CN109415734B - 抗CD11d抗体及其用途 - Google Patents
抗CD11d抗体及其用途 Download PDFInfo
- Publication number
- CN109415734B CN109415734B CN201780026161.XA CN201780026161A CN109415734B CN 109415734 B CN109415734 B CN 109415734B CN 201780026161 A CN201780026161 A CN 201780026161A CN 109415734 B CN109415734 B CN 109415734B
- Authority
- CN
- China
- Prior art keywords
- seq
- amino acid
- xaa
- acid sequence
- sequence given
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 101001035237 Homo sapiens Integrin alpha-D Proteins 0.000 claims abstract description 68
- 208000020431 spinal cord injury Diseases 0.000 claims abstract description 56
- 238000000034 method Methods 0.000 claims abstract description 17
- 102000046197 human ITGAD Human genes 0.000 claims abstract description 9
- 125000003275 alpha amino acid group Chemical group 0.000 claims description 124
- 238000011282 treatment Methods 0.000 claims description 27
- 210000004027 cell Anatomy 0.000 claims description 23
- 230000027455 binding Effects 0.000 claims description 19
- 108010047041 Complementarity Determining Regions Proteins 0.000 claims description 17
- 108020004414 DNA Proteins 0.000 claims description 13
- 239000008194 pharmaceutical composition Substances 0.000 claims description 13
- 101100341505 Rattus norvegicus Itgad gene Proteins 0.000 claims description 12
- 108091033319 polynucleotide Proteins 0.000 claims description 11
- 102000040430 polynucleotide Human genes 0.000 claims description 11
- 239000002157 polynucleotide Substances 0.000 claims description 11
- 102000053602 DNA Human genes 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 6
- 210000004962 mammalian cell Anatomy 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 239000003085 diluting agent Substances 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 3
- 238000012258 culturing Methods 0.000 claims description 2
- 102100039904 Integrin alpha-D Human genes 0.000 abstract description 56
- 210000003169 central nervous system Anatomy 0.000 abstract description 33
- 208000030886 Traumatic Brain injury Diseases 0.000 abstract description 21
- 230000009529 traumatic brain injury Effects 0.000 abstract description 21
- 239000000203 mixture Substances 0.000 abstract description 7
- 230000008718 systemic inflammatory response Effects 0.000 abstract description 3
- 208000001738 Nervous System Trauma Diseases 0.000 abstract 2
- 241000700159 Rattus Species 0.000 description 40
- 208000014674 injury Diseases 0.000 description 36
- 230000008733 trauma Effects 0.000 description 28
- 206010051379 Systemic Inflammatory Response Syndrome Diseases 0.000 description 16
- 102000003896 Myeloperoxidases Human genes 0.000 description 15
- 108090000235 Myeloperoxidases Proteins 0.000 description 15
- 150000001413 amino acids Chemical class 0.000 description 15
- 230000000694 effects Effects 0.000 description 15
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 13
- -1 acyclic amino acid Chemical class 0.000 description 10
- 208000027418 Wounds and injury Diseases 0.000 description 8
- 230000006378 damage Effects 0.000 description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 8
- 108090000623 proteins and genes Proteins 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 239000013604 expression vector Substances 0.000 description 7
- 210000003141 lower extremity Anatomy 0.000 description 7
- 229920001184 polypeptide Polymers 0.000 description 7
- 108090000765 processed proteins & peptides Proteins 0.000 description 7
- 102000004196 processed proteins & peptides Human genes 0.000 description 7
- 102000004169 proteins and genes Human genes 0.000 description 7
- 125000002015 acyclic group Chemical group 0.000 description 6
- 239000000872 buffer Substances 0.000 description 6
- 201000010099 disease Diseases 0.000 description 6
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 6
- 230000002209 hydrophobic effect Effects 0.000 description 6
- 230000007935 neutral effect Effects 0.000 description 6
- 210000000440 neutrophil Anatomy 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- 102000005396 glutamine synthetase Human genes 0.000 description 5
- 108020002326 glutamine synthetase Proteins 0.000 description 5
- 210000000278 spinal cord Anatomy 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- JBGSZRYCXBPWGX-BQBZGAKWSA-N Ala-Arg-Gly Chemical compound OC(=O)CNC(=O)[C@@H](NC(=O)[C@@H](N)C)CCCN=C(N)N JBGSZRYCXBPWGX-BQBZGAKWSA-N 0.000 description 4
- VHEVVUZDDUCAKU-FXQIFTODSA-N Ala-Met-Asp Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(O)=O VHEVVUZDDUCAKU-FXQIFTODSA-N 0.000 description 4
- PONUFVLSGMQFAI-AVGNSLFASA-N Gln-Asn-Phe Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O PONUFVLSGMQFAI-AVGNSLFASA-N 0.000 description 4
- PMNHJLASAAWELO-FOHZUACHSA-N Gly-Asp-Thr Chemical compound [H]NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O PMNHJLASAAWELO-FOHZUACHSA-N 0.000 description 4
- YJDALMUYJIENAG-QWRGUYRKSA-N Gly-Tyr-Asn Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)CN)O YJDALMUYJIENAG-QWRGUYRKSA-N 0.000 description 4
- 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 4
- TWQIYNGNYNJUFM-NHCYSSNCSA-N Leu-Asn-Val Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(O)=O TWQIYNGNYNJUFM-NHCYSSNCSA-N 0.000 description 4
- 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 4
- 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 4
- 108010076504 Protein Sorting Signals Proteins 0.000 description 4
- IFPBAGJBHSNYPR-ZKWXMUAHSA-N Ser-Ile-Gly Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(O)=O IFPBAGJBHSNYPR-ZKWXMUAHSA-N 0.000 description 4
- UIPXCLNLUUAMJU-JBDRJPRFSA-N Ser-Ile-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(O)=O UIPXCLNLUUAMJU-JBDRJPRFSA-N 0.000 description 4
- NMKJPMCEKQHRPD-IRXDYDNUSA-N Tyr-Gly-Tyr Chemical compound C([C@H](N)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C1=CC=C(O)C=C1 NMKJPMCEKQHRPD-IRXDYDNUSA-N 0.000 description 4
- WTTRJMAZPDHPGS-KKXDTOCCSA-N Tyr-Phe-Ala Chemical compound C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(O)=O WTTRJMAZPDHPGS-KKXDTOCCSA-N 0.000 description 4
- 108010086434 alanyl-seryl-glycine Proteins 0.000 description 4
- 238000007796 conventional method Methods 0.000 description 4
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 4
- 108010089804 glycyl-threonine Proteins 0.000 description 4
- 108010050848 glycylleucine Proteins 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 230000003993 interaction Effects 0.000 description 4
- 230000033001 locomotion Effects 0.000 description 4
- 230000003137 locomotive effect Effects 0.000 description 4
- 239000002953 phosphate buffered saline Substances 0.000 description 4
- 238000011084 recovery Methods 0.000 description 4
- 108010061238 threonyl-glycine Proteins 0.000 description 4
- 239000013598 vector Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- SXTAYKAGBXMACB-DPVSGNNYSA-N L-methionine sulfoximine Chemical compound CS(=N)(=O)CC[C@H](N)C(O)=O SXTAYKAGBXMACB-DPVSGNNYSA-N 0.000 description 3
- 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 3
- PRKWBYCXBBSLSK-GUBZILKMSA-N Pro-Ser-Val Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O PRKWBYCXBBSLSK-GUBZILKMSA-N 0.000 description 3
- 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 3
- 239000002671 adjuvant Substances 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 239000000427 antigen Substances 0.000 description 3
- 102000036639 antigens Human genes 0.000 description 3
- 108091007433 antigens Proteins 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 239000006071 cream Substances 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 230000007717 exclusion Effects 0.000 description 3
- 108010015792 glycyllysine Proteins 0.000 description 3
- 210000004408 hybridoma Anatomy 0.000 description 3
- 230000028709 inflammatory response Effects 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 210000002540 macrophage Anatomy 0.000 description 3
- 239000003550 marker Substances 0.000 description 3
- 239000002773 nucleotide Substances 0.000 description 3
- 125000003729 nucleotide group Chemical group 0.000 description 3
- 108010031719 prolyl-serine Proteins 0.000 description 3
- 239000012266 salt solution Substances 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 210000003462 vein Anatomy 0.000 description 3
- 108010027345 wheylin-1 peptide Proteins 0.000 description 3
- NFGXHKASABOEEW-UHFFFAOYSA-N 1-methylethyl 11-methoxy-3,7,11-trimethyl-2,4-dodecadienoate Chemical compound COC(C)(C)CCCC(C)CC=CC(C)=CC(=O)OC(C)C NFGXHKASABOEEW-UHFFFAOYSA-N 0.000 description 2
- 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 2
- CREYEAPXISDKSB-FQPOAREZSA-N Ala-Thr-Tyr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O CREYEAPXISDKSB-FQPOAREZSA-N 0.000 description 2
- GIVATXIGCXFQQA-FXQIFTODSA-N Arg-Ala-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCN=C(N)N GIVATXIGCXFQQA-FXQIFTODSA-N 0.000 description 2
- 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 2
- VOKWBBBXJONREA-DCAQKATOSA-N Asn-Met-His Chemical compound CSCC[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](CC(=O)N)N VOKWBBBXJONREA-DCAQKATOSA-N 0.000 description 2
- 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 2
- 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 2
- 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 2
- NALWOULWGHTVDA-UWVGGRQHSA-N Asp-Tyr Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 NALWOULWGHTVDA-UWVGGRQHSA-N 0.000 description 2
- NJLLRXWFPQQPHV-SRVKXCTJSA-N Asp-Tyr-Asn 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](CC(N)=O)C(O)=O NJLLRXWFPQQPHV-SRVKXCTJSA-N 0.000 description 2
- 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 2
- 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 2
- RBWKVOSARCFSQQ-FXQIFTODSA-N Gln-Gln-Ser Chemical compound NC(=O)CC[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(O)=O RBWKVOSARCFSQQ-FXQIFTODSA-N 0.000 description 2
- KPNWAJMEMRCLAL-GUBZILKMSA-N Gln-Ser-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(=O)N)N KPNWAJMEMRCLAL-GUBZILKMSA-N 0.000 description 2
- ZFBBMCKQSNJZSN-AUTRQRHGSA-N Gln-Val-Gln Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O ZFBBMCKQSNJZSN-AUTRQRHGSA-N 0.000 description 2
- 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 2
- ZYRXTRTUCAVNBQ-GVXVVHGQSA-N Glu-Val-Lys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCC(=O)O)N ZYRXTRTUCAVNBQ-GVXVVHGQSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- BYYNJRSNDARRBX-YFKPBYRVSA-N Gly-Gln-Gly Chemical compound NCC(=O)N[C@@H](CCC(N)=O)C(=O)NCC(O)=O BYYNJRSNDARRBX-YFKPBYRVSA-N 0.000 description 2
- UQJNXZSSGQIPIQ-FBCQKBJTSA-N Gly-Gly-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)CNC(=O)CN UQJNXZSSGQIPIQ-FBCQKBJTSA-N 0.000 description 2
- 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 2
- ZZWUYQXMIFTIIY-WEDXCCLWSA-N Gly-Thr-Leu Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O ZZWUYQXMIFTIIY-WEDXCCLWSA-N 0.000 description 2
- 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 2
- YGHSQRJSHKYUJY-SCZZXKLOSA-N Gly-Val-Pro Chemical compound CC(C)[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)CN YGHSQRJSHKYUJY-SCZZXKLOSA-N 0.000 description 2
- 239000012981 Hank's balanced salt solution Substances 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- GTSAALPQZASLPW-KJYZGMDISA-N Ile-His-Trp Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)N[C@@H](CC2=CNC3=CC=CC=C32)C(=O)O)N GTSAALPQZASLPW-KJYZGMDISA-N 0.000 description 2
- 108060003951 Immunoglobulin Proteins 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- 108010065920 Insulin Lispro Proteins 0.000 description 2
- 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 2
- 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 2
- TYYLDKGBCJGJGW-UHFFFAOYSA-N L-tryptophan-L-tyrosine Natural products C=1NC2=CC=CC=C2C=1CC(N)C(=O)NC(C(O)=O)CC1=CC=C(O)C=C1 TYYLDKGBCJGJGW-UHFFFAOYSA-N 0.000 description 2
- 241000880493 Leptailurus serval Species 0.000 description 2
- 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 2
- GPICTNQYKHHHTH-GUBZILKMSA-N Leu-Gln-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(O)=O GPICTNQYKHHHTH-GUBZILKMSA-N 0.000 description 2
- 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 2
- 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 2
- 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 2
- SKRGVGLIRUGANF-AVGNSLFASA-N Lys-Leu-Glu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O SKRGVGLIRUGANF-AVGNSLFASA-N 0.000 description 2
- 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 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
- 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 2
- 241001465754 Metazoa Species 0.000 description 2
- 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 2
- 108010079364 N-glycylalanine Proteins 0.000 description 2
- 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 2
- 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 2
- TUYWCHPXKQTISF-LPEHRKFASA-N Pro-Cys-Pro Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CS)C(=O)N2CCC[C@@H]2C(=O)O TUYWCHPXKQTISF-LPEHRKFASA-N 0.000 description 2
- GVUVRRPYYDHHGK-VQVTYTSYSA-N Pro-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1 GVUVRRPYYDHHGK-VQVTYTSYSA-N 0.000 description 2
- GZNYIXWOIUFLGO-ZJDVBMNYSA-N Pro-Thr-Thr Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O GZNYIXWOIUFLGO-ZJDVBMNYSA-N 0.000 description 2
- 241000700157 Rattus norvegicus Species 0.000 description 2
- QGMLKFGTGXWAHF-IHRRRGAJSA-N Ser-Arg-Phe Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O QGMLKFGTGXWAHF-IHRRRGAJSA-N 0.000 description 2
- UQFYNFTYDHUIMI-WHFBIAKZSA-N Ser-Gly-Ala Chemical compound OC(=O)[C@H](C)NC(=O)CNC(=O)[C@@H](N)CO UQFYNFTYDHUIMI-WHFBIAKZSA-N 0.000 description 2
- 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 2
- 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 2
- AZWNCEBQZXELEZ-FXQIFTODSA-N Ser-Pro-Ser Chemical compound OC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O AZWNCEBQZXELEZ-FXQIFTODSA-N 0.000 description 2
- BMKNXTJLHFIAAH-CIUDSAMLSA-N Ser-Ser-Leu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O BMKNXTJLHFIAAH-CIUDSAMLSA-N 0.000 description 2
- 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 2
- 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 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 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
- MQBTXMPQNCGSSZ-OSUNSFLBSA-N Thr-Arg-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)[C@@H](C)O)CCCN=C(N)N MQBTXMPQNCGSSZ-OSUNSFLBSA-N 0.000 description 2
- 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 2
- 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 2
- 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 2
- 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 2
- 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 2
- 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 2
- 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 2
- QUILOGWWLXMSAT-IHRRRGAJSA-N Tyr-Gln-Gln Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O QUILOGWWLXMSAT-IHRRRGAJSA-N 0.000 description 2
- YMUQBRQQCPQEQN-CXTHYWKRSA-N Tyr-Ile-Tyr Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)O)NC(=O)[C@H](CC2=CC=C(C=C2)O)N YMUQBRQQCPQEQN-CXTHYWKRSA-N 0.000 description 2
- VPEFOFYNHBWFNQ-UFYCRDLUSA-N Tyr-Pro-Tyr Chemical compound C([C@H](N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C1=CC=C(O)C=C1 VPEFOFYNHBWFNQ-UFYCRDLUSA-N 0.000 description 2
- 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 2
- JQTYTBPCSOAZHI-FXQIFTODSA-N Val-Ser-Cys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)O)N JQTYTBPCSOAZHI-FXQIFTODSA-N 0.000 description 2
- 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 2
- HTONZBWRYUKUKC-RCWTZXSCSA-N Val-Thr-Val Chemical compound CC(C)[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(O)=O HTONZBWRYUKUKC-RCWTZXSCSA-N 0.000 description 2
- 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 2
- 108010069020 alanyl-prolyl-glycine Proteins 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 108010008355 arginyl-glutamine Proteins 0.000 description 2
- 108010069205 aspartyl-phenylalanine Proteins 0.000 description 2
- 108010068265 aspartyltyrosine Proteins 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 229960000074 biopharmaceutical Drugs 0.000 description 2
- 239000007975 buffered saline Substances 0.000 description 2
- 150000001720 carbohydrates Chemical class 0.000 description 2
- 235000014633 carbohydrates Nutrition 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000007906 compression Methods 0.000 description 2
- 230000006835 compression Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 230000001747 exhibiting effect Effects 0.000 description 2
- 238000000684 flow cytometry Methods 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 108010063718 gamma-glutamylaspartic acid Proteins 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 108010078144 glutaminyl-glycine Proteins 0.000 description 2
- 108010049041 glutamylalanine Proteins 0.000 description 2
- VPZXBVLAVMBEQI-UHFFFAOYSA-N glycyl-DL-alpha-alanine Natural products OC(=O)C(C)NC(=O)CN VPZXBVLAVMBEQI-UHFFFAOYSA-N 0.000 description 2
- XKUKSGPZAADMRA-UHFFFAOYSA-N glycyl-glycyl-glycine Natural products NCC(=O)NCC(=O)NCC(O)=O XKUKSGPZAADMRA-UHFFFAOYSA-N 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 229910052588 hydroxylapatite Inorganic materials 0.000 description 2
- 102000018358 immunoglobulin Human genes 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 238000005342 ion exchange Methods 0.000 description 2
- 108010044374 isoleucyl-tyrosine Proteins 0.000 description 2
- 230000003902 lesion Effects 0.000 description 2
- 239000006210 lotion Substances 0.000 description 2
- 108010064235 lysylglycine Proteins 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 230000000926 neurological effect Effects 0.000 description 2
- 230000000324 neuroprotective effect Effects 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 238000001543 one-way ANOVA Methods 0.000 description 2
- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 description 2
- 108010070409 phenylalanyl-glycyl-glycine Proteins 0.000 description 2
- 108010051242 phenylalanylserine Proteins 0.000 description 2
- 239000008057 potassium phosphate buffer Substances 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 108010079317 prolyl-tyrosine Proteins 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 238000001542 size-exclusion chromatography Methods 0.000 description 2
- 230000009870 specific binding Effects 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 210000000115 thoracic cavity Anatomy 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- 108010044292 tryptophyltyrosine Proteins 0.000 description 2
- 238000007492 two-way ANOVA Methods 0.000 description 2
- 108010003137 tyrosyltyrosine Proteins 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- COEXAQSTZUWMRI-STQMWFEESA-N (2s)-1-[2-[[(2s)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]acetyl]pyrrolidine-2-carboxylic acid Chemical compound C([C@H](N)C(=O)NCC(=O)N1[C@@H](CCC1)C(O)=O)C1=CC=C(O)C=C1 COEXAQSTZUWMRI-STQMWFEESA-N 0.000 description 1
- IESDGNYHXIOKRW-YXMSTPNBSA-N (2s)-2-[[(2s)-1-[(2s)-6-amino-2-[[(2s,3r)-2-amino-3-hydroxybutanoyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-5-(diaminomethylideneamino)pentanoic acid Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(N)=N)C(O)=O IESDGNYHXIOKRW-YXMSTPNBSA-N 0.000 description 1
- DIBLBAURNYJYBF-XLXZRNDBSA-N (2s)-2-[[(2s)-2-[[2-[[(2s)-6-amino-2-[[(2s)-2-amino-3-methylbutanoyl]amino]hexanoyl]amino]acetyl]amino]-3-phenylpropanoyl]amino]-3-(4-hydroxyphenyl)propanoic acid Chemical compound C([C@H](NC(=O)CNC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)C(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C1=CC=CC=C1 DIBLBAURNYJYBF-XLXZRNDBSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- 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
- RLMISHABBKUNFO-WHFBIAKZSA-N Ala-Ala-Gly Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)NCC(O)=O RLMISHABBKUNFO-WHFBIAKZSA-N 0.000 description 1
- WCBVQNZTOKJWJS-ACZMJKKPSA-N Ala-Cys-Glu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(O)=O)C(O)=O WCBVQNZTOKJWJS-ACZMJKKPSA-N 0.000 description 1
- DYJJJCHDHLEFDW-FXQIFTODSA-N Ala-Pro-Cys Chemical compound C[C@@H](C(=O)N1CCC[C@H]1C(=O)N[C@@H](CS)C(=O)O)N DYJJJCHDHLEFDW-FXQIFTODSA-N 0.000 description 1
- IORKCNUBHNIMKY-CIUDSAMLSA-N Ala-Pro-Glu Chemical compound C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O IORKCNUBHNIMKY-CIUDSAMLSA-N 0.000 description 1
- 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 1
- RBOBTTLFPRSXKZ-BZSNNMDCSA-N Asn-Phe-Tyr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O RBOBTTLFPRSXKZ-BZSNNMDCSA-N 0.000 description 1
- LGCVSPFCFXWUEY-IHPCNDPISA-N Asn-Trp-Tyr Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CC3=CC=C(C=C3)O)C(=O)O)NC(=O)[C@H](CC(=O)N)N LGCVSPFCFXWUEY-IHPCNDPISA-N 0.000 description 1
- YNQIDCRRTWGHJD-ZLUOBGJFSA-N Asp-Asn-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CC(O)=O YNQIDCRRTWGHJD-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
- ODNWIBOCFGMRTP-SRVKXCTJSA-N Asp-His-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC(O)=O)CC1=CN=CN1 ODNWIBOCFGMRTP-SRVKXCTJSA-N 0.000 description 1
- UZFHNLYQWMGUHU-DCAQKATOSA-N Asp-Lys-Arg Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O UZFHNLYQWMGUHU-DCAQKATOSA-N 0.000 description 1
- AHWRSSLYSGLBGD-CIUDSAMLSA-N Asp-Pro-Glu Chemical compound OC(=O)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O AHWRSSLYSGLBGD-CIUDSAMLSA-N 0.000 description 1
- VNXQRBXEQXLERQ-CIUDSAMLSA-N Asp-Ser-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(=O)O)N VNXQRBXEQXLERQ-CIUDSAMLSA-N 0.000 description 1
- YIDFBWRHIYOYAA-LKXGYXEUSA-N Asp-Ser-Thr Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(O)=O YIDFBWRHIYOYAA-LKXGYXEUSA-N 0.000 description 1
- SQIARYGNVQWOSB-BZSNNMDCSA-N Asp-Tyr-Phe Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O SQIARYGNVQWOSB-BZSNNMDCSA-N 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 238000009010 Bradford assay Methods 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 0.000 description 1
- 208000000094 Chronic Pain Diseases 0.000 description 1
- ZXCAQANTQWBICD-DCAQKATOSA-N Cys-Lys-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CS)N ZXCAQANTQWBICD-DCAQKATOSA-N 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 239000012594 Earle’s Balanced Salt Solution Substances 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 101150074355 GS gene Proteins 0.000 description 1
- DHNWZLGBTPUTQQ-QEJZJMRPSA-N Gln-Asp-Trp Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CCC(=O)N)N DHNWZLGBTPUTQQ-QEJZJMRPSA-N 0.000 description 1
- FGYPOQPQTUNESW-IUCAKERBSA-N Gln-Gly-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)CNC(=O)[C@H](CCC(=O)N)N FGYPOQPQTUNESW-IUCAKERBSA-N 0.000 description 1
- FITIQFSXXBKFFM-NRPADANISA-N Gln-Val-Ser Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(O)=O FITIQFSXXBKFFM-NRPADANISA-N 0.000 description 1
- ITYRYNUZHPNCIK-GUBZILKMSA-N Glu-Ala-Leu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(O)=O ITYRYNUZHPNCIK-GUBZILKMSA-N 0.000 description 1
- GLWXKFRTOHKGIT-ACZMJKKPSA-N Glu-Asn-Asn Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O GLWXKFRTOHKGIT-ACZMJKKPSA-N 0.000 description 1
- HNVFSTLPVJWIDV-CIUDSAMLSA-N Glu-Glu-Gln Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O HNVFSTLPVJWIDV-CIUDSAMLSA-N 0.000 description 1
- KASDBWKLWJKTLJ-GUBZILKMSA-N Glu-Glu-Met Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCSC)C(O)=O KASDBWKLWJKTLJ-GUBZILKMSA-N 0.000 description 1
- ALMBZBOCGSVSAI-ACZMJKKPSA-N Glu-Ser-Asn Chemical compound C(CC(=O)O)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(=O)N)C(=O)O)N ALMBZBOCGSVSAI-ACZMJKKPSA-N 0.000 description 1
- DMYACXMQUABZIQ-NRPADANISA-N Glu-Ser-Val Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O DMYACXMQUABZIQ-NRPADANISA-N 0.000 description 1
- MFYLRRCYBBJYPI-JYJNAYRXSA-N Glu-Tyr-Lys Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCC(=O)O)N)O MFYLRRCYBBJYPI-JYJNAYRXSA-N 0.000 description 1
- VSVZIEVNUYDAFR-YUMQZZPRSA-N Gly-Ala-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)CN VSVZIEVNUYDAFR-YUMQZZPRSA-N 0.000 description 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
- GRIRDMVMJJDZKV-RCOVLWMOSA-N Gly-Asn-Val Chemical compound [H]NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(O)=O GRIRDMVMJJDZKV-RCOVLWMOSA-N 0.000 description 1
- PABFFPWEJMEVEC-JGVFFNPUSA-N Gly-Gln-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCC(=O)N)NC(=O)CN)C(=O)O PABFFPWEJMEVEC-JGVFFNPUSA-N 0.000 description 1
- BIRKKBCSAIHDDF-WDSKDSINSA-N Gly-Glu-Cys Chemical compound NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CS)C(O)=O BIRKKBCSAIHDDF-WDSKDSINSA-N 0.000 description 1
- UUYBFNKHOCJCHT-VHSXEESVSA-N Gly-Leu-Pro Chemical compound CC(C)C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)CN UUYBFNKHOCJCHT-VHSXEESVSA-N 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- WMKXFMUJRCEGRP-SRVKXCTJSA-N His-Asn-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC2=CN=CN2)C(=O)O)N WMKXFMUJRCEGRP-SRVKXCTJSA-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
- 101100019412 Homo sapiens ITGB2 gene Proteins 0.000 description 1
- 101001099460 Homo sapiens Myeloperoxidase Proteins 0.000 description 1
- 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 1
- 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 1
- 102100025390 Integrin beta-2 Human genes 0.000 description 1
- OIARJGNVARWKFP-YUMQZZPRSA-N Leu-Asn-Gly Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(O)=O OIARJGNVARWKFP-YUMQZZPRSA-N 0.000 description 1
- QJUWBDPGGYVRHY-YUMQZZPRSA-N Leu-Gly-Cys Chemical compound CC(C)C[C@@H](C(=O)NCC(=O)N[C@@H](CS)C(=O)O)N QJUWBDPGGYVRHY-YUMQZZPRSA-N 0.000 description 1
- HYMLKESRWLZDBR-WEDXCCLWSA-N Leu-Gly-Thr Chemical compound CC(C)C[C@H](N)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(O)=O HYMLKESRWLZDBR-WEDXCCLWSA-N 0.000 description 1
- IAJFFZORSWOZPQ-SRVKXCTJSA-N Leu-Leu-Asn Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O IAJFFZORSWOZPQ-SRVKXCTJSA-N 0.000 description 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
- 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
- MPGHETGWWWUHPY-CIUDSAMLSA-N Lys-Ala-Asp Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCCN MPGHETGWWWUHPY-CIUDSAMLSA-N 0.000 description 1
- XNKDCYABMBBEKN-IUCAKERBSA-N Lys-Gly-Gln Chemical compound NCCCC[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CCC(N)=O XNKDCYABMBBEKN-IUCAKERBSA-N 0.000 description 1
- IOQWIOPSKJOEKI-SRVKXCTJSA-N Lys-Ser-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O IOQWIOPSKJOEKI-SRVKXCTJSA-N 0.000 description 1
- DLCAXBGXGOVUCD-PPCPHDFISA-N Lys-Thr-Ile Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O DLCAXBGXGOVUCD-PPCPHDFISA-N 0.000 description 1
- YFQSSOAGMZGXFT-MEYUZBJRSA-N Lys-Thr-Tyr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O YFQSSOAGMZGXFT-MEYUZBJRSA-N 0.000 description 1
- XABXVVSWUVCZST-GVXVVHGQSA-N Lys-Val-Gln Chemical compound NC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CCCCN XABXVVSWUVCZST-GVXVVHGQSA-N 0.000 description 1
- 230000004988 N-glycosylation Effects 0.000 description 1
- 108091028043 Nucleic acid sequence Proteins 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- HXSUFWQYLPKEHF-IHRRRGAJSA-N Phe-Asn-Arg Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N HXSUFWQYLPKEHF-IHRRRGAJSA-N 0.000 description 1
- CDNPIRSCAFMMBE-SRVKXCTJSA-N Phe-Asn-Ser Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(O)=O CDNPIRSCAFMMBE-SRVKXCTJSA-N 0.000 description 1
- BWTKUQPNOMMKMA-FIRPJDEBSA-N Phe-Ile-Phe Chemical compound C([C@H](N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 BWTKUQPNOMMKMA-FIRPJDEBSA-N 0.000 description 1
- MSHZERMPZKCODG-ACRUOGEOSA-N Phe-Leu-Phe Chemical compound C([C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 MSHZERMPZKCODG-ACRUOGEOSA-N 0.000 description 1
- WWPAHTZOWURIMR-ULQDDVLXSA-N Phe-Pro-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CC1=CC=CC=C1 WWPAHTZOWURIMR-ULQDDVLXSA-N 0.000 description 1
- IIEOLPMQYRBZCN-SRVKXCTJSA-N Phe-Ser-Cys Chemical compound N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)O IIEOLPMQYRBZCN-SRVKXCTJSA-N 0.000 description 1
- 108010004729 Phycoerythrin Proteins 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- OOLOTUZJUBOMAX-GUBZILKMSA-N Pro-Ala-Val Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(O)=O OOLOTUZJUBOMAX-GUBZILKMSA-N 0.000 description 1
- UAYHMOIGIQZLFR-NHCYSSNCSA-N Pro-Gln-Val Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(O)=O UAYHMOIGIQZLFR-NHCYSSNCSA-N 0.000 description 1
- LGSANCBHSMDFDY-GARJFASQSA-N Pro-Glu-Pro Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CCC(=O)O)C(=O)N2CCC[C@@H]2C(=O)O LGSANCBHSMDFDY-GARJFASQSA-N 0.000 description 1
- VPEVBAUSTBWQHN-NHCYSSNCSA-N Pro-Glu-Val Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O VPEVBAUSTBWQHN-NHCYSSNCSA-N 0.000 description 1
- ZLXKLMHAMDENIO-DCAQKATOSA-N Pro-Lys-Asp Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(O)=O ZLXKLMHAMDENIO-DCAQKATOSA-N 0.000 description 1
- PCWLNNZTBJTZRN-AVGNSLFASA-N Pro-Pro-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 PCWLNNZTBJTZRN-AVGNSLFASA-N 0.000 description 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
- OWQXAJQZLWHPBH-FXQIFTODSA-N Pro-Ser-Asn Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O OWQXAJQZLWHPBH-FXQIFTODSA-N 0.000 description 1
- 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 1
- SEZGGSHLMROBFX-CIUDSAMLSA-N Pro-Ser-Gln Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(O)=O SEZGGSHLMROBFX-CIUDSAMLSA-N 0.000 description 1
- 238000009009 Protein Assay Kit II Methods 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 206010038687 Respiratory distress Diseases 0.000 description 1
- QVOGDCQNGLBNCR-FXQIFTODSA-N Ser-Arg-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(O)=O QVOGDCQNGLBNCR-FXQIFTODSA-N 0.000 description 1
- OYEDZGNMSBZCIM-XGEHTFHBSA-N Ser-Arg-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(O)=O OYEDZGNMSBZCIM-XGEHTFHBSA-N 0.000 description 1
- VGNYHOBZJKWRGI-CIUDSAMLSA-N Ser-Asn-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CO VGNYHOBZJKWRGI-CIUDSAMLSA-N 0.000 description 1
- GZFAWAQTEYDKII-YUMQZZPRSA-N Ser-Gly-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CO GZFAWAQTEYDKII-YUMQZZPRSA-N 0.000 description 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
- HHJFMHQYEAAOBM-ZLUOBGJFSA-N Ser-Ser-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(O)=O HHJFMHQYEAAOBM-ZLUOBGJFSA-N 0.000 description 1
- 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 1
- CUXJENOFJXOSOZ-BIIVOSGPSA-N Ser-Ser-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CO)NC(=O)[C@H](CO)N)C(=O)O CUXJENOFJXOSOZ-BIIVOSGPSA-N 0.000 description 1
- 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 1
- 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 1
- 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 1
- PCJLFYBAQZQOFE-KATARQTJSA-N Ser-Thr-Lys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CO)N)O PCJLFYBAQZQOFE-KATARQTJSA-N 0.000 description 1
- 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 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- IGROJMCBGRFRGI-YTLHQDLWSA-N Thr-Ala-Ala Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(O)=O IGROJMCBGRFRGI-YTLHQDLWSA-N 0.000 description 1
- DWYAUVCQDTZIJI-VZFHVOOUSA-N Thr-Ala-Ser Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O DWYAUVCQDTZIJI-VZFHVOOUSA-N 0.000 description 1
- ODSAPYVQSLDRSR-LKXGYXEUSA-N Thr-Cys-Asn Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(O)=O ODSAPYVQSLDRSR-LKXGYXEUSA-N 0.000 description 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
- DSLHSTIUAPKERR-XGEHTFHBSA-N Thr-Cys-Val Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(=O)N[C@@H](C(C)C)C(O)=O DSLHSTIUAPKERR-XGEHTFHBSA-N 0.000 description 1
- GKWNLDNXMMLRMC-GLLZPBPUSA-N Thr-Glu-Gln Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N)O GKWNLDNXMMLRMC-GLLZPBPUSA-N 0.000 description 1
- FIFDDJFLNVAVMS-RHYQMDGZSA-N Thr-Leu-Met Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(O)=O FIFDDJFLNVAVMS-RHYQMDGZSA-N 0.000 description 1
- NCXVJIQMWSGRHY-KXNHARMFSA-N Thr-Leu-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N1CCC[C@@H]1C(=O)O)N)O NCXVJIQMWSGRHY-KXNHARMFSA-N 0.000 description 1
- 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 1
- BDGBHYCAZJPLHX-HJGDQZAQSA-N Thr-Lys-Asn Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(O)=O BDGBHYCAZJPLHX-HJGDQZAQSA-N 0.000 description 1
- DXPURPNJDFCKKO-RHYQMDGZSA-N Thr-Lys-Val Chemical compound CC(C)[C@H](NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)[C@@H](C)O)C(O)=O DXPURPNJDFCKKO-RHYQMDGZSA-N 0.000 description 1
- MROIJTGJGIDEEJ-RCWTZXSCSA-N Thr-Pro-Pro Chemical compound C[C@@H](O)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 MROIJTGJGIDEEJ-RCWTZXSCSA-N 0.000 description 1
- 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
- SGAOHNPSEPVAFP-ZDLURKLDSA-N Thr-Ser-Gly Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)NCC(O)=O SGAOHNPSEPVAFP-ZDLURKLDSA-N 0.000 description 1
- BEZTUFWTPVOROW-KJEVXHAQSA-N Thr-Tyr-Arg Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N)O BEZTUFWTPVOROW-KJEVXHAQSA-N 0.000 description 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
- QNXZCKMXHPULME-ZNSHCXBVSA-N Thr-Val-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)O)N)O QNXZCKMXHPULME-ZNSHCXBVSA-N 0.000 description 1
- 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 1
- 239000007983 Tris buffer Substances 0.000 description 1
- UKINEYBQXPMOJO-UBHSHLNASA-N Trp-Asn-Ser Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CO)C(=O)O)N UKINEYBQXPMOJO-UBHSHLNASA-N 0.000 description 1
- VTHNLRXALGUDBS-BPUTZDHNSA-N Trp-Gln-Glu Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N VTHNLRXALGUDBS-BPUTZDHNSA-N 0.000 description 1
- NLWCSMOXNKBRLC-WDSOQIARSA-N Trp-Lys-Val Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(O)=O NLWCSMOXNKBRLC-WDSOQIARSA-N 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- SLCSPPCQWUHPPO-JYJNAYRXSA-N Tyr-Glu-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 SLCSPPCQWUHPPO-JYJNAYRXSA-N 0.000 description 1
- SINRIKQYQJRGDQ-MEYUZBJRSA-N Tyr-Lys-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 SINRIKQYQJRGDQ-MEYUZBJRSA-N 0.000 description 1
- RIVVDNTUSRVTQT-IRIUXVKKSA-N Tyr-Thr-Gln Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)N)O RIVVDNTUSRVTQT-IRIUXVKKSA-N 0.000 description 1
- QHDXUYOYTPWCSK-RCOVLWMOSA-N Val-Asp-Gly Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)NCC(=O)O)N QHDXUYOYTPWCSK-RCOVLWMOSA-N 0.000 description 1
- JXGWQYWDUOWQHA-DZKIICNBSA-N Val-Gln-Phe Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)N JXGWQYWDUOWQHA-DZKIICNBSA-N 0.000 description 1
- OQWNEUXPKHIEJO-NRPADANISA-N Val-Glu-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CO)C(=O)O)N OQWNEUXPKHIEJO-NRPADANISA-N 0.000 description 1
- UEHRGZCNLSWGHK-DLOVCJGASA-N Val-Glu-Val Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O UEHRGZCNLSWGHK-DLOVCJGASA-N 0.000 description 1
- ZIGZPYJXIWLQFC-QTKMDUPCSA-N Val-His-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CN=CN1)NC(=O)[C@H](C(C)C)N)O ZIGZPYJXIWLQFC-QTKMDUPCSA-N 0.000 description 1
- XTDDIVQWDXMRJL-IHRRRGAJSA-N Val-Leu-His Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](C(C)C)N XTDDIVQWDXMRJL-IHRRRGAJSA-N 0.000 description 1
- SYSWVVCYSXBVJG-RHYQMDGZSA-N Val-Leu-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C(C)C)N)O SYSWVVCYSXBVJG-RHYQMDGZSA-N 0.000 description 1
- RYHUIHUOYRNNIE-NRPADANISA-N Val-Ser-Gln Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N RYHUIHUOYRNNIE-NRPADANISA-N 0.000 description 1
- TVGWMCTYUFBXAP-QTKMDUPCSA-N Val-Thr-His Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](C(C)C)N)O TVGWMCTYUFBXAP-QTKMDUPCSA-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
- 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 1
- ZHWZDZFWBXWPDW-GUBZILKMSA-N Val-Val-Cys Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CS)C(O)=O ZHWZDZFWBXWPDW-GUBZILKMSA-N 0.000 description 1
- LLJLBRRXKZTTRD-GUBZILKMSA-N Val-Val-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(=O)O)N LLJLBRRXKZTTRD-GUBZILKMSA-N 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 238000001042 affinity chromatography Methods 0.000 description 1
- 108010076324 alanyl-glycyl-glycine Proteins 0.000 description 1
- 108010050025 alpha-glutamyltryptophan Proteins 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 229940125681 anticonvulsant agent Drugs 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 108010052670 arginyl-glutamyl-glutamic acid Proteins 0.000 description 1
- 108010009111 arginyl-glycyl-glutamic acid Proteins 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 239000003855 balanced salt solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 230000003139 buffering effect Effects 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 210000000748 cardiovascular system Anatomy 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000021164 cell adhesion Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000011210 chromatographic step Methods 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 230000001149 cognitive effect Effects 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 238000004520 electroporation Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 208000002854 epidermolysis bullosa simplex superficialis Diseases 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 238000010353 genetic engineering Methods 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 230000013595 glycosylation Effects 0.000 description 1
- 238000006206 glycosylation reaction Methods 0.000 description 1
- 108010000434 glycyl-alanyl-leucine Proteins 0.000 description 1
- 108010050475 glycyl-leucyl-tyrosine Proteins 0.000 description 1
- 108010037850 glycylvaline Proteins 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000005802 health problem Effects 0.000 description 1
- 239000000833 heterodimer Substances 0.000 description 1
- 102000051251 human MPO Human genes 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 210000004969 inflammatory cell Anatomy 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 102000006495 integrins Human genes 0.000 description 1
- 108010044426 integrins Proteins 0.000 description 1
- 238000001361 intraarterial administration Methods 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
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 108010073472 leucyl-prolyl-proline Proteins 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 230000006742 locomotor activity Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- 238000012433 multimodal chromatography Methods 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 210000000822 natural killer cell Anatomy 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 210000004498 neuroglial cell Anatomy 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000008816 organ damage Effects 0.000 description 1
- 230000004768 organ dysfunction Effects 0.000 description 1
- 230000000242 pagocytic effect Effects 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 108010070643 prolylglutamic acid Proteins 0.000 description 1
- 108010053725 prolylvaline Proteins 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 229940125723 sedative agent Drugs 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 108010069117 seryl-lysyl-aspartic acid Proteins 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 238000004114 suspension culture Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 230000002123 temporal effect Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 230000000472 traumatic effect Effects 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- 108010080629 tryptophan-leucine Proteins 0.000 description 1
- 108010071635 tyrosyl-prolyl-arginine Proteins 0.000 description 1
- 231100000402 unacceptable toxicity Toxicity 0.000 description 1
- 108010052774 valyl-lysyl-glycyl-phenylalanyl-tyrosine Proteins 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2839—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 integrin superfamily
- C07K16/2845—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 integrin superfamily against integrin beta2-subunit-containing molecules, e.g. CD11, CD18
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- 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
- C07K2317/20—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
- C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
- C07K2317/33—Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
- C07K2317/565—Complementarity determining region [CDR]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
- C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Immunology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Molecular Biology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Transplantation (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (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)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
Abstract
人CD11d的抗体、包括这种CD11d抗体的组合物以及使用这种CD11d抗体用于治疗中枢神经***创伤包括脊髓损伤和创伤性脑损伤,以及中枢神经***创伤后的全身炎症反应的方法。
Description
发明领域
本发明属于医药领域。特别地,本发明涉及CD11d的抗体、包括这种CD11d抗体的组合物以及使用这种CD11d抗体用于治疗中枢神经***(CNS)创伤包括脊髓损伤(SCI)和创伤性脑损伤(TBI)以及CNS创伤后的全身炎症反应(SIRS)的方法。
背景技术
β2整联蛋白分子是一类跨膜异源二聚体,其包括与β亚基非共价结合的α亚基。已报道,这种膜相连种类的分子积极参与细胞粘附。CD11d,也称为整联蛋白亚基α-d(αd),是异源二聚体β2整联蛋白CD11d/CD18的α亚基。已报道,CD11d在多种免疫细胞上表达,包括嗜中性粒细胞、单核细胞、巨噬细胞、自然杀伤细胞和B和T细胞的一些亚群。虽然CD11d的表达、调节和分布尚未被完全了解,但已报道CD11d在免疫和炎症反应中起作用。
中枢神经***(CNS)损伤是多种多样的病况(例如,CNS创伤),包括创伤性脑损伤(TBI)和脊髓损伤(SCI),造成世界范围内的主要健康问题。例如,据估计,仅美国每年就有大约170万平民遭受TBI(美国疾病控制中心),以及大约12,000人遭受SCI(国家脊髓损伤统计中心)。TBI和SCI之间的共同点是通常导致的乏力(debilitation),其常常是严重且慢性的。在TBI和SCI中,最初的创伤通常伴随着炎症,其可对周围组织(包括神经元和神经胶质)造成相当大的损害。目前针对TBI和SCI两者的治疗选择包括外科手术、身体和认知康复以及镇痛药、抗惊厥药和镇静剂。
创伤性CNS损伤后也可能出现全身炎症反应综合征(SIRS)。SIRS是一种炎症状态,影响整个身体的大部分区域,甚至整个身体。SIRS的特征在于来自循环(circulation)的炎性细胞入侵器官,可能导致器官损坏。动物模型已经显示,在TBI之后,脑源性细胞因子的释放潜在地引发SIRS,导致各种继发性器官功能障碍,其影响神经***、心理***、心血管***、肺***和新陈代谢***。治疗SIRS症状的疗法目前包括抗生素和类固醇。
CD11d的抗体是已知的。例如,美国专利No.6,620,915和美国专利公开号US 2007/0092515A1公开了抗CD11d抗体和这种抗体的用途,例如其潜在地可适用于治疗多种疾病,包括I型糖尿病、动脉粥样硬化、多发性硬化、哮喘、牛皮癣、肺部炎症、类风湿性关节炎、急性呼吸窘迫、慢性疼痛和CNS损伤。然而,迄今为止,还没有靶向CD11d的抗体被批准用于治疗用途,并且患有CNS创伤的患者的治疗选择仍然有限并且未满足的需求。因此,仍然需要替代的CD11d抗体。特别地,仍然需要特异性结合CD11d并且在CNS创伤后减少炎症反应并改善神经学结果的替代的CD11d抗体。
发明内容
现在已经开发出表现出抗炎活性的新型CD11d抗体。
在本发明的一个方面,提供了CD11d抗体,其包括轻链可变区(LCVR)和重链可变区(HCVR),其中LCVR包括互补决定区(CDR)LCDR1、LCDR2和LCDR3,且HCVR包括CDR HCDR1、HCDR2和HCDR3,其中LCDR1的氨基酸序列由SEQ ID NO:13给出,LCDR2的氨基酸序列由SEQID NO:14给出,LCDR3的氨基酸序列由SEQ ID NO:15给出,HCDR1的氨基酸序列由SEQ IDNO:16给出,HCDR2的氨基酸序列由SEQ ID NO:17给出,且HCDR3的氨基酸序列由SEQ ID NO:18给出。
在另一方面,提供了人源化抗体,其表现出针对大鼠CD11d的约0.05至5.0nM范围内的结合亲和力,并且能够结合至人CD11d。
本文通过参考以下附图描述本发明的这些和其他方面。
附图简要说明
图1图示了,在实验性地诱导SCI之后,用剂量(0.5mg/kg至3.0mg/kg)的小鼠mAb217L或236G治疗的大鼠显示在SCI后的24小时,来自其损伤中心的蛋白质匀浆中的MPO水平的降低(单向ANOVA,p<0.05)。
图2图示了,在SCI后72小时,用小鼠mAb 217L和236G治疗的大鼠显示来自其损伤中心的蛋白质匀浆中的MPO活性和ED-1水平的降低(单向ANOVA,p<0.05)。
图3图示了,在实验性地诱导SCI之后,用3mg/kg的217L或236G治疗的大鼠显示出SCI后改善的后肢运动恢复(双向ANOVA,p<0.05)。
发明详述
本发明提供了结合并中和人CD11d的抗体,且其包括轻链可变区(LCVR)和重链可变区(HCVR),其中LCVR包括互补决定区(CDR)LCDR1、LCDR2和LCDR3,且HCVR包括CDR HCDR1、HCDR2和HCDR3,其中LCDR1的氨基酸序列由SEQ ID NO:13给出,LCDR2的氨基酸序列由SEQID NO:14给出,LCDR3的氨基酸序列由SEQ ID NO:15给出、HCDR1的氨基酸序列由SEQ IDNO:16给出,HCDR2的氨基酸序列由SEQ ID NO:17给出,且HCDR3的氨基酸序列由SEQ ID NO:18给出。
在这方面,在由SEQ ID NO:13给出的氨基酸序列的位置4处的Xaa可以是具有带电实体的无环极性氨基酸(an acyclic,polar amino acid),例如Gln、Arg、Lys、Asp或Glu,在由SEQ ID NO:14给出的氨基酸序列的位置5处的Xaa可以是无环氨基酸(acyclic aminoacid),包括带电荷的氨基酸例如Asp或Glu,或极性氨基酸例如Ser或Thr,或非极性氨基酸例如Gly、Ala、Val或者Leu,在由SEQ ID NO:15给出的氨基酸序列的位置6处的Xaa可以是中性、疏水、环状或无环氨基酸,例如Trp、Phe、Gly、Ala、Val、Leu或Met,在由SEQ ID NO:16给出的氨基酸序列的位置8处的Xaa可以是中性、极性或非极性氨基酸,例如Thr、Tyr、Ser、Cys或Gly、Ala、Val或Ile,在由SEQ ID NO:17给出的氨基酸序列的位置6处的Xaa可以是无环、中性、极性氨基酸,例如Asn、Glu、Ser或Cys,在由SEQ ID NO:18给出的氨基酸序列的位置5处的Xaa可以是无环、疏水性氨基酸,例如Ile、Val、Met或Leu,且在由SEQ ID NO:18给出的氨基酸序列的位置6处的Xaa可以是环状芳族氨基酸,例如Tyr、His或Phe。
根据本发明的抗体的一些这样的实施方案,在由SEQ ID NO:5给出氨基酸序列的位置4处的Xaa,LCDR2的氨基酸序列由SEQ ID NO:6给出,LCDR3的氨基酸序列由SEQ ID NO:7给出,HCDR1的氨基酸序列由SEQ ID NO:8给出,HCDR2的氨基酸序列由SEQ ID NO:9给出,且HCDR3的氨基酸序列由SEQ ID NO:10给出。
根据本发明的抗体的其他的一些这样的实施方案,在由SEQ ID NO:5给出氨基酸序列的位置4处的Xaa,在由SEQ ID NO:6给出的氨基酸序列的位置5处的Xaa是Glu,在由SEQID NO:7给出的氨基酸序列的位置6处的Xaa是Trp,在由SEQ ID NO:8给出的氨基酸序列的位置8处的Xaa是Thr,在由SEQ ID NO:9给出的氨基酸序列的位置6处的Xaa是Asn,在由SEQID NO:10给出的氨基酸序列的位置5处的Xaa是Ile,且在由SEQ ID NO:10给出的氨基酸序列的位置6处的Xaa是Tyr。
根据本发明的抗体的其他的一些这样的实施方案,在由SEQ ID NO:5给出的氨基酸序列的位置4处的Xaa是Arg,在由SEQ ID NO:6给出的氨基酸序列的位置5处的Xaa是Gly,在由SEQ ID NO:7给出的氨基酸序列的位置6处的Xaa是Phe,在由SEQ ID NO:8给出的氨基酸序列的位置8处的Xaa是Thr,在由SEQ ID NO:9给出的氨基酸序列的位置6处的Xaa是Asn,在由SEQ ID NO:10给出的氨基酸序列的位置5处的Xaa是Val,且在由SEQ ID NO:10给出的氨基酸序列的位置6处的Xaa是His。
根据本发明的抗体的甚至更进一步的一些这样的实施方案,在由SEQ ID NO:5给出的氨基酸序列的位置4处的Xaa是Gln,在由SEQ ID NO:6给出的氨基酸序列的位置5处的Xaa是Glu,在由SEQ ID NO:7给出的氨基酸序列的位置6处的Xaa是Gly,在由SEQ ID NO:8给出的氨基酸序列的位置8处的Xaa是Thr,在由SEQ ID NO:9给出的氨基酸序列的位置6处的Xaa是Ser,在由SEQ ID NO:10给出的氨基酸序列的位置5处的Xaa是Ile,且在由SEQ ID NO:10给出的氨基酸序列的位置6处的Xaa是Tyr。
根据本发明的抗体的一些这样的实施方案,在由SEQ ID NO:5给出的氨基酸序列的位置4处的Xaa是Arg,在由SEQ ID NO:6给出的氨基酸序列的位置5处的Xaa是Gly,在由SEQ ID NO:7给出的氨基酸序列的位置6处的Xaa是Phe,在由SEQ ID NO:8给出的氨基酸序列的位置8处的Xaa是Tyr,在由SEQ ID NO:9给出的氨基酸序列的位置6处的Xaa是Asn,在由SEQ ID NO:10给出的氨基酸序列的位置5处的Xaa是Ile,且在由SEQ ID NO:10给出的氨基酸序列的位置6处的Xaa是His。
根据本发明的抗体的其他的一些这样的实施方案,在由SEQ ID NO:5给出的氨基酸序列的位置4处的Xaa是Glu,在由SEQ ID NO:6给出的氨基酸序列的位置5处的Xaa是Glu,在由SEQ ID NO:7给出的氨基酸序列的位置6处的Xaa是Trp,在由SEQ ID NO:8给出的氨基酸序列的位置8处的Xaa是Thr,在由SEQ ID NO:9给出的氨基酸序列的位置6处的Xaa是Ser,在由SEQ ID NO:10给出的氨基酸序列的位置5处的Xaa是Ile,且在由SEQ ID NO:10给出的氨基酸序列的位置6处的Xaa是Tyr。
在具体的实施方案中,本发明提供结合人CD11d的抗体,例如人源化抗体,包括LCVR和HCVR,其中LCVR的氨基酸序列由SEQ ID NO:3给出,且HCVR的氨基酸序列由SEQ IDNO:4给出。在进一步具体的实施方案中,本发明提供结合人CD11d的抗体,包括轻链(LC)和重链(HC),其中LC的氨基酸序列由SEQ ID NO:1给出,且HC的氨基酸序列由SEQ ID NO:2给出。
本发明还提供治疗CNS创伤的方法,其包括向有此需要的患者(a patient inneed thereof)施用有效量的本发明的抗体。根据一些具体的实施方案,本发明提供治疗SCI、TBI和CNS创伤后的SIRS中的一种或更多种的方法,包括向有此需要的患者施用有效量的本发明的抗体。
本发明进一步提供药物组合物,其包括本发明的抗体和一种或更多种药学上可接受的载剂(carrier)、稀释剂或赋形剂。进一步地,本发明提供治疗包括脊髓损伤(SCI)和创伤性脑损伤(TBI)的CNS创伤的方法,其包括向有此需要的患者施用有效量的本发明的药物组合物。在一些实施方案中,本发明提供治疗CNS创伤后的全身炎症反应(SIRS)的方法,其包括向有此需要的患者给予有效量的本发明的药物组合物。
本发明还提供用于治疗的本发明的抗体。根据一些实施方案,本发明提供用于治疗CNS创伤的本发明的抗体。在一些具体的实施方案中,CNS创伤是SCI和TBI中的一种或更多种。在一些实施方案中,本发明提供了本发明的抗体,其用于治疗CNS创伤后的SIRS。
在一个实施方案中,本发明提供了本发明的抗体在制备用于治疗CNS创伤的药物中的用途。根据一些具体的实施方案,CNS创伤是SCI和TBI中的一种或更多种。根据一些实施方案,本发明提供了本发明的抗体在制备用于治疗CNS创伤后的SIRS的药物中的用途。
本发明还涉及编码本发明的抗体的核酸分子和表达载体(vector)。在实施方案中,本发明提供包括编码具有SEQ ID NO:1的氨基酸序列的多核苷酸序列的DNA分子。在实施方案中,本发明提供包括编码具有SEQ ID NO:2的氨基酸序列的多核苷酸序列的DNA分子。在进一步实施方案中,本发明提供包括编码具有SEQ ID NO:1的氨基酸序列的多核苷酸序列和编码具有SEQ ID NO:2的氨基酸序列的多核苷酸序列的DNA分子。在具体的实施方案中,编码具有SEQ ID NO:1的氨基酸序列的多肽的多核苷酸序列由SEQ ID NO:11提供,且编码具有SEQ ID NO:2的氨基酸序列的多肽的多核苷酸序列由SEQ ID NO:12提供。
进一步地,本发明提供一种抗体,其根据包括在表达该抗体的条件下培养宿主细胞并从该宿主细胞中回收包括LC和HC的抗体的方法进行制备,该宿主细胞包括编码具有SEQ ID NO:1的氨基酸序列的多肽的多核苷酸序列和编码具有SEQ ID NO:2的氨基酸序列的多肽的多核苷酸序列,其中LC的氨基酸序列由SEQ ID NO:1给出,且HC的氨基酸序列由SEQ ID NO:2给出。
如本文所使用的,“抗体”是包括通过二硫键相互连接的2个HC和2个LC的免疫球蛋白分子。每个LC和HC的氨基末端部分包括约100-120个氨基酸的可变区,主要负责通过其中含有的CDR进行抗原识别。CDR中散布有更保守的区域,称为框架区(“FR”)。每个LCVR和HCVR由3个CDR和4个FR组成,从氨基末端到羧基末端按照以下顺序排列:FR1、CDR1、FR2、CDR2、FR3、CDR3、FR4。LC的3个CDR被称为“LCDR1、LCDR2和LCDR3”,且HC的3个CDR被称为“HCDR1、HCDR2和HCDR3”。CDR含有与抗原形成特异性相互作用的大多数残基。抗体结合特定抗原的功能性能力很大程度上受六个CDR的影响。针对本发明抗体的LCVR和HCVR区域内的CDR结构域的氨基酸分配基于众所周知的Kabat编号惯例(Kabat,等人,Ann.NY Acad.Sci.190:382-93(1971);Kabat等人,Sequences of Proteins of Immunological Interest,FifthEdition,U.S.Department of Health and Human Services,NIH Publication No.91-3242(1991))以及North编号惯例(North等人,A New Clustering of Antibody CDR LoopConformations,Journal of Molecular Biology,406:228-256(2011))。
LC被分类为κ或λ,其各自以本领域已知的特定恒定区为特征。本发明的单克隆抗体包括κLC。HC被分类为γ、μ、α、δ或ε,并且分别将抗体的同种型定义为IgG、IgM、IgA、IgD或IgE。本发明的单克隆抗体包括IgG HC。IgG抗体可以进一步分为亚类,例如IgG1、IgG2、IgG3、IgG4。在具体实施方案中,本发明的单克隆抗体是IgG4。每个HC的羧基末端的部分限定了主要负责效应子功能的恒定区。
根据进一步的实施方案,提供了人源化抗体,其对CD11d表现出特别的结合亲和力。在一个实施方案中,人源化抗体表现出针对大鼠CD11d的约0.05至5.0nM范围内的结合亲和力。此类人源化抗体还表现出针对人CD11d的结合亲和力。优选地,抗体表现出针对大鼠CD11d的小于0.1、0.2、0.3、0.4或0.5nM且大于4.5、4.0、3.5、3.0、2.5、2.0或1.5nM的结合亲和力。因此,在一个优选的实施方案中,抗体表现出针对大鼠CD11d的约0.5-2.0nM范围内的结合亲和力。因此,高于和低于这些范围的CD11d结合亲和力可降低抗体的治疗效用,例如,可导致抗炎性能显著降低。表现出针对CD11d的这种结合亲和力的人源化抗体可基于人IgG(例如人IgG4),其具有可变CDR,例如SEQ ID NO:13、14和15的LCDR以及SEQ ID NO:16、17和18的HCDR,且优选SEQ ID NO:5、6和7的LCDR和SEQ ID NO:8、9和10的HCDR。
CD11d抗体表达
本发明的抗体可使用已知方法(例如,基因工程)制备和纯化。能够指导其可操作地连接的基因的表达的表达载体是本领域所公知的。表达载体可以编码促进宿主细胞分泌多肽的信号肽。信号肽可以是免疫球蛋白信号肽或异源信号肽。轻链和重链中的每一个可独立地表达自它们在一个载体中可操作地连接的不同启动子,或者作为选择,它们各自可以独立地表达自它们在两个载体中可操作地连接的不同启动子-一个表达轻链且一个表达重链。用于制备本发明抗体的示例性合适载体是已知的,且包括例如可从Lonza生物制剂(Lonza Biologics)中获得的载体。
编码具有SEQ ID NO:1的氨基酸序列的本发明的示例性CD11d抗体的示例性轻链的具体DNA多核苷酸序列由SEQ ID NO:11提供。编码具有SEQ ID NO:2的氨基酸序列的本发明的CD11d抗体的示例性重链的具体DNA多核苷酸序列由SEQ ID NO:12提供。
宿主细胞包括用表达本发明轻链、重链或轻链和重链的一种或更多种表达载体稳定或瞬时转染、转化、转导或感染的细胞。产生本发明CD11d抗体的宿主细胞系的产生和分离可以使用本领域已知的标准技术完成。哺乳动物细胞是用于表达本发明的融合化合物的优选的宿主细胞。具体的哺乳动物细胞包括CHO和NS0。如本领域技术人员将理解的,抗体的哺乳动物表达将导致通常在Fc区中高度保守的N-糖基化位点的糖基化。
本发明的CD11d抗体可以分泌到培养基中,例如培养宿主细胞的培养基,并且抗体可通过常规技术从其中回收或纯化。例如,抗体可以使用常规方法使用蛋白A或G亲和层析、尺寸排阻色谱(size exclusion chromatography)或Capto多元层析(Capto multimodalchromatography)从培养基中回收抗体。此外,可通过普通技术有效除去可溶性聚集体(aggregate)和多聚体,包括尺寸排阻、疏水相互作用、离子交换或羟基磷灰石层析。产物可以例如在-70℃下立即冷冻,或者可以冻干。
药物组合物
本发明的CD11d抗体可以单独施用至患者或与药学或生理学上可接受的载剂组合以单剂量或多剂量施用至患者。表述“药学上可接受的”或“生理学上可接受的”意味着适合用于药学和兽医学领域,即不具有不可接受的毒性或不适于生理学的用途。
本发明的抗体旨在通过任何合适的施用途径施用,因此,包括抗体的药物组合物被设计成适合于所选择的施用方式。适当地使用药学上可接受的稀释剂、载剂和/或赋形剂,例如分散剂、缓冲剂、表面活性剂、防腐剂、增溶剂、等渗剂、稳定剂等。所述组合物可根据例如Remington,The Science and Practice of Pharmacy,第19版,Gennaro,Ed.,MackPublishing Co.,Easton,PA 1995中公开的常规技术设计,其提供如实践者普遍知晓的制剂技术的概要。用于药物组合物的合适的载剂包括任何材料,当与本发明的抗体组合时,其保留分子的活性并且不与患者的免疫***反应。本发明的药物组合物包括化合物和一种或更多种药学上可接受的载剂、稀释剂或赋形剂。
在一个实施方案中,配制本发明的抗体用于通过肠胃外途径(包括静脉内、皮下、腹膜内或肌肉内)施用,因此,将其配制在医药级、生理学上可接受的载剂中,例如无菌和无热原形式的水溶液,任选地,缓冲的或制成等渗的水溶液。载剂可以是蒸馏水,含有无菌碳水化合物的溶液(例如蔗糖或葡萄糖)或含有氯化钠和任选缓冲的无菌盐溶液。合适的无菌盐溶液可包括不同浓度的氯化钠,例如,生理盐水(0.9%)、半生理盐水(0.45%)、四分之一生理盐水(0.22%)和包括更大量氯化钠的溶液(例如,3%-7%或更高)。盐溶液可任选地包括额外的组分,例如,如葡萄糖等的碳水化合物。包括额外组分的盐溶液的实例包括林格氏溶液,例如乳酸或醋酸林格氏溶液、磷酸盐缓冲盐水(PBS)、TRIS(羟甲基)氨基甲烷羟甲基)氨基甲烷)-缓冲盐水(TBS)、汉克斯平衡盐溶液(HBSS)、厄尔平衡溶液(EBSS)、标准枸椽酸盐(SSC)、HEPES缓冲盐水(HBS)和格氏平衡盐溶液(GBSS)。
在其他的一些实施方案中,配制本发明的抗体用于通过包括但不限于口服、鼻内、肠内、局部、舌下、动脉内、髓内、子宫内、鞘内、吸入、眼、经皮、***或直肠途径的途径施用,并将在每种情况下包括适当的载剂。对于口服施用,抗体可配制在生理盐水中,与食物复合,在胶囊中或在具有乳化剂的液体制剂中。对于局部应用乳膏(creams)、洗剂和软膏(ointments),可使用合适的基质如甘油三酯基质制备。这些乳膏、洗液和软膏也可含有表面活性剂。还可制备气溶胶制剂,其中使用合适的推进剂佐剂(propellant adjuvants)。其他佐剂也可加入到组合物中,无论其如何施用,例如,可将抗微生物剂、抗氧化剂和其他防腐剂添加到组合物中以防止在长期储存期间微生物生长和/或降解。
治疗用途
有效量的本发明的抗体或药物组合物是指达到所需治疗结果或治疗(在剂量方面和对于持续时间以及对于施用方法)所必需的量。有效量的抗体或其药物组合物可以根据例如疾病状态、年龄、性别和个体体重等因素以及抗体或其部分在该个体中引发所需反应的能力而变化。有效量也是其中治疗有益效果超过药物组合物的抗体的任何毒性或有害作用的量。通常,有效量的抗体的量的范围为约1mg/kg至100mg/kg,优选1mg/kg至10mg/kg。
如本文所使用的,“治疗”和/或“进行治疗”意指所有过程,其中可能存在减缓、中断、阻滞、控制或停止本文所述病症的发展(例如,CNS创伤诸如SCI和TBI,以及CNS创伤后的SIRS),但并不必然表明完全消除了所有病症症状。治疗包括施用本发明的CD11d抗体或其药物组合物,用于治疗患者的疾病或病况,其将受益于CD11d的降低的水平或降低的生物活性。治疗包括:(a)抑制疾病的进一步发展,即抑制CNS创伤和/或阻止与TBI、SCI和/或CNS创伤后SIRS相关的并发症;(b)缓解该疾病,即引起CNS创伤例如TBI、SCI和/或CNS创伤后的SIRS的症状或并发症的消退或缓解。预期本发明的CD11d抗体可用于治疗CNS创伤,例如TBI和SCI之一和/或CNS创伤后的SIRS。
术语“患者”、“受试者”和“个体”,在本文中可交换使用,是指包括人类和非人哺乳动物的动物,且优选地该术语是指人类。在一些实施方案中,受试者被诊断为“需要”用于包括SCI和TBI的CNS创伤和/或CNS创伤后的SIRS的治疗,或处于需要该治疗“的风险”中。
以下实施例,其例证本发明的CD11d抗体用于治疗例如SCI和TBI的CNS创伤和/或CNS创伤后的SIRS,以举例说明而非限制的方式列出。应当理解本领域普通技术人员可进行各种修改。
实施例
实施例1-抗体筛选研究
结合亲和力-217L mAb的初步特征揭示了如使用基于流式细胞术的测定所测定的针对人CD11d的~1.9nM的亲和力,以及位于I结构域内的构象表位。为了测定人源化抗体的所需特征,首先测定对CD11d的更高亲和力是否转化为更好的体内功效。将针对CD11d的217L mAb的亲和力与许多相似单克隆抗体针对大鼠和人CD11d的亲和力进行比较。结果列于下表1中:
表1.
抗体由杂交瘤217L(美国典型培养物保藏中心No:HB-12701)、杂交瘤226C(美国典型培养物保藏中心No:HB-12592)或杂交瘤236G(美国典型培养物保藏中心No:HB-12593)之一分泌,或源自217L的细胞分泌。
在SCI模型中损伤后24小时的髓过氧化物酶活性
接下来,测定受损大鼠脊髓中损伤后24小时的针对CD11d的mAb亲和力对MPO活性的影响(反映存在的嗜中性粒细胞(neutrophils)的量)。通过用5体积(w/v)的50mM磷酸钾缓冲液和5体积(w/v)的0.5%十六烷基三甲基溴化铵(用于从嗜中性粒细胞颗粒中提取MPO)在冰上通过均质化个体脊髓段来评估MPO活性。将匀浆以10,621g离心20分钟。除去上清液并保留沉淀。通过加入含有1.25mg/mL r-联大茴香胺二盐酸盐(r-dianisidinedihydrochloride)和0.05%过氧化氢的0.3mL磷酸钾缓冲溶液测定上清液中的MPO活性。一式两份测定来自个体动物的样品。通过添加0.1mL样品开始比色酶活性反应;5分钟后,加入0.1mL 0.1%叠氮化钠,停止比色反应的显影。在460nm处测量吸光度。标准曲线使用1.0单位/100μl纯化的人MPO储备液(50单位/mg冻干蛋白,Sigma-Aldrich,密苏里州圣路易斯市)的8个稀释度(0.001、0.01、0.03、0.06、0.125、0.25、0.5和1.0)制备。测定样品的MPO活性表示为每毫克组织的相对活性单位。使用改良的Bradford方法(Bio-Rad,Protein assay kitII;Bio-Rad,Hercules,CA)以牛血清白蛋白为标准确定测定样品的蛋白质浓度。
选择三种mAb,217L、236G和226C(上表中画上阴影的),其对大鼠CD11d分别具有4.42、1.40和0.33nM的结合亲和力,以进行神经保护功效筛选研究。本研究的目的是确定施用更高亲和力的CD11d mAb是否会导致脊髓损伤大鼠的更强的神经保护作用。该研究具有以下治疗组:第1组,同种型匹配的抗体对照(1B7);第2组,217L mAb;第3组,236GmAb;第4组,226C mAb。使用35g夹钳在第4胸椎脊髓段给予大鼠(每组n=18)夹钳压迫SCI。在每组中测试抗体的0.5、1.0和3.0mg/Kg三种剂量(每组n=6)。大鼠在损伤后2小时通过静脉内注射接受其mAb治疗。在损伤后24小时,将大鼠麻醉,用冷盐水灌注,取出以损伤部位为中心的0.5cm脊髓段进行分析。将组织匀浆并测定髓过氧化物酶(MPO),针对活化的嗜中性粒细胞以及,至更小的范围,巨噬细胞的既定标记物。
结果
SCI后,217L和236G mAb治疗的大鼠比1B7同种型对照mAb治疗的大鼠恢复更好的运动活性。在217L和236G mAb治疗的大鼠中,改善的运动评分在SCI后5周达到统计学显著性,并且在SCI后6周对于236G保持显著不同(图3)。
上述研究出乎意料地阐明了对大鼠CD11d表现出特别的结合亲和力(例如小于1.4nM和大于4.4nM)的单克隆抗体,导致如改善的神经学结果的体内活性。这是出乎意料的,因为通常预期较高亲和力的mAb(例如226C)至少比具有较低亲和力的mAb(例如217L和236G)更有效。
实施例2-工程化CD11d抗体的表达
本发明的工程化CD11d抗体基本上可以被如下表达和纯化。用含有编码SEQ IDNO:1的LC氨基酸序列的DNA分子和编码SEQ ID NO:2的HC氨基酸序列的DNA分子的谷氨酰胺合成酶(GS)表达载体通过电穿孔转染中国仓鼠卵巢细胞系。例如,可使用编码表2中的示例性CD11d抗体3的LC的具有SEQ ID NO:11(其中,在位置79处的n为c;在位置80处的n为a;在位置81处的n为a;在位置158处的n为a;在位置280处的n为g;在位置281处的n为g;且在位置282处的n为g)的多核苷酸序列的DNA分子,和编码表2中的示例性CD11d抗体3的HC的具有SEQ ID NO:12(其中,在位置88处的n为a;在位置89处的n为c;在位置90处的n为c;在位置163处的n为t;在位置164处的n为c;在位置301处的n为a;在位置303处的n为c;在位置304处的n为t;且在位置306处的n为c)的多核苷酸序列的DNA分子。表达载体编码SV早期(猿猴病毒40E)启动子和GS的基因。GS的表达允许谷氨酰胺(CHO细胞所需的氨基酸)的生化合成。转染后,细胞用50μM L-甲硫氨酸亚砜亚胺(MSX)进行大量选择。MSX对GS的抑制用于增加选择的严格性。可以针对表达内源水平的GS的CHO野生型细胞选择将表达载体cDNA整合到宿主细胞基因组的转录活性区域中的细胞。将经转染的集合以低密度铺板以允许稳定表达细胞的接近克隆的外生长。筛选主孔(masterwell)以表达抗体,然后在无血清悬浮培养物中扩大以用于生产。将已经被分泌了抗体的澄清培养基应用于已经用相容缓冲液(例如磷酸盐缓冲盐水(pH7.4))平衡的蛋白A亲和柱。用1M NaCl洗涤该柱以除去非特异性结合组分。将结合的抗体例如用pH(约)3.5的柠檬酸钠洗脱,并用1M Tris缓冲液中和馏分。例如通过SDS-PAGE或分析性尺寸排除检测抗体馏分,然后合并。可通过常规技术(包括尺寸排阻、疏水相互作用、离子交换或羟基磷灰石层析)有效除去可溶性聚集体和多聚体。可以使用常规技术浓缩和/或无菌过滤本发明的工程化CD11d抗体。在这些层析步骤后CD11d抗体的纯度大于95%。本发明的CD11d抗体可以立即在-70℃冷冻或在4℃下储存数月。
基本上按照如上所述的步骤制备的本发明的示例性CD11d抗体示于表2。表2的示例性CD11d抗体包括具有SEQ ID NO:1给出的氨基酸序列的LC和具有SEQ ID NO:2给出的氨基酸序列的HC,其中在特定位置处表示为Xaa的残基列于表2中。氨基酸的编号应用线性编号:在SEQ ID NO:1的位置27处的Xaa对应于在SEQ ID NO:5的位置4处的Xaa;在SEQ ID NO:1的位置53处的Xaa对应于在SEQ ID NO:6的位置5处的Xaa;在SEQ ID NO:1的位置94处的Xaa对应于在SEQ ID NO:7的位置6处的Xaa;在SEQ ID NO:2的位置30处的Xaa对应于在SEQID NO:8的位置8处的Xaa;在SEQ ID NO:2的位置55处的Xaa对应于在SEQ ID NO:9的位置6处的Xaa;在SEQ ID NO:2的位置101处的Xaa对应于在SEQ ID NO:10的位置5处的Xaa;且在SEQ ID NO:2的位置102处的Xaa对应于在SEQ ID NO:10的位置6处的Xaa。
表2:本发明示例性工程化CD11d抗体
结合亲和力
通过荧光激活细胞分拣(FACS)分析,测定表2的示例性CD11d抗体针对人和大鼠CD11d的结合亲和力。将表达人CD11d/CD18的JY细胞或用全长大鼠CD11d转染的JY细胞悬浮于含有山羊IgG(1mg/ml)的FACS缓冲液中。将细胞溶液以4.0×104个细胞的密度在50μL溶液中加入到96孔圆底板的孔中。将表2的每一种示例性CD11d抗体(25μL)或同种型对照抗体(25μL)以1:3的稀释度加入各自的孔中,最终浓度范围为4.6ng/mL至10μg/mL。将板在冰上温育30分钟,之后加入200μL FACS缓冲液,将板以2000rpm离心3分钟,弃去液体。用50μL藻红蛋白缀合抗体(Jackson ImmunoResearch p/n.709-116-149)以1:150的稀释度重悬细胞,并在冰上温育20分钟。向每个孔中加入FACS缓冲液(200μL),并将板以2000rpm旋转3分钟。弃去液体,细胞用200μL FACS缓冲液洗涤,重悬于120μL含1%多聚甲醛的PBS中,并转移至96孔平底板中。
通过流式细胞术分析染色细胞,同时在同种型对照抗体上设置门。门控的具体百分比计算为[%门控(测试抗体)-%门控(同种型对照抗体)]。基于非线性回归单点结合模型进行Kd测定。基本上按照如上所述的程序,获得表2的示例性CD11d抗体对人和大鼠CD11d的结合亲和力。
表3:表2的示例性CD11d抗体对人和大鼠CD11d的结合亲和力
表2的示例性CD11d抗体 | 人Kd(nM) | 大鼠Kd(nM) |
抗体1 | 0.4358 | 1.453 |
抗体2 | 0.3031 | 0.1329 |
抗体3 | 0.3041 | 0.6775 |
抗体4 | 0.3327 | 0.2466 |
抗体5 | 0.3436 | 1.184 |
表3中提供的数据显示本发明的示例性人源化CD11d抗体对大鼠CD11d的结合亲和力为约0.13nM至约1.45nM。该数据还表明,每种示例性CD11d人源化抗体也与人CD11d结合,并具有约0.3nM至约0.50nM范围内的结合亲和力。
大鼠SCI模型的体内炎症反应分析
使用大鼠SCI模型中的髓过氧化物酶(MPO)活性(嗜中性粒细胞的标识物)和ED-1表达(吞噬巨噬细胞的标识物)来评估SCI后的炎症程度。通过在第8胸椎(T8)的脊柱夹钳压迫,将实验性的SCI引入84只体重为210-250克且年龄约为7-8周的雌性Wistar大鼠(CharlesRiver,St.Constant,Quebec)。将大鼠分为治疗组(用表2的示例性CD11d抗体治疗),同种型对照组或非SCI对照组(每组n=6),并进一步分为24小时(n=42)和72小时(n=42)治疗组(如下表4所示)。
在SCI后2小时,在24小时治疗组中的大鼠接受以下之一的单一(single)尾静脉注射:a.)1mg/kg示例性抗体1;b.)1mg/kg示例抗体2;c.)1mg/kg示例抗体3;d.)1mg/kg示例性抗体4;e.)1mg/kg示例抗体5;或f.)1mg/kg示例性IgG4同种型对照。在72小时治疗组中的大鼠在SCI后2小时、24小时和72小时接受治疗a.)至f.)(上文)之一的尾静脉注射。在各自的治疗期后,处死大鼠。从每个治疗组的处死的大鼠以及非SCI对照组的处死的大鼠中收集来自脊椎的T8区域的脊髓。
基本上按照如上所述的程序,获得用表2的示例性CD11d抗体治疗的SCI大鼠中的MPO活性和ED-1表达。
表4:用表2的示例性抗CD11d抗体治疗的SCI大鼠中的MPO活性或ED-1表达
表4中提供的结果说明,与用同种型对照抗体治疗的SCI大鼠相比,用表2的示例性CD11d抗体治疗的SCI大鼠中(来自脊髓损伤组织的)MPO活性和ED-1表达降低。
大鼠SCI模型的体内功能性运动能力评估
Basso、Beattie、Bresnahan(BBB)量表(scale)用于SCI引入大鼠后运动能力恢复的功能性评估。BBB是基于大鼠的运动反应的半定量量表,其具有从0到21的值。该量表(0-21)表示连续恢复阶段,并且对大鼠后肢关节运动、所有三个关节的后肢运动(但没有步行(stepping))、步行、前后肢协调性、躯干位置和稳定性、爪子放置和尾部位置的组合进行分类。一般来说:0-7的评分意味着大鼠没有后肢关节运动或1至3个关节的孤立的后肢关节运动但没有步行;8-13的评分意味着大鼠有不协调的步行的间隔,体重支撑程度越来越大;并且14-21的评分表明大鼠具有前后肢协调性。
通过在第8胸椎(T8)的脊柱夹钳压迫,将实验性的SCI引入年龄约为7-8周且体重为250-300克的雌性Wistar大鼠(Charles River,St.Constant,Quebec)。将大鼠分成两个治疗组,并且给予单一尾静脉注射a.)1mg/kg表2的示例性CD11d抗体3(n=9),或b.)1mg/kgIgG4同种型对照(n=10),在SCI引入后2、24和48小时。观察者(n=3),对大鼠治疗组不知情,在SCI引入后10周里每周进行运动恢复的BBB评分。
基本上按照如上所述的程序,获得用表2的示例性CD11d抗体3治疗的SCI大鼠的功能性运动能力评估(每个BBB量表)。结果在表5中提供(通过双向ANOVA分析的结果)。
表5:用表2的示例性CD11d抗体3治疗的SCI大鼠中的功能性运动能力(BBB量表)
在第9周没有获得数据;*P<0.01
表5中提供的结果表明,与同种型对照治疗的具有SCI的大鼠相比,施用表2的示例性抗体3的大鼠更快且更大程度地实现功能性运动能力。与用同种型对照抗体治疗的大鼠相比,用表2的示例性抗体3处理的大鼠表现出显著的治疗效果(P=0.0029)、显著的时间效应(P<0.0001)以及治疗和时间的显著相互作用(P=0.0006)。
序列
示例性LC(SEQ ID NO:1)
DIQMTQSPSSLSASVGDRVTITCRASXaaSIGTRIHWYQQKPGKAPKLLIYFASXaaSISGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSKIXaaPTTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC,其中在位置27处的Xaa是Gln、Arg或Glu;在位置53处的Xaa是Glu或Gly;在位置94处的Xaa是Trp、Phe或Gly
示例性HC(SEQ ID NO:2)
QVQLVQSGAEVKKPGASVKVSCKASGYTFXaaDYNMHWVRQAPGQGLEWMGYIYPYXaaGDTGYNQNFKSRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARGLXaaXaaYGYLNVAMDSWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG,其中在位置30处的Xaa是Thr、Tyr或Gly;在位置55处的Xaa是Asn和Ser;在位置101处的Xaa是Ile或Val;在位置102处的Xaa是Tyr或His
示例性LCVR(SEQ ID NO:3)
DIQMTQSPSSLSASVGDRVTITCRASXaaSIGTRIHWYQQKPGKAPKLLIYFASXaaSISGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSKIXaaPTTFGGGTKLEIK,其中在位置27处的Xaa是Gln、Arg或Glu;在位置53处的Xaa是Glu或Gly;在位置94处的Xaa是Trp、Phe或Gly
示例性HCVR(SEQ ID NO:4)
QVQLVQSGAEVKKPGASVKVSCKASGYTFXaaDYNMHWVRQAPGQGLEWMGYIYPYXaaGDTGYNQNFKSRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARGLXaaXaaYGYLNVAMDSWGQGTLVTVSS,其中在位置30处的Xaa是Thr、Tyr或Gly;在位置55处的Xaa是Asn和Ser;在位置101处的Xaa是Ile或Val;在位置102处的Xaa是Tyr或His
示例性LCDR1(SEQ ID NO:5)
RASXaaSIGTRIH,其中在位置4处的Xaa是Gln、Arg或Glu
示例性LCDR2(SEQ ID NO:6)
YFASXaaSIS,其中在位置5处的Xaa是Glu或Gly
示例性LCDR3(SEQ ID NO:7)
QQSKIXaaPTT,其中在位置6处的Xaa是Trp、Phe或Gly
示例性HCDR1(SEQ ID NO:8)
KASGYTFXaaDYNMH,其中在位置8处的Xaa是Thr、Tyr或Gly
示例性HCDR2(SEQ ID NO:9)
YIYPYXaaGDTGYNQNFKS,其中在位置6处的Xaa是Asn或Ser
示例性HCDR3(SEQ ID NO:10)
ARGLXaaXaaYGYLNVAMDS,其中在位置5处的Xaa是Ile或Val;在位置6处的Xaa是Tyr或His
编码由SEQ ID NO:1给出的示例性LC的核苷酸序列(SEQ ID NO:11)
其中,在位置79处的n为c、a或g;在位置80处的n为a或g;在位置81处的n为a或g;在位置158处的n为a或g;在位置280处的n为g或t;在位置281处的n为g或t;在位置282处的n为g或t
编码由SEQ ID NO:2给出的示例性HC的核苷酸序列(SEQ ID NO:12)
其中,在位置88处的n为a、g或t;在位置89处的n为c、g或a;在位置90处的n为c、a或t;在位置163处的n为a或t;在位置164处的n为a或c;在位置301处的n为a或g;在位置303处的n为c或t;在位置304处的n为t或c;且在位置306处的n为c或t。
序列表
<110> 伊莱利利公司
<120> 抗CD11d抗体及其用途
<130> P-20899
<160> 18
<170> PatentIn version 3.3
<210> 1
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> 示例LC
<220>
<221> MISC_FEATURE
<222> (27)..(27)
<223> Xaa在位置27是Gln, Arg,或Glu
<220>
<221> MISC_FEATURE
<222> (53)..(53)
<223> Xaa在位置53是Glu或Gly
<220>
<221> MISC_FEATURE
<222> (94)..(94)
<223> Xaa在位置94是Trp, Phe,或Gly
<400> 1
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Xaa Ser Ile Gly Thr Arg
20 25 30
Ile His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Phe Ala Ser Xaa Ser Ile 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 Ser Lys Ile Xaa Pro Thr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 2
<211> 449
<212> PRT
<213> 人工序列
<220>
<223> 示例HC
<220>
<221> MISC_FEATURE
<222> (30)..(30)
<223> Xaa在位置30是Thr, Tyr,或Gly
<220>
<221> MISC_FEATURE
<222> (55)..(55)
<223> Xaa在位置55是Asn或Ser
<220>
<221> MISC_FEATURE
<222> (101)..(101)
<223> Xaa在位置101是Ile或Val
<220>
<221> MISC_FEATURE
<222> (102)..(102)
<223> Xaa在位置101是Tyr或His
<400> 2
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 Xaa Asp Tyr
20 25 30
Asn Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Tyr Ile Tyr Pro Tyr Xaa Gly Asp Thr Gly Tyr Asn Gln Asn Phe
50 55 60
Lys Ser 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 Gly Leu Xaa Xaa Tyr Gly Tyr Leu Asn Val Ala Met Asp Ser
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val
195 200 205
Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys
210 215 220
Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu
260 265 270
Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu
435 440 445
Gly
<210> 3
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 示例LCVR
<220>
<221> MISC_FEATURE
<222> (27)..(27)
<223> Xaa在位置27是Gln, Arg,或Glu
<220>
<221> MISC_FEATURE
<222> (53)..(53)
<223> Xaa在位置53是Glu或Gly
<220>
<221> MISC_FEATURE
<222> (94)..(94)
<223> Xaa在位置94是Trp, Phe,或Gly
<400> 3
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Xaa Ser Ile Gly Thr Arg
20 25 30
Ile His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Phe Ala Ser Xaa Ser Ile 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 Ser Lys Ile Xaa Pro Thr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 4
<211> 123
<212> PRT
<213> 人工序列
<220>
<223> 示例HCVR
<220>
<221> MISC_FEATURE
<222> (30)..(30)
<223> Xaa在位置30是Thr, Tyr,或Gly
<220>
<221> MISC_FEATURE
<222> (53)..(53)
<223> Xaa在位置53是Asn或Ser
<220>
<221> misc_feature
<222> (55)..(55)
<223> Xaa可以是任何天然氨基酸
<220>
<221> MISC_FEATURE
<222> (101)..(101)
<223> Xaa在位置101是Ile或Val
<220>
<221> MISC_FEATURE
<222> (102)..(102)
<223> Xaa在位置102是Tyr或His
<400> 4
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 Xaa Asp Tyr
20 25 30
Asn Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Tyr Ile Tyr Pro Tyr Xaa Gly Asp Thr Gly Tyr Asn Gln Asn Phe
50 55 60
Lys Ser 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 Gly Leu Xaa Xaa Tyr Gly Tyr Leu Asn Val Ala Met Asp Ser
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 5
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 示例LCDR1
<220>
<221> MISC_FEATURE
<222> (4)..(4)
<223> Xaa在位置4是Gln, Arg,或Glu
<400> 5
Arg Ala Ser Xaa Ser Ile Gly Thr Arg Ile His
1 5 10
<210> 6
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 示例LCDR2
<220>
<221> MISC_FEATURE
<222> (5)..(5)
<223> Xaa在位置5是Glu或Gly
<400> 6
Tyr Phe Ala Ser Xaa Ser Ile Ser
1 5
<210> 7
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 示例LCDR3
<220>
<221> MISC_FEATURE
<222> (6)..(6)
<223> Xaa在位置6是Trp, Phe,或Gly
<400> 7
Gln Gln Ser Lys Ile Xaa Pro Thr Thr
1 5
<210> 8
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> 示例HCDR1
<220>
<221> MISC_FEATURE
<222> (8)..(8)
<223> Xaa在位置8是Thr, Tyr,或Gly
<400> 8
Lys Ala Ser Gly Tyr Thr Phe Xaa Asp Tyr Asn Met His
1 5 10
<210> 9
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 示例HCDR2
<220>
<221> MISC_FEATURE
<222> (6)..(6)
<223> Xaa在位置6是Asn或Ser
<400> 9
Tyr Ile Tyr Pro Tyr Xaa Gly Asp Thr Gly Tyr Asn Gln Asn Phe Lys
1 5 10 15
Ser
<210> 10
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 示例HCDR3
<220>
<221> MISC_FEATURE
<222> (5)..(5)
<223> Xaa在位置5是Ile或Val
<220>
<221> MISC_FEATURE
<222> (6)..(6)
<223> Xaa在位置6是Tyr或His
<400> 10
Ala Arg Gly Leu Xaa Xaa Tyr Gly Tyr Leu Asn Val Ala Met Asp Ser
1 5 10 15
<210> 11
<211> 642
<212> DNA
<213> 人工序列
<220>
<223> 编码由SEQ ID NO:1给出的示例LC的核苷酸序列
<220>
<221> misc_feature
<222> (79)..(79)
<223> n在位置79是c, a,或g
<220>
<221> misc_feature
<222> (80)..(80)
<223> n在位置80是a或g
<220>
<221> misc_feature
<222> (81)..(81)
<223> n在位置81是a或g
<220>
<221> misc_feature
<222> (158)..(158)
<223> n在位置158是a或g
<220>
<221> misc_feature
<222> (280)..(280)
<223> n在位置280是g或t
<220>
<221> misc_feature
<222> (281)..(281)
<223> n在位置281是g或t
<220>
<221> misc_feature
<222> (282)..(282)
<223> n在位置282是g或t
<400> 11
gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60
atcacttgca gggccagtnn nagcattggc acaagaatac actggtatca gcagaaacca 120
gggaaagccc ctaagctcct gatctatttt gcttctgngt ctatctctgg agtcccatca 180
aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240
gaagattttg caacttacta ctgtcaacaa agtaaaatcn nnccaacgac gttcggcgga 300
gggaccaagc tggagatcaa acgaactgtg gctgcaccat ctgtcttcat cttcccgcca 360
tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 420
cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 480
gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 540
ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 600
ctgagctcgc ccgtcacaaa gagcttcaac aggggagagt gc 642
<210> 12
<211> 1347
<212> DNA
<213> 人工序列
<220>
<223> 编码由SEQ ID NO:2给出的示例HC的核苷酸序列
<220>
<221> misc_feature
<222> (88)..(88)
<223> n在位置88是a, g,或t
<220>
<221> misc_feature
<222> (89)..(89)
<223> n在位置89是c, g,或a
<220>
<221> misc_feature
<222> (90)..(90)
<223> n在位置90是c, a,或t
<220>
<221> misc_feature
<222> (163)..(163)
<223> n在位置163是a或t
<220>
<221> misc_feature
<222> (164)..(164)
<223> n在位置164是a或c
<220>
<221> misc_feature
<222> (301)..(301)
<223> n在位置301是a或g
<220>
<221> misc_feature
<222> (303)..(303)
<223> n在位置303是c或t
<220>
<221> misc_feature
<222> (304)..(304)
<223> n在位置304是t或c
<220>
<221> misc_feature
<222> (306)..(306)
<223> n在位置306是c或t
<400> 12
caggtgcagc tggtgcagtc tggtgctgaa gtgaagaagc ctggggcctc agtgaaggtg 60
tcctgcaagg catctggata cacattcnnn gactacaaca tgcactgggt gcgacaggcc 120
cctggacaag ggcttgagtg gatgggatat atttatcctt acnntggtga tactgggtac 180
aaccagaatt tcaagagcag agtcaccatg accagggaca cgtccacgag cacagtctac 240
atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc gagaggatta 300
ntnnantacg gctaccttaa cgttgctatg gactcctggg gccaagggac actagtcaca 360
gtctcctcag cctccaccaa gggcccatcg gtcttcccgc tagcgccctg ctccaggagc 420
acctccgaga gcacagccgc cctgggctgc ctggtcaagg actacttccc cgaaccggtg 480
acggtgtcgt ggaactcagg cgccctgacc agcggcgtgc acaccttccc ggctgtccta 540
cagtcctcag gactctactc cctcagcagc gtggtgaccg tgccctccag cagcttgggc 600
acgaagacct acacctgcaa cgtagatcac aagcccagca acaccaaggt ggacaagaga 660
gttgagtcca aatatggtcc cccatgccca ccctgcccag cacctgaggc cgccggggga 720
ccatcagtct tcctgttccc cccaaaaccc aaggacactc tcatgatctc ccggacccct 780
gaggtcacgt gcgtggtggt ggacgtgagc caggaagacc ccgaggtcca gttcaactgg 840
tacgtggatg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagttcaac 900
agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaacggcaag 960
gagtacaagt gcaaggtctc caacaaaggc ctcccgtcct ccatcgagaa aaccatctcc 1020
aaagccaaag ggcagccccg agagccacag gtgtacaccc tgcccccatc ccaggaggag 1080
atgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctaccc cagcgacatc 1140
gccgtggagt gggaaagcaa tgggcagccg gagaacaact acaagaccac gcctcccgtg 1200
ctggactccg acggctcctt cttcctctac agcaggctaa ccgtggacaa gagcaggtgg 1260
caggagggga atgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacaca 1320
cagaagagcc tctccctgtc tctgggt 1347
<210> 13
<211> 11
<212> PRT
<213> 人工
<220>
<223> 示例LCDR1
<220>
<221> MISC_FEATURE
<222> (4)..(4)
<223> Xaa在位置4是具有带电实体的非环极性氨基酸
<400> 13
Arg Ala Ser Xaa Ser Ile Gly Thr Arg Ile His
1 5 10
<210> 14
<211> 8
<212> PRT
<213> 人工
<220>
<223> 示例LCDR2
<220>
<221> MISC_FEATURE
<222> (5)..(5)
<223> Xaa在位置5是非环氨基酸
<400> 14
Tyr Phe Ala Ser Xaa Ser Ile Ser
1 5
<210> 15
<211> 9
<212> PRT
<213> 人工
<220>
<223> 示例LCDR3
<220>
<221> MISC_FEATURE
<222> (6)..(6)
<223> Xaa在位置6可以是中性疏水性氨基酸
<400> 15
Gln Gln Ser Lys Ile Xaa Pro Thr Thr
1 5
<210> 16
<211> 13
<212> PRT
<213> 人工
<220>
<223> 示例HCDR1
<220>
<221> MISC_FEATURE
<222> (8)..(8)
<223> Xaa在位置8可以是中性的极性或非极性氨基酸
<400> 16
Lys Ala Ser Gly Tyr Thr Phe Xaa Asp Tyr Asn Met His
1 5 10
<210> 17
<211> 17
<212> PRT
<213> 人工
<220>
<223> 示例HCDR2
<220>
<221> MISC_FEATURE
<222> (6)..(6)
<223> Xaa在位置6可以是非环中性的极性氨基酸
<400> 17
Tyr Ile Tyr Pro Tyr Xaa Gly Asp Thr Gly Tyr Asn Gln Asn Phe Lys
1 5 10 15
Ser
<210> 18
<211> 16
<212> PRT
<213> 人工
<220>
<223> 示例HCDR3
<220>
<221> MISC_FEATURE
<222> (5)..(5)
<223> Xaa在位置5可以是非环疏水性氨基酸
<220>
<221> MISC_FEATURE
<222> (6)..(6)
<223> Xaa在位置6可以是环状芳香性氨基酸
<400> 18
Ala Arg Gly Leu Xaa Xaa Tyr Gly Tyr Leu Asn Val Ala Met Asp Ser
1 5 10 15
Claims (12)
1.结合人CD11d的人源化抗体,其包括轻链可变区(LCVR)和重链可变区(HCVR),其中所述LCVR包括互补决定区(CDR)LCDR1、LCDR2和LCDR3,且所述HCVR包括CDR HCDR1、HCDR2和HCDR3,其中所述LCVR的氨基酸序列由SEQ ID NO:3给出,所述HCVR的氨基酸序列由SEQ IDNO:4给出,其中所述抗体表现出针对大鼠CD11d的0.13至2.0nM范围内的结合亲和力,以及表现出针对人CD11d的0.3nM至0.5nM范围内的结合亲和力,其中:
所述LCVR的在由SEQ ID NO:5给出的氨基酸序列的位置4处的Xaa是Gln;
在由SEQ ID NO:6给出的氨基酸序列的位置5处的Xaa是Glu;且
在由SEQ ID NO:7给出的氨基酸序列的位置6处的Xaa是Trp;以及
所述HCVR的在由SEQ ID NO:8给出的氨基酸序列的位置8处的Xaa是Thr;
在由SEQ ID NO:9给出的氨基酸序列的位置6处的Xaa是Asn;
在由SEQ ID NO:10给出的氨基酸序列的位置5处的Xaa是Ile,且
在由SEQ ID NO:10给出的氨基酸序列的位置6处的Xaa是Tyr;或者
所述LCVR的在由SEQ ID NO:5给出的氨基酸序列的位置4处的Xaa是Arg;
在由SEQ ID NO:6给出的氨基酸序列的位置5处的Xaa是Gly;且
在由SEQ ID NO:7给出的氨基酸序列的位置6处的Xaa是Phe;以及
所述HCVR的在由SEQ ID NO:8给出的氨基酸序列的位置8处的Xaa是Thr;
在由SEQ ID NO:9给出的氨基酸序列的位置6处的Xaa是Asn;
在由SEQ ID NO:10给出的氨基酸序列的位置5处的Xaa是Val;且
在由SEQ ID NO:10给出的氨基酸序列的位置6处的Xaa是His;或者
所述LCVR的在由SEQ ID NO:5给出的氨基酸序列的位置4处的Xaa是Gln;
在由SEQ ID NO:6给出的氨基酸序列的位置5处的Xaa是Glu;且
在由SEQ ID NO:7给出的氨基酸序列的位置6处的Xaa是Gly;以及
所述HCVR的在由SEQ ID NO:8给出的氨基酸序列的位置8处的Xaa是Thr;
在由SEQ ID NO:9给出的氨基酸序列的位置6处的Xaa是Ser;
在由SEQ ID NO:10给出的氨基酸序列的位置5处的Xaa是Ile;且
在由SEQ ID NO:10给出的氨基酸序列的位置6处的Xaa是Tyr;或者
所述LCVR的在由SEQ ID NO:5给出的氨基酸序列的位置4处的Xaa是Arg;
在由SEQ ID NO:6给出的氨基酸序列的位置5处的Xaa是Gly;且
在由SEQ ID NO:7给出的氨基酸序列的位置6处的Xaa是Phe;以及
所述HCVR的在由SEQ ID NO:8给出的氨基酸序列的位置8处的Xaa是Tyr;
在由SEQ ID NO:9给出的氨基酸序列的位置6处的Xaa是Asn;
在由SEQ ID NO:10给出的氨基酸序列的位置5处的Xaa是Ile;且
在由SEQ ID NO:10给出的氨基酸序列的位置6处的Xaa是His;或者
所述LCVR的在由SEQ ID NO:5给出的氨基酸序列的位置4处的Xaa是Glu;
在由SEQ ID NO:6给出的氨基酸序列的位置5处的Xaa是Glu;且
在由SEQ ID NO:7给出的氨基酸序列的位置6处的Xaa是Trp;以及
所述HCVR的在由SEQ ID NO:8给出的氨基酸序列的位置8处的Xaa是Thr;
在由SEQ ID NO:9给出的氨基酸序列的位置6处的Xaa是Ser;
在由SEQ ID NO:10给出的氨基酸序列的位置5处的Xaa是Ile;且
在由SEQ ID NO:10给出的氨基酸序列的位置6处的Xaa是Tyr。
2.如权利要求1所述的人源化抗体,包括轻链(LC)和重链(HC),其中所述LC的氨基酸序列由SEQ ID NO:1给出,且所述HC的氨基酸序列由SEQ ID NO:2给出。
3.包括编码如权利要求1所述的人源化抗体的多核苷酸序列的DNA分子,所述人源化抗体包括具有SEQ ID NO:3的氨基酸序列的LCVR和具有SEQ ID NO:4的氨基酸序列的HCVR。
4.包括如权利要求3所述的DNA分子的分离的哺乳动物细胞。
5.包括如权利要求3所述的DNA分子的分离的哺乳动物细胞,其中所述细胞能够表达该抗体。
6.产生如权利要求1所述的人源化抗体的方法,所述方法包括在表达所述人源化抗体的条件下培养如权利要求5所述的分离的哺乳动物细胞,并回收所述被表达的抗体。
7.通过如权利要求6所述的方法产生的抗体。
8.药物组合物,包括如权利要求1-2中任一项所述的人源化抗体和一种或更多种药学上可接受的载剂、稀释剂或赋形剂。
9.如权利要求1-2中任一项所述的人源化抗体在制备用于治疗脊髓损伤的药物中的用途。
10.如权利要求8所述的药物组合物在制备用于治疗脊髓损伤的药物中的用途。
11.如权利要求1-2中任一项所述的人源化抗体,其特征在于用于治疗脊髓损伤。
12.如权利要求1-2中任一项所述的人源化抗体,其特征在于用于制备用于治疗脊髓损伤的药物。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201662300160P | 2016-02-26 | 2016-02-26 | |
US62/300,160 | 2016-02-26 | ||
PCT/CA2017/050240 WO2017143451A1 (en) | 2016-02-26 | 2017-02-24 | Anti-cd11d antibodies and uses thereof |
Publications (2)
Publication Number | Publication Date |
---|---|
CN109415734A CN109415734A (zh) | 2019-03-01 |
CN109415734B true CN109415734B (zh) | 2022-08-19 |
Family
ID=59684741
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201780026161.XA Expired - Fee Related CN109415734B (zh) | 2016-02-26 | 2017-02-24 | 抗CD11d抗体及其用途 |
Country Status (7)
Country | Link |
---|---|
US (1) | US11873340B2 (zh) |
EP (1) | EP3420088A4 (zh) |
JP (1) | JP7328762B2 (zh) |
CN (1) | CN109415734B (zh) |
AU (1) | AU2017222928A1 (zh) |
CA (1) | CA3015398A1 (zh) |
WO (1) | WO2017143451A1 (zh) |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1352651A (zh) * | 1998-11-16 | 2002-06-05 | 艾科斯有限公司 | 应用单克隆抗α-D-抗体抑制巨噬细胞浸润的方法 |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1691835A1 (en) | 2003-11-06 | 2006-08-23 | Icos Corporation | Methods of treating chronic pain using compositions that specifically bind cd11d (alpha-d) integrin |
PL1874818T3 (pl) * | 2005-04-22 | 2011-09-30 | Lilly Co Eli | Przeciwciała swoiste wobec TGF-beta 1 |
JO3663B1 (ar) * | 2014-08-19 | 2020-08-27 | Merck Sharp & Dohme | الأجسام المضادة لمضاد lag3 وأجزاء ربط الأنتيجين |
-
2017
- 2017-02-24 EP EP17755688.3A patent/EP3420088A4/en not_active Withdrawn
- 2017-02-24 JP JP2018563749A patent/JP7328762B2/ja active Active
- 2017-02-24 WO PCT/CA2017/050240 patent/WO2017143451A1/en active Application Filing
- 2017-02-24 AU AU2017222928A patent/AU2017222928A1/en not_active Abandoned
- 2017-02-24 CA CA3015398A patent/CA3015398A1/en active Pending
- 2017-02-24 CN CN201780026161.XA patent/CN109415734B/zh not_active Expired - Fee Related
- 2017-02-24 US US16/078,813 patent/US11873340B2/en active Active
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1352651A (zh) * | 1998-11-16 | 2002-06-05 | 艾科斯有限公司 | 应用单克隆抗α-D-抗体抑制巨噬细胞浸润的方法 |
Also Published As
Publication number | Publication date |
---|---|
CA3015398A1 (en) | 2017-08-31 |
JP2019509060A (ja) | 2019-04-04 |
AU2017222928A1 (en) | 2018-09-20 |
US11873340B2 (en) | 2024-01-16 |
US20230183355A1 (en) | 2023-06-15 |
EP3420088A4 (en) | 2019-10-30 |
EP3420088A1 (en) | 2019-01-02 |
CN109415734A (zh) | 2019-03-01 |
WO2017143451A1 (en) | 2017-08-31 |
JP7328762B2 (ja) | 2023-08-17 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AU2004212843B2 (en) | Remedy for spinal injury containing interleukin-6 antagonist | |
FI120721B (fi) | IL-6-antagonistin käyttö farmaseuttisen koostumuksen valmistamiseksi nivelreuman hoitamiseksi | |
ES2878037T3 (es) | Anticuerpos anti-IL-33 y usos de los mismos | |
AU2002210952B2 (en) | Preventives or remedies for psoriasis containing as the active ingredient IL-6 antagonist | |
AU2007208678B2 (en) | Therapeutic agents for diseases involving choroidal neovascularization | |
RU2450829C2 (ru) | Ингибитор хронического отторжения | |
KR101123487B1 (ko) | 항?스클레로스틴 항체 | |
ES2932398T3 (es) | Potenciador de la respuesta de las células T antitumorales | |
CN104220455B (zh) | 抗‑baff‑抗‑il‑17双特异性抗体 | |
SA96170384B1 (ar) | وطرق تحضيرها واستخداماتها العلاجية (rsv) الاجسام المضادة المعادلة البشرية احادية النسيلة ذات الالفة العالية المختصة ببروتين - ف للفيروس المخلوي التنفسي | |
IL167436A (en) | Human anti- ifn-gamma neutralizing antibodies as selective ifn-gamma pathway inhibitors | |
KR20080027401A (ko) | 소아 만성 관절염 관련질환 치료제 | |
ZA200506706B (en) | Remedy for spinal injury containing interleukin-6 antagonist | |
KR102453573B1 (ko) | 항-pacap 항체 | |
US20230233675A1 (en) | Methods, regimens, combinations & antagonists | |
BR112015006189B1 (pt) | Uso de um anticorpo anti-gm-csf | |
JP2010095445A (ja) | Il−6アンタゴニストを有効成分とする炎症性筋疾患治療剤 | |
KR101634636B1 (ko) | 개량형 인간화 항-인간 α9 인테그린 항체 | |
CN114053403A (zh) | 融合蛋白在制备疫苗佐剂或预防和治疗病毒感染的药物中的用途 | |
CN109415734B (zh) | 抗CD11d抗体及其用途 | |
CA3123124A1 (en) | Anti-il-17a antibody and use thereof | |
US20030211103A1 (en) | Use of primate IFN-gamma binding molecules | |
CN114945593A (zh) | 抗IL-1β抗体 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant | ||
CF01 | Termination of patent right due to non-payment of annual fee | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20220819 |