KR20170005166A - 인터류킨-1 알파 항체 및 그의 사용 방법 - Google Patents
인터류킨-1 알파 항체 및 그의 사용 방법 Download PDFInfo
- Publication number
- KR20170005166A KR20170005166A KR1020167037032A KR20167037032A KR20170005166A KR 20170005166 A KR20170005166 A KR 20170005166A KR 1020167037032 A KR1020167037032 A KR 1020167037032A KR 20167037032 A KR20167037032 A KR 20167037032A KR 20170005166 A KR20170005166 A KR 20170005166A
- Authority
- KR
- South Korea
- Prior art keywords
- ser
- val
- leu
- thr
- gly
- Prior art date
Links
- 238000000034 method Methods 0.000 title description 40
- 108010082786 Interleukin-1alpha Proteins 0.000 title description 3
- 102000004125 Interleukin-1alpha Human genes 0.000 title description 3
- 241000282414 Homo sapiens Species 0.000 claims abstract description 63
- 210000004027 cell Anatomy 0.000 claims description 89
- 101001002634 Homo sapiens Interleukin-1 alpha Proteins 0.000 claims description 52
- 150000007523 nucleic acids Chemical class 0.000 claims description 22
- 108020004707 nucleic acids Proteins 0.000 claims description 21
- 102000039446 nucleic acids Human genes 0.000 claims description 21
- 210000002469 basement membrane Anatomy 0.000 claims description 6
- 210000004881 tumor cell Anatomy 0.000 claims description 4
- 230000004709 cell invasion Effects 0.000 claims description 3
- 230000002401 inhibitory effect Effects 0.000 claims description 3
- 125000003275 alpha amino acid group Chemical group 0.000 claims 3
- 239000008194 pharmaceutical composition Substances 0.000 claims 3
- 102000006395 Globulins Human genes 0.000 claims 1
- 108010044091 Globulins Proteins 0.000 claims 1
- 238000009739 binding Methods 0.000 abstract description 25
- 239000000427 antigen Substances 0.000 abstract description 8
- 102000036639 antigens Human genes 0.000 abstract description 8
- 108091007433 antigens Proteins 0.000 abstract description 8
- 150000001413 amino acids Chemical group 0.000 description 21
- 239000000523 sample Substances 0.000 description 20
- 108090000623 proteins and genes Proteins 0.000 description 15
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 13
- 102000004169 proteins and genes Human genes 0.000 description 12
- 210000003719 b-lymphocyte Anatomy 0.000 description 11
- 239000000758 substrate Substances 0.000 description 11
- 102100023471 E-selectin Human genes 0.000 description 9
- 102100037877 Intercellular adhesion molecule 1 Human genes 0.000 description 9
- 108010031719 prolyl-serine Proteins 0.000 description 9
- 108010073969 valyllysine Proteins 0.000 description 9
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 8
- HNDMFDBQXYZSRM-IHRRRGAJSA-N Ser-Val-Phe Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O HNDMFDBQXYZSRM-IHRRRGAJSA-N 0.000 description 8
- 239000000872 buffer Substances 0.000 description 8
- 231100000599 cytotoxic agent Toxicity 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- 108020004414 DNA Proteins 0.000 description 7
- 239000001963 growth medium Substances 0.000 description 7
- 230000001404 mediated effect Effects 0.000 description 7
- 239000006228 supernatant Substances 0.000 description 7
- 239000013598 vector Substances 0.000 description 7
- OHLLDUNVMPPUMD-DCAQKATOSA-N Cys-Leu-Val Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](C(C)C)C(=O)O)NC(=O)[C@H](CS)N OHLLDUNVMPPUMD-DCAQKATOSA-N 0.000 description 6
- 108010024212 E-Selectin Proteins 0.000 description 6
- 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 6
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 6
- 101000762949 Pseudomonas aeruginosa (strain ATCC 15692 / DSM 22644 / CIP 104116 / JCM 14847 / LMG 12228 / 1C / PRS 101 / PAO1) Exotoxin A Proteins 0.000 description 6
- 108010087924 alanylproline Proteins 0.000 description 6
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 6
- 239000002619 cytotoxin Substances 0.000 description 6
- 238000001514 detection method Methods 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- XKUKSGPZAADMRA-UHFFFAOYSA-N glycyl-glycyl-glycine Natural products NCC(=O)NCC(=O)NCC(O)=O XKUKSGPZAADMRA-UHFFFAOYSA-N 0.000 description 6
- 108010015792 glycyllysine Proteins 0.000 description 6
- 239000002609 medium Substances 0.000 description 6
- 108010077112 prolyl-proline Proteins 0.000 description 6
- 108010070643 prolylglutamic acid Proteins 0.000 description 6
- 238000010186 staining Methods 0.000 description 6
- 108090000790 Enzymes Proteins 0.000 description 5
- 102000004190 Enzymes Human genes 0.000 description 5
- 108010064593 Intercellular Adhesion Molecule-1 Proteins 0.000 description 5
- BRTVHXHCUSXYRI-CIUDSAMLSA-N Leu-Ser-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O BRTVHXHCUSXYRI-CIUDSAMLSA-N 0.000 description 5
- QEDMOZUJTGEIBF-FXQIFTODSA-N Ser-Arg-Asp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(O)=O QEDMOZUJTGEIBF-FXQIFTODSA-N 0.000 description 5
- 210000002889 endothelial cell Anatomy 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 230000002147 killing effect Effects 0.000 description 5
- 108010017391 lysylvaline Proteins 0.000 description 5
- 108010082117 matrigel Proteins 0.000 description 5
- 238000001890 transfection Methods 0.000 description 5
- 238000011144 upstream manufacturing Methods 0.000 description 5
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 4
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 4
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 4
- 238000002965 ELISA Methods 0.000 description 4
- 102000009109 Fc receptors Human genes 0.000 description 4
- 108010087819 Fc receptors Proteins 0.000 description 4
- 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 4
- WGYHAAXZWPEBDQ-IFFSRLJSSA-N Glu-Val-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O WGYHAAXZWPEBDQ-IFFSRLJSSA-N 0.000 description 4
- NNCSJUBVFBDDLC-YUMQZZPRSA-N Gly-Leu-Ser Chemical compound NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O NNCSJUBVFBDDLC-YUMQZZPRSA-N 0.000 description 4
- 101000599852 Homo sapiens Intercellular adhesion molecule 1 Proteins 0.000 description 4
- 206010061218 Inflammation Diseases 0.000 description 4
- 102100020881 Interleukin-1 alpha Human genes 0.000 description 4
- 102000000588 Interleukin-2 Human genes 0.000 description 4
- 108010002350 Interleukin-2 Proteins 0.000 description 4
- 108090001005 Interleukin-6 Proteins 0.000 description 4
- QLFAPXUXEBAWEK-NHCYSSNCSA-N Lys-Val-Asp Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O QLFAPXUXEBAWEK-NHCYSSNCSA-N 0.000 description 4
- 241001529936 Murinae Species 0.000 description 4
- SITLTJHOQZFJGG-UHFFFAOYSA-N N-L-alpha-glutamyl-L-valine Natural products CC(C)C(C(O)=O)NC(=O)C(N)CCC(O)=O SITLTJHOQZFJGG-UHFFFAOYSA-N 0.000 description 4
- SJRQWEDYTKYHHL-SLFFLAALSA-N Phe-Tyr-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC2=CC=C(C=C2)O)NC(=O)[C@H](CC3=CC=CC=C3)N)C(=O)O SJRQWEDYTKYHHL-SLFFLAALSA-N 0.000 description 4
- 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 4
- YDTUEBLEAVANFH-RCWTZXSCSA-N Pro-Val-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H]1CCCN1 YDTUEBLEAVANFH-RCWTZXSCSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 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 4
- 101710120037 Toxin CcdB Proteins 0.000 description 4
- 108010052670 arginyl-glutamyl-glutamic acid Proteins 0.000 description 4
- 229910002091 carbon monoxide Inorganic materials 0.000 description 4
- 239000012636 effector Substances 0.000 description 4
- 239000012894 fetal calf serum Substances 0.000 description 4
- 108010049041 glutamylalanine Proteins 0.000 description 4
- 238000003018 immunoassay Methods 0.000 description 4
- 230000004054 inflammatory process Effects 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- JBGSZRYCXBPWGX-BQBZGAKWSA-N Ala-Arg-Gly Chemical compound OC(=O)CNC(=O)[C@@H](NC(=O)[C@@H](N)C)CCCN=C(N)N JBGSZRYCXBPWGX-BQBZGAKWSA-N 0.000 description 3
- BLGHHPHXVJWCNK-GUBZILKMSA-N Ala-Gln-Leu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(O)=O BLGHHPHXVJWCNK-GUBZILKMSA-N 0.000 description 3
- GRIFPSOFWFIICX-GOPGUHFVSA-N Ala-His-Trp Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O GRIFPSOFWFIICX-GOPGUHFVSA-N 0.000 description 3
- MNZHHDPWDWQJCQ-YUMQZZPRSA-N Ala-Leu-Gly Chemical compound C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O MNZHHDPWDWQJCQ-YUMQZZPRSA-N 0.000 description 3
- DPNZTBKGAUAZQU-DLOVCJGASA-N Ala-Leu-His Chemical compound C[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N DPNZTBKGAUAZQU-DLOVCJGASA-N 0.000 description 3
- MEFILNJXAVSUTO-JXUBOQSCSA-N Ala-Leu-Thr Chemical compound C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O MEFILNJXAVSUTO-JXUBOQSCSA-N 0.000 description 3
- MDNAVFBZPROEHO-UHFFFAOYSA-N Ala-Lys-Val Natural products CC(C)C(C(O)=O)NC(=O)C(NC(=O)C(C)N)CCCCN MDNAVFBZPROEHO-UHFFFAOYSA-N 0.000 description 3
- ADSGHMXEAZJJNF-DCAQKATOSA-N Ala-Pro-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H](C)N ADSGHMXEAZJJNF-DCAQKATOSA-N 0.000 description 3
- BTRULDJUUVGRNE-DCAQKATOSA-N Ala-Pro-Lys Chemical compound C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(O)=O BTRULDJUUVGRNE-DCAQKATOSA-N 0.000 description 3
- 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 3
- REWSWYIDQIELBE-FXQIFTODSA-N Ala-Val-Ser Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(O)=O REWSWYIDQIELBE-FXQIFTODSA-N 0.000 description 3
- OTZMRMHZCMZOJZ-SRVKXCTJSA-N Arg-Leu-Glu Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O OTZMRMHZCMZOJZ-SRVKXCTJSA-N 0.000 description 3
- FVBZXNSRIDVYJS-AVGNSLFASA-N Arg-Pro-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CCCN=C(N)N FVBZXNSRIDVYJS-AVGNSLFASA-N 0.000 description 3
- ZJBUILVYSXQNSW-YTWAJWBKSA-N Arg-Thr-Pro Chemical compound C[C@H]([C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCCN=C(N)N)N)O ZJBUILVYSXQNSW-YTWAJWBKSA-N 0.000 description 3
- SUMJNGAMIQSNGX-TUAOUCFPSA-N Arg-Val-Pro Chemical compound CC(C)[C@H](NC(=O)[C@@H](N)CCCNC(N)=N)C(=O)N1CCC[C@@H]1C(O)=O SUMJNGAMIQSNGX-TUAOUCFPSA-N 0.000 description 3
- BVLIJXXSXBUGEC-SRVKXCTJSA-N Asn-Asn-Tyr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O BVLIJXXSXBUGEC-SRVKXCTJSA-N 0.000 description 3
- SRUUBQBAVNQZGJ-LAEOZQHASA-N Asn-Gln-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CC(=O)N)N SRUUBQBAVNQZGJ-LAEOZQHASA-N 0.000 description 3
- WQLJRNRLHWJIRW-KKUMJFAQSA-N Asn-His-Tyr Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)O)NC(=O)[C@H](CC2=CN=CN2)NC(=O)[C@H](CC(=O)N)N)O WQLJRNRLHWJIRW-KKUMJFAQSA-N 0.000 description 3
- RCFGLXMZDYNRSC-CIUDSAMLSA-N Asn-Lys-Ala Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O RCFGLXMZDYNRSC-CIUDSAMLSA-N 0.000 description 3
- HPBNLFLSSQDFQW-WHFBIAKZSA-N Asn-Ser-Gly Chemical compound NC(=O)C[C@H](N)C(=O)N[C@@H](CO)C(=O)NCC(O)=O HPBNLFLSSQDFQW-WHFBIAKZSA-N 0.000 description 3
- UGXYFDQFLVCDFC-CIUDSAMLSA-N Asn-Ser-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O UGXYFDQFLVCDFC-CIUDSAMLSA-N 0.000 description 3
- HNXWVVHIGTZTBO-LKXGYXEUSA-N Asn-Ser-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O HNXWVVHIGTZTBO-LKXGYXEUSA-N 0.000 description 3
- MJIJBEYEHBKTIM-BYULHYEWSA-N Asn-Val-Asn Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CC(=O)N)N MJIJBEYEHBKTIM-BYULHYEWSA-N 0.000 description 3
- KBQOUDLMWYWXNP-YDHLFZDLSA-N Asn-Val-Phe Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)NC(=O)[C@H](CC(=O)N)N KBQOUDLMWYWXNP-YDHLFZDLSA-N 0.000 description 3
- 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 3
- 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 3
- CUQDCPXNZPDYFQ-ZLUOBGJFSA-N Asp-Ser-Asp Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(O)=O CUQDCPXNZPDYFQ-ZLUOBGJFSA-N 0.000 description 3
- QSFHZPQUAAQHAQ-CIUDSAMLSA-N Asp-Ser-Leu Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O QSFHZPQUAAQHAQ-CIUDSAMLSA-N 0.000 description 3
- 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 3
- JSNWZMFSLIWAHS-HJGDQZAQSA-N Asp-Thr-Leu Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)O)NC(=O)[C@H](CC(=O)O)N)O JSNWZMFSLIWAHS-HJGDQZAQSA-N 0.000 description 3
- QOJJMJKTMKNFEF-ZKWXMUAHSA-N Asp-Val-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CC(O)=O QOJJMJKTMKNFEF-ZKWXMUAHSA-N 0.000 description 3
- 101100505161 Caenorhabditis elegans mel-32 gene Proteins 0.000 description 3
- 108020004705 Codon Proteins 0.000 description 3
- 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 3
- YMBAVNPKBWHDAW-CIUDSAMLSA-N Cys-Asp-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CS)N YMBAVNPKBWHDAW-CIUDSAMLSA-N 0.000 description 3
- SMEYEQDCCBHTEF-FXQIFTODSA-N Cys-Pro-Ala Chemical compound [H]N[C@@H](CS)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C)C(O)=O SMEYEQDCCBHTEF-FXQIFTODSA-N 0.000 description 3
- KSMSFCBQBQPFAD-GUBZILKMSA-N Cys-Pro-Pro Chemical compound SC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 KSMSFCBQBQPFAD-GUBZILKMSA-N 0.000 description 3
- NDNZRWUDUMTITL-FXQIFTODSA-N Cys-Ser-Val Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O NDNZRWUDUMTITL-FXQIFTODSA-N 0.000 description 3
- ALTQTAKGRFLRLR-GUBZILKMSA-N Cys-Val-Val Chemical compound CC(C)[C@@H](C(=O)N[C@@H](C(C)C)C(=O)O)NC(=O)[C@H](CS)N ALTQTAKGRFLRLR-GUBZILKMSA-N 0.000 description 3
- 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 3
- NVEASDQHBRZPSU-BQBZGAKWSA-N Gln-Gln-Gly Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(O)=O NVEASDQHBRZPSU-BQBZGAKWSA-N 0.000 description 3
- GNMQDOGFWYWPNM-LAEOZQHASA-N Gln-Gly-Ile Chemical compound CC[C@H](C)[C@H](NC(=O)CNC(=O)[C@@H](N)CCC(N)=O)C(O)=O GNMQDOGFWYWPNM-LAEOZQHASA-N 0.000 description 3
- HMIXCETWRYDVMO-GUBZILKMSA-N Gln-Pro-Glu Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O HMIXCETWRYDVMO-GUBZILKMSA-N 0.000 description 3
- 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 3
- 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 3
- HUFCEIHAFNVSNR-IHRRRGAJSA-N Glu-Gln-Tyr Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 HUFCEIHAFNVSNR-IHRRRGAJSA-N 0.000 description 3
- MWMJCGBSIORNCD-AVGNSLFASA-N Glu-Leu-Leu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O MWMJCGBSIORNCD-AVGNSLFASA-N 0.000 description 3
- AAJHGGDRKHYSDH-GUBZILKMSA-N Glu-Pro-Gln Chemical compound C1C[C@H](N(C1)C(=O)[C@H](CCC(=O)O)N)C(=O)N[C@@H](CCC(=O)N)C(=O)O AAJHGGDRKHYSDH-GUBZILKMSA-N 0.000 description 3
- GPSHCSTUYOQPAI-JHEQGTHGSA-N Glu-Thr-Gly Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(O)=O GPSHCSTUYOQPAI-JHEQGTHGSA-N 0.000 description 3
- BPCLDCNZBUYGOD-BPUTZDHNSA-N Glu-Trp-Glu Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](CCC(O)=O)N)C(=O)N[C@@H](CCC(O)=O)C(O)=O)=CNC2=C1 BPCLDCNZBUYGOD-BPUTZDHNSA-N 0.000 description 3
- MIWJDJAMMKHUAR-ZVZYQTTQSA-N Glu-Trp-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)NC(=O)[C@H](CCC(=O)O)N MIWJDJAMMKHUAR-ZVZYQTTQSA-N 0.000 description 3
- KKBWDNZXYLGJEY-UHFFFAOYSA-N Gly-Arg-Pro Natural products NCC(=O)NC(CCNC(=N)N)C(=O)N1CCCC1C(=O)O KKBWDNZXYLGJEY-UHFFFAOYSA-N 0.000 description 3
- 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 3
- BUEFQXUHTUZXHR-LURJTMIESA-N Gly-Gly-Pro zwitterion Chemical compound NCC(=O)NCC(=O)N1CCC[C@H]1C(O)=O BUEFQXUHTUZXHR-LURJTMIESA-N 0.000 description 3
- GMTXWRIDLGTVFC-IUCAKERBSA-N Gly-Lys-Glu Chemical compound [H]NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(O)=O GMTXWRIDLGTVFC-IUCAKERBSA-N 0.000 description 3
- PDUHNKAFQXQNLH-ZETCQYMHSA-N Gly-Lys-Gly Chemical compound NCCCC[C@H](NC(=O)CN)C(=O)NCC(O)=O PDUHNKAFQXQNLH-ZETCQYMHSA-N 0.000 description 3
- WNZOCXUOGVYYBJ-CDMKHQONSA-N Gly-Phe-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)NC(=O)CN)O WNZOCXUOGVYYBJ-CDMKHQONSA-N 0.000 description 3
- OHUKZZYSJBKFRR-WHFBIAKZSA-N Gly-Ser-Asp Chemical compound [H]NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(O)=O OHUKZZYSJBKFRR-WHFBIAKZSA-N 0.000 description 3
- JSLVAHYTAJJEQH-QWRGUYRKSA-N Gly-Ser-Phe Chemical compound NCC(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 JSLVAHYTAJJEQH-QWRGUYRKSA-N 0.000 description 3
- CQMFNTVQVLQRLT-JHEQGTHGSA-N Gly-Thr-Gln Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(N)=O)C(O)=O CQMFNTVQVLQRLT-JHEQGTHGSA-N 0.000 description 3
- SYOJVRNQCXYEOV-XVKPBYJWSA-N Gly-Val-Glu Chemical compound [H]NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O SYOJVRNQCXYEOV-XVKPBYJWSA-N 0.000 description 3
- FULZDMOZUZKGQU-ONGXEEELSA-N Gly-Val-His Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)CN FULZDMOZUZKGQU-ONGXEEELSA-N 0.000 description 3
- KSOBNUBCYHGUKH-UWVGGRQHSA-N Gly-Val-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)CN KSOBNUBCYHGUKH-UWVGGRQHSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 239000004471 Glycine Substances 0.000 description 3
- 239000012981 Hank's balanced salt solution Substances 0.000 description 3
- SDTPKSOWFXBACN-GUBZILKMSA-N His-Glu-Asp Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O SDTPKSOWFXBACN-GUBZILKMSA-N 0.000 description 3
- TTYKEFZRLKQTHH-MELADBBJSA-N His-Lys-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCCCN)NC(=O)[C@H](CC2=CN=CN2)N)C(=O)O TTYKEFZRLKQTHH-MELADBBJSA-N 0.000 description 3
- 101000622123 Homo sapiens E-selectin Proteins 0.000 description 3
- DFJJAVZIHDFOGQ-MNXVOIDGSA-N Ile-Glu-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCCCN)C(=O)O)N DFJJAVZIHDFOGQ-MNXVOIDGSA-N 0.000 description 3
- IOVUXUSIGXCREV-DKIMLUQUSA-N Ile-Leu-Phe Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 IOVUXUSIGXCREV-DKIMLUQUSA-N 0.000 description 3
- PXKACEXYLPBMAD-JBDRJPRFSA-N Ile-Ser-Ser Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)O)N PXKACEXYLPBMAD-JBDRJPRFSA-N 0.000 description 3
- 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 3
- 241000880493 Leptailurus serval Species 0.000 description 3
- HXWALXSAVBLTPK-NUTKFTJISA-N Leu-Ala-Trp Chemical compound C[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)NC(=O)[C@H](CC(C)C)N HXWALXSAVBLTPK-NUTKFTJISA-N 0.000 description 3
- AXZGZMGRBDQTEY-SRVKXCTJSA-N Leu-Gln-Met Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCSC)C(O)=O AXZGZMGRBDQTEY-SRVKXCTJSA-N 0.000 description 3
- CQGSYZCULZMEDE-SRVKXCTJSA-N Leu-Gln-Pro Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N1CCC[C@H]1C(O)=O CQGSYZCULZMEDE-SRVKXCTJSA-N 0.000 description 3
- 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 3
- HYIFFZAQXPUEAU-QWRGUYRKSA-N Leu-Gly-Leu Chemical compound CC(C)C[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CC(C)C HYIFFZAQXPUEAU-QWRGUYRKSA-N 0.000 description 3
- BKTXKJMNTSMJDQ-AVGNSLFASA-N Leu-His-Gln Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N BKTXKJMNTSMJDQ-AVGNSLFASA-N 0.000 description 3
- DSFYPIUSAMSERP-IHRRRGAJSA-N Leu-Leu-Arg Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CCCN=C(N)N DSFYPIUSAMSERP-IHRRRGAJSA-N 0.000 description 3
- FAELBUXXFQLUAX-AJNGGQMLSA-N Leu-Leu-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC(C)C FAELBUXXFQLUAX-AJNGGQMLSA-N 0.000 description 3
- FOBUGKUBUJOWAD-IHPCNDPISA-N Leu-Leu-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC(C)C)C(O)=O)=CNC2=C1 FOBUGKUBUJOWAD-IHPCNDPISA-N 0.000 description 3
- UHNQRAFSEBGZFZ-YESZJQIVSA-N Leu-Phe-Pro Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N2CCC[C@@H]2C(=O)O)N UHNQRAFSEBGZFZ-YESZJQIVSA-N 0.000 description 3
- DPURXCQCHSQPAN-AVGNSLFASA-N Leu-Pro-Pro Chemical compound CC(C)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 DPURXCQCHSQPAN-AVGNSLFASA-N 0.000 description 3
- KIZIOFNVSOSKJI-CIUDSAMLSA-N Leu-Ser-Cys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)O)N KIZIOFNVSOSKJI-CIUDSAMLSA-N 0.000 description 3
- XOWMDXHFSBCAKQ-SRVKXCTJSA-N Leu-Ser-Leu Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CC(C)C XOWMDXHFSBCAKQ-SRVKXCTJSA-N 0.000 description 3
- SBANPBVRHYIMRR-UHFFFAOYSA-N Leu-Ser-Pro Natural products CC(C)CC(N)C(=O)NC(CO)C(=O)N1CCCC1C(O)=O SBANPBVRHYIMRR-UHFFFAOYSA-N 0.000 description 3
- AIQWYVFNBNNOLU-RHYQMDGZSA-N Leu-Thr-Val Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(O)=O AIQWYVFNBNNOLU-RHYQMDGZSA-N 0.000 description 3
- VUBIPAHVHMZHCM-KKUMJFAQSA-N Leu-Tyr-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](CO)C(O)=O)CC1=CC=C(O)C=C1 VUBIPAHVHMZHCM-KKUMJFAQSA-N 0.000 description 3
- AIMGJYMCTAABEN-GVXVVHGQSA-N Leu-Val-Glu Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O AIMGJYMCTAABEN-GVXVVHGQSA-N 0.000 description 3
- WSXTWLJHTLRFLW-SRVKXCTJSA-N Lys-Ala-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(O)=O WSXTWLJHTLRFLW-SRVKXCTJSA-N 0.000 description 3
- NTBFKPBULZGXQL-KKUMJFAQSA-N Lys-Asp-Tyr Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 NTBFKPBULZGXQL-KKUMJFAQSA-N 0.000 description 3
- GQZMPWBZQALKJO-UWVGGRQHSA-N Lys-Gly-Arg Chemical compound [H]N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(O)=O GQZMPWBZQALKJO-UWVGGRQHSA-N 0.000 description 3
- RFQATBGBLDAKGI-VHSXEESVSA-N Lys-Gly-Pro Chemical compound C1C[C@@H](N(C1)C(=O)CNC(=O)[C@H](CCCCN)N)C(=O)O RFQATBGBLDAKGI-VHSXEESVSA-N 0.000 description 3
- OIQSIMFSVLLWBX-VOAKCMCISA-N Lys-Leu-Thr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O OIQSIMFSVLLWBX-VOAKCMCISA-N 0.000 description 3
- ODTZHNZPINULEU-KKUMJFAQSA-N Lys-Phe-Asn Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CCCCN)N ODTZHNZPINULEU-KKUMJFAQSA-N 0.000 description 3
- 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 3
- MIFFFXHMAHFACR-KATARQTJSA-N Lys-Ser-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CCCCN MIFFFXHMAHFACR-KATARQTJSA-N 0.000 description 3
- UGCIQUYEJIEHKX-GVXVVHGQSA-N Lys-Val-Glu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O UGCIQUYEJIEHKX-GVXVVHGQSA-N 0.000 description 3
- GILLQRYAWOMHED-DCAQKATOSA-N Lys-Val-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CCCCN GILLQRYAWOMHED-DCAQKATOSA-N 0.000 description 3
- FBQMBZLJHOQAIH-GUBZILKMSA-N Met-Asp-Met Chemical compound [H]N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCSC)C(O)=O FBQMBZLJHOQAIH-GUBZILKMSA-N 0.000 description 3
- RNAGAJXCSPDPRK-KKUMJFAQSA-N Met-Glu-Phe Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 RNAGAJXCSPDPRK-KKUMJFAQSA-N 0.000 description 3
- RKIIYGUHIQJCBW-SRVKXCTJSA-N Met-His-Glu Chemical compound [H]N[C@@H](CCSC)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCC(O)=O)C(O)=O RKIIYGUHIQJCBW-SRVKXCTJSA-N 0.000 description 3
- FWAHLGXNBLWIKB-NAKRPEOUSA-N Met-Ile-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H](N)CCSC FWAHLGXNBLWIKB-NAKRPEOUSA-N 0.000 description 3
- SPSSJSICDYYTQN-HJGDQZAQSA-N Met-Thr-Gln Chemical compound CSCC[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@H](C(O)=O)CCC(N)=O SPSSJSICDYYTQN-HJGDQZAQSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- YTILBRIUASDGBL-BZSNNMDCSA-N Phe-Leu-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC1=CC=CC=C1 YTILBRIUASDGBL-BZSNNMDCSA-N 0.000 description 3
- JDMKQHSHKJHAHR-UHFFFAOYSA-N Phe-Phe-Leu-Tyr Natural products C=1C=C(O)C=CC=1CC(C(O)=O)NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)CC1=CC=CC=C1 JDMKQHSHKJHAHR-UHFFFAOYSA-N 0.000 description 3
- QARPMYDMYVLFMW-KKUMJFAQSA-N Phe-Pro-Glu Chemical compound C([C@H](N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(O)=O)C1=CC=CC=C1 QARPMYDMYVLFMW-KKUMJFAQSA-N 0.000 description 3
- MMJJFXWMCMJMQA-STQMWFEESA-N Phe-Pro-Gly Chemical compound C([C@H](N)C(=O)N1[C@@H](CCC1)C(=O)NCC(O)=O)C1=CC=CC=C1 MMJJFXWMCMJMQA-STQMWFEESA-N 0.000 description 3
- BPCLGWHVPVTTFM-QWRGUYRKSA-N Phe-Ser-Gly Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)NCC(O)=O BPCLGWHVPVTTFM-QWRGUYRKSA-N 0.000 description 3
- FGWUALWGCZJQDJ-URLPEUOOSA-N Phe-Thr-Ile Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O FGWUALWGCZJQDJ-URLPEUOOSA-N 0.000 description 3
- 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 3
- CGBYDGAJHSOGFQ-LPEHRKFASA-N Pro-Ala-Pro Chemical compound C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@@H]2CCCN2 CGBYDGAJHSOGFQ-LPEHRKFASA-N 0.000 description 3
- VPEVBAUSTBWQHN-NHCYSSNCSA-N Pro-Glu-Val Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O VPEVBAUSTBWQHN-NHCYSSNCSA-N 0.000 description 3
- DMKWYMWNEKIPFC-IUCAKERBSA-N Pro-Gly-Arg Chemical compound [H]N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(O)=O DMKWYMWNEKIPFC-IUCAKERBSA-N 0.000 description 3
- FMLRRBDLBJLJIK-DCAQKATOSA-N Pro-Leu-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H]1CCCN1 FMLRRBDLBJLJIK-DCAQKATOSA-N 0.000 description 3
- ULWBBFKQBDNGOY-RWMBFGLXSA-N Pro-Lys-Pro Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CCCCN)C(=O)N2CCC[C@@H]2C(=O)O ULWBBFKQBDNGOY-RWMBFGLXSA-N 0.000 description 3
- MHHQQZIFLWFZGR-DCAQKATOSA-N Pro-Lys-Ser Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(O)=O MHHQQZIFLWFZGR-DCAQKATOSA-N 0.000 description 3
- GOMUXSCOIWIJFP-GUBZILKMSA-N Pro-Ser-Arg Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O GOMUXSCOIWIJFP-GUBZILKMSA-N 0.000 description 3
- MKGIILKDUGDRRO-FXQIFTODSA-N Pro-Ser-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H]1CCCN1 MKGIILKDUGDRRO-FXQIFTODSA-N 0.000 description 3
- KHRLUIPIMIQFGT-AVGNSLFASA-N Pro-Val-Leu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O KHRLUIPIMIQFGT-AVGNSLFASA-N 0.000 description 3
- UEJYSALTSUZXFV-SRVKXCTJSA-N Rigin Chemical compound NCC(=O)N[C@@H](CCC(N)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCN=C(N)N)C(O)=O UEJYSALTSUZXFV-SRVKXCTJSA-N 0.000 description 3
- YQHZVYJAGWMHES-ZLUOBGJFSA-N Ser-Ala-Ser Chemical compound OC[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O YQHZVYJAGWMHES-ZLUOBGJFSA-N 0.000 description 3
- JJKSSJVYOVRJMZ-FXQIFTODSA-N Ser-Arg-Cys Chemical compound C(C[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CO)N)CN=C(N)N JJKSSJVYOVRJMZ-FXQIFTODSA-N 0.000 description 3
- HZWAHWQZPSXNCB-BPUTZDHNSA-N Ser-Arg-Trp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O HZWAHWQZPSXNCB-BPUTZDHNSA-N 0.000 description 3
- VAUMZJHYZQXZBQ-WHFBIAKZSA-N Ser-Asn-Gly Chemical compound OC[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(O)=O VAUMZJHYZQXZBQ-WHFBIAKZSA-N 0.000 description 3
- FIDMVVBUOCMMJG-CIUDSAMLSA-N Ser-Asn-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CO FIDMVVBUOCMMJG-CIUDSAMLSA-N 0.000 description 3
- 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 3
- UGJRQLURDVGULT-LKXGYXEUSA-N Ser-Asn-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O UGJRQLURDVGULT-LKXGYXEUSA-N 0.000 description 3
- YMTLKLXDFCSCNX-BYPYZUCNSA-N Ser-Gly-Gly Chemical compound OC[C@H](N)C(=O)NCC(=O)NCC(O)=O YMTLKLXDFCSCNX-BYPYZUCNSA-N 0.000 description 3
- 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 3
- XXXAXOWMBOKTRN-XPUUQOCRSA-N Ser-Gly-Val Chemical compound [H]N[C@@H](CO)C(=O)NCC(=O)N[C@@H](C(C)C)C(O)=O XXXAXOWMBOKTRN-XPUUQOCRSA-N 0.000 description 3
- QYSFWUIXDFJUDW-DCAQKATOSA-N Ser-Leu-Arg Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O QYSFWUIXDFJUDW-DCAQKATOSA-N 0.000 description 3
- MUJQWSAWLLRJCE-KATARQTJSA-N Ser-Leu-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O MUJQWSAWLLRJCE-KATARQTJSA-N 0.000 description 3
- HEYZPTCCEIWHRO-IHRRRGAJSA-N Ser-Met-Phe Chemical compound OC[C@H](N)C(=O)N[C@@H](CCSC)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 HEYZPTCCEIWHRO-IHRRRGAJSA-N 0.000 description 3
- XKFJENWJGHMDLI-QWRGUYRKSA-N Ser-Phe-Gly Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)NCC(O)=O XKFJENWJGHMDLI-QWRGUYRKSA-N 0.000 description 3
- RHAPJNVNWDBFQI-BQBZGAKWSA-N Ser-Pro-Gly Chemical compound OC[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O RHAPJNVNWDBFQI-BQBZGAKWSA-N 0.000 description 3
- 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 3
- SRSPTFBENMJHMR-WHFBIAKZSA-N Ser-Ser-Gly Chemical compound OC[C@H](N)C(=O)N[C@@H](CO)C(=O)NCC(O)=O SRSPTFBENMJHMR-WHFBIAKZSA-N 0.000 description 3
- 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 3
- DKGRNFUXVTYRAS-UBHSHLNASA-N Ser-Ser-Trp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O DKGRNFUXVTYRAS-UBHSHLNASA-N 0.000 description 3
- JZRYFUGREMECBH-XPUUQOCRSA-N Ser-Val-Gly Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)NCC(O)=O JZRYFUGREMECBH-XPUUQOCRSA-N 0.000 description 3
- 101150006914 TRP1 gene Proteins 0.000 description 3
- LAFLAXHTDVNVEL-WDCWCFNPSA-N Thr-Gln-Lys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CCCCN)C(=O)O)N)O LAFLAXHTDVNVEL-WDCWCFNPSA-N 0.000 description 3
- SXAGUVRFGJSFKC-ZEILLAHLSA-N Thr-His-Thr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O SXAGUVRFGJSFKC-ZEILLAHLSA-N 0.000 description 3
- 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 3
- 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 3
- KZSYAEWQMJEGRZ-RHYQMDGZSA-N Thr-Leu-Val Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(O)=O KZSYAEWQMJEGRZ-RHYQMDGZSA-N 0.000 description 3
- JMBRNXUOLJFURW-BEAPCOKYSA-N Thr-Phe-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N2CCC[C@@H]2C(=O)O)N)O JMBRNXUOLJFURW-BEAPCOKYSA-N 0.000 description 3
- ABWNZPOIUJMNKT-IXOXFDKPSA-N Thr-Phe-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(O)=O ABWNZPOIUJMNKT-IXOXFDKPSA-N 0.000 description 3
- WPSKTVVMQCXPRO-BWBBJGPYSA-N Thr-Ser-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O WPSKTVVMQCXPRO-BWBBJGPYSA-N 0.000 description 3
- ZESGVALRVJIVLZ-VFCFLDTKSA-N Thr-Thr-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)N1CCC[C@@H]1C(=O)O)N)O ZESGVALRVJIVLZ-VFCFLDTKSA-N 0.000 description 3
- RPECVQBNONKZAT-WZLNRYEVSA-N Thr-Tyr-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)NC(=O)[C@H]([C@@H](C)O)N RPECVQBNONKZAT-WZLNRYEVSA-N 0.000 description 3
- XGFGVFMXDXALEV-XIRDDKMYSA-N Trp-Leu-Asn Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)N XGFGVFMXDXALEV-XIRDDKMYSA-N 0.000 description 3
- SSSDKJMQMZTMJP-BVSLBCMMSA-N Trp-Tyr-Val Chemical compound C([C@@H](C(=O)N[C@@H](C(C)C)C(O)=O)NC(=O)[C@@H](N)CC=1C2=CC=CC=C2NC=1)C1=CC=C(O)C=C1 SSSDKJMQMZTMJP-BVSLBCMMSA-N 0.000 description 3
- 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 3
- IEESWNWYUOETOT-BVSLBCMMSA-N Trp-Val-Phe Chemical compound CC(C)[C@H](NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12)C(=O)N[C@@H](Cc1ccccc1)C(O)=O IEESWNWYUOETOT-BVSLBCMMSA-N 0.000 description 3
- QYSBJAUCUKHSLU-JYJNAYRXSA-N Tyr-Arg-Val Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(O)=O QYSBJAUCUKHSLU-JYJNAYRXSA-N 0.000 description 3
- JWHOIHCOHMZSAR-QWRGUYRKSA-N Tyr-Asp-Gly Chemical compound OC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 JWHOIHCOHMZSAR-QWRGUYRKSA-N 0.000 description 3
- 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 3
- 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 3
- NQJDICVXXIMMMB-XDTLVQLUSA-N Tyr-Glu-Ala Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(O)=O NQJDICVXXIMMMB-XDTLVQLUSA-N 0.000 description 3
- GZUIDWDVMWZSMI-KKUMJFAQSA-N Tyr-Lys-Cys Chemical compound NCCCC[C@@H](C(=O)N[C@@H](CS)C(O)=O)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 GZUIDWDVMWZSMI-KKUMJFAQSA-N 0.000 description 3
- MWUYSCVVPVITMW-IGNZVWTISA-N Tyr-Tyr-Ala Chemical compound C([C@@H](C(=O)N[C@@H](C)C(O)=O)NC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=C(O)C=C1 MWUYSCVVPVITMW-IGNZVWTISA-N 0.000 description 3
- ANHVRCNNGJMJNG-BZSNNMDCSA-N Tyr-Tyr-Cys Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CC2=CC=C(C=C2)O)C(=O)N[C@@H](CS)C(=O)O)N)O ANHVRCNNGJMJNG-BZSNNMDCSA-N 0.000 description 3
- BMGOFDMKDVVGJG-NHCYSSNCSA-N Val-Asp-Lys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CCCCN)C(=O)O)N BMGOFDMKDVVGJG-NHCYSSNCSA-N 0.000 description 3
- LMSBRIVOCYOKMU-NRPADANISA-N Val-Gln-Cys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CS)C(=O)O)N LMSBRIVOCYOKMU-NRPADANISA-N 0.000 description 3
- OACSGBOREVRSME-NHCYSSNCSA-N Val-His-Asn Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](Cc1cnc[nH]1)C(=O)N[C@@H](CC(N)=O)C(O)=O OACSGBOREVRSME-NHCYSSNCSA-N 0.000 description 3
- JZWZACGUZVCQPS-RNJOBUHISA-N Val-Ile-Pro Chemical compound CC[C@H](C)[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](C(C)C)N JZWZACGUZVCQPS-RNJOBUHISA-N 0.000 description 3
- HGJRMXOWUWVUOA-GVXVVHGQSA-N Val-Leu-Gln Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](C(C)C)N HGJRMXOWUWVUOA-GVXVVHGQSA-N 0.000 description 3
- SSYBNWFXCFNRFN-GUBZILKMSA-N Val-Pro-Ser Chemical compound CC(C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O SSYBNWFXCFNRFN-GUBZILKMSA-N 0.000 description 3
- DEGUERSKQBRZMZ-FXQIFTODSA-N Val-Ser-Ala Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(O)=O DEGUERSKQBRZMZ-FXQIFTODSA-N 0.000 description 3
- SDHZOOIGIUEPDY-JYJNAYRXSA-N Val-Ser-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](CO)NC(=O)[C@@H](N)C(C)C)C(O)=O)=CNC2=C1 SDHZOOIGIUEPDY-JYJNAYRXSA-N 0.000 description 3
- NZYNRRGJJVSSTJ-GUBZILKMSA-N Val-Ser-Val Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O NZYNRRGJJVSSTJ-GUBZILKMSA-N 0.000 description 3
- BGTDGENDNWGMDQ-KJEVXHAQSA-N Val-Tyr-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)NC(=O)[C@H](C(C)C)N)O BGTDGENDNWGMDQ-KJEVXHAQSA-N 0.000 description 3
- JVGDAEKKZKKZFO-RCWTZXSCSA-N Val-Val-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](C(C)C)N)O JVGDAEKKZKKZFO-RCWTZXSCSA-N 0.000 description 3
- 108010081404 acein-2 Proteins 0.000 description 3
- 108010069020 alanyl-prolyl-glycine Proteins 0.000 description 3
- 108010086434 alanyl-seryl-glycine Proteins 0.000 description 3
- 108010008355 arginyl-glutamine Proteins 0.000 description 3
- 108010009111 arginyl-glycyl-glutamic acid Proteins 0.000 description 3
- 108010069205 aspartyl-phenylalanine Proteins 0.000 description 3
- 108010047857 aspartylglycine Proteins 0.000 description 3
- 108010092854 aspartyllysine Proteins 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 239000011324 bead Substances 0.000 description 3
- 239000012472 biological sample Substances 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 230000004154 complement system Effects 0.000 description 3
- 229940127089 cytotoxic agent Drugs 0.000 description 3
- 239000013604 expression vector Substances 0.000 description 3
- 238000000684 flow cytometry Methods 0.000 description 3
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 3
- 108010063718 gamma-glutamylaspartic acid Proteins 0.000 description 3
- 108010013768 glutamyl-aspartyl-proline Proteins 0.000 description 3
- 108010000434 glycyl-alanyl-leucine Proteins 0.000 description 3
- 108010067216 glycyl-glycyl-glycine Proteins 0.000 description 3
- 108010050475 glycyl-leucyl-tyrosine Proteins 0.000 description 3
- 108010010147 glycylglutamine Proteins 0.000 description 3
- 108010050848 glycylleucine Proteins 0.000 description 3
- 230000036541 health Effects 0.000 description 3
- 108010027338 isoleucylcysteine Proteins 0.000 description 3
- 108010044311 leucyl-glycyl-glycine Proteins 0.000 description 3
- 108010073472 leucyl-prolyl-proline Proteins 0.000 description 3
- 108010091871 leucylmethionine Proteins 0.000 description 3
- 108010064235 lysylglycine Proteins 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000011159 matrix material Substances 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 210000001616 monocyte Anatomy 0.000 description 3
- 238000006386 neutralization reaction Methods 0.000 description 3
- 108010070409 phenylalanyl-glycyl-glycine Proteins 0.000 description 3
- 108010064486 phenylalanyl-leucyl-valine Proteins 0.000 description 3
- 108010024654 phenylalanyl-prolyl-alanine Proteins 0.000 description 3
- 108010073101 phenylalanylleucine Proteins 0.000 description 3
- 108010051242 phenylalanylserine Proteins 0.000 description 3
- 238000003127 radioimmunoassay Methods 0.000 description 3
- 108010048818 seryl-histidine Proteins 0.000 description 3
- 108010069117 seryl-lysyl-aspartic acid Proteins 0.000 description 3
- 108010071097 threonyl-lysyl-proline Proteins 0.000 description 3
- 238000012546 transfer Methods 0.000 description 3
- 108010080629 tryptophan-leucine Proteins 0.000 description 3
- 108010038745 tryptophylglycine Proteins 0.000 description 3
- 108010044292 tryptophyltyrosine Proteins 0.000 description 3
- 108010079202 tyrosyl-alanyl-cysteine Proteins 0.000 description 3
- 108010051110 tyrosyl-lysine Proteins 0.000 description 3
- 108010003137 tyrosyltyrosine Proteins 0.000 description 3
- 108010052774 valyl-lysyl-glycyl-phenylalanyl-tyrosine Proteins 0.000 description 3
- IAKHMKGGTNLKSZ-INIZCTEOSA-N (S)-colchicine Chemical compound C1([C@@H](NC(C)=O)CC2)=CC(=O)C(OC)=CC=C1C1=C2C=C(OC)C(OC)=C1OC IAKHMKGGTNLKSZ-INIZCTEOSA-N 0.000 description 2
- CXRCVCURMBFFOL-FXQIFTODSA-N Ala-Ala-Pro Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O CXRCVCURMBFFOL-FXQIFTODSA-N 0.000 description 2
- OINVDEKBKBCPLX-JXUBOQSCSA-N Ala-Lys-Thr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O OINVDEKBKBCPLX-JXUBOQSCSA-N 0.000 description 2
- 102000004127 Cytokines Human genes 0.000 description 2
- 108090000695 Cytokines Proteins 0.000 description 2
- 102000016607 Diphtheria Toxin Human genes 0.000 description 2
- 108010053187 Diphtheria Toxin Proteins 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- 241000196324 Embryophyta Species 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- NJCALAAIGREHDR-WDCWCFNPSA-N Glu-Leu-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O NJCALAAIGREHDR-WDCWCFNPSA-N 0.000 description 2
- 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 2
- QQFSKBMCAKWHLG-UHFFFAOYSA-N Ile-Phe-Pro-Pro Chemical compound C1CCC(C(=O)N2C(CCC2)C(O)=O)N1C(=O)C(NC(=O)C(N)C(C)CC)CC1=CC=CC=C1 QQFSKBMCAKWHLG-UHFFFAOYSA-N 0.000 description 2
- -1 JM-216 Chemical compound 0.000 description 2
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 2
- QQPSCXKFDSORFT-IHRRRGAJSA-N Lys-Lys-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CCCCN QQPSCXKFDSORFT-IHRRRGAJSA-N 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 206010035226 Plasma cell myeloma Diseases 0.000 description 2
- 239000004793 Polystyrene Substances 0.000 description 2
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 2
- 229920002684 Sepharose Polymers 0.000 description 2
- 108091081024 Start codon Proteins 0.000 description 2
- 241000700605 Viruses Species 0.000 description 2
- 230000003213 activating effect Effects 0.000 description 2
- 108010038633 aspartylglutamate Proteins 0.000 description 2
- 238000004166 bioassay Methods 0.000 description 2
- 229960002685 biotin Drugs 0.000 description 2
- 235000020958 biotin Nutrition 0.000 description 2
- 239000011616 biotin Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 239000002254 cytotoxic agent Substances 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- 230000004927 fusion Effects 0.000 description 2
- 210000004602 germ cell Anatomy 0.000 description 2
- 210000005260 human cell Anatomy 0.000 description 2
- 230000001900 immune effect Effects 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 210000004379 membrane Anatomy 0.000 description 2
- 229960000485 methotrexate Drugs 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 210000005087 mononuclear cell Anatomy 0.000 description 2
- 201000000050 myeloid neoplasm Diseases 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- 230000003472 neutralizing effect Effects 0.000 description 2
- 239000002773 nucleotide Substances 0.000 description 2
- 125000003729 nucleotide group Chemical group 0.000 description 2
- 239000004033 plastic Substances 0.000 description 2
- 229920003023 plastic Polymers 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 108091033319 polynucleotide Proteins 0.000 description 2
- 239000002157 polynucleotide Substances 0.000 description 2
- 102000040430 polynucleotide Human genes 0.000 description 2
- 229920001184 polypeptide Polymers 0.000 description 2
- 229920002223 polystyrene Polymers 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 238000001742 protein purification Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 238000002198 surface plasmon resonance spectroscopy Methods 0.000 description 2
- 210000004357 third molar Anatomy 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- 108010071635 tyrosyl-prolyl-arginine Proteins 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 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
- 108010066676 Abrin Proteins 0.000 description 1
- 241000589158 Agrobacterium Species 0.000 description 1
- KUDREHRZRIVKHS-UWJYBYFXSA-N Ala-Asp-Tyr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O KUDREHRZRIVKHS-UWJYBYFXSA-N 0.000 description 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
- SFNFGFDRYJKZKN-XQXXSGGOSA-N Ala-Gln-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](C)N)O SFNFGFDRYJKZKN-XQXXSGGOSA-N 0.000 description 1
- SUMYEVXWCAYLLJ-GUBZILKMSA-N Ala-Leu-Gln Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O SUMYEVXWCAYLLJ-GUBZILKMSA-N 0.000 description 1
- MDNAVFBZPROEHO-DCAQKATOSA-N Ala-Lys-Val Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(O)=O MDNAVFBZPROEHO-DCAQKATOSA-N 0.000 description 1
- XWFWAXPOLRTDFZ-FXQIFTODSA-N Ala-Pro-Ser Chemical compound C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O XWFWAXPOLRTDFZ-FXQIFTODSA-N 0.000 description 1
- IPWKGIFRRBGCJO-IMJSIDKUSA-N Ala-Ser Chemical compound C[C@H]([NH3+])C(=O)N[C@@H](CO)C([O-])=O IPWKGIFRRBGCJO-IMJSIDKUSA-N 0.000 description 1
- 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 1
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 1
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 1
- HPKSHFSEXICTLI-CIUDSAMLSA-N Arg-Glu-Ala Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(O)=O HPKSHFSEXICTLI-CIUDSAMLSA-N 0.000 description 1
- AUFHLLPVPSMEOG-YUMQZZPRSA-N Arg-Gly-Glu Chemical compound NC(N)=NCCC[C@H](N)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(O)=O AUFHLLPVPSMEOG-YUMQZZPRSA-N 0.000 description 1
- XRNXPIGJPQHCPC-RCWTZXSCSA-N Arg-Thr-Val Chemical compound CC(C)[C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)CCCNC(N)=N)[C@@H](C)O)C(O)=O XRNXPIGJPQHCPC-RCWTZXSCSA-N 0.000 description 1
- 240000003291 Armoracia rusticana Species 0.000 description 1
- 235000011330 Armoracia rusticana Nutrition 0.000 description 1
- 206010003445 Ascites Diseases 0.000 description 1
- XYOVHPDDWCEUDY-CIUDSAMLSA-N Asn-Ala-Leu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(O)=O XYOVHPDDWCEUDY-CIUDSAMLSA-N 0.000 description 1
- GXMSVVBIAMWMKO-BQBZGAKWSA-N Asn-Arg-Gly Chemical compound NC(=O)C[C@H](N)C(=O)N[C@H](C(=O)NCC(O)=O)CCCN=C(N)N GXMSVVBIAMWMKO-BQBZGAKWSA-N 0.000 description 1
- NVGWESORMHFISY-SRVKXCTJSA-N Asn-Asn-Phe Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O NVGWESORMHFISY-SRVKXCTJSA-N 0.000 description 1
- JWQWPRCDYWNVNM-ACZMJKKPSA-N Asn-Ser-Gln Chemical compound C(CC(=O)N)[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(=O)N)N JWQWPRCDYWNVNM-ACZMJKKPSA-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
- 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
- KNDCWFXCFKSEBM-AVGNSLFASA-N Asp-Tyr-Glu Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCC(O)=O)C(O)=O KNDCWFXCFKSEBM-AVGNSLFASA-N 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 241000193738 Bacillus anthracis Species 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 231100000023 Cell-mediated cytotoxicity Toxicity 0.000 description 1
- 206010057250 Cell-mediated cytotoxicity Diseases 0.000 description 1
- 241000282552 Chlorocebus aethiops Species 0.000 description 1
- 229920000742 Cotton Polymers 0.000 description 1
- 241000699800 Cricetinae Species 0.000 description 1
- 241000699802 Cricetulus griseus Species 0.000 description 1
- VIRYODQIWJNWNU-NRPADANISA-N Cys-Glu-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CS)N VIRYODQIWJNWNU-NRPADANISA-N 0.000 description 1
- WVLZTXGTNGHPBO-SRVKXCTJSA-N Cys-Leu-Leu Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O WVLZTXGTNGHPBO-SRVKXCTJSA-N 0.000 description 1
- 101710112752 Cytotoxin Proteins 0.000 description 1
- 241000702421 Dependoparvovirus Species 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 238000008157 ELISA kit Methods 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 108700024394 Exon Proteins 0.000 description 1
- 229920001917 Ficoll Polymers 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- WLODHVXYKYHLJD-ACZMJKKPSA-N Gln-Asp-Ser Chemical compound C(CC(=O)N)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CO)C(=O)O)N WLODHVXYKYHLJD-ACZMJKKPSA-N 0.000 description 1
- ZNZPKVQURDQFFS-FXQIFTODSA-N Gln-Glu-Ser Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(O)=O ZNZPKVQURDQFFS-FXQIFTODSA-N 0.000 description 1
- 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
- IULKWYSYZSURJK-AVGNSLFASA-N Gln-Leu-Lys Chemical compound NC(=O)CC[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(O)=O IULKWYSYZSURJK-AVGNSLFASA-N 0.000 description 1
- OSCLNNWLKKIQJM-WDSKDSINSA-N Gln-Ser-Gly Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)NCC(O)=O OSCLNNWLKKIQJM-WDSKDSINSA-N 0.000 description 1
- BETSEXMYBWCDAE-SZMVWBNQSA-N Gln-Trp-Lys Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCC(=O)N)N BETSEXMYBWCDAE-SZMVWBNQSA-N 0.000 description 1
- JJKKWYQVHRUSDG-GUBZILKMSA-N Glu-Ala-Lys Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(O)=O JJKKWYQVHRUSDG-GUBZILKMSA-N 0.000 description 1
- CLROYXHHUZELFX-FXQIFTODSA-N Glu-Gln-Asp Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O CLROYXHHUZELFX-FXQIFTODSA-N 0.000 description 1
- PVBBEKPHARMPHX-DCAQKATOSA-N Glu-Gln-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CCC(O)=O PVBBEKPHARMPHX-DCAQKATOSA-N 0.000 description 1
- YGLCLCMAYUYZSG-AVGNSLFASA-N Glu-Lys-His Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(O)=O)CC1=CN=CN1 YGLCLCMAYUYZSG-AVGNSLFASA-N 0.000 description 1
- YHOJJFFTSMWVGR-HJGDQZAQSA-N Glu-Met-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H]([C@@H](C)O)C(O)=O YHOJJFFTSMWVGR-HJGDQZAQSA-N 0.000 description 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
- 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
- FFJQHWKSGAWSTJ-BFHQHQDPSA-N Gly-Thr-Ala Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O FFJQHWKSGAWSTJ-BFHQHQDPSA-N 0.000 description 1
- 108010043121 Green Fluorescent Proteins Proteins 0.000 description 1
- 102000004144 Green Fluorescent Proteins Human genes 0.000 description 1
- HVCRQRQPIIRNLY-IUCAKERBSA-N His-Gln-Gly Chemical compound C1=C(NC=N1)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)NCC(=O)O)N HVCRQRQPIIRNLY-IUCAKERBSA-N 0.000 description 1
- TVMNTHXFRSXZGR-IHRRRGAJSA-N His-Lys-Val Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(O)=O TVMNTHXFRSXZGR-IHRRRGAJSA-N 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101001074035 Homo sapiens Zinc finger protein GLI2 Proteins 0.000 description 1
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 1
- VAXBXNPRXPHGHG-BJDJZHNGSA-N Ile-Ala-Leu Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)O)N VAXBXNPRXPHGHG-BJDJZHNGSA-N 0.000 description 1
- 102000017727 Immunoglobulin Variable Region Human genes 0.000 description 1
- 108010067060 Immunoglobulin Variable Region Proteins 0.000 description 1
- 102000000589 Interleukin-1 Human genes 0.000 description 1
- 108010002352 Interleukin-1 Proteins 0.000 description 1
- 108091092195 Intron Proteins 0.000 description 1
- DBVWMYGBVFCRBE-CIUDSAMLSA-N Leu-Asn-Asn Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O DBVWMYGBVFCRBE-CIUDSAMLSA-N 0.000 description 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
- AMSSKPUHBUQBOQ-SRVKXCTJSA-N Leu-Ser-Lys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)O)N AMSSKPUHBUQBOQ-SRVKXCTJSA-N 0.000 description 1
- QWWPYKKLXWOITQ-VOAKCMCISA-N Leu-Thr-Leu Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@H](C(O)=O)CC(C)C QWWPYKKLXWOITQ-VOAKCMCISA-N 0.000 description 1
- 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
- SWWCDAGDQHTKIE-RHYQMDGZSA-N Lys-Arg-Thr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(O)=O SWWCDAGDQHTKIE-RHYQMDGZSA-N 0.000 description 1
- NTSPQIONFJUMJV-AVGNSLFASA-N Lys-Arg-Val Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(O)=O NTSPQIONFJUMJV-AVGNSLFASA-N 0.000 description 1
- NRQRKMYZONPCTM-CIUDSAMLSA-N Lys-Asp-Ser Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O NRQRKMYZONPCTM-CIUDSAMLSA-N 0.000 description 1
- FGMHXLULNHTPID-KKUMJFAQSA-N Lys-His-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](CCCCN)C(O)=O)CC1=CN=CN1 FGMHXLULNHTPID-KKUMJFAQSA-N 0.000 description 1
- SBQDRNOLGSYHQA-YUMQZZPRSA-N Lys-Ser-Gly Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)NCC(O)=O SBQDRNOLGSYHQA-YUMQZZPRSA-N 0.000 description 1
- SQXZLVXQXWILKW-KKUMJFAQSA-N Lys-Ser-Phe Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O SQXZLVXQXWILKW-KKUMJFAQSA-N 0.000 description 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
- HMZPYMSEAALNAE-ULQDDVLXSA-N Lys-Val-Tyr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O HMZPYMSEAALNAE-ULQDDVLXSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 1
- 229930012538 Paclitaxel 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
- 240000007643 Phytolacca americana Species 0.000 description 1
- 235000009074 Phytolacca americana Nutrition 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 239000004743 Polypropylene Substances 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
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 101001002626 Rattus norvegicus Interleukin-1 alpha Proteins 0.000 description 1
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 1
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 108010084592 Saporins Proteins 0.000 description 1
- YUSRGTQIPCJNHQ-CIUDSAMLSA-N Ser-Arg-Glu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(O)=O YUSRGTQIPCJNHQ-CIUDSAMLSA-N 0.000 description 1
- FTVRVZNYIYWJGB-ACZMJKKPSA-N Ser-Asp-Glu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O FTVRVZNYIYWJGB-ACZMJKKPSA-N 0.000 description 1
- ZOHGLPQGEHSLPD-FXQIFTODSA-N Ser-Gln-Glu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O ZOHGLPQGEHSLPD-FXQIFTODSA-N 0.000 description 1
- BPMRXBZYPGYPJN-WHFBIAKZSA-N Ser-Gly-Asn Chemical compound [H]N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(O)=O BPMRXBZYPGYPJN-WHFBIAKZSA-N 0.000 description 1
- SFTZWNJFZYOLBD-ZDLURKLDSA-N Ser-Gly-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CO SFTZWNJFZYOLBD-ZDLURKLDSA-N 0.000 description 1
- YUJLIIRMIAGMCQ-CIUDSAMLSA-N Ser-Leu-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O YUJLIIRMIAGMCQ-CIUDSAMLSA-N 0.000 description 1
- GZSZPKSBVAOGIE-CIUDSAMLSA-N Ser-Lys-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O GZSZPKSBVAOGIE-CIUDSAMLSA-N 0.000 description 1
- PPNPDKGQRFSCAC-CIUDSAMLSA-N Ser-Lys-Asp Chemical compound NCCCC[C@H](NC(=O)[C@@H](N)CO)C(=O)N[C@@H](CC(O)=O)C(O)=O PPNPDKGQRFSCAC-CIUDSAMLSA-N 0.000 description 1
- GDUZTEQRAOXYJS-SRVKXCTJSA-N Ser-Phe-Asn Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CO)N GDUZTEQRAOXYJS-SRVKXCTJSA-N 0.000 description 1
- CKDXFSPMIDSMGV-GUBZILKMSA-N Ser-Pro-Val Chemical compound [H]N[C@@H](CO)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(O)=O CKDXFSPMIDSMGV-GUBZILKMSA-N 0.000 description 1
- PYTKULIABVRXSC-BWBBJGPYSA-N Ser-Ser-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(O)=O PYTKULIABVRXSC-BWBBJGPYSA-N 0.000 description 1
- 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
- ZKOKTQPHFMRSJP-YJRXYDGGSA-N Ser-Thr-Tyr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O ZKOKTQPHFMRSJP-YJRXYDGGSA-N 0.000 description 1
- SIEBDTCABMZCLF-XGEHTFHBSA-N Ser-Val-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O SIEBDTCABMZCLF-XGEHTFHBSA-N 0.000 description 1
- HSWXBJCBYSWBPT-GUBZILKMSA-N Ser-Val-Val Chemical compound CC(C)[C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)CO)C(C)C)C(O)=O HSWXBJCBYSWBPT-GUBZILKMSA-N 0.000 description 1
- 108010090804 Streptavidin Proteins 0.000 description 1
- 229940123237 Taxane Drugs 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
- CYVQBKQYQGEELV-NKIYYHGXSA-N Thr-His-Gln Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N)O CYVQBKQYQGEELV-NKIYYHGXSA-N 0.000 description 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
- VRUFCJZQDACGLH-UVOCVTCTSA-N Thr-Leu-Thr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O VRUFCJZQDACGLH-UVOCVTCTSA-N 0.000 description 1
- XSEPSRUDSPHMPX-KATARQTJSA-N Thr-Lys-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(O)=O XSEPSRUDSPHMPX-KATARQTJSA-N 0.000 description 1
- CYCGARJWIQWPQM-YJRXYDGGSA-N Thr-Tyr-Ser Chemical compound C[C@@H](O)[C@H]([NH3+])C(=O)N[C@H](C(=O)N[C@@H](CO)C([O-])=O)CC1=CC=C(O)C=C1 CYCGARJWIQWPQM-YJRXYDGGSA-N 0.000 description 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
- 239000007983 Tris buffer Substances 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- 239000013504 Triton X-100 Substances 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
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- QJBWZNTWJSZUOY-UWJYBYFXSA-N Tyr-Ala-Cys Chemical compound C[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)N QJBWZNTWJSZUOY-UWJYBYFXSA-N 0.000 description 1
- AUZADXNWQMBZOO-JYJNAYRXSA-N Tyr-Pro-Arg Chemical compound C([C@H](N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O)C1=CC=C(O)C=C1 AUZADXNWQMBZOO-JYJNAYRXSA-N 0.000 description 1
- MQGGXGKQSVEQHR-KKUMJFAQSA-N Tyr-Ser-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 MQGGXGKQSVEQHR-KKUMJFAQSA-N 0.000 description 1
- CGGVNFJRZJUVAE-BYULHYEWSA-N Val-Asp-Asn Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC(=O)N)C(=O)O)N CGGVNFJRZJUVAE-BYULHYEWSA-N 0.000 description 1
- LHADRQBREKTRLR-DCAQKATOSA-N Val-Cys-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CS)NC(=O)[C@H](C(C)C)N LHADRQBREKTRLR-DCAQKATOSA-N 0.000 description 1
- OXVPMZVGCAPFIG-BQFCYCMXSA-N Val-Gln-Trp Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)N OXVPMZVGCAPFIG-BQFCYCMXSA-N 0.000 description 1
- FMQGYTMERWBMSI-HJWJTTGWSA-N Val-Phe-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)NC(=O)[C@H](C(C)C)N FMQGYTMERWBMSI-HJWJTTGWSA-N 0.000 description 1
- UVHFONIHVHLDDQ-IFFSRLJSSA-N Val-Thr-Glu Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)O)NC(=O)[C@H](C(C)C)N)O UVHFONIHVHLDDQ-IFFSRLJSSA-N 0.000 description 1
- 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
- QPJSIBAOZBVELU-BPNCWPANSA-N Val-Tyr-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)NC(=O)[C@H](C(C)C)N QPJSIBAOZBVELU-BPNCWPANSA-N 0.000 description 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
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 1
- 102100035558 Zinc finger protein GLI2 Human genes 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 238000001042 affinity chromatography Methods 0.000 description 1
- 108010041407 alanylaspartic acid Proteins 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 210000004102 animal cell Anatomy 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 229940044684 anti-microtubule agent Drugs 0.000 description 1
- 229940100197 antimetabolite Drugs 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003124 biologic agent Substances 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000005880 cancer cell killing Effects 0.000 description 1
- 239000002041 carbon nanotube Substances 0.000 description 1
- 229910021393 carbon nanotube Inorganic materials 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 238000000423 cell based assay Methods 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 238000012832 cell culture technique Methods 0.000 description 1
- 230000022534 cell killing Effects 0.000 description 1
- 239000013592 cell lysate Substances 0.000 description 1
- 230000012292 cell migration Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 230000005890 cell-mediated cytotoxicity Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 238000010367 cloning Methods 0.000 description 1
- 229960001338 colchicine Drugs 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 230000001268 conjugating effect Effects 0.000 description 1
- 230000021615 conjugation Effects 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 239000012228 culture supernatant Substances 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 238000003113 dilution method Methods 0.000 description 1
- FSXRLASFHBWESK-UHFFFAOYSA-N dipeptide phenylalanyl-tyrosine Natural products C=1C=C(O)C=CC=1CC(C(O)=O)NC(=O)C(N)CC1=CC=CC=C1 FSXRLASFHBWESK-UHFFFAOYSA-N 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 229960003668 docetaxel Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000004520 electroporation Methods 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- ZMMJGEGLRURXTF-UHFFFAOYSA-N ethidium bromide Chemical compound [Br-].C12=CC(N)=CC=C2C2=CC=C(N)C=C2[N+](CC)=C1C1=CC=CC=C1 ZMMJGEGLRURXTF-UHFFFAOYSA-N 0.000 description 1
- 229960005542 ethidium bromide Drugs 0.000 description 1
- 210000003527 eukaryotic cell Anatomy 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 230000001605 fetal effect Effects 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 239000012997 ficoll-paque Substances 0.000 description 1
- 229960000390 fludarabine Drugs 0.000 description 1
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 description 1
- MHMNJMPURVTYEJ-UHFFFAOYSA-N fluorescein-5-isothiocyanate Chemical compound O1C(=O)C2=CC(N=C=S)=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 MHMNJMPURVTYEJ-UHFFFAOYSA-N 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 238000001879 gelation Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 108010078144 glutaminyl-glycine Proteins 0.000 description 1
- 229930004094 glycosylphosphatidylinositol Natural products 0.000 description 1
- 108010089804 glycyl-threonine Proteins 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 230000005484 gravity Effects 0.000 description 1
- 239000005090 green fluorescent protein Substances 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 230000011132 hemopoiesis Effects 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- ZFGMDIBRIDKWMY-PASTXAENSA-N heparin Chemical compound CC(O)=N[C@@H]1[C@@H](O)[C@H](O)[C@@H](COS(O)(=O)=O)O[C@@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](O[C@H]2[C@@H]([C@@H](OS(O)(=O)=O)[C@@H](O[C@@H]3[C@@H](OC(O)[C@H](OS(O)(=O)=O)[C@H]3O)C(O)=O)O[C@@H]2O)CS(O)(=O)=O)[C@H](O)[C@H]1O ZFGMDIBRIDKWMY-PASTXAENSA-N 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 102000055219 human IL1A Human genes 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 230000003100 immobilizing effect Effects 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 238000003119 immunoblot Methods 0.000 description 1
- 238000001114 immunoprecipitation Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- PGHMRUGBZOYCAA-ADZNBVRBSA-N ionomycin Chemical compound O1[C@H](C[C@H](O)[C@H](C)[C@H](O)[C@H](C)/C=C/C[C@@H](C)C[C@@H](C)C(/O)=C/C(=O)[C@@H](C)C[C@@H](C)C[C@@H](CCC(O)=O)C)CC[C@@]1(C)[C@@H]1O[C@](C)([C@@H](C)O)CC1 PGHMRUGBZOYCAA-ADZNBVRBSA-N 0.000 description 1
- PGHMRUGBZOYCAA-UHFFFAOYSA-N ionomycin Natural products O1C(CC(O)C(C)C(O)C(C)C=CCC(C)CC(C)C(O)=CC(=O)C(C)CC(C)CC(CCC(O)=O)C)CCC1(C)C1OC(C)(C(C)O)CC1 PGHMRUGBZOYCAA-UHFFFAOYSA-N 0.000 description 1
- 150000002540 isothiocyanates Chemical class 0.000 description 1
- 210000003292 kidney cell Anatomy 0.000 description 1
- 239000004816 latex Substances 0.000 description 1
- 229920000126 latex Polymers 0.000 description 1
- 108010034529 leucyl-lysine Proteins 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 230000004807 localization Effects 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 1
- 229960001924 melphalan Drugs 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 238000000520 microinjection Methods 0.000 description 1
- 238000010369 molecular cloning Methods 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 229960001756 oxaliplatin Drugs 0.000 description 1
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000013612 plasmid Substances 0.000 description 1
- 210000004180 plasmocyte Anatomy 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 238000002264 polyacrylamide gel electrophoresis Methods 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- 210000001236 prokaryotic cell Anatomy 0.000 description 1
- 238000002331 protein detection Methods 0.000 description 1
- 210000001938 protoplast Anatomy 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 238000002708 random mutagenesis Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- PYWVYCXTNDRMGF-UHFFFAOYSA-N rhodamine B Chemical compound [Cl-].C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=CC=C1C(O)=O PYWVYCXTNDRMGF-UHFFFAOYSA-N 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000004017 serum-free culture medium Substances 0.000 description 1
- 108010026333 seryl-proline Proteins 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 229940037128 systemic glucocorticoids Drugs 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- MPLHNVLQVRSVEE-UHFFFAOYSA-N texas red Chemical compound [O-]S(=O)(=O)C1=CC(S(Cl)(=O)=O)=CC=C1C(C1=CC=2CCCN3CCCC(C=23)=C1O1)=C2C1=C(CCC1)C3=[N+]1CCCC3=C2 MPLHNVLQVRSVEE-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 238000003151 transfection method Methods 0.000 description 1
- 230000014723 transformation of host cell by virus Effects 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 210000003606 umbilical vein Anatomy 0.000 description 1
- 241000701161 unidentified adenovirus Species 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- 239000013603 viral vector Substances 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
Classifications
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6863—Cytokines, i.e. immune system proteins modifying a biological response such as cell growth proliferation or differentiation, e.g. TNF, CNF, GM-CSF, lymphotoxin, MIF or their receptors
- G01N33/6869—Interleukin
-
- 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
- C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
- C07K16/244—Interleukins [IL]
- C07K16/245—IL-1
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/52—Cytokines; Lymphokines; Interferons
- C07K14/54—Interleukins [IL]
- C07K14/545—IL-1
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/06—Animal cells or tissues; Human cells or tissues
- C12N5/0602—Vertebrate cells
- C12N5/069—Vascular Endothelial cells
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/06—Animal cells or tissues; Human cells or tissues
- C12N5/0602—Vertebrate cells
- C12N5/0693—Tumour cells; Cancer cells
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/10—Cells modified by introduction of foreign genetic material
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6863—Cytokines, i.e. immune system proteins modifying a biological response such as cell growth proliferation or differentiation, e.g. TNF, CNF, GM-CSF, lymphotoxin, MIF or their receptors
-
- 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
-
- 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
- A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
- A61K2039/55511—Organic adjuvants
- A61K2039/55522—Cytokines; Lymphokines; Interferons
- A61K2039/55527—Interleukins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/52—Cytokines; Lymphokines; Interferons
- C07K14/54—Interleukins [IL]
- C07K14/5412—IL-6
-
- 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
- C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/10—Immunoglobulins specific features characterized by their source of isolation or production
- C07K2317/14—Specific host cells or culture conditions, e.g. components, pH or temperature
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
-
- 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
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
- C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2330/00—Production
- C12N2330/50—Biochemical production, i.e. in a transformed host cell
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
- G01N2333/52—Assays involving cytokines
- G01N2333/54—Interleukins [IL]
- G01N2333/545—IL-1
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Immunology (AREA)
- Medicinal Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- Cell Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Zoology (AREA)
- Microbiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Wood Science & Technology (AREA)
- Urology & Nephrology (AREA)
- Biophysics (AREA)
- Hematology (AREA)
- General Engineering & Computer Science (AREA)
- Physics & Mathematics (AREA)
- Pathology (AREA)
- General Physics & Mathematics (AREA)
- Analytical Chemistry (AREA)
- Food Science & Technology (AREA)
- Vascular Medicine (AREA)
- Oncology (AREA)
- Toxicology (AREA)
- Gastroenterology & Hepatology (AREA)
- Mycology (AREA)
Abstract
전체 인간 단일클론성 Abs는 (i) IL-1α에 대하여 아주 높은 결합 친화도를 보이는 항원-결합 가변 영역 및 (ii) C1q 결합을 통하여 보체계를 활성화시키고 몇 개의 상이한 Fc 수용체들과 결합하는데 효과적인 불변 영역을 포함한다.
Description
본 발명은 일반적으로 면역학, 염증, 암, 혈관 장애 및 의약 분야에 관한 것이다. 더 상세하게는, 본 발명은 인터루킨(interleukin)-1α(IL-1α)를 특이적으로 결합하는 항체들(Abs) 및 비정상적인 IL-1α 발현과 연관된 질병의 치료, 방지 또는 검출을 위한 상기 Abs의 사용방법에 관한 것이다.
본 출원은 2008년 5월 30일, 2008년 12월 10일; 및 2009년 5월 14일에 각각 제출된 미국 가출원 번호 61/057,586; 61/121,391; 및 61/178,350의 우선권을 주장한다.
IL-1α는 염증, 면역 반응, 종양 전이 및 조혈을 포함하는 수많은 상이한 활성에서 역할을 수행하는 전-염증성(pro-inflammatory) 사이토카인이다. IL-1α에 대항하는 IgG 자가항체는 전체 인구에서 자연적으로 발생하며 죽상경화증 (atherosclerosis)과 같은 질병에 유리한 것으로 생각된다.
본 발명은 (i) 인간 IL-1α에 대하여 아주 높은 결합 친화도를 보이는 항원-결합 가변 영역 및 (ii) C1q 결합을 통하여 보체계를 활성하시키고 몇 개의 상이한 Fc 수용체들과 결합하는데 효과적인 불변 영역을 포함하는 전체 인간 단일클론성 Abs(mAbs)의 개발에 기초한 것이다. 본 명세서에 기술된 IL-1α 특이적인 mAbs는 인간 IL-1α에 특이적인 가변 영역을 갖는 인간 IgG4 mAb의 불변 영역을 인간 IgG1 mAb의 불변 영역으로 교체하여 제조되었다.
따라서, 본 발명은 인간 IL-1α와 특이적으로 결합하는 정제된 인간 IgG1 mAb를 특징으로 하며, 상기 mAb는 경쇄에 공유적으로 연결된 중쇄를 포함한다. 상기 중쇄는 서열 ID 번호: 9의 아미노산 서열을 포함할 수 있으며, 상기 경쇄는 서열 ID 번호: 11의 아미노산 서열을 포함할 수 있다.
IL-1α와 특이적으로 결합하는 인간 IgG1 mAb의 중쇄를 인코딩하는 제 1 핵산 및 인간 IL-1α와 특이적으로 결합하는 인간 IgG1 mAb의 경쇄를 인코딩하는 제 2 핵산을 포함하는 단리된(isolated) 핵산들의 일 집합(set)도 본 발명 내에 속한다. 상기 제 1 핵산은 서열 ID 번호: 9의 아미노산 서열을 인코딩할 수 있으며, 상기 제 2 핵산은 서열 ID 번호: 11의 아미노산 서열을 인코딩할 수 있다. 상기 제 1 핵산은 서열 ID 번호: 10의 염기 서열을 포함할 수 있으며, 상기 제 2 핵산은 서열 ID 번호: 12의 염기 서열을 포함할 수 있다.
다른 측면에서, 본 발명은 서열 ID 번호: 9 또는 서열 ID 번호: 11의 아미노산 서열을 인코딩하는 핵산을 포함하는 발현 벡터를 특징으로 한다.
본 발명의 다른 특징은 IL-1α와 특이적으로 결합하는 인간 IgG1 mAb의 중쇄를 인코딩하는 제 1 핵산 및 인간 IL-1α와 특이적으로 결합하는 인간 IgG1 mAb의 경쇄를 인코딩하는 제 2 핵산을 포함하는 단리된 핵산들의 집합을 포함하는 단리된 숙주 세포(예컨대, CHO 세포와 같은 포유류 세포)이다. 상기 중쇄는 서열 ID 번호: 9의 아미노산 서열을 포함할 수 있으며, 경쇄는 서열 ID 번호: 11의 아미노산 서열을 포함할 수 있다.
또한, 본 발명은 인간 IL-1α를 발현하는 세포를 죽이는 방법을 특징으로 한다. 이 방법은 상기 세포를 인간 IL-1α와 특이적으로 결합하는 정제된 인간 IgG1 mAb와 접촉시키는 단계를 포함할 수 있다.
기저막 기질(basement membrane matrix)을 통한 인간 세포 이동의 억제방법도 본 발명 내에 속한다. 이 방법은 기저막 기질 및 상기 인간 세포를 포함하는 혼합물에 인간 IL-1α와 특이적으로 결합하는 정제된 mAb를 첨가하는 단계를 포함할 수 있다.
인간 내피 세포의 표면상에서 ICAM-1 및/또는 E-셀렉틴(selectin) 발현에 있어서 IL-1α-유도된 증가의 억제방법도 본 발명 내에 속한다. 이 방법은 상기 내피 세포 및 IL-1α를 포함하는 혼합물에 인간 IL-1α와 특이적으로 결합하는 정제된 mAb를 첨가하는 단계를 포함할 수 있다.
또한, 본 발명은 하기 단계들을 이전에 거친 인간 피검자에서 염증의 탐지방법을 포함한다: 제 1 시간에서 말초 혈액 단핵 세포들의 제 1 표본을 상기 피검자로부터 획득하는 단계; 상기 제 1 표본을 인간 IL-1α와 특이적으로 결합하는 정제된 mAb와 접촉시키는 단계; 및 상기 제 1 표본에 있어서 단일클론성 Ab를 결합시키는 세포들의 백분율을 측정하는 단계. 이 방법은 하기 단계들을 포함할 수 있다: (a) 제 2 시간에서 말초 혈액 단핵 세포들의 제 2 표본을 상기 피검자로부터 획득하는 단계; (b) 상기 제 2 표본을 인간 IL-1α와 특이적으로 결합하는 정제된 mAb와 접촉시키는 단계; (c) 상기 제 2 표본에 있어서 단일클론성 Ab를 결합시키는 세포들의 백분율을 측정하는 단계; 및 (d) 상기 제 1 표본에 있어서 상기 mAb를 결합시키는 세포들의 백분율과 상기 제 2 표본에 있어서 상기 단일클론성 Ab를 결합시키는 세포들의 백분율을 비교하는 단계.
앞선 방법들에 있어서, 상기 정제된 mAb는 경쇄에 공유적으로 연결된 중쇄를 포함하는 인간 IgG1 mAb일 수 있으며, 예컨대, 상기 중쇄는 서열 ID 번호: 9의 아미노산 서열을 포함하며, 상기 경쇄는 서열 ID 번호: 11의 아미노산 서열을 포함한다.
본 발명 내의 다른 방법은 하기 단계들을 특징으로 한다: (a) 인간 피검자로부터 획득한 생물학적 표본을 필터를 사용하여 농축하여 분자들을 분자량에 따라 IL-1α와 복합체 형성된(complexed with) 손상되지 않은(intact) IgG를 포함하는 제 1 분획 및 100 Kda 미만의 분자들을 포함하는 제 2 분획으로 분리하는 단계; 및 (b) 상기 제 1 분획에서 IL-1α의 양을 정량화하는 단계.
본 발명 내의 또 다른 방법은 하기 단계들을 특징으로 한다: (a) 인간 피검자로부터 획득한 혈장 표본을 분자들을 분자량에 따라 IL-1α와 복합체 형성된 손상되지 않은 IgG를 포함하는 제 1 분획 및 100 Kda 미만의 분자들을 포함하는 제 2 분획으로 분리하는 필터를 사용하여 농축하는 단계; (b) 고정화된 항-인간 IgG Abs를 포함하는 기질에 상기 제 1 분획을 첨가하는 단계로서, 상기 제 1 분획의 IgG가 상기 기질상에 고정화된 항-인간 IgG Abs를 특이적으로 결합하게 하는 조건하에서 첨가하는 단계; (c) 상기 기질을 세척하여 상기 제 1 분획에 있어서 상기 고정화된 항-인간 IgG Abs를 특이적으로 결합하지 않는 물질을 제거하는 단계; (d) 상기 단계 (c)에서 세척된 기질을 인간 IL-1α를 특이적으로 결합하는 Ab와 접촉시키는 단계로서, 인간 IL-1α를 특이적으로 결합하는 상기 Ab가 상기 기질에 결합된 임의의 인간 IL-1α 를 결합하게 하는 조건하에서 접촉시키는 단계; (e) 상기 기질을 세척하여 상기 기질에 결합되지 않은 인간 IL-1α를 특이적으로 결합하는 상기 Ab를 제거하는 단계, 및 (f) 단계 (e) 이후에 상기 기질에 결합된 잔류 인간 IL-1α를 특이적으로 결합하는 Ab의 양을 정량화하는 단계.
달리 정의되지 않으면, 본 명세서에 사용된 모든 기술적 용어들은 본 발명이 속하는 기술의 당업자가 통상적으로 이해하는 것과 동일한 의미를 가진다. 생물학적 용어들의 통상적으로 이해되는 정의는 문헌[Rieger et al., Glossary of Genetics: Classical and Moleculrar, 5th edition, Springer-Verlag: New York, 1991; 및 Lewin, Genes V, Oxford University Press: New York, 1994]에서 찾을 수 있다.
본 명세서에 사용된 바와 같이, "특이적으로 결합하다"라는 표현은 폴리펩티드(Abs 포함) 또는 수용체를 언급하는 경우, 단백질 및 다른 다른 생물제제의 이종 군(heterogeneous population)에서 상기 단백질 또는 폴리펩티드 또는 수용체의 존재를 결정하는 결합 반응을 가리킨다. 따라서, 지정된 조건(예컨대, Ab의 경우 면역검정(immunoassay) 조건)하에서, 특정화된 리간드 또는 Ab는 그 특정한 "표적"과 결합하고, 표본에 존재하는 다른 단백질들과 또는 상기 리간드 또는 Ab가 유기체에서 접촉할 수 있는 다른 단백질들과는 상당한 양으로 결합하지 않는다. 일반적으로, 제 2 분자를 "특이적으로 결합하는" 제 1 분자는 그 제 2 분자에 대해 몰당 약 105(예컨대, 106, 107, 108, 109, 1010, 1011 및 1012 이상)을 초과하는 평형 친화도 상수를 갖는다.
Ab와 같은 단백질 분자를 언급하는 경우, "정제된"은 그러한 분자들과 자연적으로 동반하는 구성요소들로부터 분리된 것을 의미한다. 통상적으로, Ab 또는 단백질은 이것이 자연적으로 회합되어 있는 비-Ab 단백질들 또는 다른 자연발생적 유기 분자들로부터 중량비로 적어도 약 10%(예컨대, 9%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98%, 99%, 99.9% 및 100%) 부재한 경우 정제된 것이다. 순도는 임의의 적당한 방법, 예컨대, 칼럼 크로마토그래피, 폴리아크릴아미드 겔 전기영동 또는 HPLC 분석에 의해 측정될 수 있다. 화학적으로 합성된 단백질 또는 자연적으로 발생하는 세포 유형과는 다른 세포 유형에서 생성된 다른 재조합 단백질은 "정제되어 있다."
본 명세서에 기술된 것과 유사하거나 동등한 방법 및 물질은 본 발명의 시행 또는 시험에 이용될 수 있지만, 적당한 방법 및 물질은 아래에 기술되어 있다. 본 명세서에 언급된 모든 발간물들은 그대로 참고로 포함되어 있다. 충돌하는 경우, 정의를 포함하는 본 명세서가 우선할 것이다. 또한, 아래에 기술된 특정한 실시예들은 단지 예시적일 뿐이며 한정적인 의도는 아니다.
본 발명은 (i) IL-1α에 대하여 아주 높은 결합 친화도를 보이는 항원-결합 가변 영역 및 (ii) C1q 결합을 통하여 보체계를 활성하시키고 몇 개의 상이한 Fc 수용체들과 결합하는데 효과적인 불변 영역을 포함하는 전체 인간 mAbs에 관한 조성물과 방법을 포함한다. 아래에 기술된 바람직한 실시예들은 이러한 조성물들과 방법들의 개조(adaptation)를 예시하고 있다. 그럼에도, 이러한 실시예들의 설명으로부터 본 발명의 다른 측면들은 아래에 제공된 설명에 기초하여 제조되고/되거나 실행된다.
종래 면역학적 및 분자 생물학적 기법들을 포함하는 방법들이 본 명세서에 기술되어 있다. 면역학적 방법들(예를 들면, 항원-Ab 복합체들의 검출 및 국소화 (localization)를 위한 검정, 면역침강, 면역블로팅(immunoblotting) 등)은 일반적으로 업계에 공지되어 있으며 문헌[Immunology, Coligan et al., ed., John Wiley & Sons, New York]에서의 현재 프로토콜들과 같은 방법론적 학술논문들에 기술되어 있다. 분자 생물학의 기법들은 문헌[Molecular Cloning: A Laboratory Manual, 2nd ed., vol. 1-3, Sambrook et al., ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 2001]; 및 [Current Protocols in Molecular Biology, Ausubel et al., ed., Greene Publishing and Wiley-Interscience, New York]와 같은 학술논물들에 상세히 기술되어 있다. Ab 방법들은 Handbook of Therapeutic Abs, Dubel, S., ed., Wiley-VCH, 2007에 기술되어 있다. 세포 배양 기법들은 일반적으로 업계에 공지되어 있으며 Culture of Animal Cells: A Manual of Basic Technique, 4th edition, by R Ian Freshney, Wiley-Liss, Hoboken, N.J., 2000; 및 General Techniques of Cell Culture, by Maureen A Harrison and Ian F Rae, Cambridge University Press, Cambridge, UK, 1994와 같은 방법론적 학술논물들에 상세히 기술되어 있다. 단백질 정제의 방법들은 Guide to Protein Purification: Methods in Enzymology, Vol. 182, Deutscher M P, ed., Academic Press, San Diego, Calif., 1990에 논의되어 있다.
일 측면에서, 본 발명은 (i) 인간 IL-1α에 대하여 아주 높은 결합 친화도를 보이는 항원-결합 가변 영역 및 (ii) C1q 결합을 통하여 보체계를 활성하시키고 몇 개의 상이한 Fc 수용체들과 결합하는데 효과적인 불변 영역을 포함하는 전체 인간 mAb를 특징으로 한다. 상기 인간 Ab는 바람직하게는 IgG1이다. 상기 Ab의 Ka는 바람직하게는 적어도 1x109 M-1 이상(예컨대, 9x1010 M-1, 8x1010 M-1, 7x1010 M-1, 6x1010 M-1, 5x1010 M-1, 4x1010 M-1, 3x1010 M-1, 2x1010 M-1 또는 1x1010 M- 1)이다.
인간 IL-1α에 대해 특이적인 Ig를 발현하는 B 림프구들은 인간에 있어서 자연적으로 발생하기 때문에, 현재 바람직한 mAbs를 성장시키는 방법은 우선 피검자로부터 상기 B 림프구를 단리시키고 배양액에서 계속 복제될 수 있도록 이후 불멸화시킨다. 인간 IL-1α에 대해 특이적인 Ig를 발현하는 수많은 자연발생적 B 림프구들이 부족한 피검자들은 하나 이상의 인간 IL-1α 항원들로 면역화되어 상기 B 림프구들의 숫자를 증가시킬 수 있다. 인간 mAb들은 인간 Ab 분비 세포(예컨대, 인간 혈장 세포)를 불멸화시켜 제조된다. 예컨대, 미국 특허 번호 4,634,664 참조.
예시적인 방법에서, 하나 이상의(예컨대, 5, 10, 25, 50, 100, 1000 이상) 인간 피검자들(예컨대, 인간 IL-1α 백신을 이전에 투여받지 않은 피검자들)은 그 혈액에서 상기 인간 IL-1α-특이적인 Ab의 존재 여부에 대하여 스크리닝된다. 소기의 Ab를 발현하는 피검자들이 이후 B 림프구 기증자들로 이용될 수 있다. 하나의 가능한 방법에 있어서, 말초 혈액은 인간 IL-1α-특이적인 Ab를 발현하는 B 림프구들을 소유하는 인간 기증자로부터 획득된다. 이러한 B 림프구들은 이후 예컨대, 인간 IL-1α-특이적인 Ig를 발현하는 B 림프구들을 선택하게 하는 세포 분류(예컨대, 형광 활성화 세포 분류, "FACS" 또는 자기 비드 세포 분류)에 의하여 혈액 표본으로부터 단리된다. 이후, 이러한 세포들은 바이러스 형질전환(예컨대, EBV 사용)에 의하여 또는 공지된 기법들에 따라 인간 골수종과 같은 다른 불멸화된 세포로의 융합에 의하여 불멸화될 수 있다. 이 군내에서 인간 IL-1α에 대하여 특이적인 Ig를 발현하는 B 림프구들은 이후 희석 방법들을 한정하여 단리될 수 있다(예컨대, 인간 IL-1α에 대하여 특이적인 Ig에 대하여 양성인, 마이크로타이터 플레이트의 웰들 내에서의 세포들은 선택되고 계대배양되며, 상기 공정은 소기의 영양계(clonal line)가 단리될 수 있을 때까지 반복된다). 예컨대, 문헌[Goding, Monoclonal Abs: Principles and Practice, pp. 59-103, Academic Press, 1986] 참조. 인간 IL-1α에 대하여 적어도 나노몰(nanomolar) 또는 피코몰(picomolar) 결합 친화도를 갖는 Ig를 발현하는 그러한 영양계들이 바람직하다. 이러한 영양계들에 의하여 분비되는 MAb들은 솔트 컷(salt cuts), 크기 배제, 이온 교환 분리 및 친화도 크로마토그래피와 같은 종래 Ig 정제 절차들에 의하여 배양 배지 또는 체액(에컨대, 복수)으로부터 정제될 수 있다.
불멸화된 B 림프구들은 시험관 내 배양액에서 사용되어 mAb들을 직접 생산하지만, 특정한 경우에 mAb들을 생성하는 이종 발현계(heterologous expression system)을 사용하는 것이 바람직할 수 있다. 예컨대, 미국 특허 출원 번호 11/754,899에 기술된 방법들을 참조. 예를 들면, 인간 IL-1α에 특이적인 mAb를 인코딩하는 유전자들은 클로닝되어 이종 숙주 세포(예컨대, CHO 세포, COS 세포, 골수종 세포 및 대장균 세포)에서 발현을 위한 발현 세포로 도입될 수 있다. Ig들은 H2L2 배열에서 중쇄[H] 및 경쇄[L]를 포함하기 때문에, 각각을 인코딩하는 유전자들은 따로 단리되어서 상이한 벡터들에서 발현될 수 있다.
일반적으로는 잘 언급이 안되지만, 상이한 동물종으로부터 유래된 상이한 부분들을 갖는 항원-결합 분자들(예컨대, 인간 Ig의 불변 영역에 융합된 마우스 Ig의 가변 영역)인 키메라 mAb들(예컨대, "인간화된" mAb들)이 본 발명에 사용될 수 있다. 그러한 키메라 Ab들은 업계에 공지된 방법에 의하여 제조될 수 있다. 문헌 [E.G., Morrison et al., Proc. Nat'l. Acad. Sci. USA, 81:6851, 1984; Neuberger et al., Nature, 312:604, 1984; Takeda et al., Nature, 314:452, 1984] 참조. 마찬가지로, Ab들은 업계에 공지된 방법에 의하여 인간화될 수 있다. 예를 들면, 소기의 결합 특이도를 갖는 단일클론성 Ab들은 미국 특허 5,693,762; 5,530,101; 또는 5,585,089에 기술된 바와 같이 상업적으로 인간화될 수 있다.
본 명세서에 기술된 mAb들은 VH 및 VL 도메인 셔플링(domain shuffling: Marks et al. Bio/Technology 10:779-783, 1992), 고도가변 영역(HVRs)의 무작위 돌연변이법(random mutagenesis) 및/또는 골격 잔기(framework residues)와 같은 공지된 방법들에 의하여 그 결합 특이도를 향상 또는 달리 변경하도록 친화도 성숙될 수 있다(문헌[Barbas et al. Proc Nat. Acad. Sci. USA 91:3809-3813, 1994; Schier et al., J. Immunol. 154(7):3310-9, 1995]; 및 [Hawkins et al, J. Mol. Biol. 226:889-896, 1992] 참조). Ab의 아미노산 서열 변이체들은 상기 Ab를 인코딩하는 염기 서열에 적당한 변화를 도입하여 제조될 수 있다. 또한, mAb들을 인코딩하는 핵산 서열들에 대한 수정은 특정 발현계 내에서 상기 mAb의 생성을 향상시키기 위하여(예컨대, 주어진 발현계에 대한 인트론 제거 및/또는 코돈 최적화) 변경될 수 있다(예컨대, 상기 mAb의 아미노산 서열을 변화시키지 않고). 또한, 본 명세서에 기술된 mAb들은 다른 단백질(예컨대, 다른 mAb) 또는 비-단백질 분자와의 접합(conjugation)에 의하여 수정될 수 있다. 예를 들면, mAb는 폴리에틸렌 글리콜 또는 탄소 나노튜브와 같은 물에 용해가능한 중합체에 접합될 수 있다(예컨대, 문헌[Kam et al., Proc. Natl. Acad. Sci. USA 102: 11600-11605, 2005] 참조). 미국 특허 출원 제 11/754,899 호 참조.
바람직하게는, 고 역가의 인간 IL-1α-특이적인 mAb가 최소한의 부작용으로 피검자에게 투여될 수 있도록 하기 위하여, 본 발명의 mAb 조성물들은 순수한(임의의 부형제 제외) 중량비로 적어도 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 95, 96, 97, 98, 99, 99.9 이상이다. 본 발명의 mAb 조성물들은 mAb의 단일 유형만을 포함할 수 있거나(즉, 단일 클론성 B 림프구계(lymphocyte line)로부터 생성된 하나) 둘 이상의(예컨대, 2, 3, 4, 5, 6, 7, 8, 9, 10 이상) 상이한 유형의 mAb들의 혼합물을 포함할 수 있다. 인간 IL-1α mAb들에 더하여, 본 발명의 Ab 조성물들도 인간 IL-1α가 아닌 항원들을 특이적으로 결합하는 다른 mAb들도 포함할 수 있다.
그 기능을 수정하거나 향상시키기 위하여, 상기 인간 IL-1α mAb들은 세포독소 또는 검출가능한 라벨과 같은 접합된 다른 분자일 수 있다. 인간 IL-1α 특이적인 mAb는 하나 이상의 세포독소들과 접합되어 IL-1α를 발현하는 세포들을 더 효과적으로 죽일 수 있다. 본 발명에 사용되는 세포독소는 인간 IL-1α 특이적인 mAb에 접합될 수 있는 임의의 세포독성제(예컨대, 세포와 접촉한 이후에 상기 세포를 죽일 수 있는 분자)일 수 있다. 세포독소들의 예로는 한정되지 않고 방사성핵종들(예컨대, 35S, 14C, 32P, 125I, 131I, 90Y, 89Zr, 201Tl, 186Re, 188Re, 57Cu, 213Bi 및 211At), 접합된 방사성핵종들 및 화학요법제들을 포함한다. 세포독소들의 다른 예로는 항대사물질들(예컨대, 5-플루우르우리실(fluorouricil)(5-FU), 메토트랙세이트(MTX), 플루다라빈(fludarabine) 등), 항-미세관 제제들(예컨대, 빈크리스틴, 빈블라스틴, 콜히친, 탁산류(파클리탁셀 및 도세탁셀) 등), 알킬화제들(예컨대, 시클로파스파미드(cyclophasphamide), 멜팔란, 비스클로로에틸니트로스우레아 (bischloroethylnitrourea: BCNU) 등), 백금제제들(예컨대, 시스플라틴(cDDP로도 칭함), 카르보플라틴, 옥살리플라틴, JM-216, CI-973 등) 또는 리신, 디프테리아 독소(DT), 슈도모나스 외독소(PE) A, PE40, 아브린, 사포린, 아메리카자리공 (pokeweed) 바이러스 단백질, 브롬화에티듐(ethidium bromide), 글루코코르티코이드, 탄저병 독소 등과 같은 다른 세포독성제들을 포함하지만, 여기에 한정되지 않는다. 예컨대, 미국 특허 제 5,932,188 호 참조.
또한, 상기 인간 IL-1α 특이적인 mAb는 검출가능한 라벨에 접합될 수 있다. 본 발명에서 유용한 검출가능한 라벨들은 비오틴 또는 스트렙타비딘, 자기 비드들, 형광 염료들(예컨대, 플루오르세인 이소티오시아네이트, 텍사스 레드(texas red), 로다민, 녹색 형광 단백질 등), 방사성핵종들(예컨대, 3H, 125I, 35S, 14C, 32P, 111In, 97Ru, 67Ga, 68Ga 또는 72As), 방사성영상용 금속들과 같은 방사선을 투과하지 않는(radioopaque) 물질들, 효소들(예컨대, 양고추냉이 과산화효소(horseradish peroxidase), 알칼리성 인산가수분해효소 및 ELISA에 통상적으로 사용되는 효소들) 및 콜로이드성 금 또는 채색 유리 또는 플라스틱(예컨대, 폴리스타이렌, 폴리프로필렌, 라텍스 등) 비드들과 같은 비색 라벨(colorimetric label)들을 포함한다. 상기 라벨들을 검출하는 수단들은 당업자에게 공지되어 있다. 따라서, 예를 들면, 방사성핵종들은 사진 필름 또는 섬광 계수기를 사용하여 검출될 수 있다. 또한, 형광 표지들이 사용될 수 있으며, 발산된 조명을 검출하는 광검출기를 사용하여 검출될 수 있다. 효소에 기질을 제공하고 상기 기질상에서 상기 효소의 작용으로 생성된 반응 생성물을 검출하여 효소 라벨들이 검출되며, 비색 라벨들은 채색 라벨을 용이하게 시각화하여 검출된다.
또한, 본 발명은 인간 IL-1α에 특이적인 전체 인간 mAb들을 인코딩하는 핵산 분자들을 포함한다. 동일한 핵산 분자가 인간 IL-1α-특이적인 mAb의 중쇄 및 경쇄 양쪽 모두를 인코딩할 수 있지만, 2 가지 상이한 핵산 분자들 중 중쇄를 인코딩하는 것과 경쇄를 인코딩하는 다른 것도 사용될 수 있다. 인간 IL-1α에 특이적인 3 가지 IgG1 mAb들의 아미노산 서열들은 본 발명에 제시되어 있다. 서열 ID 번호들: 1, 3, 5, 7, 9 및 11 참조. 또한, 3 가지 아미노산 서열들을 인코딩하는 예시적인 핵산 분자들은 본 명세서에 기술되어 있다. 서열 ID 번호들: 2, 4, 6, 8, 10 및 12 참조. 상기 2 개의 기술된 IgG1 mAb들 또는 본 발명 내의 다른 mAb들의 아미노산 서열들을 인코딩하는 임의의 다른 적당한 핵산도 사용될 수 있다.
mAb들의 생성을 위해, 본 발명의 핵산 분자들은 전사 및 번역 제어 서열들과 같은 발현 제어 서열들에 작동가능하게 연결되어 있는 배향으로 발현 벡터에 혼입 (incorporated)될 수 있다. 발현 벡터들의 예로는 플라스미드류로부터 유래한 벡터들 및 아데노바이러스류, 아데노-연관 바이러스류 및 레트로바이러스류와 같은 바이러스들로부터 유래한 벡터들을 포함한다. 경쇄 및 중쇄를 인코딩하는 핵산 분자들은 단일 벡터 또는 상이한 벡터들에 혼입될 수 있다. 또한, 본 발명의 벡터들은 프로모터들 및/또는 인헨서들과 같은 조절 서열들을 포함할 수 있다(미국 특허 제 5,168,062 호, 미국 특허 제 4,510,245 호 및 제 4,968,615호 참조), 선별가능한 표지들 또는 친화도 태그들을 인코딩하는 서열들(정제를 용이하게 하기 위함) 또는 검출가능한 라벨을 포함할 수 있다.
mAb들의 생성을 위해, 본 발명의 벡터들은 적당한 숙주 세포, 예컨대, 박테리아와 같은 원핵 세포, 또는 바람직하게는 포유류, 식물 또는 효모 숙주 세포와 같은 진핵 세포에 도입될 수 있다. 숙주 세포로의 이종 폴리뉴클레오티드들의 도입방법들의 예로는 바이러스 벡터들의 사용, 전기천공법, 리포솜에서 폴리뉴클레오티드(들)의 캡슐화, 덱스트란 매개 형질감염법(dextran mediated transfection), 인산칼슘 침강법, 폴리브렌-매개 형질감염법, 원형질체 융합, 아그로박테리움-매개 형질전환법(Agrobacterium-mediated transformation), 유전자주입 형질전환법 (biolistic transformation) 및 핵으로 DNA의 직접 미세주입을 포함한다. 포유류 숙주 세포들의 예로는 중국 햄스터 난소(CHO) 세포들(예컨대, DG44 CHO 세포주), HeLa 세포들, 아기 햄스터 신장(BHK) 세포들, 아프리카 녹색 원숭이 신장 세포들 (COS), 인간 간세포 암종 세포들(예컨대, Hep G2), NS0 세포들, SP2 세포들, HEK-293T 세포들, 293 프리스타일(Freestyle) 세포들 및 NIH-3T3 세포들을 포함한다. 또한, 본 발명의 mAb들은 형질전환된 동물들 또는 식물들에서 발현될 수 있다. 예컨대, 미국 특허 번호. 5,827,690; 5,756,687; 5,750,172; 5,741,957; 6,046,037; 및 5,959,177 참조.
본 발명은 표본 내의 인간 IL-1α-발현 세포 검출방법으로서, 상기 세포를 인간 IL-1α-특이적인 mAb와 접촉시키고 상기 세포에 결합된 상기 mAb를 검출하여 표본 내의 인간 IL-1α-발현 세포 검출방법을 제공한다. 또한, 본 발명은 인간 IL-1α-발현 세포를 죽이는 방법으로서, 상기 세포를 인간 IL-1α-특이적인 mAb와 접촉시켜 인간 IL-1α-특이적인 mAb를 죽이는 방법을 제공한다. 그러한 살상 (killing)은 보체 매개 살상(complement-mediated killing), Ab-의존성 세포 매개 세포독성(Ab-dependent cell-mediated cytotoxicity) 또는 세포독소의 Ab-매개 전달에 의하여 달성될 수 있다. 또한, 본 명세서에 기술된 Ab들은 다른 방법들에 유용한 것을 보이고 있다. 예를 들면, MABp1은 내피 세포상에서 IL-1α 유도 ICAM1 및 E-셀렉틴 발현을 감소시키는 것을 보이고 있다. 또한, MABp1은 생물학적 표본에서 IL-1α를 검출하고 정량화하는 면역검정에 사용되는 것을 보이고 있다.
실시예
[
실시예
1]
항-hIL-1αIgG1 및 카파 사슬들의 클로닝
가변 영역 중쇄(V-HC) 및 가변 영역 경쇄(V-LC) 서열들은 미국 특허 번호 5,959,085에 제공된 아미노산 서열 정보를 이용하여 유전자 합성되었다. V-HC는 ATG 시작 코돈의 상류(upstream) Hindlll/Clal 부위들 및 3' 말단의 Nhel 부위를 도입하여 증폭되었다. 인간 배선(germline) IgG1 불변 영역(엑손들 및 인트론들 포함)은 최초 2 개의 아미노산들인 Ala-Ser를 인코딩하는 2 개의 5' 삼중선들 (triplets)을 Nhel 부위로 수정하고, BamHI 부위를 3' 말단에 도입하여 PCR 증폭되었다. 상기 인간 배선 IgG1 불변 영역 아미노산 서열은 K171Q 및 V261L 교환을 제외하고는 스위스-프롯 엔트리(Swiss-Prot entry) P01857에 해당한다. 상기 V-HC 및 불변 IgG1-HC 서열은 상기 Nhel 부위를 사용하여 연결되었고 Hindlll 및 BamHI 부위들을 사용하여 pcDNA3으로 클로닝되었다.
>hIL-1a-1gG1-HC
MEFGLSVVVFLVALLRGVQCQVQLVESGGGVVQPGRSLRLSCTASGFTFSMFGVHWVRQAPGKGLEVVV AAVSYDGSNKYYAESVKGRFTISRDNSKNILFLQMDSLRLEDTAVYYCARGRPKVVIPAPLAHWGQGTLVTFSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAQTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIALEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (서열 ID 번호: 1)
>hIL-1a-IgG1-HC
gtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggatgagctgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgccctggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccttaagtccgggaaaataa (서열 ID 번호:2)
상기 V-LC는 ATG 시작 코돈의 상류 Hindlll/Clal 부위들 및 3' 말단의 BsiWI 부위를 도입하여 PCR 증폭되었다. 상기 인간 불변 카파-LC 서열은 다른 Arg 및 제 1 아미노산 Thr을 인코딩하는 5' BsiWI 부위 및 3' 말단의 BamHI 부위를 도입하여 PCR 증폭되었다. 상기 인간 불변 카파-LC 아미노산 서열은 스위스-프롯 엔트리 P01834에 해당되었다. V-HC 및 불변 카파-LC 서열들은 상기 BsiWI 부위를 사용하여 연결되고 HindIII 및 BamHI 부위들을 사용하여 pcDNA3으로 클로닝되었다.
>hIL-1a-K-LC
MDMRVPAQLLGLLLLWFPGSRCDIQMTQSPSSVSASVGDRVTITCRASQGISSWLAvrYQQKPGKAPKLLIYEASNLETGVPSRFSGSGSGSDFTLTISSLQPEDFATYYCQQTSSFLLSFGGGTKVEHRTVAAPSVFWPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC [서열 ID 번호:3]
>hIL-1a-K-LC
atggacatgcgcgtgcccgcccagctgctggggctgctgctgctgtggttccctggatctaggtgcgacattcagatgacccagtcccccagctcagtgtcagcctccgtgggcgacagagtgacaatcacctgccgcgcctctcagggaatctctagttggctggcctggtaccagcagaagcctggaaaggcccccaagctgctgatctatgaagcctccaacctggagaccggcgtgccctctcgcttcagcggctcaggctcaggcagtgattttactctgaccatcagctccctgcagccagaggatttcgctacttactactgccagcagacctcttccttcctgctgtccttcgggggaggcacaaaggtggagcaccgtacggtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagttcaccggtgacaaagagcttcaacaggggagagtgttag[서열 ID 번호:4]
[
실시예
2]
NATHMAB-hlL-1a/IgG1 중쇄를 인코딩하는 완전 서열이 유전자 합성되었다. V-HC 서열은 미국 특허 5,959,085에 기술된 아미노산 서열에 해당하였다. 인간 불변 IgG1-HC 서열은 스위스-프롯 엔트리 P01857에 해당하였다. 염기 서열은 CHO 세포에서 발현을 위해 코돈 최적화되었다. 코작(Kozac) 서열(gccacc)은 시작 ATG의 상류에 첨가되었다.
>NATHMAB-hIL-1A-IGG1-HC
MEFGLSWVFLVALLRGVQCQVQLVESGGGVVQPGRSLRLSCTASGFTFSMFGVHWVRQAPGKGLEWVAAVSYDGSNKYYAESVKGRFTISRDNSKNILFLQMDSLRLEDTAVYYCARGRPKVVIPAPLAHWGQGTLVTFSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK [서열 ID 번호:5]
>NATHMAB-hIL-1A-IGG1-HC
caaagaatataagtgtaaagtgtccaacaaggccctgccagccccaatcgaaaagacaatctctaaagccaaggggcaaccccgggaacctcaggtctatacactgccaccctctcgggatgaactgaccaagaatcaggtgagcctgacatgtcttgtgaagggtttttatccctccgacattgccgtggagtgggagagcaatggacaaccagaaaataactacaaaaccacaccccctgtgctggactccgatggttccttcttcctctactctaagctgacagtggataagtctaggtggcagcaggggaatgtgttctcctgctctgtgatgcacgaggcactgcacaatcattatacacaaaagtctctgtctctgtctccaggaaagtaa [서열 ID 번호: 6]
NATHMAB-hlL-1a/카파 경쇄를 인코딩하는 완전 서열이 유전자 합성되었다. V-LC 서열은 미국 특허 5,959,085에 기술된 아미노산 서열에 해당하였다. 인간 불변 카파-LC 서열은 스위스-프롯 엔트리 P01834에 해당하였다. 염기 서열은 CHO 세포에서 발현을 위해 코돈 최적화되었다. 코작 서열(gccacc)은 시작 ATG의 상류에 첨가되었다.
>NATHMAB-hIL-1A-K-LC
MDMRVPAQLLGLLLLWFPGSRCDIQMTQSPSSVSASVGDRVTITCRASQGISSWLAWYQQKPGKAPKLLIYEASNLETGVPSRFSGSGSGSDFTLTISSLQPEDFATYYCQQTSSFLLSFGGGTKVEHTVAAPSVFWPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC [서열 ID 번호:7]
NATHMAB-hIL-1A-K-LC
gccaccatggacatgcgcgttcctgcccagctcctcggactgctgctgctttggttcccaggctcccggtgtgatattcagatgacacagtctccctcctccgtatctgcatccgtgggcgacagggtcacaatcacttgtagggccagccaggggatctctagttggctcgcatggtaccaacaaaagccaggtaaggctccgaaactgctcatttacgaagctagtaacctcgaaacaggcgtgccaagccggtttagcggctccggttccggttctgacttcaccctcactatttcctccctgcaacctgaggattttgccacatattactgtcagcaaacttcttcttttctgctctcctttggtgggggaactaaggtggagcacacagtggccgcccccagcgtctttatcttccccccaagcgatgaacagctgaagtcagggaccgccagcgtggtctgcctgctcaataatttttaccctcgcgaggctaaggtccaatggaaagtggataacgccctccagagcggtaactctcaggagtctgtcacagagcaagacagcaaggatagcacctattccctctccagcaccctgacactgtctaaggccgactacgagaaacacaaagtgtacgcttgtgaggtgactcaccagggactgagtagccctgtgacaaaatctttcaataggggagaatgctga [서열 ID 번호:8]
[
실시예
3]
NATHMAB-IL-1-a(IgG1/k 서브유형)의 발현
NATHMAB-IL-1α는 잠정적인 형질감염 방법을 이용하여 발현되고 정제되었다. 세포 배양 상청액 또는 단백질 G 친화도 정제된 Ab는 아래에 기술된 바와 같이 더 분석되었다. 인간 배아 신장(HEK) 293T 세포들은 10% FCS를 함유하는 DMEM에서 배양되고 제작자 프로토콜에 따라서 jetPEI 시약(폴리플러스(Polyplus))을 사용하여 잠정적으로 형질감염되었다. 세포들은 형질감염 24 시간 전에 10 ㎝ 접시들(10 ㎝ 접시당 3x106 세포들)상에 살포되어 형질감염 시점에서 약 50% 밀도에 도달하였다. pcDNA3-항-hIL-1α-IgG1-HC의 접시당 5 ㎍과 pcDNA3-항-hIL-1α-카파의 2 배 몰 여분이 형질감염용으로 사용되었다. 회수된 이후에, 배지는 2% FCS(접시당 10 ㎖)를 함유하는 DMEM으로 교체되었으며 Ab는 5 내지 6 일 동안 수거되었다. 상청액이 수거, 여과되고, pH가 7.5 내지 8로 조절되며 달리 사용되기 전까지 4℃에서 보관되었다.
상기 상청액의 일부가 회전판(rotation wheel)상의 4℃에서 3 시간 동안 단백질 G 세파로스(GE 헬스케어)로 배양되었다. 이후, 상기 단백질 G 세파로스는 중력 유동 칼럼(gravity flow column)으로 적재되고 PBS로 세척되었다. Ab는 100 mM 글리신/150 mM NaCl을 사용한 1 ㎖ 분획에서 100 ㎕ Tris (pH 8)로 용출되고, 이후 10% 글리세롤을 함유하는 PBS로 투석되었다. 각각의 분획의 총 단백질 농도는 BCA 단백질 검출 키트(피어스(Pierce))를 사용하여 측정되었다. 중쇄와 경쇄 및 조립된 (assembled) 천연 Ab의 정확한 크기는 SDS-PAGE로 확인되었다.
NATHMAB-hIL-1α 정제된 Ab 를 함유하는 상청액 및 생산자 HEK 293T 세포들의 트리톤 X-100 세포 용해질을 125-I-hIL-1α를 사용한 방사선면역검정(RIA)에서 항원 결합여부를 위해 시험되었다. 결합은 단백질 G로의 흡수에 의하여 검정되었다. 모든 표본들은 용출액에서 최고의 활성을 갖는 125I-hIL-1α에 결합되었다. 0.012% 농도(RIA에서 반-최대 활성)의 정제된 NATHMAB-hIL-1α를 125I-hIL-1α로의 결합은 친화도 상수를 측정하는데 이용되었다. 이러한 조건하에서 NATHMAB-hIL-1α의 Ka는 3.03x1010 M-1이었다. 역계산방법으로 인하여 정제된 용출액에서의 약 30 ㎍/㎖ 활성 항-hIL-1α-IgG의 추정 농도를 밝혀내었다.
NATHMAB-hIL-1α의 중화 활성은 쥐 또는 인간 IL-1α로 처리되는 경우 IL-2의 고 순도를 생성하는 쥐 EL4-6.1 서브주(subline)을 사용한 생물검정에서 시험되었다(Zubler et al., J. Immunol. 134:3662-3668, 1985). NATHMAB-hIL-1α(용출액)의 표시된 농도는 96-웰 배양 플레이트(평평한 바닥)의 100 ㎕/웰의 최종 부피에서 재조합 hIL-1α(eBioscience)의 농도를 달리하여 37℃에서 30 분 동안 배양되었다. 각 점은 3 번씩 배양 배지(DMEM, 5% FCS)에서 수행되었다. 각각의 웰에 0.2 ㎍/㎖ 이오노마이신(ionomycin)을 함유하는 배양 배지에 EL4-6.1 세포들의 현탁액(5x105 세포/㎖) 100 ㎕가 첨가되었다. 5% CO2 배양기의 37℃에서 24 시간 동안 배양한 이후에, 무세포 상청액이 수거되었으며 상용가능한 ELISA(R&D Systems)를 사용하여 IL-2 농도에 대하여 검정되었다. 결과에 따르면 NATHMAB-IL-1α는 EL-4 세포들에 의하여 hIL-1α-유도 IL-2 분비를 효과적으로 중화시켰음을 보였다.
막-결합 hIL-1α의 중화여부를 시험하기 위하여, 상술한 동일 EL-4 세포계 검정을 다음과 같이 수정하여 이용하였다. 다양한 농도의 NATHMAB-hIL-1α(용출액)을 다양한 수의 인간 활성화 단핵세포들과 함께 배양시켰다. 단핵세포 제조를 위해, PBMC는 피콜-파크(Ficoll-Paque) 원심분리를 이용하여 연층(buffy coat)으로부터 단리되었다. 단핵세포들은 플라스틱 접시들상의 RPMI에서 37℃로 1.5 시간 동안 부착하도록 하였다. 미부착 림프구들을 세척하여 거의 순수한 단핵구 배양물을 얻었다. 단핵구들은 5% CO2 배양기의 37℃에서 LPS(1 ㎍/㎖)과 함께 Gln, Pyr 및 10% FCS를 함유하는 RPMI에서 24 시간 동안 배양되었다. 세포들을 PBS/2 mM EDTA로 탈착시켰으며, 플레이트들로부터 조심스럽게 벗겨내었으며, 팔콘(Falcon) 튜브로 옮겨 넣었다. 세포들은 PBS로 2 회 세척되었고, PBS/1% PFA에서 재현탁되었으며 20℃로 10 분 동안 부착되었다. 세포들은 글리신 완충제(150 mM 글리신, 75 mM NaCl, pH 7.4)로 세척되었고, 이후 배양 배지로 세척되었으며 계수되었다. 결과에 따르면 NATHMAB-hIL-1α는 막 결합 hIL-1α에 의하여 유도된 EL-4 세포들에 의하여 IL-2 분비를 효과적으로 중화시켰음을 보였다. 상술한 실험과 유사한 실험에서, NATHMAB-hIL-1α는 쥐 IL-1α의 중화여부에 대하여 시험되었다. 표시된 양의 NATHMAB-hIL-1α 상청액을 재조합 인간(h) 또는 쥐(m) IL-1α(eBioscience)로 배양하였다. 상기 Ab를 함유하는 상청액은 쥐가 아닌 인간 IL-1α를 중화시켰다.
[
실시예
4]
암 세포들의 A-매개 살상(Ab-Mediated Killing)
표준 피콜 파크 제조에 의하여 연층으로부터 단리된 인간 말초 혈액 단핵 세포들(PBMC)은 RPMI-1640 CM 또는 rhIL-2(30 ng/㎖, ebioscience)를 함유하는 RPMI-1640-CM에서 37℃ 및 5% CO2로 하룻밤동안 배양되었으며 작동 세포(E)로 사용되었다. THP1 세포들은 표적(T)으로 사용되었다. 검정은 96-웰 플레이트에서 각 점 3 벌씩 수행되었다. 15 분 동안 다른 농도의 MABp1과 함께 1x104 표적들을 배양한 이후에, 작동 세포들은 25:1 및 50;1의 ET 비율로 1x104 표적들에 첨가되었으며 4 시간 더 배양되었다. 75 ul의 검정 부피가 새로운 96-웰 플레이트에 옮겨졌으며, 세포독성은 제작자 프로토콜에 따른 LDH 세포독성 검출 키트(Roche)를 사용하여 검정되었다. % 특이적 용해 = (평균 실험 방출 - 무항체 평균 동시 방출) x 100/(표적들로부터 표적-평균 동시 방출로부터 평균 최대 방출) A. 무처리 PBMC는 작동 세포로 사용되었다. B. rhIL-2-처리된 PBMC는 작동 세포로 사용되었다. 양쪽 모두의 경우에, MABp1의 농도를 증가시키면(1.25에서 20 ug/㎖로) 양쪽 ET 비율에서 표적 세포 살상이 증가하게 되었다(최대 약 90%).
[
실시예
5]
인간 IL1α(MABp1)에 특이적인 다른 인간 항-IL-1aIgG1/카파 경쇄를 인코딩하는 완전 서열은 상술한 바와 같이 합성되고 발현되었다. 중쇄 및 경쇄를 인코딩하는 핵산들에 있어서, 코작 서열(gccacc)는 시작 ATG의 상류에 첨가되었다.
중쇄
MEFGLSWVFLVALLRGVQCQVQLVESGGGVVQPGRSLRLSCTASGFTFSMFGVHWVRQAPGKGLEWVAAVSYDGSNKYYAESVKGRFTISRDNSKNILFLQMDSLRLEDTAVYYCARGRPKVVIPAPLAHWGQGTLVTFSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK [서열 ID 번호:9]
gccaccatggagtttggtctgtcctgggtgttcttggtggctctgctgaggggggtgcagtgccaggtccagctggtggagtctggtgggggagtggtgcagcctgggagatctctgcggctgtcttgcactgcctctggtttcactttctctatgtttggtgtgcattgggtcaggcaagcaccaggcaaaggactcgagtgggtcgcagctgtgagctatgac gggtctaacaaatattacgctgagtctgtcaagggtaggtttaccatcagccgggataattccaaaaatatcctgttcctgcaaatggactctctgaggctggaagatactgcagtctactattgtgcaagggggaggccaaaggtggtgatccccgctcccctcgctcactggggacagggaaccctggtgactttcagctctgctagcaccaagggccctagcgtgttcccattggctccttcctccaaatctacttctggaggcaccgccgccctgggatgtctcgtgaaagattattttcctgagcccgtcaccgtgagctggaacagcggcgccctgactagcggcgtgcacacctttcccgcagtgctgcaatctagcgggctgtactccctgagctctgtcgtgaccgtgccctccagcagcctcggaactcagacctacatctgcaatgtcaatcataaaccctctaataccaaagtcgataagagggtcgaacctaaatcttgcgataaaacccatacctgccccccttgcccagcacccgaactgctgggcggtccctctgtgtttctgttcccccccaaacccaaagataccctgatgatctctaggacccccgaggtcacttgtgtcgtggtggatgtgtcccacgaagatccagaagtcaaattcaactggtatgtggac ggggtcgaagtgcacaacgcaaagaccaagcctagggaggaacagtataatagcacatatagggtggtcagcgtcctgaccgtcctgcatcaggactggctgaatggcaaagaatataagtgtaaagtgtccaacaaggccctgccagccccaatcgaaaagacaatctctaaagccaaggggcaaccccgggaacctcaggtctatacactgccaccctctcgggaggaaatgaccaagaatcaggtgagcctgacatgtcttgtgaagggtttttatccctccgacattgccgtggagtgggagagcaatggacaaccagaaaataactacaaaaccacaccccctgtgctggactccgatggttccttcttcctctactctaagctgacagtggataagtctaggtggcagcaggggaatgtgttctcctgctctgtgatgcacgaggcactgcacaatcattatacacaaaagtctctgtctctgtctccaggaaagtaa [서열 ID 번호: 10]
경쇄
MDMRVPAQLLGLLLLWFPGSRCDIQMTQSPSSVSASVGDRVTITCRASQGISSWLAWYQQKPGKAPKLLIYEASNLETGVPSRFSGSGSGSDFTLTISSLQPEDFATYYCQQTSSFLLSFGGGTKVEHKRTVAAPSVFWPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC [서열 ID 번호: 11]
gccaccatggacatgcgcgttcctgcccagctcctcggactgctgctgctttggttcccaggctcccggtgtgatattcagatgacacagtctccctcctccgtatctgcatccgtgggcgacagggtcacaatcacttgtagggccagccaggggatctctagttggctcgcatggtaccaacaaaagccaggtaaggctccgaaactgctcatttacgaagctagtaacctcgaaacaggcgtgccaagccggtttagcggctccggttccggttctgacttcaccctcactatttcctccctgcaacctgaggattttgccacatattactgtcagcaaacttcttcttttctgctctcctttggtggaggaactaaggtggagcacaagcggacagttgctgctcctagcgtctttatcttccctccaagcgatgaacagctgaagtcagggaccgccagcgtggtctgcctgctcaataatttttaccctcgcgaggctaaggtccaatggaaagtggataacgccctccagagcggtaactctcaggagtctgtcacagagcaagacagcaaggatagcacctattccctctccagcaccctgacactgtctaaggccgactacgagaaacacaaagtgtacgcttgtgaggtgactcaccagggactgagtagccctgtgacaaaatctttcaataggggagaatgctga [서열 ID 번호: 12]
[
실시예
6]
MABp1 결합 친화도
정제된 MABp1의 결합 친화도는 BIAcore 2000 기구상에서(GE 헬스 과학) 표면 플라즈몬 공명(SPR)을 사용하여 측정되었다. 마우스 단일클론성 항-인간 IgG(Fc) Ab는 인간 Ab 포획 키트 및 아민 커플링 키트(GE 헬스 과학)를 사용하는 CM5 센서 칩의 유동 세포들상에서 공유적으로 고정되었다. 8000 내지 14000 RU의 고정화 레벨들이 통상적으로 달성될 것이다. 상기 마우스 항-인간 IgG(Fc) 포획 Ab를 고정화시킨 이후에, HBS-EP 이동 완충액(GE 헬스 과학)을 갖는 3 개의 시작 사이클들과 MABp1을 갖는 2 개의 시작 사이클들을 가동시켜 상기 CM5 표면을 안정화시키고 임의의 비-공유적 결합 Ab를 제거하였다. 분석을 위하여, MABp1 Ab를 HBS-EP 이동 완충액으로 희석시켜 최종 농도가 1 ㎍/mL가 되게 하였고, 상기 CM5 센서 칩의 하나의 유동 세포상에 700 RU에 고정시켰다. 무담체 인간 IL-1A 사이토카인 (eBioscience, #34-8019)은 HBS-EP 이동 완충액에서 100 nM 내지 0.5 nM에 이르는 시험 범위에 걸쳐 연속적으로 희석되었다. 유량은 30 ㎕/분이었다. 각각의 사이토카인 희석에 대한 해리 데이터는 15 분 동안 기록되었다. 상기 CM5 표면은 30 ㎕/분의 유량으로 3 M MgCl2의 단일 주입을 25 초 동안 사용한 각 사이클 이후에 발생되었다. BiaEvaluation 소프트웨어 및 랑무어(Langmuir) 결합 모델을 사용하여 상기 데이터를 피팅(fit)하였다. MABp1에 대한 K D 는 2.0 x 10-10 미만으로 측정되었다.
[
실시예
7]
MABp1은 기저막 기질의 종양 세포 침습을 억제한다.
기저막 기질인 마트리겔(Matrigel, BD)은 4℃에서 하룻밤동안 해동되었으며, 무혈청 냉각된 세포 배양 배지에서 희석되었다(5 ㎎/㎖에서 1 ㎎/㎖로). 상기 희석된 마트리겔 100 ul을 24-웰 트랜스웰(Costar)의 상부 챔버에 놓았으며 상기 트랜스웰은 겔화를 위해 37℃에서 적어도 4 내지 5 시간 동안 배양되었다. 종양 세포들 (MDA-MB-231 및 THP-1)은 트립신/EDTA에 의하여 조직 배양 플라스크들로부터 수거되었고, 배양 배지로 세척되었으며 1% FBS를 함유하는 배지에서 1 X 106 세포/㎖의 밀도로 재현탁되었다. 상기 겔화된 마트리겔을 미지근한 무혈청 배양 배지로 천천히 세척하였으며, 상기 세포 현탁액 100 ul을 각각의 웰에 첨가하였다. 상기 트랜스웰의 하부 챔버를 배양 배지 600 ul로 채워 넣었으며, 상기 플레이트는 37℃에서 12 내지 24 시간 동안 배양되었다. 상기 마트리겔을 침습하지 않았던 세포들을 각각의 트랜스웰의 꼭대기로부터 면봉을 사용하여 가볍게 긁어 모았다. 이후 상기 트랜스웰들을 상기 24-웰 플레이트들로부터 제거하고 상기 침습된 세포들을 70% 에탄올 또는 메탄올로 고정시킨 이후에 크리스탈 바이올렛(crystal violet)으로 염색하였다. 상기 침습된 세포들은 광학 현미경에서 계수되었다. 상기 마트리겔을 침습한 세포들의 백분율은 MABp1의 존재하에서 현저히 억제되었다.
[
실시예
8]
MABp1은 상피 세포들에서 ICAM1 발현 증가를 차단한다.
인간 제대 정맥 내피 세포(HUVEC)(BD Biosciences)를 저혈청 성장 보충제 (Invitrogen)로 보충된 M-200 배지 1 mL에 웰당 5 x 105로 24-웰 플레이트들에 살포하였다. 세포들은 3 내지 4 시간 동안 가라앉도록 하였다. 배지를 흡입하였며 신선한 M-200 1 mL를 웰마다 첨가하였다. MABp1은 4.26 ㎍/㎖로 세포에 직접 첨가되었고, 실온에서 15 분 동안 공-배양되었으며(co-incubated), 이후 재조합 인간 IL-1α(rhIL1A, eBioscience)가 첨가되어 최종 농도가 40 pg/㎖가 되었다. 양성 제어 웰들은 IL-1α의 첨가만 받을 뿐이었다. IL-1α의 존재하거나 MABp1가 부재한 곳의 HUVEC 세포들은 음성 대조의 역할을 하였다. 37℃, 5% CO2에서 17 내지 20 시간 동안 배양한 이후에, 세포들은 CellStripper 시약(셀그로 메디아테크(Cellgro Mediatech))을 사용하여 20 분 동안 비-효소 처리에 의하여 상기 플레이트들로부터 제거되어, 이후 표준 유동 세포측정 프로토콜을 사용하여 CD54(ICAM-1) 발현 여부에 대하여 즉시 검정되었다. 염색 완충액은 2% 열-비활성화된 우태 혈청으로 보충된 Dulbecco's PBS를 포함하였다. PE-접합된 마우스 항-인간 CD54(ICAM-1) mAb (eBioscience, 클론 HA58) 또는 PE-접합된 마우스 IgG1k 동기준표본(isotype) 대조 (eBioscience, #12-4714)를 제작자 지시사상에 따라 사용하여 실온의 암실에서 20 분 동안 100 마이크로리터 염색 부피로 HUVEC 세포들을 염색하였다. 이어서, 염색 완충액에서 2회 세척을 수행하고 이후 FACSCalibur 유동 세포계측계(BD Biosciences)상에서 표본들을 획득하였다. 몇 가지 독립적인 실험들(n=5) 중에서, HUVEC 세포들의 표면상에서 rhIL1A에 의하여 유도된 ICAM-1 부착 세포들의 상향조절은 무자극(unstimulated) HUVEC 세포들에 의하여 보여지는 기저 수준으로 MABp1에 의하여 중화되었다.
[
실시예
9]
MABp1은 내피 세포에서 E-셀렉틴 발현의 증가를 차단한다.
ICAM-1 유도에 미치는 그 효과와 유사한, HUVEC 세포들에 미치는 CD62E(E-셀렉틴)의 유도의 MABp1-매개 중화도 관찰되었다. 이 효과는 HUVEC 세포들이 용해성 rhIL-1이 아닌 글리코실-포스파티딜리노시톨(glycosyl-phosphatidylinositol)에 의하여 DG44 CHO 세포들(GPI-IL1A 세포들)의 표면에 안착된 막성(membranous) IL-1a에 의하여 자극되었다. 이 실험에서, 6-웰 플레이트들에서 HUVEC 세포들의 컨플루언트(confluent) 배양물은 M-200 배지에서 5 x 106 GPI-IL1A DG44 세포들과 함께 다른 존재없이 또는 10 ㎍/㎖ MABp1의 존재하에 또는 10 ㎍/㎖ D5 동기준표본 대조 Ab의 존재하에 하룻밤동안 공-배양되었다. 17 내지 20 시간 이후에, HUVEC 단일층들이 Dulbecco's PBS로 광범위하게 세척되었으며, 이후 CellStripper 시약(셀그로 메디아테크)를 사용한 비-효소 처리에 의하여 제거되었으며, 이후 표준 유동 세포측정 프로토콜을 사용하여 CD62E(E-셀렉틴) 발현 여부에 대하여 즉시 검정되었다. 염색 완충액은 2% 열-비활성화된 우태 혈청으로 보충된 Dulbecco's PBS를 포함하였다. PE-접합된 마우스 항-인간 CD62E mAb(eBioscience, 클론 P2H3) 또는 PE-접합된 마우스 IgG1k 동기준표본 대조(eBioscience, #12-4714)를 제작자 지시사상에 따라 사용하여 상온의 암실에서 20 분 동안 100 마이크로리터 염색 부피로 HUVEC 세포들을 염색하였다. 이어서, 염색 완충액에서 2 회 세척을 수행하고 이후 FACSCalibur 유동 세포계측계(BD Biosciences)상에서 표본들을 획득하였다. 막성 GPI-IL-1a에 의하여 유도된 HUVEC 세포들의 표면상에서 상향조절된 E-셀렉틴 발현은 무자극 HUVEC 세포들에 의하여 보여지는 기저 수준으로 MABp1에 의하여 중화되었다.
[
실시예
10]
MABp1 역가에 대한 MRC-5 생물검정(rhIL1A의 중화)
인간 태아 폐 섬유아세포로부터 유래된 MRC-5 세포주를 미국 미생물 보존 센터(ATCC) 컬렉션(CCL-171)로부터 획득하였다. MABp1의 IL-1 중화 역가는 MRC-5 세포들로부터 IL-6의 IL-1A 유도 방출을 측정하여 검정되었다. MRC-5 세포들은 DMEM 완전 배지 100 마이크로리터로 구성된 96-웰 플레이트로 웰당 5 x 103으로 살포되었다. 세포들은 습한 5% CO2 배양기의 37℃에서 하룻밤동안 배양되었다. 이어서, 컨플루언트 MRC-5 세포들은 단독으로 또는 MABp1의 농도를 증가시켜 재조합 인간 IL-1A (rhIL1A, eBioscience) 20 pg/㎖와 함께 24 시간 더 배양되었다. 음성 대조 세포들은 rhIL1A로 자극되지 않았다. 상기 24 시간 이후, 상청액이 수거되었으며 eBioscience 사의 IL-6 ELISA 키트를 사용하여 IL-6 방출에 대하여 검정하였다. 최대 IL-6 방출의 50%를 억제하는데 필요한 IC50 또는 MABp1의 농도는 0.001 내지 0.01 ㎍/㎖의 범위에 있다.
[
실시예
11]
MABp1은 IL-1a+ 세포들을 확인한다.
나트륨 헤파린 항응고처리(anti-coagulated) 전혈 100 마이크로리터를 폴리스타이렌 FACS 튜브들에 분취하였다. 표본들은 열-비활성화된 우태 혈청 2 ㎖에 더하여 인간 IgG(정제된 단백질-A) 1 ㎎과 함께 실온에서 15 분 동안 배양되어 Fc 수용체들을 차단하였다. 이후 1차 Ab들이 상기 표본에 첨가되었다: 알렉사(Alexa)-488 라벨 MABp1 1 ㎎, FITC-라벨된 단일클론성 항-막 인간 IL1A Ab(FAB200F, R&D Systems) 1 ㎎ 또는 쥐 동기준표본 대조(IC002F, R&D Systems) 1 ㎎. 1차 Ab들은 표본과 함께 실온의 암실에서 배양되었다. 이후, 표본 적혈구들을 실온에서 15 분 동안 용해시키고(BD Biosciences PharmLyse 용액), 300 x g에서 5 분 동안 원심분리하고 흡입하였다. 표본 펠릿들은 2% 열-비활성 우태 혈청을 함유하는 Hank's 균형 염 용액(Hank's balanced salt solution: HBSS) 1 ㎖로 3 회 세척하였다. 표본은 0.3 ㎖ HBSS + 2% FBS에 재현탁되었으며, 데이터를 FACSCalibur 유동 세포계측계(BD Biosciences) 상에서 획득하고 CellQuest 소프트웨어를 사용하여 분석하였다. MABp1을 사용한 인간 PBMC의 유동 세포계측 분석으로 인하여 PBMC 2%만이 IL-1α에 대하여 양성임을 보였다.
[
실시예
12]
감염 및 염증반응을 검출
하고 트래킹하기 위한 MABp1
MABp1을 사용한 인간 PBMC의 유동 세포계측 분석(실시예 11에서와 같이)은 정상적인 대조에 비하여 서브-클론성 감염이 있는 피검자에서 IL-1α+에 대하여 양성인 PBMC의 백분율이 3.6-배 증가함을 보였다. 마찬가지로, 염증이 있는 사랑니를 갖는 피검자에서 IL-1α+에 대하여 양성인 PBMC의 백분율에 증가가 있었다. 상기 사랑니를 제거한 후 14 내지 45 일에 IL-1α+ PBMC의 숫자에 있어서 실질적인 감소가 관찰되었다.
[
실시예
13]
IL-1α 검출 및/또는 정량화를 위한 면역검정.
일반적으로, 인간 피검자들의 혈장에는 매우 낮은 수준의 IL-1α가 존재한다. 이러한 수준은 종종 종래 면역검정의 검출 한계를 넘어서기 때문에, 감도가 향상된 ELISA가 개발되었다. 이 ELISA에서, 외생성 항-IL-1α Ab(예컨대, MABp1)은 상기 Ab가 표본의 IL-1α를 결합하도록 하는 조건하에서 시험되는 생물학적 표본(예컨대, 인간 혈장)에 첨가될 수 있다. 인간 혈장 표본들에서 거의 모든 IL-1α가 외생성 항-IL-1α Ab에 이미 결합된 채로 존재한다는 것이 관찰되었기 때문에, 후자 단계가 종종 생략될 수 있다. 이후, IL-1a-Ab 복합체들을 갖는 표본이 약 100 kD의 분자량 컷오프(cutoff)를 갖는 필터(Amicon 원심분리 장치)에 적용되어 표본에 있는 상기 분자량 컷오프 미만의 분자들로부터 상기 IL-1α-Ab 복합체들을 분리하게 된다. 일 실험에서, 이는 50 배 농축으로 나타났다. 이후 처리된 표본(및 그 희석물들)은 항-인간 IgG 포획 Ab(2 ug/㎖ 마우스 항-인간 IgG, Fc-특이적, Southern Biotech 제품 코드 #9042-01)로 코팅된 마이크로역가 플레이트 웰들에 첨가되었다. 표본에 있는 상기 IL-1α-Ab 복합체들을 결합하도록 한 후에, 상기 웰들을 세척하여 비결합 물질을 제거하였다. 이후, 라벨링된 항-인간 IL-1α 2차 Ab는 상기 웰들(0.2 ug/㎖ 비오틴-접합된 단일클론성 마우스 항-인간 IL-1A Ab, 클론 CRM6, eBioscience 카탈로그 # 13-7017)에 첨가되었다. 상기 웰들에 있는 상기 IL-1α를 결합하도록 한 이후에, 상기 플레이트는 세척되고, 각 웰에 있는 라벨링된 항-인간 IL-1α의 양을 시험중인 표본에서의 IL-1α의 농도 표시로서 정량화하였다.
다른
실시예들
본 발명은 그 상세한 설명과 함께 연계하여 기술되었지만, 앞선 설명은 첨부된 청구항의 범위에 의하여 정의된 본 발명의 범위를 예시하는 의도이지 한정하는 것은 아니다. 다른 측면들, 장점들 및 수정사항들은 아래 청구항들의 범위 내에 있다.
<110> XBiotech USA, Inc.
Simard, John
<120> Interleukin-1alpha Antibodies and Methods of Use
<130> 5407-0024
<150> US 61/057,586
<151> 2008-05-30
<150> US 61/121,391
<151> 2008-12-10
<160> 12
<170> PatentIn version 3.5
<210> 1
<211> 471
<212> PRT
<213> homo sapiens
<400> 1
Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Leu Leu Arg Gly
1 5 10 15
Val Gln Cys Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln
20 25 30
Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe
35 40 45
Ser Met Phe Gly Val His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
50 55 60
Glu Trp Val Ala Ala Val Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala
65 70 75 80
Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn
85 90 95
Ile Leu Phe Leu Gln Met Asp Ser Leu Arg Leu Glu Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Gly Arg Pro Lys Val Val Ile Pro Ala Pro Leu
115 120 125
Ala His Trp Gly Gln Gly Thr Leu Val Thr Phe Ser Ser Ala Ser Thr
130 135 140
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser
145 150 155 160
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu
165 170 175
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His
180 185 190
Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser
195 200 205
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys
210 215 220
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu
225 230 235 240
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
245 250 255
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
260 265 270
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
275 280 285
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
290 295 300
Gly Val Glu Val His Asn Ala Gln Thr Lys Pro Arg Glu Glu Gln Tyr
305 310 315 320
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
325 330 335
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
340 345 350
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
355 360 365
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys
370 375 380
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
385 390 395 400
Ile Ala Leu Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
405 410 415
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
420 425 430
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
435 440 445
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
450 455 460
Leu Ser Leu Ser Pro Gly Lys
465 470
<210> 2
<211> 1416
<212> DNA
<213> Homo sapiens
<400> 2
atggagttcg ggctgagttg ggtgttcctg gtggctctgc tgcggggcgt gcagtgccag 60
gtgcagctgg tggagagtgg gggtggcgtg gtgcagcctg gccggtctct gcgcctgtct 120
tgcactgcct ccggttttac cttttctatg tttggtgtgc actgggtgcg ccaggctccc 180
ggcaagggac tggaatgggt ggccgccgtg agttacgacg ggtccaacaa atattacgct 240
gagagcgtga aaggcagatt caccatcagc agagataatt ccaagaatat tctgttcctg 300
cagatggaca gtctgagact ggaggacact gctgtgtact actgcgctcg tggacgccct 360
aaggtggtca tccccgcccc cctggcacat tggggccagg gaactctggt gaccttttct 420
agcgctagca ccaagggccc atcggtcttc cccctggcac cctcctccaa gagcacctct 480
gggggcacag cggccctggg ctgcctggtc aaggactact tccccgaacc ggtgacggtg 540
tcgtggaact caggcgccct gaccagcggc gtccacacct tcccggctgt cctacagtcc 600
tcaggactct actccctcag cagcgtagtg accgtgccct ccagcagctt gggcacccag 660
acctacatct gcaacgtgaa tcacaagccc agcaacacca aggtggacaa gaaagttgag 720
cccaaatctt gtgacaaaac tcacacatgc ccaccgtgcc cagcacctga actcctgggg 780
ggaccgtcag tcttcctctt ccccccaaaa cccaaggaca ccctcatgat ctcccggacc 840
cctgaggtca catgcgtggt ggtggacgtg agccacgaag accctgaggt caagttcaac 900
tggtacgtgg acggcgtgga ggtgcataat gcccagacaa agccgcggga ggagcagtac 960
aacagcacgt accgtgtggt cagcgtcctc accgtcctgc accaggactg gctgaatggc 1020
aaggagtaca agtgcaaggt ctccaacaaa gccctcccag cccccatcga gaaaaccatc 1080
tccaaagcca aagggcagcc ccgagaacca caggtgtaca ccctgccccc atcccgggat 1140
gagctgacca agaaccaggt cagcctgacc tgcctggtca aaggcttcta tcccagcgac 1200
atcgccctgg agtgggagag caatgggcag ccggagaaca actacaagac cacgcctccc 1260
gtgctggact ccgacggctc cttcttcctc tacagcaagc tcaccgtgga caagagcagg 1320
tggcagcagg ggaacgtctt ctcatgctcc gtgatgcatg aggctctgca caaccactac 1380
acgcagaaga gcctctcctt aagtccggga aaataa 1416
<210> 3
<211> 235
<212> PRT
<213> Homo sapiens
<400> 3
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Phe Pro Gly Ser Arg Cys Asp Ile Gln Met Thr Gln Ser Pro Ser Ser
20 25 30
Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser
35 40 45
Gln Gly Ile Ser Ser Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys
50 55 60
Ala Pro Lys Leu Leu Ile Tyr Glu Ala Ser Asn Leu Glu Thr Gly Val
65 70 75 80
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Ser Asp Phe Thr Leu Thr
85 90 95
Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln
100 105 110
Thr Ser Ser Phe Leu Leu Ser Phe Gly Gly Gly Thr Lys Val Glu His
115 120 125
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
130 135 140
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
145 150 155 160
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
165 170 175
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
180 185 190
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
195 200 205
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
210 215 220
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230 235
<210> 4
<211> 708
<212> DNA
<213> Homo sapiens
<400> 4
atggacatgc gcgtgcccgc ccagctgctg gggctgctgc tgctgtggtt ccctggatct 60
aggtgcgaca ttcagatgac ccagtccccc agctcagtgt cagcctccgt gggcgacaga 120
gtgacaatca cctgccgcgc ctctcaggga atctctagtt ggctggcctg gtaccagcag 180
aagcctggaa aggcccccaa gctgctgatc tatgaagcct ccaacctgga gaccggcgtg 240
ccctctcgct tcagcggctc aggctcaggc agtgatttta ctctgaccat cagctccctg 300
cagccagagg atttcgctac ttactactgc cagcagacct cttccttcct gctgtccttc 360
gggggaggca caaaggtgga gcaccgtacg gtggctgcac catctgtctt catcttcccg 420
ccatctgatg agcagttgaa atctggaact gcctctgttg tgtgcctgct gaataacttc 480
tatcccagag aggccaaagt acagtggaag gtggataacg ccctccaatc gggtaactcc 540
caggagagtg tcacagagca ggacagcaag gacagcacct acagcctcag cagcaccctg 600
acgctgagca aagcagacta cgagaaacac aaagtctacg cctgcgaagt cacccatcag 660
ggcctgagtt caccggtgac aaagagcttc aacaggggag agtgttag 708
<210> 5
<211> 471
<212> PRT
<213> Homo sapiens
<400> 5
Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Leu Leu Arg Gly
1 5 10 15
Val Gln Cys Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln
20 25 30
Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe
35 40 45
Ser Met Phe Gly Val His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
50 55 60
Glu Trp Val Ala Ala Val Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala
65 70 75 80
Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn
85 90 95
Ile Leu Phe Leu Gln Met Asp Ser Leu Arg Leu Glu Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Gly Arg Pro Lys Val Val Ile Pro Ala Pro Leu
115 120 125
Ala His Trp Gly Gln Gly Thr Leu Val Thr Phe Ser Ser Ala Ser Thr
130 135 140
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser
145 150 155 160
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu
165 170 175
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His
180 185 190
Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser
195 200 205
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys
210 215 220
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu
225 230 235 240
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
245 250 255
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
260 265 270
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
275 280 285
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
290 295 300
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
305 310 315 320
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
325 330 335
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
340 345 350
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
355 360 365
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys
370 375 380
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
385 390 395 400
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
405 410 415
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
420 425 430
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
435 440 445
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
450 455 460
Leu Ser Leu Ser Pro Gly Lys
465 470
<210> 6
<211> 1422
<212> DNA
<213> Homo sapiens
<400> 6
gccaccatgg agtttggtct gtcctgggtg ttcttggtgg ctctgctgag gggggtgcag 60
tgccaggtcc agctggtgga gtctggtggg ggagtggtgc agcctgggag atctctgcgg 120
ctgtcttgca ctgcctctgg tttcactttc tctatgtttg gtgtgcattg ggtcaggcaa 180
gcaccaggca aaggactcga gtgggtcgca gctgtgagct atgacgggtc taacaaatat 240
tacgctgagt ctgtcaaggg taggtttacc atcagccggg ataattccaa aaatatcctg 300
ttcctgcaaa tggactctct gaggctggaa gatactgcag tctactattg tgcaaggggg 360
aggccaaagg tggtgatccc cgctcccctc gctcactggg gacagggaac cctggtgact 420
ttcagctctg ctagcaccaa gggccctagc gtgttcccat tggctccttc ctccaaatct 480
acttctggag gcaccgccgc cctgggatgt ctcgtgaaag attattttcc tgagcccgtc 540
accgtgagct ggaacagcgg cgccctgact agcggcgtgc acacctttcc cgcagtgctg 600
caatctagcg ggctgtactc cctgagctct gtcgtgaccg tgccctccag cagcctcgga 660
actcagacct acatctgcaa tgtcaatcat aaaccctcta ataccaaagt cgataagaag 720
gtcgaaccta aatcttgcga taaaacccat acctgccccc cttgcccagc acccgaactg 780
ctgggcggtc cctctgtgtt tctgttcccc cccaaaccca aagataccct gatgatctct 840
aggacccccg aggtcacttg tgtcgtggtg gatgtgtccc acgaagatcc agaagtcaaa 900
ttcaactggt atgtggacgg ggtcgaagtg cacaacgcaa agaccaagcc tagggaggaa 960
cagtataata gcacatatag ggtggtcagc gtcctgaccg tcctgcatca ggactggctg 1020
aatggcaaag aatataagtg taaagtgtcc aacaaggccc tgccagcccc aatcgaaaag 1080
acaatctcta aagccaaggg gcaaccccgg gaacctcagg tctatacact gccaccctct 1140
cgggatgaac tgaccaagaa tcaggtgagc ctgacatgtc ttgtgaaggg tttttatccc 1200
tccgacattg ccgtggagtg ggagagcaat ggacaaccag aaaataacta caaaaccaca 1260
ccccctgtgc tggactccga tggttccttc ttcctctact ctaagctgac agtggataag 1320
tctaggtggc agcaggggaa tgtgttctcc tgctctgtga tgcacgaggc actgcacaat 1380
cattatacac aaaagtctct gtctctgtct ccaggaaagt aa 1422
<210> 7
<211> 234
<212> PRT
<213> Homo sapiens
<400> 7
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Phe Pro Gly Ser Arg Cys Asp Ile Gln Met Thr Gln Ser Pro Ser Ser
20 25 30
Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser
35 40 45
Gln Gly Ile Ser Ser Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys
50 55 60
Ala Pro Lys Leu Leu Ile Tyr Glu Ala Ser Asn Leu Glu Thr Gly Val
65 70 75 80
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Ser Asp Phe Thr Leu Thr
85 90 95
Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln
100 105 110
Thr Ser Ser Phe Leu Leu Ser Phe Gly Gly Gly Thr Lys Val Glu His
115 120 125
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
130 135 140
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
145 150 155 160
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
165 170 175
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
180 185 190
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
195 200 205
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
210 215 220
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230
<210> 8
<211> 711
<212> DNA
<213> Homo sapiens
<400> 8
gccaccatgg acatgcgcgt tcctgcccag ctcctcggac tgctgctgct ttggttccca 60
ggctcccggt gtgatattca gatgacacag tctccctcct ccgtatctgc atccgtgggc 120
gacagggtca caatcacttg tagggccagc caggggatct ctagttggct cgcatggtac 180
caacaaaagc caggtaaggc tccgaaactg ctcatttacg aagctagtaa cctcgaaaca 240
ggcgtgccaa gccggtttag cggctccggt tccggttctg acttcaccct cactatttcc 300
tccctgcaac ctgaggattt tgccacatat tactgtcagc aaacttcttc ttttctgctc 360
tcctttggtg ggggaactaa ggtggagcac acagtggccg cccccagcgt ctttatcttc 420
cccccaagcg atgaacagct gaagtcaggg accgccagcg tggtctgcct gctcaataat 480
ttttaccctc gcgaggctaa ggtccaatgg aaagtggata acgccctcca gagcggtaac 540
tctcaggagt ctgtcacaga gcaagacagc aaggatagca cctattccct ctccagcacc 600
ctgacactgt ctaaggccga ctacgagaaa cacaaagtgt acgcttgtga ggtgactcac 660
cagggactga gtagccctgt gacaaaatct ttcaataggg gagaatgctg a 711
<210> 9
<211> 471
<212> PRT
<213> Homo sapiens
<400> 9
Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Leu Leu Arg Gly
1 5 10 15
Val Gln Cys Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln
20 25 30
Pro Gly Arg Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe
35 40 45
Ser Met Phe Gly Val His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
50 55 60
Glu Trp Val Ala Ala Val Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala
65 70 75 80
Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn
85 90 95
Ile Leu Phe Leu Gln Met Asp Ser Leu Arg Leu Glu Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Gly Arg Pro Lys Val Val Ile Pro Ala Pro Leu
115 120 125
Ala His Trp Gly Gln Gly Thr Leu Val Thr Phe Ser Ser Ala Ser Thr
130 135 140
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser
145 150 155 160
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu
165 170 175
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His
180 185 190
Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser
195 200 205
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys
210 215 220
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu
225 230 235 240
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
245 250 255
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
260 265 270
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
275 280 285
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
290 295 300
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
305 310 315 320
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
325 330 335
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
340 345 350
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
355 360 365
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
370 375 380
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
385 390 395 400
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
405 410 415
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
420 425 430
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
435 440 445
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
450 455 460
Leu Ser Leu Ser Pro Gly Lys
465 470
<210> 10
<211> 1422
<212> DNA
<213> Homo sapiens
<400> 10
gccaccatgg agtttggtct gtcctgggtg ttcttggtgg ctctgctgag gggggtgcag 60
tgccaggtcc agctggtgga gtctggtggg ggagtggtgc agcctgggag atctctgcgg 120
ctgtcttgca ctgcctctgg tttcactttc tctatgtttg gtgtgcattg ggtcaggcaa 180
gcaccaggca aaggactcga gtgggtcgca gctgtgagct atgacgggtc taacaaatat 240
tacgctgagt ctgtcaaggg taggtttacc atcagccggg ataattccaa aaatatcctg 300
ttcctgcaaa tggactctct gaggctggaa gatactgcag tctactattg tgcaaggggg 360
aggccaaagg tggtgatccc cgctcccctc gctcactggg gacagggaac cctggtgact 420
ttcagctctg ctagcaccaa gggccctagc gtgttcccat tggctccttc ctccaaatct 480
acttctggag gcaccgccgc cctgggatgt ctcgtgaaag attattttcc tgagcccgtc 540
accgtgagct ggaacagcgg cgccctgact agcggcgtgc acacctttcc cgcagtgctg 600
caatctagcg ggctgtactc cctgagctct gtcgtgaccg tgccctccag cagcctcgga 660
actcagacct acatctgcaa tgtcaatcat aaaccctcta ataccaaagt cgataagagg 720
gtcgaaccta aatcttgcga taaaacccat acctgccccc cttgcccagc acccgaactg 780
ctgggcggtc cctctgtgtt tctgttcccc cccaaaccca aagataccct gatgatctct 840
aggacccccg aggtcacttg tgtcgtggtg gatgtgtccc acgaagatcc agaagtcaaa 900
ttcaactggt atgtggacgg ggtcgaagtg cacaacgcaa agaccaagcc tagggaggaa 960
cagtataata gcacatatag ggtggtcagc gtcctgaccg tcctgcatca ggactggctg 1020
aatggcaaag aatataagtg taaagtgtcc aacaaggccc tgccagcccc aatcgaaaag 1080
acaatctcta aagccaaggg gcaaccccgg gaacctcagg tctatacact gccaccctct 1140
cgggaggaaa tgaccaagaa tcaggtgagc ctgacatgtc ttgtgaaggg tttttatccc 1200
tccgacattg ccgtggagtg ggagagcaat ggacaaccag aaaataacta caaaaccaca 1260
ccccctgtgc tggactccga tggttccttc ttcctctact ctaagctgac agtggataag 1320
tctaggtggc agcaggggaa tgtgttctcc tgctctgtga tgcacgaggc actgcacaat 1380
cattatacac aaaagtctct gtctctgtct ccaggaaagt aa 1422
<210> 11
<211> 236
<212> PRT
<213> Homo sapiens
<400> 11
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Phe Pro Gly Ser Arg Cys Asp Ile Gln Met Thr Gln Ser Pro Ser Ser
20 25 30
Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser
35 40 45
Gln Gly Ile Ser Ser Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys
50 55 60
Ala Pro Lys Leu Leu Ile Tyr Glu Ala Ser Asn Leu Glu Thr Gly Val
65 70 75 80
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Ser Asp Phe Thr Leu Thr
85 90 95
Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln
100 105 110
Thr Ser Ser Phe Leu Leu Ser Phe Gly Gly Gly Thr Lys Val Glu His
115 120 125
Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
130 135 140
Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
145 150 155 160
Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
165 170 175
Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
180 185 190
Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr
195 200 205
Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser
210 215 220
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230 235
<210> 12
<211> 717
<212> DNA
<213> Homo sapiens
<400> 12
gccaccatgg acatgcgcgt tcctgcccag ctcctcggac tgctgctgct ttggttccca 60
ggctcccggt gtgatattca gatgacacag tctccctcct ccgtatctgc atccgtgggc 120
gacagggtca caatcacttg tagggccagc caggggatct ctagttggct cgcatggtac 180
caacaaaagc caggtaaggc tccgaaactg ctcatttacg aagctagtaa cctcgaaaca 240
ggcgtgccaa gccggtttag cggctccggt tccggttctg acttcaccct cactatttcc 300
tccctgcaac ctgaggattt tgccacatat tactgtcagc aaacttcttc ttttctgctc 360
tcctttggtg gaggaactaa ggtggagcac aagcggacag ttgctgctcc tagcgtcttt 420
atcttccctc caagcgatga acagctgaag tcagggaccg ccagcgtggt ctgcctgctc 480
aataattttt accctcgcga ggctaaggtc caatggaaag tggataacgc cctccagagc 540
ggtaactctc aggagtctgt cacagagcaa gacagcaagg atagcaccta ttccctctcc 600
agcaccctga cactgtctaa ggccgactac gagaaacaca aagtgtacgc ttgtgaggtg 660
actcaccagg gactgagtag ccctgtgaca aaatctttca ataggggaga atgctga 717
Claims (3)
- 인간 IL-1α에 특이적으로 결합하는 정제된 단일클론 항체를 포함하는, 기저막의 종양 세포 침습 억제용 약학 조성물.
- 제 1항에 있어서, 상기 단일클론 항체는 인간 IgG1 단일클론 항체인 것을 특징으로 하는, 기저막의 종양 세포 침습 억제용 약학 조성물.
- 제 1항에 있어서, 상기 단일클론 항체는 포유류 숙주 세포에서 서열 ID 번호: 9의 아미노산 서열을 인코딩하는 제 1 핵산 및 서열 ID 번호: 11의 아미노산 서열을 인코딩하는 제 2 핵산을 발현함으로써 생성되는 면역글로불린의 아미노산 서열을 포함하는 것을 특징으로 하는, 기저막의 종양 세포 침습 억제용 약학 조성물.
Applications Claiming Priority (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US5758608P | 2008-05-30 | 2008-05-30 | |
US61/057,586 | 2008-05-30 | ||
US12139108P | 2008-12-10 | 2008-12-10 | |
US61/121,391 | 2008-12-10 | ||
US17835009P | 2009-05-14 | 2009-05-14 | |
US61/178,350 | 2009-05-14 | ||
PCT/US2009/003355 WO2009148575A1 (en) | 2008-05-30 | 2009-06-01 | Interleukin-1 alpha abs and methods of use |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
KR1020157031363A Division KR20150127300A (ko) | 2008-05-30 | 2009-06-01 | 인터류킨-1 알파 항체 및 그의 사용 방법 |
Publications (1)
Publication Number | Publication Date |
---|---|
KR20170005166A true KR20170005166A (ko) | 2017-01-11 |
Family
ID=41380314
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
KR1020157031363A KR20150127300A (ko) | 2008-05-30 | 2009-06-01 | 인터류킨-1 알파 항체 및 그의 사용 방법 |
KR1020107029639A KR101567117B1 (ko) | 2008-05-30 | 2009-06-01 | 인터류킨-1 알파 항체 및 그의 사용 방법 |
KR1020167037032A KR20170005166A (ko) | 2008-05-30 | 2009-06-01 | 인터류킨-1 알파 항체 및 그의 사용 방법 |
Family Applications Before (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
KR1020157031363A KR20150127300A (ko) | 2008-05-30 | 2009-06-01 | 인터류킨-1 알파 항체 및 그의 사용 방법 |
KR1020107029639A KR101567117B1 (ko) | 2008-05-30 | 2009-06-01 | 인터류킨-1 알파 항체 및 그의 사용 방법 |
Country Status (24)
Country | Link |
---|---|
US (14) | US8034337B2 (ko) |
EP (3) | EP3085773B1 (ko) |
JP (5) | JP5670318B2 (ko) |
KR (3) | KR20150127300A (ko) |
CN (4) | CN105467136B (ko) |
AU (1) | AU2009255670B2 (ko) |
BR (1) | BRPI0909610B1 (ko) |
CA (2) | CA2726345C (ko) |
CO (1) | CO6351749A2 (ko) |
DK (1) | DK2285409T3 (ko) |
ES (2) | ES2576681T3 (ko) |
HK (2) | HK1159481A1 (ko) |
HU (1) | HUE029003T2 (ko) |
IL (5) | IL209576A (ko) |
MX (1) | MX2010012963A (ko) |
MY (1) | MY154067A (ko) |
NZ (1) | NZ590033A (ko) |
PH (1) | PH12014501773A1 (ko) |
PL (2) | PL3085773T3 (ko) |
PT (1) | PT2285409T (ko) |
RU (2) | RU2498998C2 (ko) |
SI (1) | SI2285409T1 (ko) |
WO (1) | WO2009148575A1 (ko) |
ZA (1) | ZA201009224B (ko) |
Families Citing this family (447)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9060770B2 (en) | 2003-05-20 | 2015-06-23 | Ethicon Endo-Surgery, Inc. | Robotically-driven surgical instrument with E-beam driver |
US20070084897A1 (en) | 2003-05-20 | 2007-04-19 | Shelton Frederick E Iv | Articulating surgical stapling instrument incorporating a two-piece e-beam firing mechanism |
US11896225B2 (en) | 2004-07-28 | 2024-02-13 | Cilag Gmbh International | Staple cartridge comprising a pan |
US11998198B2 (en) | 2004-07-28 | 2024-06-04 | Cilag Gmbh International | Surgical stapling instrument incorporating a two-piece E-beam firing mechanism |
US9072535B2 (en) | 2011-05-27 | 2015-07-07 | Ethicon Endo-Surgery, Inc. | Surgical stapling instruments with rotatable staple deployment arrangements |
US8215531B2 (en) | 2004-07-28 | 2012-07-10 | Ethicon Endo-Surgery, Inc. | Surgical stapling instrument having a medical substance dispenser |
ATE470151T1 (de) | 2005-08-02 | 2010-06-15 | Xbiotech Inc | Diagnose, behandlung und prävention von gefässerkrankungen mittels il-1alpha- autoantikörpern |
US7934630B2 (en) | 2005-08-31 | 2011-05-03 | Ethicon Endo-Surgery, Inc. | Staple cartridges for forming staples having differing formed staple heights |
US10159482B2 (en) | 2005-08-31 | 2018-12-25 | Ethicon Llc | Fastener cartridge assembly comprising a fixed anvil and different staple heights |
US11246590B2 (en) | 2005-08-31 | 2022-02-15 | Cilag Gmbh International | Staple cartridge including staple drivers having different unfired heights |
US9237891B2 (en) | 2005-08-31 | 2016-01-19 | Ethicon Endo-Surgery, Inc. | Robotically-controlled surgical stapling devices that produce formed staples having different lengths |
US11484312B2 (en) | 2005-08-31 | 2022-11-01 | Cilag Gmbh International | Staple cartridge comprising a staple driver arrangement |
US7669746B2 (en) | 2005-08-31 | 2010-03-02 | Ethicon Endo-Surgery, Inc. | Staple cartridges for forming staples having differing formed staple heights |
US20070106317A1 (en) | 2005-11-09 | 2007-05-10 | Shelton Frederick E Iv | Hydraulically and electrically actuated articulation joints for surgical instruments |
US11278279B2 (en) | 2006-01-31 | 2022-03-22 | Cilag Gmbh International | Surgical instrument assembly |
US11224427B2 (en) | 2006-01-31 | 2022-01-18 | Cilag Gmbh International | Surgical stapling system including a console and retraction assembly |
US20120292367A1 (en) | 2006-01-31 | 2012-11-22 | Ethicon Endo-Surgery, Inc. | Robotically-controlled end effector |
US20110024477A1 (en) | 2009-02-06 | 2011-02-03 | Hall Steven G | Driven Surgical Stapler Improvements |
US11793518B2 (en) | 2006-01-31 | 2023-10-24 | Cilag Gmbh International | Powered surgical instruments with firing system lockout arrangements |
US7845537B2 (en) | 2006-01-31 | 2010-12-07 | Ethicon Endo-Surgery, Inc. | Surgical instrument having recording capabilities |
US8708213B2 (en) | 2006-01-31 | 2014-04-29 | Ethicon Endo-Surgery, Inc. | Surgical instrument having a feedback system |
US20110295295A1 (en) | 2006-01-31 | 2011-12-01 | Ethicon Endo-Surgery, Inc. | Robotically-controlled surgical instrument having recording capabilities |
US7753904B2 (en) | 2006-01-31 | 2010-07-13 | Ethicon Endo-Surgery, Inc. | Endoscopic surgical instrument with a handle that can articulate with respect to the shaft |
US8820603B2 (en) | 2006-01-31 | 2014-09-02 | Ethicon Endo-Surgery, Inc. | Accessing data stored in a memory of a surgical instrument |
US8186555B2 (en) | 2006-01-31 | 2012-05-29 | Ethicon Endo-Surgery, Inc. | Motor-driven surgical cutting and fastening instrument with mechanical closure system |
US8992422B2 (en) | 2006-03-23 | 2015-03-31 | Ethicon Endo-Surgery, Inc. | Robotically-controlled endoscopic accessory channel |
US20090191149A1 (en) * | 2006-05-15 | 2009-07-30 | Xbiotech Inc. | IL-1alpha IMMUNIZATION INDUCES AUTOANTIBODIES PROTECTIVE AGAINST ATHEROSCLEROSIS |
US20110008282A1 (en) * | 2006-05-15 | 2011-01-13 | Xbiotech, Inc. | IL-1alpha immunization induces autoantibodies protective against atherosclerosis |
JP2009537628A (ja) * | 2006-05-22 | 2009-10-29 | エクスバイオテク インコーポレーティッド | 抗IL−1α抗体による癌の処置方法 |
US8322455B2 (en) | 2006-06-27 | 2012-12-04 | Ethicon Endo-Surgery, Inc. | Manually driven surgical cutting and fastening instrument |
US8220690B2 (en) | 2006-09-29 | 2012-07-17 | Ethicon Endo-Surgery, Inc. | Connected surgical staples and stapling instruments for deploying the same |
US10568652B2 (en) | 2006-09-29 | 2020-02-25 | Ethicon Llc | Surgical staples having attached drivers of different heights and stapling instruments for deploying the same |
US11980366B2 (en) | 2006-10-03 | 2024-05-14 | Cilag Gmbh International | Surgical instrument |
US11291441B2 (en) | 2007-01-10 | 2022-04-05 | Cilag Gmbh International | Surgical instrument with wireless communication between control unit and remote sensor |
US8652120B2 (en) | 2007-01-10 | 2014-02-18 | Ethicon Endo-Surgery, Inc. | Surgical instrument with wireless communication between control unit and sensor transponders |
US8684253B2 (en) | 2007-01-10 | 2014-04-01 | Ethicon Endo-Surgery, Inc. | Surgical instrument with wireless communication between a control unit of a robotic system and remote sensor |
US11039836B2 (en) | 2007-01-11 | 2021-06-22 | Cilag Gmbh International | Staple cartridge for use with a surgical stapling instrument |
US20080169333A1 (en) | 2007-01-11 | 2008-07-17 | Shelton Frederick E | Surgical stapler end effector with tapered distal end |
US8727197B2 (en) | 2007-03-15 | 2014-05-20 | Ethicon Endo-Surgery, Inc. | Staple cartridge cavity configuration with cooperative surgical staple |
US8893946B2 (en) | 2007-03-28 | 2014-11-25 | Ethicon Endo-Surgery, Inc. | Laparoscopic tissue thickness and clamp load measuring devices |
US11857181B2 (en) | 2007-06-04 | 2024-01-02 | Cilag Gmbh International | Robotically-controlled shaft based rotary drive systems for surgical instruments |
US8931682B2 (en) | 2007-06-04 | 2015-01-13 | Ethicon Endo-Surgery, Inc. | Robotically-controlled shaft based rotary drive systems for surgical instruments |
US7753245B2 (en) | 2007-06-22 | 2010-07-13 | Ethicon Endo-Surgery, Inc. | Surgical stapling instruments |
US11849941B2 (en) | 2007-06-29 | 2023-12-26 | Cilag Gmbh International | Staple cartridge having staple cavities extending at a transverse angle relative to a longitudinal cartridge axis |
US7866527B2 (en) | 2008-02-14 | 2011-01-11 | Ethicon Endo-Surgery, Inc. | Surgical stapling apparatus with interlockable firing system |
US9179912B2 (en) | 2008-02-14 | 2015-11-10 | Ethicon Endo-Surgery, Inc. | Robotically-controlled motorized surgical cutting and fastening instrument |
US11986183B2 (en) | 2008-02-14 | 2024-05-21 | Cilag Gmbh International | Surgical cutting and fastening instrument comprising a plurality of sensors to measure an electrical parameter |
US8636736B2 (en) | 2008-02-14 | 2014-01-28 | Ethicon Endo-Surgery, Inc. | Motorized surgical cutting and fastening instrument |
US8573465B2 (en) | 2008-02-14 | 2013-11-05 | Ethicon Endo-Surgery, Inc. | Robotically-controlled surgical end effector system with rotary actuated closure systems |
US8758391B2 (en) | 2008-02-14 | 2014-06-24 | Ethicon Endo-Surgery, Inc. | Interchangeable tools for surgical instruments |
JP5410110B2 (ja) | 2008-02-14 | 2014-02-05 | エシコン・エンド−サージェリィ・インコーポレイテッド | Rf電極を有する外科用切断・固定器具 |
US7819298B2 (en) | 2008-02-14 | 2010-10-26 | Ethicon Endo-Surgery, Inc. | Surgical stapling apparatus with control features operable with one hand |
US11272927B2 (en) | 2008-02-15 | 2022-03-15 | Cilag Gmbh International | Layer arrangements for surgical staple cartridges |
US10390823B2 (en) | 2008-02-15 | 2019-08-27 | Ethicon Llc | End effector comprising an adjunct |
RU2498998C2 (ru) * | 2008-05-30 | 2013-11-20 | ИксБиотеч, Инк. | АНТИТЕЛА К ИНТЕРЛЕЙКИНУ-1α И СПОСОБЫ ПРИМЕНЕНИЯ |
US8242074B2 (en) | 2008-09-12 | 2012-08-14 | Xbiotech, Inc. | Modulation of the amount or function of pathogenic CD14+CD16+ monocytes |
US9386983B2 (en) | 2008-09-23 | 2016-07-12 | Ethicon Endo-Surgery, Llc | Robotically-controlled motorized surgical instrument |
US11648005B2 (en) | 2008-09-23 | 2023-05-16 | Cilag Gmbh International | Robotically-controlled motorized surgical instrument with an end effector |
US9005230B2 (en) | 2008-09-23 | 2015-04-14 | Ethicon Endo-Surgery, Inc. | Motorized surgical instrument |
US8210411B2 (en) | 2008-09-23 | 2012-07-03 | Ethicon Endo-Surgery, Inc. | Motor-driven surgical cutting instrument |
US8608045B2 (en) | 2008-10-10 | 2013-12-17 | Ethicon Endo-Sugery, Inc. | Powered surgical cutting and stapling apparatus with manually retractable firing system |
US8517239B2 (en) | 2009-02-05 | 2013-08-27 | Ethicon Endo-Surgery, Inc. | Surgical stapling instrument comprising a magnetic element driver |
US8444036B2 (en) | 2009-02-06 | 2013-05-21 | Ethicon Endo-Surgery, Inc. | Motor driven surgical fastener device with mechanisms for adjusting a tissue gap within the end effector |
AU2010210795A1 (en) | 2009-02-06 | 2011-08-25 | Ethicon Endo-Surgery, Inc. | Driven surgical stapler improvements |
US8851354B2 (en) | 2009-12-24 | 2014-10-07 | Ethicon Endo-Surgery, Inc. | Surgical cutting instrument that analyzes tissue thickness |
US8220688B2 (en) | 2009-12-24 | 2012-07-17 | Ethicon Endo-Surgery, Inc. | Motor-driven surgical cutting instrument with electric actuator directional control assembly |
ES2635594T3 (es) | 2010-05-14 | 2017-10-04 | Abbvie Inc. | Proteínas de unión a IL-1 |
KR20130098279A (ko) * | 2010-06-18 | 2013-09-04 | 엑스바이오테크, 인크. | 관절염 치료 |
US8783543B2 (en) | 2010-07-30 | 2014-07-22 | Ethicon Endo-Surgery, Inc. | Tissue acquisition arrangements and methods for surgical stapling devices |
KR20210128021A (ko) | 2010-08-23 | 2021-10-25 | 얀센 바이오테크 인코포레이티드 | 종양성 질병들에 대한 치료 |
AU2015271978B2 (en) * | 2010-08-23 | 2017-10-26 | Xbiotech Inc. | Treatment for neoplastic diseases |
US9351730B2 (en) | 2011-04-29 | 2016-05-31 | Ethicon Endo-Surgery, Llc | Tissue thickness compensator comprising channels |
US9232941B2 (en) | 2010-09-30 | 2016-01-12 | Ethicon Endo-Surgery, Inc. | Tissue thickness compensator comprising a reservoir |
US9364233B2 (en) | 2010-09-30 | 2016-06-14 | Ethicon Endo-Surgery, Llc | Tissue thickness compensators for circular surgical staplers |
US9629814B2 (en) | 2010-09-30 | 2017-04-25 | Ethicon Endo-Surgery, Llc | Tissue thickness compensator configured to redistribute compressive forces |
US11298125B2 (en) | 2010-09-30 | 2022-04-12 | Cilag Gmbh International | Tissue stapler having a thickness compensator |
US8657176B2 (en) | 2010-09-30 | 2014-02-25 | Ethicon Endo-Surgery, Inc. | Tissue thickness compensator for a surgical stapler |
US11812965B2 (en) | 2010-09-30 | 2023-11-14 | Cilag Gmbh International | Layer of material for a surgical end effector |
US10945731B2 (en) | 2010-09-30 | 2021-03-16 | Ethicon Llc | Tissue thickness compensator comprising controlled release and expansion |
US11925354B2 (en) | 2010-09-30 | 2024-03-12 | Cilag Gmbh International | Staple cartridge comprising staples positioned within a compressible portion thereof |
US9592050B2 (en) | 2010-09-30 | 2017-03-14 | Ethicon Endo-Surgery, Llc | End effector comprising a distal tissue abutment member |
US9320523B2 (en) | 2012-03-28 | 2016-04-26 | Ethicon Endo-Surgery, Llc | Tissue thickness compensator comprising tissue ingrowth features |
US8695866B2 (en) | 2010-10-01 | 2014-04-15 | Ethicon Endo-Surgery, Inc. | Surgical instrument having a power control circuit |
US9724409B2 (en) * | 2011-04-01 | 2017-08-08 | Xbiotech, Inc. | Treatment of inflammatory skin disease |
DK2694107T3 (en) * | 2011-04-01 | 2018-12-10 | Xbiotech Inc | TREATMENT OF DERMATOLOGICAL DISORDERS |
RU2606493C2 (ru) | 2011-04-29 | 2017-01-10 | Этикон Эндо-Серджери, Инк. | Кассета со скобками, содержащая скобки, расположенные внутри ее сжимаемой части |
US11207064B2 (en) | 2011-05-27 | 2021-12-28 | Cilag Gmbh International | Automated end effector component reloading system for use with a robotic system |
CN102296050B (zh) * | 2011-05-30 | 2013-04-03 | 苏州大学 | 抗人IL-1α单克隆抗体及其应用 |
US10466160B2 (en) | 2011-08-01 | 2019-11-05 | Celsee Diagnostics, Inc. | System and method for retrieving and analyzing particles |
CA2842359A1 (en) | 2011-08-01 | 2013-02-07 | Denovo Sciences | Cell capture system and method of use |
US9809649B2 (en) * | 2011-09-23 | 2017-11-07 | Xbiotech, Inc. | Cachexia treatment |
US9044230B2 (en) | 2012-02-13 | 2015-06-02 | Ethicon Endo-Surgery, Inc. | Surgical cutting and fastening instrument with apparatus for determining cartridge and firing motion status |
MX353040B (es) | 2012-03-28 | 2017-12-18 | Ethicon Endo Surgery Inc | Unidad retenedora que incluye un compensador de grosor de tejido. |
CN104334098B (zh) | 2012-03-28 | 2017-03-22 | 伊西康内外科公司 | 包括限定低压强环境的胶囊剂的组织厚度补偿件 |
CN104321024B (zh) | 2012-03-28 | 2017-05-24 | 伊西康内外科公司 | 包括多个层的组织厚度补偿件 |
CN102636655B (zh) * | 2012-05-10 | 2014-07-23 | 苏州大学附属第一医院 | 一种荧光原位微量淋巴毒检测方法和试剂盒 |
US9101358B2 (en) | 2012-06-15 | 2015-08-11 | Ethicon Endo-Surgery, Inc. | Articulatable surgical instrument comprising a firing drive |
US11278284B2 (en) | 2012-06-28 | 2022-03-22 | Cilag Gmbh International | Rotary drive arrangements for surgical instruments |
US9204879B2 (en) | 2012-06-28 | 2015-12-08 | Ethicon Endo-Surgery, Inc. | Flexible drive member |
US20140001234A1 (en) | 2012-06-28 | 2014-01-02 | Ethicon Endo-Surgery, Inc. | Coupling arrangements for attaching surgical end effectors to drive systems therefor |
BR112014032776B1 (pt) | 2012-06-28 | 2021-09-08 | Ethicon Endo-Surgery, Inc | Sistema de instrumento cirúrgico e kit cirúrgico para uso com um sistema de instrumento cirúrgico |
BR112014032740A2 (pt) | 2012-06-28 | 2020-02-27 | Ethicon Endo Surgery Inc | bloqueio de cartucho de clipes vazio |
US20140001231A1 (en) | 2012-06-28 | 2014-01-02 | Ethicon Endo-Surgery, Inc. | Firing system lockout arrangements for surgical instruments |
US9282974B2 (en) | 2012-06-28 | 2016-03-15 | Ethicon Endo-Surgery, Llc | Empty clip cartridge lockout |
US9289256B2 (en) | 2012-06-28 | 2016-03-22 | Ethicon Endo-Surgery, Llc | Surgical end effectors having angled tissue-contacting surfaces |
US9545441B2 (en) | 2012-09-18 | 2017-01-17 | Xbiotech, Inc. | Treatment of diabetes |
CA2886757C (en) * | 2012-10-04 | 2022-04-05 | Xbiotech Inc. | Treatment of anxiety with il1.alpha. antagonist |
RU2671955C2 (ru) * | 2012-10-04 | 2018-11-08 | ИксБиотеч, Инк. | Лечение сосудистого заболевания и его осложнений |
US9606102B2 (en) | 2013-01-26 | 2017-03-28 | Denovo Sciences, Inc. | System and method for capturing and analyzing cells |
JP6345707B2 (ja) | 2013-03-01 | 2018-06-20 | エシコン・エンド−サージェリィ・インコーポレイテッドEthicon Endo−Surgery,Inc. | ソフトストップを備えた外科用器具 |
RU2672520C2 (ru) | 2013-03-01 | 2018-11-15 | Этикон Эндо-Серджери, Инк. | Шарнирно поворачиваемые хирургические инструменты с проводящими путями для передачи сигналов |
US9351726B2 (en) | 2013-03-14 | 2016-05-31 | Ethicon Endo-Surgery, Llc | Articulation control system for articulatable surgical instruments |
US9629629B2 (en) | 2013-03-14 | 2017-04-25 | Ethicon Endo-Surgey, LLC | Control systems for surgical instruments |
BR112015026109B1 (pt) | 2013-04-16 | 2022-02-22 | Ethicon Endo-Surgery, Inc | Instrumento cirúrgico |
US9867612B2 (en) | 2013-04-16 | 2018-01-16 | Ethicon Llc | Powered surgical stapler |
US10391490B2 (en) | 2013-05-31 | 2019-08-27 | Celsee Diagnostics, Inc. | System and method for isolating and analyzing cells |
US10624634B2 (en) | 2013-08-23 | 2020-04-21 | Ethicon Llc | Firing trigger lockout arrangements for surgical instruments |
RU2678363C2 (ru) | 2013-08-23 | 2019-01-28 | ЭТИКОН ЭНДО-СЕРДЖЕРИ, ЭлЭлСи | Устройства втягивания пускового элемента для хирургических инструментов с электропитанием |
US10028207B2 (en) * | 2014-01-16 | 2018-07-17 | Industry-University Cooperation Foundation Banyard University | Method for transmitting and receiving downlink channel for MTC terminal, and apparatus therefor |
US9962161B2 (en) | 2014-02-12 | 2018-05-08 | Ethicon Llc | Deliverable surgical instrument |
BR112016019387B1 (pt) | 2014-02-24 | 2022-11-29 | Ethicon Endo-Surgery, Llc | Sistema de instrumento cirúrgico e cartucho de prendedores para uso com um instrumento cirúrgico de fixação |
RU2556816C1 (ru) * | 2014-03-12 | 2015-07-20 | Открытое акционерное общество "Фармацевтический импорт, экспорт" (ОАО "Фармимэкс") | Штамм клеток яичников китайского хомячка - продуцент рекомбинантного антитела против фактора некроза опухоли альфа человека |
BR112016021943B1 (pt) | 2014-03-26 | 2022-06-14 | Ethicon Endo-Surgery, Llc | Instrumento cirúrgico para uso por um operador em um procedimento cirúrgico |
US10013049B2 (en) | 2014-03-26 | 2018-07-03 | Ethicon Llc | Power management through sleep options of segmented circuit and wake up control |
US9750499B2 (en) | 2014-03-26 | 2017-09-05 | Ethicon Llc | Surgical stapling instrument system |
US10004497B2 (en) | 2014-03-26 | 2018-06-26 | Ethicon Llc | Interface systems for use with surgical instruments |
US9833241B2 (en) | 2014-04-16 | 2017-12-05 | Ethicon Llc | Surgical fastener cartridges with driver stabilizing arrangements |
US20150297223A1 (en) | 2014-04-16 | 2015-10-22 | Ethicon Endo-Surgery, Inc. | Fastener cartridges including extensions having different configurations |
CN106456159B (zh) | 2014-04-16 | 2019-03-08 | 伊西康内外科有限责任公司 | 紧固件仓组件和钉保持器盖布置结构 |
US10327764B2 (en) | 2014-09-26 | 2019-06-25 | Ethicon Llc | Method for creating a flexible staple line |
CN106456158B (zh) | 2014-04-16 | 2019-02-05 | 伊西康内外科有限责任公司 | 包括非一致紧固件的紧固件仓 |
BR112016023698B1 (pt) | 2014-04-16 | 2022-07-26 | Ethicon Endo-Surgery, Llc | Cartucho de prendedores para uso com um instrumento cirúrgico |
BR112017004361B1 (pt) | 2014-09-05 | 2023-04-11 | Ethicon Llc | Sistema eletrônico para um instrumento cirúrgico |
US11311294B2 (en) | 2014-09-05 | 2022-04-26 | Cilag Gmbh International | Powered medical device including measurement of closure state of jaws |
US10016199B2 (en) | 2014-09-05 | 2018-07-10 | Ethicon Llc | Polarity of hall magnet to identify cartridge type |
US10105142B2 (en) | 2014-09-18 | 2018-10-23 | Ethicon Llc | Surgical stapler with plurality of cutting elements |
JP6648119B2 (ja) | 2014-09-26 | 2020-02-14 | エシコン エルエルシーEthicon LLC | 外科ステープル留めバットレス及び付属物材料 |
US11523821B2 (en) | 2014-09-26 | 2022-12-13 | Cilag Gmbh International | Method for creating a flexible staple line |
US20160099559A1 (en) * | 2014-10-01 | 2016-04-07 | Continental Automotive Systems, Inc. | Overcurrent protection for an automotive instrument cluster |
US10076325B2 (en) | 2014-10-13 | 2018-09-18 | Ethicon Llc | Surgical stapling apparatus comprising a tissue stop |
US9924944B2 (en) | 2014-10-16 | 2018-03-27 | Ethicon Llc | Staple cartridge comprising an adjunct material |
US11141153B2 (en) | 2014-10-29 | 2021-10-12 | Cilag Gmbh International | Staple cartridges comprising driver arrangements |
US10517594B2 (en) | 2014-10-29 | 2019-12-31 | Ethicon Llc | Cartridge assemblies for surgical staplers |
US9844376B2 (en) | 2014-11-06 | 2017-12-19 | Ethicon Llc | Staple cartridge comprising a releasable adjunct material |
US10736636B2 (en) | 2014-12-10 | 2020-08-11 | Ethicon Llc | Articulatable surgical instrument system |
US9844374B2 (en) | 2014-12-18 | 2017-12-19 | Ethicon Llc | Surgical instrument systems comprising an articulatable end effector and means for adjusting the firing stroke of a firing member |
US9844375B2 (en) | 2014-12-18 | 2017-12-19 | Ethicon Llc | Drive arrangements for articulatable surgical instruments |
US9943309B2 (en) | 2014-12-18 | 2018-04-17 | Ethicon Llc | Surgical instruments with articulatable end effectors and movable firing beam support arrangements |
BR112017012996B1 (pt) | 2014-12-18 | 2022-11-08 | Ethicon Llc | Instrumento cirúrgico com uma bigorna que é seletivamente móvel sobre um eixo geométrico imóvel distinto em relação a um cartucho de grampos |
US10188385B2 (en) | 2014-12-18 | 2019-01-29 | Ethicon Llc | Surgical instrument system comprising lockable systems |
US9987000B2 (en) | 2014-12-18 | 2018-06-05 | Ethicon Llc | Surgical instrument assembly comprising a flexible articulation system |
US10085748B2 (en) | 2014-12-18 | 2018-10-02 | Ethicon Llc | Locking arrangements for detachable shaft assemblies with articulatable surgical end effectors |
US11154301B2 (en) | 2015-02-27 | 2021-10-26 | Cilag Gmbh International | Modular stapling assembly |
US10180463B2 (en) | 2015-02-27 | 2019-01-15 | Ethicon Llc | Surgical apparatus configured to assess whether a performance parameter of the surgical apparatus is within an acceptable performance band |
US20160249910A1 (en) | 2015-02-27 | 2016-09-01 | Ethicon Endo-Surgery, Llc | Surgical charging system that charges and/or conditions one or more batteries |
US10245033B2 (en) | 2015-03-06 | 2019-04-02 | Ethicon Llc | Surgical instrument comprising a lockable battery housing |
US10617412B2 (en) | 2015-03-06 | 2020-04-14 | Ethicon Llc | System for detecting the mis-insertion of a staple cartridge into a surgical stapler |
US9901342B2 (en) | 2015-03-06 | 2018-02-27 | Ethicon Endo-Surgery, Llc | Signal and power communication system positioned on a rotatable shaft |
US9993248B2 (en) | 2015-03-06 | 2018-06-12 | Ethicon Endo-Surgery, Llc | Smart sensors with local signal processing |
US10441279B2 (en) | 2015-03-06 | 2019-10-15 | Ethicon Llc | Multiple level thresholds to modify operation of powered surgical instruments |
US9808246B2 (en) | 2015-03-06 | 2017-11-07 | Ethicon Endo-Surgery, Llc | Method of operating a powered surgical instrument |
US10687806B2 (en) | 2015-03-06 | 2020-06-23 | Ethicon Llc | Adaptive tissue compression techniques to adjust closure rates for multiple tissue types |
US10548504B2 (en) | 2015-03-06 | 2020-02-04 | Ethicon Llc | Overlaid multi sensor radio frequency (RF) electrode system to measure tissue compression |
US9924961B2 (en) | 2015-03-06 | 2018-03-27 | Ethicon Endo-Surgery, Llc | Interactive feedback system for powered surgical instruments |
JP2020121162A (ja) | 2015-03-06 | 2020-08-13 | エシコン エルエルシーEthicon LLC | 測定の安定性要素、クリープ要素、及び粘弾性要素を決定するためのセンサデータの時間依存性評価 |
US10433844B2 (en) | 2015-03-31 | 2019-10-08 | Ethicon Llc | Surgical instrument with selectively disengageable threaded drive systems |
US10617418B2 (en) | 2015-08-17 | 2020-04-14 | Ethicon Llc | Implantable layers for a surgical instrument |
US10327769B2 (en) | 2015-09-23 | 2019-06-25 | Ethicon Llc | Surgical stapler having motor control based on a drive system component |
US10105139B2 (en) | 2015-09-23 | 2018-10-23 | Ethicon Llc | Surgical stapler having downstream current-based motor control |
US10363036B2 (en) | 2015-09-23 | 2019-07-30 | Ethicon Llc | Surgical stapler having force-based motor control |
US10238386B2 (en) | 2015-09-23 | 2019-03-26 | Ethicon Llc | Surgical stapler having motor control based on an electrical parameter related to a motor current |
US10299878B2 (en) | 2015-09-25 | 2019-05-28 | Ethicon Llc | Implantable adjunct systems for determining adjunct skew |
US10980539B2 (en) | 2015-09-30 | 2021-04-20 | Ethicon Llc | Implantable adjunct comprising bonded layers |
US20170086829A1 (en) | 2015-09-30 | 2017-03-30 | Ethicon Endo-Surgery, Llc | Compressible adjunct with intermediate supporting structures |
US10561420B2 (en) | 2015-09-30 | 2020-02-18 | Ethicon Llc | Tubular absorbable constructs |
US11890015B2 (en) | 2015-09-30 | 2024-02-06 | Cilag Gmbh International | Compressible adjunct with crossing spacer fibers |
US10368865B2 (en) | 2015-12-30 | 2019-08-06 | Ethicon Llc | Mechanisms for compensating for drivetrain failure in powered surgical instruments |
US10292704B2 (en) | 2015-12-30 | 2019-05-21 | Ethicon Llc | Mechanisms for compensating for battery pack failure in powered surgical instruments |
US10265068B2 (en) | 2015-12-30 | 2019-04-23 | Ethicon Llc | Surgical instruments with separable motors and motor control circuits |
CN105573555B (zh) * | 2016-01-28 | 2018-06-29 | 京东方科技集团股份有限公司 | 一种压力触控结构、触控显示面板、显示装置 |
BR112018016098B1 (pt) | 2016-02-09 | 2023-02-23 | Ethicon Llc | Instrumento cirúrgico |
US11213293B2 (en) | 2016-02-09 | 2022-01-04 | Cilag Gmbh International | Articulatable surgical instruments with single articulation link arrangements |
US10245029B2 (en) | 2016-02-09 | 2019-04-02 | Ethicon Llc | Surgical instrument with articulating and axially translatable end effector |
US11224426B2 (en) | 2016-02-12 | 2022-01-18 | Cilag Gmbh International | Mechanisms for compensating for drivetrain failure in powered surgical instruments |
US10448948B2 (en) | 2016-02-12 | 2019-10-22 | Ethicon Llc | Mechanisms for compensating for drivetrain failure in powered surgical instruments |
US10258331B2 (en) | 2016-02-12 | 2019-04-16 | Ethicon Llc | Mechanisms for compensating for drivetrain failure in powered surgical instruments |
US11064997B2 (en) | 2016-04-01 | 2021-07-20 | Cilag Gmbh International | Surgical stapling instrument |
US10617413B2 (en) | 2016-04-01 | 2020-04-14 | Ethicon Llc | Closure system arrangements for surgical cutting and stapling devices with separate and distinct firing shafts |
US10357247B2 (en) | 2016-04-15 | 2019-07-23 | Ethicon Llc | Surgical instrument with multiple program responses during a firing motion |
US10405859B2 (en) | 2016-04-15 | 2019-09-10 | Ethicon Llc | Surgical instrument with adjustable stop/start control during a firing motion |
US11179150B2 (en) | 2016-04-15 | 2021-11-23 | Cilag Gmbh International | Systems and methods for controlling a surgical stapling and cutting instrument |
US10426467B2 (en) | 2016-04-15 | 2019-10-01 | Ethicon Llc | Surgical instrument with detection sensors |
US10456137B2 (en) | 2016-04-15 | 2019-10-29 | Ethicon Llc | Staple formation detection mechanisms |
US11607239B2 (en) | 2016-04-15 | 2023-03-21 | Cilag Gmbh International | Systems and methods for controlling a surgical stapling and cutting instrument |
US10828028B2 (en) | 2016-04-15 | 2020-11-10 | Ethicon Llc | Surgical instrument with multiple program responses during a firing motion |
US10335145B2 (en) | 2016-04-15 | 2019-07-02 | Ethicon Llc | Modular surgical instrument with configurable operating mode |
US10492783B2 (en) | 2016-04-15 | 2019-12-03 | Ethicon, Llc | Surgical instrument with improved stop/start control during a firing motion |
US20170296173A1 (en) | 2016-04-18 | 2017-10-19 | Ethicon Endo-Surgery, Llc | Method for operating a surgical instrument |
US10478181B2 (en) | 2016-04-18 | 2019-11-19 | Ethicon Llc | Cartridge lockout arrangements for rotary powered surgical cutting and stapling instruments |
US11317917B2 (en) | 2016-04-18 | 2022-05-03 | Cilag Gmbh International | Surgical stapling system comprising a lockable firing assembly |
MX2019007311A (es) | 2016-12-21 | 2019-11-18 | Ethicon Llc | Sistemas de engrapado quirurgico. |
US11191539B2 (en) | 2016-12-21 | 2021-12-07 | Cilag Gmbh International | Shaft assembly comprising a manually-operable retraction system for use with a motorized surgical instrument system |
US20180168579A1 (en) | 2016-12-21 | 2018-06-21 | Ethicon Endo-Surgery, Llc | Surgical end effector with two separate cooperating opening features for opening and closing end effector jaws |
US11090048B2 (en) | 2016-12-21 | 2021-08-17 | Cilag Gmbh International | Method for resetting a fuse of a surgical instrument shaft |
CN110099619B (zh) | 2016-12-21 | 2022-07-15 | 爱惜康有限责任公司 | 用于外科端部执行器和可替换工具组件的闭锁装置 |
MX2019007295A (es) | 2016-12-21 | 2019-10-15 | Ethicon Llc | Sistema de instrumento quirúrgico que comprende un bloqueo del efector de extremo y un bloqueo de la unidad de disparo. |
US10736629B2 (en) | 2016-12-21 | 2020-08-11 | Ethicon Llc | Surgical tool assemblies with clutching arrangements for shifting between closure systems with closure stroke reduction features and articulation and firing systems |
US10835246B2 (en) | 2016-12-21 | 2020-11-17 | Ethicon Llc | Staple cartridges and arrangements of staples and staple cavities therein |
US10617414B2 (en) | 2016-12-21 | 2020-04-14 | Ethicon Llc | Closure member arrangements for surgical instruments |
US11419606B2 (en) | 2016-12-21 | 2022-08-23 | Cilag Gmbh International | Shaft assembly comprising a clutch configured to adapt the output of a rotary firing member to two different systems |
US10426471B2 (en) | 2016-12-21 | 2019-10-01 | Ethicon Llc | Surgical instrument with multiple failure response modes |
JP7010956B2 (ja) | 2016-12-21 | 2022-01-26 | エシコン エルエルシー | 組織をステープル留めする方法 |
US10758230B2 (en) | 2016-12-21 | 2020-09-01 | Ethicon Llc | Surgical instrument with primary and safety processors |
US20180168615A1 (en) | 2016-12-21 | 2018-06-21 | Ethicon Endo-Surgery, Llc | Method of deforming staples from two different types of staple cartridges with the same surgical stapling instrument |
US10610224B2 (en) | 2016-12-21 | 2020-04-07 | Ethicon Llc | Lockout arrangements for surgical end effectors and replaceable tool assemblies |
US10779823B2 (en) | 2016-12-21 | 2020-09-22 | Ethicon Llc | Firing member pin angle |
US10758229B2 (en) | 2016-12-21 | 2020-09-01 | Ethicon Llc | Surgical instrument comprising improved jaw control |
US11134942B2 (en) | 2016-12-21 | 2021-10-05 | Cilag Gmbh International | Surgical stapling instruments and staple-forming anvils |
US10682138B2 (en) | 2016-12-21 | 2020-06-16 | Ethicon Llc | Bilaterally asymmetric staple forming pocket pairs |
US10667809B2 (en) | 2016-12-21 | 2020-06-02 | Ethicon Llc | Staple cartridge and staple cartridge channel comprising windows defined therein |
KR20190117579A (ko) * | 2017-02-16 | 2019-10-16 | 엑스바이오테크, 인크. | 화농성 한선염의 치료 |
US10368864B2 (en) | 2017-06-20 | 2019-08-06 | Ethicon Llc | Systems and methods for controlling displaying motor velocity for a surgical instrument |
US10888321B2 (en) | 2017-06-20 | 2021-01-12 | Ethicon Llc | Systems and methods for controlling velocity of a displacement member of a surgical stapling and cutting instrument |
US10813639B2 (en) | 2017-06-20 | 2020-10-27 | Ethicon Llc | Closed loop feedback control of motor velocity of a surgical stapling and cutting instrument based on system conditions |
US10779820B2 (en) | 2017-06-20 | 2020-09-22 | Ethicon Llc | Systems and methods for controlling motor speed according to user input for a surgical instrument |
US11090046B2 (en) | 2017-06-20 | 2021-08-17 | Cilag Gmbh International | Systems and methods for controlling displacement member motion of a surgical stapling and cutting instrument |
US10390841B2 (en) | 2017-06-20 | 2019-08-27 | Ethicon Llc | Control of motor velocity of a surgical stapling and cutting instrument based on angle of articulation |
US11382638B2 (en) | 2017-06-20 | 2022-07-12 | Cilag Gmbh International | Closed loop feedback control of motor velocity of a surgical stapling and cutting instrument based on measured time over a specified displacement distance |
US11653914B2 (en) | 2017-06-20 | 2023-05-23 | Cilag Gmbh International | Systems and methods for controlling motor velocity of a surgical stapling and cutting instrument according to articulation angle of end effector |
US11071554B2 (en) | 2017-06-20 | 2021-07-27 | Cilag Gmbh International | Closed loop feedback control of motor velocity of a surgical stapling and cutting instrument based on magnitude of velocity error measurements |
US10307170B2 (en) | 2017-06-20 | 2019-06-04 | Ethicon Llc | Method for closed loop control of motor velocity of a surgical stapling and cutting instrument |
US10881396B2 (en) | 2017-06-20 | 2021-01-05 | Ethicon Llc | Surgical instrument with variable duration trigger arrangement |
US10881399B2 (en) | 2017-06-20 | 2021-01-05 | Ethicon Llc | Techniques for adaptive control of motor velocity of a surgical stapling and cutting instrument |
US10646220B2 (en) | 2017-06-20 | 2020-05-12 | Ethicon Llc | Systems and methods for controlling displacement member velocity for a surgical instrument |
US10980537B2 (en) | 2017-06-20 | 2021-04-20 | Ethicon Llc | Closed loop feedback control of motor velocity of a surgical stapling and cutting instrument based on measured time over a specified number of shaft rotations |
USD879809S1 (en) | 2017-06-20 | 2020-03-31 | Ethicon Llc | Display panel with changeable graphical user interface |
USD879808S1 (en) | 2017-06-20 | 2020-03-31 | Ethicon Llc | Display panel with graphical user interface |
US10327767B2 (en) | 2017-06-20 | 2019-06-25 | Ethicon Llc | Control of motor velocity of a surgical stapling and cutting instrument based on angle of articulation |
US11517325B2 (en) | 2017-06-20 | 2022-12-06 | Cilag Gmbh International | Closed loop feedback control of motor velocity of a surgical stapling and cutting instrument based on measured displacement distance traveled over a specified time interval |
US10624633B2 (en) | 2017-06-20 | 2020-04-21 | Ethicon Llc | Systems and methods for controlling motor velocity of a surgical stapling and cutting instrument |
USD890784S1 (en) | 2017-06-20 | 2020-07-21 | Ethicon Llc | Display panel with changeable graphical user interface |
US10772629B2 (en) | 2017-06-27 | 2020-09-15 | Ethicon Llc | Surgical anvil arrangements |
US10856869B2 (en) | 2017-06-27 | 2020-12-08 | Ethicon Llc | Surgical anvil arrangements |
US11324503B2 (en) | 2017-06-27 | 2022-05-10 | Cilag Gmbh International | Surgical firing member arrangements |
US10993716B2 (en) | 2017-06-27 | 2021-05-04 | Ethicon Llc | Surgical anvil arrangements |
US11090049B2 (en) | 2017-06-27 | 2021-08-17 | Cilag Gmbh International | Staple forming pocket arrangements |
US11266405B2 (en) | 2017-06-27 | 2022-03-08 | Cilag Gmbh International | Surgical anvil manufacturing methods |
USD854151S1 (en) | 2017-06-28 | 2019-07-16 | Ethicon Llc | Surgical instrument shaft |
USD869655S1 (en) | 2017-06-28 | 2019-12-10 | Ethicon Llc | Surgical fastener cartridge |
US10211586B2 (en) | 2017-06-28 | 2019-02-19 | Ethicon Llc | Surgical shaft assemblies with watertight housings |
US11000279B2 (en) | 2017-06-28 | 2021-05-11 | Ethicon Llc | Surgical instrument comprising an articulation system ratio |
EP3420947B1 (en) | 2017-06-28 | 2022-05-25 | Cilag GmbH International | Surgical instrument comprising selectively actuatable rotatable couplers |
US11259805B2 (en) | 2017-06-28 | 2022-03-01 | Cilag Gmbh International | Surgical instrument comprising firing member supports |
USD906355S1 (en) | 2017-06-28 | 2020-12-29 | Ethicon Llc | Display screen or portion thereof with a graphical user interface for a surgical instrument |
USD851762S1 (en) | 2017-06-28 | 2019-06-18 | Ethicon Llc | Anvil |
US11246592B2 (en) | 2017-06-28 | 2022-02-15 | Cilag Gmbh International | Surgical instrument comprising an articulation system lockable to a frame |
US10903685B2 (en) | 2017-06-28 | 2021-01-26 | Ethicon Llc | Surgical shaft assemblies with slip ring assemblies forming capacitive channels |
US11564686B2 (en) | 2017-06-28 | 2023-01-31 | Cilag Gmbh International | Surgical shaft assemblies with flexible interfaces |
US10716614B2 (en) | 2017-06-28 | 2020-07-21 | Ethicon Llc | Surgical shaft assemblies with slip ring assemblies with increased contact pressure |
US10765427B2 (en) | 2017-06-28 | 2020-09-08 | Ethicon Llc | Method for articulating a surgical instrument |
US10695057B2 (en) | 2017-06-28 | 2020-06-30 | Ethicon Llc | Surgical instrument lockout arrangement |
US10898183B2 (en) | 2017-06-29 | 2021-01-26 | Ethicon Llc | Robotic surgical instrument with closed loop feedback techniques for advancement of closure member during firing |
US10258418B2 (en) | 2017-06-29 | 2019-04-16 | Ethicon Llc | System for controlling articulation forces |
US11007022B2 (en) | 2017-06-29 | 2021-05-18 | Ethicon Llc | Closed loop velocity control techniques based on sensed tissue parameters for robotic surgical instrument |
US10932772B2 (en) | 2017-06-29 | 2021-03-02 | Ethicon Llc | Methods for closed loop velocity control for robotic surgical instrument |
US10398434B2 (en) | 2017-06-29 | 2019-09-03 | Ethicon Llc | Closed loop velocity control of closure member for robotic surgical instrument |
US11944300B2 (en) | 2017-08-03 | 2024-04-02 | Cilag Gmbh International | Method for operating a surgical system bailout |
US11974742B2 (en) | 2017-08-03 | 2024-05-07 | Cilag Gmbh International | Surgical system comprising an articulation bailout |
US11471155B2 (en) | 2017-08-03 | 2022-10-18 | Cilag Gmbh International | Surgical system bailout |
US11304695B2 (en) | 2017-08-03 | 2022-04-19 | Cilag Gmbh International | Surgical system shaft interconnection |
WO2019046307A1 (en) | 2017-08-29 | 2019-03-07 | Celsee Diagnostics, Inc. | SYSTEM AND METHOD FOR ISOLATING AND ANALYZING CELLS |
JP2019043215A (ja) | 2017-08-30 | 2019-03-22 | いすゞ自動車株式会社 | ステアリング装置 |
US10743872B2 (en) | 2017-09-29 | 2020-08-18 | Ethicon Llc | System and methods for controlling a display of a surgical instrument |
USD917500S1 (en) | 2017-09-29 | 2021-04-27 | Ethicon Llc | Display screen or portion thereof with graphical user interface |
US10765429B2 (en) | 2017-09-29 | 2020-09-08 | Ethicon Llc | Systems and methods for providing alerts according to the operational state of a surgical instrument |
US10729501B2 (en) | 2017-09-29 | 2020-08-04 | Ethicon Llc | Systems and methods for language selection of a surgical instrument |
USD907648S1 (en) | 2017-09-29 | 2021-01-12 | Ethicon Llc | Display screen or portion thereof with animated graphical user interface |
USD907647S1 (en) | 2017-09-29 | 2021-01-12 | Ethicon Llc | Display screen or portion thereof with animated graphical user interface |
US10796471B2 (en) | 2017-09-29 | 2020-10-06 | Ethicon Llc | Systems and methods of displaying a knife position for a surgical instrument |
US11399829B2 (en) | 2017-09-29 | 2022-08-02 | Cilag Gmbh International | Systems and methods of initiating a power shutdown mode for a surgical instrument |
US11134944B2 (en) | 2017-10-30 | 2021-10-05 | Cilag Gmbh International | Surgical stapler knife motion controls |
US11090075B2 (en) | 2017-10-30 | 2021-08-17 | Cilag Gmbh International | Articulation features for surgical end effector |
US10842490B2 (en) | 2017-10-31 | 2020-11-24 | Ethicon Llc | Cartridge body design with force reduction based on firing completion |
US10779903B2 (en) | 2017-10-31 | 2020-09-22 | Ethicon Llc | Positive shaft rotation lock activated by jaw closure |
US10828033B2 (en) | 2017-12-15 | 2020-11-10 | Ethicon Llc | Handheld electromechanical surgical instruments with improved motor control arrangements for positioning components of an adapter coupled thereto |
US10779825B2 (en) | 2017-12-15 | 2020-09-22 | Ethicon Llc | Adapters with end effector position sensing and control arrangements for use in connection with electromechanical surgical instruments |
US10779826B2 (en) | 2017-12-15 | 2020-09-22 | Ethicon Llc | Methods of operating surgical end effectors |
US10687813B2 (en) | 2017-12-15 | 2020-06-23 | Ethicon Llc | Adapters with firing stroke sensing arrangements for use in connection with electromechanical surgical instruments |
US11006955B2 (en) | 2017-12-15 | 2021-05-18 | Ethicon Llc | End effectors with positive jaw opening features for use with adapters for electromechanical surgical instruments |
US10743874B2 (en) | 2017-12-15 | 2020-08-18 | Ethicon Llc | Sealed adapters for use with electromechanical surgical instruments |
US10743875B2 (en) | 2017-12-15 | 2020-08-18 | Ethicon Llc | Surgical end effectors with jaw stiffener arrangements configured to permit monitoring of firing member |
US10966718B2 (en) | 2017-12-15 | 2021-04-06 | Ethicon Llc | Dynamic clamping assemblies with improved wear characteristics for use in connection with electromechanical surgical instruments |
US11197670B2 (en) | 2017-12-15 | 2021-12-14 | Cilag Gmbh International | Surgical end effectors with pivotal jaws configured to touch at their respective distal ends when fully closed |
US11033267B2 (en) | 2017-12-15 | 2021-06-15 | Ethicon Llc | Systems and methods of controlling a clamping member firing rate of a surgical instrument |
US10869666B2 (en) | 2017-12-15 | 2020-12-22 | Ethicon Llc | Adapters with control systems for controlling multiple motors of an electromechanical surgical instrument |
US11071543B2 (en) | 2017-12-15 | 2021-07-27 | Cilag Gmbh International | Surgical end effectors with clamping assemblies configured to increase jaw aperture ranges |
USD910847S1 (en) | 2017-12-19 | 2021-02-16 | Ethicon Llc | Surgical instrument assembly |
US11020112B2 (en) | 2017-12-19 | 2021-06-01 | Ethicon Llc | Surgical tools configured for interchangeable use with different controller interfaces |
US10835330B2 (en) | 2017-12-19 | 2020-11-17 | Ethicon Llc | Method for determining the position of a rotatable jaw of a surgical instrument attachment assembly |
US10716565B2 (en) | 2017-12-19 | 2020-07-21 | Ethicon Llc | Surgical instruments with dual articulation drivers |
US10729509B2 (en) | 2017-12-19 | 2020-08-04 | Ethicon Llc | Surgical instrument comprising closure and firing locking mechanism |
US11045270B2 (en) | 2017-12-19 | 2021-06-29 | Cilag Gmbh International | Robotic attachment comprising exterior drive actuator |
US11311290B2 (en) | 2017-12-21 | 2022-04-26 | Cilag Gmbh International | Surgical instrument comprising an end effector dampener |
US10743868B2 (en) | 2017-12-21 | 2020-08-18 | Ethicon Llc | Surgical instrument comprising a pivotable distal head |
US11129680B2 (en) | 2017-12-21 | 2021-09-28 | Cilag Gmbh International | Surgical instrument comprising a projector |
US11076853B2 (en) | 2017-12-21 | 2021-08-03 | Cilag Gmbh International | Systems and methods of displaying a knife position during transection for a surgical instrument |
BR112020021721A2 (pt) * | 2018-04-24 | 2021-01-26 | Janssen Biotech, Inc. | tratamento da dermatite atópica |
US10975146B2 (en) | 2018-06-29 | 2021-04-13 | Cedars-Sinai Medical Center | Interleukin-1 inhibition for combination treatment of pancreatic cancer |
US11045192B2 (en) | 2018-08-20 | 2021-06-29 | Cilag Gmbh International | Fabricating techniques for surgical stapler anvils |
US11083458B2 (en) | 2018-08-20 | 2021-08-10 | Cilag Gmbh International | Powered surgical instruments with clutching arrangements to convert linear drive motions to rotary drive motions |
US10856870B2 (en) | 2018-08-20 | 2020-12-08 | Ethicon Llc | Switching arrangements for motor powered articulatable surgical instruments |
USD914878S1 (en) | 2018-08-20 | 2021-03-30 | Ethicon Llc | Surgical instrument anvil |
US11253256B2 (en) | 2018-08-20 | 2022-02-22 | Cilag Gmbh International | Articulatable motor powered surgical instruments with dedicated articulation motor arrangements |
US10779821B2 (en) | 2018-08-20 | 2020-09-22 | Ethicon Llc | Surgical stapler anvils with tissue stop features configured to avoid tissue pinch |
US11207065B2 (en) | 2018-08-20 | 2021-12-28 | Cilag Gmbh International | Method for fabricating surgical stapler anvils |
US11039834B2 (en) | 2018-08-20 | 2021-06-22 | Cilag Gmbh International | Surgical stapler anvils with staple directing protrusions and tissue stability features |
US11291440B2 (en) | 2018-08-20 | 2022-04-05 | Cilag Gmbh International | Method for operating a powered articulatable surgical instrument |
US11324501B2 (en) | 2018-08-20 | 2022-05-10 | Cilag Gmbh International | Surgical stapling devices with improved closure members |
US10842492B2 (en) | 2018-08-20 | 2020-11-24 | Ethicon Llc | Powered articulatable surgical instruments with clutching and locking arrangements for linking an articulation drive system to a firing drive system |
US10912559B2 (en) | 2018-08-20 | 2021-02-09 | Ethicon Llc | Reinforced deformable anvil tip for surgical stapler anvil |
TW202045206A (zh) | 2019-02-27 | 2020-12-16 | 美商健生生物科技公司 | 抗體調配物 |
TW202045537A (zh) | 2019-02-28 | 2020-12-16 | 美商健生生物科技公司 | 化膿性汗腺炎的治療 |
US11172929B2 (en) | 2019-03-25 | 2021-11-16 | Cilag Gmbh International | Articulation drive arrangements for surgical systems |
US11696761B2 (en) | 2019-03-25 | 2023-07-11 | Cilag Gmbh International | Firing drive arrangements for surgical systems |
US11147553B2 (en) | 2019-03-25 | 2021-10-19 | Cilag Gmbh International | Firing drive arrangements for surgical systems |
US11147551B2 (en) | 2019-03-25 | 2021-10-19 | Cilag Gmbh International | Firing drive arrangements for surgical systems |
US10633693B1 (en) | 2019-04-16 | 2020-04-28 | Celsee Diagnostics, Inc. | System and method for leakage control in a particle capture system |
US11432816B2 (en) | 2019-04-30 | 2022-09-06 | Cilag Gmbh International | Articulation pin for a surgical instrument |
US11253254B2 (en) | 2019-04-30 | 2022-02-22 | Cilag Gmbh International | Shaft rotation actuator on a surgical instrument |
US11471157B2 (en) | 2019-04-30 | 2022-10-18 | Cilag Gmbh International | Articulation control mapping for a surgical instrument |
US11426251B2 (en) | 2019-04-30 | 2022-08-30 | Cilag Gmbh International | Articulation directional lights on a surgical instrument |
US11452528B2 (en) | 2019-04-30 | 2022-09-27 | Cilag Gmbh International | Articulation actuators for a surgical instrument |
US11648009B2 (en) | 2019-04-30 | 2023-05-16 | Cilag Gmbh International | Rotatable jaw tip for a surgical instrument |
US11903581B2 (en) | 2019-04-30 | 2024-02-20 | Cilag Gmbh International | Methods for stapling tissue using a surgical instrument |
WO2020227309A1 (en) | 2019-05-07 | 2020-11-12 | Bio-Rad Laboratories, Inc. | System and method for automated single cell processing |
US11273439B2 (en) | 2019-05-07 | 2022-03-15 | Bio-Rad Laboratories, Inc. | System and method for target material retrieval from microwells |
US11553971B2 (en) | 2019-06-28 | 2023-01-17 | Cilag Gmbh International | Surgical RFID assemblies for display and communication |
US11376098B2 (en) | 2019-06-28 | 2022-07-05 | Cilag Gmbh International | Surgical instrument system comprising an RFID system |
US11426167B2 (en) | 2019-06-28 | 2022-08-30 | Cilag Gmbh International | Mechanisms for proper anvil attachment surgical stapling head assembly |
US11298132B2 (en) | 2019-06-28 | 2022-04-12 | Cilag GmbH Inlernational | Staple cartridge including a honeycomb extension |
US11627959B2 (en) | 2019-06-28 | 2023-04-18 | Cilag Gmbh International | Surgical instruments including manual and powered system lockouts |
US12004740B2 (en) | 2019-06-28 | 2024-06-11 | Cilag Gmbh International | Surgical stapling system having an information decryption protocol |
US11523822B2 (en) | 2019-06-28 | 2022-12-13 | Cilag Gmbh International | Battery pack including a circuit interrupter |
US11638587B2 (en) | 2019-06-28 | 2023-05-02 | Cilag Gmbh International | RFID identification systems for surgical instruments |
US11684434B2 (en) | 2019-06-28 | 2023-06-27 | Cilag Gmbh International | Surgical RFID assemblies for instrument operational setting control |
US11771419B2 (en) | 2019-06-28 | 2023-10-03 | Cilag Gmbh International | Packaging for a replaceable component of a surgical stapling system |
US11224497B2 (en) | 2019-06-28 | 2022-01-18 | Cilag Gmbh International | Surgical systems with multiple RFID tags |
US11464601B2 (en) | 2019-06-28 | 2022-10-11 | Cilag Gmbh International | Surgical instrument comprising an RFID system for tracking a movable component |
US11497492B2 (en) | 2019-06-28 | 2022-11-15 | Cilag Gmbh International | Surgical instrument including an articulation lock |
US11246678B2 (en) | 2019-06-28 | 2022-02-15 | Cilag Gmbh International | Surgical stapling system having a frangible RFID tag |
US11298127B2 (en) | 2019-06-28 | 2022-04-12 | Cilag GmbH Interational | Surgical stapling system having a lockout mechanism for an incompatible cartridge |
US11399837B2 (en) | 2019-06-28 | 2022-08-02 | Cilag Gmbh International | Mechanisms for motor control adjustments of a motorized surgical instrument |
US11291451B2 (en) | 2019-06-28 | 2022-04-05 | Cilag Gmbh International | Surgical instrument with battery compatibility verification functionality |
US11478241B2 (en) | 2019-06-28 | 2022-10-25 | Cilag Gmbh International | Staple cartridge including projections |
US11660163B2 (en) | 2019-06-28 | 2023-05-30 | Cilag Gmbh International | Surgical system with RFID tags for updating motor assembly parameters |
US11241235B2 (en) | 2019-06-28 | 2022-02-08 | Cilag Gmbh International | Method of using multiple RFID chips with a surgical assembly |
US11259803B2 (en) | 2019-06-28 | 2022-03-01 | Cilag Gmbh International | Surgical stapling system having an information encryption protocol |
US11051807B2 (en) | 2019-06-28 | 2021-07-06 | Cilag Gmbh International | Packaging assembly including a particulate trap |
US11219455B2 (en) | 2019-06-28 | 2022-01-11 | Cilag Gmbh International | Surgical instrument including a lockout key |
US11529139B2 (en) | 2019-12-19 | 2022-12-20 | Cilag Gmbh International | Motor driven surgical instrument |
US11304696B2 (en) | 2019-12-19 | 2022-04-19 | Cilag Gmbh International | Surgical instrument comprising a powered articulation system |
US11529137B2 (en) | 2019-12-19 | 2022-12-20 | Cilag Gmbh International | Staple cartridge comprising driver retention members |
US11844520B2 (en) | 2019-12-19 | 2023-12-19 | Cilag Gmbh International | Staple cartridge comprising driver retention members |
US11911032B2 (en) | 2019-12-19 | 2024-02-27 | Cilag Gmbh International | Staple cartridge comprising a seating cam |
US11931033B2 (en) | 2019-12-19 | 2024-03-19 | Cilag Gmbh International | Staple cartridge comprising a latch lockout |
US11291447B2 (en) | 2019-12-19 | 2022-04-05 | Cilag Gmbh International | Stapling instrument comprising independent jaw closing and staple firing systems |
US11576672B2 (en) | 2019-12-19 | 2023-02-14 | Cilag Gmbh International | Surgical instrument comprising a closure system including a closure member and an opening member driven by a drive screw |
US11701111B2 (en) | 2019-12-19 | 2023-07-18 | Cilag Gmbh International | Method for operating a surgical stapling instrument |
US11464512B2 (en) | 2019-12-19 | 2022-10-11 | Cilag Gmbh International | Staple cartridge comprising a curved deck surface |
US11446029B2 (en) | 2019-12-19 | 2022-09-20 | Cilag Gmbh International | Staple cartridge comprising projections extending from a curved deck surface |
US11559304B2 (en) | 2019-12-19 | 2023-01-24 | Cilag Gmbh International | Surgical instrument comprising a rapid closure mechanism |
US11504122B2 (en) | 2019-12-19 | 2022-11-22 | Cilag Gmbh International | Surgical instrument comprising a nested firing member |
US11607219B2 (en) | 2019-12-19 | 2023-03-21 | Cilag Gmbh International | Staple cartridge comprising a detachable tissue cutting knife |
US11234698B2 (en) | 2019-12-19 | 2022-02-01 | Cilag Gmbh International | Stapling system comprising a clamp lockout and a firing lockout |
CN111471655B (zh) * | 2020-03-19 | 2023-07-07 | 湖州正熙医学检验实验室有限公司 | 抗人il12/23稳转细胞株及其构建方法和应用 |
KR20230004638A (ko) | 2020-04-16 | 2023-01-06 | 얀센 바이오테크 인코포레이티드 | 화농성 한선염의 치료 |
WO2021211924A1 (en) | 2020-04-16 | 2021-10-21 | Janssen Biotech, Inc. | Treatment of atopic dermatitis |
USD975278S1 (en) | 2020-06-02 | 2023-01-10 | Cilag Gmbh International | Staple cartridge |
USD976401S1 (en) | 2020-06-02 | 2023-01-24 | Cilag Gmbh International | Staple cartridge |
USD967421S1 (en) | 2020-06-02 | 2022-10-18 | Cilag Gmbh International | Staple cartridge |
USD975851S1 (en) | 2020-06-02 | 2023-01-17 | Cilag Gmbh International | Staple cartridge |
USD966512S1 (en) | 2020-06-02 | 2022-10-11 | Cilag Gmbh International | Staple cartridge |
USD975850S1 (en) | 2020-06-02 | 2023-01-17 | Cilag Gmbh International | Staple cartridge |
USD974560S1 (en) | 2020-06-02 | 2023-01-03 | Cilag Gmbh International | Staple cartridge |
US11826013B2 (en) | 2020-07-28 | 2023-11-28 | Cilag Gmbh International | Surgical instruments with firing member closure features |
CA3095675A1 (en) * | 2020-10-07 | 2022-04-07 | Xbiotech Inc. | True human antibody specific for interleukin 1 alpha (il-1a) |
CA3095679A1 (en) * | 2020-10-07 | 2022-04-07 | Xbiotech Inc. | True human antibody specific for interleuken 1 alpha (il-1a) |
CA3095740A1 (en) * | 2020-10-07 | 2022-04-07 | Xbiotech Inc. | True human antibody specific for interleukin alpha (il-1a) |
CA3095676A1 (en) * | 2020-10-07 | 2022-04-07 | Xbiotech Inc. | True human antibody specific for interleukin 1 alpha (il-1a) |
USD1013170S1 (en) | 2020-10-29 | 2024-01-30 | Cilag Gmbh International | Surgical instrument assembly |
US11517390B2 (en) | 2020-10-29 | 2022-12-06 | Cilag Gmbh International | Surgical instrument comprising a limited travel switch |
US11779330B2 (en) | 2020-10-29 | 2023-10-10 | Cilag Gmbh International | Surgical instrument comprising a jaw alignment system |
USD980425S1 (en) | 2020-10-29 | 2023-03-07 | Cilag Gmbh International | Surgical instrument assembly |
US11896217B2 (en) | 2020-10-29 | 2024-02-13 | Cilag Gmbh International | Surgical instrument comprising an articulation lock |
US11931025B2 (en) | 2020-10-29 | 2024-03-19 | Cilag Gmbh International | Surgical instrument comprising a releasable closure drive lock |
US11717289B2 (en) | 2020-10-29 | 2023-08-08 | Cilag Gmbh International | Surgical instrument comprising an indicator which indicates that an articulation drive is actuatable |
US11534259B2 (en) | 2020-10-29 | 2022-12-27 | Cilag Gmbh International | Surgical instrument comprising an articulation indicator |
US11844518B2 (en) | 2020-10-29 | 2023-12-19 | Cilag Gmbh International | Method for operating a surgical instrument |
US11617577B2 (en) | 2020-10-29 | 2023-04-04 | Cilag Gmbh International | Surgical instrument comprising a sensor configured to sense whether an articulation drive of the surgical instrument is actuatable |
US11452526B2 (en) | 2020-10-29 | 2022-09-27 | Cilag Gmbh International | Surgical instrument comprising a staged voltage regulation start-up system |
US11627960B2 (en) | 2020-12-02 | 2023-04-18 | Cilag Gmbh International | Powered surgical instruments with smart reload with separately attachable exteriorly mounted wiring connections |
US11890010B2 (en) | 2020-12-02 | 2024-02-06 | Cllag GmbH International | Dual-sided reinforced reload for surgical instruments |
US11653920B2 (en) | 2020-12-02 | 2023-05-23 | Cilag Gmbh International | Powered surgical instruments with communication interfaces through sterile barrier |
US11944296B2 (en) | 2020-12-02 | 2024-04-02 | Cilag Gmbh International | Powered surgical instruments with external connectors |
US11737751B2 (en) | 2020-12-02 | 2023-08-29 | Cilag Gmbh International | Devices and methods of managing energy dissipated within sterile barriers of surgical instrument housings |
US11653915B2 (en) | 2020-12-02 | 2023-05-23 | Cilag Gmbh International | Surgical instruments with sled location detection and adjustment features |
US11849943B2 (en) | 2020-12-02 | 2023-12-26 | Cilag Gmbh International | Surgical instrument with cartridge release mechanisms |
US11678882B2 (en) | 2020-12-02 | 2023-06-20 | Cilag Gmbh International | Surgical instruments with interactive features to remedy incidental sled movements |
US11744581B2 (en) | 2020-12-02 | 2023-09-05 | Cilag Gmbh International | Powered surgical instruments with multi-phase tissue treatment |
US11950777B2 (en) | 2021-02-26 | 2024-04-09 | Cilag Gmbh International | Staple cartridge comprising an information access control system |
US11812964B2 (en) | 2021-02-26 | 2023-11-14 | Cilag Gmbh International | Staple cartridge comprising a power management circuit |
US11793514B2 (en) | 2021-02-26 | 2023-10-24 | Cilag Gmbh International | Staple cartridge comprising sensor array which may be embedded in cartridge body |
US11744583B2 (en) | 2021-02-26 | 2023-09-05 | Cilag Gmbh International | Distal communication array to tune frequency of RF systems |
US11925349B2 (en) | 2021-02-26 | 2024-03-12 | Cilag Gmbh International | Adjustment to transfer parameters to improve available power |
US11751869B2 (en) | 2021-02-26 | 2023-09-12 | Cilag Gmbh International | Monitoring of multiple sensors over time to detect moving characteristics of tissue |
US11730473B2 (en) | 2021-02-26 | 2023-08-22 | Cilag Gmbh International | Monitoring of manufacturing life-cycle |
US11723657B2 (en) | 2021-02-26 | 2023-08-15 | Cilag Gmbh International | Adjustable communication based on available bandwidth and power capacity |
US11950779B2 (en) | 2021-02-26 | 2024-04-09 | Cilag Gmbh International | Method of powering and communicating with a staple cartridge |
US11749877B2 (en) | 2021-02-26 | 2023-09-05 | Cilag Gmbh International | Stapling instrument comprising a signal antenna |
US11696757B2 (en) | 2021-02-26 | 2023-07-11 | Cilag Gmbh International | Monitoring of internal systems to detect and track cartridge motion status |
US11980362B2 (en) | 2021-02-26 | 2024-05-14 | Cilag Gmbh International | Surgical instrument system comprising a power transfer coil |
US11701113B2 (en) | 2021-02-26 | 2023-07-18 | Cilag Gmbh International | Stapling instrument comprising a separate power antenna and a data transfer antenna |
US11717291B2 (en) | 2021-03-22 | 2023-08-08 | Cilag Gmbh International | Staple cartridge comprising staples configured to apply different tissue compression |
US11737749B2 (en) | 2021-03-22 | 2023-08-29 | Cilag Gmbh International | Surgical stapling instrument comprising a retraction system |
US11759202B2 (en) | 2021-03-22 | 2023-09-19 | Cilag Gmbh International | Staple cartridge comprising an implantable layer |
US11826012B2 (en) | 2021-03-22 | 2023-11-28 | Cilag Gmbh International | Stapling instrument comprising a pulsed motor-driven firing rack |
US11723658B2 (en) | 2021-03-22 | 2023-08-15 | Cilag Gmbh International | Staple cartridge comprising a firing lockout |
US11826042B2 (en) | 2021-03-22 | 2023-11-28 | Cilag Gmbh International | Surgical instrument comprising a firing drive including a selectable leverage mechanism |
US11806011B2 (en) | 2021-03-22 | 2023-11-07 | Cilag Gmbh International | Stapling instrument comprising tissue compression systems |
US11896218B2 (en) | 2021-03-24 | 2024-02-13 | Cilag Gmbh International | Method of using a powered stapling device |
US11857183B2 (en) | 2021-03-24 | 2024-01-02 | Cilag Gmbh International | Stapling assembly components having metal substrates and plastic bodies |
US11786239B2 (en) | 2021-03-24 | 2023-10-17 | Cilag Gmbh International | Surgical instrument articulation joint arrangements comprising multiple moving linkage features |
US11832816B2 (en) | 2021-03-24 | 2023-12-05 | Cilag Gmbh International | Surgical stapling assembly comprising nonplanar staples and planar staples |
US11944336B2 (en) | 2021-03-24 | 2024-04-02 | Cilag Gmbh International | Joint arrangements for multi-planar alignment and support of operational drive shafts in articulatable surgical instruments |
US11849945B2 (en) | 2021-03-24 | 2023-12-26 | Cilag Gmbh International | Rotary-driven surgical stapling assembly comprising eccentrically driven firing member |
US11849944B2 (en) | 2021-03-24 | 2023-12-26 | Cilag Gmbh International | Drivers for fastener cartridge assemblies having rotary drive screws |
US11786243B2 (en) | 2021-03-24 | 2023-10-17 | Cilag Gmbh International | Firing members having flexible portions for adapting to a load during a surgical firing stroke |
US11896219B2 (en) | 2021-03-24 | 2024-02-13 | Cilag Gmbh International | Mating features between drivers and underside of a cartridge deck |
US11793516B2 (en) | 2021-03-24 | 2023-10-24 | Cilag Gmbh International | Surgical staple cartridge comprising longitudinal support beam |
US11903582B2 (en) | 2021-03-24 | 2024-02-20 | Cilag Gmbh International | Leveraging surfaces for cartridge installation |
US11744603B2 (en) | 2021-03-24 | 2023-09-05 | Cilag Gmbh International | Multi-axis pivot joints for surgical instruments and methods for manufacturing same |
US11723662B2 (en) | 2021-05-28 | 2023-08-15 | Cilag Gmbh International | Stapling instrument comprising an articulation control display |
US11980363B2 (en) | 2021-10-18 | 2024-05-14 | Cilag Gmbh International | Row-to-row staple array variations |
US11957337B2 (en) | 2021-10-18 | 2024-04-16 | Cilag Gmbh International | Surgical stapling assembly with offset ramped drive surfaces |
US11877745B2 (en) | 2021-10-18 | 2024-01-23 | Cilag Gmbh International | Surgical stapling assembly having longitudinally-repeating staple leg clusters |
US11937816B2 (en) | 2021-10-28 | 2024-03-26 | Cilag Gmbh International | Electrical lead arrangements for surgical instruments |
CN116568339A (zh) * | 2022-09-26 | 2023-08-08 | 成都优洛生物科技有限公司 | 一种非鼠类哺乳动物IL-1α抗体的体内药效检测方法 |
Family Cites Families (74)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CH652145A5 (de) | 1982-01-22 | 1985-10-31 | Sandoz Ag | Verfahren zur in vitro-herstellung von hybridomen welche humane monoklonale antikoerper erzeugen. |
US4510245A (en) | 1982-11-18 | 1985-04-09 | Chiron Corporation | Adenovirus promoter system |
US5672347A (en) * | 1984-07-05 | 1997-09-30 | Genentech, Inc. | Tumor necrosis factor antagonists and their use |
US5168062A (en) * | 1985-01-30 | 1992-12-01 | University Of Iowa Research Foundation | Transfer vectors and microorganisms containing human cytomegalovirus immediate-early promoter-regulatory DNA sequence |
US4968615A (en) | 1985-12-18 | 1990-11-06 | Ciba-Geigy Corporation | Deoxyribonucleic acid segment from a virus |
US4965198A (en) * | 1985-12-24 | 1990-10-23 | Konica Corporation | Monoclonal antibody and method of manufacturing hybridoma producing the same |
DE3631229A1 (de) * | 1986-09-13 | 1988-03-24 | Basf Ag | Monoklonale antikoerper gegen humanen tumornekrosefaktor (tnf) und deren verwendung |
DK590387A (da) | 1986-11-13 | 1988-05-14 | Otsuka Pharma Co Ltd | Antistoffer mod interleukin-1 |
US5034316A (en) * | 1987-03-30 | 1991-07-23 | The Regents Of The University Of California | In vitro human monoclonal IgG rheumatoid factor autoantibody |
US5750172A (en) | 1987-06-23 | 1998-05-12 | Pharming B.V. | Transgenic non human mammal milk |
US4968607A (en) | 1987-11-25 | 1990-11-06 | Immunex Corporation | Interleukin-1 receptors |
US20040101528A1 (en) * | 1988-02-25 | 2004-05-27 | Dower Steven K. | Type I IL-1 receptors |
FR2640146B1 (fr) | 1988-12-08 | 1993-12-24 | Commissariat A Energie Atomique | Anticorps monoclonaux anti-interleukines 1(alpha) et 1(beta), leur procede de production et applications desdits anticorps a la detection des interleukines 1(alpha) et 1(beta) et en therapeutique |
US5530101A (en) | 1988-12-28 | 1996-06-25 | Protein Design Labs, Inc. | Humanized immunoglobulins |
US5407431A (en) | 1989-07-11 | 1995-04-18 | Med-Design Inc. | Intravenous catheter insertion device with retractable needle |
US5959177A (en) | 1989-10-27 | 1999-09-28 | The Scripps Research Institute | Transgenic plants expressing assembled secretory antibodies |
US5633076A (en) | 1989-12-01 | 1997-05-27 | Pharming Bv | Method of producing a transgenic bovine or transgenic bovine embryo |
GB9122820D0 (en) * | 1991-10-28 | 1991-12-11 | Wellcome Found | Stabilised antibodies |
EP0664713B1 (en) | 1992-10-14 | 2000-01-19 | Nycomed Imaging As | Therapeutic and diagnostic imaging compositions and methods |
DE122009000074I1 (de) * | 1993-03-05 | 2011-12-01 | Bayer Healthcare Ag | Humane monoklonale anti-TNF alpha Antikorper. |
AU693436B2 (en) | 1993-03-09 | 1998-07-02 | Genzyme Corporation | Isolation of components of interest from milk |
US5959085A (en) | 1993-11-23 | 1999-09-28 | Schering Corporation | Human monoclonal antibodies against human cytokines and methods of making and using such antibodies |
EP0659766A1 (en) | 1993-11-23 | 1995-06-28 | Schering-Plough | Human monoclonal antibodies against human cytokines and methods of making and using such antibodies |
US5827690A (en) | 1993-12-20 | 1998-10-27 | Genzyme Transgenics Corporatiion | Transgenic production of antibodies in milk |
US6046037A (en) | 1994-12-30 | 2000-04-04 | Hiatt; Andrew C. | Method for producing immunoglobulins containing protection proteins in plants and their use |
GB9509620D0 (en) | 1995-05-12 | 1995-07-05 | Nat Blood Authority | Transepithelial transport of molecular species |
US6140470A (en) * | 1995-06-30 | 2000-10-31 | Yale University | Human monoclonal anti-tumor antibodies |
US6090382A (en) * | 1996-02-09 | 2000-07-18 | Basf Aktiengesellschaft | Human antibodies that bind human TNFα |
SE9802402D0 (sv) * | 1998-07-03 | 1998-07-03 | Karolinska Innovations Ab | Method of diagnosing cardiovascular disease and early atherosclerosis |
AU3395900A (en) * | 1999-03-12 | 2000-10-04 | Human Genome Sciences, Inc. | Human lung cancer associated gene sequences and polypeptides |
US20030040617A9 (en) * | 1999-03-12 | 2003-02-27 | Rosen Craig A. | Nucleic acids, proteins and antibodies |
IL145134A0 (en) * | 1999-03-25 | 2002-06-30 | Knoll Gmbh | Human antibodies that bind human il-12 and methods for producing |
ATE316982T1 (de) * | 1999-08-09 | 2006-02-15 | Lexigen Pharm Corp | Mehrere zytokin-antikörper komplexen |
DE19943790C2 (de) | 1999-09-13 | 2001-11-15 | Ericsson Telefon Ab L M | Verfahren und Vorrichtung zur Bestimmung eines Synchronisationsfehlers in einem Netzwerkknoten |
US6399857B1 (en) * | 1999-09-22 | 2002-06-04 | Paradigm Genetics, Inc. | Modified nucleotide sequence encoding a LexA DNA binding domain optimized for arabidopsis species |
US6380129B1 (en) | 1999-11-02 | 2002-04-30 | Richard J. Kraemer | Enhanced materials for treatment of contamination |
US20030232054A1 (en) * | 2000-01-25 | 2003-12-18 | Tang Y. Tom | Novel nucleic acids and polypeptides |
US20020131954A1 (en) | 2000-05-02 | 2002-09-19 | Tobinick Edward L. | Interleukin antagonists for the treatment of neurological, retinal and muscular disorders |
AU2007202323C1 (en) | 2000-06-29 | 2012-04-12 | Abbvie Inc. | Dual specificity antibodies and methods of making and using |
CA2426384A1 (en) | 2000-10-19 | 2003-04-17 | Kyowa Hakko Kogyo Co., Ltd. | Antibody inhibiting vplf activity |
US20030026806A1 (en) * | 2000-10-27 | 2003-02-06 | Amgen Inc. | Antibodies and other selective IL-1 binding agents that allow binding to IL-1 receptor but not activation thereof |
US7595378B2 (en) * | 2001-06-13 | 2009-09-29 | Genmab A/S | Human monoclonal antibodies to epidermal growth factor receptor (EGFR) |
US7151164B2 (en) * | 2002-02-14 | 2006-12-19 | Immunomedics, Inc. | Anti-CD20 antibodies and fusion proteins thereof and methods of use |
AR036833A1 (es) * | 2001-10-18 | 2004-10-06 | Bayer Corp | Anticuerpos humanos que se unen a mn y tienen actividad neutralizante de la adhesion celular. |
US7211602B2 (en) | 2001-11-16 | 2007-05-01 | Als Therapy Development Foundation, Inc. | Treatment of neurodegenerative disorders through the modulation of the polyamine pathway |
JP4450644B2 (ja) | 2003-03-03 | 2010-04-14 | 日本化薬株式会社 | Amf類を有効成分とする医薬製剤 |
US20040224893A1 (en) | 2003-05-06 | 2004-11-11 | Li-Hsien Wang | Methods of using IL-1 antagonists to treat neointimal hyperplasia |
US20070025961A1 (en) * | 2003-06-03 | 2007-02-01 | Kenzo Bamba | Composition for stabilizing survival of transplanted hematopoietic stem cell, kit for obtaining the composition, method of stabilizing survival of transplanted hematopoietic stem cell, human monoclonal antibody or human polyclonal antibody and method of producing the same, gene encoding human monoclonal antibody and transf |
KR100493102B1 (ko) | 2003-06-30 | 2005-06-02 | 삼성전자주식회사 | 서브 하우징 스토퍼를 구비하는 휴대용 단말기의 힌지 장치 |
HN2004000285A (es) * | 2003-08-04 | 2006-04-27 | Pfizer Prod Inc | ANTICUERPOS DIRIGIDOS A c-MET |
US7799327B2 (en) * | 2003-12-24 | 2010-09-21 | Henry John Smith | Autoantibodies utilized as carrier agents for pharmaceutical compounds used in cancer treatment |
US7105183B2 (en) * | 2004-02-03 | 2006-09-12 | The Regents Of The University Of California | Chlorite in the treatment of neurodegenerative disease |
JP5149001B2 (ja) | 2004-05-25 | 2013-02-20 | スローン−ケッタリング・インスティテュート・フォー・キャンサー・リサーチ | 癌の処置におけるマイグラスタチンアナログ |
US20050276807A1 (en) | 2004-06-15 | 2005-12-15 | Advanced Biotherapy, Inc. | Treatment of acne |
WO2006036936A2 (en) | 2004-09-27 | 2006-04-06 | Bridge Pharma, Inc. | The s-isomer of 2-{2-[n-(2-indanyl)-n-phenylamino]ethyl}piperidine and other dermal anesthetic agents |
WO2006062779A2 (en) | 2004-12-09 | 2006-06-15 | Centocor, Inc. | Anti-integrin immunoconjugates, methods and uses |
ATE470151T1 (de) | 2005-08-02 | 2010-06-15 | Xbiotech Inc | Diagnose, behandlung und prävention von gefässerkrankungen mittels il-1alpha- autoantikörpern |
US20090215992A1 (en) | 2005-08-19 | 2009-08-27 | Chengbin Wu | Dual variable domain immunoglobulin and uses thereof |
US7612181B2 (en) * | 2005-08-19 | 2009-11-03 | Abbott Laboratories | Dual variable domain immunoglobulin and uses thereof |
CA2623287A1 (en) | 2005-09-28 | 2007-04-12 | Cytos Biotechnology Ag | Interleukin-1 conjugates and uses thereof |
EP1987066B1 (en) * | 2006-02-22 | 2010-12-29 | University of Zürich | Methods for treating demyelinating diseases |
JP2009533456A (ja) | 2006-04-14 | 2009-09-17 | ノバルティス アクチエンゲゼルシャフト | 眼疾患処置のためのil−1抗体の使用 |
GEP20125628B (en) * | 2006-04-21 | 2012-09-10 | Novartis Ag | Pharmaceutical compositions containing antagonist anti-cd40 antibody |
US20090191149A1 (en) | 2006-05-15 | 2009-07-30 | Xbiotech Inc. | IL-1alpha IMMUNIZATION INDUCES AUTOANTIBODIES PROTECTIVE AGAINST ATHEROSCLEROSIS |
JP2009537628A (ja) * | 2006-05-22 | 2009-10-29 | エクスバイオテク インコーポレーティッド | 抗IL−1α抗体による癌の処置方法 |
EP2447282B1 (en) * | 2006-05-30 | 2016-01-27 | Genentech, Inc. | Anti-CD22 Antibodies, their Immunoconjugates and uses thereof |
ME02371B (me) * | 2006-09-29 | 2016-06-20 | Oncomed Pharm Inc | Sastojci i postupci za dijagnstikovanje i tretman raka |
US8324350B2 (en) | 2006-12-29 | 2012-12-04 | Abbott Laboratories | Dual-specific IL-1α/IL-1β antibodies |
US20090258070A1 (en) | 2008-04-15 | 2009-10-15 | John Burnier | Topical LFA-1 antagonists for use in localized treatment of immune related disorders |
RU2498998C2 (ru) * | 2008-05-30 | 2013-11-20 | ИксБиотеч, Инк. | АНТИТЕЛА К ИНТЕРЛЕЙКИНУ-1α И СПОСОБЫ ПРИМЕНЕНИЯ |
US8242074B2 (en) * | 2008-09-12 | 2012-08-14 | Xbiotech, Inc. | Modulation of the amount or function of pathogenic CD14+CD16+ monocytes |
EP2391652A4 (en) | 2009-01-29 | 2013-01-02 | Abbott Lab | IL-1 BINDING PROTEINS |
UY32949A (es) | 2009-10-15 | 2011-02-28 | Abbott Lab | Proteínas de unión a il-1 |
US9724409B2 (en) | 2011-04-01 | 2017-08-08 | Xbiotech, Inc. | Treatment of inflammatory skin disease |
-
2009
- 2009-06-01 RU RU2010148904/10A patent/RU2498998C2/ru active
- 2009-06-01 EP EP16164746.6A patent/EP3085773B1/en active Active
- 2009-06-01 ES ES09758739.8T patent/ES2576681T3/es active Active
- 2009-06-01 PL PL16164746T patent/PL3085773T3/pl unknown
- 2009-06-01 MY MYPI2010005659A patent/MY154067A/en unknown
- 2009-06-01 JP JP2011511656A patent/JP5670318B2/ja active Active
- 2009-06-01 EP EP20156323.6A patent/EP3705135A1/en active Pending
- 2009-06-01 PT PT97587398T patent/PT2285409T/pt unknown
- 2009-06-01 CN CN201610022556.XA patent/CN105467136B/zh active Active
- 2009-06-01 KR KR1020157031363A patent/KR20150127300A/ko not_active Application Discontinuation
- 2009-06-01 ES ES16164746T patent/ES2797126T3/es active Active
- 2009-06-01 WO PCT/US2009/003355 patent/WO2009148575A1/en active Application Filing
- 2009-06-01 AU AU2009255670A patent/AU2009255670B2/en active Active
- 2009-06-01 KR KR1020107029639A patent/KR101567117B1/ko active IP Right Grant
- 2009-06-01 CN CN2009801250336A patent/CN102112154B/zh active Active
- 2009-06-01 US US12/455,458 patent/US8034337B2/en active Active
- 2009-06-01 SI SI200931460A patent/SI2285409T1/sl unknown
- 2009-06-01 CN CN201310556893.3A patent/CN103656638B/zh active Active
- 2009-06-01 MX MX2010012963A patent/MX2010012963A/es active IP Right Grant
- 2009-06-01 PL PL09758739.8T patent/PL2285409T3/pl unknown
- 2009-06-01 NZ NZ590033A patent/NZ590033A/en unknown
- 2009-06-01 CA CA2726345A patent/CA2726345C/en active Active
- 2009-06-01 CN CN201810142794.3A patent/CN108578692B/zh active Active
- 2009-06-01 DK DK09758739.8T patent/DK2285409T3/en active
- 2009-06-01 HU HUE09758739A patent/HUE029003T2/en unknown
- 2009-06-01 CA CA3011485A patent/CA3011485A1/en not_active Abandoned
- 2009-06-01 EP EP09758739.8A patent/EP2285409B1/en active Active
- 2009-06-01 BR BRPI0909610-8A patent/BRPI0909610B1/pt active IP Right Grant
- 2009-06-01 KR KR1020167037032A patent/KR20170005166A/ko not_active Application Discontinuation
-
2010
- 2010-11-25 IL IL209576A patent/IL209576A/en active IP Right Grant
- 2010-12-22 ZA ZA2010/09224A patent/ZA201009224B/en unknown
- 2010-12-23 CO CO10161740A patent/CO6351749A2/es not_active Application Discontinuation
-
2011
- 2011-09-02 US US13/224,943 patent/US8388956B2/en active Active
- 2011-09-02 US US13/225,004 patent/US20120164665A1/en not_active Abandoned
- 2011-09-02 US US13/224,975 patent/US20120021512A1/en not_active Abandoned
- 2011-09-02 US US13/225,029 patent/US8962814B2/en active Active
- 2011-09-02 US US13/224,913 patent/US8388969B2/en active Active
- 2011-12-27 HK HK11113940.1A patent/HK1159481A1/xx unknown
- 2011-12-27 HK HK14105137.7A patent/HK1191865A1/zh unknown
-
2013
- 2013-02-08 US US13/762,453 patent/US8679489B2/en active Active
- 2013-02-14 US US13/767,292 patent/US8784817B2/en active Active
- 2013-02-17 IL IL224752A patent/IL224752A/en active IP Right Grant
- 2013-08-19 RU RU2013138469A patent/RU2666915C2/ru active
-
2014
- 2014-02-11 US US14/177,892 patent/US8956831B2/en active Active
- 2014-08-06 PH PH12014501773A patent/PH12014501773A1/en unknown
- 2014-10-02 IL IL234954A patent/IL234954B/en active IP Right Grant
- 2014-12-11 US US14/567,072 patent/US9181338B2/en active Active
- 2014-12-17 JP JP2014254716A patent/JP6133264B2/ja active Active
-
2015
- 2015-10-08 US US14/877,964 patent/US9840558B2/en active Active
-
2017
- 2017-04-19 JP JP2017082461A patent/JP2017165743A/ja active Pending
- 2017-10-20 US US15/789,774 patent/US10899833B2/en active Active
-
2019
- 2019-04-10 JP JP2019074562A patent/JP2019135250A/ja active Pending
- 2019-08-19 IL IL268776A patent/IL268776B/en active IP Right Grant
-
2020
- 2020-05-22 JP JP2020089866A patent/JP6913209B2/ja active Active
- 2020-07-06 IL IL275881A patent/IL275881B/en unknown
-
2021
- 2021-01-21 US US17/154,137 patent/US20210171623A1/en not_active Abandoned
-
2023
- 2023-10-09 US US18/483,270 patent/US20240034781A1/en active Pending
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
KR101567117B1 (ko) | 인터류킨-1 알파 항체 및 그의 사용 방법 | |
AU2019246763B2 (en) | Human anti-PD-1, PD-L1, and PD-L2 antibodies and uses therefor | |
CN110862454B (zh) | 一种抗Claudin18_2抗体及其应用 | |
KR102037541B1 (ko) | 폴리펩티드 구축물 및 이의 용도 | |
AU2016202672B2 (en) | Antibody polypeptides that antagonize cd40 | |
RU2753902C2 (ru) | Комбинированная терапия на основе активирующих т-клетки биспецифических антигенсвязывающих молекул против cd3 и фолатного рецептора 1 (folr1) и антагонистов, связывающихся с осью pd-1 | |
ES2854708T3 (es) | Anticuerpos dirigidos contra la cadena alfa del receptor de IL7: su uso para la preparación de fármacos candidatos | |
KR20180053738A (ko) | 인간 cd40과 특이적으로 결합하는 길항적 항체 및 사용 방법 | |
CN108530535B (zh) | 结合肽聚糖识别蛋白1的抗体 | |
KR20170040249A (ko) | 항-cdh6 항체 약물 접합체 | |
KR20160021849A (ko) | 렉틴-유사 산화된 ldl 수용체1 항체 및 사용 방법 | |
CN111763261B (zh) | 一种融合蛋白及其用途 | |
KR20240017912A (ko) | 항-ccr8 항체 및 이의 용도 | |
KR102019033B1 (ko) | Cd40에 특이적으로 결합하는 항체 및 그의 용도 | |
AU2013204861B2 (en) | Human anti-PD-1, PD-L1, and PD-L2 antibodies and uses therefor | |
WO2022150740A1 (en) | Cross-reactive antibodies recognizing the coronavirus spike s2 domain | |
KR102323342B1 (ko) | IL-17A 및 TNF-α에 특이적으로 결합하는 이중표적 항체 | |
CN112961239B (zh) | Tim抑制剂及其应用 | |
CN112979809B (zh) | 一种与抗原tim-3结合的靶向分子 | |
KR20230112128A (ko) | 항-cd48 항체, 항체 약물 접합체 및 이의 용도 | |
AU2022288660A1 (en) | Anti-masp-2 antibody and use thereof | |
CN115521378A (zh) | Pd-l1抗体及其用途 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A107 | Divisional application of patent | ||
A201 | Request for examination | ||
E902 | Notification of reason for refusal | ||
E601 | Decision to refuse application |