CN111253487A - Cd19抗体及其应用 - Google Patents
Cd19抗体及其应用 Download PDFInfo
- Publication number
- CN111253487A CN111253487A CN201911215734.0A CN201911215734A CN111253487A CN 111253487 A CN111253487 A CN 111253487A CN 201911215734 A CN201911215734 A CN 201911215734A CN 111253487 A CN111253487 A CN 111253487A
- Authority
- CN
- China
- Prior art keywords
- antibody
- seq
- amino acid
- antigen
- binding fragment
- 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.)
- Granted
Links
- 102100024222 B-lymphocyte antigen CD19 Human genes 0.000 title claims abstract description 97
- 101000980825 Homo sapiens B-lymphocyte antigen CD19 Proteins 0.000 title claims abstract description 96
- 239000000427 antigen Substances 0.000 claims abstract description 111
- 102000036639 antigens Human genes 0.000 claims abstract description 110
- 108091007433 antigens Proteins 0.000 claims abstract description 110
- 239000012634 fragment Substances 0.000 claims abstract description 104
- 238000004519 manufacturing process Methods 0.000 claims abstract description 11
- 239000003814 drug Substances 0.000 claims abstract description 7
- 125000003275 alpha amino acid group Chemical group 0.000 claims description 209
- 210000004027 cell Anatomy 0.000 claims description 140
- 102000037865 fusion proteins Human genes 0.000 claims description 53
- 108020001507 fusion proteins Proteins 0.000 claims description 53
- 239000013598 vector Substances 0.000 claims description 45
- 150000007523 nucleic acids Chemical class 0.000 claims description 41
- 102000039446 nucleic acids Human genes 0.000 claims description 39
- 108020004707 nucleic acids Proteins 0.000 claims description 39
- 108010019670 Chimeric Antigen Receptors Proteins 0.000 claims description 36
- 108090000623 proteins and genes Proteins 0.000 claims description 35
- 206010028980 Neoplasm Diseases 0.000 claims description 32
- 238000000034 method Methods 0.000 claims description 29
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 27
- 101000851370 Homo sapiens Tumor necrosis factor receptor superfamily member 9 Proteins 0.000 claims description 21
- 102100036856 Tumor necrosis factor receptor superfamily member 9 Human genes 0.000 claims description 21
- 102100022153 Tumor necrosis factor receptor superfamily member 4 Human genes 0.000 claims description 19
- 229920001184 polypeptide Polymers 0.000 claims description 19
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 19
- 102000004169 proteins and genes Human genes 0.000 claims description 19
- 101710165473 Tumor necrosis factor receptor superfamily member 4 Proteins 0.000 claims description 16
- 210000003719 b-lymphocyte Anatomy 0.000 claims description 14
- 208000023275 Autoimmune disease Diseases 0.000 claims description 13
- 241001529936 Murinae Species 0.000 claims description 13
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 13
- 230000004068 intracellular signaling Effects 0.000 claims description 12
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 11
- 150000001413 amino acids Chemical group 0.000 claims description 9
- 201000010099 disease Diseases 0.000 claims description 9
- 208000032839 leukemia Diseases 0.000 claims description 9
- 101000914514 Homo sapiens T-cell-specific surface glycoprotein CD28 Proteins 0.000 claims description 8
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 claims description 8
- 102100027213 T-cell-specific surface glycoprotein CD28 Human genes 0.000 claims description 8
- 239000002671 adjuvant Substances 0.000 claims description 8
- 239000012528 membrane Substances 0.000 claims description 8
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 claims description 7
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 claims description 7
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 claims description 7
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 7
- -1 CD3e Proteins 0.000 claims description 6
- 206010025323 Lymphomas Diseases 0.000 claims description 6
- 208000034578 Multiple myelomas Diseases 0.000 claims description 6
- 208000007452 Plasmacytoma Diseases 0.000 claims description 6
- 206010060862 Prostate cancer Diseases 0.000 claims description 6
- 208000004346 Smoldering Multiple Myeloma Diseases 0.000 claims description 6
- 230000000139 costimulatory effect Effects 0.000 claims description 6
- 201000005202 lung cancer Diseases 0.000 claims description 6
- 208000010721 smoldering plasma cell myeloma Diseases 0.000 claims description 6
- 102100036011 T-cell surface glycoprotein CD4 Human genes 0.000 claims description 5
- 230000004071 biological effect Effects 0.000 claims description 5
- 201000000050 myeloid neoplasm Diseases 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- 206010006187 Breast cancer Diseases 0.000 claims description 4
- 208000026310 Breast neoplasm Diseases 0.000 claims description 4
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 4
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 4
- 208000017604 Hodgkin disease Diseases 0.000 claims description 4
- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 4
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 4
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 4
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 4
- 201000010881 cervical cancer Diseases 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 claims description 4
- 238000012258 culturing Methods 0.000 claims description 4
- 208000035475 disorder Diseases 0.000 claims description 4
- 201000009277 hairy cell leukemia Diseases 0.000 claims description 4
- 230000002401 inhibitory effect Effects 0.000 claims description 4
- 208000014018 liver neoplasm Diseases 0.000 claims description 4
- 201000006417 multiple sclerosis Diseases 0.000 claims description 4
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 4
- 201000002314 small intestine cancer Diseases 0.000 claims description 4
- 208000025324 B-cell acute lymphoblastic leukemia Diseases 0.000 claims description 3
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 claims description 3
- 102100038080 B-cell receptor CD22 Human genes 0.000 claims description 3
- 206010005949 Bone cancer Diseases 0.000 claims description 3
- 208000018084 Bone neoplasm Diseases 0.000 claims description 3
- 208000011691 Burkitt lymphomas Diseases 0.000 claims description 3
- 102100037904 CD9 antigen Human genes 0.000 claims description 3
- 206010009944 Colon cancer Diseases 0.000 claims description 3
- 102100026122 High affinity immunoglobulin gamma Fc receptor I Human genes 0.000 claims description 3
- 101000884305 Homo sapiens B-cell receptor CD22 Proteins 0.000 claims description 3
- 101100383038 Homo sapiens CD19 gene Proteins 0.000 claims description 3
- 101000738354 Homo sapiens CD9 antigen Proteins 0.000 claims description 3
- 101000913074 Homo sapiens High affinity immunoglobulin gamma Fc receptor I Proteins 0.000 claims description 3
- 101000777628 Homo sapiens Leukocyte antigen CD37 Proteins 0.000 claims description 3
- 101000917858 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor III-A Proteins 0.000 claims description 3
- 101000917839 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor III-B Proteins 0.000 claims description 3
- 101000934338 Homo sapiens Myeloid cell surface antigen CD33 Proteins 0.000 claims description 3
- 101000738771 Homo sapiens Receptor-type tyrosine-protein phosphatase C Proteins 0.000 claims description 3
- 101000716102 Homo sapiens T-cell surface glycoprotein CD4 Proteins 0.000 claims description 3
- 101000934341 Homo sapiens T-cell surface glycoprotein CD5 Proteins 0.000 claims description 3
- 101000946843 Homo sapiens T-cell surface glycoprotein CD8 alpha chain Proteins 0.000 claims description 3
- 101000914484 Homo sapiens T-lymphocyte activation antigen CD80 Proteins 0.000 claims description 3
- 206010020631 Hypergammaglobulinaemia benign monoclonal Diseases 0.000 claims description 3
- 102100031586 Leukocyte antigen CD37 Human genes 0.000 claims description 3
- 102100029185 Low affinity immunoglobulin gamma Fc region receptor III-B Human genes 0.000 claims description 3
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 3
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 claims description 3
- 208000028018 Lymphocytic leukaemia Diseases 0.000 claims description 3
- 206010060880 Monoclonal gammopathy Diseases 0.000 claims description 3
- 102100025243 Myeloid cell surface antigen CD33 Human genes 0.000 claims description 3
- 208000002774 Paraproteinemias Diseases 0.000 claims description 3
- 102100037422 Receptor-type tyrosine-protein phosphatase C Human genes 0.000 claims description 3
- 108091008874 T cell receptors Proteins 0.000 claims description 3
- 102000016266 T-Cell Antigen Receptors Human genes 0.000 claims description 3
- 102100025244 T-cell surface glycoprotein CD5 Human genes 0.000 claims description 3
- 102100034922 T-cell surface glycoprotein CD8 alpha chain Human genes 0.000 claims description 3
- 102100027222 T-lymphocyte activation antigen CD80 Human genes 0.000 claims description 3
- 208000033559 Waldenström macroglobulinemia Diseases 0.000 claims description 3
- 208000024447 adrenal gland neoplasm Diseases 0.000 claims description 3
- 230000001684 chronic effect Effects 0.000 claims description 3
- 206010017758 gastric cancer Diseases 0.000 claims description 3
- 238000003306 harvesting Methods 0.000 claims description 3
- 201000011061 large intestine cancer Diseases 0.000 claims description 3
- 201000007270 liver cancer Diseases 0.000 claims description 3
- 208000020816 lung neoplasm Diseases 0.000 claims description 3
- 208000003747 lymphoid leukemia Diseases 0.000 claims description 3
- 201000000564 macroglobulinemia Diseases 0.000 claims description 3
- 201000005328 monoclonal gammopathy of uncertain significance Diseases 0.000 claims description 3
- 239000002243 precursor Substances 0.000 claims description 3
- 230000002265 prevention Effects 0.000 claims description 3
- 201000011549 stomach cancer Diseases 0.000 claims description 3
- 102100027207 CD27 antigen Human genes 0.000 claims description 2
- 101000914511 Homo sapiens CD27 antigen Proteins 0.000 claims description 2
- 239000002773 nucleotide Substances 0.000 description 46
- 125000003729 nucleotide group Chemical group 0.000 description 46
- 238000001514 detection method Methods 0.000 description 44
- 108020004414 DNA Proteins 0.000 description 22
- 238000003556 assay Methods 0.000 description 17
- 239000000243 solution Substances 0.000 description 17
- 238000012360 testing method Methods 0.000 description 17
- 238000002649 immunization Methods 0.000 description 13
- 230000003053 immunization Effects 0.000 description 13
- 108010075254 C-Peptide Proteins 0.000 description 11
- 108091007741 Chimeric antigen receptor T cells Proteins 0.000 description 11
- SOEGEPHNZOISMT-BYPYZUCNSA-N Gly-Ser-Gly Chemical compound NCC(=O)N[C@@H](CO)C(=O)NCC(O)=O SOEGEPHNZOISMT-BYPYZUCNSA-N 0.000 description 11
- 239000000203 mixture Substances 0.000 description 11
- 108010047041 Complementarity Determining Regions Proteins 0.000 description 10
- 238000002965 ELISA Methods 0.000 description 10
- 210000001744 T-lymphocyte Anatomy 0.000 description 10
- 230000000694 effects Effects 0.000 description 10
- 230000006870 function Effects 0.000 description 10
- 108010086434 alanyl-seryl-glycine Proteins 0.000 description 9
- 108010078144 glutaminyl-glycine Proteins 0.000 description 9
- 108010089804 glycyl-threonine Proteins 0.000 description 9
- 241000283707 Capra Species 0.000 description 8
- 108091028043 Nucleic acid sequence Proteins 0.000 description 8
- 238000010790 dilution Methods 0.000 description 8
- 239000012895 dilution Substances 0.000 description 8
- 230000004927 fusion Effects 0.000 description 8
- XKUKSGPZAADMRA-UHFFFAOYSA-N glycyl-glycyl-glycine Natural products NCC(=O)NCC(=O)NCC(O)=O XKUKSGPZAADMRA-UHFFFAOYSA-N 0.000 description 8
- 238000011534 incubation Methods 0.000 description 8
- 239000013612 plasmid Substances 0.000 description 8
- 108010026333 seryl-proline Proteins 0.000 description 8
- 239000006228 supernatant Substances 0.000 description 8
- 238000005406 washing Methods 0.000 description 8
- 108010077245 asparaginyl-proline Proteins 0.000 description 7
- 239000000872 buffer Substances 0.000 description 7
- 239000006285 cell suspension Substances 0.000 description 7
- 238000005119 centrifugation Methods 0.000 description 7
- 108010073969 valyllysine Proteins 0.000 description 7
- HKZAAJSTFUZYTO-LURJTMIESA-N (2s)-2-[[2-[[2-[[2-[(2-aminoacetyl)amino]acetyl]amino]acetyl]amino]acetyl]amino]-3-hydroxypropanoic acid Chemical compound NCC(=O)NCC(=O)NCC(=O)NCC(=O)N[C@@H](CO)C(O)=O HKZAAJSTFUZYTO-LURJTMIESA-N 0.000 description 6
- 101100450694 Arabidopsis thaliana HFR1 gene Proteins 0.000 description 6
- GIVATXIGCXFQQA-FXQIFTODSA-N Arg-Ala-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCN=C(N)N GIVATXIGCXFQQA-FXQIFTODSA-N 0.000 description 6
- 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 6
- 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 6
- WSPQHZOMTFFWGH-XGEHTFHBSA-N Met-Thr-Cys Chemical compound CSCC[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(O)=O WSPQHZOMTFFWGH-XGEHTFHBSA-N 0.000 description 6
- SPLBRAKYXGOFSO-UNQGMJICSA-N Pro-Phe-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)NC(=O)[C@@H]2CCCN2)O SPLBRAKYXGOFSO-UNQGMJICSA-N 0.000 description 6
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 6
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 6
- HBOABDXGTMMDSE-GUBZILKMSA-N Ser-Arg-Val Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(O)=O HBOABDXGTMMDSE-GUBZILKMSA-N 0.000 description 6
- 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 6
- ANHVRCNNGJMJNG-BZSNNMDCSA-N Tyr-Tyr-Cys Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CC2=CC=C(C=C2)O)C(=O)N[C@@H](CS)C(=O)O)N)O ANHVRCNNGJMJNG-BZSNNMDCSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- UQLDLKMNUJERMK-UHFFFAOYSA-L di(octadecanoyloxy)lead Chemical compound [Pb+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O UQLDLKMNUJERMK-UHFFFAOYSA-L 0.000 description 6
- 238000001962 electrophoresis Methods 0.000 description 6
- 108010067216 glycyl-glycyl-glycine Proteins 0.000 description 6
- 210000004408 hybridoma Anatomy 0.000 description 6
- 230000002147 killing effect Effects 0.000 description 6
- 210000001519 tissue Anatomy 0.000 description 6
- 238000013519 translation Methods 0.000 description 6
- IOFVWPYSRSCWHI-JXUBOQSCSA-N Ala-Thr-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](C)N IOFVWPYSRSCWHI-JXUBOQSCSA-N 0.000 description 5
- QFJPFPCSXOXMKI-BPUTZDHNSA-N Gln-Gln-Trp Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CCC(=O)N)N QFJPFPCSXOXMKI-BPUTZDHNSA-N 0.000 description 5
- 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 5
- 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 5
- 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 5
- 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 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
- WLJPJRGQRNCIQS-ZLUOBGJFSA-N Ser-Ser-Asn Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O WLJPJRGQRNCIQS-ZLUOBGJFSA-N 0.000 description 5
- 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 5
- 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 5
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 5
- 108010092854 aspartyllysine Proteins 0.000 description 5
- 201000011510 cancer Diseases 0.000 description 5
- 238000004113 cell culture Methods 0.000 description 5
- 239000000306 component Substances 0.000 description 5
- MHMNJMPURVTYEJ-UHFFFAOYSA-N fluorescein-5-isothiocyanate Chemical compound O1C(=O)C2=CC(N=C=S)=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 MHMNJMPURVTYEJ-UHFFFAOYSA-N 0.000 description 5
- 108010050848 glycylleucine Proteins 0.000 description 5
- 239000003550 marker Substances 0.000 description 5
- 239000013642 negative control Substances 0.000 description 5
- 108010051242 phenylalanylserine Proteins 0.000 description 5
- 239000013641 positive control Substances 0.000 description 5
- 238000013518 transcription Methods 0.000 description 5
- 230000035897 transcription Effects 0.000 description 5
- 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 4
- HGKHPCFTRQDHCU-IUCAKERBSA-N Arg-Pro-Gly Chemical compound NC(N)=NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O HGKHPCFTRQDHCU-IUCAKERBSA-N 0.000 description 4
- XZLLTYBONVKGLO-SDDRHHMPSA-N Gln-Lys-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(=O)N)N)C(=O)O XZLLTYBONVKGLO-SDDRHHMPSA-N 0.000 description 4
- JVZLZVJTIXVIHK-SXNHZJKMSA-N Glu-Trp-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)NC(=O)[C@H](CCC(=O)O)N JVZLZVJTIXVIHK-SXNHZJKMSA-N 0.000 description 4
- WCORRBXVISTKQL-WHFBIAKZSA-N Gly-Ser-Ser Chemical compound NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O WCORRBXVISTKQL-WHFBIAKZSA-N 0.000 description 4
- 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 4
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 4
- 108060003951 Immunoglobulin Proteins 0.000 description 4
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 4
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 4
- 241000880493 Leptailurus serval Species 0.000 description 4
- BQSLGJHIAGOZCD-CIUDSAMLSA-N Leu-Ala-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O BQSLGJHIAGOZCD-CIUDSAMLSA-N 0.000 description 4
- 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 4
- 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 4
- 241000699666 Mus <mouse, genus> Species 0.000 description 4
- BIYWZVCPZIFGPY-QWRGUYRKSA-N Phe-Gly-Ser Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)NCC(=O)N[C@@H](CO)C(O)=O BIYWZVCPZIFGPY-QWRGUYRKSA-N 0.000 description 4
- 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 4
- 108020004511 Recombinant DNA Proteins 0.000 description 4
- 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 4
- 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 4
- 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 4
- UIPXCLNLUUAMJU-JBDRJPRFSA-N Ser-Ile-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(O)=O UIPXCLNLUUAMJU-JBDRJPRFSA-N 0.000 description 4
- VVKVHAOOUGNDPJ-SRVKXCTJSA-N Ser-Tyr-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CO)C(O)=O VVKVHAOOUGNDPJ-SRVKXCTJSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- DGDCHPCRMWEOJR-FQPOAREZSA-N Thr-Ala-Tyr Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 DGDCHPCRMWEOJR-FQPOAREZSA-N 0.000 description 4
- 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 4
- 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 4
- OWFGFHQMSBTKLX-UFYCRDLUSA-N Val-Tyr-Tyr Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CC2=CC=C(C=C2)O)C(=O)O)N OWFGFHQMSBTKLX-UFYCRDLUSA-N 0.000 description 4
- ROOXNKNUYICQNP-UHFFFAOYSA-N ammonium persulfate Chemical compound [NH4+].[NH4+].[O-]S(=O)(=O)OOS([O-])(=O)=O ROOXNKNUYICQNP-UHFFFAOYSA-N 0.000 description 4
- 239000007853 buffer solution Substances 0.000 description 4
- 239000013604 expression vector Substances 0.000 description 4
- 239000012530 fluid Substances 0.000 description 4
- 108010001064 glycyl-glycyl-glycyl-glycine Proteins 0.000 description 4
- 210000002865 immune cell Anatomy 0.000 description 4
- 102000018358 immunoglobulin Human genes 0.000 description 4
- 108010057952 lysyl-phenylalanyl-lysine Proteins 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- NGWSAUQBWVWFCU-UHFFFAOYSA-N n-ethyl-2,3-dimethylbutan-2-amine Chemical compound CCNC(C)(C)C(C)C NGWSAUQBWVWFCU-UHFFFAOYSA-N 0.000 description 4
- 238000003752 polymerase chain reaction Methods 0.000 description 4
- 238000012216 screening Methods 0.000 description 4
- 238000007920 subcutaneous administration Methods 0.000 description 4
- 238000006467 substitution reaction Methods 0.000 description 4
- 238000010361 transduction Methods 0.000 description 4
- 230000026683 transduction Effects 0.000 description 4
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 3
- JBGSZRYCXBPWGX-BQBZGAKWSA-N Ala-Arg-Gly Chemical compound OC(=O)CNC(=O)[C@@H](NC(=O)[C@@H](N)C)CCCN=C(N)N JBGSZRYCXBPWGX-BQBZGAKWSA-N 0.000 description 3
- KTXKIYXZQFWJKB-VZFHVOOUSA-N Ala-Thr-Ser Chemical compound [H]N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(O)=O KTXKIYXZQFWJKB-VZFHVOOUSA-N 0.000 description 3
- KMFPQTITXUKJOV-DCAQKATOSA-N Arg-Ser-Leu Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O KMFPQTITXUKJOV-DCAQKATOSA-N 0.000 description 3
- HUZGPXBILPMCHM-IHRRRGAJSA-N Asn-Arg-Phe Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O HUZGPXBILPMCHM-IHRRRGAJSA-N 0.000 description 3
- IICZCLFBILYRCU-WHFBIAKZSA-N Asn-Gly-Asp Chemical compound [H]N[C@@H](CC(N)=O)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(O)=O IICZCLFBILYRCU-WHFBIAKZSA-N 0.000 description 3
- ZSJFGGSPCCHMNE-LAEOZQHASA-N Asp-Gln-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CC(=O)O)N ZSJFGGSPCCHMNE-LAEOZQHASA-N 0.000 description 3
- 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 3
- 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 3
- GEEXORWTBTUOHC-FXQIFTODSA-N Cys-Arg-Ser Chemical compound C(C[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CS)N)CN=C(N)N GEEXORWTBTUOHC-FXQIFTODSA-N 0.000 description 3
- ILKYYKRAULNYMS-JYJNAYRXSA-N Gln-Lys-Phe Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O ILKYYKRAULNYMS-JYJNAYRXSA-N 0.000 description 3
- PJBVXVBTTFZPHJ-GUBZILKMSA-N Glu-Leu-Asp Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)O)NC(=O)[C@H](CCC(=O)O)N PJBVXVBTTFZPHJ-GUBZILKMSA-N 0.000 description 3
- QGZSAHIZRQHCEQ-QWRGUYRKSA-N Gly-Asp-Tyr Chemical compound NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 QGZSAHIZRQHCEQ-QWRGUYRKSA-N 0.000 description 3
- INLIXXRWNUKVCF-JTQLQIEISA-N Gly-Gly-Tyr Chemical compound NCC(=O)NCC(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 INLIXXRWNUKVCF-JTQLQIEISA-N 0.000 description 3
- FFALDIDGPLUDKV-ZDLURKLDSA-N Gly-Thr-Ser Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(O)=O FFALDIDGPLUDKV-ZDLURKLDSA-N 0.000 description 3
- UIQGJYUEQDOODF-KWQFWETISA-N Gly-Tyr-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)CN)CC1=CC=C(O)C=C1 UIQGJYUEQDOODF-KWQFWETISA-N 0.000 description 3
- 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 3
- FBGXMKUWQFPHFB-JBDRJPRFSA-N Ile-Ser-Cys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)O)N FBGXMKUWQFPHFB-JBDRJPRFSA-N 0.000 description 3
- UYODHPPSCXBNCS-XUXIUFHCSA-N Ile-Val-Leu Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CC(C)C UYODHPPSCXBNCS-XUXIUFHCSA-N 0.000 description 3
- 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 3
- IRMLZWSRWSGTOP-CIUDSAMLSA-N Leu-Ser-Ala Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(O)=O IRMLZWSRWSGTOP-CIUDSAMLSA-N 0.000 description 3
- WRODMZBHNNPRLN-SRVKXCTJSA-N Lys-Leu-Ser Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O WRODMZBHNNPRLN-SRVKXCTJSA-N 0.000 description 3
- 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 3
- RMOKGALPSPOYKE-KATARQTJSA-N Lys-Thr-Ser Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(O)=O RMOKGALPSPOYKE-KATARQTJSA-N 0.000 description 3
- RIPJMCFGQHGHNP-RHYQMDGZSA-N Lys-Val-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CCCCN)N)O RIPJMCFGQHGHNP-RHYQMDGZSA-N 0.000 description 3
- 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 3
- 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 3
- 239000002033 PVDF binder Substances 0.000 description 3
- JJHVFCUWLSKADD-ONGXEEELSA-N Phe-Gly-Ala Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)NCC(=O)N[C@@H](C)C(O)=O JJHVFCUWLSKADD-ONGXEEELSA-N 0.000 description 3
- FZHBZMDRDASUHN-NAKRPEOUSA-N Pro-Ala-Ile Chemical compound CC[C@H](C)[C@H](NC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1)C(O)=O FZHBZMDRDASUHN-NAKRPEOUSA-N 0.000 description 3
- 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 3
- 206010039491 Sarcoma Diseases 0.000 description 3
- HBZBPFLJNDXRAY-FXQIFTODSA-N Ser-Ala-Val Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(O)=O HBZBPFLJNDXRAY-FXQIFTODSA-N 0.000 description 3
- 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 3
- 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 3
- 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 3
- KCGIREHVWRXNDH-GARJFASQSA-N Ser-Leu-Pro Chemical compound CC(C)C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CO)N KCGIREHVWRXNDH-GARJFASQSA-N 0.000 description 3
- XQJCEKXQUJQNNK-ZLUOBGJFSA-N Ser-Ser-Ser Chemical compound OC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O XQJCEKXQUJQNNK-ZLUOBGJFSA-N 0.000 description 3
- PQEQXWRVHQAAKS-SRVKXCTJSA-N Ser-Tyr-Asn Chemical compound NC(=O)C[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CO)N)CC1=CC=C(O)C=C1 PQEQXWRVHQAAKS-SRVKXCTJSA-N 0.000 description 3
- ZVBCMFDJIMUELU-BZSNNMDCSA-N Ser-Tyr-Phe Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)O)NC(=O)[C@H](CC2=CC=C(C=C2)O)NC(=O)[C@H](CO)N ZVBCMFDJIMUELU-BZSNNMDCSA-N 0.000 description 3
- KRPKYGOFYUNIGM-XVSYOHENSA-N Thr-Asp-Phe Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)N)O KRPKYGOFYUNIGM-XVSYOHENSA-N 0.000 description 3
- MECLEFZMPPOEAC-VOAKCMCISA-N Thr-Leu-Lys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)O)N)O MECLEFZMPPOEAC-VOAKCMCISA-N 0.000 description 3
- DEGCBBCMYWNJNA-RHYQMDGZSA-N Thr-Pro-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)[C@@H](C)O DEGCBBCMYWNJNA-RHYQMDGZSA-N 0.000 description 3
- 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 3
- 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 3
- NMKJPMCEKQHRPD-IRXDYDNUSA-N Tyr-Gly-Tyr Chemical compound C([C@H](N)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C1=CC=C(O)C=C1 NMKJPMCEKQHRPD-IRXDYDNUSA-N 0.000 description 3
- CVUDMNSZAIZFAE-UHFFFAOYSA-N Val-Arg-Pro Natural products NC(N)=NCCCC(NC(=O)C(N)C(C)C)C(=O)N1CCCC1C(O)=O CVUDMNSZAIZFAE-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 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 3
- IECQJCJNPJVUSB-IHRRRGAJSA-N Val-Tyr-Ser Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@@H](CO)C(O)=O IECQJCJNPJVUSB-IHRRRGAJSA-N 0.000 description 3
- 230000004075 alteration Effects 0.000 description 3
- 108010068380 arginylarginine Proteins 0.000 description 3
- 108010040443 aspartyl-aspartic acid Proteins 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 230000022534 cell killing Effects 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 238000010276 construction Methods 0.000 description 3
- 239000012636 effector Substances 0.000 description 3
- 238000004520 electroporation Methods 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 210000003414 extremity Anatomy 0.000 description 3
- 108010063718 gamma-glutamylaspartic acid Proteins 0.000 description 3
- 108010080575 glutamyl-aspartyl-alanine Proteins 0.000 description 3
- 108010057083 glutamyl-aspartyl-leucine Proteins 0.000 description 3
- VPZXBVLAVMBEQI-UHFFFAOYSA-N glycyl-DL-alpha-alanine Natural products OC(=O)C(C)NC(=O)CN VPZXBVLAVMBEQI-UHFFFAOYSA-N 0.000 description 3
- 108010079413 glycyl-prolyl-glutamic acid Proteins 0.000 description 3
- 108010084760 glycyl-tyrosyl-glycyl-aspartate Proteins 0.000 description 3
- 108010010147 glycylglutamine Proteins 0.000 description 3
- 210000000987 immune system Anatomy 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 230000000670 limiting effect Effects 0.000 description 3
- 229920000136 polysorbate Polymers 0.000 description 3
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 108010020755 prolyl-glycyl-glycine Proteins 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- 108010003137 tyrosyltyrosine Proteins 0.000 description 3
- 229910021642 ultra pure water Inorganic materials 0.000 description 3
- 239000012498 ultrapure water Substances 0.000 description 3
- 108010009962 valyltyrosine Proteins 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- FVFVNNKYKYZTJU-UHFFFAOYSA-N 6-chloro-1,3,5-triazine-2,4-diamine Chemical group NC1=NC(N)=NC(Cl)=N1 FVFVNNKYKYZTJU-UHFFFAOYSA-N 0.000 description 2
- JBVSSSZFNTXJDX-YTLHQDLWSA-N Ala-Ala-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](C)N JBVSSSZFNTXJDX-YTLHQDLWSA-N 0.000 description 2
- TTXMOJWKNRJWQJ-FXQIFTODSA-N Ala-Arg-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)C)CCCN=C(N)N TTXMOJWKNRJWQJ-FXQIFTODSA-N 0.000 description 2
- KXEVYGKATAMXJJ-ACZMJKKPSA-N Ala-Glu-Asp Chemical compound C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O KXEVYGKATAMXJJ-ACZMJKKPSA-N 0.000 description 2
- KUFVXLQLDHJVOG-SHGPDSBTSA-N Ala-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)N)O KUFVXLQLDHJVOG-SHGPDSBTSA-N 0.000 description 2
- JTXVXGXTRXMOFJ-FXQIFTODSA-N Asn-Pro-Asn Chemical compound NC(=O)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(N)=O)C(O)=O JTXVXGXTRXMOFJ-FXQIFTODSA-N 0.000 description 2
- RTFXPCYMDYBZNQ-SRVKXCTJSA-N Asn-Tyr-Asn 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(N)=O)C(O)=O RTFXPCYMDYBZNQ-SRVKXCTJSA-N 0.000 description 2
- KRXIWXCXOARFNT-ZLUOBGJFSA-N Asp-Ala-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC(O)=O KRXIWXCXOARFNT-ZLUOBGJFSA-N 0.000 description 2
- 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 2
- AYFVRYXNDHBECD-YUMQZZPRSA-N Asp-Leu-Gly Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O AYFVRYXNDHBECD-YUMQZZPRSA-N 0.000 description 2
- JSHWXQIZOCVWIA-ZKWXMUAHSA-N Asp-Ser-Val Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O JSHWXQIZOCVWIA-ZKWXMUAHSA-N 0.000 description 2
- 108091026890 Coding region Proteins 0.000 description 2
- BBQIWFFTTQTNOC-AVGNSLFASA-N Cys-Phe-Gln Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CS)N BBQIWFFTTQTNOC-AVGNSLFASA-N 0.000 description 2
- 241000588724 Escherichia coli Species 0.000 description 2
- 108700039691 Genetic Promoter Regions Proteins 0.000 description 2
- SNLOOPZHAQDMJG-CIUDSAMLSA-N Gln-Glu-Glu Chemical compound NC(=O)CC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O SNLOOPZHAQDMJG-CIUDSAMLSA-N 0.000 description 2
- FGYPOQPQTUNESW-IUCAKERBSA-N Gln-Gly-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)CNC(=O)[C@H](CCC(=O)N)N FGYPOQPQTUNESW-IUCAKERBSA-N 0.000 description 2
- 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 2
- KVQOVQVGVKDZNW-GUBZILKMSA-N Gln-Ser-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(=O)N)N KVQOVQVGVKDZNW-GUBZILKMSA-N 0.000 description 2
- LKDIBBOKUAASNP-FXQIFTODSA-N Glu-Ala-Glu Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(O)=O LKDIBBOKUAASNP-FXQIFTODSA-N 0.000 description 2
- IVGJYOOGJLFKQE-AVGNSLFASA-N Glu-Leu-Lys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCC(=O)O)N IVGJYOOGJLFKQE-AVGNSLFASA-N 0.000 description 2
- 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 2
- GMVCSRBOSIUTFC-FXQIFTODSA-N Glu-Ser-Glu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(O)=O GMVCSRBOSIUTFC-FXQIFTODSA-N 0.000 description 2
- CGWHAXBNGYQBBK-JBACZVJFSA-N Glu-Trp-Tyr Chemical compound C([C@H](NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CCC(O)=O)N)C(O)=O)C1=CC=C(O)C=C1 CGWHAXBNGYQBBK-JBACZVJFSA-N 0.000 description 2
- 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 2
- 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 2
- KMSGYZQRXPUKGI-BYPYZUCNSA-N Gly-Gly-Asn Chemical compound NCC(=O)NCC(=O)N[C@H](C(O)=O)CC(N)=O KMSGYZQRXPUKGI-BYPYZUCNSA-N 0.000 description 2
- XMPXVJIDADUOQB-RCOVLWMOSA-N Gly-Gly-Ile Chemical compound CC[C@H](C)[C@@H](C([O-])=O)NC(=O)CNC(=O)C[NH3+] XMPXVJIDADUOQB-RCOVLWMOSA-N 0.000 description 2
- YWAQATDNEKZFFK-BYPYZUCNSA-N Gly-Gly-Ser Chemical compound NCC(=O)NCC(=O)N[C@@H](CO)C(O)=O YWAQATDNEKZFFK-BYPYZUCNSA-N 0.000 description 2
- 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 2
- MIIVFRCYJABHTQ-ONGXEEELSA-N Gly-Leu-Val Chemical compound [H]NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(O)=O MIIVFRCYJABHTQ-ONGXEEELSA-N 0.000 description 2
- NTBOEZICHOSJEE-YUMQZZPRSA-N Gly-Lys-Ser Chemical compound [H]NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(O)=O NTBOEZICHOSJEE-YUMQZZPRSA-N 0.000 description 2
- ZZWUYQXMIFTIIY-WEDXCCLWSA-N Gly-Thr-Leu Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O ZZWUYQXMIFTIIY-WEDXCCLWSA-N 0.000 description 2
- 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 2
- FOCSWPCHUDVNLP-PMVMPFDFSA-N His-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](CC4=CN=CN4)N FOCSWPCHUDVNLP-PMVMPFDFSA-N 0.000 description 2
- UKTUOMWSJPXODT-GUDRVLHUSA-N Ile-Asn-Pro Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N1CCC[C@@H]1C(=O)O)N UKTUOMWSJPXODT-GUDRVLHUSA-N 0.000 description 2
- LEHPJMKVGFPSSP-ZQINRCPSSA-N Ile-Glu-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)[C@@H](C)CC)C(O)=O)=CNC2=C1 LEHPJMKVGFPSSP-ZQINRCPSSA-N 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
- DTPGSUQHUMELQB-GVARAGBVSA-N Ile-Tyr-Ala Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](C)C(O)=O)CC1=CC=C(O)C=C1 DTPGSUQHUMELQB-GVARAGBVSA-N 0.000 description 2
- REXAUQBGSGDEJY-IGISWZIWSA-N Ile-Tyr-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)O)N REXAUQBGSGDEJY-IGISWZIWSA-N 0.000 description 2
- 108010054477 Immunoglobulin Fab Fragments Proteins 0.000 description 2
- 102000001706 Immunoglobulin Fab Fragments Human genes 0.000 description 2
- 102000006496 Immunoglobulin Heavy Chains Human genes 0.000 description 2
- 108010019476 Immunoglobulin Heavy Chains Proteins 0.000 description 2
- 108010065920 Insulin Lispro Proteins 0.000 description 2
- TYYLDKGBCJGJGW-UHFFFAOYSA-N L-tryptophan-L-tyrosine Natural products C=1NC2=CC=CC=C2C=1CC(N)C(=O)NC(C(O)=O)CC1=CC=C(O)C=C1 TYYLDKGBCJGJGW-UHFFFAOYSA-N 0.000 description 2
- WNGVUZWBXZKQES-YUMQZZPRSA-N Leu-Ala-Gly Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C)C(=O)NCC(O)=O WNGVUZWBXZKQES-YUMQZZPRSA-N 0.000 description 2
- FQZPTCNSNPWHLJ-AVGNSLFASA-N Leu-Gln-Lys Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(O)=O FQZPTCNSNPWHLJ-AVGNSLFASA-N 0.000 description 2
- 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 2
- KIZIOFNVSOSKJI-CIUDSAMLSA-N Leu-Ser-Cys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)O)N KIZIOFNVSOSKJI-CIUDSAMLSA-N 0.000 description 2
- HWMQRQIFVGEAPH-XIRDDKMYSA-N Leu-Ser-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(C)C)C(O)=O)=CNC2=C1 HWMQRQIFVGEAPH-XIRDDKMYSA-N 0.000 description 2
- 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 2
- VOOINLQYUZOREH-SRVKXCTJSA-N Met-Gln-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CCSC)N VOOINLQYUZOREH-SRVKXCTJSA-N 0.000 description 2
- ABHVWYPPHDYFNY-WDSOQIARSA-N Met-His-Trp Chemical compound C([C@H](NC(=O)[C@@H](N)CCSC)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(O)=O)C1=CN=CN1 ABHVWYPPHDYFNY-WDSOQIARSA-N 0.000 description 2
- YBAFDPFAUTYYRW-UHFFFAOYSA-N N-L-alpha-glutamyl-L-leucine Natural products CC(C)CC(C(O)=O)NC(=O)C(N)CCC(O)=O YBAFDPFAUTYYRW-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 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 2
- XNQMZHLAYFWSGJ-HTUGSXCWSA-N Phe-Thr-Glu Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(O)=O)C(O)=O XNQMZHLAYFWSGJ-HTUGSXCWSA-N 0.000 description 2
- BPIMVBKDLSBKIJ-FCLVOEFKSA-N Phe-Thr-Phe Chemical compound C([C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 BPIMVBKDLSBKIJ-FCLVOEFKSA-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
- RMODQFBNDDENCP-IHRRRGAJSA-N Pro-Lys-Leu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(O)=O RMODQFBNDDENCP-IHRRRGAJSA-N 0.000 description 2
- PRKWBYCXBBSLSK-GUBZILKMSA-N Pro-Ser-Val Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O PRKWBYCXBBSLSK-GUBZILKMSA-N 0.000 description 2
- ZUGXSSFMTXKHJS-ZLUOBGJFSA-N Ser-Ala-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(O)=O ZUGXSSFMTXKHJS-ZLUOBGJFSA-N 0.000 description 2
- MESDJCNHLZBMEP-ZLUOBGJFSA-N Ser-Asp-Asp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O MESDJCNHLZBMEP-ZLUOBGJFSA-N 0.000 description 2
- KJMOINFQVCCSDX-XKBZYTNZSA-N Ser-Gln-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O KJMOINFQVCCSDX-XKBZYTNZSA-N 0.000 description 2
- 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 2
- 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 2
- MUJQWSAWLLRJCE-KATARQTJSA-N Ser-Leu-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O MUJQWSAWLLRJCE-KATARQTJSA-N 0.000 description 2
- 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 2
- CUXJENOFJXOSOZ-BIIVOSGPSA-N Ser-Ser-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CO)NC(=O)[C@H](CO)N)C(=O)O CUXJENOFJXOSOZ-BIIVOSGPSA-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
- YXGCIEUDOHILKR-IHRRRGAJSA-N Ser-Tyr-Met Chemical compound CSCC[C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)NC(=O)[C@H](CO)N YXGCIEUDOHILKR-IHRRRGAJSA-N 0.000 description 2
- 208000000453 Skin Neoplasms Diseases 0.000 description 2
- 108700026226 TATA Box Proteins 0.000 description 2
- 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 2
- PXQUBKWZENPDGE-CIQUZCHMSA-N Thr-Ala-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](C)NC(=O)[C@H]([C@@H](C)O)N PXQUBKWZENPDGE-CIQUZCHMSA-N 0.000 description 2
- DWYAUVCQDTZIJI-VZFHVOOUSA-N Thr-Ala-Ser Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O DWYAUVCQDTZIJI-VZFHVOOUSA-N 0.000 description 2
- 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 2
- LYGKYFKSZTUXGZ-ZDLURKLDSA-N Thr-Cys-Gly Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(=O)NCC(O)=O LYGKYFKSZTUXGZ-ZDLURKLDSA-N 0.000 description 2
- LHNNQVXITHUCAB-QTKMDUPCSA-N Thr-Met-His Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N)O LHNNQVXITHUCAB-QTKMDUPCSA-N 0.000 description 2
- STUAPCLEDMKXKL-LKXGYXEUSA-N Thr-Ser-Asn Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O STUAPCLEDMKXKL-LKXGYXEUSA-N 0.000 description 2
- IVDFVBVIVLJJHR-LKXGYXEUSA-N Thr-Ser-Asp Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(O)=O IVDFVBVIVLJJHR-LKXGYXEUSA-N 0.000 description 2
- IEZVHOULSUULHD-XGEHTFHBSA-N Thr-Ser-Val Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O IEZVHOULSUULHD-XGEHTFHBSA-N 0.000 description 2
- 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 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
- YOPQYBJJNSIQGZ-JNPHEJMOSA-N Thr-Tyr-Tyr Chemical compound C([C@H](NC(=O)[C@@H](N)[C@H](O)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C1=CC=C(O)C=C1 YOPQYBJJNSIQGZ-JNPHEJMOSA-N 0.000 description 2
- 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 2
- VZBWRZGNEPBRDE-HZUKXOBISA-N Trp-Ala-Pro Chemical compound C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CC2=CNC3=CC=CC=C32)N VZBWRZGNEPBRDE-HZUKXOBISA-N 0.000 description 2
- 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 2
- PKZIWSHDJYIPRH-JBACZVJFSA-N Trp-Tyr-Gln 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](CCC(N)=O)C(O)=O PKZIWSHDJYIPRH-JBACZVJFSA-N 0.000 description 2
- 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 2
- CDRYEAWHKJSGAF-BPNCWPANSA-N Tyr-Ala-Met Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](C)C(=O)N[C@@H](CCSC)C(O)=O CDRYEAWHKJSGAF-BPNCWPANSA-N 0.000 description 2
- 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 2
- XYNFFTNEQDWZNY-ULQDDVLXSA-N Tyr-Met-His Chemical compound CSCC[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](CC2=CC=C(C=C2)O)N XYNFFTNEQDWZNY-ULQDDVLXSA-N 0.000 description 2
- KHPLUFDSWGDRHD-SLFFLAALSA-N Tyr-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=C(C=C3)O)N)C(=O)O KHPLUFDSWGDRHD-SLFFLAALSA-N 0.000 description 2
- WNZSAUMKZQXHNC-UKJIMTQDSA-N Val-Ile-Gln Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](C(C)C)N WNZSAUMKZQXHNC-UKJIMTQDSA-N 0.000 description 2
- DJQIUOKSNRBTSV-CYDGBPFRSA-N Val-Ile-Val Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](C(C)C)C(=O)O)NC(=O)[C@H](C(C)C)N DJQIUOKSNRBTSV-CYDGBPFRSA-N 0.000 description 2
- VPGCVZRRBYOGCD-AVGNSLFASA-N Val-Lys-Val Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(O)=O VPGCVZRRBYOGCD-AVGNSLFASA-N 0.000 description 2
- 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 2
- NLNCNKIVJPEFBC-DLOVCJGASA-N Val-Val-Glu Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CCC(O)=O NLNCNKIVJPEFBC-DLOVCJGASA-N 0.000 description 2
- 108010081404 acein-2 Proteins 0.000 description 2
- 208000033017 acquired idiopathic inflammatory myopathy Diseases 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 108010008685 alanyl-glutamyl-aspartic acid Proteins 0.000 description 2
- 108010050025 alpha-glutamyltryptophan Proteins 0.000 description 2
- 229910001870 ammonium persulfate Inorganic materials 0.000 description 2
- 239000011324 bead Substances 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 230000005754 cellular signaling Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 208000006990 cholangiocarcinoma Diseases 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 238000010367 cloning Methods 0.000 description 2
- 238000012217 deletion Methods 0.000 description 2
- 230000037430 deletion Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 238000003745 diagnosis Methods 0.000 description 2
- 238000007865 diluting Methods 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003623 enhancer Substances 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- 238000001976 enzyme digestion Methods 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 238000005194 fractionation Methods 0.000 description 2
- 108010006664 gamma-glutamyl-glycyl-glycine Proteins 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 238000001502 gel electrophoresis Methods 0.000 description 2
- 210000004392 genitalia Anatomy 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
- 108010048994 glycyl-tyrosyl-alanine Proteins 0.000 description 2
- 108010015792 glycyllysine Proteins 0.000 description 2
- 108010037850 glycylvaline Proteins 0.000 description 2
- 208000019691 hematopoietic and lymphoid cell neoplasm Diseases 0.000 description 2
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 2
- 208000013643 idiopathic inflammatory myopathy Diseases 0.000 description 2
- 230000016784 immunoglobulin production Effects 0.000 description 2
- 230000000977 initiatory effect Effects 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 238000001155 isoelectric focusing Methods 0.000 description 2
- 108010044374 isoleucyl-tyrosine Proteins 0.000 description 2
- 238000002372 labelling Methods 0.000 description 2
- 108010073472 leucyl-prolyl-proline Proteins 0.000 description 2
- 230000003211 malignant effect Effects 0.000 description 2
- 108020004999 messenger RNA Proteins 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 239000008188 pellet Substances 0.000 description 2
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 2
- 210000001236 prokaryotic cell Anatomy 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 230000022532 regulation of transcription, DNA-dependent Effects 0.000 description 2
- 210000002345 respiratory system Anatomy 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 239000013049 sediment Substances 0.000 description 2
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 210000000952 spleen Anatomy 0.000 description 2
- 239000007929 subcutaneous injection Substances 0.000 description 2
- 238000010254 subcutaneous injection Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 230000002103 transcriptional effect Effects 0.000 description 2
- 108010038745 tryptophylglycine Proteins 0.000 description 2
- 238000001262 western blot Methods 0.000 description 2
- 108010027345 wheylin-1 peptide Proteins 0.000 description 2
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- QMOQBVOBWVNSNO-UHFFFAOYSA-N 2-[[2-[[2-[(2-azaniumylacetyl)amino]acetyl]amino]acetyl]amino]acetate Chemical compound NCC(=O)NCC(=O)NCC(=O)NCC(O)=O QMOQBVOBWVNSNO-UHFFFAOYSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 1
- 208000026872 Addison Disease Diseases 0.000 description 1
- LSLIRHLIUDVNBN-CIUDSAMLSA-N Ala-Asp-Lys Chemical compound C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CCCCN LSLIRHLIUDVNBN-CIUDSAMLSA-N 0.000 description 1
- DAEFQZCYZKRTLR-ZLUOBGJFSA-N Ala-Cys-Asp Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(O)=O)C(O)=O DAEFQZCYZKRTLR-ZLUOBGJFSA-N 0.000 description 1
- VGPWRRFOPXVGOH-BYPYZUCNSA-N Ala-Gly-Gly Chemical compound C[C@H](N)C(=O)NCC(=O)NCC(O)=O VGPWRRFOPXVGOH-BYPYZUCNSA-N 0.000 description 1
- CBCCCLMNOBLBSC-XVYDVKMFSA-N Ala-His-Ser Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CO)C(O)=O CBCCCLMNOBLBSC-XVYDVKMFSA-N 0.000 description 1
- OYJCVIGKMXUVKB-GARJFASQSA-N Ala-Leu-Pro Chemical compound C[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N1CCC[C@@H]1C(=O)O)N OYJCVIGKMXUVKB-GARJFASQSA-N 0.000 description 1
- SOBIAADAMRHGKH-CIUDSAMLSA-N Ala-Leu-Ser Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O SOBIAADAMRHGKH-CIUDSAMLSA-N 0.000 description 1
- 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 1
- REAQAWSENITKJL-DDWPSWQVSA-N Ala-Met-Asp-Tyr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O REAQAWSENITKJL-DDWPSWQVSA-N 0.000 description 1
- IPZQNYYAYVRKKK-FXQIFTODSA-N Ala-Pro-Ala Chemical compound C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C)C(O)=O IPZQNYYAYVRKKK-FXQIFTODSA-N 0.000 description 1
- MAZZQZWCCYJQGZ-GUBZILKMSA-N Ala-Pro-Arg Chemical compound [H]N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(N)=N)C(O)=O MAZZQZWCCYJQGZ-GUBZILKMSA-N 0.000 description 1
- RTZCUEHYUQZIDE-WHFBIAKZSA-N Ala-Ser-Gly Chemical compound C[C@H](N)C(=O)N[C@@H](CO)C(=O)NCC(O)=O RTZCUEHYUQZIDE-WHFBIAKZSA-N 0.000 description 1
- DYXOFPBJBAHWFY-JBDRJPRFSA-N Ala-Ser-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](C)N DYXOFPBJBAHWFY-JBDRJPRFSA-N 0.000 description 1
- SAHQGRZIQVEJPF-JXUBOQSCSA-N Ala-Thr-Lys Chemical compound C[C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@H](C(O)=O)CCCCN SAHQGRZIQVEJPF-JXUBOQSCSA-N 0.000 description 1
- QRIYOHQJRDHFKF-UWJYBYFXSA-N Ala-Tyr-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)C)CC1=CC=C(O)C=C1 QRIYOHQJRDHFKF-UWJYBYFXSA-N 0.000 description 1
- CLOMBHBBUKAUBP-LSJOCFKGSA-N Ala-Val-His Chemical compound C[C@@H](C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N CLOMBHBBUKAUBP-LSJOCFKGSA-N 0.000 description 1
- 208000007860 Anus Neoplasms Diseases 0.000 description 1
- XPSGESXVBSQZPL-SRVKXCTJSA-N Arg-Arg-Arg Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O XPSGESXVBSQZPL-SRVKXCTJSA-N 0.000 description 1
- DXQIQUIQYAGRCC-CIUDSAMLSA-N Arg-Asp-Gln Chemical compound C(C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N)CN=C(N)N DXQIQUIQYAGRCC-CIUDSAMLSA-N 0.000 description 1
- YHQGEARSFILVHL-HJGDQZAQSA-N Arg-Gln-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CCCN=C(N)N)N)O YHQGEARSFILVHL-HJGDQZAQSA-N 0.000 description 1
- 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 1
- 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 1
- LVMUGODRNHFGRA-AVGNSLFASA-N Arg-Leu-Arg Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O LVMUGODRNHFGRA-AVGNSLFASA-N 0.000 description 1
- OTZMRMHZCMZOJZ-SRVKXCTJSA-N Arg-Leu-Glu Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O OTZMRMHZCMZOJZ-SRVKXCTJSA-N 0.000 description 1
- NMRHDSAOIURTNT-RWMBFGLXSA-N Arg-Leu-Pro Chemical compound CC(C)C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCCN=C(N)N)N NMRHDSAOIURTNT-RWMBFGLXSA-N 0.000 description 1
- SSZGOKWBHLOCHK-DCAQKATOSA-N Arg-Lys-Asn Chemical compound NC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CCCN=C(N)N SSZGOKWBHLOCHK-DCAQKATOSA-N 0.000 description 1
- BTJVOUQWFXABOI-IHRRRGAJSA-N Arg-Lys-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CCCNC(N)=N BTJVOUQWFXABOI-IHRRRGAJSA-N 0.000 description 1
- PRLPSDIHSRITSF-UNQGMJICSA-N Arg-Phe-Thr Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O PRLPSDIHSRITSF-UNQGMJICSA-N 0.000 description 1
- VUGWHBXPMAHEGZ-SRVKXCTJSA-N Arg-Pro-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CCCN=C(N)N VUGWHBXPMAHEGZ-SRVKXCTJSA-N 0.000 description 1
- ADPACBMPYWJJCE-FXQIFTODSA-N Arg-Ser-Asp Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(O)=O ADPACBMPYWJJCE-FXQIFTODSA-N 0.000 description 1
- DNLQVHBBMPZUGJ-BQBZGAKWSA-N Arg-Ser-Gly Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)NCC(O)=O DNLQVHBBMPZUGJ-BQBZGAKWSA-N 0.000 description 1
- WOZDCBHUGJVJPL-AVGNSLFASA-N Arg-Val-Lys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCCN=C(N)N)N WOZDCBHUGJVJPL-AVGNSLFASA-N 0.000 description 1
- PCKRJVZAQZWNKM-WHFBIAKZSA-N Asn-Asn-Gly Chemical compound NC(=O)C[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(O)=O PCKRJVZAQZWNKM-WHFBIAKZSA-N 0.000 description 1
- JREOBWLIZLXRIS-GUBZILKMSA-N Asn-Glu-Leu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O JREOBWLIZLXRIS-GUBZILKMSA-N 0.000 description 1
- 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 1
- PNHQRQTVBRDIEF-CIUDSAMLSA-N Asn-Leu-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(=O)N)N PNHQRQTVBRDIEF-CIUDSAMLSA-N 0.000 description 1
- GKKUBLFXKRDMFC-BQBZGAKWSA-N Asn-Pro-Gly Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O GKKUBLFXKRDMFC-BQBZGAKWSA-N 0.000 description 1
- REQUGIWGOGSOEZ-ZLUOBGJFSA-N Asn-Ser-Asn Chemical compound C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(=O)N)C(=O)O)N)C(=O)N REQUGIWGOGSOEZ-ZLUOBGJFSA-N 0.000 description 1
- PBVLJOIPOGUQQP-CIUDSAMLSA-N Asp-Ala-Leu Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(O)=O PBVLJOIPOGUQQP-CIUDSAMLSA-N 0.000 description 1
- BIVYLQMZPHDUIH-WHFBIAKZSA-N Asp-Gly-Cys Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CS)C(=O)O)N)C(=O)O BIVYLQMZPHDUIH-WHFBIAKZSA-N 0.000 description 1
- 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 1
- 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 1
- 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 1
- JDDYEZGPYBBPBN-JRQIVUDYSA-N Asp-Thr-Tyr Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O JDDYEZGPYBBPBN-JRQIVUDYSA-N 0.000 description 1
- HTSSXFASOUSJQG-IHPCNDPISA-N Asp-Tyr-Trp 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=CNC2=C1C=CC=C2)C(O)=O HTSSXFASOUSJQG-IHPCNDPISA-N 0.000 description 1
- GIKOVDMXBAFXDF-NHCYSSNCSA-N Asp-Val-Leu Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O GIKOVDMXBAFXDF-NHCYSSNCSA-N 0.000 description 1
- 206010060971 Astrocytoma malignant Diseases 0.000 description 1
- 108091008875 B cell receptors Proteins 0.000 description 1
- 208000028564 B-cell non-Hodgkin lymphoma Diseases 0.000 description 1
- 208000025321 B-lymphoblastic leukemia/lymphoma Diseases 0.000 description 1
- 101710117995 B-lymphocyte antigen CD19 Proteins 0.000 description 1
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 210000001266 CD8-positive T-lymphocyte Anatomy 0.000 description 1
- 206010007953 Central nervous system lymphoma Diseases 0.000 description 1
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 description 1
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 1
- 101100007328 Cocos nucifera COS-1 gene Proteins 0.000 description 1
- 102100032768 Complement receptor type 2 Human genes 0.000 description 1
- 241000699802 Cricetulus griseus Species 0.000 description 1
- QLCPDGRAEJSYQM-LPEHRKFASA-N Cys-Arg-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CS)N)C(=O)O QLCPDGRAEJSYQM-LPEHRKFASA-N 0.000 description 1
- 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 1
- YNJBLTDKTMKEET-ZLUOBGJFSA-N Cys-Ser-Ser Chemical compound SC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O YNJBLTDKTMKEET-ZLUOBGJFSA-N 0.000 description 1
- NRVQLLDIJJEIIZ-VZFHVOOUSA-N Cys-Thr-Ala Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](C)C(=O)O)NC(=O)[C@H](CS)N)O NRVQLLDIJJEIIZ-VZFHVOOUSA-N 0.000 description 1
- 238000012270 DNA recombination Methods 0.000 description 1
- 201000003066 Diffuse Scleroderma Diseases 0.000 description 1
- 238000012286 ELISA Assay Methods 0.000 description 1
- 206010014759 Endometrial neoplasm Diseases 0.000 description 1
- 206010014967 Ependymoma Diseases 0.000 description 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 1
- 229920001917 Ficoll Polymers 0.000 description 1
- 230000005526 G1 to G0 transition Effects 0.000 description 1
- 208000022072 Gallbladder Neoplasms Diseases 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- REJJNXODKSHOKA-ACZMJKKPSA-N Gln-Ala-Asp Chemical compound C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)O)NC(=O)[C@H](CCC(=O)N)N REJJNXODKSHOKA-ACZMJKKPSA-N 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
- TWHDOEYLXXQYOZ-FXQIFTODSA-N Gln-Asn-Gln Chemical compound C(CC(=O)N)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N TWHDOEYLXXQYOZ-FXQIFTODSA-N 0.000 description 1
- RBWKVOSARCFSQQ-FXQIFTODSA-N Gln-Gln-Ser Chemical compound NC(=O)CC[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(O)=O RBWKVOSARCFSQQ-FXQIFTODSA-N 0.000 description 1
- YPMDZWPZFOZYFG-GUBZILKMSA-N Gln-Leu-Ser Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O YPMDZWPZFOZYFG-GUBZILKMSA-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
- XQDGOJPVMSWZSO-SRVKXCTJSA-N Gln-Pro-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCC(=O)N)N XQDGOJPVMSWZSO-SRVKXCTJSA-N 0.000 description 1
- MQJDLNRXBOELJW-KKUMJFAQSA-N Gln-Pro-Phe Chemical compound N[C@@H](CCC(N)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(O)=O MQJDLNRXBOELJW-KKUMJFAQSA-N 0.000 description 1
- SYZZMPFLOLSMHL-XHNCKOQMSA-N Gln-Ser-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CO)NC(=O)[C@H](CCC(=O)N)N)C(=O)O SYZZMPFLOLSMHL-XHNCKOQMSA-N 0.000 description 1
- NHMRJKKAVMENKJ-WDCWCFNPSA-N Gln-Thr-Leu Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O NHMRJKKAVMENKJ-WDCWCFNPSA-N 0.000 description 1
- VLOLPWWCNKWRNB-LOKLDPHHSA-N Gln-Thr-Pro Chemical compound C[C@H]([C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCC(=O)N)N)O VLOLPWWCNKWRNB-LOKLDPHHSA-N 0.000 description 1
- STHSGOZLFLFGSS-SUSMZKCASA-N Gln-Thr-Thr Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O STHSGOZLFLFGSS-SUSMZKCASA-N 0.000 description 1
- 206010018364 Glomerulonephritis Diseases 0.000 description 1
- RDPOETHPAQEGDP-ACZMJKKPSA-N Glu-Asp-Ala Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(O)=O RDPOETHPAQEGDP-ACZMJKKPSA-N 0.000 description 1
- 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 1
- SJPMNHCEWPTRBR-BQBZGAKWSA-N Glu-Glu-Gly Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(O)=O SJPMNHCEWPTRBR-BQBZGAKWSA-N 0.000 description 1
- OAGVHWYIBZMWLA-YFKPBYRVSA-N Glu-Gly-Gly Chemical compound OC(=O)CC[C@H](N)C(=O)NCC(=O)NCC(O)=O OAGVHWYIBZMWLA-YFKPBYRVSA-N 0.000 description 1
- ITBHUUMCJJQUSC-LAEOZQHASA-N Glu-Ile-Gly Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(O)=O ITBHUUMCJJQUSC-LAEOZQHASA-N 0.000 description 1
- VMKCPNBBPGGQBJ-GUBZILKMSA-N Glu-Leu-Asn Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CCC(=O)O)N VMKCPNBBPGGQBJ-GUBZILKMSA-N 0.000 description 1
- SJJHXJDSNQJMMW-SRVKXCTJSA-N Glu-Lys-Arg Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O SJJHXJDSNQJMMW-SRVKXCTJSA-N 0.000 description 1
- JDUKCSSHWNIQQZ-IHRRRGAJSA-N Glu-Phe-Glu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCC(O)=O)C(O)=O JDUKCSSHWNIQQZ-IHRRRGAJSA-N 0.000 description 1
- ITVBKCZZLJUUHI-HTUGSXCWSA-N Glu-Phe-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O ITVBKCZZLJUUHI-HTUGSXCWSA-N 0.000 description 1
- 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 1
- MIWJDJAMMKHUAR-ZVZYQTTQSA-N Glu-Trp-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)NC(=O)[C@H](CCC(=O)O)N MIWJDJAMMKHUAR-ZVZYQTTQSA-N 0.000 description 1
- MFVQGXGQRIXBPK-WDSKDSINSA-N Gly-Ala-Glu Chemical compound NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(O)=O MFVQGXGQRIXBPK-WDSKDSINSA-N 0.000 description 1
- 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 1
- FMNHBTKMRFVGRO-FOHZUACHSA-N Gly-Asn-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)CN FMNHBTKMRFVGRO-FOHZUACHSA-N 0.000 description 1
- XXGQRGQPGFYECI-WDSKDSINSA-N Gly-Cys-Glu Chemical compound NCC(=O)N[C@@H](CS)C(=O)N[C@H](C(O)=O)CCC(O)=O XXGQRGQPGFYECI-WDSKDSINSA-N 0.000 description 1
- XPJBQTCXPJNIFE-ZETCQYMHSA-N Gly-Gly-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)CNC(=O)CN XPJBQTCXPJNIFE-ZETCQYMHSA-N 0.000 description 1
- 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 1
- 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 1
- 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 1
- 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 1
- 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 1
- 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 1
- FGPLUIQCSKGLTI-WDSKDSINSA-N Gly-Ser-Glu Chemical compound NCC(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CCC(O)=O FGPLUIQCSKGLTI-WDSKDSINSA-N 0.000 description 1
- ZVXMEWXHFBYJPI-LSJOCFKGSA-N Gly-Val-Ile Chemical compound [H]NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O ZVXMEWXHFBYJPI-LSJOCFKGSA-N 0.000 description 1
- LSQHWKPPOFDHHZ-YUMQZZPRSA-N His-Asp-Gly Chemical compound C1=C(NC=N1)C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)NCC(=O)O)N LSQHWKPPOFDHHZ-YUMQZZPRSA-N 0.000 description 1
- 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 1
- NKRWVZQTPXPNRZ-SRVKXCTJSA-N His-Met-Gln Chemical compound NC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](CCSC)NC(=O)[C@@H](N)CC1=CN=CN1 NKRWVZQTPXPNRZ-SRVKXCTJSA-N 0.000 description 1
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 1
- 101000941929 Homo sapiens Complement receptor type 2 Proteins 0.000 description 1
- HDOYNXLPTRQLAD-JBDRJPRFSA-N Ile-Ala-Ser Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(=O)O)N HDOYNXLPTRQLAD-JBDRJPRFSA-N 0.000 description 1
- LRAUKBMYHHNADU-DKIMLUQUSA-N Ile-Phe-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)[C@@H](C)CC)CC1=CC=CC=C1 LRAUKBMYHHNADU-DKIMLUQUSA-N 0.000 description 1
- RQJUKVXWAKJDBW-SVSWQMSJSA-N Ile-Ser-Thr Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)O)N RQJUKVXWAKJDBW-SVSWQMSJSA-N 0.000 description 1
- 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 1
- 108010067060 Immunoglobulin Variable Region Proteins 0.000 description 1
- 102000017727 Immunoglobulin Variable Region Human genes 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 206010061252 Intraocular melanoma Diseases 0.000 description 1
- 208000007766 Kaposi sarcoma Diseases 0.000 description 1
- 208000001126 Keratosis Diseases 0.000 description 1
- 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 1
- IBMVEYRWAWIOTN-UHFFFAOYSA-N L-Leucyl-L-Arginyl-L-Proline Natural products CC(C)CC(N)C(=O)NC(CCCN=C(N)N)C(=O)N1CCCC1C(O)=O IBMVEYRWAWIOTN-UHFFFAOYSA-N 0.000 description 1
- JQSXWJXBASFONF-KKUMJFAQSA-N Leu-Asp-Phe Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O JQSXWJXBASFONF-KKUMJFAQSA-N 0.000 description 1
- QVFGXCVIXXBFHO-AVGNSLFASA-N Leu-Glu-Leu Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O QVFGXCVIXXBFHO-AVGNSLFASA-N 0.000 description 1
- BABSVXFGKFLIGW-UWVGGRQHSA-N Leu-Gly-Arg Chemical compound CC(C)C[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CCCNC(N)=N BABSVXFGKFLIGW-UWVGGRQHSA-N 0.000 description 1
- UCNNZELZXFXXJQ-BZSNNMDCSA-N Leu-Leu-Tyr Chemical compound CC(C)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 UCNNZELZXFXXJQ-BZSNNMDCSA-N 0.000 description 1
- BGZCJDGBBUUBHA-KKUMJFAQSA-N Leu-Lys-Leu Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(O)=O BGZCJDGBBUUBHA-KKUMJFAQSA-N 0.000 description 1
- WUHBLPVELFTPQK-KKUMJFAQSA-N Leu-Tyr-Asn 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](CC(N)=O)C(O)=O WUHBLPVELFTPQK-KKUMJFAQSA-N 0.000 description 1
- VHTIZYYHIUHMCA-JYJNAYRXSA-N Leu-Tyr-Gln 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](CCC(N)=O)C(O)=O VHTIZYYHIUHMCA-JYJNAYRXSA-N 0.000 description 1
- FBNPMTNBFFAMMH-AVGNSLFASA-N Leu-Val-Arg Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CCCN=C(N)N FBNPMTNBFFAMMH-AVGNSLFASA-N 0.000 description 1
- QESXLSQLQHHTIX-RHYQMDGZSA-N Leu-Val-Thr Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O QESXLSQLQHHTIX-RHYQMDGZSA-N 0.000 description 1
- VTAJIXDZFCRWBR-UHFFFAOYSA-N Licoricesaponin B2 Natural products C1C(C2C(C3(CCC4(C)CCC(C)(CC4C3=CC2)C(O)=O)C)(C)CC2)(C)C2C(C)(C)CC1OC1OC(C(O)=O)C(O)C(O)C1OC1OC(C(O)=O)C(O)C(O)C1O VTAJIXDZFCRWBR-UHFFFAOYSA-N 0.000 description 1
- 239000012097 Lipofectamine 2000 Substances 0.000 description 1
- 206010073099 Lobular breast carcinoma in situ Diseases 0.000 description 1
- GAOJCVKPIGHTGO-UWVGGRQHSA-N Lys-Arg-Gly Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O GAOJCVKPIGHTGO-UWVGGRQHSA-N 0.000 description 1
- YNNPKXBBRZVIRX-IHRRRGAJSA-N Lys-Arg-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(O)=O YNNPKXBBRZVIRX-IHRRRGAJSA-N 0.000 description 1
- LMVOVCYVZBBWQB-SRVKXCTJSA-N Lys-Asp-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CCCCN LMVOVCYVZBBWQB-SRVKXCTJSA-N 0.000 description 1
- GQZMPWBZQALKJO-UWVGGRQHSA-N Lys-Gly-Arg Chemical compound [H]N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(O)=O GQZMPWBZQALKJO-UWVGGRQHSA-N 0.000 description 1
- AIRZWUMAHCDDHR-KKUMJFAQSA-N Lys-Leu-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O AIRZWUMAHCDDHR-KKUMJFAQSA-N 0.000 description 1
- XFANQCRHTMOEAP-WDSOQIARSA-N Lys-Pro-Trp Chemical compound [H]N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O XFANQCRHTMOEAP-WDSOQIARSA-N 0.000 description 1
- 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 1
- 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 1
- 208000006644 Malignant Fibrous Histiocytoma Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 208000000172 Medulloblastoma Diseases 0.000 description 1
- ONGCSGVHCSAATF-CIUDSAMLSA-N Met-Ala-Glu Chemical compound CSCC[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CCC(O)=O ONGCSGVHCSAATF-CIUDSAMLSA-N 0.000 description 1
- UZWMJZSOXGOVIN-LURJTMIESA-N Met-Gly-Gly Chemical compound CSCC[C@H](N)C(=O)NCC(=O)NCC(O)=O UZWMJZSOXGOVIN-LURJTMIESA-N 0.000 description 1
- AXHNAGAYRGCDLG-UWVGGRQHSA-N Met-Lys-Gly Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)NCC(O)=O AXHNAGAYRGCDLG-UWVGGRQHSA-N 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 206010027761 Mixed hepatocellular cholangiocarcinoma Diseases 0.000 description 1
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 1
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 1
- 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 1
- 208000001894 Nasopharyngeal Neoplasms Diseases 0.000 description 1
- 206010061306 Nasopharyngeal cancer Diseases 0.000 description 1
- 208000009277 Neuroectodermal Tumors Diseases 0.000 description 1
- 108091034117 Oligonucleotide Proteins 0.000 description 1
- 206010031096 Oropharyngeal cancer Diseases 0.000 description 1
- 206010057444 Oropharyngeal neoplasm Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 208000002471 Penile Neoplasms Diseases 0.000 description 1
- CGOMLCQJEMWMCE-STQMWFEESA-N Phe-Arg-Gly Chemical compound NC(N)=NCCC[C@@H](C(=O)NCC(O)=O)NC(=O)[C@@H](N)CC1=CC=CC=C1 CGOMLCQJEMWMCE-STQMWFEESA-N 0.000 description 1
- LLGTYVHITPVGKR-RYUDHWBXSA-N Phe-Gln-Gly Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(O)=O LLGTYVHITPVGKR-RYUDHWBXSA-N 0.000 description 1
- KRYSMKKRRRWOCZ-QEWYBTABSA-N Phe-Ile-Glu Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(O)=O KRYSMKKRRRWOCZ-QEWYBTABSA-N 0.000 description 1
- WEDZFLRYSIDIRX-IHRRRGAJSA-N Phe-Ser-Arg Chemical compound NC(=N)NCCC[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC1=CC=CC=C1 WEDZFLRYSIDIRX-IHRRRGAJSA-N 0.000 description 1
- 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 1
- 208000007641 Pinealoma Diseases 0.000 description 1
- 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 1
- 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 1
- UTAUEDINXUMHLG-FXQIFTODSA-N Pro-Asp-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@@H]1CCCN1 UTAUEDINXUMHLG-FXQIFTODSA-N 0.000 description 1
- 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 1
- ZCXQTRXYZOSGJR-FXQIFTODSA-N Pro-Asp-Ser Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O ZCXQTRXYZOSGJR-FXQIFTODSA-N 0.000 description 1
- LSIWVWRUTKPXDS-DCAQKATOSA-N Pro-Gln-Arg Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O LSIWVWRUTKPXDS-DCAQKATOSA-N 0.000 description 1
- UPJGUQPLYWTISV-GUBZILKMSA-N Pro-Gln-Glu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O UPJGUQPLYWTISV-GUBZILKMSA-N 0.000 description 1
- LHALYDBUDCWMDY-CIUDSAMLSA-N Pro-Glu-Ala Chemical compound C[C@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H]1CCCN1)C(O)=O LHALYDBUDCWMDY-CIUDSAMLSA-N 0.000 description 1
- FRKBNXCFJBPJOL-GUBZILKMSA-N Pro-Glu-Glu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O FRKBNXCFJBPJOL-GUBZILKMSA-N 0.000 description 1
- VOZIBWWZSBIXQN-SRVKXCTJSA-N Pro-Glu-Lys Chemical compound NCCCC[C@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H]1CCCN1)C(O)=O VOZIBWWZSBIXQN-SRVKXCTJSA-N 0.000 description 1
- CLNJSLSHKJECME-BQBZGAKWSA-N Pro-Gly-Ala Chemical compound OC(=O)[C@H](C)NC(=O)CNC(=O)[C@@H]1CCCN1 CLNJSLSHKJECME-BQBZGAKWSA-N 0.000 description 1
- UUHXBJHVTVGSKM-BQBZGAKWSA-N Pro-Gly-Asn Chemical compound [H]N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](CC(N)=O)C(O)=O UUHXBJHVTVGSKM-BQBZGAKWSA-N 0.000 description 1
- HAAQQNHQZBOWFO-LURJTMIESA-N Pro-Gly-Gly Chemical compound OC(=O)CNC(=O)CNC(=O)[C@@H]1CCCN1 HAAQQNHQZBOWFO-LURJTMIESA-N 0.000 description 1
- 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 1
- RCYUBVHMVUHEBM-RCWTZXSCSA-N Pro-Pro-Thr Chemical compound [H]N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)O)C(O)=O RCYUBVHMVUHEBM-RCWTZXSCSA-N 0.000 description 1
- QMABBZHZMDXHKU-FKBYEOEOSA-N Pro-Tyr-Trp Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O QMABBZHZMDXHKU-FKBYEOEOSA-N 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 208000015634 Rectal Neoplasms Diseases 0.000 description 1
- 201000000582 Retinoblastoma Diseases 0.000 description 1
- 108091028664 Ribonucleotide Proteins 0.000 description 1
- 208000004337 Salivary Gland Neoplasms Diseases 0.000 description 1
- LVVBAKCGXXUHFO-ZLUOBGJFSA-N Ser-Ala-Asp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(O)=O)C(O)=O LVVBAKCGXXUHFO-ZLUOBGJFSA-N 0.000 description 1
- 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 1
- 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 1
- BLPYXIXXCFVIIF-FXQIFTODSA-N Ser-Cys-Arg Chemical compound C(C[C@@H](C(=O)O)NC(=O)[C@H](CS)NC(=O)[C@H](CO)N)CN=C(N)N BLPYXIXXCFVIIF-FXQIFTODSA-N 0.000 description 1
- KMWFXJCGRXBQAC-CIUDSAMLSA-N Ser-Cys-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CS)NC(=O)[C@H](CO)N KMWFXJCGRXBQAC-CIUDSAMLSA-N 0.000 description 1
- JFWDJFULOLKQFY-QWRGUYRKSA-N Ser-Gly-Phe Chemical compound [H]N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O JFWDJFULOLKQFY-QWRGUYRKSA-N 0.000 description 1
- QGAHMVHBORDHDC-YUMQZZPRSA-N Ser-His-Gly Chemical compound OC[C@H](N)C(=O)N[C@H](C(=O)NCC(O)=O)CC1=CN=CN1 QGAHMVHBORDHDC-YUMQZZPRSA-N 0.000 description 1
- QYSFWUIXDFJUDW-DCAQKATOSA-N Ser-Leu-Arg Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O QYSFWUIXDFJUDW-DCAQKATOSA-N 0.000 description 1
- 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 1
- JAWGSPUJAXYXJA-IHRRRGAJSA-N Ser-Phe-Arg Chemical compound NC(N)=NCCC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CO)N)CC1=CC=CC=C1 JAWGSPUJAXYXJA-IHRRRGAJSA-N 0.000 description 1
- XGQKSRGHEZNWIS-IHRRRGAJSA-N Ser-Pro-Tyr Chemical compound N[C@@H](CO)C(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccc(O)cc1)C(O)=O XGQKSRGHEZNWIS-IHRRRGAJSA-N 0.000 description 1
- PURRNJBBXDDWLX-ZDLURKLDSA-N Ser-Thr-Gly Chemical compound C[C@H]([C@@H](C(=O)NCC(=O)O)NC(=O)[C@H](CO)N)O PURRNJBBXDDWLX-ZDLURKLDSA-N 0.000 description 1
- MFQMZDPAZRZAPV-NAKRPEOUSA-N Ser-Val-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CO)N MFQMZDPAZRZAPV-NAKRPEOUSA-N 0.000 description 1
- 108010003723 Single-Domain Antibodies Proteins 0.000 description 1
- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- 108700005078 Synthetic Genes Proteins 0.000 description 1
- 201000009594 Systemic Scleroderma Diseases 0.000 description 1
- 206010042953 Systemic sclerosis Diseases 0.000 description 1
- 208000031673 T-Cell Cutaneous Lymphoma Diseases 0.000 description 1
- 208000024313 Testicular Neoplasms Diseases 0.000 description 1
- TWLMXDWFVNEFFK-FJXKBIBVSA-N Thr-Arg-Gly Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O TWLMXDWFVNEFFK-FJXKBIBVSA-N 0.000 description 1
- LKEKWDJCJSPXNI-IRIUXVKKSA-N Thr-Glu-Tyr Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 LKEKWDJCJSPXNI-IRIUXVKKSA-N 0.000 description 1
- 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 1
- WRQLCVIALDUQEQ-UNQGMJICSA-N Thr-Phe-Arg Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O WRQLCVIALDUQEQ-UNQGMJICSA-N 0.000 description 1
- 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 1
- VTMGKRABARCZAX-OSUNSFLBSA-N Thr-Pro-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)[C@@H](C)O VTMGKRABARCZAX-OSUNSFLBSA-N 0.000 description 1
- 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 1
- HUPLKEHTTQBXSC-YJRXYDGGSA-N Thr-Ser-Tyr Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 HUPLKEHTTQBXSC-YJRXYDGGSA-N 0.000 description 1
- NDZYTIMDOZMECO-SHGPDSBTSA-N Thr-Thr-Ala Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O NDZYTIMDOZMECO-SHGPDSBTSA-N 0.000 description 1
- GRIUMVXCJDKVPI-IZPVPAKOSA-N Thr-Thr-Tyr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O GRIUMVXCJDKVPI-IZPVPAKOSA-N 0.000 description 1
- 102100023935 Transmembrane glycoprotein NMB Human genes 0.000 description 1
- UGFOSENEZHEQKX-PJODQICGSA-N Trp-Val-Ala Chemical compound CC(C)[C@H](NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12)C(=O)N[C@@H](C)C(O)=O UGFOSENEZHEQKX-PJODQICGSA-N 0.000 description 1
- 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 1
- SWSUXOKZKQRADK-FDARSICLSA-N Trp-Val-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)N SWSUXOKZKQRADK-FDARSICLSA-N 0.000 description 1
- GLNADSQYFUSGOU-GPTZEZBUSA-J Trypan blue Chemical compound [Na+].[Na+].[Na+].[Na+].C1=C(S([O-])(=O)=O)C=C2C=C(S([O-])(=O)=O)C(/N=N/C3=CC=C(C=C3C)C=3C=C(C(=CC=3)\N=N\C=3C(=CC4=CC(=CC(N)=C4C=3O)S([O-])(=O)=O)S([O-])(=O)=O)C)=C(O)C2=C1N GLNADSQYFUSGOU-GPTZEZBUSA-J 0.000 description 1
- XGEUYEOEZYFHRL-KKXDTOCCSA-N Tyr-Ala-Phe Chemical compound C([C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=C(O)C=C1 XGEUYEOEZYFHRL-KKXDTOCCSA-N 0.000 description 1
- NKUGCYDFQKFVOJ-JYJNAYRXSA-N Tyr-Leu-Gln Chemical compound NC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 NKUGCYDFQKFVOJ-JYJNAYRXSA-N 0.000 description 1
- 208000023915 Ureteral Neoplasms Diseases 0.000 description 1
- 206010046458 Urethral neoplasms Diseases 0.000 description 1
- 201000005969 Uveal melanoma Diseases 0.000 description 1
- JIODCDXKCJRMEH-NHCYSSNCSA-N Val-Arg-Gln Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N JIODCDXKCJRMEH-NHCYSSNCSA-N 0.000 description 1
- VFOHXOLPLACADK-GVXVVHGQSA-N Val-Gln-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](C(C)C)N VFOHXOLPLACADK-GVXVVHGQSA-N 0.000 description 1
- XGJLNBNZNMVJRS-NRPADANISA-N Val-Glu-Ala Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(O)=O XGJLNBNZNMVJRS-NRPADANISA-N 0.000 description 1
- 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 1
- BZMIYHIJVVJPCK-QSFUFRPTSA-N Val-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(C)C)N BZMIYHIJVVJPCK-QSFUFRPTSA-N 0.000 description 1
- WBAJDGWKRIHOAC-GVXVVHGQSA-N Val-Lys-Gln Chemical compound [H]N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(N)=O)C(O)=O WBAJDGWKRIHOAC-GVXVVHGQSA-N 0.000 description 1
- DIOSYUIWOQCXNR-ONGXEEELSA-N Val-Lys-Gly Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)NCC(O)=O DIOSYUIWOQCXNR-ONGXEEELSA-N 0.000 description 1
- CXWJFWAZIVWBOS-XQQFMLRXSA-N Val-Lys-Pro Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N1CCC[C@@H]1C(=O)O)N CXWJFWAZIVWBOS-XQQFMLRXSA-N 0.000 description 1
- 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 1
- PZTZYZUTCPZWJH-FXQIFTODSA-N Val-Ser-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)O)N PZTZYZUTCPZWJH-FXQIFTODSA-N 0.000 description 1
- 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 1
- 241000700605 Viruses Species 0.000 description 1
- 208000004354 Vulvar Neoplasms Diseases 0.000 description 1
- RUXQWZJWMCHCHH-IZZDOVSWSA-N [(e)-1-pyridin-2-ylethylideneamino]urea Chemical compound NC(=O)N\N=C(/C)C1=CC=CC=N1 RUXQWZJWMCHCHH-IZZDOVSWSA-N 0.000 description 1
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 238000007792 addition Methods 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 108010076324 alanyl-glycyl-glycine Proteins 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 102000025171 antigen binding proteins Human genes 0.000 description 1
- 108091000831 antigen binding proteins Proteins 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 108010008355 arginyl-glutamine Proteins 0.000 description 1
- 108010029539 arginyl-prolyl-proline Proteins 0.000 description 1
- 108010036999 aspartyl-alanyl-histidyl-lysine Proteins 0.000 description 1
- 108010068265 aspartyltyrosine Proteins 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 230000006472 autoimmune response Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 208000030224 brain astrocytoma Diseases 0.000 description 1
- 210000000133 brain stem Anatomy 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- UDSAIICHUKSCKT-UHFFFAOYSA-N bromophenol blue Chemical compound C1=C(Br)C(O)=C(Br)C=C1C1(C=2C=C(Br)C(O)=C(Br)C=2)C2=CC=CC=C2S(=O)(=O)O1 UDSAIICHUKSCKT-UHFFFAOYSA-N 0.000 description 1
- 201000002143 bronchus adenoma Diseases 0.000 description 1
- 210000005252 bulbus oculi Anatomy 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 238000005251 capillar electrophoresis Methods 0.000 description 1
- 230000011748 cell maturation Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 201000007335 cerebellar astrocytoma Diseases 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 208000025302 chronic primary adrenal insufficiency Diseases 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 208000011588 combined hepatocellular carcinoma and cholangiocarcinoma Diseases 0.000 description 1
- 230000004154 complement system Effects 0.000 description 1
- 239000008358 core component Substances 0.000 description 1
- 201000007241 cutaneous T cell lymphoma Diseases 0.000 description 1
- 208000035250 cutaneous malignant susceptibility to 1 melanoma Diseases 0.000 description 1
- 108010060199 cysteinylproline Proteins 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 210000001151 cytotoxic T lymphocyte Anatomy 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 239000005547 deoxyribonucleotide Substances 0.000 description 1
- 125000002637 deoxyribonucleotide group Chemical group 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 238000003113 dilution method Methods 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 208000028715 ductal breast carcinoma in situ Diseases 0.000 description 1
- 230000002357 endometrial effect Effects 0.000 description 1
- 210000003527 eukaryotic cell Anatomy 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 210000001508 eye Anatomy 0.000 description 1
- 208000024519 eye neoplasm Diseases 0.000 description 1
- 238000000684 flow cytometry Methods 0.000 description 1
- 102000034287 fluorescent proteins Human genes 0.000 description 1
- 108091006047 fluorescent proteins Proteins 0.000 description 1
- 210000000285 follicular dendritic cell Anatomy 0.000 description 1
- 210000000232 gallbladder Anatomy 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 238000012215 gene cloning Methods 0.000 description 1
- 238000010353 genetic engineering Methods 0.000 description 1
- 210000001102 germinal center b cell Anatomy 0.000 description 1
- 108010055341 glutamyl-glutamic acid Proteins 0.000 description 1
- 108010079547 glutamylmethionine Proteins 0.000 description 1
- 108010050475 glycyl-leucyl-tyrosine Proteins 0.000 description 1
- 108010020688 glycylhistidine Proteins 0.000 description 1
- 108010087823 glycyltyrosine Proteins 0.000 description 1
- LPLVUJXQOOQHMX-UHFFFAOYSA-N glycyrrhetinic acid glycoside Natural products C1CC(C2C(C3(CCC4(C)CCC(C)(CC4C3=CC2=O)C(O)=O)C)(C)CC2)(C)C2C(C)(C)C1OC1OC(C(O)=O)C(O)C(O)C1OC1OC(C(O)=O)C(O)C(O)C1O LPLVUJXQOOQHMX-UHFFFAOYSA-N 0.000 description 1
- 229960004949 glycyrrhizic acid Drugs 0.000 description 1
- UYRUBYNTXSDKQT-UHFFFAOYSA-N glycyrrhizic acid Natural products CC1(C)C(CCC2(C)C1CCC3(C)C2C(=O)C=C4C5CC(C)(CCC5(C)CCC34C)C(=O)O)OC6OC(C(O)C(O)C6OC7OC(O)C(O)C(O)C7C(=O)O)C(=O)O UYRUBYNTXSDKQT-UHFFFAOYSA-N 0.000 description 1
- 239000001685 glycyrrhizic acid Substances 0.000 description 1
- 235000019410 glycyrrhizin Nutrition 0.000 description 1
- LPLVUJXQOOQHMX-QWBHMCJMSA-N glycyrrhizinic acid Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@@H]1C([C@H]2[C@]([C@@H]3[C@@]([C@@]4(CC[C@@]5(C)CC[C@@](C)(C[C@H]5C4=CC3=O)C(O)=O)C)(C)CC2)(C)CC1)(C)C)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O LPLVUJXQOOQHMX-QWBHMCJMSA-N 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 210000003128 head Anatomy 0.000 description 1
- 201000010536 head and neck cancer Diseases 0.000 description 1
- 208000014829 head and neck neoplasm Diseases 0.000 description 1
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- 238000012165 high-throughput sequencing Methods 0.000 description 1
- 210000003630 histaminocyte Anatomy 0.000 description 1
- 238000002868 homogeneous time resolved fluorescence Methods 0.000 description 1
- 229920001477 hydrophilic polymer Polymers 0.000 description 1
- 230000003463 hyperproliferative effect Effects 0.000 description 1
- 230000002267 hypothalamic effect Effects 0.000 description 1
- 239000012642 immune effector Substances 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 208000026278 immune system disease Diseases 0.000 description 1
- 229940121354 immunomodulator Drugs 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 208000000509 infertility Diseases 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 231100000535 infertility Toxicity 0.000 description 1
- 230000006749 inflammatory damage Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 201000007450 intrahepatic cholangiocarcinoma Diseases 0.000 description 1
- 201000008893 intraocular retinoblastoma Diseases 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 206010073095 invasive ductal breast carcinoma Diseases 0.000 description 1
- 201000010985 invasive ductal carcinoma Diseases 0.000 description 1
- 206010073096 invasive lobular breast carcinoma Diseases 0.000 description 1
- 238000004255 ion exchange chromatography Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 210000000244 kidney pelvis Anatomy 0.000 description 1
- 210000002429 large intestine Anatomy 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 108010034529 leucyl-lysine Proteins 0.000 description 1
- 208000012987 lip and oral cavity carcinoma Diseases 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 238000004020 luminiscence type Methods 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 210000003563 lymphoid tissue Anatomy 0.000 description 1
- 108010003700 lysyl aspartic acid Proteins 0.000 description 1
- 108010038320 lysylphenylalanine Proteins 0.000 description 1
- 208000020984 malignant renal pelvis neoplasm Diseases 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 210000000716 merkel cell Anatomy 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Chemical class 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000010369 molecular cloning Methods 0.000 description 1
- 201000005962 mycosis fungoides Diseases 0.000 description 1
- 210000000822 natural killer cell Anatomy 0.000 description 1
- 210000003739 neck Anatomy 0.000 description 1
- 201000008383 nephritis Diseases 0.000 description 1
- 238000007857 nested PCR Methods 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 201000002575 ocular melanoma Diseases 0.000 description 1
- 201000006958 oropharynx cancer Diseases 0.000 description 1
- 201000008968 osteosarcoma Diseases 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 244000045947 parasite Species 0.000 description 1
- 230000000849 parathyroid Effects 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 230000000149 penetrating effect Effects 0.000 description 1
- 238000005220 pharmaceutical analysis Methods 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 210000004180 plasmocyte Anatomy 0.000 description 1
- 208000005987 polymyositis Diseases 0.000 description 1
- 108091033319 polynucleotide Proteins 0.000 description 1
- 239000002157 polynucleotide Substances 0.000 description 1
- 102000040430 polynucleotide Human genes 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 208000017426 precursor B-cell acute lymphoblastic leukemia Diseases 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 208000016800 primary central nervous system lymphoma Diseases 0.000 description 1
- 208000025638 primary cutaneous T-cell non-Hodgkin lymphoma Diseases 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 108010077112 prolyl-proline Proteins 0.000 description 1
- 108010087846 prolyl-prolyl-glycine Proteins 0.000 description 1
- 108010070643 prolylglutamic acid Proteins 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 238000002331 protein detection Methods 0.000 description 1
- 239000012460 protein solution Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000012175 pyrosequencing Methods 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 201000007444 renal pelvis carcinoma Diseases 0.000 description 1
- 230000003362 replicative effect Effects 0.000 description 1
- 230000001850 reproductive effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 201000009410 rhabdomyosarcoma Diseases 0.000 description 1
- 239000002336 ribonucleotide Substances 0.000 description 1
- 125000002652 ribonucleotide group Chemical group 0.000 description 1
- 238000007480 sanger sequencing Methods 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 238000010187 selection method Methods 0.000 description 1
- 238000012163 sequencing technique Methods 0.000 description 1
- 102000034285 signal transducing proteins Human genes 0.000 description 1
- 108091006024 signal transducing proteins Proteins 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 235000020183 skimmed milk Nutrition 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 201000008261 skin carcinoma Diseases 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 239000012089 stop solution Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 108010061238 threonyl-glycine Proteins 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
- 108091007466 transmembrane glycoproteins Proteins 0.000 description 1
- 108010044292 tryptophyltyrosine Proteins 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000005909 tumor killing Effects 0.000 description 1
- 239000000439 tumor marker Substances 0.000 description 1
- 208000025421 tumor of uterus Diseases 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 210000000626 ureter Anatomy 0.000 description 1
- 208000024722 urethra neoplasm Diseases 0.000 description 1
- 210000001635 urinary tract Anatomy 0.000 description 1
- 206010046766 uterine cancer Diseases 0.000 description 1
- 208000013139 vaginal neoplasm Diseases 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 108010000998 wheylin-2 peptide Proteins 0.000 description 1
- 210000005253 yeast cell Anatomy 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0008—Antigens related to auto-immune diseases; Preparations to induce self-tolerance
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/001102—Receptors, cell surface antigens or cell surface determinants
- A61K39/001111—Immunoglobulin superfamily
- A61K39/001112—CD19 or B4
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/46—Cellular immunotherapy
- A61K39/461—Cellular immunotherapy characterised by the cell type used
- A61K39/4611—T-cells, e.g. tumor infiltrating lymphocytes [TIL], lymphokine-activated killer cells [LAK] or regulatory T cells [Treg]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/46—Cellular immunotherapy
- A61K39/463—Cellular immunotherapy characterised by recombinant expression
- A61K39/4631—Chimeric Antigen Receptors [CAR]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/46—Cellular immunotherapy
- A61K39/464—Cellular immunotherapy characterised by the antigen targeted or presented
- A61K39/4643—Vertebrate antigens
- A61K39/4644—Cancer antigens
- A61K39/464402—Receptors, cell surface antigens or cell surface determinants
- A61K39/464411—Immunoglobulin superfamily
- A61K39/464412—CD19 or B4
-
- 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
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
- C07K14/70503—Immunoglobulin superfamily
- C07K14/7051—T-cell receptor (TcR)-CD3 complex
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
- C07K14/70578—NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
-
- 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
- C07K17/00—Carrier-bound or immobilised peptides; Preparation thereof
-
- 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
- C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
- C12N15/62—DNA sequences coding for fusion proteins
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/10—Cells modified by introduction of foreign genetic material
-
- 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]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
- C07K2317/62—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising only variable region components
- C07K2317/622—Single chain antibody (scFv)
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
- C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/01—Fusion polypeptide containing a localisation/targetting motif
- C07K2319/03—Fusion polypeptide containing a localisation/targetting motif containing a transmembrane segment
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/33—Fusion polypeptide fusions for targeting to specific cell types, e.g. tissue specific targeting, targeting of a bacterial subspecies
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/70—Fusion polypeptide containing domain for protein-protein interaction
- C07K2319/74—Fusion polypeptide containing domain for protein-protein interaction containing a fusion for binding to a cell surface receptor
Abstract
本申请涉及一种可以特异性结合CD19的抗体或其抗原结合片段,其以3.5μg/mL或更低的IC50值与CD19蛋白相结合。本申请还涉及了所述抗体或其抗原结合片段在制备药物中的用途。
Description
技术领域
本申请涉及生物医药领域,具体涉及一种与CD19蛋白特异性结合的抗体或其抗原结合片段。
背景技术
B淋巴细胞抗原CD19,也称为CD19分子(分化簇19)。在正常的淋巴组织中,CD19表达于生发中心的B细胞和滤泡树突状细胞、套细胞、滤泡间T细胞区的树突状大细胞。CD19在人体B细胞中主要起到两个作用,一是充当衔接蛋白以将细胞质信号蛋白募集到膜上,二是在CD19/CD21复合物内起作用以降低B细胞受体信号传导途径的阈值。CD19蛋白是B淋巴细胞表面稳定存在的一种靶蛋白,存在于B细胞成熟的各个阶段,大多数血液瘤相关的肿瘤(B-ALL/CLL/B-NHL等)都高表达CD19,而在造血干细胞、其他正常细胞中不表达,因此CD19成为治疗血液瘤相关肿瘤的重要靶点。
然而,目前已研发的CD19抗体特异性较低,且对肿瘤的抑制能力有限,因此亟待开发新的抗CD19药物以用于新药研发。
发明内容
本申请提供了一种特异性结合CD19的抗体或其抗原结合片段及其应用。本申请还提供了包含所述抗体或其抗原结合片段融合蛋白,编码所述抗体或其抗原结合蛋白的核酸分子,包含所述核酸分子的载体,包含所述载体或所述核酸分子的细胞等。本申请提供的抗CD19抗体具有下列性质中的一种或多种:1)能特异性结合CD19蛋白;2)针对CD19蛋白不同表位拥有不同亲和特征;3)具有良好的靶向杀伤效果;4)具有较高稳定性;5)具有较高纯度;6)能够用于治疗癌症。
一方面,本申请提供了一种抗体、其抗原结合片段或变体,其以3.5μg/ml或更低的IC50值与CD19蛋白相结合。
在某些实施方式中,所述抗体选自下组中任一项:单克隆抗体、单链抗体、嵌合抗体、鼠源抗体和人源化抗体。
在某些实施方式中,所述抗原结合片段选自:Fab、Fab’、F(ab)2、F(ab’)2、Fv和scFv。
在某些实施方式中,所述变体选自下组:1)在所述抗体或所述其抗原结合片段中经过取代、缺失或添加一个或多个氨基酸的蛋白质或多肽;和2)与所述抗体或所述其抗原结合片段具有90%以上序列同源性的蛋白质或多肽。
另一方面,本申请提供了一种抗体、其抗原结合片段或变体,所述抗体、其抗原结合片段或变体与参比抗体竞争结合所述CD19蛋白,其中所述参比抗体包含轻链可变区和重链可变区,所述参比抗体的轻链可变区包含LCDR1-3,所述LCDR1的氨基酸序列选自下组中任一项所示的氨基酸序列:SEQ ID NO:4和SEQ ID NO:18;所述LCDR2的氨基酸序列选自下组中任一项所示的氨基酸序列:SEQ ID NO:5和SEQ ID NO:19;以及所述LCDR3的氨基酸序列选自下组中任一项所示的氨基酸序列:SEQ ID NO:6和SEQ ID NO:20;且所述参比抗体的重链可变区包含HCDR1-3,所述HCDR1的氨基酸序列选自下组中任一项所示的氨基酸序列:SEQ ID NO:7、SEQ ID NO:21和SEQ ID NO:32;所述HCDR2的氨基酸序列选自下组中任一项所示的氨基酸序列:SEQ ID NO:8、SEQ ID NO:22和SEQ ID NO:33;以及所述HCDR3的氨基酸序列选自下组中任一项所示的氨基酸序列:SEQ ID NO:9、SEQ ID NO:23和SEQ ID NO:34。
在某些实施方式中,所述参比抗体的轻链可变区的氨基酸序列选自下组中任一项所示的氨基酸序列:SEQ ID NO:42、SEQ ID NO:44和SEQ ID NO:46,且所述参比抗体的重链可变区的氨基酸序列选自下组中任一项所示的氨基酸序列:SEQ ID NO:48、SEQ ID NO:50和SEQ ID NO:52。
在某些实施方式中,所述抗体以3.5μg/ml或更低的IC50值与CD19蛋白相结合。
在某些实施方式中,所述抗体选自下组中任一项:单克隆抗体、单链抗体、嵌合抗体、鼠源抗体和人源化抗体。
在某些实施方式中,所述抗原结合片段选自:Fab、Fab’、F(ab)2、F(ab’)2、Fv和scFv。
在某些实施方式中,所述变体选自下组:1)在所述抗体或所述其抗原结合片段中经过取代、缺失或添加一个或多个氨基酸的蛋白质或多肽;和2)与所述抗体或所述其抗原结合片段具有90%以上序列同源性的蛋白质或多肽。
另一方面,本申请提供了一种抗体、其抗原结合片段或变体,所述抗体、其抗原结合片段或变体包含LCDR1,且所述LCDR1包含选自下组任一项所示的氨基酸序列:SEQ IDNO:4和SEQ ID NO:18。在某些实施方式中,其包含LCDR2,且所述LCDR2包含选自下组任一项所示的氨基酸序列:SEQ ID NO:5和SEQ ID NO:19。在某些实施方式中,其包含LCDR3,且所述LCDR3包含选自下组任一项所示的氨基酸序列:SEQ ID NO:6和SEQ ID NO:20。在某些实施方式中,其包含轻链可变区VL,且所述轻链可变区VL包含选自下组任一项所示的氨基酸序列:SEQ ID NO:42、SEQ ID NO:44和SEQ ID NO:46。
在某些实施方式中,其包含HCDR1,且所述HCDR1包含选自下组任一项所示的氨基酸序列:SEQ ID NO:7、SEQ ID NO:21和SEQ ID NO:32。在某些实施方式中,其包含HCDR2,且所述HCDR2包含选自下组任一项所示的氨基酸序列:SEQ ID NO:8、SEQ ID NO:22和SEQ IDNO:33。在某些实施方式中,其包含HCDR3,且所述HCDR3包含选自下组任一项所示的氨基酸序列:SEQ ID NO:9和SEQ ID NO:23和SEQ ID NO:34。在某些实施方式中,其包含重链可变区VH,且所述重链可变区VH包含选自下组任一项所示的氨基酸序列:SEQ ID NO:48、SEQ IDNO:50和SEQ ID NO:52。
在某些实施方式中,所述抗体或其抗原结合片段为scFv。在某些实施方式中,所述scFv包含选自下组任一项所示的氨基酸序列:SEQ ID NO:56、SEQ ID NO:58和SEQ ID NO:60。
在某些实施方式中,所述抗体以3.5μg/ml或更低的IC50值与CD19蛋白相结合。
在某些实施方式中,所述抗体选自下组中任一项:单克隆抗体、单链抗体、嵌合抗体、鼠源抗体和人源化抗体。
在某些实施方式中,所述抗原结合片段选自:Fab、Fab’、F(ab)2、F(ab’)2、Fv和scFv。
在某些实施方式中,所述变体选自下组:1)在所述抗体或所述其抗原结合片段中经过取代、缺失或添加一个或多个氨基酸的蛋白质或多肽;和2)与所述抗体或所述其抗原结合片段具有90%以上序列同源性的蛋白质或多肽。
在某些实施方式中,所述CD19蛋白为小鼠CD19蛋白。
另一方面,本申请提供了一种融合蛋白,其包含本申请所述的抗体、其抗原结合片段或变体。在某些实施方式中,所述融合蛋白为嵌合抗原受体。
在某些实施方式中,所述嵌合抗原受体包含胞外铰链区、跨膜结构域、共刺激结构域和CD3ζ胞内信号转导结构域。
在某些实施方式中,所述胞外铰链区选自CD8铰链或IgG4铰链。
在某些实施方式中,所述跨膜结构域选自T细胞受体的α,β或ζ链、CD28、CD3e、CD45、CD4、CD5、CD8、CD9、CD16、CD22、CD33、CD37、CD64、CD80、CD86、CD134、CD137和CD154。在某些实施方式中,所述跨膜结构域选自CD8-1或CD8-2。
在某些实施方式中,所述共刺激结构域选自CD27、CD28、4-1BB、OX40或ICOS。
在某些实施方式中,所述的嵌合抗原受体,所述胞外铰链区选自CD8铰链或IgG4铰链;所述跨膜结构域选自CD8-1或CD8-2;所述共刺激结构域选自4-1BB或OX40。
在某些实施方式中,所述的嵌合抗原受体,所述CD8-1跨膜的N端与所述CD8铰链的C端相连,所述CD8-1跨膜的C端与所述4-1BB的N端相连,所述4-1BB的C端与所述OX40的N端相连,所述OX40的C端与所述CD3ζ的N端相连。
在某些实施方式中,所述的嵌合抗原受体,所述CD8-2跨膜的N端与所述IgG4铰链的C端相连,所述CD8-2跨膜的C端与所述4-1BB的N端相连,所述4-1BB的C端与所述OX40的N端相连,所述OX40的C端与所述CD3ζ的N端相连。
另一方面,本申请提供了分离的一种或多种核酸分子,其编码本申请所述的抗体、其抗原结合片段或变体,和/或,其编码本申请所述的融合蛋白。
另一方面,本申请提供了一种或多种载体,其包含本申请所述的一种或多种核酸分子。
另一方面,本申请提供了一种或多种细胞,其包含本申请所述的一种或多种核酸分子或本申请所述的一种或多种载体。
另一方面,本申请提供了制备本申请所述的抗体、其抗原结合片段或变体,和/或,本申请所述的融合蛋白的方法,所述方法包括在使得本申请所述抗体、其抗原结合片段或变体,和/或,本申请所述的融合蛋白表达的条件下,培养本申请所述的细胞。在某些实施方式中,本申请所述方法包含收获所述抗体、其抗原结合片段或变体,和/或,所述的融合蛋白。
另一方面,本申请提供了一种药物组合物,其包含本申请所述的抗体、其抗原结合片段或变体、本申请所述的核酸分子、本申请所述的载体、本申请所述的细胞和/或本申请所述的融合蛋白,以及任选地药学上可接受的佐剂。
另一方面,本申请提供了所述的抗体、其抗原结合片段或变体,和/或,所述的融合蛋白在制备预防或治疗疾病或病症的药物中的用途。
在某些实施方式中,所述疾病或病症选自下组中的任一项:肿瘤和自体免疫疾病。
在某些实施方式中,所述肿瘤选自下组中的任一项:B细胞亚型非霍奇金氏恶性淋巴瘤(NHL)、伯基特氏淋巴瘤、多发性骨髓瘤、前B急性淋巴母细胞性白血病及其他来源于早期B细胞前体的恶性肺瘤、普通急性淋巴细胞白血病、T慢性淋巴细胞性白血病、毛细胞白血病、非急性淋巴母细胞性白血病、华氏巨球蛋白血症、前淋巴细胞性白血病、浆细胞瘤、骨硬化骨髓瘤、浆细胞性白血病、单克隆丙种球蛋白病(MGUS)、郁积性多发性骨髓瘤(SMM)、缓慢性多发性骨髓瘤(IMM)、霍奇金氏恶性淋巴瘤、胃癌、肝癌、白血病、肾脏肿瘤、肺癌、小肠癌、骨癌、前列腺癌、结直肠癌、乳腺癌、大肠癌、前列腺癌、宫颈癌、肾上腺肿瘤和膀胱肿瘤。
在某些实施方式中,所述自体免疫疾病选自下组中的任一项:类风湿性关节炎、多发性硬化症和CD19+白血病。
另一方面,本申请提供了一种抑制CD19蛋白生物学活性的方法,其包括施用本申请所述的抗体、其抗原结合片段或变体、所述的核酸分子、所述的载体、所述的细胞和/或所述的融合蛋白。
另一方面,本申请提供了本申请所述的抗体、其抗原结合片段或变体、所述的核酸分子、所述的载体、所述的细胞和/或所述的融合蛋白在制备诊断或检测肿瘤的试剂中的应用。
本领域技术人员能够从下文的详细描述中容易地洞察到本申请的其它方面和优势。下文的详细描述中仅显示和描述了本申请的示例性实施方式。如本领域技术人员将认识到的,本申请的内容使得本领域技术人员能够对所公开的具体实施方式进行改动而不脱离本申请所涉及发明的精神和范围。相应地,本申请的附图和说明书中的描述仅仅是示例性的,而非为限制性的。
附图说明
本申请所涉及的发明的具体特征如所附权利要求书所显示。通过参考下文中详细描述的示例性实施方式和附图能够更好地理解本申请所涉及发明的特点和优势。对附图简要说明书如下:
图1显示的是本申请所述的CD19抗体ELISA活性检测结果。
图2显示的是本申请所述的CD19抗体流式活性检测结果。
图3显示的是本申请所述的CD19抗体蛋白印迹法检测结果。
图4显示的是不同浓度本申请所述的CD19抗体流式活性检测结果。
图5显示的是本申请实施例中构建的CAR结构示意图。
图6显示的是anti-CD19CAR-T阳性率检测结果。
具体实施方式
以下由特定的具体实施例说明本申请发明的实施方式,熟悉此技术的人士可由本说明书所公开的内容容易地了解本申请发明的其他优点及效果。本申请提供了一种可以特异性结合CD19蛋白的抗体,其可以能特异性结合CD19蛋白并且针对CD19不同表位拥有不同亲和特征。所述CD19抗体具有良好的靶向杀伤效果、较高的稳定性、较高的纯度。所述CD19抗体能够用于治疗癌症。
以下对本发明做进一步描述:在本发明中,除非另有说明,否则本申请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,本申请中所用的蛋白质和核酸化学、分子生物学、细胞和组织培养、微生物学、免疫学相关术语和实验室操作步骤均为相应领域内广泛使用的术语和常规步骤。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。
在本申请中,术语“抗体”通常是指一种能够特异性识别和/或中和特定抗原的多肽分子。例如,抗体可包含通过二硫键相互连接的至少两条重(H)链和两条轻(L)链组成的免疫球蛋白,并且包括任何包含其抗原结合部分的分子。术语“抗体”包括单克隆抗体、抗体片段或抗体衍生物,包括但不限于人抗体、人源化抗体、嵌合抗体、单域抗体(例如,dAb),单链抗体(例如,scFv),以及与抗原结合的抗体片段(例如,Fab、Fab’和(Fab)2片段)。在本申请中,术语“单克隆抗体”(monoclonal antibody,mAb)通常是指仅由一种类型的免疫细胞制造出来的抗体,也可以由制造这种抗体的免疫细胞与癌细胞融合后产生的杂交瘤细胞产生。在本申请中,术语“单链抗体”(single chain antibody fragment,scFv)通常是指由抗体重链可变区和轻链可变区通过连接子连接而成的抗体。scFv可以较好地保留其对抗原的亲和活力,并且具有分子量小、穿透力强和抗原性弱等特点。在本申请中,术语“人源化抗体”通常是指鼠源单克隆抗体以基因克隆及DNA重组技术改造,重新表达的抗体,其大部分氨基酸序列为人源序列取代,基本保留亲本鼠单克隆抗体的亲和力和特异性,又降低了其异源性,有利应用于人体。在本申请中,术语“嵌合抗体”通常是指由鼠源性抗体的V区基因与人抗体的C区基因拼接而成的抗体,因其减少了鼠源的成分,从而减低了鼠源性抗体引起的不良反映,并有助于提高疗效。在本申请中,术语“鼠源抗体”通常是指将来源于免疫接种过的小鼠的B细胞与骨髓瘤细胞融合,继而筛选出既能无线增殖又能分泌抗体的鼠杂交融合细胞,进而筛选、制备抗体以及纯化。术语“抗体”还包括抗体的所有重组体形式,例如在原核细胞中表达的抗体以及本申请所述的任何与抗原结合的抗体片段及其衍生物。每条重链可由重链可变区(VH)和重链恒定区构成。每条轻链可由轻链可变区(VL)和轻链恒定区构成。VH和VL区可进一步被区分为称为互补决定区(CDR)的高变区,它们散布在称为构架区(FR)的更保守的区域中。每个VH和VL可由三个CDR和四个FR区构成,它们从氨基端至羧基端可按以下顺序排列:FR1、CDR1、FR2、CDR2、FR3、CDR3和FR4。重链和轻链的可变区含有与抗原相互作用的结合结构域。抗体的恒定区可介导该免疫球蛋白与宿主组织或因子的结合,所述宿主组织或因子包括免疫系统的多种细胞(例如,效应细胞)和经典补体系统的第一成分(Clq)。
在本申请中,术语“抗体结合片段”通常是指抗体中发挥特异性结合抗原功能的一个或多个片段。抗体的抗原结合功能可通过抗体的全长片段来实现。抗体的抗原结合功能也可通过以下的片段来实现:(1)Fab片段,即由VL、VH、CL和CH结构域组成的一价片段;(2)F(ab’)2片段,包含通过铰链区处的二硫键连接的两个Fab片段的二价片段;(3)由VH和CH结构域组成的Fd片段;(4)由抗体单臂的VL和VH结构域组成的Fv片段;(5)由VH结构域组成的dAb片段(Ward等,(1989)Nature 341:544-546);(6)分离的互补决定区(CDR)和(7)可任选地通过接头连接的两个或以上分离的CDR的组合。此外,还可包括由VL和VH配对形成的一价单链分子Fv(scFv)(参见Bird等(1988)Science 242:423-426;以及Huston等(1988)Proc.Natl.Acad.Sci.85:5879-5883)。所述“抗原结合部分”还可包括免疫球蛋白融合蛋白,所述融合蛋白包含选自以下的结合结构域:(1)与免疫球蛋白铰链区多肽融合的结合结构域多肽;(2)与铰链区融合的免疫球蛋白重链CH2恒定区;和(3)与CH2恒定区融合的免疫球蛋白重链CH3恒定区。本申请提供的特异性结合CD19蛋白的抗体,其中所述抗体或其抗原结合片段选自由下述组成的组:Fab、scFv、Fab’、F(ab)2、F(ab’)2和dAb。
在本申请中,术语“CD19蛋白”通常是指主要表达于早期的B细胞的、95kDa左右的B细胞系特有的跨膜糖蛋白。CD19蛋白在正常及恶性B淋巴细胞中均有表达,被视为B细胞发育过程中最为可靠的表面标记物。在本申请中,所述CD19蛋白可以为人CD19蛋白。例如,本申请所述表达的人CD19蛋白可以包含如NCBI中登录号AAB60697所示的氨基酸序列。在某些实施方式中,所述CD19蛋白可为CD19重组蛋白,所述重组蛋白可为CD19蛋白的胞外区。例如,CD19重组蛋白可为abcam的ab234966,氨基酸序列编号第20位至291位的蛋白。
在本申请中,术语“融合蛋白”(fusion proteins)又称嵌合蛋白(chimericproteins),通常是指通过DNA重组技术得到的两个基因重组后的表达产物。融合蛋白技术是为了获得大量标准融合蛋白而进行的由目的性的基因融合和蛋白表达方法。利用融合蛋白技术,可构建和表达具有多种功能的新型目的蛋白。所述融合基因的翻译产生具有衍生子每种原始蛋白质的功能特性的单个或多个多肽。通过重组DNA技术人工产生重组的融合蛋白可用于生物研究或治疗。所述嵌合或嵌合体通常表示具有不同功能或物理化学特征的多肽制成的融合蛋白。融合蛋白可包括将抗体的抗原结合区scFv、CD3ζ链或胞内部分融合形成的嵌合抗原受体,其可包括肿瘤相关抗原结合区、胞外铰链区、跨膜区等结构域,所述肿瘤相关抗原结合区可来源于抗体的抗原结合区,例如scFv。
在本申请中,术语“嵌合抗原受体”(chimeric antigen receptor,CAR)是单链抗体的可变区和T细胞信号分子的融合蛋白。它使T细胞可以通过非MHC限制性的方式识别特异性抗原,发挥杀伤作用。在本申请中,术语“单链抗体”可以是由所述重链可变区和所述轻链可变区通过连接肽连接而成的抗体。CAR是嵌合抗原受体T细胞(CAR-T)的核心部件,其可包括CD19结合结构域、跨膜结构域、共刺激结构域和胞内信号转导结构域。
在本申请中,术语“跨膜结构域”(transmembrane domain)通常是指CAR中穿过细胞膜的结构域,其与细胞内信号转导结构域相连接,起着传递信号的作用。
在本申请中,术语“共刺激结构域”通常是指可以提供免疫共刺激分子的胞内结构域,所述共刺激分子为淋巴细胞对抗原的有效应答所需要的细胞表面分子。
在本申请中,术语“胞内信号传导结构域”通常是指CAR位于细胞内信号传导的组分,其包含信号传导结构域和特异性结合所述受体组分的结构域,例如:其可选自CD3ζ胞内域,CD28胞内域,4-1BB胞内域和OX40胞内域。
与抗体相关的术语“变体”在本申请中指,包含已经通过至少1个,例如1-30,或1-20或1-10个,例如1或2或3或4或5个氨基酸取代、缺失和/或插入而具有氨基酸改变的目标抗体区域(例如重链可变区或轻链可变区或重链CDR区或轻链CDR区)的抗体,其中变体基本上保持改变之前的抗体分子的生物学特性。在一方面,本申请涵盖在本申请中所述的任何抗体的变体。在某些实施方式中,抗体变体保持改变前抗体的至少60%,70%,80%,90%,或100%的生物学活性(例如抗原结合能力)。在某些实施方式中,所述改变不会导致抗体变体丧失对抗原的结合,但任选地可以赋予诸如提高的抗原亲和力和不同的效应子功能等性质。可以理解的,抗体的重链可变区或轻链可变区、或各CDR区可以单独改变或组合改变。在某些实施方案中,在一个或多个或全部三个重链CDR中的氨基酸改变不超过1个、2个、3个、4个、5个、6个、7个、8个、9个或10个。在某些实施方式中,所述氨基酸改变可以为氨基酸取代,例如可以为保守取代。在某些实施方式中,抗体变体与亲本抗体在目的抗体序列区域上具有至少80%、85%、90%或95%或99%或更高的氨基酸同一性。
在本申请中,术语“分离的”通常是指抗体是已经与它的天然环境中的组分分离的抗体。在某些实施方式中,将抗体纯化至大于95%或99%纯度,所述纯度通过例如电泳(例如,SDS-PAGE、等电聚焦(IEF)、毛细管电泳)或色谱(例如,离子交换或反相HPLC)确定。关于评价抗体纯度的方法的综述可参见Flatman,S.等,J.Chrom.B 848(2007)79-87。
在本申请中,术语“核酸分子”通常是指从其天然环境中分离的或人工合成的任何长度的分离形式的核苷酸、脱氧核糖核苷酸或核糖核苷酸或其类似物。本申请所述的核酸分子可以为分离的。例如,其可以是通过以下方法产生或合成的:(i)在体外扩增的,例如通过聚合酶链式反应(PCR)扩增产生的,(ii)通过克隆重组产生的,(iii)纯化的,例如通过酶切和凝胶电泳分级分离,或者(iv)合成的,例如通过化学合成。在某些实施方式中,所述分离的核酸是通过重组DNA技术制备的核酸分子。在本申请中,可以通过本领域已知的多种方法来制备编码所述抗体或其抗原结合片段的核酸,这些方法包括但不限于,采用限制性片段操作或采用合成性寡核苷酸的重叠延伸PCR,具体操作可参见Sambrook等人,MolecularCloning,A Laboratory Manual,Cold Spring Harbor Laboratory Press,Cold SpringHarbor,N.Y.,1989;和Ausube等人Current Protocols in Molecular Biology,GreenePublishing and Wiley-Interscience,New York N.Y.,1993。
在本申请中,术语“载体”通常是指能够在合适的宿主中自我复制的核酸分子,用以将插入的核酸分子转移到宿主细胞中和/或宿主细胞之间。所述载体可包括主要用于将DNA或RNA插入细胞中的载体、主要用于复制DNA或RNA的载体,以及主要用于DNA或RNA的转录和/或翻译的表达的载体。所述载体还包括具有多种上述功能的载体。所述载体可以是当引入合适的宿主细胞时能够转录并翻译成多肽的多核苷酸。通常,通过培养包含所述载体的合适的宿主细胞,所述载体可以产生期望的表达产物。在本申请中,所述载体中可包含一种或多种所述核酸分子。此外,所述载体中还可包含其他基因,例如允许在适当的宿主细胞中和在适当的条件下选择该载体的标记基因。此外,所述载体还可包含允许编码区在适当宿主中正确表达的表达控制元件。这样的控制元件为本领域技术人员所熟知的,例如,可包括启动子、核糖体结合位点、增强子和调节基因转录或mRNA翻译的其他控制元件等。在某些实施方式中,所述表达控制序列为可调的元件。所述表达控制序列的具体结构可根据物种或细胞类型的功能而变化,但通常包含分别参与转录和翻译起始的5’非转录序列和5’及3’非翻译序列,例如TATA盒、加帽序列、CAAT序列等。例如,5’非转录表达控制序列可包含启动子区,启动子区可包含用于转录控制功能性连接核酸的启动子序列。
在本申请中,术语“细胞”通常是指可以表达本申请所述的抗体、其抗原结合片段或变体,可以或已经含有包括本申请所述的核酸分子的质粒或载体的个体细胞、细胞系或细胞培养物。所述细胞可以是原核细胞(例如大肠杆菌),也可以是真核细胞(例如酵母细胞,COS细胞,中国仓鼠卵巢(CHO)细胞,HeLa细胞,HEK293细胞,COS-1细胞,NS0细胞或骨髓瘤细胞)。在某些实施方式中,所述细胞可以为免疫细胞。例如,浆细胞、细胞毒性T细胞、NK细胞、APSC多能细胞、肥大细胞、Ramos细胞、NALM-6细胞。
在本申请中,术语“药学上可接受的佐剂”通常是指药学可接受的制剂载体、溶液或加强制剂特性的添加剂。此类添加剂是所属领域技术人员熟知的。
在本申请中,术语“癌症”通常是指或描述哺乳动物的生理状况,其典型特征在于细胞增殖或存活失调。在本申请中,被称为癌症的过度增殖性疾病包括但不限于实体瘤,例如发生在乳腺、呼吸道、脑、生殖器官、消化道、尿道、眼、肝脏、皮肤、头颈、甲状腺、甲状旁腺的癌症,以及它们的远端转移。这类疾病还包括淋巴瘤、肉瘤和白血病。乳腺癌的实例包括但不限于浸润性导管癌、浸润性小叶癌、乳腺导管原位癌和乳腺小叶原位癌。呼吸道癌症的实例包括但不限于小细胞肺癌和非小细胞肺癌,以及支气管腺瘤和胸膜肺母细胞瘤。脑癌的实例包括但不限于脑干和下丘脑角质瘤、小脑和大脑星状细胞瘤、髓母细胞瘤、室管膜瘤,以及神经外胚层和松果体肿瘤。男性生殖器肿瘤包括但不限于前列腺和睾丸癌。女性生殖器肿瘤包括但不限于子宫内膜癌、宫颈癌、卵巢癌、阴道癌和外阴癌,以及子宫瘤。消化道肿瘤包括但不限于肛门、结肠、结肠直肠、食管、胆囊、胃、胰腺、直肠、小肠和唾液腺癌。尿道肿瘤包括但不限于膀胱、阴茎、肾、肾盂、输尿管和尿道癌。眼癌包括但不限于眼球内黑素瘤和视网膜母细胞瘤。肝癌的实例包括但不限于肝细胞癌(有或没有纤维板层变异的肝细胞瘤)、胆管癌(肝内胆管癌)和混合型肝细胞胆管细胞癌。皮肤癌包括但不限于鳞状细胞癌、卡波西(Kaposi’s)肉瘤、恶性黑素瘤、Merkel细胞皮肤癌和非黑素瘤型皮肤癌。头颈癌包括但不限于喉/下咽/鼻咽/口咽癌,和嘴唇和口腔癌。淋巴癌包括但不限于AIDS相关的淋巴癌、非霍奇金淋巴癌、皮肤T细胞淋巴癌、霍奇金氏病,以及中枢神经系统淋巴癌。肉瘤包括但不限于软组织肉瘤、骨肉瘤、恶性纤维组织细胞瘤、淋巴肉瘤和横纹肌肉瘤。白血病包括但不限于急性髓样白血病、急性淋巴细胞白血病、慢性淋巴细胞白血病、慢性粒细胞白血病和毛细胞白血病。
在本申请中,术语“自体免疫疾病”通常是指自身免疫性疾病是指机体对自身抗原发生免疫反应而导致自身组织损害所引起的疾病。免疫系统防御机体免受外来的或危险的物质侵袭(识别),这些物质包括微生物、寄生虫、恶性肿瘤细胞以及移植的器官和组织。正常情况下,免疫系统仅对外来或者危险的物质有反应,而不会对自身组织的抗原出现反应。然而,有时候会出现免疫功能异常,把自身的组织当作外来的,而产生抗体(被称为自身抗体)或免疫细胞攻击自身的细胞或组织。这种反应被称为自身免疫反应。它导致炎症和组织损伤。这种反应可能会导致自身免疫病,但有些人产生的自身抗体量非常少而不发生自身免疫病。常见的自身免疫病包括类风湿性关节炎、多发性硬化症和CD19+白血病。认为属于自身免疫性的额外疾病包括阿狄森病、多肌炎、综合征、进行性全身性硬化症、多个肾小球肾炎病例(肾脏炎症)和一些不育病例。
术语“和/或”应理解为意指可选项中的任一项或可选项的两项。
在本申请中,术语“约”通常是指在指定数值以上或以下0.5%-10%的范围内变动,例如在指定数值以上或以下0.5%、1%、1.5%、2%、2.5%、3%、3.5%、4%、4.5%、5%、5.5%、6%、6.5%、7%、7.5%、8%、8.5%、9%、9.5%、或10%的范围内变动。
在本申请中,术语“包括”通常是指包含、总括、含有或包涵的含义。在某些情况下,也表示“为”、“由……组成”的含义。
抗体或其抗原结合片段
本申请提供了一种抗体、其抗原结合片段或变体,其可以3.5μg/mL或更低(例如,3.5μg/ml或更低,3.4μg/mL或更低,3.3μg/mL或更低,3.2μg/mL或更低,3.15μg/mL或更低,3.1μg/ml或更低,3.0μg/mL或更低,2.9μg/mL或更低,2.8μg/mL或更低,2.5μg/mL或更低或2.1μg/mL或更低)的IC50值与CD19蛋白相结合。例如,所述IC50值通过ELISA法测定,所述IC50值可以为3.12μg/mL或更低。
在本申请中,所述抗体、其抗原结合片段或变体,其可以5μg/mL或更低(例如,5μg/mL或更低,4.5μg/mL或更低,4μg/mL或更低,3.5μg/mL或更低,3μg/mL或更低,2.5μg/mL或更低,2μg/mL或更低,1.5μg/mL或更低,1μg/mL或更低)的IC50值与CD19蛋白相结合。例如,所述IC50值通过流式细胞法测定,所述IC50值可以为5μg/mL或更低。
在本申请中,所述抗体可选择下组中任一项:单克隆抗体、单链抗体、嵌合抗体、鼠源抗体和人源化抗体。在本申请中,所述抗原结合片段可选自:Fab、Fab’、F(ab)2、F(ab’)2、Fv和scFv。
在本申请中,所述变体可选自下组:1)在所述抗体或所述其抗原结合片段中经过取代、缺失或添加一个或多个(例如,1-2个、1-3个、1-4个、1-5个、1-6个、1-7个、1-8个、1-9个、1-10个或更多个)氨基酸的蛋白质或多肽;和2)与所述抗体或所述其抗原结合片段具有90%以上(例如,具有至少约90%、约91%、约92%、约93%、约94%、约95%、约96%、约97%、约98%、约99%或更高的)序列同源性的蛋白质或多肽。在本申请中,所述变体与所述抗体、其抗原结合片段具有基本上相同的功能(例如,能够特异性结合CD19蛋白)。
在本申请中,所述抗体、其抗原结合片段或变体可与参比抗体竞争结合所述CD19蛋白。在本申请中,所述参比抗体可包含轻链可变区和重链可变区,所述参比抗体的轻链可变区可包含LCDR1-3,所述LCDR1的氨基酸序列可选自下组中任一项所示的氨基酸序列或其变体:SEQ ID NO:4和SEQ ID NO:18;所述LCDR2的氨基酸序列可选自下组中任一项所示的氨基酸序列或其变体:SEQ ID NO:5和SEQ ID NO:19;以及所述LCDR3的氨基酸序列可选自下组中任一项所示的氨基酸序列或其变体:SEQ ID NO:6和SEQ ID NO:20;且所述参比抗体的重链可变区可包含HCDR1-3,所述HCDR1的氨基酸序列可选自下组中任一项所示的氨基酸序列或其变体:SEQ ID NO:7、SEQ ID NO:21和SEQ ID NO:32;所述HCDR2的氨基酸序列可选自下组中任一项所示的氨基酸序列或其变体:SEQ ID NO:8、SEQ ID NO:22和SEQ ID NO:33;以及所述HCDR3的氨基酸序列可选自下组中任一项所示的氨基酸序列或其变体:SEQ IDNO:9、SEQ ID NO:23和SEQ ID NO:34。
在本申请中,所述参比抗体的轻链可变区的序列可选自下组中任一项所示的氨基酸序列或其变体:SEQ ID NO:42、SEQ ID NO:44和SEQ ID NO:46;所述参比抗体的重链可变区的序列可选自下组中任一项所示的氨基酸序列或其变体:SEQ ID NO:48、SEQ ID NO:50和SEQ ID NO:52。
本申请所述的抗体、其抗原结合片段或变体可包含抗体轻链或其片段。
在本申请中,所述轻链可包括轻链可变区,所述轻链可变区可包含LCDR1,所述LCDR1的氨基酸序列可选自下组中任一项所示的氨基酸序列或其变体:SEQ ID NO:4和SEQID NO:18。所述轻链可变区可包含LCDR2,所述LCDR2的氨基酸序列可选自下组中任一项所示的氨基酸序列或其变体:SEQ ID NO:5和SEQ ID NO:19。所述轻链可变区可包含LCDR3,所述LCDR3的氨基酸序列可选自下组中任一项所示的氨基酸序列或其变体:SEQ ID NO:6和SEQ ID NO:20。
在本申请中,所述抗体、其抗原结合片段或变体的轻链可变区可包含LFR1,所述LFR1的氨基酸序列可选自下组中任一项所示的氨基酸序列或其变体:SEQ ID NO:10、SEQID NO:24和SEQ ID NO:35。所述轻链可变区可包含LFR2,所述LFR2的氨基酸序列可选自下组中任一项所示的氨基酸序列或其变体:SEQ ID NO:11和SEQ ID NO:25。所述轻链可变区可包含LFR3,所述LFR3的氨基酸序列可选自下组中任一项所示的氨基酸序列或其变体:SEQID NO:12和SEQ ID NO:26。所述轻链可变区可包含LFR4,所述FR4的氨基酸序列可选自下组中任一项所示的氨基酸序列或其变体:SEQ ID NO:13、SEQ ID NO:27和SEQ ID NO:36。
在本申请中,所述轻链可变区的序列可选自下组中任一项所示的氨基酸序列或其变体:SEQ ID NO:42、SEQ ID NO:44和SEQ ID NO:46。
本申请所述的抗体、其抗原结合片段或变体可包含抗体重链或其片段。
在本申请中,所述轻链可包括重链可变区,所述重链可变区可包含HCDR1,所述HCDR1的氨基酸序列可选自下组中任一项所示的氨基酸序列或其变体:SEQ ID NO:7、SEQID NO:21和SEQ ID NO:32。所述重链可变区可包含HCDR2,所述HCDR2的氨基酸序列可选自下组中任一项所示的氨基酸序列或其变体:SEQ ID NO:8、SEQ ID NO:22和SEQ ID NO:33。所述重链可变区可包含HCDR3,所述HCDR3的氨基酸序列可选自下组中任一项所示的氨基酸序列或其变体:SEQ ID NO:9、SEQ ID NO:23和SEQ ID NO:34。
在本申请中,所述抗体、其抗原结合片段或变体的重链可变区可包含HFR1,所述HFR1的氨基酸序列可选自下组中任一项所示的氨基酸序列或其变体:SEQ ID NO:14、SEQID NO:28和SEQ ID NO:37。所述重链可变区可包含HFR2,所述HFR2的氨基酸序列可选自下组中任一项所示的氨基酸序列或其变体:SEQ ID NO:15、SEQ ID NO:29和SEQ ID NO:38。所述重链可变区可包含HFR3,所述HFR3的氨基酸序列可选自下组中任一项所示的氨基酸序列或其变体:SEQ ID NO:16、SEQ ID NO:30和SEQ ID NO:39。所述重链可变区可包含HFR4,所述HFR4的氨基酸序列可选自下组中任一项所示的氨基酸序列或其变体:SEQ ID NO:17、SEQID NO:31和SEQ ID NO:40。
在本申请中,所述重链可变区的序列可选自下组中任一项所示的氨基酸序列或其变体:SEQ ID NO:48、SEQ ID NO:50和SEQ ID NO:52。
在某些实施方式中,本申请所述的抗体或其抗原结合片段中LCDR1的氨基酸序列可包括SEQ ID NO:4或其变体;LCDR2的氨基酸序列可包括SEQ ID NO:5或其变体;LCDR3的氨基酸序列可包括SEQ ID NO:6或其变体;且HCDR1的氨基酸序列可包括SEQ ID NO:7或其变体;HCDR2的氨基酸序列可包括SEQ ID NO:8或其变体;HCDR3的氨基酸序列可包括SEQ IDNO:9或其变体。例如,该抗体或其抗原结合片段可包括抗体25C5-2或与其具有相同的LCDR1-3及HCDR1-3的抗体。本申请所述的抗体或其抗原结合片段中LFR1的氨基酸序列可包括SEQ ID NO:10或其变体;LFR2的氨基酸序列可包括SEQ ID NO:11或其变体;LFR3的氨基酸序列可包括SEQ ID NO:12或其变体;LFR4的氨基酸序列可包括SEQ ID NO:13或其变体;且HFR1的氨基酸序列可包括SEQ ID NO:14或其变体;HFR2的氨基酸序列可包括SEQ ID NO:15或其变体;HFR3的氨基酸序列可包括SEQ ID NO:16或其变体;HFR4的氨基酸序列可包括SEQ ID NO:17或其变体。例如,该抗体或其抗原结合片段可包括抗体25C5-2或与其具有相同的LFR1-4及HFR1-4的抗体。在某些实施方式中,本申请所述的抗体或其抗原结合片段的轻链可包含轻链可变区,所述轻链可变区的氨基酸序列可包括SEQ ID NO:42或其变体;且其中重链可包含重链可变区,所述重链可变区的氨基酸序列可包括SEQ ID NO:48或其变体。例如,该抗体或其抗原结合片段可包括抗体25C5-2或与其具有相同的轻链可变区及重链可变区的抗体。
例如,本申请所述抗体可为25C5-2。其中,抗体25C5-2的LCDR1-3的氨基酸序列分别如SEQ ID NO:4、SEQ ID NO:5和SEQ ID NO:6所示;LFR1-4的氨基酸序列分别如SEQ IDNO:10、SEQ ID NO:11、SEQ ID NO:12和SEQ ID NO:13所示;VL的氨基酸序列如SEQ ID NO:42所示;HCDR1-3的氨基酸序列分别如SEQ ID NO:7、SEQ ID NO:8和SEQ ID NO:9所示;HFR1-4的氨基酸序列分别如SEQ ID NO:14、SEQ ID NO:15、SEQ ID NO:16和SEQ ID NO:17所示;VH的氨基酸序列如SEQ ID NO:48所示。
在某些实施方式中,所述抗体25C5-2可以为scFv,所述scFv为VL-VH(即VL通过所述连接肽连接在VH的N端),其中所述连接肽的氨基酸序列可以如SEQ ID NO:54所示。所述scFv的氨基酸序列可以如SEQ ID NO:56所示。
例如,本申请所述抗体可为10H10-1。其中,抗体10H10-1的LCDR1-3的氨基酸序列分别如SEQ ID NO:18、SEQ ID NO:19和SEQ ID NO:20所示;LFR1-4的氨基酸序列分别如SEQID NO:24、SEQ ID NO:25、SEQ ID NO:26和SEQ ID NO:27所示;VL的氨基酸序列如SEQ IDNO:44所示;HCDR1-3的氨基酸序列分别如SEQ ID NO:21、SEQ ID NO:22和SEQ ID NO:23所示;HFR1-4的氨基酸序列分别如SEQ ID NO:28、SEQ ID NO:29、SEQ ID NO:30和SEQ ID NO:31所示;VH的氨基酸序列如SEQ ID NO:50所示。
在某些实施方式中,所述抗体10H10-1可以为scFv,所述scFv为VL-VH(即VL通过所述连接肽连接在VH的N端),其中所述连接肽的氨基酸序列可以如SEQ ID NO:54所示。所述scFv的氨基酸序列可以如SEQ ID NO:58所示。
例如,本申请所述抗体可为16F10。其中,抗体16F10的LCDR1-3的氨基酸序列分别如SEQ ID NO:4、SEQ ID NO:5和SEQ ID NO:6所示;LFR1-4的氨基酸序列分别如SEQ ID NO:35、SEQ ID NO:11、SEQ ID NO:12和SEQ ID NO:36所示;VL的氨基酸序列如SEQ ID NO:46所示;HCDR1-3的氨基酸序列分别如SEQ ID NO:32、SEQ ID NO:33和SEQ ID NO:34所示;HFR1-4的氨基酸序列分别如SEQ ID NO:37、SEQ ID NO:38、SEQ ID NO:39和SEQ ID NO:40所示;VH的氨基酸序列如SEQ ID NO:52所示。
在某些实施方式中,所述抗体16F10可以为scFv,所述scFv为VL-VH(即VL通过所述连接肽连接在VH的N端),其中所述连接肽的氨基酸序列可以如SEQ ID NO:54所示。所述scFv的氨基酸序列可以如SEQ ID NO:60所示。
融合蛋白
另一方面,本申请提供了一种包含所述抗体、其抗原结合片段或变体的融合蛋白。在本申请中,所述融合蛋白可为嵌合抗原受体(CAR),其可包括本申请所述的抗体和T细胞信号分子。例如,所述CAR可包括CD19结合结构域、跨膜结构域、铰链区、共刺激结构域和胞内信号转导结构域等结构域。
在本申请中,所述抗体可为单链抗体。在某些实施方式中,所述抗体可包含SEQ IDNO:56、SEQ ID NO:58、SEQ ID NO:60所示的氨基酸序列或其功能性变体。
例如,所述单链抗体可包括25C5-2,其氨基酸序列如SEQ ID NO:56所示。单链抗体25C5-2的LCDR1-3的氨基酸序列分别如SEQ ID NO:4、SEQ ID NO:5和SEQ ID NO:6所示;VL的氨基酸序列如SEQ ID NO:42所示;HCDR1-3的氨基酸序列分别如SEQ ID NO:7、SEQ IDNO:8和SEQ ID NO:9所示;VH的氨基酸序列如SEQ ID NO:48所示。
例如,所述单链抗体可包括10H10-1,其氨基酸序列如SEQ ID NO:58所示。单链抗体10H10-1的LCDR1-3的氨基酸序列分别如SEQ ID NO:18、SEQ ID NO:19和SEQ ID NO:20所示;VL的氨基酸序列如SEQ ID NO:44所示;HCDR1-3的氨基酸序列分别如SEQ ID NO:21、SEQID NO:22和SEQ ID NO:23所示;VH的氨基酸序列如SEQ ID NO:50所示。
又例如,所述单链抗体可包括16F10,其氨基酸序列如SEQ ID NO:60所示。单链抗体16F10的LCDR1-3的氨基酸序列分别如SEQ ID NO:4、SEQ ID NO:5和SEQ ID NO:6所示;VL的氨基酸序列如SEQ ID NO:46所示;HCDR1-3的氨基酸序列分别如SEQ ID NO:32、SEQ IDNO:33和SEQ ID NO:34所示;VH的氨基酸序列如SEQ ID NO:52所示。
在本申请中,所述CD19结合结构域可包含特异性结合CD19的抗体、抗原结合片段或变体。本申请所述的抗体、其抗原结合片段或变体可包含抗体轻链或其片段。所述轻链可包括轻链可变区,所述轻链可变区可包含LCDR1,LCDR2和LCDR3。所述LCDR1的氨基酸序列可选自下组中任一项所示的氨基酸序列或其变体:SEQ ID NO:4和SEQ ID NO:18。所述LCDR2的氨基酸序列可选自下组中任一项所示的氨基酸序列或其变体:SEQ ID NO:5和SEQ IDNO:19。所述LCDR3的氨基酸序列可选自下组中任一项所示的氨基酸序列或其变体:SEQ IDNO:6和SEQ ID NO:20。在本申请中,所述轻链可变区的序列可选自下组中任一项所示的氨基酸序列或其变体:SEQ ID NO:42、SEQ ID NO:44和SEQ ID NO:46。在本申请中,所述轻链可包括重链可变区,所述重链可变区可包含HCDR1,所述HCDR1的氨基酸序列可选自下组中任一项所示的氨基酸序列或其变体:SEQ ID NO:7、SEQ ID NO:21和SEQ ID NO:32。所述重链可变区可包含HCDR2,所述HCDR2的氨基酸序列可选自下组中任一项所示的氨基酸序列或其变体:SEQ ID NO:8、SEQ ID NO:22和SEQ ID NO:33。所述重链可变区可包含HCDR3,所述HCDR3的氨基酸序列可选自下组中任一项所示的氨基酸序列或其变体:SEQ ID NO:9、SEQID NO:23和SEQ ID NO:34。在本申请中,所述重链可变区的序列可选自下组中任一项所示的氨基酸序列或其变体:SEQ ID NO:48、SEQ ID NO:50和SEQ ID NO:52。
在本申请中,所述CAR可包括铰链区,其可连接所述抗体和所述跨膜结构域。例如,所述铰链区可选自CD8,其氨基酸序列如SEQ ID NO:62所示;也可选自IgG4,其氨基酸序列如SEQ ID NO:64所示。
在本申请中,所述CAR可包括跨膜结构域。例如,所述跨膜结构域可选自T细胞受体的α,β或ζ链、CD28、CD3e、CD45、CD4、CD5、CD8、CD9、CD16、CD22、CD33、CD37、CD64、CD80、CD86、CD134、CD137和CD154等多肽。在本申请中,所述跨膜结构域可为CD8-1,其可包含SEQ IDNO:66所示的氨基酸序列或其功能性变体;也可为CD8-2,其可包含SEQ ID NO:68所示的氨基酸序列或其功能性变体。
在本申请中,所述CAR可包括共刺激域。例如,所述共刺激域可选自CD28、4-1BB、OX40和ICOS等多肽。在本申请中,所述共刺激域可为4-1BB,其可包含SEQ ID NO:70所示的氨基酸序列或其功能性变体;也可为OX40,其可包含SEQ ID NO:72所示的氨基酸序列或其功能性变体。
在本申请中,所述CAR可包括标记检测信号,所述标记检测信号可为荧光蛋白。例如,GFP、RFP或YFP。所述标记检测信号可位于所述CAR的C端。
在本申请中,所述CAR可包括Kozak序列,其核苷酸序列如SEQ ID NO:1所示。所述Kozak序列可位于CAR的N端。
在本申请中,所述CAR可包括前导序列,其核苷酸序列如SEQ ID NO:2所示(所述核苷酸序列不包括Kozak序列)。所述前导序列可位于CAR的N端。
在某些实施方式中,本申请所述CAR可自N端依次包括Kozak序列、前导序列、CD19结合结构域、跨膜结构域、共刺激结构域和胞内信号传导结构域。在某些是事实方式中,本申请所述CAR可自N端依次包括Kozak序列、前导序列、CD19结合结构域、跨膜结构域、共刺激结构域、胞内信号传导结构域和标记检测信号。
例如,本申请所述的CAR可以为CAR25C5-2,其LCDR1-3的氨基酸序列分别如SEQ IDNO:4、SEQ ID NO:5和SEQ ID NO:6所示;VL的氨基酸序列如SEQ ID NO:42所示;HCDR1-3的氨基酸序列分别如SEQ ID NO:7、SEQ ID NO:8和SEQ ID NO:9所示;VH的氨基酸序列如SEQID NO:48所示;VH与VL之间的连接肽的序列如SEQ ID NO:54所示;其Kozak序列的核苷酸序列如SEQ ID NO:1所示;其前导序列的氨基酸序列如SEQ ID NO:3所示;其铰链区的氨基酸序列如SEQ ID NO:62所示;其跨膜结构域的氨基酸序列如SEQ ID NO:66所示;其共刺激结构域的氨基酸序列如SEQ ID NO:70所示;其CD3ζ胞内信号传导结构域的氨基酸序列如SEQID NO:74所示。
又例如,本申请所述CAR可以为CAR10H10-1,其LCDR1-3的氨基酸序列分别如SEQID NO:18、SEQ ID NO:19和SEQ ID NO:20所示;VL的氨基酸序列如SEQ ID NO:44所示;HCDR1-3的氨基酸序列分别如SEQ ID NO:21、SEQ ID NO:22和SEQ ID NO:23所示;VH的氨基酸序列如SEQ ID NO:50所示;VH与VL之间的连接肽的氨基酸序列如SEQ ID NO:54所示;其Kozak序列的核苷酸序列如SEQ ID NO:1所示;其前导序列的氨基酸序列如SEQ ID NO:3所示;其铰链区的氨基酸序列如SEQ ID NO:62所示;其跨膜结构域的氨基酸序列如SEQ IDNO:66所示;其共刺激结构域的氨基酸序列如SEQ ID NO:70所示;其CD3ζ胞内信号传导结构域的氨基酸序列如SEQ ID NO:74所示。
又例如,本申请所述CAR可以为CAR16F10,其LCDR1-3的氨基酸序列分别如SEQ IDNO:4、SEQ ID NO:5和SEQ ID NO:6所示;VL的氨基酸序列如SEQ ID NO:46所示;HCDR1-3的氨基酸序列分别如SEQ ID NO:32、SEQ ID NO:33和SEQ ID NO:34所示;VH的氨基酸序列如SEQ ID NO:52所示;VH与VL之间的连接肽的氨基酸序列如SEQ ID NO:54所示;其Kozak序列的核苷酸序列如SEQ ID NO:1所示;其前导序列的氨基酸序列如SEQ ID NO:3所示;其铰链区的氨基酸序列如SEQ ID NO:62所示;其跨膜结构域的氨基酸序列如SEQ ID NO:66所示;其共刺激结构域的氨基酸序列为如SEQ ID NO:70所示;其CD3ζ胞内信号传导结构域的氨基酸序列如SEQ ID NO:74所示。
核酸分子、载体、细胞及制备方法
另一方面,本申请提供了分离的一种或多种核酸分子,其可编码本申请所述的抗体、其抗原结合片段或变体,和/或,其编码所述的融合蛋白。本申请所述编码抗体的分离的核酸分子可包含SEQ ID NO:55、SEQ ID NO:57、SEQ ID NO:59所示的核酸序列或其功能性变体。本申请所述的核酸分子可以为分离的。例如,其可以是通过以下方法产生或合成的:(i)在体外扩增的,例如通过聚合酶链式反应(PCR)扩增产生的,(ii)通过克隆重组产生的,(iii)纯化的,例如通过酶切和凝胶电泳分级分离,或者(iv)合成的,例如通过化学合成。在某些实施方式中,所述分离的核酸是通过重组DNA技术制备的核酸分子。
另一方面,本申请提供了一种或多种载体,其可包含本申请所述的一种或多种核酸分子。在本申请中,所述载体可为PXC17.4或pCDNA3.4。例如,PXC17.4或pCDNA3.4载体可包含SEQ ID NO:55、SEQ ID NO:57、SEQ ID NO:59所示的核酸序列或其功能性变体。此外,所述载体中还可包含其他基因,例如允许在适当的宿主细胞中和在适当的条件下选择该载体的标记基因。此外,所述载体还可包含允许编码区在适当宿主中正确表达的表达控制元件。这样的控制元件为本领域技术人员所熟知的,例如,可包括启动子、核糖体结合位点、增强子和调节基因转录或mRNA翻译的其他控制元件等。在某些实施方式中,所述表达控制序列为可调的元件。所述表达控制序列的具体结构可根据物种或细胞类型的功能而变化,但通常包含分别参与转录和翻译起始的5’非转录序列和5’及3’非翻译序列,例如TATA盒、加帽序列、CAAT序列等。例如,5’非转录表达控制序列可包含启动子区,启动子区可包含用于转录控制功能性连接核酸的启动子序列。本申请所述的一种或多种核酸分子可以与所述表达控制元件可操作地连接。所述载体可以包括,例如质粒、粘粒、病毒、噬菌体或者在例如遗传工程中通常使用的其他载体。
另一方面,本申请提供了一种或多种细胞,其可包含本申请所述的一种或多种核酸分子或本申请所述的一种或多种载体。在本申请中,所述细胞可选自PBMC、CD4、CD8、NK等细胞。在某些实施方式中,每种或每个细胞可包含一个或一种本申请所述的载体。在某些实施方式中,每种或每个细胞可包含多个(例如,2个或以上)或多种(例如,2种或以上)本申请所述的载体。在本申请中,可将所述载体引入免疫效应细胞中可通过本领域已知的方法将本申请所述的载体引入所述细胞中。在本申请中,可通过本领域已知的方法将本申请所述的载体引入所述细胞中,例如电穿孔、脂质体法转染(lipofectamine 2000,Invitrogen)等。例如,可以通过Bio-Rad的电转导工具进行电转导。又例如可以通过Gibco的转染试剂盒进行转导。
另一方面,本申请提供了制备本申请所述的抗体、其抗原结合片段或变体,和/或本申请所述的融合蛋白的方法,所述方法可包括在使得本申请所述抗体、其抗原结合片段或变体,和/或本申请所述的融合蛋白表达的条件下,培养本申请所述的细胞,还可包含收获所述抗体、其抗原结合片段或变体,和/或,所述的融合蛋白。
药物组合物、制药用途
另一方面,本申请提供了一种药物组合物,其可包含本申请所述的抗体、其抗原结合片段或变体、本申请所述的核酸分子、本申请所述的载体、本申请所述的细胞和/或本申请所述的融合蛋白,以及任选地药学上可接受的佐剂。所述药学上可接受的佐剂可以包括缓冲剂、抗氧化剂、防腐剂、低分子量多肽、蛋白质、亲水聚合物、氨基酸、糖、螯合剂、反离子、金属复合物和/或非离子表面活性剂等。在本申请中,所述药物组合物可被配制用于口服给药,静脉内给药(例如,静脉注射,I.V.),肌肉内给药(例如,肌肉注射,I.M.),在肿瘤部位的原位给药,吸入,直肠给药,阴道给药,经皮给药(例如,皮下注射,I.C.)或通过皮下储存库给药。
另一方面,本申请提供了所述的抗体、其抗原结合片段或变体,和/或,所述的融合蛋白在制备预防或治疗疾病或病症的药物中的用途,其中所述药物用于治疗肿瘤和自体免疫疾病。
另一方面,本申请提供了所述的抗体、其抗原结合片段或变体,和/或,所述的融合蛋白,其治疗肿瘤和自体免疫疾病。
另一方面,本申请提供了一种治疗肿瘤和自体免疫疾病的方法,包括向患者施用所述的抗体、其抗原结合片段或变体,和/或,所述的融合蛋白。
在某些实施方式中,所述肿瘤选自下组中的任一项:B细胞亚型非霍奇金氏恶性淋巴瘤(NHL)、伯基特氏淋巴瘤、多发性骨髓瘤、前B急性淋巴母细胞性白血病及其他来源于早期B细胞前体的恶性肺瘤、普通急性淋巴细胞白血病、T慢性淋巴细胞性白血病、毛细胞白血病、非急性淋巴母细胞性白血病、华氏巨球蛋白血症、前淋巴细胞性白血病、浆细胞瘤、骨硬化骨髓瘤、浆细胞性白血病、单克隆丙种球蛋白病(MGUS)、郁积性多发性骨髓瘤(SMM)、缓慢性多发性骨髓瘤(IMM)、霍奇金氏恶性淋巴瘤、胃癌、肝癌、白血病、肾脏肿瘤、肺癌、小肠癌、骨癌、前列腺癌、结直肠癌、乳腺癌、大肠癌、前列腺癌、宫颈癌、肾上腺肿瘤和膀胱肿瘤。在某些实施方式中,所述自体免疫疾病选自下组中的任一项:类风湿性关节炎、多发性硬化症和CD19+白血病。
另一方面,本申请提供了一种抑制CD19蛋白生物学活性的方法,其包括施用本申请所述的抗体、其抗原结合片段或变体、本申请所述的核酸分子、本申请所述的载体、本申请所述的细胞和/或本申请所述的融合蛋白。
另一方面,本申请提供了本申请所述的抗体、其抗原结合片段或变体、本申请所述的核酸分子、本申请所述的载体、本申请所述的细胞和/或本申请所述的融合蛋白在制备诊断或检测肿瘤的试剂中的应用。在某些实施方式中,所述诊断或检测肿瘤的试剂可以特异性地识别CD19蛋白和/或带有CD19蛋白的癌细胞。在某些实施方式中,所述诊断或检测肿瘤的试剂就可以通过酶联免疫法,化学发光法,免疫比浊法等方法进行体外诊断。例如,所述检测可以通过酶联免疫吸附法进行,将肿瘤标记物CD19蛋白作为固定相,与待测样品共同竞争本申请所述抗体。在某些实施方式中,所述诊断或检测肿瘤的试剂可以同辣根过氧化酶的底物反应显色,用于诊断肿瘤。
不欲被任何理论所限,下文中的实施例仅仅是为了阐释本申请的装置、方法和系统的工作方式,而不用于限制本申请发明的范围。
实施例
实施例1CD19抗体的制备
1.1免疫实验动物
为产生CD19抗体,用纯化的重组CD19蛋白(ACRO,CD9-H52H2)和CD19+Ramos细胞(ATCC)免疫六周龄Babl/c雌鼠(湖南斯莱克生物技术有限公司),所用小鼠为SPF级(无特定病原体,specfic pathogen free)。可根据重组蛋白皮下免疫和Ramos细胞(购自ATCC)腹腔注射免疫对小鼠进行免疫,小鼠第一次输注抗原后为六周龄。第一次免疫使用重组CD19蛋白和弗氏完全佐剂(购自Sigma)免疫按v:v=1:1的比例充分混匀后进行四肢皮下免疫,每只50μg。一周后进行第二次免疫,使用重组CD19蛋白和弗氏非完全佐剂(购自Sigma)按v:v=1:1的比例充分混匀后进行四肢皮下免疫,每只50μg。一周后进行第三次免疫,使用Ramos细胞(购自ATCC)进行腹腔免疫。收集Ramos细胞,用无血清RPMI-1640培养基(购自Sigma)洗涤两遍,将细胞密度稀释至107个/mL。然后向每只小鼠皮下注射1mL Ramos细胞溶液进行免疫。一周后再进行第四次免疫,用所述的Ramos细胞溶液进行免疫,向每只小鼠皮下注射1mLRamos细胞溶液进行免疫。第四次免疫后一周取眼球血,用ELISA检测血清抗体滴度,抗体的稀释度若不小于105,则免疫完成;若抗体稀释度大于105,则用上述重组CD19蛋白和弗氏非完全佐剂(购自Sigma)按v:v=1:1的比例充分混匀后再进行四肢皮下免疫,每只50μg,然后再次进行检测,直到免疫完成。
1.2杂交瘤细胞的融合与筛选
为筛选生产特异性结合CD19的抗体的Babl/c免疫小鼠,通过如Fishwild等人(1996)所述的ELISA测试免疫的小鼠的血清。简而言之,取实施例1.2中经重组CD19蛋白免疫后血清抗体稀释度达到105以上的小鼠,脱颈处死后去脾脏,用70μm的筛网(corning)将脾脏研碎分离得到单个B细胞,按照1:10的比例将B细胞和SP2/0细胞混合,借助PEG(购自Sigma)将B细胞和SP2/0细胞融合成杂交瘤细胞。将融合后的细胞按照每孔200μL的量分装到96孔细胞培养板中,共计30块96孔细胞培养板。将96孔细胞培养板放在37℃、5%CO2细胞培养箱(Thermo 150i)中培养,然后通过如Fishwild等人(1996)所述的ELISA来筛选分泌高活性抗体的融合细胞株。
将溶于PBS中的1ng/μL的纯化的重组CD19包被ELISA检测板(购自厦门怡佳美),每孔100μL。在37℃温育2小时后,然后溶于PBS/Tween(0.05%)中的5%鸡血清封闭,每孔280μL,然后于37℃温育2小时后备用。向每个孔中加入100μL来自杂交瘤融合细胞上清液,然后在37℃环境温度温育30分钟。用PBS/Tween洗涤平板5次,然后每孔加入100μL与辣根过氧化物酶(HRP)缀合的山羊-抗-人IgGFc多克隆抗体37℃温育30分钟。然后用PBS/Tween洗涤5次后,每孔加入100μLTMB显色液(山东淄博云桥生物技术有限公司),37℃温育5分钟后加入50μL 2M的硫酸终止反应,并通过酶标仪(波长450nm)读取OD值,取OD值高于1.0的杂交瘤融合细胞株,通过有限稀释法筛选符合条件的可特异性结合CD19的单克隆细胞株(参见张越,屈会化,吴婷婷,等。甘草酸单克隆抗体的制备与鉴定[J].药物分析杂志,2013,33(5):770-774.)。
1.3抗CD19不同表位及亲和力抗体筛选
通过杂交瘤融合技术筛选到三株具有不同亲和力和结合表位的抗CD19鼠源抗体,分别命名为25C5-2,10H10-1和16F10。通过Sanger高通量测序技术测序(参见Tsiatis A C,Norris-Kirby A,Rich R G等人.Comparison of Sanger sequencing,pyrosequencing,and melting curve analysis for the detection of KRAS mutations:diagnostic andclinical implications[J].The Journal of Molecular Diagnostics,2010,12(4):425-432.)获得三株抗体的重链和轻链可变区核苷酸序列,其中25C5-2的VL氨基酸序列如SEQID NO:42所示,其VH氨基酸序列如SEQ ID NO:48所示;10H10-1的VL氨基酸序列如SEQ IDNO:44所示,其VH氨基酸序列如SEQ ID NO:50所示;16F10的VL氨基酸序列如SEQ ID NO:46所示,其VH氨基酸序列如SEQ ID NO:52所示。
1.4人工合成scFv形式的CD19抗体
人工合成VL与VH之间的连接肽VL-VH连接肽,其核苷酸序列如SEQ ID NO:53所示。并且人工合成上一步中测序得到的三株可特异性结合CD19的抗体的VL和VH的核苷酸序列,然后首位连接构建scFv形式的CD19抗体。
具体而言,为获得25C5-2抗体,首先合成其VL,其核苷酸序列如SEQ ID NO:41所示;然后合成VL-VH连接肽,其核苷酸序列如SEQ ID NO:53所示;然后合成其VH,其核苷酸序列如SEQ ID NO:47所示。将VL、VL-VH连接肽和VL的核苷酸序列依次首尾连接获得完整的25C5-2scFv序列,其核苷酸序列如SEQ ID NO:55所示。
相似地,为获得10H10-1抗体,首先合成其VL,其核苷酸序列如SEQ ID NO:43所示;然后合成VL-VH连接肽,其核苷酸序列如SEQ ID NO:53所示;然后合成其VH,其核苷酸序列如SEQ ID NO:49所示。将VL、VL-VH连接肽和VH的核苷酸序列依次首尾连接获得完整的10H10-1scFv序列,其核苷酸序列如SEQ ID NO:57所示。
相似地,为获得16F10抗体,首先合成其VL,其核苷酸序列如SEQ ID NO:45所示;然后合成VL-VH连接肽,其核苷酸序列如SEQ ID NO:53所示;然后合成其VH,其核苷酸序列如SEQ ID NO:51所示。将VL、VL-VH连接肽和VL的核苷酸序列依次首尾连接获得完整的16F10scFv序列,其核苷酸序列如SEQ ID NO:59所示。
1.5载体的构建与抗体表达
将上一步合成的scFv基因通过大肠杆菌扩增后提取质粒,利用BamHI和SaiL酶切后连入表达载体PXC17.4等,利用Bio-Rad的电转导工具进行电穿孔,将表达载体导入CHO细胞进行表达,随后对所述抗体的表达情况进行检测。
实施例2CD19抗体活性检测(ELISA)
运用ELISA法检测实施例1中制得CD19抗体。取CD19蛋白(购自acro)100μg,加入300μL超纯水(超纯水仪购自PALL)充分溶解,获得浓度为0.33μg/μL的CD19蛋白稀释液。按照每孔100ng的量包被96孔检测板。
用PBS缓冲溶液将CD19蛋白稀释至1μg/μL,取40mL;并取上述用超纯水溶解的CD19蛋白120μL CD19蛋白到40mL PBS缓冲溶液中,将两者充分混匀后按照每孔100μL的量加入到96孔检测板中,于37℃温育2小时。温育完成后除去96孔板中残余的蛋白溶液,在每孔中加入280μL(1%BSA+PBS)封闭液,37℃温育2小时后4℃保存备用。
取实施例1中制得的抗体16F10、25C5-2、10H10-1进行检测,并以FMC-63(Merck,选择MAB1794)作为阳性对照(本申请所有实施例所使用的anti-CD19阳性对照均是FMC-63,其scfv核苷酸序列请参见CN201180067173.X SEQ ID NO.14,氨基酸序列为SEQ ID NO.20),以不加一抗、二抗作为阴性对照。
将待检测抗体用PBS统一稀释到0.1mg/mL的浓度备用。按照倍比稀释的方法在检测板中加入100μL的PBS。在第一个检测孔中加入100μL稀释的0.1mg/mL抗体溶液,充分混匀后依次取100μL到下一个梯度,类似地进行11个梯度稀释,每个样品重复一次。稀释完成的检测板,于37℃温育30分钟。
温育完成后洗板5次,每次280μL,洗板完成后,轻轻拍板几次以除干净残余的洗液。然后,按照每孔100μL的量加入配置好的羊抗人二抗稀释液(羊抗人二抗购自abcam,按照1:10000的比例用PBS稀释),于37℃温育30分钟后洗板。洗板完成后按照每孔100μL加入TMB显色液,于37℃温育5分钟按照每孔50μL的量加入2M硫酸终止液,终止反应。置MD-M2E(美国分子仪器公司)酶标仪上读取450nm处的OD值,应用软件MD-M2E进行数据处理。结果如图1所示。结果显示,10H10-1与CD19蛋白的亲和力最强,即使在低浓度情况下依然有很强的结合能力,16F10、25C5-2的检测结果类似。
实施例3CD19抗体活性检测
3.1细胞处理
收集NALM-6细胞到50mL离心管中,以400g离心5分钟离心收集细胞,取20mL预冷至4℃的PBS重悬细胞,离心收集细胞,按照该方法将细胞用PBS洗涤三次后,用13mL PBS重悬细胞后计数,细胞浓度为3.92×106个/mL,细胞存活率为98%。将细胞按照每管600μL分装到流式检测管中备用,共计25支。
3.2CD19抗体稀释
将CD19抗体按照如下梯度用PBS稀释。具体操作如下:取实施例1中制得的抗体16F10、10H10-1、25C5-2将其各自分别稀释至50μg/mL、10μg/mL、5μg/mL、2.5μg/mL、1.25μg/mL。取200μL加入到离心收集的细胞沉淀中重悬细胞,于4℃反应1小时后离心收集细胞用PBS洗涤三次。反应完成后,按照以400g的速度于4℃离心5min,收集细胞,加入1mL预冷至4℃的PBS按照上述离心条件离心洗涤两遍,后收集细胞沉淀弃上清。
3.3二抗孵育
将FITC标记的羊抗鼠抗体(Abcam Goat Anti-Mouse IgG H&L(FITC)ab6785)按照1:300(PBS稀释)的比例稀释后,每个检测管中每管加入500μL的FITC标记的羊抗鼠抗体稀释液重悬细胞,FITC标记的羊抗鼠抗体对照组也加入500μLFITC标记的羊抗鼠抗体稀释液,阴性对照组加入500μL PBS,4℃孵育1小时后,按照上述方法用PBS洗涤细胞三次,最后用200μL PBS重悬洗涤离心后的细胞,以用于流式检测。
3.4流式检测
首先将从上一步骤中获得的细胞重悬于PBS缓冲液中,加入实施例1中获得的CD19抗体16F10、10H10-1、25C5-2,以不加一抗、二抗作为阴性对照。
流式检测电压按下述步骤进行设置:在流式鞘液桶中装入足量鞘液后,开机流式细胞仪(BD verse)预热20分钟后,打开流式检测软件,设置FSC/SSC的去黏连,在FSC和SSC检测图中画适当的检测门,设置检测门的细胞检测量为104个,再画第二个检测图FSC-A和FSC-H的检测图,定义第二个检测图上的检测细胞来自P1门,并在第二个检测图上设置合适的P2门,设置第三个检测图COUNT和FITC-A,定义第三个图的检测数据来自P2门,相关检测图绘制完成后,用对照NALM-6细胞设置检测电压使NALM-6细胞显示在第一个检测图的中心位置,FITC-A的检测信号在101-102之间后,开始检测NALM-6细胞,收集数据设置对照组,保存检测电压和相关参数后开始检测样品检测,记录相关数据。取16F10、10H10-1、25C5-2抗体浓度5μg/mL、FMC63浓度0.025μg/mL的结果作图,结果如图2所示。
结果显示,16F10、25C5-2、10H10-1都具有相似的对表达在肿瘤细胞NALM-6表面的CD19结合能力,其中16F10的结合能力最强,其次是10H10-1和25C5-2。
实施例4CD19抗体蛋白印迹法检测
取浓度为1mg/mL CD19胞外区蛋白(购自abcam,ab234966,氨基酸序列编号第20位至291位)10μL,与10mL 2×的加样缓冲液(其包含20mMDTT),充分混匀,于95℃沸水浴5分钟。然后按照现有技术中的常规操作进行SDS-PAGE电泳实验(含12%的SDS),从实施1中获得的CD19抗体10H10-1、25C5-1进行电泳测试,并以不加一抗和二抗作为阴性对照,在电泳时使用的标记物Marker购自全式金,目录号:DM201,lot:K51027,每种样品加样5μL。在电泳时。使用浓缩胶(5%的浓缩胶,2mL,纯化水1.4mL、30%Acr-Bis 0.33mL、1M pH8.8Tris0.25mL、12%SDS(十二烷基磺酸钠)0.02mL、10%过硫酸铵0.02ml、TEMED(四甲基二乙胺)0.002mL)进行浓缩,浓缩时电压为100V;使用分离胶(10%的浓缩胶,5mL,纯化水1.3mL、30%Acr-Bis 1.7mL、1M pH8.8Tris 1.9mL、12%SDS(十二烷基磺酸钠)0.05mL、10%过硫酸铵0.05mL、TEMED(四甲基二乙胺)0.002mL)进行分离,分离时电压为140V。当溴酚蓝到达胶底部时停止电泳。
于100V恒定电压进行转膜,转膜时间为45分钟。将聚偏二氟乙烯(PVDF)膜放入5%脱脂奶粉溶液(PBST溶液配置)中封闭1小时,用PBST溶液洗涤3次,每次在侧摆摇床上缓慢摇动洗涤5分钟左右。封闭完成后将实施例1中获得的CD19抗体10H10-1、25C5-1以及阳性对照FMC-63,用PBST稀释到20μg/mL的浓度后与5%脱脂奶封闭的PVDF膜室温反应1小时,然后用PBST洗涤三次,每次在侧摆摇床上缓慢摇动洗涤5min左右。PBST洗涤完成后加入用1:5000PBST稀释的HRP标记的羊抗鼠二抗,于室温反应45min后,反应完成后用PBST洗涤三次,每次洗涤5分钟左右。添加ECL发光液(购自BIO-RAD)拍片来检测蛋白,采集时曝光时间为1秒。
结果如图3所示,结果显示10H10-1可以和变性的CD19重组蛋白反应,阳性对照FMC63和25C5-2与变性的CD19重组蛋白不反应。
实施例5CD19scfv抗体流式检测
5.1细胞处理
取与实施例3中相同的NALM-6细胞,将NALM-6细胞收集到15ml离心管中,以400g的速度离心5分钟收集细胞,弃去上清液,用与所弃上清液等体积的PBS缓冲溶液重悬离心收集的细胞,重复3次后用10mL PBS缓冲溶液重悬细胞。取PBS洗涤后的细胞悬液20μl加入到无菌的1.5ml离心管中,再加入等体积台盼蓝轻轻混匀后取20μL加入到Count Sart细胞计数板中,将计数板放入Count Sart细胞计数仪中,点击细胞计数后读取数据。计数得到细胞浓度为5.37×105/mL。然后将洗涤后的细胞悬液分装到流式检测管中,每管1mL。预留一管作为阴性对照。
5.2CD19scfv抗体稀释
将待检测的CD19抗体10H10-1、25C5-2分别用PBS稀释到200μg/mL的浓度,然后分别各自按照1:20、1:80、1:320、1:1280、1:5120的比例稀释至10μg/mL、2.5μg/mL、0.625μg/mL、0.312μg/mL、0.156μg/mL,然后加入到1mL NALM-6的细胞悬液中,充分混匀后4℃反应2小时。按照400g的速度于4℃离心5分钟收集细胞,加入1mL预冷至4℃的PBS缓冲溶液。按照上述离心条件离心洗涤两遍,后收集细胞沉淀弃上清,在细胞沉淀中加入预先按照1:1000稀释的PE标记的羊抗人抗体,于4℃反应1h。反应完成后,按照400g的速度于4℃离心5min收集细胞,加入1mL预冷至4℃的PBS缓冲溶液按照上述离心条件离心洗涤两遍后收集细胞沉淀,弃去上清液,最后用200μLPBS缓冲溶液重悬洗涤离心后的细胞,做流式检测用。
5.3流式检测
首先将从上一步骤中获得的细胞重悬于PBS缓冲液中,加入实施例1中获得的CD19抗体10H10-1、25C5-2的scFv,以不加一抗、二抗作为阴性对照。
流式检测电压按下述步骤进行设置:在流式鞘液桶中装入足量鞘液后,开机流式细胞仪(BD verse)预热20分钟后,打开流式检测软件,设置FSC/SSC的去黏连,在FSC和SSC检测图中画适当的检测门,设置检测门的细胞检测量为104个,再画第二个检测图FSC-A和FSC-H的检测图,定义第二个检测图的检测细胞来自P1门,并在第二个检测图上设置合适的P2门,设置第三个检测图COUNT和FITC-A,定义第三个图的检测数据来自P2门,相关检测图绘制完成后,用对照NALM-6细胞设置检测电压使NALM-6细胞显示在第一个检测图的中心位置,FITC-A的检测信号在10-102之间后,开始检测NALM-6细胞,收集数据设置对照组,保存检测电压和相关参数后开始检测样品检测,记录相关数据。
结果如图4所示,25C5-2、10H10-1都有明显的结合CD19阳性细胞的能力,其中10H10-1的结合能力最强,其次是25C5-2。
实施例6Anti-CD19CAR-T构建及阳性率检测
6.1合成anti-CD19CAR结构
得到的anti-CD19scfv和不同的功能区组成CAR结构后通过基因合成的方法获得CAR结构(CAR结构示意图如图5所示)
其中,leader的核苷酸序列如SEQ ID NO.2所示;铰链区(Hinge)的核苷酸序列如SEQ ID NO.61所示,跨膜结构(TM)的核苷酸序列如SEQ ID NO.65所示,4-1BB的核苷酸序列如SEQ ID NO.69所示,OX40的核苷酸序列如SEQ ID NO.71所示,CD3zeta的核苷酸序列如SEQ ID NO.73所示。本申请筛选获得的anti-CD19scfv,以10H10-1(SEQ ID NO.57)和25C5-2(SEQ ID NO.55)为例构建CAR-T,并同时构建阳性药CAR-T(anti-CD19scfv为FMC-63(Merck))
合成基因借助大肠扩增后提取质粒利用BamHI和SaiL酶切后连入表达载体通过stabl3扩增提质粒,为构建CAR-T细胞准备质粒
6.2T细胞分离激活
利用Ficoll试剂法分离采集全血中的PBMC细胞,通过磁珠阴选的方法分离CD4+和CD8+T细胞,在分离的T细胞中按照1:1(个数比)的比例加入激活磁珠CD3/CD28,T细胞激活24小时进行电转试验。
6.3电转构建CAR-T细胞
将构建好的anti-CD19CAR-T表达载体按照3.3μg对应4×106个T细胞的量配制电转条件按照一起设置的程序电转后收集T细胞,24小时检测CAR-T细胞阳性率及CAR-T细胞杀伤活力。
6.4流式检测CAR-T细胞的阳性率
收集培养24小时后的电转T细胞,PBS洗涤3遍后按照106个细胞一管的量分装到不同的流式检测管中,按照106个细胞加入2μLFITC标记的CD19蛋白4℃抚育2小时后,PBS洗涤3次,用300μLPBS重悬细胞后上流式检测CAR-T细胞的阳性率。结果如图6所示。
实施例7Anti-CD19CAR-T肿瘤杀伤活性检测
7.1靶细胞标记
收集对数生长期NALM-6,用0.01MPBS洗涤细胞一次。再用完全培养基将细胞重悬为密度1×106cell/mL悬液。取3mL该细胞悬液,加入5μLBATDA并充分混匀,37℃,5%CO2条件下孵育5min。
用清洗液(1×PBS+20mMHepes)洗涤标记的NALM-6细胞4次。末次清洗后将细胞重悬于完全培养基中,并将细胞密度调节至8×104cell/mL。
2、效靶细胞共孵育
待上述1)靶细胞重悬后,立即取适量细胞悬液离心后,取上清作为背景测试孔。
取1)的细胞悬液100μL(8000cell/well)接种于96wellV-bottom板中。最大释放孔加入含1%TritonX-100100μL完全培养基溶液,自发释放孔加入100μL完全培养基溶液,试验孔加入效应细胞100μL(效靶比1:1)。
孵育1-4h后,500g室温离心5min。
3、细胞杀伤活性测定
取20μL上清液至平底96孔板中,加入200μLEuropiumSolution。
室温避光振荡混匀15min。
利用HTRF法测定荧光值(激发光340nm,发射光615nm)。
4、数据处理
按下式计算受试细胞杀伤率(%):
细胞杀伤率(%)=(试验孔读数-自发释放孔读数)/(最大释放孔读数-自发释放孔读数)×100
5、如表1结果所示,以25C5为例构建的CAR-T比阳性对照具有更强的杀伤活力。
表1 CD19-CAR-T对NALM-6杀伤率(%,(Mean±SEM,n=3)
前述详细说明是以解释和举例的方式提供的,并非要限制所附权利要求的范围。目前本申请所列举的实施方式的多种变化对本领域普通技术人员来说是显而易见的,且保留在所附的权利要求和其等同方案的范围内。
SEQUENCE LISTING
<110> 广东东阳光药业有限公司
<120> CD19抗体及其应用
<130> PP0841CNP2
<160> 74
<170> PatentIn version 3.5
<210> 1
<211> 9
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> Kozak序列 (核苷酸)
<400> 1
gccgccacc 9
<210> 2
<211> 51
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 前导序列(核苷酸)
<400> 2
atgggcgtca aggtcctgtt cgccctgatc tgcatcgccg tcgccgaggc c 51
<210> 3
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 前导序列
<400> 3
Met Gly Val Lys Val Leu Phe Ala Leu Ile Cys Ile Ala Val Ala Glu
1 5 10 15
Ala
<210> 4
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 25C5-2/16F10 LCDR1
<400> 4
Ser Ser Val Ser Tyr
1 5
<210> 5
<211> 3
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 25C5-2/16F10 LCDR2
<400> 5
Ala Thr Ser
1
<210> 6
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 25C5-2/16F10 LCDR3
<400> 6
Gln Gln Trp Ser Ser Asn Pro Phe Thr
1 5
<210> 7
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 25C5-2 HCDR1
<400> 7
Gly Tyr Thr Phe Thr Glu Tyr Thr
1 5
<210> 8
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 25C5-2 HCDR2
<400> 8
Ile Asn Pro Asn Asn Gly Gly Thr
1 5
<210> 9
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 25C5-2 HCDR3
<400> 9
Ala Arg Gly Gly Gly Tyr Tyr Gly Tyr Gly Asp Tyr
1 5 10
<210> 10
<211> 6
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 25C5-2 LFR1
<400> 10
Met Thr Cys Arg Ala Ser
1 5
<210> 11
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 25C5-2/16F10 LFR2
<400> 11
Met His Trp Tyr Gln Gln Lys Pro Gly Ser Ser Pro Lys Pro Trp Ile
1 5 10 15
Tyr
<210> 12
<211> 36
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 25C5-2/16F10 LFR3
<400> 12
Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly
1 5 10 15
Thr Ser Tyr Ser Leu Thr Ile Ser Arg Val Glu Ala Glu Asp Ala Ala
20 25 30
Thr Tyr Tyr Cys
35
<210> 13
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 25C5-2 LFR4
<400> 13
Phe Gly Ser Gly Thr Lys Leu Glu
1 5
<210> 14
<211> 25
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 25C5-2 HFR1
<400> 14
Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Thr Ser
20 25
<210> 15
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 25C5-2 HFR2
<400> 15
Met His Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile Gly
1 5 10 15
Gly
<210> 16
<211> 38
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 25C5-2 HFR3
<400> 16
Ser Tyr Asn Gln Lys Phe Lys Gly Lys Ala Thr Leu Thr Val Asp Lys
1 5 10 15
Ser Ser Ser Thr Ala Tyr Met Glu Leu Arg Ser Leu Thr Ser Glu Asp
20 25 30
Ser Ala Val Tyr Tyr Cys
35
<210> 17
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 25C5-2 HFR4
<400> 17
Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser
1 5 10
<210> 18
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 10H10-1 LCDR1
<400> 18
Gln Thr Leu Val Tyr Ser Asn Gly Asp Thr Tyr
1 5 10
<210> 19
<211> 3
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 10H10-1 LCDR2
<400> 19
Lys Leu Ser
1
<210> 20
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 10H10-1 LCDR3
<400> 20
Phe Gln Gly Ser Tyr Phe Pro Phe Thr
1 5
<210> 21
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 10H10-1 HCDR1
<400> 21
Gly Tyr Ala Phe Thr Asn Tyr Phe
1 5
<210> 22
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 10H10-1 HCDR2
<400> 22
Ile Asn Pro Gly Asn Ser Asn Thr
1 5
<210> 23
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 10H10-1 HCDR3
<400> 23
Ala Arg Ser Gly Thr Thr Ala Thr Thr Tyr Ala Met Asp Tyr
1 5 10
<210> 24
<211> 26
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 10H10-1 LFR1
<400> 24
Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly
1 5 10 15
Asp Gln Val Ser Ile Ser Cys Arg Ser Ser
20 25
<210> 25
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 10H10-1 LFR2
<400> 25
Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile
1 5 10 15
Tyr
<210> 26
<211> 36
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 10H10-1 LFR3
<400> 26
Asn Arg Phe Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly
1 5 10 15
Thr Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ser Glu Asp Leu Gly
20 25 30
Val Tyr Tyr Cys
35
<210> 27
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 10H10-1 LFR4
<400> 27
Phe Gly Ala Gly Thr Lys Leu Glu Ile Lys
1 5 10
<210> 28
<211> 25
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 10H10-1 HFR1
<400> 28
Glu Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Thr
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser
20 25
<210> 29
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 10H10-1 HFR2
<400> 29
Ile Glu Trp Val Ile Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile Gly
1 5 10 15
Val
<210> 30
<211> 38
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 10H10-1 HFR3
<400> 30
Asn Tyr Asn Glu Lys Phe Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys
1 5 10 15
Ser Ser Ser Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser Asp Asp
20 25 30
Ser Ala Val Tyr Phe Cys
35
<210> 31
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 10H10-1 HFR4
<400> 31
Trp Gly Gln Gly Thr Ser Val Ile Val Ser Ser
1 5 10
<210> 32
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 16F10 HCDR1
<400> 32
Gly Phe Thr Phe Arg Gly Tyr Ala
1 5
<210> 33
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 16F10 HCDR2
<400> 33
Ile Ser Thr Gly Gly Asn Thr
1 5
<210> 34
<211> 4
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 16F10 HCDR3
<400> 34
Ser Ser Pro Tyr
1
<210> 35
<211> 28
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 16F10 LFR1
<400> 35
Glu Leu Asp Ile Val Leu Ser Gln Ser Pro Ala Ile Leu Ser Ala Ser
1 5 10 15
Pro Gly Glu Lys Val Thr Met Thr Cys Arg Ala Ser
20 25
<210> 36
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 16F10 LFR4
<400> 36
Phe Gly Ser Gly Thr Lys Leu Glu Leu Lys
1 5 10
<210> 37
<211> 25
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 16F10 HFR1
<400> 37
Glu Val Lys Val Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Thr Ala Ser
20 25
<210> 38
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 16F10 HFR2
<400> 38
Leu Ser Trp Val Arg Gln Thr Pro Glu Lys Arg Leu Glu Trp Val Ala
1 5 10 15
Ser
<210> 39
<211> 38
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 16F10 HFR3
<400> 39
Tyr Tyr Pro Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
1 5 10 15
Ala Arg Asn Ile Leu Tyr Leu Gln Met Ser Arg Leu Arg Ser Asp Asp
20 25 30
Thr Ala Ile Tyr Phe Cys
35
<210> 40
<211> 19
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 16F10 HFR4
<400> 40
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala Ala Lys Thr Thr Pro
1 5 10 15
Pro Ser Val
<210> 41
<211> 252
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 25C5-2 VL(核苷酸)
<400> 41
atgacttgca gggccagctc aagtgtaagt tacatgcact ggtaccagca gaagccagga 60
tcttccccca aaccctggat ttatgccaca tccaacctgg cttctggagt ccctgctcgc 120
ttcagtggca gtgggtctgg gacctcttac tctctcacaa tcagcagagt ggaggctgaa 180
gatgctgcca cttattactg ccagcagtgg agtagtaacc cattcacgtt cggctcgggg 240
accaagctgg aa 252
<210> 42
<211> 84
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 25C5-2 VL
<400> 42
Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Met His Trp Tyr Gln
1 5 10 15
Gln Lys Pro Gly Ser Ser Pro Lys Pro Trp Ile Tyr Ala Thr Ser Asn
20 25 30
Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr
35 40 45
Ser Tyr Ser Leu Thr Ile Ser Arg Val Glu Ala Glu Asp Ala Ala Thr
50 55 60
Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Phe Thr Phe Gly Ser Gly
65 70 75 80
Thr Lys Leu Glu
<210> 43
<211> 336
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 10H10-1 VL (核苷酸)
<400> 43
gatattgtga tgacccaaac tccactctcc ctgcctgtca gtcttggaga tcaagtctcc 60
atctcttgca gatctagtca gacccttgtg tatagtaatg gagacaccta tttagaatgg 120
tacctgcaga aaccaggcca gtctccaaag ctcctgatct acaaactttc caaccgattt 180
tctggggtcc cagacaggtt cagtggcagt ggatcaggga cagatttcac actcaagatc 240
agcagagtgg agtctgagga tctgggagtt tattactgct ttcagggttc atattttcca 300
ttcacgttcg gcgcggggac caaactggaa atcaaa 336
<210> 44
<211> 112
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 10H10-1 VL
<400> 44
Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly
1 5 10 15
Asp Gln Val Ser Ile Ser Cys Arg Ser Ser Gln Thr Leu Val Tyr Ser
20 25 30
Asn Gly Asp Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Leu Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ser Glu Asp Leu Gly Val Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser Tyr Phe Pro Phe Thr Phe Gly Ala Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 45
<211> 324
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 16F10 VL (核苷酸)
<400> 45
gagctcgata ttgttctctc ccagtctcca gcaatcctgt ctgcatctcc aggggagaag 60
gtcacaatga cttgcagggc cagctcaagt gtaagttaca tgcactggta ccagcagaag 120
ccaggatcct cccccaaacc ctggatttat gccacatcca acctggcttc tggagtccct 180
gctcgcttca gtggcagtgg gtctgggacc tcttactctc tcacaatcag cagagtggag 240
gctgaagatg ctgccactta ttactgccag cagtggagta gtaacccatt cacgttcggc 300
tcggggacca agctggagct gaaa 324
<210> 46
<211> 108
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 16F10 VL
<400> 46
Glu Leu Asp Ile Val Leu Ser Gln Ser Pro Ala Ile Leu Ser Ala Ser
1 5 10 15
Pro Gly Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser
20 25 30
Tyr Met His Trp Tyr Gln Gln Lys Pro Gly Ser Ser Pro Lys Pro Trp
35 40 45
Ile Tyr Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Val Glu
65 70 75 80
Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro
85 90 95
Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Leu Lys
100 105
<210> 47
<211> 357
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 25C5-2 VH (核苷酸)
<400> 47
gaggtccagc tgcagcagtc tggacctgag ctggtgaagc ctggggcttc agtgaagata 60
tcctgcaaga cttctggata cacattcact gaatacacca tgcactgggt gaagcagagc 120
catggaaaga gccttgagtg gattggaggt attaatccta acaatggtgg tactagctac 180
aaccagaagt tcaagggcaa ggccacattg actgtagaca agtcctccag cacagcctac 240
atggagctcc gcagcctgac atctgaggat tctgcagtct attactgtgc aagagggggg 300
gggtactacg gctacgggga ctactggggt caaggaacct cagtcaccgt ctcctca 357
<210> 48
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 25C5-2 VH
<400> 48
Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Thr Ser Gly Tyr Thr Phe Thr Glu Tyr
20 25 30
Thr Met His Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile
35 40 45
Gly Gly Ile Asn Pro Asn Asn Gly Gly Thr Ser Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Gly Tyr Tyr Gly Tyr Gly Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Ser Val Thr Val Ser Ser
115
<210> 49
<211> 363
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 10H10-1 VH (核苷酸)
<400> 49
gaggttcagc ttcagcagtc tggagctgag ctggtaaggc ctgggacttc agtgaaggtg 60
tcctgcaagg cttctggata cgccttcact aattacttca tagagtgggt aatacagagg 120
cctggacagg gccttgagtg gattggagtg attaatcctg gaaatagtaa tactaactac 180
aatgagaagt tcaagggcaa ggcaacactg actgcggaca aatcctccag cactgcctac 240
atgcagctca gcagcctgac atctgatgac tctgcggtct atttctgtgc aagatcgggg 300
actacggcta cgacctatgc tatggactac tggggtcaag gaacctcagt catcgtctcc 360
tca 363
<210> 50
<211> 121
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 10H10-1 VH
<400> 50
Glu Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Thr
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Thr Asn Tyr
20 25 30
Phe Ile Glu Trp Val Ile Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Val Ile Asn Pro Gly Asn Ser Asn Thr Asn Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Asp Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Ser Gly Thr Thr Ala Thr Thr Tyr Ala Met Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Ser Val Ile Val Ser Ser
115 120
<210> 51
<211> 354
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 16F10 VH (核苷酸)
<400> 51
gaggtgaagg tggtggagtc tgggggaggc ttagtgaagc ctggagggtc cctgaaactc 60
tcttgtacag cctctggatt cactttcaga ggctatgcct tatcttgggt tcgccagact 120
ccagagaaga ggctggagtg ggtcgcttcc attagtactg gtggtaatac ttactatcca 180
gacagtgtga agggccgatt caccatctcc agagataatg ccaggaacat cctgtacctt 240
caaatgagca ggctgaggtc tgatgacacg gccatttatt tctgttcctc tccttactgg 300
ggccaaggga ctctggtcac tgtctctgca gccaaaacaa cacccccatc tgtc 354
<210> 52
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 16F10 VH
<400> 52
Glu Val Lys Val Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Arg Gly Tyr
20 25 30
Ala Leu Ser Trp Val Arg Gln Thr Pro Glu Lys Arg Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Thr Gly Gly Asn Thr Tyr Tyr Pro Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Arg Asn Ile Leu Tyr Leu
65 70 75 80
Gln Met Ser Arg Leu Arg Ser Asp Asp Thr Ala Ile Tyr Phe Cys Ser
85 90 95
Ser Pro Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala Ala Lys
100 105 110
Thr Thr Pro Pro Ser Val
115
<210> 53
<211> 45
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> VL-VH连接肽 (核苷酸)
<400> 53
ggcggcggag gatctggcgg aggtggcagc ggaggcggtg gatct 45
<210> 54
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> VL-VH连接肽
<400> 54
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
<210> 55
<211> 654
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 25C5-2 scFv (核苷酸)
<400> 55
atgacttgca gggccagctc aagtgtaagt tacatgcact ggtaccagca gaagccagga 60
tcttccccca aaccctggat ttatgccaca tccaacctgg cttctggagt ccctgctcgc 120
ttcagtggca gtgggtctgg gacctcttac tctctcacaa tcagcagagt ggaggctgaa 180
gatgctgcca cttattactg ccagcagtgg agtagtaacc cattcacgtt cggctcgggg 240
accaagctgg aaggcggcgg aggatctggc ggaggtggca gcggaggcgg tggatctgag 300
gtccagctgc agcagtctgg acctgagctg gtgaagcctg gggcttcagt gaagatatcc 360
tgcaagactt ctggatacac attcactgaa tacaccatgc actgggtgaa gcagagccat 420
ggaaagagcc ttgagtggat tggaggtatt aatcctaaca atggtggtac tagctacaac 480
cagaagttca agggcaaggc cacattgact gtagacaagt cctccagcac agcctacatg 540
gagctccgca gcctgacatc tgaggattct gcagtctatt actgtgcaag aggggggggg 600
tactacggct acggggacta ctggggtcaa ggaacctcag tcaccgtctc ctca 654
<210> 56
<211> 218
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 25C5-2 scFv
<400> 56
Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Met His Trp Tyr Gln
1 5 10 15
Gln Lys Pro Gly Ser Ser Pro Lys Pro Trp Ile Tyr Ala Thr Ser Asn
20 25 30
Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr
35 40 45
Ser Tyr Ser Leu Thr Ile Ser Arg Val Glu Ala Glu Asp Ala Ala Thr
50 55 60
Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Phe Thr Phe Gly Ser Gly
65 70 75 80
Thr Lys Leu Glu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
85 90 95
Gly Gly Ser Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys
100 105 110
Pro Gly Ala Ser Val Lys Ile Ser Cys Lys Thr Ser Gly Tyr Thr Phe
115 120 125
Thr Glu Tyr Thr Met His Trp Val Lys Gln Ser His Gly Lys Ser Leu
130 135 140
Glu Trp Ile Gly Gly Ile Asn Pro Asn Asn Gly Gly Thr Ser Tyr Asn
145 150 155 160
Gln Lys Phe Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser
165 170 175
Thr Ala Tyr Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val
180 185 190
Tyr Tyr Cys Ala Arg Gly Gly Gly Tyr Tyr Gly Tyr Gly Asp Tyr Trp
195 200 205
Gly Gln Gly Thr Ser Val Thr Val Ser Ser
210 215
<210> 57
<211> 744
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 10H10-1 scFv (核苷酸)
<400> 57
gatattgtga tgacccaaac tccactctcc ctgcctgtca gtcttggaga tcaagtctcc 60
atctcttgca gatctagtca gacccttgtg tatagtaatg gagacaccta tttagaatgg 120
tacctgcaga aaccaggcca gtctccaaag ctcctgatct acaaactttc caaccgattt 180
tctggggtcc cagacaggtt cagtggcagt ggatcaggga cagatttcac actcaagatc 240
agcagagtgg agtctgagga tctgggagtt tattactgct ttcagggttc atattttcca 300
ttcacgttcg gcgcggggac caaactggaa atcaaaggcg gcggaggatc tggcggaggt 360
ggcagcggag gcggtggatc tgaggttcag cttcagcagt ctggagctga gctggtaagg 420
cctgggactt cagtgaaggt gtcctgcaag gcttctggat acgccttcac taattacttc 480
atagagtggg taatacagag gcctggacag ggccttgagt ggattggagt gattaatcct 540
ggaaatagta atactaacta caatgagaag ttcaagggca aggcaacact gactgcggac 600
aaatcctcca gcactgccta catgcagctc agcagcctga catctgatga ctctgcggtc 660
tatttctgtg caagatcggg gactacggct acgacctatg ctatggacta ctggggtcaa 720
ggaacctcag tcatcgtctc ctca 744
<210> 58
<211> 248
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 10H10-1 scFv
<400> 58
Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly
1 5 10 15
Asp Gln Val Ser Ile Ser Cys Arg Ser Ser Gln Thr Leu Val Tyr Ser
20 25 30
Asn Gly Asp Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Leu Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ser Glu Asp Leu Gly Val Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser Tyr Phe Pro Phe Thr Phe Gly Ala Gly Thr Lys Leu Glu Ile Lys
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu
115 120 125
Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Thr Ser
130 135 140
Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Thr Asn Tyr Phe
145 150 155 160
Ile Glu Trp Val Ile Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile Gly
165 170 175
Val Ile Asn Pro Gly Asn Ser Asn Thr Asn Tyr Asn Glu Lys Phe Lys
180 185 190
Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr Met
195 200 205
Gln Leu Ser Ser Leu Thr Ser Asp Asp Ser Ala Val Tyr Phe Cys Ala
210 215 220
Arg Ser Gly Thr Thr Ala Thr Thr Tyr Ala Met Asp Tyr Trp Gly Gln
225 230 235 240
Gly Thr Ser Val Ile Val Ser Ser
245
<210> 59
<211> 723
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 16F10 scFv (核苷酸)
<400> 59
gagctcgata ttgttctctc ccagtctcca gcaatcctgt ctgcatctcc aggggagaag 60
gtcacaatga cttgcagggc cagctcaagt gtaagttaca tgcactggta ccagcagaag 120
ccaggatcct cccccaaacc ctggatttat gccacatcca acctggcttc tggagtccct 180
gctcgcttca gtggcagtgg gtctgggacc tcttactctc tcacaatcag cagagtggag 240
gctgaagatg ctgccactta ttactgccag cagtggagta gtaacccatt cacgttcggc 300
tcggggacca agctggagct gaaaggcggc ggaggatctg gcggaggtgg cagcggaggc 360
ggtggatctg aggtgaaggt ggtggagtct gggggaggct tagtgaagcc tggagggtcc 420
ctgaaactct cttgtacagc ctctggattc actttcagag gctatgcctt atcttgggtt 480
cgccagactc cagagaagag gctggagtgg gtcgcttcca ttagtactgg tggtaatact 540
tactatccag acagtgtgaa gggccgattc accatctcca gagataatgc caggaacatc 600
ctgtaccttc aaatgagcag gctgaggtct gatgacacgg ccatttattt ctgttcctct 660
ccttactggg gccaagggac tctggtcact gtctctgcag ccaaaacaac acccccatct 720
gtc 723
<210> 60
<211> 241
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 16F10 scFv
<400> 60
Glu Leu Asp Ile Val Leu Ser Gln Ser Pro Ala Ile Leu Ser Ala Ser
1 5 10 15
Pro Gly Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser
20 25 30
Tyr Met His Trp Tyr Gln Gln Lys Pro Gly Ser Ser Pro Lys Pro Trp
35 40 45
Ile Tyr Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Val Glu
65 70 75 80
Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro
85 90 95
Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Leu Lys Gly Gly Gly Gly
100 105 110
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Lys Val Val
115 120 125
Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly Ser Leu Lys Leu Ser
130 135 140
Cys Thr Ala Ser Gly Phe Thr Phe Arg Gly Tyr Ala Leu Ser Trp Val
145 150 155 160
Arg Gln Thr Pro Glu Lys Arg Leu Glu Trp Val Ala Ser Ile Ser Thr
165 170 175
Gly Gly Asn Thr Tyr Tyr Pro Asp Ser Val Lys Gly Arg Phe Thr Ile
180 185 190
Ser Arg Asp Asn Ala Arg Asn Ile Leu Tyr Leu Gln Met Ser Arg Leu
195 200 205
Arg Ser Asp Asp Thr Ala Ile Tyr Phe Cys Ser Ser Pro Tyr Trp Gly
210 215 220
Gln Gly Thr Leu Val Thr Val Ser Ala Ala Lys Thr Thr Pro Pro Ser
225 230 235 240
Val
<210> 61
<211> 141
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> CD8铰链区(核苷酸)
<400> 61
gaattcacca cgacgccagc gccgcgacca ccaacaccgg cgcccaccat cgcgtcgcag 60
cccctgtccc tgcgcccaga ggcgtgccgg ccagcggcgg ggggcgcagt gcacacgagg 120
gggctggact tcgcctgtga t 141
<210> 62
<211> 47
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> CD8铰链区
<400> 62
Glu Phe Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr
1 5 10 15
Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala
20 25 30
Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp
35 40 45
<210> 63
<211> 42
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> IgG4铰链区(核苷酸)
<400> 63
gaattcgaga gcaagtacgg ccccccctgc cccccctgcc cc 42
<210> 64
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> IgG4铰链区
<400> 64
Glu Phe Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro
1 5 10
<210> 65
<211> 72
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> CD8-1跨膜区(核苷酸)
<400> 65
atctacatct gggcgccctt ggccgggact tgtggggtcc ttctcctgtc actggttatc 60
accctttact gc 72
<210> 66
<211> 24
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> CD8-1跨膜区
<400> 66
Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu
1 5 10 15
Ser Leu Val Ile Thr Leu Tyr Cys
20
<210> 67
<211> 63
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> CD8-2跨膜区(核苷酸)
<400> 67
atctacatct gggcccccct ggccggcacc tgcggcgtgc tgctgctgag cctggtgatc 60
acc 63
<210> 68
<211> 21
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> CD8-2跨膜区
<400> 68
Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu
1 5 10 15
Ser Leu Val Ile Thr
20
<210> 69
<211> 126
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 4-1BB (核苷酸)
<400> 69
aagcgcggcc gcaagaagct gctgtacatc ttcaagcagc ccttcatgcg ccccgtgcag 60
accacccagg aggaggacgg ctgtagctgc cgcttccccg aggaggagga gggcggctgc 120
gagctg 126
<210> 70
<211> 42
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 4-1BB
<400> 70
Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met
1 5 10 15
Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe
20 25 30
Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu
35 40
<210> 71
<211> 108
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> OX40(核苷酸)
<400> 71
cgcgaccagc gcctgccccc cgacgcccac aagccccccg gcggcggcag cttccgcacc 60
cccatccagg aggagcaggc cgacgcccac agcaccctgg ccaagatc 108
<210> 72
<211> 36
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> OX40
<400> 72
Arg Asp Gln Arg Leu Pro Pro Asp Ala His Lys Pro Pro Gly Gly Gly
1 5 10 15
Ser Phe Arg Thr Pro Ile Gln Glu Glu Gln Ala Asp Ala His Ser Thr
20 25 30
Leu Ala Lys Ile
35
<210> 73
<211> 339
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> CD3ζ(核苷酸)
<400> 73
cgcgtgaaat ttagccgcag cgccgacgcc cccgcctacc agcagggcca gaaccagctg 60
tacaacgagc tgaacctggg ccgccgcgag gagtacgacg tgctggacaa gcgccggggc 120
cgcgaccccg agatgggcgg caagccccag cgccgcaaga acccccagga gggcctgtac 180
aacgagctgc agaaggacaa gatggccgaa gcctacagcg agatcggcat gaagggcgag 240
cgccgccggg gcaagggcca cgacggcctg taccagggcc tgagcaccgc caccaaggac 300
acctacgacg ccctgcacat gcaggccctg cccccccgc 339
<210> 74
<211> 113
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> CD3ζ
<400> 74
Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly
1 5 10 15
Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr
20 25 30
Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys
35 40 45
Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln
50 55 60
Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu
65 70 75 80
Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr
85 90 95
Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro
100 105 110
Arg
Claims (39)
1.抗体、其抗原结合片段或变体,其以3.5μg/mL或更低的IC50值与CD19蛋白相结合。
2.根据权利要求1所述的抗体、其抗原结合片段或变体,所述抗体选自下组中任一项:单克隆抗体、单链抗体、嵌合抗体、鼠源抗体和人源化抗体。
3.根据权利要求1-2中任一项所述的抗体、其抗原结合片段或变体,所述抗原结合片段选自:Fab、Fab’、F(ab)2、F(ab’)2、Fv和scFv。
4.根据权利要求1-3中任一项的抗体、其抗原结合片段或变体,所述变体选自下组:
1)在所述抗体或所述其抗原结合片段中经过取代、缺失或添加一个或多个氨基酸的蛋白质或多肽;和
2)与所述抗体或所述其抗原结合片段具有90%以上序列同源性的蛋白质或多肽。
5.抗体、其抗原结合片段或变体,其与参比抗体竞争结合所述CD19蛋白,其中所述参比抗体包含轻链可变区和重链可变区,所述参比抗体的轻链可变区包含LCDR1-3,所述LCDR1的氨基酸序列选自下组中任一项所示的氨基酸序列:SEQ ID NO:4和SEQ ID NO:18;所述LCDR2的氨基酸序列选自下组中任一项所示的氨基酸序列:SEQ ID NO:5和SEQ ID NO:19;以及所述LCDR3的氨基酸序列选自下组中任一项所示的氨基酸序列:SEQ ID NO:6和SEQ IDNO:20;且,
所述参比抗体的重链可变区包含HCDR1-3,所述HCDR1的氨基酸序列选自下组中任一项所示的氨基酸序列:SEQ ID NO:7、SEQ ID NO:21和SEQ ID NO:32;所述HCDR2的氨基酸序列选自下组中任一项所示的氨基酸序列:SEQ ID NO:8、SEQ ID NO:22和SEQ ID NO:33;以及所述HCDR3的氨基酸序列选自下组中任一项所示的氨基酸序列:SEQ ID NO:9、SEQ ID NO:23和SEQ ID NO:34。
6.根据权利要求5所述的抗体、其抗原结合片段或变体,其中所述参比抗体的轻链可变区的氨基酸序列选自下组中任一项所示的氨基酸序列:SEQ ID NO:42、SEQ ID NO:44和SEQID NO:46,且所述参比抗体的重链可变区的氨基酸序列选自下组中任一项所示的氨基酸序列:SEQ ID NO:48、SEQ ID NO:50和SEQ ID NO:52。
7.抗体、其抗原结合片段或变体,其包含LCDR1,且所述LCDR1包含选自下组任一项所示的氨基酸序列:SEQ ID NO:4和SEQ ID NO:18。
8.根据权利要求7中所述的抗体、其抗原结合片段或变体,其包含LCDR2,且所述LCDR2包含选自下组任一项所示的氨基酸序列:SEQ ID NO:5和SEQ ID NO:19。
9.根据权利要求7或8中所述的抗体、其抗原结合片段或变体,其包含LCDR3,且所述LCDR3包含选自下组任一项所示的氨基酸序列:SEQ ID NO:6和SEQ ID NO:20。
10.根据权利要求7-9中任一项所述的抗体、其抗原结合片段或变体,其包含轻链可变区VL,且所述轻链可变区VL包含选自下组任一项所示的氨基酸序列:SEQ ID NO:42、SEQ IDNO:44和SEQ ID NO:46。
11.根据权利要求7-10中任一项所述的抗体、其抗原结合片段或变体,其包含HCDR1,且所述HCDR1包含选自下组任一项所示的氨基酸序列:SEQ ID NO:7、SEQ ID NO:21、SEQ IDNO:32。
12.根据权利要求7-11中任一项所述的抗体、其抗原结合片段或变体,其包含HCDR2,且所述HCDR2包含选自下组任一项所示的氨基酸序列:SEQ ID NO:8、SEQ ID NO:22和SEQ IDNO:33。
13.根据权利要求7-12中任一项所述的抗体、其抗原结合片段或变体,其包含HCDR3,且所述HCDR3包含选自下组任一项所示的氨基酸序列:SEQ ID NO:9、SEQ ID NO:23和SEQ IDNO:34。
14.根据权利要求7-13中任一项所述的抗体、其抗原结合片段或变体,其包含重链可变区VH,且所述重链可变区VH包含选自下组任一项所示的氨基酸序列:SEQ ID NO:48、SEQ IDNO:50和SEQ ID NO:52。
15.根据权利要求1-14中任一项所述的抗体、其抗原结合片段或变体,其中所述抗体或其抗原结合片段为scFv。
16.根据权利要求15所述的抗体、其抗原结合片段或变体,其中所述scFv包含选自下组任一项所示的氨基酸序列:SEQ ID NO:56、SEQ ID NO:58和SEQ ID NO:60。
17.根据权利要求1-16中任一项所述的抗体、其抗原结合片段或变体,其中所述CD19蛋白为人CD19蛋白。
18.融合蛋白,其包含权利要求1-17中任一项所述的抗体、其抗原结合片段或变体。
19.根据权利要求18所述的融合蛋白,其中所述融合蛋白为嵌合抗原受体。
20.根据权利要求19所述的融合蛋白,其中所述嵌合抗原受体包含胞外铰链区、跨膜结构域、共刺激结构域和CD3ζ胞内信号转导结构域。
21.根据权利要求20所述的融合蛋白,其中所述胞外铰链区选自CD8铰链或IgG4铰链。
22.根据权利要求20或21所述的融合蛋白,其中所述跨膜结构域选自T细胞受体的α,β或ζ链、CD28、CD3e、CD45、CD4、CD5、CD8、CD9、CD16、CD22、CD33、CD37、CD64、CD80、CD86、CD134、CD137和CD154。
23.根据权利要求22所述的融合蛋白,其中所述跨膜结构域选自CD8-1或CD8-2。
24.根据权利要求20-23任意一项所述的融合蛋白,其中所述共刺激结构域选自CD27、CD28、4-1BB、OX40或ICOS。
25.根据权利要求20-24任意一项所述的融合蛋白,其中所述的嵌合抗原受体,所述胞外铰链区选自CD8铰链或IgG4铰链;所述跨膜结构域选自CD8-1或CD8-2;所述共刺激结构域选自4-1BB或OX40。
26.根据权利要求25所述的融合蛋白,其中所述的嵌合抗原受体,所述CD8-1跨膜的N端与所述CD8铰链的C端相连,所述CD8-1跨膜的C端与所述4-1BB的N端相连,所述4-1BB的C端与所述OX40的N端相连,所述OX40的C端与所述CD3ζ的N端相连。
27.根据权利要求25所述的融合蛋白,其中所述的嵌合抗原受体,所述CD8-2跨膜的N端与所述IgG4铰链的C端相连,所述CD8-2跨膜的C端与所述4-1BB的N端相连,所述4-1BB的C端与所述OX40的N端相连,所述OX40的C端与所述CD3ζ的N端相连。
28.分离的一种或多种核酸分子,其编码权利要求1-17中任一项所述的抗体、其抗原结合片段或变体,和/或,其编码权利要求18-27中任一项所述的融合蛋白。
29.一种或多种载体,其包含权利要求28所述的一种或多种核酸分子。
30.一种或多种细胞,其包含权利要求28所述的一种或多种核酸分子或权利要求29所述的一种或多种载体。
31.制备权利要求1-17中任一项所述的抗体、其抗原结合片段或变体,和/或,权利要求18-28中任一项所述的融合蛋白的方法,所述方法包括在使得权利要求1-17中任一项所述抗体、其抗原结合片段或变体,和/或,权利要求18-27中任一项所述的融合蛋白表达的条件下,培养权利要求30所述的细胞。
32.根据权利要求31所述的方法,其包含收获所述抗体、其抗原结合片段或变体,和/或,所述的融合蛋白。
33.药物组合物,其包含权利要求1-17中任一项所述的抗体、其抗原结合片段或变体、权利要求18-27中任一项所述的融合蛋白、权利要求28所述的核酸分子、权利要求29所述的载体,和/或,权利要求30所述的细胞,以及任选地药学上可接受的佐剂。
34.权利要求1-17中任一项所述的抗体、其抗原结合片段或变体,和/或,权利要求18-27中任一项所述的融合蛋白在制备预防或治疗疾病或病症的药物中的用途。
35.根据权利要求34所述的用途,所述疾病或病症选自下组中的任一项:肿瘤和自体免疫疾病。
36.根据权利要求35所述的用途,所述肿瘤选自下组中的任一项:B细胞亚型非霍奇金氏恶性淋巴瘤(NHL)、伯基特氏淋巴瘤、多发性骨髓瘤、前B急性淋巴母细胞性白血病及其他来源于早期B细胞前体的恶性肺瘤、普通急性淋巴细胞白血病、T慢性淋巴细胞性白血病、毛细胞白血病、非急性淋巴母细胞性白血病、华氏巨球蛋白血症、前淋巴细胞性白血病、浆细胞瘤、骨硬化骨髓瘤、浆细胞性白血病、单克隆丙种球蛋白病(MGUS)、郁积性多发性骨髓瘤(SMM)、缓慢性多发性骨髓瘤(IMM)、霍奇金氏恶性淋巴瘤、胃癌、肝癌、白血病、肾脏肿瘤、肺癌、小肠癌、骨癌、前列腺癌、结直肠癌、乳腺癌、大肠癌、前列腺癌、宫颈癌、肾上腺肿瘤和膀胱肿瘤。
37.根据权利要求36所述的用途,所述自体免疫疾病选自下组中的任一项:类风湿性关节炎、多发性硬化症和CD19+白血病。
38.抑制CD19蛋白生物学活性的方法,其包括施用权利要求1-17中任一项所述的抗体、其抗原结合片段或变体、权利要求18-27中任一项所述的融合蛋白、权利要求28所述的核酸分子、权利要求29所述的载体,和/或,权利要求30所述的细胞。
39.权利要求1-17中任一项所述的抗体、其抗原结合片段或变体、权利要求18-27中任一项所述的融合蛋白、权利要求28所述的核酸分子、权利要求29所述的载体,和/或,权利要求30所述的细胞,在制备诊断或检测肿瘤的试剂中的应用。
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2018114655473 | 2018-12-03 | ||
CN201811465547 | 2018-12-03 | ||
CN2019107407717 | 2019-08-12 | ||
CN201910740771 | 2019-08-12 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN111253487A true CN111253487A (zh) | 2020-06-09 |
CN111253487B CN111253487B (zh) | 2024-02-02 |
Family
ID=70945072
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201911215734.0A Active CN111253487B (zh) | 2018-12-03 | 2019-12-02 | Cd19抗体及其应用 |
Country Status (2)
Country | Link |
---|---|
CN (1) | CN111253487B (zh) |
WO (1) | WO2020114358A1 (zh) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2021027795A1 (en) * | 2019-08-12 | 2021-02-18 | Sunshine Lake Pharma Co., Ltd. | Chimeric antigen receptors and uses thereof |
CN114685659A (zh) * | 2020-12-30 | 2022-07-01 | 创新生物有限公司 | Cd22特异性人源化抗体及利用其的嵌合抗原受体 |
WO2023280297A1 (zh) * | 2021-07-09 | 2023-01-12 | 江苏先声药业有限公司 | Cd19抗体及其应用 |
Citations (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2015212278A (ja) * | 2008-11-07 | 2015-11-26 | イミューノメディクス、インコーポレイテッドImmunomedics, Inc. | 改良された抗cd19抗体 |
CN105950645A (zh) * | 2016-01-11 | 2016-09-21 | 灏灵赛奥(天津)生物科技有限公司 | Car-cd19抗原受体的人源化融合基因片段、其构建方法及应用 |
CN106117366A (zh) * | 2016-06-24 | 2016-11-16 | 安徽未名细胞治疗有限公司 | 一种cd19特异性嵌合抗原受体及其编码基因、应用 |
CN106536564A (zh) * | 2014-06-02 | 2017-03-22 | 美国卫生和人力服务部 | 靶向cd‑19的嵌合抗原受体 |
CN106800601A (zh) * | 2017-01-19 | 2017-06-06 | 广东昭泰体内生物医药科技有限公司 | 一种嵌合抗原受体及其应用 |
US20170183407A1 (en) * | 2014-02-14 | 2017-06-29 | Board Of Regents, The University Of Texas System | Chimeric antigen receptors and methods of making |
CN106922147A (zh) * | 2014-08-28 | 2017-07-04 | 朱诺治疗学股份有限公司 | Cd19特异性抗体和嵌合抗原受体 |
CN107312091A (zh) * | 2017-05-02 | 2017-11-03 | 重庆精准生物技术有限公司 | 靶向人cd19抗原的人源化单克隆抗体 |
CN107759700A (zh) * | 2017-10-18 | 2018-03-06 | 银丰生物工程集团有限公司 | 靶向cd19抗原的转基因t细胞及其制备方法与应用 |
CN108047332A (zh) * | 2018-01-15 | 2018-05-18 | 浙江阿思科力生物科技有限公司 | 以cd19为靶点的特异性抗体、car-nk细胞及其制备和应用 |
CN108330133A (zh) * | 2017-01-20 | 2018-07-27 | 上海恒润达生生物科技有限公司 | 靶向cd19嵌合抗原受体并对其双重修饰的方法及其用途 |
-
2019
- 2019-12-02 WO PCT/CN2019/122486 patent/WO2020114358A1/zh active Application Filing
- 2019-12-02 CN CN201911215734.0A patent/CN111253487B/zh active Active
Patent Citations (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2015212278A (ja) * | 2008-11-07 | 2015-11-26 | イミューノメディクス、インコーポレイテッドImmunomedics, Inc. | 改良された抗cd19抗体 |
US20170183407A1 (en) * | 2014-02-14 | 2017-06-29 | Board Of Regents, The University Of Texas System | Chimeric antigen receptors and methods of making |
CN106536564A (zh) * | 2014-06-02 | 2017-03-22 | 美国卫生和人力服务部 | 靶向cd‑19的嵌合抗原受体 |
CN106922147A (zh) * | 2014-08-28 | 2017-07-04 | 朱诺治疗学股份有限公司 | Cd19特异性抗体和嵌合抗原受体 |
CN105950645A (zh) * | 2016-01-11 | 2016-09-21 | 灏灵赛奥(天津)生物科技有限公司 | Car-cd19抗原受体的人源化融合基因片段、其构建方法及应用 |
CN106117366A (zh) * | 2016-06-24 | 2016-11-16 | 安徽未名细胞治疗有限公司 | 一种cd19特异性嵌合抗原受体及其编码基因、应用 |
CN106800601A (zh) * | 2017-01-19 | 2017-06-06 | 广东昭泰体内生物医药科技有限公司 | 一种嵌合抗原受体及其应用 |
CN108330133A (zh) * | 2017-01-20 | 2018-07-27 | 上海恒润达生生物科技有限公司 | 靶向cd19嵌合抗原受体并对其双重修饰的方法及其用途 |
CN107312091A (zh) * | 2017-05-02 | 2017-11-03 | 重庆精准生物技术有限公司 | 靶向人cd19抗原的人源化单克隆抗体 |
CN107759700A (zh) * | 2017-10-18 | 2018-03-06 | 银丰生物工程集团有限公司 | 靶向cd19抗原的转基因t细胞及其制备方法与应用 |
CN108047332A (zh) * | 2018-01-15 | 2018-05-18 | 浙江阿思科力生物科技有限公司 | 以cd19为靶点的特异性抗体、car-nk细胞及其制备和应用 |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2021027795A1 (en) * | 2019-08-12 | 2021-02-18 | Sunshine Lake Pharma Co., Ltd. | Chimeric antigen receptors and uses thereof |
CN114685659A (zh) * | 2020-12-30 | 2022-07-01 | 创新生物有限公司 | Cd22特异性人源化抗体及利用其的嵌合抗原受体 |
WO2023280297A1 (zh) * | 2021-07-09 | 2023-01-12 | 江苏先声药业有限公司 | Cd19抗体及其应用 |
Also Published As
Publication number | Publication date |
---|---|
CN111253487B (zh) | 2024-02-02 |
WO2020114358A1 (zh) | 2020-06-11 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
TWI830774B (zh) | 抗cd47抗體及其應用 | |
CN107973854B (zh) | Pdl1单克隆抗体及其应用 | |
EP3689909A1 (en) | Tigit antibody, antigen-binding fragment thereof, and medical use thereof | |
KR102022734B1 (ko) | 신규 조절제 및 용법 | |
CN108350084B (zh) | 新的间皮素抗体和包含其的组合物 | |
CN115286695A (zh) | 抗hla-g特异性抗体 | |
KR20190101989A (ko) | 항 gpc3 항체 | |
CN110066336B (zh) | 抗cd47单克隆抗体、片段及其医药用途 | |
AU2020352382A1 (en) | Anti-human claudin 18.2 antibody and application thereof | |
CN111253487B (zh) | Cd19抗体及其应用 | |
CN111620949A (zh) | 结合人lag-3的抗体、其制备方法和用途 | |
WO2023125888A1 (zh) | 一种gprc5d抗体及其应用 | |
KR102249981B1 (ko) | 단클론성 항-gpc-1 항체 및 이의 용도 | |
CN113583127A (zh) | 一种靶向nkg2a和pd-l1的双特异性抗体及应用 | |
CN115386007A (zh) | 抗gprc5d抗体、其制备方法与用途 | |
JP2023109923A (ja) | グロボhに対するヒト化抗体および癌治療におけるその使用 | |
CN113683697B (zh) | 抗b7-h3抗体、其制备方法及用途 | |
CN114478769B (zh) | 抗tigit抗体、其药物组合物及用途 | |
CN112969715B (zh) | 一种抗cd47抗原结合蛋白及其应用 | |
TW202229359A (zh) | Her2標靶藥物 | |
CN116284426A (zh) | 一种抗gucy2c/cd3双特异性抗体及其用途 | |
CN115838424A (zh) | 靶向tigit的单克隆抗体 | |
CN115386006A (zh) | 抗gprc5d抗体、其制备方法与用途 | |
CN114957468A (zh) | 一种抗Siglec15抗体及其用途 | |
CN112876563A (zh) | 药物组合物及其制备方法和应用 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
CB02 | Change of applicant information | ||
CB02 | Change of applicant information |
Address after: 523808 No.1, Gongye North Road, Songshanhu Park, Dongguan City, Guangdong Province Applicant after: Guangdong Dongyangguang Pharmaceutical Co.,Ltd. Address before: 523808 No. 1 Industrial North Road, Songshan Industrial Park, Songshan, Guangdong, Dongguan, Hubei Applicant before: SUNSHINE LAKE PHARMA Co.,Ltd. |
|
GR01 | Patent grant | ||
GR01 | Patent grant |