly 225 230 235 240 Gly Gly Thr Lys Val Glu Ile Lys 245 <![CDATA[<210> 249]]> <![CDATA[<211> 257]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-C*07抗原結合結構域C7-14]]> <![CDATA[<400> 249]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ser Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Tyr Ile Ser Ser Ser Ser Ser Thr Ile Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Ile Gln Trp Ile Tyr Ile Tyr Ile Asn Pro Arg Gly Phe Ile Phe 100 105 110 Leu His Asp Ala Phe Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val 115 120 125 Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 130 135 140 Ser Gly Gly Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr 145 150 155 160 Pro Gly Gln Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile 165 170 175 Gly Ser Asn Thr Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro 180 185 190 Lys Leu Leu Ile Tyr Ser Asn Asn Gln Arg Pro Ser Gly Val Pro Asp 195 200 205 Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser 210 215 220 Gly Leu Gln Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp 225 230 235 240 Asp Ser Leu Asn Gly Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val 245 250 255 Leu <![CDATA[<210> 250]]> <![CDATA[<211> 248]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-C*07抗原結合結構域C7-13]]> <![CDATA[<400> 250]]> Gln Val Gln Leu Gln Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Ala Ile Ser Gly Asp Ser Val Ser Ser Asn 20 25 30 Ser Ala Ala Trp Asn Trp Ile Arg Gln Ser Pro Ser Arg Gly Leu Glu 35 40 45 Trp Leu Gly Arg Thr Tyr Tyr Arg Ser Lys Trp Tyr Asn Asp Tyr Ala 50 55 60 Val Ser Val Lys Ser Arg Ile Thr Ile Asn Pro Asp Thr Ser Lys Asn 65 70 75 80 Gln Phe Ser Leu Gln Leu Asn Ser Val Thr Pro Glu Asp Thr Ala Val 85 90 95 Tyr Tyr Cys Ala Lys Glu Asp Val Asp Phe His His Asp Ala Phe Asp 100 105 110 Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser Gly Gly Gly Gly 115 120 125 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Asp Ile Gln 130 135 140 Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val 145 150 155 160 Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn Trp 165 170 175 Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala 180 185 190 Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser 195 200 205 Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe 210 215 220 Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Leu Thr Phe Gly 225 230 235 240 Gly Gly Thr Lys Val Glu Ile Lys 245 <![CDATA[<210> 251]]> <![CDATA[<211> 253]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-C*07抗原結合結構域C7-12]]> <![CDATA[<400> 251]]> Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly 20 25 30 Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe 65 70 75 80 Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Glu Gly Val Asp Lys Asn Thr Ser Thr Ile Tyr Tyr Tyr 100 105 110 Tyr Tyr Tyr Met Asp Val Trp Gly Lys Gly Thr Thr Val Thr Val Ser 115 120 125 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 130 135 140 Gly Gly Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser 145 150 155 160 Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser 165 170 175 Ser Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu 180 185 190 Leu Ile Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe 195 200 205 Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu 210 215 220 Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr 225 230 235 240 Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 245 250 <![CDATA[<210> 252]]> <![CDATA[<211> 241]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-C*07抗原結合結構域C7-11]]> <![CDATA[<400> 252]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ser Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Tyr Ile Ser Ser Ser Ser Ser Thr Ile Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Arg Arg Gly Tyr Phe Asp Leu Trp Gly Arg Gly Thr Leu 100 105 110 Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 115 120 125 Gly Gly Gly Ser Gly Gly Asp Ile Gln Met Thr Gln Ser Pro Ser Ser 130 135 140 Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser 145 150 155 160 Gln Gly Ile Ser Ser Trp Leu Ala Trp Tyr Gln Gln Lys Pro Glu Lys 165 170 175 Ala Pro Lys Ser Leu Ile Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val 180 185 190 Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 195 200 205 Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln 210 215 220 Tyr Asn Ser Tyr Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile 225 230 235 240 Lys <![CDATA[<210> 253]]> <![CDATA[<211> 248]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-C*07抗原結合結構域C7-10]]> <![CDATA[<400> 253]]> Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Thr Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Tyr Met His Trp Val Gln Gln Ala Pro Gly Lys Gly Leu Glu Trp Met 35 40 45 Gly Leu Val Asp Pro Glu Asp Gly Glu Thr Ile Tyr Ala Glu Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Thr Ser Thr Asp Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Thr Gly Ile His Val Asp Ile Arg Ser Met Glu Asp Trp Phe Asp 100 105 110 Pro Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly 115 120 125 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Asp Ile Gln 130 135 140 Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val 145 150 155 160 Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn Trp 165 170 175 Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala 180 185 190 Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser 195 200 205 Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe 210 215 220 Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Leu Thr Phe Gly 225 230 235 240 Gly Gly Thr Lys Val Glu Ile Lys 245 <![CDATA[<210> 254]]> <![CDATA[<211> 246]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-C*07抗原結合結構域C7-9]]> <![CDATA[<400> 254]]> Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly 20 25 30 Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe 65 70 75 80 Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Asp Ile Gly Thr Ser Tyr Tyr Tyr Tyr Met Asp Val Trp 100 105 110 Gly Lys Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly 115 120 125 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Asp Ile Gln Met Thr 130 135 140 Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile 145 150 155 160 Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr Gln 165 170 175 Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ser 180 185 190 Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr 195 200 205 Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr 210 215 220 Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Leu Thr Phe Gly Gly Gly 225 230 235 240 Thr Lys Val Glu Ile Lys 245 <![CDATA[<210> 255]]> <![CDATA[<211> 249]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-C*07抗原結合結構域C7-8]]> <![CDATA[<400> 255]]> Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly 20 25 30 Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe 65 70 75 80 Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Glu Val Val Glu Val Phe Leu Tyr Tyr Tyr Tyr Tyr Met 100 105 110 Asp Val Trp Gly Lys Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly 115 120 125 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Asp Ile 130 135 140 Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg 145 150 155 160 Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn 165 170 175 Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala 180 185 190 Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly 195 200 205 Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp 210 215 220 Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Leu Thr Phe 225 230 235 240 Gly Gly Gly Thr Lys Val Glu Ile Lys 245 <![CDATA[<210> 256]]> <![CDATA[<211> 246]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-C*07抗原結合結構域C7-7]]> <![CDATA[<400> 256]]> Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly 20 25 30 Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe 65 70 75 80 Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Asp Leu Tyr Tyr Tyr Tyr Tyr Tyr Tyr Met Asp Val Trp 100 105 110 Gly Lys Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly 115 120 125 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Asp Ile Gln Met Thr 130 135 140 Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile 145 150 155 160 Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr Gln 165 170 175 Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ser 180 185 190 Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr 195 200 205 Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr 210 215 220 Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Leu Thr Phe Gly Gly Gly 225 230 235 240 Thr Lys Val Glu Ile Lys 245 <![CDATA[<210> 257]]> <![CDATA[<211> 256]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-C*07抗原結合結構域C7-6]]> <![CDATA[<400> 257]]> Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly 20 25 30 Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe 65 70 75 80 Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Glu Ser Trp Lys Tyr Phe Tyr Pro Arg Gly Ser Ile Phe 100 105 110 Ile His Tyr Tyr Tyr Tyr Met Asp Val Trp Gly Lys Gly Thr Thr Val 115 120 125 Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 130 135 140 Gly Gly Ser Gly Gly Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu 145 150 155 160 Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln 165 170 175 Ser Ile Ser Ser Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala 180 185 190 Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro 195 200 205 Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile 210 215 220 Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser 225 230 235 240 Tyr Ser Thr Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 245 250 255 <![CDATA[<210> 258]]> <![CDATA[<211> 248]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-C*07抗原結合結構域C7-5]]> <![CDATA[<400> 258]]> Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly 20 25 30 Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe 65 70 75 80 Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Asp Arg Ile Val Glu Val Phe Tyr Tyr Tyr Tyr Met Asp 100 105 110 Val Trp Gly Lys Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly 115 120 125 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Asp Ile Gln 130 135 140 Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val 145 150 155 160 Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn Trp 165 170 175 Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala 180 185 190 Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser 195 200 205 Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe 210 215 220 Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Leu Thr Phe Gly 225 230 235 240 Gly Gly Thr Lys Val Glu Ile Lys 245 <![CDATA[<210> 259]]> <![CDATA[<211> 250]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-C*07抗原結合結構域C7-4]]> <![CDATA[<400> 259]]> Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly 20 25 30 Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe 65 70 75 80 Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Glu Lys Tyr Phe His Asp Trp Leu Tyr Tyr Tyr Tyr Tyr 100 105 110 Met Asp Val Trp Gly Lys Gly Thr Thr Val Thr Val Ser Ser Gly Gly 115 120 125 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Asp 130 135 140 Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp 145 150 155 160 Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu 165 170 175 Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr 180 185 190 Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser 195 200 205 Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu 210 215 220 Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Leu Thr 225 230 235 240 Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 245 250 <![CDATA[<210> 260]]> <![CDATA[<211> 250]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-C*07抗原結合結構域C7-3]]> <![CDATA[<400> 260]]> Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly 20 25 30 Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe 65 70 75 80 Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Asp Leu Val Asp Lys Asn Thr Ser Tyr Tyr Tyr Tyr Tyr 100 105 110 Met Asp Val Trp Gly Lys Gly Thr Thr Val Thr Val Ser Ser Gly Gly 115 120 125 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Asp 130 135 140 Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp 145 150 155 160 Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu 165 170 175 Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr 180 185 190 Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser 195 200 205 Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu 210 215 220 Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Leu Thr 225 230 235 240 Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 245 250 <![CDATA[<210> 261]]> <![CDATA[<211> 244]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-C*07抗原結合結構域C7-2]]> <![CDATA[<400> 261]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Ala Tyr Asn Gly Asn Thr Asn Tyr Ala Gln Lys Leu 50 55 60 Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Val Gln Asn Glu Tyr Phe Gln His Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 115 120 125 Gly Gly Gly Ser Gly Gly Gln Ser Ala Leu Thr Gln Pro Pro Ser Ala 130 135 140 Ser Gly Ser Pro Gly Gln Ser Val Thr Ile Ser Cys Thr Gly Thr Ser 145 150 155 160 Ser Asp Val Gly Gly Tyr Asn Tyr Val Ser Trp Tyr Gln Gln His Pro 165 170 175 Gly Lys Ala Pro Lys Leu Met Ile Tyr Glu Val Ser Lys Arg Pro Ser 180 185 190 Gly Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser 195 200 205 Leu Thr Val Ser Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys 210 215 220 Ser Ser Tyr Ala Gly Ser Asn Asn Trp Val Phe Gly Gly Gly Thr Lys 225 230 235 240 Leu Thr Val Leu <![CDATA[<210> 262]]> <![CDATA[<211> 239]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-C*07抗原結合結構域C7-1]]> <![CDATA[<400> 262]]> Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Tyr Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Tyr Ile Ser Ser Ser Gly Ser Thr Ile Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Thr Ala Asn Trp Phe Asp Pro Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 115 120 125 Gly Ser Gly Gly Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser 130 135 140 Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly 145 150 155 160 Ile Ser Ser Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro 165 170 175 Lys Leu Leu Ile Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser 180 185 190 Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser 195 200 205 Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asn 210 215 220 Ser Phe Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 225 230 235 <![CDATA[<210> 263]]> <![CDATA[<211> 244]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-A*03 scFv 15]]> <![CDATA[<400> 263]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Ala Tyr Asn Gly Asn Thr Asn Tyr Ala Gln Lys Leu 50 55 60 Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Arg Val Ser Gln Arg Gly Ala Phe Asp Ile Trp Gly Gln 100 105 110 Gly Thr Met Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly 115 120 125 Gly Ser Gly Gly Gly Gly Ser Gly Gly Asp Ile Gln Met Thr Gln Ser 130 135 140 Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys 145 150 155 160 Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr Gln Gln Lys 165 170 175 Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ser Leu Gln 180 185 190 Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe 195 200 205 Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr 210 215 220 Cys Gln Gln Ser Tyr Ser Thr Pro Leu Thr Phe Gly Gly Gly Thr Lys 225 230 235 240 Val Glu Ile Lys <![CDATA[<210> 264]]> <![CDATA[<211> 243]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-A*03 scFv 16]]> <![CDATA[<400> 264]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ser Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Tyr Ile Ser Ser Ser Ser Ser Thr Ile Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Asn Pro Asp Lys Asp Pro Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 115 120 125 Ser Gly Gly Gly Gly Ser Gly Gly Asp Ile Gln Met Thr Gln Ser Pro 130 135 140 Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg 145 150 155 160 Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr Gln Gln Lys Pro 165 170 175 Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ser Leu Gln Ser 180 185 190 Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 195 200 205 Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys 210 215 220 Gln Gln Ser Tyr Ser Thr Pro Leu Thr Phe Gly Gly Gly Thr Lys Val 225 230 235 240 Glu Ile Lys <![CDATA[<210> 265]]> <![CDATA[<211> 245]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-A*03 scFv 17]]> <![CDATA[<400> 265]]> Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Val Ser Ser Gly 20 25 30 Ser Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Asn Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe 65 70 75 80 Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Asp Phe Tyr Cys Thr Asn Trp Tyr Phe Asp Leu Trp Gly 100 105 110 Arg Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly 115 120 125 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Asp Ile Gln Met Thr Gln 130 135 140 Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr 145 150 155 160 Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr Gln Gln 165 170 175 Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ser Leu 180 185 190 Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp 195 200 205 Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr 210 215 220 Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Leu Thr Phe Gly Gly Gly Thr 225 230 235 240 Lys Val Glu Ile Lys 245 <![CDATA[<210> 266]]> <![CDATA[<211> 244]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-A*03 scFv 18]]> <![CDATA[<400> 266]]> Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Tyr 20 25 30 Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60 Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu 65 70 75 80 Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Arg Glu Ser Ser Ser Gly Ser Tyr Trp Tyr Phe Asp Leu Trp Gly Arg 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly 115 120 125 Gly Ser Gly Gly Gly Gly Ser Gly Gly Asp Ile Gln Met Thr Gln Ser 130 135 140 Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys 145 150 155 160 Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr Gln Gln Lys 165 170 175 Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ser Leu Gln 180 185 190 Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe 195 200 205 Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr 210 215 220 Cys Gln Gln Ser Tyr Ser Thr Pro Leu Thr Phe Gly Gly Gly Thr Lys 225 230 235 240 Val Glu Ile Lys <![CDATA[<210> 267]]> <![CDATA[<211> 250]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-A*03 scFv 19]]> <![CDATA[<400> 267]]> Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu 1 5 10 15 Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Ser Tyr 20 25 30 Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45 Gly Ile Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe 50 55 60 Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr 65 70 75 80 Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Arg Asp Ser Gly Tyr Lys Tyr Asn Leu Tyr Tyr Tyr Tyr Tyr Tyr 100 105 110 Met Asp Val Trp Gly Lys Gly Thr Thr Val Thr Val Ser Ser Gly Gly 115 120 125 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Asp 130 135 140 Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp 145 150 155 160 Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu 165 170 175 Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr 180 185 190 Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser 195 200 205 Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu 210 215 220 Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Leu Thr 225 230 235 240 Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 245 250 <![CDATA[<210> 268]]> <![CDATA[<211> 249]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-A*03 scFv 20]]> <![CDATA[<400> 268]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Ala Tyr Asn Gly Asn Thr Asn Tyr Ala Gln Lys Leu 50 55 60 Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Gly Asp Leu Ser His Tyr Tyr Tyr Tyr Met Asp Val Trp 100 105 110 Gly Lys Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly 115 120 125 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gln Thr Val Val Thr 130 135 140 Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr 145 150 155 160 Cys Ala Ser Ser Thr Gly Ala Val Thr Ser Gly Tyr Tyr Pro Asn Trp 165 170 175 Phe Gln Gln Lys Pro Gly Gln Ala Pro Arg Ala Leu Ile Tyr Ser Thr 180 185 190 Ser Asn Lys His Ser Trp Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu 195 200 205 Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp Glu 210 215 220 Ala Glu Tyr Tyr Cys Leu Leu Tyr Tyr Gly Gly Ala Gln Trp Val Phe 225 230 235 240 Gly Gly Gly Thr Lys Leu Thr Val Leu 245 <![CDATA[<210> 269]]> <![CDATA[<211> 246]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-A*03 scFv 21]]> <![CDATA[<400> 269]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Ala Tyr Asn Gly Asn Thr Asn Tyr Ala Gln Lys Leu 50 55 60 Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Asn Arg Arg Tyr Asn Ser Cys Tyr Tyr Phe Asp Tyr Trp 100 105 110 Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly 115 120 125 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Asp Ile Gln Met Thr 130 135 140 Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile 145 150 155 160 Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr Gln 165 170 175 Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ser 180 185 190 Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr 195 200 205 Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr 210 215 220 Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Leu Thr Phe Gly Gly Gly 225 230 235 240 Thr Lys Val Glu Ile Lys 245 <![CDATA[<210> 270]]> <![CDATA[<211> 249]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-A*03 scFv 22]]> <![CDATA[<400> 270]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Ala Tyr Asn Gly Asn Thr Asn Tyr Ala Gln Lys Leu 50 55 60 Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Gly Asp Leu Ser His Tyr Tyr Tyr Tyr Leu Asp Val Trp 100 105 110 Gly Lys Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly 115 120 125 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gln Thr Val Val Thr 130 135 140 Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr 145 150 155 160 Cys Ala Ser Ser Thr Gly Ala Val Thr Ser Gly Tyr Tyr Pro Asn Trp 165 170 175 Phe Gln Gln Lys Pro Gly Gln Ala Pro Arg Ala Leu Ile Tyr Ser Thr 180 185 190 Ser Asn Lys His Ser Trp Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu 195 200 205 Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp Glu 210 215 220 Ala Glu Tyr Tyr Cys Leu Leu Tyr Tyr Gly Gly Ala Gln Trp Val Phe 225 230 235 240 Gly Gly Gly Thr Lys Leu Thr Val Leu 245 <![CDATA[<210> 271]]> <![CDATA[<211> 245]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-A*03 scFv 23]]> <![CDATA[<400> 271]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Val Ser Ser Asn 20 25 30 Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Val Ile Tyr Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Arg Ala Thr Leu Leu Ser Leu Ser Tyr Asp Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly 115 120 125 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Asp Ile Gln Met Thr Gln 130 135 140 Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr 145 150 155 160 Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr Gln Gln 165 170 175 Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ser Leu 180 185 190 Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp 195 200 205 Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr 210 215 220 Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Leu Thr Phe Gly Gly Gly Thr 225 230 235 240 Lys Val Glu Ile Lys 245 <![CDATA[<210> 272]]> <![CDATA[<211> 248]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-A*03 scFv 24]]> <![CDATA[<400> 272]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Ala Tyr Asn Gly Asn Thr Asn Tyr Ala Gln Lys Leu 50 55 60 Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Gly Asp Leu Ser His Tyr Tyr Tyr Met Asp Val Trp Gly 100 105 110 Lys Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly 115 120 125 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gln Thr Val Val Thr Gln 130 135 140 Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys 145 150 155 160 Ala Ser Ser Thr Gly Ala Val Thr Ser Gly Tyr Tyr Pro Asn Trp Phe 165 170 175 Gln Gln Lys Pro Gly Gln Ala Pro Arg Ala Leu Ile Tyr Ser Thr Ser 180 185 190 Asn Lys His Ser Trp Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly 195 200 205 Gly Lys Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala 210 215 220 Glu Tyr Tyr Cys Leu Leu Tyr Tyr Gly Gly Ala Gln Trp Val Phe Gly 225 230 235 240 Gly Gly Thr Lys Leu Thr Val Leu 245 <![CDATA[<210> 273]]> <![CDATA[<211> 241]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-A*03 scFv 25]]> <![CDATA[<400> 273]]> Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu 1 5 10 15 Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Ser Tyr 20 25 30 Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met 35 40 45 Gly Ile Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe 50 55 60 Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr 65 70 75 80 Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Arg Glu Arg Asp Arg Trp Phe Asp Pro Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 115 120 125 Gly Gly Gly Ser Gly Gly Asp Ile Gln Met Thr Gln Ser Pro Ser Ser 130 135 140 Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser 145 150 155 160 Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys 165 170 175 Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val 180 185 190 Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 195 200 205 Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln 210 215 220 Ser Tyr Ser Thr Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile 225 230 235 240 Lys <![CDATA[<210> 274]]> <![CDATA[<211> 247]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-A*03 scFv 26]]> <![CDATA[<400> 274]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Ala Tyr Asn Gly Asn Thr Asn Tyr Ala Gln Lys Leu 50 55 60 Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Thr Pro Pro Ser Leu Gly Ala Phe Asp Ile Trp Gly Gln 100 105 110 Gly Thr Met Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly 115 120 125 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gln Ser Ala Leu Thr Gln Pro 130 135 140 Pro Ser Ala Ser Gly Ser Pro Gly Gln Ser Val Thr Ile Ser Cys Thr 145 150 155 160 Gly Thr Ser Ser Asp Val Gly Gly Tyr Asn Tyr Val Ser Trp Tyr Gln 165 170 175 Gln His Pro Gly Lys Ala Pro Lys Leu Met Ile Tyr Glu Val Ser Lys 180 185 190 Arg Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Asn 195 200 205 Thr Ala Ser Leu Thr Val Ser Gly Leu Gln Ala Glu Asp Glu Ala Asp 210 215 220 Tyr Tyr Cys Ser Ser Tyr Ala Gly Ser Asn Asn Trp Val Phe Gly Gly 225 230 235 240 Gly Thr Lys Leu Thr Val Leu 245 <![CDATA[<210> 275]]> <![CDATA[<211> 251]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-A*03 scFv 27]]> <![CDATA[<400> 275]]> Gln Leu Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Ser 20 25 30 Ser Tyr Tyr Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Ser Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe 65 70 75 80 Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Glu Ala Tyr Cys Leu Ser Asp Ser Tyr Trp Tyr Phe Asp 100 105 110 Leu Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly 115 120 125 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gln Ser Val 130 135 140 Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln Arg Val Thr 145 150 155 160 Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn Thr Val Asn 165 170 175 Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu Ile Tyr Ser 180 185 190 Asn Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Lys 195 200 205 Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Gln Ser Glu Asp 210 215 220 Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Asp Ser Leu Asn Gly Trp 225 230 235 240 Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 245 250 <![CDATA[<210> 276]]> <![CDATA[<211> 248]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-A*03 scFv 28]]> <![CDATA[<400> 276]]> Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly 20 25 30 Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe 65 70 75 80 Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Glu Ser Trp Lys Tyr Phe Tyr Pro Arg Gly Tyr Met Asp 100 105 110 Val Trp Gly Lys Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly 115 120 125 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Asp Ile Gln 130 135 140 Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val 145 150 155 160 Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn Trp 165 170 175 Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala 180 185 190 Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser 195 200 205 Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe 210 215 220 Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Leu Thr Phe Gly 225 230 235 240 Gly Gly Thr Lys Val Glu Ile Lys 245 <![CDATA[<210> 277]]> <![CDATA[<211> 248]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-A*01 scFv A1-9]]> <![CDATA[<400> 277]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Ala Tyr Asn Gly Asn Thr Asn Tyr Ala Gln Lys Leu 50 55 60 Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Gly Trp Thr Ala Trp Tyr Tyr Tyr Met Asp Val Trp Gly 100 105 110 Lys Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly 115 120 125 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gln Thr Val Val Thr Gln 130 135 140 Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys 145 150 155 160 Ala Ser Ser Thr Gly Ala Val Thr Ser Gly Tyr Tyr Pro Asn Trp Phe 165 170 175 Gln Gln Lys Pro Gly Gln Ala Pro Arg Ala Leu Ile Tyr Ser Thr Ser 180 185 190 Asn Lys His Ser Trp Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly 195 200 205 Gly Lys Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala 210 215 220 Glu Tyr Tyr Cys Leu Leu Tyr Tyr Gly Gly Ala Gln Trp Val Phe Gly 225 230 235 240 Gly Gly Thr Lys Leu Thr Val Leu 245 <![CDATA[<210> 278]]> <![CDATA[<211> 244]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-A*01 scFv A1-8]]> <![CDATA[<400> 278]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ser Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Tyr Ile Ser Ser Ser Ser Ser Thr Ile Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ala Lys Tyr Tyr Tyr Met Asp Val Trp Gly Lys Gly Thr Thr 100 105 110 Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 115 120 125 Gly Gly Gly Ser Gly Gly Gln Ser Val Leu Thr Gln Pro Pro Ser Ala 130 135 140 Ser Gly Thr Pro Gly Gln Arg Val Thr Ile Ser Cys Ser Gly Ser Ser 145 150 155 160 Ser Asn Ile Gly Ser Asn Thr Val Asn Trp Tyr Gln Gln Leu Pro Gly 165 170 175 Thr Ala Pro Lys Leu Leu Ile Tyr Ser Asn Asn Gln Arg Pro Ser Gly 180 185 190 Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu 195 200 205 Ala Ile Ser Gly Leu Gln Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala 210 215 220 Ala Trp Asp Asp Ser Leu Asn Gly Trp Val Phe Gly Gly Gly Thr Lys 225 230 235 240 Leu Thr Val Leu <![CDATA[<210> 279]]> <![CDATA[<211> 248]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-A*01 scFv A1-7]]> <![CDATA[<400> 279]]> Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly 20 25 30 Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe 65 70 75 80 Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Asp Gln Val Asp Lys Asn Thr Tyr Tyr Tyr Tyr Met Asp 100 105 110 Val Trp Gly Lys Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly 115 120 125 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Asp Ile Gln 130 135 140 Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val 145 150 155 160 Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn Trp 165 170 175 Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala 180 185 190 Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser 195 200 205 Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe 210 215 220 Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Leu Thr Phe Gly 225 230 235 240 Gly Gly Thr Lys Val Glu Ile Lys 245 <![CDATA[<210> 280]]> <![CDATA[<211> 243]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-A*01 scFv A1-6]]> <![CDATA[<400> 280]]> Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Tyr Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Tyr Ile Ser Ser Ser Gly Ser Thr Ile Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ala Cys Gln Leu Ala Glu Tyr Phe Gln His Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 115 120 125 Ser Gly Gly Gly Gly Ser Gly Gly Asp Ile Gln Met Thr Gln Ser Pro 130 135 140 Ser Ser Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg 145 150 155 160 Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala Trp Tyr Gln Gln Lys Pro 165 170 175 Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ser Leu Gln Ser 180 185 190 Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 195 200 205 Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys 210 215 220 Gln Gln Ala Asn Ser Phe Pro Leu Thr Phe Gly Gly Gly Thr Lys Val 225 230 235 240 Glu Ile Lys <![CDATA[<210> 281]]> <![CDATA[<211> 248]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-A*01 scFv A1-5]]> <![CDATA[<400> 281]]> Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly 20 25 30 Gly Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe 65 70 75 80 Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Asp Arg Val Asp Lys Asn Thr Ser Tyr Tyr Tyr Met Asp 100 105 110 Val Trp Gly Lys Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly 115 120 125 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Asp Ile Gln 130 135 140 Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val 145 150 155 160 Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn Trp 165 170 175 Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala 180 185 190 Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser 195 200 205 Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe 210 215 220 Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Leu Thr Phe Gly 225 230 235 240 Gly Gly Thr Lys Val Glu Ile Lys 245 <![CDATA[<210> 282]]> <![CDATA[<211> 245]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-A*01 scFv A1-4]]> <![CDATA[<400> 282]]> Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Asp 1 5 10 15 Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Tyr Ser Ile Ser Ser Ser 20 25 30 Asn Trp Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp 35 40 45 Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu 50 55 60 Lys Ser Arg Val Thr Met Ser Val Asp Thr Ser Lys Asn Gln Phe Ser 65 70 75 80 Leu Lys Leu Ser Ser Val Thr Ala Val Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Val Gln Leu Lys Leu Val His Trp Phe Asp Pro Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly 115 120 125 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Asp Ile Gln Met Thr Gln 130 135 140 Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr 145 150 155 160 Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr Gln Gln 165 170 175 Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ser Leu 180 185 190 Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp 195 200 205 Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr 210 215 220 Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Leu Thr Phe Gly Gly Gly Thr 225 230 235 240 Lys Val Glu Ile Lys 245 <![CDATA[<210> 283]]> <![CDATA[<211> 245]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-A*01 scFv A1-3]]> <![CDATA[<400> 283]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Asp Ile Asn Trp Val Arg Gln Ala Thr Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Met Asn Pro Asn Ser Gly Asn Thr Gly Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Arg Asn Thr Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Thr Tyr Tyr Asp Tyr Val Thr Val Phe Tyr Phe Gln His Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly 115 120 125 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Asp Ile Gln Met Thr Gln 130 135 140 Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr 145 150 155 160 Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr Gln Gln 165 170 175 Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ser Leu 180 185 190 Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp 195 200 205 Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr 210 215 220 Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Leu Thr Phe Gly Gly Gly Thr 225 230 235 240 Lys Val Glu Ile Lys 245 <![CDATA[<210> 284]]> <![CDATA[<211> 245]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-A*01 scFv A1-2]]> <![CDATA[<400> 284]]> Gln Leu Gln Leu Gln Glu Ser Gly Ser Gly Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Gly 20 25 30 Gly Tyr Ser Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Tyr Ile Tyr His Ser Gly Ser Thr Tyr Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Val Thr Ile Ser Val Asp Arg Ser Lys Asn Gln Phe 65 70 75 80 Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Arg Glu Ser Tyr Pro Ser Phe Tyr Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly 115 120 125 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Asp Ile Gln Met Thr Gln 130 135 140 Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr 145 150 155 160 Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr Gln Gln 165 170 175 Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ser Leu 180 185 190 Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp 195 200 205 Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr 210 215 220 Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Leu Thr Phe Gly Gly Gly Thr 225 230 235 240 Lys Val Glu Ile Lys 245 <![CDATA[<210> 285]]> <![CDATA[<211> 249]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-A*01 scFv A1-1]]> <![CDATA[<400> 285]]> Gln Ile Thr Leu Lys Glu Ser Gly Pro Thr Leu Val Lys Pro Thr Gln 1 5 10 15 Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Ser Thr Ser 20 25 30 Gly Val Gly Val Gly Trp Ile Arg Gln Pro Pro Gly Lys Ala Leu Glu 35 40 45 Trp Leu Ala Leu Ile Tyr Trp Asn Asp Asp Lys Arg Tyr Ser Pro Ser 50 55 60 Leu Lys Ser Arg Leu Thr Ile Thr Lys Asp Thr Ser Lys Asn Gln Val 65 70 75 80 Val Leu Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr 85 90 95 Cys Ala His Ser Asn Met Trp Ser Tyr Ser Leu Asn Asp Tyr Tyr Phe 100 105 110 Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly 115 120 125 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Asp Ile 130 135 140 Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg 145 150 155 160 Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn 165 170 175 Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala 180 185 190 Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly 195 200 205 Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp 210 215 220 Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Leu Thr Phe 225 230 235 240 Gly Gly Gly Thr Lys Val Glu Ile Lys 245 <![CDATA[<210> 286]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-L1]]> <![CDATA[<400> 286]]> Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn 1 5 10 <![CDATA[<210> 287]]> <![CDATA[<211> 14]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-L1]]> <![CDATA[<400> 287]]> Ala Ser Ser Thr Gly Ala Val Thr Ser Gly Tyr Tyr Pro Asn 1 5 10 <![CDATA[<210> 288]]> <![CDATA[<211> 14]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-L1]]> <![CDATA[<400> 288]]> Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr Asn Tyr Val Ser 1 5 10 <![CDATA[<210> 289]]> <![CDATA[<211> 13]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-L1]]> <![CDATA[<400> 289]]> Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn Thr Val Asn 1 5 10 <![CDATA[<210> 290]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-L1]]> <![CDATA[<400> 290]]> Arg Ala Ser Glu Asn Ile Tyr Ser Asn Leu Ala 1 5 10 <![CDATA[<210> 291]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-L1]]> <![CDATA[<400> 291]]> Arg Ala Ser Gln Gly Ile Ser Ser Ala Leu Ala 1 5 10 <![CDATA[<210> 292]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-L1]]> <![CDATA[<400> 292]]> Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala 1 5 10 <![CDATA[<210> 293]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-L2]]> <![CDATA[<400> 293]]> Ala Ala Ser Ser Leu Gln Ser 1 5 <![CDATA[<210> 294]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-L2]]> <![CDATA[<400> 294]]> Ser Thr Ser Asn Lys His Ser 1 5 <![CDATA[<210> 295]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-L2]]> <![CDATA[<400> 295]]> Glu Val Ser Lys Arg Pro Ser 1 5 <![CDATA[<210> 296]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-L2]]> <![CDATA[<400> 296]]> Ser Asn Asn Gln Arg Pro Ser 1 5 <![CDATA[<210> 297]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-L2]]> <![CDATA[<400> 297]]> Ala Ala Thr Tyr Leu Pro Asp 1 5 <![CDATA[<210> 298]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-L3]]> <![CDATA[<400> 298]]> Gln Gln Ser Tyr Ser Thr Pro Leu Thr 1 5 <![CDATA[<210> 299]]> <![CDATA[<211> 10]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-L3]]> <![CDATA[<400> 299]]> Leu Leu Tyr Tyr Gly Gly Ala Gln Trp Val 1 5 10 <![CDATA[<210> 300]]> <![CDATA[<211> 10]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-L3]]> <![CDATA[<400> 300]]> Ser Ser Tyr Ala Gly Ser Asn Asn Trp Val 1 5 10 <![CDATA[<210> 301]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-L3]]> <![CDATA[<400> 301]]> Ala Ala Trp Asp Asp Ser Leu Asn Gly Trp Val 1 5 10 <![CDATA[<210> 302]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-L3]]> <![CDATA[<400> 302]]> Gln His Phe Trp Val Thr Pro Tyr Thr 1 5 <![CDATA[<210> 303]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-L3]]> <![CDATA[<400> 303]]> Gln Gln Tyr Asn Ser Tyr Pro Leu Thr 1 5 <![CDATA[<210> 304]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-L3]]> <![CDATA[<400> 304]]> Gln Gln Ala Asn Ser Phe Pro Leu Thr 1 5 <![CDATA[<210> 305]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H1]]> <![CDATA[<400> 305]]> Ser Tyr Gly Ile Ser 1 5 <![CDATA[<210> 306]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H1]]> <![CDATA[<400> 306]]> Ser Tyr Ser Met Asn 1 5 <![CDATA[<210> 307]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H1]]> <![CDATA[<400> 307]]> Ser Gly Ser Tyr Tyr Trp Ser 1 5 <![CDATA[<210> 308]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H1]]> <![CDATA[<400> 308]]> Ser Tyr Tyr Trp Ser 1 5 <![CDATA[<210> 309]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H1]]> <![CDATA[<400> 309]]> Ser Tyr Trp Ile Gly 1 5 <![CDATA[<210> 310]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H1]]> <![CDATA[<400> 310]]> Ser Asn Tyr Met Ser 1 5 <![CDATA[<210> 311]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H1]]> <![CDATA[<400> 311]]> Ser Ser Ser Tyr Tyr Trp Gly 1 5 <![CDATA[<210> 312]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H1]]> <![CDATA[<400> 312]]> Ser Gly Gly Tyr Tyr Trp Ser 1 5 <![CDATA[<210> 313]]> <![CDATA[<211> 6]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H1]]> <![CDATA[<400> 313]]> Ser Gly Tyr Ser Trp His 1 5 <![CDATA[<210> 314]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H1]]> <![CDATA[<400> 314]]> Thr Ser Gly Val Gly Val Gly 1 5 <![CDATA[<210> 315]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H1]]> <![CDATA[<400> 315]]> Ser Tyr Trp Met His 1 5 <![CDATA[<210> 316]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H1]]> <![CDATA[<400> 316]]> Ser Tyr Asp Met His 1 5 <![CDATA[<210> 317]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H1]]> <![CDATA[<400> 317]]> Ser Tyr Ala Met His 1 5 <![CDATA[<210> 318]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H1]]> <![CDATA[<400> 318]]> Ser Tyr Ala Met Ser 1 5 <![CDATA[<210> 319]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H1]]> <![CDATA[<400> 319]]> Ser Tyr Ala Met Asn 1 5 <![CDATA[<210> 320]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H1]]> <![CDATA[<400> 320]]> Asp Tyr Tyr Met Ser 1 5 <![CDATA[<210> 321]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H1]]> <![CDATA[<400> 321]]> Ser Asn Ser Ala Ala Trp Asn 1 5 <![CDATA[<210> 322]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H1]]> <![CDATA[<400> 322]]> Asp Tyr Tyr Met His 1 5 <![CDATA[<210> 323]]> <![CDATA[<211> 6]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H1]]> <![CDATA[<400> 323]]> Ser Ser Asn Trp Trp Gly 1 5 <![CDATA[<210> 324]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H1]]> <![CDATA[<400> 324]]> Ser Tyr Asp Ile Asn 1 5 <![CDATA[<210> 325]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H1]]> <![CDATA[<400> 325]]> Ser Gly Gly Tyr Ser Trp Ser 1 5 <![CDATA[<210> 326]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H2]]> <![CDATA[<400> 326]]> Trp Ile Ser Ala Tyr Asn Gly Asn Thr Asn Tyr Ala Gln Lys Leu Gln 1 5 10 15 Gly <![CDATA[<210> 327]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H2]]> <![CDATA[<400> 327]]> Tyr Ile Ser Ser Ser Ser Ser Thr Ile Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <![CDATA[<210> 328]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H2]]> <![CDATA[<400> 328]]> Tyr Ile Tyr Tyr Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys Ser 1 5 10 15 <![CDATA[<210> 329]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H2]]> <![CDATA[<400> 329]]> Ile Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe Gln 1 5 10 15 Gly <![CDATA[<210> 330]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H2]]> <![CDATA[<400> 330]]> Val Ile Tyr Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly 1 5 10 15 <![CDATA[<210> 331]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H2]]> <![CDATA[<400> 331]]> Ser Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys Ser 1 5 10 15 <![CDATA[<210> 332]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H2]]> <![CDATA[<400> 332]]> Tyr Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys Ser 1 5 10 15 <![CDATA[<210> 333]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H2]]> <![CDATA[<400> 333]]> Tyr Ile His Phe Ser Gly Ser Thr His Tyr His Pro Ser Leu Lys Ser 1 5 10 15 <![CDATA[<210> 334]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H2]]> <![CDATA[<400> 334]]> Leu Ile Tyr Trp Asn Asp Asp Lys Arg Tyr Ser Pro Ser Leu Lys Ser 1 5 10 15 <![CDATA[<210> 335]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H2]]> <![CDATA[<400> 335]]> Arg Ile Asn Ser Asp Gly Ser Ser Thr Ser Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <![CDATA[<210> 336]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H2]]> <![CDATA[<400> 336]]> Ala Ile Gly Thr Ala Gly Asp Thr Tyr Tyr Pro Gly Ser Val Lys Gly 1 5 10 15 <![CDATA[<210> 337]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H2]]> <![CDATA[<400> 337]]> Trp Ile Asn Ala Gly Asn Gly Asn Thr Lys Tyr Ser Gln Lys Phe Gln 1 5 10 15 Gly <![CDATA[<210> 338]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H2]]> <![CDATA[<400> 338]]> Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <![CDATA[<210> 339]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H2]]> <![CDATA[<400> 339]]> Trp Ile Asn Thr Asn Thr Gly Asn Pro Thr Tyr Ala Gln Gly Phe Thr 1 5 10 15 Gly <![CDATA[<210> 340]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H2]]> <![CDATA[<400> 340]]> Tyr Ile Ser Ser Ser Gly Ser Thr Ile Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <![CDATA[<210> 341]]> <![CDATA[<211> 18]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H2]]> <![CDATA[<400> 341]]> Arg Thr Tyr Tyr Arg Ser Lys Trp Tyr Asn Asp Tyr Ala Val Ser Val 1 5 10 15 Lys Ser <![CDATA[<210> 342]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H2]]> <![CDATA[<400> 342]]> Leu Val Asp Pro Glu Asp Gly Glu Thr Ile Tyr Ala Glu Lys Phe Gln 1 5 10 15 Gly <![CDATA[<210> 343]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H2]]> <![CDATA[<400> 343]]> Trp Met Asn Pro Asn Ser Gly Asn Thr Gly Tyr Ala Gln Lys Phe Gln 1 5 10 15 Gly <![CDATA[<210> 344]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H2]]> <![CDATA[<400> 344]]> Tyr Ile Tyr His Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys Ser 1 5 10 15 <![CDATA[<210> 345]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H2]]> <![CDATA[<400> 345]]> Glu Arg Val Ser Gln Arg Gly Ala Phe Asp Ile 1 5 10 <![CDATA[<210> 346]]> <![CDATA[<211> 10]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H2]]> <![CDATA[<400> 346]]> Gly Asn Pro Asp Lys Asp Pro Phe Asp Tyr 1 5 10 <![CDATA[<210> 347]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H2]]> <![CDATA[<400> 347]]> Asp Phe Tyr Cys Thr Asn Trp Tyr Phe Asp Leu 1 5 10 <![CDATA[<210> 348]]> <![CDATA[<211> 12]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H2]]> <![CDATA[<400> 348]]> Glu Ser Ser Ser Gly Ser Tyr Trp Tyr Phe Asp Leu 1 5 10 <![CDATA[<210> 349]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H2]]> <![CDATA[<400> 349]]> Asp Ser Gly Tyr Lys Tyr Asn Leu Tyr Tyr Tyr Tyr Tyr Tyr Met Asp 1 5 10 15 Val <![CDATA[<210> 350]]> <![CDATA[<211> 13]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H2]]> <![CDATA[<400> 350]]> Gly Gly Asp Leu Ser His Tyr Tyr Tyr Tyr Met Asp Val 1 5 10 <![CDATA[<210> 351]]> <![CDATA[<211> 13]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H2]]> <![CDATA[<400> 351]]> Glu Asn Arg Arg Tyr Asn Ser Cys Tyr Tyr Phe Asp Tyr 1 5 10 <![CDATA[<210> 352]]> <![CDATA[<211> 13]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H2]]> <![CDATA[<400> 352]]> Gly Gly Asp Leu Ser His Tyr Tyr Tyr Tyr Leu Asp Val 1 5 10 <![CDATA[<210> 353]]> <![CDATA[<211> 13]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H2]]> <![CDATA[<400> 353]]> Ala Thr Leu Leu Ser Leu Ser Tyr Asp Ala Phe Asp Ile 1 5 10 <![CDATA[<210> 354]]> <![CDATA[<211> 12]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H2]]> <![CDATA[<400> 354]]> Gly Gly Asp Leu Ser His Tyr Tyr Tyr Met Asp Val 1 5 10 <![CDATA[<210> 355]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H2]]> <![CDATA[<400> 355]]> Glu Arg Asp Arg Trp Phe Asp Pro 1 5 <![CDATA[<210> 356]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H2]]> <![CDATA[<400> 356]]> Glu Thr Pro Pro Ser Leu Gly Ala Phe Asp Ile 1 5 10 <![CDATA[<210> 357]]> <![CDATA[<211> 14]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H2]]> <![CDATA[<400> 357]]> Glu Ala Tyr Cys Leu Ser Asp Ser Tyr Trp Tyr Phe Asp Leu 1 5 10 <![CDATA[<210> 358]]> <![CDATA[<211> 14]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H2]]> <![CDATA[<400> 358]]> Glu Ser Trp Lys Tyr Phe Tyr Pro Arg Gly Tyr Met Asp Val 1 5 10 <![CDATA[<210> 359]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H2]]> <![CDATA[<400> 359]]> Gly Gly Val Val Ser His Tyr Ala Met Asp Cys 1 5 10 <![CDATA[<210> 360]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H2]]> <![CDATA[<400> 360]]> His Tyr Tyr Tyr Tyr Tyr Met Asp Val 1 5 <![CDATA[<210> 361]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H2]]> <![CDATA[<400> 361]]> Lys Thr Thr Ser Phe Tyr Phe Asp Tyr 1 5 <![CDATA[<210> 362]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H2]]> <![CDATA[<400> 362]]> His Tyr Tyr Tyr Tyr Met Asp Val 1 5 <![CDATA[<210> 363]]> <![CDATA[<211> 10]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H2]]> <![CDATA[<400> 363]]> Gly Val Leu Leu Tyr Asn Trp Phe Asp Pro 1 5 10 <![CDATA[<210> 364]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H2]]> <![CDATA[<400> 364]]> His Tyr Tyr Tyr Tyr Tyr Leu Asp Val 1 5 <![CDATA[<210> 365]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H2]]> <![CDATA[<400> 365]]> Asp Leu Pro Gly Ser Tyr Trp Tyr Phe Asp Leu 1 5 10 <![CDATA[<210> 366]]> <![CDATA[<211> 12]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H2]]> <![CDATA[<400> 366]]> Glu Gly Asn Gly Ala Asn Pro Asp Ala Phe Asp Ile 1 5 10 <![CDATA[<210> 367]]> <![CDATA[<211> 10]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H2]]> <![CDATA[<400> 367]]> Arg His Met Arg Leu Ser Cys Phe Asp Tyr 1 5 10 <![CDATA[<210> 368]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H2]]> <![CDATA[<400> 368]]> His Tyr Tyr Tyr Tyr Ser Met Asp Val 1 5 <![CDATA[<210> 369]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H2]]> <![CDATA[<400> 369]]> Ser Phe Asp Trp Phe Asp Pro 1 5 <![CDATA[<210> 370]]> <![CDATA[<211> 14]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H2]]> <![CDATA[<400> 370]]> Glu Arg Ser Ile Ser Pro Tyr Tyr Tyr Tyr Tyr Met Asp Val 1 5 10 <![CDATA[<210> 371]]> <![CDATA[<211> 10]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H2]]> <![CDATA[<400> 371]]> Asp Ser Val Ile Trp Tyr Trp Phe Asp Pro 1 5 10 <![CDATA[<210> 372]]> <![CDATA[<211> 15]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H2]]> <![CDATA[<400> 372]]> Glu Glu Ile Leu Pro Arg Leu Ser Tyr Tyr Tyr Tyr Met Asp Val 1 5 10 15 <![CDATA[<210> 373]]> <![CDATA[<211> 12]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H2]]> <![CDATA[<400> 373]]> Gly Gly Arg Ala His Ser Ser Trp Tyr Phe Asp Leu 1 5 10 <![CDATA[<210> 374]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H3]]> <![CDATA[<400> 374]]> Asp Arg Ile Lys Ile Leu Pro Arg Leu Gly Tyr Tyr Tyr Tyr Met Asp 1 5 10 15 Val <![CDATA[<210> 375]]> <![CDATA[<211> 12]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H3]]> <![CDATA[<400> 375]]> Asp Thr Val Ile His Tyr Tyr Tyr Tyr Met Asp Val 1 5 10 <![CDATA[<210> 376]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H3]]> <![CDATA[<400> 376]]> Asp Val Ile Val Glu Val Phe Leu Ser Tyr Tyr Tyr Tyr Met Asp Val 1 5 10 15 <![CDATA[<210> 377]]> <![CDATA[<211> 12]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H3]]> <![CDATA[<400> 377]]> Asp Ile Phe Ile His Tyr Tyr Tyr Tyr Met Asp Val 1 5 10 <![CDATA[<210> 378]]> <![CDATA[<211> 14]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H3]]> <![CDATA[<400> 378]]> Asp Gly Thr Phe Tyr Ser Tyr Ser Pro Tyr Tyr Phe Asp Tyr 1 5 10 <![CDATA[<210> 379]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H3]]> <![CDATA[<400> 379]]> Glu Trp Ile Lys Ile Leu Pro Arg Leu Gly Tyr Tyr Tyr Tyr Met Asp 1 5 10 15 Val <![CDATA[<210> 380]]> <![CDATA[<211> 12]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H3]]> <![CDATA[<400> 380]]> Asp Arg Ser Leu Tyr Tyr Tyr Tyr Tyr Met Asp Val 1 5 10 <![CDATA[<210> 381]]> <![CDATA[<211> 14]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H3]]> <![CDATA[<400> 381]]> Asp Lys Ile Leu Ala Pro Asn Tyr Tyr Tyr Tyr Met Asp Val 1 5 10 <![CDATA[<210> 382]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H3]]> <![CDATA[<400> 382]]> Glu Lys Ser Trp Lys Tyr Phe Tyr Tyr Tyr Tyr Tyr Tyr Met Asp Val 1 5 10 15 <![CDATA[<210> 383]]> <![CDATA[<211> 15]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H3]]> <![CDATA[<400> 383]]> Glu Asn Thr Ser Thr Ile Pro Tyr Tyr Tyr Tyr Tyr Met Asp Val 1 5 10 15 <![CDATA[<210> 384]]> <![CDATA[<211> 19]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H3]]> <![CDATA[<400> 384]]> Glu Asp Val Asp Lys Asn Thr Ser Thr Ile Tyr Tyr Tyr Tyr Tyr Tyr 1 5 10 15 Met Asp Val <![CDATA[<210> 385]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H3]]> <![CDATA[<400> 385]]> Asp Gly Gly Asp Ile Val Ser Ser Ser Ala Ile Tyr Trp Tyr Phe Asp 1 5 10 15 Leu <![CDATA[<210> 386]]> <![CDATA[<211> 14]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H3]]> <![CDATA[<400> 386]]> Asp Leu Ile Leu Pro Pro Tyr Tyr Tyr Tyr Tyr Met Asp Val 1 5 10 <![CDATA[<210> 387]]> <![CDATA[<211> 19]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H3]]> <![CDATA[<400> 387]]> Glu Thr Trp Ile Lys Ile Leu Pro Arg Tyr Tyr Tyr Tyr Tyr Tyr Tyr 1 5 10 15 Met Asp Val <![CDATA[<210> 388]]> <![CDATA[<211> 12]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H3]]> <![CDATA[<400> 388]]> Asp Leu Ser Arg Tyr Tyr Tyr Tyr Tyr Met Asp Val 1 5 10 <![CDATA[<210> 389]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H3]]> <![CDATA[<400> 389]]> Glu His Ile Val Leu Cys Phe Asp Tyr 1 5 <![CDATA[<210> 390]]> <![CDATA[<211> 15]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H3]]> <![CDATA[<400> 390]]> Asp Lys Ile Leu Pro Arg Pro Tyr Tyr Tyr Tyr Tyr Met Asp Val 1 5 10 15 <![CDATA[<210> 391]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H3]]> <![CDATA[<400> 391]]> Gly Ser Asn Glu Tyr Phe Gln His 1 5 <![CDATA[<210> 392]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H3]]> <![CDATA[<400> 392]]> Gly Thr Ser Tyr Trp Tyr Phe Asp Leu 1 5 <![CDATA[<210> 393]]> <![CDATA[<211> 14]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H3]]> <![CDATA[<400> 393]]> Glu Glu Ile Val Glu Val Phe Tyr Tyr Tyr Tyr Met Asp Val 1 5 10 <![CDATA[<210> 394]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H3]]> <![CDATA[<400> 394]]> Val Asp Asp Tyr Tyr Phe Asp Tyr 1 5 <![CDATA[<210> 395]]> <![CDATA[<211> 14]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H3]]> <![CDATA[<400> 395]]> Ser Thr Asn Ile Leu Leu Ser Tyr Thr Lys Ala Phe Asp Ile 1 5 10 <![CDATA[<210> 396]]> <![CDATA[<211> 12]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H3]]> <![CDATA[<400> 396]]> Asp Lys Thr Tyr Tyr Tyr Tyr Tyr Tyr Met Asp Val 1 5 10 <![CDATA[<210> 397]]> <![CDATA[<211> 19]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H3]]> <![CDATA[<400> 397]]> Glu Lys Tyr Phe His Asp Lys Tyr Phe His Asp Tyr Tyr Tyr Tyr Tyr 1 5 10 15 Met Asp Val <![CDATA[<210> 398]]> <![CDATA[<211> 12]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H3]]> <![CDATA[<400> 398]]> Asp Thr Ser Val Tyr Tyr Tyr Tyr Tyr Met Asp Val 1 5 10 <![CDATA[<210> 399]]> <![CDATA[<211> 14]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H3]]> <![CDATA[<400> 399]]> Glu Lys Ile Leu Pro Tyr Tyr Tyr Tyr Tyr Tyr Met Asp Val 1 5 10 <![CDATA[<210> 400]]> <![CDATA[<211> 21]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H3]]> <![CDATA[<400> 400]]> Gln Trp Ile Tyr Ile Tyr Ile Asn Pro Arg Gly Phe Ile Phe Leu His 1 5 10 15 Asp Ala Phe Asp Ile 20 <![CDATA[<210> 401]]> <![CDATA[<211> 12]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H3]]> <![CDATA[<400> 401]]> Glu Asp Val Asp Phe His His Asp Ala Phe Asp Ile 1 5 10 <![CDATA[<210> 402]]> <![CDATA[<211> 19]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H3]]> <![CDATA[<400> 402]]> Glu Gly Val Asp Lys Asn Thr Ser Thr Ile Tyr Tyr Tyr Tyr Tyr Tyr 1 5 10 15 Met Asp Val <![CDATA[<210> 403]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H3]]> <![CDATA[<400> 403]]> Asp Arg Arg Gly Tyr Phe Asp Leu 1 5 <![CDATA[<210> 404]]> <![CDATA[<211> 15]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H3]]> <![CDATA[<400> 404]]> Gly Ile His Val Asp Ile Arg Ser Met Glu Asp Trp Phe Asp Pro 1 5 10 15 <![CDATA[<210> 405]]> <![CDATA[<211> 12]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H3]]> <![CDATA[<400> 405]]> Asp Ile Gly Thr Ser Tyr Tyr Tyr Tyr Met Asp Val 1 5 10 <![CDATA[<210> 406]]> <![CDATA[<211> 15]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H3]]> <![CDATA[<400> 406]]> Glu Val Val Glu Val Phe Leu Tyr Tyr Tyr Tyr Tyr Met Asp Val 1 5 10 15 <![CDATA[<210> 407]]> <![CDATA[<211> 12]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H3]]> <![CDATA[<400> 407]]> Asp Leu Tyr Tyr Tyr Tyr Tyr Tyr Tyr Met Asp Val 1 5 10 <![CDATA[<210> 408]]> <![CDATA[<211> 22]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H3]]> <![CDATA[<400> 408]]> Glu Ser Trp Lys Tyr Phe Tyr Pro Arg Gly Ser Ile Phe Ile His Tyr 1 5 10 15 Tyr Tyr Tyr Met Asp Val 20 <![CDATA[<210> 409]]> <![CDATA[<211> 14]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H3]]> <![CDATA[<400> 409]]> Asp Arg Ile Val Glu Val Phe Tyr Tyr Tyr Tyr Met Asp Val 1 5 10 <![CDATA[<210> 410]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H3]]> <![CDATA[<400> 410]]> Glu Lys Tyr Phe His Asp Trp Leu Tyr Tyr Tyr Tyr Tyr Met Asp Val 1 5 10 15 <![CDATA[<210> 411]]> <![CDATA[<211> 16]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H3]]> <![CDATA[<400> 411]]> Asp Leu Val Asp Lys Asn Thr Ser Tyr Tyr Tyr Tyr Tyr Met Asp Val 1 5 10 15 <![CDATA[<210> 412]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H3]]> <![CDATA[<400> 412]]> Val Gln Asn Glu Tyr Phe Gln His 1 5 <![CDATA[<210> 413]]> <![CDATA[<211> 6]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H3]]> <![CDATA[<400> 413]]> Ala Asn Trp Phe Asp Pro 1 5 <![CDATA[<210> 414]]> <![CDATA[<211> 12]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H3]]> <![CDATA[<400> 414]]> Gly Gly Trp Thr Ala Trp Tyr Tyr Tyr Met Asp Val 1 5 10 <![CDATA[<210> 415]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H3]]> <![CDATA[<400> 415]]> Ala Lys Tyr Tyr Tyr Met Asp Val 1 5 <![CDATA[<210> 416]]> <![CDATA[<211> 14]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H3]]> <![CDATA[<400> 416]]> Asp Gln Val Asp Lys Asn Thr Tyr Tyr Tyr Tyr Met Asp Val 1 5 10 <![CDATA[<210> 417]]> <![CDATA[<211> 10]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H3]]> <![CDATA[<400> 417]]> Ala Cys Gln Leu Ala Glu Tyr Phe Gln His 1 5 10 <![CDATA[<210> 418]]> <![CDATA[<211> 14]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H3]]> <![CDATA[<400> 418]]> Asp Arg Val Asp Lys Asn Thr Ser Tyr Tyr Tyr Met Asp Val 1 5 10 <![CDATA[<210> 419]]> <![CDATA[<211> 12]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H3]]> <![CDATA[<400> 419]]> Arg Val Gln Leu Lys Leu Val His Trp Phe Asp Pro 1 5 10 <![CDATA[<210> 420]]> <![CDATA[<211> 12]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H3]]> <![CDATA[<400> 420]]> Tyr Tyr Asp Tyr Val Thr Val Phe Tyr Phe Gln His 1 5 10 <![CDATA[<210> 421]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H3]]> <![CDATA[<400> 421]]> Glu Ser Tyr Pro Ser Phe Tyr Ala Phe Asp Ile 1 5 10 <![CDATA[<210> 422]]> <![CDATA[<211> 15]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> CDR-H3]]> <![CDATA[<400> 422]]> Ser Asn Met Trp Ser Tyr Ser Leu Asn Asp Tyr Tyr Phe Asp Tyr 1 5 10 15 <![CDATA[<210> 423]]> <![CDATA[<211> 6]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 未知(Unknown)]]> <![CDATA[<220>]]> <![CDATA[<223> 基於免疫受體酪胺酸之抑制基元]]> <![CDATA[<220>]]> <![CDATA[<221> 位點]]> <![CDATA[<222> (1)..(1)]]> <![CDATA[<223> Xaa為Ser、Ile、Val或Leu]]> <![CDATA[<220>]]> <![CDATA[<221> 位點]]> <![CDATA[<222> (2)..(2)]]> <![CDATA[<223> Xaa為任何胺基酸]]> <![CDATA[<220>]]> <![CDATA[<221> 位點]]> <![CDATA[<222> (4)..(5)]]> <![CDATA[<223> Xaa為任何胺基酸]]> <![CDATA[<220>]]> <![CDATA[<221> 位點]]> <![CDATA[<222> (6)..(6)]]> <![CDATA[<223> Xaa為Ile、Val或Leu]]> <![CDATA[<400> 423]]> Xaa Xaa Tyr Xaa Xaa Xaa 1 5 <![CDATA[<210> 424]]> <![CDATA[<211> 64]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 鉸鏈(iTIM鉸鏈)]]> <![CDATA[<400> 424]]> Tyr Gly Ser Gln Ser Ser Lys Pro Tyr Leu Leu Thr His Pro Ser Asp 1 5 10 15 Pro Leu Glu Leu Val Val Ser Gly Pro Ser Gly Gly Pro Ser Ser Pro 20 25 30 Thr Thr Gly Pro Thr Ser Thr Ser Gly Pro Glu Asp Gln Pro Leu Thr 35 40 45 Pro Thr Gly Ser Asp Pro Gln Ser Gly Leu Gly Arg His Leu Gly Val 50 55 60 <![CDATA[<210> 425]]> <![CDATA[<211> 44]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 短鉸鏈2]]> <![CDATA[<400> 425]]> Val Val Ser Gly Pro Ser Gly Gly Pro Ser Ser Pro Thr Thr Gly Pro 1 5 10 15 Thr Ser Thr Ser Gly Pro Glu Asp Gln Pro Leu Thr Pro Thr Gly Ser 20 25 30 Asp Pro Gln Ser Gly Leu Gly Arg His Leu Gly Val 35 40 <![CDATA[<210> 426]]> <![CDATA[<211> 67]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 長鉸鏈1]]> <![CDATA[<400> 426]]> Ala Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Pro Val Pro Ser 1 5 10 15 Thr Pro Pro Thr Pro Ser Pro Ser Thr Pro Pro Thr Pro Ser Pro Ser 20 25 30 Gly Gly Ser Gly Asn Ser Ser Gly Ser Gly Gly Ser Pro Val Pro Ser 35 40 45 Thr Pro Pro Thr Pro Ser Pro Ser Thr Pro Pro Thr Pro Ser Pro Ser 50 55 60 Ala Ser Val 65 <![CDATA[<210> 427]]> <![CDATA[<211> 75]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 長鉸鏈2]]> <![CDATA[<400> 427]]> Ala Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Pro Val Pro Ser 1 5 10 15 Thr Pro Pro Thr Asn Ser Ser Ser Thr Pro Pro Thr Pro Ser Pro Ser 20 25 30 Pro Val Pro Ser Thr Pro Pro Thr Asn Ser Ser Ser Thr Pro Pro Thr 35 40 45 Pro Ser Pro Ser Pro Val Pro Ser Thr Pro Pro Thr Asn Ser Ser Ser 50 55 60 Thr Pro Pro Thr Pro Ser Pro Ser Ala Ser Val 65 70 75 <![CDATA[<210> 428]]> <![CDATA[<211> 85]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 2x短鉸鏈]]> <![CDATA[<400> 428]]> Val Val Ser Gly Pro Ser Gly Gly Pro Ser Ser Pro Thr Thr Gly Pro 1 5 10 15 Thr Ser Thr Ser Gly Pro Glu Asp Gln Pro Leu Thr Pro Thr Gly Ser 20 25 30 Asp Pro Gln Ser Gly Leu Gly Arg His Val Val Ser Gly Pro Ser Gly 35 40 45 Gly Pro Ser Ser Pro Thr Thr Gly Pro Thr Ser Thr Ser Gly Pro Glu 50 55 60 Asp Gln Pro Leu Thr Pro Thr Gly Ser Asp Pro Gln Ser Gly Leu Gly 65 70 75 80 Arg His Leu Gly Val 85 <![CDATA[<210> 429]]> <![CDATA[<211> 32]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 鉸鏈(截短)]]> <![CDATA[<400> 429]]> Thr Thr Gly Pro Thr Ser Thr Ser Gly Pro Glu Asp Gln Pro Leu Thr 1 5 10 15 Pro Thr Gly Ser Asp Pro Gln Ser Gly Leu Gly Arg His Leu Gly Val 20 25 30 <![CDATA[<210> 430]]> <![CDATA[<211> 18]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> T2A自裂解肽]]> <![CDATA[<400> 430]]> Glu Gly Arg Gly Ser Leu Leu Thr Cys Gly Asp Val Glu Glu Asn Pro 1 5 10 15 Gly Pro <![CDATA[<210> 431]]> <![CDATA[<211> 19]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> P2A自裂解肽]]> <![CDATA[<400> 431]]> Ala Thr Asn Phe Ser Leu Leu Lys Gln Ala Gly Asp Val Glu Glu Asn 1 5 10 15 Pro Gly Pro <![CDATA[<210> 432]]> <![CDATA[<211> 20]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> E2A自裂解肽]]> <![CDATA[<400> 432]]> Gln Cys Thr Asn Tyr Ala Leu Leu Lys Leu Ala Gly Asp Val Glu Ser 1 5 10 15 Asn Pro Gly Pro 20 <![CDATA[<210> 433]]> <![CDATA[<211> 22]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> F2A自裂解肽]]> <![CDATA[<400> 433]]> Val Lys Gln Thr Leu Asn Phe Asp Leu Leu Lys Leu Ala Gly Asp Val 1 5 10 15 Glu Ser Asn Pro Gly Pro 20 <![CDATA[<210> 434]]> <![CDATA[<211> 63]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 未知(Unknown)]]> <![CDATA[<220>]]> <![CDATA[<223> 編碼T2A自裂解肽]]> <![CDATA[<400> 434]]> ggatccggag agggcagagg cagcctgctg acatgtggcg acgtggaaga gaaccctggc 60 ccc 63 <![CDATA[<210> 435]]> <![CDATA[<211> 83]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 未知(Unknown)]]> <![CDATA[<220>]]> <![CDATA[<223> 編碼支架序列]]> <![CDATA[<400> 435]]> gttttagagc tagaaatagc aagttaaaat aaggctagtc cgttatcaac ttgaaaaagt 60 ggcaccgagt cggtgctttt ttt 83 <![CDATA[<210> 436]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 436]]> tggacgacac gcagttcgtg 20 <![CDATA[<210> 437]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 437]]> cagatacctg gagaacggga 20 <![CDATA[<210> 438]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 438]]> tcccgttctc caggtatctg 20 <![CDATA[<210> 439]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 439]]> ccgccgcggt ccaagagcgc 20 <![CDATA[<210> 440]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 440]]> cctgcgctct tggaccgcgg 20 <![CDATA[<210> 441]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 441]]> ggacctgcgc tcttggaccg c 21 <![CDATA[<210> 442]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 442]]> aaggagacgc tgcagcgcac ggg 23 <![CDATA[<210> 443]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 443]]> gaaggagacg ctgcagcgca cgg 23 <![CDATA[<210> 444]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 444]]> gcgggcgccg tggatagagc agg 23 <![CDATA[<210> 445]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 445]]> tgctctatcc acggcgcccg cgg 23 <![CDATA[<210> 446]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 446]]> cgatgaagcg gggctccccg cgg 23 <![CDATA[<210> 447]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 447]]> cgtgtcccgg cccggccgcg ggg 23 <![CDATA[<210> 448]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 448]]> cggctccatc ctctggctcg cgg 23 <![CDATA[<210> 449]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 449]]> gatgtaatcc ttgccgtcgt agg 23 <![CDATA[<210> 450]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 450]]> acagcgacgc cgcgagccag agg 23 <![CDATA[<210> 451]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 451]]> ggatggagcc gcgggcgccg tgg 23 <![CDATA[<210> 452]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 452]]> ggcgccgtgg atagagcagg agg 23 <![CDATA[<210> 453]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 453]]> gcgccgtgga tagagcagga ggg 23 <![CDATA[<210> 454]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 454]]> cggctactac aaccagagcg agg 23 <![CDATA[<210> 455]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 455]]> ctggttgtag tagccgcgca ggg 23 <![CDATA[<210> 456]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 456]]> tactacaacc agagcgaggc cgg 23 <![CDATA[<210> 457]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 457]]> ctacctggag ggcacgtgcg tgg 23 <![CDATA[<210> 458]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 458]]> cacgcacgtg ccctccaggt agg 23 <![CDATA[<210> 459]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 459]]> gcagggtccc caggtccact cgg 23 <![CDATA[<210> 460]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 460]]> gtggacctgg ggaccctgcg cgg 23 <![CDATA[<210> 461]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 461]]> tggagggcac gtgcgtggag tgg 23 <![CDATA[<210> 462]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 462]]> gtatggctgc gacgtggggt cgg 23 <![CDATA[<210> 463]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 463]]> ctgagctgcc atgtccgccg cgg 23 <![CDATA[<210> 464]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 464]]> ggattacatc gccctgaaag agg 23 <![CDATA[<210> 465]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 465]]> caagtgggag gcggcccatg tgg 23 <![CDATA[<210> 466]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 466]]> gtgggaggcg gcccatgtgg cgg 23 <![CDATA[<210> 467]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 467]]> cagttgagag cctacctgga ggg 23 <![CDATA[<210> 468]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 468]]> gcagttgaga gcctacctgg agg 23 <![CDATA[<210> 469]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 469]]> taccaccagt acgcctacga cgg 23 <![CDATA[<210> 470]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 470]]> tgccgtcgta ggcgtactgg tgg 23 <![CDATA[<210> 471]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 471]]> ccagtacgcc tacgacggca agg 23 <![CDATA[<210> 472]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 472]]> ggatgtgaag aaatacctca tgg 23 <![CDATA[<210> 473]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 473]]> atttcttcac atccgtgtcc cgg 23 <![CDATA[<210> 474]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 474]]> aggcgtactg gtggtacccg cgg 23 <![CDATA[<210> 475]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 475]]> cgtactggtg gtacccgcgg agg 23 <![CDATA[<210> 476]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 476]]> gaggatgtat ggctgcgacg tgg 23 <![CDATA[<210> 477]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 477]]> ggatgtatgg ctgcgacgtg ggg 23 <![CDATA[<210> 478]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 478]]> ctcagaccac caagcacaag tgg 23 <![CDATA[<210> 479]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 479]]> tcagaccacc aagcacaagt ggg 23 <![CDATA[<210> 480]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 480]]> caccaagcac aagtgggagg cgg 23 <![CDATA[<210> 481]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 481]]> gaccaccaag cacaagtggg agg 23 <![CDATA[<210> 482]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 482]]> gagccccgct tcatcgcagt ggg 23 <![CDATA[<210> 483]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 483]]> gtagcccact gcgatgaagc ggg 23 <![CDATA[<210> 484]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 484]]> tagcccactg cgatgaagcg ggg 23 <![CDATA[<210> 485]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 485]]> cgtagcccac tgcgatgaag cgg 23 <![CDATA[<210> 486]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 486]]> cttcatcgca gtgggctacg tgg 23 <![CDATA[<210> 487]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 487]]> ggagccccgc ttcatcgcag tgg 23 <![CDATA[<210> 488]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 488]]> cggggagaca cggaaagtga agg 23 <![CDATA[<210> 489]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 489]]> agtattggga cggggagaca cgg 23 <![CDATA[<210> 490]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 490]]> agggtccgga gtattgggac ggg 23 <![CDATA[<210> 491]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 491]]> gagggtccgg agtattggga cgg 23 <![CDATA[<210> 492]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 492]]> ggaccctcct gctctatcca cgg 23 <![CDATA[<210> 493]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 493]]> gtggatagag caggagggtc cgg 23 <![CDATA[<210> 494]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 494]]> agactcaccg agtggacctg ggg 23 <![CDATA[<210> 495]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 495]]> cactcggtga gtctgtgagt ggg 23 <![CDATA[<210> 496]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 496]]> cagactcacc gagtggacct ggg 23 <![CDATA[<210> 497]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 497]]> ccactcacag actcaccgag tgg 23 <![CDATA[<210> 498]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 498]]> ccactcggtg agtctgtgag tgg 23 <![CDATA[<210> 499]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 499]]> tcggactggc gcttcctccg cgg 23 <![CDATA[<210> 500]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 500]]> gcagccatac atcctctgga cgg 23 <![CDATA[<210> 501]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 501]]> tctcaactgc tccgccacat ggg 23 <![CDATA[<210> 502]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 502]]> accctcatgc tgcacatggc agg 23 <![CDATA[<210> 503]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 503]]> acctgccatg tgcagcatga ggg 23 <![CDATA[<210> 504]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 504]]> cacctgccat gtgcagcatg agg 23 <![CDATA[<210> 505]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 505]]> ggaggaccag acccaggaca cgg 23 <![CDATA[<210> 506]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 506]]> ggatggggag gaccagaccc agg 23 <![CDATA[<210> 507]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 507]]> gacctggcag cgggatgggg agg 23 <![CDATA[<210> 508]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 508]]> agatcacact gacctggcag cgg 23 <![CDATA[<210> 509]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 509]]> gatcacactg acctggcagc ggg 23 <![CDATA[<210> 510]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 510]]> aggtcagtgt gatctccgca ggg 23 <![CDATA[<210> 511]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 511]]> aagcccctca ccctgagatg ggg 23 <![CDATA[<210> 512]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 512]]> ctgcggagat cacactgacc tgg 23 <![CDATA[<210> 513]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 513]]> cagcaatgat gcccacgatg ggg 23 <![CDATA[<210> 514]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 514]]> ccagcaatga tgcccacgat ggg 23 <![CDATA[<210> 515]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 515]]> gccagcaatg atgcccacga tgg 23 <![CDATA[<210> 516]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 516]]> ggatggaacc ttccagaagt ggg 23 <![CDATA[<210> 517]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 517]]> gggatggaac cttccagaag tgg 23 <![CDATA[<210> 518]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 518]]> atgcccacga tggggatggt ggg 23 <![CDATA[<210> 519]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 519]]> cagcccacca tccccatcgt ggg 23 <![CDATA[<210> 520]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 520]]> ccagcccacc atccccatcg tgg 23 <![CDATA[<210> 521]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 521]]> gatgcccacg atggggatgg tgg 23 <![CDATA[<210> 522]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 522]]> cagggcccag cacctcaggg tgg 23 <![CDATA[<210> 523]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 523]]> aatgatgccc acgatgggga tgg 23 <![CDATA[<210> 524]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 524]]> ggccctgacc cagacctggg cgg 23 <![CDATA[<210> 525]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 525]]> gacccaggac acggagctcg tgg 23 <![CDATA[<210> 526]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 526]]> acacggagct cgtggagacc agg 23 <![CDATA[<210> 527]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 527]]> cgtggagacc aggcctgcag ggg 23 <![CDATA[<210> 528]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 528]]> tcgtggagac caggcctgca ggg 23 <![CDATA[<210> 529]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 529]]> agctgtgatc actggagctg tgg 23 <![CDATA[<210> 530]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 530]]> aaaaggaggg agctactctc agg 23 <![CDATA[<210> 531]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 531]]> atgtggagga ggaagagctc agg 23 <![CDATA[<210> 532]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 532]]> gtgtctctca cagcttgtaa agg 23 <![CDATA[<210> 533]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 533]]> gagagacaca tcagagccct ggg 23 <![CDATA[<210> 534]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 534]]> ctccgcaggg tagaagctca ggg 23 <![CDATA[<210> 535]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 535]]> ggccctgagc ttctaccctg cgg 23 <![CDATA[<210> 536]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 536]]> gctcagggcc cagcacctca ggg 23 <![CDATA[<210> 537]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 537]]> tatctctgct cctgtccaga agg 23 <![CDATA[<210> 538]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 538]]> agtagcagga cgagggttcg ggg 23 <![CDATA[<210> 539]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 539]]> ccccgagagt agcaggacga ggg 23 <![CDATA[<210> 540]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 540]]> ccctcgtcct gctactctcg ggg 23 <![CDATA[<210> 541]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 541]]> cctcgtcctg ctactctcgg ggg 23 <![CDATA[<210> 542]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 542]]> ctgtggtcgc tgctgtgatg tgg 23 <![CDATA[<210> 543]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 543]]> tcgctgctgt gatgtggagg agg 23 <![CDATA[<210> 544]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 544]]> tggtcgctgc tgtgatgtgg agg 23 <![CDATA[<210> 545]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 545]]> cacagccgcc cacttctgga agg 23 <![CDATA[<210> 546]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 546]]> ccagaagtgg gcggctgtgg tgg 23 <![CDATA[<210> 547]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 547]]> tggaaccttc cagaagtggg cgg 23 <![CDATA[<210> 548]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 548]]> tcacagctcc aaagagaacc agg 23 <![CDATA[<210> 549]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 549]]> ctgaccatga agccaccctg agg 23 <![CDATA[<210> 550]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 550]]> gcaaaccctc atgctgcaca tgg 23 <![CDATA[<210> 551]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 551]]> tgaagccacc ctgaggtgct ggg 23 <![CDATA[<210> 552]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 552]]> ggtgagtcat atgcgttttg ggg 23 <![CDATA[<210> 553]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 553]]> gtgagtcata tgcgttttgg ggg 23 <![CDATA[<210> 554]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 554]]> cttcatggtc agagacagcg tgg 23 <![CDATA[<210> 555]]> <![CDATA[<211> 23]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 嚮導核酸靶向序列]]> <![CDATA[<400> 555]]> tctggccctg acccagacct ggg 23 <![CDATA[<210> 556]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 556]]> cgcgagcaca gctaaggcca 20 <![CDATA[<210> 557]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 557]]> gagtagcgcg agcacagcta 20 <![CDATA[<210> 558]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 558]]> agggtaggag agactcacgc 20 <![CDATA[<210> 559]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 559]]> ctgaatcttt ggagtacctg 20 <![CDATA[<210> 560]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 560]]> tcacgtcatc cagcagagaa 20 <![CDATA[<210> 561]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 561]]> tcctgaattg ctatgtgtct 20 <![CDATA[<210> 562]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 562]]> aagtcaactt caatgtcgga 20 <![CDATA[<210> 563]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 563]]> gtcttttccc gatattcctc 20 <![CDATA[<210> 564]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 564]]> tggagtacct gaggaatatc 20 <![CDATA[<210> 565]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 565]]> cagcccaaga tagttaagtg 20 <![CDATA[<210> 566]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 566]]> acaaagtcac atggttcaca 20 <![CDATA[<210> 567]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 567]]> actctctctt tctggcctgg 20 <![CDATA[<210> 568]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 568]]> tgggctgtga caaagtcaca 20 <![CDATA[<210> 569]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 569]]> ggccgagatg tctcgctccg 20 <![CDATA[<210> 570]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 570]]> cagtaagtca acttcaatgt 20 <![CDATA[<210> 571]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 571]]> actcacgctg gatagcctcc 20 <![CDATA[<210> 572]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 572]]> catactcatc tttttcagtg 20 <![CDATA[<210> 573]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 573]]> cacagcccaa gatagttaag 20 <![CDATA[<210> 574]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 574]]> ttcagacttg tctttcagca 20 <![CDATA[<210> 575]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 575]]> agtcacatgg ttcacacggc 20 <![CDATA[<210> 576]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 576]]> atactcatct ttttcagtgg 20 <![CDATA[<210> 577]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 577]]> ggcatactca tctttttcag 20 <![CDATA[<210> 578]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 578]]> acagcccaag atagttaagt 20 <![CDATA[<210> 579]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 579]]> gctactctct ctttctggcc 20 <![CDATA[<210> 580]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 580]]> tggagagaga attgaaaaag 20 <![CDATA[<210> 581]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 581]]> acttgtcttt cagcaaggac 20 <![CDATA[<210> 582]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 582]]> gaagttgact tactgaagaa 20 <![CDATA[<210> 583]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 583]]> ggccacggag cgagacatct 20 <![CDATA[<210> 584]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 584]]> gcatactcat ctttttcagt 20 <![CDATA[<210> 585]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 585]]> cgtgagtaaa cctgaatctt 20 <![CDATA[<210> 586]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 586]]> ttaccccact taactatctt 20 <![CDATA[<210> 587]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 587]]> ttggagtacc tgaggaatat 20 <![CDATA[<210> 588]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 588]]> acccagacac atagcaattc 20 <![CDATA[<210> 589]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 589]]> tttgactttc cattctctgc 20 <![CDATA[<210> 590]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 590]]> ttcctgaatt gctatgtgtc 20 <![CDATA[<210> 591]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 591]]> ctcaggtact ccaaagattc 20 <![CDATA[<210> 592]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 592]]> cttaccccac ttaactatct 20 <![CDATA[<210> 593]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 593]]> ctcgcgctac tctctctttc 20 <![CDATA[<210> 594]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 594]]> tcgatctatg aaaaagacag 20 <![CDATA[<210> 595]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 595]]> gagacatgta agcagcatca 20 <![CDATA[<210> 596]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 596]]> acatgtaagc agcatcatgg 20 <![CDATA[<210> 597]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 597]]> gaagtcctag aatgagcgcc 20 <![CDATA[<210> 598]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 598]]> gagcgcccgg tgtcccaagc 20 <![CDATA[<210> 599]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 599]]> agcgcccggt gtcccaagct 20 <![CDATA[<210> 600]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 600]]> gcgcccggtg tcccaagctg 20 <![CDATA[<210> 601]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 601]]> ctggggcgcg caccccagat 20 <![CDATA[<210> 602]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 602]]> gggcgcgcac cccagatcgg 20 <![CDATA[<210> 603]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 603]]> ggcgcgcacc ccagatcgga 20 <![CDATA[<210> 604]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 604]]> catcacgaga ctctaagaaa 20 <![CDATA[<210> 605]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 605]]> taagaaaagg aaactgaaaa 20 <![CDATA[<210> 606]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 606]]> aagaaaagga aactgaaaac 20 <![CDATA[<210> 607]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 607]]> gaaagtccct ctctctaacc 20 <![CDATA[<210> 608]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 608]]> ctaacctggc actgcgtcgc 20 <![CDATA[<210> 609]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 609]]> ctggcactgc gtcgctggct 20 <![CDATA[<210> 610]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 610]]> tgcgtcgctg gcttggagac 20 <![CDATA[<210> 611]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 611]]> gctggcttgg agacaggtga 20 <![CDATA[<210> 612]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 612]]> gagacaggtg acggtccctg 20 <![CDATA[<210> 613]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 613]]> agacaggtga cggtccctgc 20 <![CDATA[<210> 614]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 614]]> cctgcgggcc ttgtcctgat 20 <![CDATA[<210> 615]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 615]]> cgggccttgt cctgattggc 20 <![CDATA[<210> 616]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 616]]> gggccttgtc ctgattggct 20 <![CDATA[<210> 617]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 617]]> gggcacgcgt ttaatataag 20 <![CDATA[<210> 618]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 618]]> cacgcgttta atataagtgg 20 <![CDATA[<210> 619]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 619]]> tataagtgga ggcgtcgcgc 20 <![CDATA[<210> 620]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 620]]> aagtggaggc gtcgcgctgg 20 <![CDATA[<210> 621]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 621]]> agtggaggcg tcgcgctggc 20 <![CDATA[<210> 622]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 622]]> ttcctgaagc tgacagcatt 20 <![CDATA[<210> 623]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 623]]> tcctgaagct gacagcattc 20 <![CDATA[<210> 624]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 624]]> gcccgaatgc tgtcagcttc 20 <![CDATA[<210> 625]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 625]]> aaacgcgtgc ccagccaatc 20 <![CDATA[<210> 626]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 626]]> gtgcccagcc aatcaggaca 20 <![CDATA[<210> 627]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 627]]> ccaatcagga caaggcccgc 20 <![CDATA[<210> 628]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 628]]> caatcaggac aaggcccgca 20 <![CDATA[<210> 629]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 629]]> caagccagcg acgcagtgcc 20 <![CDATA[<210> 630]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 630]]> cgcagtgcca ggttagagag 20 <![CDATA[<210> 631]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 631]]> gcagtgccag gttagagaga 20 <![CDATA[<210> 632]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 632]]> gagtctcgtg atgtttaaga 20 <![CDATA[<210> 633]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 633]]> taagaaggca tgcactagac 20 <![CDATA[<210> 634]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 634]]> aagaaggcat gcactagact 20 <![CDATA[<210> 635]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 635]]> tgagtttgct gtctgtacat 20 <![CDATA[<210> 636]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 636]]> tacatcggcg ccctccgatc 20 <![CDATA[<210> 637]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 637]]> acatcggcgc cctccgatct 20 <![CDATA[<210> 638]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 638]]> catcggcgcc ctccgatctg 20 <![CDATA[<210> 639]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 639]]> ctggggtgcg cgccccagct 20 <![CDATA[<210> 640]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 640]]> tggggtgcgc gccccagctt 20 <![CDATA[<210> 641]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 641]]> cgcgccccag cttgggacac 20 <![CDATA[<210> 642]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 642]]> gcgccccagc ttgggacacc 20 <![CDATA[<210> 643]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 643]]> caagtcactt agcatctctg 20 <![CDATA[<210> 644]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 644]]> acagaagttc tccttctgct 20 <![CDATA[<210> 645]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 645]]> attcaaagat cttaatcttc 20 <![CDATA[<210> 646]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 646]]> ttcaaagatc ttaatcttct 20 <![CDATA[<210> 647]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 647]]> ttttctcgaa tgaaaaatgc 20 <![CDATA[<210> 648]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 648]]> tgcaggtccg agcagttaac 20 <![CDATA[<210> 649]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 649]]> ggtccgagca gttaactggc 20 <![CDATA[<210> 650]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 650]]> gtccgagcag ttaactggct 20 <![CDATA[<210> 651]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 651]]> tccgagcagt taactggctg 20 <![CDATA[<210> 652]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 652]]> agcaagtcac ttagcatctc 20 <![CDATA[<210> 653]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 653]]> gcaagtcact tagcatctct 20 <![CDATA[<210> 654]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 654]]> tggggccagt ctgcaaagcg 20 <![CDATA[<210> 655]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 655]]> ggggccagtc tgcaaagcga 20 <![CDATA[<210> 656]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 656]]> gggccagtct gcaaagcgag 20 <![CDATA[<210> 657]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 657]]> ggccagtctg caaagcgagg 20 <![CDATA[<210> 658]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 658]]> ggacaccggg cgctcattct 20 <![CDATA[<210> 659]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 659]]> ggcgctcatt ctaggacttc 20 <![CDATA[<210> 660]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 660]]> ctcattctag gacttcaggc 20 <![CDATA[<210> 661]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 661]]> attctaggac ttcaggctgg 20 <![CDATA[<210> 662]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 662]]> ttcaggctgg aggcacatta 20 <![CDATA[<210> 663]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 663]]> tgccccctcg ctttgcagac 20 <![CDATA[<210> 664]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 664]]> gatgctaagt gacttgctaa 20 <![CDATA[<210> 665]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 665]]> gccccagcca gttaactgct 20 <![CDATA[<210> 666]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 666]]> gcatttttca ttcgagaaaa 20 <![CDATA[<210> 667]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 667]]> tttgaatgct acctagcaga 20 <![CDATA[<210> 668]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 668]]> ttctgtttat aactacagct 20 <![CDATA[<210> 669]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M靶向序列]]> <![CDATA[<400> 669]]> tctgtttata actacagctt 20 <![CDATA[<210> 670]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 670]]> agagaatgga aagtcaaatt t 21 <![CDATA[<210> 671]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 671]]> atggacatga tcttctttat a 21 <![CDATA[<210> 672]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 672]]> tggacatgat cttctttata a 21 <![CDATA[<210> 673]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 673]]> ggacatgatc ttctttataa t 21 <![CDATA[<210> 674]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 674]]> tgacaggatt attggaaatt t 21 <![CDATA[<210> 675]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 675]]> ttgtggttaa tctggtttat t 21 <![CDATA[<210> 676]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 676]]> tgtggttaat ctggtttatt t 21 <![CDATA[<210> 677]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 677]]> gcagagaatg gaaagtcaaa t 21 <![CDATA[<210> 678]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 678]]> cagagaatgg aaagtcaaat t 21 <![CDATA[<210> 679]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 679]]> gagaatggaa agtcaaattt c 21 <![CDATA[<210> 680]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 680]]> gtcacagccc aagatagtta a 21 <![CDATA[<210> 681]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 681]]> tgcttataca cttacacttt a 21 <![CDATA[<210> 682]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 682]]> gcttatacac ttacacttta t 21 <![CDATA[<210> 683]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 683]]> cttatacact tacactttat g 21 <![CDATA[<210> 684]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 684]]> acatggacat gatcttcttt a 21 <![CDATA[<210> 685]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 685]]> catggacatg atcttcttta t 21 <![CDATA[<210> 686]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 686]]> atcaacatct tggtcagatt t 21 <![CDATA[<210> 687]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 687]]> cttgcactca aagcttgtta a 21 <![CDATA[<210> 688]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 688]]> agttaagcgt gcataagtta a 21 <![CDATA[<210> 689]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 689]]> gcataagtta acttccaatt t 21 <![CDATA[<210> 690]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 690]]> tacatactct gcttagaatt t 21 <![CDATA[<210> 691]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 691]]> acatactctg cttagaattt g 21 <![CDATA[<210> 692]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 692]]> ttgacaggat tattggaaat t 21 <![CDATA[<210> 693]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 693]]> gacaggatta ttggaaattt g 21 <![CDATA[<210> 694]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 694]]> taaggcatgg ttgtggttaa t 21 <![CDATA[<210> 695]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 695]]> gttgtggtta atctggttta t 21 <![CDATA[<210> 696]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 696]]> gttccacaag ttaaataaat c 21 <![CDATA[<210> 697]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 697]]> tccagcgtac tccaaagatt c 21 <![CDATA[<210> 698]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 698]]> tactccaaag attcaggttt a 21 <![CDATA[<210> 699]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 699]]> actccaaaga ttcaggttta c 21 <![CDATA[<210> 700]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 700]]> cacgtcatcc agcagagaat g 21 <![CDATA[<210> 701]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 701]]> ggtttcatcc atccgacatt g 21 <![CDATA[<210> 702]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 702]]> ccgacattga agttgactta c 21 <![CDATA[<210> 703]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 703]]> tgaagaatgg agagagaatt g 21 <![CDATA[<210> 704]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 704]]> gagcattcag acttgtcttt c 21 <![CDATA[<210> 705]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 705]]> ttcagcaagg actggtcttt c 21 <![CDATA[<210> 706]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 706]]> gcaaggactg gtctttctat c 21 <![CDATA[<210> 707]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 707]]> cgtgtgaacc atgtgacttt g 21 <![CDATA[<210> 708]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 708]]> ctttgtcaca gcccaagata g 21 <![CDATA[<210> 709]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 709]]> tcacagccca agatagttaa g 21 <![CDATA[<210> 710]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 710]]> agtgggatcg agacatgtaa g 21 <![CDATA[<210> 711]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 711]]> aggtttgaag atgccgcatt t 21 <![CDATA[<210> 712]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 712]]> ggtttgaaga tgccgcattt g 21 <![CDATA[<210> 713]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 713]]> ttgatatgct tatacactta c 21 <![CDATA[<210> 714]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 714]]> tgagtgctgt ctccatgttt g 21 <![CDATA[<210> 715]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 715]]> tgtctccatg tttgatgtat c 21 <![CDATA[<210> 716]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 716]]> tcaacatctt ggtcagattt g 21 <![CDATA[<210> 717]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 717]]> tcagatttga actcttcaat c 21 <![CDATA[<210> 718]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 718]]> ttcaatctct tgcactcaaa g 21 <![CDATA[<210> 719]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 719]]> ttgcactcaa agcttgttaa g 21 <![CDATA[<210> 720]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 720]]> actcaaagct tgttaagata g 21 <![CDATA[<210> 721]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 721]]> agatagttaa gcgtgcataa g 21 <![CDATA[<210> 722]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 722]]> tgcataagtt aacttccaat t 21 <![CDATA[<210> 723]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 723]]> gttaacttcc aatttacata c 21 <![CDATA[<210> 724]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 724]]> attgacagga ttattggaaa t 21 <![CDATA[<210> 725]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 725]]> gtaaggcatg gttgtggtta a 21 <![CDATA[<210> 726]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 726]]> ggttgtggtt aatctggttt a 21 <![CDATA[<210> 727]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 727]]> ttcctgaagc tgacagcatt c 21 <![CDATA[<210> 728]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 728]]> gctatccagc gtactccaaa g 21 <![CDATA[<210> 729]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 729]]> catccagcag agaatggaaa g 21 <![CDATA[<210> 730]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 730]]> caaatttcct gaattgctat g 21 <![CDATA[<210> 731]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 731]]> attgctatgt gtctgggttt c 21 <![CDATA[<210> 732]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 732]]> gaagatgccg catttggatt g 21 <![CDATA[<210> 733]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 733]]> caatttacat actctgctta g 21 <![CDATA[<210> 734]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 734]]> tatccagcgt actccaaaga t 21 <![CDATA[<210> 735]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 735]]> atccagcgta ctccaaagat t 21 <![CDATA[<210> 736]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 736]]> ctccaaagat tcaggtttac t 21 <![CDATA[<210> 737]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 737]]> tgctatgtgt ctgggtttca t 21 <![CDATA[<210> 738]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 738]]> tttcatccat ccgacattga a 21 <![CDATA[<210> 739]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 739]]> gaagttgact tactgaagaa t 21 <![CDATA[<210> 740]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 740]]> gaagaatgga gagagaattg a 21 <![CDATA[<210> 741]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 741]]> agaatggaga gagaattgaa a 21 <![CDATA[<210> 742]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 742]]> cagcaaggac tggtctttct a 21 <![CDATA[<210> 743]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 743]]> agcaaggact ggtctttcta t 21 <![CDATA[<210> 744]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 744]]> actttgtcac agcccaagat a 21 <![CDATA[<210> 745]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 745]]> ttgtcacagc ccaagatagt t 21 <![CDATA[<210> 746]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 746]]> tgtcacagcc caagatagtt a 21 <![CDATA[<210> 747]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 747]]> cacagcccaa gatagttaag t 21 <![CDATA[<210> 748]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 748]]> gcagcatcat ggaggtttga a 21 <![CDATA[<210> 749]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 749]]> ccgcatttgg attggatgaa t 21 <![CDATA[<210> 750]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 750]]> ttgagtgctg tctccatgtt t 21 <![CDATA[<210> 751]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 751]]> agtgctgtct ccatgtttga t 21 <![CDATA[<210> 752]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 752]]> ctgtctccat gtttgatgta t 21 <![CDATA[<210> 753]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 753]]> tctaggaggg ctggcaactt a 21 <![CDATA[<210> 754]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 754]]> caacatcttg gtcagatttg a 21 <![CDATA[<210> 755]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 755]]> gtcagatttg aactcttcaa t 21 <![CDATA[<210> 756]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 756]]> tcttgcactc aaagcttgtt a 21 <![CDATA[<210> 757]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 757]]> tgcactcaaa gcttgttaag a 21 <![CDATA[<210> 758]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 758]]> gcactcaaag cttgttaaga t 21 <![CDATA[<210> 759]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 759]]> cactcaaagc ttgttaagat a 21 <![CDATA[<210> 760]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 760]]> tcaaagcttg ttaagatagt t 21 <![CDATA[<210> 761]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 761]]> caaagcttgt taagatagtt a 21 <![CDATA[<210> 762]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 762]]> gatagttaag cgtgcataag t 21 <![CDATA[<210> 763]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 763]]> atagttaagc gtgcataagt t 21 <![CDATA[<210> 764]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 764]]> tagttaagcg tgcataagtt a 21 <![CDATA[<210> 765]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 765]]> ttaagcgtgc ataagttaac t 21 <![CDATA[<210> 766]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 766]]> taagcgtgca taagttaact t 21 <![CDATA[<210> 767]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 767]]> atttacatac tctgcttaga a 21 <![CDATA[<210> 768]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 768]]> tttacatact ctgcttagaa t 21 <![CDATA[<210> 769]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 769]]> acaggattat tggaaatttg t 21 <![CDATA[<210> 770]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 770]]> caggattatt ggaaatttgt t 21 <![CDATA[<210> 771]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 771]]> aggcatggtt gtggttaatc t 21 <![CDATA[<210> 772]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 772]]> cagcagagaa tggaaagtca a 21 <![CDATA[<210> 773]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 773]]> tccgacattg aagttgactt a 21 <![CDATA[<210> 774]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 774]]> ctggtctttc tatctcttgt a 21 <![CDATA[<210> 775]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 775]]> ccgtgtgaac catgtgactt t 21 <![CDATA[<210> 776]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 776]]> cccaagatag ttaagtggga t 21 <![CDATA[<210> 777]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 777]]> ggttgctcca caggtagctc t 21 <![CDATA[<210> 778]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 778]]> gctccacagg tagctctagg a 21 <![CDATA[<210> 779]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 779]]> gggagcagag aattctctta t 21 <![CDATA[<210> 780]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 780]]> ggagcagaga attctcttat c 21 <![CDATA[<210> 781]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 781]]> gagcagagaa ttctcttatc c 21 <![CDATA[<210> 782]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 782]]> gagaattctc ttatccaaca t 21 <![CDATA[<210> 783]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 783]]> gaattctctt atccaacatc a 21 <![CDATA[<210> 784]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 784]]> aagtggagca ttcagacttg t 21 <![CDATA[<210> 785]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 785]]> aaggactggt ctttctatct c 21 <![CDATA[<210> 786]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 786]]> aagcttgtta agatagttaa g 21 <![CDATA[<210> 787]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 787]]> aagcgtgcat aagttaactt c 21 <![CDATA[<210> 788]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 788]]> aagatgccgc atttggattg g 21 <![CDATA[<210> 789]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 789]]> aagaatggag agagaattga a 21 <![CDATA[<210> 790]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 790]]> aacatcaaca tcttggtcag a 21 <![CDATA[<210> 791]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 791]]> aaggcatggt tgtggttaat c 21 <![CDATA[<210> 792]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 792]]> aagcagcatc atggaggttt g 21 <![CDATA[<210> 793]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 793]]> aagatgagta tgcctgccgt g 21 <![CDATA[<210> 794]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 794]]> aagttgactt actgaagaat g 21 <![CDATA[<210> 795]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 795]]> aagatagtta agcgtgcata a 21 <![CDATA[<210> 796]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 796]]> aacttccaat ttacatactc t 21 <![CDATA[<210> 797]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 797]]> aacatcttgg tcagatttga a 21 <![CDATA[<210> 798]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 798]]> aactcttcaa tctcttgcac t 21 <![CDATA[<210> 799]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 799]]> aatttcctga attgctatgt g 21 <![CDATA[<210> 800]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 800]]> aatggaaagt caaatttcct g 21 <![CDATA[<210> 801]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 801]]> aaccatgtga ctttgtcaca g 21 <![CDATA[<210> 802]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 802]]> aattgacagg attattggaa a 21 <![CDATA[<210> 803]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 803]]> aattctctta tccaacatca a 21 <![CDATA[<210> 804]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 804]]> aaagtggagc attcagactt g 21 <![CDATA[<210> 805]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 805]]> aaagtcaaat ttcctgaatt g 21 <![CDATA[<210> 806]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 806]]> gttgctccac aggtagctct a 21 <![CDATA[<210> 807]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶B2M序列補體]]> <![CDATA[<400> 807]]> aatttacata ctctgcttag a 21 <![CDATA[<210> 808]]> <![CDATA[<211> 46]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> B2M shRNA]]> <![CDATA[<400> 808]]> gttaacttcc aatttacata ccgaagtatg taaattggaa gttaac 46 <![CDATA[<210> 809]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 809]]> cttcttcctt ccctattaaa a 21 <![CDATA[<210> 810]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 810]]> tctcactcca tgaggtattt c 21 <![CDATA[<210> 811]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 811]]> ctctcactcc atgaggtatt t 21 <![CDATA[<210> 812]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 812]]> gaggaggaag agctcagata g 21 <![CDATA[<210> 813]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 813]]> gctctcactc catgaggtat t 21 <![CDATA[<210> 814]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 814]]> aggattacat cgccctgaaa g 21 <![CDATA[<210> 815]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 815]]> acaccgtcca gaggatgtat g 21 <![CDATA[<210> 816]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 816]]> agggtccttc ttcctggata c 21 <![CDATA[<210> 817]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 817]]> cctacgacgg caaggattac a 21 <![CDATA[<210> 818]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 818]]> tcactccatg aggtatttct t 21 <![CDATA[<210> 819]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 819]]> ctacgacggc aaggattaca t 21 <![CDATA[<210> 820]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 820]]> ctcactccat gaggtatttc t 21 <![CDATA[<210> 821]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 821]]> ggaggaagag ctcagataga a 21 <![CDATA[<210> 822]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 822]]> cacaccgtcc agaggatgta t 21 <![CDATA[<210> 823]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 823]]> cacgctgtct ctgaccatga a 21 <![CDATA[<210> 824]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 824]]> ctggacagga gcagagatac a 21 <![CDATA[<210> 825]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 825]]> tggaggagga agagctcaga t 21 <![CDATA[<210> 826]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 826]]> ggctctcact ccatgaggta t 21 <![CDATA[<210> 827]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 827]]> catctctgtc tcaacttcat g 21 <![CDATA[<210> 828]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 828]]> tacgacggca aggattacat c 21 <![CDATA[<210> 829]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 829]]> ggattacatc gccctgaaag a 21 <![CDATA[<210> 830]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 830]]> gattacatcg ccctgaaaga g 21 <![CDATA[<210> 831]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 831]]> ctcagaccac caagcacaag t 21 <![CDATA[<210> 832]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 832]]> tcacaccgtc cagaggatgt a 21 <![CDATA[<210> 833]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 833]]> actccatgag gtatttcttc a 21 <![CDATA[<210> 834]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 834]]> cactccatga ggtatttctt c 21 <![CDATA[<210> 835]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 835]]> ccatgaggta tttcttcaca t 21 <![CDATA[<210> 836]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 836]]> acttcttcct tccctattaa a 21 <![CDATA[<210> 837]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 837]]> gtgtctctca cagcttgtaa a 21 <![CDATA[<210> 838]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 838]]> ctgtgttcgt gtaggcataa t 21 <![CDATA[<210> 839]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 839]]> tgtgttcgtg taggcataat g 21 <![CDATA[<210> 840]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 840]]> taacttcttc cttccctatt a 21 <![CDATA[<210> 841]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 841]]> tctggacagg agcagagata c 21 <![CDATA[<210> 842]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 842]]> ttgctggcct ggttctcttt g 21 <![CDATA[<210> 843]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 843]]> tgtctctcac agcttgtaaa g 21 <![CDATA[<210> 844]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 844]]> acttgaagaa ccctgacttt g 21 <![CDATA[<210> 845]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 845]]> gaagaaccct gactttgttt c 21 <![CDATA[<210> 846]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 846]]> tctgtgttcg tgtaggcata a 21 <![CDATA[<210> 847]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 847]]> catggtgcac tgagctgtaa c 21 <![CDATA[<210> 848]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 848]]> gtaacttctt ccttccctat t 21 <![CDATA[<210> 849]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 849]]> catgtgcagc atgagggttt g 21 <![CDATA[<210> 850]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 850]]> ttgttcctgc ccttcccttt g 21 <![CDATA[<210> 851]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 851]]> acccagttct cactcccatt g 21 <![CDATA[<210> 852]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 852]]> gggtttccag agaagccaat c 21 <![CDATA[<210> 853]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 853]]> ttctccctct cccaacctat g 21 <![CDATA[<210> 854]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 854]]> gtctctcaca gcttgtaaag t 21 <![CDATA[<210> 855]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 855]]> tgtgtctctc acagcttgta a 21 <![CDATA[<210> 856]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 856]]> gaggaagagc tcagatagaa a 21 <![CDATA[<210> 857]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 857]]> tgaagaaccc tgactttgtt t 21 <![CDATA[<210> 858]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 858]]> ttgaagaacc ctgactttgt t 21 <![CDATA[<210> 859]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 859]]> gtgttcgtgt aggcataatg t 21 <![CDATA[<210> 860]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 860]]> tggtgcactg agctgtaact t 21 <![CDATA[<210> 861]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 861]]> ctccctctcc caacctatgt a 21 <![CDATA[<210> 862]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 862]]> aggaggaaga gctcagatag a 21 <![CDATA[<210> 863]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 863]]> acctatgtag ggtccttctt c 21 <![CDATA[<210> 864]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 864]]> gggtccttct tcctggatac t 21 <![CDATA[<210> 865]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 865]]> ggtccttctt cctggatact c 21 <![CDATA[<210> 866]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 866]]> gtccttcttc ctggatactc a 21 <![CDATA[<210> 867]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 867]]> aagccaatca gtgtcgtcgc g 21 <![CDATA[<210> 868]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 868]]> aagaggacct gcgctcttgg a 21 <![CDATA[<210> 869]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 869]]> aagtgtgaga cagctgcctt g 21 <![CDATA[<210> 870]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 870]]> aaggcacctg catgtgtctg t 21 <![CDATA[<210> 871]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 871]]> aatcatcttt cctgttccag a 21 <![CDATA[<210> 872]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 872]]> aaaggcacct gcatgtgtct g 21 <![CDATA[<210> 873]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 873]]> aaagaggacc tgcgctcttg g 21 <![CDATA[<210> 874]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 874]]> aaacgcatat gactcaccac g 21 <![CDATA[<210> 875]]> <![CDATA[<211> 19]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 875]]> ggaagagctc agatagaaa 19 <![CDATA[<210> 876]]> <![CDATA[<211> 19]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 876]]> gggagacacg gaaagtgaa 19 <![CDATA[<210> 877]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 877]]> cacctgccat gtgcagcatg a 21 <![CDATA[<210> 878]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 878]]> ggagatcaca ctgacctggc a 21 <![CDATA[<210> 879]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 879]]> ggattacatc gccctgaaag 20 <![CDATA[<210> 880]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 880]]> gcaggagggt ccggagtatt 20 <![CDATA[<210> 881]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 881]]> ggacggggag acacggaaag 20 <![CDATA[<210> 882]]> <![CDATA[<211> 19]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 882]]> gaaagtgaag gcccactca 19 <![CDATA[<210> 883]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 883]]> gatacctgga gaacgggaag 20 <![CDATA[<210> 884]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 884]]> gctgtggtgg tgccttctgg 20 <![CDATA[<210> 885]]> <![CDATA[<211> 20]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 885]]> gctactacaa ccagagcgag 20 <![CDATA[<210> 886]]> <![CDATA[<211> 19]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 886]]> gtggctccgc agatacctg 19 <![CDATA[<210> 887]]> <![CDATA[<211> 19]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 887]]> gccaatcagt gtcgtcgcg 19 <![CDATA[<210> 888]]> <![CDATA[<211> 19]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 888]]> gaggacctgc gctcttgga 19 <![CDATA[<210> 889]]> <![CDATA[<211> 19]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 889]]> gtgtgagaca gctgccttg 19 <![CDATA[<210> 890]]> <![CDATA[<211> 19]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 890]]> ggcacctgca tgtgtctgt 19 <![CDATA[<210> 891]]> <![CDATA[<211> 19]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 891]]> tcatctttcc tgttccaga 19 <![CDATA[<210> 892]]> <![CDATA[<211> 19]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 892]]> aggcacctgc atgtgtctg 19 <![CDATA[<210> 893]]> <![CDATA[<211> 19]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 893]]> agaggacctg cgctcttgg 19 <![CDATA[<210> 894]]> <![CDATA[<211> 19]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 靶HLA序列補體]]> <![CDATA[<400> 894]]> acgcatatga ctcaccacg 19 <![CDATA[<210> 895]]> <![CDATA[<211> 2]]> <![CDATA[<212> RNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 5'側翼序列]]> <![CDATA[<400> 895]]> gg 2 <![CDATA[<210> 896]]> <![CDATA[<211> 23]]> <![CDATA[<212> RNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 5'側翼序列]]> <![CDATA[<400> 896]]> acaccauguu gccagucucu agg 23 <![CDATA[<210> 897]]> <![CDATA[<211> 23]]> <![CDATA[<212> RNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 5'側翼序列]]> <![CDATA[<400> 897]]> ugauagcaau gucagcagug ccu 23 <![CDATA[<210> 898]]> <![CDATA[<211> 23]]> <![CDATA[<212> RNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 5'側翼序列]]> <![CDATA[<400> 898]]> uauugcuguu gacagugagc gac 23 <![CDATA[<210> 899]]> <![CDATA[<211> 21]]> <![CDATA[<212> RNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 3'側翼序列]]> <![CDATA[<400> 899]]> uggcgucugg cccaaccaca c 21 <![CDATA[<210> 900]]> <![CDATA[<211> 21]]> <![CDATA[<212> RNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 3'側翼序列]]> <![CDATA[<400> 900]]> guaagguuga ccauacucua c 21 <![CDATA[<210> 901]]> <![CDATA[<211> 4]]> <![CDATA[<212> RNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 環區序列]]> <![CDATA[<400> 901]]> cgaa 4 <![CDATA[<210> 902]]> <![CDATA[<211> 7]]> <![CDATA[<212> RNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 環區序列]]> <![CDATA[<400> 902]]> uucaaga 7 <![CDATA[<210> 903]]> <![CDATA[<211> 7]]> <![CDATA[<212> RNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 環區序列]]> <![CDATA[<400> 903]]> auauuca 7 <![CDATA[<210> 904]]> <![CDATA[<211> 9]]> <![CDATA[<212> RNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 環區序列]]> <![CDATA[<400> 904]]> ugugcuguc 9 <![CDATA[<210> 905]]> <![CDATA[<211> 6]]> <![CDATA[<212> RNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 環區序列]]> <![CDATA[<400> 905]]> cucgag 6 <![CDATA[<210> 906]]> <![CDATA[<211> 12]]> <![CDATA[<212> RNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 環區序列]]> <![CDATA[<400> 906]]> cuuccuguca ga 12 <![CDATA[<210> 907]]> <![CDATA[<211> 15]]> <![CDATA[<212> RNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 環區序列]]> <![CDATA[<400> 907]]> cuucccuuug ucaga 15 <![CDATA[<210> 908]]> <![CDATA[<211> 12]]> <![CDATA[<212> RNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 環區序列]]> <![CDATA[<400> 908]]> guguuauucu ug 12 <![CDATA[<210> 909]]> <![CDATA[<211> 12]]> <![CDATA[<212> RNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 環區序列]]> <![CDATA[<400> 909]]> gugucuuaau ug 12 <![CDATA[<210> 910]]> <![CDATA[<211> 12]]> <![CDATA[<212> RNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 環區序列]]> <![CDATA[<400> 910]]> guguuagucu ug 12 <![CDATA[<210> 911]]> <![CDATA[<211> 7]]> <![CDATA[<212> RNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 環區序列]]> <![CDATA[<400> 911]]> ucaagag 7 <![CDATA[<210> 912]]> <![CDATA[<211> 12]]> <![CDATA[<212> RNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 環區序列]]> <![CDATA[<400> 912]]> ggacauccag gg 12 <![CDATA[<210> 913]]> <![CDATA[<211> 15]]> <![CDATA[<212> RNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 環區序列]]> <![CDATA[<400> 913]]> gugaagccac agaug 15 <![CDATA[<210> 914]]> <![CDATA[<211> 10]]> <![CDATA[<212> RNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 環區序列]]> <![CDATA[<400> 914]]> gauucuaaaa 10 <![CDATA[<210> 915]]> <![CDATA[<211> 518]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-A*11阻斷劑4]]> <![CDATA[<400> 915]]> Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp 1 5 10 15 Leu Arg Gly Ala Arg Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly 20 25 30 Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly 35 40 45 Phe Thr Phe Ser Ser Tyr Trp Met His Trp Val Arg Gln Ala Pro Gly 50 55 60 Lys Gly Leu Val Trp Val Ser Arg Ile Asn Ser Asp Gly Ser Ser Thr 65 70 75 80 Ser Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn 85 90 95 Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp 100 105 110 Thr Ala Val Tyr Tyr Cys Cys Leu Gly Val Leu Leu Tyr Asn Trp Phe 115 120 125 Asp Pro Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly 130 135 140 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Asp Ile 145 150 155 160 Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg 165 170 175 Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn 180 185 190 Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala 195 200 205 Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly 210 215 220 Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp 225 230 235 240 Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Leu Thr Phe 245 250 255 Gly Gly Gly Thr Lys Val Glu Ile Lys Tyr Gly Ser Gln Ser Ser Lys 260 265 270 Pro Tyr Leu Leu Thr His Pro Ser Asp Pro Leu Glu Leu Val Val Ser 275 280 285 Gly Pro Ser Gly Gly Pro Ser Ser Pro Thr Thr Gly Pro Thr Ser Thr 290 295 300 Ser Gly Pro Glu Asp Gln Pro Leu Thr Pro Thr Gly Ser Asp Pro Gln 305 310 315 320 Ser Gly Leu Gly Arg His Leu Gly Val Val Ile Gly Ile Leu Val Ala 325 330 335 Val Ile Leu Leu Leu Leu Leu Leu Leu Leu Leu Phe Leu Ile Leu Arg 340 345 350 His Arg Arg Gln Gly Lys His Trp Thr Ser Thr Gln Arg Lys Ala Asp 355 360 365 Phe Gln His Pro Ala Gly Ala Val Gly Pro Glu Pro Thr Asp Arg Gly 370 375 380 Leu Gln Trp Arg Ser Ser Pro Ala Ala Asp Ala Gln Glu Glu Asn Leu 385 390 395 400 Tyr Ala Ala Val Lys His Thr Gln Pro Glu Asp Gly Val Glu Met Asp 405 410 415 Thr Arg Ser Pro His Asp Glu Asp Pro Gln Ala Val Thr Tyr Ala Glu 420 425 430 Val Lys His Ser Arg Pro Arg Arg Glu Met Ala Ser Pro Pro Ser Pro 435 440 445 Leu Ser Gly Glu Phe Leu Asp Thr Lys Asp Arg Gln Ala Glu Glu Asp 450 455 460 Arg Gln Met Asp Thr Glu Ala Ala Ala Ser Glu Ala Pro Gln Asp Val 465 470 475 480 Thr Tyr Ala Gln Leu His Ser Leu Thr Leu Arg Arg Glu Ala Thr Glu 485 490 495 Pro Pro Pro Ser Gln Glu Gly Pro Ser Pro Ala Val Pro Ser Ile Tyr 500 505 510 Ala Thr Leu Ala Ile His 515 <![CDATA[<210> 916]]> <![CDATA[<211> 1554]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> HLA-A*11阻斷劑4]]> <![CDATA[<400> 916]]> atggacatga gggtccccgc tcagctcctg gggctcctgc tactctggct ccgaggtgcc 60 agatgtgaag tgcagctggt ggaaagcggc ggaggcctgg tgcagcctgg cggcagcctg 120 agactgtctt gcgccgccag cggcttcacc ttcagcagct actggatgca ctgggtccgc 180 caggcccctg gcaagggact ggtctgggtg tctcgaatca acagcgacgg cagcagcacc 240 agctacgccg acagcgtgaa gggccggttc accatcagcc gggacaacgc caagaacacc 300 ctgtacctgc agatgaacag cctgcgggcc gaggacaccg ccgtgtatta ctgttgtttg 360 ggtgttttat tatacaactg gttcgacccc tggggccagg gaaccctggt caccgtgtcc 420 tcaggcggag gtggaagcgg agggggagga tctggcggcg gaggaagcgg aggcgacatc 480 cagatgaccc agtctccatc ctccctgtct gcatctgtag gagacagagt caccatcact 540 tgccgggcaa gtcagagcat tagcagctat ttaaattggt atcagcagaa accagggaaa 600 gcccctaagc tcctgatcta tgctgcatcc agtttgcaaa gtggggtccc atcaaggttc 660 agtggcagtg gatctgggac agatttcact ctcaccatca gcagtctgca acctgaagat 720 tttgcaactt actactgtca acagagttac agtacccctc tcactttcgg cggcggaaca 780 aaggtggaga tcaagtacgg ctcacagagc tccaaaccct acctgctgac tcaccccagt 840 gaccccctgg agctcgtggt ctcaggaccg tctgggggcc ccagctcccc gacaacaggc 900 cccacctcca catctggccc tgaggaccag cccctcaccc ccaccgggtc ggatccccag 960 agtggtctgg gaaggcacct gggggttgtg atcggcatct tggtggccgt catcctactg 1020 ctcctcctcc tcctcctcct cttcctcatc ctccgacatc gacgtcaggg caaacactgg 1080 acatcgaccc agagaaaggc tgatttccaa catcctgcag gggctgtggg gccagagccc 1140 acagacagag gcctgcagtg gaggtccagc ccagctgccg atgcccagga agaaaacctc 1200 tatgctgccg tgaagcacac acagcctgag gatggggtgg agatggacac tcggagccca 1260 cacgatgaag acccccaggc agtgacgtat gccgaggtga aacactccag acctaggaga 1320 gaaatggcct ctcctccttc cccactgtct ggggaattcc tggacacaaa ggacagacag 1380 gcggaagagg acaggcagat ggacactgag gctgctgcat ctgaagcccc ccaggatgtg 1440 acctacgccc agctgcacag cttgaccctc agacgggagg caactgagcc tcctccatcc 1500 caggaagggc cctctccagc tgtgcccagc atctacgcca ctctggccat ccac 1554 <![CDATA[<210> 917]]> <![CDATA[<211> 66]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列(Artificial Sequence)]]> <![CDATA[<220>]]> <![CDATA[<223> 信號序列]]> <![CDATA[<400> 917]]> atggatatga gagtgcctgc ccagctgctc ggactgctcc ttctgtggtt gagaggagct 60 cggtgc 66 <![CDATA[<210> 918]]> <![CDATA[<211> 1210]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人(Homo sapiens)]]> <![CDATA[<400> 918]]> Met Arg Pro Ser Gly Thr Ala Gly Ala Ala Leu Leu Ala Leu Leu Ala 1 5 10 15 Ala Leu Cys Pro Ala Ser Arg Ala Leu Glu Glu Lys Lys Val Cys Gln 20 25 30 Gly Thr Ser Asn Lys Leu Thr Gln Leu Gly Thr Phe Glu Asp His Phe 35 40 45 Leu Ser Leu Gln Arg Met Phe Asn Asn Cys Glu Val Val Leu Gly Asn 50 55 60 Leu Glu Ile Thr Tyr Val Gln Arg Asn Tyr Asp Leu Ser Phe Leu Lys 65 70 75 80 Thr Ile Gln Glu Val Ala Gly Tyr Val Leu Ile Ala Leu Asn Thr Val 85 90 95 Glu Arg Ile Pro Leu Glu Asn Leu Gln Ile Ile Arg Gly Asn Met Tyr 100 105 110 Tyr Glu Asn Ser Tyr Ala Leu Ala Val Leu Ser Asn Tyr Asp Ala Asn 115 120 125 Lys Thr Gly Leu Lys Glu Leu Pro Met Arg Asn Leu Gln Glu Ile Leu 130 135 140 His Gly Ala Val Arg Phe Ser Asn Asn Pro Ala Leu Cys Asn Val Glu 145 150 155 160 Ser Ile Gln Trp Arg Asp Ile Val Ser Ser Asp Phe Leu Ser Asn Met 165 170 175 Ser Met Asp Phe Gln Asn His Leu Gly Ser Cys Gln Lys Cys Asp Pro 180 185 190 Ser Cys Pro Asn Gly Ser Cys Trp Gly Ala Gly Glu Glu Asn Cys Gln 195 200 205 Lys Leu Thr Lys Ile Ile Cys Ala Gln Gln Cys Ser Gly Arg Cys Arg 210 215 220 Gly Lys Ser Pro Ser Asp Cys Cys His Asn Gln Cys Ala Ala Gly Cys 225 230 235 240 Thr Gly Pro Arg Glu Ser Asp Cys Leu Val Cys Arg Lys Phe Arg Asp 245 250 255 Glu Ala Thr Cys Lys Asp Thr Cys Pro Pro Leu Met Leu Tyr Asn Pro 260 265 270 Thr Thr Tyr Gln Met Asp Val Asn Pro Glu Gly Lys Tyr Ser Phe Gly 275 280 285 Ala Thr Cys Val Lys Lys Cys Pro Arg Asn Tyr Val Val Thr Asp His 290 295 300 Gly Ser Cys Val Arg Ala Cys Gly Ala Asp Ser Tyr Glu Met Glu Glu 305 310 315 320 Asp Gly Val Arg Lys Cys Lys Lys Cys Glu Gly Pro Cys Arg Lys Val 325 330 335 Cys Asn Gly Ile Gly Ile Gly Glu Phe Lys Asp Ser Leu Ser Ile Asn 340 345 350 Ala Thr Asn Ile Lys His Phe Lys Asn Cys Thr Ser Ile Ser Gly Asp 355 360 365 Leu His Ile Leu Pro Val Ala Phe Arg Gly Asp Ser Phe Thr His Thr 370 375 380 Pro Pro Leu Asp Pro Gln Glu Leu Asp Ile Leu Lys Thr Val Lys Glu 385 390 395 400 Ile Thr Gly Phe Leu Leu Ile Gln Ala Trp Pro Glu Asn Arg Thr Asp 405 410 415 Leu His Ala Phe Glu Asn Leu Glu Ile Ile Arg Gly Arg Thr Lys Gln 420 425 430 His Gly Gln Phe Ser Leu Ala Val Val Ser Leu Asn Ile Thr Ser Leu 435 440 445 Gly Leu Arg Ser Leu Lys Glu Ile Ser Asp Gly Asp Val Ile Ile Ser 450 455 460 Gly Asn Lys Asn Leu Cys Tyr Ala Asn Thr Ile Asn Trp Lys Lys Leu 465 470 475 480 Phe Gly Thr Ser Gly Gln Lys Thr Lys Ile Ile Arg Asn Arg Gly Glu 485 490 495 Asn Ser Cys Lys Ala Thr Gly Gln Val Cys His Ala Leu Cys Ser Pro 500 505 510 Glu Gly Cys Trp Gly Pro Glu Pro Arg Asp Cys Val Ser Cys Arg Asn 515 520 525 Val Ser Arg Gly Arg Glu Cys Val Asp Lys Cys Asn Leu Leu Glu Gly 530 535 540 Glu Pro Arg Glu Phe Val Glu Asn Ser Glu Cys Ile Gln Cys His Pro 545 550 555 560 Glu Cys Leu Pro Gln Ala Met Asn Ile Thr Cys Thr Gly Arg Gly Pro 565 570 575 Asp Asn Cys Ile Gln Cys Ala His Tyr Ile Asp Gly Pro His Cys Val 580 585 590 Lys Thr Cys Pro Ala Gly Val Met Gly Glu Asn Asn Thr Leu Val Trp 595 600 605 Lys Tyr Ala Asp Ala Gly His Val Cys His Leu Cys His Pro Asn Cys 610 615 620 Thr Tyr Gly Cys Thr Gly Pro Gly Leu Glu Gly Cys Pro Thr Asn Gly 625 630 635 640 Pro Lys Ile Pro Ser Ile Ala Thr Gly Met Val Gly Ala Leu Leu Leu 645 650 655 Leu Leu Val Val Ala Leu Gly Ile Gly Leu Phe Met Arg Arg Arg His 660 665 670 Ile Val Arg Lys Arg Thr Leu Arg Arg Leu Leu Gln Glu Arg Glu Leu 675 680 685 Val Glu Pro Leu Thr Pro Ser Gly Glu Ala Pro Asn Gln Ala Leu Leu 690 695 700 Arg Ile Leu Lys Glu Thr Glu Phe Lys Lys Ile Lys Val Leu Gly Ser 705 710 715 720 Gly Ala Phe Gly Thr Val Tyr Lys Gly Leu Trp Ile Pro Glu Gly Glu 725 730 735 Lys Val Lys Ile Pro Val Ala Ile Lys Glu Leu Arg Glu Ala Thr Ser 740 745 750 Pro Lys Ala Asn Lys Glu Ile Leu Asp Glu Ala Tyr Val Met Ala Ser 755 760 765 Val Asp Asn Pro His Val Cys Arg Leu Leu Gly Ile Cys Leu Thr Ser 770 775 780 Thr Val Gln Leu Ile Thr Gln Leu Met Pro Phe Gly Cys Leu Leu Asp 785 790 795 800 Tyr Val Arg Glu His Lys Asp Asn Ile Gly Ser Gln Tyr Leu Leu Asn 805 810 815 Trp Cys Val Gln Ile Ala Lys Gly Met Asn Tyr Leu Glu Asp Arg Arg 820 825 830 Leu Val His Arg Asp Leu Ala Ala Arg Asn Val Leu Val Lys Thr Pro 835 840 845 Gln His Val Lys Ile Thr Asp Phe Gly Leu Ala Lys Leu Leu Gly Ala 850 855 860 Glu Glu Lys Glu Tyr His Ala Glu Gly Gly Lys Val Pro Ile Lys Trp 865 870 875 880 Met Ala Leu Glu Ser Ile Leu His Arg Ile Tyr Thr His Gln Ser Asp 885 890 895 Val Trp Ser Tyr Gly Val Thr Val Trp Glu Leu Met Thr Phe Gly Ser 900 905 910 Lys Pro Tyr Asp Gly Ile Pro Ala Ser Glu Ile Ser Ser Ile Leu Glu 915 920 925 Lys Gly Glu Arg Leu Pro Gln Pro Pro Ile Cys Thr Ile Asp Val Tyr 930 935 940 Met Ile Met Val Lys Cys Trp Met Ile Asp Ala Asp Ser Arg Pro Lys 945 950 955 960 Phe Arg Glu Leu Ile Ile Glu Phe Ser Lys Met Ala Arg Asp Pro Gln 965 970 975 Arg Tyr Leu Val Ile Gln Gly Asp Glu Arg Met His Leu Pro Ser Pro 980 985 990 Thr Asp Ser Asn Phe Tyr Arg Ala Leu Met Asp Glu Glu Asp Met Asp 995 1000 1005 Asp Val Val Asp Ala Asp Glu Tyr Leu Ile Pro Gln Gln Gly Phe 1010 1015 1020 Phe Ser Ser Pro Ser Thr Ser Arg Thr Pro Leu Leu Ser Ser Leu 1025 1030 1035 Ser Ala Thr Ser Asn Asn Ser Thr Val Ala Cys Ile Asp Arg Asn 1040 1045 1050 Gly Leu Gln Ser Cys Pro Ile Lys Glu Asp Ser Phe Leu Gln Arg 1055 1060 1065 Tyr Ser Ser Asp Pro Thr Gly Ala Leu Thr Glu Asp Ser Ile Asp 1070 1075 1080 Asp Thr Phe Leu Pro Val Pro Glu Tyr Ile Asn Gln Ser Val Pro 1085 1090 1095 Lys Arg Pro Ala Gly Ser Val Gln Asn Pro Val Tyr His Asn Gln 1100 1105 1110 Pro Leu Asn Pro Ala Pro Ser Arg Asp Pro His Tyr Gln Asp Pro 1115 1120 1125 His Ser Thr Ala Val Gly Asn Pro Glu Tyr Leu Asn Thr Val Gln 1130 1135 1140 Pro Thr Cys Val Asn Ser Thr Phe Asp Ser Pro Ala His Trp Ala 1145 1150 1155 Gln Lys Gly Ser His Gln Ile Ser Leu Asp Asn Pro Asp Tyr Gln 1160 1165 1170 Gln Asp Phe Phe Pro Lys Glu Ala Lys Pro Asn Gly Ile Phe Lys 1175 1180 1185 Gly Ser Thr Ala Glu Asn Ala Glu Tyr Leu Arg Val Ala Pro Gln 1190 1195 1200 Ser Ser Glu Phe Ile Gly Ala 1205 1210 <![CDATA[<210> 919]]> <![CDATA[<211> 1210]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人(Homo sapiens)]]> <![CDATA[<400> 919]]> Met Arg Pro Ser Gly Thr Ala Gly Ala Ala Leu Leu Ala Leu Leu Ala 1 5 10 15 Ala Leu Cys Pro Ala Ser Arg Ala Leu Glu Glu Lys Lys Val Cys Gln 20 25 30 Gly Thr Ser Asn Lys Leu Thr Gln Leu Gly Thr Phe Glu Asp His Phe 35 40 45 Leu Ser Leu Gln Arg Met Phe Asn Asn Cys Glu Val Val Leu Gly Asn 50 55 60 Leu Glu Ile Thr Tyr Val Gln Arg Asn Tyr Asp Leu Ser Phe Leu Lys 65 70 75 80 Thr Ile Gln Glu Val Ala Gly Tyr Val Leu Ile Ala Leu Asn Thr Val 85 90 95 Glu Arg Ile Pro Leu Glu Asn Leu Gln Ile Ile Arg Gly Asn Met Tyr 100 105 110 Tyr Glu Asn Ser Tyr Ala Leu Ala Val Leu Ser Asn Tyr Asp Ala Asn 115 120 125 Lys Thr Gly Leu Lys Glu Leu Pro Met Arg Asn Leu Gln Glu Ile Leu 130 135 140 His Gly Ala Val Arg Phe Ser Asn Asn Pro Ala Leu Cys Asn Val Glu 145 150 155 160 Ser Ile Gln Trp Arg Asp Ile Val Ser Ser Asp Phe Leu Ser Asn Met 165 170 175 Ser Met Asp Phe Gln Asn His Leu Gly Ser Cys Gln Lys Cys Asp Pro 180 185 190 Ser Cys Pro Asn Gly Ser Cys Trp Gly Ala Gly Glu Glu Asn Cys Gln 195 200 205 Lys Leu Thr Lys Ile Ile Cys Ala Gln Gln Cys Ser Gly Arg Cys Arg 210 215 220 Gly Lys Ser Pro Ser Asp Cys Cys His Asn Gln Cys Ala Ala Gly Cys 225 230 235 240 Thr Gly Pro Arg Glu Ser Asp Cys Leu Val Cys Arg Lys Phe Arg Asp 245 250 255 Glu Ala Thr Cys Lys Asp Thr Cys Pro Pro Leu Met Leu Tyr Asn Pro 260 265 270 Thr Thr Tyr Gln Met Asp Val Asn Pro Glu Gly Lys Tyr Ser Phe Gly 275 280 285 Ala Thr Cys Val Lys Lys Cys Pro Arg Asn Tyr Val Val Thr Asp His 290 295 300 Gly Ser Cys Val Arg Ala Cys Gly Ala Asp Ser Tyr Glu Met Glu Glu 305 310 315 320 Asp Gly Val Arg Lys Cys Lys Lys Cys Glu Gly Pro Cys Arg Lys Val 325 330 335 Cys Asn Gly Ile Gly Ile Gly Glu Phe Lys Asp Ser Leu Ser Ile Asn 340 345 350 Ala Thr Asn Ile Lys His Phe Lys Asn Cys Thr Ser Ile Ser Gly Asp 355 360 365 Leu His Ile Leu Pro Val Ala Phe Arg Gly Asp Ser Phe Thr His Thr 370 375 380 Pro Pro Leu Asp Pro Gln Glu Leu Asp Ile Leu Lys Thr Val Lys Glu 385 390 395 400 Ile Thr Gly Phe Leu Leu Ile Gln Ala Trp Pro Glu Asn Arg Thr Asp 405 410 415 Leu His Ala Phe Glu Asn Leu Glu Ile Ile Arg Gly Arg Thr Lys Gln 420 425 430 His Gly Gln Phe Ser Leu Ala Val Val Ser Leu Asn Ile Thr Ser Leu 435 440 445 Gly Leu Arg Ser Leu Lys Glu Ile Ser Asp Gly Asp Val Ile Ile Ser 450 455 460 Gly Asn Lys Asn Leu Cys Tyr Ala Asn Thr Ile Asn Trp Lys Lys Leu 465 470 475 480 Phe Gly Thr Ser Gly Gln Lys Thr Lys Ile Ile Arg Asn Arg Gly Glu 485 490 495 Asn Ser Cys Lys Ala Thr Gly Gln Val Cys His Ala Leu Cys Ser Pro 500 505 510 Glu Gly Cys Trp Gly Pro Glu Pro Arg Asp Cys Val Ser Cys Arg Asn 515 520 525 Val Ser Arg Gly Arg Glu Cys Val Asp Lys Cys Asn Leu Leu Glu Gly 530 535 540 Glu Pro Arg Glu Phe Val Glu Asn Ser Glu Cys Ile Gln Cys His Pro 545 550 555 560 Glu Cys Leu Pro Gln Ala Met Asn Ile Thr Cys Thr Gly Arg Gly Pro 565 570 575 Asp Asn Cys Ile Gln Cys Ala His Tyr Ile Asp Gly Pro His Cys Val 580 585 590 Lys Thr Cys Pro Ala Gly Val Met Gly Glu Asn Asn Thr Leu Val Trp 595 600 605 Lys Tyr Ala Asp Ala Gly His Val Cys His Leu Cys His Pro Asn Cys 610 615 620 Thr Tyr Gly Cys Thr Gly Pro Gly Leu Glu Gly Cys Pro Thr Asn Gly 625 630 635 640 Pro Lys Ile Pro Ser Ile Ala Thr Gly Met Val Gly Ala Leu Leu Leu 645 650 655 Leu Leu Val Val Ala Leu Gly Ile Gly Leu Phe Met Arg Arg Arg His 660 665 670 Ile Val Arg Lys Arg Thr Leu Arg Arg Leu Leu Gln Glu Arg Glu Leu 675 680 685 Val Glu Pro Leu Thr Pro Ser Gly Glu Ala Pro Asn Gln Ala Leu Leu 690 695 700 Arg Ile Leu Lys Glu Thr Glu Phe Lys Lys Ile Lys Val Leu Gly Ser 705 710 715 720 Gly Ala Phe Gly Thr Val Tyr Lys Gly Leu Trp Ile Pro Glu Gly Glu 725 730 735 Lys Val Lys Ile Pro Val Ala Ile Lys Glu Leu Arg Glu Ala Thr Ser 740 745 750 Pro Lys Ala Asn Lys Glu Ile Leu Asp Glu Ala Tyr Val Met Ala Ser 755 760 765 Val Asp Asn Pro His Val Cys Arg Leu Leu Gly Ile Cys Leu Thr Ser 770 775 780 Thr Val Gln Leu Ile Thr Gln Leu Met Pro Phe Gly Cys Leu Leu Asp 785 790 795 800 Tyr Val Arg Glu His Lys Asp Asn Ile Gly Ser Gln Tyr Leu Leu Asn 805 810 815 Trp Cys Val Gln Ile Ala Lys Gly Met Asn Tyr Leu Glu Asp Arg Arg 820 825 830 Leu Val His Arg Asp Leu Ala Ala Arg Asn Val Leu Val Lys Thr Pro 835 840 845 Gln His Val Lys Ile Thr Asp Phe Gly Leu Ala Lys Leu Leu Gly Ala 850 855 860 Glu Glu Lys Glu Tyr His Ala Glu Gly Gly Lys Val Pro Ile Lys Trp 865 870 875 880 Met Ala Leu Glu Ser Ile Leu His Arg Ile Tyr Thr His Gln Ser Asp 885 890 895 Val Trp Ser Tyr Gly Val Thr Val Trp Glu Leu Met Thr Phe Gly Ser 900 905 910 Lys Pro Tyr Asp Gly Ile Pro Ala Ser Glu Ile Ser Ser Ile Leu Glu 915 920 925 Lys Gly Glu Arg Leu Pro Gln Pro Pro Ile Cys Thr Ile Asp Val Tyr 930 935 940 Met Ile Met Val Lys Cys Trp Met Ile Asp Ala Asp Ser Arg Pro Lys 945 950 955 960 Phe Arg Glu Leu Ile Ile Glu Phe Ser Lys Met Ala Arg Asp Pro Gln 965 970 975 Arg Tyr Leu Val Ile Gln Gly Asp Glu Arg Met His Leu Pro Ser Pro 980 985 990 Thr Asp Ser Asn Phe Tyr Arg Ala Leu Met Asp Glu Glu Asp Met Asp 995 1000 1005 Asp Val Val Asp Ala Asp Glu Tyr Leu Ile Pro Gln Gln Gly Phe 1010 1015 1020 Phe Ser Ser Pro Ser Thr Ser Arg Thr Pro Leu Leu Ser Ser Leu 1025 1030 1035 Ser Ala Thr Ser Asn Asn Ser Thr Val Ala Cys Ile Asp Arg Asn 1040 1045 1050 Gly Leu Gln Ser Cys Pro Ile Lys Glu Asp Ser Phe Leu Gln Arg 1055 1060 1065 Tyr Ser Ser Asp Pro Thr Gly Ala Leu Thr Glu Asp Ser Ile Asp 1070 1075 1080 Asp Thr Phe Leu Pro Val Pro Glu Tyr Ile Asn Gln Ser Val Pro 1085 1090 1095 Lys Arg Pro Ala Gly Ser Val Gln Asn Pro Val Tyr His Asn Gln 1100 1105 1110 Pro Leu Asn Pro Ala Pro Ser Arg Asp Pro His Tyr Gln Asp Pro 1115 1120 1125 His Ser Thr Ala Val Gly Asn Pro Glu Tyr Leu Asn Thr Val Gln 1130 1135 1140 Pro Thr Cys Val Asn Ser Thr Phe Asp Ser Pro Ala His Trp Ala 1145 1150 1155 Gln Lys Gly Ser His Gln Ile Ser Leu Asp Asn Pro Asp Tyr Gln 1160 1165 1170 Gln Asp Phe Phe Pro Lys Glu Ala Lys Pro Asn Gly Ile Phe Lys 1175 1180 1185 Gly Ser Thr Ala Glu Asn Ala Glu Tyr Leu Arg Val Ala Pro Gln 1190 1195 1200 Ser Ser Glu Phe Ile Gly Ala 1205 1210
Claims (87)
- 一種免疫細胞,該免疫細胞包含: a. 第一受體,其包含對表皮生長因子受體(EGFR)具有特異性之細胞外配位體結合結構域;及 b. 第二受體,其包含對由於雜合性損失而在EGFR+癌症中損失之非靶抗原具有特異性之細胞外配位體結合結構域, 其中該第一受體為對EGFR有反應之活化劑受體;且其中該第二受體為對該非靶抗原有反應之抑制性受體。
- 如請求項1之免疫細胞,其中該第二受體之該細胞外配位體結合結構域特異性結合MHC蛋白之對偶基因變異體。
- 如請求項1之免疫細胞,其中該第二受體之該細胞外配位體結合結構域特異性結合HLA-A、HLA-B或HLA-C蛋白之對偶基因變異體。
- 如請求項1之免疫細胞,其中該第二受體之該細胞外配位體結合結構域特異性結合HLA-A*02。
- 如請求項1之免疫細胞,其中該第二受體之該細胞外配位體結合結構域特異性結合 HLA-A*01、HLA-A*03、HLA-A*11、HLA-C*07或HLA-B*07。
- 如請求項3至5中任一項之免疫細胞,其中該第二受體之該細胞外配位體結合結構域包含如表5所揭示之互補決定區(CDR) CDR-L1、CDR-L2、CDR-L3、CDR-H1、CDR-H2、CDR-H3;或相對於表5之該等CDR具有至多1個、2個或3個取代、缺失或插入之CDR序列。
- 如請求項3至5中任一項之免疫細胞,其中該第二受體之該細胞外配位體結合結構域包含SEQ ID NO: 101-106或SEQ ID NO: 106-112之互補決定區(CDR) CDR-L1、CDR-L2、CDR-L3、CDR-H1、CDR-H2、CDR-H3;或相對於表5之該等CDR具有至多1個、2個或3個取代、缺失或插入之CDR序列。
- 如請求項3至5中任一項之免疫細胞,其中該第二受體之該細胞外配位體結合結構域包含選自表4中所揭示之多肽序列的多肽序列;或與其具有至少85%、至少90%、至少95%、至少97%或至少99%一致性之序列。
- 如請求項4之免疫細胞,其中該第二受體之該細胞外配位體結合結構域包含SEQ ID NO: 89-100中之任一者;或與其具有至少85%、至少90%、至少95%、至少97%或至少99%一致性之序列。
- 如請求項1至9中任一項之免疫細胞,其中該第一受體為嵌合抗原受體(CAR)。
- 如請求項1至10中任一項之免疫細胞,其中該第一受體之該細胞外配位體結合結構域包含可變重(VH)部分,其包含選自表3所列之序列之群的一組重鏈互補決定區(HC-CDR);及/或可變輕(VL)部分,其包含來自表3中所列之序列之群的一組輕鏈互補決定區(LC-CDR);或在各CDR中具有至多1個、2個、3個、4個取代、插入或缺失之CDR序列。
- 如請求項1至11中任一項之免疫細胞,其中該第一受體之該細胞外配位體結合結構域包含具有選自表2中所列之VH序列之序列的可變重(VH)部分;及/或包含表2中所列之序列的可變輕(VL)部分;或與其具有至少70%、至少85%、至少90%或至少95%一致性之序列。
- 如請求項1至12中任一項之免疫細胞,其中該第一受體之該細胞外配位體結合結構域包含選自表1中所列之序列之群的序列;或與其具有至少85%、至少90%、至少95%、至少97%或至少99%一致性之序列。
- 如請求項1至13中任一項之免疫細胞,其中該第一受體之該細胞外配位體結合結構域包含選自由SEQ ID NO: 9-18組成之群的scFv序列;或與其具有至少85%、至少90%、至少95%、至少97%或至少99%一致性之序列。
- 如請求項1至14中任一項之免疫細胞,其中該第二受體包含LILRB1細胞內結構域或其功能變異體。
- 如請求項15之免疫細胞,其中該LILRB1細胞內結構域包含與SEQ ID NO: 129至少90%、至少95%、至少97%、至少99%或一致之序列。
- 如請求項1至16中任一項之免疫細胞,其中該第二受體包含LILRB1跨膜結構域或其功能變異體。
- 如請求項17之免疫細胞,其中該LILRB1跨膜結構域或其功能變異體包含與SEQ ID NO: 133至少90%、至少95%、至少97%、至少99%或一致之序列。
- 如請求項1至18中任一項之免疫細胞,其中該第二受體包含LILRB1鉸鏈結構域或其功能變異體。
- 如請求項19之免疫細胞,其中該LILRB1鉸鏈結構域包含與SEQ ID NO: 132、SEQ ID NO: 125、SEQ ID NO: 126至少90%、至少95%、至少97%、至少99%或一致之序列。
- 如請求項1至20中任一項之免疫細胞,其中該第二受體包含LILRB1細胞內結構域、LILRB1跨膜結構域、LILRB1鉸鏈結構域、此等中之任一者之功能變異體,或其組合。
- 如請求項21之免疫細胞,其中該LILRB1細胞內結構域及該LILRB1跨膜結構域包含SEQ ID NO: 128或與SEQ ID NO: 128至少95%一致之序列。
- 如請求項1至22中任一項之免疫細胞,其中該EGFR+癌細胞為肺癌細胞、小細胞肺癌細胞、非小細胞肺癌細胞、胰管癌細胞、結腸直腸癌細胞、頭頸癌細胞、食道及胃腺癌細胞、卵巢癌細胞、多形性神經膠質母細胞瘤細胞、子宮頸鱗狀細胞癌細胞、腎癌細胞、乳頭狀腎癌細胞、腎臟腎透明細胞癌細胞、膀胱癌細胞、乳癌細胞、膽管癌細胞、肝癌細胞、前列腺癌細胞、肉瘤細胞、甲狀腺癌細胞、胸腺癌細胞、胃癌細胞或子宮癌細胞。
- 如請求項23之免疫細胞,其中該EGFR+癌細胞為肺癌細胞。
- 如請求項1至24中任一項之免疫細胞,其中該EGFR+癌細胞為不表現HLA-A*02之EGFR+/HLA-A*02-癌細胞;或不表現HLA-A*02之來源於HLA-A*02+個體之癌細胞。
- 如請求項25之免疫細胞,其中該EGFR+/HLA-A*02-癌細胞藉由在HLA-A處雜合性損失,導致HLA-A*02損失而來源於EGFR+/HLA-A*02+細胞。
- 如請求項1至26中任一項之免疫細胞,其中該第一受體及該第二受體在具有雜合性損失之該EGFR/HLA-A*02-癌細胞存在下一起特異性活化該免疫細胞。
- 如請求項1至27中任一項之免疫細胞,其中該第一受體及該第二受體在未因雜合性損失而損失HLA-A*02之EGFR+細胞存在下一起不特異性活化該免疫細胞。
- 如請求項1至28中任一項之免疫細胞,其中該免疫細胞為T細胞、巨噬細胞、NK細胞、iNKT細胞或γδ T細胞。
- 如請求項29之免疫細胞,其中該T細胞為CD8+ CD4- T細胞。
- 如請求項1至30中任一項之免疫細胞,其中MHC I類基因之表現及/或功能已降低或消除。
- 如請求項30之免疫細胞,其中該MHC I類基因為β-2-微球蛋白(B2M)。
- 如請求項32之免疫細胞,該免疫細胞進一步包含含有干擾RNA之多核苷酸,該干擾RNA包含與B2M mRNA (SEQ ID NO: 172)之序列互補之序列。
- 如請求項33之免疫細胞,其中該干擾RNA能夠誘導RNAi介導之該B2M mRNA之降解。
- 如請求項33之免疫細胞,其中該干擾RNA為短髮夾RNA (shRNA)。
- 如請求項35之免疫細胞,其中該shRNA包含: a. 第一序列,其自5'末端至3'末端具有與該B2M mRNA之序列互補之序列;及 b. 第二序列,其自5'末端至3'末端具有與該第一序列互補之序列, 其中該第一序列及該第二序列形成該shRNA。
- 如請求項32之免疫細胞,該免疫細胞包含對編碼B2M之序列(SEQ ID NO: 170)的一或多個修飾,其中該一或多個修飾降低B2M之表現及/或消除B2M之功能。
- 如請求項37之免疫細胞,其中該一或多個修飾包括編碼B2M之內源基因的一或多個失活突變。
- 如請求項38之免疫細胞,其中該一或多個失活突變包括缺失、插入、取代或框移突變。
- 如請求項38至39中任一項之免疫細胞,其中用核酸引導之核酸內切酶與特異性靶向該編碼B2M之內源基因之序列(SEQ ID NO: 170)的至少一個嚮導核酸(gNA)復合來引入該一或多個失活突變。
- 如請求項31之免疫細胞,其中該MHC I類基因為HLA-A*02。
- 如請求項41之免疫細胞,該免疫細胞進一步包含含有干擾RNA之多核苷酸,該干擾RNA包含與HLA-A*02 mRNA (SEQ ID NO: 171)之序列互補之序列。
- 如請求項42之免疫細胞,其中該干擾RNA能夠誘導RNA干擾(RNAi)介導之該HLA-A*02 mRNA之降解。
- 如請求項43之免疫細胞,其中該干擾RNA為包含以下之短髮夾RNA (shRNA): a. 第一序列,其自5'末端至3'末端具有與該HLA-A*02 mRNA之序列互補之序列;及 b. 第二序列,其自5'末端至3'末端具有與該第一序列互補之序列, 其中該第一序列及該第二序列形成該shRNA。
- 如請求項41之免疫細胞,該免疫細胞包含對編碼HLA-A*02之內源基因之序列(SEQ ID NO: 169)的一或多個修飾,其中該一或多個修飾降低HLA-A*02之表現及/或消除HLA-A*02之功能。
- 如請求項45之免疫細胞,其中該一或多個修飾包括該編碼HLA-A*02之內源基因的一或多個失活突變。
- 如請求項45或請求項46之免疫細胞,其中用核酸引導之核酸內切酶與特異性靶向該編碼HLA-A*02之內源基因之序列的至少一個嚮導核酸(gNA)復合來引入該一或多個失活突變。
- 如請求項1之免疫細胞,其中: a. 該第一受體包含SEQ ID NO: 177,或與其共享至少75%、至少80%、至少85%、至少90%、至少95%或至少98%一致性之序列;及 b. 該第二受體包含SEQ ID NO: 174,或與其共享至少75%、至少80%、至少85%、至少90%、至少95%或至少98%一致性之序列。
- 如請求項1之免疫細胞,其中: a. 該第一受體包含SEQ ID NO: 177,或與其共享至少75%、至少80%、至少85%、至少90%、至少95%或至少98%一致性之序列;及 b. 該第二受體包含SEQ ID NO: 173,或與其共享至少75%、至少80%、至少85%、至少90%、至少95%或至少98%一致性之序列。
- 如請求項1之免疫細胞,其中: a. 該第一受體包含SEQ ID NO: 175,或與其共享至少75%、至少80%、至少85%、至少90%、至少95%或至少98%一致性之序列;及 b. 該第二受體包含SEQ ID NO: 174,或與其共享至少75%、至少80%、至少85%、至少90%、至少95%或至少98%一致性之序列。
- 如請求項1之免疫細胞,其中: a. 該第一受體包含SEQ ID NO: 175,或與其共享至少75%、至少80%、至少85%、至少90%、至少95%或至少98%一致性之序列;及 b. 該第二受體包含SEQ ID NO: 173,或與其共享至少75%、至少80%、至少85%、至少90%、至少95%或至少98%一致性之序列。
- 如請求項1之免疫細胞,其中: a. 該第一受體包含SEQ ID NO: 176,或與其共享至少75%、至少80%、至少85%、至少90%、至少95%或至少98%一致性之序列;及 b. 該第二受體包含SEQ ID NO: 173,或與其共享至少75%、至少80%、至少85%、至少90%、至少95%或至少98%一致性之序列。
- 如請求項1之免疫細胞,其中: a. 該第一受體包含SEQ ID NO: 176,或與其共享至少75%、至少80%、至少85%、至少90%、至少95%或至少98%一致性之序列;及 b. 該第二受體包含SEQ ID NO: 173,或與其共享至少75%、至少80%、至少85%、至少90%、至少95%或至少98%一致性之序列。
- 如請求項48至53中任一項之免疫細胞,該免疫細胞進一步包含T2A自裂解肽,其中該T2A自裂解肽包含SEQ ID NO: 178,或與其共享至少75%、至少80%、至少85%、至少90%、至少95%或至少98%一致性之序列。
- 如請求項48至54中任一項之免疫細胞,該免疫細胞進一步包含干擾RNA,其中該干擾RNA包含SEQ ID NO: 179,或與其共享至少75%、至少80%、至少85%、至少90%、至少95%或至少98%一致性之序列。
- 如請求項1至55中任一項之免疫細胞,其中該免疫細胞為自體的。
- 如請求項1至55中任一項之免疫細胞,其中該免疫細胞為同種異體的。
- 一種醫藥組合物,該醫藥組合物包含治療有效量之如請求項1至57中任一項之免疫細胞。
- 如請求項58之醫藥組合物,其中該免疫細胞表現該第一受體及該第二受體兩者。
- 如請求項59之醫藥組合物,其中至少約50%、約55%、約60%、約65%、約70%、約75%、約80%、約85%、約90%或約95%之該等免疫細胞表現該第一受體及該第二受體兩者。
- 如請求項59之醫藥組合物,其中至少90%之該等免疫細胞表現該第一受體及該第二受體兩者。
- 如請求項58至61中任一項之醫藥組合物,該醫藥組合物進一步包含醫藥學上可接受之載劑、稀釋劑或賦形劑。
- 如請求項58至62中任一項之醫藥組合物,該醫藥組合物係用作治療EGFR+癌症之藥劑。
- 一種多核苷酸或多核苷酸系統,該多核苷酸或多核苷酸系統包含含有編碼以下之多核苷酸序列之一或多個多核苷酸: a. 第一受體,其包含對內皮生長因子受體(EGFR)具有特異性之細胞外配位體結合結構域;及 b. 第二受體,其包含對由於雜合性損失而在EGFR+癌細胞中已損失之非靶抗原具有特異性之細胞外配位體結合結構域, 其中該第一受體為對該EGFR+癌細胞上之EGFR有反應之活化劑受體;且其中該第二受體為對該非靶抗原有反應之抑制性受體。
- 一種多核苷酸或多核苷酸系統,該多核苷酸或多核苷酸系統包含含有編碼該第一受體及該第二受體之多核苷酸序列之一或多個多核苷酸,用於產生如請求項1至57中任一項之免疫細胞。
- 一種載體,該載體包含如請求項64或65之一或多個多核苷酸。
- 一種殺死在MHC I類基因座處具有雜合性損失之EGFR+癌細胞的方法,該方法包括向個體投與有效量之如請求項1至57中任一項之免疫細胞或如請求項58至62中任一項之醫藥組合物。
- 如請求項67之方法,其中該EGFR+癌細胞為肺癌細胞、小細胞肺癌細胞、非小細胞肺癌細胞、胰管癌細胞、結腸直腸癌細胞、頭頸癌細胞、食道及胃腺癌細胞、卵巢癌細胞、多形性神經膠質母細胞瘤細胞、子宮頸鱗狀細胞癌細胞、腎癌細胞、乳頭狀腎癌細胞、腎臟腎透明細胞癌細胞、膀胱癌細胞、乳癌細胞、膽管癌細胞、肝癌細胞、前列腺癌細胞、肉瘤細胞、甲狀腺癌細胞、胸腺癌細胞、胃癌細胞或子宮癌細胞。
- 如請求項67之方法,其中該EGFR+癌細胞為肺癌細胞。
- 如請求項67之方法,其中該EGFR+癌細胞為不表現HLA-A*02之EGFR+/HLA-A*02-癌細胞;或不表現HLA-A*02之來源於HLA-A*02+個體之癌細胞。
- 如請求項70之方法,其中該EGFR+/HLA-A*02-癌細胞藉由在HLA-A處雜合性損失,導致HLA-A*02損失而來源於EGFR+/HLA-A*02+細胞。
- 一種治療患有在編碼非靶抗原之基因座處具有雜合性損失之EGFR+腫瘤之個體之EGFR+癌症的方法,該方法包括向該個體投與有效量之如請求項1至57中任一項之免疫細胞或如請求項58至62中任一項之醫藥組合物。
- 如請求項72之方法,其中該個體為患有表現EGFR且已損失HLA-A*02表現之惡性病的雜合HLA-A*02患者。
- 如請求項72之方法,其中該個體為患有表現EGFR且已損失HLA-A*02表現之復發性不可切除性或轉移性實體腫瘤的雜合HLA-A*02患者。
- 一種治療個體之癌症的方法,該方法包括: a. 確定該個體之非惡性細胞及癌細胞中非靶抗原之基因型或表現水準; b. 確定該個體之癌細胞中EGFR之表現水準;及 c. 若該非惡性細胞表現該非靶抗原且該癌細胞不表現該非靶抗原,且該等癌細胞為EGFR陽性的,則向該個體投與有效量之如請求項1至57中任一項之免疫細胞或如請求項58至62中任一項之醫藥組合物。
- 如請求項67至75中任一項之方法,其中如請求項1至57中任一項之免疫細胞或如請求項58至62中任一項之醫藥組合物的投與減小該個體中之腫瘤的大小。
- 如請求項76之方法,其中該腫瘤減小約5%、約10%、約15%、約20%、約25%、約30%、約35%、約40%、約45%、約50%、約55%、約60%、約65%、約70%、約75%、約80%、約85%、約90%、約95%或約100%。
- 如請求項76之方法,其中該腫瘤得以消除。
- 如請求項67至75中任一項之方法,其中該免疫細胞或該醫藥組合物之投與阻止該個體中之腫瘤的生長。
- 如請求項67至75中任一項之方法,其中如請求項1至57中任一項之免疫細胞或如請求項58至62中任一項之醫藥組合物的投與減少該個體中之腫瘤的數目。
- 如請求項67至80中任一項之方法,其中該免疫細胞或該醫藥組合物之投與選擇性殺死該個體中之癌細胞而非正常細胞。
- 如請求項81之方法,其中所殺死之至少約60%之細胞為癌細胞,所殺死之至少約65%之細胞為癌細胞,所殺死之至少約70%之細胞為癌細胞,所殺死之至少約75%之細胞為癌細胞,所殺死之至少約80%之細胞為癌細胞,所殺死之至少約85%之細胞為癌細胞,所殺死之至少約90%之細胞為癌細胞,所殺死之至少約95%之細胞為癌細胞,或所殺死之約100%之細胞為癌細胞。
- 如請求項81之方法,其中該免疫細胞或該醫藥組合物之投與殺死該個體之約40%、約50%、約60%、約70%、約80%、約90%或所有癌細胞。
- 如請求項67至83中任一項之方法,其中與包含該第一活化劑受體但不含第二抑制性受體之其他方面等效之免疫細胞的投與相比,該免疫細胞或該醫藥組合物之投與對該個體產生較少副作用。
- 一種製造複數個免疫細胞之方法,該方法包括: a. 提供複數個免疫細胞,及 b. 用如請求項64或請求項65之多核苷酸系統或如請求項66之載體將該複數個免疫細胞轉型。
- 一種套組,該套組包含如請求項1至57中任一項之免疫細胞或如請求項58至62中任一項之醫藥組合物。
- 如請求項86之套組,該套組進一步包括使用說明書。
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US202063068249P | 2020-08-20 | 2020-08-20 | |
US63/068,249 | 2020-08-20 | ||
US202063105639P | 2020-10-26 | 2020-10-26 | |
US63/105,639 | 2020-10-26 | ||
US202163230632P | 2021-08-06 | 2021-08-06 | |
US63/230,632 | 2021-08-06 |
Publications (1)
Publication Number | Publication Date |
---|---|
TW202214846A true TW202214846A (zh) | 2022-04-16 |
Family
ID=77711489
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
TW110130697A TW202214846A (zh) | 2020-08-20 | 2021-08-19 | 用於治療egfr陽性癌症之組合物及方法 |
Country Status (11)
Country | Link |
---|---|
US (2) | US11602544B2 (zh) |
EP (1) | EP4058474B1 (zh) |
JP (1) | JP2023538116A (zh) |
KR (1) | KR20230052289A (zh) |
AU (1) | AU2021328478A1 (zh) |
BR (1) | BR112023002668A2 (zh) |
CA (1) | CA3189510A1 (zh) |
IL (1) | IL300629A (zh) |
MX (1) | MX2023002104A (zh) |
TW (1) | TW202214846A (zh) |
WO (1) | WO2022040444A1 (zh) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2022040444A1 (en) | 2020-08-20 | 2022-02-24 | A2 Biotherapeutics, Inc. | Compositions and methods for treating egfr positive cancers |
Family Cites Families (68)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4690915A (en) | 1985-08-08 | 1987-09-01 | The United States Of America As Represented By The Department Of Health And Human Services | Adoptive immunotherapy as a treatment modality in humans |
US6352694B1 (en) | 1994-06-03 | 2002-03-05 | Genetics Institute, Inc. | Methods for inducing a population of T cells to proliferate using agents which recognize TCR/CD3 and ligands which stimulate an accessory molecule on the surface of the T cells |
US5858358A (en) | 1992-04-07 | 1999-01-12 | The United States Of America As Represented By The Secretary Of The Navy | Methods for selectively stimulating proliferation of T cells |
US6534055B1 (en) | 1988-11-23 | 2003-03-18 | Genetics Institute, Inc. | Methods for selectively stimulating proliferation of T cells |
US6905680B2 (en) | 1988-11-23 | 2005-06-14 | Genetics Institute, Inc. | Methods of treating HIV infected subjects |
US5585362A (en) | 1989-08-22 | 1996-12-17 | The Regents Of The University Of Michigan | Adenovirus vectors for gene therapy |
US5350674A (en) | 1992-09-04 | 1994-09-27 | Becton, Dickinson And Company | Intrinsic factor - horse peroxidase conjugates and a method for increasing the stability thereof |
US7175843B2 (en) | 1994-06-03 | 2007-02-13 | Genetics Institute, Llc | Methods for selectively stimulating proliferation of T cells |
US6692964B1 (en) | 1995-05-04 | 2004-02-17 | The United States Of America As Represented By The Secretary Of The Navy | Methods for transfecting T cells |
US7067318B2 (en) | 1995-06-07 | 2006-06-27 | The Regents Of The University Of Michigan | Methods for transfecting T cells |
AU1086501A (en) | 1999-10-15 | 2001-04-30 | Carnegie Institution Of Washington | Rna interference pathway genes as tools for targeted genetic interference |
US6326193B1 (en) | 1999-11-05 | 2001-12-04 | Cambria Biosciences, Llc | Insect control agent |
US6867041B2 (en) | 2000-02-24 | 2005-03-15 | Xcyte Therapies, Inc. | Simultaneous stimulation and concentration of cells |
US6797514B2 (en) | 2000-02-24 | 2004-09-28 | Xcyte Therapies, Inc. | Simultaneous stimulation and concentration of cells |
JP2004500095A (ja) | 2000-02-24 | 2004-01-08 | エクサイト セラピーズ, インコーポレイテッド | 細胞の同時の刺激および濃縮 |
US7572631B2 (en) | 2000-02-24 | 2009-08-11 | Invitrogen Corporation | Activation and expansion of T cells |
AU2001275474A1 (en) | 2000-06-12 | 2001-12-24 | Akkadix Corporation | Materials and methods for the control of nematodes |
US7745140B2 (en) | 2002-01-03 | 2010-06-29 | The Trustees Of The University Of Pennsylvania | Activation and expansion of T-cells using an engineered multivalent signaling platform as a research tool |
US20030170238A1 (en) | 2002-03-07 | 2003-09-11 | Gruenberg Micheal L. | Re-activated T-cells for adoptive immunotherapy |
US20050277610A1 (en) | 2004-03-15 | 2005-12-15 | City Of Hope | Methods and compositions for the specific inhibition of gene expression by double-stranded RNA |
WO2005118788A2 (en) | 2004-05-27 | 2005-12-15 | The Trustees Of The University Of Pennsylvania | Novel artificial antigen presenting cells and uses therefor |
CA3084919A1 (en) | 2012-02-22 | 2013-08-29 | The Trustees Of The University Of Pennsylvania | Compositions and methods for generating a persisting population of t cells useful for the treatment of cancer |
MA37663B1 (fr) | 2012-05-25 | 2019-12-31 | Univ California | Procédés et compositions permettant la modification de l'adn cible dirigée par l'arn et la modulation de la transcription dirigée par l'arn |
US8697359B1 (en) | 2012-12-12 | 2014-04-15 | The Broad Institute, Inc. | CRISPR-Cas systems and methods for altering expression of gene products |
KR20150105634A (ko) | 2012-12-12 | 2015-09-17 | 더 브로드 인스티튜트, 인코퍼레이티드 | 서열 조작을 위한 개선된 시스템, 방법 및 효소 조성물의 유전자 조작 및 최적화 |
WO2014093595A1 (en) | 2012-12-12 | 2014-06-19 | The Broad Institute, Inc. | Crispr-cas component systems, methods and compositions for sequence manipulation |
US9745368B2 (en) | 2013-03-15 | 2017-08-29 | The Trustees Of The University Of Pennsylvania | Targeting cytotoxic cells with chimeric receptors for adoptive immunotherapy |
EP4098275A1 (en) | 2013-03-15 | 2022-12-07 | Memorial Sloan-Kettering Cancer Center | Compositions and methods for immunotherapy |
ES2910004T3 (es) | 2013-07-29 | 2022-05-11 | 2Seventy Bio Inc | Proteínas de señalización de múltiples partes y sus usos |
JP6433498B2 (ja) | 2013-11-21 | 2018-12-05 | ユーシーエル ビジネス ピーエルシー | 細胞 |
KR20220119176A (ko) | 2014-02-04 | 2022-08-26 | 카이트 파마 인코포레이티드 | B 세포 악성종양 및 다른 암을 치료하는데 유용한 자가 t 세포 및 그의 조성물의 생산 방법 |
JP6681837B2 (ja) * | 2014-03-11 | 2020-04-15 | セレクティスCellectis | 同種移植に適合するt細胞を作製するための方法 |
AU2015344769B2 (en) | 2014-11-12 | 2020-07-09 | Allogene Therapeutics, Inc. | Inhibitory chimeric antigen receptors |
JP2018504104A (ja) | 2014-12-17 | 2018-02-15 | セレクティスCellectis | 非T細胞伝達ドメインを発現する阻害性キメラ抗原受容体(iCARまたはN−CAR) |
US11161907B2 (en) | 2015-02-02 | 2021-11-02 | Novartis Ag | Car-expressing cells against multiple tumor antigens and uses thereof |
CN108064283B (zh) | 2015-02-24 | 2024-01-09 | 加利福尼亚大学董事会 | 结合触发的转录开关及其使用方法 |
RU2017134441A (ru) | 2015-03-11 | 2019-04-03 | Селлектис | Способы конструирования аллогенных т-клеток для повышения их персистенции и/или приживления у пациентов |
WO2016160622A2 (en) | 2015-03-27 | 2016-10-06 | University Of Southern California | Hla-g as a novel target for car t-cell immunotherapy |
GB201509413D0 (en) | 2015-06-01 | 2015-07-15 | Ucl Business Plc | Fusion protein |
MA42895A (fr) | 2015-07-15 | 2018-05-23 | Juno Therapeutics Inc | Cellules modifiées pour thérapie cellulaire adoptive |
MA44314A (fr) | 2015-11-05 | 2018-09-12 | Juno Therapeutics Inc | Récepteurs chimériques contenant des domaines induisant traf, et compositions et méthodes associées |
EP3377523A4 (en) | 2015-11-19 | 2019-06-19 | The Regents of The University of California | IMMUNITY CELL RECEIVERS REPRESSIBLE UNDER CONDITIONS AND METHODS OF USING THE SAME |
CN108495927A (zh) | 2015-11-23 | 2018-09-04 | 波士顿大学董事会 | 嵌合抗原受体相关的方法和组合物 |
EP3383893A4 (en) | 2015-12-02 | 2019-06-26 | Innovative Targeting Solutions Inc. | T CELL RECEPTORS WITH VARIABLE SINGLE DOMAIN |
AU2017230011A1 (en) | 2016-03-11 | 2018-09-27 | 2Seventy Bio, Inc. | Genome edited immune effector cells |
WO2018002719A1 (en) | 2016-06-29 | 2018-01-04 | Crispr Therapeutics Ag | Compositions and methods for gene editing |
EP3263595A1 (en) | 2016-06-30 | 2018-01-03 | Medizinische Hochschule Hannover | Fusion protein for use in the treatment of hvg disease |
JP2019530456A (ja) | 2016-09-28 | 2019-10-24 | ガビッシュ−ガリラヤ バイオ アプリケーションズ リミテッド | 癌の新規抗原性シグネチャーを標的としたcar療法のためのユニバーサルプラットフォーム |
CN110582509A (zh) | 2017-01-31 | 2019-12-17 | 诺华股份有限公司 | 使用具有多特异性的嵌合t细胞受体蛋白治疗癌症 |
WO2018148454A1 (en) | 2017-02-09 | 2018-08-16 | The Regents Of The University Of California | Chimeric t cell antigen receptors and methods of use thereof |
GB201707783D0 (en) | 2017-05-15 | 2017-06-28 | Autolus Ltd | Cell |
GB201707779D0 (en) | 2017-05-15 | 2017-06-28 | Autolus Ltd | Cell |
JP7132249B2 (ja) | 2017-05-15 | 2022-09-06 | オートラス リミテッド | キメラ抗原受容体(car)を含む細胞 |
KR20200067845A (ko) | 2017-09-19 | 2020-06-12 | 더 유니버시티 오브 브리티쉬 콜롬비아 | 항-hla-a2 항체 및 그 사용 방법 |
MX2020003526A (es) * | 2017-09-28 | 2020-09-14 | Immpact Bio Ltd | Una plataforma universal para la preparación de un receptor antigénico quimérico inhibidor (icar). |
WO2019090215A2 (en) | 2017-11-06 | 2019-05-09 | Monticello Daniel J | Dominant negative ligand chimeric antigen receptor systems |
WO2019241549A1 (en) | 2018-06-15 | 2019-12-19 | A2 Biotherapeutics, Inc. | Foxp3-expressing car-t regulatory cells |
EP3856236B1 (en) * | 2018-09-28 | 2023-05-17 | ImmPACT-Bio Ltd. | Methods for identifying activating antigen receptor (acar)/inhibitory chimeric antigen receptor (icar) pairs for use in cancer therapies |
EP3632461A1 (en) | 2018-10-05 | 2020-04-08 | St. Anna Kinderkrebsforschung | A group of chimeric antigen receptors (cars) |
JP2022512594A (ja) | 2018-10-05 | 2022-02-07 | ザンクト アンナ キンダークレプスフォルシュング | キメラ抗原受容体(car)の群 |
WO2021030182A1 (en) | 2019-08-09 | 2021-02-18 | A2 Biotherapeutics, Inc. | Bifunctional single variable domain t cell receptors and uses thereof |
KR20220053587A (ko) * | 2019-08-09 | 2022-04-29 | 에이투 바이오쎄라퓨틱스, 인크. | 이형접합성 소실에 반응성인 세포 표면 수용체 |
WO2021030153A2 (en) | 2019-08-09 | 2021-02-18 | A2 Biotherapeutics, Inc. | Engineered t cell receptors and uses thereof |
JP2022546315A (ja) | 2019-08-20 | 2022-11-04 | センティ バイオサイエンシズ インコーポレイテッド | キメラ抑制性受容体 |
EP4058561A1 (en) | 2019-11-12 | 2022-09-21 | A2 Biotherapeutics, Inc. | Engineered t cell receptors and uses thereof |
EP4073103A1 (en) | 2019-12-11 | 2022-10-19 | A2 Biotherapeutics, Inc. | Lilrb1-based chimeric antigen receptor |
WO2021222576A1 (en) | 2020-05-01 | 2021-11-04 | A2 Biotherapeutics, Inc. | Pag1 fusion proteins and methods of making and using same |
WO2022040444A1 (en) | 2020-08-20 | 2022-02-24 | A2 Biotherapeutics, Inc. | Compositions and methods for treating egfr positive cancers |
-
2021
- 2021-08-19 WO PCT/US2021/046733 patent/WO2022040444A1/en active Application Filing
- 2021-08-19 AU AU2021328478A patent/AU2021328478A1/en active Pending
- 2021-08-19 CA CA3189510A patent/CA3189510A1/en active Pending
- 2021-08-19 TW TW110130697A patent/TW202214846A/zh unknown
- 2021-08-19 EP EP21769291.2A patent/EP4058474B1/en active Active
- 2021-08-19 IL IL300629A patent/IL300629A/en unknown
- 2021-08-19 BR BR112023002668A patent/BR112023002668A2/pt unknown
- 2021-08-19 KR KR1020237009181A patent/KR20230052289A/ko unknown
- 2021-08-19 MX MX2023002104A patent/MX2023002104A/es unknown
- 2021-08-19 JP JP2023512379A patent/JP2023538116A/ja active Pending
-
2022
- 2022-05-17 US US17/663,758 patent/US11602544B2/en active Active
-
2023
- 2023-02-07 US US18/165,623 patent/US20230277593A1/en active Pending
Also Published As
Publication number | Publication date |
---|---|
AU2021328478A1 (en) | 2023-04-20 |
US20220273721A1 (en) | 2022-09-01 |
IL300629A (en) | 2023-04-01 |
EP4058474A1 (en) | 2022-09-21 |
EP4058474B1 (en) | 2024-05-08 |
KR20230052289A (ko) | 2023-04-19 |
MX2023002104A (es) | 2023-07-10 |
US20230277593A1 (en) | 2023-09-07 |
BR112023002668A2 (pt) | 2023-05-02 |
US11602544B2 (en) | 2023-03-14 |
CA3189510A1 (en) | 2022-02-24 |
JP2023538116A (ja) | 2023-09-06 |
WO2022040444A1 (en) | 2022-02-24 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN110494451B (zh) | 靶向tim-1的嵌合抗原受体 | |
KR20220053587A (ko) | 이형접합성 소실에 반응성인 세포 표면 수용체 | |
US20230074800A1 (en) | Car-t cell therapies with enhanced efficacy | |
KR20190036551A (ko) | Pro-m2 대식세포 분자의 억제제를 병용하는, 키메라 항원 수용체를 이용한 암의 치료 | |
CA3057306A1 (en) | Biomarkers and car t cell therapies with enhanced efficacy | |
AU2016297014A1 (en) | Methods for improving the efficacy and expansion of immune cells | |
KR20180099768A (ko) | 증진된 효능을 갖는 면역 이펙터 세포 요법 | |
CA2999070A1 (en) | Car t cell therapies with enhanced efficacy | |
KR20230052291A (ko) | Ceacam 양성 암을 치료하기 위한 조성물 및 방법 | |
CN114269372A (zh) | 嵌合抗原受体t细胞和nk细胞抑制剂用于治疗癌症的用途 | |
US11730764B2 (en) | Compositions and methods for treating HER2 positive cancers | |
KR20230051677A (ko) | 메소텔린 양성 암을 치료하기 위한 조성물 및 방법 | |
US20240000938A1 (en) | Adoptive cell therapy for treatment of cancer associated with loss of heterozygosity | |
WO2022040470A1 (en) | Compositions and methods for treating ceacam positive cancers | |
US20230277593A1 (en) | Compositions and methods for treating egfr positive cancers | |
US20220370498A1 (en) | Immune cells expressing receptor specific to class i mhc molecule and interfering rna for hla gene | |
KR20240027117A (ko) | B7h3을 표적으로 하는 항원 결합 폴리펩티드 및 이의 응용 | |
RU2809160C2 (ru) | Виды комбинированной терапии с использованием химерных антигенных рецепторов и ингибиторов pd-1 | |
CN116635043A (zh) | 用于治疗egfr阳性癌症的组合物和方法 | |
WO2023172954A2 (en) | Engineered receptors specific to hla-e and methods of use | |
WO2023147019A2 (en) | Compositions and methods for treating mesothelin positive cancers | |
CN116761817A (zh) | 用于治疗间皮素阳性癌症的组合物和方法 |