CN115558023A - 抗cd3抗体及其用途 - Google Patents
抗cd3抗体及其用途 Download PDFInfo
- Publication number
- CN115558023A CN115558023A CN202110752589.0A CN202110752589A CN115558023A CN 115558023 A CN115558023 A CN 115558023A CN 202110752589 A CN202110752589 A CN 202110752589A CN 115558023 A CN115558023 A CN 115558023A
- Authority
- CN
- China
- Prior art keywords
- cdr
- amino acid
- sequence
- substitutions
- seq
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 230000027455 binding Effects 0.000 claims abstract description 130
- 239000000427 antigen Substances 0.000 claims abstract description 110
- 108091007433 antigens Proteins 0.000 claims abstract description 110
- 102000036639 antigens Human genes 0.000 claims abstract description 110
- 239000012634 fragment Substances 0.000 claims abstract description 81
- 238000000034 method Methods 0.000 claims abstract description 45
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 21
- 239000013604 expression vector Substances 0.000 claims abstract description 21
- 210000000056 organ Anatomy 0.000 claims abstract description 17
- 208000023275 Autoimmune disease Diseases 0.000 claims abstract description 16
- 239000003814 drug Substances 0.000 claims abstract description 15
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 10
- 201000010099 disease Diseases 0.000 claims abstract description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 9
- 125000003275 alpha amino acid group Chemical group 0.000 claims description 393
- 238000006467 substitution reaction Methods 0.000 claims description 381
- 238000007792 addition Methods 0.000 claims description 192
- 238000012217 deletion Methods 0.000 claims description 192
- 230000037430 deletion Effects 0.000 claims description 192
- 210000004027 cell Anatomy 0.000 claims description 85
- 108010047041 Complementarity Determining Regions Proteins 0.000 claims description 58
- 241001529936 Murinae Species 0.000 claims description 53
- 108090000623 proteins and genes Proteins 0.000 claims description 30
- 150000001413 amino acids Chemical class 0.000 claims description 29
- 108020004414 DNA Proteins 0.000 claims description 24
- 239000013598 vector Substances 0.000 claims description 22
- 239000002773 nucleotide Substances 0.000 claims description 20
- 125000003729 nucleotide group Chemical group 0.000 claims description 20
- 102000004169 proteins and genes Human genes 0.000 claims description 20
- 108060003951 Immunoglobulin Proteins 0.000 claims description 16
- 102000018358 immunoglobulin Human genes 0.000 claims description 16
- 238000011282 treatment Methods 0.000 claims description 12
- 230000028993 immune response Effects 0.000 claims description 11
- 210000004962 mammalian cell Anatomy 0.000 claims description 11
- -1 c-MET Proteins 0.000 claims description 10
- 238000004519 manufacturing process Methods 0.000 claims description 10
- 230000035772 mutation Effects 0.000 claims description 10
- 239000013612 plasmid Substances 0.000 claims description 10
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 9
- 102000053602 DNA Human genes 0.000 claims description 8
- 206010052779 Transplant rejections Diseases 0.000 claims description 8
- 230000001225 therapeutic effect Effects 0.000 claims description 7
- 210000004978 chinese hamster ovary cell Anatomy 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- 201000000050 myeloid neoplasm Diseases 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- 210000001519 tissue Anatomy 0.000 claims description 6
- 238000012258 culturing Methods 0.000 claims description 5
- 208000032839 leukemia Diseases 0.000 claims description 5
- 230000002265 prevention Effects 0.000 claims description 5
- 210000001236 prokaryotic cell Anatomy 0.000 claims description 5
- 241000894006 Bacteria Species 0.000 claims description 4
- 102000003735 Mesothelin Human genes 0.000 claims description 4
- 108090000015 Mesothelin Proteins 0.000 claims description 4
- 240000004808 Saccharomyces cerevisiae Species 0.000 claims description 4
- 102000007000 Tenascin Human genes 0.000 claims description 4
- 108010008125 Tenascin Proteins 0.000 claims description 4
- 208000031981 Thrombocytopenic Idiopathic Purpura Diseases 0.000 claims description 4
- 201000003710 autoimmune thrombocytopenic purpura Diseases 0.000 claims description 4
- 201000011510 cancer Diseases 0.000 claims description 4
- 206010012601 diabetes mellitus Diseases 0.000 claims description 4
- 238000010353 genetic engineering Methods 0.000 claims description 4
- 208000024908 graft versus host disease Diseases 0.000 claims description 4
- 230000002209 hydrophobic effect Effects 0.000 claims description 4
- 102000006495 integrins Human genes 0.000 claims description 4
- 108010044426 integrins Proteins 0.000 claims description 4
- 210000004185 liver Anatomy 0.000 claims description 4
- 206010006187 Breast cancer Diseases 0.000 claims description 3
- 208000026310 Breast neoplasm Diseases 0.000 claims description 3
- 208000009329 Graft vs Host Disease Diseases 0.000 claims description 3
- 208000034578 Multiple myelomas Diseases 0.000 claims description 3
- 241000700605 Viruses Species 0.000 claims description 3
- 238000004587 chromatography analysis Methods 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- 210000002216 heart Anatomy 0.000 claims description 3
- 210000003734 kidney Anatomy 0.000 claims description 3
- 230000003902 lesion Effects 0.000 claims description 3
- 201000001441 melanoma Diseases 0.000 claims description 3
- 230000001394 metastastic effect Effects 0.000 claims description 3
- 206010061289 metastatic neoplasm Diseases 0.000 claims description 3
- 238000000746 purification Methods 0.000 claims description 3
- 210000005253 yeast cell Anatomy 0.000 claims description 3
- BGFTWECWAICPDG-UHFFFAOYSA-N 2-[bis(4-chlorophenyl)methyl]-4-n-[3-[bis(4-chlorophenyl)methyl]-4-(dimethylamino)phenyl]-1-n,1-n-dimethylbenzene-1,4-diamine Chemical compound C1=C(C(C=2C=CC(Cl)=CC=2)C=2C=CC(Cl)=CC=2)C(N(C)C)=CC=C1NC(C=1)=CC=C(N(C)C)C=1C(C=1C=CC(Cl)=CC=1)C1=CC=C(Cl)C=C1 BGFTWECWAICPDG-UHFFFAOYSA-N 0.000 claims description 2
- 102100022464 5'-nucleotidase Human genes 0.000 claims description 2
- 102100031585 ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1 Human genes 0.000 claims description 2
- 208000032467 Aplastic anaemia Diseases 0.000 claims description 2
- 101001005269 Arabidopsis thaliana Ceramide synthase 1 LOH3 Proteins 0.000 claims description 2
- 101001005312 Arabidopsis thaliana Ceramide synthase LOH1 Proteins 0.000 claims description 2
- 206010003827 Autoimmune hepatitis Diseases 0.000 claims description 2
- 108010008014 B-Cell Maturation Antigen Proteins 0.000 claims description 2
- 102000006942 B-Cell Maturation Antigen Human genes 0.000 claims description 2
- 102100038080 B-cell receptor CD22 Human genes 0.000 claims description 2
- 102100024222 B-lymphocyte antigen CD19 Human genes 0.000 claims description 2
- 102100022005 B-lymphocyte antigen CD20 Human genes 0.000 claims description 2
- 208000023328 Basedow disease Diseases 0.000 claims description 2
- 208000008439 Biliary Liver Cirrhosis Diseases 0.000 claims description 2
- 208000033222 Biliary cirrhosis primary Diseases 0.000 claims description 2
- 102100024217 CAMPATH-1 antigen Human genes 0.000 claims description 2
- 101150013553 CD40 gene Proteins 0.000 claims description 2
- 108010065524 CD52 Antigen Proteins 0.000 claims description 2
- 102000000905 Cadherin Human genes 0.000 claims description 2
- 108050007957 Cadherin Proteins 0.000 claims description 2
- 101100314454 Caenorhabditis elegans tra-1 gene Proteins 0.000 claims description 2
- 102100028801 Calsyntenin-1 Human genes 0.000 claims description 2
- 102100040835 Claudin-18 Human genes 0.000 claims description 2
- 108050009324 Claudin-18 Proteins 0.000 claims description 2
- 206010009944 Colon cancer Diseases 0.000 claims description 2
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 2
- 102100036466 Delta-like protein 3 Human genes 0.000 claims description 2
- 102100033553 Delta-like protein 4 Human genes 0.000 claims description 2
- 101150084967 EPCAM gene Proteins 0.000 claims description 2
- 101150016325 EPHA3 gene Proteins 0.000 claims description 2
- 102100029722 Ectonucleoside triphosphate diphosphohydrolase 1 Human genes 0.000 claims description 2
- 102100030324 Ephrin type-A receptor 3 Human genes 0.000 claims description 2
- 102100041003 Glutamate carboxypeptidase 2 Human genes 0.000 claims description 2
- 208000015023 Graves' disease Diseases 0.000 claims description 2
- 102100030595 HLA class II histocompatibility antigen gamma chain Human genes 0.000 claims description 2
- 208000035186 Hemolytic Autoimmune Anemia Diseases 0.000 claims description 2
- 101000678236 Homo sapiens 5'-nucleotidase Proteins 0.000 claims description 2
- 101000777636 Homo sapiens ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1 Proteins 0.000 claims description 2
- 101000884305 Homo sapiens B-cell receptor CD22 Proteins 0.000 claims description 2
- 101000980825 Homo sapiens B-lymphocyte antigen CD19 Proteins 0.000 claims description 2
- 101000897405 Homo sapiens B-lymphocyte antigen CD20 Proteins 0.000 claims description 2
- 101000914324 Homo sapiens Carcinoembryonic antigen-related cell adhesion molecule 5 Proteins 0.000 claims description 2
- 101000914321 Homo sapiens Carcinoembryonic antigen-related cell adhesion molecule 7 Proteins 0.000 claims description 2
- 101000928513 Homo sapiens Delta-like protein 3 Proteins 0.000 claims description 2
- 101000872077 Homo sapiens Delta-like protein 4 Proteins 0.000 claims description 2
- 101001012447 Homo sapiens Ectonucleoside triphosphate diphosphohydrolase 1 Proteins 0.000 claims description 2
- 101000892862 Homo sapiens Glutamate carboxypeptidase 2 Proteins 0.000 claims description 2
- 101001082627 Homo sapiens HLA class II histocompatibility antigen gamma chain Proteins 0.000 claims description 2
- 101001034652 Homo sapiens Insulin-like growth factor 1 receptor Proteins 0.000 claims description 2
- 101001057504 Homo sapiens Interferon-stimulated gene 20 kDa protein Proteins 0.000 claims description 2
- 101001055144 Homo sapiens Interleukin-2 receptor subunit alpha Proteins 0.000 claims description 2
- 101000998120 Homo sapiens Interleukin-3 receptor subunit alpha Proteins 0.000 claims description 2
- 101000868279 Homo sapiens Leukocyte surface antigen CD47 Proteins 0.000 claims description 2
- 101000623901 Homo sapiens Mucin-16 Proteins 0.000 claims description 2
- 101000934338 Homo sapiens Myeloid cell surface antigen CD33 Proteins 0.000 claims description 2
- 101001024605 Homo sapiens Next to BRCA1 gene 1 protein Proteins 0.000 claims description 2
- 101000617725 Homo sapiens Pregnancy-specific beta-1-glycoprotein 2 Proteins 0.000 claims description 2
- 101000610551 Homo sapiens Prominin-1 Proteins 0.000 claims description 2
- 101000932478 Homo sapiens Receptor-type tyrosine-protein kinase FLT3 Proteins 0.000 claims description 2
- 101000633784 Homo sapiens SLAM family member 7 Proteins 0.000 claims description 2
- 101000874179 Homo sapiens Syndecan-1 Proteins 0.000 claims description 2
- 101000610604 Homo sapiens Tumor necrosis factor receptor superfamily member 10B Proteins 0.000 claims description 2
- 101000851376 Homo sapiens Tumor necrosis factor receptor superfamily member 8 Proteins 0.000 claims description 2
- 101000851007 Homo sapiens Vascular endothelial growth factor receptor 2 Proteins 0.000 claims description 2
- 101000851030 Homo sapiens Vascular endothelial growth factor receptor 3 Proteins 0.000 claims description 2
- 206010021245 Idiopathic thrombocytopenic purpura Diseases 0.000 claims description 2
- 102220622573 Inositol-tetrakisphosphate 1-kinase_N297L_mutation Human genes 0.000 claims description 2
- 102100039688 Insulin-like growth factor 1 receptor Human genes 0.000 claims description 2
- 102100026878 Interleukin-2 receptor subunit alpha Human genes 0.000 claims description 2
- 102100033493 Interleukin-3 receptor subunit alpha Human genes 0.000 claims description 2
- 208000003456 Juvenile Arthritis Diseases 0.000 claims description 2
- 206010059176 Juvenile idiopathic arthritis Diseases 0.000 claims description 2
- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 2
- 102100032913 Leukocyte surface antigen CD47 Human genes 0.000 claims description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 2
- 206010025323 Lymphomas Diseases 0.000 claims description 2
- 102100023123 Mucin-16 Human genes 0.000 claims description 2
- 102100025243 Myeloid cell surface antigen CD33 Human genes 0.000 claims description 2
- 208000012654 Primary biliary cholangitis Diseases 0.000 claims description 2
- 102100040120 Prominin-1 Human genes 0.000 claims description 2
- 102220562703 Protein Tob2_L234A_mutation Human genes 0.000 claims description 2
- 201000004681 Psoriasis Diseases 0.000 claims description 2
- 102000014128 RANK Ligand Human genes 0.000 claims description 2
- 108010025832 RANK Ligand Proteins 0.000 claims description 2
- 101001039269 Rattus norvegicus Glycine N-methyltransferase Proteins 0.000 claims description 2
- 101710100969 Receptor tyrosine-protein kinase erbB-3 Proteins 0.000 claims description 2
- 102100029986 Receptor tyrosine-protein kinase erbB-3 Human genes 0.000 claims description 2
- 102100020718 Receptor-type tyrosine-protein kinase FLT3 Human genes 0.000 claims description 2
- 206010038389 Renal cancer Diseases 0.000 claims description 2
- 101000668858 Spinacia oleracea 30S ribosomal protein S1, chloroplastic Proteins 0.000 claims description 2
- 101000898746 Streptomyces clavuligerus Clavaminate synthase 1 Proteins 0.000 claims description 2
- 102100035721 Syndecan-1 Human genes 0.000 claims description 2
- 102100040112 Tumor necrosis factor receptor superfamily member 10B Human genes 0.000 claims description 2
- 102100040245 Tumor necrosis factor receptor superfamily member 5 Human genes 0.000 claims description 2
- 102100036857 Tumor necrosis factor receptor superfamily member 8 Human genes 0.000 claims description 2
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 claims description 2
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 claims description 2
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 claims description 2
- 102100033179 Vascular endothelial growth factor receptor 3 Human genes 0.000 claims description 2
- 230000002159 abnormal effect Effects 0.000 claims description 2
- 238000001042 affinity chromatography Methods 0.000 claims description 2
- 201000000448 autoimmune hemolytic anemia Diseases 0.000 claims description 2
- 208000019069 chronic childhood arthritis Diseases 0.000 claims description 2
- 229940127276 delta-like ligand 3 Drugs 0.000 claims description 2
- 201000002491 encephalomyelitis Diseases 0.000 claims description 2
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 claims description 2
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 claims description 2
- 238000009472 formulation Methods 0.000 claims description 2
- 208000019691 hematopoietic and lymphoid cell neoplasm Diseases 0.000 claims description 2
- 238000005342 ion exchange Methods 0.000 claims description 2
- 201000002215 juvenile rheumatoid arthritis Diseases 0.000 claims description 2
- 201000010982 kidney cancer Diseases 0.000 claims description 2
- 201000007270 liver cancer Diseases 0.000 claims description 2
- 208000014018 liver neoplasm Diseases 0.000 claims description 2
- 201000005202 lung cancer Diseases 0.000 claims description 2
- 208000020816 lung neoplasm Diseases 0.000 claims description 2
- 239000002808 molecular sieve Substances 0.000 claims description 2
- 201000006417 multiple sclerosis Diseases 0.000 claims description 2
- 206010028417 myasthenia gravis Diseases 0.000 claims description 2
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 claims description 2
- 229920001481 poly(stearyl methacrylate) Polymers 0.000 claims description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 2
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims description 2
- 201000000596 systemic lupus erythematosus Diseases 0.000 claims description 2
- 101150047061 tag-72 gene Proteins 0.000 claims description 2
- 102100025475 Carcinoembryonic antigen-related cell adhesion molecule 5 Human genes 0.000 claims 1
- 150000007523 nucleic acids Chemical class 0.000 abstract description 18
- 102000039446 nucleic acids Human genes 0.000 abstract description 16
- 108020004707 nucleic acids Proteins 0.000 abstract description 16
- 238000002054 transplantation Methods 0.000 abstract description 10
- 229940079593 drug Drugs 0.000 abstract description 7
- 238000002360 preparation method Methods 0.000 abstract description 4
- 235000001014 amino acid Nutrition 0.000 description 116
- NFGXHKASABOEEW-UHFFFAOYSA-N 1-methylethyl 11-methoxy-3,7,11-trimethyl-2,4-dodecadienoate Chemical compound COC(C)(C)CCCC(C)CC=CC(C)=CC(=O)OC(C)C NFGXHKASABOEEW-UHFFFAOYSA-N 0.000 description 43
- XKUKSGPZAADMRA-UHFFFAOYSA-N glycyl-glycyl-glycine Natural products NCC(=O)NCC(=O)NCC(O)=O XKUKSGPZAADMRA-UHFFFAOYSA-N 0.000 description 39
- 108090000765 processed proteins & peptides Proteins 0.000 description 35
- 229920001184 polypeptide Polymers 0.000 description 34
- 102000004196 processed proteins & peptides Human genes 0.000 description 34
- 210000001744 T-lymphocyte Anatomy 0.000 description 30
- 229940024606 amino acid Drugs 0.000 description 30
- AIQWYVFNBNNOLU-RHYQMDGZSA-N Leu-Thr-Val Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(O)=O AIQWYVFNBNNOLU-RHYQMDGZSA-N 0.000 description 28
- 108010067216 glycyl-glycyl-glycine Proteins 0.000 description 26
- 108010069020 alanyl-prolyl-glycine Proteins 0.000 description 25
- 230000000694 effects Effects 0.000 description 25
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 24
- YQPFCZVKMUVZIN-AUTRQRHGSA-N Glu-Val-Gln Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O YQPFCZVKMUVZIN-AUTRQRHGSA-N 0.000 description 22
- 241000880493 Leptailurus serval Species 0.000 description 22
- FEHQLKKBVJHSEC-SZMVWBNQSA-N Leu-Glu-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CC(C)C)C(O)=O)=CNC2=C1 FEHQLKKBVJHSEC-SZMVWBNQSA-N 0.000 description 22
- 108010086434 alanyl-seryl-glycine Proteins 0.000 description 22
- 108010050848 glycylleucine Proteins 0.000 description 20
- HMIXCETWRYDVMO-GUBZILKMSA-N Gln-Pro-Glu Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O HMIXCETWRYDVMO-GUBZILKMSA-N 0.000 description 19
- MNYNCKZAEIAONY-XGEHTFHBSA-N Thr-Val-Ser Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(O)=O MNYNCKZAEIAONY-XGEHTFHBSA-N 0.000 description 19
- OYTPNWYZORARHL-XHNCKOQMSA-N Gln-Ala-Pro Chemical compound C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCC(=O)N)N OYTPNWYZORARHL-XHNCKOQMSA-N 0.000 description 18
- XHVONGZZVUUORG-WEDXCCLWSA-N Gly-Thr-Lys Chemical compound NCC(=O)N[C@@H]([C@H](O)C)C(=O)N[C@H](C(O)=O)CCCCN XHVONGZZVUUORG-WEDXCCLWSA-N 0.000 description 18
- PMGDADKJMCOXHX-UHFFFAOYSA-N L-Arginyl-L-glutamin-acetat Natural products NC(=N)NCCCC(N)C(=O)NC(CCC(N)=O)C(O)=O PMGDADKJMCOXHX-UHFFFAOYSA-N 0.000 description 18
- FQPDRTDDEZXCEC-SVSWQMSJSA-N Thr-Ile-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(O)=O FQPDRTDDEZXCEC-SVSWQMSJSA-N 0.000 description 18
- MBLJBGZWLHTJBH-SZMVWBNQSA-N Trp-Val-Arg Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O)=CNC2=C1 MBLJBGZWLHTJBH-SZMVWBNQSA-N 0.000 description 18
- 108010008355 arginyl-glutamine Proteins 0.000 description 18
- 235000018102 proteins Nutrition 0.000 description 18
- BYYNJRSNDARRBX-YFKPBYRVSA-N Gly-Gln-Gly Chemical compound NCC(=O)N[C@@H](CCC(N)=O)C(=O)NCC(O)=O BYYNJRSNDARRBX-YFKPBYRVSA-N 0.000 description 17
- 108010087924 alanylproline Proteins 0.000 description 17
- 108010092854 aspartyllysine Proteins 0.000 description 17
- 230000006870 function Effects 0.000 description 17
- YYSWCHMLFJLLBJ-ZLUOBGJFSA-N Ala-Ala-Ser Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O YYSWCHMLFJLLBJ-ZLUOBGJFSA-N 0.000 description 16
- MEFILNJXAVSUTO-JXUBOQSCSA-N Ala-Leu-Thr Chemical compound C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O MEFILNJXAVSUTO-JXUBOQSCSA-N 0.000 description 16
- MIIVFRCYJABHTQ-ONGXEEELSA-N Gly-Leu-Val Chemical compound [H]NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(O)=O MIIVFRCYJABHTQ-ONGXEEELSA-N 0.000 description 16
- PDUHNKAFQXQNLH-ZETCQYMHSA-N Gly-Lys-Gly Chemical compound NCCCC[C@H](NC(=O)CN)C(=O)NCC(O)=O PDUHNKAFQXQNLH-ZETCQYMHSA-N 0.000 description 16
- KIZIOFNVSOSKJI-CIUDSAMLSA-N Leu-Ser-Cys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)O)N KIZIOFNVSOSKJI-CIUDSAMLSA-N 0.000 description 16
- YMTLKLXDFCSCNX-BYPYZUCNSA-N Ser-Gly-Gly Chemical compound OC[C@H](N)C(=O)NCC(=O)NCC(O)=O YMTLKLXDFCSCNX-BYPYZUCNSA-N 0.000 description 16
- UBRMZSHOOIVJPW-SRVKXCTJSA-N Ser-Leu-Lys Chemical compound OC[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(O)=O UBRMZSHOOIVJPW-SRVKXCTJSA-N 0.000 description 16
- LGIMRDKGABDMBN-DCAQKATOSA-N Ser-Val-Lys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CO)N LGIMRDKGABDMBN-DCAQKATOSA-N 0.000 description 16
- HNDMFDBQXYZSRM-IHRRRGAJSA-N Ser-Val-Phe Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O HNDMFDBQXYZSRM-IHRRRGAJSA-N 0.000 description 16
- 108010031719 prolyl-serine Proteins 0.000 description 16
- FRBAHXABMQXSJQ-FXQIFTODSA-N Arg-Ser-Ser Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O FRBAHXABMQXSJQ-FXQIFTODSA-N 0.000 description 15
- FQCILXROGNOZON-YUMQZZPRSA-N Gln-Pro-Gly Chemical compound NC(=O)CC[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O FQCILXROGNOZON-YUMQZZPRSA-N 0.000 description 15
- 108010065920 Insulin Lispro Proteins 0.000 description 15
- QNBVTHNJGCOVFA-AVGNSLFASA-N Leu-Leu-Glu Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CCC(O)=O QNBVTHNJGCOVFA-AVGNSLFASA-N 0.000 description 15
- QOEZFICGUZTRFX-IHRRRGAJSA-N Tyr-Cys-Val Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CS)C(=O)N[C@@H](C(C)C)C(O)=O QOEZFICGUZTRFX-IHRRRGAJSA-N 0.000 description 15
- 108010037850 glycylvaline Proteins 0.000 description 15
- 108010044311 leucyl-glycyl-glycine Proteins 0.000 description 15
- 108010020755 prolyl-glycyl-glycine Proteins 0.000 description 15
- BVLIJXXSXBUGEC-SRVKXCTJSA-N Asn-Asn-Tyr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O BVLIJXXSXBUGEC-SRVKXCTJSA-N 0.000 description 14
- WNZOCXUOGVYYBJ-CDMKHQONSA-N Gly-Phe-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)NC(=O)CN)O WNZOCXUOGVYYBJ-CDMKHQONSA-N 0.000 description 14
- LCRDMSSAKLTKBU-ZDLURKLDSA-N Gly-Ser-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)CN LCRDMSSAKLTKBU-ZDLURKLDSA-N 0.000 description 14
- RHAPJNVNWDBFQI-BQBZGAKWSA-N Ser-Pro-Gly Chemical compound OC[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O RHAPJNVNWDBFQI-BQBZGAKWSA-N 0.000 description 14
- BMKNXTJLHFIAAH-CIUDSAMLSA-N Ser-Ser-Leu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O BMKNXTJLHFIAAH-CIUDSAMLSA-N 0.000 description 14
- KZSYAEWQMJEGRZ-RHYQMDGZSA-N Thr-Leu-Val Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(O)=O KZSYAEWQMJEGRZ-RHYQMDGZSA-N 0.000 description 14
- 125000000539 amino acid group Chemical group 0.000 description 14
- 102000000588 Interleukin-2 Human genes 0.000 description 13
- 108010002350 Interleukin-2 Proteins 0.000 description 13
- LINKCQUOMUDLKN-KATARQTJSA-N Leu-Thr-Cys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC(C)C)N)O LINKCQUOMUDLKN-KATARQTJSA-N 0.000 description 13
- NAXPHWZXEXNDIW-JTQLQIEISA-N Phe-Gly-Gly Chemical compound OC(=O)CNC(=O)CNC(=O)[C@@H](N)CC1=CC=CC=C1 NAXPHWZXEXNDIW-JTQLQIEISA-N 0.000 description 13
- UIGMAMGZOJVTDN-WHFBIAKZSA-N Ser-Gly-Ser Chemical compound OC[C@H](N)C(=O)NCC(=O)N[C@@H](CO)C(O)=O UIGMAMGZOJVTDN-WHFBIAKZSA-N 0.000 description 13
- LGNBRHZANHMZHK-NUMRIWBASA-N Thr-Glu-Asp Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CC(=O)O)C(=O)O)N)O LGNBRHZANHMZHK-NUMRIWBASA-N 0.000 description 13
- 108010064235 lysylglycine Proteins 0.000 description 13
- 108010077112 prolyl-proline Proteins 0.000 description 13
- NFDVJAKFMXHJEQ-HERUPUMHSA-N Ala-Asp-Trp Chemical compound C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)N NFDVJAKFMXHJEQ-HERUPUMHSA-N 0.000 description 12
- RAAWHFXHAACDFT-FXQIFTODSA-N Ala-Met-Asn Chemical compound CSCC[C@H](NC(=O)[C@H](C)N)C(=O)N[C@@H](CC(N)=O)C(O)=O RAAWHFXHAACDFT-FXQIFTODSA-N 0.000 description 12
- NTAZNGWBXRVEDJ-FXQIFTODSA-N Arg-Asp-Asp Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O NTAZNGWBXRVEDJ-FXQIFTODSA-N 0.000 description 12
- BMNVSPMWMICFRV-DCAQKATOSA-N Arg-His-Asp Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](CC(O)=O)C(O)=O)CC1=CN=CN1 BMNVSPMWMICFRV-DCAQKATOSA-N 0.000 description 12
- JOTRDIXZHNQYGP-DCAQKATOSA-N Arg-Ser-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CCCN=C(N)N)N JOTRDIXZHNQYGP-DCAQKATOSA-N 0.000 description 12
- AIFHRTPABBBHKU-RCWTZXSCSA-N Arg-Thr-Arg Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O AIFHRTPABBBHKU-RCWTZXSCSA-N 0.000 description 12
- YVXRYLVELQYAEQ-SRVKXCTJSA-N Asn-Leu-Lys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC(=O)N)N YVXRYLVELQYAEQ-SRVKXCTJSA-N 0.000 description 12
- MRQQMVZUHXUPEV-IHRRRGAJSA-N Asp-Arg-Phe Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O MRQQMVZUHXUPEV-IHRRRGAJSA-N 0.000 description 12
- OHLLDUNVMPPUMD-DCAQKATOSA-N Cys-Leu-Val Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](C(C)C)C(=O)O)NC(=O)[C@H](CS)N OHLLDUNVMPPUMD-DCAQKATOSA-N 0.000 description 12
- OCQUNKSFDYDXBG-QXEWZRGKSA-N Gly-Arg-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)CN)CCCN=C(N)N OCQUNKSFDYDXBG-QXEWZRGKSA-N 0.000 description 12
- GBYYQVBXFVDJPJ-WLTAIBSBSA-N Gly-Tyr-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)NC(=O)CN)O GBYYQVBXFVDJPJ-WLTAIBSBSA-N 0.000 description 12
- QYZYJFXHXYUZMZ-UGYAYLCHSA-N Ile-Asn-Asn Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC(=O)N)C(=O)O)N QYZYJFXHXYUZMZ-UGYAYLCHSA-N 0.000 description 12
- BRTVHXHCUSXYRI-CIUDSAMLSA-N Leu-Ser-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O BRTVHXHCUSXYRI-CIUDSAMLSA-N 0.000 description 12
- PDIDTSZKKFEDMB-UWVGGRQHSA-N Lys-Pro-Gly Chemical compound [H]N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O PDIDTSZKKFEDMB-UWVGGRQHSA-N 0.000 description 12
- QLFAPXUXEBAWEK-NHCYSSNCSA-N Lys-Val-Asp Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O QLFAPXUXEBAWEK-NHCYSSNCSA-N 0.000 description 12
- PESQCPHRXOFIPX-UHFFFAOYSA-N N-L-methionyl-L-tyrosine Natural products CSCCC(N)C(=O)NC(C(O)=O)CC1=CC=C(O)C=C1 PESQCPHRXOFIPX-UHFFFAOYSA-N 0.000 description 12
- GFDUZZACIWNMPE-KZVJFYERSA-N Thr-Ala-Met Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCSC)C(O)=O GFDUZZACIWNMPE-KZVJFYERSA-N 0.000 description 12
- NOXKHHXSHQFSGJ-FQPOAREZSA-N Tyr-Ala-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 NOXKHHXSHQFSGJ-FQPOAREZSA-N 0.000 description 12
- MWUYSCVVPVITMW-IGNZVWTISA-N Tyr-Tyr-Ala Chemical compound C([C@@H](C(=O)N[C@@H](C)C(O)=O)NC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=C(O)C=C1 MWUYSCVVPVITMW-IGNZVWTISA-N 0.000 description 12
- 108010018691 arginyl-threonyl-arginine Proteins 0.000 description 12
- 239000012636 effector Substances 0.000 description 12
- 210000004986 primary T-cell Anatomy 0.000 description 12
- 108010038745 tryptophylglycine Proteins 0.000 description 12
- ZJLORAAXDAJLDC-CQDKDKBSSA-N Ala-Tyr-Leu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(C)C)C(O)=O ZJLORAAXDAJLDC-CQDKDKBSSA-N 0.000 description 11
- VAWNQIGQPUOPQW-ACZMJKKPSA-N Asp-Glu-Ala Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(O)=O VAWNQIGQPUOPQW-ACZMJKKPSA-N 0.000 description 11
- MAGNEQBFSBREJL-DCAQKATOSA-N Gln-Glu-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CCC(=O)N)N MAGNEQBFSBREJL-DCAQKATOSA-N 0.000 description 11
- MSHXWFKYXJTLEZ-CIUDSAMLSA-N Gln-Met-Asn Chemical compound CSCC[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CCC(=O)N)N MSHXWFKYXJTLEZ-CIUDSAMLSA-N 0.000 description 11
- BIYNPVYAZOUVFQ-CIUDSAMLSA-N Glu-Pro-Ser Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O BIYNPVYAZOUVFQ-CIUDSAMLSA-N 0.000 description 11
- DZMWFIRHFFVBHS-ZEWNOJEFSA-N Ile-Tyr-Phe Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CC2=CC=CC=C2)C(=O)O)N DZMWFIRHFFVBHS-ZEWNOJEFSA-N 0.000 description 11
- HTKNPQZCMLBOTQ-XVSYOHENSA-N Phe-Asn-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CC1=CC=CC=C1)N)O HTKNPQZCMLBOTQ-XVSYOHENSA-N 0.000 description 11
- ZOHGLPQGEHSLPD-FXQIFTODSA-N Ser-Gln-Glu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O ZOHGLPQGEHSLPD-FXQIFTODSA-N 0.000 description 11
- HDBOEVPDIDDEPC-CIUDSAMLSA-N Ser-Lys-Asn Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(O)=O HDBOEVPDIDDEPC-CIUDSAMLSA-N 0.000 description 11
- JKGGPMOUIAAJAA-YEPSODPASA-N Thr-Gly-Val Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](C(C)C)C(O)=O JKGGPMOUIAAJAA-YEPSODPASA-N 0.000 description 11
- KZTLZZQTJMCGIP-ZJDVBMNYSA-N Thr-Val-Thr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O KZTLZZQTJMCGIP-ZJDVBMNYSA-N 0.000 description 11
- GBIUHAYJGWVNLN-UHFFFAOYSA-N Val-Ser-Pro Natural products CC(C)C(N)C(=O)NC(CO)C(=O)N1CCCC1C(O)=O GBIUHAYJGWVNLN-UHFFFAOYSA-N 0.000 description 11
- UQMPYVLTQCGRSK-IFFSRLJSSA-N Val-Thr-Gln Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](C(C)C)N)O UQMPYVLTQCGRSK-IFFSRLJSSA-N 0.000 description 11
- JAIZPWVHPQRYOU-ZJDVBMNYSA-N Val-Thr-Thr Chemical compound C[C@H]([C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)O)NC(=O)[C@H](C(C)C)N)O JAIZPWVHPQRYOU-ZJDVBMNYSA-N 0.000 description 11
- 230000010056 antibody-dependent cellular cytotoxicity Effects 0.000 description 11
- 108010047857 aspartylglycine Proteins 0.000 description 11
- 108010068265 aspartyltyrosine Proteins 0.000 description 11
- 108010044374 isoleucyl-tyrosine Proteins 0.000 description 11
- 108010017391 lysylvaline Proteins 0.000 description 11
- OLGCWMNDJTWQAG-GUBZILKMSA-N Asn-Glu-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CC(N)=O OLGCWMNDJTWQAG-GUBZILKMSA-N 0.000 description 10
- RBOBTTLFPRSXKZ-BZSNNMDCSA-N Asn-Phe-Tyr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O RBOBTTLFPRSXKZ-BZSNNMDCSA-N 0.000 description 10
- LPIKVBWNNVFHCQ-GUBZILKMSA-N Gln-Ser-Leu Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O LPIKVBWNNVFHCQ-GUBZILKMSA-N 0.000 description 10
- WGYHAAXZWPEBDQ-IFFSRLJSSA-N Glu-Val-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O WGYHAAXZWPEBDQ-IFFSRLJSSA-N 0.000 description 10
- WTUSRDZLLWGYAT-KCTSRDHCSA-N Gly-Trp-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)NC(=O)CN WTUSRDZLLWGYAT-KCTSRDHCSA-N 0.000 description 10
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 10
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 10
- IHCXPSYCHXFXKT-DCAQKATOSA-N Pro-Arg-Glu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(O)=O IHCXPSYCHXFXKT-DCAQKATOSA-N 0.000 description 10
- DZKFGCNKEVMXFA-JUKXBJQTSA-N Tyr-Ile-His Chemical compound CC[C@H](C)[C@H](NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)N[C@@H](Cc1cnc[nH]1)C(O)=O DZKFGCNKEVMXFA-JUKXBJQTSA-N 0.000 description 10
- SZEIFUXUTBBQFQ-STQMWFEESA-N Tyr-Pro-Gly Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O SZEIFUXUTBBQFQ-STQMWFEESA-N 0.000 description 10
- PLVVHGFEMSDRET-IHPCNDPISA-N Tyr-Ser-Trp Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC3=CC=C(C=C3)O)N PLVVHGFEMSDRET-IHPCNDPISA-N 0.000 description 10
- 108010052670 arginyl-glutamyl-glutamic acid Proteins 0.000 description 10
- 108010059459 arginyl-threonyl-phenylalanine Proteins 0.000 description 10
- 108010063718 gamma-glutamylaspartic acid Proteins 0.000 description 10
- 108010013768 glutamyl-aspartyl-proline Proteins 0.000 description 10
- 108010000434 glycyl-alanyl-leucine Proteins 0.000 description 10
- 108010050475 glycyl-leucyl-tyrosine Proteins 0.000 description 10
- 108010073472 leucyl-prolyl-proline Proteins 0.000 description 10
- 108010038320 lysylphenylalanine Proteins 0.000 description 10
- 108010024654 phenylalanyl-prolyl-alanine Proteins 0.000 description 10
- 108010035534 tyrosyl-leucyl-alanine Proteins 0.000 description 10
- WQLJRNRLHWJIRW-KKUMJFAQSA-N Asn-His-Tyr Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)O)NC(=O)[C@H](CC2=CN=CN2)NC(=O)[C@H](CC(=O)N)N)O WQLJRNRLHWJIRW-KKUMJFAQSA-N 0.000 description 9
- WLVLIYYBPPONRJ-GCJQMDKQSA-N Asn-Thr-Ala Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O WLVLIYYBPPONRJ-GCJQMDKQSA-N 0.000 description 9
- GJBUAAAIZSRCDC-GVXVVHGQSA-N Glu-Leu-Val Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(O)=O GJBUAAAIZSRCDC-GVXVVHGQSA-N 0.000 description 9
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 9
- VUBIPAHVHMZHCM-KKUMJFAQSA-N Leu-Tyr-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](CO)C(O)=O)CC1=CC=C(O)C=C1 VUBIPAHVHMZHCM-KKUMJFAQSA-N 0.000 description 9
- SITLTJHOQZFJGG-UHFFFAOYSA-N N-L-alpha-glutamyl-L-valine Natural products CC(C)C(C(O)=O)NC(=O)C(N)CCC(O)=O SITLTJHOQZFJGG-UHFFFAOYSA-N 0.000 description 9
- KIGGUSRFHJCIEJ-DCAQKATOSA-N Pro-Asp-His Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC2=CN=CN2)C(=O)O KIGGUSRFHJCIEJ-DCAQKATOSA-N 0.000 description 9
- AFXCXDQNRXTSBD-FJXKBIBVSA-N Pro-Gly-Thr Chemical compound [H]N1CCC[C@H]1C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(O)=O AFXCXDQNRXTSBD-FJXKBIBVSA-N 0.000 description 9
- YDTUEBLEAVANFH-RCWTZXSCSA-N Pro-Val-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H]1CCCN1 YDTUEBLEAVANFH-RCWTZXSCSA-N 0.000 description 9
- AVYVKJMBNLPWRX-WFBYXXMGSA-N Trp-Ala-Ser Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O)=CNC2=C1 AVYVKJMBNLPWRX-WFBYXXMGSA-N 0.000 description 9
- HSVPZJLMPLMPOX-BPNCWPANSA-N Tyr-Arg-Ala Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(O)=O HSVPZJLMPLMPOX-BPNCWPANSA-N 0.000 description 9
- MCRPZFQGVZLTAI-UHFFFAOYSA-N Val-Leu-Trp-Tyr Natural products C=1NC2=CC=CC=C2C=1CC(NC(=O)C(NC(=O)C(N)C(C)C)CC(C)C)C(=O)NC(C(O)=O)CC1=CC=C(O)C=C1 MCRPZFQGVZLTAI-UHFFFAOYSA-N 0.000 description 9
- 230000004540 complement-dependent cytotoxicity Effects 0.000 description 9
- 108010025306 histidylleucine Proteins 0.000 description 9
- 230000001900 immune effect Effects 0.000 description 9
- MNZHHDPWDWQJCQ-YUMQZZPRSA-N Ala-Leu-Gly Chemical compound C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O MNZHHDPWDWQJCQ-YUMQZZPRSA-N 0.000 description 8
- XQNRANMFRPCFFW-GCJQMDKQSA-N Ala-Thr-Asn Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](C)N)O XQNRANMFRPCFFW-GCJQMDKQSA-N 0.000 description 8
- HPBNLFLSSQDFQW-WHFBIAKZSA-N Asn-Ser-Gly Chemical compound NC(=O)C[C@H](N)C(=O)N[C@@H](CO)C(=O)NCC(O)=O HPBNLFLSSQDFQW-WHFBIAKZSA-N 0.000 description 8
- MNQMTYSEKZHIDF-GCJQMDKQSA-N Asp-Thr-Ala Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O MNQMTYSEKZHIDF-GCJQMDKQSA-N 0.000 description 8
- AAJHGGDRKHYSDH-GUBZILKMSA-N Glu-Pro-Gln Chemical compound C1C[C@H](N(C1)C(=O)[C@H](CCC(=O)O)N)C(=O)N[C@@H](CCC(=O)N)C(=O)O AAJHGGDRKHYSDH-GUBZILKMSA-N 0.000 description 8
- JSLVAHYTAJJEQH-QWRGUYRKSA-N Gly-Ser-Phe Chemical compound NCC(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 JSLVAHYTAJJEQH-QWRGUYRKSA-N 0.000 description 8
- ZNTSGDNUITWTRA-WDSOQIARSA-N His-Trp-Val Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](C(C)C)C(O)=O ZNTSGDNUITWTRA-WDSOQIARSA-N 0.000 description 8
- UHNQRAFSEBGZFZ-YESZJQIVSA-N Leu-Phe-Pro Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N2CCC[C@@H]2C(=O)O)N UHNQRAFSEBGZFZ-YESZJQIVSA-N 0.000 description 8
- DPURXCQCHSQPAN-AVGNSLFASA-N Leu-Pro-Pro Chemical compound CC(C)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 DPURXCQCHSQPAN-AVGNSLFASA-N 0.000 description 8
- WSXTWLJHTLRFLW-SRVKXCTJSA-N Lys-Ala-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(O)=O WSXTWLJHTLRFLW-SRVKXCTJSA-N 0.000 description 8
- YFQSSOAGMZGXFT-MEYUZBJRSA-N Lys-Thr-Tyr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O YFQSSOAGMZGXFT-MEYUZBJRSA-N 0.000 description 8
- GILLQRYAWOMHED-DCAQKATOSA-N Lys-Val-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CCCCN GILLQRYAWOMHED-DCAQKATOSA-N 0.000 description 8
- 241000699666 Mus <mouse, genus> Species 0.000 description 8
- FMLRRBDLBJLJIK-DCAQKATOSA-N Pro-Leu-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H]1CCCN1 FMLRRBDLBJLJIK-DCAQKATOSA-N 0.000 description 8
- UGJRQLURDVGULT-LKXGYXEUSA-N Ser-Asn-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O UGJRQLURDVGULT-LKXGYXEUSA-N 0.000 description 8
- ZKOKTQPHFMRSJP-YJRXYDGGSA-N Ser-Thr-Tyr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O ZKOKTQPHFMRSJP-YJRXYDGGSA-N 0.000 description 8
- BBPCSGKKPJUYRB-UVOCVTCTSA-N Thr-Thr-Leu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O BBPCSGKKPJUYRB-UVOCVTCTSA-N 0.000 description 8
- CYCGARJWIQWPQM-YJRXYDGGSA-N Thr-Tyr-Ser Chemical compound C[C@@H](O)[C@H]([NH3+])C(=O)N[C@H](C(=O)N[C@@H](CO)C([O-])=O)CC1=CC=C(O)C=C1 CYCGARJWIQWPQM-YJRXYDGGSA-N 0.000 description 8
- HGJRMXOWUWVUOA-GVXVVHGQSA-N Val-Leu-Gln Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](C(C)C)N HGJRMXOWUWVUOA-GVXVVHGQSA-N 0.000 description 8
- HTONZBWRYUKUKC-RCWTZXSCSA-N Val-Thr-Val Chemical compound CC(C)[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(O)=O HTONZBWRYUKUKC-RCWTZXSCSA-N 0.000 description 8
- BGTDGENDNWGMDQ-KJEVXHAQSA-N Val-Tyr-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)NC(=O)[C@H](C(C)C)N)O BGTDGENDNWGMDQ-KJEVXHAQSA-N 0.000 description 8
- 108010081404 acein-2 Proteins 0.000 description 8
- 239000013543 active substance Substances 0.000 description 8
- 108010069205 aspartyl-phenylalanine Proteins 0.000 description 8
- 238000001514 detection method Methods 0.000 description 8
- 238000010494 dissociation reaction Methods 0.000 description 8
- 230000005593 dissociations Effects 0.000 description 8
- 108010049041 glutamylalanine Proteins 0.000 description 8
- 108010010147 glycylglutamine Proteins 0.000 description 8
- 108010070409 phenylalanyl-glycyl-glycine Proteins 0.000 description 8
- 108010070643 prolylglutamic acid Proteins 0.000 description 8
- 108010061238 threonyl-glycine Proteins 0.000 description 8
- 108010071097 threonyl-lysyl-proline Proteins 0.000 description 8
- 108010073969 valyllysine Proteins 0.000 description 8
- YQPSDMUGFKJZHR-QRTARXTBSA-N Asn-Trp-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)NC(=O)[C@H](CC(=O)N)N YQPSDMUGFKJZHR-QRTARXTBSA-N 0.000 description 7
- JPPLRQVZMZFOSX-UWJYBYFXSA-N Asn-Tyr-Ala Chemical compound NC(=O)C[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](C)C(O)=O)CC1=CC=C(O)C=C1 JPPLRQVZMZFOSX-UWJYBYFXSA-N 0.000 description 7
- KSMSFCBQBQPFAD-GUBZILKMSA-N Cys-Pro-Pro Chemical compound SC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 KSMSFCBQBQPFAD-GUBZILKMSA-N 0.000 description 7
- KZZYVYWSXMFYEC-DCAQKATOSA-N Cys-Val-Leu Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O KZZYVYWSXMFYEC-DCAQKATOSA-N 0.000 description 7
- 102000004127 Cytokines Human genes 0.000 description 7
- 108090000695 Cytokines Proteins 0.000 description 7
- 238000002965 ELISA Methods 0.000 description 7
- 108010087819 Fc receptors Proteins 0.000 description 7
- 102000009109 Fc receptors Human genes 0.000 description 7
- AQPZYBSRDRZBAG-AVGNSLFASA-N Gln-Phe-Asn Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CCC(=O)N)N AQPZYBSRDRZBAG-AVGNSLFASA-N 0.000 description 7
- ZYRXTRTUCAVNBQ-GVXVVHGQSA-N Glu-Val-Lys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCC(=O)O)N ZYRXTRTUCAVNBQ-GVXVVHGQSA-N 0.000 description 7
- VBOBNHSVQKKTOT-YUMQZZPRSA-N Gly-Lys-Ala Chemical compound [H]NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O VBOBNHSVQKKTOT-YUMQZZPRSA-N 0.000 description 7
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 7
- 101100438942 Homo sapiens CD3E gene Proteins 0.000 description 7
- STAVRDQLZOTNKJ-RHYQMDGZSA-N Leu-Arg-Thr Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(O)=O STAVRDQLZOTNKJ-RHYQMDGZSA-N 0.000 description 7
- QJXHMYMRGDOHRU-NHCYSSNCSA-N Leu-Ile-Gly Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(O)=O QJXHMYMRGDOHRU-NHCYSSNCSA-N 0.000 description 7
- YOKVEHGYYQEQOP-QWRGUYRKSA-N Leu-Leu-Gly Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O YOKVEHGYYQEQOP-QWRGUYRKSA-N 0.000 description 7
- YWKNKRAKOCLOLH-OEAJRASXSA-N Leu-Phe-Thr Chemical compound CC(C)C[C@H](N)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)O)C(O)=O)CC1=CC=CC=C1 YWKNKRAKOCLOLH-OEAJRASXSA-N 0.000 description 7
- RGUXWMDNCPMQFB-YUMQZZPRSA-N Leu-Ser-Gly Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CO)C(=O)NCC(O)=O RGUXWMDNCPMQFB-YUMQZZPRSA-N 0.000 description 7
- XOWMDXHFSBCAKQ-SRVKXCTJSA-N Leu-Ser-Leu Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CC(C)C XOWMDXHFSBCAKQ-SRVKXCTJSA-N 0.000 description 7
- CDNPIRSCAFMMBE-SRVKXCTJSA-N Phe-Asn-Ser Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(O)=O CDNPIRSCAFMMBE-SRVKXCTJSA-N 0.000 description 7
- JDMKQHSHKJHAHR-UHFFFAOYSA-N Phe-Phe-Leu-Tyr Natural products C=1C=C(O)C=CC=1CC(C(O)=O)NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)CC1=CC=CC=C1 JDMKQHSHKJHAHR-UHFFFAOYSA-N 0.000 description 7
- VXCHGLYSIOOZIS-GUBZILKMSA-N Pro-Ala-Arg Chemical compound NC(N)=NCCC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1 VXCHGLYSIOOZIS-GUBZILKMSA-N 0.000 description 7
- MKGIILKDUGDRRO-FXQIFTODSA-N Pro-Ser-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H]1CCCN1 MKGIILKDUGDRRO-FXQIFTODSA-N 0.000 description 7
- FMDHKPRACUXATF-ACZMJKKPSA-N Ser-Gln-Ser Chemical compound OC[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(O)=O FMDHKPRACUXATF-ACZMJKKPSA-N 0.000 description 7
- XXXAXOWMBOKTRN-XPUUQOCRSA-N Ser-Gly-Val Chemical compound [H]N[C@@H](CO)C(=O)NCC(=O)N[C@@H](C(C)C)C(O)=O XXXAXOWMBOKTRN-XPUUQOCRSA-N 0.000 description 7
- YUJLIIRMIAGMCQ-CIUDSAMLSA-N Ser-Leu-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O YUJLIIRMIAGMCQ-CIUDSAMLSA-N 0.000 description 7
- ZJPSMXCFEKMZFE-IHPCNDPISA-N Trp-Tyr-Ser Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CO)C(O)=O ZJPSMXCFEKMZFE-IHPCNDPISA-N 0.000 description 7
- JVGDAEKKZKKZFO-RCWTZXSCSA-N Val-Val-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](C(C)C)N)O JVGDAEKKZKKZFO-RCWTZXSCSA-N 0.000 description 7
- 230000004913 activation Effects 0.000 description 7
- VPZXBVLAVMBEQI-UHFFFAOYSA-N glycyl-DL-alpha-alanine Natural products OC(=O)C(C)NC(=O)CN VPZXBVLAVMBEQI-UHFFFAOYSA-N 0.000 description 7
- 210000004408 hybridoma Anatomy 0.000 description 7
- 108010025153 lysyl-alanyl-alanine Proteins 0.000 description 7
- 230000004048 modification Effects 0.000 description 7
- 238000012986 modification Methods 0.000 description 7
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- 108010051110 tyrosyl-lysine Proteins 0.000 description 7
- 108010077037 tyrosyl-tyrosyl-phenylalanine Proteins 0.000 description 7
- DPNZTBKGAUAZQU-DLOVCJGASA-N Ala-Leu-His Chemical compound C[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N DPNZTBKGAUAZQU-DLOVCJGASA-N 0.000 description 6
- OINVDEKBKBCPLX-JXUBOQSCSA-N Ala-Lys-Thr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O OINVDEKBKBCPLX-JXUBOQSCSA-N 0.000 description 6
- MDNAVFBZPROEHO-UHFFFAOYSA-N Ala-Lys-Val Natural products CC(C)C(C(O)=O)NC(=O)C(NC(=O)C(C)N)CCCCN MDNAVFBZPROEHO-UHFFFAOYSA-N 0.000 description 6
- ZJBUILVYSXQNSW-YTWAJWBKSA-N Arg-Thr-Pro Chemical compound C[C@H]([C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCCN=C(N)N)N)O ZJBUILVYSXQNSW-YTWAJWBKSA-N 0.000 description 6
- SVABRQFIHCSNCI-FOHZUACHSA-N Asp-Gly-Thr Chemical compound [H]N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(O)=O SVABRQFIHCSNCI-FOHZUACHSA-N 0.000 description 6
- KYQNAIMCTRZLNP-QSFUFRPTSA-N Asp-Ile-Val Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C(C)C)C(O)=O KYQNAIMCTRZLNP-QSFUFRPTSA-N 0.000 description 6
- CUQDCPXNZPDYFQ-ZLUOBGJFSA-N Asp-Ser-Asp Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(O)=O CUQDCPXNZPDYFQ-ZLUOBGJFSA-N 0.000 description 6
- NIXHTNJAGGFBAW-CIUDSAMLSA-N Cys-Lys-Ser Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CS)N NIXHTNJAGGFBAW-CIUDSAMLSA-N 0.000 description 6
- BPCLDCNZBUYGOD-BPUTZDHNSA-N Glu-Trp-Glu Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](CCC(O)=O)N)C(=O)N[C@@H](CCC(O)=O)C(O)=O)=CNC2=C1 BPCLDCNZBUYGOD-BPUTZDHNSA-N 0.000 description 6
- BUEFQXUHTUZXHR-LURJTMIESA-N Gly-Gly-Pro zwitterion Chemical compound NCC(=O)NCC(=O)N1CCC[C@H]1C(O)=O BUEFQXUHTUZXHR-LURJTMIESA-N 0.000 description 6
- GMTXWRIDLGTVFC-IUCAKERBSA-N Gly-Lys-Glu Chemical compound [H]NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(O)=O GMTXWRIDLGTVFC-IUCAKERBSA-N 0.000 description 6
- NVTPVQLIZCOJFK-FOHZUACHSA-N Gly-Thr-Asp Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(O)=O NVTPVQLIZCOJFK-FOHZUACHSA-N 0.000 description 6
- WZOGEMJIZBNFBK-CIUDSAMLSA-N His-Asp-Asn Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O WZOGEMJIZBNFBK-CIUDSAMLSA-N 0.000 description 6
- TTYKEFZRLKQTHH-MELADBBJSA-N His-Lys-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCCCN)NC(=O)[C@H](CC2=CN=CN2)N)C(=O)O TTYKEFZRLKQTHH-MELADBBJSA-N 0.000 description 6
- DFJJAVZIHDFOGQ-MNXVOIDGSA-N Ile-Glu-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCCCN)C(=O)O)N DFJJAVZIHDFOGQ-MNXVOIDGSA-N 0.000 description 6
- PXKACEXYLPBMAD-JBDRJPRFSA-N Ile-Ser-Ser Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)O)N PXKACEXYLPBMAD-JBDRJPRFSA-N 0.000 description 6
- HXWALXSAVBLTPK-NUTKFTJISA-N Leu-Ala-Trp Chemical compound C[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)NC(=O)[C@H](CC(C)C)N HXWALXSAVBLTPK-NUTKFTJISA-N 0.000 description 6
- FAELBUXXFQLUAX-AJNGGQMLSA-N Leu-Leu-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC(C)C FAELBUXXFQLUAX-AJNGGQMLSA-N 0.000 description 6
- 239000005089 Luciferase Substances 0.000 description 6
- UWKNTTJNVSYXPC-CIUDSAMLSA-N Lys-Ala-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCCN UWKNTTJNVSYXPC-CIUDSAMLSA-N 0.000 description 6
- PXHCFKXNSBJSTQ-KKUMJFAQSA-N Lys-Asn-Tyr Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CCCCN)N)O PXHCFKXNSBJSTQ-KKUMJFAQSA-N 0.000 description 6
- NTBFKPBULZGXQL-KKUMJFAQSA-N Lys-Asp-Tyr Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 NTBFKPBULZGXQL-KKUMJFAQSA-N 0.000 description 6
- RFQATBGBLDAKGI-VHSXEESVSA-N Lys-Gly-Pro Chemical compound C1C[C@@H](N(C1)C(=O)CNC(=O)[C@H](CCCCN)N)C(=O)O RFQATBGBLDAKGI-VHSXEESVSA-N 0.000 description 6
- RKIIYGUHIQJCBW-SRVKXCTJSA-N Met-His-Glu Chemical compound [H]N[C@@H](CCSC)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCC(O)=O)C(O)=O RKIIYGUHIQJCBW-SRVKXCTJSA-N 0.000 description 6
- FWAHLGXNBLWIKB-NAKRPEOUSA-N Met-Ile-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H](N)CCSC FWAHLGXNBLWIKB-NAKRPEOUSA-N 0.000 description 6
- KZNQNBZMBZJQJO-UHFFFAOYSA-N N-glycyl-L-proline Natural products NCC(=O)N1CCCC1C(O)=O KZNQNBZMBZJQJO-UHFFFAOYSA-N 0.000 description 6
- 108010079364 N-glycylalanine Proteins 0.000 description 6
- QARPMYDMYVLFMW-KKUMJFAQSA-N Phe-Pro-Glu Chemical compound C([C@H](N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(O)=O)C1=CC=CC=C1 QARPMYDMYVLFMW-KKUMJFAQSA-N 0.000 description 6
- JHSRGEODDALISP-XVSYOHENSA-N Phe-Thr-Asn Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(O)=O JHSRGEODDALISP-XVSYOHENSA-N 0.000 description 6
- KLYYKKGCPOGDPE-OEAJRASXSA-N Phe-Thr-Leu Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O KLYYKKGCPOGDPE-OEAJRASXSA-N 0.000 description 6
- GNRMAQSIROFNMI-IXOXFDKPSA-N Phe-Thr-Ser Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(O)=O GNRMAQSIROFNMI-IXOXFDKPSA-N 0.000 description 6
- SJRQWEDYTKYHHL-SLFFLAALSA-N Phe-Tyr-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC2=CC=C(C=C2)O)NC(=O)[C@H](CC3=CC=CC=C3)N)C(=O)O SJRQWEDYTKYHHL-SLFFLAALSA-N 0.000 description 6
- CGBYDGAJHSOGFQ-LPEHRKFASA-N Pro-Ala-Pro Chemical compound C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@@H]2CCCN2 CGBYDGAJHSOGFQ-LPEHRKFASA-N 0.000 description 6
- JARJPEMLQAWNBR-GUBZILKMSA-N Pro-Asp-Arg Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O JARJPEMLQAWNBR-GUBZILKMSA-N 0.000 description 6
- KHRLUIPIMIQFGT-AVGNSLFASA-N Pro-Val-Leu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O KHRLUIPIMIQFGT-AVGNSLFASA-N 0.000 description 6
- HZWAHWQZPSXNCB-BPUTZDHNSA-N Ser-Arg-Trp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O HZWAHWQZPSXNCB-BPUTZDHNSA-N 0.000 description 6
- VAUMZJHYZQXZBQ-WHFBIAKZSA-N Ser-Asn-Gly Chemical compound OC[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(O)=O VAUMZJHYZQXZBQ-WHFBIAKZSA-N 0.000 description 6
- SFTZWNJFZYOLBD-ZDLURKLDSA-N Ser-Gly-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CO SFTZWNJFZYOLBD-ZDLURKLDSA-N 0.000 description 6
- FUMGHWDRRFCKEP-CIUDSAMLSA-N Ser-Leu-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(O)=O FUMGHWDRRFCKEP-CIUDSAMLSA-N 0.000 description 6
- MUJQWSAWLLRJCE-KATARQTJSA-N Ser-Leu-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O MUJQWSAWLLRJCE-KATARQTJSA-N 0.000 description 6
- NMZXJDSKEGFDLJ-DCAQKATOSA-N Ser-Pro-Lys Chemical compound C1C[C@H](N(C1)C(=O)[C@H](CO)N)C(=O)N[C@@H](CCCCN)C(=O)O NMZXJDSKEGFDLJ-DCAQKATOSA-N 0.000 description 6
- SRSPTFBENMJHMR-WHFBIAKZSA-N Ser-Ser-Gly Chemical compound OC[C@H](N)C(=O)N[C@@H](CO)C(=O)NCC(O)=O SRSPTFBENMJHMR-WHFBIAKZSA-N 0.000 description 6
- RXUOAOOZIWABBW-XGEHTFHBSA-N Ser-Thr-Arg Chemical compound OC[C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@H](C(O)=O)CCCN=C(N)N RXUOAOOZIWABBW-XGEHTFHBSA-N 0.000 description 6
- JMZKMSTYXHFYAK-VEVYYDQMSA-N Thr-Arg-Asn Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC(=O)N)C(=O)O)N)O JMZKMSTYXHFYAK-VEVYYDQMSA-N 0.000 description 6
- JMBRNXUOLJFURW-BEAPCOKYSA-N Thr-Phe-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N2CCC[C@@H]2C(=O)O)N)O JMBRNXUOLJFURW-BEAPCOKYSA-N 0.000 description 6
- QYSBJAUCUKHSLU-JYJNAYRXSA-N Tyr-Arg-Val Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(O)=O QYSBJAUCUKHSLU-JYJNAYRXSA-N 0.000 description 6
- QUILOGWWLXMSAT-IHRRRGAJSA-N Tyr-Gln-Gln Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O QUILOGWWLXMSAT-IHRRRGAJSA-N 0.000 description 6
- GZUIDWDVMWZSMI-KKUMJFAQSA-N Tyr-Lys-Cys Chemical compound NCCCC[C@@H](C(=O)N[C@@H](CS)C(O)=O)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 GZUIDWDVMWZSMI-KKUMJFAQSA-N 0.000 description 6
- LMKKMCGTDANZTR-BZSNNMDCSA-N Tyr-Phe-Asp Chemical compound C([C@H](N)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC(O)=O)C(O)=O)C1=CC=C(O)C=C1 LMKKMCGTDANZTR-BZSNNMDCSA-N 0.000 description 6
- MQGGXGKQSVEQHR-KKUMJFAQSA-N Tyr-Ser-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 MQGGXGKQSVEQHR-KKUMJFAQSA-N 0.000 description 6
- ZYVAAYAOTVJBSS-GMVOTWDCSA-N Tyr-Trp-Ala Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](C)C(O)=O ZYVAAYAOTVJBSS-GMVOTWDCSA-N 0.000 description 6
- HNWQUBBOBKSFQV-AVGNSLFASA-N Val-Arg-His Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N HNWQUBBOBKSFQV-AVGNSLFASA-N 0.000 description 6
- BMGOFDMKDVVGJG-NHCYSSNCSA-N Val-Asp-Lys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CCCCN)C(=O)O)N BMGOFDMKDVVGJG-NHCYSSNCSA-N 0.000 description 6
- OACSGBOREVRSME-NHCYSSNCSA-N Val-His-Asn Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](Cc1cnc[nH]1)C(=O)N[C@@H](CC(N)=O)C(O)=O OACSGBOREVRSME-NHCYSSNCSA-N 0.000 description 6
- SSYBNWFXCFNRFN-GUBZILKMSA-N Val-Pro-Ser Chemical compound CC(C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O SSYBNWFXCFNRFN-GUBZILKMSA-N 0.000 description 6
- VHIZXDZMTDVFGX-DCAQKATOSA-N Val-Ser-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](C(C)C)N VHIZXDZMTDVFGX-DCAQKATOSA-N 0.000 description 6
- SDHZOOIGIUEPDY-JYJNAYRXSA-N Val-Ser-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](CO)NC(=O)[C@@H](N)C(C)C)C(O)=O)=CNC2=C1 SDHZOOIGIUEPDY-JYJNAYRXSA-N 0.000 description 6
- 108010008685 alanyl-glutamyl-aspartic acid Proteins 0.000 description 6
- 230000004075 alteration Effects 0.000 description 6
- 108010009111 arginyl-glycyl-glutamic acid Proteins 0.000 description 6
- 210000004899 c-terminal region Anatomy 0.000 description 6
- FSXRLASFHBWESK-UHFFFAOYSA-N dipeptide phenylalanyl-tyrosine Natural products C=1C=C(O)C=CC=1CC(C(O)=O)NC(=O)C(N)CC1=CC=CC=C1 FSXRLASFHBWESK-UHFFFAOYSA-N 0.000 description 6
- 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 6
- 108010073101 phenylalanylleucine Proteins 0.000 description 6
- 239000002953 phosphate buffered saline Substances 0.000 description 6
- 108010069117 seryl-lysyl-aspartic acid Proteins 0.000 description 6
- 239000003381 stabilizer Substances 0.000 description 6
- 239000006228 supernatant Substances 0.000 description 6
- 108010044292 tryptophyltyrosine Proteins 0.000 description 6
- 108010052774 valyl-lysyl-glycyl-phenylalanyl-tyrosine Proteins 0.000 description 6
- SVBXIUDNTRTKHE-CIUDSAMLSA-N Ala-Arg-Glu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(O)=O SVBXIUDNTRTKHE-CIUDSAMLSA-N 0.000 description 5
- RMAWDDRDTRSZIR-ZLUOBGJFSA-N Ala-Ser-Asp Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(O)=O RMAWDDRDTRSZIR-ZLUOBGJFSA-N 0.000 description 5
- WQKAQKZRDIZYNV-VZFHVOOUSA-N Ala-Ser-Thr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(O)=O WQKAQKZRDIZYNV-VZFHVOOUSA-N 0.000 description 5
- ZDILXFDENZVOTL-BPNCWPANSA-N Ala-Val-Tyr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O ZDILXFDENZVOTL-BPNCWPANSA-N 0.000 description 5
- ULBHWNVWSCJLCO-NHCYSSNCSA-N Arg-Val-Glu Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CCCN=C(N)N ULBHWNVWSCJLCO-NHCYSSNCSA-N 0.000 description 5
- SRUUBQBAVNQZGJ-LAEOZQHASA-N Asn-Gln-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CC(=O)N)N SRUUBQBAVNQZGJ-LAEOZQHASA-N 0.000 description 5
- NYGILGUOUOXGMJ-YUMQZZPRSA-N Asn-Lys-Gly Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)NCC(O)=O NYGILGUOUOXGMJ-YUMQZZPRSA-N 0.000 description 5
- HNXWVVHIGTZTBO-LKXGYXEUSA-N Asn-Ser-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O HNXWVVHIGTZTBO-LKXGYXEUSA-N 0.000 description 5
- KBQOUDLMWYWXNP-YDHLFZDLSA-N Asn-Val-Phe Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)NC(=O)[C@H](CC(=O)N)N KBQOUDLMWYWXNP-YDHLFZDLSA-N 0.000 description 5
- HOQGTAIGQSDCHR-SRVKXCTJSA-N Asp-Asn-Phe Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O HOQGTAIGQSDCHR-SRVKXCTJSA-N 0.000 description 5
- JSNWZMFSLIWAHS-HJGDQZAQSA-N Asp-Thr-Leu Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)O)NC(=O)[C@H](CC(=O)O)N)O JSNWZMFSLIWAHS-HJGDQZAQSA-N 0.000 description 5
- SMEYEQDCCBHTEF-FXQIFTODSA-N Cys-Pro-Ala Chemical compound [H]N[C@@H](CS)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C)C(O)=O SMEYEQDCCBHTEF-FXQIFTODSA-N 0.000 description 5
- NDNZRWUDUMTITL-FXQIFTODSA-N Cys-Ser-Val Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O NDNZRWUDUMTITL-FXQIFTODSA-N 0.000 description 5
- ALTQTAKGRFLRLR-GUBZILKMSA-N Cys-Val-Val Chemical compound CC(C)[C@@H](C(=O)N[C@@H](C(C)C)C(=O)O)NC(=O)[C@H](CS)N ALTQTAKGRFLRLR-GUBZILKMSA-N 0.000 description 5
- KCJJFESQRXGTGC-BQBZGAKWSA-N Gln-Glu-Gly Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(O)=O KCJJFESQRXGTGC-BQBZGAKWSA-N 0.000 description 5
- JXFLPKSDLDEOQK-JHEQGTHGSA-N Gln-Gly-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CCC(N)=O JXFLPKSDLDEOQK-JHEQGTHGSA-N 0.000 description 5
- CKOFNWCLWRYUHK-XHNCKOQMSA-N Glu-Asp-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC(=O)O)NC(=O)[C@H](CCC(=O)O)N)C(=O)O CKOFNWCLWRYUHK-XHNCKOQMSA-N 0.000 description 5
- YHOJJFFTSMWVGR-HJGDQZAQSA-N Glu-Met-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H]([C@@H](C)O)C(O)=O YHOJJFFTSMWVGR-HJGDQZAQSA-N 0.000 description 5
- DNAZKGFYFRGZIH-QWRGUYRKSA-N Gly-Tyr-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)CN)CC1=CC=C(O)C=C1 DNAZKGFYFRGZIH-QWRGUYRKSA-N 0.000 description 5
- SYOJVRNQCXYEOV-XVKPBYJWSA-N Gly-Val-Glu Chemical compound [H]NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O SYOJVRNQCXYEOV-XVKPBYJWSA-N 0.000 description 5
- FULZDMOZUZKGQU-ONGXEEELSA-N Gly-Val-His Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)CN FULZDMOZUZKGQU-ONGXEEELSA-N 0.000 description 5
- MKWSZEHGHSLNPF-NAKRPEOUSA-N Ile-Ala-Val Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)O)N MKWSZEHGHSLNPF-NAKRPEOUSA-N 0.000 description 5
- OGCQGUIWMSBHRZ-CIUDSAMLSA-N Leu-Asn-Ser Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(O)=O OGCQGUIWMSBHRZ-CIUDSAMLSA-N 0.000 description 5
- BKTXKJMNTSMJDQ-AVGNSLFASA-N Leu-His-Gln Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N BKTXKJMNTSMJDQ-AVGNSLFASA-N 0.000 description 5
- YIRIDPUGZKHMHT-ACRUOGEOSA-N Leu-Tyr-Tyr Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O YIRIDPUGZKHMHT-ACRUOGEOSA-N 0.000 description 5
- 108060001084 Luciferase Proteins 0.000 description 5
- NKKFVJRLCCUJNA-QWRGUYRKSA-N Lys-Gly-Lys Chemical compound NCCCC[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CCCCN NKKFVJRLCCUJNA-QWRGUYRKSA-N 0.000 description 5
- 241000699670 Mus sp. Species 0.000 description 5
- XMBSYZWANAQXEV-UHFFFAOYSA-N N-alpha-L-glutamyl-L-phenylalanine Natural products OC(=O)CCC(N)C(=O)NC(C(O)=O)CC1=CC=CC=C1 XMBSYZWANAQXEV-UHFFFAOYSA-N 0.000 description 5
- 108091028043 Nucleic acid sequence Proteins 0.000 description 5
- OYQBFWWQSVIHBN-FHWLQOOXSA-N Phe-Glu-Phe Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O OYQBFWWQSVIHBN-FHWLQOOXSA-N 0.000 description 5
- BSKMOCNNLNDIMU-CDMKHQONSA-N Phe-Thr-Gly Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(O)=O BSKMOCNNLNDIMU-CDMKHQONSA-N 0.000 description 5
- HQVPQXMCQKXARZ-FXQIFTODSA-N Pro-Cys-Ser Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CS)C(=O)N[C@@H](CO)C(=O)O HQVPQXMCQKXARZ-FXQIFTODSA-N 0.000 description 5
- ULWBBFKQBDNGOY-RWMBFGLXSA-N Pro-Lys-Pro Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CCCCN)C(=O)N2CCC[C@@H]2C(=O)O ULWBBFKQBDNGOY-RWMBFGLXSA-N 0.000 description 5
- UEJYSALTSUZXFV-SRVKXCTJSA-N Rigin Chemical compound NCC(=O)N[C@@H](CCC(N)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCN=C(N)N)C(O)=O UEJYSALTSUZXFV-SRVKXCTJSA-N 0.000 description 5
- SNXUIBACCONSOH-BWBBJGPYSA-N Ser-Thr-Ser Chemical compound OC[C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@@H](CO)C(O)=O SNXUIBACCONSOH-BWBBJGPYSA-N 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 108010092262 T-Cell Antigen Receptors Proteins 0.000 description 5
- 102000016266 T-Cell Antigen Receptors Human genes 0.000 description 5
- LAFLAXHTDVNVEL-WDCWCFNPSA-N Thr-Gln-Lys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CCCCN)C(=O)O)N)O LAFLAXHTDVNVEL-WDCWCFNPSA-N 0.000 description 5
- SPVHQURZJCUDQC-VOAKCMCISA-N Thr-Lys-Leu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(O)=O SPVHQURZJCUDQC-VOAKCMCISA-N 0.000 description 5
- QNCFWHZVRNXAKW-OEAJRASXSA-N Thr-Lys-Phe Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O QNCFWHZVRNXAKW-OEAJRASXSA-N 0.000 description 5
- KKPOGALELPLJTL-MEYUZBJRSA-N Thr-Lys-Tyr Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 KKPOGALELPLJTL-MEYUZBJRSA-N 0.000 description 5
- ZESGVALRVJIVLZ-VFCFLDTKSA-N Thr-Thr-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)N1CCC[C@@H]1C(=O)O)N)O ZESGVALRVJIVLZ-VFCFLDTKSA-N 0.000 description 5
- XGFGVFMXDXALEV-XIRDDKMYSA-N Trp-Leu-Asn Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)N XGFGVFMXDXALEV-XIRDDKMYSA-N 0.000 description 5
- SSSDKJMQMZTMJP-BVSLBCMMSA-N Trp-Tyr-Val Chemical compound C([C@@H](C(=O)N[C@@H](C(C)C)C(O)=O)NC(=O)[C@@H](N)CC=1C2=CC=CC=C2NC=1)C1=CC=C(O)C=C1 SSSDKJMQMZTMJP-BVSLBCMMSA-N 0.000 description 5
- AZGZDDNKFFUDEH-QWRGUYRKSA-N Tyr-Gly-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CC1=CC=C(O)C=C1 AZGZDDNKFFUDEH-QWRGUYRKSA-N 0.000 description 5
- PWKMJDQXKCENMF-MEYUZBJRSA-N Tyr-Thr-Leu Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O PWKMJDQXKCENMF-MEYUZBJRSA-N 0.000 description 5
- NUQZCPSZHGIYTA-HKUYNNGSSA-N Tyr-Trp-Gly Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)NCC(=O)O)NC(=O)[C@H](CC3=CC=C(C=C3)O)N NUQZCPSZHGIYTA-HKUYNNGSSA-N 0.000 description 5
- NZYNRRGJJVSSTJ-GUBZILKMSA-N Val-Ser-Val Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O NZYNRRGJJVSSTJ-GUBZILKMSA-N 0.000 description 5
- ZLNYBMWGPOKSLW-LSJOCFKGSA-N Val-Val-Asp Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O ZLNYBMWGPOKSLW-LSJOCFKGSA-N 0.000 description 5
- KOSRFJWDECSPRO-UHFFFAOYSA-N alpha-L-glutamyl-L-glutamic acid Natural products OC(=O)CCC(N)C(=O)NC(CCC(O)=O)C(O)=O KOSRFJWDECSPRO-UHFFFAOYSA-N 0.000 description 5
- 238000003556 assay Methods 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 230000000295 complement effect Effects 0.000 description 5
- UQLDLKMNUJERMK-UHFFFAOYSA-L di(octadecanoyloxy)lead Chemical compound [Pb+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O UQLDLKMNUJERMK-UHFFFAOYSA-L 0.000 description 5
- 238000010790 dilution Methods 0.000 description 5
- 239000012895 dilution Substances 0.000 description 5
- 238000011156 evaluation Methods 0.000 description 5
- 210000004602 germ cell Anatomy 0.000 description 5
- 108010055341 glutamyl-glutamic acid Proteins 0.000 description 5
- 108010015792 glycyllysine Proteins 0.000 description 5
- 230000005847 immunogenicity Effects 0.000 description 5
- 238000000338 in vitro Methods 0.000 description 5
- 108010091871 leucylmethionine Proteins 0.000 description 5
- 239000002609 medium Substances 0.000 description 5
- 108010024607 phenylalanylalanine Proteins 0.000 description 5
- 108010051242 phenylalanylserine Proteins 0.000 description 5
- 108091033319 polynucleotide Proteins 0.000 description 5
- 102000040430 polynucleotide Human genes 0.000 description 5
- 239000002157 polynucleotide Substances 0.000 description 5
- 230000002829 reductive effect Effects 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 108010079202 tyrosyl-alanyl-cysteine Proteins 0.000 description 5
- CXRCVCURMBFFOL-FXQIFTODSA-N Ala-Ala-Pro Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O CXRCVCURMBFFOL-FXQIFTODSA-N 0.000 description 4
- KUDREHRZRIVKHS-UWJYBYFXSA-N Ala-Asp-Tyr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O KUDREHRZRIVKHS-UWJYBYFXSA-N 0.000 description 4
- ARHJJAAWNWOACN-FXQIFTODSA-N Ala-Ser-Val Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O ARHJJAAWNWOACN-FXQIFTODSA-N 0.000 description 4
- YNOCMHZSWJMGBB-GCJQMDKQSA-N Ala-Thr-Asp Chemical compound [H]N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(O)=O YNOCMHZSWJMGBB-GCJQMDKQSA-N 0.000 description 4
- XPBVBZPVNFIHOA-UVBJJODRSA-N Ala-Trp-Val Chemical compound C1=CC=C2C(C[C@@H](C(=O)N[C@@H](C(C)C)C(O)=O)NC(=O)[C@H](C)N)=CNC2=C1 XPBVBZPVNFIHOA-UVBJJODRSA-N 0.000 description 4
- HQIZDMIGUJOSNI-IUCAKERBSA-N Arg-Gly-Arg Chemical compound N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(O)=O HQIZDMIGUJOSNI-IUCAKERBSA-N 0.000 description 4
- ISJWBVIYRBAXEB-CIUDSAMLSA-N Arg-Ser-Glu Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(O)=O ISJWBVIYRBAXEB-CIUDSAMLSA-N 0.000 description 4
- MOGMYRUNTKYZFB-UNQGMJICSA-N Arg-Thr-Phe Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 MOGMYRUNTKYZFB-UNQGMJICSA-N 0.000 description 4
- XYOVHPDDWCEUDY-CIUDSAMLSA-N Asn-Ala-Leu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(O)=O XYOVHPDDWCEUDY-CIUDSAMLSA-N 0.000 description 4
- GXMSVVBIAMWMKO-BQBZGAKWSA-N Asn-Arg-Gly Chemical compound NC(=O)C[C@H](N)C(=O)N[C@H](C(=O)NCC(O)=O)CCCN=C(N)N GXMSVVBIAMWMKO-BQBZGAKWSA-N 0.000 description 4
- DAPLJWATMAXPPZ-CIUDSAMLSA-N Asn-Asn-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CC(N)=O DAPLJWATMAXPPZ-CIUDSAMLSA-N 0.000 description 4
- SNDBKTFJWVEVPO-WHFBIAKZSA-N Asp-Gly-Ser Chemical compound [H]N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@@H](CO)C(O)=O SNDBKTFJWVEVPO-WHFBIAKZSA-N 0.000 description 4
- VNXQRBXEQXLERQ-CIUDSAMLSA-N Asp-Ser-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(=O)O)N VNXQRBXEQXLERQ-CIUDSAMLSA-N 0.000 description 4
- 241000283707 Capra Species 0.000 description 4
- VIRYODQIWJNWNU-NRPADANISA-N Cys-Glu-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CS)N VIRYODQIWJNWNU-NRPADANISA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- IULKWYSYZSURJK-AVGNSLFASA-N Gln-Leu-Lys Chemical compound NC(=O)CC[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(O)=O IULKWYSYZSURJK-AVGNSLFASA-N 0.000 description 4
- JJKKWYQVHRUSDG-GUBZILKMSA-N Glu-Ala-Lys Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(O)=O JJKKWYQVHRUSDG-GUBZILKMSA-N 0.000 description 4
- AVZHGSCDKIQZPQ-CIUDSAMLSA-N Glu-Arg-Ala Chemical compound C[C@H](NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](N)CCC(O)=O)C(O)=O AVZHGSCDKIQZPQ-CIUDSAMLSA-N 0.000 description 4
- WATXSTJXNBOHKD-LAEOZQHASA-N Glu-Asp-Val Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O WATXSTJXNBOHKD-LAEOZQHASA-N 0.000 description 4
- CLROYXHHUZELFX-FXQIFTODSA-N Glu-Gln-Asp Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O CLROYXHHUZELFX-FXQIFTODSA-N 0.000 description 4
- RAUDKMVXNOWDLS-WDSKDSINSA-N Glu-Gly-Ser Chemical compound OC(=O)CC[C@H](N)C(=O)NCC(=O)N[C@@H](CO)C(O)=O RAUDKMVXNOWDLS-WDSKDSINSA-N 0.000 description 4
- XTZDZAXYPDISRR-MNXVOIDGSA-N Glu-Ile-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCC(=O)O)N XTZDZAXYPDISRR-MNXVOIDGSA-N 0.000 description 4
- INGJLBQKTRJLFO-UKJIMTQDSA-N Glu-Ile-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H](N)CCC(O)=O INGJLBQKTRJLFO-UKJIMTQDSA-N 0.000 description 4
- FMBWLLMUPXTXFC-SDDRHHMPSA-N Glu-Lys-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(=O)O)N)C(=O)O FMBWLLMUPXTXFC-SDDRHHMPSA-N 0.000 description 4
- NNCSJUBVFBDDLC-YUMQZZPRSA-N Gly-Leu-Ser Chemical compound NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O NNCSJUBVFBDDLC-YUMQZZPRSA-N 0.000 description 4
- HAOUOFNNJJLVNS-BQBZGAKWSA-N Gly-Pro-Ser Chemical compound NCC(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O HAOUOFNNJJLVNS-BQBZGAKWSA-N 0.000 description 4
- QQFSKBMCAKWHLG-UHFFFAOYSA-N Ile-Phe-Pro-Pro Chemical compound C1CCC(C(=O)N2C(CCC2)C(O)=O)N1C(=O)C(NC(=O)C(N)C(C)CC)CC1=CC=CC=C1 QQFSKBMCAKWHLG-UHFFFAOYSA-N 0.000 description 4
- NXRNRBOKDBIVKQ-CXTHYWKRSA-N Ile-Tyr-Tyr Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CC2=CC=C(C=C2)O)C(=O)O)N NXRNRBOKDBIVKQ-CXTHYWKRSA-N 0.000 description 4
- 102000006496 Immunoglobulin Heavy Chains Human genes 0.000 description 4
- 108010019476 Immunoglobulin Heavy Chains Proteins 0.000 description 4
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 4
- DBVWMYGBVFCRBE-CIUDSAMLSA-N Leu-Asn-Asn Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O DBVWMYGBVFCRBE-CIUDSAMLSA-N 0.000 description 4
- PVMPDMIKUVNOBD-CIUDSAMLSA-N Leu-Asp-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O PVMPDMIKUVNOBD-CIUDSAMLSA-N 0.000 description 4
- VQPPIMUZCZCOIL-GUBZILKMSA-N Leu-Gln-Ala Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(O)=O VQPPIMUZCZCOIL-GUBZILKMSA-N 0.000 description 4
- AXZGZMGRBDQTEY-SRVKXCTJSA-N Leu-Gln-Met Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCSC)C(O)=O AXZGZMGRBDQTEY-SRVKXCTJSA-N 0.000 description 4
- NRFGTHFONZYFNY-MGHWNKPDSA-N Leu-Ile-Tyr Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 NRFGTHFONZYFNY-MGHWNKPDSA-N 0.000 description 4
- AMSSKPUHBUQBOQ-SRVKXCTJSA-N Leu-Ser-Lys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)O)N AMSSKPUHBUQBOQ-SRVKXCTJSA-N 0.000 description 4
- MVJRBCJCRYGCKV-GVXVVHGQSA-N Leu-Val-Gln Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O MVJRBCJCRYGCKV-GVXVVHGQSA-N 0.000 description 4
- YQFZRHYZLARWDY-IHRRRGAJSA-N Leu-Val-Lys Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CCCCN YQFZRHYZLARWDY-IHRRRGAJSA-N 0.000 description 4
- SQXZLVXQXWILKW-KKUMJFAQSA-N Lys-Ser-Phe Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O SQXZLVXQXWILKW-KKUMJFAQSA-N 0.000 description 4
- DIBZLYZXTSVGLN-CIUDSAMLSA-N Lys-Ser-Ser Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O DIBZLYZXTSVGLN-CIUDSAMLSA-N 0.000 description 4
- MIFFFXHMAHFACR-KATARQTJSA-N Lys-Ser-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CCCCN MIFFFXHMAHFACR-KATARQTJSA-N 0.000 description 4
- QVTDVTONTRSQMF-WDCWCFNPSA-N Lys-Thr-Glu Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H]([C@H](O)C)NC(=O)[C@@H](N)CCCCN QVTDVTONTRSQMF-WDCWCFNPSA-N 0.000 description 4
- SJDQOYTYNGZZJX-SRVKXCTJSA-N Met-Glu-Leu Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O SJDQOYTYNGZZJX-SRVKXCTJSA-N 0.000 description 4
- SPSSJSICDYYTQN-HJGDQZAQSA-N Met-Thr-Gln Chemical compound CSCC[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@H](C(O)=O)CCC(N)=O SPSSJSICDYYTQN-HJGDQZAQSA-N 0.000 description 4
- ATBJCCFCJXCNGZ-UFYCRDLUSA-N Met-Tyr-Phe Chemical compound C([C@H](NC(=O)[C@@H](N)CCSC)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=C(O)C=C1 ATBJCCFCJXCNGZ-UFYCRDLUSA-N 0.000 description 4
- 108010002311 N-glycylglutamic acid Proteins 0.000 description 4
- BPCLGWHVPVTTFM-QWRGUYRKSA-N Phe-Ser-Gly Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)NCC(O)=O BPCLGWHVPVTTFM-QWRGUYRKSA-N 0.000 description 4
- GCFNFKNPCMBHNT-IRXDYDNUSA-N Phe-Tyr-Gly Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC2=CC=C(C=C2)O)C(=O)NCC(=O)O)N GCFNFKNPCMBHNT-IRXDYDNUSA-N 0.000 description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 4
- FDMKYQQYJKYCLV-GUBZILKMSA-N Pro-Pro-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 FDMKYQQYJKYCLV-GUBZILKMSA-N 0.000 description 4
- PRKWBYCXBBSLSK-GUBZILKMSA-N Pro-Ser-Val Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O PRKWBYCXBBSLSK-GUBZILKMSA-N 0.000 description 4
- FTVRVZNYIYWJGB-ACZMJKKPSA-N Ser-Asp-Glu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O FTVRVZNYIYWJGB-ACZMJKKPSA-N 0.000 description 4
- UQFYNFTYDHUIMI-WHFBIAKZSA-N Ser-Gly-Ala Chemical compound OC(=O)[C@H](C)NC(=O)CNC(=O)[C@@H](N)CO UQFYNFTYDHUIMI-WHFBIAKZSA-N 0.000 description 4
- PPNPDKGQRFSCAC-CIUDSAMLSA-N Ser-Lys-Asp Chemical compound NCCCC[C@H](NC(=O)[C@@H](N)CO)C(=O)N[C@@H](CC(O)=O)C(O)=O PPNPDKGQRFSCAC-CIUDSAMLSA-N 0.000 description 4
- PJIQEIFXZPCWOJ-FXQIFTODSA-N Ser-Pro-Asp Chemical compound [H]N[C@@H](CO)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(O)=O)C(O)=O PJIQEIFXZPCWOJ-FXQIFTODSA-N 0.000 description 4
- VAIWUNAAPZZGRI-IHPCNDPISA-N Ser-Trp-Phe Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)O)NC(=O)[C@H](CC2=CNC3=CC=CC=C32)NC(=O)[C@H](CO)N VAIWUNAAPZZGRI-IHPCNDPISA-N 0.000 description 4
- SIEBDTCABMZCLF-XGEHTFHBSA-N Ser-Val-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O SIEBDTCABMZCLF-XGEHTFHBSA-N 0.000 description 4
- HSWXBJCBYSWBPT-GUBZILKMSA-N Ser-Val-Val Chemical compound CC(C)[C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)CO)C(C)C)C(O)=O HSWXBJCBYSWBPT-GUBZILKMSA-N 0.000 description 4
- 230000006044 T cell activation Effects 0.000 description 4
- GLQFKOVWXPPFTP-VEVYYDQMSA-N Thr-Arg-Asp Chemical compound [H]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)=O GLQFKOVWXPPFTP-VEVYYDQMSA-N 0.000 description 4
- NAXBBCLCEOTAIG-RHYQMDGZSA-N Thr-Arg-Lys Chemical compound NC(N)=NCCC[C@H](NC(=O)[C@@H](N)[C@H](O)C)C(=O)N[C@@H](CCCCN)C(O)=O NAXBBCLCEOTAIG-RHYQMDGZSA-N 0.000 description 4
- CYVQBKQYQGEELV-NKIYYHGXSA-N Thr-His-Gln Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N)O CYVQBKQYQGEELV-NKIYYHGXSA-N 0.000 description 4
- VRUFCJZQDACGLH-UVOCVTCTSA-N Thr-Leu-Thr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O VRUFCJZQDACGLH-UVOCVTCTSA-N 0.000 description 4
- XHWCDRUPDNSDAZ-XKBZYTNZSA-N Thr-Ser-Glu Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N)O XHWCDRUPDNSDAZ-XKBZYTNZSA-N 0.000 description 4
- SVGAWGVHFIYAEE-JSGCOSHPSA-N Trp-Gly-Gln Chemical compound C1=CC=C2C(C[C@H](N)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(O)=O)=CNC2=C1 SVGAWGVHFIYAEE-JSGCOSHPSA-N 0.000 description 4
- BGWSLEYVITZIQP-DCPHZVHLSA-N Trp-Phe-Ala Chemical compound C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12)C(O)=O BGWSLEYVITZIQP-DCPHZVHLSA-N 0.000 description 4
- UOXPLPBMEPLZBW-WDSOQIARSA-N Trp-Val-Lys Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(O)=O)=CNC2=C1 UOXPLPBMEPLZBW-WDSOQIARSA-N 0.000 description 4
- LHADRQBREKTRLR-DCAQKATOSA-N Val-Cys-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CS)NC(=O)[C@H](C(C)C)N LHADRQBREKTRLR-DCAQKATOSA-N 0.000 description 4
- OXVPMZVGCAPFIG-BQFCYCMXSA-N Val-Gln-Trp Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)N OXVPMZVGCAPFIG-BQFCYCMXSA-N 0.000 description 4
- VCAWFLIWYNMHQP-UKJIMTQDSA-N Val-Glu-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](C(C)C)N VCAWFLIWYNMHQP-UKJIMTQDSA-N 0.000 description 4
- JQTYTBPCSOAZHI-FXQIFTODSA-N Val-Ser-Cys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)O)N JQTYTBPCSOAZHI-FXQIFTODSA-N 0.000 description 4
- QPJSIBAOZBVELU-BPNCWPANSA-N Val-Tyr-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)NC(=O)[C@H](C(C)C)N QPJSIBAOZBVELU-BPNCWPANSA-N 0.000 description 4
- LLJLBRRXKZTTRD-GUBZILKMSA-N Val-Val-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(=O)O)N LLJLBRRXKZTTRD-GUBZILKMSA-N 0.000 description 4
- 230000003321 amplification Effects 0.000 description 4
- 108010040443 aspartyl-aspartic acid Proteins 0.000 description 4
- 230000004663 cell proliferation Effects 0.000 description 4
- 230000001413 cellular effect Effects 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 4
- 231100000433 cytotoxic Toxicity 0.000 description 4
- 230000001472 cytotoxic effect Effects 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 238000000684 flow cytometry Methods 0.000 description 4
- 108010078144 glutaminyl-glycine Proteins 0.000 description 4
- 210000002865 immune cell Anatomy 0.000 description 4
- 230000001939 inductive effect Effects 0.000 description 4
- 238000003780 insertion Methods 0.000 description 4
- 230000037431 insertion Effects 0.000 description 4
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 4
- 230000003993 interaction Effects 0.000 description 4
- 108010034529 leucyl-lysine Proteins 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- 229960000485 methotrexate Drugs 0.000 description 4
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 4
- 238000003199 nucleic acid amplification method Methods 0.000 description 4
- 108010083476 phenylalanyltryptophan Proteins 0.000 description 4
- 230000035755 proliferation Effects 0.000 description 4
- 108010029020 prolylglycine Proteins 0.000 description 4
- 230000010076 replication Effects 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 108010071635 tyrosyl-prolyl-arginine Proteins 0.000 description 4
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 3
- LRPZJPMQGKGHSG-XGEHTFHBSA-N Arg-Ser-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CCCN=C(N)N)N)O LRPZJPMQGKGHSG-XGEHTFHBSA-N 0.000 description 3
- XRNXPIGJPQHCPC-RCWTZXSCSA-N Arg-Thr-Val Chemical compound CC(C)[C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)CCCNC(N)=N)[C@@H](C)O)C(O)=O XRNXPIGJPQHCPC-RCWTZXSCSA-N 0.000 description 3
- QNNBHTFDFFFHGC-KKUMJFAQSA-N Asn-Tyr-Lys Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC(=O)N)N)O QNNBHTFDFFFHGC-KKUMJFAQSA-N 0.000 description 3
- MJIJBEYEHBKTIM-BYULHYEWSA-N Asn-Val-Asn Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CC(=O)N)N MJIJBEYEHBKTIM-BYULHYEWSA-N 0.000 description 3
- JZLFYAAGGYMRIK-BYULHYEWSA-N Asn-Val-Asp Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O JZLFYAAGGYMRIK-BYULHYEWSA-N 0.000 description 3
- WSGVTKZFVJSJOG-RCOVLWMOSA-N Asp-Gly-Val Chemical compound [H]N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@@H](C(C)C)C(O)=O WSGVTKZFVJSJOG-RCOVLWMOSA-N 0.000 description 3
- KGHLGJAXYSVNJP-WHFBIAKZSA-N Asp-Ser-Gly Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CO)C(=O)NCC(O)=O KGHLGJAXYSVNJP-WHFBIAKZSA-N 0.000 description 3
- UTLCRGFJFSZWAW-OLHMAJIHSA-N Asp-Thr-Asn Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CC(=O)O)N)O UTLCRGFJFSZWAW-OLHMAJIHSA-N 0.000 description 3
- YUELDQUPTAYEGM-XIRDDKMYSA-N Asp-Trp-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)NC(=O)[C@H](CC(=O)O)N YUELDQUPTAYEGM-XIRDDKMYSA-N 0.000 description 3
- YMBAVNPKBWHDAW-CIUDSAMLSA-N Cys-Asp-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CS)N YMBAVNPKBWHDAW-CIUDSAMLSA-N 0.000 description 3
- 108010010803 Gelatin Proteins 0.000 description 3
- NVEASDQHBRZPSU-BQBZGAKWSA-N Gln-Gln-Gly Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(O)=O NVEASDQHBRZPSU-BQBZGAKWSA-N 0.000 description 3
- CGVWDTRDPLOMHZ-FXQIFTODSA-N Gln-Glu-Asp Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O CGVWDTRDPLOMHZ-FXQIFTODSA-N 0.000 description 3
- ZNZPKVQURDQFFS-FXQIFTODSA-N Gln-Glu-Ser Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(O)=O ZNZPKVQURDQFFS-FXQIFTODSA-N 0.000 description 3
- ZEEPYMXTJWIMSN-GUBZILKMSA-N Gln-Lys-Ser Chemical compound NCCCC[C@@H](C(=O)N[C@@H](CO)C(O)=O)NC(=O)[C@@H](N)CCC(N)=O ZEEPYMXTJWIMSN-GUBZILKMSA-N 0.000 description 3
- XUMFMAVDHQDATI-DCAQKATOSA-N Gln-Pro-Arg Chemical compound NC(=O)CC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCN=C(N)N)C(O)=O XUMFMAVDHQDATI-DCAQKATOSA-N 0.000 description 3
- RFDHKPSHTXZKLL-IHRRRGAJSA-N Glu-Gln-Phe Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CCC(=O)O)N RFDHKPSHTXZKLL-IHRRRGAJSA-N 0.000 description 3
- MFNUFCFRAZPJFW-JYJNAYRXSA-N Glu-Lys-Phe Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 MFNUFCFRAZPJFW-JYJNAYRXSA-N 0.000 description 3
- RFTVTKBHDXCEEX-WDSKDSINSA-N Glu-Ser-Gly Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)NCC(O)=O RFTVTKBHDXCEEX-WDSKDSINSA-N 0.000 description 3
- JWNZHMSRZXXGTM-XKBZYTNZSA-N Glu-Ser-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(O)=O JWNZHMSRZXXGTM-XKBZYTNZSA-N 0.000 description 3
- UQJNXZSSGQIPIQ-FBCQKBJTSA-N Gly-Gly-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)CNC(=O)CN UQJNXZSSGQIPIQ-FBCQKBJTSA-N 0.000 description 3
- OOCFXNOVSLSHAB-IUCAKERBSA-N Gly-Pro-Pro Chemical compound NCC(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 OOCFXNOVSLSHAB-IUCAKERBSA-N 0.000 description 3
- CQMFNTVQVLQRLT-JHEQGTHGSA-N Gly-Thr-Gln Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(N)=O)C(O)=O CQMFNTVQVLQRLT-JHEQGTHGSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- FYVHHKMHFPMBBG-GUBZILKMSA-N His-Gln-Asp Chemical compound C1=C(NC=N1)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CC(=O)O)C(=O)O)N FYVHHKMHFPMBBG-GUBZILKMSA-N 0.000 description 3
- NSPNUMNLZNOPAQ-SJWGOKEGSA-N Ile-Tyr-Pro Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N2CCC[C@@H]2C(=O)O)N NSPNUMNLZNOPAQ-SJWGOKEGSA-N 0.000 description 3
- 108010054477 Immunoglobulin Fab Fragments Proteins 0.000 description 3
- 102000001706 Immunoglobulin Fab Fragments Human genes 0.000 description 3
- 108010067060 Immunoglobulin Variable Region Proteins 0.000 description 3
- 102000017727 Immunoglobulin Variable Region Human genes 0.000 description 3
- RCFDOSNHHZGBOY-UHFFFAOYSA-N L-isoleucyl-L-alanine Natural products CCC(C)C(N)C(=O)NC(C)C(O)=O RCFDOSNHHZGBOY-UHFFFAOYSA-N 0.000 description 3
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 3
- IAJFFZORSWOZPQ-SRVKXCTJSA-N Leu-Leu-Asn Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O IAJFFZORSWOZPQ-SRVKXCTJSA-N 0.000 description 3
- BIZNDKMFQHDOIE-KKUMJFAQSA-N Leu-Phe-Asn Chemical compound CC(C)C[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](CC(N)=O)C(O)=O)CC1=CC=CC=C1 BIZNDKMFQHDOIE-KKUMJFAQSA-N 0.000 description 3
- CHJKEDSZNSONPS-DCAQKATOSA-N Leu-Pro-Ser Chemical compound [H]N[C@@H](CC(C)C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O CHJKEDSZNSONPS-DCAQKATOSA-N 0.000 description 3
- SBANPBVRHYIMRR-UHFFFAOYSA-N Leu-Ser-Pro Natural products CC(C)CC(N)C(=O)NC(CO)C(=O)N1CCCC1C(O)=O SBANPBVRHYIMRR-UHFFFAOYSA-N 0.000 description 3
- KCXUCYYZNZFGLL-SRVKXCTJSA-N Lys-Ala-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(O)=O KCXUCYYZNZFGLL-SRVKXCTJSA-N 0.000 description 3
- NTSPQIONFJUMJV-AVGNSLFASA-N Lys-Arg-Val Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(O)=O NTSPQIONFJUMJV-AVGNSLFASA-N 0.000 description 3
- YKIRNDPUWONXQN-GUBZILKMSA-N Lys-Asn-Gln Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N YKIRNDPUWONXQN-GUBZILKMSA-N 0.000 description 3
- KWUKZRFFKPLUPE-HJGDQZAQSA-N Lys-Asp-Thr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O KWUKZRFFKPLUPE-HJGDQZAQSA-N 0.000 description 3
- FGMHXLULNHTPID-KKUMJFAQSA-N Lys-His-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](CCCCN)C(O)=O)CC1=CN=CN1 FGMHXLULNHTPID-KKUMJFAQSA-N 0.000 description 3
- OIQSIMFSVLLWBX-VOAKCMCISA-N Lys-Leu-Thr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O OIQSIMFSVLLWBX-VOAKCMCISA-N 0.000 description 3
- LUTDBHBIHHREDC-IHRRRGAJSA-N Lys-Pro-Lys Chemical compound NCCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(O)=O LUTDBHBIHHREDC-IHRRRGAJSA-N 0.000 description 3
- CAVRAQIDHUPECU-UVOCVTCTSA-N Lys-Thr-Thr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O CAVRAQIDHUPECU-UVOCVTCTSA-N 0.000 description 3
- 239000004472 Lysine Substances 0.000 description 3
- IHRFZLQEQVHXFA-RHYQMDGZSA-N Met-Thr-Lys Chemical compound CSCC[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@H](C(O)=O)CCCCN IHRFZLQEQVHXFA-RHYQMDGZSA-N 0.000 description 3
- 108091007491 NSP3 Papain-like protease domains Proteins 0.000 description 3
- 229930040373 Paraformaldehyde Natural products 0.000 description 3
- JOXIIFVCSATTDH-IHPCNDPISA-N Phe-Asn-Trp Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC2=CNC3=CC=CC=C32)C(=O)O)N JOXIIFVCSATTDH-IHPCNDPISA-N 0.000 description 3
- SWZKMTDPQXLQRD-XVSYOHENSA-N Phe-Asp-Thr Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O SWZKMTDPQXLQRD-XVSYOHENSA-N 0.000 description 3
- DVOCGBNHAUHKHJ-DKIMLUQUSA-N Phe-Ile-Leu Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(O)=O DVOCGBNHAUHKHJ-DKIMLUQUSA-N 0.000 description 3
- WFHYFCWBLSKEMS-KKUMJFAQSA-N Pro-Glu-Phe Chemical compound N([C@@H](CCC(=O)O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C(=O)[C@@H]1CCCN1 WFHYFCWBLSKEMS-KKUMJFAQSA-N 0.000 description 3
- VPEVBAUSTBWQHN-NHCYSSNCSA-N Pro-Glu-Val Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O VPEVBAUSTBWQHN-NHCYSSNCSA-N 0.000 description 3
- MHHQQZIFLWFZGR-DCAQKATOSA-N Pro-Lys-Ser Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(O)=O MHHQQZIFLWFZGR-DCAQKATOSA-N 0.000 description 3
- GMJDSFYVTAMIBF-FXQIFTODSA-N Pro-Ser-Asp Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(O)=O GMJDSFYVTAMIBF-FXQIFTODSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- YQHZVYJAGWMHES-ZLUOBGJFSA-N Ser-Ala-Ser Chemical compound OC[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O YQHZVYJAGWMHES-ZLUOBGJFSA-N 0.000 description 3
- YUSRGTQIPCJNHQ-CIUDSAMLSA-N Ser-Arg-Glu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(O)=O YUSRGTQIPCJNHQ-CIUDSAMLSA-N 0.000 description 3
- WDXYVIIVDIDOSX-DCAQKATOSA-N Ser-Arg-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CO)CCCN=C(N)N WDXYVIIVDIDOSX-DCAQKATOSA-N 0.000 description 3
- QPFJSHSJFIYDJZ-GHCJXIJMSA-N Ser-Asp-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](N)CO QPFJSHSJFIYDJZ-GHCJXIJMSA-N 0.000 description 3
- MOVJSUIKUNCVMG-ZLUOBGJFSA-N Ser-Cys-Ser Chemical compound C([C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CO)C(=O)O)N)O MOVJSUIKUNCVMG-ZLUOBGJFSA-N 0.000 description 3
- BPMRXBZYPGYPJN-WHFBIAKZSA-N Ser-Gly-Asn Chemical compound [H]N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(O)=O BPMRXBZYPGYPJN-WHFBIAKZSA-N 0.000 description 3
- XNCUYZKGQOCOQH-YUMQZZPRSA-N Ser-Leu-Gly Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O XNCUYZKGQOCOQH-YUMQZZPRSA-N 0.000 description 3
- QJKPECIAWNNKIT-KKUMJFAQSA-N Ser-Lys-Tyr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O QJKPECIAWNNKIT-KKUMJFAQSA-N 0.000 description 3
- KZPRPBLHYMZIMH-MXAVVETBSA-N Ser-Phe-Ile Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O KZPRPBLHYMZIMH-MXAVVETBSA-N 0.000 description 3
- PYTKULIABVRXSC-BWBBJGPYSA-N Ser-Ser-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(O)=O PYTKULIABVRXSC-BWBBJGPYSA-N 0.000 description 3
- OQSQCUWQOIHECT-YJRXYDGGSA-N Ser-Tyr-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O OQSQCUWQOIHECT-YJRXYDGGSA-N 0.000 description 3
- 230000006052 T cell proliferation Effects 0.000 description 3
- 102100035794 T-cell surface glycoprotein CD3 epsilon chain Human genes 0.000 description 3
- NJEMRSFGDNECGF-GCJQMDKQSA-N Thr-Ala-Asp Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CC(O)=O NJEMRSFGDNECGF-GCJQMDKQSA-N 0.000 description 3
- UKBSDLHIKIXJKH-HJGDQZAQSA-N Thr-Arg-Glu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(O)=O UKBSDLHIKIXJKH-HJGDQZAQSA-N 0.000 description 3
- SXAGUVRFGJSFKC-ZEILLAHLSA-N Thr-His-Thr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O SXAGUVRFGJSFKC-ZEILLAHLSA-N 0.000 description 3
- PCMDGXKXVMBIFP-VEVYYDQMSA-N Thr-Met-Asn Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(O)=O PCMDGXKXVMBIFP-VEVYYDQMSA-N 0.000 description 3
- LVRFMARKDGGZMX-IZPVPAKOSA-N Thr-Tyr-Thr Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)O)C(O)=O)CC1=CC=C(O)C=C1 LVRFMARKDGGZMX-IZPVPAKOSA-N 0.000 description 3
- 108010022394 Threonine synthase Proteins 0.000 description 3
- WNZRNOGHEONFMS-PXDAIIFMSA-N Trp-Ile-Tyr Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O WNZRNOGHEONFMS-PXDAIIFMSA-N 0.000 description 3
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 3
- FFCRCJZJARTYCG-KKUMJFAQSA-N Tyr-Cys-Lys Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CCCCN)C(=O)O)N)O FFCRCJZJARTYCG-KKUMJFAQSA-N 0.000 description 3
- JJNXZIPLIXIGBX-HJPIBITLSA-N Tyr-Ile-Cys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)N JJNXZIPLIXIGBX-HJPIBITLSA-N 0.000 description 3
- AUZADXNWQMBZOO-JYJNAYRXSA-N Tyr-Pro-Arg Chemical compound C([C@H](N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O)C1=CC=C(O)C=C1 AUZADXNWQMBZOO-JYJNAYRXSA-N 0.000 description 3
- TYGHOWWWMTWVKM-HJOGWXRNSA-N Tyr-Tyr-Phe Chemical compound C([C@H](N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=C(O)C=C1 TYGHOWWWMTWVKM-HJOGWXRNSA-N 0.000 description 3
- SQUMHUZLJDUROQ-YDHLFZDLSA-N Tyr-Val-Asp Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O SQUMHUZLJDUROQ-YDHLFZDLSA-N 0.000 description 3
- SCBITHMBEJNRHC-LSJOCFKGSA-N Val-Asp-Val Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](C(C)C)C(=O)O)N SCBITHMBEJNRHC-LSJOCFKGSA-N 0.000 description 3
- KTEZUXISLQTDDQ-NHCYSSNCSA-N Val-Lys-Asp Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(=O)O)C(=O)O)N KTEZUXISLQTDDQ-NHCYSSNCSA-N 0.000 description 3
- KISFXYYRKKNLOP-IHRRRGAJSA-N Val-Phe-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)O)N KISFXYYRKKNLOP-IHRRRGAJSA-N 0.000 description 3
- KRAHMIJVUPUOTQ-DCAQKATOSA-N Val-Ser-His Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N KRAHMIJVUPUOTQ-DCAQKATOSA-N 0.000 description 3
- 230000003213 activating effect Effects 0.000 description 3
- 230000002776 aggregation Effects 0.000 description 3
- 238000004220 aggregation Methods 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 230000005888 antibody-dependent cellular phagocytosis Effects 0.000 description 3
- 108010013835 arginine glutamate Proteins 0.000 description 3
- 108010093581 aspartyl-proline Proteins 0.000 description 3
- 210000003719 b-lymphocyte Anatomy 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 3
- 235000018417 cysteine Nutrition 0.000 description 3
- 102000004419 dihydrofolate reductase Human genes 0.000 description 3
- 230000009977 dual effect Effects 0.000 description 3
- 230000008030 elimination Effects 0.000 description 3
- 238000003379 elimination reaction Methods 0.000 description 3
- 239000003623 enhancer Substances 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 230000004927 fusion Effects 0.000 description 3
- 229920000159 gelatin Polymers 0.000 description 3
- 239000008273 gelatin Substances 0.000 description 3
- 235000019322 gelatine Nutrition 0.000 description 3
- 235000011852 gelatine desserts Nutrition 0.000 description 3
- 239000001963 growth medium Substances 0.000 description 3
- 230000036541 health Effects 0.000 description 3
- 230000003053 immunization Effects 0.000 description 3
- 238000002649 immunization Methods 0.000 description 3
- 229940072221 immunoglobulins Drugs 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 108010053037 kyotorphin Proteins 0.000 description 3
- 108010057821 leucylproline Proteins 0.000 description 3
- 230000000670 limiting effect Effects 0.000 description 3
- 238000004020 luminiscence type Methods 0.000 description 3
- 108010003700 lysyl aspartic acid Proteins 0.000 description 3
- 210000002540 macrophage Anatomy 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 229920002866 paraformaldehyde Polymers 0.000 description 3
- 108010073025 phenylalanylphenylalanine Proteins 0.000 description 3
- 230000004481 post-translational protein modification Effects 0.000 description 3
- 239000003755 preservative agent Substances 0.000 description 3
- 230000003248 secreting effect Effects 0.000 description 3
- 230000028327 secretion Effects 0.000 description 3
- 108010048397 seryl-lysyl-leucine Proteins 0.000 description 3
- 241000894007 species Species 0.000 description 3
- 230000000638 stimulation Effects 0.000 description 3
- 235000000346 sugar Nutrition 0.000 description 3
- 150000008163 sugars Chemical class 0.000 description 3
- 108010033670 threonyl-aspartyl-tyrosine Proteins 0.000 description 3
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 3
- 108010003137 tyrosyltyrosine Proteins 0.000 description 3
- COEXAQSTZUWMRI-STQMWFEESA-N (2s)-1-[2-[[(2s)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]acetyl]pyrrolidine-2-carboxylic acid Chemical compound C([C@H](N)C(=O)NCC(=O)N1[C@@H](CCC1)C(O)=O)C1=CC=C(O)C=C1 COEXAQSTZUWMRI-STQMWFEESA-N 0.000 description 2
- SUMYEVXWCAYLLJ-GUBZILKMSA-N Ala-Leu-Gln Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O SUMYEVXWCAYLLJ-GUBZILKMSA-N 0.000 description 2
- MDNAVFBZPROEHO-DCAQKATOSA-N Ala-Lys-Val Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(O)=O MDNAVFBZPROEHO-DCAQKATOSA-N 0.000 description 2
- DYJJJCHDHLEFDW-FXQIFTODSA-N Ala-Pro-Cys Chemical compound C[C@@H](C(=O)N1CCC[C@H]1C(=O)N[C@@H](CS)C(=O)O)N DYJJJCHDHLEFDW-FXQIFTODSA-N 0.000 description 2
- IORKCNUBHNIMKY-CIUDSAMLSA-N Ala-Pro-Glu Chemical compound C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O IORKCNUBHNIMKY-CIUDSAMLSA-N 0.000 description 2
- XWFWAXPOLRTDFZ-FXQIFTODSA-N Ala-Pro-Ser Chemical compound C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O XWFWAXPOLRTDFZ-FXQIFTODSA-N 0.000 description 2
- CREYEAPXISDKSB-FQPOAREZSA-N Ala-Thr-Tyr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O CREYEAPXISDKSB-FQPOAREZSA-N 0.000 description 2
- YJHKTAMKPGFJCT-NRPADANISA-N Ala-Val-Glu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O YJHKTAMKPGFJCT-NRPADANISA-N 0.000 description 2
- 108010088751 Albumins Proteins 0.000 description 2
- 102000009027 Albumins Human genes 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- KMSHNDWHPWXPEC-BQBZGAKWSA-N Arg-Asp-Gly Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(O)=O KMSHNDWHPWXPEC-BQBZGAKWSA-N 0.000 description 2
- PNQWAUXQDBIJDY-GUBZILKMSA-N Arg-Glu-Glu Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O PNQWAUXQDBIJDY-GUBZILKMSA-N 0.000 description 2
- AUFHLLPVPSMEOG-YUMQZZPRSA-N Arg-Gly-Glu Chemical compound NC(N)=NCCC[C@H](N)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(O)=O AUFHLLPVPSMEOG-YUMQZZPRSA-N 0.000 description 2
- NVUIWHJLPSZZQC-CYDGBPFRSA-N Arg-Ile-Arg Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O NVUIWHJLPSZZQC-CYDGBPFRSA-N 0.000 description 2
- JEOCWTUOMKEEMF-RHYQMDGZSA-N Arg-Leu-Thr Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O JEOCWTUOMKEEMF-RHYQMDGZSA-N 0.000 description 2
- ZUVMUOOHJYNJPP-XIRDDKMYSA-N Arg-Trp-Gln Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CCC(N)=O)C(O)=O ZUVMUOOHJYNJPP-XIRDDKMYSA-N 0.000 description 2
- SLKLLQWZQHXYSV-CIUDSAMLSA-N Asn-Ala-Lys Chemical compound NC(=O)C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(O)=O SLKLLQWZQHXYSV-CIUDSAMLSA-N 0.000 description 2
- NVGWESORMHFISY-SRVKXCTJSA-N Asn-Asn-Phe Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O NVGWESORMHFISY-SRVKXCTJSA-N 0.000 description 2
- WONGRTVAMHFGBE-WDSKDSINSA-N Asn-Gly-Gln Chemical compound C(CC(=O)N)[C@@H](C(=O)O)NC(=O)CNC(=O)[C@H](CC(=O)N)N WONGRTVAMHFGBE-WDSKDSINSA-N 0.000 description 2
- OLVIPTLKNSAYRJ-YUMQZZPRSA-N Asn-Gly-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)CNC(=O)[C@H](CC(=O)N)N OLVIPTLKNSAYRJ-YUMQZZPRSA-N 0.000 description 2
- LGCVSPFCFXWUEY-IHPCNDPISA-N Asn-Trp-Tyr Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CC3=CC=C(C=C3)O)C(=O)O)NC(=O)[C@H](CC(=O)N)N LGCVSPFCFXWUEY-IHPCNDPISA-N 0.000 description 2
- DATSKXOXPUAOLK-KKUMJFAQSA-N Asn-Tyr-Leu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(C)C)C(O)=O DATSKXOXPUAOLK-KKUMJFAQSA-N 0.000 description 2
- HSWYMWGDMPLTTH-FXQIFTODSA-N Asp-Glu-Gln Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O HSWYMWGDMPLTTH-FXQIFTODSA-N 0.000 description 2
- ODNWIBOCFGMRTP-SRVKXCTJSA-N Asp-His-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC(O)=O)CC1=CN=CN1 ODNWIBOCFGMRTP-SRVKXCTJSA-N 0.000 description 2
- KTTCQQNRRLCIBC-GHCJXIJMSA-N Asp-Ile-Ala Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O KTTCQQNRRLCIBC-GHCJXIJMSA-N 0.000 description 2
- UZFHNLYQWMGUHU-DCAQKATOSA-N Asp-Lys-Arg Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O UZFHNLYQWMGUHU-DCAQKATOSA-N 0.000 description 2
- DPNWSMBUYCLEDG-CIUDSAMLSA-N Asp-Lys-Ser Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(O)=O DPNWSMBUYCLEDG-CIUDSAMLSA-N 0.000 description 2
- AHWRSSLYSGLBGD-CIUDSAMLSA-N Asp-Pro-Glu Chemical compound OC(=O)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O AHWRSSLYSGLBGD-CIUDSAMLSA-N 0.000 description 2
- WMLFFCRUSPNENW-ZLUOBGJFSA-N Asp-Ser-Ala Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(O)=O WMLFFCRUSPNENW-ZLUOBGJFSA-N 0.000 description 2
- KNDCWFXCFKSEBM-AVGNSLFASA-N Asp-Tyr-Glu Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCC(O)=O)C(O)=O KNDCWFXCFKSEBM-AVGNSLFASA-N 0.000 description 2
- SQIARYGNVQWOSB-BZSNNMDCSA-N Asp-Tyr-Phe Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O SQIARYGNVQWOSB-BZSNNMDCSA-N 0.000 description 2
- QOJJMJKTMKNFEF-ZKWXMUAHSA-N Asp-Val-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CC(O)=O QOJJMJKTMKNFEF-ZKWXMUAHSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- NDUSUIGBMZCOIL-ZKWXMUAHSA-N Cys-Asn-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CS)N NDUSUIGBMZCOIL-ZKWXMUAHSA-N 0.000 description 2
- WVLZTXGTNGHPBO-SRVKXCTJSA-N Cys-Leu-Leu Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O WVLZTXGTNGHPBO-SRVKXCTJSA-N 0.000 description 2
- GDNWBSFSHJVXKL-GUBZILKMSA-N Cys-Lys-Gln Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(N)=O)C(O)=O GDNWBSFSHJVXKL-GUBZILKMSA-N 0.000 description 2
- IOLWXFWVYYCVTJ-NRPADANISA-N Cys-Val-Gln Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CS)N IOLWXFWVYYCVTJ-NRPADANISA-N 0.000 description 2
- 206010050685 Cytokine storm Diseases 0.000 description 2
- 101150074155 DHFR gene Proteins 0.000 description 2
- 241000588724 Escherichia coli Species 0.000 description 2
- WLODHVXYKYHLJD-ACZMJKKPSA-N Gln-Asp-Ser Chemical compound C(CC(=O)N)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CO)C(=O)O)N WLODHVXYKYHLJD-ACZMJKKPSA-N 0.000 description 2
- DHNWZLGBTPUTQQ-QEJZJMRPSA-N Gln-Asp-Trp Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CCC(=O)N)N DHNWZLGBTPUTQQ-QEJZJMRPSA-N 0.000 description 2
- JILRMFFFCHUUTJ-ACZMJKKPSA-N Gln-Ser-Ser Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O JILRMFFFCHUUTJ-ACZMJKKPSA-N 0.000 description 2
- BETSEXMYBWCDAE-SZMVWBNQSA-N Gln-Trp-Lys Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCC(=O)N)N BETSEXMYBWCDAE-SZMVWBNQSA-N 0.000 description 2
- ZFBBMCKQSNJZSN-AUTRQRHGSA-N Gln-Val-Gln Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O ZFBBMCKQSNJZSN-AUTRQRHGSA-N 0.000 description 2
- FITIQFSXXBKFFM-NRPADANISA-N Gln-Val-Ser Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(O)=O FITIQFSXXBKFFM-NRPADANISA-N 0.000 description 2
- ITYRYNUZHPNCIK-GUBZILKMSA-N Glu-Ala-Leu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(O)=O ITYRYNUZHPNCIK-GUBZILKMSA-N 0.000 description 2
- GLWXKFRTOHKGIT-ACZMJKKPSA-N Glu-Asn-Asn Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O GLWXKFRTOHKGIT-ACZMJKKPSA-N 0.000 description 2
- JVSBYEDSSRZQGV-GUBZILKMSA-N Glu-Asp-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](N)CCC(O)=O JVSBYEDSSRZQGV-GUBZILKMSA-N 0.000 description 2
- HUFCEIHAFNVSNR-IHRRRGAJSA-N Glu-Gln-Tyr Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 HUFCEIHAFNVSNR-IHRRRGAJSA-N 0.000 description 2
- HNVFSTLPVJWIDV-CIUDSAMLSA-N Glu-Glu-Gln Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O HNVFSTLPVJWIDV-CIUDSAMLSA-N 0.000 description 2
- KASDBWKLWJKTLJ-GUBZILKMSA-N Glu-Glu-Met Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCSC)C(O)=O KASDBWKLWJKTLJ-GUBZILKMSA-N 0.000 description 2
- MWMJCGBSIORNCD-AVGNSLFASA-N Glu-Leu-Leu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O MWMJCGBSIORNCD-AVGNSLFASA-N 0.000 description 2
- QDMVXRNLOPTPIE-WDCWCFNPSA-N Glu-Lys-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O QDMVXRNLOPTPIE-WDCWCFNPSA-N 0.000 description 2
- QNJNPKSWAHPYGI-JYJNAYRXSA-N Glu-Phe-Leu Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(O)=O)CC1=CC=CC=C1 QNJNPKSWAHPYGI-JYJNAYRXSA-N 0.000 description 2
- NNQDRRUXFJYCCJ-NHCYSSNCSA-N Glu-Pro-Val Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(O)=O NNQDRRUXFJYCCJ-NHCYSSNCSA-N 0.000 description 2
- ALMBZBOCGSVSAI-ACZMJKKPSA-N Glu-Ser-Asn Chemical compound C(CC(=O)O)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(=O)N)C(=O)O)N ALMBZBOCGSVSAI-ACZMJKKPSA-N 0.000 description 2
- QOXDAWODGSIDDI-GUBZILKMSA-N Glu-Ser-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(=O)O)N QOXDAWODGSIDDI-GUBZILKMSA-N 0.000 description 2
- MFYLRRCYBBJYPI-JYJNAYRXSA-N Glu-Tyr-Lys Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCC(=O)O)N)O MFYLRRCYBBJYPI-JYJNAYRXSA-N 0.000 description 2
- ZALGPUWUVHOGAE-GVXVVHGQSA-N Glu-Val-His Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](CCC(=O)O)N ZALGPUWUVHOGAE-GVXVVHGQSA-N 0.000 description 2
- VSVZIEVNUYDAFR-YUMQZZPRSA-N Gly-Ala-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)CN VSVZIEVNUYDAFR-YUMQZZPRSA-N 0.000 description 2
- XCLCVBYNGXEVDU-WHFBIAKZSA-N Gly-Asn-Ser Chemical compound NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(O)=O XCLCVBYNGXEVDU-WHFBIAKZSA-N 0.000 description 2
- GRIRDMVMJJDZKV-RCOVLWMOSA-N Gly-Asn-Val Chemical compound [H]NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(O)=O GRIRDMVMJJDZKV-RCOVLWMOSA-N 0.000 description 2
- IXKRSKPKSLXIHN-YUMQZZPRSA-N Gly-Cys-Leu Chemical compound [H]NCC(=O)N[C@@H](CS)C(=O)N[C@@H](CC(C)C)C(O)=O IXKRSKPKSLXIHN-YUMQZZPRSA-N 0.000 description 2
- XTQFHTHIAKKCTM-YFKPBYRVSA-N Gly-Glu-Gly Chemical compound NCC(=O)N[C@@H](CCC(O)=O)C(=O)NCC(O)=O XTQFHTHIAKKCTM-YFKPBYRVSA-N 0.000 description 2
- UUYBFNKHOCJCHT-VHSXEESVSA-N Gly-Leu-Pro Chemical compound CC(C)C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)CN UUYBFNKHOCJCHT-VHSXEESVSA-N 0.000 description 2
- AFWYPMDMDYCKMD-KBPBESRZSA-N Gly-Leu-Tyr Chemical compound NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 AFWYPMDMDYCKMD-KBPBESRZSA-N 0.000 description 2
- GAFKBWKVXNERFA-QWRGUYRKSA-N Gly-Phe-Asp Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)CN)CC1=CC=CC=C1 GAFKBWKVXNERFA-QWRGUYRKSA-N 0.000 description 2
- FFJQHWKSGAWSTJ-BFHQHQDPSA-N Gly-Thr-Ala Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O FFJQHWKSGAWSTJ-BFHQHQDPSA-N 0.000 description 2
- 239000004471 Glycine Substances 0.000 description 2
- 241000238631 Hexapoda Species 0.000 description 2
- TVQGUFGDVODUIF-LSJOCFKGSA-N His-Arg-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC1=CN=CN1)N TVQGUFGDVODUIF-LSJOCFKGSA-N 0.000 description 2
- MAABHGXCIBEYQR-XVYDVKMFSA-N His-Asn-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CC1=CN=CN1)N MAABHGXCIBEYQR-XVYDVKMFSA-N 0.000 description 2
- HVCRQRQPIIRNLY-IUCAKERBSA-N His-Gln-Gly Chemical compound C1=C(NC=N1)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)NCC(=O)O)N HVCRQRQPIIRNLY-IUCAKERBSA-N 0.000 description 2
- HIAHVKLTHNOENC-HGNGGELXSA-N His-Glu-Ala Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(O)=O HIAHVKLTHNOENC-HGNGGELXSA-N 0.000 description 2
- TVMNTHXFRSXZGR-IHRRRGAJSA-N His-Lys-Val Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(O)=O TVMNTHXFRSXZGR-IHRRRGAJSA-N 0.000 description 2
- ALPXXNRQBMRCPZ-MEYUZBJRSA-N His-Thr-Phe Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O ALPXXNRQBMRCPZ-MEYUZBJRSA-N 0.000 description 2
- 101000946860 Homo sapiens T-cell surface glycoprotein CD3 epsilon chain Proteins 0.000 description 2
- JHNJNTMTZHEDLJ-NAKRPEOUSA-N Ile-Ser-Arg Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O JHNJNTMTZHEDLJ-NAKRPEOUSA-N 0.000 description 2
- VGSPNSSCMOHRRR-BJDJZHNGSA-N Ile-Ser-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)O)N VGSPNSSCMOHRRR-BJDJZHNGSA-N 0.000 description 2
- 108090001061 Insulin Proteins 0.000 description 2
- 102000004877 Insulin Human genes 0.000 description 2
- 102000004889 Interleukin-6 Human genes 0.000 description 2
- 108090001005 Interleukin-6 Proteins 0.000 description 2
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 2
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 2
- LHSGPCFBGJHPCY-UHFFFAOYSA-N L-leucine-L-tyrosine Natural products CC(C)CC(N)C(=O)NC(C(O)=O)CC1=CC=C(O)C=C1 LHSGPCFBGJHPCY-UHFFFAOYSA-N 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
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-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
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- OIARJGNVARWKFP-YUMQZZPRSA-N Leu-Asn-Gly Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(O)=O OIARJGNVARWKFP-YUMQZZPRSA-N 0.000 description 2
- KAFOIVJDVSZUMD-DCAQKATOSA-N Leu-Gln-Gln Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O KAFOIVJDVSZUMD-DCAQKATOSA-N 0.000 description 2
- KAFOIVJDVSZUMD-UHFFFAOYSA-N Leu-Gln-Gln Natural products CC(C)CC(N)C(=O)NC(CCC(N)=O)C(=O)NC(CCC(N)=O)C(O)=O KAFOIVJDVSZUMD-UHFFFAOYSA-N 0.000 description 2
- HPBCTWSUJOGJSH-MNXVOIDGSA-N Leu-Glu-Ile Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O HPBCTWSUJOGJSH-MNXVOIDGSA-N 0.000 description 2
- VWHGTYCRDRBSFI-ZETCQYMHSA-N Leu-Gly-Gly Chemical compound CC(C)C[C@H](N)C(=O)NCC(=O)NCC(O)=O VWHGTYCRDRBSFI-ZETCQYMHSA-N 0.000 description 2
- APFJUBGRZGMQFF-QWRGUYRKSA-N Leu-Gly-Lys Chemical compound CC(C)C[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CCCCN APFJUBGRZGMQFF-QWRGUYRKSA-N 0.000 description 2
- HYMLKESRWLZDBR-WEDXCCLWSA-N Leu-Gly-Thr Chemical compound CC(C)C[C@H](N)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(O)=O HYMLKESRWLZDBR-WEDXCCLWSA-N 0.000 description 2
- BTNXKBVLWJBTNR-SRVKXCTJSA-N Leu-His-Asn Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC(N)=O)C(O)=O BTNXKBVLWJBTNR-SRVKXCTJSA-N 0.000 description 2
- VCHVSKNMTXWIIP-SRVKXCTJSA-N Leu-Lys-Ser Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(O)=O VCHVSKNMTXWIIP-SRVKXCTJSA-N 0.000 description 2
- AUNMOHYWTAPQLA-XUXIUFHCSA-N Leu-Met-Ile Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O AUNMOHYWTAPQLA-XUXIUFHCSA-N 0.000 description 2
- QWWPYKKLXWOITQ-VOAKCMCISA-N Leu-Thr-Leu Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@H](C(O)=O)CC(C)C QWWPYKKLXWOITQ-VOAKCMCISA-N 0.000 description 2
- 208000030289 Lymphoproliferative disease Diseases 0.000 description 2
- NRQRKMYZONPCTM-CIUDSAMLSA-N Lys-Asp-Ser Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O NRQRKMYZONPCTM-CIUDSAMLSA-N 0.000 description 2
- MWVUEPNEPWMFBD-SRVKXCTJSA-N Lys-Cys-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CS)C(=O)N[C@H](C(O)=O)CCCCN MWVUEPNEPWMFBD-SRVKXCTJSA-N 0.000 description 2
- ODUQLUADRKMHOZ-JYJNAYRXSA-N Lys-Glu-Tyr Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CCCCN)N)O ODUQLUADRKMHOZ-JYJNAYRXSA-N 0.000 description 2
- XNKDCYABMBBEKN-IUCAKERBSA-N Lys-Gly-Gln Chemical compound NCCCC[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CCC(N)=O XNKDCYABMBBEKN-IUCAKERBSA-N 0.000 description 2
- PBLLTSKBTAHDNA-KBPBESRZSA-N Lys-Gly-Phe Chemical compound [H]N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O PBLLTSKBTAHDNA-KBPBESRZSA-N 0.000 description 2
- ODTZHNZPINULEU-KKUMJFAQSA-N Lys-Phe-Asn Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CCCCN)N ODTZHNZPINULEU-KKUMJFAQSA-N 0.000 description 2
- AFLBTVGQCQLOFJ-AVGNSLFASA-N Lys-Pro-Arg Chemical compound NCCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCN=C(N)N)C(O)=O AFLBTVGQCQLOFJ-AVGNSLFASA-N 0.000 description 2
- YTJFXEDRUOQGSP-DCAQKATOSA-N Lys-Pro-Ser Chemical compound [H]N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O YTJFXEDRUOQGSP-DCAQKATOSA-N 0.000 description 2
- WQDKIVRHTQYJSN-DCAQKATOSA-N Lys-Ser-Arg Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N WQDKIVRHTQYJSN-DCAQKATOSA-N 0.000 description 2
- IOQWIOPSKJOEKI-SRVKXCTJSA-N Lys-Ser-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O IOQWIOPSKJOEKI-SRVKXCTJSA-N 0.000 description 2
- DLCAXBGXGOVUCD-PPCPHDFISA-N Lys-Thr-Ile Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O DLCAXBGXGOVUCD-PPCPHDFISA-N 0.000 description 2
- YKBSXQFZWFXFIB-VOAKCMCISA-N Lys-Thr-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@@H](CCCCN)C(O)=O YKBSXQFZWFXFIB-VOAKCMCISA-N 0.000 description 2
- RQILLQOQXLZTCK-KBPBESRZSA-N Lys-Tyr-Gly Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)NCC(O)=O RQILLQOQXLZTCK-KBPBESRZSA-N 0.000 description 2
- 241000282567 Macaca fascicularis Species 0.000 description 2
- 101100438943 Macaca fascicularis CD3E gene Proteins 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- OIFHHODAXVWKJN-ULQDDVLXSA-N Met-Phe-Leu Chemical compound CSCC[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(O)=O)CC1=CC=CC=C1 OIFHHODAXVWKJN-ULQDDVLXSA-N 0.000 description 2
- WRXOPYNEKGZWAZ-FXQIFTODSA-N Met-Ser-Cys Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(O)=O WRXOPYNEKGZWAZ-FXQIFTODSA-N 0.000 description 2
- ZDJICAUBMUKVEJ-CIUDSAMLSA-N Met-Ser-Gln Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CCC(N)=O ZDJICAUBMUKVEJ-CIUDSAMLSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- HCTXJGRYAACKOB-SRVKXCTJSA-N Phe-Asn-Asp Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC(=O)O)C(=O)O)N HCTXJGRYAACKOB-SRVKXCTJSA-N 0.000 description 2
- SMFGCTXUBWEPKM-KBPBESRZSA-N Phe-Leu-Gly Chemical compound OC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC1=CC=CC=C1 SMFGCTXUBWEPKM-KBPBESRZSA-N 0.000 description 2
- JLLJTMHNXQTMCK-UBHSHLNASA-N Phe-Pro-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CC1=CC=CC=C1 JLLJTMHNXQTMCK-UBHSHLNASA-N 0.000 description 2
- IIEOLPMQYRBZCN-SRVKXCTJSA-N Phe-Ser-Cys Chemical compound N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)O IIEOLPMQYRBZCN-SRVKXCTJSA-N 0.000 description 2
- FGWUALWGCZJQDJ-URLPEUOOSA-N Phe-Thr-Ile Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O FGWUALWGCZJQDJ-URLPEUOOSA-N 0.000 description 2
- 229920001213 Polysorbate 20 Polymers 0.000 description 2
- OOLOTUZJUBOMAX-GUBZILKMSA-N Pro-Ala-Val Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(O)=O OOLOTUZJUBOMAX-GUBZILKMSA-N 0.000 description 2
- BNBBNGZZKQUWCD-IUCAKERBSA-N Pro-Arg-Gly Chemical compound NC(N)=NCCC[C@@H](C(=O)NCC(O)=O)NC(=O)[C@@H]1CCCN1 BNBBNGZZKQUWCD-IUCAKERBSA-N 0.000 description 2
- TUYWCHPXKQTISF-LPEHRKFASA-N Pro-Cys-Pro Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CS)C(=O)N2CCC[C@@H]2C(=O)O TUYWCHPXKQTISF-LPEHRKFASA-N 0.000 description 2
- UAYHMOIGIQZLFR-NHCYSSNCSA-N Pro-Gln-Val Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(O)=O UAYHMOIGIQZLFR-NHCYSSNCSA-N 0.000 description 2
- LGSANCBHSMDFDY-GARJFASQSA-N Pro-Glu-Pro Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CCC(=O)O)C(=O)N2CCC[C@@H]2C(=O)O LGSANCBHSMDFDY-GARJFASQSA-N 0.000 description 2
- ULIWFCCJIOEHMU-BQBZGAKWSA-N Pro-Gly-Asp Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H]1CCCN1 ULIWFCCJIOEHMU-BQBZGAKWSA-N 0.000 description 2
- JMVQDLDPDBXAAX-YUMQZZPRSA-N Pro-Gly-Gln Chemical compound NC(=O)CC[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H]1CCCN1 JMVQDLDPDBXAAX-YUMQZZPRSA-N 0.000 description 2
- ZLXKLMHAMDENIO-DCAQKATOSA-N Pro-Lys-Asp Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(O)=O ZLXKLMHAMDENIO-DCAQKATOSA-N 0.000 description 2
- HWLKHNDRXWTFTN-GUBZILKMSA-N Pro-Pro-Cys Chemical compound C1C[C@H](NC1)C(=O)N2CCC[C@H]2C(=O)N[C@@H](CS)C(=O)O HWLKHNDRXWTFTN-GUBZILKMSA-N 0.000 description 2
- PCWLNNZTBJTZRN-AVGNSLFASA-N Pro-Pro-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 PCWLNNZTBJTZRN-AVGNSLFASA-N 0.000 description 2
- KBUAPZAZPWNYSW-SRVKXCTJSA-N Pro-Pro-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 KBUAPZAZPWNYSW-SRVKXCTJSA-N 0.000 description 2
- 108020004511 Recombinant DNA Proteins 0.000 description 2
- QEDMOZUJTGEIBF-FXQIFTODSA-N Ser-Arg-Asp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(O)=O QEDMOZUJTGEIBF-FXQIFTODSA-N 0.000 description 2
- QVOGDCQNGLBNCR-FXQIFTODSA-N Ser-Arg-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(O)=O QVOGDCQNGLBNCR-FXQIFTODSA-N 0.000 description 2
- OYEDZGNMSBZCIM-XGEHTFHBSA-N Ser-Arg-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(O)=O OYEDZGNMSBZCIM-XGEHTFHBSA-N 0.000 description 2
- WXWDPFVKQRVJBJ-CIUDSAMLSA-N Ser-Asn-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CO)N WXWDPFVKQRVJBJ-CIUDSAMLSA-N 0.000 description 2
- VGNYHOBZJKWRGI-CIUDSAMLSA-N Ser-Asn-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CO VGNYHOBZJKWRGI-CIUDSAMLSA-N 0.000 description 2
- ICHZYBVODUVUKN-SRVKXCTJSA-N Ser-Asn-Tyr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O ICHZYBVODUVUKN-SRVKXCTJSA-N 0.000 description 2
- VQBCMLMPEWPUTB-ACZMJKKPSA-N Ser-Glu-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(O)=O VQBCMLMPEWPUTB-ACZMJKKPSA-N 0.000 description 2
- GZFAWAQTEYDKII-YUMQZZPRSA-N Ser-Gly-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CO GZFAWAQTEYDKII-YUMQZZPRSA-N 0.000 description 2
- KDGARKCAKHBEDB-NKWVEPMBSA-N Ser-Gly-Pro Chemical compound C1C[C@@H](N(C1)C(=O)CNC(=O)[C@H](CO)N)C(=O)O KDGARKCAKHBEDB-NKWVEPMBSA-N 0.000 description 2
- DJACUBDEDBZKLQ-KBIXCLLPSA-N Ser-Ile-Glu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(O)=O DJACUBDEDBZKLQ-KBIXCLLPSA-N 0.000 description 2
- JWOBLHJRDADHLN-KKUMJFAQSA-N Ser-Leu-Tyr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O JWOBLHJRDADHLN-KKUMJFAQSA-N 0.000 description 2
- GZSZPKSBVAOGIE-CIUDSAMLSA-N Ser-Lys-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O GZSZPKSBVAOGIE-CIUDSAMLSA-N 0.000 description 2
- LRWBCWGEUCKDTN-BJDJZHNGSA-N Ser-Lys-Ile Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O LRWBCWGEUCKDTN-BJDJZHNGSA-N 0.000 description 2
- GDUZTEQRAOXYJS-SRVKXCTJSA-N Ser-Phe-Asn Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CO)N GDUZTEQRAOXYJS-SRVKXCTJSA-N 0.000 description 2
- AZWNCEBQZXELEZ-FXQIFTODSA-N Ser-Pro-Ser Chemical compound OC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O AZWNCEBQZXELEZ-FXQIFTODSA-N 0.000 description 2
- HHJFMHQYEAAOBM-ZLUOBGJFSA-N Ser-Ser-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(O)=O HHJFMHQYEAAOBM-ZLUOBGJFSA-N 0.000 description 2
- JCLAFVNDBJMLBC-JBDRJPRFSA-N Ser-Ser-Ile Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O JCLAFVNDBJMLBC-JBDRJPRFSA-N 0.000 description 2
- VGQVAVQWKJLIRM-FXQIFTODSA-N Ser-Ser-Val Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O VGQVAVQWKJLIRM-FXQIFTODSA-N 0.000 description 2
- XJDMUQCLVSCRSJ-VZFHVOOUSA-N Ser-Thr-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O XJDMUQCLVSCRSJ-VZFHVOOUSA-N 0.000 description 2
- PCJLFYBAQZQOFE-KATARQTJSA-N Ser-Thr-Lys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CO)N)O PCJLFYBAQZQOFE-KATARQTJSA-N 0.000 description 2
- AXKJPUBALUNJEO-UBHSHLNASA-N Ser-Trp-Asn Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CC(N)=O)C(O)=O AXKJPUBALUNJEO-UBHSHLNASA-N 0.000 description 2
- RCOUFINCYASMDN-GUBZILKMSA-N Ser-Val-Met Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCSC)C(O)=O RCOUFINCYASMDN-GUBZILKMSA-N 0.000 description 2
- 108010003723 Single-Domain Antibodies Proteins 0.000 description 2
- 208000000102 Squamous Cell Carcinoma of Head and Neck Diseases 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 108010083312 T-Cell Antigen Receptor-CD3 Complex Proteins 0.000 description 2
- IGROJMCBGRFRGI-YTLHQDLWSA-N Thr-Ala-Ala Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(O)=O IGROJMCBGRFRGI-YTLHQDLWSA-N 0.000 description 2
- ODSAPYVQSLDRSR-LKXGYXEUSA-N Thr-Cys-Asn Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(O)=O ODSAPYVQSLDRSR-LKXGYXEUSA-N 0.000 description 2
- ASJDFGOPDCVXTG-KATARQTJSA-N Thr-Cys-Leu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(C)C)C(O)=O ASJDFGOPDCVXTG-KATARQTJSA-N 0.000 description 2
- DSLHSTIUAPKERR-XGEHTFHBSA-N Thr-Cys-Val Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(=O)N[C@@H](C(C)C)C(O)=O DSLHSTIUAPKERR-XGEHTFHBSA-N 0.000 description 2
- PAXANSWUSVPFNK-IUKAMOBKSA-N Thr-Ile-Asn Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H]([C@@H](C)O)N PAXANSWUSVPFNK-IUKAMOBKSA-N 0.000 description 2
- FIFDDJFLNVAVMS-RHYQMDGZSA-N Thr-Leu-Met Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(O)=O FIFDDJFLNVAVMS-RHYQMDGZSA-N 0.000 description 2
- BDGBHYCAZJPLHX-HJGDQZAQSA-N Thr-Lys-Asn Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(O)=O BDGBHYCAZJPLHX-HJGDQZAQSA-N 0.000 description 2
- JLNMFGCJODTXDH-WEDXCCLWSA-N Thr-Lys-Gly Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)NCC(O)=O JLNMFGCJODTXDH-WEDXCCLWSA-N 0.000 description 2
- DXPURPNJDFCKKO-RHYQMDGZSA-N Thr-Lys-Val Chemical compound CC(C)[C@H](NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)[C@@H](C)O)C(O)=O DXPURPNJDFCKKO-RHYQMDGZSA-N 0.000 description 2
- XKWABWFMQXMUMT-HJGDQZAQSA-N Thr-Pro-Glu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O XKWABWFMQXMUMT-HJGDQZAQSA-N 0.000 description 2
- MROIJTGJGIDEEJ-RCWTZXSCSA-N Thr-Pro-Pro Chemical compound C[C@@H](O)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 MROIJTGJGIDEEJ-RCWTZXSCSA-N 0.000 description 2
- SGAOHNPSEPVAFP-ZDLURKLDSA-N Thr-Ser-Gly Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)NCC(O)=O SGAOHNPSEPVAFP-ZDLURKLDSA-N 0.000 description 2
- LECUEEHKUFYOOV-ZJDVBMNYSA-N Thr-Thr-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@@H](N)[C@@H](C)O LECUEEHKUFYOOV-ZJDVBMNYSA-N 0.000 description 2
- BEZTUFWTPVOROW-KJEVXHAQSA-N Thr-Tyr-Arg Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N)O BEZTUFWTPVOROW-KJEVXHAQSA-N 0.000 description 2
- JAWUQFCGNVEDRN-MEYUZBJRSA-N Thr-Tyr-Leu Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CC(C)C)C(=O)O)N)O JAWUQFCGNVEDRN-MEYUZBJRSA-N 0.000 description 2
- OGOYMQWIWHGTGH-KZVJFYERSA-N Thr-Val-Ala Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C)C(O)=O OGOYMQWIWHGTGH-KZVJFYERSA-N 0.000 description 2
- FYBFTPLPAXZBOY-KKHAAJSZSA-N Thr-Val-Asp Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O FYBFTPLPAXZBOY-KKHAAJSZSA-N 0.000 description 2
- QNXZCKMXHPULME-ZNSHCXBVSA-N Thr-Val-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)O)N)O QNXZCKMXHPULME-ZNSHCXBVSA-N 0.000 description 2
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 2
- 239000004473 Threonine Substances 0.000 description 2
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 2
- UDCHKDYNMRJYMI-QEJZJMRPSA-N Trp-Glu-Ser Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(O)=O UDCHKDYNMRJYMI-QEJZJMRPSA-N 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
- BURPTJBFWIOHEY-UWJYBYFXSA-N Tyr-Ala-Asp Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 BURPTJBFWIOHEY-UWJYBYFXSA-N 0.000 description 2
- QJBWZNTWJSZUOY-UWJYBYFXSA-N Tyr-Ala-Cys Chemical compound C[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)N QJBWZNTWJSZUOY-UWJYBYFXSA-N 0.000 description 2
- SINRIKQYQJRGDQ-MEYUZBJRSA-N Tyr-Lys-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 SINRIKQYQJRGDQ-MEYUZBJRSA-N 0.000 description 2
- LRHBBGDMBLFYGL-FHWLQOOXSA-N Tyr-Phe-Glu Chemical compound C([C@H](N)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCC(O)=O)C(O)=O)C1=CC=C(O)C=C1 LRHBBGDMBLFYGL-FHWLQOOXSA-N 0.000 description 2
- WURLIFOWSMBUAR-SLFFLAALSA-N Tyr-Phe-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC2=CC=CC=C2)NC(=O)[C@H](CC3=CC=C(C=C3)O)N)C(=O)O WURLIFOWSMBUAR-SLFFLAALSA-N 0.000 description 2
- YYLHVUCSTXXKBS-IHRRRGAJSA-N Tyr-Pro-Ser Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O YYLHVUCSTXXKBS-IHRRRGAJSA-N 0.000 description 2
- RWOKVQUCENPXGE-IHRRRGAJSA-N Tyr-Ser-Arg Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O RWOKVQUCENPXGE-IHRRRGAJSA-N 0.000 description 2
- SOAUMCDLIUGXJJ-SRVKXCTJSA-N Tyr-Ser-Asn Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O SOAUMCDLIUGXJJ-SRVKXCTJSA-N 0.000 description 2
- QFHRUCJIRVILCK-YJRXYDGGSA-N Tyr-Thr-Cys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)N)O QFHRUCJIRVILCK-YJRXYDGGSA-N 0.000 description 2
- RIVVDNTUSRVTQT-IRIUXVKKSA-N Tyr-Thr-Gln Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)N)O RIVVDNTUSRVTQT-IRIUXVKKSA-N 0.000 description 2
- CGGVNFJRZJUVAE-BYULHYEWSA-N Val-Asp-Asn Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC(=O)N)C(=O)O)N CGGVNFJRZJUVAE-BYULHYEWSA-N 0.000 description 2
- QHDXUYOYTPWCSK-RCOVLWMOSA-N Val-Asp-Gly Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)NCC(=O)O)N QHDXUYOYTPWCSK-RCOVLWMOSA-N 0.000 description 2
- ZQGPWORGSNRQLN-NHCYSSNCSA-N Val-Asp-His Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N ZQGPWORGSNRQLN-NHCYSSNCSA-N 0.000 description 2
- CFSSLXZJEMERJY-NRPADANISA-N Val-Gln-Ala Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(O)=O CFSSLXZJEMERJY-NRPADANISA-N 0.000 description 2
- OQWNEUXPKHIEJO-NRPADANISA-N Val-Glu-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CO)C(=O)O)N OQWNEUXPKHIEJO-NRPADANISA-N 0.000 description 2
- RKIGNDAHUOOIMJ-BQFCYCMXSA-N Val-Glu-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)C(C)C)C(O)=O)=CNC2=C1 RKIGNDAHUOOIMJ-BQFCYCMXSA-N 0.000 description 2
- UEHRGZCNLSWGHK-DLOVCJGASA-N Val-Glu-Val Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O UEHRGZCNLSWGHK-DLOVCJGASA-N 0.000 description 2
- ZIGZPYJXIWLQFC-QTKMDUPCSA-N Val-His-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CN=CN1)NC(=O)[C@H](C(C)C)N)O ZIGZPYJXIWLQFC-QTKMDUPCSA-N 0.000 description 2
- XTDDIVQWDXMRJL-IHRRRGAJSA-N Val-Leu-His Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](C(C)C)N XTDDIVQWDXMRJL-IHRRRGAJSA-N 0.000 description 2
- SYSWVVCYSXBVJG-RHYQMDGZSA-N Val-Leu-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C(C)C)N)O SYSWVVCYSXBVJG-RHYQMDGZSA-N 0.000 description 2
- SBJCTAZFSZXWSR-AVGNSLFASA-N Val-Met-His Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N SBJCTAZFSZXWSR-AVGNSLFASA-N 0.000 description 2
- FMQGYTMERWBMSI-HJWJTTGWSA-N Val-Phe-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)NC(=O)[C@H](C(C)C)N FMQGYTMERWBMSI-HJWJTTGWSA-N 0.000 description 2
- HJSLDXZAZGFPDK-ULQDDVLXSA-N Val-Phe-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)NC(=O)[C@H](C(C)C)N HJSLDXZAZGFPDK-ULQDDVLXSA-N 0.000 description 2
- VCIYTVOBLZHFSC-XHSDSOJGSA-N Val-Phe-Pro Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N2CCC[C@@H]2C(=O)O)N VCIYTVOBLZHFSC-XHSDSOJGSA-N 0.000 description 2
- DEGUERSKQBRZMZ-FXQIFTODSA-N Val-Ser-Ala Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(O)=O DEGUERSKQBRZMZ-FXQIFTODSA-N 0.000 description 2
- RYHUIHUOYRNNIE-NRPADANISA-N Val-Ser-Gln Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N RYHUIHUOYRNNIE-NRPADANISA-N 0.000 description 2
- UVHFONIHVHLDDQ-IFFSRLJSSA-N Val-Thr-Glu Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)O)NC(=O)[C@H](C(C)C)N)O UVHFONIHVHLDDQ-IFFSRLJSSA-N 0.000 description 2
- GVNLOVJNNDZUHS-RHYQMDGZSA-N Val-Thr-Lys Chemical compound [H]N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(O)=O GVNLOVJNNDZUHS-RHYQMDGZSA-N 0.000 description 2
- PGBMPFKFKXYROZ-UFYCRDLUSA-N Val-Tyr-Phe Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CC2=CC=CC=C2)C(=O)O)N PGBMPFKFKXYROZ-UFYCRDLUSA-N 0.000 description 2
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 108010041407 alanylaspartic acid Proteins 0.000 description 2
- 108010047495 alanylglycine Proteins 0.000 description 2
- 108010050025 alpha-glutamyltryptophan Proteins 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 229940121375 antifungal agent Drugs 0.000 description 2
- 239000003429 antifungal agent Substances 0.000 description 2
- 210000000612 antigen-presenting cell Anatomy 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 230000008827 biological function Effects 0.000 description 2
- 238000007664 blowing Methods 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 230000003915 cell function Effects 0.000 description 2
- 239000006285 cell suspension Substances 0.000 description 2
- 230000003833 cell viability Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 229960004926 chlorobutanol Drugs 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 239000002299 complementary DNA Substances 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 108010060199 cysteinylproline Proteins 0.000 description 2
- 206010052015 cytokine release syndrome Diseases 0.000 description 2
- 210000001151 cytotoxic T lymphocyte Anatomy 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 230000002950 deficient Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 238000007865 diluting Methods 0.000 description 2
- 238000004520 electroporation Methods 0.000 description 2
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 2
- 210000003527 eukaryotic cell Anatomy 0.000 description 2
- 235000013922 glutamic acid Nutrition 0.000 description 2
- 239000004220 glutamic acid Substances 0.000 description 2
- 230000013595 glycosylation Effects 0.000 description 2
- 238000006206 glycosylation reaction Methods 0.000 description 2
- XBGGUPMXALFZOT-UHFFFAOYSA-N glycyl-L-tyrosine hemihydrate Natural products NCC(=O)NC(C(O)=O)CC1=CC=C(O)C=C1 XBGGUPMXALFZOT-UHFFFAOYSA-N 0.000 description 2
- 108010079413 glycyl-prolyl-glutamic acid Proteins 0.000 description 2
- 108010074027 glycyl-seryl-phenylalanine Proteins 0.000 description 2
- 108010077515 glycylproline Proteins 0.000 description 2
- 210000003714 granulocyte Anatomy 0.000 description 2
- 201000000459 head and neck squamous cell carcinoma Diseases 0.000 description 2
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 2
- FDGQSTZJBFJUBT-UHFFFAOYSA-N hypoxanthine Chemical compound O=C1NC=NC2=C1NC=N2 FDGQSTZJBFJUBT-UHFFFAOYSA-N 0.000 description 2
- 210000000987 immune system Anatomy 0.000 description 2
- 230000002998 immunogenetic effect Effects 0.000 description 2
- 229940125396 insulin Drugs 0.000 description 2
- 229940100601 interleukin-6 Drugs 0.000 description 2
- 229960000310 isoleucine Drugs 0.000 description 2
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 108010012058 leucyltyrosine Proteins 0.000 description 2
- 210000004698 lymphocyte Anatomy 0.000 description 2
- 229920002521 macromolecule Polymers 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 230000003204 osmotic effect Effects 0.000 description 2
- 229940043515 other immunoglobulins in atc Drugs 0.000 description 2
- 239000003002 pH adjusting agent Substances 0.000 description 2
- 244000052769 pathogen Species 0.000 description 2
- 229960003742 phenol Drugs 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
- 108010012581 phenylalanylglutamate Proteins 0.000 description 2
- 229920005862 polyol Polymers 0.000 description 2
- 150000003077 polyols Chemical class 0.000 description 2
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 2
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 108010090894 prolylleucine Proteins 0.000 description 2
- 108010053725 prolylvaline Proteins 0.000 description 2
- 230000005180 public health Effects 0.000 description 2
- 238000003259 recombinant expression Methods 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 108010026333 seryl-proline Proteins 0.000 description 2
- 230000019491 signal transduction Effects 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 229940075582 sorbic acid Drugs 0.000 description 2
- 235000010199 sorbic acid Nutrition 0.000 description 2
- 239000004334 sorbic acid Substances 0.000 description 2
- 210000004989 spleen cell Anatomy 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 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
- 239000004094 surface-active agent Substances 0.000 description 2
- 208000011580 syndromic disease Diseases 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- 229950010127 teplizumab Drugs 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 125000003396 thiol group Chemical group [H]S* 0.000 description 2
- 238000001890 transfection Methods 0.000 description 2
- 108010080629 tryptophan-leucine Proteins 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- 239000004474 valine Substances 0.000 description 2
- 239000013603 viral vector Substances 0.000 description 2
- 230000003612 virological effect Effects 0.000 description 2
- 108010027345 wheylin-1 peptide Proteins 0.000 description 2
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 1
- QCDWFXQBSFUVSP-UHFFFAOYSA-N 2-phenoxyethanol Chemical compound OCCOC1=CC=CC=C1 QCDWFXQBSFUVSP-UHFFFAOYSA-N 0.000 description 1
- TVZGACDUOSZQKY-LBPRGKRZSA-N 4-aminofolic acid Chemical compound C1=NC2=NC(N)=NC(N)=C2N=C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 TVZGACDUOSZQKY-LBPRGKRZSA-N 0.000 description 1
- GOZMBJCYMQQACI-UHFFFAOYSA-N 6,7-dimethyl-3-[[methyl-[2-[methyl-[[1-[3-(trifluoromethyl)phenyl]indol-3-yl]methyl]amino]ethyl]amino]methyl]chromen-4-one;dihydrochloride Chemical compound Cl.Cl.C=1OC2=CC(C)=C(C)C=C2C(=O)C=1CN(C)CCN(C)CC(C1=CC=CC=C11)=CN1C1=CC=CC(C(F)(F)F)=C1 GOZMBJCYMQQACI-UHFFFAOYSA-N 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
- 208000010507 Adenocarcinoma of Lung Diseases 0.000 description 1
- RGQCNKIDEQJEBT-CQDKDKBSSA-N Ala-Leu-Tyr Chemical compound C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 RGQCNKIDEQJEBT-CQDKDKBSSA-N 0.000 description 1
- 206010061424 Anal cancer Diseases 0.000 description 1
- 208000007860 Anus Neoplasms Diseases 0.000 description 1
- PHHRSPBBQUFULD-UWVGGRQHSA-N Arg-Gly-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)CNC(=O)[C@H](CCCN=C(N)N)N PHHRSPBBQUFULD-UWVGGRQHSA-N 0.000 description 1
- AOHKLEBWKMKITA-IHRRRGAJSA-N Arg-Phe-Ser Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CCCN=C(N)N)N AOHKLEBWKMKITA-IHRRRGAJSA-N 0.000 description 1
- SUMJNGAMIQSNGX-TUAOUCFPSA-N Arg-Val-Pro Chemical compound CC(C)[C@H](NC(=O)[C@@H](N)CCCNC(N)=N)C(=O)N1CCC[C@@H]1C(O)=O SUMJNGAMIQSNGX-TUAOUCFPSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- ACRYGQFHAQHDSF-ZLUOBGJFSA-N Asn-Asn-Asn Chemical compound NC(=O)C[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O ACRYGQFHAQHDSF-ZLUOBGJFSA-N 0.000 description 1
- RAKKBBHMTJSXOY-XVYDVKMFSA-N Asn-His-Ala Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](C)C(O)=O RAKKBBHMTJSXOY-XVYDVKMFSA-N 0.000 description 1
- BKZFBJYIVSBXCO-KKUMJFAQSA-N Asn-Phe-His Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC1=CNC=N1)C(O)=O BKZFBJYIVSBXCO-KKUMJFAQSA-N 0.000 description 1
- BCADFFUQHIMQAA-KKHAAJSZSA-N Asn-Thr-Val Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(O)=O BCADFFUQHIMQAA-KKHAAJSZSA-N 0.000 description 1
- VBVKSAFJPVXMFJ-CIUDSAMLSA-N Asp-Asn-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CC(=O)O)N VBVKSAFJPVXMFJ-CIUDSAMLSA-N 0.000 description 1
- PGUYEUCYVNZGGV-QWRGUYRKSA-N Asp-Gly-Tyr Chemical compound OC(=O)C[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 PGUYEUCYVNZGGV-QWRGUYRKSA-N 0.000 description 1
- WSXDIZFNQYTUJB-SRVKXCTJSA-N Asp-His-Leu Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC(C)C)C(O)=O WSXDIZFNQYTUJB-SRVKXCTJSA-N 0.000 description 1
- PLNJUJGNLDSFOP-UWJYBYFXSA-N Asp-Tyr-Ala Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](C)C(O)=O PLNJUJGNLDSFOP-UWJYBYFXSA-N 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 1
- 208000032116 Autoimmune Experimental Encephalomyelitis Diseases 0.000 description 1
- 108091008875 B cell receptors Proteins 0.000 description 1
- 208000003950 B-cell lymphoma Diseases 0.000 description 1
- 208000028564 B-cell non-Hodgkin lymphoma Diseases 0.000 description 1
- 230000003844 B-cell-activation Effects 0.000 description 1
- DWRXFEITVBNRMK-UHFFFAOYSA-N Beta-D-1-Arabinofuranosylthymine Natural products O=C1NC(=O)C(C)=CN1C1C(O)C(O)C(CO)O1 DWRXFEITVBNRMK-UHFFFAOYSA-N 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 208000014644 Brain disease Diseases 0.000 description 1
- 101100454808 Caenorhabditis elegans lgg-2 gene Proteins 0.000 description 1
- 102000014914 Carrier Proteins Human genes 0.000 description 1
- 102000011632 Caseins Human genes 0.000 description 1
- 108010076119 Caseins Proteins 0.000 description 1
- 102000000844 Cell Surface Receptors Human genes 0.000 description 1
- 108010001857 Cell Surface Receptors Proteins 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- 108020004705 Codon Proteins 0.000 description 1
- 102000014447 Complement C1q Human genes 0.000 description 1
- 108010078043 Complement C1q Proteins 0.000 description 1
- 108020004635 Complementary DNA Proteins 0.000 description 1
- 206010010904 Convulsion Diseases 0.000 description 1
- 241000699802 Cricetulus griseus Species 0.000 description 1
- SWJYSDXMTPMBHO-FXQIFTODSA-N Cys-Pro-Ser Chemical compound [H]N[C@@H](CS)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O SWJYSDXMTPMBHO-FXQIFTODSA-N 0.000 description 1
- 241000701022 Cytomegalovirus Species 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 241000702421 Dependoparvovirus Species 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 101150029707 ERBB2 gene Proteins 0.000 description 1
- 206010049119 Emotional distress Diseases 0.000 description 1
- 208000032274 Encephalopathy Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 108091006020 Fc-tagged proteins Proteins 0.000 description 1
- 108010008177 Fd immunoglobulins Proteins 0.000 description 1
- 206010062878 Gastrooesophageal cancer Diseases 0.000 description 1
- XOKGKOQWADCLFQ-GARJFASQSA-N Gln-Arg-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CCC(=O)N)N)C(=O)O XOKGKOQWADCLFQ-GARJFASQSA-N 0.000 description 1
- LHMWTCWZARHLPV-CIUDSAMLSA-N Gln-Met-Ser Chemical compound CSCC[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CCC(=O)N)N LHMWTCWZARHLPV-CIUDSAMLSA-N 0.000 description 1
- MFORDNZDKAVNSR-SRVKXCTJSA-N Gln-Pro-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CCC(N)=O MFORDNZDKAVNSR-SRVKXCTJSA-N 0.000 description 1
- OSCLNNWLKKIQJM-WDSKDSINSA-N Gln-Ser-Gly Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)NCC(O)=O OSCLNNWLKKIQJM-WDSKDSINSA-N 0.000 description 1
- RUFHOVYUYSNDNY-ACZMJKKPSA-N Glu-Ala-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCC(O)=O RUFHOVYUYSNDNY-ACZMJKKPSA-N 0.000 description 1
- RLZBLVSJDFHDBL-KBIXCLLPSA-N Glu-Ala-Ile Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O RLZBLVSJDFHDBL-KBIXCLLPSA-N 0.000 description 1
- XMPAXPSENRSOSV-RYUDHWBXSA-N Glu-Gly-Tyr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O XMPAXPSENRSOSV-RYUDHWBXSA-N 0.000 description 1
- YGLCLCMAYUYZSG-AVGNSLFASA-N Glu-Lys-His Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(O)=O)CC1=CN=CN1 YGLCLCMAYUYZSG-AVGNSLFASA-N 0.000 description 1
- SUIAHERNFYRBDZ-GVXVVHGQSA-N Glu-Lys-Val Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(O)=O SUIAHERNFYRBDZ-GVXVVHGQSA-N 0.000 description 1
- YUXIEONARHPUTK-JBACZVJFSA-N Glu-Phe-Trp Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC2=CNC3=CC=CC=C32)C(=O)O)NC(=O)[C@H](CCC(=O)O)N YUXIEONARHPUTK-JBACZVJFSA-N 0.000 description 1
- DLISPGXMKZTWQG-IFFSRLJSSA-N Glu-Thr-Val Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(O)=O DLISPGXMKZTWQG-IFFSRLJSSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- MBOAPAXLTUSMQI-JHEQGTHGSA-N Gly-Glu-Thr Chemical compound [H]NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O MBOAPAXLTUSMQI-JHEQGTHGSA-N 0.000 description 1
- ADZGCWWDPFDHCY-ZETCQYMHSA-N Gly-His-Gly Chemical compound OC(=O)CNC(=O)[C@@H](NC(=O)CN)CC1=CN=CN1 ADZGCWWDPFDHCY-ZETCQYMHSA-N 0.000 description 1
- WNGHUXFWEWTKAO-YUMQZZPRSA-N Gly-Ser-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)CN WNGHUXFWEWTKAO-YUMQZZPRSA-N 0.000 description 1
- TVTZEOHWHUVYCG-KYNKHSRBSA-N Gly-Thr-Thr Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O TVTZEOHWHUVYCG-KYNKHSRBSA-N 0.000 description 1
- YGHSQRJSHKYUJY-SCZZXKLOSA-N Gly-Val-Pro Chemical compound CC(C)[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)CN YGHSQRJSHKYUJY-SCZZXKLOSA-N 0.000 description 1
- KSOBNUBCYHGUKH-UWVGGRQHSA-N Gly-Val-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)CN KSOBNUBCYHGUKH-UWVGGRQHSA-N 0.000 description 1
- 206010051269 Graft thrombosis Diseases 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- FYTCLUIYTYFGPT-YUMQZZPRSA-N His-Gly-Ser Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)NCC(=O)N[C@@H](CO)C(O)=O FYTCLUIYTYFGPT-YUMQZZPRSA-N 0.000 description 1
- SAPLASXFNUYUFE-CQDKDKBSSA-N His-Phe-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)NC(=O)[C@H](CC2=CN=CN2)N SAPLASXFNUYUFE-CQDKDKBSSA-N 0.000 description 1
- RXKFKJVJVHLRIE-XIRDDKMYSA-N His-Ser-Trp Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC3=CN=CN3)N RXKFKJVJVHLRIE-XIRDDKMYSA-N 0.000 description 1
- PZUZIHRPOVVHOT-KBPBESRZSA-N His-Tyr-Gly Chemical compound C([C@H](N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)NCC(O)=O)C1=CN=CN1 PZUZIHRPOVVHOT-KBPBESRZSA-N 0.000 description 1
- 102000018713 Histocompatibility Antigens Class II Human genes 0.000 description 1
- 108010027412 Histocompatibility Antigens Class II Proteins 0.000 description 1
- 101000917858 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor III-A Proteins 0.000 description 1
- 101000917839 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor III-B Proteins 0.000 description 1
- 101000914514 Homo sapiens T-cell-specific surface glycoprotein CD28 Proteins 0.000 description 1
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 1
- UGQMRVRMYYASKQ-UHFFFAOYSA-N Hypoxanthine nucleoside Natural products OC1C(O)C(CO)OC1N1C(NC=NC2=O)=C2N=C1 UGQMRVRMYYASKQ-UHFFFAOYSA-N 0.000 description 1
- 108010073807 IgG Receptors Proteins 0.000 description 1
- 102000009490 IgG Receptors Human genes 0.000 description 1
- 102100026120 IgG receptor FcRn large subunit p51 Human genes 0.000 description 1
- 101710177940 IgG receptor FcRn large subunit p51 Proteins 0.000 description 1
- NULSANWBUWLTKN-NAKRPEOUSA-N Ile-Arg-Ser Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CO)C(=O)O)N NULSANWBUWLTKN-NAKRPEOUSA-N 0.000 description 1
- NZOCIWKZUVUNDW-ZKWXMUAHSA-N Ile-Gly-Ala Chemical compound CC[C@H](C)[C@H](N)C(=O)NCC(=O)N[C@@H](C)C(O)=O NZOCIWKZUVUNDW-ZKWXMUAHSA-N 0.000 description 1
- KFVUBLZRFSVDGO-BYULHYEWSA-N Ile-Gly-Asp Chemical compound CC[C@H](C)[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CC(O)=O KFVUBLZRFSVDGO-BYULHYEWSA-N 0.000 description 1
- 108010091135 Immunoglobulin Fc Fragments Proteins 0.000 description 1
- 102000018071 Immunoglobulin Fc Fragments Human genes 0.000 description 1
- 102000013463 Immunoglobulin Light Chains Human genes 0.000 description 1
- 108010065825 Immunoglobulin Light Chains Proteins 0.000 description 1
- 102000012745 Immunoglobulin Subunits Human genes 0.000 description 1
- 108010079585 Immunoglobulin Subunits Proteins 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 102000019223 Interleukin-1 receptor Human genes 0.000 description 1
- 108050006617 Interleukin-1 receptor Proteins 0.000 description 1
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- 208000031671 Large B-Cell Diffuse Lymphoma Diseases 0.000 description 1
- LJBVRCDPWOJOEK-PPCPHDFISA-N Leu-Thr-Ile Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O LJBVRCDPWOJOEK-PPCPHDFISA-N 0.000 description 1
- JGKHAFUAPZCCDU-BZSNNMDCSA-N Leu-Tyr-Leu Chemical compound CC(C)C[C@H]([NH3+])C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C([O-])=O)CC1=CC=C(O)C=C1 JGKHAFUAPZCCDU-BZSNNMDCSA-N 0.000 description 1
- AIMGJYMCTAABEN-GVXVVHGQSA-N Leu-Val-Glu Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O AIMGJYMCTAABEN-GVXVVHGQSA-N 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- 102100029185 Low affinity immunoglobulin gamma Fc region receptor III-B Human genes 0.000 description 1
- 208000028018 Lymphocytic leukaemia Diseases 0.000 description 1
- FZIJIFCXUCZHOL-CIUDSAMLSA-N Lys-Ala-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCCN FZIJIFCXUCZHOL-CIUDSAMLSA-N 0.000 description 1
- NNCDAORZCMPZPX-GUBZILKMSA-N Lys-Gln-Ser Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CO)C(=O)O)N NNCDAORZCMPZPX-GUBZILKMSA-N 0.000 description 1
- KYNNSEJZFVCDIV-ZPFDUUQYSA-N Lys-Ile-Asn Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(N)=O)C(O)=O KYNNSEJZFVCDIV-ZPFDUUQYSA-N 0.000 description 1
- PELXPRPDQRFBGQ-KKUMJFAQSA-N Lys-Tyr-Asn Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CCCCN)N)O PELXPRPDQRFBGQ-KKUMJFAQSA-N 0.000 description 1
- 108700018351 Major Histocompatibility Complex Proteins 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 201000009906 Meningitis Diseases 0.000 description 1
- 206010027406 Mesothelioma Diseases 0.000 description 1
- 208000001894 Nasopharyngeal Neoplasms Diseases 0.000 description 1
- 206010061306 Nasopharyngeal cancer Diseases 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 206010061534 Oesophageal squamous cell carcinoma Diseases 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 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
- 206010057249 Phagocytosis Diseases 0.000 description 1
- SFKOEHXABNPLRT-KBPBESRZSA-N Phe-His-Gly Chemical compound N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1cnc[nH]1)C(=O)NCC(O)=O SFKOEHXABNPLRT-KBPBESRZSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 102100022019 Pregnancy-specific beta-1-glycoprotein 2 Human genes 0.000 description 1
- VYWNORHENYEQDW-YUMQZZPRSA-N Pro-Gly-Glu Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H]1CCCN1 VYWNORHENYEQDW-YUMQZZPRSA-N 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 1
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- 208000006265 Renal cell carcinoma Diseases 0.000 description 1
- 108700008625 Reporter Genes Proteins 0.000 description 1
- MOQDPPUMFSMYOM-KKUMJFAQSA-N Ser-His-Phe Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)O)NC(=O)[C@H](CC2=CN=CN2)NC(=O)[C@H](CO)N MOQDPPUMFSMYOM-KKUMJFAQSA-N 0.000 description 1
- IFLVBVIYADZIQO-DCAQKATOSA-N Ser-Met-Lys Chemical compound CSCC[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CO)N IFLVBVIYADZIQO-DCAQKATOSA-N 0.000 description 1
- CKDXFSPMIDSMGV-GUBZILKMSA-N Ser-Pro-Val Chemical compound [H]N[C@@H](CO)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(O)=O CKDXFSPMIDSMGV-GUBZILKMSA-N 0.000 description 1
- QNBVFKZSSRYNFX-CUJWVEQBSA-N Ser-Thr-His Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](CO)N)O QNBVFKZSSRYNFX-CUJWVEQBSA-N 0.000 description 1
- XTWXRUWACCXBMU-XIRDDKMYSA-N Ser-Trp-His Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CC3=CN=CN3)C(=O)O)NC(=O)[C@H](CO)N XTWXRUWACCXBMU-XIRDDKMYSA-N 0.000 description 1
- OSFZCEQJLWCIBG-BZSNNMDCSA-N Ser-Tyr-Tyr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O OSFZCEQJLWCIBG-BZSNNMDCSA-N 0.000 description 1
- IAOHCSQDQDWRQU-GUBZILKMSA-N Ser-Val-Arg Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O IAOHCSQDQDWRQU-GUBZILKMSA-N 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 208000036765 Squamous cell carcinoma of the esophagus Diseases 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 230000005867 T cell response Effects 0.000 description 1
- 206010042971 T-cell lymphoma Diseases 0.000 description 1
- 208000027585 T-cell non-Hodgkin lymphoma Diseases 0.000 description 1
- 102100027213 T-cell-specific surface glycoprotein CD28 Human genes 0.000 description 1
- JVTHIXKSVYEWNI-JRQIVUDYSA-N Thr-Asn-Tyr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O JVTHIXKSVYEWNI-JRQIVUDYSA-N 0.000 description 1
- NRUPKQSXTJNQGD-XGEHTFHBSA-N Thr-Cys-Arg Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O NRUPKQSXTJNQGD-XGEHTFHBSA-N 0.000 description 1
- SLUWOCTZVGMURC-BFHQHQDPSA-N Thr-Gly-Ala Chemical compound C[C@@H](O)[C@H](N)C(=O)NCC(=O)N[C@@H](C)C(O)=O SLUWOCTZVGMURC-BFHQHQDPSA-N 0.000 description 1
- KRGDDWVBBDLPSJ-CUJWVEQBSA-N Thr-His-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CO)C(O)=O KRGDDWVBBDLPSJ-CUJWVEQBSA-N 0.000 description 1
- WRUWXBBEFUTJOU-XGEHTFHBSA-N Thr-Met-Ser Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CO)C(=O)O)N)O WRUWXBBEFUTJOU-XGEHTFHBSA-N 0.000 description 1
- AHERARIZBPOMNU-KATARQTJSA-N Thr-Ser-Leu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O AHERARIZBPOMNU-KATARQTJSA-N 0.000 description 1
- VUXIQSUQQYNLJP-XAVMHZPKSA-N Thr-Ser-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CO)C(=O)N1CCC[C@@H]1C(=O)O)N)O VUXIQSUQQYNLJP-XAVMHZPKSA-N 0.000 description 1
- ZMYCLHFLHRVOEA-HEIBUPTGSA-N Thr-Thr-Ser Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(O)=O ZMYCLHFLHRVOEA-HEIBUPTGSA-N 0.000 description 1
- LXXCHJKHJYRMIY-FQPOAREZSA-N Thr-Tyr-Ala Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](C)C(O)=O LXXCHJKHJYRMIY-FQPOAREZSA-N 0.000 description 1
- BKVICMPZWRNWOC-RHYQMDGZSA-N Thr-Val-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)[C@@H](C)O BKVICMPZWRNWOC-RHYQMDGZSA-N 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- 101710120037 Toxin CcdB Proteins 0.000 description 1
- 208000003721 Triple Negative Breast Neoplasms Diseases 0.000 description 1
- ORQGVWIUHICVKE-KCTSRDHCSA-N Trp-His-Ala Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](C)C(O)=O ORQGVWIUHICVKE-KCTSRDHCSA-N 0.000 description 1
- UUZYQOUJTORBQO-ZVZYQTTQSA-N Trp-Val-Gln Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O)=CNC2=C1 UUZYQOUJTORBQO-ZVZYQTTQSA-N 0.000 description 1
- IEESWNWYUOETOT-BVSLBCMMSA-N Trp-Val-Phe Chemical compound CC(C)[C@H](NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12)C(=O)N[C@@H](Cc1ccccc1)C(O)=O IEESWNWYUOETOT-BVSLBCMMSA-N 0.000 description 1
- JONPRIHUYSPIMA-UWJYBYFXSA-N Tyr-Ala-Asn Chemical compound NC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 JONPRIHUYSPIMA-UWJYBYFXSA-N 0.000 description 1
- UPODKYBYUBTWSV-BZSNNMDCSA-N Tyr-Phe-Cys Chemical compound C([C@H](N)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CS)C(O)=O)C1=CC=C(O)C=C1 UPODKYBYUBTWSV-BZSNNMDCSA-N 0.000 description 1
- BCOBSVIZMQXKFY-KKUMJFAQSA-N Tyr-Ser-His Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC2=CN=CN2)C(=O)O)N)O BCOBSVIZMQXKFY-KKUMJFAQSA-N 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- PWRITNSESKQTPW-NRPADANISA-N Val-Gln-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CO)C(=O)O)N PWRITNSESKQTPW-NRPADANISA-N 0.000 description 1
- LCHZBEUVGAVMKS-RHYQMDGZSA-N Val-Thr-Leu Chemical compound CC(C)C[C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)C(C)C)[C@@H](C)O)C(O)=O LCHZBEUVGAVMKS-RHYQMDGZSA-N 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 239000005862 Whey Substances 0.000 description 1
- 108010046377 Whey Proteins Proteins 0.000 description 1
- 102000007544 Whey Proteins Human genes 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 229960000643 adenine Drugs 0.000 description 1
- 208000009956 adenocarcinoma Diseases 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 108010076324 alanyl-glycyl-glycine Proteins 0.000 description 1
- 108010044940 alanylglutamine Proteins 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 230000006229 amino acid addition Effects 0.000 description 1
- 229960003896 aminopterin Drugs 0.000 description 1
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 description 1
- 229960000723 ampicillin Drugs 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 239000003945 anionic surfactant Substances 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 210000000628 antibody-producing cell Anatomy 0.000 description 1
- 201000011165 anus cancer Diseases 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 239000012062 aqueous buffer Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 235000009582 asparagine Nutrition 0.000 description 1
- 229960001230 asparagine Drugs 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 230000005784 autoimmunity Effects 0.000 description 1
- 210000003651 basophil Anatomy 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 230000002457 bidirectional effect Effects 0.000 description 1
- 108091008324 binding proteins Proteins 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 239000007975 buffered saline Substances 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 239000012830 cancer therapeutic Substances 0.000 description 1
- 230000002612 cardiopulmonary effect Effects 0.000 description 1
- 239000005018 casein Substances 0.000 description 1
- BECPQYXYKAMYBN-UHFFFAOYSA-N casein, tech. Chemical compound NCCCCC(C(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(CC(C)C)N=C(O)C(CCC(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(C(C)O)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(COP(O)(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(N)CC1=CC=CC=C1 BECPQYXYKAMYBN-UHFFFAOYSA-N 0.000 description 1
- 235000021240 caseins Nutrition 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 239000003093 cationic surfactant Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000012707 chemical precursor Substances 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 239000013599 cloning vector Substances 0.000 description 1
- 238000000975 co-precipitation Methods 0.000 description 1
- 230000024203 complement activation Effects 0.000 description 1
- 230000004154 complement system Effects 0.000 description 1
- 230000009918 complex formation Effects 0.000 description 1
- 238000004590 computer program Methods 0.000 description 1
- 239000003636 conditioned culture medium Substances 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 239000000356 contaminant Substances 0.000 description 1
- 230000009260 cross reactivity Effects 0.000 description 1
- 239000012228 culture supernatant Substances 0.000 description 1
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 231100000599 cytotoxic agent Toxicity 0.000 description 1
- 239000002619 cytotoxin Substances 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 210000004443 dendritic cell Anatomy 0.000 description 1
- 238000000432 density-gradient centrifugation Methods 0.000 description 1
- 238000000586 desensitisation Methods 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 239000000032 diagnostic agent Substances 0.000 description 1
- 229940039227 diagnostic agent Drugs 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 206010012818 diffuse large B-cell lymphoma Diseases 0.000 description 1
- PXEDJBXQKAGXNJ-QTNFYWBSSA-L disodium L-glutamate Chemical compound [Na+].[Na+].[O-]C(=O)[C@@H](N)CCC([O-])=O PXEDJBXQKAGXNJ-QTNFYWBSSA-L 0.000 description 1
- 230000009429 distress Effects 0.000 description 1
- 230000003828 downregulation Effects 0.000 description 1
- 239000012893 effector ligand Substances 0.000 description 1
- 230000005684 electric field Effects 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 210000003979 eosinophil Anatomy 0.000 description 1
- 208000007276 esophageal squamous cell carcinoma Diseases 0.000 description 1
- 102000015694 estrogen receptors Human genes 0.000 description 1
- 108010038795 estrogen receptors Proteins 0.000 description 1
- 239000012894 fetal calf serum Substances 0.000 description 1
- 238000013467 fragmentation Methods 0.000 description 1
- 238000006062 fragmentation reaction Methods 0.000 description 1
- 201000006974 gastroesophageal cancer Diseases 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 108010051307 glycyl-glycyl-proline Proteins 0.000 description 1
- 108010033719 glycyl-histidyl-glycine Proteins 0.000 description 1
- 108010089804 glycyl-threonine Proteins 0.000 description 1
- 230000003394 haemopoietic effect Effects 0.000 description 1
- 201000010536 head and neck cancer Diseases 0.000 description 1
- 208000014829 head and neck neoplasm Diseases 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 201000005787 hematologic cancer Diseases 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- 210000003630 histaminocyte Anatomy 0.000 description 1
- 108010040030 histidinoalanine Proteins 0.000 description 1
- 108010092114 histidylphenylalanine Proteins 0.000 description 1
- 108010018006 histidylserine Proteins 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 239000000413 hydrolysate Substances 0.000 description 1
- 230000002519 immonomodulatory effect Effects 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 238000003018 immunoassay Methods 0.000 description 1
- 238000003119 immunoblot Methods 0.000 description 1
- 229940127121 immunoconjugate Drugs 0.000 description 1
- 230000002163 immunogen Effects 0.000 description 1
- 230000009851 immunogenic response Effects 0.000 description 1
- 229940027941 immunoglobulin g Drugs 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000005305 interferometry Methods 0.000 description 1
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- 238000011694 lewis rat Methods 0.000 description 1
- 238000001638 lipofection Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000002796 luminescence method Methods 0.000 description 1
- 201000005249 lung adenocarcinoma Diseases 0.000 description 1
- 208000003747 lymphoid leukemia Diseases 0.000 description 1
- 239000008176 lyophilized powder Substances 0.000 description 1
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 108010057952 lysyl-phenylalanyl-lysine Proteins 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000006371 metabolic abnormality Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 238000010369 molecular cloning Methods 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 235000013923 monosodium glutamate Nutrition 0.000 description 1
- 229940126619 mouse monoclonal antibody Drugs 0.000 description 1
- 238000002703 mutagenesis Methods 0.000 description 1
- 231100000350 mutagenesis Toxicity 0.000 description 1
- 210000000066 myeloid cell Anatomy 0.000 description 1
- 208000025113 myeloid leukemia Diseases 0.000 description 1
- 210000000822 natural killer cell Anatomy 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 238000007857 nested PCR Methods 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 210000000440 neutrophil Anatomy 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 229950002610 otelixizumab Drugs 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 235000020030 perry Nutrition 0.000 description 1
- 238000002823 phage display Methods 0.000 description 1
- 210000001539 phagocyte Anatomy 0.000 description 1
- 230000008782 phagocytosis Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229960005323 phenoxyethanol Drugs 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 238000003752 polymerase chain reaction Methods 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 102000003998 progesterone receptors Human genes 0.000 description 1
- 108090000468 progesterone receptors Proteins 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000000644 propagated effect Effects 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 210000001938 protoplast Anatomy 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 238000010188 recombinant method Methods 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 108091008146 restriction endonucleases Proteins 0.000 description 1
- 238000010839 reverse transcription Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000002864 sequence alignment Methods 0.000 description 1
- 238000012163 sequencing technique Methods 0.000 description 1
- 239000012679 serum free medium Substances 0.000 description 1
- 108010048818 seryl-histidine Proteins 0.000 description 1
- 108010071207 serylmethionine Proteins 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 238000002741 site-directed mutagenesis Methods 0.000 description 1
- 235000020183 skimmed milk Nutrition 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 229940073490 sodium glutamate Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 230000009295 sperm incapacitation Effects 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 210000004988 splenocyte Anatomy 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000012916 structural analysis Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 230000020382 suppression by virus of host antigen processing and presentation of peptide antigen via MHC class I Effects 0.000 description 1
- 238000002198 surface plasmon resonance spectroscopy Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000010257 thawing Methods 0.000 description 1
- 229940126622 therapeutic monoclonal antibody Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- 229940104230 thymidine Drugs 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 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 1
- 208000022679 triple-negative breast carcinoma Diseases 0.000 description 1
- 108010029384 tryptophyl-histidine Proteins 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 241000701161 unidentified adenovirus Species 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 210000003501 vero cell Anatomy 0.000 description 1
- 229950004393 visilizumab Drugs 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
-
- 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
- C07K16/2809—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 the T-cell receptor (TcR)-CD3 complex
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K19/00—Hybrid peptides, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
-
- 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
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/51—Complete heavy chain or Fd fragment, i.e. VH + CH1
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/515—Complete light chain, i.e. VL + CL
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/52—Constant or Fc region; Isotype
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
- C07K2317/565—Complementarity determining region [CDR]
Abstract
本发明提供针对人CD3的抗体或其抗原结合片段,还提供了编码所述抗体的核酸分子,用于表达所述抗体的表达载体和宿主细胞,以及所述抗体的生产方法。此外,本发明还提供了包含所述抗体或其抗原结合片段的药物组合物,以及其在制备药物中的用途,所述药物用于预防和/或治疗多种疾病(包括肿瘤、器官移植和自身免疫性疾病)的药物中的用途。
Description
技术领域
本发明属于治疗性单克隆抗体领域,更具体地,本发明涉及一种针对人CD3的抗体或其抗原结合片段;还涉及所述抗体在抗肿瘤、器官移植和自身免疫疾病等方面的用途。
背景技术
免疫细胞,尤其是T细胞在免疫应答整个过程中处于核心地位,T细胞表面存在众多的CD分子,如CD3,CD4,CD8和CD28等,这些CD分子广泛参与了T细胞识别抗原、活化增殖或失能、凋亡及清除异体抗原或对自身耐受等免疫效应全过程。在这些CD分子中,CD3分子尤为重要。CD3分子是T细胞膜上的重要分化抗原,是成熟T细胞的特征性标志,由ε、γ、δ和ζ链四条不同多肽链构成,以非共价键与T细胞抗原受体(TCR)组成TCR-CD3复合体,不仅参与TCR-CD3复合体的胞浆内组装,而且通过各多肽链胞浆区的免疫受体酪氨酸活化基序传递抗原刺激信号。CD3分子的主要功能是稳定TCR结构,传递T细胞活化信号,当TCR特异性识别并结合抗原后,CD3参与将信号转导到T细胞胞浆内,作为诱导T细胞活化的第一信号,在T细胞抗原识别和免疫应答产生过程中具有极其重要的作用。
已有的研究表明抗人CD3抗体具有激活和抑制T细胞的双向功能。因此,可以通过单克隆抗体特异性结合CD3分子,激发或阻断T细胞活化信号转导,其疗效已在急性抗排异冲击疗法、治疗移植物抗宿主反应及器官移植前的预防性脱敏中得到充分的证实,并在抗肿瘤、抗多种器官移植排斥反应及自身免疫疾病等的治疗中显示出广阔的应用前景。抗CD3单克隆抗体单药治疗或与IL-1受体拮抗剂联用,已经被证明能够预防和逆转NOD小鼠自身免疫性糖尿病并增强免疫调节作用(Belghith M等,Nat Med,2003,9(9):1202-1208;Ablamunits V等,Diabetes,2012,61(1):145-154)。在治疗患有1型糖尿病的受试者的临床实验中,CD3抗体也有效改善了胰岛素生产和代谢控制,1型糖尿病的患者接受抗CD3单克隆抗体Teplizumab治疗后,胰岛素水平和代谢异常症状显著改善(Herold KC等,N Engl JMed,2002,346(22):1692-1698;Herold KC等,Diabetes,2005,54(6):1763-1769)。抗CD3抗体也逆转了Lewis大鼠中的实验性变应性脑脊髓炎,对T辅助1型(Th1)介导的免疫性具有抑制效应(Tran G T等,Intl Immunol,2001,13(9):1109-1120)。此外,CD3抗体也广泛应用于介导细胞功能型双特异性抗体。靶向CD3的双特异性抗体则能够分别结合T细胞表面CD3和肿瘤细胞表面抗原,从而拉近细胞毒性T细胞(cytotoxic T cell,CTL)与肿瘤细胞的距离,并直接激活T细胞,诱导T细胞直接杀伤癌细胞,而不再依赖于传统的T细胞的双重激活信号(Hipp S等,Leukemia,2017,31(8):1743-1751;Benonisson H等,Molecular cancertherapeutics,2019,18(2):312-322.)。
最早上市的OKT3是由美国Ortho药物公司生产的鼠源抗人CD3的单抗,它对预防和治疗器官移植免疫排斥反应有良好的效果,被批准用于治疗肾脏、肝脏和心脏移植中的同种异体移植排斥。但是,OKT3作为鼠源性单抗,其免疫原性导致50%以上的病人产生抗OKT3抗体,这些抗体主要有两种:抗个体型和抗同种型。前者通过中和抗原结合位点而阻断OKT3与CD3的结合,后者除加速单抗的清除外还可能引起严重的副反应。OKT3可促进T细胞过度激活而大量释放炎症因子,如白介素-2(IL-2)、TNF-α、IFN-γ和白介素-6(IL-6),引发多种副作用,包括发烧,发冷恶心,呕吐和头痛,概括为“流感样”、“细胞因子释放”或“首剂综合征”。一小部分患者可能发生更严重的副作用,如心肺窘迫,癫痫发作,脑病,脑膜炎,肾功能不全和移植血栓形成等。
目前新一代的人源化抗CD3单克隆抗体,包括otelixizumab、teplizumab和visilizumab等,对Fc受体的亲和力大大降低,副作用显著降低,然而,仍然存在T细胞过度活化和细胞因子分泌等问题。因而,开发靶向CD3的抗体,如何削弱或避免过度的细胞因子风暴是首要考虑的问题,开发具有更高的特异性、更优的临床药效CD3抗体迫切而必要,这将给肿瘤、器官移植和自身免疫类疾病患者提供更多的用药选择。
发明内容
本发明中公开了以高亲和性和特异性与CD3ε链结合的抗体或其抗原结合片段。还提供了编码该抗体或其抗原结合片段的核酸分子、表达载体、宿主细胞和用于制造抗体的方法。还提供了包含抗体或其抗原结合片段的双特异性抗体、多双特异性抗体、和药物组合物。另外,还提供了本发明公开的抗CD3抗体或其抗原结合片段(单独或与其它活性剂或治疗方式组合)在制备用于预防和/或治疗多种疾病(包括肿瘤、器官移植和自身免疫性疾病等)的药物中的用途。
在本发明的的第一个方面,本发明提供了一种能够特异性结合CD3的抗体或其抗原结合片段,其中,
所述抗体或其抗原结合片段包含的重链可变区(VH)包含至少一个、两个或三个选自下组的互补决定区(CDR):
(i)CDR-H1,其具有如SEQ ID NO:7、13、18、24、29、35、85、86、87或88所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;
(ii)CDR-H2,其具有如SEQ ID NO:8、14、19、25、30、36、51、55或57所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;和
(iii)CDR-H3,其具有如SEQ ID NO:9、15、20、26、31、37、52、56、96、97、98、99、100、101、102、103、104或105所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;
和/或,其包含的轻链可变区(VL)包含至少一个、两个或三个选自下组的互补决定区(CDR):
(iv)CDR-L1,其具有如SEQ ID NO:10、16、21、27、32、38、50、53、93或94所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;
(v)CDR-L2,其具有如SEQ ID NO:11、17、22、28、33、39、54、58、89、90、91、92或95所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;和
(vi)CDR-L3,其具有如SEQ ID NO:12、23或34所示的序列,或者与上述序列相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列。
在某些优选的实施方案中,(i)-(vi)任一项中所述的置换为保守置换。
在某些优选的实施方案中,所述重链可变区中含有的CDR-H1、CDR-H2及CDR-H3,和/或所述轻链可变区中含有的CDR-L1、CDR-L2及CDR-L3由Kabat或IMGT编号***定义。实施例5中的表4示例性地给出了鼠源抗体按Kabat或IMGT编号***定义出的CDR氨基酸序列。
在某些优选的实施方案中,所述抗体或其抗原结合片段包含3个VH可变区CDR和3个VL可变区CDR,其选自下述33组:
(1)其CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2和CDR-L3分别具有如SEQ ID NO:7、8、9、10、11、12所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;
(2)其CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2和CDR-L3分别具有如SEQ ID NO:7、51、52、53、54、12所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;
(3)其CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2和CDR-L3分别具有如SEQ ID NO:7、51、52、10、11、12所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;
(4)其CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2和CDR-L3分别具有如SEQ ID NO:13、14、15、16、17、12所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;
(5)其CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2和CDR-L3分别具有如SEQ ID NO:13、55、56、16、17、12所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;
(6)其CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2和CDR-L3分别具有如SEQ ID NO:18、19、20、21、22、23所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;
(7)其CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2和CDR-L3分别具有如SEQ ID NO:18、57、20、21、58、23所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;
(8)其CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2和CDR-L3分别具有如SEQ ID NO:24、25、26、27、28、23所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;
(9)其CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2和CDR-L3分别具有如SEQ ID NO:29、30、31、32、33、34所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;
(10)其CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2和CDR-L3分别具有如SEQ ID NO:29、30、31、50、33、34所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;
(11)其CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2和CDR-L3分别具有如SEQ ID NO:35、36、37、38、39、34所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;
(12)其CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2和CDR-L3分别具有如SEQ ID NO:87、57、20、21、58、23所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;
(13)其CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2和CDR-L3分别具有如SEQ ID NO:18、57、20、21、89、23所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;
(14)其CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2和CDR-L3分别具有如SEQ ID NO:18、57、20、21、91、23所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;
(15)其CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2和CDR-L3分别具有如SEQ ID NO:18、57、20、93、58、23所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;
(16)其CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2和CDR-L3分别具有如SEQ ID NO:18、57、20、21、95、23所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;
(17)其CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2和CDR-L3分别具有如SEQ ID NO:18、57、96、21、58、23所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;
(18)其CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2和CDR-L3分别具有如SEQ ID NO:18、57、98、21、58、23所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;
(19)其CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2和CDR-L3分别具有如SEQ ID NO:18、57、100、21、58、23所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;
(20)其CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2和CDR-L3分别具有如SEQ ID NO:18、57、102、21、58、23所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;
(21)其CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2和CDR-L3分别具有如SEQ ID NO:18、57、104、21、58、23所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;
(22)其CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2和CDR-L3分别具有如SEQ ID NO:85、25、26、27、28、23所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;
(23)其CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2和CDR-L3分别具有如SEQ ID NO:86、25、26、27、28、23所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;
(24)其CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2和CDR-L3分别具有如SEQ ID NO:88、25、26、27、28、23所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;
(25)其CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2和CDR-L3分别具有如SEQ ID NO:24、25、26、27、90、23所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;
(26)其CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2和CDR-L3分别具有如SEQ ID NO:24、25、26、27、92、23所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;
(27)其CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2和CDR-L3分别具有如SEQ ID NO:86、25、26、27、92、23所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;
(28)其CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2和CDR-L3分别具有如SEQ ID NO:24、25、26、94、28、23所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;
(29)其CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2和CDR-L3分别具有如SEQ ID NO:24、25、97、27、28、23所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;
(30)其CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2和CDR-L3分别具有如SEQ ID NO:24、25、99、27、28、23所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;
(31)其CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2和CDR-L3分别具有如SEQ ID NO:24、25、101、27、28、23所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;
(32)其CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2和CDR-L3分别具有如SEQ ID NO:24、25、103、27、28、23所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;
(33)其CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2和CDR-L3分别具有如SEQ ID NO:24、25、105、27、28、23所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列。
在某些实施方案中,所述抗体或其抗原结合片段为鼠源的或嵌合的,其重链可变区包含鼠源IgG1、IgG2、IgG3或其变体的重链FR区;和其轻链可变区包含鼠源κ、λ链或其变体的轻链FR区。实施例5中给出了优选的鼠源抗体的可变区氨基酸序列编号。
在某些优选的实施方案中,所述鼠源或嵌合抗体或其抗原结合片段包含选自下述3组的VH和VL序列:
(i)VH结构域包含如SEQ ID NO:1所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列;和其VL结构域包含如SEQ ID NO:2所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列;
(ii)VH结构域包含如SEQ ID NO:3所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列;和其VL结构域包含如SEQ ID NO:4所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列;
(iii)VH结构域包含如SEQ ID NO:5所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列;和其VL结构域包含如SEQ ID NO:6所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列。
在某些实施方案中,所述抗体或其抗原结合片段为人源化的。实施例6给出了人源化策略的基本流程,表3中给出了优选的人源化抗体的可变区氨基酸序列编号。
在某些优选的实施方案中,所述人源化抗体或其抗原结合片段包含选自下述的VH和VL序列:
(1)VH结构域包含如SEQ ID NO:40所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列;和其VL结构域包含如SEQ ID NO:41所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列;
(2)VH结构域包含如SEQ ID NO:42所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列;和其VL结构域包含如SEQ ID NO:43所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列;
(3)VH结构域包含如SEQ ID NO:44所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列;和其VL结构域包含如SEQ ID NO:45所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列;
(4)VH结构域包含如SEQ ID NO:46所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列;和其VL结构域包含如SEQ ID NO:47所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列;
(5)VH结构域包含如SEQ ID NO:48所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列;和其VL结构域包含如SEQ ID NO:49所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列;
(6)VH结构域包含如SEQ ID NO:106所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列;和其VL结构域包含如SEQ ID NO:49所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列;
(7)VH结构域包含如SEQ ID NO:107所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列;和其VL结构域包含如SEQ ID NO:49所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列;
(8)VH结构域包含如SEQ ID NO:108所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列;和其VL结构域包含如SEQ ID NO:49所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列;
(9)VH结构域包含如SEQ ID NO:48所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列;和其VL结构域包含如SEQ ID NO:109所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列;
(10)VH结构域包含如SEQ ID NO:48所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列;和其VL结构域包含如SEQ ID NO:110所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列;
(11)VH结构域包含如SEQ ID NO:111所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列;和其VL结构域包含如SEQ ID NO:112所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列;
(12)VH结构域包含如SEQ ID NO:48所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列;和其VL结构域包含如SEQ ID NO:113所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列;
(13)VH结构域包含如SEQ ID NO:48所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列;和其VL结构域包含如SEQ ID NO:114所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列;
(14)VH结构域包含如SEQ ID NO:115所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列;和其VL结构域包含如SEQ ID NO:49所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列;
(15)VH结构域包含如SEQ ID NO:116所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列;和其VL结构域包含如SEQ ID NO:49所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列;
(16)VH结构域包含如SEQ ID NO:117所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列;和其VL结构域包含如SEQ ID NO:49所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列;
(17)VH结构域包含如SEQ ID NO:118所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列;和其VL结构域包含如SEQ ID NO:49所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列;
(18)VH结构域包含如SEQ ID NO:119所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列;和其VL结构域包含如SEQ ID NO:49所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列。
在某些实施方案中,本发明的抗体或其抗原结合片段进一步包含来源于哺乳动物(例如,鼠或人)免疫球蛋白的恒定区序列或其变体,所述变体与其所源自的序列相比具有一个或多个置换、缺失或添加。在某些优选的实施方案中,所述变体与其所源自的序列相比具有一个或多个保守置换。在某些实施方案中,抗CD3抗体分子具有重链恒定区(Fc),其选自例如IgG1、IgG2、IgG3、IgG4、IgM、IgA1、IgA2、IgD和IgE的重链恒定区;特别地选自例如IgG1、IgG2、IgG3和IgG4的重链恒定区,更特别地选自IgG1、IgG2或IgG4(例如是人IgG1、IgG2或IgG4)的重链恒定区。在一些实施方案中,抗CD3抗体分子具有轻链恒定区,其选自例如κ或λ的轻链恒定区,优选κ轻链恒定区(例如人κ轻链)。
在一些实施方案中,恒定区被改变,例如被突变,以修饰抗CD3抗体分子的性质(例如改变下列中的一个或更多个特性:Fc受体结合、抗体糖基化、半胱氨酸残基的数目、效应细胞功能或补体功能)。可以通过将抗体恒定区中的至少一个氨基酸残基替换为不同残基,产生功能改变,例如,改变抗体对效应子配体(如FcR或补体C1q)的亲和力,从而改变效应子功能(例如增强、降低或消除)。替换抗体的Fc区中的氨基酸残基以改变其效应子功能的方法是本领域已知的(参见,例如EP388,151A1,US564,8260,US562,4821)。抗体的Fc区介导几种重要的效应子功能,例如ADCC、吞噬作用、CDC等。在某些情况下,这些效应子功能对于治疗性抗体是需要的;但在其他情况下,这些效应子功能可能是不必要的或甚至是有害的,这取决于预期目的。因此,在某些实施方案中,本发明的抗体或其抗原结合片段具有降低或甚至消除的效应子功能(例如ADCC和/或CDC活性)。也考虑在人IgG4中使抗体结构稳定的氨基酸突变,例如S228P(EU命名法,在Kabat命名法中为S241P)。
在此类实施方案中,本发明的抗体或其抗原结合片段包含人IgG重链恒定区的变体,所述变体与其所源自的野生型序列相比具有以下置换中的至少一个:Ser228Pro、Leu234Ala、Leu235Ala、Gly237Ala、Asp265Ala、Asn297Ala、Pro329Ala、Asp356Glu和Leu358Met(以上提及的氨基酸位置是根据EU编号***的位置,Edelman GM等,Proc NatlAcad USA,63,78-85(1969).PMID:5257969)。
在某些示例性实施方案中,本发明的抗体或其抗原结合片段包含人IgG1重链恒定区的变体,所述变体与其所源自的野生型序列相比具有以下置换:Leu234Ala、Leu235Ala(根据EU编号***的位置)。在此类实施方案中,本发明的抗体或其抗原结合片段具有降低的ADCC和CDC活性。
在某些示例性实施方案中,本发明的抗体或其抗原结合片段包含人IgG1重链恒定区的变体,所述变体与其所源自的野生型序列相比具有以下置换:Asn297Ala(根据EU编号***的位置)。在此类实施方案中,本发明的抗体或其抗原结合片段具有消除的ADCC活性。
在某些示例性实施方案中,本发明的抗体或其抗原结合片段包含人IgG1重链恒定区的变体,所述变体与其所源自的野生型序列相比具有以下置换:Asp265Ala、Pro329Ala(根据EU编号***的位置)。在此类实施方案中,本发明的抗体或其抗原结合片段具有消除的ADCC活性。
在某些示例性实施方案中,本发明的抗体或其抗原结合片段包含人IgG4重链恒定区的变体,所述变体与其所源自的野生型序列相比具有以下置换:Ser228Pro(根据EU编号***的位置)。在此类实施方案中,本发明的抗体或其抗原结合片段结构稳定,可以降低Fab-arm的交换,从而不易形成半抗体。
在某些优选的实施方案中,所述抗体的重链具有如SEQ ID NO:65所示的氨基酸序列;或与上述序列中的任何相比具有一个或几个置换、缺失或添加(例如1个,2个,3个,4个或5个置换、缺失或添加)的序列;或与上述序列中的任何相比具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%、或更高同一性的序列;和/或,所述抗体的轻链具有如SEQ ID NO:66所示的氨基酸序列;或与上述序列中的任何相比具有一个或几个置换、缺失或添加(例如1个,2个,3个,4个或5个置换、缺失或添加)的序列;或与上述序列中的任何相比具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%、或更高同一性的序列。
在某些优选的实施方案中,所述抗体的重链具有如SEQ ID NO:69所示的氨基酸序列;或与上述序列中的任何相比具有一个或几个置换、缺失或添加(例如1个,2个,3个,4个或5个置换、缺失或添加)的序列;或与上述序列中的任何相比具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%、或更高同一性的序列;和/或,所述抗体的轻链具有如SEQ ID NO:70所示的氨基酸序列;或与上述序列中的任何相比具有一个或几个置换、缺失或添加(例如1个,2个,3个,4个或5个置换、缺失或添加)的序列;或与上述序列中的任何相比具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%、或更高同一性的序列。
在某些优选的实施方案中,所述抗体的重链具有如SEQ ID NO:73所示的氨基酸序列;或与上述序列中的任何相比具有一个或几个置换、缺失或添加(例如1个,2个,3个,4个或5个置换、缺失或添加)的序列;或与上述序列中的任何相比具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%、或更高同一性的序列;和/或,所述抗体的轻链具有如SEQ ID NO:74所示的氨基酸序列;或与上述序列中的任何相比具有一个或几个置换、缺失或添加(例如1个,2个,3个,4个或5个置换、缺失或添加)的序列;或与上述序列中的任何相比具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%、或更高同一性的序列。
在某些优选的实施方案中,所述抗体的重链具有如SEQ ID NO:77所示的氨基酸序列;或与上述序列中的任何相比具有一个或几个置换、缺失或添加(例如1个,2个,3个,4个或5个置换、缺失或添加)的序列;或与上述序列中的任何相比具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%、或更高同一性的序列;和/或,所述抗体的轻链具有如SEQ ID NO:78所示的氨基酸序列;或与上述序列中的任何相比具有一个或几个置换、缺失或添加(例如1个,2个,3个,4个或5个置换、缺失或添加)的序列;或与上述序列中的任何相比具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%、或更高同一性的序列。
在某些优选的实施方案中,所述抗体的重链具有如SEQ ID NO:81所示的氨基酸序列;或与上述序列中的任何相比具有一个或几个置换、缺失或添加(例如1个,2个,3个,4个或5个置换、缺失或添加)的序列;或与上述序列中的任何相比具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%、或更高同一性的序列;和/或,所述抗体的轻链具有如SEQ ID NO:82所示的氨基酸序列;或与上述序列中的任何相比具有一个或几个置换、缺失或添加(例如1个,2个,3个,4个或5个置换、缺失或添加)的序列;或与上述序列中的任何相比具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%、或更高同一性的序列。
在某些较优选的实施方案中,上述的置换是保守置换。
在某些优选的实施方案中,本发明的抗体或其抗原结合片段是嵌合抗体或人源化抗体。在某些优选的实施方案中,本发明的抗体或其抗原结合片段选自scFv、Fab、Fab’、(Fab’)2、Fv片段、双抗体(diabody)、双特异性抗体、多特异性抗体。
本发明的抗体或其抗原结合片段对CD3(特别是人CD3)具有高特异性和高亲和力。在某些优选的实施方案中,本发明的抗体或其抗原结合片段能够以约1nM或更低的KD结合CD3(特别是人CD3)。
本发明第二方面,公开了包含编码本发明所述抗CD3抗体分子的核苷酸序列。在某些实施方案中,编码所述抗CD3抗体分子的核苷酸序列是密码子最优化的。例如本发明的特征是分别地编码抗CD3的抗体分子的重链和轻链可变区的第一和第二核酸,该抗体分子选自下列中的任一种:AP191、AP591、AP831、AB610、AB611、AB612、AB613、AB614;或与其基本上相同的序列。例如,核酸可以包含表6中所示的AB610、AB611、AB612、AB613、AB614核苷酸序列或与其基本上相同的序列(例如与其至少大约85%、90%、95%、99%或更高度相似的序列或具有一个或更多个核苷酸取代(例如保守性取代))的序列,或与表6中所示的序列相差不超过3、6、15、30或45个核苷酸的序列)。
本发明的优选实施例中,编码所述抗体重链的DNA分子具有如SEQ ID NO:67、71、75、79或83所示的核苷酸序列,和编码所述抗体轻链的DNA分子具有如SEQ ID NO:68、72、76、80或84所示的核苷酸序列。
本发明第三方面,本发明提供了一种载体(例如克隆载体或表达载体),其包含本发明的分离的核酸分子。在某些优选的实施方案中,本发明的载体是例如质粒,粘粒,噬菌体等。在某些优选的实施方案中,所述载体能够在受试者(例如哺乳动物,例如人)体内表达本发明的抗体或其抗原结合片段。
本发明第四方面,本发明提供了一种宿主细胞,其包含本发明的分离的核酸分子或本发明的载体。宿主细胞可以是真核细胞(例如哺乳动物细胞、昆虫细胞、酵母细胞)或原核细胞(例如大肠杆菌)。合适的真核细胞包括但不限于NS0细胞、Vero细胞、Hela细胞、COS细胞、CHO细胞、HEK293细胞、BHK细胞、和MDCKII细胞。适宜的昆虫细胞包括但不限于Sf9细胞。在某些优选的实施方案中,本发明的宿主细胞是哺乳动物细胞,例如CHO(例如CHO-K1、CHO-S、CHO DXB11、CHO DG44)。
本发明第五方面,公开了药物组合物,其包含本发明中描述的抗CD3抗体分子,以及药学上可接受的载体、和/或赋形剂和/或稳定剂。
在某些优选的实施方案中,所述药物组合物还可以包含另外的药学活性剂。在某些优选的实施方案中,所述另外的药学活性剂是具有抗肿瘤活性的药物。在某些优选的实施方案中,所述另外的药学活性剂是用于治疗器官移植排斥反应的药物。在某些优选的实施方案中,所述另外的药学活性剂是用于治疗自身免疫性疾病的药物。
某些优选的实施方案中,在所述药物组合物中,本发明的抗体或其抗原结合片段与所述另外的药学活性剂作为分离的组分或作为同一组合物的组分提供。因此,本发明的抗体或其抗原结合片段与所述另外的药学活性剂可以同时、分开或相继施用。
本发明的第六方面,还提供了制备本发明所述抗体或其抗原结合片段的方法,其包括:(a)获得抗体或其抗原结合片段的基因,构建抗体或其抗原结合片段的表达载体;(b)通过基因工程方法将上述表达载体转染到宿主细胞中;(c)在允许产生所述抗体或其抗原结合片段的条件下培养上述宿主细胞;(d)分离、纯化产生的所述抗体或其抗原结合片段。
其中,步骤(a)中所述表达载体选自质粒、细菌和病毒中的一种或多种,优选地,所述表达载体为pcDNA3.1;
其中,步骤(b)通过基因工程方法将所构建的载体转染入宿主细胞中,所述宿主细胞包括原核细胞、酵母或哺乳动物细胞,如CHO细胞、NS0细胞或其它哺乳动物细胞,优选为CHO细胞。
其中,步骤(d)通过常规的免疫球蛋白纯化方法,包含蛋白质A亲和层析和离子交换、疏水层析或分子筛方法分离、纯化所述抗体或其抗原结合片段。
本发明第七方面,本发明涉及本发明的抗体或其抗原结合片段在制备药物中的用途,所述药物用于:
(1)在体外或受试者(例如人)体内激活或抑制T细胞活性;
(2)在受试者(例如人)中***;
(3)在受试者(例如人)中治疗器官移植排斥反应;或
(4)在受试者(例如人)中治疗自生免疫性疾病。
在一些实施方案中,所述肿瘤选自实体肿瘤、血液肿瘤(例如,白血病、淋巴瘤、骨髓瘤,例如,多发性骨髓瘤)和转移性病灶;所述癌症更多的特殊实例包括但不限于肺癌(例如,肺腺癌或非小细胞肺癌,NSCLC)(例如,具有鳞状和/或非鳞状病史的NSCLC,或NSCLC腺癌)、黑色素瘤(例如,晚期黑色素瘤)、肾癌(例如,肾细胞癌)、肝癌(例如肝细胞癌)、骨髓瘤(例如,多发性骨髓瘤)、***癌、乳腺癌(例如,不表达***受体、孕酮受体或Her2/neu中的一种、两种或全部的乳腺癌,例如,三阴性乳腺癌)、卵巢癌、结直肠癌、胰腺癌、头颈癌(例如,头颈鳞状细胞癌(HNSCC))、***癌、胃-食道癌(例如食管鳞状细胞癌)、间皮瘤、鼻咽癌、甲状腺癌、***、淋巴增殖性疾病(例如,移植后淋巴增殖性疾病)或血液学癌症(例如弥漫性大B细胞淋巴瘤、T-细胞淋巴瘤、B-细胞淋巴瘤、或非霍奇金淋巴瘤)、或白血病(例如,髓性白血病或淋巴细胞性白血病)。
在一些实施方案中,所述器官移植排斥反应选自与细胞、组织或诸如肾、肝和心脏移植的器官移植相关的非正常或不希望的免疫应答,例如移植物抗宿主疾病(GVHD),或减少同种异体移植排斥的风险。
在一些实施方案中,所述自身免疫性疾病选自类风湿性关节炎、青少年类风湿性关节炎、银屑病、***性红斑狼疮、原发性胆汁性肝硬化、自身免疫性溶血性贫血、再生障碍性贫血、自身免疫性血小板减少性紫癜、特发性血小板减少性紫癜、糖尿病、脑脊髓炎、格雷夫斯病、重症肌无力、韦格纳氏病、自生免疫肝炎和多发性硬化。
本发明第八方面,提供了包含本发明所述抗体的任何一种双特异性分子。例如,可以将上述CD3抗体与具有另一种抗原结合特性的抗体或抗体片段功能性连接组成双特异性抗体。诸如,所述双特异性抗体包括但不限于针对以下分子的抗体:CD19、CD20、CD22、CD25、CD30、CD33、CD38、CD39、CD40、CD47、CD52、CD73、CD74、CD123、CD133、CD138、BCMA、CA125、CEA、CS1、DLL3、DLL4、EGFR、EpCAM、FLT3、gpA33、GPC-3、Her2、MEGE-A3、NYESO1、PSMA、TAG-72、CIX、叶酸盐结合蛋白、GD2、GD3、GM2、VEGF、VEGFR2、VEGFR3、钙黏素(Cadherin)、整合素(Integrin)、间皮素(Mesothelin)、Claudin18、αVβ3、α5β1、ERBB3、c-MET、IGF1R、EPHA3、TRAILR1、TRAILR2、RANKL、B7蛋白家族、粘蛋白家族(Mucin)、FAP和肌腱蛋白(Tenascin)。
本发明第九方面,提供了一种治疗(例如,抑制和/或延迟进展)对象肿瘤、器官移植排斥反应或自身免疫性疾病的方法。该方法包括:将本文中所述的抗CD3抗体分子,例如,治疗有效量的抗CD3抗体分子,单独地或组合一种或多种活性剂或程序,施用于对象。
本发明第十方面,提供了诊断性或治疗性试剂盒,其包括本发明中描述的抗CD3抗体分子和使用说明书。
本发明制备的抗CD3人源化抗体与CD3的结合亲和力高,且具有极强的特异性。体外生物学研究数据显示,本发明所提供的人源化抗体能显著的促进T细胞增殖并活化T细胞,削弱和避免了过度的细胞因子风暴。此外,本发明所述抗体采用CHO细胞表达,具有产量高、活性高、纯化工艺简单以及生产成本低的优势。
缩写及术语定义
在本文中使用以下缩写:
CDR 免疫球蛋白可变区中的互补决定区
FR 抗体构架区:抗体可变区中除CDR残基以外的氨基酸残基
IgG 免疫球蛋白G
IMGT 基于由Lefranc等人发起的国际免疫遗传学信息***(TheinternationalImMunoGeneTics information(IMGT))的编号***,可参阅Lefrancet al.,Dev.Comparat.Immunol.27:55-77,2003。
mAb 单克隆抗体
EC50 产生50%功效或结合的浓度
IC50 产生50%抑制的浓度
ELISA 酶联免疫吸附测定
PCR 聚合酶链式反应
HRP 辣根过氧化物酶
IL-2 白细胞介素2
KD 平衡解离常数
ka 结合速率常数
kd 解离速率常数
在本发明中,除非另有说明,否则本文中使用的科学和技术名词具有本领域技术人员所通常理解的含义。并且,本文中所用的细胞培养、生物化学、核酸化学、免疫学实验室等操作步骤均为相应领域内广泛使用的常规步骤。同时,为了更好地理解本发明,下面提供相关术语的定义和解释。
术语“EU编号***”(EU Numbering System or Scheme):Eu是指上个世纪60年代末(1968-1969),Gerald M Edelman等人分离纯化得到第一个人IgG1免疫球蛋白,命名为Eu,测定了其氨基酸序列并为其编号(Edelman GM et al,1969,Proc Natl Acad USA,63:78-85)。其它的免疫球蛋白的重链恒定区与Eu进行氨基酸序列比对,对应氨基酸位置就是Eu编号。Eu编号***主要针对的是免疫球蛋白重链恒定区,包括CH1,CH2,CH3和铰链区。
术语“Kabat编号***”(Kabat Numbering System or Scheme):1979年,Kabat等人首先提出了标准化的人免疫球蛋白可变区的编号方案(Kabat EA,Wu TT,Bilofsky H,Sequences of Immunoglobulin Chains:Tabulation and Analysis of Amino AcidSequences of Precursors,V-regions,C-regions,J-Chain andβ2-Microglobulins.1979.Department of Health,Education,and Welfare,Public HealthService,National Institutes of Health)。在“免疫学相关蛋白质序列”一书中(KabatEA,Wu TT,Perry HM,Gottesman KS,Foeller C.1991.Sequences of Proteins ofImmunological Interest,5th edition.Bethesda,MD:US Department of Health andHuman Services,National Institutes for Health),Kabat等人对抗体轻链和重链的氨基酸序列进行了比对并编号。他们发现这些被分析序列表现出可变的长度,缺省和***的氨基酸或氨基酸片段只能出现在特定的位置。有趣的是,***点多位于CDR内部,但也可能出现在在框架区的某些位置。在Kabat编号方案中,轻链可变区编号到109位置,重链可变区编号到113位置,轻重链的***氨基酸通过字母识别并注释(例如,27a,27b...)。所有Lambda轻链不包含位置10残基,而Lambda和Kappa轻链由两个不同的基因编码,位于不同的染色体上。Lambda和Kappa轻链可以通过它们的恒定区氨基酸序列的不同来区分。与EU编号***只针对重链恒定区不同,Kabat编号***的编号范围覆盖全长免疫球蛋白序列,包括免疫球蛋白轻链和重链的可变区和恒定区。
术语“结合”定义抗原上的特定表位与其对应抗体之间的亲和性相互作用,一般也理解为“特异性识别”。“特异性识别”的意思是本发明的抗体不与或基本上不与目标抗原以外的任意多肽交叉反应。其特异性的程度可以通过免疫学技术来判断,包括但不限于免疫印迹,免疫亲和层析,流式细胞分析等。在本发明中,特异性识别优选通过流式细胞技术来确定,而具体情况下特异性识别的标准可由本领域一般技术人员根据其掌握的本领域常识来判断。
术语“抗原”是外来能引发生物自身或人产生抗体的物质,是任何可诱发免疫反应的物质,如细菌、病毒等。外来抗原分子经过B细胞或抗原呈递细胞(如巨噬细胞、树突状细胞、内皮细胞和B细胞等)的辨识和加工处理,并与主要组织相容性复合体(如MHC II分子)结合成复合物再活化T细胞,引发连续的免疫反应。
术语“抗体”通常指具有免疫球蛋白一类功能的蛋白质结合分子。抗体的典型实例是免疫球蛋白,以及其衍生物或功能片段,只要其显示所需的结合特异性即可。用于制备抗体的技术是本领域熟知的。“抗体”包括不同类的天然免疫球蛋白(例如IgA、IgG、IgM、IgD和IgE)和亚类(如IgG1、lgG2、IgA1、IgA2等)。“抗体”还包括非天然免疫球蛋白,包括例如单链抗体,嵌合抗体(例如,人源化鼠抗体)和异源偶联抗体(例如,双特异性抗体),以及其抗原结合片段(例如,Fab',F(ab')2,Fab,Fv和rIgG)。还可参见,例如,Pierce Catalog andHandbook,1994-1995(Pierce Chemical Co,Rockford,Ill);Kuby J,Immunology,3rd Ed,WH Freeman&Co,New York,1997。抗体可以结合至一种抗原,称为“单特异性”;或结合至两种不同的抗原,称为“双特异性”;或结合至多于一种的不同的抗原,称为“多特异性”。抗体可以是单价、二价或多价的,即抗体可以一次结合至一个、两个或多个抗原分子。抗体“单价地”结合至某特定蛋白质,即一分子的抗体仅结合至一分子的蛋白质,但是该抗体也可以结合到不同的蛋白质。当抗体仅结合至两种不同蛋白质的每一种分子时,该抗体为“单价地”结合至每一种蛋白质,并且该抗体是“双特异性的”且“单价地”结合至两种不同蛋白质的每一种。抗体可以是“单体的”,即其包含单个多肽链。抗体可包含多个多肽链(“多聚体的”)或可包含两个(“二聚体的”)、三个(“三聚体的”)或四个(“四聚体的”)多肽链。若抗体为多聚体的,则该抗体可以是同源多聚体(homomulitmer),即抗体包含多于一分子的仅一种多肽链,包括同源二聚体、同源三聚体或同源四聚体。可选的,多聚体抗体可以是异源多聚体,即抗体包含多于一种不同的多肽链,包括异源二聚体、异源三聚体或异源四聚体。
术语“单克隆抗体(mAb)”指获自基本均一抗体群体的抗体,例如除了可能少量存在的突变如天然产生的突变外,群体包含的单独抗体是相同的。因此,定语“单克隆”表示所述抗体特征为不是离散抗体的混合物。单克隆抗体由本领域技术人员所知晓的方法产生,例如通过将骨髓瘤细胞和免疫脾细胞融合制备杂合的抗体产生细胞。通过杂交瘤培养来合成,不会被其它免疫球蛋白污染。单克隆抗体也可以用如重组技术、噬菌体展示技术、合成技术,或其它现有技术得到。
术语“完整抗体”是指由两条抗体重链和两条抗体轻链组成的抗体。“完整抗体重链”是在N-端到C-端方向上由抗体重链可变结构域(VH)、抗体恒定重链结构域1(CH1)、抗体铰链区(HR)、抗体重链恒定结构域2(CH2)和抗体重链恒定结构域3(CH3)组成,缩写为VH-CH1-HR-CH2-CH3;并且在IgE亚类的抗体的情形中,任选地还包括抗体重链恒定结构域4(CH4)。优选地“完整抗体重链”是在N-端到C-端方向上由VH、CH1、HR、CH2和CH3组成的多肽。“完整抗体轻链”是在N-端到C-端方向上由抗体轻链可变结构域(VL)和抗体轻链恒定结构域(CL)组成的多肽,缩写为VL-CL。所述抗体轻链恒定结构域(CL)可以是κ(kappa)或λ(lambda)。完整抗体链通过在CL结构域和CH1结构域之间(即轻链和重链之间)的多肽间二硫键和完整抗体重链的铰链区之间的多肽间二硫键连接在一起。典型的完整抗体的实例是天然抗体如IgG(例如,IgG1和IgG2)、IgM、IgA、IgD和IgE。
术语“抗体片段”或“抗原结合片段”是指保留与抗原特异性结合能力的抗体的抗原结合片段及抗体类似物,其通常包括至少部分母体抗体(Parental Antibody)的抗原结合区或可变区。抗体片段保留母体抗体的至少某些结合特异性。通常,当用摩尔单位(KD)来表示活性时,抗体片段保留至少10%的母体结合活性。优选地,抗体片段保留至少20%、50%、70%、80%、90%、95%或100%的母体抗体对靶标的结合亲和力。抗体片段包括但不限于:Fab片段、Fab'片段、F(ab')2片段、Fv片段、Fd片段、互补决定区(CDR)片段、二硫键稳定性蛋白(dsFv)等;线性抗体(Linear Antibody)、单链抗体(例如scFv单抗体)、单抗体(Unibody,技术来自Genmab)、二价单链抗体、单链噬菌体抗体、单域抗体(Single DomainAntibody)(例如VH结构域抗体)、结构域抗体(Domantis,技术来自Domantis)、纳米抗体(nanobodies,技术来自Ablynx);由抗体片段形成的多特异性抗体(例如三链抗体、四链抗体等);和工程改造抗体如嵌合抗体(Chimeric Antibody)(例如人源化鼠抗体)、异缀合抗体(Heteroconjugate Antibody)等。这些抗体片段用本领域技术人员已知的常规技术获得,并用与完整抗体相同的方法对这些片段的实用性进行筛选。
术语“单链Fv抗体”(或“scFv抗体”)是指包含抗体的VH和VL结构域的抗体片段,是通过接头(linker)连接的重链可变区(VH)和轻链可变区(VL)的重组蛋白,接头使得这两个结构域相交联以形成抗原结合位点,接头序列一般由柔性肽组成,例如但不限于G2(GGGGS)3。scFv的大小一般是一个完整抗体的1/6。单链抗体优选是由一个核苷酸链编码的一条氨基酸链序列。对于scFv综述,可参见Pluckthun A,1994.Antibodies fromEscherichia coli,in The Pharmacology of Monoclonal Antibodies,Vol 113,Rosenberg M and Moore GP(EDs.),Springer-Verlag,New York,pp 269-315。还可参见国际专利申请公开号WO 88/01649和美国专利第4946778号和第5260203号。
术语“VL结构域”是指免疫球蛋白轻链的氨基末端可变区结构域。
术语“VH结构域”是指免疫球蛋白重链的氨基末端可变区结构域。
术语“铰链区”包括重链分子的将CH1结构域连接至CH2结构域的那一部分。该铰链区包含约25个残基并且是柔性的,从而使两个N-末端抗原结合区独立地移动。铰链区可分为三个不同的结构域:上部、中部、和下部铰链结构域(Roux KH et al,1998,J Immunol,161:4083-4090)。
术语“Fab片段”由一条重链的可变区及CH1区和一条轻链组成。Fab分子的重链不能与另一个重链分子形成二硫键。“Fab抗体”的大小是完整抗体的1/3,其只包含一个抗原结合位点。
术语“Fab'片段”含有一条轻链、一条重链的VH结构域和CH1结构域、以及CH1和CH2结构域之间的恒定区部分。
术语“F(ab')2片段”含有两条轻链和两条重链的VH结构域和CH1结构域以及CH1和CH2结构域之间的恒定区部分,由此在两条重链间形成链间二硫键。因此,F(ab′)2片段由通过两条重链间的二硫键保持在一起的两个Fab'片段组成。
术语“Fd片段”由一条重链的可变区和CH1组成,是Fab片段除去轻链后剩下的重链部分。
术语“Fv区”包含来自重链和轻链二者的可变区,但缺少恒定区,是包含完整抗原识别和结合位点的最小片段。
术语“二硫键稳定性蛋白(dsFv)”在VH和VL区分别引入一个半胱氨酸突变点,从而在VH和VL之间形成二硫键而实现结构稳定性。术语“二硫键”包括两个硫原子之间形成的共价键。氨基酸半胱氨酸含有巯基,该巯基可以与第二个巯基形成二硫键或桥连。在大多数天然存在的IgG分子中,CH1和CK区由二硫键连接并且两个重链由两个二硫键连接,在对应于使用Kabat编号***的239和242处(位置226或229,EU编号***)连接。
术语“重链恒定区”包括来自免疫球蛋白重链的氨基酸序列。包含重链恒定区的多肽至少包含以下一种:CH1结构域、铰链(例如,上部铰链区、中间铰链区,和/或下部铰链区)结构域,CH2结构域、CH3结构域或其变体或片段。例如,本申请中使用的抗原结合多肽可包含具有CH1结构域的多肽链;具有CH1结构域、至少一部分的铰链结构域和CH2结构域的多肽;具有CH1结构域和CH3结构域的多肽链;具有CH1结构域、至少一部分铰链结构域和CH3结构域的多肽链,或者具有CH1结构域,至少一部分铰链结构,CH2结构域,和CH3结构域的多肽链。在另一个实施例中,本申请的多肽包括具有CH3结构域的多肽链。另外,在本申请中使用的抗体可能缺少至少一部分CH2结构域(例如,所有的或一部分的CH2结构域)。如上文所述,但本技术领域的普通技术人员应理解,重链恒定区可能会被修改,使得它们在氨基酸序列上与天然存在的免疫球蛋白分子不同。
术语“轻链恒定区”包括来自抗体轻链的氨基酸序列。优选地,所述轻链恒定区包括恒定kappa结构域和恒定lambda结构域中的至少一个。
术语“Fc区”或“Fc片段”是指免疫球蛋白重链的C端区,其含有铰链区的至少一部分、CH2结构域和CH3结构域,其介导免疫球蛋白与宿主组织或因子的结合,包括与位于免疫***的各种细胞(例如,效应细胞)上的Fc受体结合或与经典补体***的第一组分(C1q)结合。Fc区包括天然序列Fc区和变异Fc区。
通常,人IgG重链Fc区为自其Cys 226或Pro 230位置的氨基酸残基至羧基末端的区段,但其边界可能有变化。Fc区的C末端赖氨酸(残基447,依照EU编号***)可以存在或可以不存在。Fc还可以指独立存在的,或在包含Fc的蛋白多肽的情况下的这一区域,例如“包含Fc区的结合蛋白”,还称为“Fc融合蛋白”(例如,抗体或免疫粘合素)。本发明的抗体中天然序列Fc区来自包括哺乳动物(例如人)的IgG1、IgG2(IgG2A,IgG2B)、IgG3和IgG4。在某些实施方案中,相对于哺乳动物Fc多肽氨基酸序列,两条Fc多肽链的氨基酸序列中每100个氨基酸中具有10个左右氨基酸的单一氨基酸的置换、***和/或缺失。在一些实施方案中,上述Fc区氨基酸差异可以是延长半衰期的Fc改变、增加FcRn结合的改变、增强Fcγ受体(FcγR)结合的改变和/或增强ADCC、ADCP和/或CDC的改变。
在IgG、IgA和IgD抗体同种型中,Fc区包含抗体两条重链中的每一条的CH2和CH3恒定结构域;IgM和IgE Fc区包含在每条多肽链中的三个重链恒定结构域(CH2-4结构域)。
术语“嵌合抗体”是指重链和/或轻链的一部分与衍生自特定物种或属于特定抗体类别或亚类的抗体中的相应序列相同或同源,而链的剩余部分与衍生自另一物种或属于另一抗体类别或亚类的抗体中的相应序列相同或同源,以及此类抗体的片段,只要它们展现出期望的生物学活性(美国专利US4816567;Morrison SL et al,1984,Proc Natl AcadSci USA,81:6851-6855)。例如,术语“嵌合抗体”可包括这样的抗体(例如人鼠嵌合抗体),其中抗体的重链和轻链可变区来自第一抗体(例如鼠源抗体),而抗体的重链和轻链恒定区来自第二抗体(例如人抗体)。
术语“人源化抗体”是指经基因工程改造的非人源抗体,其氨基酸序列经修饰以提高与人源抗体的序列的同源性。非人抗体的CDR域外的大部分或全部氨基酸,例如小鼠抗体被来自人免疫球蛋白的相应氨基酸置换,而一个或多个CDR区内的大部分或全部氨基酸未改变。氨基酸的添加,删除,***,替换或修饰是允许的,只要它们不会消除抗体结合特定抗原的能力。“人源化”抗体保留与原始抗体类似的抗原特异性。CDR的来源没有特别限制,可来源于任何动物。例如,可以利用源于小鼠抗体、大鼠抗体、兔抗体或非人灵长类动物(例如,食蟹猴)抗体的CDR区。框架区可以通过搜索IMGT antibody germline database(http://www.imgt.org/3Dstructure-DB/cgi/DomainGapAlign.cgi)获得人类抗体胚系序列,一般选取与被改造的非人源抗体同源度高的人类胚系抗体序列做人源化抗体的框架区。
术语“超变区”或“CDR区”或“互补决定区”是指负责抗原结合的抗体氨基酸残基,是非连续的氨基酸序列。CDR区序列可以由Kabat、Chothia、IMGT(Lefranc et al,2003,DevComparat Immunol,27:55-77)和AbM(Martin ACR et al,1989,Proc Natl Acad Sci USA,86:9268–9272)方法来定义或本领域熟知的任何CDR区序列确定方法而鉴定的可变区内的氨基酸残基。例如,超变区包含以下氨基酸残基:来自序列比对所界定的“互补决定区”或“CDR”的氨基酸残基(Kabat编号***),例如,轻链可变结构域的24-34(CDR-L1)、50-56(CDR-L2)和89-97(CDR-L3)位残基和重链可变结构域的31-35(CDR-H1)、50-65(CDR-H2)和95-102(CDR-H3)位残基,参见Kabat et al,1991,Sequences of Proteins ofImmunological Interest,5th Edition,Public Health Service,National Institutesof Health,Bethesda,Md.;和/或来自根据结构来界定的“超变环”(HVL)的残基(Chothia编号***),例如,轻链可变结构域的26-32(CDR-L1)、50-52(CDR-L2)和91-96(CDR-L3)位残基和重链可变结构域的26-32(CDR-H1)、53-55(CDR-H2)和96-101(CDR-H3)位残基,参见Chothia Cand Lesk AM,1987,J Mol Biol,196:901-917;Chothia C et al,1989,Nature,342:878-883。“框架”残基或“FR”残基为除本文定义的超变区残基之外的可变结构域残基。在某些实施方案中,本发明的抗体或其抗原结合片段含有的CDR优选地通过Kabat、IMGT或Chothia编号***确定。本领域技术人员可以明确地将每种编号***赋予任何可变结构域序列,而不依赖于超出序列本身之外的任何实验数据。例如,给定抗体的Kabat残基编号方式可通过将抗体序列与每种“标准”编号序列对比同源区来确定。基于本文提供的序列编号方案,确定序列表中任何可变区序列的编号完全在本领域技术人员的常规技术范围内。
术语“重组”,在涉及多肽或多核苷酸时指自然状态下不存在的多肽或多核苷酸的形式,其中一个非限制性的例子,可以通过将通常不会一起出现的多核苷酸或多肽组合在一起来实现。
术语“载体”是指能够运输与其连接的另一种核酸的核酸分子。一种类型的载体是“质粒”,其是指其中可以连接另外的DNA区段的环状双链DNA环。另一种类型的载体是病毒载体,其中额外的DNA区段可以连接到病毒基因组中。某些载体能够在它们被导入的宿主细胞中自主复制(例如,具有细菌复制起点和游离型哺乳动物载体的细菌载体)。其它载体(例如非附加型哺乳动物载体)可以在导入宿主细胞后整合到宿主细胞的基因组中,并由此与宿主基因组一起复制。此外,某些载体能够指导它们有效连接的基因的表达。这种载体在本文中被称为“重组表达载体”(或简称为“表达载体”)。通常,在重组DNA技术中有用的表达载体通常以质粒的形式存在。然而,也包括其它形式的表达载体,如病毒载体(例如,复制缺陷型逆转录病毒,腺病毒和腺伴随病毒),其起到等同的功能。
术语“分离的抗体分子”指的是已经从其自然环境的组分中识别和分离和/或回收的抗体分子。其自然环境的污染组分是会干扰抗体的诊断或治疗用途的物质,并可能包括酶、激素和其它蛋白质的或非蛋白质的溶质。
本文使用的关于核酸(如DNA或RNA)的术语“分离的”,是指分别从其它的以天然来源的大分子存在的DNA或RNA分离的分子。本文使用的术语“分离的”也指通过重组DNA技术生产时基本不含细胞材料,病毒材料或培养基的核酸或多肽,或经化学合成制备时基本不含化学前体或其它化学品。此外,“分离的核酸”是指包括不是天然存在的片段并且不会以天然状态发现的核酸片段。本文中术语“分离的”也用于指从其它细胞蛋白或组织分离的细胞或多肽。分离的多肽是指包括纯化的和重组的多肽。
术语“交叉反应”是指本文所述的抗体结合来自不同物种的抗原的能力。交叉反应性可通过检测在结合测定法(例如,SPR、ELISA)中与纯化抗原的特定反应性,或与生理表达抗原的细胞的结合或以其它方式与生理表达抗原的细胞的功能相互作用来测量。本领域中已知测定结合亲和力的分析的实例包括表面等离子共振(例如,Biacore)或类似技术(例如,Kinexa或Octet)。
术语“免疫结合”和“免疫结合性质”是指一种非共价相互作用,其发生在免疫球蛋白分子和抗原(对于该抗原而言免疫球蛋白为特异性的)之间。免疫结合相互作用的强度或亲和力可以用相互作用的平衡解离常数(KD)表示,其中KD值越小,表示亲和力越高。所选多肽的免疫结合性质可使用本领域中公知的方法测定。一种测定方法涉及测量抗原/抗体复合物形成和解离的速度。“结合速率常数”(Ka或Kon)和“解离速率常数”(Kd或Koff)两者都可通过浓度及缔合和解离的实际速率而计算得出(参见Malmqvist M,1993,Nature,361:186-187)。kd/ka的比率等于平衡解离常数KD(参见Davies DR et al,1990,Annual RevBiochem,59:439-473)。可用任何有效的方法测量KD、ka和kd值。
术语“免疫原性”指特定物质引发免疫应答的能力。
术语“宿主细胞”指在其中载体可以增殖并且其DNA可以表达的细胞,所述细胞可以是原核细胞或者真核细胞。该术语还包括受试宿主细胞的任何后代。应理解,并不是所有的后代都与亲本细胞相同,因为在复制过程中可能会发生突变,这类后代被包括在内。宿主细胞包含原核细胞、酵母或哺乳动物细胞,如CHO细胞、NS0细胞或其它哺乳动物细胞。
术语“同一性”用于指两个多肽之间或两个核酸之间序列的匹配情况。当两个进行比较的序列中的某个位置都被相同的碱基或氨基酸单体亚单元占据时(例如,两个DNA分子的每一个中的某个位置都被腺嘌呤占据,或两个多肽的每一个中的某个位置都被赖氨酸占据),那么各分子在该位置上是同一的。两个序列之间的“百分数同一性”是由这两个序列共有的匹配位置数目除以进行比较的位置数目×100的函数。例如,如果两个序列的10个位置中有6个匹配,那么这两个序列具有60%的同一性。例如,DNA序列CTGACT和CAGGTT共有50%的同一性(总共6个位置中有3个位置匹配)。通常,在将两个序列比对以产生最大同一性时进行比较。这样的比对可通过计算机程序例如Align程序(DNAstar,Inc.)方便地进行,通过使用Needleman和Wunsch的方法(Needleman SB and Wunsch CD,1970,J Mol Biol,48:443-453)来实现。
术语“突变的”、“突变体”和“突变”分别指与天然核酸或多肽相比(即可以用来定义野生型的参照序列),置换、缺失或***一个或多个核苷酸或氨基酸。
术语“保守修饰”意图指氨基酸修饰不会显著影响或改变含有该氨基酸序列的抗体的结合特征。此类保守修饰包括氨基酸的取代、添加和缺失。修饰可以通过本领域已知的标准技术,例如定点突变和PCR介导的突变引入到本发明的抗体中。保守氨基酸取代指氨基酸残基用具有类似侧链的氨基酸残基替换。本领域中对具有类似侧链的氨基酸残基家族已有详细说明。这些家族包括具有碱性侧链(例如赖氨酸、精氨酸、组氨酸)、酸性侧链(例如天冬氨酸、谷氨酸)、不带电荷的极性侧链(例如甘氨酸、天冬酰胺、谷酰胺、丝氨酸、苏氨酸、酪氨酸、半胱氨酸、色氨酸)、非极性侧链(例如丙氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸、苯丙氨酸、甲硫氨酸)、β-分支侧链(例如苏氨酸、缬氨酸、异亮氨酸)和芳香侧链(例如酪氨酸、苯丙氨酸、色氨酸、组氨酸)的氨基酸。因此,可以用来自同一侧链家族的其它氨基酸残基替换本发明抗体CDR区中的一个或多个氨基酸残基。
本发明的抗体或编码本申请抗体的核酸或多核苷酸,可以应用于制备药物组合物或无菌组合物,例如,将抗体与药学上可接受的载体、赋形剂或稳定剂混合。药物组合物可包括一种或组合的(如两种或更多不同的)本发明的抗体。例如,本发明的药物组合物可包含与靶抗原上的不同表位结合的具有互补活性的抗体或抗体片段(或免疫缀合物)的组合。治疗和诊断剂的制剂可通过以例如冻干粉末、浆液、水性溶液或悬浮液的形式与药学可接受的载体、赋形剂或稳定剂混合来制备。术语“药学上可接受的”指当分子本体、分子片段或组合物适当地给予动物或人时,它们不会产生不利的、过敏的或其它不良反应。可作为药学上可接受的载体或其组分的一些物质的具体示例包括糖类(如乳糖)、淀粉、纤维素及其衍生物、植物油、明胶、多元醇(如丙二醇)、海藻酸等。本发明的抗体或编码本申请抗体的核酸或多核苷酸可单独使用,或可与一种或更多种其它治疗剂共同使用,所述治疗剂例如疫苗。
术语“药学上可接受的载体和/或赋形剂和/或稳定剂”,是指在药理学和/或生理学上与受试者和活性成分相容的载体和/或赋形剂和/或稳定剂,它们在所采用的剂量和浓度对暴露于其的细胞或哺乳动物是无毒的。包括但不限于:pH调节剂,表面活性剂,佐剂,离子强度增强剂,稀释剂,维持渗透压的试剂,延迟吸收的试剂,防腐剂。例如,pH调节剂包括但不限于磷酸盐缓冲液。表面活性剂包括但不限于阳离子,阴离子或者非离子型表面活性剂,例如Tween-80。离子强度增强剂包括但不限于氯化钠。防腐剂包括但不限于各种抗细菌试剂和抗真菌试剂,例如对羟苯甲酸酯,三氯叔丁醇,苯酚,山梨酸等。维持渗透压的试剂包括但不限于糖、NaCl及其类似物。延迟吸收的试剂包括但不限于单硬脂酸盐和明胶。稀释剂包括但不限于水,水性缓冲液(如缓冲盐水),醇和多元醇(如甘油)等。防腐剂包括但不限于各种抗细菌试剂和抗真菌试剂,例如硫柳汞,2-苯氧乙醇,对羟苯甲酸酯,三氯叔丁醇,苯酚,山梨酸等。稳定剂具有本领域技术人员通常理解的含义,其能够稳定药物中的活性成分的期望活性,包括但不限于谷氨酸钠,明胶,SPGA,糖类(如山梨醇,甘露醇,淀粉,蔗糖,乳糖,葡聚糖,或葡萄糖),氨基酸(如谷氨酸,甘氨酸),蛋白质(如干燥乳清,白蛋白或酪蛋白)或其降解产物(如乳白蛋白水解物)等。
如本文中所使用的,术语“有效量”是指足以获得或至少部分获得期望的效果的量。例如,预防疾病(例如,肿瘤、感染或自身免疫性疾病)有效量是指,足以预防,阻止,或延迟疾病(例如,肿瘤、感染或自身免疫性疾病)的发生的量;治疗疾病有效量是指,足以治愈或至少部分阻止已患有疾病的患者的疾病和其并发症的量。测定这样的有效量完全在本领域技术人员的能力范围之内。例如,对于治疗用途有效的量将取决于待治疗的疾病的严重度、患者自己的免疫***的总体状态、患者的一般情况例如年龄,体重和性别,药物的施用方式,以及同时施用的其他治疗等等。
如本文中所使用的,术语“免疫细胞”包括具有造血的起源并在免疫应答中起作用的细胞,例如淋巴细胞,例如B细胞和T细胞;天然杀伤细胞;髓样细胞,例如单核细胞、巨噬细胞、嗜曙红细胞、肥大细胞、嗜碱细胞和粒细胞。
如本文中所使用的,术语“免疫应答”是指,免疫细胞(例如淋巴细胞、抗原呈递细胞、吞噬细胞或粒细胞)以及由免疫细胞或肝脏所产生的可溶性大分子(包括抗体、细胞因子、以及补体)的作用,该作用导致对侵入性病原体、被病原体感染的细胞或组织、癌细胞、或者在自身免疫或病理炎症情况下的正常人类细胞或组织的选择性损害、破坏或将它们从人体中清除。在本发明中,术语“抗原特异性T细胞应答”指由T细胞产生的免疫应答,该应答产生于当该T细胞特异的抗原对该T细胞的刺激之时。由T细胞在抗原特异性刺激时产生的反应的非限制性实例包括T细胞的增殖以及细胞因子(例如IL-2)的产生。
如本文中所使用的,术语“效应子功能(effector function)”是指,那些可归因于抗体Fc区(天然序列Fc区或氨基酸序列变体Fc区)的生物学活性,且其随抗体同种型而变化。抗体效应子功能的例子包括但不限于:Fc受体结合亲和性、抗体依赖性细胞介导的细胞毒性(ADCC)、补体依赖的细胞毒性(CDC)、抗体依赖性细胞吞噬作用(ADCP)、细胞表面受体(例如B细胞受体)的下调、B细胞活化、细胞因子分泌、抗体和抗原-抗体复合物的半衰期/清除率等。改变抗体的效应子功能的方法是本领域已知的,例如通过在Fc区引入突变来完成。
如本文中所使用的,术语“抗体依赖性细胞介导的细胞毒性(ADCC)”是指,一种细胞毒性形式,Ig通过与细胞毒性细胞(例如自然杀伤(NK)细胞、中性粒细胞或巨噬细胞)上存在的Fc受体(FcR)结合,使这些细胞毒性效应细胞特异性结合到抗原附着的靶细胞上,然后通过分泌细胞毒素杀死靶细胞。检测抗体的ADCC活性的方法是本领域已知的,例如可通过测定待测抗体与Fc受体(例如CD16a)之间的结合活性来评价。
如本文中所使用的,术语“补体依赖的细胞毒性(CDC)”是指,通过使补体成分C1q与抗体Fc结合来激活补体级联的细胞毒性形式。检测抗体的CDC活性的方法是本领域已知的,例如可通过测定待测抗体与Fc受体(例如C1q)之间的结合活性来评价。
通过下列实施例对本发明的实施方案进一步说明,但本领域技术人员应理解,下列附图和实施例仅用于说明本发明,而不是对本发明的进一步限制。
与现有技术相比,本发明的技术方案具有以下有益效果:
(1)本发明的抗体不仅能够特异性识别/结合CD3,并且能够诱发抗原调节,包括细胞表面表达水平的改变(例如降低),或CD3或TCR活性的改变。因此,本发明的抗体具有用于预防和/或***、器官移植排斥反应或自身免疫性疾病的潜力。
(2)本发明的抗体(特别是人源化抗体)不仅保留了亲本鼠源抗体的功能和性质,从而具有用于预防和***、感染或自身免疫性疾病的潜力;而且具有极高的人源化程度,从而可安全地施用给人受试者,而不引发免疫原性反应。因此,本发明的抗体(特别是人源化抗体)具有重大的临床价值。
(3)本发明的抗体能显著的促进T细胞增殖并活化T细胞,且细胞激活程度(IL-2等细胞因子的释放)控制在安全、有效的范围内,并未引起细胞因子的过度释放,因而具有更高的安全性,减小其在临床治疗中的毒副作用。
附图说明
附图1、鼠源抗体AP191、AP591和AP831与人CD3抗原的结合能力测定。
附图2、鼠源抗体AP191、AP591和AP831与人原代T细胞的结合活性测定。
附图3、鼠源抗体AP191、AP591和AP831促进PBMC细胞增殖的能力检测。
附图4、人源化抗体AB611和AB614与人和食蟹猴CD3抗原的结合能力测定。
附图5、人源化抗体AB611和AB614与人原代T细胞的结合活性测定。
附图6、人源化抗体AB610、AB611和AB614促进PBMC细胞增殖的能力检测
附图7、人源化抗体AB614活化T细胞能力评价。
具体实施方式
现参照下列意在举例说明本发明(而非限定本发明)的实施例来描述本发明。
除非特别指明,本发明中所使用的分子生物学实验方法和免疫检测法,基本上参照J.Sambrook等人,分子克隆:实验室手册,第2版,冷泉港实验室出版社,1989,以及F.M.Ausubel等人,精编分子生物学实验指南,第3版,John Wiley&Sons,Inc.,1995中所述的方法进行;限制性内切酶的使用依照产品制造商推荐的条件。本领域技术人员知晓,实施例以举例方式描述本发明,且不意欲限制本发明所要求保护的范围。
实施例1、抗人CD3鼠源单克隆抗体的制备
将人CD3E抗原(蛋白序列:Uniprot entry号P07766)50μg/只以完全弗氏佐剂充分乳化后,采用多点免疫方式免疫雄性Balb/C小鼠,免疫周期为三周一次。在第3次免疫后第10天,通过尾静脉取血,ELISA测试血浆抗人CD3抗体滴度以监测小鼠免疫应答程度,然后在融合前3天,对产生抗人CD3抗体滴度最高的小鼠加强免疫一次。3天后,处死小鼠并取出该小鼠脾脏与小鼠骨髓瘤Sp2/0细胞株融合。混合2×108个Sp2/0细胞与2×108个脾细胞在50%聚乙二醇(分子量为1450)和5%二甲基亚砜(DMSO)溶液中融合。用Iscove培养基(含有10%胎牛血清,100U/mL青霉素,100μg/mL链霉素,0.1mM次黄嘌呤,0.4μM氨基蝶呤和16μg胸苷)来调整脾脏细胞数至5×105/mL,以0.3mL加入96孔培养板孔内,并置于37℃,5%CO2培养箱内。培养10天后,采用高通量ELISA法分别检测上清中抗体与CD3E高亲和结合的克隆。再将上述单克隆抗体的孔内融合细胞进行亚克隆,进一步筛选获得杂交瘤细胞株#191、#591和#831。
在补充10%FCS的RPMI 1640培养基中培养产生特异性抗体的克隆。当细胞密度达到大约5×105个细胞/mL时,用无血清培养基替换该培养基。2至4天后,将培养过的培养基离心,以收集培养物上清液。将蛋白G柱用于纯化抗体。用150mM NaCl透析单克隆抗体洗脱液。通过0.2μm滤器将透析的溶液过滤除菌,以获得待测试的纯化的鼠源单克隆抗体AP191、AP591和AP831。
实施例2、ELISA法测定鼠源抗体与人CD3抗原的结合能力
以100μL 0.1μg/mL人CD3E(购自Acro Biosystems)包被酶标板,室温过夜。弃去包被溶液,用溶解在磷酸盐缓冲盐水(PBS)的脱脂奶封闭各孔0.5小时,用含有0.05%吐温-20的PBS(PBST)洗孔。然后加入每孔50μL纯化的抗人CD3鼠源抗体AP191、AP591和AP831,室温孵育1小时,用0.05%PBST洗孔,然后每孔加入50μL HRP标记的羊抗鼠IgG多克隆抗体(购自Jackson Laboratory)作为检测抗体,37℃孵育1h。用0.05%PBST清洗3次,加入TMB,100μL/孔,室温显色5min。加入0.2M H2SO4终止反应,50μL/孔。酶标仪在双波长450nm/620nm处读取吸收值。以OD 450nm/620nm作为Y轴,抗体浓度作为X轴,通过软件GraphPad Prism 6进行作图。
结果如图1所示,鼠源抗体AP191、AP591和AP831与人CD3E都具有较高的亲和力,AP191、AP591和AP831与人CD3E分子结合的EC50值分别为0.01491nM、0.02826nM和0.04038nM。
实施例3、CD3鼠源抗体亲和力测定及动力学研究
采用生物薄膜干涉技术(BLI)对纯化的鼠单克隆抗体与抗原CD3E的结合亲和力常数进行测定,仪器为PALL公司的ForteBio Octet RED&QK***。多通道平行定量分析浓度梯度设定为:3.125、6.25、12.5、25、50和100nM,His标签的人CD3E 10μg/mL偶联Ni-NTA传感器。亲和力测定结果如表1所示,结果显示,鼠单克隆抗体对人CD3具有极高的结合亲和力,可达到10-10M数量级。
表1、鼠单抗的亲和力测定结果
抗体 | K<sub>D</sub>(M) | Ka(1/Ms) | Kd(1/s) |
AP191 | 1.210E-10 | 8.020E+05 | 9.730E-05 |
AP591 | 1.937E-11 | 5.390E+05 | 1.044E-05 |
AP831 | 2.333E-10 | 6.922E+05 | 1.615E-05 |
实施例4、CD3鼠源抗体的体外生物学功能评价
4.1、CD3鼠源抗体与人原代T细胞的结合活性
培养人原代T细胞,离心收集细胞用1%BSA的PBS溶液(PBSB)重悬,调整细胞密度1×106个/mL,加入96孔U底板中,100μL/孔,4℃封闭30min。用1%PBSB洗涤细胞1次。然后加入稀释好的一系列浓度的CD3鼠源抗体AP591、AP191、AP831,100μL/孔,4℃孵育1h。离心去上清,用1%PBSB清洗2遍,加入稀释好的AF647羊抗鼠IgG(H+L)抗体(Jackson ImmunoResearch Inc.,1:250稀释),100μL/孔,4℃避光孵育1h。离心去上清,1%PBSB洗板2遍,加入4%多聚甲醛(PFA)重悬细胞,200μL/孔,流式细胞仪检测信号强度。以平均荧光强度作为Y轴,抗体浓度作为X轴,通过软件GraphPad Prism 6进行分析,计算CD3鼠源抗体与人原代T细胞结合的EC50值。
如图2所示,在细胞水平上,CD3鼠源抗体与人原代T细胞有结合,其信号强度与抗体浓度成正比,结合效果:AP831>AP191>AP591,AP591、AP191以及AP831与人原代T细胞结合的EC50值分别为8.907nM、2.743nM以及0.825nM。
4.2、CD3鼠源抗体促进PBMC细胞增殖能力检测
采用密度梯度离心法从人外周血获得新鲜的PBMC,并冻存储存于液氮中,待用。复苏冻存的PBMC,用含10%FBS的1640培养基调整细胞密度为5×105个/mL,100μL/孔,加入96孔板中。将CD3鼠源抗体AP591、AP191、AP831用培养基稀释成10μg/mL,10倍稀释7梯度,100μL/孔加入96孔板,设置两个复孔,37℃、5%CO2培养箱中孵育20h。加入1000IU/mL IL-2,50μL/孔,加入上述96孔板中,37℃、5%CO2继续培养48h,同时设置不加抗体和IL-2处理的对照组(Blank),和不加抗体只加IL-2的对照组(Blank(IL-2))。吹匀96孔板中的细胞,吸取100μL细胞悬液于96孔白板中,加入100μL发光法细胞活力检测试剂(Promega,G7571),摇床震荡孵育10min。用酶标仪检测冷发光值。以萤光素酶强度作为Y轴,抗体浓度作为X轴,通过软件GraphPad Prism 6进行作图分析。
如图3所示,CD3鼠源抗体AP591、AP191、AP831均能促进T细胞增殖,增殖效果AP591最优,其次为AP191和AP831。
实施例5、抗人CD3鼠源抗体的抗体亚型鉴定及可变区扩增
取杂交瘤细胞培养上清液,采用IsoStripTM小鼠单克隆抗体亚型鉴定试剂盒(Santa Cruz Biotechnology)鉴定抗体亚型。鼠源抗体AP591的亚型经鉴定为IgG1(Lambda),AP191的亚型经鉴定为IgG1(Kappa),AP831的亚型经鉴定为IgG1(Kappa)。
抗体可变区扩增:将候选杂交瘤细胞株培养至总数量107个细胞,1000rpm离心10min收集细胞,并以Trizol试剂盒(Invitrogen)提取总RNA,用反转录试剂盒SMARTerRACE合成第一链cDNA,以第一链cDNA为后续模板扩增杂交瘤细胞所对应的抗体可变区DNA序列。根据亚型鉴定结果,获取该抗体亚型的重链和轻链恒定区序列,设计特异性的巢式PCR引物,该扩增反应中所使用的引物序列与抗体可变区第一框架区和恒定区互补。采用常规PCR方法扩增目的基因,将扩增产物测序后,得到杂交瘤细胞株#191分泌抗体AP191的重链可变区序列SEQ ID NO:1和轻链可变区序列SEQ ID NO:2;杂交瘤细胞株#591分泌抗体AP591的重链可变区序列SEQ ID NO:3和轻链可变区序列SEQ ID NO:4;杂交瘤细胞株#831分泌抗体AP831的重链可变区序列SEQ ID NO:5和轻链可变区序列SEQ ID NO:6。以上抗体的重链CDR(CDR-H1、CDR-H2和CDR-H3)和轻链CDR(CDR-L1、CDR-L2和CDR-L3)的氨基酸序列分别如下表2-1至2-3所示:
表2-1、鼠源抗体AP191的重链和轻链CDR
表2-2、鼠源抗体AP591的重链和轻链CDR
表2-3、鼠源抗体AP831的重链和轻链CDR
以上CDR区序列分别采用Kabat和IMGT方法定义,也可以采用任何其他的本领域公知的CDR区序列确定方法来鉴定可变区内CDR区的氨基酸残基。
实施例6、抗人CD3鼠源抗体的人源化改造
采用CDR移植方法(CDR grafting)对鼠源抗体进行人源化改造。CDR移植的基本原理是通过把鼠抗的CDR区移植到人源抗体模板上,同时把稳定CDR构象和对抗原-抗体结合重要的几个或一些关键鼠抗FR区残基,也一并引入到人源抗体模板上(backmutations),从而达到既降低鼠抗的免疫原性又保持鼠抗的亲和力的目的。除了上述CDR grafting操作外,我们还进一步对CDR grafting后的人源化抗体的等电点(PI)、疏水聚集(aggregation)、翻译后修饰(PTM,如糖基化、断裂、异构化位点等)和免疫原性(immunogenicity)四方面进行计算,对于造成这四方面问题的氨基酸进行突变,以便使人源化抗体在临床使用时充分发挥出药效。
抗体人源化的具体流程如下。搜索IMGT网站的人抗体胚系数据库(IMGT humanantibody germline database,http://www.imgt.org/3Dstructure-DB/cgi/DomainGapAlign.cgi),获得与鼠抗具有高相似度的人源抗体模板。用Discovery Studio对鼠抗和人源抗体模板进行CDR区注释,按Kabat或IMGT方案定义出CDR区。用鼠抗的六个CDR区分别替换人源抗体模板的六个CDR区。移植的6个CDR区中的单独每个CDR区可以是按Kabat定义出的氨基酸区域,或按IMGT定义出的氨基酸区域。CDR移植后进行从鼠源抗体到人源化模板FR区的回复突变。稳定抗体CDR区构象和对抗原-抗体结合重要的关键鼠抗FR区氨基酸包括4类氨基酸残基:1)CDR区以内埋藏在抗体表面下的氨基酸;2)CDR区以内暴露在抗体表面的氨基酸;3)抗体轻链和重链结构域之间的界面氨基酸;和4)稳定抗体CDR区构象的vernier zone residues(Foote J and Winter G,1992,J Mol Biol,224:487-499)。以上4类关键鼠抗FR区残基是通过建立鼠抗三维结构模型确定的。对于与鼠抗序列不一致的人源模板的这4类氨基酸,通过三维结构分析,选择对保持CDR构象和抗原-抗体结合重要的氨基酸,进行从鼠抗到人源模板的氨基酸移植或替换。然后,对4类氨基酸移植后产生的人源化抗体进一步计算等电点、疏水聚集、翻译后修饰和免疫原性,对问题氨基酸进行突变,从而得到最终的人源化抗体序列。
根据以上方法,以鼠源抗体AP191、AP591和AP831的CDR为基础,共构建了18株人源化抗体,分别命名为AB610至AB627,上述人源化抗体的可变区氨基酸序列如表3所示。
表3、人源化抗体可变区氨基酸序列
抗体编号 | 重链可变区氨基酸序列 | 轻链可变区氨基酸序列 |
AB610 | SEQ ID NO:40 | SEQ ID NO:41 |
AB611 | SEQ ID NO:42 | SEQ ID NO:43 |
AB612 | SEQ ID NO:44 | SEQ ID NO:45 |
AB613 | SEQ ID NO:46 | SEQ ID NO:47 |
AB614 | SEQ ID NO:48 | SEQ ID NO:49 |
AB615 | SEQ ID NO:106 | SEQ ID NO:49 |
AB616 | SEQ ID NO:107 | SEQ ID NO:49 |
AB617 | SEQ ID NO:108 | SEQ ID NO:49 |
AB618 | SEQ ID NO:48 | SEQ ID NO:109 |
AB619 | SEQ ID NO:48 | SEQ ID NO:110 |
AB620 | SEQ ID NO:111 | SEQ ID NO:112 |
AB621 | SEQ ID NO:48 | SEQ ID NO:113 |
AB622 | SEQ ID NO:48 | SEQ ID NO:114 |
AB623 | SEQ ID NO:115 | SEQ ID NO:49 |
AB624 | SEQ ID NO:116 | SEQ ID NO:49 |
AB625 | SEQ ID NO:117 | SEQ ID NO:49 |
AB626 | SEQ ID NO:118 | SEQ ID NO:49 |
AB627 | SEQ ID NO:119 | SEQ ID NO:49 |
示例性的,本发明制备的人源化抗体AB610、AB611、AB612、AB613和AB614的可变区所包含的CDR区的氨基酸序列如表4所示,分别采用Kabat和IMGT方法来定义。
表4、关于示例性的抗CD3人源化抗体的CDR区序列
为了获得由两条重链和两条轻链组成的全长抗体序列,将表3中所示VH和VL序列的与抗体重链恒定区(优选自人IgG1或IgG4)和轻链恒定区(优选自人κ轻链)序列采用常规技术进行拼接或组装。例如,在一种实施方案中,抗CD3抗体分子包含表5中所示的野生型人IgG4的重链恒定区和人κ轻链恒定区。或采用修饰的人IgG4恒定区序列,例如,在一种实施方案中,如表5所示,抗CD3抗体分子包括在根据EU编号的第228位突变(例如S变为P)的人IgG4。在另一种实施方案中,抗CD3抗体分子包含野生型人IgG1的重链恒定区和人κ轻链恒定区。或采用修饰的人IgG1恒定区序列,例如,如表5所示,人IgG1在根据EU编号的第297位包含取代(例如Asn取代为Ala)。在又一种实施方案中,如表5所示,人IgG1在根据EU编号的第234位包含取代、在根据EU编号的第235位包含取代或包含这两种取代(例如在第234位Leu取代为Ala和/或在第235位Leu取代为Ala)。
表5、人IgG重链和人κ轻链的恒定区氨基酸序列
在一种示例性的实施方案中,本发明的人源化抗体包括在根据EU编号的第228位突变(S变为P)的人IgG4和人κ轻链恒定区。具体的,本发明示例性的人源化抗体的重链和轻链氨基酸序列及对应的核苷酸序列如表6所示。
表6、人源化抗体的重链和轻链氨基酸序列及对应的核苷酸序列
抗体编号 | 重链氨基酸序列 | 轻链氨基酸序列 | 重链核苷酸序列 | 轻链核苷酸序列 |
AB610 | SEQ ID NO:65 | SEQ ID NO:66 | SEQ ID NO:67 | SEQ ID NO:68 |
AB611 | SEQ ID NO:69 | SEQ ID NO:70 | SEQ ID NO:71 | SEQ ID NO:72 |
AB612 | SEQ ID NO:73 | SEQ ID NO:74 | SEQ ID NO:75 | SEQ ID NO:76 |
AB613 | SEQ ID NO:77 | SEQ ID NO:78 | SEQ ID NO:79 | SEQ ID NO:80 |
AB614 | SEQ ID NO:81 | SEQ ID NO:82 | SEQ ID NO:83 | SEQ ID NO:84 |
实施例7、抗人CD3抗体表达载体构建、表达、制备
根据上述实施例中获得的重链和轻链序列,设计编码cDNA***到pCMAB2M真核表达载体中,构建人源化表达载体。该表达载体质粒含有在哺乳动物细胞中高水平表达所需的巨细胞病毒早期基因启动因子-增强子。同时,载体质粒中含有可选择标记基因,从而在细菌中赋予氨苄青霉素抗性,而在哺乳动物细胞中赋予G418抗性。另外,载体质粒中含有二氢叶酸还原酶(DHFR)基因,在合适的宿主细胞中,能以氨甲喋呤(Methotrexate,MTX)共扩增抗体基因和DHFR基因。
将上述已构建的重组表达载体质粒转染入哺乳动物宿主细胞系,以表达人源化抗体。为了稳定高水平的表达,优选的宿主细胞系是DHFR缺陷型的中国仓鼠卵巢(CHO)细胞(参见美国专利No.4,818,679)。优选的转染方法是电穿孔,也可以使用其他方法,包括磷酸钙共沉降,脂转染和原生质融合等。在电穿孔中,用设为300V电场和1050μFd电容的GenePulser(Bio-Rad Laboratories),在比色杯内加入2×107个细胞悬浮在0.8mL的PBS中,并含有20μg的表达载体质粒。转染2天后,加入含有0.2mg/mL G418以及200nM MTX(Sigma)。为了实现较高水平的表达,用受MTX药物抑制的DHFR基因共扩增转染的抗体基因。用极限稀释亚克隆转染子及ELISA方法测定各细胞系的分泌率,选出高水平表达抗体的细胞株。收集抗体的条件培养基,用于测定其体外和体内生物学活性。
实施例8、CD3人源化候选抗体的体外生物学功能评价
8.1、CD3人源化抗体与CD3抗原的结合能力
以0.1μg/mL His标签的人或食蟹猴CD3E(购自Acro Biosystems)包被酶标板,100μL/孔,4℃包被过夜。弃去包被溶液,用1%PBSB封闭,200μL/孔,37℃孵育1h,用含有0.05%Tween-20的PBS洗板。然后加入稀释好的一系列浓度的CD3人源化抗体AB611、AB614,100μL/孔,37℃孵育1h,用0.05%PBST洗板,然后加入HRP标记的羊抗人IgG(H+L)(JacksonLaboratory)作为检测抗体,37℃孵育1h。用0.05%PBST清洗3次,加入TMB,100μL/孔,室温显色5min。加入0.2M H2SO4终止反应,50μL/孔。酶标仪在双波长450nm/620nm处读取吸收值。以OD450 nm/620nm作为Y轴,抗体浓度作为X轴,通过软件GraphPad Prism 6进行作图。
如图4和表7所示,分子水平上,人源化抗体AB611和AB614能很好的结合人或食蟹猴的CD3E抗原,结合效果相当。
表7、CD3人源化抗体与人或食蟹猴CD3结合活性测定结果
8.2、CD3人源化抗体与人的原代T细胞的结合活性
培养人的原代T细胞,离心收集细胞用1%PBSB重悬,分别调整细胞密度1×106个/mL,加入96孔U底板中,100μL/孔,4℃封闭30min。用1%PBSB洗涤细胞1次。然后加入稀释好的一系列浓度的CD3人源化抗体AB611和AB614,100μL/孔,4℃孵育1h。离心去上清,用1%PBSB清洗2遍,加入稀释好的AF647羊抗人IgG(H+L)抗体(Jackson Immuno Research Inc.,1:250稀释),100μL/孔,4℃避光孵育1h。离心去上清,1%PBSB洗板两遍,加入4%PFA重悬细胞,200μL/孔,流式细胞仪检测信号强度。再以平均荧光强度作为Y轴,抗体浓度作为X轴,通过软件GraphPad Prism 6进行分析,计算上述CD3人源化抗体AB611和AB614与人的原代T细胞结合的EC50值。
如图5所示,在细胞水平上,不同的CD3人源化抗体能很好的结合人原代T细胞,AB611结合的信号值低于AB614。AB611和AB614与人的原代T细胞结合的EC50值分别为0.174nM和1.180nM。
8.3、CD3人源化抗体促进PBMC细胞增殖的能力检测
复苏冻存的PBMC,用含10%FBS的1640培养基调整细胞密度为5×105个/mL,100μL/孔,加入96孔板中。将CD3人源化抗体AB610、AB611、AB614用培养基稀释成1μg/mL,10倍稀释,6梯度,100μL/孔,加入96孔板,两个复孔,37℃、5%CO2培养箱中孵育20h。加入1000IU/mL IL-2,50μL/孔,加入上述96孔板中,37℃、5%CO2继续培养48h,同时设置不加抗体和IL-2处理的对照组(Blank),和不加抗体只加IL-2的对照组(Blank(IL-2))。吹匀96孔板中的细胞,吸取100μL细胞悬液于96孔白板中,加入100μL发光法细胞活力检测试剂(Promega,G7571),摇床震荡孵育10min。用酶标仪检测冷发光值。以萤光素酶强度作为Y轴,抗体浓度作为X轴,通过软件GraphPad Prism 6进行作图。
如图6所示,CD3人源化抗体AB610、AB611和AB614均能促进T细胞增殖,其中AB614效果最好,AB611、AB610次之。
8.4、CD3人源化候选抗体活化T细胞能力评价
含有NFAT RE报告基因的Jurkat T细胞(购自BPS Bioscience),在CD3单抗存在的情况下可以过表达萤光素酶,通过检测萤光素酶的活性来定量Jurkat T细胞的活化程度。具体的,NFAT-Jurkat细胞调整细胞密度到2×106个/mL,50μL/孔。加入一系列浓度的CD3人源化抗体AB614,50μL/孔,设置两个复孔,37℃、5%CO2培养箱中孵育4h。加入Luciferase(购自Promega),100μL/孔,反应5min后,用酶标仪检测冷发光值。以萤光素酶强度作为Y轴,抗体浓度作为X轴,通过软件GraphPad Prism 6进行分析,计算CD3人源化抗体AB614活化T细胞的EC50。
如图7所示激活实验评价中,CD3人源化抗体AB614对T细胞具有良好的激活效果,EC50为0.142nM。
8.5、生物薄膜干涉技术测定抗CD3人源化抗体的动力学常数和亲和力
示例性的,人源化抗体动力学常数和亲和力平衡解离常数测定的实验方法参见实施例3。人源化抗体亲和力结果见表8。
表8、人源化抗体的亲和力测定结果
抗体 | K<sub>D</sub>(M) | Ka(1/Ms) | Kd(1/s) |
AB614 | 1.959E-11 | 7.410E05 | 1.452E-05 |
AB615 | 6.683E-10 | 2.539E05 | 1.697E-04 |
AB616 | 1.159E-10 | 2.559E05 | 2.966E-05 |
AB617 | 2.765E-09 | 2.525E05 | 6.982E-04 |
AB618 | <1.0E-12 | 5.119E04 | <1.0E-07 |
AB619 | 1.234E-10 | 2.759E05 | 3.405E-05 |
AB620 | 1.689E-10 | 2.526E05 | 4.265E-05 |
AB621 | 2.121E-09 | 1.740E05 | 3.691E-04 |
AB622 | 1.446E-09 | 2.701E05 | 3.907E-04 |
AB623 | 2.334E-08 | 5.116E04 | 1.194E-03 |
AB624 | 6.769E-10 | 2.964E05 | 2.006E-04 |
AB625 | 1.803E-09 | 1.767E05 | 3.185E-04 |
AB626 | 1.816E-07 | 9.299E03 | 1.689E-03 |
AB627 | 2.643E-12 | 7.303E03 | <1.0E-07 |
虽然说明并描述了本发明的优选例,应理解本领域的技术人员可根据本文的教导做出各种改变,这些改变不违背本发明的范围。
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可对本发明做各种修改或改动,这些等价形式同样落后于本申请所附权利要求书所限定的范围。
序列表
<110> 安源医药科技(上海)有限公司
<120> 抗CD3抗体及其用途
<130> 202105
<160> 119
<170> SIPOSequenceListing 1.0
<210> 1
<211> 119
<212> PRT
<213> AP191重链可变区()
<400> 1
Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Met Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Tyr Ile His 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 Lys Phe Asn Glu Lys Phe
50 55 60
Arg Gly Lys Thr Ser Leu Thr Ala Asp Lys Ser Ser Asn Thr Ala Tyr
65 70 75 80
Met Phe Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Ile Tyr Phe Cys
85 90 95
Ala Arg Asp Gly Tyr Ser Leu Tyr Tyr Phe Glu Phe Trp Gly His Gly
100 105 110
Thr Thr Leu Thr Val Ser Ser
115
<210> 2
<211> 112
<212> PRT
<213> AP191轻链可变区()
<400> 2
Asp Ile Val Met Ser Gln Ser Pro Ser Ser Leu Ala Val Ser Ala Gly
1 5 10 15
Glu Thr Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Arg Thr Arg Lys Thr Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Asp Ser Gly Val
50 55 60
Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys Val Gln
85 90 95
Ser Tyr Thr Leu Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 3
<211> 125
<212> PRT
<213> AP591重链可变区()
<400> 3
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Lys Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr
20 25 30
Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Arg Ser Lys Ile Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp
50 55 60
Ser Val Arg Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Gln Ser Met
65 70 75 80
Leu Tyr Leu Gln Met Ser Asn Leu Lys Thr Glu Asp Thr Ala Met Tyr
85 90 95
Tyr Cys Val Arg His Asp Asn Phe Tyr Gly Ser Thr Tyr Ser Trp Phe
100 105 110
Ala Asp Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala
115 120 125
<210> 4
<211> 108
<212> PRT
<213> AP591轻链可变区()
<400> 4
Ala Val Val Thr Gln Glu Ser Ala Leu Thr Thr Ser Pro Gly Glu Thr
1 5 10 15
Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Val Val Thr Thr Ser Asn
20 25 30
Tyr Ala Asn Trp Val Gln Glu Lys Pro Asp His Leu Phe Thr Gly Leu
35 40 45
Ile Gly Ala Thr Asn Tyr Arg Val Pro Gly Val Pro Ala Arg Phe Ser
50 55 60
Gly Ser Leu Ile Gly Asp Lys Ala Ala Leu Thr Ile Thr Gly Ala Gln
65 70 75 80
Thr Glu Asp Glu Ala Ile Tyr Phe Cys Val Leu Trp Tyr Ser Asn His
85 90 95
Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 5
<211> 117
<212> PRT
<213> AP831重链可变区()
<400> 5
Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Thr
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Asn
20 25 30
Tyr Ile His Trp Val Lys Glu Lys Pro Gly Glu Gly Leu Glu Trp Ile
35 40 45
Gly Trp Ile Tyr Pro Gly Asp Gly Thr Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Thr Thr Leu Ala Ser Asp Lys Ser Ser Asn Thr Val Tyr
65 70 75 80
Met Phe Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Ile Tyr Phe Cys
85 90 95
Thr Arg Asn Asn Asn Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Thr
100 105 110
Leu Thr Val Ser Ser
115
<210> 6
<211> 112
<212> PRT
<213> AP831轻链可变区()
<400> 6
Asp Ile Val Met Ser Gln Ser Pro Ser Ser Leu Ala Val Ser Ala Gly
1 5 10 15
Glu Lys Val Thr Met Asn Cys Lys Ser Ser Gln Ser Leu Phe Asn Ser
20 25 30
Arg Thr Arg Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Leu Tyr Tyr Cys Lys Gln
85 90 95
Ser Phe Ile Leu Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 7
<211> 5
<212> PRT
<213> Kabat AP191 CDR-H1
<400> 7
Ser Tyr Tyr Ile His
1 5
<210> 8
<211> 17
<212> PRT
<213> Kabat AP191 CDR-H2
<400> 8
Trp Ile Tyr Pro Gly Asp Gly Ser Thr Lys Phe Asn Glu Lys Phe Arg
1 5 10 15
Gly
<210> 9
<211> 10
<212> PRT
<213> Kabat AP191 CDR-H3
<400> 9
Asp Gly Tyr Ser Leu Tyr Tyr Phe Glu Phe
1 5 10
<210> 10
<211> 17
<212> PRT
<213> Kabat AP191 CDR-L1
<400> 10
Lys Ser Ser Gln Ser Leu Leu Asn Ser Arg Thr Arg Lys Thr Tyr Leu
1 5 10 15
Ala
<210> 11
<211> 7
<212> PRT
<213> Kabat AP191 CDR-L2
<400> 11
Trp Ala Ser Thr Arg Asp Ser
1 5
<210> 12
<211> 8
<212> PRT
<213> Kabat/IMGT AP191 CDR-L3
<400> 12
Val Gln Ser Tyr Thr Leu Arg Thr
1 5
<210> 13
<211> 8
<212> PRT
<213> IMGT AP191 CDR-H1
<400> 13
Gly Tyr Thr Phe Thr Ser Tyr Tyr
1 5
<210> 14
<211> 8
<212> PRT
<213> IMGT AP191 CDR-H2
<400> 14
Ile Tyr Pro Gly Asp Gly Ser Thr
1 5
<210> 15
<211> 12
<212> PRT
<213> IMGT AP191 CDR-H3
<400> 15
Ala Arg Asp Gly Tyr Ser Leu Tyr Tyr Phe Glu Phe
1 5 10
<210> 16
<211> 12
<212> PRT
<213> IMGT AP191 CDR-L1
<400> 16
Gln Ser Leu Leu Asn Ser Arg Thr Arg Lys Thr Tyr
1 5 10
<210> 17
<211> 3
<212> PRT
<213> IMGT AP191 CDR-L2
<400> 17
Trp Ala Ser
1
<210> 18
<211> 5
<212> PRT
<213> Kabat AP591 CDR-H1
<400> 18
Thr Tyr Ala Met Asn
1 5
<210> 19
<211> 19
<212> PRT
<213> Kabat AP591 CDR-H2
<400> 19
Arg Ile Arg Ser Lys Ile Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser
1 5 10 15
Val Arg Asp
<210> 20
<211> 14
<212> PRT
<213> Kabat AP591 CDR-H3
<400> 20
His Asp Asn Phe Tyr Gly Ser Thr Tyr Ser Trp Phe Ala Asp
1 5 10
<210> 21
<211> 14
<212> PRT
<213> Kabat AP591 CDR-L1
<400> 21
Arg Ser Ser Thr Gly Val Val Thr Thr Ser Asn Tyr Ala Asn
1 5 10
<210> 22
<211> 7
<212> PRT
<213> Kabat AP591 CDR-L2
<400> 22
Ala Thr Asn Tyr Arg Val Pro
1 5
<210> 23
<211> 9
<212> PRT
<213> Kabat/IMGT AP591 CDR-L3
<400> 23
Val Leu Trp Tyr Ser Asn His Trp Val
1 5
<210> 24
<211> 8
<212> PRT
<213> IMGT AP591 CDR-H1
<400> 24
Gly Phe Thr Phe Asn Thr Tyr Ala
1 5
<210> 25
<211> 10
<212> PRT
<213> IMGT AP591 CDR-H2
<400> 25
Ile Arg Ser Lys Ile Asn Asn Tyr Ala Thr
1 5 10
<210> 26
<211> 16
<212> PRT
<213> IMGT AP591 CDR-H3
<400> 26
Val Arg His Asp Asn Phe Tyr Gly Ser Thr Tyr Ser Trp Phe Ala Asp
1 5 10 15
<210> 27
<211> 9
<212> PRT
<213> IMGT AP591 CDR-L1
<400> 27
Thr Gly Val Val Thr Thr Ser Asn Tyr
1 5
<210> 28
<211> 3
<212> PRT
<213> IMGT AP591 CDR-L2
<400> 28
Ala Thr Asn
1
<210> 29
<211> 5
<212> PRT
<213> Kabat AP831 CDR-H1
<400> 29
Asn Asn Tyr Ile His
1 5
<210> 30
<211> 17
<212> PRT
<213> Kabat AP831 CDR-H2
<400> 30
Trp Ile Tyr Pro Gly Asp Gly Thr Thr Lys Tyr Asn Glu Lys Phe Lys
1 5 10 15
Gly
<210> 31
<211> 8
<212> PRT
<213> Kabat AP831 CDR-H3
<400> 31
Asn Asn Asn Tyr Tyr Phe Asp Tyr
1 5
<210> 32
<211> 17
<212> PRT
<213> Kabat AP831 CDR-L1
<400> 32
Lys Ser Ser Gln Ser Leu Phe Asn Ser Arg Thr Arg Lys Asn Tyr Leu
1 5 10 15
Ala
<210> 33
<211> 7
<212> PRT
<213> Kabat AP831 CDR-L2
<400> 33
Trp Ala Ser Thr Arg Glu Ser
1 5
<210> 34
<211> 8
<212> PRT
<213> Kabat/IMGT AP831 CDR-L3
<400> 34
Lys Gln Ser Phe Ile Leu Arg Thr
1 5
<210> 35
<211> 8
<212> PRT
<213> IMGT AP831 CDR-H1
<400> 35
Gly Tyr Thr Phe Thr Asn Asn Tyr
1 5
<210> 36
<211> 8
<212> PRT
<213> IMGT AP831 CDR-H2
<400> 36
Ile Tyr Pro Gly Asp Gly Thr Thr
1 5
<210> 37
<211> 10
<212> PRT
<213> IMGT AP831 CDR-H3
<400> 37
Thr Arg Asn Asn Asn Tyr Tyr Phe Asp Tyr
1 5 10
<210> 38
<211> 12
<212> PRT
<213> IMGT AP831 CDR-L1
<400> 38
Gln Ser Leu Phe Asn Ser Arg Thr Arg Lys Asn Tyr
1 5 10
<210> 39
<211> 3
<212> PRT
<213> IMGT AP831 CDR-L2
<400> 39
Trp Ala Ser
1
<210> 40
<211> 117
<212> PRT
<213> AB610重链可变区()
<400> 40
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Asn Asn
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Trp Ile Tyr Pro Gly Asp Gly Thr Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Thr Thr Leu Ala Ser Asp Asp Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Met Tyr Phe Cys
85 90 95
Thr Arg Asn Asn Asn Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 41
<211> 111
<212> PRT
<213> AB610轻链可变区()
<400> 41
Glu Ile Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
1 5 10 15
Thr Val Thr Leu Thr Cys Arg Ser Ser Gln Ser Leu Phe Asn Ser Arg
20 25 30
Thr Arg Lys Asn Tyr Leu Ala Trp Val Gln Glu Lys Pro Gly Gln Ala
35 40 45
Pro Arg Gly Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Thr Pro
50 55 60
Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu
65 70 75 80
Ser Gly Val Gln Pro Glu Asp Glu Ala Ile Tyr Tyr Cys Lys Gln Ser
85 90 95
Phe Ile Leu Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 42
<211> 117
<212> PRT
<213> AB611重链可变区()
<400> 42
Glu 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 Asn Asn
20 25 30
Tyr Ile His Trp Val Lys Glu Lys Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Trp Ile Tyr Pro Gly Asp Gly Thr Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Thr Thr Leu Ala Ser Asp Lys Ser Thr Asn Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Ile Tyr Phe Cys
85 90 95
Thr Arg Asn Asn Asn Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Thr
100 105 110
Val Thr Val Ser Ser
115
<210> 43
<211> 112
<212> PRT
<213> AB611轻链可变区()
<400> 43
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Met Asn Cys Lys Ser Ser Gln Ser Leu Phe Asn Ser
20 25 30
Arg Thr Arg Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Glu
35 40 45
Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Lys Gln
85 90 95
Ser Phe Ile Leu Arg Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 44
<211> 119
<212> PRT
<213> AB612重链可变区()
<400> 44
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Trp Ile Tyr Pro Gly Glu Gly Ser Thr Lys Phe Asn Glu Lys Phe
50 55 60
Arg Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Met Tyr Phe Cys
85 90 95
Ala Arg Glu Gly Tyr Ser Leu Tyr Tyr Phe Glu Phe Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 45
<211> 111
<212> PRT
<213> AB612轻链可变区()
<400> 45
Glu Ile Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
1 5 10 15
Thr Val Thr Leu Thr Cys Arg Ser Ser Gln Ser Leu Leu Asn Ser Arg
20 25 30
Thr Arg Lys Thr Tyr Leu Ala Trp Val Gln Glu Lys Pro Asp His Leu
35 40 45
Phe Thr Gly Leu Ile Tyr Trp Ala Ser Thr Arg Asp Pro Gly Thr Pro
50 55 60
Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu
65 70 75 80
Ser Gly Val Gln Pro Glu Asp Glu Ala Ile Tyr Tyr Cys Val Gln Ser
85 90 95
Tyr Thr Leu Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 46
<211> 119
<212> PRT
<213> AB613重链可变区()
<400> 46
Glu 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
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Tyr Pro Gly Glu Gly Ser Thr Lys Phe Asn Glu Lys Phe
50 55 60
Arg Gly Arg Thr 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 Gly Tyr Ser Leu Tyr Tyr Phe Glu Phe Trp Gly Gln Gly
100 105 110
Thr Thr Val Thr Val Ser Ser
115
<210> 47
<211> 112
<212> PRT
<213> AB613轻链可变区()
<400> 47
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Arg Thr Arg Lys Thr Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Glu
35 40 45
Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Asp Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Val Gln
85 90 95
Ser Tyr Thr Leu Arg Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 48
<211> 125
<212> PRT
<213> AB614重链可变区()
<400> 48
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr
20 25 30
Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Arg Ser Lys Ile Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp
50 55 60
Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Met Tyr
85 90 95
Tyr Cys Val Arg His Asp Asn Phe Tyr Gly Ser Thr Tyr Ser Trp Phe
100 105 110
Ala Asp Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 49
<211> 109
<212> PRT
<213> AB614轻链可变区()
<400> 49
Glu Leu Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
1 5 10 15
Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Val Val Thr Thr Ser
20 25 30
Asn Tyr Ala Asn Trp Val Gln Glu Lys Pro Asp His Leu Phe Thr Gly
35 40 45
Leu Ile Gly Ala Thr Asn Tyr Arg Ala Pro Gly Thr Pro Ala Arg Phe
50 55 60
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val
65 70 75 80
Gln Pro Glu Asp Glu Ala Ile Tyr Phe Cys Val Leu Trp Tyr Ser Asn
85 90 95
His Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 50
<211> 17
<212> PRT
<213> Kabat AB610 CDR-L1
<400> 50
Arg Ser Ser Gln Ser Leu Phe Asn Ser Arg Thr Arg Lys Asn Tyr Leu
1 5 10 15
Ala
<210> 51
<211> 17
<212> PRT
<213> Kabat AB612 CDR-H2
<400> 51
Trp Ile Tyr Pro Gly Glu Gly Ser Thr Lys Phe Asn Glu Lys Phe Arg
1 5 10 15
Gly
<210> 52
<211> 10
<212> PRT
<213> Kabat AB612 CDR-H3
<400> 52
Glu Gly Tyr Ser Leu Tyr Tyr Phe Glu Phe
1 5 10
<210> 53
<211> 17
<212> PRT
<213> Kabat AB612 CDR-L1
<400> 53
Arg Ser Ser Gln Ser Leu Leu Asn Ser Arg Thr Arg Lys Thr Tyr Leu
1 5 10 15
Ala
<210> 54
<211> 7
<212> PRT
<213> Kabat AB612 CDR-L2
<400> 54
Trp Ala Ser Thr Arg Asp Pro
1 5
<210> 55
<211> 8
<212> PRT
<213> IMGT AB612 CDR-H2
<400> 55
Ile Tyr Pro Gly Glu Gly Ser Thr
1 5
<210> 56
<211> 12
<212> PRT
<213> IMGT AB612 CDR-H3
<400> 56
Ala Arg Glu Gly Tyr Ser Leu Tyr Tyr Phe Glu Phe
1 5 10
<210> 57
<211> 19
<212> PRT
<213> Kabat AB614 CDR-H2
<400> 57
Arg Ile Arg Ser Lys Ile Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser
1 5 10 15
Val Lys Asp
<210> 58
<211> 7
<212> PRT
<213> Kabat AB614 CDR-L2
<400> 58
Ala Thr Asn Tyr Arg Ala Pro
1 5
<210> 59
<211> 107
<212> PRT
<213> 人κ恒定区氨基酸序列()
<400> 59
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
1 5 10 15
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
20 25 30
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
35 40 45
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
50 55 60
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
65 70 75 80
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
85 90 95
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
100 105
<210> 60
<211> 330
<212> PRT
<213> IgG1野生型氨基酸序列()
<400> 60
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
225 230 235 240
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 61
<211> 330
<212> PRT
<213> IgG1(N297A突变体恒定区氨基酸序列)
<400> 61
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
225 230 235 240
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 62
<211> 330
<212> PRT
<213> IgG1(L234A,L235A突变体恒定区氨基酸序列)
<400> 62
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
225 230 235 240
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 63
<211> 327
<212> PRT
<213> IgG4野生型氨基酸序列()
<400> 63
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro Ala Pro
100 105 110
Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 64
<211> 327
<212> PRT
<213> IgG4(S228P突变体恒定区氨基酸序列)
<400> 64
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 65
<211> 444
<212> PRT
<213> AB610重链氨基酸序列()
<400> 65
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Asn Asn
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Trp Ile Tyr Pro Gly Asp Gly Thr Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Thr Thr Leu Ala Ser Asp Asp Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Met Tyr Phe Cys
85 90 95
Thr Arg Asn Asn Asn Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro
210 215 220
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
225 230 235 240
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
245 250 255
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
260 265 270
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
275 280 285
Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
290 295 300
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
305 310 315 320
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
325 330 335
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
340 345 350
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
355 360 365
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
370 375 380
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
385 390 395 400
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
405 410 415
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
420 425 430
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440
<210> 66
<211> 218
<212> PRT
<213> AB610轻链氨基酸序列()
<400> 66
Glu Ile Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
1 5 10 15
Thr Val Thr Leu Thr Cys Arg Ser Ser Gln Ser Leu Phe Asn Ser Arg
20 25 30
Thr Arg Lys Asn Tyr Leu Ala Trp Val Gln Glu Lys Pro Gly Gln Ala
35 40 45
Pro Arg Gly Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Thr Pro
50 55 60
Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu
65 70 75 80
Ser Gly Val Gln Pro Glu Asp Glu Ala Ile Tyr Tyr Cys Lys Gln Ser
85 90 95
Phe Ile Leu Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg
100 105 110
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
115 120 125
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
130 135 140
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
145 150 155 160
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
165 170 175
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
180 185 190
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
195 200 205
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 67
<211> 1332
<212> DNA
<213> AB610重链核苷酸序列()
<400> 67
gaggtgcagc tgctggagtc tggaggagga ctggtgcagc ctggaggaag cctgaagctg 60
tcttgcgccg cttccggcta caccttcaca aacaattata tccattgggt gaggcaggct 120
ccaggcaagg gactggagtg gatcggctgg atctaccctg gcgatggcac cacaaagtat 180
aacgagaagt ttaagggcaa gaccacactg gcctctgacg attccaagaa taccgcttac 240
ctgcagatga acaatctgaa gaccgaggat acagctatgt acttctgcac ccggaacaat 300
aactactatt ttgactattg gggccagggc accctggtga cagtgtccag cgcctctacc 360
aagggccctt ccgtgttccc tctggcccca tgttcccgca gcacctctga gtccacagcc 420
gctctgggct gcctggtgaa ggactatttc cccgagcctg tgaccgtgtc ctggaacagc 480
ggcgctctga cctccggagt gcacacattt cccgccgtgc tgcagtcttc cggcctgtac 540
agcctgagct ctgtggtgac cgtgccatcc agctctctgg gcaccaagac atatacctgt 600
aacgtggatc ataagccctc caatacaaag gtggacaagc gcgtggagag caagtacgga 660
ccaccatgtc ctccatgccc agctcccgag tttctgggcg gccctagcgt gttcctgttt 720
ccccctaagc caaaggatac cctgatgatc agcaggaccc ctgaggtgac atgcgtggtg 780
gtggacgtgt cccaggagga cccagaggtg cagttcaact ggtacgtgga cggcgtggag 840
gtgcacaatg ccaagaccaa gcctcgggag gagcagttta attccaccta cagagtggtg 900
agcgtgctga cagtgctgca tcaggactgg ctgaacggca aggagtataa gtgtaaggtg 960
tccaataagg gcctgccatc cagcatcgag aagaccatca gcaaggctaa gggccagccc 1020
agggagcctc aggtgtacac actgccaccc tctcaggagg agatgaccaa gaaccaggtg 1080
tccctgacat gcctggtgaa gggcttctat ccttccgata tcgccgtgga gtgggagagc 1140
aatggccagc cagagaacaa ttacaagacc acacctccag tgctggattc tgacggctcc 1200
ttctttctgt attcccggct gaccgtggac aagagcagat ggcaggaggg caacgtgttt 1260
agctgttctg tgatgcatga ggctctgcac aatcattaca cacagaagtc cctgagcctg 1320
tctctgggca ag 1332
<210> 68
<211> 654
<212> DNA
<213> AB610轻链核苷酸序列()
<400> 68
gagatcgtgg tgacccagga gccaagcctg acagtgtctc ccggcggcac cgtgacactg 60
acctgtagat cttcccagtc cctgttcaac agcaggaccc ggaagaatta cctggcctgg 120
gtgcaggaga agccaggaca ggctccaagg ggactgatct attgggcttc taccagggag 180
tccggcacac cagctcggtt tagcggatct ctgctgggag gcaaggctgc cctgaccctg 240
tccggagtgc agcccgagga cgaggctatc tactattgca agcagagctt catcctgagg 300
acctttggcg gcggcacaaa gctggagatc aagaggaccg tggctgcccc ctccgtgttc 360
atctttcccc cttccgatga gcagctgaag tccggcacag ccagcgtggt gtgcctgctg 420
aacaatttct accctagaga ggctaaggtg cagtggaagg tggacaacgc cctgcagagc 480
ggcaattctc aggagtccgt gaccgagcag gatagcaagg actctacata ttccctgtcc 540
agcacactga ccctgagcaa ggctgattac gagaagcaca aggtgtatgc ctgtgaggtg 600
acccatcagg gcctgtcttc ccctgtgaca aagtctttca accggggcga gtgc 654
<210> 69
<211> 444
<212> PRT
<213> AB611重链氨基酸序列()
<400> 69
Glu 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 Asn Asn
20 25 30
Tyr Ile His Trp Val Lys Glu Lys Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Trp Ile Tyr Pro Gly Asp Gly Thr Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Thr Thr Leu Ala Ser Asp Lys Ser Thr Asn Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Ile Tyr Phe Cys
85 90 95
Thr Arg Asn Asn Asn Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Thr
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro
210 215 220
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
225 230 235 240
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
245 250 255
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
260 265 270
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
275 280 285
Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
290 295 300
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
305 310 315 320
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
325 330 335
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
340 345 350
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
355 360 365
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
370 375 380
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
385 390 395 400
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
405 410 415
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
420 425 430
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440
<210> 70
<211> 219
<212> PRT
<213> AB611轻链氨基酸序列()
<400> 70
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Met Asn Cys Lys Ser Ser Gln Ser Leu Phe Asn Ser
20 25 30
Arg Thr Arg Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Glu
35 40 45
Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Lys Gln
85 90 95
Ser Phe Ile Leu Arg Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 71
<211> 1332
<212> DNA
<213> AB611重链核苷酸序列()
<400> 71
gaggtgcagc tggtgcagag cggagctgag gtgaagaagc caggcagctc tgtgaaggtg 60
agctgtaagg cttctggcta cacattcacc aataactata tccactgggt gaaagaaaag 120
ccaggacagg gcctggaatg gatcggatgg atctaccccg gcgatggtac taccaaatac 180
aatgaaaagt ttaagggcaa gaccacactg gcgagcgaca agtctacaaa taccgcttac 240
atggagctgt ccagcctgag gtctgaggat accgccatct acttctgcac acggaacaac 300
aactactact tcgactactg gggccagggc accacagtga ccgtgtcttc cgcctctacc 360
aagggccctt ccgtgttccc tctggcccca tgttcccgca gcacctctga gtccacagcc 420
gctctgggct gcctggtgaa ggactatttc cccgagcctg tgaccgtgtc ctggaacagc 480
ggcgctctga cctccggagt gcacacattt cccgccgtgc tgcagtcttc cggcctgtac 540
agcctgagct ctgtggtgac cgtgccatcc agctctctgg gcaccaagac atatacctgt 600
aacgtggatc ataagccctc caatacaaag gtggacaagc gcgtggagag caagtacgga 660
ccaccatgtc ctccatgccc agctcccgag tttctgggcg gccctagcgt gttcctgttt 720
ccccctaagc caaaggatac cctgatgatc agcaggaccc ctgaggtgac atgcgtggtg 780
gtggacgtgt cccaggagga cccagaggtg cagttcaact ggtacgtgga cggcgtggag 840
gtgcacaatg ccaagaccaa gcctcgggag gagcagttta attccaccta cagagtggtg 900
agcgtgctga cagtgctgca tcaggactgg ctgaacggca aggagtataa gtgtaaggtg 960
tccaataagg gcctgccatc cagcatcgag aagaccatca gcaaggctaa gggccagccc 1020
agggagcctc aggtgtacac actgccaccc tctcaggagg agatgaccaa gaaccaggtg 1080
tccctgacat gcctggtgaa gggcttctat ccttccgata tcgccgtgga gtgggagagc 1140
aatggccagc cagagaacaa ttacaagacc acacctccag tgctggattc tgacggctcc 1200
ttctttctgt attcccggct gaccgtggac aagagcagat ggcaggaggg caacgtgttt 1260
agctgttctg tgatgcatga ggctctgcac aatcattaca cacagaagtc cctgagcctg 1320
tctctgggca ag 1332
<210> 72
<211> 657
<212> DNA
<213> AB611轻链核苷酸序列()
<400> 72
gatatcgtga tgacacagtc cccagacagc ctggccgtga gcctgggaga gcgggctacc 60
atgaactgta agagctctca gtctctgttc aactctagaa cacgcaaaaa ctacctggcc 120
tggtatcagc agaagcctgg cgagtctcca aagctgctga tctactgggc ttctaccaga 180
gagtccggag tgcctgatcg cttctccgga agcggctctg gcacagactt tacactgacc 240
atctccagcc tgcaggccga ggatgtggcc gtgtactact gtaaacaaag cttcatcctg 300
aggacctttg gcggaggcac aaaggtggag atcaagagga ccgtggctgc cccctccgtg 360
ttcatctttc ccccttccga tgagcagctg aagtccggca cagccagcgt ggtgtgcctg 420
ctgaacaatt tctaccctag agaggctaag gtgcagtgga aggtggacaa cgccctgcag 480
agcggcaatt ctcaggagtc cgtgaccgag caggatagca aggactctac atattccctg 540
tccagcacac tgaccctgag caaggctgat tacgagaagc acaaggtgta tgcctgtgag 600
gtgacccatc agggcctgtc ttcccctgtg acaaagtctt tcaaccgggg cgagtgc 657
<210> 73
<211> 446
<212> PRT
<213> AB612重链氨基酸序列()
<400> 73
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Trp Ile Tyr Pro Gly Glu Gly Ser Thr Lys Phe Asn Glu Lys Phe
50 55 60
Arg Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Met Tyr Phe Cys
85 90 95
Ala Arg Glu Gly Tyr Ser Leu Tyr Tyr Phe Glu Phe Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro
210 215 220
Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe
225 230 235 240
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255
Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val
260 265 270
Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val
290 295 300
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
305 310 315 320
Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser
325 330 335
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
340 345 350
Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
355 360 365
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440 445
<210> 74
<211> 218
<212> PRT
<213> AB612轻链氨基酸序列()
<400> 74
Glu Ile Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
1 5 10 15
Thr Val Thr Leu Thr Cys Arg Ser Ser Gln Ser Leu Leu Asn Ser Arg
20 25 30
Thr Arg Lys Thr Tyr Leu Ala Trp Val Gln Glu Lys Pro Asp His Leu
35 40 45
Phe Thr Gly Leu Ile Tyr Trp Ala Ser Thr Arg Asp Pro Gly Thr Pro
50 55 60
Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu
65 70 75 80
Ser Gly Val Gln Pro Glu Asp Glu Ala Ile Tyr Tyr Cys Val Gln Ser
85 90 95
Tyr Thr Leu Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg
100 105 110
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
115 120 125
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
130 135 140
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
145 150 155 160
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
165 170 175
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
180 185 190
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
195 200 205
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 75
<211> 1338
<212> DNA
<213> AB612重链核苷酸序列()
<400> 75
gaagtccagc tgctggagag cggcggcgga ctggtgcagc caggcggcag cctgaagctg 60
tcttgtgccg cttccggcta cacattcacc tcttactata tccattgggt gcggcaggct 120
cctggcaagg gcctggaatg ggtgggctgg atctatccag gcgagggctc caccaagttt 180
aacgagaagt tcaggggccg gtttaccatc agcagggacg attctaagaa tacagcctac 240
ctgcagatga ataatctgaa gaccgaggac acagccatgt acttttgcgc tcgggagggc 300
tatagcctgt actattttga gttctggggt cagggcaccc tggtcacagt gtcttccgcc 360
tctaccaagg gcccttccgt gttccctctg gccccatgtt cccgcagcac ctctgagtcc 420
acagccgctc tgggctgcct ggtgaaggac tatttccccg agcctgtgac cgtgtcctgg 480
aacagcggcg ctctgacctc cggagtgcac acatttcccg ccgtgctgca gtcttccggc 540
ctgtacagcc tgagctctgt ggtgaccgtg ccatccagct ctctgggcac caagacatat 600
acctgtaacg tggatcataa gccctccaat acaaaggtgg acaagcgcgt ggagagcaag 660
tacggaccac catgtcctcc atgcccagct cccgagtttc tgggcggccc tagcgtgttc 720
ctgtttcccc ctaagccaaa ggataccctg atgatcagca ggacccctga ggtgacatgc 780
gtggtggtgg acgtgtccca ggaggaccca gaggtgcagt tcaactggta cgtggacggc 840
gtggaggtgc acaatgccaa gaccaagcct cgggaggagc agtttaattc cacctacaga 900
gtggtgagcg tgctgacagt gctgcatcag gactggctga acggcaagga gtataagtgt 960
aaggtgtcca ataagggcct gccatccagc atcgagaaga ccatcagcaa ggctaagggc 1020
cagcccaggg agcctcaggt gtacacactg ccaccctctc aggaggagat gaccaagaac 1080
caggtgtccc tgacatgcct ggtgaagggc ttctatcctt ccgatatcgc cgtggagtgg 1140
gagagcaatg gccagccaga gaacaattac aagaccacac ctccagtgct ggattctgac 1200
ggctccttct ttctgtattc ccggctgacc gtggacaaga gcagatggca ggagggcaac 1260
gtgtttagct gttctgtgat gcatgaggct ctgcacaatc attacacaca gaagtccctg 1320
agcctgtctc tgggcaag 1338
<210> 76
<211> 654
<212> DNA
<213> AB612轻链核苷酸序列()
<400> 76
gaaattgtgg tgacccagga gccttccctg acagtgagcc caggcggcac agtgaccctg 60
acatgtagaa gctctcagtc tctgctgaac tccagaaccc gcaagacata cctggcttgg 120
gtccaggaga agcctgatca tctgttcacc ggcctgatct attgggcttc caccagggac 180
ccaggaacac ctgctcggtt ttccggaagc ctgctgggag gcaaggccgc tctgaccctg 240
tctggagtgc agccagaaga tgaagccatc tactattgcg tgcagtccta caccctgaga 300
acattcggcg gcggcaccaa gctggagatc aagaggaccg tggctgcccc ctccgtgttc 360
atctttcccc cttccgatga gcagctgaag tccggcacag ccagcgtggt gtgcctgctg 420
aacaatttct accctagaga ggctaaggtg cagtggaagg tggacaacgc cctgcagagc 480
ggcaattctc aggagtccgt gaccgagcag gatagcaagg actctacata ttccctgtcc 540
agcacactga ccctgagcaa ggctgattac gagaagcaca aggtgtatgc ctgtgaggtg 600
acccatcagg gcctgtcttc ccctgtgaca aagtctttca accggggcga gtgc 654
<210> 77
<211> 446
<212> PRT
<213> AB613重链氨基酸序列()
<400> 77
Glu 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
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Tyr Pro Gly Glu Gly Ser Thr Lys Phe Asn Glu Lys Phe
50 55 60
Arg Gly Arg Thr 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 Gly Tyr Ser Leu Tyr Tyr Phe Glu Phe Trp Gly Gln Gly
100 105 110
Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro
210 215 220
Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe
225 230 235 240
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255
Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val
260 265 270
Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val
290 295 300
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
305 310 315 320
Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser
325 330 335
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
340 345 350
Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
355 360 365
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440 445
<210> 78
<211> 219
<212> PRT
<213> AB613轻链氨基酸序列()
<400> 78
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Arg Thr Arg Lys Thr Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Glu
35 40 45
Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Asp Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Val Gln
85 90 95
Ser Tyr Thr Leu Arg Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 79
<211> 1338
<212> DNA
<213> AB613重链核苷酸序列()
<400> 79
gaagtgcagc tggtgcagtc tggcgctgag gtgaagaagc ctggctccag cgtcaaggtg 60
agctgcaagg cttctggcta cacctttaca agctactata tccactgggt gcgccaggct 120
ccaggacagg gactggagtg gatgggctgg atctatcctg gcgagggcag caccaagttc 180
aacgagaagt ttaggggccg gaccacactg acagccgata agagcaccaa tacagcttac 240
atggagctgt cttccctgag atctgaggac accgccgtgt acttctgcgc tcgcgagggc 300
tattctctgt attactttga gttttggggt cagggtacta cagtgaccgt gagctctgcc 360
tctaccaagg gcccttccgt gttccctctg gccccatgtt cccgcagcac ctctgagtcc 420
acagccgctc tgggctgcct ggtgaaggac tatttccccg agcctgtgac cgtgtcctgg 480
aacagcggcg ctctgacctc cggagtgcac acatttcccg ccgtgctgca gtcttccggc 540
ctgtacagcc tgagctctgt ggtgaccgtg ccatccagct ctctgggcac caagacatat 600
acctgtaacg tggatcataa gccctccaat acaaaggtgg acaagcgcgt ggagagcaag 660
tacggaccac catgtcctcc atgcccagct cccgagtttc tgggcggccc tagcgtgttc 720
ctgtttcccc ctaagccaaa ggataccctg atgatcagca ggacccctga ggtgacatgc 780
gtggtggtgg acgtgtccca ggaggaccca gaggtgcagt tcaactggta cgtggacggc 840
gtggaggtgc acaatgccaa gaccaagcct cgggaggagc agtttaattc cacctacaga 900
gtggtgagcg tgctgacagt gctgcatcag gactggctga acggcaagga gtataagtgt 960
aaggtgtcca ataagggcct gccatccagc atcgagaaga ccatcagcaa ggctaagggc 1020
cagcccaggg agcctcaggt gtacacactg ccaccctctc aggaggagat gaccaagaac 1080
caggtgtccc tgacatgcct ggtgaagggc ttctatcctt ccgatatcgc cgtggagtgg 1140
gagagcaatg gccagccaga gaacaattac aagaccacac ctccagtgct ggattctgac 1200
ggctccttct ttctgtattc ccggctgacc gtggacaaga gcagatggca ggagggcaac 1260
gtgtttagct gttctgtgat gcatgaggct ctgcacaatc attacacaca gaagtccctg 1320
agcctgtctc tgggcaag 1338
<210> 80
<211> 657
<212> DNA
<213> AB613轻链核苷酸序列()
<400> 80
gacattgtga tgacacagtc tccagactcc ctggccgtgt ccctgggaga gagagctacc 60
atcaactgta agtccagcca gtccctgctg aactctagga ctagaaagac atacctggca 120
tggtaccagc agaagcccgg cgagtctcct aaactgctga tctactgggc ctctaccaga 180
gattccggag tgccagaccg cttctctgga tccggcagcg gcacagactt caccctgaca 240
atctcttccc tgcaggccga ggacgtggcc gtgtactact gcgtgcagtc ttataccctg 300
cgcacatttg gcggcggcac caaggtggag atcaagagga ccgtggctgc cccctccgtg 360
ttcatctttc ccccttccga tgagcagctg aagtccggca cagccagcgt ggtgtgcctg 420
ctgaacaatt tctaccctag agaggctaag gtgcagtgga aggtggacaa cgccctgcag 480
agcggcaatt ctcaggagtc cgtgaccgag caggatagca aggactctac atattccctg 540
tccagcacac tgaccctgag caaggctgat tacgagaagc acaaggtgta tgcctgtgag 600
gtgacccatc agggcctgtc ttcccctgtg acaaagtctt tcaaccgggg cgagtgc 657
<210> 81
<211> 452
<212> PRT
<213> AB614重链氨基酸序列()
<400> 81
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr
20 25 30
Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Arg Ser Lys Ile Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp
50 55 60
Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Met Tyr
85 90 95
Tyr Cys Val Arg His Asp Asn Phe Tyr Gly Ser Thr Tyr Ser Trp Phe
100 105 110
Ala Asp Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr
115 120 125
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser
130 135 140
Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu
145 150 155 160
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His
165 170 175
Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser
180 185 190
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys
195 200 205
Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu
210 215 220
Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu
225 230 235 240
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
245 250 255
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
260 265 270
Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
275 280 285
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
290 295 300
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
305 310 315 320
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser
325 330 335
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
340 345 350
Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val
355 360 365
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
370 375 380
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
385 390 395 400
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr
405 410 415
Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val
420 425 430
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
435 440 445
Ser Leu Gly Lys
450
<210> 82
<211> 216
<212> PRT
<213> AB614轻链氨基酸序列()
<400> 82
Glu Leu Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
1 5 10 15
Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Val Val Thr Thr Ser
20 25 30
Asn Tyr Ala Asn Trp Val Gln Glu Lys Pro Asp His Leu Phe Thr Gly
35 40 45
Leu Ile Gly Ala Thr Asn Tyr Arg Ala Pro Gly Thr Pro Ala Arg Phe
50 55 60
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val
65 70 75 80
Gln Pro Glu Asp Glu Ala Ile Tyr Phe Cys Val Leu Trp Tyr Ser Asn
85 90 95
His Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Arg Thr Val
100 105 110
Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys
115 120 125
Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg
130 135 140
Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn
145 150 155 160
Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser
165 170 175
Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys
180 185 190
Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr
195 200 205
Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 83
<211> 1356
<212> DNA
<213> AB614重链核苷酸序列()
<400> 83
gaggtgcagc tgctggagtc cggaggagga ctggtgcagc caggaggctc cctgaagctg 60
agctgtgctg cctctggctt taccttcaac acatatgcca tgaattgggt gcggcaggct 120
ccaggcaagg gactggagtg ggtgggcagg atcaggtcta agatcaacaa ttatgccacc 180
tactatgctg attccgtgaa ggacaggttc accatctccc gcgacgatag caagaacaca 240
gcctacctgc agatgaacaa tctgaagacc gaggataccg ccatgtacta ctgcgtgaga 300
catgacaact tttacggcag cacatactcc tggttcgctg actggggaca gggcaccctg 360
gtcacagtga gctctgcctc taccaagggc ccttccgtgt tccctctggc cccatgttcc 420
cgcagcacct ctgagtccac agccgctctg ggctgcctgg tgaaggacta tttccccgag 480
cctgtgaccg tgtcctggaa cagcggcgct ctgacctccg gagtgcacac atttcccgcc 540
gtgctgcagt cttccggcct gtacagcctg agctctgtgg tgaccgtgcc atccagctct 600
ctgggcacca agacatatac ctgtaacgtg gatcataagc cctccaatac aaaggtggac 660
aagcgcgtgg agagcaagta cggaccacca tgtcctccat gcccagctcc cgagtttctg 720
ggcggcccta gcgtgttcct gtttccccct aagccaaagg ataccctgat gatcagcagg 780
acccctgagg tgacatgcgt ggtggtggac gtgtcccagg aggacccaga ggtgcagttc 840
aactggtacg tggacggcgt ggaggtgcac aatgccaaga ccaagcctcg ggaggagcag 900
tttaattcca cctacagagt ggtgagcgtg ctgacagtgc tgcatcagga ctggctgaac 960
ggcaaggagt ataagtgtaa ggtgtccaat aagggcctgc catccagcat cgagaagacc 1020
atcagcaagg ctaagggcca gcccagggag cctcaggtgt acacactgcc accctctcag 1080
gaggagatga ccaagaacca ggtgtccctg acatgcctgg tgaagggctt ctatccttcc 1140
gatatcgccg tggagtggga gagcaatggc cagccagaga acaattacaa gaccacacct 1200
ccagtgctgg attctgacgg ctccttcttt ctgtattccc ggctgaccgt ggacaagagc 1260
agatggcagg agggcaacgt gtttagctgt tctgtgatgc atgaggctct gcacaatcat 1320
tacacacaga agtccctgag cctgtctctg ggcaag 1356
<210> 84
<211> 648
<212> DNA
<213> AB614轻链核苷酸序列()
<400> 84
gagctggtgg tgacccagga gccatctctg acagtgtccc ccggcggcac agtgaccctg 60
acatgtagat ccagcaccgg cgtggtgacc acatccaact acgctaattg ggtgcaggag 120
aagccagatc acctgttcac aggactgatc ggagctacca actacagggc tcctggaaca 180
ccagctcggt ttagcggatc tctgctggga ggcaaggctg ccctgaccct gtccggagtg 240
cagccagagg atgaggccat ctacttctgc gtgctgtggt atagcaatca ttgggtgttc 300
ggaggaggaa ccaagctgac agtgctgagg accgtggctg ccccctccgt gttcatcttt 360
cccccttccg atgagcagct gaagtccggc acagccagcg tggtgtgcct gctgaacaat 420
ttctacccta gagaggctaa ggtgcagtgg aaggtggaca acgccctgca gagcggcaat 480
tctcaggagt ccgtgaccga gcaggatagc aaggactcta catattccct gtccagcaca 540
ctgaccctga gcaaggctga ttacgagaag cacaaggtgt atgcctgtga ggtgacccat 600
cagggcctgt cttcccctgt gacaaagtct ttcaaccggg gcgagtgc 648
<210> 85
<211> 8
<212> PRT
<213> CDR-H1
<400> 85
Gly Phe Asp Phe Asn Thr Tyr Ala
1 5
<210> 86
<211> 8
<212> PRT
<213> CDR-H1
<400> 86
Gly Phe Thr Phe Asp Thr Tyr Ala
1 5
<210> 87
<211> 5
<212> PRT
<213> CDR-H1
<400> 87
Asp Tyr Ala Met Asn
1 5
<210> 88
<211> 8
<212> PRT
<213> CDR-H1
<400> 88
Gly Phe Thr Phe Asn Asp Tyr Ala
1 5
<210> 89
<211> 7
<212> PRT
<213> CDR-L2
<400> 89
Asp Thr Asn Tyr Arg Ala Pro
1 5
<210> 90
<211> 3
<212> PRT
<213> CDR-L2
<400> 90
Asp Thr Asn
1
<210> 91
<211> 7
<212> PRT
<213> CDR-L2
<400> 91
Ala Thr Asp Tyr Arg Ala Pro
1 5
<210> 92
<211> 3
<212> PRT
<213> CDR-L2
<400> 92
Ala Thr Asp
1
<210> 93
<211> 14
<212> PRT
<213> CDR-L1
<400> 93
Arg Ser Ser Thr Gly Val Val Thr Thr Ser Asn His Ala Asn
1 5 10
<210> 94
<211> 9
<212> PRT
<213> CDR-L1
<400> 94
Thr Gly Val Val Thr Thr Ser Asn His
1 5
<210> 95
<211> 7
<212> PRT
<213> CDR-L2
<400> 95
Ala Thr Asn His Arg Ala Pro
1 5
<210> 96
<211> 14
<212> PRT
<213> CDR-H3
<400> 96
His Asp Asn His Tyr Gly Ser Thr Tyr Ser Trp Phe Ala Asp
1 5 10
<210> 97
<211> 16
<212> PRT
<213> CDR-H3
<400> 97
Val Arg His Asp Asn His Tyr Gly Ser Thr Tyr Ser Trp Phe Ala Asp
1 5 10 15
<210> 98
<211> 14
<212> PRT
<213> CDR-H3
<400> 98
His Asp Asn Phe His Gly Ser Thr Tyr Ser Trp Phe Ala Asp
1 5 10
<210> 99
<211> 16
<212> PRT
<213> CDR-H3
<400> 99
Val Arg His Asp Asn Phe His Gly Ser Thr Tyr Ser Trp Phe Ala Asp
1 5 10 15
<210> 100
<211> 14
<212> PRT
<213> CDR-H3
<400> 100
His Asp Asn Phe Tyr Gly Ser Thr His Ser Trp Phe Ala Asp
1 5 10
<210> 101
<211> 16
<212> PRT
<213> CDR-H3
<400> 101
Val Arg His Asp Asn Phe Tyr Gly Ser Thr His Ser Trp Phe Ala Asp
1 5 10 15
<210> 102
<211> 14
<212> PRT
<213> CDR-H3
<400> 102
His Asp Asn Phe Tyr Gly Ser Thr Tyr Ser His Phe Ala Asp
1 5 10
<210> 103
<211> 16
<212> PRT
<213> CDR-H3
<400> 103
Val Arg His Asp Asn Phe Tyr Gly Ser Thr Tyr Ser His Phe Ala Asp
1 5 10 15
<210> 104
<211> 14
<212> PRT
<213> CDR-H3
<400> 104
His Asp Asn Phe Tyr Gly Ser Thr Tyr Ser Trp His Ala Asp
1 5 10
<210> 105
<211> 16
<212> PRT
<213> CDR-H3
<400> 105
Val Arg His Asp Asn Phe Tyr Gly Ser Thr Tyr Ser Trp His Ala Asp
1 5 10 15
<210> 106
<211> 125
<212> PRT
<213> AB615重链可变区()
<400> 106
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Asp Phe Asn Thr Tyr
20 25 30
Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Arg Ser Lys Ile Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp
50 55 60
Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Met Tyr
85 90 95
Tyr Cys Val Arg His Asp Asn Phe Tyr Gly Ser Thr Tyr Ser Trp Phe
100 105 110
Ala Asp Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 107
<211> 125
<212> PRT
<213> AB616重链可变区()
<400> 107
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Thr Tyr
20 25 30
Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Arg Ser Lys Ile Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp
50 55 60
Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Met Tyr
85 90 95
Tyr Cys Val Arg His Asp Asn Phe Tyr Gly Ser Thr Tyr Ser Trp Phe
100 105 110
Ala Asp Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 108
<211> 125
<212> PRT
<213> AB617重链可变区()
<400> 108
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Asp Tyr
20 25 30
Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Arg Ser Lys Ile Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp
50 55 60
Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Met Tyr
85 90 95
Tyr Cys Val Arg His Asp Asn Phe Tyr Gly Ser Thr Tyr Ser Trp Phe
100 105 110
Ala Asp Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 109
<211> 109
<212> PRT
<213> AB618轻链可变区()
<400> 109
Glu Leu Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
1 5 10 15
Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Val Val Thr Thr Ser
20 25 30
Asn Tyr Ala Asn Trp Val Gln Glu Lys Pro Asp His Leu Phe Thr Gly
35 40 45
Leu Ile Gly Asp Thr Asn Tyr Arg Ala Pro Gly Thr Pro Ala Arg Phe
50 55 60
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val
65 70 75 80
Gln Pro Glu Asp Glu Ala Ile Tyr Phe Cys Val Leu Trp Tyr Ser Asn
85 90 95
His Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 110
<211> 109
<212> PRT
<213> AB619轻链可变区()
<400> 110
Glu Leu Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
1 5 10 15
Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Val Val Thr Thr Ser
20 25 30
Asn Tyr Ala Asn Trp Val Gln Glu Lys Pro Asp His Leu Phe Thr Gly
35 40 45
Leu Ile Gly Ala Thr Asp Tyr Arg Ala Pro Gly Thr Pro Ala Arg Phe
50 55 60
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val
65 70 75 80
Gln Pro Glu Asp Glu Ala Ile Tyr Phe Cys Val Leu Trp Tyr Ser Asn
85 90 95
His Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 111
<211> 125
<212> PRT
<213> AB620重链可变区()
<400> 111
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Thr Tyr
20 25 30
Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Arg Ser Lys Ile Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp
50 55 60
Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Met Tyr
85 90 95
Tyr Cys Val Arg His Asp Asn Phe Tyr Gly Ser Thr Tyr Ser Trp Phe
100 105 110
Ala Asp Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 112
<211> 109
<212> PRT
<213> AB620轻链可变区()
<400> 112
Glu Leu Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
1 5 10 15
Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Val Val Thr Thr Ser
20 25 30
Asn Tyr Ala Asn Trp Val Gln Glu Lys Pro Asp His Leu Phe Thr Gly
35 40 45
Leu Ile Gly Ala Thr Asp Tyr Arg Ala Pro Gly Thr Pro Ala Arg Phe
50 55 60
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val
65 70 75 80
Gln Pro Glu Asp Glu Ala Ile Tyr Phe Cys Val Leu Trp Tyr Ser Asn
85 90 95
His Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 113
<211> 109
<212> PRT
<213> AB621轻链可变区()
<400> 113
Glu Leu Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
1 5 10 15
Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Val Val Thr Thr Ser
20 25 30
Asn His Ala Asn Trp Val Gln Glu Lys Pro Asp His Leu Phe Thr Gly
35 40 45
Leu Ile Gly Ala Thr Asn Tyr Arg Ala Pro Gly Thr Pro Ala Arg Phe
50 55 60
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val
65 70 75 80
Gln Pro Glu Asp Glu Ala Ile Tyr Phe Cys Val Leu Trp Tyr Ser Asn
85 90 95
His Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 114
<211> 109
<212> PRT
<213> AB622轻链可变区()
<400> 114
Glu Leu Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
1 5 10 15
Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Val Val Thr Thr Ser
20 25 30
Asn Tyr Ala Asn Trp Val Gln Glu Lys Pro Asp His Leu Phe Thr Gly
35 40 45
Leu Ile Gly Ala Thr Asn His Arg Ala Pro Gly Thr Pro Ala Arg Phe
50 55 60
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val
65 70 75 80
Gln Pro Glu Asp Glu Ala Ile Tyr Phe Cys Val Leu Trp Tyr Ser Asn
85 90 95
His Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 115
<211> 125
<212> PRT
<213> AB623重链可变区()
<400> 115
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr
20 25 30
Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Arg Ser Lys Ile Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp
50 55 60
Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Met Tyr
85 90 95
Tyr Cys Val Arg His Asp Asn His Tyr Gly Ser Thr Tyr Ser Trp Phe
100 105 110
Ala Asp Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 116
<211> 125
<212> PRT
<213> AB624重链可变区()
<400> 116
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr
20 25 30
Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Arg Ser Lys Ile Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp
50 55 60
Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Met Tyr
85 90 95
Tyr Cys Val Arg His Asp Asn Phe His Gly Ser Thr Tyr Ser Trp Phe
100 105 110
Ala Asp Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 117
<211> 125
<212> PRT
<213> AB625重链可变区()
<400> 117
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr
20 25 30
Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Arg Ser Lys Ile Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp
50 55 60
Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Met Tyr
85 90 95
Tyr Cys Val Arg His Asp Asn Phe Tyr Gly Ser Thr His Ser Trp Phe
100 105 110
Ala Asp Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 118
<211> 125
<212> PRT
<213> AB626重链可变区()
<400> 118
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr
20 25 30
Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Arg Ser Lys Ile Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp
50 55 60
Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Met Tyr
85 90 95
Tyr Cys Val Arg His Asp Asn Phe Tyr Gly Ser Thr Tyr Ser His Phe
100 105 110
Ala Asp Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 119
<211> 125
<212> PRT
<213> AB627重链可变区()
<400> 119
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr
20 25 30
Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Arg Ser Lys Ile Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp
50 55 60
Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Met Tyr
85 90 95
Tyr Cys Val Arg His Asp Asn Phe Tyr Gly Ser Thr Tyr Ser Trp His
100 105 110
Ala Asp Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
Claims (20)
1.一种能够特异性结合CD3的抗体或其抗原结合片段,其中,所述抗体或其抗原结合片段包含的重链可变区(VH)包含至少一个、两个或三个选自下组的互补决定区(CDR):
(i)CDR-H1,其具有如SEQ ID NO:7、13、18、24、29、35、85、86、87或88所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;
(ii)CDR-H2,其具有如SEQ ID NO:8、14、19、25、30、36、51、55或57所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;和
(iii)CDR-H3,其具有如SEQ ID NO:9、15、20、26、31、37、52、56、96、97、98、99、100、101、102、103、104或105所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;
和/或,其包含的轻链可变区(VL)包含至少一个、两个或三个选自下组的互补决定区(CDR):
(iv)CDR-L1,其具有如SEQ ID NO:10、16、21、27、32、38、50、53、93或94所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;
(v)CDR-L2,其具有如SEQ ID NO:11、17、22、28、33、39、54、58、89、90、91、92或95所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;和
(vi)CDR-L3,其具有如SEQ ID NO:12、23或34所示的序列,或者与上述序列相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;
优选的,(i)-(vi)任一项中所述的置换为保守置换。
2.如权利要求1所述抗体或其抗原结合片段,其特征在于,所述抗体或其抗原结合片段包含3个VH可变区CDR和3个VL可变区CDR,其选自下组:
(1)其CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2和CDR-L3分别具有如SEQ ID NO:7、8、9、10、11、12所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;
(2)其CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2和CDR-L3分别具有如SEQ ID NO:7、51、52、53、54、12所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;
(3)其CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2和CDR-L3分别具有如SEQ ID NO:7、51、52、10、11、12所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;
(4)其CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2和CDR-L3分别具有如SEQ ID NO:13、14、15、16、17、12所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;
(5)其CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2和CDR-L3分别具有如SEQ ID NO:13、55、56、16、17、12所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;
(6)其CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2和CDR-L3分别具有如SEQ ID NO:18、19、20、21、22、23所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;
(7)其CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2和CDR-L3分别具有如SEQ ID NO:18、57、20、21、58、23所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;
(8)其CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2和CDR-L3分别具有如SEQ ID NO:24、25、26、27、28、23所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;
(9)其CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2和CDR-L3分别具有如SEQ ID NO:29、30、31、32、33、34所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;
(10)其CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2和CDR-L3分别具有如SEQ ID NO:29、30、31、50、33、34所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;
(11)其CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2和CDR-L3分别具有如SEQ ID NO:35、36、37、38、39、34所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;
(12)其CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2和CDR-L3分别具有如SEQ ID NO:87、57、20、21、58、23所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;
(13)其CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2和CDR-L3分别具有如SEQ ID NO:18、57、20、21、89、23所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;
(14)其CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2和CDR-L3分别具有如SEQ ID NO:18、57、20、21、91、23所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;
(15)其CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2和CDR-L3分别具有如SEQ ID NO:18、57、20、93、58、23所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;
(16)其CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2和CDR-L3分别具有如SEQ ID NO:18、57、20、21、95、23所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;
(17)其CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2和CDR-L3分别具有如SEQ ID NO:18、57、96、21、58、23所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;
(18)其CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2和CDR-L3分别具有如SEQ ID NO:18、57、98、21、58、23所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;
(19)其CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2和CDR-L3分别具有如SEQ ID NO:18、57、100、21、58、23所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;
(20)其CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2和CDR-L3分别具有如SEQ ID NO:18、57、102、21、58、23所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;
(21)其CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2和CDR-L3分别具有如SEQ ID NO:18、57、104、21、58、23所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;
(22)其CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2和CDR-L3分别具有如SEQ ID NO:85、25、26、27、28、23所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;
(23)其CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2和CDR-L3分别具有如SEQ ID NO:86、25、26、27、28、23所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;
(24)其CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2和CDR-L3分别具有如SEQ ID NO:88、25、26、27、28、23所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;
(25)其CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2和CDR-L3分别具有如SEQ ID NO:24、25、26、27、90、23所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;
(26)其CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2和CDR-L3分别具有如SEQ ID NO:24、25、26、27、92、23所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;
(27)其CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2和CDR-L3分别具有如SEQ ID NO:86、25、26、27、92、23所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;
(28)其CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2和CDR-L3分别具有如SEQ ID NO:24、25、26、94、28、23所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;
(29)其CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2和CDR-L3分别具有如SEQ ID NO:24、25、97、27、28、23所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;
(30)其CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2和CDR-L3分别具有如SEQ ID NO:24、25、99、27、28、23所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;
(31)其CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2和CDR-L3分别具有如SEQ ID NO:24、25、101、27、28、23所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;
(32)其CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2和CDR-L3分别具有如SEQ ID NO:24、25、103、27、28、23所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列;
(33)其CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2和CDR-L3分别具有如SEQ ID NO:24、25、105、27、28、23所示的序列,或者与上述序列中的任何相比具有一个或几个氨基酸置换、缺失或添加(例如1个,2个或3个置换、缺失或添加)的序列。
3.如权利要求2所述抗体或其抗原结合片段,其特征在于,所述抗体或其抗原结合片段为鼠源的或嵌合的,其重链可变区包含鼠源IgG1、IgG2、IgG3或其变体的重链FR区;和其轻链可变区包含鼠源κ、λ链或其变体的轻链FR区。
4.如权利要求3所述抗体或其抗原结合片段,其特征在于,所述抗体或其抗原结合片段包含选自下组的VH和VL序列:
(i)VH结构域包含如SEQ ID NO:1所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列;和其VL结构域包含如SEQ ID NO:2所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列;
(ii)VH结构域包含如SEQ ID NO:3所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列;和其VL结构域包含如SEQ ID NO:4所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列;
(iii)VH结构域包含如SEQ ID NO:5所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列;和其VL结构域包含如SEQ ID NO:6所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列。
5.如权利要求2所述抗体或其抗原结合片段,其特征在于,所述抗体或其抗原结合片段为人源化的。
6.如权利要求5所述抗体或其抗原结合片段,其特征在于,所述抗体或其抗原结合片段包含选自下组的VH和VL序列:
(1)VH结构域包含如SEQ ID NO:40所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列;和其VL结构域包含如SEQ ID NO:41所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列;
(2)VH结构域包含如SEQ ID NO:42所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列;和其VL结构域包含如SEQ ID NO:43所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列;
(3)VH结构域包含如SEQ ID NO:44所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列;和其VL结构域包含如SEQ ID NO:45所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列;
(4)VH结构域包含如SEQ ID NO:46所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列;和其VL结构域包含如SEQ ID NO:47所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列;
(5)VH结构域包含如SEQ ID NO:48所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列;和其VL结构域包含如SEQ ID NO:49所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列;
(6)VH结构域包含如SEQ ID NO:106所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列;和其VL结构域包含如SEQ ID NO:49所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列;
(7)VH结构域包含如SEQ ID NO:107所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列;和其VL结构域包含如SEQ ID NO:49所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列;
(8)VH结构域包含如SEQ ID NO:108所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列;和其VL结构域包含如SEQ ID NO:49所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列;
(9)VH结构域包含如SEQ ID NO:48所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列;和其VL结构域包含如SEQ ID NO:109所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列;
(10)VH结构域包含如SEQ ID NO:48所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列;和其VL结构域包含如SEQ ID NO:110所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列;
(11)VH结构域包含如SEQ ID NO:111所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列;和其VL结构域包含如SEQ ID NO:112所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列;
(12)VH结构域包含如SEQ ID NO:48所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列;和其VL结构域包含如SEQ ID NO:113所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列;
(13)VH结构域包含如SEQ ID NO:48所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列;和其VL结构域包含如SEQ ID NO:114所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列;
(14)VH结构域包含如SEQ ID NO:115所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列;和其VL结构域包含如SEQ ID NO:49所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列;
(15)VH结构域包含如SEQ ID NO:116所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列;和其VL结构域包含如SEQ ID NO:49所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列;
(16)VH结构域包含如SEQ ID NO:117所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列;和其VL结构域包含如SEQ ID NO:49所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列;
(17)VH结构域包含如SEQ ID NO:118所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列;和其VL结构域包含如SEQ ID NO:49所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列;
(18)VH结构域包含如SEQ ID NO:119所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列;和其VL结构域包含如SEQ ID NO:49所示的氨基酸序列,或与上述序列基本上相同(例如至少80%、85%、90%、92%、95%、97%、98%、99%或更高同一性或具有一个或更多个氨基酸取代(例如保守性取代))的序列。
7.如权利要求6所述抗体,其特征在于,所述抗体包含来源于人免疫球蛋白的重链恒定区和轻链恒定区;较优选地,所述重链恒定区选自人IgG1、IgG2、IgG3、IgG4、IgM、IgA1、IgA2、IgD和IgE的重链恒定区;更优选地,所述重链恒定区选自人IgG1、IgG2、IgG3和IgG4的重链恒定区;并且,所述重链恒定区具有天然序列或与其所源自的天然序列相比具有一个或多个氨基酸的置换、缺失或添加的序列;和所述轻链恒定区优选如SEQ ID NO:59所示的人κappa链的恒定区。
8.如权利要求7所述抗体,其特征在于,所述抗体包含的重链恒定区选自下组:
(i)如SEQ ID NO:60所示的野生型人IgG1的重链恒定区;
(ii)如SEQ ID NO:61所示的含有Asn297Ala突变的人IgG1的重链恒定区;
(iii)如SEQ ID NO:62所示的含有Leu234Ala、Leu235Ala突变的人IgG1的重链恒定区;
(iv)如SEQ ID NO:63所示的野生型人IgG4的重链恒定区;
(v)如SEQ ID NO:64所示的含有S228P突变的人IgG4的重链恒定区。
9.如权利要求7或8所述的抗体,其特征在于,所述抗体包含选自具有下列的全长氨基酸序列:
(i)其重链具有如SEQ ID NO:65所示的氨基酸序列,和其轻链具有如SEQ ID NO:66所示的氨基酸序列;或与上述序列中的任何相比具有一个或几个置换、缺失或添加(例如1个,2个,3个,4个或5个置换、缺失或添加)的序列;或与上述序列中的任何相比具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%、或更高同一性的序列;
(ii)其重链具有如SEQ ID NO:69所示的氨基酸序列,和其轻链具有如SEQ ID NO:70所示的氨基酸序列;或与上述序列中的任何相比具有一个或几个置换、缺失或添加(例如1个,2个,3个,4个或5个置换、缺失或添加)的序列;或与上述序列中的任何相比具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%、或更高同一性的序列;
(iii)其重链具有如SEQ ID NO:73所示的氨基酸序列,和其轻链具有如SEQ ID NO:74所示的氨基酸序列;或与上述序列中的任何相比具有一个或几个置换、缺失或添加(例如1个,2个,3个,4个或5个置换、缺失或添加)的序列;或与上述序列中的任何相比具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%、或更高同一性的序列;
(iv)其重链具有如SEQ ID NO:77所示的氨基酸序列,和其轻链具有如SEQ ID NO:78所示的氨基酸序列;或与上述序列中的任何相比具有一个或几个置换、缺失或添加(例如1个,2个,3个,4个或5个置换、缺失或添加)的序列;或与上述序列中的任何相比具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%、或更高同一性的序列;
(v)其重链具有如SEQ ID NO:81所示的氨基酸序列,和其轻链具有如SEQ ID NO:82所示的氨基酸序列;或与上述序列中的任何相比具有一个或几个置换、缺失或添加(例如1个,2个,3个,4个或5个置换、缺失或添加)的序列;或与上述序列中的任何相比具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、至少99%、或更高同一性的序列。
10.编码如权利要求1-9任一项所述抗体或其抗原结合片段的DNA分子。
11.如权利要求10所述的DNA分子,其特征在于,编码所述抗体重链的DNA分子具有如SEQ ID NO:67、71、75、79或83所示的核苷酸序列,和编码所述抗体轻链的DNA分子具有如SEQ ID NO:68、72、76、80或84所示的核苷酸序列。
12.一种载体,其包含权利要求10或11所述的DNA分子。
13.包含如权利要求12所述载体的宿主细胞;所述宿主细胞包含原核细胞、酵母或哺乳动物细胞。
14.一种药物组合物,所述组合物包含如权利要求1-9任一项所述的抗体或其抗原结合片段以及可药用赋形剂、载体或稀释剂。
15.制备如权利要求1-9任一项所述抗体或其抗原结合片段的方法,其包括:(a)获得抗体或其抗原结合片段的基因,构建抗体或其抗原结合片段的表达载体;(b)通过基因工程方法将上述表达载体转染到宿主细胞中;(c)在允许产生所述抗体或其抗原结合片段的条件下培养上述宿主细胞;(d)分离、纯化产生的所述抗体或其抗原结合片段;
其中,步骤(a)中所述表达载体选自质粒、细菌和病毒中的一种或多种,优选地,所述表达载体为pcDNA3.1载体;
其中,步骤(b)通过基因工程方法将所构建的载体转染入宿主细胞中,所述宿主细胞包含原核细胞、酵母或哺乳动物细胞,如CHO细胞、NS0细胞或其它哺乳动物细胞;
其中,步骤(d)通过常规的免疫球蛋白纯化方法,包含蛋白质A亲和层析和离子交换、疏水层析或分子筛方法分离、纯化所述抗体或其抗原结合片段。
16.如权利要求1-9任一项所述抗体或其抗原结合片段在制备药物中的用途,所述药物用于制备预防和/或***、器官移植排斥反应或自身免疫性疾病的药物或制剂。
17.如权利要求16所述的用途,其特征在于,所述癌症选自实体肿瘤、血液肿瘤(例如,白血病、淋巴瘤、骨髓瘤,例如,多发性骨髓瘤)和转移性病灶;例如,包括但不限于肺癌、黑色素瘤、肾癌、肝癌、骨髓瘤、乳腺癌、结直肠癌、白血病或癌症的转移性病灶;所述器官移植排斥反应选自与细胞、组织或诸如肾、肝和心脏移植的器官移植相关的非正常免疫应答,包括但不限于移植物抗宿主疾病和同种异体移植排斥;所述自身免疫性疾病选自类风湿性关节炎、青少年类风湿性关节炎、银屑病、***性红斑狼疮、原发性胆汁性肝硬化、自身免疫性溶血性贫血、再生障碍性贫血、自身免疫性血小板减少性紫癜、特发性血小板减少性紫癜、糖尿病、脑脊髓炎、格雷夫斯病、重症肌无力、韦格纳氏病、自生免疫肝炎和多发性硬化。
18.包含如权利要求1-9任一项所述抗体或其抗原结合片段的双特异性分子,优选的所述双特异性抗体还包括但不限于针对以下分子的抗体:CD19、CD20、CD22、CD25、CD30、CD33、CD38、CD39、CD40、CD47、CD52、CD73、CD74、CD123、CD133、CD138、BCMA、CA125、CEA、CS1、DLL3、DLL4、EGFR、EpCAM、FLT3、gpA33、GPC-3、Her2、MEGE-A3、NYESO1、PSMA、TAG-72、CIX、叶酸盐结合蛋白、GD2、GD3、GM2、VEGF、VEGFR2、VEGFR3、钙黏素(Cadherin)、整合素(Integrin)、间皮素(Mesothelin)、Claudin18、αVβ3、α5β1、ERBB3、c-MET、IGF1R、EPHA3、TRAILR1、TRAILR2、RANKL、B7蛋白家族、粘蛋白家族(Mucin)、FAP和肌腱蛋白(Tenascin)。
19.一种用于在受试者(例如人)中预防和/或***、器官移植排斥反应或自身免疫性疾病的方法,所述方法包括向有此需要的受试者施用有效量的权利要求1-9任一项所述的抗体或其抗原结合片段或权利要求14所述的药物组合物。
20.一种诊断性或治疗性试剂盒,其包括权利要求1-9任一项所述的抗体或其抗原结合片段和使用说明书。
Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202110752589.0A CN115558023A (zh) | 2021-07-02 | 2021-07-02 | 抗cd3抗体及其用途 |
CN202280046573.0A CN117616047A (zh) | 2021-07-02 | 2022-06-17 | 抗cd3抗体及其用途 |
CA3224398A CA3224398A1 (en) | 2021-07-02 | 2022-06-17 | Anti-cd3 antibody and use thereof |
PCT/CN2022/099345 WO2023273914A1 (zh) | 2021-07-02 | 2022-06-17 | 抗cd3抗体及其用途 |
KR1020247002630A KR20240023653A (ko) | 2021-07-02 | 2022-06-17 | 항-cd3 항체 및 그의 용도 |
AU2022301381A AU2022301381A1 (en) | 2021-07-02 | 2022-06-17 | Anti-cd3 antibody and use thereof |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202110752589.0A CN115558023A (zh) | 2021-07-02 | 2021-07-02 | 抗cd3抗体及其用途 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN115558023A true CN115558023A (zh) | 2023-01-03 |
Family
ID=84689713
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202110752589.0A Pending CN115558023A (zh) | 2021-07-02 | 2021-07-02 | 抗cd3抗体及其用途 |
CN202280046573.0A Pending CN117616047A (zh) | 2021-07-02 | 2022-06-17 | 抗cd3抗体及其用途 |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202280046573.0A Pending CN117616047A (zh) | 2021-07-02 | 2022-06-17 | 抗cd3抗体及其用途 |
Country Status (5)
Country | Link |
---|---|
KR (1) | KR20240023653A (zh) |
CN (2) | CN115558023A (zh) |
AU (1) | AU2022301381A1 (zh) |
CA (1) | CA3224398A1 (zh) |
WO (1) | WO2023273914A1 (zh) |
Family Cites Families (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4816567A (en) | 1983-04-08 | 1989-03-28 | Genentech, Inc. | Recombinant immunoglobin preparations |
US4818679A (en) | 1985-02-19 | 1989-04-04 | The Trustees Of Columbia University In The City Of New York | Method for recovering mutant cells |
US4946778A (en) | 1987-09-21 | 1990-08-07 | Genex Corporation | Single polypeptide chain binding molecules |
US5260203A (en) | 1986-09-02 | 1993-11-09 | Enzon, Inc. | Single polypeptide chain binding molecules |
EP0281604B1 (en) | 1986-09-02 | 1993-03-31 | Enzon Labs Inc. | Single polypeptide chain binding molecules |
EP0307434B2 (en) | 1987-03-18 | 1998-07-29 | Scotgen Biopharmaceuticals, Inc. | Altered antibodies |
GB8905669D0 (en) | 1989-03-13 | 1989-04-26 | Celltech Ltd | Modified antibodies |
US10465006B2 (en) * | 2013-07-05 | 2019-11-05 | Genmab A/S | Humanized or chimeric CD3 antibodies |
DK3083689T3 (da) * | 2013-12-17 | 2020-08-03 | Genentech Inc | Anti-CD3-antistoffer og fremgangsmåder til anvendelse |
WO2016204966A1 (en) * | 2015-06-16 | 2016-12-22 | Genentech, Inc. | Anti-cd3 antibodies and methods of use |
EP3684806A4 (en) * | 2017-09-21 | 2021-09-22 | Wuxi Biologics (Cayman) Inc. | NEW ANTI-CD3EPSILON ANTIBODIES |
WO2019175658A1 (en) * | 2018-03-14 | 2019-09-19 | Novimmune Sa | Anti-cd3 epsilon antibodies and methods of use thereof |
-
2021
- 2021-07-02 CN CN202110752589.0A patent/CN115558023A/zh active Pending
-
2022
- 2022-06-17 AU AU2022301381A patent/AU2022301381A1/en active Pending
- 2022-06-17 KR KR1020247002630A patent/KR20240023653A/ko unknown
- 2022-06-17 CN CN202280046573.0A patent/CN117616047A/zh active Pending
- 2022-06-17 WO PCT/CN2022/099345 patent/WO2023273914A1/zh active Application Filing
- 2022-06-17 CA CA3224398A patent/CA3224398A1/en active Pending
Also Published As
Publication number | Publication date |
---|---|
KR20240023653A (ko) | 2024-02-22 |
CA3224398A1 (en) | 2023-01-05 |
AU2022301381A1 (en) | 2024-02-01 |
WO2023273914A1 (zh) | 2023-01-05 |
CN117616047A (zh) | 2024-02-27 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN111138542B (zh) | 双特异性抗体及其用途 | |
JP7287963B2 (ja) | 抗tigit抗体並びに治療剤及び診断剤としてのその使用 | |
JP7089470B2 (ja) | 抗体およびその使用方法 | |
RU2753493C2 (ru) | Анти-ох40 антитела и их применение | |
WO2022042690A1 (zh) | Ccr8抗体及其应用 | |
JP2023011774A (ja) | 抗gprc5d抗体、gprc5dとcd3を結合する二重特異性抗原結合分子、及びその使用 | |
TWI754800B (zh) | 新型抗ox40/pd-l1雙特異性抗體分子、新型抗vegf/gitr雙特異性抗體分子及其用途 | |
US10618962B2 (en) | Anti-CTLA4 antibodies | |
TW201806972A (zh) | 雙特異性結合蛋白 | |
JP2021524249A (ja) | 抗cd3抗体及びその使用 | |
KR20160006168A (ko) | 인간화 항-cd134(ox40) 항체 및 이의 용도 | |
KR20210076918A (ko) | 4-1bb 및 종양-관련 항원에 결합하는 항체 작제물 및 이의 용도 | |
TW202235104A (zh) | 雙功能分子 | |
KR20230070238A (ko) | 4-1bb를 표적으로 하는 단일 도메인 항체, 이의 융합 단백질, 이의 약제학적 조성물 및 용도 | |
CN115768482A (zh) | 结合siglec-3/cd33的材料和方法 | |
CN115558023A (zh) | 抗cd3抗体及其用途 | |
WO2023273913A1 (zh) | 抗b7-h3单克隆抗体及其用途 | |
WO2022247826A1 (zh) | 靶向pd-l1和cd73的特异性结合蛋白 | |
TW202305007A (zh) | 靶向pd-l1和cd73的特異性結合蛋白 | |
EA045935B1 (ru) | Антитела к cd3 и их применение | |
EA042181B1 (ru) | Анти-tim-3 антитела и их применение |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication |