TW202344518A - Bcma抗體及其用於治療癌症及免疫病症之用途 - Google Patents
Bcma抗體及其用於治療癌症及免疫病症之用途 Download PDFInfo
- Publication number
- TW202344518A TW202344518A TW112104791A TW112104791A TW202344518A TW 202344518 A TW202344518 A TW 202344518A TW 112104791 A TW112104791 A TW 112104791A TW 112104791 A TW112104791 A TW 112104791A TW 202344518 A TW202344518 A TW 202344518A
- Authority
- TW
- Taiwan
- Prior art keywords
- cdata
- antibody
- ser
- seq
- thr
- Prior art date
Links
- 206010028980 Neoplasm Diseases 0.000 title claims abstract description 71
- 208000026278 immune system disease Diseases 0.000 title claims abstract description 14
- 201000011510 cancer Diseases 0.000 title claims description 48
- 101100425747 Mus musculus Tnfrsf17 gene Proteins 0.000 title description 3
- 102000006942 B-Cell Maturation Antigen Human genes 0.000 claims abstract description 95
- 108010008014 B-Cell Maturation Antigen Proteins 0.000 claims abstract description 95
- BGFTWECWAICPDG-UHFFFAOYSA-N 2-[bis(4-chlorophenyl)methyl]-4-n-[3-[bis(4-chlorophenyl)methyl]-4-(dimethylamino)phenyl]-1-n,1-n-dimethylbenzene-1,4-diamine Chemical compound C1=C(C(C=2C=CC(Cl)=CC=2)C=2C=CC(Cl)=CC=2)C(N(C)C)=CC=C1NC(C=1)=CC=C(N(C)C)C=1C(C=1C=CC(Cl)=CC=1)C1=CC=C(Cl)C=C1 BGFTWECWAICPDG-UHFFFAOYSA-N 0.000 claims abstract description 93
- 241000282414 Homo sapiens Species 0.000 claims description 158
- 210000004027 cell Anatomy 0.000 claims description 117
- NFGXHKASABOEEW-UHFFFAOYSA-N 1-methylethyl 11-methoxy-3,7,11-trimethyl-2,4-dodecadienoate Chemical compound COC(C)(C)CCCC(C)CC=CC(C)=CC(=O)OC(C)C NFGXHKASABOEEW-UHFFFAOYSA-N 0.000 claims description 105
- 230000027455 binding Effects 0.000 claims description 95
- 238000000034 method Methods 0.000 claims description 45
- SHZGCJCMOBCMKK-DHVFOXMCSA-N L-fucopyranose Chemical compound C[C@@H]1OC(O)[C@@H](O)[C@H](O)[C@@H]1O SHZGCJCMOBCMKK-DHVFOXMCSA-N 0.000 claims description 29
- SHZGCJCMOBCMKK-UHFFFAOYSA-N D-mannomethylose Natural products CC1OC(O)C(O)C(O)C1O SHZGCJCMOBCMKK-UHFFFAOYSA-N 0.000 claims description 27
- PNNNRSAQSRJVSB-SLPGGIOYSA-N Fucose Natural products C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C=O PNNNRSAQSRJVSB-SLPGGIOYSA-N 0.000 claims description 27
- 239000002254 cytotoxic agent Substances 0.000 claims description 25
- 229940127089 cytotoxic agent Drugs 0.000 claims description 24
- 125000003275 alpha amino acid group Chemical group 0.000 claims description 23
- 150000008267 fucoses Chemical class 0.000 claims description 23
- 231100000599 cytotoxic agent Toxicity 0.000 claims description 22
- 230000001404 mediated effect Effects 0.000 claims description 22
- 230000033581 fucosylation Effects 0.000 claims description 20
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 17
- 201000005787 hematologic cancer Diseases 0.000 claims description 16
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 claims description 16
- 101000801255 Homo sapiens Tumor necrosis factor receptor superfamily member 17 Proteins 0.000 claims description 14
- 239000008194 pharmaceutical composition Substances 0.000 claims description 14
- 102000046935 human TNFRSF17 Human genes 0.000 claims description 13
- 206010025323 Lymphomas Diseases 0.000 claims description 12
- 210000003719 b-lymphocyte Anatomy 0.000 claims description 12
- 235000000346 sugar Nutrition 0.000 claims description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 11
- 108010073807 IgG Receptors Proteins 0.000 claims description 10
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 claims description 9
- 201000000050 myeloid neoplasm Diseases 0.000 claims description 9
- 208000011580 syndromic disease Diseases 0.000 claims description 9
- 201000003793 Myelodysplastic syndrome Diseases 0.000 claims description 8
- 231100000433 cytotoxic Toxicity 0.000 claims description 8
- 230000001472 cytotoxic effect Effects 0.000 claims description 8
- 208000032839 leukemia Diseases 0.000 claims description 8
- 230000002829 reductive effect Effects 0.000 claims description 8
- 201000000596 systemic lupus erythematosus Diseases 0.000 claims description 8
- 208000017604 Hodgkin disease Diseases 0.000 claims description 7
- 208000010747 Hodgkins lymphoma Diseases 0.000 claims description 7
- 102000009490 IgG Receptors Human genes 0.000 claims description 7
- 208000034578 Multiple myelomas Diseases 0.000 claims description 7
- 229930182474 N-glycoside Natural products 0.000 claims description 7
- 239000000824 cytostatic agent Substances 0.000 claims description 7
- 208000035475 disorder Diseases 0.000 claims description 7
- 208000024908 graft versus host disease Diseases 0.000 claims description 7
- 210000002865 immune cell Anatomy 0.000 claims description 7
- 239000003937 drug carrier Substances 0.000 claims description 6
- 239000012626 DNA minor groove binder Substances 0.000 claims description 5
- 206010012438 Dermatitis atopic Diseases 0.000 claims description 5
- 201000004681 Psoriasis Diseases 0.000 claims description 5
- 208000033559 Waldenström macroglobulinemia Diseases 0.000 claims description 5
- 208000006673 asthma Diseases 0.000 claims description 5
- 201000008937 atopic dermatitis Diseases 0.000 claims description 5
- 201000006417 multiple sclerosis Diseases 0.000 claims description 5
- 208000008439 Biliary Liver Cirrhosis Diseases 0.000 claims description 4
- 208000033222 Biliary cirrhosis primary Diseases 0.000 claims description 4
- 208000011691 Burkitt lymphomas Diseases 0.000 claims description 4
- 206010072579 Granulomatosis with polyangiitis Diseases 0.000 claims description 4
- 208000015023 Graves' disease Diseases 0.000 claims description 4
- 208000030836 Hashimoto thyroiditis Diseases 0.000 claims description 4
- 208000021519 Hodgkin lymphoma Diseases 0.000 claims description 4
- 208000012654 Primary biliary cholangitis Diseases 0.000 claims description 4
- 206010039085 Rhinitis allergic Diseases 0.000 claims description 4
- 206010043561 Thrombocytopenic purpura Diseases 0.000 claims description 4
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 claims description 4
- 201000010105 allergic rhinitis Diseases 0.000 claims description 4
- 201000010099 disease Diseases 0.000 claims description 4
- 230000002071 myeloproliferative effect Effects 0.000 claims description 4
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 4
- 201000008827 tuberculosis Diseases 0.000 claims description 4
- MFRNYXJJRJQHNW-DEMKXPNLSA-N (2s)-2-[[(2r,3r)-3-methoxy-3-[(2s)-1-[(3r,4s,5s)-3-methoxy-5-methyl-4-[methyl-[(2s)-3-methyl-2-[[(2s)-3-methyl-2-(methylamino)butanoyl]amino]butanoyl]amino]heptanoyl]pyrrolidin-2-yl]-2-methylpropanoyl]amino]-3-phenylpropanoic acid Chemical compound CN[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N(C)[C@@H]([C@@H](C)CC)[C@H](OC)CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 MFRNYXJJRJQHNW-DEMKXPNLSA-N 0.000 claims description 3
- 208000009329 Graft vs Host Disease Diseases 0.000 claims description 3
- 208000003807 Graves Disease Diseases 0.000 claims description 3
- IEDXPSOJFSVCKU-HOKPPMCLSA-N [4-[[(2S)-5-(carbamoylamino)-2-[[(2S)-2-[6-(2,5-dioxopyrrolidin-1-yl)hexanoylamino]-3-methylbutanoyl]amino]pentanoyl]amino]phenyl]methyl N-[(2S)-1-[[(2S)-1-[[(3R,4S,5S)-1-[(2S)-2-[(1R,2R)-3-[[(1S,2R)-1-hydroxy-1-phenylpropan-2-yl]amino]-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl]-3-methoxy-5-methyl-1-oxoheptan-4-yl]-methylamino]-3-methyl-1-oxobutan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]-N-methylcarbamate Chemical group CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C)[C@@H](O)c1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OCc1ccc(NC(=O)[C@H](CCCNC(N)=O)NC(=O)[C@@H](NC(=O)CCCCCN2C(=O)CCC2=O)C(C)C)cc1)C(C)C IEDXPSOJFSVCKU-HOKPPMCLSA-N 0.000 claims description 3
- 230000000919 anti-host Effects 0.000 claims 1
- 238000011282 treatment Methods 0.000 abstract description 22
- 102100035360 Cerebellar degeneration-related antigen 1 Human genes 0.000 description 150
- 101710117290 Aldo-keto reductase family 1 member C4 Proteins 0.000 description 107
- 239000003814 drug Substances 0.000 description 62
- 235000001014 amino acid Nutrition 0.000 description 58
- 241000700159 Rattus Species 0.000 description 55
- 229940024606 amino acid Drugs 0.000 description 54
- 150000001413 amino acids Chemical class 0.000 description 53
- 230000000694 effects Effects 0.000 description 46
- 238000006467 substitution reaction Methods 0.000 description 46
- 125000005647 linker group Chemical group 0.000 description 45
- 229940079593 drug Drugs 0.000 description 44
- 230000035772 mutation Effects 0.000 description 29
- 239000000611 antibody drug conjugate Substances 0.000 description 27
- 230000010056 antibody-dependent cellular cytotoxicity Effects 0.000 description 27
- 241000880493 Leptailurus serval Species 0.000 description 26
- 241000700157 Rattus norvegicus Species 0.000 description 25
- 229940049595 antibody-drug conjugate Drugs 0.000 description 25
- 108010061238 threonyl-glycine Proteins 0.000 description 25
- 108010086434 alanyl-seryl-glycine Proteins 0.000 description 24
- 230000013595 glycosylation Effects 0.000 description 24
- 238000006206 glycosylation reaction Methods 0.000 description 24
- 239000012636 effector Substances 0.000 description 23
- 108090000623 proteins and genes Proteins 0.000 description 21
- 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 20
- 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 20
- 239000000203 mixture Substances 0.000 description 20
- 241001465754 Metazoa Species 0.000 description 19
- 108010079364 N-glycylalanine Proteins 0.000 description 19
- VPZXBVLAVMBEQI-UHFFFAOYSA-N glycyl-DL-alpha-alanine Natural products OC(=O)C(C)NC(=O)CN VPZXBVLAVMBEQI-UHFFFAOYSA-N 0.000 description 19
- OYTPNWYZORARHL-XHNCKOQMSA-N Gln-Ala-Pro Chemical compound C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCC(=O)N)N OYTPNWYZORARHL-XHNCKOQMSA-N 0.000 description 18
- PMGDADKJMCOXHX-UHFFFAOYSA-N L-Arginyl-L-glutamin-acetat Natural products NC(=N)NCCCC(N)C(=O)NC(CCC(N)=O)C(O)=O PMGDADKJMCOXHX-UHFFFAOYSA-N 0.000 description 18
- 108010069020 alanyl-prolyl-glycine Proteins 0.000 description 18
- 108010008355 arginyl-glutamine Proteins 0.000 description 18
- 108010050475 glycyl-leucyl-tyrosine Proteins 0.000 description 18
- 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 17
- 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 17
- 102000005962 receptors Human genes 0.000 description 17
- 108020003175 receptors Proteins 0.000 description 17
- 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 16
- SNXUIBACCONSOH-BWBBJGPYSA-N Ser-Thr-Ser Chemical compound OC[C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@@H](CO)C(O)=O SNXUIBACCONSOH-BWBBJGPYSA-N 0.000 description 16
- 239000000427 antigen Substances 0.000 description 16
- 108091007433 antigens Proteins 0.000 description 16
- 102000036639 antigens Human genes 0.000 description 16
- 210000004602 germ cell Anatomy 0.000 description 16
- 108010089804 glycyl-threonine Proteins 0.000 description 16
- 239000003446 ligand Substances 0.000 description 16
- 102000004169 proteins and genes Human genes 0.000 description 16
- KIZIOFNVSOSKJI-CIUDSAMLSA-N Leu-Ser-Cys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)O)N KIZIOFNVSOSKJI-CIUDSAMLSA-N 0.000 description 15
- 230000000903 blocking effect Effects 0.000 description 15
- 230000004540 complement-dependent cytotoxicity Effects 0.000 description 15
- 235000018102 proteins Nutrition 0.000 description 15
- 229940124597 therapeutic agent Drugs 0.000 description 15
- QLSRIZIDQXDQHK-RCWTZXSCSA-N Arg-Val-Thr Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O QLSRIZIDQXDQHK-RCWTZXSCSA-N 0.000 description 14
- 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 14
- FEUPVVCGQLNXNP-IRXDYDNUSA-N Gly-Phe-Phe Chemical compound C([C@H](NC(=O)CN)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 FEUPVVCGQLNXNP-IRXDYDNUSA-N 0.000 description 14
- JZXKNNOWPBVZEV-XIRDDKMYSA-N Met-Trp-Glu Chemical compound CSCC[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N JZXKNNOWPBVZEV-XIRDDKMYSA-N 0.000 description 14
- HCTXJGRYAACKOB-SRVKXCTJSA-N Phe-Asn-Asp Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC(=O)O)C(=O)O)N HCTXJGRYAACKOB-SRVKXCTJSA-N 0.000 description 14
- CUMXHKAOHNWRFQ-BZSNNMDCSA-N Phe-Asp-Tyr Chemical compound C([C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C1=CC=CC=C1 CUMXHKAOHNWRFQ-BZSNNMDCSA-N 0.000 description 14
- 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 14
- UNURFMVMXLENAZ-KJEVXHAQSA-N Thr-Arg-Tyr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O UNURFMVMXLENAZ-KJEVXHAQSA-N 0.000 description 14
- VUXIQSUQQYNLJP-XAVMHZPKSA-N Thr-Ser-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CO)C(=O)N1CCC[C@@H]1C(=O)O)N)O VUXIQSUQQYNLJP-XAVMHZPKSA-N 0.000 description 14
- 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 14
- 102100036922 Tumor necrosis factor ligand superfamily member 13B Human genes 0.000 description 14
- 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 14
- 230000014509 gene expression Effects 0.000 description 14
- XKUKSGPZAADMRA-UHFFFAOYSA-N glycyl-glycyl-glycine Natural products NCC(=O)NCC(=O)NCC(O)=O XKUKSGPZAADMRA-UHFFFAOYSA-N 0.000 description 14
- 238000001727 in vivo Methods 0.000 description 14
- IFOHPTVCEBWEEQ-UHFFFAOYSA-N pyrrolo[2,3-i][1,4]benzodiazepine Chemical compound N1=CC=NC2=C3C=CN=C3C=CC2=C1 IFOHPTVCEBWEEQ-UHFFFAOYSA-N 0.000 description 14
- 108010073969 valyllysine Proteins 0.000 description 14
- 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 13
- 102100029193 Low affinity immunoglobulin gamma Fc region receptor III-A Human genes 0.000 description 13
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 13
- 241000699666 Mus <mouse, genus> Species 0.000 description 13
- NZYNRRGJJVSSTJ-GUBZILKMSA-N Val-Ser-Val Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O NZYNRRGJJVSSTJ-GUBZILKMSA-N 0.000 description 13
- 239000003795 chemical substances by application Substances 0.000 description 13
- 108010077112 prolyl-proline Proteins 0.000 description 13
- 230000004083 survival effect Effects 0.000 description 13
- HPBNLFLSSQDFQW-WHFBIAKZSA-N Asn-Ser-Gly Chemical compound NC(=O)C[C@H](N)C(=O)N[C@@H](CO)C(=O)NCC(O)=O HPBNLFLSSQDFQW-WHFBIAKZSA-N 0.000 description 12
- MKJBPDLENBUHQU-CIUDSAMLSA-N Asn-Ser-Leu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O MKJBPDLENBUHQU-CIUDSAMLSA-N 0.000 description 12
- 101100315624 Caenorhabditis elegans tyr-1 gene Proteins 0.000 description 12
- 102000004190 Enzymes Human genes 0.000 description 12
- 108090000790 Enzymes Proteins 0.000 description 12
- 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 12
- IMPKSPYRPUXYAP-SZMVWBNQSA-N His-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](CC3=CN=CN3)N IMPKSPYRPUXYAP-SZMVWBNQSA-N 0.000 description 12
- PDIDTSZKKFEDMB-UWVGGRQHSA-N Lys-Pro-Gly Chemical compound [H]N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O PDIDTSZKKFEDMB-UWVGGRQHSA-N 0.000 description 12
- PESQCPHRXOFIPX-UHFFFAOYSA-N N-L-methionyl-L-tyrosine Natural products CSCCC(N)C(=O)NC(C(O)=O)CC1=CC=C(O)C=C1 PESQCPHRXOFIPX-UHFFFAOYSA-N 0.000 description 12
- 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 12
- FUMGHWDRRFCKEP-CIUDSAMLSA-N Ser-Leu-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(O)=O FUMGHWDRRFCKEP-CIUDSAMLSA-N 0.000 description 12
- PPCZVWHJWJFTFN-ZLUOBGJFSA-N Ser-Ser-Asp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(O)=O PPCZVWHJWJFTFN-ZLUOBGJFSA-N 0.000 description 12
- 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 12
- 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 12
- 101710181056 Tumor necrosis factor ligand superfamily member 13B Proteins 0.000 description 12
- 108010069205 aspartyl-phenylalanine Proteins 0.000 description 12
- 108010093581 aspartyl-proline Proteins 0.000 description 12
- 108010044540 auristatin Proteins 0.000 description 12
- 229940088598 enzyme Drugs 0.000 description 12
- 210000004408 hybridoma Anatomy 0.000 description 12
- 230000001965 increasing effect Effects 0.000 description 12
- 101100505161 Caenorhabditis elegans mel-32 gene Proteins 0.000 description 11
- 241000699670 Mus sp. Species 0.000 description 11
- 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 11
- FQPDRTDDEZXCEC-SVSWQMSJSA-N Thr-Ile-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(O)=O FQPDRTDDEZXCEC-SVSWQMSJSA-N 0.000 description 11
- 108010092854 aspartyllysine Proteins 0.000 description 11
- 108010073025 phenylalanylphenylalanine Proteins 0.000 description 11
- YYSWCHMLFJLLBJ-ZLUOBGJFSA-N Ala-Ala-Ser Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O YYSWCHMLFJLLBJ-ZLUOBGJFSA-N 0.000 description 10
- FMNBYVSGRCXWEK-FOHZUACHSA-N Asn-Thr-Gly Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(O)=O FMNBYVSGRCXWEK-FOHZUACHSA-N 0.000 description 10
- OOXKFYNWRVGYFM-XIRDDKMYSA-N Asp-His-Trp Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)O)NC(=O)[C@H](CC3=CN=CN3)NC(=O)[C@H](CC(=O)O)N OOXKFYNWRVGYFM-XIRDDKMYSA-N 0.000 description 10
- 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 10
- NPTGGVQJYRSMCM-GLLZPBPUSA-N Gln-Gln-Thr Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O NPTGGVQJYRSMCM-GLLZPBPUSA-N 0.000 description 10
- FQCILXROGNOZON-YUMQZZPRSA-N Gln-Pro-Gly Chemical compound NC(=O)CC[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O FQCILXROGNOZON-YUMQZZPRSA-N 0.000 description 10
- IESFZVCAVACGPH-PEFMBERDSA-N Glu-Asp-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](N)CCC(O)=O IESFZVCAVACGPH-PEFMBERDSA-N 0.000 description 10
- 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 10
- QSDKBRMVXSWAQE-BFHQHQDPSA-N Gly-Ala-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)CN QSDKBRMVXSWAQE-BFHQHQDPSA-N 0.000 description 10
- CCQOOWAONKGYKQ-BYPYZUCNSA-N Gly-Gly-Ala Chemical compound OC(=O)[C@H](C)NC(=O)CNC(=O)CN CCQOOWAONKGYKQ-BYPYZUCNSA-N 0.000 description 10
- 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 10
- SAEWJTCJQVZQNZ-IUKAMOBKSA-N Ile-Thr-Asn Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(=O)N)C(=O)O)N SAEWJTCJQVZQNZ-IUKAMOBKSA-N 0.000 description 10
- AXZGZMGRBDQTEY-SRVKXCTJSA-N Leu-Gln-Met Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCSC)C(O)=O AXZGZMGRBDQTEY-SRVKXCTJSA-N 0.000 description 10
- 239000005089 Luciferase Substances 0.000 description 10
- 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 10
- 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 10
- 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 10
- 101150006914 TRP1 gene Proteins 0.000 description 10
- PQLXHSACXPGWPD-GSSVUCPTSA-N Thr-Asn-Thr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O PQLXHSACXPGWPD-GSSVUCPTSA-N 0.000 description 10
- XPNSAQMEAVSQRD-FBCQKBJTSA-N Thr-Gly-Gly Chemical compound C[C@@H](O)[C@H](N)C(=O)NCC(=O)NCC(O)=O XPNSAQMEAVSQRD-FBCQKBJTSA-N 0.000 description 10
- MICFJCRQBFSKPA-UMPQAUOISA-N Trp-Met-Thr Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H](CCSC)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)=CNC2=C1 MICFJCRQBFSKPA-UMPQAUOISA-N 0.000 description 10
- CWVHKVVKAQIJKY-ACRUOGEOSA-N Tyr-Lys-Phe Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC2=CC=C(C=C2)O)N CWVHKVVKAQIJKY-ACRUOGEOSA-N 0.000 description 10
- SSYBNWFXCFNRFN-GUBZILKMSA-N Val-Pro-Ser Chemical compound CC(C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O SSYBNWFXCFNRFN-GUBZILKMSA-N 0.000 description 10
- 108010040443 aspartyl-aspartic acid Proteins 0.000 description 10
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 10
- 230000006870 function Effects 0.000 description 10
- 108010067216 glycyl-glycyl-glycine Proteins 0.000 description 10
- 230000003834 intracellular effect Effects 0.000 description 10
- 239000002207 metabolite Substances 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- 150000003839 salts Chemical class 0.000 description 10
- 230000001225 therapeutic effect Effects 0.000 description 10
- 108010038745 tryptophylglycine Proteins 0.000 description 10
- VKKYFICVTYKFIO-CIUDSAMLSA-N Arg-Ala-Glu Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCN=C(N)N VKKYFICVTYKFIO-CIUDSAMLSA-N 0.000 description 9
- 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 9
- 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 9
- 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 9
- OVRNDRQMDRJTHS-UHFFFAOYSA-N N-acelyl-D-glucosamine Natural products CC(=O)NC1C(O)OC(CO)C(O)C1O OVRNDRQMDRJTHS-UHFFFAOYSA-N 0.000 description 9
- MBLBDJOUHNCFQT-LXGUWJNJSA-N N-acetylglucosamine Natural products CC(=O)N[C@@H](C=O)[C@@H](O)[C@H](O)[C@H](O)CO MBLBDJOUHNCFQT-LXGUWJNJSA-N 0.000 description 9
- 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 9
- RHAPJNVNWDBFQI-BQBZGAKWSA-N Ser-Pro-Gly Chemical compound OC[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O RHAPJNVNWDBFQI-BQBZGAKWSA-N 0.000 description 9
- 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 9
- 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 9
- RCOUFINCYASMDN-GUBZILKMSA-N Ser-Val-Met Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCSC)C(O)=O RCOUFINCYASMDN-GUBZILKMSA-N 0.000 description 9
- LVTKHGUGBGNBPL-UHFFFAOYSA-N Trp-P-1 Chemical compound N1C2=CC=CC=C2C2=C1C(C)=C(N)N=C2C LVTKHGUGBGNBPL-UHFFFAOYSA-N 0.000 description 9
- 108010008685 alanyl-glutamyl-aspartic acid Proteins 0.000 description 9
- 108010077245 asparaginyl-proline Proteins 0.000 description 9
- 239000000562 conjugate Substances 0.000 description 9
- 108010050848 glycylleucine Proteins 0.000 description 9
- 238000011068 loading method Methods 0.000 description 9
- 239000000178 monomer Substances 0.000 description 9
- 150000007523 nucleic acids Chemical class 0.000 description 9
- 150000002482 oligosaccharides Chemical class 0.000 description 9
- 108010070643 prolylglutamic acid Proteins 0.000 description 9
- 125000006850 spacer group Chemical group 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- 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 8
- OHLLDUNVMPPUMD-DCAQKATOSA-N Cys-Leu-Val Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](C(C)C)C(=O)O)NC(=O)[C@H](CS)N OHLLDUNVMPPUMD-DCAQKATOSA-N 0.000 description 8
- ZFBBMCKQSNJZSN-AUTRQRHGSA-N Gln-Val-Gln Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O ZFBBMCKQSNJZSN-AUTRQRHGSA-N 0.000 description 8
- DYFJZDDQPNIPAB-NHCYSSNCSA-N Glu-Arg-Val Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(O)=O DYFJZDDQPNIPAB-NHCYSSNCSA-N 0.000 description 8
- SBANPBVRHYIMRR-UHFFFAOYSA-N Leu-Ser-Pro Natural products CC(C)CC(N)C(=O)NC(CO)C(=O)N1CCCC1C(O)=O SBANPBVRHYIMRR-UHFFFAOYSA-N 0.000 description 8
- VUBIPAHVHMZHCM-KKUMJFAQSA-N Leu-Tyr-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](CO)C(O)=O)CC1=CC=C(O)C=C1 VUBIPAHVHMZHCM-KKUMJFAQSA-N 0.000 description 8
- MVJRBCJCRYGCKV-GVXVVHGQSA-N Leu-Val-Gln Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O MVJRBCJCRYGCKV-GVXVVHGQSA-N 0.000 description 8
- 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 8
- UGCIQUYEJIEHKX-GVXVVHGQSA-N Lys-Val-Glu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O UGCIQUYEJIEHKX-GVXVVHGQSA-N 0.000 description 8
- 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 8
- FUVBEZJCRMHWEM-FXQIFTODSA-N Pro-Asn-Ser Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(O)=O FUVBEZJCRMHWEM-FXQIFTODSA-N 0.000 description 8
- WDXYVIIVDIDOSX-DCAQKATOSA-N Ser-Arg-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CO)CCCN=C(N)N WDXYVIIVDIDOSX-DCAQKATOSA-N 0.000 description 8
- GJFYFGOEWLDQGW-GUBZILKMSA-N Ser-Leu-Gln Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CO)N GJFYFGOEWLDQGW-GUBZILKMSA-N 0.000 description 8
- YOOAQCZYZHGUAZ-KATARQTJSA-N Thr-Leu-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O YOOAQCZYZHGUAZ-KATARQTJSA-N 0.000 description 8
- LMKKMCGTDANZTR-BZSNNMDCSA-N Tyr-Phe-Asp Chemical compound C([C@H](N)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC(O)=O)C(O)=O)C1=CC=C(O)C=C1 LMKKMCGTDANZTR-BZSNNMDCSA-N 0.000 description 8
- 230000001154 acute effect Effects 0.000 description 8
- 238000004458 analytical method Methods 0.000 description 8
- 238000010171 animal model Methods 0.000 description 8
- 108010047857 aspartylglycine Proteins 0.000 description 8
- 108010068265 aspartyltyrosine Proteins 0.000 description 8
- 230000000295 complement effect Effects 0.000 description 8
- 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 8
- 108010015792 glycyllysine Proteins 0.000 description 8
- 230000005764 inhibitory process Effects 0.000 description 8
- 108020004707 nucleic acids Proteins 0.000 description 8
- 102000039446 nucleic acids Human genes 0.000 description 8
- 230000004044 response Effects 0.000 description 8
- WLVLIYYBPPONRJ-GCJQMDKQSA-N Asn-Thr-Ala Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O WLVLIYYBPPONRJ-GCJQMDKQSA-N 0.000 description 7
- KOWYNSKRPUWSFG-IHPCNDPISA-N Asp-Phe-Trp Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC2=CNC3=CC=CC=C32)C(=O)O)NC(=O)[C@H](CC(=O)O)N KOWYNSKRPUWSFG-IHPCNDPISA-N 0.000 description 7
- ALMIMUZAWTUNIO-BZSNNMDCSA-N Asp-Tyr-Tyr Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O ALMIMUZAWTUNIO-BZSNNMDCSA-N 0.000 description 7
- 101100512078 Caenorhabditis elegans lys-1 gene Proteins 0.000 description 7
- 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 7
- 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 7
- LHSGPCFBGJHPCY-UHFFFAOYSA-N L-leucine-L-tyrosine Natural products CC(C)CC(N)C(=O)NC(C(O)=O)CC1=CC=C(O)C=C1 LHSGPCFBGJHPCY-UHFFFAOYSA-N 0.000 description 7
- 101100068676 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) gln-1 gene Proteins 0.000 description 7
- 108091005804 Peptidases Proteins 0.000 description 7
- DJPXNKUDJKGQEE-BZSNNMDCSA-N Phe-Asp-Phe Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O DJPXNKUDJKGQEE-BZSNNMDCSA-N 0.000 description 7
- RAGOJJCBGXARPO-XVSYOHENSA-N Phe-Thr-Asp Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)[C@H]([C@H](O)C)NC(=O)[C@@H](N)CC1=CC=CC=C1 RAGOJJCBGXARPO-XVSYOHENSA-N 0.000 description 7
- FKLSMYYLJHYPHH-UWVGGRQHSA-N Pro-Gly-Leu Chemical compound [H]N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](CC(C)C)C(O)=O FKLSMYYLJHYPHH-UWVGGRQHSA-N 0.000 description 7
- 238000011579 SCID mouse model Methods 0.000 description 7
- 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 7
- OQPNSDWGAMFJNU-QWRGUYRKSA-N Ser-Gly-Tyr Chemical compound OC[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 OQPNSDWGAMFJNU-QWRGUYRKSA-N 0.000 description 7
- ZOPISOXXPQNOCO-SVSWQMSJSA-N Ser-Ile-Thr Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)O)NC(=O)[C@H](CO)N ZOPISOXXPQNOCO-SVSWQMSJSA-N 0.000 description 7
- JCLAFVNDBJMLBC-JBDRJPRFSA-N Ser-Ser-Ile Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O JCLAFVNDBJMLBC-JBDRJPRFSA-N 0.000 description 7
- 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 7
- ZTPXSEUVYNNZRB-CDMKHQONSA-N Thr-Gly-Phe Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O ZTPXSEUVYNNZRB-CDMKHQONSA-N 0.000 description 7
- 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 7
- 102100029690 Tumor necrosis factor receptor superfamily member 13C Human genes 0.000 description 7
- QQCCSDWLVIEPSF-BVSLBCMMSA-N Tyr-Met-Trp Chemical compound C([C@H](N)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(O)=O)C1=CC=C(O)C=C1 QQCCSDWLVIEPSF-BVSLBCMMSA-N 0.000 description 7
- ROLGIBMFNMZANA-GVXVVHGQSA-N Val-Glu-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](C(C)C)N ROLGIBMFNMZANA-GVXVVHGQSA-N 0.000 description 7
- 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 7
- 230000005888 antibody-dependent cellular phagocytosis Effects 0.000 description 7
- 238000003556 assay Methods 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 108010078144 glutaminyl-glycine Proteins 0.000 description 7
- 108010087823 glycyltyrosine Proteins 0.000 description 7
- 230000001976 improved effect Effects 0.000 description 7
- 230000003993 interaction Effects 0.000 description 7
- 108010012058 leucyltyrosine Proteins 0.000 description 7
- 210000004698 lymphocyte Anatomy 0.000 description 7
- 229950006780 n-acetylglucosamine Drugs 0.000 description 7
- 229920001542 oligosaccharide Polymers 0.000 description 7
- 108010020755 prolyl-glycyl-glycine Proteins 0.000 description 7
- 108010033670 threonyl-aspartyl-tyrosine Proteins 0.000 description 7
- 230000003442 weekly effect Effects 0.000 description 7
- AWAXZRDKUHOPBO-GUBZILKMSA-N Ala-Gln-Lys Chemical compound C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(O)=O AWAXZRDKUHOPBO-GUBZILKMSA-N 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
- 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 6
- QNFRBNZGVVKBNJ-PEFMBERDSA-N Asp-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](CC(=O)O)N QNFRBNZGVVKBNJ-PEFMBERDSA-N 0.000 description 6
- BKOIIURTQAJHAT-GUBZILKMSA-N Asp-Pro-Pro Chemical compound OC(=O)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 BKOIIURTQAJHAT-GUBZILKMSA-N 0.000 description 6
- 102100021277 Beta-secretase 2 Human genes 0.000 description 6
- SZQCDCKIGWQAQN-FXQIFTODSA-N Cys-Arg-Ala Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(O)=O SZQCDCKIGWQAQN-FXQIFTODSA-N 0.000 description 6
- VTJLJQGUMBWHBP-GUBZILKMSA-N Cys-His-Gln Chemical compound C1=C(NC=N1)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CS)N VTJLJQGUMBWHBP-GUBZILKMSA-N 0.000 description 6
- KXUKWRVYDYIPSQ-CIUDSAMLSA-N Cys-Leu-Ala Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(O)=O KXUKWRVYDYIPSQ-CIUDSAMLSA-N 0.000 description 6
- IKFZXRLDMYWNBU-YUMQZZPRSA-N Gln-Gly-Arg Chemical compound NC(=O)CC[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CCCN=C(N)N IKFZXRLDMYWNBU-YUMQZZPRSA-N 0.000 description 6
- 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 6
- 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 6
- INGJLBQKTRJLFO-UKJIMTQDSA-N Glu-Ile-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H](N)CCC(O)=O INGJLBQKTRJLFO-UKJIMTQDSA-N 0.000 description 6
- 108090000288 Glycoproteins Proteins 0.000 description 6
- 102000003886 Glycoproteins Human genes 0.000 description 6
- SENJXOPIZNYLHU-UHFFFAOYSA-N L-leucyl-L-arginine Natural products CC(C)CC(N)C(=O)NC(C(O)=O)CCCN=C(N)N SENJXOPIZNYLHU-UHFFFAOYSA-N 0.000 description 6
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 6
- HXWALXSAVBLTPK-NUTKFTJISA-N Leu-Ala-Trp Chemical compound C[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)NC(=O)[C@H](CC(C)C)N HXWALXSAVBLTPK-NUTKFTJISA-N 0.000 description 6
- 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 6
- FAELBUXXFQLUAX-AJNGGQMLSA-N Leu-Leu-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC(C)C FAELBUXXFQLUAX-AJNGGQMLSA-N 0.000 description 6
- LCNASHSOFMRYFO-WDCWCFNPSA-N Leu-Thr-Gln Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@H](C(O)=O)CCC(N)=O LCNASHSOFMRYFO-WDCWCFNPSA-N 0.000 description 6
- 101710099301 Low affinity immunoglobulin gamma Fc region receptor III-A Proteins 0.000 description 6
- 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 6
- IIHMNTBFPMRJCN-RCWTZXSCSA-N Met-Val-Thr Chemical compound CSCC[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O IIHMNTBFPMRJCN-RCWTZXSCSA-N 0.000 description 6
- OVRNDRQMDRJTHS-FMDGEEDCSA-N N-acetyl-beta-D-glucosamine Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O OVRNDRQMDRJTHS-FMDGEEDCSA-N 0.000 description 6
- 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 6
- JARJPEMLQAWNBR-GUBZILKMSA-N Pro-Asp-Arg Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O JARJPEMLQAWNBR-GUBZILKMSA-N 0.000 description 6
- 239000004365 Protease Substances 0.000 description 6
- 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 6
- 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 6
- HNDMFDBQXYZSRM-IHRRRGAJSA-N Ser-Val-Phe Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O HNDMFDBQXYZSRM-IHRRRGAJSA-N 0.000 description 6
- GXUWHVZYDAHFSV-FLBSBUHZSA-N Thr-Ile-Thr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(O)=O GXUWHVZYDAHFSV-FLBSBUHZSA-N 0.000 description 6
- ARKBYVBCEOWRNR-UBHSHLNASA-N Trp-Ser-Ser Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O ARKBYVBCEOWRNR-UBHSHLNASA-N 0.000 description 6
- QUILOGWWLXMSAT-IHRRRGAJSA-N Tyr-Gln-Gln Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O QUILOGWWLXMSAT-IHRRRGAJSA-N 0.000 description 6
- RZAGEHHVNYESNR-RNXOBYDBSA-N Tyr-Trp-Tyr Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O RZAGEHHVNYESNR-RNXOBYDBSA-N 0.000 description 6
- 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 6
- 108010081404 acein-2 Proteins 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 108010044940 alanylglutamine Proteins 0.000 description 6
- 210000004369 blood Anatomy 0.000 description 6
- 239000008280 blood Substances 0.000 description 6
- 150000001720 carbohydrates Chemical class 0.000 description 6
- 238000005859 coupling reaction Methods 0.000 description 6
- 108010049041 glutamylalanine Proteins 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- 108010000761 leucylarginine Proteins 0.000 description 6
- 108010038320 lysylphenylalanine Proteins 0.000 description 6
- 108010031719 prolyl-serine Proteins 0.000 description 6
- 230000009870 specific binding Effects 0.000 description 6
- 108010044292 tryptophyltyrosine Proteins 0.000 description 6
- 239000013598 vector Substances 0.000 description 6
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 5
- GJLXVWOMRRWCIB-MERZOTPQSA-N (2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-6-aminohexanoyl]amino]-6-aminohexanoyl]amino]-6-aminohexanoyl]amino]-6-aminohexanoyl]amino]-6-aminohexanoyl]amino]-6-aminohexanoyl]amino]-6-aminohexanamide Chemical compound C([C@H](NC(=O)[C@H](CCCN=C(N)N)NC(=O)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(N)=O)C1=CC=C(O)C=C1 GJLXVWOMRRWCIB-MERZOTPQSA-N 0.000 description 5
- OMRPLUKQNWNZAV-CONSDPRKSA-N (6as)-3-[3-[[(6as)-2-methoxy-8-(4-methoxyphenyl)-11-oxo-6a,7-dihydropyrrolo[2,1-c][1,4]benzodiazepin-3-yl]oxy]propoxy]-8-(4-aminophenyl)-2-methoxy-6a,7-dihydropyrrolo[2,1-c][1,4]benzodiazepin-11-one Chemical compound C1=CC(OC)=CC=C1C1=CN2C(=O)C3=CC(OC)=C(OCCCOC=4C(=CC=5C(=O)N6C=C(C[C@H]6C=NC=5C=4)C=4C=CC(N)=CC=4)OC)C=C3N=C[C@@H]2C1 OMRPLUKQNWNZAV-CONSDPRKSA-N 0.000 description 5
- BUDNAJYVCUHLSV-ZLUOBGJFSA-N Ala-Asp-Ser Chemical compound C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O BUDNAJYVCUHLSV-ZLUOBGJFSA-N 0.000 description 5
- 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 5
- ARHJJAAWNWOACN-FXQIFTODSA-N Ala-Ser-Val Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O ARHJJAAWNWOACN-FXQIFTODSA-N 0.000 description 5
- ISCYZXFOCXWUJU-KZVJFYERSA-N Ala-Thr-Met Chemical compound [H]N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCSC)C(O)=O ISCYZXFOCXWUJU-KZVJFYERSA-N 0.000 description 5
- 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 5
- SLKLLQWZQHXYSV-CIUDSAMLSA-N Asn-Ala-Lys Chemical compound NC(=O)C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(O)=O SLKLLQWZQHXYSV-CIUDSAMLSA-N 0.000 description 5
- UGXYFDQFLVCDFC-CIUDSAMLSA-N Asn-Ser-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O UGXYFDQFLVCDFC-CIUDSAMLSA-N 0.000 description 5
- JBDLMLZNDRLDIX-HJGDQZAQSA-N Asn-Thr-Leu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O JBDLMLZNDRLDIX-HJGDQZAQSA-N 0.000 description 5
- XYBJLTKSGFBLCS-QXEWZRGKSA-N Asp-Arg-Val Chemical compound NC(N)=NCCC[C@@H](C(=O)N[C@@H](C(C)C)C(O)=O)NC(=O)[C@@H](N)CC(O)=O XYBJLTKSGFBLCS-QXEWZRGKSA-N 0.000 description 5
- GYWQGGUCMDCUJE-DLOVCJGASA-N Asp-Phe-Ala Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](C)C(O)=O GYWQGGUCMDCUJE-DLOVCJGASA-N 0.000 description 5
- 108020004414 DNA Proteins 0.000 description 5
- OSCLNNWLKKIQJM-WDSKDSINSA-N Gln-Ser-Gly Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)NCC(O)=O OSCLNNWLKKIQJM-WDSKDSINSA-N 0.000 description 5
- XKPACHRGOWQHFH-IRIUXVKKSA-N Gln-Thr-Tyr Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O XKPACHRGOWQHFH-IRIUXVKKSA-N 0.000 description 5
- PAQUJCSYVIBPLC-AVGNSLFASA-N Glu-Asp-Phe Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 PAQUJCSYVIBPLC-AVGNSLFASA-N 0.000 description 5
- WGYHAAXZWPEBDQ-IFFSRLJSSA-N Glu-Val-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O WGYHAAXZWPEBDQ-IFFSRLJSSA-N 0.000 description 5
- NVTPVQLIZCOJFK-FOHZUACHSA-N Gly-Thr-Asp Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(O)=O NVTPVQLIZCOJFK-FOHZUACHSA-N 0.000 description 5
- 101000795167 Homo sapiens Tumor necrosis factor receptor superfamily member 13B Proteins 0.000 description 5
- 102100026120 IgG receptor FcRn large subunit p51 Human genes 0.000 description 5
- 101710177940 IgG receptor FcRn large subunit p51 Proteins 0.000 description 5
- DFJJAVZIHDFOGQ-MNXVOIDGSA-N Ile-Glu-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCCCN)C(=O)O)N DFJJAVZIHDFOGQ-MNXVOIDGSA-N 0.000 description 5
- 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 5
- JZNVOBUNTWNZPW-GHCJXIJMSA-N Ile-Ser-Asp Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(=O)O)C(=O)O)N JZNVOBUNTWNZPW-GHCJXIJMSA-N 0.000 description 5
- 108010065920 Insulin Lispro Proteins 0.000 description 5
- PVMPDMIKUVNOBD-CIUDSAMLSA-N Leu-Asp-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O PVMPDMIKUVNOBD-CIUDSAMLSA-N 0.000 description 5
- QNBVTHNJGCOVFA-AVGNSLFASA-N Leu-Leu-Glu Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CCC(O)=O QNBVTHNJGCOVFA-AVGNSLFASA-N 0.000 description 5
- BRTVHXHCUSXYRI-CIUDSAMLSA-N Leu-Ser-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O BRTVHXHCUSXYRI-CIUDSAMLSA-N 0.000 description 5
- AIMGJYMCTAABEN-GVXVVHGQSA-N Leu-Val-Glu Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O AIMGJYMCTAABEN-GVXVVHGQSA-N 0.000 description 5
- IXHKPDJKKCUKHS-GARJFASQSA-N Lys-Ala-Pro Chemical compound C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCCCN)N IXHKPDJKKCUKHS-GARJFASQSA-N 0.000 description 5
- AEIIJFBQVGYVEV-YESZJQIVSA-N Lys-Phe-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC2=CC=CC=C2)NC(=O)[C@H](CCCCN)N)C(=O)O AEIIJFBQVGYVEV-YESZJQIVSA-N 0.000 description 5
- LUTDBHBIHHREDC-IHRRRGAJSA-N Lys-Pro-Lys Chemical compound NCCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(O)=O LUTDBHBIHHREDC-IHRRRGAJSA-N 0.000 description 5
- WYBVBIHNJWOLCJ-UHFFFAOYSA-N N-L-arginyl-L-leucine Natural products CC(C)CC(C(O)=O)NC(=O)C(N)CCCN=C(N)N WYBVBIHNJWOLCJ-UHFFFAOYSA-N 0.000 description 5
- AUEJLPRZGVVDNU-UHFFFAOYSA-N N-L-tyrosyl-L-leucine Natural products CC(C)CC(C(O)=O)NC(=O)C(N)CC1=CC=C(O)C=C1 AUEJLPRZGVVDNU-UHFFFAOYSA-N 0.000 description 5
- FSPGBMWPNMRWDB-AVGNSLFASA-N Phe-Cys-Gln Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N FSPGBMWPNMRWDB-AVGNSLFASA-N 0.000 description 5
- YYKZDTVQHTUKDW-RYUDHWBXSA-N Phe-Gly-Gln Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)NCC(=O)N[C@@H](CCC(=O)N)C(=O)O)N YYKZDTVQHTUKDW-RYUDHWBXSA-N 0.000 description 5
- KLYYKKGCPOGDPE-OEAJRASXSA-N Phe-Thr-Leu Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O KLYYKKGCPOGDPE-OEAJRASXSA-N 0.000 description 5
- IHCXPSYCHXFXKT-DCAQKATOSA-N Pro-Arg-Glu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(O)=O IHCXPSYCHXFXKT-DCAQKATOSA-N 0.000 description 5
- 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 5
- HJEBZBMOTCQYDN-ACZMJKKPSA-N Ser-Glu-Asp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O HJEBZBMOTCQYDN-ACZMJKKPSA-N 0.000 description 5
- 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 5
- AZWNCEBQZXELEZ-FXQIFTODSA-N Ser-Pro-Ser Chemical compound OC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O AZWNCEBQZXELEZ-FXQIFTODSA-N 0.000 description 5
- JGUWRQWULDWNCM-FXQIFTODSA-N Ser-Val-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(O)=O JGUWRQWULDWNCM-FXQIFTODSA-N 0.000 description 5
- 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 5
- GUHLYMZJVXUIPO-RCWTZXSCSA-N Thr-Met-Val Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](C(C)C)C(O)=O GUHLYMZJVXUIPO-RCWTZXSCSA-N 0.000 description 5
- BIBYEFRASCNLAA-CDMKHQONSA-N Thr-Phe-Gly Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@H](C(=O)NCC(O)=O)CC1=CC=CC=C1 BIBYEFRASCNLAA-CDMKHQONSA-N 0.000 description 5
- ZMYCLHFLHRVOEA-HEIBUPTGSA-N Thr-Thr-Ser Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(O)=O ZMYCLHFLHRVOEA-HEIBUPTGSA-N 0.000 description 5
- 102100029675 Tumor necrosis factor receptor superfamily member 13B Human genes 0.000 description 5
- 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 5
- KLQPIEVIKOQRAW-IZPVPAKOSA-N Tyr-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](CC1=CC=C(C=C1)O)N)O KLQPIEVIKOQRAW-IZPVPAKOSA-N 0.000 description 5
- MWUYSCVVPVITMW-IGNZVWTISA-N Tyr-Tyr-Ala Chemical compound C([C@@H](C(=O)N[C@@H](C)C(O)=O)NC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=C(O)C=C1 MWUYSCVVPVITMW-IGNZVWTISA-N 0.000 description 5
- HZDQUVQEVVYDDA-ACRUOGEOSA-N Tyr-Tyr-Leu Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=C(O)C=C1 HZDQUVQEVVYDDA-ACRUOGEOSA-N 0.000 description 5
- 108010038633 aspartylglutamate Proteins 0.000 description 5
- 210000004899 c-terminal region Anatomy 0.000 description 5
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 5
- 238000003776 cleavage reaction Methods 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- 230000008878 coupling Effects 0.000 description 5
- 238000010168 coupling process Methods 0.000 description 5
- 108010063718 gamma-glutamylaspartic acid Proteins 0.000 description 5
- 108010037850 glycylvaline Proteins 0.000 description 5
- 238000001990 intravenous administration Methods 0.000 description 5
- 108010057821 leucylproline Proteins 0.000 description 5
- 108010003700 lysyl aspartic acid Proteins 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 210000000822 natural killer cell Anatomy 0.000 description 5
- 108010073101 phenylalanylleucine Proteins 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 230000007017 scission Effects 0.000 description 5
- 230000011664 signaling Effects 0.000 description 5
- 208000011317 telomere syndrome Diseases 0.000 description 5
- 108010051110 tyrosyl-lysine Proteins 0.000 description 5
- 108010027345 wheylin-1 peptide Proteins 0.000 description 5
- MNZHHDPWDWQJCQ-YUMQZZPRSA-N Ala-Leu-Gly Chemical compound C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O MNZHHDPWDWQJCQ-YUMQZZPRSA-N 0.000 description 4
- DPNZTBKGAUAZQU-DLOVCJGASA-N Ala-Leu-His Chemical compound C[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N DPNZTBKGAUAZQU-DLOVCJGASA-N 0.000 description 4
- MEFILNJXAVSUTO-JXUBOQSCSA-N Ala-Leu-Thr Chemical compound C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O MEFILNJXAVSUTO-JXUBOQSCSA-N 0.000 description 4
- 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 4
- WQKAQKZRDIZYNV-VZFHVOOUSA-N Ala-Ser-Thr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(O)=O WQKAQKZRDIZYNV-VZFHVOOUSA-N 0.000 description 4
- CREYEAPXISDKSB-FQPOAREZSA-N Ala-Thr-Tyr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O CREYEAPXISDKSB-FQPOAREZSA-N 0.000 description 4
- 102100021266 Alpha-(1,6)-fucosyltransferase Human genes 0.000 description 4
- ISJWBVIYRBAXEB-CIUDSAMLSA-N Arg-Ser-Glu Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(O)=O ISJWBVIYRBAXEB-CIUDSAMLSA-N 0.000 description 4
- ZJBUILVYSXQNSW-YTWAJWBKSA-N Arg-Thr-Pro Chemical compound C[C@H]([C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCCN=C(N)N)N)O ZJBUILVYSXQNSW-YTWAJWBKSA-N 0.000 description 4
- 239000004475 Arginine Substances 0.000 description 4
- SRUUBQBAVNQZGJ-LAEOZQHASA-N Asn-Gln-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CC(=O)N)N SRUUBQBAVNQZGJ-LAEOZQHASA-N 0.000 description 4
- WQLJRNRLHWJIRW-KKUMJFAQSA-N Asn-His-Tyr Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)O)NC(=O)[C@H](CC2=CN=CN2)NC(=O)[C@H](CC(=O)N)N)O WQLJRNRLHWJIRW-KKUMJFAQSA-N 0.000 description 4
- HNXWVVHIGTZTBO-LKXGYXEUSA-N Asn-Ser-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O HNXWVVHIGTZTBO-LKXGYXEUSA-N 0.000 description 4
- JPPLRQVZMZFOSX-UWJYBYFXSA-N Asn-Tyr-Ala Chemical compound NC(=O)C[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](C)C(O)=O)CC1=CC=C(O)C=C1 JPPLRQVZMZFOSX-UWJYBYFXSA-N 0.000 description 4
- QNNBHTFDFFFHGC-KKUMJFAQSA-N Asn-Tyr-Lys Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC(=O)N)N)O QNNBHTFDFFFHGC-KKUMJFAQSA-N 0.000 description 4
- MJIJBEYEHBKTIM-BYULHYEWSA-N Asn-Val-Asn Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CC(=O)N)N MJIJBEYEHBKTIM-BYULHYEWSA-N 0.000 description 4
- CUQDCPXNZPDYFQ-ZLUOBGJFSA-N Asp-Ser-Asp Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(O)=O CUQDCPXNZPDYFQ-ZLUOBGJFSA-N 0.000 description 4
- JSNWZMFSLIWAHS-HJGDQZAQSA-N Asp-Thr-Leu Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)O)NC(=O)[C@H](CC(=O)O)N)O JSNWZMFSLIWAHS-HJGDQZAQSA-N 0.000 description 4
- 208000023275 Autoimmune disease Diseases 0.000 description 4
- YMBAVNPKBWHDAW-CIUDSAMLSA-N Cys-Asp-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CS)N YMBAVNPKBWHDAW-CIUDSAMLSA-N 0.000 description 4
- 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 4
- NDNZRWUDUMTITL-FXQIFTODSA-N Cys-Ser-Val Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O NDNZRWUDUMTITL-FXQIFTODSA-N 0.000 description 4
- 238000002965 ELISA Methods 0.000 description 4
- 108010087819 Fc receptors Proteins 0.000 description 4
- 102000009109 Fc receptors Human genes 0.000 description 4
- NVEASDQHBRZPSU-BQBZGAKWSA-N Gln-Gln-Gly Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(O)=O NVEASDQHBRZPSU-BQBZGAKWSA-N 0.000 description 4
- NNXIQPMZGZUFJJ-AVGNSLFASA-N Gln-His-Lys Chemical compound C1=C(NC=N1)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCC(=O)N)N NNXIQPMZGZUFJJ-AVGNSLFASA-N 0.000 description 4
- ZEEPYMXTJWIMSN-GUBZILKMSA-N Gln-Lys-Ser Chemical compound NCCCC[C@@H](C(=O)N[C@@H](CO)C(O)=O)NC(=O)[C@@H](N)CCC(N)=O ZEEPYMXTJWIMSN-GUBZILKMSA-N 0.000 description 4
- XUMFMAVDHQDATI-DCAQKATOSA-N Gln-Pro-Arg Chemical compound NC(=O)CC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCN=C(N)N)C(O)=O XUMFMAVDHQDATI-DCAQKATOSA-N 0.000 description 4
- HMIXCETWRYDVMO-GUBZILKMSA-N Gln-Pro-Glu Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O HMIXCETWRYDVMO-GUBZILKMSA-N 0.000 description 4
- AVZHGSCDKIQZPQ-CIUDSAMLSA-N Glu-Arg-Ala Chemical compound C[C@H](NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](N)CCC(O)=O)C(O)=O AVZHGSCDKIQZPQ-CIUDSAMLSA-N 0.000 description 4
- CKOFNWCLWRYUHK-XHNCKOQMSA-N Glu-Asp-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC(=O)O)NC(=O)[C@H](CCC(=O)O)N)C(=O)O CKOFNWCLWRYUHK-XHNCKOQMSA-N 0.000 description 4
- HUFCEIHAFNVSNR-IHRRRGAJSA-N Glu-Gln-Tyr Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 HUFCEIHAFNVSNR-IHRRRGAJSA-N 0.000 description 4
- MWMJCGBSIORNCD-AVGNSLFASA-N Glu-Leu-Leu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O MWMJCGBSIORNCD-AVGNSLFASA-N 0.000 description 4
- AAJHGGDRKHYSDH-GUBZILKMSA-N Glu-Pro-Gln Chemical compound C1C[C@H](N(C1)C(=O)[C@H](CCC(=O)O)N)C(=O)N[C@@H](CCC(=O)N)C(=O)O AAJHGGDRKHYSDH-GUBZILKMSA-N 0.000 description 4
- BPCLDCNZBUYGOD-BPUTZDHNSA-N Glu-Trp-Glu Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](CCC(O)=O)N)C(=O)N[C@@H](CCC(O)=O)C(O)=O)=CNC2=C1 BPCLDCNZBUYGOD-BPUTZDHNSA-N 0.000 description 4
- BUEFQXUHTUZXHR-LURJTMIESA-N Gly-Gly-Pro zwitterion Chemical compound NCC(=O)NCC(=O)N1CCC[C@H]1C(O)=O BUEFQXUHTUZXHR-LURJTMIESA-N 0.000 description 4
- GMTXWRIDLGTVFC-IUCAKERBSA-N Gly-Lys-Glu Chemical compound [H]NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(O)=O GMTXWRIDLGTVFC-IUCAKERBSA-N 0.000 description 4
- JSLVAHYTAJJEQH-QWRGUYRKSA-N Gly-Ser-Phe Chemical compound NCC(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 JSLVAHYTAJJEQH-QWRGUYRKSA-N 0.000 description 4
- CQMFNTVQVLQRLT-JHEQGTHGSA-N Gly-Thr-Gln Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(N)=O)C(O)=O CQMFNTVQVLQRLT-JHEQGTHGSA-N 0.000 description 4
- KOYUSMBPJOVSOO-XEGUGMAKSA-N Gly-Tyr-Ile Chemical compound [H]NCC(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O KOYUSMBPJOVSOO-XEGUGMAKSA-N 0.000 description 4
- SYOJVRNQCXYEOV-XVKPBYJWSA-N Gly-Val-Glu Chemical compound [H]NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O SYOJVRNQCXYEOV-XVKPBYJWSA-N 0.000 description 4
- FULZDMOZUZKGQU-ONGXEEELSA-N Gly-Val-His Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)CN FULZDMOZUZKGQU-ONGXEEELSA-N 0.000 description 4
- MUGLKCQHTUFLGF-WPRPVWTQSA-N Gly-Val-Met Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCSC)C(=O)O)NC(=O)CN MUGLKCQHTUFLGF-WPRPVWTQSA-N 0.000 description 4
- FYVHHKMHFPMBBG-GUBZILKMSA-N His-Gln-Asp Chemical compound C1=C(NC=N1)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CC(=O)O)C(=O)O)N FYVHHKMHFPMBBG-GUBZILKMSA-N 0.000 description 4
- 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 4
- 101000819490 Homo sapiens Alpha-(1,6)-fucosyltransferase Proteins 0.000 description 4
- 101000869050 Homo sapiens Caveolae-associated protein 2 Proteins 0.000 description 4
- 101000917858 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor III-A Proteins 0.000 description 4
- MKWSZEHGHSLNPF-NAKRPEOUSA-N Ile-Ala-Val Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)O)N MKWSZEHGHSLNPF-NAKRPEOUSA-N 0.000 description 4
- NZGTYCMLUGYMCV-XUXIUFHCSA-N Ile-Lys-Arg Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N NZGTYCMLUGYMCV-XUXIUFHCSA-N 0.000 description 4
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 4
- CQGSYZCULZMEDE-UHFFFAOYSA-N Leu-Gln-Pro Natural products CC(C)CC(N)C(=O)NC(CCC(N)=O)C(=O)N1CCCC1C(O)=O CQGSYZCULZMEDE-UHFFFAOYSA-N 0.000 description 4
- OGUUKPXUTHOIAV-SDDRHHMPSA-N Leu-Glu-Pro Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N1CCC[C@@H]1C(=O)O)N OGUUKPXUTHOIAV-SDDRHHMPSA-N 0.000 description 4
- UHNQRAFSEBGZFZ-YESZJQIVSA-N Leu-Phe-Pro Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N2CCC[C@@H]2C(=O)O)N UHNQRAFSEBGZFZ-YESZJQIVSA-N 0.000 description 4
- DPURXCQCHSQPAN-AVGNSLFASA-N Leu-Pro-Pro Chemical compound CC(C)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 DPURXCQCHSQPAN-AVGNSLFASA-N 0.000 description 4
- XOWMDXHFSBCAKQ-SRVKXCTJSA-N Leu-Ser-Leu Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CC(C)C XOWMDXHFSBCAKQ-SRVKXCTJSA-N 0.000 description 4
- SBANPBVRHYIMRR-GARJFASQSA-N Leu-Ser-Pro Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CO)C(=O)N1CCC[C@@H]1C(=O)O)N SBANPBVRHYIMRR-GARJFASQSA-N 0.000 description 4
- DAYQSYGBCUKVKT-VOAKCMCISA-N Leu-Thr-Lys Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(O)=O DAYQSYGBCUKVKT-VOAKCMCISA-N 0.000 description 4
- AIQWYVFNBNNOLU-RHYQMDGZSA-N Leu-Thr-Val Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(O)=O AIQWYVFNBNNOLU-RHYQMDGZSA-N 0.000 description 4
- 108060001084 Luciferase Proteins 0.000 description 4
- KCXUCYYZNZFGLL-SRVKXCTJSA-N Lys-Ala-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(O)=O KCXUCYYZNZFGLL-SRVKXCTJSA-N 0.000 description 4
- WSXTWLJHTLRFLW-SRVKXCTJSA-N Lys-Ala-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(O)=O WSXTWLJHTLRFLW-SRVKXCTJSA-N 0.000 description 4
- NTBFKPBULZGXQL-KKUMJFAQSA-N Lys-Asp-Tyr Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 NTBFKPBULZGXQL-KKUMJFAQSA-N 0.000 description 4
- RFQATBGBLDAKGI-VHSXEESVSA-N Lys-Gly-Pro Chemical compound C1C[C@@H](N(C1)C(=O)CNC(=O)[C@H](CCCCN)N)C(=O)O RFQATBGBLDAKGI-VHSXEESVSA-N 0.000 description 4
- OIQSIMFSVLLWBX-VOAKCMCISA-N Lys-Leu-Thr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O OIQSIMFSVLLWBX-VOAKCMCISA-N 0.000 description 4
- JOSAKOKSPXROGQ-BJDJZHNGSA-N Lys-Ser-Ile Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O JOSAKOKSPXROGQ-BJDJZHNGSA-N 0.000 description 4
- QLFAPXUXEBAWEK-NHCYSSNCSA-N Lys-Val-Asp Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O QLFAPXUXEBAWEK-NHCYSSNCSA-N 0.000 description 4
- DRRXXZBXDMLGFC-IHRRRGAJSA-N Lys-Val-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CCCCN DRRXXZBXDMLGFC-IHRRRGAJSA-N 0.000 description 4
- GILLQRYAWOMHED-DCAQKATOSA-N Lys-Val-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CCCCN GILLQRYAWOMHED-DCAQKATOSA-N 0.000 description 4
- RKIIYGUHIQJCBW-SRVKXCTJSA-N Met-His-Glu Chemical compound [H]N[C@@H](CCSC)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCC(O)=O)C(O)=O RKIIYGUHIQJCBW-SRVKXCTJSA-N 0.000 description 4
- FWAHLGXNBLWIKB-NAKRPEOUSA-N Met-Ile-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H](N)CCSC FWAHLGXNBLWIKB-NAKRPEOUSA-N 0.000 description 4
- 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 4
- OVRNDRQMDRJTHS-RTRLPJTCSA-N N-acetyl-D-glucosamine Chemical compound CC(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O OVRNDRQMDRJTHS-RTRLPJTCSA-N 0.000 description 4
- 102000035195 Peptidases Human genes 0.000 description 4
- JOXIIFVCSATTDH-IHPCNDPISA-N Phe-Asn-Trp Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC2=CNC3=CC=CC=C32)C(=O)O)N JOXIIFVCSATTDH-IHPCNDPISA-N 0.000 description 4
- QARPMYDMYVLFMW-KKUMJFAQSA-N Phe-Pro-Glu Chemical compound C([C@H](N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(O)=O)C1=CC=CC=C1 QARPMYDMYVLFMW-KKUMJFAQSA-N 0.000 description 4
- XDMMOISUAHXXFD-SRVKXCTJSA-N Phe-Ser-Asp Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(O)=O XDMMOISUAHXXFD-SRVKXCTJSA-N 0.000 description 4
- FMLRRBDLBJLJIK-DCAQKATOSA-N Pro-Leu-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H]1CCCN1 FMLRRBDLBJLJIK-DCAQKATOSA-N 0.000 description 4
- MHHQQZIFLWFZGR-DCAQKATOSA-N Pro-Lys-Ser Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(O)=O MHHQQZIFLWFZGR-DCAQKATOSA-N 0.000 description 4
- GMJDSFYVTAMIBF-FXQIFTODSA-N Pro-Ser-Asp Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(O)=O GMJDSFYVTAMIBF-FXQIFTODSA-N 0.000 description 4
- MKGIILKDUGDRRO-FXQIFTODSA-N Pro-Ser-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H]1CCCN1 MKGIILKDUGDRRO-FXQIFTODSA-N 0.000 description 4
- KHRLUIPIMIQFGT-AVGNSLFASA-N Pro-Val-Leu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O KHRLUIPIMIQFGT-AVGNSLFASA-N 0.000 description 4
- YDTUEBLEAVANFH-RCWTZXSCSA-N Pro-Val-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H]1CCCN1 YDTUEBLEAVANFH-RCWTZXSCSA-N 0.000 description 4
- 108010076504 Protein Sorting Signals Proteins 0.000 description 4
- HZWAHWQZPSXNCB-BPUTZDHNSA-N Ser-Arg-Trp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O HZWAHWQZPSXNCB-BPUTZDHNSA-N 0.000 description 4
- VAUMZJHYZQXZBQ-WHFBIAKZSA-N Ser-Asn-Gly Chemical compound OC[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(O)=O VAUMZJHYZQXZBQ-WHFBIAKZSA-N 0.000 description 4
- 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 4
- IOVHBRCQOGWAQH-ZKWXMUAHSA-N Ser-Gly-Ile Chemical compound [H]N[C@@H](CO)C(=O)NCC(=O)N[C@@H]([C@@H](C)CC)C(O)=O IOVHBRCQOGWAQH-ZKWXMUAHSA-N 0.000 description 4
- SRSPTFBENMJHMR-WHFBIAKZSA-N Ser-Ser-Gly Chemical compound OC[C@H](N)C(=O)N[C@@H](CO)C(=O)NCC(O)=O SRSPTFBENMJHMR-WHFBIAKZSA-N 0.000 description 4
- 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 4
- SXAGUVRFGJSFKC-ZEILLAHLSA-N Thr-His-Thr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O SXAGUVRFGJSFKC-ZEILLAHLSA-N 0.000 description 4
- JMBRNXUOLJFURW-BEAPCOKYSA-N Thr-Phe-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N2CCC[C@@H]2C(=O)O)N)O JMBRNXUOLJFURW-BEAPCOKYSA-N 0.000 description 4
- 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 4
- GQHAIUPYZPTADF-FDARSICLSA-N Trp-Ile-Arg Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O)=CNC2=C1 GQHAIUPYZPTADF-FDARSICLSA-N 0.000 description 4
- XGFGVFMXDXALEV-XIRDDKMYSA-N Trp-Leu-Asn Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)N XGFGVFMXDXALEV-XIRDDKMYSA-N 0.000 description 4
- QYSBJAUCUKHSLU-JYJNAYRXSA-N Tyr-Arg-Val Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(O)=O QYSBJAUCUKHSLU-JYJNAYRXSA-N 0.000 description 4
- NXRGXTBPMOGFID-CFMVVWHZSA-N Tyr-Ile-Asn Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(N)=O)C(O)=O NXRGXTBPMOGFID-CFMVVWHZSA-N 0.000 description 4
- JJNXZIPLIXIGBX-HJPIBITLSA-N Tyr-Ile-Cys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)N JJNXZIPLIXIGBX-HJPIBITLSA-N 0.000 description 4
- DZKFGCNKEVMXFA-JUKXBJQTSA-N Tyr-Ile-His Chemical compound CC[C@H](C)[C@H](NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)N[C@@H](Cc1cnc[nH]1)C(O)=O DZKFGCNKEVMXFA-JUKXBJQTSA-N 0.000 description 4
- GZUIDWDVMWZSMI-KKUMJFAQSA-N Tyr-Lys-Cys Chemical compound NCCCC[C@@H](C(=O)N[C@@H](CS)C(O)=O)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 GZUIDWDVMWZSMI-KKUMJFAQSA-N 0.000 description 4
- SQUMHUZLJDUROQ-YDHLFZDLSA-N Tyr-Val-Asp Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O SQUMHUZLJDUROQ-YDHLFZDLSA-N 0.000 description 4
- BMGOFDMKDVVGJG-NHCYSSNCSA-N Val-Asp-Lys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CCCCN)C(=O)O)N BMGOFDMKDVVGJG-NHCYSSNCSA-N 0.000 description 4
- OACSGBOREVRSME-NHCYSSNCSA-N Val-His-Asn Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](Cc1cnc[nH]1)C(=O)N[C@@H](CC(N)=O)C(O)=O OACSGBOREVRSME-NHCYSSNCSA-N 0.000 description 4
- HGJRMXOWUWVUOA-GVXVVHGQSA-N Val-Leu-Gln Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](C(C)C)N HGJRMXOWUWVUOA-GVXVVHGQSA-N 0.000 description 4
- KISFXYYRKKNLOP-IHRRRGAJSA-N Val-Phe-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)O)N KISFXYYRKKNLOP-IHRRRGAJSA-N 0.000 description 4
- JQTYTBPCSOAZHI-FXQIFTODSA-N Val-Ser-Cys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)O)N JQTYTBPCSOAZHI-FXQIFTODSA-N 0.000 description 4
- KRAHMIJVUPUOTQ-DCAQKATOSA-N Val-Ser-His Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N KRAHMIJVUPUOTQ-DCAQKATOSA-N 0.000 description 4
- SDHZOOIGIUEPDY-JYJNAYRXSA-N Val-Ser-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](CO)NC(=O)[C@@H](N)C(C)C)C(O)=O)=CNC2=C1 SDHZOOIGIUEPDY-JYJNAYRXSA-N 0.000 description 4
- BGTDGENDNWGMDQ-KJEVXHAQSA-N Val-Tyr-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)NC(=O)[C@H](C(C)C)N)O BGTDGENDNWGMDQ-KJEVXHAQSA-N 0.000 description 4
- ZLNYBMWGPOKSLW-LSJOCFKGSA-N Val-Val-Asp Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O ZLNYBMWGPOKSLW-LSJOCFKGSA-N 0.000 description 4
- JVGDAEKKZKKZFO-RCWTZXSCSA-N Val-Val-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](C(C)C)N)O JVGDAEKKZKKZFO-RCWTZXSCSA-N 0.000 description 4
- 125000003295 alanine group Chemical group N[C@@H](C)C(=O)* 0.000 description 4
- 108010087924 alanylproline Proteins 0.000 description 4
- -1 also known as BlyS Proteins 0.000 description 4
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 4
- 125000000637 arginyl group Chemical group N[C@@H](CCCNC(N)=N)C(=O)* 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 210000001185 bone marrow Anatomy 0.000 description 4
- 230000015556 catabolic process Effects 0.000 description 4
- 230000010261 cell growth Effects 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- 238000002512 chemotherapy Methods 0.000 description 4
- 230000001684 chronic effect Effects 0.000 description 4
- 230000024203 complement activation Effects 0.000 description 4
- 230000009089 cytolysis Effects 0.000 description 4
- 230000001085 cytostatic effect Effects 0.000 description 4
- 229960002204 daratumumab Drugs 0.000 description 4
- 230000007423 decrease Effects 0.000 description 4
- 230000001419 dependent effect Effects 0.000 description 4
- 238000013461 design Methods 0.000 description 4
- 239000012634 fragment Substances 0.000 description 4
- 108010013768 glutamyl-aspartyl-proline Proteins 0.000 description 4
- 108010000434 glycyl-alanyl-leucine Proteins 0.000 description 4
- 108010010147 glycylglutamine Proteins 0.000 description 4
- 230000005847 immunogenicity Effects 0.000 description 4
- 150000002500 ions Chemical class 0.000 description 4
- 108010044311 leucyl-glycyl-glycine Proteins 0.000 description 4
- 108010073472 leucyl-prolyl-proline Proteins 0.000 description 4
- 108010091871 leucylmethionine Proteins 0.000 description 4
- 238000004020 luminiscence type Methods 0.000 description 4
- 108010064235 lysylglycine Proteins 0.000 description 4
- 230000002101 lytic effect Effects 0.000 description 4
- 210000002540 macrophage Anatomy 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 230000036961 partial effect Effects 0.000 description 4
- 230000037361 pathway Effects 0.000 description 4
- 108010070409 phenylalanyl-glycyl-glycine Proteins 0.000 description 4
- 108010024654 phenylalanyl-prolyl-alanine Proteins 0.000 description 4
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 4
- 102000004196 processed proteins & peptides Human genes 0.000 description 4
- 108090000765 processed proteins & peptides Proteins 0.000 description 4
- 108010048397 seryl-lysyl-leucine Proteins 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 108010071097 threonyl-lysyl-proline Proteins 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- 108010052774 valyl-lysyl-glycyl-phenylalanyl-tyrosine Proteins 0.000 description 4
- 239000003981 vehicle Substances 0.000 description 4
- WOWDZACBATWTAU-FEFUEGSOSA-N (2s)-2-[[(2s)-2-(dimethylamino)-3-methylbutanoyl]amino]-n-[(3r,4s,5s)-1-[(2s)-2-[(1r,2r)-3-[[(1s,2r)-1-hydroxy-1-phenylpropan-2-yl]amino]-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl]-3-methoxy-5-methyl-1-oxoheptan-4-yl]-n,3-dimethylbutanamide Chemical compound CC(C)[C@H](N(C)C)C(=O)N[C@@H](C(C)C)C(=O)N(C)[C@@H]([C@@H](C)CC)[C@H](OC)CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C)[C@@H](O)C1=CC=CC=C1 WOWDZACBATWTAU-FEFUEGSOSA-N 0.000 description 3
- SQTFKIKSQNCWGJ-KCDKBNATSA-N (2s,3r,4r,5s)-2-fluoro-3,4,5-trihydroxyhexanal Chemical compound C[C@H](O)[C@@H](O)[C@@H](O)[C@H](F)C=O SQTFKIKSQNCWGJ-KCDKBNATSA-N 0.000 description 3
- 102100031585 ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1 Human genes 0.000 description 3
- DWINFPQUSSHSFS-UVBJJODRSA-N Ala-Arg-Trp Chemical compound N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CNC2=CC=CC=C12)C(=O)O DWINFPQUSSHSFS-UVBJJODRSA-N 0.000 description 3
- FRMQITGHXMUNDF-GMOBBJLQSA-N Arg-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](CCCN=C(N)N)N FRMQITGHXMUNDF-GMOBBJLQSA-N 0.000 description 3
- XVAPVJNJGLWGCS-ACZMJKKPSA-N Asn-Glu-Asn Chemical compound C(CC(=O)O)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CC(=O)N)N XVAPVJNJGLWGCS-ACZMJKKPSA-N 0.000 description 3
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 3
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 3
- 208000017667 Chronic Disease Diseases 0.000 description 3
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 description 3
- SBYVDRJAXWSXQL-AVGNSLFASA-N Glu-Asn-Phe Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O SBYVDRJAXWSXQL-AVGNSLFASA-N 0.000 description 3
- OCQUNKSFDYDXBG-QXEWZRGKSA-N Gly-Arg-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)CN)CCCN=C(N)N OCQUNKSFDYDXBG-QXEWZRGKSA-N 0.000 description 3
- BXDLTKLPPKBVEL-FJXKBIBVSA-N Gly-Thr-Met Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCSC)C(O)=O BXDLTKLPPKBVEL-FJXKBIBVSA-N 0.000 description 3
- 241000282412 Homo Species 0.000 description 3
- 101000777636 Homo sapiens ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1 Proteins 0.000 description 3
- 101000917839 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor III-B Proteins 0.000 description 3
- 108060003951 Immunoglobulin Proteins 0.000 description 3
- FADYJNXDPBKVCA-UHFFFAOYSA-N L-Phenylalanyl-L-lysin Natural products NCCCCC(C(O)=O)NC(=O)C(N)CC1=CC=CC=C1 FADYJNXDPBKVCA-UHFFFAOYSA-N 0.000 description 3
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 3
- 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 3
- XBBKIIGCUMBKCO-JXUBOQSCSA-N Leu-Ala-Thr Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O XBBKIIGCUMBKCO-JXUBOQSCSA-N 0.000 description 3
- MIFFFXHMAHFACR-KATARQTJSA-N Lys-Ser-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CCCCN MIFFFXHMAHFACR-KATARQTJSA-N 0.000 description 3
- PELXPRPDQRFBGQ-KKUMJFAQSA-N Lys-Tyr-Asn Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CCCCN)N)O PELXPRPDQRFBGQ-KKUMJFAQSA-N 0.000 description 3
- 239000004472 Lysine Substances 0.000 description 3
- 238000012228 RNA interference-mediated gene silencing Methods 0.000 description 3
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 3
- 241000283984 Rodentia Species 0.000 description 3
- GXXTUIUYTWGPMV-FXQIFTODSA-N Ser-Arg-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(O)=O GXXTUIUYTWGPMV-FXQIFTODSA-N 0.000 description 3
- 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 3
- NADLKBTYNKUJEP-KATARQTJSA-N Ser-Thr-Leu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O NADLKBTYNKUJEP-KATARQTJSA-N 0.000 description 3
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 3
- DCLBXIWHLVEPMQ-JRQIVUDYSA-N Thr-Asp-Tyr Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 DCLBXIWHLVEPMQ-JRQIVUDYSA-N 0.000 description 3
- KKPOGALELPLJTL-MEYUZBJRSA-N Thr-Lys-Tyr Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 KKPOGALELPLJTL-MEYUZBJRSA-N 0.000 description 3
- WPSKTVVMQCXPRO-BWBBJGPYSA-N Thr-Ser-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O WPSKTVVMQCXPRO-BWBBJGPYSA-N 0.000 description 3
- 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 3
- 101710178300 Tumor necrosis factor receptor superfamily member 13C Proteins 0.000 description 3
- USXYVSTVPHELAF-RCWTZXSCSA-N Val-Thr-Met Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCSC)C(=O)O)NC(=O)[C@H](C(C)C)N)O USXYVSTVPHELAF-RCWTZXSCSA-N 0.000 description 3
- 230000009798 acute exacerbation Effects 0.000 description 3
- 108010005233 alanylglutamic acid Proteins 0.000 description 3
- 239000002246 antineoplastic agent Substances 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 235000009582 asparagine Nutrition 0.000 description 3
- 229960001230 asparagine Drugs 0.000 description 3
- 125000000613 asparagine group Chemical group N[C@@H](CC(N)=O)C(=O)* 0.000 description 3
- 125000004429 atom Chemical group 0.000 description 3
- 238000005415 bioluminescence Methods 0.000 description 3
- 230000029918 bioluminescence Effects 0.000 description 3
- 230000030833 cell death Effects 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 239000000356 contaminant Substances 0.000 description 3
- 230000003013 cytotoxicity Effects 0.000 description 3
- 231100000135 cytotoxicity Toxicity 0.000 description 3
- 238000006731 degradation reaction Methods 0.000 description 3
- 229960004137 elotuzumab Drugs 0.000 description 3
- 230000002255 enzymatic effect Effects 0.000 description 3
- 239000013604 expression vector Substances 0.000 description 3
- 230000009368 gene silencing by RNA Effects 0.000 description 3
- 230000036541 health Effects 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 230000001900 immune effect Effects 0.000 description 3
- 230000003053 immunization Effects 0.000 description 3
- 238000002649 immunization Methods 0.000 description 3
- 102000018358 immunoglobulin Human genes 0.000 description 3
- 229940072221 immunoglobulins Drugs 0.000 description 3
- 238000002513 implantation Methods 0.000 description 3
- 230000001939 inductive effect Effects 0.000 description 3
- 238000003780 insertion Methods 0.000 description 3
- 230000037431 insertion Effects 0.000 description 3
- 230000002452 interceptive effect Effects 0.000 description 3
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 3
- 108010017391 lysylvaline Proteins 0.000 description 3
- 125000005439 maleimidyl group Chemical group C1(C=CC(N1*)=O)=O 0.000 description 3
- 238000002703 mutagenesis Methods 0.000 description 3
- 231100000350 mutagenesis Toxicity 0.000 description 3
- 210000000440 neutrophil Anatomy 0.000 description 3
- 239000002773 nucleotide Substances 0.000 description 3
- 125000003729 nucleotide group Chemical group 0.000 description 3
- 210000004180 plasmocyte Anatomy 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 238000012545 processing Methods 0.000 description 3
- 235000019419 proteases Nutrition 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 238000012216 screening Methods 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000007920 subcutaneous administration Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 238000012546 transfer Methods 0.000 description 3
- AGGWFDNPHKLBBV-YUMQZZPRSA-N (2s)-2-[[(2s)-2-amino-3-methylbutanoyl]amino]-5-(carbamoylamino)pentanoic acid Chemical compound CC(C)[C@H](N)C(=O)N[C@H](C(O)=O)CCCNC(N)=O AGGWFDNPHKLBBV-YUMQZZPRSA-N 0.000 description 2
- WXTMDXOMEHJXQO-UHFFFAOYSA-N 2,5-dihydroxybenzoic acid Chemical compound OC(=O)C1=CC(O)=CC=C1O WXTMDXOMEHJXQO-UHFFFAOYSA-N 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 2
- 229920000936 Agarose Polymers 0.000 description 2
- KUDREHRZRIVKHS-UWJYBYFXSA-N Ala-Asp-Tyr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O KUDREHRZRIVKHS-UWJYBYFXSA-N 0.000 description 2
- LXAARTARZJJCMB-CIQUZCHMSA-N Ala-Ile-Thr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(O)=O LXAARTARZJJCMB-CIQUZCHMSA-N 0.000 description 2
- JWUZOJXDJDEQEM-ZLIFDBKOSA-N Ala-Lys-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)C)C(O)=O)=CNC2=C1 JWUZOJXDJDEQEM-ZLIFDBKOSA-N 0.000 description 2
- NZGRHTKZFSVPAN-BIIVOSGPSA-N Ala-Ser-Pro Chemical compound C[C@@H](C(=O)N[C@@H](CO)C(=O)N1CCC[C@@H]1C(=O)O)N NZGRHTKZFSVPAN-BIIVOSGPSA-N 0.000 description 2
- GMFAGHNRXPSSJS-SRVKXCTJSA-N Arg-Leu-Gln Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O GMFAGHNRXPSSJS-SRVKXCTJSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- VLDRQOHCMKCXLY-SRVKXCTJSA-N Asn-Ser-Phe Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O VLDRQOHCMKCXLY-SRVKXCTJSA-N 0.000 description 2
- 108010028006 B-Cell Activating Factor Proteins 0.000 description 2
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 2
- 238000011740 C57BL/6 mouse Methods 0.000 description 2
- 206010008583 Chloroma Diseases 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 2
- 102000016574 Complement C3-C5 Convertases Human genes 0.000 description 2
- 108010067641 Complement C3-C5 Convertases Proteins 0.000 description 2
- 241000699802 Cricetulus griseus Species 0.000 description 2
- ZXGDAZLSOSYSBA-IHRRRGAJSA-N Cys-Val-Phe Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O ZXGDAZLSOSYSBA-IHRRRGAJSA-N 0.000 description 2
- SRBFZHDQGSBBOR-IOVATXLUSA-N D-xylopyranose Chemical compound O[C@@H]1COC(O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-IOVATXLUSA-N 0.000 description 2
- 238000011765 DBA/2 mouse Methods 0.000 description 2
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 2
- LQEBEXMHBLQMDB-UHFFFAOYSA-N GDP-L-fucose Natural products OC1C(O)C(O)C(C)OC1OP(O)(=O)OP(O)(=O)OCC1C(O)C(O)C(N2C3=C(C(N=C(N)N3)=O)N=C2)O1 LQEBEXMHBLQMDB-UHFFFAOYSA-N 0.000 description 2
- LQEBEXMHBLQMDB-JGQUBWHWSA-N GDP-beta-L-fucose Chemical compound O[C@H]1[C@H](O)[C@H](O)[C@H](C)O[C@@H]1OP(O)(=O)OP(O)(=O)OC[C@@H]1[C@@H](O)[C@@H](O)[C@H](N2C3=C(C(NC(N)=N3)=O)N=C2)O1 LQEBEXMHBLQMDB-JGQUBWHWSA-N 0.000 description 2
- LPYPANUXJGFMGV-FXQIFTODSA-N Gln-Gln-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CCC(=O)N)N LPYPANUXJGFMGV-FXQIFTODSA-N 0.000 description 2
- MADFVRSKEIEZHZ-DCAQKATOSA-N Gln-Gln-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CCC(=O)N)N MADFVRSKEIEZHZ-DCAQKATOSA-N 0.000 description 2
- GNMQDOGFWYWPNM-LAEOZQHASA-N Gln-Gly-Ile Chemical compound CC[C@H](C)[C@H](NC(=O)CNC(=O)[C@@H](N)CCC(N)=O)C(O)=O GNMQDOGFWYWPNM-LAEOZQHASA-N 0.000 description 2
- AAHSHTLISQUZJL-QSFUFRPTSA-N Gly-Ile-Ile Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O AAHSHTLISQUZJL-QSFUFRPTSA-N 0.000 description 2
- 102100026122 High affinity immunoglobulin gamma Fc receptor I Human genes 0.000 description 2
- 101000690301 Homo sapiens Aldo-keto reductase family 1 member C4 Proteins 0.000 description 2
- 101000913074 Homo sapiens High affinity immunoglobulin gamma Fc receptor I Proteins 0.000 description 2
- 101000917826 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor II-a Proteins 0.000 description 2
- 101000917824 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor II-b Proteins 0.000 description 2
- 101001116548 Homo sapiens Protein CBFA2T1 Proteins 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- 206010020751 Hypersensitivity Diseases 0.000 description 2
- SVBAHOMTJRFSIC-SXTJYALSSA-N Ile-Ile-Asn Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(=O)N)C(=O)O)N SVBAHOMTJRFSIC-SXTJYALSSA-N 0.000 description 2
- YIRIDPUGZKHMHT-ACRUOGEOSA-N Leu-Tyr-Tyr Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O YIRIDPUGZKHMHT-ACRUOGEOSA-N 0.000 description 2
- NTXYXFDMIHXTHE-WDSOQIARSA-N Leu-Val-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CC(C)C)C(O)=O)=CNC2=C1 NTXYXFDMIHXTHE-WDSOQIARSA-N 0.000 description 2
- 102100029204 Low affinity immunoglobulin gamma Fc region receptor II-a Human genes 0.000 description 2
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 2
- SBQDRNOLGSYHQA-YUMQZZPRSA-N Lys-Ser-Gly Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)NCC(O)=O SBQDRNOLGSYHQA-YUMQZZPRSA-N 0.000 description 2
- TVHCDSBMFQYPNA-RHYQMDGZSA-N Lys-Thr-Arg Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O TVHCDSBMFQYPNA-RHYQMDGZSA-N 0.000 description 2
- 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 2
- 241001529936 Murinae Species 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 230000004989 O-glycosylation Effects 0.000 description 2
- 108091034117 Oligonucleotide Proteins 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 206010057249 Phagocytosis Diseases 0.000 description 2
- ZENDEDYRYVHBEG-SRVKXCTJSA-N Phe-Asp-Asp Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](N)CC1=CC=CC=C1 ZENDEDYRYVHBEG-SRVKXCTJSA-N 0.000 description 2
- 208000007452 Plasmacytoma Diseases 0.000 description 2
- 108020004511 Recombinant DNA Proteins 0.000 description 2
- WTWGOQRNRFHFQD-JBDRJPRFSA-N Ser-Ala-Ile Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O WTWGOQRNRFHFQD-JBDRJPRFSA-N 0.000 description 2
- DKGRNFUXVTYRAS-UBHSHLNASA-N Ser-Ser-Trp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O DKGRNFUXVTYRAS-UBHSHLNASA-N 0.000 description 2
- PIQRHJQWEPWFJG-UWJYBYFXSA-N Ser-Tyr-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](C)C(O)=O PIQRHJQWEPWFJG-UWJYBYFXSA-N 0.000 description 2
- 108010003723 Single-Domain Antibodies Proteins 0.000 description 2
- 229940123237 Taxane Drugs 0.000 description 2
- GLQFKOVWXPPFTP-VEVYYDQMSA-N Thr-Arg-Asp Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(O)=O GLQFKOVWXPPFTP-VEVYYDQMSA-N 0.000 description 2
- 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 2
- 239000004473 Threonine Substances 0.000 description 2
- 108090000190 Thrombin Proteins 0.000 description 2
- 108060008683 Tumor Necrosis Factor Receptor Proteins 0.000 description 2
- 229940122803 Vinca alkaloid Drugs 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 208000026935 allergic disease Diseases 0.000 description 2
- KOSRFJWDECSPRO-UHFFFAOYSA-N alpha-L-glutamyl-L-glutamic acid Natural products OC(=O)CCC(N)C(=O)NC(CCC(O)=O)C(O)=O KOSRFJWDECSPRO-UHFFFAOYSA-N 0.000 description 2
- 230000003321 amplification Effects 0.000 description 2
- 230000000340 anti-metabolite Effects 0.000 description 2
- 229940100197 antimetabolite Drugs 0.000 description 2
- 239000002256 antimetabolite Substances 0.000 description 2
- 230000005784 autoimmunity Effects 0.000 description 2
- SQVRNKJHWKZAKO-UHFFFAOYSA-N beta-N-Acetyl-D-neuraminic acid Natural products CC(=O)NC1C(O)CC(O)(C(O)=O)OC1C(O)C(O)CO SQVRNKJHWKZAKO-UHFFFAOYSA-N 0.000 description 2
- 230000001588 bifunctional effect Effects 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 235000014633 carbohydrates Nutrition 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 210000000170 cell membrane Anatomy 0.000 description 2
- 230000004087 circulation Effects 0.000 description 2
- 210000001072 colon Anatomy 0.000 description 2
- 230000004154 complement system Effects 0.000 description 2
- 239000012228 culture supernatant Substances 0.000 description 2
- 238000012217 deletion Methods 0.000 description 2
- 230000037430 deletion Effects 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 238000000132 electrospray ionisation Methods 0.000 description 2
- 239000003623 enhancer Substances 0.000 description 2
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 2
- 229960005420 etoposide Drugs 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000000684 flow cytometry Methods 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 108020001507 fusion proteins Proteins 0.000 description 2
- 102000037865 fusion proteins Human genes 0.000 description 2
- 229930182830 galactose Natural products 0.000 description 2
- 238000003209 gene knockout Methods 0.000 description 2
- 150000004676 glycans Chemical class 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 102000054751 human RUNX1T1 Human genes 0.000 description 2
- 230000004727 humoral immunity Effects 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000003018 immunoassay Methods 0.000 description 2
- 229940127121 immunoconjugate Drugs 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 230000002147 killing effect Effects 0.000 description 2
- 230000003902 lesion Effects 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- 230000002132 lysosomal effect Effects 0.000 description 2
- 230000003211 malignant effect Effects 0.000 description 2
- 238000004949 mass spectrometry Methods 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 108020004999 messenger RNA Proteins 0.000 description 2
- XMYQHJDBLRZMLW-UHFFFAOYSA-N methanolamine Chemical compound NCO XMYQHJDBLRZMLW-UHFFFAOYSA-N 0.000 description 2
- 229940087646 methanolamine Drugs 0.000 description 2
- 238000000302 molecular modelling Methods 0.000 description 2
- 229940125645 monoclonal antibody drug Drugs 0.000 description 2
- 210000001616 monocyte Anatomy 0.000 description 2
- 206010028417 myasthenia gravis Diseases 0.000 description 2
- 208000025113 myeloid leukemia Diseases 0.000 description 2
- 201000005987 myeloid sarcoma Diseases 0.000 description 2
- 230000009871 nonspecific binding Effects 0.000 description 2
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- 230000000242 pagocytic effect Effects 0.000 description 2
- 125000001151 peptidyl group Chemical group 0.000 description 2
- 230000008782 phagocytosis Effects 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 210000003720 plasmablast Anatomy 0.000 description 2
- 150000003057 platinum Chemical class 0.000 description 2
- 229910052697 platinum Inorganic materials 0.000 description 2
- 229920001184 polypeptide Polymers 0.000 description 2
- 239000011148 porous material Substances 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 230000003449 preventive effect Effects 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 230000001737 promoting effect Effects 0.000 description 2
- 230000000069 prophylactic effect Effects 0.000 description 2
- 238000000159 protein binding assay Methods 0.000 description 2
- RXWNCPJZOCPEPQ-NVWDDTSBSA-N puromycin Chemical compound C1=CC(OC)=CC=C1C[C@H](N)C(=O)N[C@H]1[C@@H](O)[C@H](N2C3=NC=NC(=C3N=C2)N(C)C)O[C@@H]1CO RXWNCPJZOCPEPQ-NVWDDTSBSA-N 0.000 description 2
- 238000004064 recycling Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 230000035945 sensitivity Effects 0.000 description 2
- SQVRNKJHWKZAKO-OQPLDHBCSA-N sialic acid Chemical compound CC(=O)N[C@@H]1[C@@H](O)C[C@@](O)(C(O)=O)OC1[C@H](O)[C@H](O)CO SQVRNKJHWKZAKO-OQPLDHBCSA-N 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 230000002269 spontaneous effect Effects 0.000 description 2
- 238000011301 standard therapy Methods 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 125000004434 sulfur atom Chemical group 0.000 description 2
- 125000003396 thiol group Chemical group [H]S* 0.000 description 2
- 150000003573 thiols Chemical class 0.000 description 2
- 125000000341 threoninyl group Chemical group [H]OC([H])(C([H])([H])[H])C([H])(N([H])[H])C(*)=O 0.000 description 2
- 229960004072 thrombin Drugs 0.000 description 2
- 238000004448 titration Methods 0.000 description 2
- 239000003053 toxin Substances 0.000 description 2
- 231100000765 toxin Toxicity 0.000 description 2
- 108700012359 toxins Proteins 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- 102000003298 tumor necrosis factor receptor Human genes 0.000 description 2
- 238000002424 x-ray crystallography Methods 0.000 description 2
- GHOKWGTUZJEAQD-ZETCQYMHSA-N (D)-(+)-Pantothenic acid Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-ZETCQYMHSA-N 0.000 description 1
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- OTLLEIBWKHEHGU-UHFFFAOYSA-N 2-[5-[[5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methoxy]-3,4-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-3,5-dihydroxy-4-phosphonooxyhexanedioic acid Chemical compound C1=NC=2C(N)=NC=NC=2N1C(C(C1O)O)OC1COC1C(CO)OC(OC(C(O)C(OP(O)(O)=O)C(O)C(O)=O)C(O)=O)C(O)C1O OTLLEIBWKHEHGU-UHFFFAOYSA-N 0.000 description 1
- VXOWGOAKTRJAMM-UHFFFAOYSA-N 2-benzylpentanoic acid Chemical compound CCCC(C(O)=O)CC1=CC=CC=C1 VXOWGOAKTRJAMM-UHFFFAOYSA-N 0.000 description 1
- WAVYAFBQOXCGSZ-UHFFFAOYSA-N 2-fluoropyrimidine Chemical compound FC1=NC=CC=N1 WAVYAFBQOXCGSZ-UHFFFAOYSA-N 0.000 description 1
- SZFHAHACWVROGM-UHFFFAOYSA-N 2-phenyl-1,3-oxazolidine Chemical compound N1CCOC1C1=CC=CC=C1 SZFHAHACWVROGM-UHFFFAOYSA-N 0.000 description 1
- PTCRWTNAXLUFEZ-UHFFFAOYSA-N 3-(2,3-dihydroindol-1-yl)-1H-1,2-benzodiazepine Chemical compound N1C2=CC=CC=C2C=CC(N2C3=CC=CC=C3CC2)=N1 PTCRWTNAXLUFEZ-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-M 3-carboxy-2,3-dihydroxypropanoate Chemical compound OC(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-M 0.000 description 1
- QUHGSDZVAPFNLV-UHFFFAOYSA-N 4-[(5-acetamidofuran-2-carbonyl)amino]-n-[3-(dimethylamino)propyl]-1-propylpyrrole-2-carboxamide Chemical compound C1=C(C(=O)NCCCN(C)C)N(CCC)C=C1NC(=O)C1=CC=C(NC(C)=O)O1 QUHGSDZVAPFNLV-UHFFFAOYSA-N 0.000 description 1
- QBHDSQZASIBAAI-UHFFFAOYSA-N 4-acetylbenzoic acid Chemical compound CC(=O)C1=CC=C(C(O)=O)C=C1 QBHDSQZASIBAAI-UHFFFAOYSA-N 0.000 description 1
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 description 1
- 229940117976 5-hydroxylysine Drugs 0.000 description 1
- 108010066676 Abrin Proteins 0.000 description 1
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 1
- 206010000890 Acute myelomonocytic leukaemia Diseases 0.000 description 1
- 208000026872 Addison Disease Diseases 0.000 description 1
- STACJSVFHSEZJV-GHCJXIJMSA-N Ala-Asn-Ile Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O STACJSVFHSEZJV-GHCJXIJMSA-N 0.000 description 1
- NJIFPLAJSVUQOZ-JBDRJPRFSA-N Ala-Cys-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CS)NC(=O)[C@H](C)N NJIFPLAJSVUQOZ-JBDRJPRFSA-N 0.000 description 1
- OBVSBEYOMDWLRJ-BFHQHQDPSA-N Ala-Gly-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)CNC(=O)[C@H](C)N OBVSBEYOMDWLRJ-BFHQHQDPSA-N 0.000 description 1
- SUMYEVXWCAYLLJ-GUBZILKMSA-N Ala-Leu-Gln Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O SUMYEVXWCAYLLJ-GUBZILKMSA-N 0.000 description 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
- MDNAVFBZPROEHO-DCAQKATOSA-N Ala-Lys-Val Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(O)=O MDNAVFBZPROEHO-DCAQKATOSA-N 0.000 description 1
- MDNAVFBZPROEHO-UHFFFAOYSA-N Ala-Lys-Val Natural products CC(C)C(C(O)=O)NC(=O)C(NC(=O)C(C)N)CCCCN MDNAVFBZPROEHO-UHFFFAOYSA-N 0.000 description 1
- DWYROCSXOOMOEU-CIUDSAMLSA-N Ala-Met-Glu Chemical compound C[C@@H](C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N DWYROCSXOOMOEU-CIUDSAMLSA-N 0.000 description 1
- XWFWAXPOLRTDFZ-FXQIFTODSA-N Ala-Pro-Ser Chemical compound C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O XWFWAXPOLRTDFZ-FXQIFTODSA-N 0.000 description 1
- HOVPGJUNRLMIOZ-CIUDSAMLSA-N Ala-Ser-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](C)N HOVPGJUNRLMIOZ-CIUDSAMLSA-N 0.000 description 1
- LSMDIAAALJJLRO-XQXXSGGOSA-N Ala-Thr-Glu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(O)=O)C(O)=O LSMDIAAALJJLRO-XQXXSGGOSA-N 0.000 description 1
- DHONNEYAZPNGSG-UBHSHLNASA-N Ala-Val-Phe Chemical compound C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 DHONNEYAZPNGSG-UBHSHLNASA-N 0.000 description 1
- 206010027654 Allergic conditions Diseases 0.000 description 1
- 102100021761 Alpha-mannosidase 2 Human genes 0.000 description 1
- 206010002412 Angiocentric lymphomas Diseases 0.000 description 1
- 108010032595 Antibody Binding Sites Proteins 0.000 description 1
- AUFHLLPVPSMEOG-YUMQZZPRSA-N Arg-Gly-Glu Chemical compound NC(N)=NCCC[C@H](N)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(O)=O AUFHLLPVPSMEOG-YUMQZZPRSA-N 0.000 description 1
- YKZJPIPFKGYHKY-DCAQKATOSA-N Arg-Leu-Asp Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O YKZJPIPFKGYHKY-DCAQKATOSA-N 0.000 description 1
- BNYNOWJESJJIOI-XUXIUFHCSA-N Arg-Lys-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCN=C(N)N)N BNYNOWJESJJIOI-XUXIUFHCSA-N 0.000 description 1
- BFDDUDQCPJWQRQ-IHRRRGAJSA-N Arg-Tyr-Cys Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CCCN=C(N)N)N)O BFDDUDQCPJWQRQ-IHRRRGAJSA-N 0.000 description 1
- XWGJDUSDTRPQRK-ZLUOBGJFSA-N Asn-Ala-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC(N)=O XWGJDUSDTRPQRK-ZLUOBGJFSA-N 0.000 description 1
- NVGWESORMHFISY-SRVKXCTJSA-N Asn-Asn-Phe Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O NVGWESORMHFISY-SRVKXCTJSA-N 0.000 description 1
- GMUOCGCDOYYWPD-FXQIFTODSA-N Asn-Pro-Ser Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O GMUOCGCDOYYWPD-FXQIFTODSA-N 0.000 description 1
- GZXOUBTUAUAVHD-ACZMJKKPSA-N Asn-Ser-Glu Chemical compound NC(=O)C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CCC(O)=O GZXOUBTUAUAVHD-ACZMJKKPSA-N 0.000 description 1
- 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 1
- HSWYMWGDMPLTTH-FXQIFTODSA-N Asp-Glu-Gln Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O HSWYMWGDMPLTTH-FXQIFTODSA-N 0.000 description 1
- OVPHVTCDVYYTHN-AVGNSLFASA-N Asp-Glu-Phe Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 OVPHVTCDVYYTHN-AVGNSLFASA-N 0.000 description 1
- CMCIMCAQIULNDJ-CIUDSAMLSA-N Asp-His-Cys Chemical compound C1=C(NC=N1)C[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC(=O)O)N CMCIMCAQIULNDJ-CIUDSAMLSA-N 0.000 description 1
- DWOGMPWRQQWPPF-GUBZILKMSA-N Asp-Leu-Glu Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O DWOGMPWRQQWPPF-GUBZILKMSA-N 0.000 description 1
- 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 1
- ITGFVUYOLWBPQW-KKHAAJSZSA-N Asp-Thr-Val Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(O)=O ITGFVUYOLWBPQW-KKHAAJSZSA-N 0.000 description 1
- KNDCWFXCFKSEBM-AVGNSLFASA-N Asp-Tyr-Glu Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCC(O)=O)C(O)=O KNDCWFXCFKSEBM-AVGNSLFASA-N 0.000 description 1
- 208000032116 Autoimmune Experimental Encephalomyelitis Diseases 0.000 description 1
- 208000035404 Autolysis Diseases 0.000 description 1
- 108010046304 B-Cell Activation Factor Receptor Proteins 0.000 description 1
- 208000004736 B-Cell Leukemia Diseases 0.000 description 1
- 208000003950 B-cell lymphoma Diseases 0.000 description 1
- 208000032568 B-cell prolymphocytic leukaemia Diseases 0.000 description 1
- 208000037398 BCR-ABL1 negative atypical chronic myeloid leukemia Diseases 0.000 description 1
- 208000023328 Basedow disease Diseases 0.000 description 1
- 102100027314 Beta-2-microglobulin Human genes 0.000 description 1
- 101710150190 Beta-secretase 2 Proteins 0.000 description 1
- 241000701822 Bovine papillomavirus Species 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 108010065524 CD52 Antigen Proteins 0.000 description 1
- 102000013135 CD52 Antigen Human genes 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 description 1
- 108010078791 Carrier Proteins Proteins 0.000 description 1
- VYZAMTAEIAYCRO-BJUDXGSMSA-N Chromium-51 Chemical compound [51Cr] VYZAMTAEIAYCRO-BJUDXGSMSA-N 0.000 description 1
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 1
- 108091026890 Coding region Proteins 0.000 description 1
- 108010047041 Complementarity Determining Regions Proteins 0.000 description 1
- 108091035707 Consensus sequence Proteins 0.000 description 1
- 241000557626 Corvus corax Species 0.000 description 1
- 102000001493 Cyclophilins Human genes 0.000 description 1
- 108010068682 Cyclophilins Proteins 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 1
- 108010036949 Cyclosporine Proteins 0.000 description 1
- WVLZTXGTNGHPBO-SRVKXCTJSA-N Cys-Leu-Leu Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O WVLZTXGTNGHPBO-SRVKXCTJSA-N 0.000 description 1
- 241000701022 Cytomegalovirus Species 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- AEMOLEFTQBMNLQ-AQKNRBDQSA-N D-glucopyranuronic acid Chemical compound OC1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-AQKNRBDQSA-N 0.000 description 1
- 239000012624 DNA alkylating agent Substances 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 1
- 108010016626 Dipeptides Proteins 0.000 description 1
- 102000016607 Diphtheria Toxin Human genes 0.000 description 1
- 108010053187 Diphtheria Toxin Proteins 0.000 description 1
- 101150050927 Fcgrt gene Proteins 0.000 description 1
- 239000004606 Fillers/Extenders Substances 0.000 description 1
- OVBPIULPVIDEAO-LBPRGKRZSA-N Folic acid Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- 108010045674 Fucose-1-phosphate guanylyltransferase Proteins 0.000 description 1
- 102000006471 Fucosyltransferases Human genes 0.000 description 1
- 108010019236 Fucosyltransferases Proteins 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 101710203794 GDP-fucose transporter Proteins 0.000 description 1
- 108010062427 GDP-mannose 4,6-dehydratase Proteins 0.000 description 1
- 102000002312 GDPmannose 4,6-dehydratase Human genes 0.000 description 1
- 108700039691 Genetic Promoter Regions Proteins 0.000 description 1
- 108700007698 Genetic Terminator Regions Proteins 0.000 description 1
- 208000032612 Glial tumor Diseases 0.000 description 1
- 206010018338 Glioma Diseases 0.000 description 1
- WUAYFMZULZDSLB-ACZMJKKPSA-N Gln-Ala-Asn Chemical compound NC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCC(N)=O WUAYFMZULZDSLB-ACZMJKKPSA-N 0.000 description 1
- PHZYLYASFWHLHJ-FXQIFTODSA-N Gln-Asn-Glu Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O PHZYLYASFWHLHJ-FXQIFTODSA-N 0.000 description 1
- WQWMZOIPXWSZNE-WDSKDSINSA-N Gln-Asp-Gly Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(O)=O WQWMZOIPXWSZNE-WDSKDSINSA-N 0.000 description 1
- WLODHVXYKYHLJD-ACZMJKKPSA-N Gln-Asp-Ser Chemical compound C(CC(=O)N)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CO)C(=O)O)N WLODHVXYKYHLJD-ACZMJKKPSA-N 0.000 description 1
- MFLMFRZBAJSGHK-ACZMJKKPSA-N Gln-Cys-Ser Chemical compound C(CC(=O)N)[C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CO)C(=O)O)N MFLMFRZBAJSGHK-ACZMJKKPSA-N 0.000 description 1
- ZNZPKVQURDQFFS-FXQIFTODSA-N Gln-Glu-Ser Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(O)=O ZNZPKVQURDQFFS-FXQIFTODSA-N 0.000 description 1
- 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 1
- BETSEXMYBWCDAE-SZMVWBNQSA-N Gln-Trp-Lys Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCC(=O)N)N BETSEXMYBWCDAE-SZMVWBNQSA-N 0.000 description 1
- ICRKQMRFXYDYMK-LAEOZQHASA-N Gln-Val-Asn Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O ICRKQMRFXYDYMK-LAEOZQHASA-N 0.000 description 1
- VEYGCDYMOXHJLS-GVXVVHGQSA-N Gln-Val-Leu Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O VEYGCDYMOXHJLS-GVXVVHGQSA-N 0.000 description 1
- MXOODARRORARSU-ACZMJKKPSA-N Glu-Ala-Ser Chemical compound C[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CCC(=O)O)N MXOODARRORARSU-ACZMJKKPSA-N 0.000 description 1
- NADWTMLCUDMDQI-ACZMJKKPSA-N Glu-Asp-Cys Chemical compound C(CC(=O)O)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CS)C(=O)O)N NADWTMLCUDMDQI-ACZMJKKPSA-N 0.000 description 1
- XXCDTYBVGMPIOA-FXQIFTODSA-N Glu-Asp-Glu Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O XXCDTYBVGMPIOA-FXQIFTODSA-N 0.000 description 1
- UENPHLAAKDPZQY-XKBZYTNZSA-N Glu-Cys-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CS)NC(=O)[C@H](CCC(=O)O)N)O UENPHLAAKDPZQY-XKBZYTNZSA-N 0.000 description 1
- AIGROOHQXCACHL-WDSKDSINSA-N Glu-Gly-Ala Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](C)C(O)=O AIGROOHQXCACHL-WDSKDSINSA-N 0.000 description 1
- SUIAHERNFYRBDZ-GVXVVHGQSA-N Glu-Lys-Val Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(O)=O SUIAHERNFYRBDZ-GVXVVHGQSA-N 0.000 description 1
- DLISPGXMKZTWQG-IFFSRLJSSA-N Glu-Thr-Val Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(O)=O DLISPGXMKZTWQG-IFFSRLJSSA-N 0.000 description 1
- RJIVPOXLQFJRTG-LURJTMIESA-N Gly-Arg-Gly Chemical compound OC(=O)CNC(=O)[C@@H](NC(=O)CN)CCCN=C(N)N RJIVPOXLQFJRTG-LURJTMIESA-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
- 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 1
- SCWYHUQOOFRVHP-MBLNEYKQSA-N Gly-Ile-Thr Chemical compound NCC(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(O)=O SCWYHUQOOFRVHP-MBLNEYKQSA-N 0.000 description 1
- 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
- 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 1
- LCRDMSSAKLTKBU-ZDLURKLDSA-N Gly-Ser-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)CN LCRDMSSAKLTKBU-ZDLURKLDSA-N 0.000 description 1
- FFJQHWKSGAWSTJ-BFHQHQDPSA-N Gly-Thr-Ala Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O FFJQHWKSGAWSTJ-BFHQHQDPSA-N 0.000 description 1
- YXTFLTJYLIAZQG-FJXKBIBVSA-N Gly-Thr-Arg Chemical compound NCC(=O)N[C@@H]([C@H](O)C)C(=O)N[C@H](C(O)=O)CCCN=C(N)N YXTFLTJYLIAZQG-FJXKBIBVSA-N 0.000 description 1
- NGBGZCUWFVVJKC-IRXDYDNUSA-N Gly-Tyr-Tyr Chemical compound C([C@H](NC(=O)CN)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C1=CC=C(O)C=C1 NGBGZCUWFVVJKC-IRXDYDNUSA-N 0.000 description 1
- AEMRFAOFKBGASW-UHFFFAOYSA-M Glycolate Chemical compound OCC([O-])=O AEMRFAOFKBGASW-UHFFFAOYSA-M 0.000 description 1
- 102000051366 Glycosyltransferases Human genes 0.000 description 1
- 108700023372 Glycosyltransferases Proteins 0.000 description 1
- 102100036242 HLA class II histocompatibility antigen, DQ alpha 2 chain Human genes 0.000 description 1
- 239000012981 Hank's balanced salt solution Substances 0.000 description 1
- HVCRQRQPIIRNLY-IUCAKERBSA-N His-Gln-Gly Chemical compound C1=C(NC=N1)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)NCC(=O)O)N HVCRQRQPIIRNLY-IUCAKERBSA-N 0.000 description 1
- TVMNTHXFRSXZGR-IHRRRGAJSA-N His-Lys-Val Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(O)=O TVMNTHXFRSXZGR-IHRRRGAJSA-N 0.000 description 1
- 101000930801 Homo sapiens HLA class II histocompatibility antigen, DQ alpha 2 chain Proteins 0.000 description 1
- 101000851376 Homo sapiens Tumor necrosis factor receptor superfamily member 8 Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- NCSIQAFSIPHVAN-IUKAMOBKSA-N Ile-Asn-Thr Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H]([C@@H](C)O)C(=O)O)N NCSIQAFSIPHVAN-IUKAMOBKSA-N 0.000 description 1
- TWPSALMCEHCIOY-YTFOTSKYSA-N Ile-Ile-Leu Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(=O)O)N TWPSALMCEHCIOY-YTFOTSKYSA-N 0.000 description 1
- PFPUFNLHBXKPHY-HTFCKZLJSA-N Ile-Ile-Ser Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)O)N PFPUFNLHBXKPHY-HTFCKZLJSA-N 0.000 description 1
- RQQCJTLBSJMVCR-DSYPUSFNSA-N Ile-Leu-Trp Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)N RQQCJTLBSJMVCR-DSYPUSFNSA-N 0.000 description 1
- AKOYRLRUFBZOSP-BJDJZHNGSA-N Ile-Lys-Ser Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)O)N AKOYRLRUFBZOSP-BJDJZHNGSA-N 0.000 description 1
- PXKACEXYLPBMAD-JBDRJPRFSA-N Ile-Ser-Ser Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)O)N PXKACEXYLPBMAD-JBDRJPRFSA-N 0.000 description 1
- 206010061598 Immunodeficiency Diseases 0.000 description 1
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 1
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 1
- 108010067060 Immunoglobulin Variable Region Proteins 0.000 description 1
- 102000017727 Immunoglobulin Variable Region Human genes 0.000 description 1
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 1
- HGCNKOLVKRAVHD-UHFFFAOYSA-N L-Met-L-Phe Natural products CSCCC(N)C(=O)NC(C(O)=O)CC1=CC=CC=C1 HGCNKOLVKRAVHD-UHFFFAOYSA-N 0.000 description 1
- 102100040648 L-fucose kinase Human genes 0.000 description 1
- 102100020870 La-related protein 6 Human genes 0.000 description 1
- 108050008265 La-related protein 6 Proteins 0.000 description 1
- 108090001090 Lectins Proteins 0.000 description 1
- 102000004856 Lectins Human genes 0.000 description 1
- CNNQBZRGQATKNY-DCAQKATOSA-N Leu-Arg-Cys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CS)C(=O)O)N CNNQBZRGQATKNY-DCAQKATOSA-N 0.000 description 1
- LLBQJYDYOLIQAI-JYJNAYRXSA-N Leu-Glu-Tyr Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O LLBQJYDYOLIQAI-JYJNAYRXSA-N 0.000 description 1
- QPXBPQUGXHURGP-UWVGGRQHSA-N Leu-Gly-Met Chemical compound CC(C)C[C@@H](C(=O)NCC(=O)N[C@@H](CCSC)C(=O)O)N QPXBPQUGXHURGP-UWVGGRQHSA-N 0.000 description 1
- JNDYEOUZBLOVOF-AVGNSLFASA-N Leu-Leu-Gln Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O JNDYEOUZBLOVOF-AVGNSLFASA-N 0.000 description 1
- KYIIALJHAOIAHF-KKUMJFAQSA-N Leu-Leu-His 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=CN=CN1 KYIIALJHAOIAHF-KKUMJFAQSA-N 0.000 description 1
- JLWZLIQRYCTYBD-IHRRRGAJSA-N Leu-Lys-Arg Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O JLWZLIQRYCTYBD-IHRRRGAJSA-N 0.000 description 1
- VCHVSKNMTXWIIP-SRVKXCTJSA-N Leu-Lys-Ser Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(O)=O VCHVSKNMTXWIIP-SRVKXCTJSA-N 0.000 description 1
- QWWPYKKLXWOITQ-VOAKCMCISA-N Leu-Thr-Leu Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@H](C(O)=O)CC(C)C QWWPYKKLXWOITQ-VOAKCMCISA-N 0.000 description 1
- YQFZRHYZLARWDY-IHRRRGAJSA-N Leu-Val-Lys Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CCCCN YQFZRHYZLARWDY-IHRRRGAJSA-N 0.000 description 1
- QUCDKEKDPYISNX-HJGDQZAQSA-N Lys-Asn-Thr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O QUCDKEKDPYISNX-HJGDQZAQSA-N 0.000 description 1
- NRQRKMYZONPCTM-CIUDSAMLSA-N Lys-Asp-Ser Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O NRQRKMYZONPCTM-CIUDSAMLSA-N 0.000 description 1
- JYXBNQOKPRQNQS-YTFOTSKYSA-N Lys-Ile-Ile Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O JYXBNQOKPRQNQS-YTFOTSKYSA-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
- WQDKIVRHTQYJSN-DCAQKATOSA-N Lys-Ser-Arg Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N WQDKIVRHTQYJSN-DCAQKATOSA-N 0.000 description 1
- WZVSHTFTCYOFPL-GARJFASQSA-N Lys-Ser-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CO)NC(=O)[C@H](CCCCN)N)C(=O)O WZVSHTFTCYOFPL-GARJFASQSA-N 0.000 description 1
- YKBSXQFZWFXFIB-VOAKCMCISA-N Lys-Thr-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@@H](CCCCN)C(O)=O YKBSXQFZWFXFIB-VOAKCMCISA-N 0.000 description 1
- RIPJMCFGQHGHNP-RHYQMDGZSA-N Lys-Val-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CCCCN)N)O RIPJMCFGQHGHNP-RHYQMDGZSA-N 0.000 description 1
- 201000003791 MALT lymphoma Diseases 0.000 description 1
- 241000829100 Macaca mulatta polyomavirus 1 Species 0.000 description 1
- PEEHTFAAVSWFBL-UHFFFAOYSA-N Maleimide Chemical compound O=C1NC(=O)C=C1 PEEHTFAAVSWFBL-UHFFFAOYSA-N 0.000 description 1
- 108010090665 Mannosyl-Glycoprotein Endo-beta-N-Acetylglucosaminidase Proteins 0.000 description 1
- 208000025205 Mantle-Cell Lymphoma Diseases 0.000 description 1
- 229930126263 Maytansine Natural products 0.000 description 1
- GAELMDJMQDUDLJ-BQBZGAKWSA-N Met-Ala-Gly Chemical compound CSCC[C@H](N)C(=O)N[C@@H](C)C(=O)NCC(O)=O GAELMDJMQDUDLJ-BQBZGAKWSA-N 0.000 description 1
- UYAKZHGIPRCGPF-CIUDSAMLSA-N Met-Glu-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CCSC)N UYAKZHGIPRCGPF-CIUDSAMLSA-N 0.000 description 1
- OGAZPKJHHZPYFK-GARJFASQSA-N Met-Glu-Pro Chemical compound CSCC[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N1CCC[C@@H]1C(=O)O)N OGAZPKJHHZPYFK-GARJFASQSA-N 0.000 description 1
- ZIIMORLEZLVRIP-SRVKXCTJSA-N Met-Leu-Gln Chemical compound [H]N[C@@H](CCSC)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O ZIIMORLEZLVRIP-SRVKXCTJSA-N 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 1
- 102000057613 Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Human genes 0.000 description 1
- 108700026676 Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Proteins 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
- 208000033835 Myelomonocytic Acute Leukemia Diseases 0.000 description 1
- OVRNDRQMDRJTHS-CBQIKETKSA-N N-Acetyl-D-Galactosamine Chemical compound CC(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@H](O)[C@@H]1O OVRNDRQMDRJTHS-CBQIKETKSA-N 0.000 description 1
- XZFYRXDAULDNFX-UHFFFAOYSA-N N-L-cysteinyl-L-phenylalanine Natural products SCC(N)C(=O)NC(C(O)=O)CC1=CC=CC=C1 XZFYRXDAULDNFX-UHFFFAOYSA-N 0.000 description 1
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 description 1
- MBLBDJOUHNCFQT-UHFFFAOYSA-N N-acetyl-D-galactosamine Natural products CC(=O)NC(C=O)C(O)C(O)C(O)CO MBLBDJOUHNCFQT-UHFFFAOYSA-N 0.000 description 1
- 230000004988 N-glycosylation Effects 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- 208000002454 Nasopharyngeal Carcinoma Diseases 0.000 description 1
- 206010061306 Nasopharyngeal cancer Diseases 0.000 description 1
- 108010006232 Neuraminidase Proteins 0.000 description 1
- 102000005348 Neuraminidase Human genes 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 206010029461 Nodal marginal zone B-cell lymphomas Diseases 0.000 description 1
- 108091028043 Nucleic acid sequence Proteins 0.000 description 1
- 108010058846 Ovalbumin Proteins 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 206010034277 Pemphigoid Diseases 0.000 description 1
- 201000011152 Pemphigus Diseases 0.000 description 1
- 208000027086 Pemphigus foliaceus Diseases 0.000 description 1
- 102000000447 Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase Human genes 0.000 description 1
- 108010055817 Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase Proteins 0.000 description 1
- 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 1
- RFCVXVPWSPOMFJ-STQMWFEESA-N Phe-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H](N)CC1=CC=CC=C1 RFCVXVPWSPOMFJ-STQMWFEESA-N 0.000 description 1
- YTILBRIUASDGBL-BZSNNMDCSA-N Phe-Leu-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC1=CC=CC=C1 YTILBRIUASDGBL-BZSNNMDCSA-N 0.000 description 1
- UNBFGVQVQGXXCK-KKUMJFAQSA-N Phe-Ser-Leu Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O UNBFGVQVQGXXCK-KKUMJFAQSA-N 0.000 description 1
- BSKMOCNNLNDIMU-CDMKHQONSA-N Phe-Thr-Gly Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(O)=O BSKMOCNNLNDIMU-CDMKHQONSA-N 0.000 description 1
- GNRMAQSIROFNMI-IXOXFDKPSA-N Phe-Thr-Ser Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(O)=O GNRMAQSIROFNMI-IXOXFDKPSA-N 0.000 description 1
- 206010036524 Precursor B-lymphoblastic lymphomas Diseases 0.000 description 1
- BNBBNGZZKQUWCD-IUCAKERBSA-N Pro-Arg-Gly Chemical compound NC(N)=NCCC[C@@H](C(=O)NCC(O)=O)NC(=O)[C@@H]1CCCN1 BNBBNGZZKQUWCD-IUCAKERBSA-N 0.000 description 1
- DIZLUAZLNDFDPR-CIUDSAMLSA-N Pro-Cys-Gln Chemical compound NC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](CS)NC(=O)[C@@H]1CCCN1 DIZLUAZLNDFDPR-CIUDSAMLSA-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
- 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
- MRYUJHGPZQNOAD-IHRRRGAJSA-N Pro-Leu-Lys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@@H]1CCCN1 MRYUJHGPZQNOAD-IHRRRGAJSA-N 0.000 description 1
- MCWHYUWXVNRXFV-RWMBFGLXSA-N Pro-Leu-Pro Chemical compound CC(C)C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@@H]2CCCN2 MCWHYUWXVNRXFV-RWMBFGLXSA-N 0.000 description 1
- CGSOWZUPLOKYOR-AVGNSLFASA-N Pro-Pro-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 CGSOWZUPLOKYOR-AVGNSLFASA-N 0.000 description 1
- FDMKYQQYJKYCLV-GUBZILKMSA-N Pro-Pro-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 FDMKYQQYJKYCLV-GUBZILKMSA-N 0.000 description 1
- BGWKULMLUIUPKY-BQBZGAKWSA-N Pro-Ser-Gly Chemical compound OC(=O)CNC(=O)[C@H](CO)NC(=O)[C@@H]1CCCN1 BGWKULMLUIUPKY-BQBZGAKWSA-N 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- 208000035416 Prolymphocytic B-Cell Leukemia Diseases 0.000 description 1
- 241000589516 Pseudomonas Species 0.000 description 1
- 201000001263 Psoriatic Arthritis Diseases 0.000 description 1
- 208000036824 Psoriatic arthropathy Diseases 0.000 description 1
- 102220566606 Recombining binding protein suppressor of hairless-like protein_H82A_mutation Human genes 0.000 description 1
- 208000006265 Renal cell carcinoma Diseases 0.000 description 1
- 108700008625 Reporter Genes Proteins 0.000 description 1
- 108091027981 Response element Proteins 0.000 description 1
- 108010039491 Ricin Proteins 0.000 description 1
- 241000220317 Rosa Species 0.000 description 1
- 241000242680 Schistosoma mansoni Species 0.000 description 1
- XWCYBVBLJRWOFR-WDSKDSINSA-N Ser-Gln-Gly Chemical compound OC[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(O)=O XWCYBVBLJRWOFR-WDSKDSINSA-N 0.000 description 1
- DJACUBDEDBZKLQ-KBIXCLLPSA-N Ser-Ile-Glu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(O)=O DJACUBDEDBZKLQ-KBIXCLLPSA-N 0.000 description 1
- 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 1
- 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 1
- 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 1
- YUJLIIRMIAGMCQ-CIUDSAMLSA-N Ser-Leu-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O YUJLIIRMIAGMCQ-CIUDSAMLSA-N 0.000 description 1
- GZSZPKSBVAOGIE-CIUDSAMLSA-N Ser-Lys-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O GZSZPKSBVAOGIE-CIUDSAMLSA-N 0.000 description 1
- ZGFRMNZZTOVBOU-CIUDSAMLSA-N Ser-Met-Gln Chemical compound N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(N)=O)C(=O)O ZGFRMNZZTOVBOU-CIUDSAMLSA-N 0.000 description 1
- GDUZTEQRAOXYJS-SRVKXCTJSA-N Ser-Phe-Asn Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CO)N GDUZTEQRAOXYJS-SRVKXCTJSA-N 0.000 description 1
- RWDVVSKYZBNDCO-MELADBBJSA-N Ser-Phe-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC2=CC=CC=C2)NC(=O)[C@H](CO)N)C(=O)O RWDVVSKYZBNDCO-MELADBBJSA-N 0.000 description 1
- ADJDNJCSPNFFPI-FXQIFTODSA-N Ser-Pro-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CO ADJDNJCSPNFFPI-FXQIFTODSA-N 0.000 description 1
- NMZXJDSKEGFDLJ-DCAQKATOSA-N Ser-Pro-Lys Chemical compound C1C[C@H](N(C1)C(=O)[C@H](CO)N)C(=O)N[C@@H](CCCCN)C(=O)O NMZXJDSKEGFDLJ-DCAQKATOSA-N 0.000 description 1
- FLONGDPORFIVQW-XGEHTFHBSA-N Ser-Pro-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CO FLONGDPORFIVQW-XGEHTFHBSA-N 0.000 description 1
- 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 1
- PYTKULIABVRXSC-BWBBJGPYSA-N Ser-Ser-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(O)=O PYTKULIABVRXSC-BWBBJGPYSA-N 0.000 description 1
- 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 1
- BDMWLJLPPUCLNV-XGEHTFHBSA-N Ser-Thr-Val Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(O)=O BDMWLJLPPUCLNV-XGEHTFHBSA-N 0.000 description 1
- OSFZCEQJLWCIBG-BZSNNMDCSA-N Ser-Tyr-Tyr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O OSFZCEQJLWCIBG-BZSNNMDCSA-N 0.000 description 1
- HSWXBJCBYSWBPT-GUBZILKMSA-N Ser-Val-Val Chemical compound CC(C)[C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)CO)C(C)C)C(O)=O HSWXBJCBYSWBPT-GUBZILKMSA-N 0.000 description 1
- 201000002661 Spondylitis Diseases 0.000 description 1
- 101000895926 Streptomyces plicatus Endo-beta-N-acetylglucosaminidase H Proteins 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 201000009594 Systemic Scleroderma Diseases 0.000 description 1
- 206010042953 Systemic sclerosis Diseases 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 229920002253 Tannate Polymers 0.000 description 1
- 239000004098 Tetracycline Substances 0.000 description 1
- SWIKDOUVROTZCW-GCJQMDKQSA-N Thr-Asn-Ala Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](C)C(=O)O)N)O SWIKDOUVROTZCW-GCJQMDKQSA-N 0.000 description 1
- YLXAMFZYJTZXFH-OLHMAJIHSA-N Thr-Asn-Asp Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC(=O)O)C(=O)O)N)O YLXAMFZYJTZXFH-OLHMAJIHSA-N 0.000 description 1
- UTCFSBBXPWKLTG-XKBZYTNZSA-N Thr-Cys-Gln Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N)O UTCFSBBXPWKLTG-XKBZYTNZSA-N 0.000 description 1
- ASJDFGOPDCVXTG-KATARQTJSA-N Thr-Cys-Leu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(C)C)C(O)=O ASJDFGOPDCVXTG-KATARQTJSA-N 0.000 description 1
- NIEWSKWFURSECR-FOHZUACHSA-N Thr-Gly-Asp Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(O)=O NIEWSKWFURSECR-FOHZUACHSA-N 0.000 description 1
- ADPHPKGWVDHWML-PPCPHDFISA-N Thr-Ile-Leu Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)O)NC(=O)[C@H]([C@@H](C)O)N ADPHPKGWVDHWML-PPCPHDFISA-N 0.000 description 1
- 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 1
- NQQMWWVVGIXUOX-SVSWQMSJSA-N Thr-Ser-Ile Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O NQQMWWVVGIXUOX-SVSWQMSJSA-N 0.000 description 1
- RVMNUBQWPVOUKH-HEIBUPTGSA-N Thr-Ser-Thr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(O)=O RVMNUBQWPVOUKH-HEIBUPTGSA-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
- XVHAUVJXBFGUPC-RPTUDFQQSA-N Thr-Tyr-Phe Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O XVHAUVJXBFGUPC-RPTUDFQQSA-N 0.000 description 1
- OGOYMQWIWHGTGH-KZVJFYERSA-N Thr-Val-Ala Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C)C(O)=O OGOYMQWIWHGTGH-KZVJFYERSA-N 0.000 description 1
- KPMIQCXJDVKWKO-IFFSRLJSSA-N Thr-Val-Glu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O KPMIQCXJDVKWKO-IFFSRLJSSA-N 0.000 description 1
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 1
- 101000980463 Treponema pallidum (strain Nichols) Chaperonin GroEL Proteins 0.000 description 1
- 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 1
- 102000004243 Tubulin Human genes 0.000 description 1
- 108090000704 Tubulin Proteins 0.000 description 1
- 102100033726 Tumor necrosis factor receptor superfamily member 17 Human genes 0.000 description 1
- 102100036857 Tumor necrosis factor receptor superfamily member 8 Human genes 0.000 description 1
- VCXWRWYFJLXITF-AUTRQRHGSA-N Tyr-Ala-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 VCXWRWYFJLXITF-AUTRQRHGSA-N 0.000 description 1
- QJBWZNTWJSZUOY-UWJYBYFXSA-N Tyr-Ala-Cys Chemical compound C[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)N QJBWZNTWJSZUOY-UWJYBYFXSA-N 0.000 description 1
- QOIKZODVIPOPDD-AVGNSLFASA-N Tyr-Cys-Gln Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(O)=O QOIKZODVIPOPDD-AVGNSLFASA-N 0.000 description 1
- FFCRCJZJARTYCG-KKUMJFAQSA-N Tyr-Cys-Lys Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CCCCN)C(=O)O)N)O FFCRCJZJARTYCG-KKUMJFAQSA-N 0.000 description 1
- MQGGXGKQSVEQHR-KKUMJFAQSA-N Tyr-Ser-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 MQGGXGKQSVEQHR-KKUMJFAQSA-N 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- HSRXSKHRSXRCFC-WDSKDSINSA-N Val-Ala Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](C)C(O)=O HSRXSKHRSXRCFC-WDSKDSINSA-N 0.000 description 1
- AZSHAZJLOZQYAY-FXQIFTODSA-N Val-Ala-Ser Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O AZSHAZJLOZQYAY-FXQIFTODSA-N 0.000 description 1
- CGGVNFJRZJUVAE-BYULHYEWSA-N Val-Asp-Asn Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC(=O)N)C(=O)O)N CGGVNFJRZJUVAE-BYULHYEWSA-N 0.000 description 1
- YODDULVCGFQRFZ-ZKWXMUAHSA-N Val-Asp-Ser Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O YODDULVCGFQRFZ-ZKWXMUAHSA-N 0.000 description 1
- VCAWFLIWYNMHQP-UKJIMTQDSA-N Val-Glu-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](C(C)C)N VCAWFLIWYNMHQP-UKJIMTQDSA-N 0.000 description 1
- BZOSBRIDWSSTFN-AVGNSLFASA-N Val-Leu-Met Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCSC)C(=O)O)NC(=O)[C@H](C(C)C)N BZOSBRIDWSSTFN-AVGNSLFASA-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
- OFQGGTGZTOTLGH-NHCYSSNCSA-N Val-Met-Gln Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N OFQGGTGZTOTLGH-NHCYSSNCSA-N 0.000 description 1
- FMQGYTMERWBMSI-HJWJTTGWSA-N Val-Phe-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)NC(=O)[C@H](C(C)C)N FMQGYTMERWBMSI-HJWJTTGWSA-N 0.000 description 1
- PQSNETRGCRUOGP-KKHAAJSZSA-N Val-Thr-Asn Chemical compound CC(C)[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@H](C(O)=O)CC(N)=O PQSNETRGCRUOGP-KKHAAJSZSA-N 0.000 description 1
- UVHFONIHVHLDDQ-IFFSRLJSSA-N Val-Thr-Glu Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)O)NC(=O)[C@H](C(C)C)N)O UVHFONIHVHLDDQ-IFFSRLJSSA-N 0.000 description 1
- GVNLOVJNNDZUHS-RHYQMDGZSA-N Val-Thr-Lys Chemical compound [H]N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(O)=O GVNLOVJNNDZUHS-RHYQMDGZSA-N 0.000 description 1
- OFTXTCGQJXTNQS-XGEHTFHBSA-N Val-Thr-Ser Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](C(C)C)N)O OFTXTCGQJXTNQS-XGEHTFHBSA-N 0.000 description 1
- JAIZPWVHPQRYOU-ZJDVBMNYSA-N Val-Thr-Thr Chemical compound C[C@H]([C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)O)NC(=O)[C@H](C(C)C)N)O JAIZPWVHPQRYOU-ZJDVBMNYSA-N 0.000 description 1
- 238000005411 Van der Waals force Methods 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
- KYIKRXIYLAGAKQ-UHFFFAOYSA-N abcn Chemical compound C1CCCCC1(C#N)N=NC1(C#N)CCCCC1 KYIKRXIYLAGAKQ-UHFFFAOYSA-N 0.000 description 1
- 239000008351 acetate buffer Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 208000011912 acute myelomonocytic leukemia M4 Diseases 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 238000001042 affinity chromatography Methods 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 108010041407 alanylaspartic acid Proteins 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- WQZGKKKJIJFFOK-PHYPRBDBSA-N alpha-D-galactose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-PHYPRBDBSA-N 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 238000005571 anion exchange chromatography Methods 0.000 description 1
- 229940045799 anthracyclines and related substance Drugs 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 210000000628 antibody-producing cell Anatomy 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 229940125715 antihistaminic agent Drugs 0.000 description 1
- 229940045719 antineoplastic alkylating agent nitrosoureas Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Natural products OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 description 1
- 108010009111 arginyl-glycyl-glutamic acid Proteins 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 229940072107 ascorbate Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 238000011717 athymic nude mouse Methods 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 1
- LMEKQMALGUDUQG-UHFFFAOYSA-N azathioprine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC=NC2=C1NC=N2 LMEKQMALGUDUQG-UHFFFAOYSA-N 0.000 description 1
- 229960002170 azathioprine Drugs 0.000 description 1
- 239000007640 basal medium Substances 0.000 description 1
- 230000037429 base substitution Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- PXXJHWLDUBFPOL-UHFFFAOYSA-N benzamidine Chemical compound NC(=N)C1=CC=CC=C1 PXXJHWLDUBFPOL-UHFFFAOYSA-N 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- 229940049706 benzodiazepine Drugs 0.000 description 1
- 150000001557 benzodiazepines Chemical class 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 108010081355 beta 2-Microglobulin Proteins 0.000 description 1
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 208000000594 bullous pemphigoid Diseases 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 1
- 229940127093 camptothecin Drugs 0.000 description 1
- 238000012511 carbohydrate analysis Methods 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000012219 cassette mutagenesis Methods 0.000 description 1
- 239000003518 caustics Substances 0.000 description 1
- 210000004323 caveolae Anatomy 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 230000011712 cell development Effects 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000032823 cell division Effects 0.000 description 1
- 238000011965 cell line development Methods 0.000 description 1
- 230000011748 cell maturation Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000010001 cellular homeostasis Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 1
- 208000025302 chronic primary adrenal insufficiency Diseases 0.000 description 1
- 229960001265 ciclosporin Drugs 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 229940001468 citrate Drugs 0.000 description 1
- 229960002173 citrulline Drugs 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000012875 competitive assay Methods 0.000 description 1
- 102000006834 complement receptors Human genes 0.000 description 1
- 108010047295 complement receptors Proteins 0.000 description 1
- 235000021310 complex sugar Nutrition 0.000 description 1
- 230000021615 conjugation Effects 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 229960001334 corticosteroids Drugs 0.000 description 1
- 230000009260 cross reactivity Effects 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- 229930182912 cyclosporin Natural products 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 231100000409 cytocidal Toxicity 0.000 description 1
- 230000000445 cytocidal effect Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- YSMODUONRAFBET-UHFFFAOYSA-N delta-DL-hydroxylysine Natural products NCC(O)CCC(N)C(O)=O YSMODUONRAFBET-UHFFFAOYSA-N 0.000 description 1
- 210000001787 dendrite Anatomy 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- AAOVKJBEBIDNHE-UHFFFAOYSA-N diazepam Chemical compound N=1CC(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 AAOVKJBEBIDNHE-UHFFFAOYSA-N 0.000 description 1
- 229960003529 diazepam Drugs 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 238000006471 dimerization reaction Methods 0.000 description 1
- FSXRLASFHBWESK-UHFFFAOYSA-N dipeptide phenylalanyl-tyrosine Natural products C=1C=C(O)C=CC=1CC(C(O)=O)NC(=O)C(N)CC1=CC=CC=C1 FSXRLASFHBWESK-UHFFFAOYSA-N 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 description 1
- 239000003534 dna topoisomerase inhibitor Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- VQNATVDKACXKTF-XELLLNAOSA-N duocarmycin Chemical compound COC1=C(OC)C(OC)=C2NC(C(=O)N3C4=CC(=O)C5=C([C@@]64C[C@@H]6C3)C=C(N5)C(=O)OC)=CC2=C1 VQNATVDKACXKTF-XELLLNAOSA-N 0.000 description 1
- 229960005501 duocarmycin Drugs 0.000 description 1
- 229930184221 duocarmycin Natural products 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 230000002121 endocytic effect Effects 0.000 description 1
- 210000001163 endosome Anatomy 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 230000006862 enzymatic digestion Effects 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 210000003979 eosinophil Anatomy 0.000 description 1
- YSMODUONRAFBET-UHNVWZDZSA-N erythro-5-hydroxy-L-lysine Chemical compound NC[C@H](O)CC[C@H](N)C(O)=O YSMODUONRAFBET-UHNVWZDZSA-N 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 231100000776 exotoxin Toxicity 0.000 description 1
- 239000002095 exotoxin Substances 0.000 description 1
- 208000012997 experimental autoimmune encephalomyelitis Diseases 0.000 description 1
- 229960000304 folic acid Drugs 0.000 description 1
- 235000019152 folic acid Nutrition 0.000 description 1
- 239000011724 folic acid Substances 0.000 description 1
- 201000003444 follicular lymphoma Diseases 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 108010083136 fucokinase Proteins 0.000 description 1
- 125000002446 fucosyl group Chemical group C1([C@@H](O)[C@H](O)[C@H](O)[C@@H](O1)C)* 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 101150023212 fut8 gene Proteins 0.000 description 1
- 238000001502 gel electrophoresis Methods 0.000 description 1
- 238000005227 gel permeation chromatography Methods 0.000 description 1
- 229940114119 gentisate Drugs 0.000 description 1
- 210000001280 germinal center Anatomy 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 229940097042 glucuronate Drugs 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 108010055341 glutamyl-glutamic acid Proteins 0.000 description 1
- YMAWOPBAYDPSLA-UHFFFAOYSA-N glycylglycine Chemical compound [NH3+]CC(=O)NCC([O-])=O YMAWOPBAYDPSLA-UHFFFAOYSA-N 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 201000009277 hairy cell leukemia Diseases 0.000 description 1
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 1
- 208000007475 hemolytic anemia Diseases 0.000 description 1
- 108010040030 histidinoalanine Proteins 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 229940048921 humira Drugs 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 238000004191 hydrophobic interaction chromatography Methods 0.000 description 1
- 125000002349 hydroxyamino group Chemical group [H]ON([H])[*] 0.000 description 1
- 229960002591 hydroxyproline Drugs 0.000 description 1
- 230000009610 hypersensitivity Effects 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 230000016784 immunoglobulin production Effects 0.000 description 1
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 230000008863 intramolecular interaction Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 239000002555 ionophore Substances 0.000 description 1
- 230000000236 ionophoric effect Effects 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 108010078274 isoleucylvaline Proteins 0.000 description 1
- TWBYWOBDOCUKOW-UHFFFAOYSA-M isonicotinate Chemical compound [O-]C(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-M 0.000 description 1
- 238000005304 joining Methods 0.000 description 1
- 108010011519 keratan-sulfate endo-1,4-beta-galactosidase Proteins 0.000 description 1
- 150000004715 keto acids Chemical class 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical class CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 1
- 239000002523 lectin Substances 0.000 description 1
- 231100000225 lethality Toxicity 0.000 description 1
- 108010034529 leucyl-lysine Proteins 0.000 description 1
- 229940063725 leukeran Drugs 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 108700009084 lexitropsin Proteins 0.000 description 1
- 108020001756 ligand binding domains Proteins 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 206010025135 lupus erythematosus Diseases 0.000 description 1
- 230000000998 lymphohematopoietic effect Effects 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 102000036209 mannose binding proteins Human genes 0.000 description 1
- 108020003928 mannose binding proteins Proteins 0.000 description 1
- 108010083819 mannosyl-oligosaccharide 1,3 - 1,6-alpha-mannosidase Proteins 0.000 description 1
- 238000013507 mapping Methods 0.000 description 1
- 201000007924 marginal zone B-cell lymphoma Diseases 0.000 description 1
- 208000021937 marginal zone lymphoma Diseases 0.000 description 1
- 230000008774 maternal effect Effects 0.000 description 1
- WKPWGQKGSOKKOO-RSFHAFMBSA-N maytansine Chemical compound CO[C@@H]([C@@]1(O)C[C@](OC(=O)N1)([C@H]([C@@H]1O[C@@]1(C)[C@@H](OC(=O)[C@H](C)N(C)C(C)=O)CC(=O)N1C)C)[H])\C=C\C=C(C)\CC2=CC(OC)=C(Cl)C1=C2 WKPWGQKGSOKKOO-RSFHAFMBSA-N 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 210000001806 memory b lymphocyte Anatomy 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 230000008880 microtubule cytoskeleton organization Effects 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 108010093470 monomethyl auristatin E Proteins 0.000 description 1
- DASWEROEPLKSEI-UIJRFTGLSA-N monomethyl auristatin e Chemical compound CN[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N(C)[C@@H]([C@@H](C)CC)[C@H](OC)CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C)[C@@H](O)C1=CC=CC=C1 DASWEROEPLKSEI-UIJRFTGLSA-N 0.000 description 1
- MFRNYXJJRJQHNW-NARUGQRUSA-N monomethyl auristatin f Chemical compound CN[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N(C)C([C@@H](C)CC)[C@H](OC)CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 MFRNYXJJRJQHNW-NARUGQRUSA-N 0.000 description 1
- 108010059074 monomethylauristatin F Proteins 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- ASXCJONOVQSZRF-LXGUWJNJSA-N n-[(2s,3r,4r,5r)-2,3,4,5,6-pentahydroxyhexyl]acetamide Chemical compound CC(=O)NC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO ASXCJONOVQSZRF-LXGUWJNJSA-N 0.000 description 1
- 201000011216 nasopharynx carcinoma Diseases 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000007524 negative regulation of DNA replication Effects 0.000 description 1
- 230000009826 neoplastic cell growth Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 229940092253 ovalbumin Drugs 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 238000006213 oxygenation reaction Methods 0.000 description 1
- 229940014662 pantothenate Drugs 0.000 description 1
- 235000019161 pantothenic acid Nutrition 0.000 description 1
- 239000011713 pantothenic acid Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 208000031223 plasma cell leukemia Diseases 0.000 description 1
- 239000013612 plasmid Substances 0.000 description 1
- 229940063179 platinol Drugs 0.000 description 1
- 230000008488 polyadenylation Effects 0.000 description 1
- 229920002857 polybutadiene Polymers 0.000 description 1
- 108091033319 polynucleotide Proteins 0.000 description 1
- 102000040430 polynucleotide Human genes 0.000 description 1
- 239000002157 polynucleotide Substances 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 230000004537 potential cytotoxicity Effects 0.000 description 1
- 229940124606 potential therapeutic agent Drugs 0.000 description 1
- 201000006037 primary mediastinal B-cell lymphoma Diseases 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 235000019833 protease Nutrition 0.000 description 1
- 230000004853 protein function Effects 0.000 description 1
- 238000001742 protein purification Methods 0.000 description 1
- 230000002797 proteolythic effect Effects 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 229950010131 puromycin Drugs 0.000 description 1
- 238000012797 qualification Methods 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000003259 recombinant expression Methods 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 210000001350 reed-sternberg cell Anatomy 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 201000006845 reticulosarcoma Diseases 0.000 description 1
- 208000029922 reticulum cell sarcoma Diseases 0.000 description 1
- 229960004641 rituximab Drugs 0.000 description 1
- 238000010079 rubber tapping Methods 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 238000010187 selection method Methods 0.000 description 1
- 238000009394 selective breeding Methods 0.000 description 1
- 108010069117 seryl-lysyl-aspartic acid Proteins 0.000 description 1
- 108010026333 seryl-proline Proteins 0.000 description 1
- 125000005629 sialic acid group Chemical group 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 210000004989 spleen cell Anatomy 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 238000011255 standard chemotherapy Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000009168 stem cell therapy Methods 0.000 description 1
- 238000009580 stem-cell therapy Methods 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 230000001839 systemic circulation Effects 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 206010043554 thrombocytopenia Diseases 0.000 description 1
- 206010043778 thyroiditis Diseases 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 229940044693 topoisomerase inhibitor Drugs 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 230000005030 transcription termination Effects 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 108010080629 tryptophan-leucine Proteins 0.000 description 1
- 239000003744 tubulin modulator Substances 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 108010079202 tyrosyl-alanyl-cysteine Proteins 0.000 description 1
- 108010003137 tyrosyltyrosine Proteins 0.000 description 1
- 229940079023 tysabri Drugs 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 241000701161 unidentified adenovirus Species 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/05—Dipeptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
- A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
- A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
-
- 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
- C07K16/2878—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 NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/10—Immunoglobulins specific features characterized by their source of isolation or production
- C07K2317/14—Specific host cells or culture conditions, e.g. components, pH or temperature
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/40—Immunoglobulins specific features characterized by post-translational modification
- C07K2317/41—Glycosylation, sialylation, or fucosylation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/52—Constant or Fc region; Isotype
- C07K2317/522—CH1 domain
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/52—Constant or Fc region; Isotype
- C07K2317/524—CH2 domain
-
- 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
- C07K2317/72—Increased effector function due to an Fc-modification
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
- C07K2317/732—Antibody-dependent cellular cytotoxicity [ADCC]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
- C07K2317/734—Complement-dependent cytotoxicity [CDC]
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Immunology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Organic Chemistry (AREA)
- Cell Biology (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Gastroenterology & Hepatology (AREA)
- Peptides Or Proteins (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
本發明提供特異性結合至BCMA之人類化抗體。該等抗體可用於治療及診斷多種癌症及免疫病症以及檢測BCMA。
Description
B細胞成熟抗原(BCMA、CD269)係TNF受體超家族之成員。BCMA之表現限制於B細胞系,其中其主要在生髮中心之濾泡間區域中及已分化漿細胞及漿母細胞上表現。BCMA結合至兩個不同配體,即增殖誘導配體(APRIL)及B細胞活化因子(BAFF,亦稱為BlyS、TALL-1及THANK)。BCMA之配體結合另外兩種TNF受體、跨膜活化劑及鈣調節劑及親環素配體相互作用因子(TACI)及BAFF受體(BAFF-R,亦稱為BR3)。TACI結合APRIL及BAFF,而BAFF-R顯示與BAFF之受限但高親和性之結合。BCMA、TACI、BAFF-R及其相應配體一起調節體液性免疫性、B細胞發育及穩態之不同態樣。
BCMA在幼稚記憶體B細胞上實際上不存在(Novak等人,Blood 103, 689-94 (2004)),但其在漿細胞分化期間被選擇性誘導,其中其可藉由促進正常漿細胞及漿母細胞之存活來支持體液性免疫性(O’Conner等人,J. Exp Med. 199, 91-98 (2004))。已報導BCMA在原發性多發性骨髓瘤(MM)樣品中表現。亦已在來自患有霍奇金氏病(Hodgkin's disease)之患者之Reed-Sternberg細胞(CD30
+)上檢測到BCMA。已基於敲低實驗報導,該BCMA有助於霍奇金氏病細胞系之增殖及存活二者(Chiu等人,Blood 109,729-39 (2007))。
本發明提供人類化、嵌合或飾面抗體,其係以ATCC PTC-6937保藏之抗體之人類化或嵌合形式。視情況,抗體包含與hSG16.17 VH3 (SEQ ID NO: 13)具有至少90%序列一致性之成熟重鏈可變區及與hSG16.17 VK2 (SEQ ID NO: 19)具有至少90%序列一致性之成熟輕鏈可變區。視情況,抗體包含與hSG16.17 VH3 (SEQ ID NO: 13)具有至少95%序列一致性之成熟重鏈可變區及與hSG16.17 VK2 (SEQ ID NO: 19)具有至少95%序列一致性之成熟輕鏈可變區。視情況,抗體包含hSG16.17 VH3 (SEQ ID NO: 13)之三個Kabat CDR (SEQ ID NO: 60-62)及hSG16.17 VK2 (SEQ ID NO: 19)之三個Kabat CDR (SEQ ID NO: 90-92),條件係位置H58可由N或K佔據,位置H60可由A或N佔據,位置H61可由Q或E佔據,位置H62可由K或N佔據,位置H64可由Q或K佔據,位置H65可由G或T佔據,位置L24可由R或L佔據且位置L53可由S或R佔據。視情況,抗體包含hSG16.17 VH3 (SEQ ID NO: 13)之三個Kabat CDR (SEQ ID NO: 60-62)及hSG16.17 VK2 (SEQ ID NO: 19)之三個Kabat CDR (SEQ ID NO: 90-92)。視情況,位置H58、H60、H61、H62、H64及H65分別由N、A、Q、K、Q及G佔據,且L24及L53分別由R及S佔據。視情況,位置H20、H48、H69、H71、H73、H76、H80、H88、H91及H93分別由L、I、M、A、K、N、V、A、F及T佔據,且位置L46、L48及L87分別由V、V及F佔據。視情況,成熟重鏈可變區具有hSG16.17 VH3 (SEQ ID NO: 13)之序列且成熟輕鏈可變區具有hSG16.17 VK2 (SEQ ID NO: 19)之序列。
本發明進一步提供人類化、嵌合或飾面抗體,其係具有VH (SEQ ID NO: 23)及VK (SEQ ID NO: 33)序列之大鼠SG16.45抗體之人類化、嵌合或飾面形式。視情況,抗體包含與hSG16.45 VH5 (SEQ ID NO: 31)具有至少90%序列一致性之重鏈成熟可變區及與hSG16.45 VK2 (SEQ ID NO: 36)具有至少90%序列一致性之成熟輕鏈可變區。視情況,抗體包含與hSG16.45 VH5 (SEQ ID NO: 31)具有至少95%序列一致性之成熟重鏈可變區及與hSG16.45 VK2 (SEQ ID NO: 36)具有至少95%序列一致性之成熟輕鏈可變區。視情況,抗體包含hSG16.45 VH5 (SEQ ID NO: 31)之三個Kabat CDR (SEQ ID NO: 152-154)及hSG16.45 VK2 (SEQ ID NO: 36)之三個Kabat CDR (SEQ ID NO: 179-181),條件係位置H50可由A或S佔據且位置L24可由R或L佔據且位置L26可由S或T佔據。視情況,抗體包含hSG16.45 VH5 (SEQ ID NO: 31)之三個Kabat CDR (SEQ ID NO: 152-154)及hSG16.45 VK2 (SEQ ID NO: 36)之三個Kabat CDR (SEQ ID NO: 179-181)。視情況,位置H30、H93及H94分別由N、T及S佔據。視情況,成熟重鏈可變區具有hSG16.45 VH5 (SEQ ID NO: 31)之序列且成熟輕鏈可變區具有hSG16.45 VK2 (SEQ ID NO: 36)之序列,或成熟重鏈可變區具有hSG16.45 VH1 (SEQ ID NO: 27)之序列且成熟輕鏈可變區具有hSG16.45 VK1 (SEQ ID NO: 35)之序列,或成熟重鏈可變區具有hSG16.45 VH1 (SEQ ID NO: 27)之序列,且成熟輕鏈可變區具有hSG16.45 VK3 (SEQ ID NO: 37)之序列。
在上文抗體中之任一者中,成熟重鏈可變區可融合至重鏈恆定區且成熟輕鏈可變區可融合至輕鏈恆定區。視情況,重鏈恆定區係天然人類恆定區之突變體形式,其與Fcγ受體之結合相對於該天然人類恆定區有所降低。視情況,重鏈恆定區係IgG1同型。視情況,重鏈恆定區具有包含SEQ ID NO: 5之胺基酸序列且輕鏈恆定區具有包含SEQ ID NO: 3之胺基酸序列。視情況,重鏈恆定區具有包含SEQ ID NO:7 (S239C)之胺基酸序列且輕鏈恆定區具有包含SEQ ID NO:3之胺基酸序列。視情況,抗體係裸抗體。視情況,抗體偶聯至細胞毒性或細胞生長抑制劑。視情況,抗體偶聯至細胞毒性劑。視情況,細胞毒性劑經由酶可裂解連接體偶聯至抗體。視情況,細胞毒性劑係DNA小溝黏合劑,例如具有下式之細胞毒性劑
。
視情況,細胞毒性劑係MMAE或MMAF。
本發明進一步提供醫藥組合物,其包含上述任一抗體及醫藥上可接受之載劑。
在一個實施例中,本發明提供抗體,其包含hSG16.17 VH3 (SEQ ID NO: 13)之三個Kabat CDR (SEQ ID NO: 60-62)及hSG16.17 VK2 (SEQ ID NO: 19)之三個Kabat CDR (SEQ ID NO: 90-92)。在另一實施例中, 本發明提供抗體,其具有具有hSG16.17 VH3 (SEQ ID NO: 13)之序列之成熟重鏈可變區及具有hSG16.17 VK2 (SEQ ID NO: 19)之序列之成熟輕鏈可變區。在另一實施例中,成熟重鏈可變區融合至重鏈恆定區且成熟輕鏈可變區融合至輕鏈恆定區。抗體可為例如IgG1抗體。在另一實施例中,抗體未經岩藻糖或岩藻糖類似物之核心岩藻糖基化。抗體可例如藉由添加醫藥上可接受之載劑調配為醫藥組合物。
在另一實施例中,醫藥組合物具有複數種抗體,該等抗體具有具有hSG16.17 VH3 (SEQ ID NO: 13)之序列之成熟重鏈可變區及具有hSG16.17 VK2 (SEQ ID NO: 19)之序列之成熟輕鏈可變區。該等抗體之可變區較佳融合至適當重鏈及輕鏈恆定區。在另一實施例中,抗體係IgG1抗體。在另一實施例中,該複數種抗體中有少於約5%之抗體已經岩藻糖或岩藻糖類似物核心岩藻糖基化。在另一實施例中,該複數種抗體中有少於約10%之抗體已經岩藻糖或岩藻糖類似物核心岩藻糖基化。在另一實施例中,該複數種抗體包括約2%抗體經岩藻糖或岩藻糖類似物核心岩藻糖基化。在另一實施例中,該複數種抗體包括2%抗體經岩藻糖或岩藻糖類似物核心岩藻糖基化。
本發明進一步提供治療患有表現BCMA之癌症或具有罹患該癌症之風險之患者之方法,其包含向該患者如上所述抗體之有效方案。視情況,該癌症係血液癌症。視情況,該血液癌症係骨髓瘤、白血病或淋巴瘤。視情況,該血液癌症係多發性骨髓瘤。視情況,該血液癌症係非霍奇金氏淋巴瘤(NHL)或霍奇金氏淋巴瘤。視情況,該血液癌症係骨髓發育不良症候群(MDS)、骨髓增生性症候群(MPS)、華氏巨球蛋白血症(Waldenström’s macroglobulinemia)或柏基特淋巴瘤(Burkett’s lymphoma)。
本發明進一步提供治療患有由表現BCMA之免疫細胞介導之免疫病症或具有罹患該免疫病症之風險之患者之方法,其包含向該患者投與上述任一抗體之有效方案。視情況,該病症係B細胞介導病症。視情況,該免疫病症係類風濕性關節炎、全身性紅斑狼瘡(SLE)、I型糖尿病、氣喘、異位性皮膚炎、過敏性鼻炎、血小板減少紫斑症、多發性硬化、牛皮癬、薛格連氏症候群(Sjorgren’s syndrome)、橋本氏甲狀腺炎(Hashimoto’s thyroiditis)、格雷氏病(Grave’s disease)、原發性膽汁性肝硬化、韋格納肉芽腫(Wegener’s granulomatosis)、結核症及移植物抗宿主病。
相關申請案的交叉參考本申請案主張於2016年2月17日提出申請之美國臨時申請案第US 62/296,594號及於2016年9月16日提出申請之美國臨時申請案第62/396,084號之權益,出於所有目的,兩個案件皆係全文皆以引用方式併入本文中。
參考序列表本申請案中所揭示之序列含於與本案一起提出申請之序列表中。
定義「經分離」抗體係指已經鑑別且自其天然環境之組分分離及/或回收之抗體及/或重組產生之抗體。「純化抗體」係對於自其產生或純化產生之干擾蛋白質及其他污染物通常至少50% w/w純之抗體,但不排除單株抗體與過量之意欲促進其使用之醫藥上可接受之載劑或其他媒劑組合之可能性。干擾蛋白質及其他污染物可包括例如自其分離或重組產生抗體之細胞中之細胞組分。有時,單株抗體對於來自產生或純化之干擾蛋白質及污染物至少60%、70%、80%、90%、95%或99% w/w純。本文所述抗體包括大鼠、嵌合、飾面及人類化抗體,可以經分離及/或純化形式來提供。
「單克隆抗體」係指從實質上同質之抗體群獲得之抗體,即構成該群之個別抗體除了可少量存在之可能的天然突變以外係相同的。修飾詞「單株」指示抗體之特徵係自實質上同質之抗體群獲得,且不應理解為需要藉由任一特定方法來產生該抗體。舉例而言,欲根據本發明使用之單株抗體可藉由首先闡述於Kohler等人(1975)
Nature256:495中之雜交瘤方法製得,或可藉由重組體DNA方法製得(例如,參見美國專利第4816567號)。「單株抗體」亦可例如使用Clackson等人(1991)
Nature,352:624-628及Marks等人(1991)
J. Mol. Biol.,222:581-597中所述之技術自噬菌體抗體庫分離,或可藉由其他方法製得。本文所述抗體係單株抗體。
單株抗體與其靶抗原之特異性結合意指至少10
6、10
7、10
8、10
9或10
10M
-1之親和性。特異性結合之量值可檢測地較高且可與對至少一種無關靶發生之非特異性結合相區別。特異性結合可為在特定官能基之間形成鍵或特定空間配合(例如,鎖鑰型)之結果,而非特異性結合通常係凡得瓦力(van der Waals force)之結果。
基礎抗體結構單元係亞單元之四聚體。各四聚物包括兩對相同多肽鏈,每對具有一條「輕」鏈(約25 kDa)及一條「重」鏈(約50 - 70 kDa)。各鏈之胺基端部分包括主要負責抗原識別之約100至110個或更多胺基酸之可變區。此可變區最初經表現連接至可裂解信號肽。無信號肽之可變區有時成為成熟可變區。因此,例如,輕鏈成熟可變區意指無輕鏈信號肽之輕鏈可變區。各鏈之羧基端部分界定主要負責效應物功能之恆定區。
將輕鏈歸類為κ或λ。將重鏈歸類為γ、μ、α、δ或ε,且將抗體之同型分別定義為IgG、IgM、IgA、IgD及IgE。在輕鏈及重鏈內,可變區及恆定區係藉由約12個或更多胺基酸之「J」區接合,且重鏈亦包括約10個或更多胺基酸之「D」區。(一般參見
Fundamental Immunology(Paul, W.編輯,第2版,Raven Press, N.Y., 1989,第7章),出於所有目的,其係全文以引用方式併入)。
每一輕鏈/重鏈對之成熟可變區形成抗體結合位點。因此,完整抗體具有兩個結合位點。除了在雙功能或雙特異性抗體中以外,兩個結合位點相同。該等鏈皆呈現藉由三個超變區(亦稱為互補決定區或CDR)接合之相對保守框架區(FR)之相同通用結構。來自各對之兩條鏈之CDR係藉由框架區對齊,使得能夠結合至特異性表位。輕鏈及重鏈二者自N末端至C末端包含結構域FR1、CDR1、FR2、CDR2、FR3、CDR3及FR4。將胺基酸根據以下之定義分配至各結構域:Kabat,
Sequences of Proteins of Immunological Interest(National Institutes of Health, Bethesda, MD, 1987及1991),或Chothia及Lesk,
J. Mol. Biol. 196:901-917 (1987);Chothia等人,
Nature342:878-883 (1989),或Kabat與Chothia之組合,或IMGT、AbM或Contact或CDR之其他習用定義。Kabat亦提供廣泛使用之編號慣例(Kabat編號),其中不同重鏈之間或不同輕鏈之間之相應殘基分配相同編號。除非上下文另有明確說明,否則使用Kabat編號指明胺基酸在可變區中之位置。除非上下文另有明確說明,否則使用EU編號指明在恆定區中之位置。
術語「抗體」包括完整抗體及其結合片段。通常,抗體片段與產生其之完整抗體競爭特異性結合至靶,該等片段包括單獨的重鏈、輕鏈Fab、Fab'、F(ab')
2、F(ab)c、雙價抗體、Dab、奈米抗體及Fv。片段可藉由重組DNA技術或藉由完整免疫球蛋白之酶促或化學分離來產生。術語「抗體」亦包括雙價抗體(同二聚Fv片段)或微小抗體(V
L-V
H-C
H3)、雙特異性抗體或諸如此類。雙特異性或雙功能抗體係具有兩個不同重鏈/輕鏈對及兩個不同結合位點之人工雜合抗體(例如,參見Songsivilai及Lachmann, Clin. Exp. Immunol., 79:315-321 (1990);Kostelny等人,J. Immunol., 148:1547-53 (1992))。
術語「抗體」包括抗體自身(裸抗體)或偶聯至細胞毒性或細胞生長抑制藥物之抗體。
嵌合抗體係其中非人類抗體(例如,小鼠)之輕鏈及重鏈之成熟可變區與人類輕鏈及重鏈恆定區組合之抗體。該等抗體實質上或完全保留小鼠抗體之結合特異性,且為人類序列之約三分之二。
飾面抗體係一類人類化抗體,其保留非人類抗體之一些且通常所有CDR及一些非人類可變區框架殘基,但用來自人類抗體序列之相應位置之殘基替代可有助於B細胞或T細胞表位之其他可變區框架殘基,例如暴露殘基(Padlan, Mol. Immunol. 28:489, 1991)。從而得到其中CDR完全或實質上來自非人類抗體且藉由取代使非人類抗體之可變區框架更接近人類之抗體。
術語「表位」係指抗原上與抗體結合之位點。表位可自鄰接胺基酸或藉由一或多個蛋白質之三級摺疊相鄰之非鄰接胺基酸形成。自鄰接胺基酸形成之表位通常在暴露於變性溶劑時保留,而藉由三級摺疊形成之表位通常在用變性溶劑處理時丟失。表位通常在唯一空間構象中包括至少3個、且更通常至少5個或8-10個胺基酸。測定表位空間構象之方法包括例如x射線結晶學及二維核磁共振。例如,參見Epitope Mapping Protocols,Methods in Molecular Biology,第66卷,Glenn E. Morris編輯(1996)。
識別相同或重疊表位之抗體可在顯示一種抗體與另一種抗體競爭結合至靶抗原之能力之簡單免疫分析中鑑別。抗體之表位亦可藉由結合至其抗原以鑑別接觸殘基之抗體之X射線結晶學來界定。或者,若抗原中降低或消除一種抗體之結合之所有胺基酸突變皆降低或消除另一種抗體之結合,則該兩種抗體具有相同表位。若降低或消除一種抗體之結合之一些胺基酸突變降低或消除另一種抗體之結合,則該兩種抗體具有重疊表位。
抗體之間之競爭係藉由分析來測定,其中所測試抗體抑制參考抗體與共同抗原之特異性結合(例如,參見Junghans等人,
Cancer Res.50:1495, 1990)。若如在競爭性結合分析中所量測,過量測試抗體(例如,至少2x、5x、10x、20x或100x)將參考抗體之結合抑制至少50%、但較佳75%、90%或99%,則測試抗體與參考抗體競爭。藉由競爭分析鑑別之抗體(競爭抗體)包括與參考抗體結合至相同表位之抗體及由於存在立體阻礙而結合至足夠靠近參考抗體所結合表位之毗鄰表位之抗體。與h2H12抗體競爭結合至人類BCMA蛋白之抗體包括在本發明中。
術語「患者」包括接受預防性或治療性治療之人類及其他哺乳動物個體。
出於將胺基酸取代歸類為保守或非保守之目的,將胺基酸分組如下:組I (疏水側鏈):met、ala、val、leu、ile;組II (中性親水側鏈):cys、ser、thr;組III (酸性側鏈):asp、glu;組IV (鹼性側鏈):asn、gln、his、lys、arg;組V (影響鏈取向之殘基):gly、pro;及組VI (芳香族側鏈):trp、tyr、phe。保守取代涉及同一類別中胺基酸之間之取代。非保守取代係指用該等類別中一者之成員與另一類別之成員交換。
序列一致性百分比係用藉由Kabat編號慣例最大對齊之抗體序列來測定。在對齊後,若將受試抗體區域(例如,重鏈或輕鏈之完整成熟可變區)與參考抗體之相同區域相比,則受試抗體區域與參考抗體區域之間之序列一致性百分比係將受試抗體區域與參考抗體區域二者中相同胺基酸所佔據之位置數除以兩個區域之對齊位置總數(不計數空位),乘以100以轉化為百分比。
「包含」一或多個所列舉要素之組合物或方法可包括未明確列舉之其他要素。舉例而言,包含抗體之組合物可含有單獨或與其他成分組合之該抗體。
值之範圍之指定包括該範圍內或界定該範圍之所有整數。
抗體效應物功能係指由Ig之Fc結構域貢獻之功能。該等功能可為例如抗體依賴性細胞毒性、抗體依賴性細胞吞噬作用或補體依賴性細胞毒性。該功能可藉由(例如) Fc效應物結構域與具有吞噬或溶解活性之免疫細胞上之Fc受體之結合或藉由Fc效應物結構域與補體系統之組分之結合來實現。通常,由Fc結合細胞或補體組分介導之效應導致BCMA靶向細胞之抑制及/或耗竭。抗體之Fc區可招募Fc受體(FcR)表現細胞並使其與經抗體覆蓋之靶細胞相鄰。表現針對IgG之表面FcR (包括FcγRIII (CD16)、FcγRII (CD32)及FcγRIII (CD64))之細胞可用作破壞經IgG覆蓋之細胞之效應細胞。該等效應細胞包括單核球、巨噬細胞、天然殺手(NK)細胞、嗜中性球及嗜酸性球。IgG嚙合FcγR活化抗體依賴性細胞毒性(ADCC)或抗體依賴性細胞吞噬作用(ADCP)。ADCC係由CD16
+效應細胞經由分泌膜成孔蛋白及蛋白酶來介導,而吞噬作用係由CD32
+及CD64
+效應細胞介導(參見
Fundamental Immunology,第4版,Paul編輯,Lippincott-Raven, N.Y., 1997,第3、17及30章;Uchida等人,2004,
J. Exp. Med.199:1659-69;Akewanlop等人,2001,
Cancer Res.61:4061-65;Watanabe等人,1999,
Breast Cancer Res. Treat.53:199-207)。除了ADCC及ADCP以外,細胞結合抗體之Fc區亦可活化補體古典路徑以引發補體依賴性細胞毒性(CDC)。補體系統之C1q在抗體與抗原複合時結合至該等抗體之Fc區。C1q與細胞結合抗體之結合可起始涉及C4及C2之蛋白水解活化之一系列事件以生成C3轉化酶。C3藉由C3轉化酶裂解為C3b使得能活化末端補體組分,包括C5b、C6、C7、C8及C9。該等蛋白質在經抗體覆蓋之細胞上共同形成攻膜複合物孔。該等孔破壞細胞膜完整性,從而殺死靶細胞(參見
Immunobiology,第6版,Janeway等人,Garland Science, N. Y., 2005,第2章)。
術語「抗體依賴性細胞毒性」或ADCC係誘導細胞死亡之機制,其依賴於經抗體覆蓋之靶細胞與具有溶解活性之免疫細胞(亦稱為效應細胞)之相互作用。該等效應細胞包括天然殺手細胞、單核球/巨噬細胞及嗜中性球。效應細胞附著至經由其抗原組合位點結合至靶細胞之Ig之Fc效應物結構域。經抗體覆蓋之靶細胞因效應細胞活性而死亡。
術語「抗體依賴性細胞吞噬作用」(簡稱「ADCP」)係指經抗體覆蓋之細胞由結合至Ig之Fc效應物結構域之吞噬性免疫細胞(例如巨噬細胞、嗜中性球及樹突細胞)完全或部分內化之過程。
術語「補體依賴性細胞毒性」或CDC係指誘導細胞死亡之機制,其中靶結合抗體之Fc效應物結構域活化一系列酶促反應,最終在靶細胞膜上形成孔洞。通常,抗原-抗體複合物(例如在經抗體覆蓋之靶細胞上之彼等)結合並活化補體組分C1q,其進而活化補體級聯,從而導致靶細胞死亡。活化補體亦可導致補體組分沈積於靶細胞表面上,從而藉由結合白血球上之補體受體(例如,CR3)來促進ADCC。
「細胞毒性效應」係指耗竭、消除及/或殺死靶細胞。「細胞毒性劑」係指對細胞具有細胞毒性效應之試劑。
細胞毒性劑可偶聯至抗體或與抗體組合投與。
「細胞生長抑制效應」係指抑制細胞增殖。「細胞生長抑制劑」係指對細胞具有細胞生長抑制效應,由此抑制特定細胞亞組之生長及/或擴增之試劑。細胞生長抑制劑可偶聯至抗體或與抗體組合投與。
術語「醫藥上可接受之」意指已由或可由聯邦或州政府管理機構批准或已列於美國藥典(U.S. Pharmacopeia)或其他公認藥典中可用於動物、且更具體而言用於人類中。術語「醫藥上相容之成分」係指與抗BCMA抗體一起投與個體之醫藥上可接受之稀釋劑、佐劑、賦形劑或媒劑。
片語「醫藥上可接受之鹽」係指醫藥上可接受之抗BCMA-1抗體或其偶聯物或與抗BCMA-1抗體一起投與之試劑之有機或無機鹽。實例性鹽包括硫酸鹽、檸檬酸鹽、乙酸鹽、草酸鹽、鹽酸鹽、溴化物、碘化物、硝酸鹽、硫酸氫鹽、磷酸鹽、酸式磷酸鹽、異菸鹼酸鹽、乳酸鹽、柳酸鹽、酸式檸檬酸鹽、酒石酸鹽、油酸鹽、鞣酸鹽、泛酸鹽、酒石酸氫鹽、抗壞血酸鹽、琥珀酸鹽、馬來酸鹽、龍膽酸鹽、富馬酸鹽、葡糖酸鹽、葡糖醛酸鹽、糖質酸鹽、甲酸鹽、苯甲酸鹽、麩胺酸鹽、甲磺酸鹽、乙磺酸鹽、苯磺酸鹽、對甲苯磺酸鹽及雙羥萘酸鹽(即1,1’-亞甲基雙-(2-羥基3-萘酸鹽))。醫藥上可接受之鹽可涉及引入另一分子,例如乙酸根離子、琥珀酸根離子或其他相對離子。相對離子可為使母化合物上之電荷穩定之任何有機或無機部分。此外,醫藥上可接受之鹽可在其結構中具有一個以上帶電原子。其中多個帶電原子係醫藥上可接受之鹽之部分之情況可具有多個相對離子。因此,醫藥上可接受之鹽可具有一或多個帶電原子及/或一或多個相對離子。
除非上下文另有明確說明,否則術語「約」涵蓋對功能性質無顯著效應之非實質性差異(例如,在誤差邊際或實驗量測內)。
I.
概述本發明提供特異性結合至BCMA之單株抗體。該等抗體可用於治療及診斷多種癌症及免疫病症以及檢測BCMA。
II.
靶分子除非另外指示,否則BCMA意指人類BCMA。實例性人類核酸及胺基酸序列係由SEQ ID NO:1及2提供。除非上下文另有明確說明,否則提及BMCA時意指蛋白質之至少細胞外結構域(SEQ ID NO: 2之大約殘基1-54)且有時意指完整蛋白質。同樣,除非上下文另有明確說明,否則提及BAFF及APRIL及其除BCMA以外的受體時係指野生型人類序列,例如如在Swiss Prot資料庫中所提供。
III.
本發明抗體A.
結合特異性及功能性質SG16.17抗體係特異性結合至人類BCMA之大鼠單株抗體,如實例中所述。ATCC保藏物係於2005年8月15日根據布達佩斯條約(Budapest Treaty)製得。ATCC位於10801 University Boulevard, Manassas, Va. 20110-2209, USA。ATCC保藏物經分配登錄號為PTA-6937。SG16.17抗體抑制BCMA與其配體APRIL及BAFF二者之結合。SG16.17抗體在連接至人類IgG1時引發ADCC,結合至Fcγ受體並經由Fcγ受體引發信號傳導。亦可將SG16.17抗體納入抗體-藥物偶聯物中以將所連接藥物遞送至表現BCMA之細胞之內部。SG16.45抗體係另一大鼠單株抗體,其特異性結合至人類BCMA,抑制其與其配體之結合且可將所連接藥物遞送至表現BCMA之細胞之內部。
本發明提供SG16.17抗體(命名為hSG16.17、cSG16.17或vSG16.17)及SG16.45 (以類似方式命名)之人類化、嵌合及飾面形式。該等抗體通常保留上文所述SG16.17或SG16.45之一些或全部性質。對於任一給定性質,人類化、嵌合或飾面抗體可以在實驗誤差內或大於或小於大鼠SG16.17或SG16.45之相同程度展現該性質。對於人類BCMA,大鼠SG16.17抗體之人類化、嵌合或飾面形式之親和性(即,Ka)可大於大鼠SG16.17抗體,或在大鼠SG16.17抗體之5的因數或2的因數內(即,大於或小於)。較佳人類化、嵌合或飾面SG16.17抗體與大鼠SG16.17抗體結合至相同表位及/或競爭結合至人類BCMA。對於人類BCMA,大鼠SG16.45抗體之人類化、嵌合或飾面形式之親和性(即,Ka)可大於大鼠SG16.45抗體,或在大鼠SG16.45抗體之5的因數或2的因數內(即,大於或小於)。較佳人類化、嵌合或飾面SG16.45抗體與大鼠SG16.45抗體結合至相同表位及/或競爭結合至人類BCMA。
較佳人類化、嵌合及飾面抗體抑制癌症(例如,細胞生長、轉移及/或對生物體之致死性)或B細胞介導之免疫病症,如在活體外、在動物模型或臨床試驗中所顯示。
B.
抗體人類化抗體係遺傳改造抗體,其中將來自非人類「供體」抗體之CDR移植至人類「接受體」抗體序列中(例如,參見Queen, US 5,530,101及5,585,089;Winter, US 5,225,539;Carter, US 6,407,213;Adair, US 5,859,205;及Foote, US 6,881,557)。接受體抗體序列可為例如成熟人類抗體序列、該等序列之複合物、人類抗體序列之共有序列或種系區域序列。對於SG16.17之人類化,重鏈之較佳接受體序列係種系V
H外顯子V
H1-2及外顯子J
H-3 (對於J外顯子(J
H))。對於輕鏈,較佳接受體序列係外顯子V
L1-12及J外顯子J
K5。對於SG16.45之人類化,較佳重鏈接受體序列係HV3-23/HJ3 (SEQ ID NO: 24)且較佳輕鏈接受體序列係KV3-20/KJ2 (SEQ ID NO: 34)。
因此,人類化抗體係具有至少4個完全或實質上來自非人類供體抗體之CDR及完全或實質上來自人類抗體序列之可變區框架序列及恆定區(若存在)之抗體。類似地,人類化重鏈具有至少兩個且通常全部三個完全或實質上來自供體抗體重鏈之CDR及實質上來自人類重鏈可變區框架及恆定區序列之重鏈可變區框架序列及重鏈恆定區(若存在)。類似地,人類化輕鏈具有至少兩個且通常全部三個完全或實質上來自供體抗體輕鏈之CDR及實質上來自人類輕鏈可變區框架及恆定區序列之輕鏈可變區框架序列及輕鏈恆定區(若存在)。除了奈米抗體及dAb以外,人類化抗體包含人類化重鏈及人類化輕鏈。在各別CDR之間至少60%、85%、90%、95%或100%之相應殘基(如藉由Kabat所定義)一致時,人類化或人類抗體中之CDR實質上來自非人類抗體中之相應CDR或與其實質上一致。在至少70%、80%、85%、90%、95%或100%之藉由Kabat所定義之相應殘基一致時,抗體鏈之可變區框架序列或抗體鏈之恆定區分別實質上來自人類可變區框架序列或人類恆定區。
儘管人類化抗體通常納入全部6個來自小鼠抗體之CDR (較佳如藉由Kabat所定義,但替代地如藉由IMGT、Chothia、組合Kabat-Chothia、AbM或Contact或其他習用定義所定義),但亦可使其具有少於全部來自小鼠抗體之CDR (例如,至少4個或5個CDR) (例如,Pascalis等人,
J. Immunol. 169:3076, 2002;Vajdos等人,
Journal of Molecular Biology, 320: 415-428, 2002;Iwahashi等人,
Mol. Immunol. 36:1079-1091, 1999;Tamura等人,
Journal of Immunology, 164:1432-1441, 2000)。
某些來自人類可變區框架殘基之胺基酸可基於其對CDR構象及/或與抗原之結合之可能影響經選擇用於取代。對該等可能影響之研究係藉由建模、檢查特定位置的胺基酸之特徵或憑經驗觀察特定胺基酸之取代或誘變之效應來進行。
舉例而言,在鼠類可變區框架殘基與所選人類可變區框架殘基之間之胺基酸不同時,在合理地預期該胺基酸有如下情況時,人類框架胺基酸可經來自小鼠抗體之等效框架胺基酸取代:
(1) 直接非共價結合抗原,
(2) 毗鄰CDR區域,
(3) 以其他方式與CDR區域相互作用(例如在CDR區域之約6 Å內);或
(4) 介導重鏈與輕鏈之間之相互作用。
本發明提供大鼠SG16.17抗體之人類化形式,其包括
6個所例示人類化重鏈成熟可變區(hSG16.17 VH1-6) ( SEQ ID No: 11-16)及4個所例示人類化輕鏈成熟可變區(hSG16.17 VK2-5) (SEQ ID NO: 19-22)。重鏈及輕鏈可以任何排列組合,且包括hSG16.17 VH1、VH3或VH5中之任一者之排列較佳。具有結合親和性、與人類種系之序列一致性百分比、表現及單體含量百分比之最佳組合之排列係hSG16.17 VH3 VK2。此抗體顯示在實驗誤差內與大鼠SG16.17類似之親和性、在重鏈及輕鏈可變區二者中與人類種系之大於85%序列一致性(由此,根據新INN準則具有「人類化」名稱之資格)、在CHO細胞中之高表現及高單體比例。與大多數其他人類化抗體相比,hSG16.17 VH3 VK2之獨特之處在於具有大量可變區框架突變,其中人類接受體殘基變為相應大鼠殘基(13),但亦具有大量「正向」CDR突變,其中Kabat CDR中之大鼠殘基變為人類接受體序列中之相應殘基,使得整體上該抗體與人類種系序列具有足夠序列一致性而根據INN準則歸類為人類化。大多數先前人類化抗體具有完全來自供體抗體之Kabat CDR。
本發明提供抗體,其中重鏈可變區顯示與hSG16.17 VH3 (SEQ ID NO: 13)至少90%一致且輕鏈可變區顯示與hSG16.17 VK2 (SEQ ID NO: 19)至少90%一致。一些抗體顯示與HV3之至少95%、96%、97%、98%或99%序列一致性及與VK2之至少95%、96%、97%、98%或99%序列一致性。一些該等抗體包括hSG16.17 VH3 (SEQ ID NO: 13)之三個Kabat CDR (SEQ ID NO: 60-62)及hSG16.17 VK2 (SEQ ID NO: 19)之三個Kabat CDR (SEQ ID NO: 90-92)。一些該等抗體包括hSG16.17 VH3 (SEQ ID NO: 13)之三個Kabat CDR (SEQ ID NO: 60-62)及hSG16.17 VK2 (SEQ ID NO: 19)之三個Kabat CDR (SEQ ID NO: 90-92),條件係位置H58可由N或K佔據,位置H60可由A或N佔據,位置H61可由Q或E佔據,位置H62可由K或N佔據,位置H64可由Q或K佔據,位置H65可由G或T佔據,位置L24可由R或L佔據且位置L53可由S或R佔據。較佳地,位置H58、H60、H61、H62、H64及H65分別由N、A、Q、K、Q及G佔據且L24及L53分別由R及S佔據。所列舉之該等殘基代表佔據Kabat CDR內之位置之來自人類接受體序列之胺基酸。一些抗體在人類Kabat CDR內有至少1、2、3、4、5、6、7或8個大鼠殘基由來自人類接受體序列之相應殘基替代。在一些抗體中,位置H58、H60、H61、H62、H64及H65分別由N、A、Q、K、Q及G佔據,且L24及L53分別由R及S佔據。一些抗體包括至少1、2、3、4、5、6、7、8、9、10、11、12、13或14個回復突變,代表可變區人類接受體序列殘基經相應大鼠殘基替代。
在一些抗體中,位置H20、H48、H69、H71、H73、H76、H80、H88、H91及H93中之至少1、2、3、4、5、6、7、8、9、10或11個分別由L、I、M、A、K、N、V、A、F及T佔據。在一些抗體中,位置L46、L48及L87中之至少1、2或3個分別由V、V及F佔據。在一些抗體中,位置H20、H48、H69、H71、H73、H76、H80、H88、H91及H93各自分別由L、I、M、A、K、N、V、A、F及T佔據且L46、L48及L87各自分別由V、V及F佔據。
在人類化抗體顯示自所例示hSG16.17 VH3 VK2人類化抗體之任何變異之範圍內,該額外變異之一種可能性係可變區框架中之額外回復突變。在其他所例示人類化重鏈或輕鏈成熟可變區中發生回復突變之任一或所有位置亦可由如下組成:由R佔據之H8、由A佔據之H67及由A佔據之H78;由S佔據之L40、由M佔據之L78及由D佔據之L85 (即,其中之1、2、3、4、5或所有6個),或重鏈中由N佔據之H38、由R佔據之H40、由K佔據之H73、由S佔據之H82A及由T佔據之H83中之所有5個,及輕鏈中由K佔據之L3及由I佔據之L20中之1個或兩個。然而,該等額外回復突變並非較佳,此乃因其一般不改良親和性且引入更多小鼠殘基可增加免疫原性之風險。
另一可能變異係用來自人類CDR序列、通常來自用於設計所例示人類化抗體之人類接受體序列CDR之相應殘基取代小鼠抗體CDR中之更多或更少殘基。在一些抗體中,僅需要部分CDR (即結合所需CDR殘基亞組,稱為SDR)來保持人類化抗體中之結合。不接觸抗原且不在SDR中之CDR殘基可基於根據其他定義(例如Chothia超變環(Chothia,
J. Mol. Biol.196:901, 1987))位於CDR外部之Kabat CDR區域、藉由分子建模及/或憑經驗或如Gonzales等人,Mol. Immunol. 41: 863 (2004)中所述來鑑別。在該等人類化抗體中在其中一或多個供體CDR殘基不存在或其中整個供體CDR被省略之位置,佔據該位置之胺基酸可為佔據接受體抗體序列中之相應位置(依照Kabat編號)之胺基酸。欲包括CDR中接受體取代供體胺基酸之該等取代數反映競爭考慮因素之平衡。該等取代在減少人類化抗體中之小鼠胺基酸數且因此降低潛在免疫原性方面可能係有利的。然而,取代亦可引起親和性變化,且較佳避免親和性顯著降低。CDR內之取代位置及欲取代之胺基酸亦可憑經驗來選擇。
儘管並非較佳,但可進行其他胺基酸取代,例如在不與CDR接觸之框架殘基中,或甚至CDR內一些潛在的CDR接觸殘基胺基酸。通常在變體人類化序列中進行之替代關於所替代hSG16.17 VH3 VK2胺基係保守的。較佳地,關於hSG16.17 VH3 VK2之替代(保守抑或不保守)對人類化mAb之結合親和性或功效、亦即其結合人類BCMA並抑制癌細胞生長之能力不具有顯著效應。
變體通常與hSG16.17 VH3 VK2之重鏈及輕鏈成熟可變區序列相差少量(例如,輕鏈或重鏈成熟可變區或二者中通常不多於1、2、3、5或10個)替代、缺失或插入。
人類化重鏈及輕鏈之其他較佳組合包括以下中之任一者:hSG16.17 VH1 VK2、VH1 VK3、VH1 VK4、VH1 VK4、VH3 VK2、VH3 VK3、VH3 VK4及VH3 VK5及VH5 VK2、VH5 VK3、VH5 VK4、VH5 VK5,以及其中重鏈及輕鏈可變區與任一該等抗體之重鏈及輕鏈可變區顯示至少90、95、96、97、98或99%一致性之人類化抗體。
本發明提供大鼠SG16.45抗體之人類化形式,其包括6個所例示人類化重鏈成熟可變區(hSG16.45 VH1-6) (SEQ ID NO: 27-32)及4個所例示人類化輕鏈成熟可變區(hSG16.45 VK1、2、3及5) (SEQ ID NO: 35-38)。重鏈及輕鏈可以任何排列組合,且排列hSG16.45 VH5 VK2、VH1 VK1及VH1 VK5較佳。hSG16.45 HV5 VK2顯示在重鏈及輕鏈可變區二者中與人類種系之大於85%序列一致性(由此,根據新INN準則具有「人類化」名稱之資格)、在CHO細胞中之高表現、高單體比例及足夠結合(即使略低於大鼠或嵌合SG16.45)。hSG16.45 VH5 VK2具有3個可變區回復突變(皆在重鏈中)及3個Kabat CDR正向突變,其中Kabat CDR中之大鼠殘基變為人類接受體序列中之相應殘基,使得整體上該抗體與人類種系序列具有足夠序列一致性以根據INN準則歸類為人類化。
本發明提供抗體,其中重鏈可變區顯示與hSG16.45 VH5 (SEQ ID NO: 31)至少90%一致且輕鏈可變區顯示與hSG16.45 VK2至少90%一致。一些抗體顯示與hSG16.45 VH5之至少95%、96%、97%、98%或99%序列一致性及與VK2之至少95%、96%、97%、98%或99%序列一致性。一些該等抗體包括hSG16.45 VH5 (SEQ ID NO: 31)之三個Kabat CDR (SEQ ID NO: 152-154)及hSG16.45 VK2 (SEQ ID NO: 36)之三個Kabat CDR (SEQ ID NO: 179-181)。一些該等抗體包括hSG16.45 VH5 (SEQ ID NO: 31)之三個Kabat CDR (SEQ ID NO: 152-154)及hSG16.45 VK2 (SEQ ID NO: 36)之三個Kabat CDR (SEQ ID NO: 179-181),條件係位置H50可由A或S佔據且位置L24可由R或L佔據且位置L26可由S或T佔據。較佳地,位置H50由A佔據且位置L24及L26由R及S佔據。所列舉之該等殘基代表佔據Kabat CDR內之位置之來自人類接受體序列之胺基酸。一些抗體在人類Kabat CDR中有至少1、2或3個大鼠殘基經來自人類接受體序列之相應殘基替代。在一些抗體中,位置H50、L24及L26分別由A、R及S佔據。一些抗體包括至少1、2或3個回復突變,代表可變區人類接受體序列殘基經相應大鼠殘基替代。
在一些抗體中,位置H30、H93及H94中之至少1、2或3個分別由N、T及S佔據。在一些抗體中,位置H30、H93及H94各自分別由N、T及S佔據。
在人類化抗體顯示自所例示hSG16.45 VH5 VK2人類化抗體之任何變異之範圍內,該額外變異之一種可能性係可變區框架中之額外回復突變。在其他所例示人類化重鏈或輕鏈成熟可變區中回復突變之任一或所有位置亦可由如下組成:分別由I、I、N及V佔據之H37、H48、H76、H107 (即,其中之1、2、3或4個)及/或分別由A、V、I、H、V、Y及M佔據之L14、L19、L21、L38、L58、L71及L78中之1、2、3、4、5、6或7個。然而,該等額外回復突變並非較佳,此乃因其一般不改良親和性且引入更多小鼠殘基可增加免疫原性之風險。
另一可能變異係用來自人類CDR序列、通常來自用於設計所例示人類化抗體之人類接受體序列CDR之相應殘基取代小鼠抗體CDR中之更多或更少殘基。在一些抗體中,僅需要部分CDR (即結合所需CDR殘基亞組,稱為SDR)以保持人類化抗體中之結合。不接觸抗原且不在SDR中之CDR殘基可基於根據其他定義(例如Chothia超變環(Chothia,
J. Mol. Biol.196:901, 1987))位於CDR外部之Kabat CDR區域、藉由分子建模及/或憑經驗或如Gonzales等人,Mol. Immunol. 41: 863 (2004)中所述來鑑別。在該等人類化抗體中在其中一或多個供體CDR殘基不存在或其中整個供體CDR被省略之位置,佔據該位置之胺基酸可為佔據接受體抗體序列中之相應位置(依照Kabat編號)之胺基酸。欲包括CDR中接受體取代供體胺基酸之該等取代數反映競爭考慮因素之平衡。該等取代在減少人類化抗體中之小鼠胺基酸數且因此降低潛在免疫原性方面可能係有利的。然而,取代亦可引起親和性變化,且較佳避免親和性顯著降低。CDR內之取代位置及欲取代之胺基酸亦可憑經驗來選擇。
儘管並非較佳,但可進行其他胺基酸取代,例如在不與CDR接觸之框架殘基中,或甚至CDR內一些潛在的CDR接觸殘基胺基酸。通常在變體人類化序列中進行的替代關於所替代hSG16.45 VH3 VK2係保守的。較佳地,關於hSG16.45 VH5 VK2之替代(保守抑或不保守)對人類化mAb之結合親和性或功效、亦即其結合人類BCMA並抑制癌細胞生長之能力不具有顯著效應。
變體通常與SG16.45 VH5 VK2之重鏈及輕鏈成熟可變區序列相差少量(例如,在輕鏈或重鏈成熟可變區或二者中通常不多於1、2、3、5或10個)替代、缺失或插入。
人類化重鏈及輕鏈之其他較佳組合包括以下中之任一者:hSG16.45 VH1 VK1及VH1 VK5,以及其中重鏈及輕鏈可變區與任一該等抗體之重鏈及輕鏈可變區顯示至少90、95、96、97、98或99%一致性之人類化抗體。
C.
恆定區之選擇人類化抗體之重鏈及輕鏈可變區可連接至人類恆定區之至少一部分。恆定區之選擇部分依賴於是否期望抗體依賴性細胞介導之細胞毒性、抗體依賴性細胞吞噬作用及/或補體依賴性細胞毒性。舉例而言,人類同型IgG1及IgG3具有強補體依賴性細胞毒性、人類同型IgG2具有弱補體依賴性細胞毒性,且人類IgG4缺少補體依賴性細胞毒性。人類IgG1及IgG3亦誘導強於人類IgG2及IgG4之細胞介導之效應物功能。輕鏈恆定區可為λ或κ。抗體可表現為含有兩條重鏈及兩條重鏈之四聚體,表現為單獨重鏈、輕鏈,表現為Fab、Fab'、F(ab')2及Fv,或表現為其中重鏈及輕鏈可變結構域經由間隔體連接之單鏈抗體。
人類恆定區顯示不同個體之間之同種異型變異及同族同種異型變異,亦即恆定區可在不同個體之間在一或多個多態性位置不同。同族同種異型與同種異型(allotype)之差異在於識別同族同種異型(isoallotype)之血清結合至一或多個其他同型之非多態性區域。實例性野生型人類κ及IgG1恆定區序列(後者具有或不具有C-末端離胺酸)係於SEQ ID NO: 3-5中提供。
輕鏈及/或重鏈之胺基或羧基末端之一或多個胺基酸、例如重鏈之C-末端離胺酸可在一部分或所有分子中丟失或衍生。可在恆定區中進行取代以降低或增加效應物功能,例如補體介導之細胞毒性或ADCC (例如,參見Winter等人,美國專利第5,624,821號;Tso等人,美國專利第5,834,597號;及Lazar等人,Proc. Natl. Acad. Sci. USA 103:4005, 2006),或延長在人類中之半衰期(例如,參見Hinton等人,J. Biol. Chem. 279:6213, 2004)。
實例性取代包括在胺基酸位置234、235、237、239、267、298、299、326、330或332引入之天然胺基酸至半胱胺酸殘基之胺基酸取代,較佳人類IgG1同型中之S239C突變(根據EU索引編號(Kabat,
Sequences of Proteins of Immunological Interest(國立衛生研究院, Bethesda, MD, 1987及1991);參見US 20100158909,其係以引用方式併入本文中)。具有及不具有C-末端離胺酸之具有S239C之重鏈恆定區之序列由SEQ ID NO: 6及7提供。額外半胱胺酸殘基之存在容許形成鏈間二硫鍵。該鏈間二硫鍵形成可造成立體阻礙,從而降低Fc區-FcγR結合相互作用之親和性。在IgG恆定區之Fc區中或在其附近引入之半胱胺酸殘基亦可用作偶聯至治療劑之位點(即,使用硫醇特異性試劑偶合細胞毒性藥物,例如藥物之馬來醯亞胺衍生物)。治療劑之存在造成立體阻礙,從而進一步降低Fc區-FcγR結合相互作用之親和性。在位置234、235、236及/或237中任一處之其他取代降低對Fcγ受體、尤其FcγRI受體之親和性(例如,參見US 6,624,821、US 5,624,821)。突變之較佳組合係S239D、A330L及I332E,其增加Fc結構域對FcγRIIIA之親和性且因此增加ADCC。
抗體之活體內半衰期亦可影響其效應物功能。抗體之半衰期可延長或縮短以改變其治療活性。FcRn係結構類似於與β2-微球蛋白非共價結合之MHC I類抗原之受體。FcRn調節IgG之分解代謝及其跨越組織之胞吞轉送作用(Ghetie及Ward, 2000,
Annu. Rev. Immunol.18:739-766;Ghetie及Ward, 2002,
Immunol. Res.25:97-113)。IgG-FcRn相互作用在pH 6.0 (細胞內囊泡之pH)下發生,但在pH 7.4 (血液pH)下不發生;此相互作用使得IgG能再循環回至循環中(Ghetie及Ward, 2000,
Ann. Rev. Immunol.18:739-766;Ghetie及Ward, 2002,
Immunol. Res.25:97-113)。人類IgG1上參與FcRn結合之區域已經定位(Shields等人,2001,
J. Biol. Chem.276:6591-604)。在人類IgG1之位置Pro238、Thr256、Thr307、Gln311、Asp312、Glu380、Glu382或Asn434之丙胺酸取代增強FcRn結合(Shields等人,2001,
J. Biol. Chem.276:6591-604)。具有該等取代之IgG1分子具有較長血清半衰期。因此,與未修飾IgG1相比,該等經修飾IgG1分子可在較長時間段期間能夠實施其效應物功能,且因此發揮其治療功效。用於增加與FcRn之結合之其他實例性取代包括在位置250之Gln及/或在位置428之Leu。恆定區中之所有位置皆使用EU編號。
IgG之Fc區結合FcγR之能力涉及共價附接至保守Asn297之寡醣(Lund等人,1996,
J. Immunol.157:4963-69;Wright及Morrison, 1997,
Trends Biotechnol.15:26-31)。IgG上此糖型之工程化可顯著改良IgG介導之ADCC。將平分型N-乙醯基葡糖胺修飾(Umana等人,1999,
Nat. Biotechnol.17:176-180;Davies等人,2001,
Biotech. Bioeng.74:288-94)添加至此糖型或自此糖型移除岩藻糖(Shields等人,2002,
J. Biol. Chem.277:26733-40;Shinkawa等人,2003,
J. Biol. Chem.278:6591-604;Niwa等人,2004,
Cancer Res.64:2127-33)係改良IgG Fc與FcγR之間之結合,從而增強Ig介導之ADCC活性之IgG Fc工程化之兩個實例。
人類IgG1 Fc區之溶劑暴露胺基酸之系統性取代生成具有改變FcγR結合親和性之IgG變體(Shields等人,2001,
J. Biol. Chem.276:6591-604)。在與親代IgG1相比時,包括Thr256/Ser298、Ser298/Glu333、Ser298/Lys334或Ser298/Glu333/Lys334至Ala之取代之該等變體之亞組顯示對FcγR之結合親和性及ADCC活性二者增加(Shields等人,2001,
J. Biol. Chem.276:6591-604;Okazaki等人,2004,
J. Mol. Biol.336:1239-49)。
抗體之補體結合活性(C1q結合及CDC活性二者)可藉由Lys326及Glu333之取代而改良(Idusogie等人,2001,
J. Immunol.166:2571-2575)。人類IgG2主鏈上之相同取代可將對C1q結合較差且嚴重缺乏補體活化活性之抗體同型轉化為既可結合C1q亦可介導CDC之抗體同型(Idusogie等人,2001,
J. Immunol.166:2571-75)。亦可應用若干種其他方法來改良抗體之補體結合活性。舉例而言,將IgM之18個胺基酸之羧基-末端尾段移植至IgG之羧基-末端顯著增強其CDC活性。此即使在使用通常不具有可檢測CDC活性之IgG4時亦可觀察到(Smith等人,1995,
J. Immunol.154:2226-36)。同樣,用Cys取代位置接近IgG1重鏈之羧基末端之Ser444誘導IgG1之尾對尾二聚化,且使CDC活性相對於單體IgG1增加200倍(Shopes等人,1992,
J. Immunol.148:2918-22)。另外,具有對C1q之特異性之雙特異性雙價抗體構築體亦賦予CDC活性(Kontermann等人,1997,
Nat. Biotech.15:629-31)。
補體活性可藉由使重鏈之胺基酸殘基318、320及322中之至少一者突變為具有不同側鏈之殘基(例如Ala)來降低。代替該三個殘基中之任一者之其他烷基取代之非離子殘基(例如Gly、Ile、Leu或Val)或芳香族非極性殘基(例如Phe、Tyr、Trp及Pro)亦降低或消除C1q結合。Ser、Thr、Cys及Met可在殘基320及322而非318用於降低或消除C1q結合活性。用極性殘基替代318 (Glu)殘基可改變但不消除C1q結合活性。用Ala替代殘基297 (Asn)導致溶解活性移除,但僅略微降低(降低約3倍)對C1q之親和性。此改變破壞醣基化位點及為補體活化所需之碳水化合物之存在。在此位點之任何其他取代亦破壞醣基化位點。以下突變及其任何組合亦降低C1q結合:D270A、K322A、P329A及P311S (參見WO 06/036291)。
在提及人類恆定區時包括具有任何天然同種異型或佔據天然同種異型中之多態性位置之殘基之任何排列之恆定區。同樣,相對於天然人類恆定區可存在至多1、2、5或10個突變,例如上文所指示之彼等,以降低Fcγ受體結合或增加與FcRN之結合。
D.
重組體抗體之表現人類化、嵌合或飾面抗體通常係藉由重組體表現來產生。重組體多核苷酸構築體通常包括可操作連接至抗體鏈之編碼序列之表現控制序列,包括天然相關之或異源啟動子區域。較佳地,表現控制序列係能轉變或轉染真核宿主細胞之載體中之真核啟動子系統。一旦已將載體納入適當宿主中,即將宿主維持在適於核苷酸序列之高水平表現及交叉反應抗體之收集及純化之條件下。
哺乳動物細胞係用於表現編碼免疫球蛋白或其片段之核苷酸區段之較佳宿主。參見Winnacker
, From Genes to Clones, (VCH Publishers, NY, 1987)。業內已研發出多種能分泌完整異源蛋白質之適宜宿主細胞系,且包括CHO細胞系(例如,DG44)、多種COS細胞系、HeLa細胞、HEK293細胞、L細胞及不產生抗體之骨髓瘤(包括Sp2/0及NS0)。較佳地,該等細胞係非人類細胞。用於該等細胞之表現載體可包括表現控制序列,例如複製起點、啟動子、增強子(Queen等人,
Immunol. Rev.89:49 (1986))及所需處理資訊位點(例如核糖體結合位點、RNA剪接位點、多聚腺苷酸化位點及轉錄終止子序列)。較佳表現控制序列係源自內源基因、巨細胞病毒、SV40、腺病毒、牛乳頭瘤病毒及諸如此類之啟動子。參見Co等人,
J. Immunol.148:1149 (1992)。
一旦經表現,抗體可根據業內標準程序來純化,包括HPLC純化、管柱層析、凝膠電泳及諸如此類(通常參見Scopes,
Protein Purification(Springer-Verlag, NY, 1982))。
E.
醣基化 變體抗體可在其恆定區中之保守位置醣基化(Jefferis及Lund, (1997) Chem. Immunol. 65:111-128;Wright及Morrison, (1997) TibTECH 15:26-32)。免疫球蛋白之寡醣側鏈影響蛋白質功能(Boyd等人,(1996) Mol. Immunol. 32:1311-1318;Wittwe及Howard, (1990) Biochem. 29:4175-4180)以及醣蛋白各部分之間之分子內相互作用,其可影響醣蛋白之構象及所呈現之三維表面(Hefferis及Lund,上文文獻;Wyss及Wagner, (1996) Current Opin. Biotech. 7:409-416)。寡醣亦可用於基於特異性識別結構將給定醣蛋白靶向某些分子。舉例而言,已報導在無半乳糖基化IgG中,寡醣部分「翻轉」出CH2間空間且末端N-乙醯基葡糖胺殘基變得可用於結合甘露糖結合蛋白(Malhotra等人,(1995) Nature Med. 1:237-243)。藉由糖肽酶自中國倉鼠卵巢(CHO)細胞中產生之CAMPATH-1H (重組體人類化鼠類單株IgG1抗體,其識別人類淋巴球之CDw52抗原)移除寡醣導致完全降低補體介導之溶解(CMCL) (Boyd等人,(1996) Mol. Immunol. 32:1311-1318),而使用神經胺酸酶選擇性移除唾液酸殘基不導致DMCL損失。亦已報導抗體醣基化影響抗體依賴性細胞毒性(ADCC)。具體而言,報導具有四環素調節之β(1,4)-N-乙醯基葡糖胺基轉移酶III (GnTIII,催化平分型GlcNAc形成之醣基轉移酶)表現之CHO細胞具有改良之ADCC活性(Umana等人(1999) Mature Biotech. 17:176-180)。
抗體之醣基化通常係N-連接或O-連接。N-連接係指碳水化合物部分附接至天冬醯胺殘基之側鏈。三肽序列天冬醯胺-X-絲胺酸及天冬醯胺-X-蘇胺酸(其中X係除脯胺酸外之任何胺基酸)係將碳水化合物部分酶促附接至天冬醯胺側鏈之識別序列。因此,多肽中該等三肽序列中之任一者之存在皆產生潛在醣基化位點。O-連接醣基化係指糖N-乙醯半乳糖胺、半乳糖或木糖中之一者附接至羥基胺基酸,最常見為絲胺酸或蘇胺酸,但亦可使用5-羥基脯胺酸或5-羥基離胺酸。
抗體之醣基化變體係其中抗體之醣基化模式改變之變體。改變意指缺失一或多個發現於抗體中之碳水化合物部分,將一或多個碳水化合物部分添加至抗體,改變醣基化之組成(醣基化模式)、醣基化程度等。
將醣基化位點添加至抗體可藉由改變胺基酸序列使得其含有上述三肽序列中之一或多者來完成(對於N-連接醣基化位點)。該改變亦可藉由在將一或多個絲胺酸或蘇胺酸殘基添加至初始抗體序列中或藉由該一或多個絲胺酸或蘇胺酸殘基取代來達成(對於O-連接醣基化位點)。類似地,移除醣基化位點可藉由改變抗體天然醣基化位點內之胺基酸來完成。
胺基酸序列通常藉由改變基礎核酸序列來改變。該等方法包括自天然來源分離(在天然胺基酸序列變體情形中)或藉由抗體之較早製備之變體或非變體形式之寡核苷酸介導之(或定點)誘變、PCR誘變及盒式誘變來製備。
抗體之醣基化(包括醣基化模式)亦可在不改變胺基酸序列或基礎核苷酸序列之情況下改變。醣基化主要依賴於用於表現抗體之宿主細胞。由於用於表現作為潛在治療劑之重組體醣蛋白(例如抗體)之細胞類型很少為天然細胞,故可預期抗體醣基化模式之顯著變異。例如,參見Hse等人,(1997) J. Biol. Chem. 272:9062-9070。除了宿主細胞之選擇以外,在抗體之重組體產生期間影響醣基化之因素包括生長模式、培養基配方、培養密度、加氧作用、pH、純化方案及諸如此類。已提出多種改變在特定宿主生物體中達成之醣基化模式之方法,包括引入或過表現某些參與寡醣產生之酶(美國專利第5047335號;第5510261號;第5278299號)。醣基化或某些醣基化類型可以酶促方式自醣蛋白移除,例如使用內切醣苷酶H (Endo H)移除。另外,重組體宿主細胞可經遺傳改造,例如使得某些類型多醣之處理有缺陷。該等及類似技術為業內所熟知。
抗體之醣基化結構可容易地藉由習用碳水化合物分析技術來分析,包括凝集素層析、NMR、質譜、HPLC、GPC、單醣組成分析、連續酶消化及HPAEC-PAD (其使用高pH陰離子交換層析基於電荷來分離寡醣)。出於分析目的釋放寡醣之方法亦為人已知,且包括(但不限於)酶處理(通常使用肽-N-醣苷酶F/內切-β-半乳糖苷酶來實施)、使用嚴苛的鹼性環境消除以主要釋放O-連接結構及使用無水肼釋放N-及O-連接寡醣二者之化學方法。
抗體醣基化修飾之較佳形式係還原核心岩藻醣基化。「核心岩藻醣基化」係指將岩藻糖(「岩藻醣基化」)添加至N-連接聚醣之還原性末端之N-乙醯基葡糖胺(「GlcNAc」)。
「複合N-醣苷連接之糖鏈」通常結合至天冬醯胺297 (根據Kabat編號)。如本文所用複合N-醣苷連接之糖鏈具有主要具有以下結構之二天線複合糖鏈:
其中±指示糖分子可存在或不存在,且數字指示糖分子之間之連接位置。在上文結構中,結合至天冬醯胺之糖鏈末端稱為還原性末端(在右側),且對側稱為非還原性末端。岩藻糖通常結合至還原性末端之N-乙醯基葡糖胺(「GlcNAc」),通常藉由α1,6鍵(GlcNAc之6位連接至岩藻糖之1位)結合。「Gal」係指半乳糖,且「Man」係指甘露糖。
「複合N-醣苷連接之糖鏈」包括1) 複合型,其中核心結構之非還原性末端側具有半乳糖-N-乙醯基葡糖胺(亦稱為「gal-GlcNAc」)之一或多個分支,且Gal-GlcNAc之非還原性末端側視情況具有唾液酸、平分型N-乙醯基葡糖胺或諸如此類;或2) 雜合型,其中核心結構之非還原性末端側具有高甘露糖N-醣苷連接之糖鏈及複合N-醣苷連接之糖鏈之兩個分支。
在一些實施例中,「複合N-醣苷連接之糖鏈」包括複合型,其中核心結構之非還原性末端側具有0個、1個或多個半乳糖-N-乙醯基葡糖胺(亦稱為「gal-GlcNAc」)之分支,且Gal-GlcNAc之非還原性末端側視情況進一步具有例如唾液酸、平分型N-乙醯基葡糖胺或諸如此類之結構。
根據本發明方法,通常僅少量岩藻糖納入人類化、嵌合或飾面SG16.17或SG16.45抗體之複合N-醣苷連接之糖鏈中。舉例而言,在多個實施例中,少於60%、少於50%、少於40%、少於30%、少於20%、少於15%、少於10%、少於5%或少於3%之抗體分子具有岩藻糖之核心岩藻醣基化。在一些實施例中,約2%之抗體分子具有岩藻糖之核心岩藻醣基化。
在某些實施例中,僅少量岩藻糖類似物(或岩藻糖類似物之代謝物或產物)納入複合N-醣苷連接之糖鏈中。舉例而言,在多個實施例中,少於約60%、少於約50%、少於約40%、少於約30%、少於約20%、少於約15%、少於約10%、少於約5%或少於約3%之人類化、嵌合或飾面SG16.17或SG16.45抗體具有岩藻糖類似物或岩藻糖類似物之代謝物或產物之核心岩藻醣基化。在一些實施例中,約2%之人類化、嵌合或飾面SG16.17抗體具有岩藻糖類似物或岩藻糖類似物之代謝物或產物之核心岩藻醣基化。
藉由用岩藻糖類似物培育產生抗體之細胞來製備非岩藻糖基化抗體之方法闡述於例如WO2009/135181中。簡言之,在岩藻糖類似物或岩藻糖類似物之細胞內代謝物或產物之存在下培育已經工程化以表現人類化、嵌合或飾面SG16.17抗體之細胞。細胞內代謝物可為例如GDP修飾之類似物或完全或部分去酯化類似物。產物可為例如完全或部分去酯化類似物。在一些實施例中,岩藻糖類似物可抑制岩藻糖再利用路徑中之酶。舉例而言,岩藻糖類似物(或岩藻糖類似物之細胞內代謝物或產物)可抑制岩藻糖激酶(fucokinase)或GDP-岩藻糖-焦磷酸化酶之活性。在一些實施例中,岩藻糖類似物(或岩藻糖類似物之細胞內代謝物或產物)抑制岩藻糖基轉移酶(較佳1,6-岩藻糖基轉移酶,例如FUT8蛋白質)。在一些實施例中,岩藻糖類似物(或岩藻糖類似物之細胞內代謝物或產物)可抑制岩藻糖之重新合成路徑中之酶之活性。舉例而言,岩藻糖類似物(或岩藻糖類似物之細胞內代謝物或產物)可抑制GDP-甘露糖4,6-去水酶及/或GDP-岩藻糖合成酶之活性。在一些實施例中,岩藻糖類似物(或岩藻糖類似物之細胞內代謝物或產物)可抑制岩藻糖運輸蛋白(例如,GDP-岩藻糖運輸蛋白)。
在一個實施例中,岩藻糖類似物係2-氟岩藻糖。使用生長培養基中之岩藻糖類似物及其他岩藻糖類似物之方法揭示於例如WO/2009/135181中,其係以引用方式併入本文中。
用於工程化細胞系以降低核心岩藻醣基化之其他方法包括基因剔除、基因敲入及RNA干擾(RNAi)。在基因剔除中,使編碼FUT8 (α 1,6-岩藻糖基轉移酶)之基因不活化。FUT8催化將岩藻糖基殘基自GDP-岩藻糖轉移至N-聚醣之Asn連接(N-連接) GlcNac之位置6。報導FUT8係唯一負責將岩藻糖添加至Asn297之N-連接二天線碳水化合物之酶。基因敲入添加編碼酶(例如GNTIII或高爾基體α甘露糖苷酶II)之基因。細胞中該等酶之含量增加使單株抗體自岩藻醣基化路徑轉向(導致核心岩藻醣基化減少),且具有增加量之平分型N-乙醯基葡糖胺。RNAi通常亦靶向FUT8基因表現,導致降低mRNA轉錄物含量或完全敲除基因表現。該等方法中之任一者可用於生成能產生非岩藻糖基化抗體(例如人類化、嵌合或飾面SG16.17抗體)之細胞系。
可使用多種方法測定抗體上之岩藻醣基化之量。方法包括例如經由PLRP-S層析之LC-MS及電噴霧離子化四極TOF MS。
IV.
核酸本發明進一步提供編碼上文所述人類化重鏈及輕鏈中之任一者之核酸。通常,核酸亦編碼融合至成熟重鏈及輕鏈之信號肽。核酸上之編碼序列可與調節序列可操作連接以確保編碼序列(例如啟動子、增強子、核糖體結合位點、轉錄終止信號及諸如此類)之表現。編碼重鏈及輕鏈之核酸可以經分離形式存在或可選殖至一或多個載體中。核酸可藉由例如固態合成或重疊寡核苷酸之PCR來合成。編碼重鏈及輕鏈之核酸可例如在表現載體內接合為一個鄰接核酸,或可分開,例如各自選殖至其自有表現載體中。
V.
抗體藥物偶聯物抗MCMA抗體可偶聯至細胞毒性部分以形成抗體-藥物偶聯物(ADC)。用於偶聯至抗體之尤其適宜部分係細胞毒性劑(例如,化學治療劑)、前藥轉化酶、放射性同位素或化合物或毒素(該等部分被統稱為治療劑或藥物)。舉例而言,抗BCMA抗體可偶聯至細胞毒性劑,例如化學治療劑或毒素(例如,細胞生長抑制或殺細胞劑,例如相思子素、蓖麻毒蛋白A、假單胞菌屬(pseudomonas)外毒素或白喉毒素)。可用細胞毒性劑類別之實例包括例如DNA小溝黏合劑、DNA烷基化劑及微管蛋白抑制劑。實例性細胞毒性劑包括例如奧裡斯他汀(auristatin)、喜樹鹼(camptothecin)、多卡米星(duocarmycin)、依託泊苷(etoposide)、美登素(maytansine)及類美登素(maytansinoid,例如,DM1及DM4)、紫杉烷、苯并二氮呯(例如,吡咯并[1,4]苯并二氮呯(PBD)、吲哚啉基苯并二氮呯及噁唑啶基苯并二氮呯)及長春花生物鹼。用於將治療劑偶聯至蛋白質、且尤其偶聯至抗體之技術眾所周知。(例如,參見Alley等人,
Current Opinion in Chemical Biology2010 14:1-9;Senter,
Cancer J., 2008, 14(3):154-169。)
治療劑(例如,細胞毒性劑)可以除非其自抗體脫離(例如,藉由水解、藉由抗體降解或藉由裂解劑)否則降低抗體活性之方式偶聯至抗體。該治療劑可經由連接體附接至抗體。偶聯至連接體之治療劑在本文中亦稱為藥物連接體。連接體之性質可廣泛變化。構成連接體之組分可基於其特徵來選擇,此可部分取決於將偶聯物遞送至其之位點之條件。
治療劑可經對表現抗BCMA之癌細胞之細胞內環境中之裂解敏感但對細胞外環境顯著不敏感之可裂解連接體附接至抗體,使得偶聯物在其由表現抗BCMA之癌細胞內化(例如,在胞內體中,或例如由於pH敏感性或蛋白酶敏感性,在溶酶體環境中或在胞膜窖環境中)時自抗體裂解。治療劑亦可以不可裂解連接體附接至抗體。
如所指示,連接體可包含可裂解單元。在一些所述實施例中,可裂解單元之結構及/或序列經選擇使得其由存在於靶位點(例如,靶細胞)之酶的作用而被裂解。在其他實施例中,亦可使用可藉由pH變化(例如酸或鹼不穩定)、溫度或在輻照後(例如光不穩定)裂解之可裂解單元。
在一些實施例中,可裂解單元可包含一個胺基酸或胺基酸之鄰接序列。胺基酸序列可為酶之靶受質。
在一些態樣中,可裂解單元係肽基單元且長為至少兩個胺基酸。裂解劑可包括細胞自溶酶B及D及胞漿素(例如,參見Dubowchik及Walker, 1999,
Pharm.
Therapeutics83:67-123)。更典型者係可藉由存在於表現抗BCMA之細胞中之酶裂解之可裂解單元,即酶可裂解連接體。因此,連接體可藉由細胞內肽酶或蛋白酶(包括溶酶體或胞內體蛋白酶)裂解。舉例而言,可使用可藉由在癌性組織中大量表現之硫醇依賴性蛋白酶細胞自溶酶-B裂解之連接體(例如,包含Phe-Leu或Val-Cit肽或Val-Ala肽之連接體)。
在一些實施例中,連接體將包含可裂解單元(例如,肽基單元)且可裂解單元將直接偶聯至治療劑。在其他實施例中,可裂解單元將經由額外功能性單元(例如自消性間隔體單元或非自消性間隔體單元)偶聯至治療劑。非自消性間隔體單元係其中一部分或全部間隔體單元在可裂解單元(例如胺基酸)自抗體藥物偶聯物裂解後仍保持結合至藥物單元之間隔體單元。為釋放藥物,在靶細胞內發生獨立水解反應以自藥物裂解間隔體單元。
使用自消性間隔體單元,無需藥物之單獨水解步驟即可釋放藥物。在一個實施例中,其中連接體包含可裂解單元及自消性基團,可裂解單元可藉由酶作用裂解,且在可裂解單元裂解後,自消性基團釋放治療劑。在一些實施例中,連接體之可裂解單元將在一端直接或間接偶聯至治療劑且在另一端將直接或間接偶聯至抗體。在一些所述實施例中,可裂解單元將在一端直接或間接(例如,經由自消性或非自消性間隔體單元)偶聯至治療劑且在另一端將經由延伸體單元偶聯至抗體。延伸體單元將抗體連接至藥物其餘部分及/或藥物連接體。在一個實施例中,抗體與藥物其餘部分或藥物連接體之連接係經由馬來醯亞胺基團、例如經由馬來醯亞胺基己醯基連接體進行。在一些實施例中,抗體將經由二硫化物連接至藥物,例如二硫化物連接之類美登素偶聯物SPDB-DM4及SPP-DM1。
抗體與連接體之間之連接可經由多種不同途徑(例如經由硫醚鍵、經由二硫鍵、經由醯胺鍵或經由酯鍵)來進行。在一個實施例中,抗BCMA抗體與連接體之間之連接係在抗體之半胱胺酸殘基之硫醇基團與連接體之馬來醯亞胺之間形成。在一些實施例中,在與連接體之官能基反應之前,抗體之鏈間鍵轉化為游離硫醇基團。在一些實施例中,將半胱胺酸殘基引入抗體重鏈或輕鏈中並與連接體反應。藉由抗體重鏈或輕鏈中之取代插入半胱胺酸之位置包括闡述於以下文獻中之彼等:已公開美國申請案第2007-0092940號及國際專利公開案WO2008070593,其各自以全文且出於所有目的以引用方式併入本文中。
在一些實施例中,抗體-藥物偶聯物具有下式I:
L - (LU-D)
p(I)
其中L係抗BCMA抗體,LU係連接體單元且D係藥物單元(即,治療劑)。下標p在1至20範圍內。該等偶聯物包含經由連接體共價連接至至少一種藥物之抗BCMA抗體。連接體單元在一端連接至抗體且在另一端連接至藥物。
載藥量表示為p,即每抗體之藥物分子數。載藥量可在1至20個藥物單元(D)/抗體範圍內。在一些態樣中,下標p將在1至20範圍內(即,1至20之整數及非整數值二者)。在一些態樣中,下標p將為1至20之整數,且將表示單一抗體上之藥物-連接體數。在其他態樣中,p表示每抗體之藥物-連接體分子之平均數,例如反應混合物或組合物(例如,醫藥組合物)中每抗體之藥物-連接體之平均數,且可為整數或非整數值。因此,在一些態樣中,對於組合物(例如,醫藥組合物),p代表組合物中抗體-藥物偶聯物之平均載藥量,且p在1至20範圍內。
在一些實施例中,p為約1至約8個藥物/抗體。在一些實施例中,p為1。在一些實施例中,p為2。在一些實施例中,p為約2至約8個藥物/抗體。在一些實施例中,p為約2至約6、2至約5、或2至約4個藥物/抗體。在一些實施例中,p為約2、約4、約6或約8個藥物/抗體。
來自偶聯反應之製劑中每個抗體單元之藥物平均數可藉由習用方式來表徵,例如質譜術、ELISA分析、HIC及HPLC。亦可測定以p表示之偶聯物之定量分佈。
實例性抗體-藥物偶聯物包括基於奧裡斯他汀之抗體-藥物偶聯物,即其中藥物組分係奧裡斯他汀藥物之偶聯物。奧裡斯他汀結合微管蛋白,已顯示可干擾微管動力學及細胞核及細胞分裂,且具有抗癌活性。通常,基於奧裡斯他汀之抗體-藥物偶聯物包含奧裡斯他汀藥物與抗BCMA抗體之間之連接體。奧裡斯他汀可在適於偶聯至連接體之任一位置連接至抗BCMA抗體。連接體可為例如可裂解連接體(例如,肽基連接體)或不可裂解連接體(例如,藉由抗體降解而釋放之連接體)。奧裡斯他汀可為奧裡斯他汀E或其衍生物。奧裡斯他汀可為(例如)在奧裡斯他汀E與酮酸之間形成之酯。例如,可使奧裡斯他汀E與對乙醯基苯甲酸或苯甲醯基戊酸反應以分別產生AEB及AEVB。其他典型奧裡斯他汀包括MMAF (單甲基奧裡斯他汀F)及MMAE (單甲基奧裡斯他汀E)。實例性奧裡斯他汀之合成及結構闡述於美國公開案第7,659,241號、第7,498,298號、第2009-0111756號、第2009-0018086號及第7,968,687號中,其各自以其全文且出於所有目的以引用方式併入本文中。
實例性基於奧裡斯他汀之抗體-藥物偶聯物包括如下文所示之vcMMAE、vcMMAF及mcMMAF抗體-藥物偶聯物,其中Ab係如本文所述之抗體且val-cit代表纈胺酸-瓜胺酸二肽:
Ab-vcMMAE
Ab-vcMMAF
Ab-mcMMAF
或其醫藥上可接受之鹽。載藥量表示為p,即每抗體之藥物-連接體分子數。端視情況,p可表示每抗體之藥物-連接體分子之平均數,亦稱為平均載藥量。變量p在1至20範圍內且較佳為1至8。在一些較佳實施例中,在p表示平均載藥量時,p在約2至約5範圍內。在一些實施例中,p為約2、約3、約4或約5。在一些態樣中,抗體經由半胱胺酸殘基之硫原子偶聯至連接體。在一些態樣中,半胱胺酸殘基係工程化至抗體中之殘基。在其他態樣中,半胱胺酸殘基係鏈間二硫化物半胱胺酸殘基。
實例性抗體-藥物偶聯物包括基於PBD之抗體-藥物偶聯物;即其中藥物組分係PBD藥物之抗體-藥物偶聯物。
PBD具有以下通用結構:
。
其不同之處在於其芳香族A環及吡咯并C環中取代基之數目、類型及位置以及C環之飽和度。在B環中在N10-C11位置存在亞胺(N=C)、甲醇胺(NH-CH(OH))或甲醇胺甲醚(NH-CH(OMe)),該位置係負責烷基化DNA之親電子中心。所有已知天然產物皆在手性C11a位置具有(S)構形,此使其在自C環朝向A環觀看時具有右撚。此使其具有對於等螺旋性適當之具有B型DNA小溝之三維形狀,從而在結合位點導致適貼配合。PBD在小溝中形成加成物之能力使得其能干擾DNA處理,因此使得其能用作抗腫瘤劑。
該等分子之生物活性可藉由將兩個PBD單元藉助其C8/C’-羥基官能基經由撓性伸烷基連接體接合在一起來強化。認為PBD二聚體可形成序列選擇性DNA損傷,例如復發性5’-Pu-GATC-Py-3’鏈間交聯,認為該鏈間交聯主要負責其生物活性。
在一些實施例中,基於PBD之抗體-藥物偶聯物包含連接至抗BCMA抗體之PBD二聚體。形成PBD二聚體之單體可相同或不同,即對稱或不對稱。PBD二聚體可在適於偶聯至連接體之任一位置連接至抗BCMA抗體。舉例而言,在一些實施例中,PBD二聚體將具有在C2位置之取代基,其為將化合物連接至抗BCMA抗體提供錨。在替代實施例中,PBD二聚體之N10位置將為將化合物連接至抗BCMA抗體提供錨。
通常,基於PBD之抗體-藥物偶聯物包含PBD藥物與抗BCMA抗體之間之連接體。連接體可包含可裂解單元(例如,胺基酸或胺基酸之鄰接序列,其係酶之靶受質)或不可裂解連接體(例如,藉由抗體降解而釋放之連接體)。連接體可進一步包含用於連接至抗體之馬來醯亞胺基團,例如馬來醯亞胺基己醯基。在一些實施例中,連接體可進一步包含自消性基團,例如對胺基苄醇(PAB)單元。
用作偶聯物之實例性PBD闡述於國際申請案第WO 2011/130613號中且如下所示,其中波形線指示附接至連接體之位點:
或其醫藥上可接受之鹽。實例性連接體如下所示,其中波形線指示附接至藥物之位點,且抗體係經由馬來醯亞胺基團連接。
。
實例性基於PBD之抗體-藥物偶聯物包括如下所示之抗體-藥物偶聯物,其中Ab係如本文所述之抗體:
或其醫藥上可接受之鹽。載藥量表示為p,即每抗體之藥物-連接體分子數。端視情況,p可表示每抗體之藥物-連接體分子之平均數,亦稱為平均載藥量。變量p在1至20範圍內且較佳為1至8。在一些較佳實施例中,在p表示平均載藥量時,p在約2至約5範圍內。在一些實施例中,p為約2、約3、約4或約5。在一些態樣中,抗體經由工程化至抗體中之半胱胺酸殘基之硫原子偶聯至藥物連接體。在一些態樣中,半胱胺酸殘基在位置239工程化至抗體中(IgG1),如藉由EU索引所確定(Kabat,
Sequences of Proteins of Immunological Interest(國立衛生研究院, Bethesda, MD, 1987及1991))。
VI.
免疫病症或表現 BCMA 之癌症之動物模型可在免疫病症或表現BCMA之癌症之動物模型中測試或驗證抗BCMA抗體或衍生物。全身性及器官特異性自體免疫疾病(包括糖尿病、狼瘡、全身性硬化、薛格連氏症候群、實驗性自體免疫腦脊髓炎(多發性硬化)、甲狀腺炎、重症肌無力、關節炎、眼色素層炎、發炎性腸病)之動物模型之實例已闡述於以下文獻中:Bigazzi, 「Animal Models of Autoimmunity: Spontaneous and Induced」,The Autoimmune Diseases (Rose及Mackay編輯,Academic Press, 1998)及「Animal Models for Autoimmune and Inflammatory Disease」,Current Protocols in Immunology (Coligan等人編輯,Wiley and Sons, 1997)。
過敏性病況(例如氣喘及皮膚炎)亦可在齧齒類動物中建模。氣道過敏性可在小鼠中藉由卵白蛋白(Tomkinson等人,2001, J. Immunol. 166:5792-800)或曼森氏住血吸蟲(Schistosoma mansoni)卵抗原(Tesciuba等人,2001, J. Immunol. 167:1996-2003)誘導。小鼠之Nc/Nga品系顯示血清IgE之顯著增加且自發發展異位性皮膚炎樣病灶(Vestergaard等人,2000, Mol. Med. Today 6:209-10;Watanabe等人,1997, Int. Immunol. 9:461-66;Saskawa等人,2001, Int. Arch. Allergy Immunol. 126:239-47)。
將免疫勝任之供體淋巴球注射至經致死輻照之組織不相容宿主中係在小鼠中誘導GVHD之古典方法。或者,親代B6D2F1鼠類模型提供系統以誘導急性及慢性GVHD二者。在此模型中,B6D2F1小鼠係來自C57BL/6及DBA/2小鼠之親代品系之間之雜交之F1後代。將DBA/2淋巴樣細胞轉移至未經輻照之B6D2F1小鼠引起慢性GVHD,而轉移C57BL/6、C57BL/10或B10.D2淋巴樣細胞引起急性GVHD (Slayback等人,2000, Bone Marrow Transpl. 26:931-938;Kataoka等人,2001, Immunology 103:310-318)。
另外,可將人類造血幹細胞及成熟末梢血淋巴樣細胞植入SCID小鼠中,且該等人類淋巴造血細胞在SCID小鼠中保持功能(McCune等人,1988, Science 241:1632-1639;Kamel-Reid及Dick, 1988, Science 242:1706-1709;Mosier等人,1988, Nature 335:256-259)。此提供小型動物模型系統用於直接測試對人類淋巴樣細胞之潛在治療劑。(例如,參見Tournoy等人,2001, J. Immunol. 166:6982-6991)。
此外,可藉由將表現BCMA之人類腫瘤細胞系植入適當免疫缺陷齧齒類動物品系(例如,無胸腺裸小鼠或SCID小鼠)中來創建小型動物模型以檢查抗BCMA抗體或衍生物之活體內功效。表現BCMA之人類淋巴瘤細胞系之實例包括例如Daudi (Ghetie等人,1994, Blood 83:1329-36;Ghetie等人,1990, Int. J. Cancer 15:481-85;de Mont等人,2001, Cancer Res. 61:7654-59)、Ramos (Ma等人,2002, Leukemia 16:60-6;Press等人,2001, Blood 98:2535-43)、HS-Sultan (Cattan及Maung, 1996, Cancer Chemother. Pharmacol. 38:548-52;Cattan及Douglas, 1994, Leuk. Res. 18:513-22)、Raji (Ochakovskaya等人,2001, Clin. Cancer Res. 7:1505-10;Breisto等人,1999, Cancer Res. 59:2944-49)及CA46 (Kreitman等人,1999, Int. J. Cancer 81:148-55)。表現BCMA之霍奇金氏淋巴瘤譜系之非限制性實例係L540cy (Barth等人,2000, Blood 95:3909-14;Wahl等人,2002, Cancer Res. 62:3736-42)。表現BCMA之人類腎細胞癌細胞系之非限制性實例包括786-O (Ananth等人,1999, Cancer Res. 59:2210-16;Datta等人,2001, Cancer Res. 61:1768-75)、ACHN (Hara等人,2001, J. Urol. 166:2491-94;Miyake等人,2002, J. Urol. 167:2203-08)、Caki-1 (Prewett等人,1998, Clin. Cancer Res. 4:2957-66;Shi及Siemann, 2002, Br. J. Cancer 87:119-26)及Caki-2 (Zellweger等人,2001, Neoplasia 3:360-67)。表現BCMA之鼻咽癌細胞系之非限制性實例包括C15及C17 (Busson等人,1988, Int. J. Cancer 42:599-606;Bernheim等人,1993, Cancer Genet. Cytogenet. 66:11-5)。表現BCMA之人類神經膠質瘤細胞系之非限制性實例包括U373 (Palma等人,2000, Br. J. Cancer 82:480-7)及U87MG (Johns等人,2002, Int. J. Cancer 98:398-408)。該等腫瘤細胞系可作為實體腫瘤藉由皮下注射或作為播散性腫瘤藉由靜脈內注射在免疫缺陷齧齒類動物宿主中建立。在宿主內建立後,可將該等腫瘤模型應用於評估如本文所述之抗BCMA抗體或衍生物對調節活體內腫瘤生長之治療功效。
VII.
治療應用本發明抗BCMA抗體可用於治療癌症。一些該等癌症顯示在蛋白質(例如,藉由免疫分析使用所例示抗體之一)或mRNA層面上量測之可檢測含量之BCMA。一些該等癌症顯示相對於相同類型、較佳來自相同患者之非癌性組織含量升高之BCMA。適於治療之癌細胞上之BCMA之實例性含量係5000-150000個BCMA分子/細胞,但可治療更高或更低含量。視情況,癌症中之BCMA含量係在實施治療前量測。
可用本發明抗體治療之癌症包括實體腫瘤及血液癌症,例如白血病及淋巴瘤。該等抗體尤其適用於B細胞之癌症。可用該等抗體治療之癌症的實例包括:成人及兒童急性骨髓性白血病(AML)、慢性骨髓性白血病(CML)、急性淋巴球性白血病(ALL)、慢性淋巴球性白血病(CLL)及繼發性白血病;非霍奇金氏淋巴瘤(NHL)及霍奇金氏病;骨髓發育不良症候群(MDS)、骨髓增生性症候群(MPS)、多發性骨髓瘤、華氏巨球蛋白血症或柏基特淋巴瘤、惡性漿細胞瘤、BCMA+高惡性度淋巴瘤、卡勒氏病(Kahler's disease)及骨髓瘤病;漿細胞白血病;漿細胞瘤;B細胞幼淋巴球性白血病;毛細胞白血病;濾泡性淋巴瘤(包括濾泡性非霍奇金氏淋巴瘤類型);柏基特淋巴瘤(地方性柏基特淋巴瘤;散發性柏基特淋巴瘤);邊緣區淋巴瘤(黏膜相關淋巴樣組織;MALT 1 MALToma;單核細胞樣B細胞淋巴瘤;具有伴絨毛淋巴球之脾淋巴瘤);外套細胞淋巴瘤;大細胞淋巴瘤(瀰漫性大細胞;瀰漫性混合細胞;免疫母細胞淋巴瘤;原發性縱膈B細胞淋巴瘤;血管中心性淋巴瘤肺B細胞);小淋巴球性淋巴瘤(SLL);前體B-淋巴母細胞性淋巴瘤;骨髓性白血病(顆粒球;骨髓性;急性骨髓性白血病;慢性骨髓性白血病;亞急性骨髓性白血病;骨髓性肉瘤;綠色瘤;顆粒球型肉瘤;急性前骨髓細胞性白血病;急性骨髓單核球性白血病);瓦登斯特隆巨球蛋白血症(Waldenstrom's macroglobulinemia)或其他B細胞白血病或淋巴瘤。
本發明抗體亦可用於由表現BCMA之免疫細胞介導之免疫病症、尤其B細胞介導病症。該等疾病之實例包括類風濕性關節炎、全身性紅斑狼瘡(SLE)、I型糖尿病、氣喘、異位性皮膚炎、過敏性鼻炎、血小板減少紫斑症、多發性硬化、牛皮癬、薛格連氏症候群、橋本氏甲狀腺炎、格雷氏病、原發性膽汁性肝硬化、韋格納肉芽腫、結核症及移植物抗宿主病、免疫介導之血小板減少症、溶血性貧血、大皰性類天皰瘡、重症肌無力、格雷氏病(Graves' disease)、艾迪森氏病(Addison's disease)、落葉型天皰瘡、牛皮癬、牛皮癬關節炎及關節黏連性脊椎炎。
單獨的或作為其藥物偶聯物之抗BCMA抗體係以延遲癌症之至少一個體徵或症狀之發作、降低其嚴重性、抑制其進一步劣化及/或加以改善之有效方案(意指劑量、投與途徑及投與頻率)投與。若患者已患有癌症,則該方案可稱為治療有效方案。若患者相對於一般群體具有升高之癌症風險但尚未經歷症狀,則該方案可稱為預防有效方案。在一些情況下,治療或預防效能可在個別患者中相對於歷史對照或相同患者之過去經歷而觀察到。在其他情況下,治療或預防效能可在經治療患者群體之臨床前或臨床試驗中相對於未經治療患者之對照群體來證實。
單株抗體之實例性劑量係0.1 mg/kg至50 mg/kg患者體重,更通常1 mg/kg至30 mg/kg、1 mg/kg至20 mg/kg、1 mg/kg至15 mg/kg、1 mg/kg至12 mg/kg、或1 mg/kg至10 mg/kg、或2 mg/kg至30 mg/kg、2 mg/kg至20 mg/kg、2 mg/kg至15 mg/kg、2 mg/kg至12 mg/kg、或2 mg/kg至10 mg/kg、或3 mg/kg至30 mg/kg、3 mg/kg至20 mg/kg、3 mg/kg至15 mg/kg、3 mg/kg至12 mg/kg、或3 mg/kg至10 mg/kg。作為固定劑量,其活性單株抗體-藥物偶聯物(例如奧裡斯他汀)之實例性劑量係1 mg/kg至7.5 mg/kg、或2 mg/kg至7.5 mg/kg或3 mg/kg至7.5 mg/kg個體體重,或0.1-20或0.5-5 mg/kg體重(例如,0.5、1、2、3、4、5、6、7、8、9或10 mg/kg)或10-1500或200-1500 mg。其高活性單株抗體-藥物偶聯物(例如PBD)之實例性劑量係1.0 µg/kg至1.0 mg/kg、或1.0 µg/kg至500.0 µg/kg個體體重。在一些方法中,隨後每兩週、每三週或每四週向患者投與抗體或ADC。除其他因素外,劑量尤其取決於投與頻率、患者之狀況及對先前治療(若存在)之反應、治療係預防性抑或治療性、及病症係急性抑或慢性。
投與可為非經腸、靜脈內、經口、皮下、動脈內、顱內、鞘內、腹膜內、局部、鼻內或肌內。投與亦可直接集中於腫瘤中。藉由靜脈內或皮下投與來投與至體循環中較佳。靜脈內投與可例如藉由經例如30-90 min時段輸注或藉由單次濃注注射來實施。
除其他因素外,投與頻率尤其取決於抗體或抗體-藥物偶聯物在循環中之半衰期、患者之狀況及投與途徑。頻率可為每天、每週、每月、每季或因應患者狀況或所治療癌症之進展以不規律間隔投與。靜脈內投與之實例性頻率介於在連續療程期間一週兩次與每季之間,但較高或較低頻率之給藥亦係可能的。靜脈內投與之其他實例性頻率介於在連續療程期間每週一次或每月一次之間,但較高或較低頻率之給藥亦係可能的。對於皮下投與,實例性給藥頻率係每天至每月,但較高或較低頻率之給藥亦係可能的。
所投與劑量數取決於癌症或自體免疫疾病之性質(例如,呈現急性抑或慢性症狀)及病症對治療之反應。對於急性病症或慢性病症之急性惡化,介於1次劑量與10次劑量之間通常足夠。有時視情況呈分開形式之單次濃注劑量對於急性病症或慢性病症之急性惡化係足夠的。對於急性病症或急性惡化之復發可重複治療。對於慢性病症,抗體可以規律間隔投與,例如每週、每兩週、每月、每季、每六個月,持續至少1、5或10年或患者之生命。
非經腸投與之醫藥組合物較佳無菌且實質上等滲且在GMP條件下製造。醫藥組合物可以單位劑型(即,用於單次投與之劑量)提供。醫藥組合物可使用一或多種生理上可接受之載劑、稀釋劑、賦形劑或輔助劑來調配。調配取決於所選投與途徑。對於注射,抗體可在水溶液中、較佳在生理相容緩衝液(例如漢克氏溶液(Hank’s solution)、林格氏溶液(Ringer’s solution)或生理鹽水或乙酸鹽緩衝液)中調配(以降低注射部位的不適感)。溶液可含有調配劑,例如懸浮劑、穩定劑及/或分散劑。或者,抗體可呈凍乾形式用於在使用前用適宜媒劑(例如無菌無熱原水)構成。抗體在液體調配物中之濃度可為例如0.01-10 mg/ml,例如1.0 mg/ml。
用本發明抗體治療可與化學療法、輻射、幹細胞治療、手術或針對所治療病症有效之其他治療組合。可與針對BCMA之抗體一起投與之其他藥劑之有用類別包括例如針對癌細胞上表現之其他受體之抗體、抗微管蛋白劑(例如,奧裡斯他汀)、DNA小溝黏合劑(例如,PBD)、DNA複製抑制劑、烷基化劑(例如,鉑錯合物,例如順鉑、單(鉑)、雙(鉑)及三核鉑錯合物及卡鉑)、蒽環、抗生素、抗葉酸劑、抗代謝物、化學療法敏化劑、多卡米星、依託泊苷、氟化嘧啶、離子載體、來西托辛(lexitropsin)、亞硝基脲、鉑帝爾(platinol)、預成型化合物、嘌呤抗代謝物、嘌呤黴素、輻射敏化劑、類固醇、紫杉烷、拓樸異構酶抑制劑、長春花生物鹼及諸如此類。剛剛提及之用於癌症之相同其他治療亦可用於免疫介導病症。用於免疫介導病症之其他藥劑包括免疫抑制劑,例如肥胖細胞去粒化抑制劑、抗組織胺、皮質類固醇、NSAID、硫唑嘌呤、環磷醯胺、瘤克寧(leukeran)及環孢素;及生物抗炎劑,例如Tysabri®或Humira®。
與不使用抗BCMA抗體之相同治療(例如,化學療法)相比,視情況與上述任何其他藥劑或方案組合之使用單獨或作為抗體-藥物偶聯物之抗BCMA抗體之治療可將癌症患者(尤其在復發或難治時)之中值無進展存活或總體存活時間增加至少30%或40%,但較佳50%、60%至70%或甚至100%或更長。另外或或者,與不使用抗BCMA抗體之相同治療(例如,化學療法)相比,包括單獨或作為抗體-藥物偶聯物之抗BCMA抗體之治療(例如,標準化學療法)可將腫瘤患者之完全反應率、部分反應率或客觀反應率(完全+部分)增加至少30%或40%,但較佳50%、60%至70%或甚至100%。
通常,在臨床試驗(例如,II期、II/III期或III期試驗)中,相對於僅接受標準療法(或加安慰劑)之患者之對照組,經標準療法加抗BCMA抗體治療之患者之上文所提及之中值無進展存活及/或反應率之增加在統計學上顯著,例如在p = 0.05或0.01或甚至0.001程度。完全及部分反應率係藉由癌症臨床試驗中常用之客觀準則來測定,例如如國家癌症研究院及/或食品藥品管理局所列示或認可之客觀準則。
VIII.
其他應用本文所揭示之抗BCMA抗體可用於在臨床診斷或治療情況下或研究中檢測BCMA。癌症中BCMA之表現提供指示,該癌症適於用本發明抗體來治療。抗體亦可作為研究試劑來出售,用於實驗室研究中檢測攜帶BCMA之細胞及其對各種刺激之反應。在該等應用中,單株抗體可經螢光分子、自旋標記分子、酶或放射性同型標記,且可以含有實施BCMA分析之所有所需試劑之套組形式來提供。抗體亦可用於例如藉由親和層析純化BCMA蛋白。
除非另有明確指示,否則本發明之任何特徵、步驟、要素、實施例或態樣可與任何其他特徵、步驟、要素、實施例或態樣組合使用。儘管已出於清晰理解之目的藉助闡釋及實例略微詳細地闡述了本發明,但顯而易見,可在隨附申請專利範圍之範疇內實踐某些變化及修改。
實例 實例 1 :抗體研發 重組體 BCMA 細胞外結構域 (BCMA ECD) 之製備 人類(胺基酸1-51)及小鼠BCMA (胺基酸1-46)之細胞外結構域(ECD)經選殖並表現為GST融合蛋白(pGEX4T1;Amersham Biosciences)。純化BCMA ECD係藉由用麩胱甘肽-瓊脂糖捕獲BCMA融合蛋白且藉由用凝血酶進行蛋白酶消化釋放BCMA ECD來獲得。隨後藉由苯甲脒瓊脂糖移除凝血酶。
惡性 B 細胞系上 BCMA 表現之鑑別 使用Vicky-1對多發性骨髓瘤細胞系實施定量流式細胞術,該Vicky-1係針對BCMA之市售抗體(Alexis Biotechnology)。結果顯示,BCMA在所測試骨髓瘤系中普遍存在。NCI H929顯示針對BCMA之陽性細胞表面染色,但缺少BR3或TACI之表現。由於NCI H929表現BCMA但不表現BR3或TACI,故其可用於BCMA雜交瘤之基於細胞之篩選。
經轉染 BCMA 細胞系之研發 . 藉由用全長BCMA純系或空載體轉染HEK 293細胞來研發穩定細胞系。流式細胞術確認BCMA在BCMA轉染(293: BCMA)而非載體空對照質體(293: 載體)之表面上之陽性表現。隨後使用該等細胞系作為工具確認經選殖BCMA抗體之特異性。
實例 2 :未經選殖雜交瘤孔之免疫及篩選 抗血清之免疫及篩選 本發明免疫策略使用BCMA ECD之胺基酸1-50,使得抗體可靶向配體結合結構域內部及外部之表位(圖1A及1B)。KLH偶聯之BCMA ECD係自商業來源(Alexis Biochemicals)生成。用KLH偶聯之BCMA使用Titermax佐劑對大鼠進行免疫,直至藉由ELISA檢測到最大免疫反應為止。在基於板之分析中亦針對阻斷APRIL結合之能力篩選經免疫大鼠血清。選擇大鼠2-3用於融合,此乃因抗血清具有人類BCMA抗體之顯著效價且其顯示穩健阻斷活性。
如所述採集來自大鼠2-3之脾細胞,融合至X-63.Ag8.653.3.12.11小鼠骨髓瘤細胞並加以選擇(Goding, 1989)。藉由ELISA使用純化hBCMA-GST篩選來自所得雜交瘤之培養上清液(見圖2中之流程圖)。鑑別並選擇80個陽性孔用於擴增。藉由擴增後之ELISA,80個陽性孔中的60個孔繼續顯示OD > 0.5。然後在二次分析中針對基於細胞之結合、配體阻斷活性及與小鼠BCMA之交叉反應性篩選該60個未選殖雜交瘤孔。此導致鑑別12個主要BCMA雜交瘤孔。來自該12個主要孔之細胞結合資料及配體阻斷活性歸納於圖3中。雜交瘤孔17顯示代替市售單株Vicky-1 (Alexis Biochemicals)之細胞結合及配體阻斷活性。採用8個孔(在圖3中以紅色星號指示)用於基於其結合BCMA陽性細胞或阻斷配體結合之能力進行選殖。
實例 3 :純系雜交瘤之表徵 細胞結合及配體阻斷活性 . 取雜交瘤孔11、17、20、29、40、45及70經過2輪有限稀釋選殖。自此時起,抗體將以表1中所示之正式純系ID命名。抗體與293:BCMA細胞而非與293:載體對照細胞之特異性結合確認,該等抗體結合至BCMA。
表 1 :正式純系 ID.
使用來自未選殖母孔之上清液、來自經選殖孔之上清液及來自經選殖孔之純化抗體比較新BCMA抗體之配體阻斷活性(圖4)。使用市售抗體作為陽性對照。SG-16.17使用來自經選殖雜交瘤孔之培養上清液給予對APRIL結合之顯著阻斷。在單獨實驗中使用純化SG16.17及市售抗體實施對APRIL結合之SG16.17阻斷之滴定(圖5)。在與市售抗體相比時,純化SG16.17在類似濃度之間顯示改良阻斷活性。SG-16.45顯示對April結合之劑量依賴性抑制,但並非如同SG-16.17一般強。其餘BCMA抗體(SG-16.11、SG16.20、SG16.29、SG16.40及SG16.70)之配體阻斷活性更弱。某些阻斷性BCMA抗體顯示對APRIL結合之>75%抑制,如使用SG-16.17所觀察。包括SG-16.11、SG-16.20、SG-16.29、SG-16.40及SG-16.70之更「弱」阻斷性抗體顯示對APRIL結合之約30%抑制(圖4)。
亦在純化BCMA抗體之存在及不存在下分析BAFF結合經固定BCMA之能力。用BCMA抗體SG16.17、SG16.40、SG16.20及SG17.70預處理皆導致對BAFF與BCMA之結合之可滴定抑制(圖6)。藉由在抗體處理不存在下使BAFF結合至經固定BCMA來測定相對抑制(圖6,星號)。綜上所述,圖5及6中之資料顯示,BCMA抗體可阻斷APRIL及BAFF與BCMA之配體結合且由此干擾B細胞存活信號。
實例 4 :測試 SG16.17 及 SG16.45 抗體作為 ADC 之 ADCC 及細胞毒性藉由將大鼠V
H及V
L結構域分別融合至野生型人類IgG1重鏈及κ輕鏈恆定結構域中來將SG16.17抗體轉化至大鼠-人類嵌合IgG中。命名為cSG16.17野生型之嵌合抗體在與親代抗體SG16.17相比時顯示類似抗原結合性質。隨後,設置已知可增強ADCC之Fc突變S239D:A330L:I332E以生成cSG16.17突變體。與cSG16.17野生型類似,Fc三重突變體之生成不改變cSG16.17突變體之抗原結合性質。在使用純化天然殺手細胞之ADCC分析中評估cSG16.17野生型及cSG16.17突變體導致JJN3及U266細胞之劑量依賴性溶解,而使用非結合性人類IgG對照未觀察到顯著溶解。cSG16.17野生型抗體顯示對JJN3細胞之有限ADCC活性,cSG16.17突變體使其功效增加約100倍且效能增加>2倍(最大溶解)。類似地,對於U266細胞,與親代嵌合抗體相比,cSG16.17突變體之ADCC活性之功效增強約100倍且效能增強2倍。JJN3及U266細胞二者之最大溶解所需cSG16.17突變體之濃度為約100 pmol/L。與之相比, cSG16.17對JJN3及U266細胞之解離常數(
K D)分別估計為15 nmol/L及10 nmol/L。因此,在遠低於達到飽和結合所需濃度之濃度下達成藉由cSG16.17突變體之最大溶解。
本發明使用vcMMAF以8個藥物/抗體之化學計量學評價SG16.17及SG16.45作為ADC誘導細胞毒性之能力。SG16.17或SG16.45-vcMMAF8具有針對H929細胞之潛在細胞毒性。使用非結合性對照ADC或未偶聯抗體未觀察到細胞存活率下降。亦檢查SG16.17 ADC在其他MM細胞系(包括JJN3及U266細胞系)中之功效。SG16.17-vcMMAF8在所有三個MM細胞系中顯示恆定高功效(IC
50值≤130 pmol/L),而SG16.45-vcMMAF8顯示更高可變性及較低總體功效。
實例 5 :測試 SG16.17 抗體與 Fcγ
RIIIa 之結合及經由 Fcγ
RIIIa 之信號傳導對於結合分析,用FcγRIIIa (hCD16)轉染CHO細胞且在與具有野生型IgG1及IgG1 S239D、A330L、I332E基因型之嵌合SG16.17及多種IgG1對照抗體之競爭下量測經標記h00抗體之結合。圖12顯示,嵌合SG16.17較兩種對照抗體利妥昔單抗(rituximab)及cOKT9更強地競爭。SG16.17之突變體形式較野生型IgG1形式更強地競爭。信號傳導分析使用表現BCMA之U266靶細胞、表現FcγRIIIa且經工程化以表現來自NFAT反應元件之螢光素酶報導基因之Jurkat效應細胞及Bio-Glo指示劑。cSG16.17 G1 WT及S239D、A330L、I332E二者皆引發FcγRIIIa信號傳導,且來自S239D、A330L、I332E形式之FcγRIIIa信號傳導更強(圖13)。
實例 6 : SG16.17 之人類化 表 2 : hSG16.17 重鏈變體中之人類化突變
表 3 : hSG16.17 κ 輕鏈變體中之人類化突變
表 4 : hSG16.17 重鏈變體中之特異性框架突變
*大鼠殘基
表 5 : hSG16.17 κ 輕鏈變體中之特異性框架突變
*大鼠殘基
對表現SG16.17之大鼠雜交瘤之大鼠重鏈及輕鏈可變區進行測序。使用HV1-2/HJ3 (SEQ ID NO: 9)或HV1-46/HJ3 (SEQ ID NO: 10)作為重鏈之人類接受體序列且使用KV1-12/KJ5 (SEQ ID NO: 18)作為輕鏈之人類接受體序列。
大鼠供體與人類接受體序列之間不同之位置包括H8、H20、H48、H67、H69、H71、H76、H78、H80、H88、H91、H93、L40、L46、L48、L78、L85及L87。不同人類化重鏈及輕鏈序列中包括該等殘基之不同排列作為回復突變。亦針對用人類接受體序列中之相應殘基替代來測試Kabat CDR中之若干個大鼠殘基。該等殘基之位置係H34、H50、H58、H60、H61、H62、H64及H65以及L24及L53。設計並表現6個人類化重鏈變體及4個人類化輕鏈變體。表2及3指示每一人類化變體鏈中之人類接受體序列、回復突變(供體框架殘基)及CDR取代(接受體CDR殘基)。表4及5指示在每一人類化變體鏈中佔據認為用於回復突變之每一位置之胺基酸。該等表格亦指示與最接近之人類種系序列一致之殘基百分比。根據最新INN導則,盡在重鏈及輕鏈二者中具有與人類種系序列至少85%一致性之抗體可稱為經人類化。圖7-9顯示人類化重鏈可變區與大鼠可變區及人類接受體序列之比對。圖10及11顯示人類化輕鏈可變區與大鼠可變區及人類接受體序列之比對。可變輕鏈之C-末端精胺酸(R)可替代地視為輕鏈恆定區之N-末端精胺酸。
以所有24個可能排列測試6個人類化重鏈及4個人類化輕鏈與NCI-H929細胞上表現之BCMA之結合,該等NCI-H929細胞表現約50,000個BCMA分子/細胞。結果顯示於下表6中。簡言之,所有人類化輕鏈皆顯示良好結合。在人類化重鏈中,變體VH1、VH3及VH5皆顯示與嵌合或大鼠SG16.17抗體相比改良之結合。
表 6 :結合至 NCI-H929 細胞上表現之 BCMA 之人類化抗體 hSG16.17
在全範圍濃度點下進一步測試在NCI-H929分析中表現最佳之人類化抗體(即,含有VH1、VH3或VH5重鏈之彼等)與U266細胞之結合。在此分析中,含有VH1重鏈(不管包括何種人類化輕鏈變體)之人類化抗體顯示相對於大鼠或嵌合SG16.17增強之結合。含有VH3或VH5重鏈(不管包括何種人類化輕鏈變體)之人類化抗體顯示在實驗誤差內與大鼠或嵌合SG16.17結合相同之結合。含有VH2或VH6可變區之人類化抗體(不管包括何種人類化輕鏈變體)顯示相對於大鼠或嵌合SG16.17降低之結合。
亦針對蛋白質表現程度、單體含量及與人類種系之序列一致性百分比來比較在NCI-H929分析中表現最佳之人類化抗體,如下表7中所示。
表 7 :
選擇VH3 VK2人類化抗體作為主要人類化抗體,此係基於其與大鼠及小鼠SG16.17抗體對人類BCMA具有相同結合親和性(在實驗誤差內);在重鏈及輕鏈可變區二者中與人類種系序列之大於85%一致性、良好表現及高單體百分比。
實例 7 : SG16.45 之人類化 表 8 : hSG16.45 重鏈變體中之人類化突變
表 9 : hSG16.45 κ 輕鏈變體中之人類化突變
表 10 : hSG16.45 重鏈變體中之特異性框架突變
*大鼠殘基
表 11 : hSG16.45 κ 輕鏈變體中之特異性框架突變
*大鼠殘基
對表現SG16.45之大鼠雜交瘤之大鼠重鏈及輕鏈可變區進行測序。使用HV3-23/HJ3 (SEQ ID NO: 24)作為重鏈之人類接受體序列且使用KV3-20/KJ2 (SEQ ID NO: 34)作為輕鏈之人類接受體序列。
在大鼠供體與人類接受體序列之間不同之可變區框架位置包括H30、H37、H48、H67、H93、H94及H107以及位置L14、L19、L21、L38、L58、L71及L78。不同人類化重鏈及輕鏈序列中包括該等殘基之不同排列作為回復突變。亦針對用人類接受體序列中之相應殘基替代來測試Kabat CDR中之若干大鼠殘基。該等殘基之位置係H50、H60、L24及L26。設計並表現6個人類化重鏈變體及4個人類化輕鏈變體。表8及9指示每一人類化變體鏈中之人類接受體序列、回復突變(供體框架殘基)及CDR取代(接受體CDR殘基)。表10及11指示在每一人類化變體鏈中佔據認為用於回復突變之每一位置之胺基酸。該等表格亦指示與最接近之人類種系序列一致之殘基之百分比。根據最新INN導則,盡在重鏈及輕鏈二者中與人類種系序列具有至少85%一致性之抗體可稱為經人類化。圖14-17顯示人類化重鏈可變區與大鼠可變區及人類接受體序列之比對。圖18及19顯示輕鏈可變區之比對。可變輕鏈之C-末端精胺酸(R)可替代地視為輕鏈恆定區之N-末端精胺酸。
以所有24種可能排列針對與NCI-H929細胞上表現之BCMA之結合測試6個人類化重鏈及4個人類化輕鏈,該等NCI-H929細胞表現約50,000個BCMA分子/細胞。結果顯示於下表12中。
表 12 :結合至 NCI-H929 細胞上表現之 BCMA 之人類化抗體 hSG16.45
在全範圍濃度點下進一步測試在NCI-H929分析中表現最佳之人類化抗體與U266細胞之結合、以及表現及單體含量、以及與人類種系之序列一致性(表13)。
表 13 :
總體上基於對人類之結合親和性、在重鏈及輕鏈可變區二者中與人類種系序列之序列一致性、良好表現及高單體百分比,VH5 VK2、VH1 VK1及VH1 VK3係最佳抗體。VH1 VK1及VH1 VK3具有略高結合(在實驗誤差內與大鼠或嵌合相同)但與人類種系之序列一致性較低。
實例 8 :減少岩藻糖基化 hSG16.17 或 hSG16.45 抗體之合成在CHO細胞中表現hSG16.17 VH3 VK2或hSG16.45 VH5 VK2抗體。在抗體產生期間在細胞培養基中包括岩藻醣基化抑制劑2-氟岩藻糖得到非岩藻糖基化抗體。例如,參見Okeley等人,
Proc. Nat’l Acad. Sci.110:5404-55409 (2013)。用於細胞生長之基礎培養基不含岩藻糖且將2-氟岩藻糖添加至培養基以抑制蛋白質岩藻醣基化。同上。將岩藻糖納入抗體中係藉由LC-MS經由PLRP-S層析及電噴霧離子化四極桿TOF MS來量測。同上。
實例 9 : hSG16.17-SEA 在 SCID 或 NSG 小鼠中之活體內活性圖20A-C顯示多次投藥之hSG16.17-SEA在SCID小鼠之MM1S播散性腫瘤模型中之活體內活性。在動物中植入MM1S細胞IV,且在植入後9天起始抗體給藥。隨時間跟蹤動物存活。N=8隻動物/組。BCMA拷貝數=7,000,CD38拷貝數= 14,000。A) 1mg/kg每週ip持續5週,B) 3mg/kg每週ip持續5週,及C) 10 mg/kg每週ip持續5週。SCID動物含有效應細胞以介導ADCC及ADCP。此圖中之資料顯示,hSG16.17 SEA改良與達雷木單抗(daratumumab,CD38靶向Ab)相當之存活。非結合性h00對照顯示無活性。
圖21A-C顯示單次投藥之hSG16.17-SEA在NSG小鼠之EJM播散性腫瘤模型中之活體內活性。NSG動物不含NK細胞且含有活性極小之巨噬細胞。在動物中植入EJM細胞IV,且在植入後5天ip給予單一劑量之抗體。隨時間跟蹤動物存活。N=8隻動物/組。BCMA拷貝數=45,000。CD38拷貝數=47,000。CS1拷貝數= 14,000。A) 1mg/kg劑量,B) 3mg/kg劑量,C) 10 mg/kg劑量。此圖中之資料顯示,hSG16.17 SEA增加存活至等於或大於達雷木單抗(CD38靶向Ab)及埃羅妥珠單抗(elotuzumab,CS1靶向Ab)之程度。WT SG16.17亦可誘導存活增加。非結合性h00對照在最高劑量下顯示無活性。由於該等動物中效應細胞極少,WT及SEA hSG16.17抗體之活性可能係由於阻斷APRIL及BAFF增殖信號所致。
圖22顯示多次投藥之hSG16.17-SEA在NSG小鼠之NCI-H929-螢光素酶播散性腫瘤模型中之活體內活性。在NSG動物中植入NCI-H929螢光素酶細胞。在植入後21天在骨髓中觀察到生物發光時起始抗體給藥。每週ip給藥總計5次劑量。N=5隻動物/組。BCMA拷貝數=25,000。CD38拷貝數=45,000。CS1拷貝數= 3,000。與未經治療且首次用於實驗之動物相比較繪製平均發光相對於時間之圖。hSG16.17 SEA顯示與達雷木單抗(CD38靶向Ab)及埃羅妥珠單抗(CS1靶向Ab)相比顯著更佳之活性。在hSG16.17-SEA 10mg/kg組中觀察到之增加之發光係由單一動物驅動。
圖23A及23B顯示單次投藥之hSG16.17-SEA在NSG小鼠之NCI-H929-螢光素酶播散性腫瘤模型中之活體內活性。在NSG動物中植入NCI-H929螢光素酶細胞。在注射後21天在骨髓中觀察到生物發光時起始抗體給藥。IP給藥一次。N=5隻動物/組。A) 3mg/kg WT相對於SEA抗體。B) hSG16.17 SEA之劑量範圍。此圖中之資料顯示,hSG16.17 SEA可在0.3mg/kg單一劑量下具有活性且hSG16.17SEA之活性可高於其WT (岩藻糖基化)對應體。對發光之效應轉化為延長的動物存活(數據未顯示)。
圖24單次投藥之hSG16.17-SEA在SCID小鼠之MOLP-8-螢光素酶播散性腫瘤模型中之活體內活性。在SCID動物中IV植入MOLP-8螢光素酶細胞。在注射後13天在骨髓中觀察到生物發光時起始抗體給藥。IP給藥一次。N=5隻動物/組。BCMA拷貝數=2,000。繪製發光相對於時間之圖。該等資料顯示,即使僅使用2000個BCMA拷貝,hSG16.17-SEA亦顯示顯著抗腫瘤活性。不結合FcγRII或FcγRIII之去醣基化SEA BCMA抗體顯示無活性,與h00 SEA非結合性對照類似。此揭示Fc介導活性在此模型中之重要性。
圖25 SG16.17 SEA抗體顯示與WT抗體相比在活體外改良之對MM1R靶細胞之ADCC活性。NK細胞係經由負向選擇使用EasySep人類NK細胞富集套組自PBMC分離,且對所得CD16+細胞進行定量。用鉻-51將多發性骨髓瘤MM1R ADCC靶細胞標記1 hr。將一系列抗體稀釋物添加至分析板,之後以13:1 E:T比率添加靶細胞(T)及NK效應細胞(E)。在37℃下4hr後基於總計及自發釋放對照來計算溶解。該等資料顯示無岩藻醣基化SEA SG16.17抗體之ADCC活性相對於WT抗體以及臨床抗體(達雷木單抗及埃羅妥珠單抗)顯著改良。
儘管已出於清晰理解之目的詳細闡述本發明,但在隨附申請專利範圍之範疇內可實踐某些修改。在本申請案中引用之所有出版物(包括登記號、網站及諸如此類)及專利文件係出於所有目的全文以引用方式併入本文中,其併入程度如同各自如此個別指明一般。在序列、網站或其他參考文獻在不同時間可存在不同版本之情形下,意指在有效申請日與該參考文獻相關之版本。有效申請日期意指揭示所述登錄號之最早優先日期。除非上下文另有明確說明,否則本發明之任何要素、實施例、步驟、特徵或態樣可與任何其他要素、實施例、步驟、特徵或態樣組合實施。
未經選殖之命名 | 經選殖ID |
11 | SG16.11 |
17 | SG16.17 |
20 | SG16.20 |
29 | SG16.29 |
40 | SG16.40 |
45 | SG16.45 |
70 | SG16.70 |
vH 變體 | HV 外顯子接受體序列 | 供體框架殘基 | 接受體 CDR 殘基 |
hvH1 | HV1-2/HJ3 | H8、H20、H48、H67、H69、H71、H73、H76、H80、H88、H91、H93 | 無 |
hvH2 | HV1-2/HJ3 | H20、H48、H69、H71、H73、H76、H80、H88、H91、H93 | H34、H50、H58、H60、H61、H62、H64、H65 |
hvH3 | HV1-2/HJ3 | H20、H48、H67、H69、H71、H73、H76、H80、H88、H91、H93 | H58、H60、H61、H62、H64、H65 |
hvH4 | HV1-2/HJ3 | H48、H67、H69、H71、H73、H76、H80、H88、H91、H93 | H34、H50、H58、H60、H61、H62、H64、H65 |
hvH5 | HV1-46/HJ3 | H48、H67、H71、H73、H76、H78、H80、H91、H93 | 無 |
hvH6 | HV1-46/HJ3 | H8、H20、H48、H71、H73、H76、H78、H80、H91、H93 | 無 |
vK 變體 | KV 外顯子接受體序列 | 供體框架殘基 | 接受體 CDR 殘基 |
hVK2 | KV1-12/KJ5 | L46、L48、L87 | L53 |
hVK3 | KV1-12/KJ5 | L46、L48、L87 | L24、L53 |
hVK4 | KV1-12/KJ5 | L46、L48、L78、L85、L87 | 無 |
hVK5 | KV1-12/KJ5 | L40、L46、L48、L87 | L24、L53 |
變體 | H8 | H20 | H48 | H67 | H69 | H71 | H73 | H76 | H78 | H80 | H88 | H91 | H93 | 人類 % |
hvH1 | R* | L* | I* | A* | M* | A* | K* | N* | A | V* | A* | F* | T* | 79.6 |
hvH2 | G | L* | I* | V | M* | A* | K* | N* | A | V* | A* | F* | T* | 88.8 |
hvH3 | G | L* | I* | A* | M* | A* | K* | N* | A | V* | A* | F* | T* | 86.7 |
hvH4 | G | V | I* | A* | M* | A* | K* | N* | A | V* | A* | F* | T* | 88.8 |
hvH5 | G | V | I* | A* | M | A* | K* | N* | A* | V* | A | F* | T* | 78.6 |
hvH6 | R* | L* | I* | V | M | A* | K* | N* | A* | V* | A | F* | T* | 85.7 |
變體 | L40 | L46 | L48 | L78 | L85 | L87 | 人類 % |
hvK2 | P | V* | V* | L | T | F* | 86.3 |
hvK3 | P | V* | V* | L | T | F* | 87.4 |
hvK4 | P | V* | V* | M* | D* | F* | 83.2 |
hvK5 | S* | V* | V* | L | T | F* | 86.3 |
hSG16.17 | vH | vK | NCI-H929 3-pt 分析 | |
1 | vH1 | vK2 | ++++ | |
2 | vH1 | vK3 | ++++ | |
3 | vH1 | vK4 | ++++ | |
4 | vH1 | vK5 | ++++ | |
5 | vH2 | vK2 | - | |
6 | vH2 | vK3 | - | |
7 | vH2 | vK4 | - | |
8 | vH2 | vK5 | - | |
9 | vH3 | vK2 | ++++ | |
10 | vH3 | vK3 | ++++ | |
11 | vH3 | vK4 | ++++ | |
12 | vH3 | vK5 | ++++ | |
13 | vH4 | vK2 | - | |
14 | vH4 | vK3 | - | |
15 | vH4 | vK4 | - | |
16 | vH4 | vK5 | - | |
17 | vH5 | vK2 | ++++ | |
18 | vH5 | vK3 | ++++ | |
19 | vH5 | vK4 | ++++ | |
20 | vH5 | vK5 | ++++ | |
21 | vH6 | vK2 | ++ | |
22 | vH6 | vK3 | ++ | |
23 | vH6 | vK4 | ++ | |
24 | vH6 | vK5 | ++ | |
cSG16.17 | +++ | |||
rSG16.17 | +++ | |||
hSG16.17 | vH | vK | hBCMA 結合 | 瞬時效價 (mg/L) | aSEC ( 單體 %) | ≥ 85% 人類 (vH 、 vK) 及 INN 命名 | 主要選擇 | ||
1 | vH1 | vK2 | ++++ | 139 | 90.4 | 79.6 | 86.3 | 混合 | Y |
2 | vH1 | vK3 | ++++ | 126 | 89.6 | 79.6 | 87.4 | 混合 | Y |
3 | vH1 | vK4 | ++++ | 80 | 94.6 | 79.6 | 83.2 | 嵌合 | N |
4 | vH1 | vK5 | ++++ | 119 | 89.5 | 79.6 | 86.3 | 混合 | N |
9 | vH3 | vK2 | ++++ | 129 | 94.1 | 86.7 | 86.3 | 人類化 | Y |
10 | vH3 | vK3 | ++++ | 116 | 94.1 | 86.7 | 87.4 | 人類化 | Y |
11 | vH3 | vK4 | ++++ | 82 | 95.2 | 86.7 | 83.2 | 混合 | Y |
12 | vH3 | vK5 | ++++ | 117 | 93.5 | 86.7 | 86.3 | 人類化 | Y |
17 | vH5 | vK2 | ++++ | 97 | 96.2 | 78.6 | 86.3 | 混合 | Y |
18 | vH5 | vK3 | ++++ | 86 | 96.1 | 78.6 | 87.4 | 混合 | Y |
19 | vH5 | vK4 | ++++ | 65 | 96.5 | 78.6 | 83.2 | 嵌合 | N |
20 | vH5 | vK5 | ++++ | 73 | 95.0 | 78.6 | 86.3 | 混合 | Y |
vH 變體 | HV 外顯子接受體序列 | 供體框架殘基 | 接受體 CDR 殘基 |
hvH1 | HV3-23/HJ3 | H30、H37、H48、H93、H94、H107 | 無 |
hvH2 | HV3-23/HJ3 | H30、H37、H48、H93、H94、H107 | H50、H60 |
hvH3 | HV3-23/HJ3 | H30、H37、H48、H76、H93、H94、H107 | H50、H60 |
hvH4 | HV3-23/HJ3 | H30、H48、H76、H93、H94 | H50 |
hvH5 | HV3-74/HJ3 | H30、H93、H94 | H50 |
hvH6 | HV3-9/HJ3 | H30、H93、H94 | H50、H60 |
vK 變體 | KV 外顯子接受體序列 | 供體框架殘基 | 接受體 CDR 殘基 |
hvK1 | KV3-20/KJ2 | L14、L19、L21、L38、L58、L71、L78 | L24、L26 |
hvK2 | KV3-20/KJ2 | 無 | L24、L26 |
hvK3 | KV3-20/KJ2 | L21、L38、L58、L71 | L24、L26 |
hvK5 | KV3-20/KJ2 | L38、L71 | 無 |
變體 | H30 | H37 | H48 | H76 | H93 | H94 | H107 | 人類 % |
hvH1 | N* | I* | I* | N | T* | S* | V* | 86.5 |
hvH2 | N* | I* | I* | N | T* | S* | V* | 88.5 |
hvH3 | N* | I* | I* | S* | T* | S* | V* | 87.5 |
hvH4 | N* | V | I* | S* | T* | S* | T | 87.5 |
hvH5 | N* | V | V | N | T* | S* | T | 88.5 |
hvH6 | N* | V | V | N | T* | S* | T | 88.5 |
變體 | L14 | L19 | L21 | L38 | L58 | L71 | L78 | 人類% |
hvK1 | A* | V* | I* | H* | V* | Y* | M* | 79.2 |
hvK2 | L | A | L | Q | I | F | L | 86.5 |
hvK3 | L | A | I* | H* | V* | Y* | L | 82.3 |
hvK5 | L | A | L | H* | I | Y* | L | 82.3 |
hSG16.45 | vH | vK | NCI-H929 3-pt 分析 |
1 | vH1 | vK1 | +++ |
2 | vH1 | vK2 | +++ |
3 | vH1 | vK3 | +++ |
4 | vH1 | vK5 | +++ |
5 | vH2 | vK1 | - |
6 | vH2 | vK2 | - |
7 | vH2 | vK3 | - |
8 | vH2 | vK5 | - |
9 | vH3 | vK1 | - |
10 | vH3 | vK2 | - |
11 | vH3 | vK3 | - |
12 | vH3 | vK5 | ++ |
13 | vH4 | vK1 | + |
14 | vH4 | vK2 | + |
15 | vH4 | vK3 | + |
16 | vH4 | vK5 | ++ |
17 | vH5 | vK1 | ++ |
18 | vH5 | vK2 | ++ |
19 | vH5 | vK3 | ++ |
20 | vH5 | vK5 | ++ |
21 | vH6 | vK1 | + |
22 | vH6 | vK2 | + |
23 | vH6 | vK3 | + |
24 | vH6 | vK5 | ++ |
cSG16.45 | +++ | ||
rSG16.45 | +++ |
hSG16.45 | VH | VK | hBCMA | IgG mg | aSEC% | VH% | VK% | INN |
1 | VH1 | VK1 | +++ | 0.67 | 94.5 | 86.5 | 79.2 | 混合 |
3 | VH1 | VK3 | +++ | 0.54 | 94.6 | 86.5 | 82.3 | 混合 |
4 | VH1 | VK5 | +++ | 0.16 | 76.0 | 86.5 | 82.3 | 混合 |
17 | VH5 | VK1 | ++ | 0.64 | 94.4 | 88.5 | 79.2 | 混合 |
18 | VH5 | VK2 | ++ | 0.65 | 93.7 | 88.5 | 86.5 | Hu |
19 | VH5 | VK3 | ++ | 0.64 | 94.1 | 88.5 | 82.3 | 混合 |
圖1A顯示BCMA之結構。
圖1B顯示BCMA之細胞外結構域與BAFF之結構相互作用。
圖2顯示抗體選擇程序。
圖3顯示未選殖雜交瘤孔之細胞結合資料及配體阻斷活性。
圖4顯示抗BCMA抗體之阻斷活性/抑制百分比。
圖5顯示經抗BCMA抗體滴定之對APRIL阻斷之抑制。
圖6顯示使用抗BCMA抗體對BAFF阻斷之滴定。
圖7顯示hSG16.17重鏈變體與人類VH接受體序列HV1-2/HJ3之比對。其顯示具有Kabat CDR (SEQ ID No: 39-41)及IMGT CDR (SEQ ID NO: 42及43)之大鼠SG16.17 vH (SEQ ID NO: 8);具有Kabat CDR (SEQ ID NO: 44及45)及IMGT CDR (SEQ ID NO: 46及「AR」)之Hu HV1-2/HJ3 (SEQ ID NO: 9);具有Kabat CDR (SEQ ID NO: 50-52)及IMGT CDR (SEQ ID NO: 53及54)之hSG16.17 vH1 (SEQ ID NO: 11);具有Kabat CDR (SEQ ID NO: 55-57)及IMGT CDR (SEQ ID NO: 58及59)之hSG16.17 vH2 (SEQ ID NO: 12);具有Kabat CDR (SEQ ID NO: 60-62)及IMGT CDR (SEQ ID NO: 63及64)之hSG16.17 vH3 (SEQ ID NO: 13);以及具有Kabat CDR (SEQ ID NO: 65-67)及IMGT CDR (SEQ ID NO: 68及69)之hSG16.17 vH4 (SEQ ID NO: 14)。
圖8顯示hSG16.17重鏈變體與人類VH接受體序列HV1-46/HJ3之比對。其顯示以下之序列:具有Kabat CDR (SEQ ID NO: 39-41)及IMGT CDR (SEQ ID NO: 42及43)之大鼠SG16.17 vH (SEQ ID NO: 8);具有Kabat CDR (SEQ ID NO: 47及48)及IMGT CDR (SEQ ID NO: 49及「AR」)之Hu HV1-46/HJ3 (SEQ ID NO: 10);具有Kabat CDR (SEQ ID NO: 70-72)及IMGT CDR (SEQ ID NO: 73及74)之hSG16.17 vH5 (SEQ ID NO: 15);以及具有Kabat CDR (SEQ ID NO: 75-77)及IMGT CDR (SEQ ID NO: 78及79)之hSG16.17 vH6 (SEQ ID NO: 16)。
圖9顯示hSG16.17重鏈變體之比對。其顯示hSG16.17 vH1-6 (SEQ ID NO: 11-16)之序列。
圖10顯示hSG16.17輕鏈變體與人類VK接受體序列KV1-12/KJ5之比對。其顯示以下之序列:具有Kabat CDR (SEQ ID NO: 80-82)及IMGT CDR (分別SEQ ID NO: 83、「TTS」及SEQ ID NO: 84)之大鼠SG16.17 vK (SEQ ID NO: 17);具有Kabat CDR (SEQ ID NO: 85-87)及IMGT CDR (分別SEQ ID NO: 88、「AAS」及SEQ ID NO: 89)之Hu KV1-12/KJ5 (SEQ ID NO: 18);具有Kabat CDR (SEQ ID NO: 90-92)及IMGT CDR (分別SEQ ID NO: 93、「TTS」及SEQ ID NO: 94)之hSG16.17 vK2 (SEQ ID NO: 19);具有Kabat CDR (SEQ ID NO: 95-97)及IMGT CDR (分別SEQ ID NO: 98、「TTS」及SEQ ID NO: 99)之hSG16.17 vK3 (SEQ ID NO: 20);具有Kabat CDR (SEQ ID NO. 100-102)及IMGT CDR (分別SEQ ID NO: 103、「TTS」及SEQ ID NO: 104)之hSG16.17 vK4 (SEQ ID NO: 21);以及具有Kabat CDR (SEQ ID NO: 105-107)及IMGT CDR (分別SEQ ID NO: 108、「TTS」及SEQ ID NO: 109)之hSG16.17 vK5(SEQ ID NO: 22)。
圖11顯示hSG16.17輕鏈變體之比對。其顯示hSG16.17 vK2、vK3、vK4、vK5 (SEQ ID NO: 19-22)之序列。
圖12顯示競爭結合分析,其顯示嵌合SG16.17與人類FcRIIIa之結合。
圖13顯示嵌合SG16.17誘導經由FcγRIIIA信號傳導。
圖14顯示hSG16.45重鏈變體與人類HV接受體序列HV3-23/HJ3之比對。其顯示以下之序列:具有Kabat CDR (SEQ ID NO: 110-112)及IMGT CDR (SEQ ID NO: 113-115)之大鼠SG16.45 vH (SEQ ID NO: 23);具有Kabat CDR (SEQ ID NO: 116及117)及IMGT CDR (分別SEQ ID NO: 118及119及「AK」)之Hu HV3-23/HJ3 (SEQ ID NO: 24);具有Kabat CDR (SEQ ID NO: 128-130)及IMGT CDR (SEQ ID NO: 131-133)之hSG16.45 vH1 (SEQ ID NO: 27);具有Kabat CDR (SEQ ID NO: 134-136)及IMGT CDR (SEQ ID NO: 137-139)之hSG16.45 vH2 (SEQ ID NO: 28);具有Kabat CDR (SEQ ID NO: 140-142)及IMGT CDR (SEQ ID NO: 143-145)之hSG16.45 vH3 (SEQ ID NO: 29);以及具有Kabat CDR (SEQ ID NO: 146-148)及IMGT CDR (SEQ ID NO: 149-151)之hSG16.45 vH4 (SEQ ID NO: 30)。
圖15顯示hSG16.45重鏈變體與人類HV接受體序列HV3-74/HJ3之比對。其顯示以下之序列:具有Kabat CDR (SEQ ID NO: 110-112)及IMGT CDR (SEQ ID NO: 113-115)之大鼠SG16.45 vH (SEQ ID NO: 23);具有Kabat CDR (SEQ ID NO: 120及121)及IMGT CDR (分別SEQ ID NO: 122及123及「AR」)之Hu HV3-74/HJ3 (SEQ ID NO: 25);具有Kabat CDR (SEQ ID NO: 152-154)及IMGT CDR (SEQ ID NO: 155-157)之hSG16.45 vH5 (SEQ ID NO: 31)。
圖16顯示hSG16.45重鏈變體與人類HV接受體序列HV3-9/HJ3之比對。其顯示以下之序列:具有Kabat CDR (SEQ ID NO: 110-112)及IMGT CDR (SEQ ID NO: 113-115)之大鼠SG16.45 vH (SEQ ID NO: 23);具有Kabat CDR (SEQ ID NO: 124及125)及IMGT CDR (分別SEQ ID NO: 126及127及「AR」)之Hu HV3-9/HJ3 (SEQ ID NO: 26);具有Kabat CDR (SEQ ID NO: 158-160)及IMGT CDR (SEQ ID NO: 161-163)之hSG16.45 vH6 (SEQ ID NO: 32)。
圖17顯示hSG16.45重鏈變體之比對。其顯示hSG16.45 vH1-6 (SEQ ID NO: 27-32)之序列。
圖18顯示hSG16.45輕鏈變體與人類KV接受體序列KV3-20/KJ2之比對。其顯示以下之序列:具有Kabat CDR (SEQ ID NO: 164-166)及IMGT CDR (分別SEQ ID NO: 167、「STS」及SEQ ID NO: 168)之大鼠SG16.45 vK (SEQ ID NO: 33);具有Kabat CDR (SEQ ID NO: 169-171)及IMGT CDR (分別SEQ ID NO: 172、「STS」及SEQ ID NO: 173)之Hu KV3-20/KJ2 (SEQ ID NO: 34);具有Kabat CDR (SEQ ID NO: 174-176)及IMGT CDR (分別SEQ ID NO: 177、「STS」及SEQ ID NO: 178)之hSG16.45 vK1 (SEQ ID NO: 35);具有Kabat CDR (SEQ ID NO: 179-181)及IMGT CDR (分別SEQ ID NO: 182、「STS」及SEQ ID NO: 183)之hSG16.45 vK2 (SEQ ID NO: 36);具有Kabat CDR (SEQ ID NO: 184-186)及IMGT CDR (分別SEQ ID NO: 187、「STS」及SEQ ID NO: 188)之hSG16.45 vK3 (SEQ ID NO: 37);以及具有Kabat CDR (SEQ ID NO: 189-191)及IMGT CDR (分別SEQ ID NO: 192、「STS」及SEQ ID NO: 193)之hSG16.45 vK5 (SEQ ID NO: 38)。
圖19顯示hSG16.45輕鏈變體之比對。其顯示hSG16.45 vK1、vK2、vK3、vK5 (SEQ ID NO: 35-38)之序列。
圖20A-C顯示多次投藥之hSG16.17-SEA在SCID小鼠中之MM1S播散性腫瘤模型中之活體內活性。
圖21A-C顯示單次投藥之hSG16.17-SEA在NSG小鼠中之EJM播散性腫瘤模型中之活體內活性。
圖22顯示多次投藥之hSG16.17-SEA在NSG小鼠中之NCI-H929-螢光素酶播散性腫瘤模型中之活體內活性。
圖23A-B顯示單次投藥之hSG16.17-SEA在NSG小鼠中之NCI-H929-螢光素酶播散性腫瘤模型中之活體內活性。
圖24提供單次投藥之hSG16.17-SEA在SCID小鼠中之MOLP-8-螢光素酶播散性腫瘤模型中之活體內活性。
圖25提供SG16.17 SEA抗體對MM1R靶細胞之ADCC活性。
<![CDATA[<110> 舒思曼 迪強格]]> 萊恩 穆林 維思登朵芙 蘿莉 菲爾德豪斯 邁可 <![CDATA[<120> BCMA抗體及其用於治療癌症及免疫病症之用途]]> <![CDATA[<130> 0269-00212PC]]> <![CDATA[<150> 62/396,084]]> <![CDATA[<151> 2016-09-16]]> <![CDATA[<150> 62/296,594 ]]> <![CDATA[<151> 2016-02-17 ]]> <![CDATA[<160> 193]]> <![CDATA[<170> FastSEQ for Windows Version 4.0]]> <![CDATA[<210> 1]]> <![CDATA[<211> 994]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 1]]> aagactcaaa cttagaaact tgaattagat gtggtattca aatccttagc tgccgcgaag 60 acacagacag cccccgtaag aacccacgaa gcaggcgaag ttcattgttc tcaacattct 120 agctgctctt gctgcatttg ctctggaatt cttgtagaga tattacttgt ccttccaggc 180 tgttctttct gtagctccct tgttttcttt ttgtgatcat gttgcagatg gctgggcagt 240 gctcccaaaa tgaatatttt gacagtttgt tgcatgcttg cataccttgt caacttcgat 300 gttcttctaa tactcctcct ctaacatgtc agcgttattg taatgcaagt gtgaccaatt 360 cagtgaaagg aacgaatgcg attctctgga cctgtttggg actgagctta ataatttctt 420 tggcagtttt cgtgctaatg tttttgctaa ggaagataaa ctctgaacca ttaaaggacg 480 agtttaaaaa cacaggatca ggtctcctgg gcatggctaa cattgacctg gaaaagagca 540 ggactggtga tgaaattatt cttccgagag gcctcgagta cacggtggaa gaatgcacct 600 gtgaagactg catcaagagc aaaccgaagg tcgactctga ccattgcttt ccactcccag 660 ctatggagga aggcgcaacc attcttgtca ccacgaaaac gaatgactat tgcaagagcc 720 tgccagctgc tttgagtgct acggagatag agaaatcaat ttctgctagg taattaacca 780 tttcgactcg agcagtgcca ctttaaaaat cttttgtcag aatagatgat gtgtcagatc 840 tctttaggat gactgtattt ttcagttgcc gatacagctt tttgtcctct aactgtggaa 900 actctttatg ttagatatat ttctctaggt tactgttggg agcttaatgg tagaaacttc 960 cttggtttca tgattaaact cttttttttc ctga 994 <![CDATA[<210> 2]]> <![CDATA[<211> 184]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 2]]> Met Leu Gln Met Ala Gly Gln Cys Ser Gln Asn Glu Tyr Phe Asp Ser 1 5 10 15 Leu Leu His Ala Cys Ile Pro Cys Gln Leu Arg Cys Ser Ser Asn Thr 20 25 30 Pro Pro Leu Thr Cys Gln Arg Tyr Cys Asn Ala Ser Val Thr Asn Ser 35 40 45 Val Lys Gly Thr Asn Ala Ile Leu Trp Thr Cys Leu Gly Leu Ser Leu 50 55 60 Ile Ile Ser Leu Ala Val Phe Val Leu Met Phe Leu Leu Arg Lys Ile 65 70 75 80 Asn Ser Glu Pro Leu Lys Asp Glu Phe Lys Asn Thr Gly Ser Gly Leu 85 90 95 Leu Gly Met Ala Asn Ile Asp Leu Glu Lys Ser Arg Thr Gly Asp Glu 100 105 110 Ile Ile Leu Pro Arg Gly Leu Glu Tyr Thr Val Glu Glu Cys Thr Cys 115 120 125 Glu Asp Cys Ile Lys Ser Lys Pro Lys Val Asp Ser Asp His Cys Phe 130 135 140 Pro Leu Pro Ala Met Glu Glu Gly Ala Thr Ile Leu Val Thr Thr Lys 145 150 155 160 Thr Asn Asp Tyr Cys Lys Ser Leu Pro Ala Ala Leu Ser Ala Thr Glu 165 170 175 Ile Glu Lys Ser Ile Ser Ala Arg 180 <![CDATA[<210> 3]]> <![CDATA[<211> 106]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 3]]> Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln 1 5 10 15 Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr 20 25 30 Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser 35 40 45 Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr 50 55 60 Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys 65 70 75 80 His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro 85 90 95 Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 100 105 <![CDATA[<210> 4]]> <![CDATA[<211> 330]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 4]]> Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60 Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys 100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 115 120 125 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 130 135 140 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 195 200 205 Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu 225 230 235 240 Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 305 310 315 320 Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 325 330 <![CDATA[<210> 5]]> <![CDATA[<211> 329]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 5]]> Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60 Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys 100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 115 120 125 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 130 135 140 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 195 200 205 Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu 225 230 235 240 Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 305 310 315 320 Gln Lys Ser Leu Ser Leu Ser Pro Gly 325 <![CDATA[<210> 6]]> <![CDATA[<211> 330]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 6]]> Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60 Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys 100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Pro Cys Val Phe Leu Phe Pro Pro 115 120 125 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 130 135 140 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 195 200 205 Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu 225 230 235 240 Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 305 310 315 320 Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 325 330 <![CDATA[<210> 7]]> <![CDATA[<211> 329]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 7]]> Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60 Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys 100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Pro Cys Val Phe Leu Phe Pro Pro 115 120 125 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 130 135 140 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 195 200 205 Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu 225 230 235 240 Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 305 310 315 320 Gln Lys Ser Leu Ser Leu Ser Pro Gly 325 <![CDATA[<210> 8]]> <![CDATA[<211> 121]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 褐鼠]]> <![CDATA[<400> 8]]> Gln Val Asn Leu Leu Gln Ser Arg Ala Ala Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Leu Ser Cys Glu Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Tyr Ile His Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile 35 40 45 Gly Tyr Ile Asn Pro Asn Ser Gly Tyr Thr Lys Tyr Asn Glu Asn Phe 50 55 60 Lys Thr Lys Ala Thr Met Thr Ala Asp Lys Ser Thr Asn Thr Ala Tyr 65 70 75 80 Val Glu Leu Ser Arg Leu Thr Ser Glu Asp Ser Ala Thr Tyr Phe Cys 85 90 95 Thr Arg Tyr Met Trp Glu Arg Val Thr Gly Phe Phe Asp Phe Trp Gly 100 105 110 Pro Gly Thr Lys Val Thr Val Ser Ser 115 120 <![CDATA[<210> 9]]> <![CDATA[<211> 109]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 9]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30 Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Asn Pro Asn Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ser Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Val Val Tyr Tyr Cys 85 90 95 Ala Arg Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser 100 105 <![CDATA[<210>]]> 10 <![CDATA[<211> 109]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 10]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Ile Ile Asn Pro Ser Gly Gly Ser Thr Ser Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser 100 105 <![CDATA[<210> 11]]> <![CDATA[<211> 121]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.17 vH1]]> <![CDATA[<400> 11]]> Gln Val Gln Leu Val Gln Ser Arg Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Tyr Ile Asn Pro Asn Ser Gly Tyr Thr Lys Tyr Asn Glu Asn Phe 50 55 60 Lys Thr Arg Ala Thr Met Thr Ala Asp Lys Ser Ile Asn Thr Ala Tyr 65 70 75 80 Val Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Phe Cys 85 90 95 Thr Arg Tyr Met Trp Glu Arg Val Thr Gly Phe Phe Asp Phe Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser 115 120 <![CDATA[<210> 12]]> <![CDATA[<211> 121]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.17 vH2]]> <![CDATA[<400> 12]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Arg Ile Asn Pro Asn Ser Gly Tyr Thr Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Ala Asp Lys Ser Ile Asn Thr Ala Tyr 65 70 75 80 Val Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Phe Cys 85 90 95 Thr Arg Tyr Met Trp Glu Arg Val Thr Gly Phe Phe Asp Phe Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser 115 120 <![CDATA[<210> 13]]> <![CDATA[<211> 121]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.17 vH3]]> <![CDATA[<400> 13]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Tyr Ile Asn Pro Asn Ser Gly Tyr Thr Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Ala Thr Met Thr Ala Asp Lys Ser Ile Asn Thr Ala Tyr 65 70 75 80 Val Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Phe Cys 85 90 95 Thr Arg Tyr Met Trp Glu Arg Val Thr Gly Phe Phe Asp Phe Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser 115 120 <![CDATA[<210> 14]]> <![CDATA[<211> 121]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.17 vH4]]> <![CDATA[<400> 14]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Arg Ile Asn Pro Asn Ser Gly Tyr Thr Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Ala Thr Met Thr Ala Asp Lys Ser Ile Asn Thr Ala Tyr 65 70 75 80 Val Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Phe Cys 85 90 95 Thr Arg Tyr Met Trp Glu Arg Val Thr Gly Phe Phe Asp Phe Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser 115 120 <![CDATA[<210> 15]]> <![CDATA[<211> 121]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.17 vH5]]> <![CDATA[<400> 15]]> Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Tyr Ile Asn Pro Asn Ser Gly Tyr Thr Lys Tyr Asn Glu Asn Phe 50 55 60 Lys Thr Arg Ala Thr Met Thr Ala Asp Lys Ser Thr Asn Thr Ala Tyr 65 70 75 80 Val Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Phe Cys 85 90 95 Thr Arg Tyr Met Trp Glu Arg Val Thr Gly Phe Phe Asp Phe Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser 115 120 <![CDATA[<210> 16]]> <![CDATA[<211> 121]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223>]]> hSG16.17 vH6 <![CDATA[<400> 16]]> Gln Val Gln Leu Val Gln Ser Arg Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Ile Ile Asn Pro Asn Ser Gly Tyr Thr Ser Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Ala Asp Lys Ser Thr Asn Thr Ala Tyr 65 70 75 80 Val Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Phe Cys 85 90 95 Thr Arg Tyr Met Trp Glu Arg Val Thr Gly Phe Phe Asp Phe Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser 115 120 <![CDATA[<210> 17]]> <![CDATA[<211> 108]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 褐鼠]]> <![CDATA[<400> 17]]> Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Leu Ser Ala Ser Leu Gly 1 5 10 15 Glu Thr Val Ser Ile Glu Cys Leu Ala Ser Glu Asp Ile Ser Asp Asp 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Ser Gly Lys Ser Pro Gln Val Leu Val 35 40 45 Tyr Thr Thr Ser Arg Leu Gln Asp Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Arg Phe Ser Leu Lys Ile Ile Val Met Gln Pro 65 70 75 80 Glu Asp Glu Ala Asp Tyr Phe Cys Gln Gln Thr Tyr Lys Phe Pro Pro 85 90 95 Thr Phe Gly Ala Gly Thr Arg Leu Asp Leu Lys Arg 100 105 <![CDATA[<210> 18]]> <![CDATA[<211> 106]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 18]]> Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Ser Phe Pro Phe 85 90 95 Gly Gly Gly Thr Lys Val Glu Ile Lys Arg 100 105 <![CDATA[<210> 19]]> <![CDATA[<211> 108]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.17 vK2]]> <![CDATA[<400> 19]]> Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Leu Ala Ser Glu Asp Ile Ser Asp Asp 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Val 35 40 45 Tyr Thr Thr Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Phe Cys Gln Gln Thr Tyr Lys Phe Pro Pro 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg 100 105 <![CDATA[<210> 20]]> <![CDATA[<211> 108]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223>]]> hSG16.17 vK3 <![CDATA[<400> 20]]> Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Glu Asp Ile Ser Asp Asp 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Val 35 40 45 Tyr Thr Thr Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Phe Cys Gln Gln Thr Tyr Lys Phe Pro Pro 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg 100 105 <![CDATA[<210> 21]]> <![CDATA[<211> 108]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.17 vK4]]> <![CDATA[<400> 21]]> Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Leu Ala Ser Glu Asp Ile Ser Asp Asp 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Val 35 40 45 Tyr Thr Thr Ser Arg Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Met Gln Pro 65 70 75 80 Glu Asp Phe Ala Asp Tyr Phe Cys Gln Gln Thr Tyr Lys Phe Pro Pro 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg 100 105 <![CDATA[<210> 22]]> <![CDATA[<211> 108]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.17 vK5]]> <![CDATA[<400> 22]]> Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Glu Asp Ile Ser Asp Asp 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Ser Gly Lys Ala Pro Lys Val Leu Val 35 40 45 Tyr Thr Thr Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Phe Cys Gln Gln Thr Tyr Lys Phe Pro Pro 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg 100 105 <![CDATA[<210> 23]]> <![CDATA[<211> 116]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 褐鼠]]> <![CDATA[<400> 23]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Asn Asp His 20 25 30 Trp Met Thr Trp Ile Arg Gln Ala Pro Gly Arg Gly Leu Glu Trp Ile 35 40 45 Ser Ser Ile Thr Asn Thr Gly Gly Ala Thr Tyr Tyr Leu Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Ser Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys 85 90 95 Thr Ser Pro Gly Leu Tyr Phe Asp Tyr Trp Gly Gln Gly Val Met Val 100 105 110 Thr Val Ser Ser 115 <![CDATA[<210> 24]]> <![CDATA[<211> 109]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 24]]> Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp His 20 25 30 Trp Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ser Ile Thr Asn Thr Gly Gly Ala Thr Tyr Tyr Leu Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser 100 105 <![CDATA[<210> 25]]> <![CDATA[<211> 109]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 25]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp His 20 25 30 Trp Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Val Trp Val 35 40 45 Ser Ser Ile Thr Asn Thr Gly Gly Ala Thr Tyr Tyr Leu Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser 100 105 <![CDATA[<210> 26]]> <![CDATA[<211> 109]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 26]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp His 20 25 30 Trp Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ser Ile Thr Asn Thr Gly Gly Ala Thr Tyr Tyr Leu Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Ala Lys Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser 100 105 <![CDATA[<210> 27]]> <![CDATA[<211> 116]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.45 vH1]]> <![CDATA[<400> 27]]> Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Asp His 20 25 30 Trp Met Thr Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Ser Ser Ile Thr Asn Thr Gly Gly Ala Thr Tyr Tyr Leu Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Thr Ser Pro Gly Leu Tyr Phe Asp Tyr Trp Gly Gln Gly Val Met Val 100 105 110 Thr Val Ser Ser 115 <![CDATA[<210> 28]]> <![CDATA[<211> 116]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.45 vH2]]> <![CDATA[<400> 28]]> Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Asp His 20 25 30 Trp Met Thr Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Ser Ala Ile Thr Asn Thr Gly Gly Ala Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Thr Ser Pro Gly Leu Tyr Phe Asp Tyr Trp Gly Gln Gly Val Met Val 100 105 110 Thr Val Ser Ser 115 <![CDATA[<210> 29]]> <![CDATA[<211> 116]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.45 vH3]]> <![CDATA[<400> 29]]> Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Asp His 20 25 30 Trp Met Thr Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Ser Ala Ile Thr Asn Thr Gly Gly Ala Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Ser Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Thr Ser Pro Gly Leu Tyr Phe Asp Tyr Trp Gly Gln Gly Val Met Val 100 105 110 Thr Val Ser Ser 115 <![CDATA[<210> 30]]> <![CDATA[<211> 116]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.45 vH4]]> <![CDATA[<400> 30]]> Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Asp His 20 25 30 Trp Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Ser Ser Ile Thr Asn Thr Gly Gly Ala Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Ser Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Thr Ser Pro Gly Leu Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Met Val 100 105 110 Thr Val Ser Ser 115 <![CDATA[<210> 31]]> <![CDATA[<211> 116]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.45 vH5]]> <![CDATA[<400> 31]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Asp His 20 25 30 Trp Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Val Trp Val 35 40 45 Ser Ser Ile Thr Asn Thr Gly Gly Ala Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Thr Ser Pro Gly Leu Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Met Val 100 105 110 Thr Val Ser Ser 115 <![CDATA[<210> 32]]> <![CDATA[<211> 116]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.45 vH6]]> <![CDATA[<400> 32]]> Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Asp His 20 25 30 Trp Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Thr Asn Thr Gly Gly Ala Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Thr Ser Pro Gly Leu Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Met Val 100 105 110 Thr Val Ser Ser 115 <![CDATA[<210> 33]]> <![CDATA[<211> 107]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 褐鼠]]> <![CDATA[<400> 33]]> Glu Ile Val Leu Thr Gln Ser Pro Thr Thr Thr Ala Ala Ser Pro Gly 1 5 10 15 Glu Lys Val Thr Ile Thr Cys Leu Ala Thr Ser Ser Val Ser Val Met 20 25 30 Tyr Trp Tyr Gln His Lys Ser Gly Ala Ser Pro Lys Leu Leu Ile Tyr 35 40 45 Ser Thr Ser Ser Leu Ala Ser Gly Val Pro Asp Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Asn Thr Met Glu Ala Glu 65 70 75 80 Asp Ala Ala Thr Tyr Tyr Cys His Gln Trp Ser Ser Asp Pro Pro Thr 85 90 95 Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Arg 100 105 <![CDATA[<210> 34]]> <![CDATA[<211> 107]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 34]]> Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Leu Ala Thr Ser Ser Val Ser Val Met 20 25 30 Tyr Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr 35 40 45 Ser Thr Ser Ser Leu Ala Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu 65 70 75 80 Asp Phe Ala Val Tyr Tyr Cys His Gln Trp Ser Ser Asp Pro Pro Thr 85 90 95 Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg 100 105 <![CDATA[<210> 35]]> <![CDATA[<211> 107]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.45 vK1]]> <![CDATA[<400> 35]]> Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Ala Ser Pro Gly 1 5 10 15 Glu Arg Val Thr Ile Ser Cys Arg Ala Ser Ser Ser Val Ser Val Met 20 25 30 Tyr Trp Tyr Gln His Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr 35 40 45 Ser Thr Ser Ser Leu Ala Ser Gly Val Pro Asp Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Arg Met Glu Pro Glu 65 70 75 80 Asp Phe Ala Val Tyr Tyr Cys His Gln Trp Ser Ser Asp Pro Pro Thr 85 90 95 Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg 100 105 <![CDATA[<210> 36]]> <![CDATA[<211> 107]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.45 vK2]]> <![CDATA[<400> 36]]> Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Ser Ser Val Ser Val Met 20 25 30 Tyr Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr 35 40 45 Ser Thr Ser Ser Leu Ala Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu 65 70 75 80 Asp Phe Ala Val Tyr Tyr Cys His Gln Trp Ser Ser Asp Pro Pro Thr 85 90 95 Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg 100 105 <![CDATA[<210> 37]]> <![CDATA[<211> 107]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.45 vK3]]> <![CDATA[<400> 37]]> Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Ile Ser Cys Arg Ala Ser Ser Ser Val Ser Val Met 20 25 30 Tyr Trp Tyr Gln His Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr 35 40 45 Ser Thr Ser Ser Leu Ala Ser Gly Val Pro Asp Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu 65 70 75 80 Asp Phe Ala Val Tyr Tyr Cys His Gln Trp Ser Ser Asp Pro Pro Thr 85 90 95 Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg 100 105 <![CDATA[<210> 38]]> <![CDATA[<211> 107]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.45 vK5]]> <![CDATA[<400> 38]]> Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Leu Ala Thr Ser Ser Val Ser Val Met 20 25 30 Tyr Trp Tyr Gln His Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr 35 40 45 Ser Thr Ser Ser Leu Ala Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu 65 70 75 80 Asp Phe Ala Val Tyr Tyr Cys His Gln Trp Ser Ser Asp Pro Pro Thr 85 90 95 Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg 100 105 <![CDATA[<210> 39]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 褐鼠]]> <![CDATA[<400> 39]]> Asp Tyr Tyr Ile His 1 5 <![CDATA[<210> 40]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 褐鼠]]> <![CDATA[<400> 40]]> Tyr Ile Asn Pro Asn Ser Gly Tyr Thr Lys Tyr Asn Glu Asn Phe Lys 1 5 10 15 Thr <![CDATA[<210> 41]]> <![CDATA[<211> 12]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 褐鼠]]> <![CDATA[<400> 41]]> Tyr Met Trp Glu Arg Val Thr Gly Phe Phe Asp Phe 1 5 10 <![CDATA[<210> 42]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 褐鼠]]> <![CDATA[<400> 42]]> Ile Asn Pro Asn Ser Gly Tyr Thr 1 5 <![CDATA[<210> 43]]> <![CDATA[<211> 14]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 褐鼠]]> <![CDATA[<400> 43]]> Thr Arg Tyr Met Trp Glu Arg Val Thr Gly Phe Phe Asp Phe 1 5 10 <![CDATA[<210> 44]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 44]]> Gly Tyr Tyr Met His 1 5 <![CDATA[<210> 45]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 45]]> Arg Ile Asn Pro Asn Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe Gln 1 5 10 15 Gly <![CDATA[<210> 46]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 46]]> Ile Asn Pro Asn Ser Gly Gly Thr 1 5 <![CDATA[<210> 47]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 47]]> Ser Tyr Tyr Met His 1 5 <![CDATA[<210> 48]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 48]]> Ile Ile Asn Pro Ser Gly Gly Ser Thr Ser Tyr Ala Gln Lys Phe Gln 1 5 10 15 Gly <![CDATA[<210> 49]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 49]]> Ile Asn Pro Ser Gly Gly Ser Thr 1 5 <![CDATA[<210> 50]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.17 vH1 Kabat CDR1]]> <![CDATA[<400> 50]]> Asp Tyr Tyr Ile His 1 5 <![CDATA[<210> 51]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.17 vH1 Kabat CDR2]]> <![CDATA[<400> 51]]> Tyr Ile Asn Pro Asn Ser Gly Tyr Thr Lys Tyr Asn Glu Asn Phe Lys 1 5 10 15 Thr <![CDATA[<210> 52]]> <![CDATA[<211> 12]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.17 vH1 Kabat CDR3]]> <![CDATA[<400> 52]]> Tyr Met Trp Glu Arg Val Thr Gly Phe Phe Asp Phe 1 5 10 <![CDATA[<210> 53]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.17 vH1 IMGT CDR1]]> <![CDATA[<400> 53]]> Ile Asn Pro Asn Ser Gly Tyr Thr 1 5 <![CDATA[<210> 54]]> <![CDATA[<211> 14]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.17 vH1 IMGT CDR2]]> <![CDATA[<400> 54]]> Thr Arg Tyr Met Trp Glu Arg Val Thr Gly Phe Phe Asp Phe 1 5 10 <![CDATA[<210> 55]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.17 vH2 Kabat CDR1]]> <![CDATA[<400> 55]]> Asp Tyr Tyr Met His 1 5 <![CDATA[<210> 56]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.17 vH2 Kabat CDR2]]> <![CDATA[<400> 56]]> Arg Ile Asn Pro Asn Ser Gly Tyr Thr Asn Tyr Ala Gln Lys Phe Gln 1 5 10 15 Gly <![CDATA[<210> 57]]> <![CDATA[<211> 12]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.17 vH2 Kabat CDR3]]> <![CDATA[<400> 57]]> Tyr Met Trp Glu Arg Val Thr Gly Phe Phe Asp Phe 1 5 10 <![CDATA[<210> 58]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.17 vH2 IMGT CDR1]]> <![CDATA[<400> 58]]> Ile Asn Pro Asn Ser Gly Tyr Thr 1 5 <![CDATA[<210> 59]]> <![CDATA[<211> 14]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG]]>16.17 vH2 IMGT CDR2 <![CDATA[<400> 59]]> Thr Arg Tyr Met Trp Glu Arg Val Thr Gly Phe Phe Asp Phe 1 5 10 <![CDATA[<210> 60]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.17 vH3 Kabat CDR1]]> <![CDATA[<400> 60]]> Asp Tyr Tyr Ile His 1 5 <![CDATA[<210> 61]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.17 vH3 Kabat CDR2]]> <![CDATA[<400> 61]]> Tyr Ile Asn Pro Asn Ser Gly Tyr Thr Asn Tyr Ala Gln Lys Phe Gln 1 5 10 15 Gly <![CDATA[<210> 62]]> <![CDATA[<211> 12]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.17 vH3 Kabat CDR3]]> <![CDATA[<400> 62]]> Tyr Met Trp Glu Arg Val Thr Gly Phe Phe Asp Phe 1 5 10 <![CDATA[<210> 63]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.17 vH3 IMGT CDR1]]> <![CDATA[<400> 63]]> Ile Asn Pro Asn Ser Gly Tyr Thr 1 5 <![CDATA[<210> 64]]> <![CDATA[<211> 14]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.17 vH3 IMGT CDR2]]> <![CDATA[<400> 64]]> Thr Arg Tyr Met Trp Glu Arg Val Thr Gly Phe Phe Asp Phe 1 5 10 <![CDATA[<210> 65]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.17 vH4 Kabat CDR1]]> <![CDATA[<400> 65]]> Asp Tyr Tyr Met His 1 5 <![CDATA[<210> 66]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.17 vH4 Kabat CDR2]]> <![CDATA[<400> 66]]> Arg Ile Asn Pro Asn Ser Gly Tyr Thr Asn Tyr Ala Gln Lys Phe Gln 1 5 10 15 Gly <![CDATA[<210> 67]]> <![CDATA[<211> 12]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.17 vH4 Kabat CDR3]]> <![CDATA[<400> 67]]> Tyr Met Trp Glu Arg Val Thr Gly Phe Phe Asp Phe 1 5 10 <![CDATA[<210> 68]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.17 vH4 IMGT CDR1]]> <![CDATA[<400> 68]]> Ile Asn Pro Asn Ser Gly Tyr Thr 1 5 <![CDATA[<210> 69]]> <![CDATA[<211> 14]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.17 vH4 IMGT CDR2]]> <![CDATA[<400> 69]]> Thr Arg Tyr Met Trp Glu Arg Val Thr Gly Phe Phe Asp Phe 1 5 10 <![CDATA[<210> 70]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.17 vH5 Kabat CDR1]]> <![CDATA[<400> 70]]> Asp Tyr Tyr Ile His 1 5 <![CDATA[<210> 71]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.17 vH5 Kabat CDR2]]> <![CDATA[<400> 71]]> Tyr Ile Asn Pro Asn Ser Gly Tyr Thr Lys Tyr Asn Glu Asn Phe Lys 1 5 10 15 Thr <![CDATA[<210> 72]]> <![CDATA[<211> 12]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.17 vH5 Kabat CDR3]]> <![CDATA[<400> 72]]> Tyr Met Trp Glu Arg Val Thr Gly Phe Phe Asp Phe 1 5 10 <![CDATA[<210> 73]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.17 vH5 IMGT CDR1]]> <![CDATA[<400> 73]]> Ile Asn Pro Asn Ser Gly Tyr Thr 1 5 <![CDATA[<210> 74]]> <![CDATA[<211> 14]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.17 vH5 IMGT CDR2]]> <![CDATA[<400> 74]]> Thr Arg Tyr Met Trp Glu Arg Val Thr Gly Phe Phe Asp Phe 1 5 10 <![CDATA[<210> 75]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.17 vH]]>6 Kabat CDR1 <![CDATA[<400> 75]]> Asp Tyr Tyr Met His 1 5 <![CDATA[<210> 76]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.17 vH6 Kabat CDR2]]> <![CDATA[<400> 76]]> Ile Ile Asn Pro Asn Ser Gly Tyr Thr Ser Tyr Ala Gln Lys Phe Gln 1 5 10 15 Gly <![CDATA[<210> 77]]> <![CDATA[<211> 12]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.17 vH6 Kabat CDR3]]> <![CDATA[<400> 77]]> Tyr Met Trp Glu Arg Val Thr Gly Phe Phe Asp Phe 1 5 10 <![CDATA[<210> 78]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.17 vH6 IMGT CDR1]]> <![CDATA[<400> 78]]> Ile Asn Pro Asn Ser Gly Tyr Thr 1 5 <![CDATA[<210> 79]]> <![CDATA[<211> 14]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.17 vH6 IMGT CDR2]]> <![CDATA[<400> 79]]> Thr Arg Tyr Met Trp Glu Arg Val Thr Gly Phe Phe Asp Phe 1 5 10 <![CDATA[<210> 80]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 褐鼠]]> <![CDATA[<400> 80]]> Leu Ala Ser Glu Asp Ile Ser Asp Asp Leu Ala 1 5 10 <![CDATA[<210> 81]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 褐鼠]]> <![CDATA[<400> 81]]> Thr Thr Ser Arg Leu Gln Asp 1 5 <![CDATA[<210> 82]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> ]]>褐鼠 <![CDATA[<400> 82]]> Gln Gln Thr Tyr Lys Phe Pro Pro Thr 1 5 <![CDATA[<210> 83]]> <![CDATA[<211> 6]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 褐鼠]]> <![CDATA[<400> 83]]> Glu Asp Ile Ser Asp Asp 1 5 <![CDATA[<210> 84]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 褐鼠]]> <![CDATA[<400> 84]]> Gln Gln Thr Tyr Lys Phe Pro Pro Thr 1 5 <![CDATA[<210> 85]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 85]]> Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala 1 5 10 <![CDATA[<210> 86]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 86]]> Ala Ala Ser Ser Leu Gln Ser 1 5 <![CDATA[<210> 87]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 87]]> Gln Gln Ala Asn Ser Phe Pro 1 5 <![CDATA[<210> 88]]> <![CDATA[<211> 6]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 88]]> Gln Gly Ile Ser Ser Trp 1 5 <![CDATA[<210> 89]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 89]]> Gln Gln Ala Asn Ser Phe Pro 1 5 <![CDATA[<210> 90]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.17 vK2 Kabat CDR1]]> <![CDATA[<400> 90]]> Leu Ala Ser Glu Asp Ile Ser Asp Asp Leu Ala 1 5 10 <![CDATA[<210> 91]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220]]>> ]]> <br/><![CDATA[<223> hSG16.17 vK2 Kabat CDR2]]> <br/> <br/><![CDATA[<400> 91]]> <br/><![CDATA[Thr Thr Ser Ser Leu Gln Ser 1 5 <![CDATA[<210> 92]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.17 vK2 Kabat CDR3]]> <![CDATA[<400> 92]]> Gln Gln Thr Tyr Lys Phe Pro Pro Thr 1 5 <![CDATA[<210> 93]]> <![CDATA[<211> 6]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.17 vK2 IMGT CDR1]]> <![CDATA[<400> 93]]> Glu Asp Ile Ser Asp Asp 1 5 <![CDATA[<210> 94]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.17 vK2 IMGT CDR3]]> <![CDATA[<400> 94]]> Gln Gln Thr Tyr Lys Phe Pro Pro Thr 1 5 <![CDATA[<210> 95]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.17 vK3 Kabat CDR1]]> <![CDATA[<400> 95]]> Arg Ala Ser Glu Asp Ile Ser Asp Asp Leu Ala 1 5 10 <![CDATA[<210> 96]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.17 vK3 Kabat CDR2]]> <![CDATA[<400> 96]]> Thr Thr Ser Ser Leu Gln Ser 1 5 <![CDATA[<210> 97]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.17 vK3 Kabat CDR3]]> <![CDATA[<400> 97]]> Gln Gln Thr Tyr Lys Phe Pro Pro Thr 1 5 <![CDATA[<210> 98]]> <![CDATA[<211> 6]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.17 vK3 IMGT CDR1]]> <![CDATA[<400> 98]]> Glu Asp Ile Ser Asp Asp 1 5 <![CDATA[<210> 99]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.17 vK3 IMGT CDR3]]> <![CDATA[<400> 99]]> Gln Gln Thr Tyr Lys Phe Pro Pro Thr 1 5 <![CDATA[<210> 100]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> hSG16.17 vK4 Kabat CDR1]]> <![CDATA[<400> 100]]> Leu Ala Ser Glu Asp Ile Ser Asp Asp Leu Ala 1 5 10 <![CDATA[<210> 101]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.17 vK4 Kabat CDR2]]> <![CDATA[<400> 101]]> Thr Thr Ser Arg Leu Gln Ser 1 5 <![CDATA[<210> 102]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.17 vK4 Kabat CDR3]]> <![CDATA[<400> 102]]> Gln Gln Thr Tyr Lys Phe Pro Pro Thr 1 5 <![CDATA[<210> 103]]> <![CDATA[<211> 6]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.17 vK4 IMGT CDR1]]> <![CDATA[<400> 103]]> Glu Asp Ile Ser Asp Asp 1 5 <![CDATA[<210> 104]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.17 vK4 IMGT CDR3]]> <![CDATA[<400> 104]]> Gln Gln Thr Tyr Lys Phe Pro Pro Thr 1 5 <![CDATA[<210> 105]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.17 vK5 Kabat CDR1]]> <![CDATA[<400> 105]]> Arg Ala Ser Glu Asp Ile Ser Asp Asp Leu Ala 1 5 10 <![CDATA[<210> 106]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.17 vK5 Kabat CDR2]]> <![CDATA[<400> 106]]> Thr Thr Ser Ser Leu Gln Ser 1 5 <![CDATA[<210> 107]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.17 vK5 Kabat CDR3]]> <![CDATA[<400> 107]]> Gln Gln Thr Tyr Lys Phe Pro Pro Thr 1 5 <![CDATA[<210> 108]]> <![CDATA[<211> 6]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.17 vK5 IMGT CDR1]]> <![CDATA[<400> 108]]> Glu Asp Ile Ser Asp Asp 1 5 <![CDATA[<210> 109]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.17 vK5 IMGT CDR3]]> <![CDATA[<400> 109]]> Gln Gln Thr Tyr Lys Phe Pro Pro Thr 1 5 <![CDATA[<210> 110]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 褐鼠]]> <![CDATA[<400> 110]]> Asp His Trp Met Thr 1 5 <![CDATA[<210> 111]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 褐鼠]]> <![CDATA[<400> 111]]> Ser Ile Thr Asn Thr Gly Gly Ala Thr Tyr Tyr Leu Asp Ser Val Lys 1 5 10 15 Gly <![CDATA[<210> 112]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 褐鼠]]> <![CDATA[<400> 112]]> Pro Gly Leu Tyr Phe Asp Tyr 1 5 <![CDATA[<210> 113]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 褐鼠]]> <![CDATA[<400> 113]]> Gly Phe Thr Phe Asn Asp His 1 5 <![CDATA[<210> 114]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 褐鼠]]> <![CDATA[<400> 114]]> Ile Thr Asn Thr Gly Gly Ala Thr 1 5 <![CDATA[<210> 115]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 褐鼠]]> <![CDATA[<400> 115]]> Thr Ser Pro Gly Leu Tyr Phe Asp Tyr 1 5 <![CDATA[<210> 116]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 116]]> Asp His Trp Met Thr 1 5 <![CDATA[<210> 117]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 117]]> Ser Ile Thr Asn Thr Gly Gly Ala Thr Tyr Tyr Leu Asp Ser Val Lys 1 5 10 15 Gly <![CDATA[<210> 118]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 118]]> Gly Phe Thr Phe Ser Asp His Trp 1 5 <![CDATA[<210> 119]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 119]]> Ile Thr Asn Thr Gly Gly Ala Thr 1 5 <![CDATA[<210> 120]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 120]]> Asp His Trp Met Thr 1 5 <![CDATA[<210> 121]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 121]]> Ser Ile Thr Asn Thr Gly Gly Ala Thr Tyr Tyr Leu Asp Ser Val Lys 1 5 10 15 Gly <![CDATA[<210> 122]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 122]]> Gly Phe Thr Phe Ser Asp His Trp 1 5 <![CDATA[<210> 123]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 123]]> Ile Thr Asn Thr Gly Gly Ala Thr 1 5 <![CDATA[<210> 124]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 124]]> Asp His Trp Met Thr 1 5 <![CDATA[<210> 125]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 125]]> Ser Ile Thr Asn Thr Gly Gly Ala Thr Tyr Tyr Leu Asp Ser Val Lys 1 5 10 15 Gly <![CDATA[<210> 126]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 126]]> Gly Phe Thr Phe Asp Asp His Trp 1 5 <![CDATA[<210> 127]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 127]]> Ile Thr Asn Thr Gly Gly Ala Thr 1 5 <![CDATA[<210> 128]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.45 vH1 Kabat CDR1]]> <![CDATA[<400> 128]]> Asp His Trp Met Thr 1 5 <![CDATA[<210> 129]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.45 vH1 Kabat CDR2]]> <![CDATA[<400> 129]]> Ser Ile Thr Asn Thr Gly Gly Ala Thr Tyr Tyr Leu Asp Ser Val Lys 1 5 10 15 Gly <![CDATA[<210> 130]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.45 vH1 Kabat CDR3]]> <![CDATA[<400> 130]]> Pro Gly Leu Tyr Phe Asp Tyr 1 5 <![CDATA[<210> 131]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.45 vH1 IMGT CDR1]]> <![CDATA[<400> 131]]> Gly Phe Thr Phe Asn Asp His Trp 1 5 <![CDATA[<210> 132]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.45 vH1 IMGT CDR1]]> <![CDATA[<400> 132]]> Ile Thr Asn Thr Gly Gly Ala Thr 1 5 <![CDATA[<210> 133]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.45 vH1 IMGT CDR1]]> <![CDATA[<400> 133]]> Thr Ser Pro Gly Leu Tyr Phe Asp Tyr 1 5 <![CDATA[<210> 134]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.45 vH2 Kabat CDR1]]> <![CDATA[<400> 134]]> Asp His Trp Met Thr 1 5 <![CDATA[<210> 135]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.45 vH2 Kabat CDR2]]> <![CDATA[<400> 135]]> Ala Ile Thr Asn Thr Gly Gly Ala Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <![CDATA[<210> 136]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.45 vH2 Kabat CDR3]]> <![CDATA[<400> 136]]> Pro Gly Leu Tyr Phe Asp Tyr 1 5 <![CDATA[<210> 137]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.45 vH2 IMGT CDR1]]> <![CDATA[<400> 137]]> Gly Phe Thr Phe Asn Asp His Trp 1 5 <![CDATA[<210> 138]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.45 vH2 IMGT CDR2]]> <![CDATA[<400> 138]]> Ile Thr Asn Thr Gly Gly Ala Thr 1 5 <![CDATA[<210> 139]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.45 vH2 IMGT CDR3]]> <![CDATA[<400> 139]]> Thr Ser Pro Gly Leu Tyr Phe Asp Tyr 1 5 <![CDATA[<210> 140]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.45 vH3 Kabat CDR1]]> <![CDATA[<400> 140]]> Asp His Trp Met Thr 1 5 <![CDATA[<210> 141]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.45 vH3 Kabat CDR2]]> <![CDATA[<400> 141]]> Ala Ile Thr Asn Thr Gly Gly Ala Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <![CDATA[<210> 142]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.45 vH3 Kabat CDR3]]> <![CDATA[<400> 142]]> Pro Gly Leu Tyr Phe Asp Tyr 1 5 <![CDATA[<210> 143]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.45 vH3 IMGT CDR1]]> <![CDATA[<400> 143]]> Gly Phe Thr Phe Asn Asp His Trp 1 5 <![CDATA[<210> 144]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.45 vH3 IMGT CDR2]]> <![CDATA[<400> 144]]> Ile Thr Asn Thr Gly Gly Ala Thr 1 5 <![CDATA[<210> 145]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.45 vH3 IMGT CDR3]]> <![CDATA[<400> 145]]> Thr Ser Pro Gly Leu Tyr Phe Asp Tyr 1 5 <![CDATA[<210> 146]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.45 vH4 Kabat CDR1]]> <![CDATA[<400> 146]]> Asp His Trp Met Thr 1 5 <![CDATA[<210> 147]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.45 vH4 Kabat CDR2]]> <![CDATA[<400> 147]]> Ser Ile Thr Asn Thr Gly Gly Ala Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <![CDATA[<210> 148]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.45 vH4 Kabat CDR3]]> <![CDATA[<400> 148]]> Pro Gly Leu Tyr Phe Asp Tyr 1 5 <![CDATA[<210> 149]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.45 vH4 IMGT CDR1]]> <![CDATA[<400> 149]]> Gly Phe Thr Phe Asn Asp His Trp 1 5 <![CDATA[<210> 150]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.45 vH4 IMGT CDR2]]> <![CDATA[<400> 150]]> Ile Thr Asn Thr Gly Gly Ala Thr 1 5 <![CDATA[<210> 151]]> <![CDATA[<211> 9]]> <![CDATA[<212> P]]>RT <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.45 vH4 IMGT CDR3]]> <![CDATA[<400> 151]]> Thr Ser Pro Gly Leu Tyr Phe Asp Tyr 1 5 <![CDATA[<210> 152]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.45 vH5 Kabat CDR1]]> <![CDATA[<400> 152]]> Asp His Trp Met Thr 1 5 <![CDATA[<210> 153]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.45 vH5 Kabat CDR2]]> <![CDATA[<400> 153]]> Ser Ile Thr Asn Thr Gly Gly Ala Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <![CDATA[<210> 154]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.45 vH5 Kabat CDR3]]> <![CDATA[<400> 154]]> Pro Gly Leu Tyr Phe Asp Tyr 1 5 <![CDATA[<210> 155]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.45 vH5 IMGT CDR1]]> <![CDATA[<400> 155]]> Gly Phe Thr Phe Asn Asp His Trp 1 5 <![CDATA[<210> 156]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.45 vH5 IMGT CDR2]]> <![CDATA[<400> 156]]> Ile Thr Asn Thr Gly Gly Ala Thr 1 5 <![CDATA[<210> 157]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.45 vH5 IMGT CDR3]]> <![CDATA[<400> 157]]> Thr Ser Pro Gly Leu Tyr Phe Asp Tyr 1 5 <![CDATA[<210> 158]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.45 vH6 Kabat CDR1]]> <![CDATA[<400> 158]]> Asp His Trp Met Thr 1 5 <![CDATA[<210> 159]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.45 vH6 Kabat CDR2]]> <![CDATA[<400> 159]]> Gly Ile Thr Asn Thr Gly Gly Ala Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <![CDATA[<210> 160]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.45 vH6 Kabat CDR3]]> <![CDATA[<400> 160]]> Pro Gly Leu Tyr Phe Asp Tyr 1 5 <![CDATA[<210> 161]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.45 vH6 IMGT CDR1]]> <![CDATA[<400> 161]]> Gly Phe Thr Phe Asn Asp His Trp 1 5 <![CDATA[<210> 162]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.45 vH6 IMGT CDR2]]> <![CDATA[<400> 162]]> Ile Thr Asn Thr Gly Gly Ala Thr 1 5 <![CDATA[<210> 163]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.45 vH6 IMGT CDR3]]> <![CDATA[<400> 163]]> Thr Ser Pro Gly Leu Tyr Phe Asp Tyr 1 5 <![CDATA[<210> 164]]> <![CDATA[<211> 10]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 褐鼠]]> <![CDATA[<400> 164]]> Leu Ala Thr Ser Ser Val Ser Val Met Tyr 1 5 10 <![CDATA[<210> 165]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 褐鼠]]> <![CDATA[<400> 165]]> Ser Thr Ser Ser Leu Ala Ser 1 5 <![CDATA[<210> 166]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 褐鼠]]> <![CDATA[<400> 166]]> His Gln Trp Ser Ser Asp Pro Pro Thr 1 5 <![CDATA[<210> 167]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 褐鼠]]> <![CDATA[<400> 167]]> Ser Ser Val Ser Val Met Tyr 1 5 <![CDATA[<210> 168]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 褐鼠]]> <![CDATA[<400> 168]]> His Gln Trp Ser Ser Asp Pro Pro Thr 1 5 <![CDATA[<210> 169]]> <![CDATA[<211> 10]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 169]]> Leu Ala Thr Ser Ser Val Ser Val Met Tyr 1 5 10 <![CDATA[<210> 170]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 170]]> Ser Thr Ser Ser Leu Ala Ser 1 5 <![CDATA[<210> 171]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 171]]> His Gln Trp Ser Ser Asp Pro Pro Thr 1 5 <![CDATA[<210> 172]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 172]]> Ser Ser Val Ser Val Met Tyr 1 5 <![CDATA[<210> 173]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 173]]> His Gln Trp Ser Ser Asp Pro Pro Thr 1 5 <![CDATA[<210> 174]]> <![CDATA[<211> 10]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.45 vK1 Kabat CDR1]]> <![CDATA[<400> 174]]> Arg Ala Ser Ser Ser Val Ser Val Met Tyr 1 5 10 <![CDATA[<210> 175]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.45 vK1 Kabat CDR2]]> <![CDATA[<400> 175]]> Ser Thr Ser Ser Leu Ala Ser 1 5 <![CDATA[<210> 176]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.45 vK1 Kabat CDR3]]> <![CDATA[<400> 176]]> His Gln Trp Ser Ser Asp Pro Pro 1 5 <![CDATA[<210> 177]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.45 vK1 IMGT CDR1]]> <![CDATA[<400> 177]]> Ser Ser Val Ser Val Met Tyr 1 5 <![CDATA[<210> 178]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.45 vK1 IMGT CDR3]]> <![CDATA[<400> 178]]> His Gln Trp Ser Ser Asp Pro Pro 1 5 <![CDATA[<210> 179]]> <![CDATA[<211> 10]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.45 vK2 Kabat CDR1]]> <![CDATA[<400> 179]]> Arg Ala Ser Ser Ser Val Ser Val Met Tyr 1 5 10 <![CDATA[<210> 180]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.45 vK2 Ka]]>bat CDR2 <![CDATA[<400> 180]]> Ser Thr Ser Ser Leu Ala Ser 1 5 <![CDATA[<210> 181]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.45 vK2 Kabat CDR3]]> <![CDATA[<400> 181]]> His Gln Trp Ser Ser Asp Pro Pro Thr 1 5 <![CDATA[<210> 182]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.45 vK2 IMGT CDR1]]> <![CDATA[<400> 182]]> Ser Ser Val Ser Val Met Tyr 1 5 <![CDATA[<210> 183]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.45 vK2 IMGT CDR3]]> <![CDATA[<400> 183]]> His Gln Trp Ser Ser Asp Pro Pro Thr 1 5 <![CDATA[<210> 184]]> <![CDATA[<211> 10]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.45 vK3 Kabat CDR1]]> <![CDATA[<400> 184]]> Arg Ala Ser Ser Ser Val Ser Val Met Tyr 1 5 10 <![CDATA[<210> 185]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.45 vK3 Kabat CDR2]]> <![CDATA[<400> 185]]> Ser Thr Ser Ser Leu Ala Ser 1 5 <![CDATA[<210> 186]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.45 vK3 Kabat CDR3]]> <![CDATA[<400> 186]]> His Gln Trp Ser Ser Asp Pro Pro Thr 1 5 <![CDATA[<210> 187]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.45 vK3 IMGT CDR1]]> <![CDATA[<400> 187]]> Ser Ser Val Ser Val Met Tyr 1 5 <![CDATA[<210> 188]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.45 vK3 IMGT CDR3]]> <![CDATA[<400> 188]]> His Gln Trp Ser Ser Asp Pro Pro Thr 1 5 <![CDATA[<210> 189]]> <![CDATA[<211> 10]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.45 vK5 Kabat CDR1]]> <![CDATA[<400> 189]]> Leu Ala Thr Ser Ser Val Ser Val Met Tyr 1 5 10 <![CDATA[<210> 190]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.45 vK5 Kabat CDR2]]> <![CDATA[<400> 190]]> Ser Thr Ser Ser Leu Ala Ser 1 5 <![CDATA[<210> 191]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.45 vK5 Kabat CDR3]]> <![CDATA[<400> 191]]> His Gln Trp Ser Ser Asp Pro Pro Thr 1 5 <![CDATA[<210> 192]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.45 vK5 IMGT CDR1]]> <![CDATA[<400> 192]]> Ser Ser Val Ser Val Met Tyr 1 5 <![CDATA[<210> 193]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220> ]]> <![CDATA[<223> hSG16.45 vK5 IMGT CDR3]]> <![CDATA[<400> 193]]> His Gln Trp Ser Ser Asp Pro Pro Thr 1 5
Claims (71)
- 一種人類化、嵌合或飾面抗體,其係以ATCC PTC-6937保藏之抗體之人類化、嵌合或飾面形式。
- 如請求項1之抗體,其包含與hSG16.17 VH3 (SEQ ID NO: 13)具有至少90%序列一致性之成熟重鏈可變區及與hSG16.17 VK2 (SEQ ID NO: 19)具有至少90%序列一致性之成熟輕鏈可變區。
- 如請求項2之抗體,其包含與hSG16.17 VH3 (SEQ ID NO: 13)具有至少95%序列一致性之成熟重鏈可變區及與hSG16.17 VK2 (SEQ ID NO: 19)具有至少95%序列一致性之成熟輕鏈可變區。
- 如任一前述請求項之抗體,其包含hSG16.17 VH3 (SEQ ID NO: 13)之三個Kabat CDR (SEQ ID NO: 60-62)及hSG16.17 VK2 (SEQ ID NO: 19)之三個Kabat CDR (SEQ ID NO: 90-92),條件係位置H58可由N或K佔據,位置H60可由A或N佔據,位置H61可由Q或E佔據,位置H62可由K或N佔據,位置H64可由Q或K佔據,位置H65可由G或T佔據,位置L24可由R或L佔據,且位置L53可由S或R佔據。
- 如任一前述請求項之抗體,其包含hSG16.17 VH3 (SEQ ID NO: 13)之三個Kabat CDR (SEQ ID NO: 60-62)及hSG16.17 VK2 (SEQ ID NO: 19)之三個Kabat CDR (SEQ ID NO: 90-92)。
- 如任一前述請求項之抗體,其中位置H20、H48、H69、H71、H73、H76、H80、H88、H91及H93分別由L、I、M、A、K、N、V、A、F及T佔據,且位置L46、L48及L87分別由V、V及F佔據。
- 如請求項1之抗體,其中該成熟重鏈可變區具有hSG16.17 VH3 (SEQ ID NO: 13)之序列,且該成熟輕鏈可變區具有hSG16.17 VK2 (SEQ ID NO: 19)之序列。
- 如任一前述請求項之抗體,其中該成熟重鏈可變區融合至重鏈恆定區且該成熟輕鏈可變區融合至輕鏈恆定區。
- 如請求項6之抗體,其中該重鏈恆定區係天然人類恆定區之突變體形式,其與Fcγ受體之結合相對於該天然人類恆定區有所降低。
- 如請求項8或9之抗體,其中該重鏈恆定區係IgG1同型。
- 如請求項8之抗體,其中該重鏈恆定區具有包含SEQ ID NO: 5之胺基酸序列且該輕鏈恆定區具有包含SEQ ID NO: 3之胺基酸序列。
- 如請求項8之抗體,其中該重鏈恆定區具有包含SEQ ID NO:7 (S239C)之胺基酸序列且該輕鏈恆定區具有包含SEQ ID NO:3之胺基酸序列。
- 如任一前述請求項之抗體,其係裸抗體。
- 如請求項1至12中任一項之抗體,其中該抗體偶聯至細胞毒性或細胞生長抑制劑。
- 如請求項14之抗體,其中該抗體偶聯至細胞毒性劑。
- 如請求項15之抗體,其中該細胞毒性劑經由酶可裂解連接體偶聯至該抗體。
- 如請求項15或16之抗體,其中該細胞毒性劑係DNA小溝黏合劑。
- 如請求項17之抗體,其中該細胞毒性劑具有下式 。
- 如請求項15或16之抗體,其中該細胞毒性劑係MMAE或MMAF。
- 一種醫藥組合物,其包含如任一前述請求項之抗體及醫藥上可接受之載劑。
- 一種治療患有表現BCMA之癌症或具有患該癌症之風險之患者之方法,其包含向該患者投與如前述請求項中任一項之抗體之有效方案。
- 如請求項20之方法,其中該癌症係血液癌症。
- 如請求項22之方法,其中該血液癌症係骨髓瘤、白血病或淋巴瘤。
- 如請求項22之方法,其中該血液癌症係多發性骨髓瘤。
- 如請求項22之方法,其中該血液癌症係非霍奇金氏淋巴瘤(non-Hodgkin's lymphoma,NHL)或霍奇金氏淋巴瘤。
- 如請求項22之方法,其中該血液癌症係骨髓發育不良症候群(MDS)、骨髓增生性症候群(MPS)、華氏巨球蛋白血症(Waldenström’s macroglobulinemia)或柏基特淋巴瘤(Burkett’s lymphoma)。
- 一種治療患有由表現BCMA之免疫細胞介導之免疫病症或具有罹患該免疫病症之風險之患者之方法,其包含向該患者投與如前述請求項中任一項之人類化抗體之有效方案。
- 如請求項27之方法,其係B細胞介導病症。
- 如請求項27之方法,其中該免疫病症係類風濕性關節炎、全身性紅斑狼瘡(SLE)、I型糖尿病、氣喘、異位性皮膚炎、過敏性鼻炎、血小板減少紫斑症、多發性硬化、牛皮癬、薛格連氏症候群(Sjorgren’s syndrome)、橋本氏甲狀腺炎(Hashimoto’s thyroiditis)、格雷氏病(Grave’s disease)、原發性膽汁性肝硬化、韋格納肉芽腫(Wegener’s granulomatosis)、結核症及移植物抗宿主病。
- 一種人類化、嵌合或飾面抗體,其係具有SEQ ID NO: 23之成熟重鏈可變區及SEQ ID NO: 33之成熟輕鏈可變區之大鼠SG16.45抗體之人類化、嵌合或飾面形式。
- 如請求項30之抗體,其包含與hSG16.45 VH5 (SEQ ID NO: 31)具有至少90%序列一致性之成熟重鏈可變區及與hSG16.45 VK2 (SEQ ID NO: 36)具有至少90%序列一致性之成熟輕鏈可變區。
- 如請求項31之抗體,其包含與hSG16.45 VH5 (SEQ ID NO: 31)具有至少95%序列一致性之成熟重鏈可變區及與hSG16.45 VK2 (SEQ ID NO: 36)具有至少95%序列一致性之成熟輕鏈可變區。
- 如請求項30至32中任一項之抗體,其包含hSG16.45 VH5 (SEQ ID NO: 31)之三個Kabat CDR (SEQ ID NO: 152-154)及hSG16.45 VK2 (SEQ ID NO: 36)之三個Kabat CDR (SEQ ID NO: 179-181),條件係位置H50可由A或S佔據,位置L24可由R或L佔據且位置L26可由S或T佔據。
- 如請求項30至33中任一項之抗體,其包含hSG16.45 VH5 (SEQ ID NO: 31)之三個Kabat CDR (SEQ ID NO: 152-154)及hSG16.45 VK2 (SEQ ID NO: 36)之三個Kabat CDR (SEQ ID NO: 179-181)。
- 如請求項30至34中任一項之抗體,其中位置H30、H93及H94分別由N、T及S佔據。
- 如請求項30之抗體,其中該成熟重鏈可變區具有hSG16.45 VH5 (SEQ ID NO: 31)之序列,且該成熟輕鏈可變區具有hSG16.45 VK2 (SEQ ID NO: 36)之序列,或該成熟重鏈可變區具有hSG16.45 VH1 (SEQ ID NO: 27)之序列,且該成熟輕鏈可變區具有hSG16.45 VK1 (SEQ ID NO: 35)之序列,或該成熟重鏈可變區具有hSG16.45 VH1 (SEQ ID NO: 27)之序列,且該成熟輕鏈可變區具有hSG16.45 VK3 (SEQ ID NO: 37)之序列。
- 如請求項30至36中任一項之抗體,其中該成熟重鏈可變區融合至重鏈恆定區且該成熟輕鏈可變區融合至輕鏈恆定區。
- 如請求項37之抗體,其中該重鏈恆定區係天然人類恆定區之突變體形式,其與Fcγ受體之結合相對於該天然人類恆定區有所降低。
- 如請求項37或38之抗體,其中該重鏈恆定區係IgG1同型。
- 如請求項37之抗體,其中該重鏈恆定區具有包含SEQ ID NO: 5之胺基酸序列且該輕鏈恆定區具有包含SEQ ID NO: 3之胺基酸序列。
- 如請求項37之抗體,其中該重鏈恆定區具有包含SEQ ID NO:7 (S239C)之胺基酸序列且該輕鏈恆定區具有包含SEQ ID NO:3之胺基酸序列。
- 如請求項30至41中任一項之抗體,其係裸抗體。
- 如請求項30至41中任一項之抗體,其中該抗體偶聯至細胞毒性或細胞生長抑制劑。
- 如請求項43之抗體,其中該抗體偶聯至細胞毒性劑。
- 如請求項44之抗體,其中該細胞毒性劑經由酶可裂解連接體偶聯至該抗體。
- 如請求項43或44之抗體,其中該細胞毒性劑係DNA小溝黏合劑。
- 如請求項46之抗體,其中該細胞毒性劑具有下式 。
- 如請求項44或45之抗體,其中該細胞毒性劑係MMAE或MMAF。
- 如任一前述請求項之抗體,其中在重鏈恆定區之EU位置297之asn殘基處之少於5%之N-醣苷連接糖鏈包括岩藻糖或其類似物,其中培養表現該抗體之細胞以減少該抗體之岩藻醣基化。
- 一種醫藥組合物,其包含如請求項30至48中任一項之抗體及醫藥上可接受之載劑。
- 一種治療患有表現BCMA之癌症或具有患該癌症之風險之患者之方法,其包含向該患者投與如請求項30至49中任一項之人類化抗體之有效方案。
- 如請求項51之方法,其中該癌症係血液癌症。
- 如請求項52之方法,其中該血液癌症係骨髓瘤、白血病或淋巴瘤。
- 如請求項52之方法,其中該血液癌症係多發性骨髓瘤。
- 如請求項52之方法,其中該血液癌症係非霍奇金氏淋巴瘤(NHL)或霍奇金氏淋巴瘤。
- 如請求項52之方法,其中該血液癌症係骨髓發育不良症候群(MDS)、骨髓增生性症候群(MPS)、華氏巨球蛋白血症或柏基特淋巴瘤。
- 一種治療患有由表現BCMA之免疫細胞介導之免疫病症或具有罹患該免疫病症之風險之患者之方法,其包含向該患者投與如前述請求項中任一項之抗體之有效方案。
- 如請求項56之方法,其係B細胞介導病症。
- 如請求項56之方法,其中該免疫病症係類風濕性關節炎、全身性紅斑狼瘡(SLE)、I型糖尿病、氣喘、異位性皮膚炎、過敏性鼻炎、血小板減少紫斑症、多發性硬化、牛皮癬、薛格連氏症候群、橋本氏甲狀腺炎、格雷氏病、原發性膽汁性肝硬化、韋格納肉芽腫、結核症及移植物抗宿主病。
- 一種特異性結合至人類BCMA蛋白之人類化抗體,該抗體包含與hSG16.17 VH3 (SEQ ID NO: 13)具有至少90%序列一致性之成熟重鏈可變區及與hSG16.17 VK2 (SEQ ID NO: 19)具有至少90%序列一致性之成熟輕鏈可變區。
- 如請求項60之抗體,其包含與hSG16.17 VH3 (SEQ ID NO: 13)具有至少95%序列一致性之成熟重鏈可變區及與hSG16.17 VK2 (SEQ ID NO: 19)具有至少95%序列一致性之成熟輕鏈可變區。
- 如請求項60之抗體,其包含hSG16.17 VH3 (SEQ ID NO: 13)之三個Kabat CDR (SEQ ID NO: 60-62)及hSG16.17 VK2 (SEQ ID NO: 19)之三個Kabat CDR (SEQ ID NO: 90-92),條件係位置H58可由N或K佔據,位置H60可由A或N佔據,位置H61可由Q或E佔據,位置H62可由K或N佔據,位置H64可由Q或K佔據,位置H65可由G或T佔據,位置L24可由R或L佔據,且位置L53可由S或R佔據。
- 如請求項60之抗體,其包含hSG16.17 VH3 (SEQ ID NO: 13)之三個Kabat CDR (SEQ ID NO: 60-62)及hSG16.17 VK2 (SEQ ID NO: 19)之三個Kabat CDR (SEQ ID NO: 90-92)。
- 如請求項60之抗體,其中位置H20、H48、H69、H71、H73、H76、H80、H88、H91及H93分別由L、I、M、A、K、N、V、A、F及T佔據,且位置L46、L48及L87分別由V、V及F佔據。
- 如請求項60之抗體,其中該成熟重鏈可變區具有hSG16.17 VH3 (SEQ ID NO: 13)之序列,且該成熟輕鏈可變區具有hSG16.17 VK2 (SEQ ID NO: 19)之序列。
- 如請求項60之抗體,其中該成熟重鏈可變區融合至重鏈恆定區且該成熟輕鏈可變區融合至輕鏈恆定區。
- 如請求項65之抗體,其中該成熟重鏈可變區融合至重鏈恆定區且該成熟輕鏈可變區融合至輕鏈恆定區。
- 一種醫藥組合物,其包含如請求項67之抗體及醫藥上可接受之載劑。
- 如請求項68之醫藥組合物,其中少於約10%之該等抗體具有藉由岩藻糖或岩藻糖類似物之核心岩藻醣基化。
- 如請求項68之醫藥組合物,其中少於約5%之該等抗體具有藉由岩藻糖或岩藻糖類似物之核心岩藻醣基化。
- 如請求項69之醫藥組合物,其中約2%之該等抗體具有藉由岩藻糖或岩藻糖類似物之核心岩藻醣基化。
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201662396084P | 2016-09-16 | 2016-09-16 | |
US62/396,084 | 2016-09-16 | ||
PCT/US2017/018177 WO2017143069A1 (en) | 2016-02-17 | 2017-02-16 | Bcma antibodies and use of same to treat cancer and immunological disorders |
WOPCT/US2017/018177 | 2017-02-16 |
Publications (1)
Publication Number | Publication Date |
---|---|
TW202344518A true TW202344518A (zh) | 2023-11-16 |
Family
ID=62639290
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
TW112104791A TW202344518A (zh) | 2016-09-16 | 2017-06-05 | Bcma抗體及其用於治療癌症及免疫病症之用途 |
TW106118504A TWI793075B (zh) | 2016-09-16 | 2017-06-05 | Bcma抗體及其用於治療癌症及免疫病症之用途 |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
TW106118504A TWI793075B (zh) | 2016-09-16 | 2017-06-05 | Bcma抗體及其用於治療癌症及免疫病症之用途 |
Country Status (2)
Country | Link |
---|---|
EA (1) | EA201891851A1 (zh) |
TW (2) | TW202344518A (zh) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN115279781A (zh) * | 2020-03-26 | 2022-11-01 | 上海翰森生物医药科技有限公司 | 抗体药物偶联物及其医药用途 |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
HUE052806T2 (hu) * | 2010-12-06 | 2021-05-28 | Seagen Inc | LIV-1 elleni humanizált antitestek és azok alkalmazása a rák kezelésében |
BR112016024546A2 (pt) * | 2014-04-30 | 2018-01-23 | Max-Delbrück-Centrum Für Molekulare Medizin In Der Helmholtz-Gemeinschaft | anticorpo ou fragmento de anticorpo, anticorpo ou fragmento de anticorpo isolado, conjugado de anticorpo-fármaco, molécula de ácido nucleico, célula hospedeira, e, composição farmacêutica |
-
2017
- 2017-02-16 EA EA201891851A patent/EA201891851A1/ru unknown
- 2017-06-05 TW TW112104791A patent/TW202344518A/zh unknown
- 2017-06-05 TW TW106118504A patent/TWI793075B/zh active
Also Published As
Publication number | Publication date |
---|---|
TW201813980A (zh) | 2018-04-16 |
EA201891851A1 (ru) | 2019-04-30 |
TWI793075B (zh) | 2023-02-21 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US11767365B2 (en) | BCMA antibodies and use of same to treat cancer and immunological disorders | |
US20210047404A1 (en) | Cd33 antibodies and use of same to treat cancer | |
US20230137032A1 (en) | Antigen binding proteins | |
US20230218776A1 (en) | Anti-ntb-a antibodies and related compositions and methods | |
ES2953190T3 (es) | Proteínas de unión a BCMA (CD269/TNFRSF17) | |
EP2814509B1 (en) | Antibodies to integrin v 6 and use of same to treat cancer | |
JP6449777B2 (ja) | 抗ntb−a抗体ならびに関連する組成物および方法 | |
TWI793075B (zh) | Bcma抗體及其用於治療癌症及免疫病症之用途 | |
EA045016B1 (ru) | Антитела против bcma и их применение для лечения злокачественных новообразований и иммунологических нарушений |