KR20200020902A - 간세포암(hepatocellular carcinoma: HCC)에 대한 면역 치료 - Google Patents
간세포암(hepatocellular carcinoma: HCC)에 대한 면역 치료 Download PDFInfo
- Publication number
- KR20200020902A KR20200020902A KR1020207002309A KR20207002309A KR20200020902A KR 20200020902 A KR20200020902 A KR 20200020902A KR 1020207002309 A KR1020207002309 A KR 1020207002309A KR 20207002309 A KR20207002309 A KR 20207002309A KR 20200020902 A KR20200020902 A KR 20200020902A
- Authority
- KR
- South Korea
- Prior art keywords
- ser
- val
- thr
- pro
- gly
- Prior art date
Links
- 206010073071 hepatocellular carcinoma Diseases 0.000 title claims abstract description 131
- 231100000844 hepatocellular carcinoma Toxicity 0.000 title claims abstract description 126
- 238000011282 treatment Methods 0.000 title claims description 46
- 238000000034 method Methods 0.000 claims abstract description 43
- 230000027455 binding Effects 0.000 claims abstract description 32
- 239000000427 antigen Substances 0.000 claims abstract description 14
- 102000036639 antigens Human genes 0.000 claims abstract description 14
- 108091007433 antigens Proteins 0.000 claims abstract description 14
- 239000012634 fragment Substances 0.000 claims abstract description 13
- 241000700721 Hepatitis B virus Species 0.000 claims description 20
- 239000012636 effector Substances 0.000 claims description 13
- 238000009169 immunotherapy Methods 0.000 claims description 10
- 208000015181 infectious disease Diseases 0.000 claims description 9
- 230000001394 metastastic effect Effects 0.000 claims description 8
- 206010061289 metastatic neoplasm Diseases 0.000 claims description 8
- 102000008096 B7-H1 Antigen Human genes 0.000 claims description 7
- 108010074708 B7-H1 Antigen Proteins 0.000 claims description 7
- 108010047041 Complementarity Determining Regions Proteins 0.000 claims description 6
- 210000002540 macrophage Anatomy 0.000 claims description 6
- 102100040678 Programmed cell death protein 1 Human genes 0.000 claims description 5
- 230000001419 dependent effect Effects 0.000 claims description 5
- 102220315568 rs1039799564 Human genes 0.000 claims description 5
- 206010057249 Phagocytosis Diseases 0.000 claims description 4
- 101710089372 Programmed cell death protein 1 Proteins 0.000 claims description 4
- 230000008782 phagocytosis Effects 0.000 claims description 4
- 230000009385 viral infection Effects 0.000 claims description 4
- 238000007911 parenteral administration Methods 0.000 claims 1
- 101000611936 Homo sapiens Programmed cell death protein 1 Proteins 0.000 abstract description 4
- 102000048362 human PDCD1 Human genes 0.000 abstract description 3
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 90
- 108010031719 prolyl-serine Proteins 0.000 description 68
- 108010077112 prolyl-proline Proteins 0.000 description 53
- 108010087924 alanylproline Proteins 0.000 description 49
- 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 46
- 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 46
- 108010010147 glycylglutamine Proteins 0.000 description 46
- 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 44
- 241000880493 Leptailurus serval Species 0.000 description 43
- 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 38
- 108010073969 valyllysine Proteins 0.000 description 38
- 108010051242 phenylalanylserine Proteins 0.000 description 35
- 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 34
- 108010050848 glycylleucine Proteins 0.000 description 32
- 206010028980 Neoplasm Diseases 0.000 description 31
- 108010076324 alanyl-glycyl-glycine Proteins 0.000 description 30
- 108010049041 glutamylalanine Proteins 0.000 description 30
- JXFLPKSDLDEOQK-JHEQGTHGSA-N Gln-Gly-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CCC(N)=O JXFLPKSDLDEOQK-JHEQGTHGSA-N 0.000 description 29
- 241000699660 Mus musculus Species 0.000 description 29
- 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 26
- 108010008355 arginyl-glutamine Proteins 0.000 description 26
- 108010092854 aspartyllysine Proteins 0.000 description 26
- 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 25
- 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 25
- 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 25
- 201000010099 disease Diseases 0.000 description 25
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 25
- 108010034529 leucyl-lysine Proteins 0.000 description 25
- 230000035772 mutation Effects 0.000 description 25
- 108010070643 prolylglutamic acid Proteins 0.000 description 25
- 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 24
- 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 24
- 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 24
- KCJJFESQRXGTGC-BQBZGAKWSA-N Gln-Glu-Gly Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(O)=O KCJJFESQRXGTGC-BQBZGAKWSA-N 0.000 description 24
- XHVONGZZVUUORG-WEDXCCLWSA-N Gly-Thr-Lys Chemical compound NCC(=O)N[C@@H]([C@H](O)C)C(=O)N[C@H](C(O)=O)CCCCN XHVONGZZVUUORG-WEDXCCLWSA-N 0.000 description 24
- 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 24
- 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 24
- 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 24
- 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 24
- 108010047857 aspartylglycine Proteins 0.000 description 24
- 108010050475 glycyl-leucyl-tyrosine Proteins 0.000 description 24
- 108010073472 leucyl-prolyl-proline Proteins 0.000 description 24
- 230000004044 response Effects 0.000 description 24
- 108010044292 tryptophyltyrosine Proteins 0.000 description 24
- 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 23
- WQKAQKZRDIZYNV-VZFHVOOUSA-N Ala-Ser-Thr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(O)=O WQKAQKZRDIZYNV-VZFHVOOUSA-N 0.000 description 23
- ULBHWNVWSCJLCO-NHCYSSNCSA-N Arg-Val-Glu Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CCCN=C(N)N ULBHWNVWSCJLCO-NHCYSSNCSA-N 0.000 description 23
- 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 23
- 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 23
- NYGILGUOUOXGMJ-YUMQZZPRSA-N Asn-Lys-Gly Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)NCC(O)=O NYGILGUOUOXGMJ-YUMQZZPRSA-N 0.000 description 23
- JZLFYAAGGYMRIK-BYULHYEWSA-N Asn-Val-Asp Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O JZLFYAAGGYMRIK-BYULHYEWSA-N 0.000 description 23
- 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 23
- 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 23
- 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 23
- 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 23
- 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 23
- CGVWDTRDPLOMHZ-FXQIFTODSA-N Gln-Glu-Asp Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O CGVWDTRDPLOMHZ-FXQIFTODSA-N 0.000 description 23
- AQPZYBSRDRZBAG-AVGNSLFASA-N Gln-Phe-Asn Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CCC(=O)N)N AQPZYBSRDRZBAG-AVGNSLFASA-N 0.000 description 23
- 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 23
- 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 23
- JWNZHMSRZXXGTM-XKBZYTNZSA-N Glu-Ser-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(O)=O JWNZHMSRZXXGTM-XKBZYTNZSA-N 0.000 description 23
- 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 23
- 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 23
- 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 23
- OOCFXNOVSLSHAB-IUCAKERBSA-N Gly-Pro-Pro Chemical compound NCC(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 OOCFXNOVSLSHAB-IUCAKERBSA-N 0.000 description 23
- 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 23
- 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 23
- 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 23
- 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 23
- 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 23
- 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 23
- 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 23
- 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 23
- 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 23
- 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 23
- 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 23
- 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 23
- 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 23
- 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 23
- 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 23
- 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 23
- 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 23
- 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 23
- 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 23
- HQVPQXMCQKXARZ-FXQIFTODSA-N Pro-Cys-Ser Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CS)C(=O)N[C@@H](CO)C(=O)O HQVPQXMCQKXARZ-FXQIFTODSA-N 0.000 description 23
- 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 23
- 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 23
- 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 23
- 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 23
- 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 23
- 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 23
- XNCUYZKGQOCOQH-YUMQZZPRSA-N Ser-Leu-Gly Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O XNCUYZKGQOCOQH-YUMQZZPRSA-N 0.000 description 23
- QJKPECIAWNNKIT-KKUMJFAQSA-N Ser-Lys-Tyr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O QJKPECIAWNNKIT-KKUMJFAQSA-N 0.000 description 23
- 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 23
- SNXUIBACCONSOH-BWBBJGPYSA-N Ser-Thr-Ser Chemical compound OC[C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@@H](CO)C(O)=O SNXUIBACCONSOH-BWBBJGPYSA-N 0.000 description 23
- 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 23
- 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 23
- 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 23
- 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 23
- 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 23
- 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 23
- 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 23
- QFHRUCJIRVILCK-YJRXYDGGSA-N Tyr-Thr-Cys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)N)O QFHRUCJIRVILCK-YJRXYDGGSA-N 0.000 description 23
- 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 23
- 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 23
- 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 23
- KOSRFJWDECSPRO-UHFFFAOYSA-N alpha-L-glutamyl-L-glutamic acid Natural products OC(=O)CCC(N)C(=O)NC(CCC(O)=O)C(O)=O KOSRFJWDECSPRO-UHFFFAOYSA-N 0.000 description 23
- 108010052670 arginyl-glutamyl-glutamic acid Proteins 0.000 description 23
- 108010013768 glutamyl-aspartyl-proline Proteins 0.000 description 23
- 108010055341 glutamyl-glutamic acid Proteins 0.000 description 23
- 108010000434 glycyl-alanyl-leucine Proteins 0.000 description 23
- 108010091871 leucylmethionine Proteins 0.000 description 23
- 108010064235 lysylglycine Proteins 0.000 description 23
- 108010024654 phenylalanyl-prolyl-alanine Proteins 0.000 description 23
- 108010073101 phenylalanylleucine Proteins 0.000 description 23
- 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 22
- 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 22
- 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 22
- 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 22
- 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 22
- 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 22
- 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 22
- 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 22
- 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 22
- 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 22
- 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 22
- 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 22
- 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 22
- 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 22
- 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 22
- 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 22
- 108010071097 threonyl-lysyl-proline Proteins 0.000 description 22
- 108010051110 tyrosyl-lysine Proteins 0.000 description 22
- 108010052774 valyl-lysyl-glycyl-phenylalanyl-tyrosine Proteins 0.000 description 22
- RFDHKPSHTXZKLL-IHRRRGAJSA-N Glu-Gln-Phe Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CCC(=O)O)N RFDHKPSHTXZKLL-IHRRRGAJSA-N 0.000 description 21
- 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 21
- ZDILXFDENZVOTL-BPNCWPANSA-N Ala-Val-Tyr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O ZDILXFDENZVOTL-BPNCWPANSA-N 0.000 description 20
- WLRYGVYQFXRJDA-DCAQKATOSA-N Gln-Pro-Pro Chemical compound NC(=O)CC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 WLRYGVYQFXRJDA-DCAQKATOSA-N 0.000 description 20
- FEHQLKKBVJHSEC-SZMVWBNQSA-N Leu-Glu-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CC(C)C)C(O)=O)=CNC2=C1 FEHQLKKBVJHSEC-SZMVWBNQSA-N 0.000 description 19
- KDGARKCAKHBEDB-NKWVEPMBSA-N Ser-Gly-Pro Chemical compound C1C[C@@H](N(C1)C(=O)CNC(=O)[C@H](CO)N)C(=O)O KDGARKCAKHBEDB-NKWVEPMBSA-N 0.000 description 19
- KZTLZZQTJMCGIP-ZJDVBMNYSA-N Thr-Val-Thr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O KZTLZZQTJMCGIP-ZJDVBMNYSA-N 0.000 description 19
- TYYLDKGBCJGJGW-UHFFFAOYSA-N L-tryptophan-L-tyrosine Natural products C=1NC2=CC=CC=C2C=1CC(N)C(=O)NC(C(O)=O)CC1=CC=C(O)C=C1 TYYLDKGBCJGJGW-UHFFFAOYSA-N 0.000 description 18
- 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 18
- PGNNQOJOEGFAOR-KWQFWETISA-N Ala-Tyr-Gly Chemical compound OC(=O)CNC(=O)[C@@H](NC(=O)[C@@H](N)C)CC1=CC=C(O)C=C1 PGNNQOJOEGFAOR-KWQFWETISA-N 0.000 description 17
- 241000282414 Homo sapiens Species 0.000 description 17
- 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 17
- 101100519207 Mus musculus Pdcd1 gene Proteins 0.000 description 17
- KIJLSRYAUGGZIN-CFMVVWHZSA-N Tyr-Ile-Asp Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(O)=O)C(O)=O KIJLSRYAUGGZIN-CFMVVWHZSA-N 0.000 description 17
- JEOCWTUOMKEEMF-RHYQMDGZSA-N Arg-Leu-Thr Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O JEOCWTUOMKEEMF-RHYQMDGZSA-N 0.000 description 16
- CGYKCTPUGXFPMG-IHPCNDPISA-N Asn-Tyr-Trp Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O CGYKCTPUGXFPMG-IHPCNDPISA-N 0.000 description 16
- PDUHNKAFQXQNLH-ZETCQYMHSA-N Gly-Lys-Gly Chemical compound NCCCC[C@H](NC(=O)CN)C(=O)NCC(O)=O PDUHNKAFQXQNLH-ZETCQYMHSA-N 0.000 description 16
- ILDSIMPXNFWKLH-KATARQTJSA-N Leu-Thr-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(O)=O ILDSIMPXNFWKLH-KATARQTJSA-N 0.000 description 16
- MNYNCKZAEIAONY-XGEHTFHBSA-N Thr-Val-Ser Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(O)=O MNYNCKZAEIAONY-XGEHTFHBSA-N 0.000 description 16
- ACRYGQFHAQHDSF-ZLUOBGJFSA-N Asn-Asn-Asn Chemical compound NC(=O)C[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O ACRYGQFHAQHDSF-ZLUOBGJFSA-N 0.000 description 15
- RTFXPCYMDYBZNQ-SRVKXCTJSA-N Asn-Tyr-Asn Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(N)=O)C(O)=O RTFXPCYMDYBZNQ-SRVKXCTJSA-N 0.000 description 15
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 15
- GGAPHLIUUTVYMX-QWRGUYRKSA-N Gly-Phe-Ser Chemical compound OC[C@@H](C([O-])=O)NC(=O)[C@@H](NC(=O)C[NH3+])CC1=CC=CC=C1 GGAPHLIUUTVYMX-QWRGUYRKSA-N 0.000 description 15
- LCRDMSSAKLTKBU-ZDLURKLDSA-N Gly-Ser-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)CN LCRDMSSAKLTKBU-ZDLURKLDSA-N 0.000 description 15
- ZVXMEWXHFBYJPI-LSJOCFKGSA-N Gly-Val-Ile Chemical compound [H]NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O ZVXMEWXHFBYJPI-LSJOCFKGSA-N 0.000 description 15
- 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 15
- GQHAIUPYZPTADF-FDARSICLSA-N Trp-Ile-Arg Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O)=CNC2=C1 GQHAIUPYZPTADF-FDARSICLSA-N 0.000 description 15
- PZTZYZUTCPZWJH-FXQIFTODSA-N Val-Ser-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)O)N PZTZYZUTCPZWJH-FXQIFTODSA-N 0.000 description 15
- QHSSPPHOHJSTML-HOCLYGCPSA-N Val-Trp-Gly Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)NCC(=O)O)N QHSSPPHOHJSTML-HOCLYGCPSA-N 0.000 description 15
- 108010077245 asparaginyl-proline Proteins 0.000 description 15
- 108010087846 prolyl-prolyl-glycine Proteins 0.000 description 15
- BTYTYHBSJKQBQA-GCJQMDKQSA-N Ala-Asp-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](C)N)O BTYTYHBSJKQBQA-GCJQMDKQSA-N 0.000 description 14
- MIIVFRCYJABHTQ-ONGXEEELSA-N Gly-Leu-Val Chemical compound [H]NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(O)=O MIIVFRCYJABHTQ-ONGXEEELSA-N 0.000 description 14
- GBYYQVBXFVDJPJ-WLTAIBSBSA-N Gly-Tyr-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)NC(=O)CN)O GBYYQVBXFVDJPJ-WLTAIBSBSA-N 0.000 description 14
- 241000711549 Hepacivirus C Species 0.000 description 14
- LINKCQUOMUDLKN-KATARQTJSA-N Leu-Thr-Cys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC(C)C)N)O LINKCQUOMUDLKN-KATARQTJSA-N 0.000 description 14
- LNICFEXCAHIJOR-DCAQKATOSA-N Pro-Ser-Leu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O LNICFEXCAHIJOR-DCAQKATOSA-N 0.000 description 14
- 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 14
- SMLCYZYQFRTLCO-UWJYBYFXSA-N Tyr-Cys-Ala Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CS)C(=O)N[C@@H](C)C(O)=O SMLCYZYQFRTLCO-UWJYBYFXSA-N 0.000 description 14
- 108010069205 aspartyl-phenylalanine Proteins 0.000 description 14
- 108010072986 threonyl-seryl-lysine Proteins 0.000 description 14
- SSSROGPPPVTHLX-FXQIFTODSA-N Ala-Arg-Asp Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(O)=O SSSROGPPPVTHLX-FXQIFTODSA-N 0.000 description 13
- KYQNAIMCTRZLNP-QSFUFRPTSA-N Asp-Ile-Val Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C(C)C)C(O)=O KYQNAIMCTRZLNP-QSFUFRPTSA-N 0.000 description 13
- 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 13
- ZTLGVASZOIKNIX-DCAQKATOSA-N Leu-Gln-Glu Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N ZTLGVASZOIKNIX-DCAQKATOSA-N 0.000 description 13
- UWKNTTJNVSYXPC-CIUDSAMLSA-N Lys-Ala-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCCN UWKNTTJNVSYXPC-CIUDSAMLSA-N 0.000 description 13
- WRODMZBHNNPRLN-SRVKXCTJSA-N Lys-Leu-Ser Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O WRODMZBHNNPRLN-SRVKXCTJSA-N 0.000 description 13
- YTJFXEDRUOQGSP-DCAQKATOSA-N Lys-Pro-Ser Chemical compound [H]N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O YTJFXEDRUOQGSP-DCAQKATOSA-N 0.000 description 13
- JHSRGEODDALISP-XVSYOHENSA-N Phe-Thr-Asn Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(O)=O JHSRGEODDALISP-XVSYOHENSA-N 0.000 description 13
- 108010079005 RDV peptide Proteins 0.000 description 13
- HBOABDXGTMMDSE-GUBZILKMSA-N Ser-Arg-Val Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(O)=O HBOABDXGTMMDSE-GUBZILKMSA-N 0.000 description 13
- BIBYEFRASCNLAA-CDMKHQONSA-N Thr-Phe-Gly Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@H](C(=O)NCC(O)=O)CC1=CC=CC=C1 BIBYEFRASCNLAA-CDMKHQONSA-N 0.000 description 13
- OJOMXGVLFKYDKP-QXEWZRGKSA-N Val-Met-Asp Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(=O)O)C(=O)O)N OJOMXGVLFKYDKP-QXEWZRGKSA-N 0.000 description 13
- 108010068265 aspartyltyrosine Proteins 0.000 description 13
- AOHKLEBWKMKITA-IHRRRGAJSA-N Arg-Phe-Ser Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CCCN=C(N)N)N AOHKLEBWKMKITA-IHRRRGAJSA-N 0.000 description 12
- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 description 12
- 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 12
- 239000005511 L01XE05 - Sorafenib Substances 0.000 description 12
- AIRZWUMAHCDDHR-KKUMJFAQSA-N Lys-Leu-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O AIRZWUMAHCDDHR-KKUMJFAQSA-N 0.000 description 12
- FUMGHWDRRFCKEP-CIUDSAMLSA-N Ser-Leu-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(O)=O FUMGHWDRRFCKEP-CIUDSAMLSA-N 0.000 description 12
- 108010086434 alanyl-seryl-glycine Proteins 0.000 description 12
- 230000000694 effects Effects 0.000 description 12
- 108010063718 gamma-glutamylaspartic acid Proteins 0.000 description 12
- 229960003787 sorafenib Drugs 0.000 description 12
- 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 11
- 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 11
- IVGJYOOGJLFKQE-AVGNSLFASA-N Glu-Leu-Lys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCC(=O)O)N IVGJYOOGJLFKQE-AVGNSLFASA-N 0.000 description 11
- ICUTTWWCDIIIEE-BQBZGAKWSA-N Gly-Met-Asn Chemical compound CSCC[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)CN ICUTTWWCDIIIEE-BQBZGAKWSA-N 0.000 description 11
- WTUSRDZLLWGYAT-KCTSRDHCSA-N Gly-Trp-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)NC(=O)CN WTUSRDZLLWGYAT-KCTSRDHCSA-N 0.000 description 11
- RSFGIMMPWAXNML-MNXVOIDGSA-N Leu-Gln-Ile Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O RSFGIMMPWAXNML-MNXVOIDGSA-N 0.000 description 11
- MVJRBCJCRYGCKV-GVXVVHGQSA-N Leu-Val-Gln Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O MVJRBCJCRYGCKV-GVXVVHGQSA-N 0.000 description 11
- 108010079364 N-glycylalanine Proteins 0.000 description 11
- VVAWNPIOYXAMAL-KJEVXHAQSA-N Pro-Thr-Tyr Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O VVAWNPIOYXAMAL-KJEVXHAQSA-N 0.000 description 11
- XZKQVQKUZMAADP-IMJSIDKUSA-N Ser-Ser Chemical compound OC[C@H](N)C(=O)N[C@@H](CO)C(O)=O XZKQVQKUZMAADP-IMJSIDKUSA-N 0.000 description 11
- XJDMUQCLVSCRSJ-VZFHVOOUSA-N Ser-Thr-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O XJDMUQCLVSCRSJ-VZFHVOOUSA-N 0.000 description 11
- LGIMRDKGABDMBN-DCAQKATOSA-N Ser-Val-Lys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CO)N LGIMRDKGABDMBN-DCAQKATOSA-N 0.000 description 11
- FWTFAZKJORVTIR-VZFHVOOUSA-N Thr-Ser-Ala Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(O)=O FWTFAZKJORVTIR-VZFHVOOUSA-N 0.000 description 11
- CXUFDWZBHKUGKK-CABZTGNLSA-N Trp-Ala-Gly Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H](C)C(=O)NCC(O)=O)=CNC2=C1 CXUFDWZBHKUGKK-CABZTGNLSA-N 0.000 description 11
- NUQZCPSZHGIYTA-HKUYNNGSSA-N Tyr-Trp-Gly Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)NCC(=O)O)NC(=O)[C@H](CC3=CC=C(C=C3)O)N NUQZCPSZHGIYTA-HKUYNNGSSA-N 0.000 description 11
- 108010069020 alanyl-prolyl-glycine Proteins 0.000 description 11
- VPZXBVLAVMBEQI-UHFFFAOYSA-N glycyl-DL-alpha-alanine Natural products OC(=O)C(C)NC(=O)CN VPZXBVLAVMBEQI-UHFFFAOYSA-N 0.000 description 11
- XKUKSGPZAADMRA-UHFFFAOYSA-N glycyl-glycyl-glycine Natural products NCC(=O)NCC(=O)NCC(O)=O XKUKSGPZAADMRA-UHFFFAOYSA-N 0.000 description 11
- 108010070409 phenylalanyl-glycyl-glycine Proteins 0.000 description 11
- HQIZDMIGUJOSNI-IUCAKERBSA-N Arg-Gly-Arg Chemical compound N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(O)=O HQIZDMIGUJOSNI-IUCAKERBSA-N 0.000 description 10
- QVTDVTONTRSQMF-WDCWCFNPSA-N Lys-Thr-Glu Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H]([C@H](O)C)NC(=O)[C@@H](N)CCCCN QVTDVTONTRSQMF-WDCWCFNPSA-N 0.000 description 10
- VDTYRPWRWRCROL-UFYCRDLUSA-N Phe-Val-Phe Chemical compound C([C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 VDTYRPWRWRCROL-UFYCRDLUSA-N 0.000 description 10
- VQBCMLMPEWPUTB-ACZMJKKPSA-N Ser-Glu-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(O)=O VQBCMLMPEWPUTB-ACZMJKKPSA-N 0.000 description 10
- NLOAIFSWUUFQFR-CIUDSAMLSA-N Ser-Leu-Asp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O NLOAIFSWUUFQFR-CIUDSAMLSA-N 0.000 description 10
- HDBOEVPDIDDEPC-CIUDSAMLSA-N Ser-Lys-Asn Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(O)=O HDBOEVPDIDDEPC-CIUDSAMLSA-N 0.000 description 10
- 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 10
- JQTYTBPCSOAZHI-FXQIFTODSA-N Val-Ser-Cys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)O)N JQTYTBPCSOAZHI-FXQIFTODSA-N 0.000 description 10
- 238000001990 intravenous administration Methods 0.000 description 10
- 108010069117 seryl-lysyl-aspartic acid Proteins 0.000 description 10
- 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 9
- OPEPUCYIGFEGSW-WDSKDSINSA-N Asn-Gly-Glu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(O)=O OPEPUCYIGFEGSW-WDSKDSINSA-N 0.000 description 9
- RBWKVOSARCFSQQ-FXQIFTODSA-N Gln-Gln-Ser Chemical compound NC(=O)CC[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(O)=O RBWKVOSARCFSQQ-FXQIFTODSA-N 0.000 description 9
- UQJNXZSSGQIPIQ-FBCQKBJTSA-N Gly-Gly-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)CNC(=O)CN UQJNXZSSGQIPIQ-FBCQKBJTSA-N 0.000 description 9
- SOEGEPHNZOISMT-BYPYZUCNSA-N Gly-Ser-Gly Chemical compound NCC(=O)N[C@@H](CO)C(=O)NCC(O)=O SOEGEPHNZOISMT-BYPYZUCNSA-N 0.000 description 9
- DNAZKGFYFRGZIH-QWRGUYRKSA-N Gly-Tyr-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)CN)CC1=CC=C(O)C=C1 DNAZKGFYFRGZIH-QWRGUYRKSA-N 0.000 description 9
- QTVUPXHPSXZJKH-ULQDDVLXSA-N Phe-Met-His Chemical compound CSCC[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](CC2=CC=CC=C2)N QTVUPXHPSXZJKH-ULQDDVLXSA-N 0.000 description 9
- 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 9
- OWFGFHQMSBTKLX-UFYCRDLUSA-N Val-Tyr-Tyr Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CC2=CC=C(C=C2)O)C(=O)O)N OWFGFHQMSBTKLX-UFYCRDLUSA-N 0.000 description 9
- 125000003275 alpha amino acid group Chemical group 0.000 description 9
- 201000011510 cancer Diseases 0.000 description 9
- 208000006454 hepatitis Diseases 0.000 description 9
- 230000036961 partial effect Effects 0.000 description 9
- 238000002560 therapeutic procedure Methods 0.000 description 9
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 8
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 8
- LJBVRCDPWOJOEK-PPCPHDFISA-N Leu-Thr-Ile Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O LJBVRCDPWOJOEK-PPCPHDFISA-N 0.000 description 8
- KWUKZRFFKPLUPE-HJGDQZAQSA-N Lys-Asp-Thr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O KWUKZRFFKPLUPE-HJGDQZAQSA-N 0.000 description 8
- 102000004169 proteins and genes Human genes 0.000 description 8
- 108090000623 proteins and genes Proteins 0.000 description 8
- 230000009467 reduction Effects 0.000 description 8
- 238000006467 substitution reaction Methods 0.000 description 8
- 230000004083 survival effect Effects 0.000 description 8
- KLALXKYLOMZDQT-ZLUOBGJFSA-N Ala-Ser-Asn Chemical compound C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CC(N)=O KLALXKYLOMZDQT-ZLUOBGJFSA-N 0.000 description 7
- 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 7
- RGXXLQWXBFNXTG-CIUDSAMLSA-N Gln-Arg-Ala Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(O)=O RGXXLQWXBFNXTG-CIUDSAMLSA-N 0.000 description 7
- XZLLTYBONVKGLO-SDDRHHMPSA-N Gln-Lys-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(=O)N)N)C(=O)O XZLLTYBONVKGLO-SDDRHHMPSA-N 0.000 description 7
- UESYBOXFJWJVSB-AVGNSLFASA-N Gln-Phe-Ser Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(O)=O UESYBOXFJWJVSB-AVGNSLFASA-N 0.000 description 7
- FITIQFSXXBKFFM-NRPADANISA-N Gln-Val-Ser Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(O)=O FITIQFSXXBKFFM-NRPADANISA-N 0.000 description 7
- KXRORHJIRAOQPG-SOUVJXGZSA-N Glu-Tyr-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC2=CC=C(C=C2)O)NC(=O)[C@H](CCC(=O)O)N)C(=O)O KXRORHJIRAOQPG-SOUVJXGZSA-N 0.000 description 7
- PABFFPWEJMEVEC-JGVFFNPUSA-N Gly-Gln-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCC(=O)N)NC(=O)CN)C(=O)O PABFFPWEJMEVEC-JGVFFNPUSA-N 0.000 description 7
- YGHSQRJSHKYUJY-SCZZXKLOSA-N Gly-Val-Pro Chemical compound CC(C)[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)CN YGHSQRJSHKYUJY-SCZZXKLOSA-N 0.000 description 7
- HQLSBZFLOUHQJK-STECZYCISA-N Ile-Tyr-Arg Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N HQLSBZFLOUHQJK-STECZYCISA-N 0.000 description 7
- 108060003951 Immunoglobulin Proteins 0.000 description 7
- WQWSMEOYXJTFRU-GUBZILKMSA-N Leu-Glu-Ser Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(O)=O WQWSMEOYXJTFRU-GUBZILKMSA-N 0.000 description 7
- FIICHHJDINDXKG-IHPCNDPISA-N Leu-Lys-Trp Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O FIICHHJDINDXKG-IHPCNDPISA-N 0.000 description 7
- LCNASHSOFMRYFO-WDCWCFNPSA-N Leu-Thr-Gln Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@H](C(O)=O)CCC(N)=O LCNASHSOFMRYFO-WDCWCFNPSA-N 0.000 description 7
- SKRGVGLIRUGANF-AVGNSLFASA-N Lys-Leu-Glu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O SKRGVGLIRUGANF-AVGNSLFASA-N 0.000 description 7
- IMNVAOPEMFDAQD-NHCYSSNCSA-N Pro-Val-Glu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O IMNVAOPEMFDAQD-NHCYSSNCSA-N 0.000 description 7
- ADJDNJCSPNFFPI-FXQIFTODSA-N Ser-Pro-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CO ADJDNJCSPNFFPI-FXQIFTODSA-N 0.000 description 7
- 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 7
- PKZIWSHDJYIPRH-JBACZVJFSA-N Trp-Tyr-Gln Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCC(N)=O)C(O)=O PKZIWSHDJYIPRH-JBACZVJFSA-N 0.000 description 7
- 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 7
- 108010081404 acein-2 Proteins 0.000 description 7
- 238000013461 design Methods 0.000 description 7
- 239000003814 drug Substances 0.000 description 7
- 102000018358 immunoglobulin Human genes 0.000 description 7
- 230000001225 therapeutic effect Effects 0.000 description 7
- NKJBKNVQHBZUIX-ACZMJKKPSA-N Ala-Gln-Asp Chemical compound C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O NKJBKNVQHBZUIX-ACZMJKKPSA-N 0.000 description 6
- JPPLRQVZMZFOSX-UWJYBYFXSA-N Asn-Tyr-Ala Chemical compound NC(=O)C[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](C)C(O)=O)CC1=CC=C(O)C=C1 JPPLRQVZMZFOSX-UWJYBYFXSA-N 0.000 description 6
- USNJAPJZSGTTPX-XVSYOHENSA-N Asp-Phe-Thr Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O USNJAPJZSGTTPX-XVSYOHENSA-N 0.000 description 6
- 101100505161 Caenorhabditis elegans mel-32 gene Proteins 0.000 description 6
- 206010061818 Disease progression Diseases 0.000 description 6
- KZKBJEUWNMQTLV-XDTLVQLUSA-N Gln-Ala-Tyr Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O KZKBJEUWNMQTLV-XDTLVQLUSA-N 0.000 description 6
- QNJNPKSWAHPYGI-JYJNAYRXSA-N Glu-Phe-Leu Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(O)=O)CC1=CC=CC=C1 QNJNPKSWAHPYGI-JYJNAYRXSA-N 0.000 description 6
- NVTPVQLIZCOJFK-FOHZUACHSA-N Gly-Thr-Asp Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(O)=O NVTPVQLIZCOJFK-FOHZUACHSA-N 0.000 description 6
- QESXLSQLQHHTIX-RHYQMDGZSA-N Leu-Val-Thr Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O QESXLSQLQHHTIX-RHYQMDGZSA-N 0.000 description 6
- 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 6
- 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 6
- SPSSJSICDYYTQN-HJGDQZAQSA-N Met-Thr-Gln Chemical compound CSCC[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@H](C(O)=O)CCC(N)=O SPSSJSICDYYTQN-HJGDQZAQSA-N 0.000 description 6
- 241000699666 Mus <mouse, genus> Species 0.000 description 6
- SWCOXQLDICUYOL-ULQDDVLXSA-N Phe-His-Arg Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O SWCOXQLDICUYOL-ULQDDVLXSA-N 0.000 description 6
- BSKMOCNNLNDIMU-CDMKHQONSA-N Phe-Thr-Gly Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(O)=O BSKMOCNNLNDIMU-CDMKHQONSA-N 0.000 description 6
- UIGMAMGZOJVTDN-WHFBIAKZSA-N Ser-Gly-Ser Chemical compound OC[C@H](N)C(=O)NCC(=O)N[C@@H](CO)C(O)=O UIGMAMGZOJVTDN-WHFBIAKZSA-N 0.000 description 6
- OQPNSDWGAMFJNU-QWRGUYRKSA-N Ser-Gly-Tyr Chemical compound OC[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 OQPNSDWGAMFJNU-QWRGUYRKSA-N 0.000 description 6
- GJFYFGOEWLDQGW-GUBZILKMSA-N Ser-Leu-Gln Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CO)N GJFYFGOEWLDQGW-GUBZILKMSA-N 0.000 description 6
- PJIQEIFXZPCWOJ-FXQIFTODSA-N Ser-Pro-Asp Chemical compound [H]N[C@@H](CO)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(O)=O)C(O)=O PJIQEIFXZPCWOJ-FXQIFTODSA-N 0.000 description 6
- CUXJENOFJXOSOZ-BIIVOSGPSA-N Ser-Ser-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CO)NC(=O)[C@H](CO)N)C(=O)O CUXJENOFJXOSOZ-BIIVOSGPSA-N 0.000 description 6
- DFTCYYILCSQGIZ-GCJQMDKQSA-N Thr-Ala-Asn Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(N)=O)C(O)=O DFTCYYILCSQGIZ-GCJQMDKQSA-N 0.000 description 6
- QUILOGWWLXMSAT-IHRRRGAJSA-N Tyr-Gln-Gln Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O QUILOGWWLXMSAT-IHRRRGAJSA-N 0.000 description 6
- VJOWWOGRNXRQMF-UVBJJODRSA-N Val-Ala-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](C)NC(=O)[C@@H](N)C(C)C)C(O)=O)=CNC2=C1 VJOWWOGRNXRQMF-UVBJJODRSA-N 0.000 description 6
- ZXYPHBKIZLAQTL-QXEWZRGKSA-N Val-Pro-Asp Chemical compound CC(C)[C@@H](C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(=O)O)C(=O)O)N ZXYPHBKIZLAQTL-QXEWZRGKSA-N 0.000 description 6
- VHIZXDZMTDVFGX-DCAQKATOSA-N Val-Ser-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](C(C)C)N VHIZXDZMTDVFGX-DCAQKATOSA-N 0.000 description 6
- GBIUHAYJGWVNLN-AEJSXWLSSA-N Val-Ser-Pro Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CO)C(=O)N1CCC[C@@H]1C(=O)O)N GBIUHAYJGWVNLN-AEJSXWLSSA-N 0.000 description 6
- GBIUHAYJGWVNLN-UHFFFAOYSA-N Val-Ser-Pro Natural products CC(C)C(N)C(=O)NC(CO)C(=O)N1CCCC1C(O)=O GBIUHAYJGWVNLN-UHFFFAOYSA-N 0.000 description 6
- 235000001014 amino acid Nutrition 0.000 description 6
- 150000001413 amino acids Chemical class 0.000 description 6
- 108010045126 glycyl-tyrosyl-glycine Proteins 0.000 description 6
- 108010044311 leucyl-glycyl-glycine Proteins 0.000 description 6
- AVZHGSCDKIQZPQ-CIUDSAMLSA-N Glu-Arg-Ala Chemical compound C[C@H](NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](N)CCC(O)=O)C(O)=O AVZHGSCDKIQZPQ-CIUDSAMLSA-N 0.000 description 5
- WATXSTJXNBOHKD-LAEOZQHASA-N Glu-Asp-Val Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O WATXSTJXNBOHKD-LAEOZQHASA-N 0.000 description 5
- KLYYKKGCPOGDPE-OEAJRASXSA-N Phe-Thr-Leu Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O KLYYKKGCPOGDPE-OEAJRASXSA-N 0.000 description 5
- XDKKMRPRRCOELJ-GUBZILKMSA-N Pro-Val-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](C(C)C)NC(=O)[C@@H]1CCCN1 XDKKMRPRRCOELJ-GUBZILKMSA-N 0.000 description 5
- OYEDZGNMSBZCIM-XGEHTFHBSA-N Ser-Arg-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(O)=O OYEDZGNMSBZCIM-XGEHTFHBSA-N 0.000 description 5
- PAXANSWUSVPFNK-IUKAMOBKSA-N Thr-Ile-Asn Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H]([C@@H](C)O)N PAXANSWUSVPFNK-IUKAMOBKSA-N 0.000 description 5
- BVOCLAPFOBSJHR-KKUMJFAQSA-N Tyr-Cys-His Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC2=CN=CN2)C(=O)O)N)O BVOCLAPFOBSJHR-KKUMJFAQSA-N 0.000 description 5
- OVLIFGQSBSNGHY-KKHAAJSZSA-N Val-Asp-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](C(C)C)N)O OVLIFGQSBSNGHY-KKHAAJSZSA-N 0.000 description 5
- SDSCOOZQQGUQFC-GVXVVHGQSA-N Val-His-Gln Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N SDSCOOZQQGUQFC-GVXVVHGQSA-N 0.000 description 5
- KSFXWENSJABBFI-ZKWXMUAHSA-N Val-Ser-Asn Chemical compound [H]N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O KSFXWENSJABBFI-ZKWXMUAHSA-N 0.000 description 5
- 230000002411 adverse Effects 0.000 description 5
- 230000005750 disease progression Effects 0.000 description 5
- 108010079413 glycyl-prolyl-glutamic acid Proteins 0.000 description 5
- 231100000283 hepatitis Toxicity 0.000 description 5
- 230000003902 lesion Effects 0.000 description 5
- 201000007270 liver cancer Diseases 0.000 description 5
- 208000014018 liver neoplasm Diseases 0.000 description 5
- GFBLJMHGHAXGNY-ZLUOBGJFSA-N Ala-Asn-Asp Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O GFBLJMHGHAXGNY-ZLUOBGJFSA-N 0.000 description 4
- IFTVANMRTIHKML-WDSKDSINSA-N Ala-Gln-Gly Chemical compound C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(O)=O IFTVANMRTIHKML-WDSKDSINSA-N 0.000 description 4
- GIVATXIGCXFQQA-FXQIFTODSA-N Arg-Ala-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCN=C(N)N GIVATXIGCXFQQA-FXQIFTODSA-N 0.000 description 4
- 101100112922 Candida albicans CDR3 gene Proteins 0.000 description 4
- NIXHTNJAGGFBAW-CIUDSAMLSA-N Cys-Lys-Ser Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CS)N NIXHTNJAGGFBAW-CIUDSAMLSA-N 0.000 description 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
- JBCLFWXMTIKCCB-UHFFFAOYSA-N H-Gly-Phe-OH Natural products NCC(=O)NC(C(O)=O)CC1=CC=CC=C1 JBCLFWXMTIKCCB-UHFFFAOYSA-N 0.000 description 4
- 206010027476 Metastases Diseases 0.000 description 4
- 206010061309 Neoplasm progression Diseases 0.000 description 4
- FPCGZYMRFFIYIH-CIUDSAMLSA-N Ser-Lys-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(O)=O FPCGZYMRFFIYIH-CIUDSAMLSA-N 0.000 description 4
- SQHKXWODKJDZRC-LKXGYXEUSA-N Ser-Thr-Asn Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(O)=O SQHKXWODKJDZRC-LKXGYXEUSA-N 0.000 description 4
- LXXCHJKHJYRMIY-FQPOAREZSA-N Thr-Tyr-Ala Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](C)C(O)=O LXXCHJKHJYRMIY-FQPOAREZSA-N 0.000 description 4
- AZBIIKDSDLVJAK-VHWLVUOQSA-N Trp-Ile-Asn Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)N AZBIIKDSDLVJAK-VHWLVUOQSA-N 0.000 description 4
- 108010047495 alanylglycine Proteins 0.000 description 4
- 125000000539 amino acid group Chemical group 0.000 description 4
- 230000000259 anti-tumor effect Effects 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- 108010089804 glycyl-threonine Proteins 0.000 description 4
- 108010081551 glycylphenylalanine Proteins 0.000 description 4
- 230000036541 health Effects 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 230000009401 metastasis Effects 0.000 description 4
- 235000018102 proteins Nutrition 0.000 description 4
- 238000012552 review Methods 0.000 description 4
- 108010026333 seryl-proline Proteins 0.000 description 4
- 108010061238 threonyl-glycine Proteins 0.000 description 4
- 230000000699 topical effect Effects 0.000 description 4
- 230000005751 tumor progression Effects 0.000 description 4
- 229930195730 Aflatoxin Natural products 0.000 description 3
- XWIYFDMXXLINPU-UHFFFAOYSA-N Aflatoxin G Chemical compound O=C1OCCC2=C1C(=O)OC1=C2C(OC)=CC2=C1C1C=COC1O2 XWIYFDMXXLINPU-UHFFFAOYSA-N 0.000 description 3
- VGPWRRFOPXVGOH-BYPYZUCNSA-N Ala-Gly-Gly Chemical compound C[C@H](N)C(=O)NCC(=O)NCC(O)=O VGPWRRFOPXVGOH-BYPYZUCNSA-N 0.000 description 3
- VKKYFICVTYKFIO-CIUDSAMLSA-N Arg-Ala-Glu Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCN=C(N)N VKKYFICVTYKFIO-CIUDSAMLSA-N 0.000 description 3
- 206010003445 Ascites Diseases 0.000 description 3
- BEQGFMIBZFNROK-JGVFFNPUSA-N Gly-Glu-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCC(=O)O)NC(=O)CN)C(=O)O BEQGFMIBZFNROK-JGVFFNPUSA-N 0.000 description 3
- 108010067060 Immunoglobulin Variable Region Proteins 0.000 description 3
- 102000017727 Immunoglobulin Variable Region Human genes 0.000 description 3
- DIBZLYZXTSVGLN-CIUDSAMLSA-N Lys-Ser-Ser Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O DIBZLYZXTSVGLN-CIUDSAMLSA-N 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- YBAFDPFAUTYYRW-UHFFFAOYSA-N N-L-alpha-glutamyl-L-leucine Natural products CC(C)CC(C(O)=O)NC(=O)C(N)CCC(O)=O YBAFDPFAUTYYRW-UHFFFAOYSA-N 0.000 description 3
- DZZCICYRSZASNF-FXQIFTODSA-N Pro-Ala-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1 DZZCICYRSZASNF-FXQIFTODSA-N 0.000 description 3
- 208000003251 Pruritus Diseases 0.000 description 3
- 241000283984 Rodentia Species 0.000 description 3
- UBRXAVQWXOWRSJ-ZLUOBGJFSA-N Ser-Asn-Asp Chemical compound C([C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)O)NC(=O)[C@H](CO)N)C(=O)N UBRXAVQWXOWRSJ-ZLUOBGJFSA-N 0.000 description 3
- UBRMZSHOOIVJPW-SRVKXCTJSA-N Ser-Leu-Lys Chemical compound OC[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(O)=O UBRMZSHOOIVJPW-SRVKXCTJSA-N 0.000 description 3
- 210000001744 T-lymphocyte Anatomy 0.000 description 3
- VTFWAGGJDRSQFG-MELADBBJSA-N Tyr-Asn-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC(=O)N)NC(=O)[C@H](CC2=CC=C(C=C2)O)N)C(=O)O VTFWAGGJDRSQFG-MELADBBJSA-N 0.000 description 3
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 3
- 231100000354 acute hepatitis Toxicity 0.000 description 3
- 239000005409 aflatoxin Substances 0.000 description 3
- 108010044940 alanylglutamine Proteins 0.000 description 3
- 102000013529 alpha-Fetoproteins Human genes 0.000 description 3
- 108010026331 alpha-Fetoproteins Proteins 0.000 description 3
- 238000002512 chemotherapy Methods 0.000 description 3
- 238000001647 drug administration Methods 0.000 description 3
- 210000004408 hybridoma Anatomy 0.000 description 3
- 230000006872 improvement Effects 0.000 description 3
- 238000001802 infusion Methods 0.000 description 3
- 108010044374 isoleucyl-tyrosine Proteins 0.000 description 3
- 210000004185 liver Anatomy 0.000 description 3
- 230000001404 mediated effect Effects 0.000 description 3
- 229960003301 nivolumab Drugs 0.000 description 3
- COLNVLDHVKWLRT-QMMMGPOBSA-N phenylalanine group Chemical class N[C@@H](CC1=CC=CC=C1)C(=O)O COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 3
- 229920001184 polypeptide Polymers 0.000 description 3
- 230000002265 prevention Effects 0.000 description 3
- 102000004196 processed proteins & peptides Human genes 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 230000005855 radiation Effects 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 230000002441 reversible effect Effects 0.000 description 3
- 230000009885 systemic effect Effects 0.000 description 3
- 239000004474 valine Substances 0.000 description 3
- NFGXHKASABOEEW-UHFFFAOYSA-N 1-methylethyl 11-methoxy-3,7,11-trimethyl-2,4-dodecadienoate Chemical compound COC(C)(C)CCCC(C)CC=CC(C)=CC(=O)OC(C)C NFGXHKASABOEEW-UHFFFAOYSA-N 0.000 description 2
- KXEVYGKATAMXJJ-ACZMJKKPSA-N Ala-Glu-Asp Chemical compound C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O KXEVYGKATAMXJJ-ACZMJKKPSA-N 0.000 description 2
- OSRZOHXQCUFIQG-FPMFFAJLSA-N Ala-Phe-Pro Chemical compound C([C@H](NC(=O)[C@@H]([NH3+])C)C(=O)N1[C@H](CCC1)C([O-])=O)C1=CC=CC=C1 OSRZOHXQCUFIQG-FPMFFAJLSA-N 0.000 description 2
- 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 2
- VWVPYNGMOCSSGK-GUBZILKMSA-N Arg-Arg-Asn Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(N)=O)C(O)=O VWVPYNGMOCSSGK-GUBZILKMSA-N 0.000 description 2
- IASNWHAGGYTEKX-IUCAKERBSA-N Arg-Arg-Gly Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)NCC(O)=O IASNWHAGGYTEKX-IUCAKERBSA-N 0.000 description 2
- WVNFNPGXYADPPO-BQBZGAKWSA-N Arg-Gly-Ser Chemical compound NC(N)=NCCC[C@H](N)C(=O)NCC(=O)N[C@@H](CO)C(O)=O WVNFNPGXYADPPO-BQBZGAKWSA-N 0.000 description 2
- BSYKSCBTTQKOJG-GUBZILKMSA-N Arg-Pro-Ala Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C)C(O)=O BSYKSCBTTQKOJG-GUBZILKMSA-N 0.000 description 2
- IARGXWMWRFOQPG-GCJQMDKQSA-N Asn-Ala-Thr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O IARGXWMWRFOQPG-GCJQMDKQSA-N 0.000 description 2
- HDHZCEDPLTVHFZ-GUBZILKMSA-N Asn-Leu-Glu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O HDHZCEDPLTVHFZ-GUBZILKMSA-N 0.000 description 2
- VCJCPARXDBEGNE-GUBZILKMSA-N Asn-Pro-Pro Chemical compound NC(=O)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 VCJCPARXDBEGNE-GUBZILKMSA-N 0.000 description 2
- RYEWQKQXRJCHIO-SRVKXCTJSA-N Asp-Asn-Tyr Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 RYEWQKQXRJCHIO-SRVKXCTJSA-N 0.000 description 2
- KGHLGJAXYSVNJP-WHFBIAKZSA-N Asp-Ser-Gly Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CO)C(=O)NCC(O)=O KGHLGJAXYSVNJP-WHFBIAKZSA-N 0.000 description 2
- 208000023275 Autoimmune disease Diseases 0.000 description 2
- 206010004593 Bile duct cancer Diseases 0.000 description 2
- 101100512078 Caenorhabditis elegans lys-1 gene Proteins 0.000 description 2
- 208000000419 Chronic Hepatitis B Diseases 0.000 description 2
- CVLIHKBUPSFRQP-WHFBIAKZSA-N Cys-Gly-Ala Chemical compound [H]N[C@@H](CS)C(=O)NCC(=O)N[C@@H](C)C(O)=O CVLIHKBUPSFRQP-WHFBIAKZSA-N 0.000 description 2
- 239000012591 Dulbecco’s Phosphate Buffered Saline Substances 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 208000010201 Exanthema Diseases 0.000 description 2
- JKPGHIQCHIIRMS-AVGNSLFASA-N Gln-Asp-Phe Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CCC(=O)N)N JKPGHIQCHIIRMS-AVGNSLFASA-N 0.000 description 2
- RUFHOVYUYSNDNY-ACZMJKKPSA-N Glu-Ala-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCC(O)=O RUFHOVYUYSNDNY-ACZMJKKPSA-N 0.000 description 2
- HNVFSTLPVJWIDV-CIUDSAMLSA-N Glu-Glu-Gln Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O HNVFSTLPVJWIDV-CIUDSAMLSA-N 0.000 description 2
- MTAOBYXRYJZRGQ-WDSKDSINSA-N Glu-Gly-Asp Chemical compound OC(=O)CC[C@H](N)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(O)=O MTAOBYXRYJZRGQ-WDSKDSINSA-N 0.000 description 2
- KIEICAOUSNYOLM-NRPADANISA-N Glu-Val-Ala Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C)C(O)=O KIEICAOUSNYOLM-NRPADANISA-N 0.000 description 2
- CJGDTAHEMXLRMB-ULQDDVLXSA-N His-Arg-Phe Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O CJGDTAHEMXLRMB-ULQDDVLXSA-N 0.000 description 2
- UPGJWSUYENXOPV-HGNGGELXSA-N His-Gln-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CC1=CN=CN1)N UPGJWSUYENXOPV-HGNGGELXSA-N 0.000 description 2
- 206010020772 Hypertension Diseases 0.000 description 2
- PELCGFMHLZXWBQ-BJDJZHNGSA-N Ile-Ser-Leu Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)O)N PELCGFMHLZXWBQ-BJDJZHNGSA-N 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- 108010074328 Interferon-gamma Proteins 0.000 description 2
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 2
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 2
- USTCFDAQCLDPBD-XIRDDKMYSA-N Leu-Asn-Trp Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)N USTCFDAQCLDPBD-XIRDDKMYSA-N 0.000 description 2
- RXGLHDWAZQECBI-SRVKXCTJSA-N Leu-Leu-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O RXGLHDWAZQECBI-SRVKXCTJSA-N 0.000 description 2
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 2
- KPJJOZUXFOLGMQ-CIUDSAMLSA-N Lys-Asp-Asn Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC(=O)N)C(=O)O)N KPJJOZUXFOLGMQ-CIUDSAMLSA-N 0.000 description 2
- ODUQLUADRKMHOZ-JYJNAYRXSA-N Lys-Glu-Tyr Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CCCCN)N)O ODUQLUADRKMHOZ-JYJNAYRXSA-N 0.000 description 2
- MYZMQWHPDAYKIE-SRVKXCTJSA-N Lys-Leu-Ala Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(O)=O MYZMQWHPDAYKIE-SRVKXCTJSA-N 0.000 description 2
- AFLBTVGQCQLOFJ-AVGNSLFASA-N Lys-Pro-Arg Chemical compound NCCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCN=C(N)N)C(O)=O AFLBTVGQCQLOFJ-AVGNSLFASA-N 0.000 description 2
- 108010002311 N-glycylglutamic acid Proteins 0.000 description 2
- 108010047562 NGR peptide Proteins 0.000 description 2
- 108091007491 NSP3 Papain-like protease domains Proteins 0.000 description 2
- 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 2
- FNGOXVQBBCMFKV-CIUDSAMLSA-N Pro-Ser-Glu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(O)=O FNGOXVQBBCMFKV-CIUDSAMLSA-N 0.000 description 2
- QKWYXRPICJEQAJ-KJEVXHAQSA-N Pro-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]2CCCN2)O QKWYXRPICJEQAJ-KJEVXHAQSA-N 0.000 description 2
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 2
- 206010039491 Sarcoma Diseases 0.000 description 2
- WDXYVIIVDIDOSX-DCAQKATOSA-N Ser-Arg-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CO)CCCN=C(N)N WDXYVIIVDIDOSX-DCAQKATOSA-N 0.000 description 2
- QVOGDCQNGLBNCR-FXQIFTODSA-N Ser-Arg-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(O)=O QVOGDCQNGLBNCR-FXQIFTODSA-N 0.000 description 2
- FMDHKPRACUXATF-ACZMJKKPSA-N Ser-Gln-Ser Chemical compound OC[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(O)=O FMDHKPRACUXATF-ACZMJKKPSA-N 0.000 description 2
- UQFYNFTYDHUIMI-WHFBIAKZSA-N Ser-Gly-Ala Chemical compound OC(=O)[C@H](C)NC(=O)CNC(=O)[C@@H](N)CO UQFYNFTYDHUIMI-WHFBIAKZSA-N 0.000 description 2
- 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 2
- 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 2
- AZWNCEBQZXELEZ-FXQIFTODSA-N Ser-Pro-Ser Chemical compound OC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O AZWNCEBQZXELEZ-FXQIFTODSA-N 0.000 description 2
- VGQVAVQWKJLIRM-FXQIFTODSA-N Ser-Ser-Val Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O VGQVAVQWKJLIRM-FXQIFTODSA-N 0.000 description 2
- XHWCDRUPDNSDAZ-XKBZYTNZSA-N Thr-Ser-Glu Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N)O XHWCDRUPDNSDAZ-XKBZYTNZSA-N 0.000 description 2
- HUPLKEHTTQBXSC-YJRXYDGGSA-N Thr-Ser-Tyr Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 HUPLKEHTTQBXSC-YJRXYDGGSA-N 0.000 description 2
- JAWUQFCGNVEDRN-MEYUZBJRSA-N Thr-Tyr-Leu Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CC(C)C)C(=O)O)N)O JAWUQFCGNVEDRN-MEYUZBJRSA-N 0.000 description 2
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 2
- 239000004473 Threonine Substances 0.000 description 2
- 208000007536 Thrombosis Diseases 0.000 description 2
- UOXPLPBMEPLZBW-WDSOQIARSA-N Trp-Val-Lys Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(O)=O)=CNC2=C1 UOXPLPBMEPLZBW-WDSOQIARSA-N 0.000 description 2
- DLZKEQQWXODGGZ-KWQFWETISA-N Tyr-Ala-Gly Chemical compound OC(=O)CNC(=O)[C@H](C)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 DLZKEQQWXODGGZ-KWQFWETISA-N 0.000 description 2
- XGEUYEOEZYFHRL-KKXDTOCCSA-N Tyr-Ala-Phe Chemical compound C([C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=C(O)C=C1 XGEUYEOEZYFHRL-KKXDTOCCSA-N 0.000 description 2
- OLWFDNLLBWQWCP-STQMWFEESA-N Tyr-Gly-Met Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)NCC(=O)N[C@@H](CCSC)C(O)=O OLWFDNLLBWQWCP-STQMWFEESA-N 0.000 description 2
- CTDPLKMBVALCGN-JSGCOSHPSA-N Tyr-Gly-Val Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)NCC(=O)N[C@@H](C(C)C)C(O)=O CTDPLKMBVALCGN-JSGCOSHPSA-N 0.000 description 2
- UMSZZGTXGKHTFJ-SRVKXCTJSA-N Tyr-Ser-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 UMSZZGTXGKHTFJ-SRVKXCTJSA-N 0.000 description 2
- MYLNLEIZWHVENT-VKOGCVSHSA-N Val-Ile-Trp Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)NC(=O)[C@H](C(C)C)N MYLNLEIZWHVENT-VKOGCVSHSA-N 0.000 description 2
- BZWUSZGQOILYEU-STECZYCISA-N Val-Ile-Tyr Chemical compound CC(C)[C@H](N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 BZWUSZGQOILYEU-STECZYCISA-N 0.000 description 2
- UQMPYVLTQCGRSK-IFFSRLJSSA-N Val-Thr-Gln Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](C(C)C)N)O UQMPYVLTQCGRSK-IFFSRLJSSA-N 0.000 description 2
- AEFJNECXZCODJM-UWVGGRQHSA-N Val-Val-Gly Chemical compound CC(C)[C@H]([NH3+])C(=O)N[C@@H](C(C)C)C(=O)NCC([O-])=O AEFJNECXZCODJM-UWVGGRQHSA-N 0.000 description 2
- 235000004279 alanine Nutrition 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 108010069926 arginyl-glycyl-serine Proteins 0.000 description 2
- 108010060035 arginylproline Proteins 0.000 description 2
- 235000003704 aspartic acid Nutrition 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 2
- 208000026900 bile duct neoplasm Diseases 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 208000006990 cholangiocarcinoma Diseases 0.000 description 2
- CVSVTCORWBXHQV-UHFFFAOYSA-N creatine Chemical compound NC(=[NH2+])N(C)CC([O-])=O CVSVTCORWBXHQV-UHFFFAOYSA-N 0.000 description 2
- DDRJAANPRJIHGJ-UHFFFAOYSA-N creatinine Chemical compound CN1CC(=O)NC1=N DDRJAANPRJIHGJ-UHFFFAOYSA-N 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 230000004069 differentiation Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 201000005884 exanthem Diseases 0.000 description 2
- 210000002950 fibroblast Anatomy 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 108010001064 glycyl-glycyl-glycyl-glycine Proteins 0.000 description 2
- 108010015792 glycyllysine Proteins 0.000 description 2
- 208000002672 hepatitis B Diseases 0.000 description 2
- 108010092114 histidylphenylalanine Proteins 0.000 description 2
- 210000002865 immune cell Anatomy 0.000 description 2
- 230000001900 immune effect Effects 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 230000002458 infectious effect Effects 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 238000011221 initial treatment Methods 0.000 description 2
- 238000007917 intracranial administration Methods 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 230000007803 itching Effects 0.000 description 2
- 125000001909 leucine group Chemical class [H]N(*)C(C(*)=O)C([H])([H])C(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 230000036210 malignancy Effects 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 230000000683 nonmetastatic effect Effects 0.000 description 2
- 230000008520 organization Effects 0.000 description 2
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 2
- 210000003240 portal vein Anatomy 0.000 description 2
- 201000001474 proteinuria Diseases 0.000 description 2
- 206010037844 rash Diseases 0.000 description 2
- 230000000306 recurrent effect Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 238000009121 systemic therapy Methods 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000440 toxicity profile Toxicity 0.000 description 2
- 210000003171 tumor-infiltrating lymphocyte Anatomy 0.000 description 2
- 108010020532 tyrosyl-proline Proteins 0.000 description 2
- 210000001631 vena cava inferior Anatomy 0.000 description 2
- OZFAFGSSMRRTDW-UHFFFAOYSA-N (2,4-dichlorophenyl) benzenesulfonate Chemical compound ClC1=CC(Cl)=CC=C1OS(=O)(=O)C1=CC=CC=C1 OZFAFGSSMRRTDW-UHFFFAOYSA-N 0.000 description 1
- IESDGNYHXIOKRW-YXMSTPNBSA-N (2s)-2-[[(2s)-1-[(2s)-6-amino-2-[[(2s,3r)-2-amino-3-hydroxybutanoyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-5-(diaminomethylideneamino)pentanoic acid Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(N)=N)C(O)=O IESDGNYHXIOKRW-YXMSTPNBSA-N 0.000 description 1
- ONEGZXHXCLCVRF-UHFFFAOYSA-N 2-[[2-[[1-(2-amino-3-methylbutanoyl)pyrrolidine-2-carbonyl]amino]-3-methylbutanoyl]amino]-4-methylpentanoic acid Chemical compound CC(C)CC(C(O)=O)NC(=O)C(C(C)C)NC(=O)C1CCCN1C(=O)C(N)C(C)C ONEGZXHXCLCVRF-UHFFFAOYSA-N 0.000 description 1
- VHRSUDSXCMQTMA-PJHHCJLFSA-N 6alpha-methylprednisolone Chemical compound C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@](O)(C(=O)CO)CC[C@H]21 VHRSUDSXCMQTMA-PJHHCJLFSA-N 0.000 description 1
- 208000004998 Abdominal Pain Diseases 0.000 description 1
- WYPUMLRSQMKIJU-BPNCWPANSA-N Ala-Arg-Tyr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O WYPUMLRSQMKIJU-BPNCWPANSA-N 0.000 description 1
- NHCPCLJZRSIDHS-ZLUOBGJFSA-N Ala-Asp-Ala Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(O)=O NHCPCLJZRSIDHS-ZLUOBGJFSA-N 0.000 description 1
- WXERCAHAIKMTKX-ZLUOBGJFSA-N Ala-Asp-Asp Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O WXERCAHAIKMTKX-ZLUOBGJFSA-N 0.000 description 1
- KIUYPHAMDKDICO-WHFBIAKZSA-N Ala-Asp-Gly Chemical compound C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(O)=O KIUYPHAMDKDICO-WHFBIAKZSA-N 0.000 description 1
- FVSOUJZKYWEFOB-KBIXCLLPSA-N Ala-Gln-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)N FVSOUJZKYWEFOB-KBIXCLLPSA-N 0.000 description 1
- FUSPCLTUKXQREV-ACZMJKKPSA-N Ala-Glu-Ala Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(O)=O FUSPCLTUKXQREV-ACZMJKKPSA-N 0.000 description 1
- WKOBSJOZRJJVRZ-FXQIFTODSA-N Ala-Glu-Glu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O WKOBSJOZRJJVRZ-FXQIFTODSA-N 0.000 description 1
- VBRDBGCROKWTPV-XHNCKOQMSA-N Ala-Glu-Pro Chemical compound C[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N1CCC[C@@H]1C(=O)O)N VBRDBGCROKWTPV-XHNCKOQMSA-N 0.000 description 1
- OMMDTNGURYRDAC-NRPADANISA-N Ala-Glu-Val Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O OMMDTNGURYRDAC-NRPADANISA-N 0.000 description 1
- OBVSBEYOMDWLRJ-BFHQHQDPSA-N Ala-Gly-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)CNC(=O)[C@H](C)N OBVSBEYOMDWLRJ-BFHQHQDPSA-N 0.000 description 1
- FAJIYNONGXEXAI-CQDKDKBSSA-N Ala-His-Phe Chemical compound C([C@H](NC(=O)[C@@H](N)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CNC=N1 FAJIYNONGXEXAI-CQDKDKBSSA-N 0.000 description 1
- HUUOZYZWNCXTFK-INTQDDNPSA-N Ala-His-Pro Chemical compound C[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)N2CCC[C@@H]2C(=O)O)N HUUOZYZWNCXTFK-INTQDDNPSA-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
- YYAVDNKUWLAFCV-ACZMJKKPSA-N Ala-Ser-Gln Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(O)=O YYAVDNKUWLAFCV-ACZMJKKPSA-N 0.000 description 1
- IOFVWPYSRSCWHI-JXUBOQSCSA-N Ala-Thr-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](C)N IOFVWPYSRSCWHI-JXUBOQSCSA-N 0.000 description 1
- 208000007848 Alcoholism Diseases 0.000 description 1
- 108010032595 Antibody Binding Sites Proteins 0.000 description 1
- TTXYKSADPSNOIF-IHRRRGAJSA-N Arg-Asp-Phe Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O TTXYKSADPSNOIF-IHRRRGAJSA-N 0.000 description 1
- MFAMTAVAFBPXDC-LPEHRKFASA-N Arg-Asp-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC(=O)O)NC(=O)[C@H](CCCN=C(N)N)N)C(=O)O MFAMTAVAFBPXDC-LPEHRKFASA-N 0.000 description 1
- ZZZWQALDSQQBEW-STQMWFEESA-N Arg-Gly-Tyr Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O ZZZWQALDSQQBEW-STQMWFEESA-N 0.000 description 1
- FSNVAJOPUDVQAR-AVGNSLFASA-N Arg-Lys-Arg Chemical compound NC(=N)NCCC[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O FSNVAJOPUDVQAR-AVGNSLFASA-N 0.000 description 1
- PYZPXCZNQSEHDT-GUBZILKMSA-N Arg-Met-Asn Chemical compound CSCC[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CCCN=C(N)N)N PYZPXCZNQSEHDT-GUBZILKMSA-N 0.000 description 1
- JCROZIFVIYMXHM-GUBZILKMSA-N Arg-Met-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CCSC)NC(=O)[C@@H](N)CCCN=C(N)N JCROZIFVIYMXHM-GUBZILKMSA-N 0.000 description 1
- INXWADWANGLMPJ-JYJNAYRXSA-N Arg-Phe-Arg Chemical compound NC(=N)NCCC[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)CC1=CC=CC=C1 INXWADWANGLMPJ-JYJNAYRXSA-N 0.000 description 1
- PRLPSDIHSRITSF-UNQGMJICSA-N Arg-Phe-Thr Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O PRLPSDIHSRITSF-UNQGMJICSA-N 0.000 description 1
- HGKHPCFTRQDHCU-IUCAKERBSA-N Arg-Pro-Gly Chemical compound NC(N)=NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O HGKHPCFTRQDHCU-IUCAKERBSA-N 0.000 description 1
- QHVRVUNEAIFTEK-SZMVWBNQSA-N Arg-Pro-Trp Chemical compound N[C@@H](CCCNC(N)=N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(O)=O QHVRVUNEAIFTEK-SZMVWBNQSA-N 0.000 description 1
- QLSRIZIDQXDQHK-RCWTZXSCSA-N Arg-Val-Thr Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O QLSRIZIDQXDQHK-RCWTZXSCSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 208000006820 Arthralgia Diseases 0.000 description 1
- LEFKSBYHUGUWLP-ACZMJKKPSA-N Asn-Ala-Glu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(O)=O LEFKSBYHUGUWLP-ACZMJKKPSA-N 0.000 description 1
- HZPSDHRYYIORKR-WHFBIAKZSA-N Asn-Ala-Gly Chemical compound OC(=O)CNC(=O)[C@H](C)NC(=O)[C@@H](N)CC(N)=O HZPSDHRYYIORKR-WHFBIAKZSA-N 0.000 description 1
- SLKLLQWZQHXYSV-CIUDSAMLSA-N Asn-Ala-Lys Chemical compound NC(=O)C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(O)=O SLKLLQWZQHXYSV-CIUDSAMLSA-N 0.000 description 1
- DAPLJWATMAXPPZ-CIUDSAMLSA-N Asn-Asn-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CC(N)=O DAPLJWATMAXPPZ-CIUDSAMLSA-N 0.000 description 1
- WPOLSNAQGVHROR-GUBZILKMSA-N Asn-Gln-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CC(=O)N)N WPOLSNAQGVHROR-GUBZILKMSA-N 0.000 description 1
- OKZOABJQOMAYEC-NUMRIWBASA-N Asn-Gln-Thr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O OKZOABJQOMAYEC-NUMRIWBASA-N 0.000 description 1
- WONGRTVAMHFGBE-WDSKDSINSA-N Asn-Gly-Gln Chemical compound C(CC(=O)N)[C@@H](C(=O)O)NC(=O)CNC(=O)[C@H](CC(=O)N)N WONGRTVAMHFGBE-WDSKDSINSA-N 0.000 description 1
- DJIMLSXHXKWADV-CIUDSAMLSA-N Asn-Leu-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC(N)=O DJIMLSXHXKWADV-CIUDSAMLSA-N 0.000 description 1
- GMUOCGCDOYYWPD-FXQIFTODSA-N Asn-Pro-Ser Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O GMUOCGCDOYYWPD-FXQIFTODSA-N 0.000 description 1
- AMGQTNHANMRPOE-LKXGYXEUSA-N Asn-Thr-Ser Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(O)=O AMGQTNHANMRPOE-LKXGYXEUSA-N 0.000 description 1
- LGCVSPFCFXWUEY-IHPCNDPISA-N Asn-Trp-Tyr Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CC3=CC=C(C=C3)O)C(=O)O)NC(=O)[C@H](CC(=O)N)N LGCVSPFCFXWUEY-IHPCNDPISA-N 0.000 description 1
- QNNBHTFDFFFHGC-KKUMJFAQSA-N Asn-Tyr-Lys Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC(=O)N)N)O QNNBHTFDFFFHGC-KKUMJFAQSA-N 0.000 description 1
- DXHINQUXBZNUCF-MELADBBJSA-N Asn-Tyr-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC2=CC=C(C=C2)O)NC(=O)[C@H](CC(=O)N)N)C(=O)O DXHINQUXBZNUCF-MELADBBJSA-N 0.000 description 1
- KRXIWXCXOARFNT-ZLUOBGJFSA-N Asp-Ala-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC(O)=O KRXIWXCXOARFNT-ZLUOBGJFSA-N 0.000 description 1
- DBWYWXNMZZYIRY-LPEHRKFASA-N Asp-Arg-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(=O)O)N)C(=O)O DBWYWXNMZZYIRY-LPEHRKFASA-N 0.000 description 1
- FAEIQWHBRBWUBN-FXQIFTODSA-N Asp-Arg-Ser Chemical compound C(C[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CC(=O)O)N)CN=C(N)N FAEIQWHBRBWUBN-FXQIFTODSA-N 0.000 description 1
- 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 1
- VIRHEUMYXXLCBF-WDSKDSINSA-N Asp-Gly-Glu Chemical compound [H]N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(O)=O VIRHEUMYXXLCBF-WDSKDSINSA-N 0.000 description 1
- QCVXMEHGFUMKCO-YUMQZZPRSA-N Asp-Gly-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CC(O)=O QCVXMEHGFUMKCO-YUMQZZPRSA-N 0.000 description 1
- RTXQQDVBACBSCW-CFMVVWHZSA-N Asp-Ile-Tyr Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O RTXQQDVBACBSCW-CFMVVWHZSA-N 0.000 description 1
- GKWFMNNNYZHJHV-SRVKXCTJSA-N Asp-Lys-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CC(O)=O GKWFMNNNYZHJHV-SRVKXCTJSA-N 0.000 description 1
- FQHBAQLBIXLWAG-DCAQKATOSA-N Asp-Lys-Met Chemical compound CSCC[C@@H](C(=O)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC(=O)O)N FQHBAQLBIXLWAG-DCAQKATOSA-N 0.000 description 1
- WMLFFCRUSPNENW-ZLUOBGJFSA-N Asp-Ser-Ala Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(O)=O WMLFFCRUSPNENW-ZLUOBGJFSA-N 0.000 description 1
- HRVQDZOWMLFAOD-BIIVOSGPSA-N Asp-Ser-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CO)NC(=O)[C@H](CC(=O)O)N)C(=O)O HRVQDZOWMLFAOD-BIIVOSGPSA-N 0.000 description 1
- GCACQYDBDHRVGE-LKXGYXEUSA-N Asp-Thr-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H]([C@H](O)C)NC(=O)[C@@H](N)CC(O)=O GCACQYDBDHRVGE-LKXGYXEUSA-N 0.000 description 1
- 208000014644 Brain disease Diseases 0.000 description 1
- 206010008909 Chronic Hepatitis Diseases 0.000 description 1
- 208000006154 Chronic hepatitis C Diseases 0.000 description 1
- 102000012437 Copper-Transporting ATPases Human genes 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- JTNKVWLMDHIUOG-IHRRRGAJSA-N Cys-Arg-Phe Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O JTNKVWLMDHIUOG-IHRRRGAJSA-N 0.000 description 1
- QLCPDGRAEJSYQM-LPEHRKFASA-N Cys-Arg-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CS)N)C(=O)O QLCPDGRAEJSYQM-LPEHRKFASA-N 0.000 description 1
- OZHXXYOHPLLLMI-CIUDSAMLSA-N Cys-Lys-Ala Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O OZHXXYOHPLLLMI-CIUDSAMLSA-N 0.000 description 1
- ZOKPRHVIFAUJPV-GUBZILKMSA-N Cys-Pro-Arg Chemical compound C1C[C@H](N(C1)C(=O)[C@H](CS)N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O ZOKPRHVIFAUJPV-GUBZILKMSA-N 0.000 description 1
- SWJYSDXMTPMBHO-FXQIFTODSA-N Cys-Pro-Ser Chemical compound [H]N[C@@H](CS)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O SWJYSDXMTPMBHO-FXQIFTODSA-N 0.000 description 1
- 206010061819 Disease recurrence Diseases 0.000 description 1
- 208000032274 Encephalopathy Diseases 0.000 description 1
- 101100153154 Escherichia phage T5 thy gene Proteins 0.000 description 1
- 108010021468 Fc gamma receptor IIA Proteins 0.000 description 1
- 108010021472 Fc gamma receptor IIB Proteins 0.000 description 1
- 206010016334 Feeling hot Diseases 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- KWUSGAIFNHQCBY-DCAQKATOSA-N Gln-Arg-Arg Chemical compound NC(=O)CC[C@H](N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O KWUSGAIFNHQCBY-DCAQKATOSA-N 0.000 description 1
- XOKGKOQWADCLFQ-GARJFASQSA-N Gln-Arg-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CCC(=O)N)N)C(=O)O XOKGKOQWADCLFQ-GARJFASQSA-N 0.000 description 1
- KYFSMWLWHYZRNW-ACZMJKKPSA-N Gln-Asp-Cys Chemical compound C(CC(=O)N)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CS)C(=O)O)N KYFSMWLWHYZRNW-ACZMJKKPSA-N 0.000 description 1
- 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 1
- MADFVRSKEIEZHZ-DCAQKATOSA-N Gln-Gln-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CCC(=O)N)N MADFVRSKEIEZHZ-DCAQKATOSA-N 0.000 description 1
- QFJPFPCSXOXMKI-BPUTZDHNSA-N Gln-Gln-Trp Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CCC(=O)N)N QFJPFPCSXOXMKI-BPUTZDHNSA-N 0.000 description 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
- VGTDBGYFVWOQTI-RYUDHWBXSA-N Gln-Gly-Phe Chemical compound NC(=O)CC[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 VGTDBGYFVWOQTI-RYUDHWBXSA-N 0.000 description 1
- GQZDDFRXSDGUNG-YVNDNENWSA-N Gln-Ile-Gln Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(N)=O)C(O)=O GQZDDFRXSDGUNG-YVNDNENWSA-N 0.000 description 1
- MTCXQQINVAFZKW-MNXVOIDGSA-N Gln-Ile-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCC(=O)N)N MTCXQQINVAFZKW-MNXVOIDGSA-N 0.000 description 1
- XFAUJGNLHIGXET-AVGNSLFASA-N Gln-Leu-Leu Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O XFAUJGNLHIGXET-AVGNSLFASA-N 0.000 description 1
- ILKYYKRAULNYMS-JYJNAYRXSA-N Gln-Lys-Phe Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O ILKYYKRAULNYMS-JYJNAYRXSA-N 0.000 description 1
- QKWBEMCLYTYBNI-GVXVVHGQSA-N Gln-Lys-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CCC(N)=O QKWBEMCLYTYBNI-GVXVVHGQSA-N 0.000 description 1
- HHRAEXBUNGTOGZ-IHRRRGAJSA-N Gln-Phe-Gln Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCC(N)=O)C(O)=O HHRAEXBUNGTOGZ-IHRRRGAJSA-N 0.000 description 1
- FQCILXROGNOZON-YUMQZZPRSA-N Gln-Pro-Gly Chemical compound NC(=O)CC[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O FQCILXROGNOZON-YUMQZZPRSA-N 0.000 description 1
- SYZZMPFLOLSMHL-XHNCKOQMSA-N Gln-Ser-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CO)NC(=O)[C@H](CCC(=O)N)N)C(=O)O SYZZMPFLOLSMHL-XHNCKOQMSA-N 0.000 description 1
- OTQSTOXRUBVWAP-NRPADANISA-N Gln-Ser-Val Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O OTQSTOXRUBVWAP-NRPADANISA-N 0.000 description 1
- VOUSELYGTNGEPB-NUMRIWBASA-N Gln-Thr-Asp Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(O)=O VOUSELYGTNGEPB-NUMRIWBASA-N 0.000 description 1
- NHMRJKKAVMENKJ-WDCWCFNPSA-N Gln-Thr-Leu Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O NHMRJKKAVMENKJ-WDCWCFNPSA-N 0.000 description 1
- ZMXZGYLINVNTKH-DZKIICNBSA-N Gln-Val-Phe Chemical compound NC(=O)CC[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 ZMXZGYLINVNTKH-DZKIICNBSA-N 0.000 description 1
- LKDIBBOKUAASNP-FXQIFTODSA-N Glu-Ala-Glu Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(O)=O LKDIBBOKUAASNP-FXQIFTODSA-N 0.000 description 1
- ATRHMOJQJWPVBQ-DRZSPHRISA-N Glu-Ala-Phe Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O ATRHMOJQJWPVBQ-DRZSPHRISA-N 0.000 description 1
- WOMUDRVDJMHTCV-DCAQKATOSA-N Glu-Arg-Arg Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O WOMUDRVDJMHTCV-DCAQKATOSA-N 0.000 description 1
- QPRZKNOOOBWXSU-CIUDSAMLSA-N Glu-Asp-Arg Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CCCN=C(N)N QPRZKNOOOBWXSU-CIUDSAMLSA-N 0.000 description 1
- JVSBYEDSSRZQGV-GUBZILKMSA-N Glu-Asp-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](N)CCC(O)=O JVSBYEDSSRZQGV-GUBZILKMSA-N 0.000 description 1
- YLJHCWNDBKKOEB-IHRRRGAJSA-N Glu-Glu-Phe Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O YLJHCWNDBKKOEB-IHRRRGAJSA-N 0.000 description 1
- BUAKRRKDHSSIKK-IHRRRGAJSA-N Glu-Glu-Tyr Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 BUAKRRKDHSSIKK-IHRRRGAJSA-N 0.000 description 1
- CXRWMMRLEMVSEH-PEFMBERDSA-N Glu-Ile-Asn Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(N)=O)C(O)=O CXRWMMRLEMVSEH-PEFMBERDSA-N 0.000 description 1
- HVYWQYLBVXMXSV-GUBZILKMSA-N Glu-Leu-Ala Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(O)=O HVYWQYLBVXMXSV-GUBZILKMSA-N 0.000 description 1
- DNPCBMNFQVTHMA-DCAQKATOSA-N Glu-Leu-Gln Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O DNPCBMNFQVTHMA-DCAQKATOSA-N 0.000 description 1
- SUIAHERNFYRBDZ-GVXVVHGQSA-N Glu-Lys-Val Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(O)=O SUIAHERNFYRBDZ-GVXVVHGQSA-N 0.000 description 1
- QMOSCLNJVKSHHU-YUMQZZPRSA-N Glu-Met-Gly Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCSC)C(=O)NCC(O)=O QMOSCLNJVKSHHU-YUMQZZPRSA-N 0.000 description 1
- PMSMKNYRZCKVMC-DRZSPHRISA-N Glu-Phe-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)NC(=O)[C@H](CCC(=O)O)N PMSMKNYRZCKVMC-DRZSPHRISA-N 0.000 description 1
- JDUKCSSHWNIQQZ-IHRRRGAJSA-N Glu-Phe-Glu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCC(O)=O)C(O)=O JDUKCSSHWNIQQZ-IHRRRGAJSA-N 0.000 description 1
- IDEODOAVGCMUQV-GUBZILKMSA-N Glu-Ser-Leu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O IDEODOAVGCMUQV-GUBZILKMSA-N 0.000 description 1
- BXSZPACYCMNKLS-AVGNSLFASA-N Glu-Ser-Phe Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O BXSZPACYCMNKLS-AVGNSLFASA-N 0.000 description 1
- JVZLZVJTIXVIHK-SXNHZJKMSA-N Glu-Trp-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)NC(=O)[C@H](CCC(=O)O)N JVZLZVJTIXVIHK-SXNHZJKMSA-N 0.000 description 1
- FVGOGEGGQLNZGH-DZKIICNBSA-N Glu-Val-Phe Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 FVGOGEGGQLNZGH-DZKIICNBSA-N 0.000 description 1
- UPOJUWHGMDJUQZ-IUCAKERBSA-N Gly-Arg-Arg Chemical compound NC(=N)NCCC[C@H](NC(=O)CN)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O UPOJUWHGMDJUQZ-IUCAKERBSA-N 0.000 description 1
- CLODWIOAKCSBAN-BQBZGAKWSA-N Gly-Arg-Asp Chemical compound NC(N)=NCCC[C@H](NC(=O)CN)C(=O)N[C@@H](CC(O)=O)C(O)=O CLODWIOAKCSBAN-BQBZGAKWSA-N 0.000 description 1
- GRIRDMVMJJDZKV-RCOVLWMOSA-N Gly-Asn-Val Chemical compound [H]NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(O)=O GRIRDMVMJJDZKV-RCOVLWMOSA-N 0.000 description 1
- JMQFHZWESBGPFC-WDSKDSINSA-N Gly-Gln-Asp Chemical compound NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O JMQFHZWESBGPFC-WDSKDSINSA-N 0.000 description 1
- JUGQPPOVWXSPKJ-RYUDHWBXSA-N Gly-Gln-Phe Chemical compound [H]NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O JUGQPPOVWXSPKJ-RYUDHWBXSA-N 0.000 description 1
- BHPQOIPBLYJNAW-NGZCFLSTSA-N Gly-Ile-Pro Chemical compound CC[C@H](C)[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)CN BHPQOIPBLYJNAW-NGZCFLSTSA-N 0.000 description 1
- YTSVAIMKVLZUDU-YUMQZZPRSA-N Gly-Leu-Asp Chemical compound [H]NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O YTSVAIMKVLZUDU-YUMQZZPRSA-N 0.000 description 1
- WDEHMRNSGHVNOH-VHSXEESVSA-N Gly-Lys-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCCCN)NC(=O)CN)C(=O)O WDEHMRNSGHVNOH-VHSXEESVSA-N 0.000 description 1
- WNZOCXUOGVYYBJ-CDMKHQONSA-N Gly-Phe-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)NC(=O)CN)O WNZOCXUOGVYYBJ-CDMKHQONSA-N 0.000 description 1
- NSVOVKWEKGEOQB-LURJTMIESA-N Gly-Pro-Gly Chemical compound NCC(=O)N1CCC[C@H]1C(=O)NCC(O)=O NSVOVKWEKGEOQB-LURJTMIESA-N 0.000 description 1
- CSMYMGFCEJWALV-WDSKDSINSA-N Gly-Ser-Gln Chemical compound NCC(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CCC(N)=O CSMYMGFCEJWALV-WDSKDSINSA-N 0.000 description 1
- FFALDIDGPLUDKV-ZDLURKLDSA-N Gly-Thr-Ser Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(O)=O FFALDIDGPLUDKV-ZDLURKLDSA-N 0.000 description 1
- KOYUSMBPJOVSOO-XEGUGMAKSA-N Gly-Tyr-Ile Chemical compound [H]NCC(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O KOYUSMBPJOVSOO-XEGUGMAKSA-N 0.000 description 1
- 208000018565 Hemochromatosis Diseases 0.000 description 1
- 208000031220 Hemophilia Diseases 0.000 description 1
- 208000009292 Hemophilia A Diseases 0.000 description 1
- 208000005176 Hepatitis C Diseases 0.000 description 1
- 208000002972 Hepatolenticular Degeneration Diseases 0.000 description 1
- ZPVJJPAIUZLSNE-DCAQKATOSA-N His-Arg-Ser Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(O)=O ZPVJJPAIUZLSNE-DCAQKATOSA-N 0.000 description 1
- FJCGVRRVBKYYOU-DCAQKATOSA-N His-Met-Ser Chemical compound CSCC[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CC1=CN=CN1)N FJCGVRRVBKYYOU-DCAQKATOSA-N 0.000 description 1
- YEKYGQZUBCRNGH-DCAQKATOSA-N His-Pro-Ser Chemical compound C1C[C@H](N(C1)C(=O)[C@H](CC2=CN=CN2)N)C(=O)N[C@@H](CO)C(=O)O YEKYGQZUBCRNGH-DCAQKATOSA-N 0.000 description 1
- OWYIDJCNRWRSJY-QTKMDUPCSA-N His-Pro-Thr Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)O)C(O)=O OWYIDJCNRWRSJY-QTKMDUPCSA-N 0.000 description 1
- CSRRMQFXMBPSIL-SIXJUCDHSA-N His-Trp-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)NC(=O)[C@H](CC3=CN=CN3)N CSRRMQFXMBPSIL-SIXJUCDHSA-N 0.000 description 1
- YKUAGFAXQRYUQW-KKUMJFAQSA-N His-Tyr-Cys Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC2=CN=CN2)N)O YKUAGFAXQRYUQW-KKUMJFAQSA-N 0.000 description 1
- 101000917839 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor III-B Proteins 0.000 description 1
- 206010020850 Hyperthyroidism Diseases 0.000 description 1
- 201000003838 Idiopathic interstitial pneumonia Diseases 0.000 description 1
- VCYVLFAWCJRXFT-HJPIBITLSA-N Ile-Cys-Tyr Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)O)N VCYVLFAWCJRXFT-HJPIBITLSA-N 0.000 description 1
- JHCVYQKVKOLAIU-NAKRPEOUSA-N Ile-Cys-Val Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](C(C)C)C(=O)O)N JHCVYQKVKOLAIU-NAKRPEOUSA-N 0.000 description 1
- LWWILHPVAKKLQS-QXEWZRGKSA-N Ile-Gly-Met Chemical compound CC[C@H](C)[C@@H](C(=O)NCC(=O)N[C@@H](CCSC)C(=O)O)N LWWILHPVAKKLQS-QXEWZRGKSA-N 0.000 description 1
- XLXPYSDGMXTTNQ-UHFFFAOYSA-N Ile-Phe-Leu Natural products CCC(C)C(N)C(=O)NC(C(=O)NC(CC(C)C)C(O)=O)CC1=CC=CC=C1 XLXPYSDGMXTTNQ-UHFFFAOYSA-N 0.000 description 1
- FBGXMKUWQFPHFB-JBDRJPRFSA-N Ile-Ser-Cys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)O)N FBGXMKUWQFPHFB-JBDRJPRFSA-N 0.000 description 1
- RKQAYOWLSFLJEE-SVSWQMSJSA-N Ile-Thr-Cys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(=O)O)N RKQAYOWLSFLJEE-SVSWQMSJSA-N 0.000 description 1
- JTBFQNHKNRZJDS-SYWGBEHUSA-N Ile-Trp-Ala Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)N[C@@H](C)C(=O)O)N JTBFQNHKNRZJDS-SYWGBEHUSA-N 0.000 description 1
- UYODHPPSCXBNCS-XUXIUFHCSA-N Ile-Val-Leu Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CC(C)C UYODHPPSCXBNCS-XUXIUFHCSA-N 0.000 description 1
- 102000037982 Immune checkpoint proteins Human genes 0.000 description 1
- 108091008036 Immune checkpoint proteins Proteins 0.000 description 1
- 102000009786 Immunoglobulin Constant Regions Human genes 0.000 description 1
- 108010009817 Immunoglobulin Constant Regions Proteins 0.000 description 1
- 102100037850 Interferon gamma Human genes 0.000 description 1
- 102000008070 Interferon-gamma Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 102000015696 Interleukins Human genes 0.000 description 1
- 108010063738 Interleukins Proteins 0.000 description 1
- 208000029523 Interstitial Lung disease Diseases 0.000 description 1
- FADYJNXDPBKVCA-UHFFFAOYSA-N L-Phenylalanyl-L-lysin Natural products NCCCCC(C(O)=O)NC(=O)C(N)CC1=CC=CC=C1 FADYJNXDPBKVCA-UHFFFAOYSA-N 0.000 description 1
- SITWEMZOJNKJCH-UHFFFAOYSA-N L-alanine-L-arginine Natural products CC(N)C(=O)NC(C(O)=O)CCCNC(N)=N SITWEMZOJNKJCH-UHFFFAOYSA-N 0.000 description 1
- SENJXOPIZNYLHU-UHFFFAOYSA-N L-leucyl-L-arginine Natural products CC(C)CC(N)C(=O)NC(C(O)=O)CCCN=C(N)N SENJXOPIZNYLHU-UHFFFAOYSA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical group NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical group C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 1
- 239000002138 L01XE21 - Regorafenib Substances 0.000 description 1
- WNGVUZWBXZKQES-YUMQZZPRSA-N Leu-Ala-Gly Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C)C(=O)NCC(O)=O WNGVUZWBXZKQES-YUMQZZPRSA-N 0.000 description 1
- JKGHDYGZRDWHGA-SRVKXCTJSA-N Leu-Asn-Leu Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(O)=O JKGHDYGZRDWHGA-SRVKXCTJSA-N 0.000 description 1
- MYGQXVYRZMKRDB-SRVKXCTJSA-N Leu-Asp-Lys Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CCCCN MYGQXVYRZMKRDB-SRVKXCTJSA-N 0.000 description 1
- QLQHWWCSCLZUMA-KKUMJFAQSA-N Leu-Asp-Tyr Chemical compound CC(C)C[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 QLQHWWCSCLZUMA-KKUMJFAQSA-N 0.000 description 1
- KAFOIVJDVSZUMD-DCAQKATOSA-N Leu-Gln-Gln Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O KAFOIVJDVSZUMD-DCAQKATOSA-N 0.000 description 1
- KAFOIVJDVSZUMD-UHFFFAOYSA-N Leu-Gln-Gln Natural products CC(C)CC(N)C(=O)NC(CCC(N)=O)C(=O)NC(CCC(N)=O)C(O)=O KAFOIVJDVSZUMD-UHFFFAOYSA-N 0.000 description 1
- JRJLGNFWYFSJHB-HOCLYGCPSA-N Leu-Gly-Trp Chemical compound [H]N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O JRJLGNFWYFSJHB-HOCLYGCPSA-N 0.000 description 1
- SEMUSFOBZGKBGW-YTFOTSKYSA-N Leu-Ile-Ile Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O SEMUSFOBZGKBGW-YTFOTSKYSA-N 0.000 description 1
- YOKVEHGYYQEQOP-QWRGUYRKSA-N Leu-Leu-Gly Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O YOKVEHGYYQEQOP-QWRGUYRKSA-N 0.000 description 1
- HVHRPWQEQHIQJF-AVGNSLFASA-N Leu-Lys-Glu Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(O)=O HVHRPWQEQHIQJF-AVGNSLFASA-N 0.000 description 1
- HDHQQEDVWQGBEE-DCAQKATOSA-N Leu-Met-Ser Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CO)C(O)=O HDHQQEDVWQGBEE-DCAQKATOSA-N 0.000 description 1
- RRVCZCNFXIFGRA-DCAQKATOSA-N Leu-Pro-Asn Chemical compound [H]N[C@@H](CC(C)C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(N)=O)C(O)=O RRVCZCNFXIFGRA-DCAQKATOSA-N 0.000 description 1
- PPGBXYKMUMHFBF-KATARQTJSA-N Leu-Ser-Thr Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(O)=O PPGBXYKMUMHFBF-KATARQTJSA-N 0.000 description 1
- WUHBLPVELFTPQK-KKUMJFAQSA-N Leu-Tyr-Asn Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(N)=O)C(O)=O WUHBLPVELFTPQK-KKUMJFAQSA-N 0.000 description 1
- FBNPMTNBFFAMMH-AVGNSLFASA-N Leu-Val-Arg Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CCCN=C(N)N FBNPMTNBFFAMMH-AVGNSLFASA-N 0.000 description 1
- FBNPMTNBFFAMMH-UHFFFAOYSA-N Leu-Val-Arg Natural products CC(C)CC(N)C(=O)NC(C(C)C)C(=O)NC(C(O)=O)CCCN=C(N)N FBNPMTNBFFAMMH-UHFFFAOYSA-N 0.000 description 1
- YQFZRHYZLARWDY-IHRRRGAJSA-N Leu-Val-Lys Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CCCCN YQFZRHYZLARWDY-IHRRRGAJSA-N 0.000 description 1
- NTXYXFDMIHXTHE-WDSOQIARSA-N Leu-Val-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CC(C)C)C(O)=O)=CNC2=C1 NTXYXFDMIHXTHE-WDSOQIARSA-N 0.000 description 1
- 102100029204 Low affinity immunoglobulin gamma Fc region receptor II-a Human genes 0.000 description 1
- 102100029205 Low affinity immunoglobulin gamma Fc region receptor II-b Human genes 0.000 description 1
- 102100029193 Low affinity immunoglobulin gamma Fc region receptor III-A Human genes 0.000 description 1
- 101710099301 Low affinity immunoglobulin gamma Fc region receptor III-A Proteins 0.000 description 1
- 102100029185 Low affinity immunoglobulin gamma Fc region receptor III-B Human genes 0.000 description 1
- 208000019693 Lung disease Diseases 0.000 description 1
- QYOXSYXPHUHOJR-GUBZILKMSA-N Lys-Asn-Glu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O QYOXSYXPHUHOJR-GUBZILKMSA-N 0.000 description 1
- NCTDKZKNBDZDOL-GARJFASQSA-N Lys-Asn-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC(=O)N)NC(=O)[C@H](CCCCN)N)C(=O)O NCTDKZKNBDZDOL-GARJFASQSA-N 0.000 description 1
- LMVOVCYVZBBWQB-SRVKXCTJSA-N Lys-Asp-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CCCCN LMVOVCYVZBBWQB-SRVKXCTJSA-N 0.000 description 1
- VEGLGAOVLFODGC-GUBZILKMSA-N Lys-Glu-Ser Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(O)=O VEGLGAOVLFODGC-GUBZILKMSA-N 0.000 description 1
- GQZMPWBZQALKJO-UWVGGRQHSA-N Lys-Gly-Arg Chemical compound [H]N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(O)=O GQZMPWBZQALKJO-UWVGGRQHSA-N 0.000 description 1
- LCMWVZLBCUVDAZ-IUCAKERBSA-N Lys-Gly-Glu Chemical compound [NH3+]CCCC[C@H]([NH3+])C(=O)NCC(=O)N[C@H](C([O-])=O)CCC([O-])=O LCMWVZLBCUVDAZ-IUCAKERBSA-N 0.000 description 1
- UETQMSASAVBGJY-QWRGUYRKSA-N Lys-Gly-His Chemical compound NCCCC[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CC1=CNC=N1 UETQMSASAVBGJY-QWRGUYRKSA-N 0.000 description 1
- CANPXOLVTMKURR-WEDXCCLWSA-N Lys-Gly-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN CANPXOLVTMKURR-WEDXCCLWSA-N 0.000 description 1
- WAIHHELKYSFIQN-XUXIUFHCSA-N Lys-Ile-Val Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C(C)C)C(O)=O WAIHHELKYSFIQN-XUXIUFHCSA-N 0.000 description 1
- JYVCOTWSRGFABJ-DCAQKATOSA-N Lys-Met-Ser Chemical compound CSCC[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CCCCN)N JYVCOTWSRGFABJ-DCAQKATOSA-N 0.000 description 1
- LUTDBHBIHHREDC-IHRRRGAJSA-N Lys-Pro-Lys Chemical compound NCCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(O)=O LUTDBHBIHHREDC-IHRRRGAJSA-N 0.000 description 1
- WQDKIVRHTQYJSN-DCAQKATOSA-N Lys-Ser-Arg Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N WQDKIVRHTQYJSN-DCAQKATOSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- YLLWCSDBVGZLOW-CIUDSAMLSA-N Met-Gln-Ala Chemical compound [H]N[C@@H](CCSC)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(O)=O YLLWCSDBVGZLOW-CIUDSAMLSA-N 0.000 description 1
- AWOMRHGUWFBDNU-ZPFDUUQYSA-N Met-Gln-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CCSC)N AWOMRHGUWFBDNU-ZPFDUUQYSA-N 0.000 description 1
- VOOINLQYUZOREH-SRVKXCTJSA-N Met-Gln-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CCSC)N VOOINLQYUZOREH-SRVKXCTJSA-N 0.000 description 1
- KQBJYJXPZBNEIK-DCAQKATOSA-N Met-Glu-Arg Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@H](C(O)=O)CCCNC(N)=N KQBJYJXPZBNEIK-DCAQKATOSA-N 0.000 description 1
- CIDICGYKRUTYLE-FXQIFTODSA-N Met-Ser-Ala Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(O)=O CIDICGYKRUTYLE-FXQIFTODSA-N 0.000 description 1
- WRXOPYNEKGZWAZ-FXQIFTODSA-N Met-Ser-Cys Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(O)=O WRXOPYNEKGZWAZ-FXQIFTODSA-N 0.000 description 1
- PESQCPHRXOFIPX-UHFFFAOYSA-N N-L-methionyl-L-tyrosine Natural products CSCCC(N)C(=O)NC(C(O)=O)CC1=CC=C(O)C=C1 PESQCPHRXOFIPX-UHFFFAOYSA-N 0.000 description 1
- AJHCSUXXECOXOY-UHFFFAOYSA-N N-glycyl-L-tryptophan Natural products C1=CC=C2C(CC(NC(=O)CN)C(O)=O)=CNC2=C1 AJHCSUXXECOXOY-UHFFFAOYSA-N 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 101100068676 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) gln-1 gene Proteins 0.000 description 1
- -1 Pdcd-1 Proteins 0.000 description 1
- 208000005228 Pericardial Effusion Diseases 0.000 description 1
- MDHZEOMXGNBSIL-DLOVCJGASA-N Phe-Ala-Cys Chemical compound C[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)N MDHZEOMXGNBSIL-DLOVCJGASA-N 0.000 description 1
- LBSARGIQACMGDF-WBAXXEDZSA-N Phe-Ala-Phe Chemical compound C([C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 LBSARGIQACMGDF-WBAXXEDZSA-N 0.000 description 1
- QEPZQAPZKIPVDV-KKUMJFAQSA-N Phe-Cys-His Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC2=CN=CN2)C(=O)O)N QEPZQAPZKIPVDV-KKUMJFAQSA-N 0.000 description 1
- BIYWZVCPZIFGPY-QWRGUYRKSA-N Phe-Gly-Ser Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)NCC(=O)N[C@@H](CO)C(O)=O BIYWZVCPZIFGPY-QWRGUYRKSA-N 0.000 description 1
- PBXYXOAEQQUVMM-ULQDDVLXSA-N Phe-His-Met Chemical compound CSCC[C@@H](C(=O)O)NC(=O)[C@H](CC1=CN=CN1)NC(=O)[C@H](CC2=CC=CC=C2)N PBXYXOAEQQUVMM-ULQDDVLXSA-N 0.000 description 1
- BWTKUQPNOMMKMA-FIRPJDEBSA-N Phe-Ile-Phe Chemical compound C([C@H](N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 BWTKUQPNOMMKMA-FIRPJDEBSA-N 0.000 description 1
- YKUGPVXSDOOANW-KKUMJFAQSA-N Phe-Leu-Asp Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O YKUGPVXSDOOANW-KKUMJFAQSA-N 0.000 description 1
- YMIZSYUAZJSOFL-SRVKXCTJSA-N Phe-Ser-Asn Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O YMIZSYUAZJSOFL-SRVKXCTJSA-N 0.000 description 1
- UNBFGVQVQGXXCK-KKUMJFAQSA-N Phe-Ser-Leu Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O UNBFGVQVQGXXCK-KKUMJFAQSA-N 0.000 description 1
- QSWKNJAPHQDAAS-MELADBBJSA-N Phe-Ser-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CO)NC(=O)[C@H](CC2=CC=CC=C2)N)C(=O)O QSWKNJAPHQDAAS-MELADBBJSA-N 0.000 description 1
- YDUGVDGFKNXFPL-IXOXFDKPSA-N Phe-Thr-Cys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)N)O YDUGVDGFKNXFPL-IXOXFDKPSA-N 0.000 description 1
- 208000002151 Pleural effusion Diseases 0.000 description 1
- 241000276498 Pollachius virens Species 0.000 description 1
- FZHBZMDRDASUHN-NAKRPEOUSA-N Pro-Ala-Ile Chemical compound CC[C@H](C)[C@H](NC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1)C(O)=O FZHBZMDRDASUHN-NAKRPEOUSA-N 0.000 description 1
- IFMDQWDAJUMMJC-DCAQKATOSA-N Pro-Ala-Leu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(O)=O IFMDQWDAJUMMJC-DCAQKATOSA-N 0.000 description 1
- LCRSGSIRKLXZMZ-BPNCWPANSA-N Pro-Ala-Tyr Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O LCRSGSIRKLXZMZ-BPNCWPANSA-N 0.000 description 1
- XROLYVMNVIKVEM-BQBZGAKWSA-N Pro-Asn-Gly Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC(N)=O)C(=O)NCC(O)=O XROLYVMNVIKVEM-BQBZGAKWSA-N 0.000 description 1
- JFNPBBOGGNMSRX-CIUDSAMLSA-N Pro-Gln-Ala Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(O)=O JFNPBBOGGNMSRX-CIUDSAMLSA-N 0.000 description 1
- LSIWVWRUTKPXDS-DCAQKATOSA-N Pro-Gln-Arg Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O LSIWVWRUTKPXDS-DCAQKATOSA-N 0.000 description 1
- KIPIKSXPPLABPN-CIUDSAMLSA-N Pro-Glu-Asn Chemical compound NC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H]1CCCN1 KIPIKSXPPLABPN-CIUDSAMLSA-N 0.000 description 1
- MGDFPGCFVJFITQ-CIUDSAMLSA-N Pro-Glu-Asp Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O MGDFPGCFVJFITQ-CIUDSAMLSA-N 0.000 description 1
- WFHYFCWBLSKEMS-KKUMJFAQSA-N Pro-Glu-Phe Chemical compound N([C@@H](CCC(=O)O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C(=O)[C@@H]1CCCN1 WFHYFCWBLSKEMS-KKUMJFAQSA-N 0.000 description 1
- LGSANCBHSMDFDY-GARJFASQSA-N Pro-Glu-Pro Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CCC(=O)O)C(=O)N2CCC[C@@H]2C(=O)O LGSANCBHSMDFDY-GARJFASQSA-N 0.000 description 1
- CLNJSLSHKJECME-BQBZGAKWSA-N Pro-Gly-Ala Chemical compound OC(=O)[C@H](C)NC(=O)CNC(=O)[C@@H]1CCCN1 CLNJSLSHKJECME-BQBZGAKWSA-N 0.000 description 1
- FFSLAIOXRMOFIZ-GJZGRUSLSA-N Pro-Gly-Trp Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)CNC(=O)[C@@H]1CCCN1 FFSLAIOXRMOFIZ-GJZGRUSLSA-N 0.000 description 1
- JUJCUYWRJMFJJF-AVGNSLFASA-N Pro-Lys-Arg Chemical compound NC(N)=NCCC[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H]1CCCN1 JUJCUYWRJMFJJF-AVGNSLFASA-N 0.000 description 1
- SPLBRAKYXGOFSO-UNQGMJICSA-N Pro-Phe-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)NC(=O)[C@@H]2CCCN2)O SPLBRAKYXGOFSO-UNQGMJICSA-N 0.000 description 1
- OWQXAJQZLWHPBH-FXQIFTODSA-N Pro-Ser-Asn Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O OWQXAJQZLWHPBH-FXQIFTODSA-N 0.000 description 1
- SNGZLPOXVRTNMB-LPEHRKFASA-N Pro-Ser-Pro Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CO)C(=O)N2CCC[C@@H]2C(=O)O SNGZLPOXVRTNMB-LPEHRKFASA-N 0.000 description 1
- KIDXAAQVMNLJFQ-KZVJFYERSA-N Pro-Thr-Ala Chemical compound C[C@@H](O)[C@H](NC(=O)[C@@H]1CCCN1)C(=O)N[C@@H](C)C(O)=O KIDXAAQVMNLJFQ-KZVJFYERSA-N 0.000 description 1
- SNSYSBUTTJBPDG-OKZBNKHCSA-N Pro-Trp-Pro Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CC2=CNC3=CC=CC=C32)C(=O)N4CCC[C@@H]4C(=O)O SNSYSBUTTJBPDG-OKZBNKHCSA-N 0.000 description 1
- HRNQLKCLPVKZNE-CIUDSAMLSA-N Ser-Ala-Leu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(O)=O HRNQLKCLPVKZNE-CIUDSAMLSA-N 0.000 description 1
- 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 1
- BQWCDDAISCPDQV-XHNCKOQMSA-N Ser-Gln-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CO)N)C(=O)O BQWCDDAISCPDQV-XHNCKOQMSA-N 0.000 description 1
- UAJAYRMZGNQILN-BQBZGAKWSA-N Ser-Gly-Met Chemical compound [H]N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CCSC)C(O)=O UAJAYRMZGNQILN-BQBZGAKWSA-N 0.000 description 1
- JFWDJFULOLKQFY-QWRGUYRKSA-N Ser-Gly-Phe Chemical compound [H]N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O JFWDJFULOLKQFY-QWRGUYRKSA-N 0.000 description 1
- UIPXCLNLUUAMJU-JBDRJPRFSA-N Ser-Ile-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(O)=O UIPXCLNLUUAMJU-JBDRJPRFSA-N 0.000 description 1
- ZIFYDQAFEMIZII-GUBZILKMSA-N Ser-Leu-Glu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O ZIFYDQAFEMIZII-GUBZILKMSA-N 0.000 description 1
- IXZHZUGGKLRHJD-DCAQKATOSA-N Ser-Leu-Val Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(O)=O IXZHZUGGKLRHJD-DCAQKATOSA-N 0.000 description 1
- MQUZANJDFOQOBX-SRVKXCTJSA-N Ser-Phe-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(O)=O MQUZANJDFOQOBX-SRVKXCTJSA-N 0.000 description 1
- QMCDMHWAKMUGJE-IHRRRGAJSA-N Ser-Phe-Val Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](C(C)C)C(O)=O QMCDMHWAKMUGJE-IHRRRGAJSA-N 0.000 description 1
- 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 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
- WLJPJRGQRNCIQS-ZLUOBGJFSA-N Ser-Ser-Asn Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O WLJPJRGQRNCIQS-ZLUOBGJFSA-N 0.000 description 1
- AXKJPUBALUNJEO-UBHSHLNASA-N Ser-Trp-Asn Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CC(N)=O)C(O)=O AXKJPUBALUNJEO-UBHSHLNASA-N 0.000 description 1
- YXGCIEUDOHILKR-IHRRRGAJSA-N Ser-Tyr-Met Chemical compound CSCC[C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)NC(=O)[C@H](CO)N YXGCIEUDOHILKR-IHRRRGAJSA-N 0.000 description 1
- JGUWRQWULDWNCM-FXQIFTODSA-N Ser-Val-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(O)=O JGUWRQWULDWNCM-FXQIFTODSA-N 0.000 description 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
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 108010003723 Single-Domain Antibodies Proteins 0.000 description 1
- 206010040914 Skin reaction Diseases 0.000 description 1
- GFDUZZACIWNMPE-KZVJFYERSA-N Thr-Ala-Met Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCSC)C(O)=O GFDUZZACIWNMPE-KZVJFYERSA-N 0.000 description 1
- DGDCHPCRMWEOJR-FQPOAREZSA-N Thr-Ala-Tyr Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 DGDCHPCRMWEOJR-FQPOAREZSA-N 0.000 description 1
- UNURFMVMXLENAZ-KJEVXHAQSA-N Thr-Arg-Tyr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O UNURFMVMXLENAZ-KJEVXHAQSA-N 0.000 description 1
- JVTHIXKSVYEWNI-JRQIVUDYSA-N Thr-Asn-Tyr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O JVTHIXKSVYEWNI-JRQIVUDYSA-N 0.000 description 1
- YOSLMIPKOUAHKI-OLHMAJIHSA-N Thr-Asp-Asp Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O YOSLMIPKOUAHKI-OLHMAJIHSA-N 0.000 description 1
- MMTOHPRBJKEZHT-BWBBJGPYSA-N Thr-Cys-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(=O)N[C@@H](CO)C(O)=O MMTOHPRBJKEZHT-BWBBJGPYSA-N 0.000 description 1
- LIXBDERDAGNVAV-XKBZYTNZSA-N Thr-Gln-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(O)=O LIXBDERDAGNVAV-XKBZYTNZSA-N 0.000 description 1
- FHDLKMFZKRUQCE-HJGDQZAQSA-N Thr-Glu-Arg Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O FHDLKMFZKRUQCE-HJGDQZAQSA-N 0.000 description 1
- ZSPQUTWLWGWTPS-HJGDQZAQSA-N Thr-Lys-Asp Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(O)=O ZSPQUTWLWGWTPS-HJGDQZAQSA-N 0.000 description 1
- LHNNQVXITHUCAB-QTKMDUPCSA-N Thr-Met-His Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N)O LHNNQVXITHUCAB-QTKMDUPCSA-N 0.000 description 1
- KPNSNVTUVKSBFL-ZJDVBMNYSA-N Thr-Met-Thr Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCSC)C(=O)N[C@@H]([C@@H](C)O)C(=O)O)N)O KPNSNVTUVKSBFL-ZJDVBMNYSA-N 0.000 description 1
- 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 1
- GFRIEEKFXOVPIR-RHYQMDGZSA-N Thr-Pro-Lys Chemical compound C[C@@H](O)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(O)=O GFRIEEKFXOVPIR-RHYQMDGZSA-N 0.000 description 1
- DOBIBIXIHJKVJF-XKBZYTNZSA-N Thr-Ser-Gln Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CCC(N)=O DOBIBIXIHJKVJF-XKBZYTNZSA-N 0.000 description 1
- YRJOLUDFVAUXLI-GSSVUCPTSA-N Thr-Thr-Asp Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@H](C(O)=O)CC(O)=O YRJOLUDFVAUXLI-GSSVUCPTSA-N 0.000 description 1
- BBPCSGKKPJUYRB-UVOCVTCTSA-N Thr-Thr-Leu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O BBPCSGKKPJUYRB-UVOCVTCTSA-N 0.000 description 1
- CSNBWOJOEOPYIJ-UVOCVTCTSA-N Thr-Thr-Lys Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(O)=O CSNBWOJOEOPYIJ-UVOCVTCTSA-N 0.000 description 1
- BZTSQFWJNJYZSX-JRQIVUDYSA-N Thr-Tyr-Asp Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(O)=O)C(O)=O BZTSQFWJNJYZSX-JRQIVUDYSA-N 0.000 description 1
- XVHAUVJXBFGUPC-RPTUDFQQSA-N Thr-Tyr-Phe Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O XVHAUVJXBFGUPC-RPTUDFQQSA-N 0.000 description 1
- YOPQYBJJNSIQGZ-JNPHEJMOSA-N Thr-Tyr-Tyr Chemical compound C([C@H](NC(=O)[C@@H](N)[C@H](O)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C1=CC=C(O)C=C1 YOPQYBJJNSIQGZ-JNPHEJMOSA-N 0.000 description 1
- FYBFTPLPAXZBOY-KKHAAJSZSA-N Thr-Val-Asp Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O FYBFTPLPAXZBOY-KKHAAJSZSA-N 0.000 description 1
- QGVBFDIREUUSHX-IFFSRLJSSA-N Thr-Val-Gln Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O QGVBFDIREUUSHX-IFFSRLJSSA-N 0.000 description 1
- PWONLXBUSVIZPH-RHYQMDGZSA-N Thr-Val-Lys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)O)N)O PWONLXBUSVIZPH-RHYQMDGZSA-N 0.000 description 1
- VTHNLRXALGUDBS-BPUTZDHNSA-N Trp-Gln-Glu Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N VTHNLRXALGUDBS-BPUTZDHNSA-N 0.000 description 1
- UDCHKDYNMRJYMI-QEJZJMRPSA-N Trp-Glu-Ser Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(O)=O UDCHKDYNMRJYMI-QEJZJMRPSA-N 0.000 description 1
- WNZRNOGHEONFMS-PXDAIIFMSA-N Trp-Ile-Tyr Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O WNZRNOGHEONFMS-PXDAIIFMSA-N 0.000 description 1
- PWPJLBWYRTVYQS-PMVMPFDFSA-N Trp-Phe-Leu Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(C)C)C(O)=O PWPJLBWYRTVYQS-PMVMPFDFSA-N 0.000 description 1
- BURPTJBFWIOHEY-UWJYBYFXSA-N Tyr-Ala-Asp Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 BURPTJBFWIOHEY-UWJYBYFXSA-N 0.000 description 1
- JBBYKPZAPOLCPK-JYJNAYRXSA-N Tyr-Arg-Met 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](CCSC)C(O)=O JBBYKPZAPOLCPK-JYJNAYRXSA-N 0.000 description 1
- PEVVXUGSAKEPEN-AVGNSLFASA-N Tyr-Asn-Glu Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O PEVVXUGSAKEPEN-AVGNSLFASA-N 0.000 description 1
- SCCKSNREWHMKOJ-SRVKXCTJSA-N Tyr-Asn-Ser Chemical compound N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(O)=O SCCKSNREWHMKOJ-SRVKXCTJSA-N 0.000 description 1
- BEIGSKUPTIFYRZ-SRVKXCTJSA-N Tyr-Asp-Asp Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC(=O)O)C(=O)O)N)O BEIGSKUPTIFYRZ-SRVKXCTJSA-N 0.000 description 1
- RYSNTWVRSLCAJZ-RYUDHWBXSA-N Tyr-Gln-Gly Chemical compound OC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 RYSNTWVRSLCAJZ-RYUDHWBXSA-N 0.000 description 1
- QFXVAFIHVWXXBJ-AVGNSLFASA-N Tyr-Ser-Glu Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(O)=O QFXVAFIHVWXXBJ-AVGNSLFASA-N 0.000 description 1
- ZLFHAAGHGQBQQN-GUBZILKMSA-N Val-Ala-Pro Natural products CC(C)[C@H](N)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O ZLFHAAGHGQBQQN-GUBZILKMSA-N 0.000 description 1
- SLLKXDSRVAOREO-KZVJFYERSA-N Val-Ala-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](C)NC(=O)[C@H](C(C)C)N)O SLLKXDSRVAOREO-KZVJFYERSA-N 0.000 description 1
- XIFAHCUNWWKUDE-DCAQKATOSA-N Val-Cys-Lys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CCCCN)C(=O)O)N XIFAHCUNWWKUDE-DCAQKATOSA-N 0.000 description 1
- HQYVQDRYODWONX-DCAQKATOSA-N Val-His-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)N[C@@H](CO)C(=O)O)N HQYVQDRYODWONX-DCAQKATOSA-N 0.000 description 1
- KDKLLPMFFGYQJD-CYDGBPFRSA-N Val-Ile-Arg Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)NC(=O)[C@H](C(C)C)N KDKLLPMFFGYQJD-CYDGBPFRSA-N 0.000 description 1
- HPANGHISDXDUQY-ULQDDVLXSA-N Val-Lys-Phe Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)N HPANGHISDXDUQY-ULQDDVLXSA-N 0.000 description 1
- MIKHIIQMRFYVOR-RCWTZXSCSA-N Val-Pro-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@@H]1CCCN1C(=O)[C@H](C(C)C)N)O MIKHIIQMRFYVOR-RCWTZXSCSA-N 0.000 description 1
- DEGUERSKQBRZMZ-FXQIFTODSA-N Val-Ser-Ala Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(O)=O DEGUERSKQBRZMZ-FXQIFTODSA-N 0.000 description 1
- CEKSLIVSNNGOKH-KZVJFYERSA-N Val-Thr-Ala Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](C)C(=O)O)NC(=O)[C@H](C(C)C)N)O CEKSLIVSNNGOKH-KZVJFYERSA-N 0.000 description 1
- HTONZBWRYUKUKC-RCWTZXSCSA-N Val-Thr-Val Chemical compound CC(C)[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(O)=O HTONZBWRYUKUKC-RCWTZXSCSA-N 0.000 description 1
- PGBMPFKFKXYROZ-UFYCRDLUSA-N Val-Tyr-Phe Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CC2=CC=CC=C2)C(=O)O)N PGBMPFKFKXYROZ-UFYCRDLUSA-N 0.000 description 1
- RTJPAGFXOWEBAI-SRVKXCTJSA-N Val-Val-Arg Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CCCN=C(N)N RTJPAGFXOWEBAI-SRVKXCTJSA-N 0.000 description 1
- WHNSHJJNWNSTSU-BZSNNMDCSA-N Val-Val-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)C(C)C)C(O)=O)=CNC2=C1 WHNSHJJNWNSTSU-BZSNNMDCSA-N 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 208000018839 Wilson disease Diseases 0.000 description 1
- 238000002679 ablation Methods 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 238000009098 adjuvant therapy Methods 0.000 description 1
- 108010008685 alanyl-glutamyl-aspartic acid Proteins 0.000 description 1
- 108010005233 alanylglutamic acid Proteins 0.000 description 1
- 108010070944 alanylhistidine Proteins 0.000 description 1
- 201000007930 alcohol dependence Diseases 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 102000015395 alpha 1-Antitrypsin Human genes 0.000 description 1
- 108010050122 alpha 1-Antitrypsin Proteins 0.000 description 1
- 229940024142 alpha 1-antitrypsin Drugs 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000011319 anticancer therapy Methods 0.000 description 1
- 210000000612 antigen-presenting cell Anatomy 0.000 description 1
- 230000000890 antigenic effect Effects 0.000 description 1
- 230000036528 appetite Effects 0.000 description 1
- 235000019789 appetite Nutrition 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 238000011888 autopsy Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000001588 bifunctional effect Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 125000000837 carbohydrate group Chemical group 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- 230000010109 chemoembolization Effects 0.000 description 1
- 238000009104 chemotherapy regimen Methods 0.000 description 1
- 208000020403 chronic hepatitis C virus infection Diseases 0.000 description 1
- 230000007882 cirrhosis Effects 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 229960003624 creatine Drugs 0.000 description 1
- 239000006046 creatine Substances 0.000 description 1
- 229940109239 creatinine Drugs 0.000 description 1
- 239000012228 culture supernatant Substances 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 229910003460 diamond Inorganic materials 0.000 description 1
- 239000010432 diamond Substances 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 229960000980 entecavir Drugs 0.000 description 1
- YXPVEXCTPGULBZ-WQYNNSOESA-N entecavir hydrate Chemical compound O.C1=NC=2C(=O)NC(N)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)C1=C YXPVEXCTPGULBZ-WQYNNSOESA-N 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 125000000291 glutamic acid group Chemical class N[C@@H](CCC(O)=O)C(=O)* 0.000 description 1
- 108010057083 glutamyl-aspartyl-leucine Proteins 0.000 description 1
- 108010073628 glutamyl-valyl-phenylalanine Proteins 0.000 description 1
- 108010079547 glutamylmethionine Proteins 0.000 description 1
- 108010067216 glycyl-glycyl-glycine Proteins 0.000 description 1
- 108010051307 glycyl-glycyl-proline Proteins 0.000 description 1
- 108010084389 glycyltryptophan Proteins 0.000 description 1
- 108010037850 glycylvaline Proteins 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 208000007386 hepatic encephalopathy Diseases 0.000 description 1
- 208000010710 hepatitis C virus infection Diseases 0.000 description 1
- 210000003494 hepatocyte Anatomy 0.000 description 1
- 208000003532 hypothyroidism Diseases 0.000 description 1
- 230000002989 hypothyroidism Effects 0.000 description 1
- 230000005746 immune checkpoint blockade Effects 0.000 description 1
- 229940027941 immunoglobulin g Drugs 0.000 description 1
- 229940072221 immunoglobulins Drugs 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 229940125721 immunosuppressive agent Drugs 0.000 description 1
- 230000001024 immunotherapeutic effect Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 108091008042 inhibitory receptors Proteins 0.000 description 1
- 229940079322 interferon Drugs 0.000 description 1
- 229960003130 interferon gamma Drugs 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 108010000761 leucylarginine Proteins 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 230000005976 liver dysfunction Effects 0.000 description 1
- 230000003908 liver function Effects 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 108010057952 lysyl-phenylalanyl-lysine Proteins 0.000 description 1
- 108010009298 lysylglutamic acid Proteins 0.000 description 1
- 108010038320 lysylphenylalanine Proteins 0.000 description 1
- 231100000682 maximum tolerated dose Toxicity 0.000 description 1
- 229930182817 methionine Chemical group 0.000 description 1
- 125000001360 methionine group Chemical group N[C@@H](CCSC)C(=O)* 0.000 description 1
- 108010056582 methionylglutamic acid Proteins 0.000 description 1
- 229960004584 methylprednisolone Drugs 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 238000009521 phase II clinical trial Methods 0.000 description 1
- 108010018625 phenylalanylarginine Proteins 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 238000010837 poor prognosis Methods 0.000 description 1
- 229960004618 prednisone Drugs 0.000 description 1
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000002250 progressing effect Effects 0.000 description 1
- 208000037821 progressive disease Diseases 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 125000001500 prolyl group Chemical group [H]N1C([H])(C(=O)[*])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 108010004914 prolylarginine Proteins 0.000 description 1
- 108010029020 prolylglycine Proteins 0.000 description 1
- 108010053725 prolylvaline Proteins 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 208000005069 pulmonary fibrosis Diseases 0.000 description 1
- 229960004836 regorafenib Drugs 0.000 description 1
- FNHKPVJBJVTLMP-UHFFFAOYSA-N regorafenib Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=C(F)C(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 FNHKPVJBJVTLMP-UHFFFAOYSA-N 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 201000009890 sinusitis Diseases 0.000 description 1
- 238000005549 size reduction Methods 0.000 description 1
- 230000035483 skin reaction Effects 0.000 description 1
- 231100000430 skin reaction Toxicity 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000011285 therapeutic regimen Methods 0.000 description 1
- 125000000341 threoninyl group Chemical group [H]OC([H])(C([H])([H])[H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 108700004896 tripeptide FEG Proteins 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 108010003137 tyrosyltyrosine Proteins 0.000 description 1
- 125000002987 valine group Chemical group [H]N([H])C([H])(C(*)=O)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- IBIDRSSEHFLGSD-UHFFFAOYSA-N valinyl-arginine Natural products CC(C)C(N)C(=O)NC(C(O)=O)CCCN=C(N)N IBIDRSSEHFLGSD-UHFFFAOYSA-N 0.000 description 1
- 230000009790 vascular invasion Effects 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 108010000998 wheylin-2 peptide Proteins 0.000 description 1
Images
Classifications
-
- 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
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
- C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
-
- 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
- A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
-
- 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
- A61K2039/55—Medicinal preparations containing antigens or antibodies characterised by the host/recipient, e.g. newborn with maternal antibodies
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/52—Constant or Fc region; Isotype
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/71—Decreased effector function due to an Fc-modification
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Immunology (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Genetics & Genomics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Molecular Biology (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Microbiology (AREA)
- Mycology (AREA)
- Epidemiology (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
인간 PD-1에 특이적으로 결합하는 항체 또는 이의 항원 결합 단편인, 항-PD-1 항체를 이를 필요로 하는 대상체에게 치료적 유효량으로 투여하는 단계를 포함하는, 대상체에서 간세포암 (hepatocellular carcinoma)을 예방, 진행의 지연, 치료하기 위한 방법이 본원에 개시된다.
Description
본 출원은 미국 가출원 번호 62/524,967 및 국제 특허출원번호 PCT/CN2017 /090397에 우선권이 있음을 주장하고, 이들 각각의 개시 내용은 모든 목적을 위해 그 전문이 본원에 참조로 포함된다.
항체 의존성 포식작용(phagocytosis)을 제거하기 위하여 대식세포(macrophages)에서 FcγR 결합을 최소화하도록 특이적으로 조작된 항-PD-1 항체를 환자에게 투여하는 단계를 포함하는 간세포암(hepatocellular carcinoma: HCC) 환자의 면역치료방법이 본원에 개시된다.
간세포암 (hepatocellular carcinoma: HCC)은 세계에서 가장 흔한 암 중 하나이며, 그 악성 (malignancy)으로 인해 암 관련 사망률이 세계적으로 세 번째로 높은 질환이다. 만성 B 형 간염 또는 C 바이러스 감염 또는 아플라톡신(aflatoxin) 섭취 후 염증으로 인해 또는 과도한 알코올 소비로 인해 간세포암(hepatocellular carcinoma: HCC)은 만성 간염 환자에서 발병한다.
대부분의 간세포암 (hepatocellular carcinoma: HCC) 환자는 진행성(advanced) 단계 또는 간 기능이 좋지 않은 상태에서 최초 진단되어, 잠재적인 치료 용법의 사용을 막는다. 진행성 단계 질병의 환자에 대한 치료 옵션은 중등도의 효능 및 상당한 독성을 갖는 유일하게 승인된 1차 치료제인 소라페닙 (sorafenib)을 포함하는 화학색전술 (chemoembolization) 또는 전신 요법 (systemic therapies)으로 제한된다 [Samonakis DN, Kouroumalis EA. Systemic treatment for hepatocellular carcinoma: Still unmet expectations. World J Hepatol. 2017;9(2):80-90.]. 이러한 접근법은 임상 결과를 개선시켰지만, 진행성 단계의 질병이 있는 환자의 경우, HCC 환자의 생존은 1년 미만으로 남아 있고, 잠재적인 치료적 수술 및 절제 (ablation) 후에도 환자는 질병 재발 위험이 높다. 간 기능 장애로 인한 이러한 환자는 독성 화학 요법에 종종 잘 견디지 못하기 때문에, 신규한 면역요법이 진행성 HCC에 대한 가능성을 갖게 된다.
면역 체크 포인트(immune checkpoint) 억제 수용체, programmed cell death-1 (PD-1)에 대한 단일 클론 항체는 HCC를 포함하여 [El-Khoueiry AB, Sangro B, Yau T, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet. 2017;389(10088):2492-2502] 다수의 악성 종양에 대해 항종양 활성을 입증하였다 [Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366(26):2443?2454.]. 그러나 HBV에 감염된 그룹의 반응률은 니볼루맙 (Nivolumab)에 대해 보고된 바와 같이 상대적으로 낮다(7%)[M. Kudo, Immune Checkpoint Blockade in Hepatocellular Carcinoma: 2017 Update, Liver Cancer 2017; 6:1-12]. 지금까지 HBV에 감염된 HCC는 예후가 좋지 않다. 따라서, 진행성(advanced) HCC, 특히 감염에 의한 HCC에 대한 높은 반응률을 갖는 새로운 면역 요법이 필요하다.
본원에는 치료적 유효량의 항-PD-1 항체 또는 이의 항원 결합 단편을 환자에게 투여하는 단계를 포함하는 간세포암(hepatocellular carcinoma: HCC) 환자의 면역 요법 방법이 개시된다. 일부 양태에서, 상기 항-PD-1 항체 또는 이의 항원 결합 단편은 대식세포(macrophages)에서 FcγR 결합을 최소화하여 항체-의존성 식균작용(antibody-dependent phagocytosis)을 제거하도록 특이적으로 조작되었다.
일 양태에서, 상기 HCC는 진행성(advanced) HCC 및/또는 전이성(metastatic) HCC이다. 다른 양태에서, 상기 진행성 HCC는 HBV-감염 HCC, 또는 HCV-감염 HCC, 또는 HBV/HCV 공동-감염 HCC이다. 바람직하게는,상기 진행성(advanced) HCC는 진행성(advanced) HBV-감염 HCC, 전이성(metastatic) HBV-감염 HCC, HCV-감염 HCC 또는 전이성(metastatic) HCV-감염 HCC이다.
일부 양태에서, 상기 항-PD-1 항체는 WO2015/035606A1 또는 미국 특허번호 8,735,553에 개시된 것이며, 이의 전체 내용은 본원에 참고로 포함된다. WO2015 / 035606A1 및 미국 특허번호 8,735,553에 개시된 항체는 PD-1 (Programmed Death-1)에 특이적으로 결합하고 면역 세포에서 PD-1 매개되는 세포 신호 및 활성을 억제한다. 일부 양태에서, 항체는 그의 리간드(Programmed death-ligand 1, PD-L1) 결합에 필요한 아미노산 잔기 세트에 결합한다. 특히, 상기 항-PD-1 항체는 PD-1에 특이적으로 결합하는, 중쇄 가변영역(Vh) 및 경쇄 가변영역(Vk)(각각 서열번호 24 및 서열번호 26을 포함함) 및 IgG4 중쇄 효과기(effector) 또는 불변 도메인(서열번호 88을 포함함), 이하 Mab-1,을 포함하는 인간화된 단일클론 항체(humanized monoclonal antibody)이다. 일부 양태에서, 상기 항체는 K45 및 I93; 또는, I93, L95 및 P97를 포함하는 PD-1 잔기에 결합하여 면역 세포에서 PD-1-매개된 세포 신호 전달 및 활성을 억제하고, 상기 항체는 그의 리간드 결합에 필요한 아미노산 잔기 세트에 결합한다. 본원에 개시된 면역치료방법은 HCC, 또는 진행성(advanced) HCC, 특히 감염성 진행성(advanced) HCC를 예방, 진행 지연, 완화 및 따라서 치료하는 것으로 입증되었으며, 본원에 개시된 항-PD-1 항체의 독성 프로파일은 일반적으로 부작용 (AE)의 심각도가 낮고, 관리 가능하고 가역적임을 입증한다. 따라서, 본 발명은 다른 PD-1 항체에 비해 HCC에서 우수한 효과를 갖는 PD-1 항체를 제공한다.
본 출원의 발명자들은 Mab-1 치료가 진행성(advanced) HCC를 갖는 기치료된 환자(pretreated patients)에서 내약성이 우수하다는 것을 발견하였다. 예비 안전성 프로파일 및 항종양 활성은 진행성(advanced) HCC 환자, 특히 HBV 감염 HCC, HCV 감염 HCC 및 HBV/HCV- 감염 HCC를 포함한 전염성 HCC 환자에서 Mab-1의 지속적인 개발을 지지한다.
도 1은 본 출원에서 사용된 항-PD-1 항체의 T-세포 제거(T-cell clearance)의 잠재적 메카니즘, 즉 FcγR 결합의 결여 또는 감소가 대식세포(macrophages)-매개 T- 세포 제거를 방지함을 보여준다.
도 2는 1a/1b 상 연구의 연구 설계의 개략도를 보여준다.
도 3은 1a/1b 상 연구에서 간염 바이러스 감염 상태(hepatitis virus infection status)에 의한 종양 크기의 최상의 변화를 보여준다.
도 4는 1a/1b 상 연구에서의 치료 기간 및 반응을 보여준다.
도 5는 1a/1b 상 연구에서 부분 반응을 보이는 3명의 환자에서 기준선 (baseline) 및 가장 최근의 CT 평가를 보여준다.
도 6은 1a/1b 상 연구에서 시간에 따른 종양 크기(tumor burden)의 변화를 보여준다.
도 7은 1a/1b 단계 연구에서 기준선으로부터 알파-페토 프로테인(AFP)의 변화를 보여준다.
도 8은 3 상 연구의 연구 설계를 보여준다.
도 2는 1a/1b 상 연구의 연구 설계의 개략도를 보여준다.
도 3은 1a/1b 상 연구에서 간염 바이러스 감염 상태(hepatitis virus infection status)에 의한 종양 크기의 최상의 변화를 보여준다.
도 4는 1a/1b 상 연구에서의 치료 기간 및 반응을 보여준다.
도 5는 1a/1b 상 연구에서 부분 반응을 보이는 3명의 환자에서 기준선 (baseline) 및 가장 최근의 CT 평가를 보여준다.
도 6은 1a/1b 상 연구에서 시간에 따른 종양 크기(tumor burden)의 변화를 보여준다.
도 7은 1a/1b 단계 연구에서 기준선으로부터 알파-페토 프로테인(AFP)의 변화를 보여준다.
도 8은 3 상 연구의 연구 설계를 보여준다.
약어 (Abbreviations)
본원에 개시된 상세한 설명 및 실시예를 통해, 표 1에 제공된 하기 약어가 사용될 것이다:
| AE BID CDR DPBS IgG i.p. i.v. IFN-γ mAb MTD NK PD-1 PDX p.o. QW Q2W Q3W Q4W TILs Vh Vk |
부작용 (Adverse event) 매일 두 번 (Twice daily) 상보성 결정 영역 (Complementarity determining region) 둘베코 인산염 완충 식염수 (Dulbecco's Phosphate Buffered Saline) 면역글로불린 G (immunoglobulin G) 복강 내 (Intraperitoneal or Intraperitoneally) 정맥 내 (intravenous or intravenously) 인터페론-γ (Interferon-γ) 단일클론 항체 (Monoclonal antibodies) 최대 허용량 (Maximum tolerated dose) 자연 살상 (Natural killer) Programmed Death 1 단백질, Pdcd-1, 또는 CD279 환자 유래 이종 이식 (Patient-derived xenograft) "입으로" 또는 "os 당" ("by mouth" or "per os") 일주일에 한 번 (Once weekly) 2주에 한 번 (Once every two weeks) 3주에 한 번 (Once every three weeks) 4주에 한 번 (Once every four weeks) 종양 침윤 림프구 (Tumor-infiltrating lymphocytes) 중쇄 가변영역 (Heavy chain variable region) 경쇄 가변영역 (Light chain variable region) |
정의 (Definitions)
본 명세서의 다른 부분에서 구체적으로 정의되지 않는 한, 본원에서 사용된 모든 다른 기술적 및 과학적 용어는 본 발명이 속하는 기술 분야의 당업자에 의해 일반적으로 이해되는 의미를 갖는다.
첨부된 청구 범위를 포함하여 본 명세서에 사용된 바와 같이, " a ", " an " 및 " the "와 같은 단수 형태의 단어는 문맥상 명백하게 다르게 지시되지 않는 한, 대응하는 복수의 참조 (references)를 포함한다.
본원에서 용어 " 항체 (antibody) "는 가장 넓은 의미로 사용되며, 구체적으로 PD-1을 인식하는 한, 항체(전장 단일클론 항체 포함) 및 항체 단편을 포함한다. 항체 분자는 일반적으로 단일 특이적이지만, 특정 특이성 (idiospecific), 이종 특이성 (heterospecific) 또는 다중 특이성 (polyspecific)으로 기술될 수도 있다. 항체 분자는 특이적 결합 부위에 의해 항원 상의 특이적 항원 결정기 또는 에피토프에 결합한다. "항체 단편(antibody fragments)" 또는 "항원 결합 단편(antigen binding fragments"는 전장 항체의 일부, 일반적으로 그의 항원 결합 또는 가변영역을 포함한다. 항체 단편의 예는 Fab, Fab', F(ab')2 및 Fv 단편; 다이아바디(diabodies); 선형 항체(linear antibodies); 단일쇄 항체 분자(single-chain antibody molecules); 및 항체 단편으로부터 형성된 다중 특이적 항체를 포함한다.
본원에서 용어 " 단일클론 항체(monoclonal antibody) " 또는 " mAb " 또는 " Mab "는 실질적으로 균질한 항체의 집단을 의미하고, 즉 집단에 포함되는 상기 항체 분자는 소량으로 존재할 수 있는 자연 발생 가능한 돌연변이를 제외하고 아미노산 서열이 동일하다. 대조적으로, 통상적인 (폴리클로날)항체 제제는 전형적으로 상이한 에피토프에 특이적인 그들의 가변 도메인에서, 특히 그들의 CDR에서, 상이한 아미노산 서열을 가지는 다수의 상이한 항체를 포함한다. 이의 변형된 표현인 "단일클론의(monoclonal)"는 실질적으로 균질한 항체 집단으로부터 수득된 항체의 특성을 나타내며, 임의의 특정 방법에 의한 항체의 생산을 요구하는 것으로 해석되지 않아야 한다. 단일클론 항체(mAbs)는 당업자에게 공지된 방법으로 수득될 수 있다. 예를 들어, Kohler et al (1975); 미국특허번호 4,376,110; Ausubel et al (1987- 1999); Harlow et al (1988); 및 Colligan et al (1993)의 공지가 있다. 본원에 개시된 mAb는 IgG, IgM, IgD, IgE, IgA 및 그의 서브 클래스를 포함하는 임의의 면역 글로불린 클래스일 수 있다. mAb를 생산하는 하이브리도마는 시험관 내 또는 생체 내에서 배양될 수 있다. 개별 하이브리도마로부터의 세포가 고농도의 원하는 mAb를 함유하는 복수액을 생성하기 위한 pristine-primed Balb/c 마우스와 같은 마우스에 복강 내 주사되는 생체 내 생산에서 높은 역가의 mAb를 얻을 수 있다. 이소타입 IgM 또는 IgG의 MAb는 당업자에게 공지된 컬럼 크로마토그래피 방법을 사용하여 이러한 복수액 또는 배양 상청액으로부터 정제될 수 있다.
일반적으로, 기본 항체 구조 단위는 사량체(tetramer)를 포함한다. 각 사량체는 2개의 동일한 쌍의 폴리펩타이드 쇄를 포함하고, 각각의 쌍은 하나의 "경쇄" (약 25kDa) 및 하나의 "중쇄" (약 50-70kDa)를 갖는다. 각 쇄의 아미노-말단 부분은 주로 항원 인식을 담당하는 약 100 내지 110개 이상의 아미노산의 가변영역을 포함하고. 중쇄의 카르복시-말단 부분은 주로 이펙터 기능을 담당하는 불변 영역을 정의할 수 있다. 전형적으로, 인간 경쇄는 카파 및 람다 경쇄로 구분된다. 또한, 인간 중쇄는 전형적으로 α, δ, ε, γ 또는 μ로 분류되며, 항체의 이소 타입을 각각 IgA, IgD, IgE, IgG 및 IgM으로 정의한다. 경쇄 및 중쇄 내에서, 가변 및 불변 영역은 약 12개 이상의 아미노산의 "J" 영역에 의해 연결되고, 중쇄는 또한 약 10 개 이상의 아미노산의 "D"영역을 포함한다.
각각의 경쇄/중쇄(Vk/Vh) 쌍의 가변영역은 항체 결합 부위를 형성한다. 따라서, 온전한 항체는 일반적으로 2 개의 결합 부위를 갖는다. 이중 기능성 또는 이중 특이적 항체를 제외하고, 두 결합 부위는 일반적으로 동일하다.
전형적으로, 중쇄 및 경쇄 둘 모두의 가변 도메인은 또한 비교적 보존된 프레임워크 영역(framework region, FR) 내에 위치한 "상보성 결정 영역 (complementarity decision region)"이라고도 불리는 3 개의 초가변영역을 포함한다. CDR은 일반적으로 프레임워크 영역에 의해 정렬되어 특이적 에피토프에 결합할 수 있게 한다. 일반적으로, N- 말단에서 C- 말단으로, 경쇄 및 중쇄 가변 도메인 모두는 FR-1, CDR-1, FR-2, CDR-2, FR-3, CDR-3 및 FR-4를 포함한다. 각 도메인에 아미노산을 할당하는 것은 일반적으로 Sequences of Proteins of Immunological Interest, Kabat, et al. National Institutes of Health, Bethesda, Md. 5th ed., NIH Publ. No. 91-3242 (1991); Kabat (1978) Adv. Prot. Chem. 32: 1-75; Kabat, et al., (1977) J. Biol. Chem. 252:6609-6616; Chothia, et al, (1987) J. Mol. Biol. 196:901-917 또는 Chothia, et al, (1989) Nature 342:878-883의 정의에 따른다.
용어 " 초가변 영역 ( hypervariable region) "은 항원-결합을 담당하는 항체의 아미노산 잔기를 의미한다. 초가변영역은 "상보성 결정 영역(Complementarity determining region)" 또는 "CDR"(즉, 경쇄 가변 도메인에서 CDR-L1, CDR-L2 및 CDR-L3 및 중쇄 가변 도메인에서 CDR-H1, CDR-H2 및 CDR-H3)의 아미노산 잔기를 포함한다. Kabat et al. ( 1991 ) Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (서열에 의해 항체의 CDR 영역을 정의함)을 보라; 또한 Chothia and Lesk ( 1987 ) J. Mol . Biol . 196: 901 -917 (구조에 의해 항체의 CDR 영역을 정의함)를 보라. 용어 "프레임워크" 또는 "FR" 잔기는 본원에서 CDR 잔기로 정의되는 초가변영역 잔기 이외의 가변 도메인 잔기를 의미한다.
달리 지시되지 않는 한, " 항체 단편(antibody fragment) " 또는 " 항원 결합 단편(antigen binding fragment) "은 항체의 항원 결합 단편, 즉 전장 항체에 의해 결합되는 항원에 특이적으로 결합할 수 있는 능력을 보유하는 항체 단편, 예를 들어 하나 이상의 CDR 영역을 보유하는 단편을 의미한다. 항체 결합 단편의 예는 이에 제한되는 것은 아니나, Fab, Fab', F(ab')2 및 Fv 단편; 다이아바디; 선형 항체; 단일-쇄 항체 분자, 예를 들어 sc-Fv; 항체 단편으로부터 형성된 나노바디 및 다중 특이적 항체를 포함한다.
특정 표적 단백질에 " 특이적으로 결합하는(specifically binds to) " 항체는 다른 단백질과 비교하여 그 표적에 우선적으로 결합하는 항체이지만, 이 특이성은 절대적 결합 특이성을 요구하지는 않는다. 항체는 그의 결합이 샘플에서 표적 단백질의 존재를 결정하는 경우(예를 들어, 위양성과 같은 원하지 않는 결과의 생성 없이) 그의 의도된 표적에 대해 "특이적(specific)"인 것으로 간주된다. 본 발명에서 유용한 항체 또는 이의 결합 단편은 비-표적 단백질에 대한 친화도보다 최소 2배, 바람직하게는 최소 10배, 더 바람직하게는 최소 20배, 가장 바람직하게는 최소 100배의 친화도로 표적 단백질에 결합할 것이다. 본원의 항체는 주어진 아미노산 서열, 예를 들어 성숙된 인간 PD-1 분자의 아미노산 서열을 포함하는 폴리펩타이드에 특이적으로 결합하는 것으로 말할 수 있으며, 이는 해당 서열을 포함하는 폴리펩타이드에 결합하지만 해당 서열이 결여된 단백질에는 결합하지 않는다.
본원에서 용어 " 인간 항체(human antibody) "는 인간 면역 글로불린 단백질 서열만을 포함하는 항체를 의미한다. 인간 항체는 마우스, 마우스의 세포 또는 마우스 세포에서 유래된 하이브리도마에서 생산되는 경우 마우스 탄수화물 쇄를 함유할 수 있다. 유사하게, "마우스 항체(mouse antibody)" 또는 "랫트 항체(rat antibody)"는 각각 마우스 또는 랫트 면역 글로불린 서열만을 포함하는 항체를 의미한다.
용어 "인간화 항체(humanized antibody)"는 인간 항체 뿐만 아니라 비인간 (예: 마우스) 항체로부터의 서열을 함유하는 항체의 형태를 의미한다. 이러한 항체는 비인간 면역 글로불린으로부터 유래된 최소의 서열을 함유한다. 일반적으로 인간화 항체는 비-인간 면역글로불린과 상응하는 초가변 루프(hypervariable loops) 전체 또는 실질적인 전체와 인간 면역글로불린 서열인 FR 영역 전체 또는 실질적인 전체이로 구성된 가변 도메인을 적어도 하나, 전형적으로는 2개를 포함한다. 상기 인간화 항체는 추가적으로 면역 글로불린 불변 영역(Fc)의 적어도 일부, 전형적으로는 인간 면역글로불린을 포함한다. 접두산 "hum", "hu" 또는 "h"는 인간화 항체를 설치류 항체와 구별하는 목적으로 항체 클론 명칭에 추가된다. 인간화 형태의 설치류 항체는 일반적으로 설치류 항체의 CDR 서열을 포함하나, 인간화 항체와의 친화성 증가, 안정성 증가, 또는 다른 이유로 인해 특정 아미노산 치환기가 포함될 수 있다.
용어 "간세포암(hepatocellular carcinoma: HCC)"은 당 업계에서 통상적으로 간세포에서 발생된 암을 의미한다. 일반적으로, 간암은 간세포암종을 나타낸다. HCC는 과도한 알코올 섭취(알코올성 지방 간염) 또는 아플라톡신 섭취 후의 염증(비 알코올성 지방 간염, NASH라고도 함)에 의해 발생할 수 있다. HCC는 B 형 간염 바이러스(HBV에 의해 감염된 HCC라고도 함), C 형 간염 바이러스(HCV에 의해 감염된 HCC라고도 함) 또는 HBV와 HCV의 동시 감염(HBV/HCV에 의해 감염된 HCC라고도 함)에 의해 발생할 수 있다. 일부 실시 양태에서, HCC는 만성 B 형 간염, 만성 C 형 간염, 아플라톡신, 알코올 중독, 간경변, 비 알콜 성 지방 간염, 혈색소 침착증, 알파 1- 안티 트립신 결핍 윌슨 병, 2 형 당뇨병, 혈우병 등으로부터 발생된다. 일부 실시 양태에서, HCC는 초기 HCC, 비-전이성(non-metastatic) HCC, 1 차(primary) HCC, 진행성(advanced) HCC, 국소 진행성(locally advanced) HCC, 전이성(non-metastatic) HCC, 완화성(remission) HCC 또는 재발성(recurrent) HCC이 있다.
용어 "치료(treatment)" 또는 "치료하는(treatmenting)"는 다음의 하나 또는 하나 이상의 임상 결과에 유익하거나 바람직한 접근법을 의미할 수 있으나, 이에 제한되지 않는다: 질병으로 인한 하나 이상의 증상 완화, 질병의 정도 감소, 질병 안정화(예 : 질병 악화 예방 또는 지연), 질병의 전이(예 : 전이(metastasis)) 예방 또는 지연, 예방 또는 지연 질병의 재발, 질병의 진행 지연 또는 지연, 질병 상태 개선, 질병의 완화(부분적 또는 전체적) 제공, 질병 치료에 필요한 하나 이상의 다른 약물의 복용량 감소, 진행 지연 질병의 질, 삶의 질 향상 및/또는 생존 연장. 그러므로, HCC의 병리학적 결과의 감소는 "치료"라는 용어에 포함된다. 본 출원에서 개시된 방법은 이러한 치료 측면 중 임의의 하나 이상을 포함한다.
본 출원의 용어 "환자"는 "대상체" 용어 등과 상호 교환적으로 사용된다. 특정 실시 양태에서, 환자는 인간 환자이다. 특정 실시 양태에서, 환자는 진단을 받았거나, 치료가 필요하거니 및/또는 HCC의 위험에 처한 인간 환자이다.
달리 정의되지 않는 한, 용어 "CDR"은 Kabat 넘버링 시스템을 사용하여 정의 된 면역 글로불린 가변영역에서의 상보결정영역(Complementarity determining region: CDRs)(들)을 의미한다.
항-PD-1 항체(Anti-PD-1 antibody)
본원에서 기재된 바와 같이, 항-PD-1 항체는 인간 PD-1에 특이적으로 결합하는 항체 또는 이의 단편 항원 결합이다.
본원에서 기재된 바와 같이, 항-PD-1 항체는 표 2에 제공된 보체결정영역 (CDR)을 포함하는 중쇄 가변영역(Vh)및 경쇄 가변영역(Vk)을 포함하는 항체이다:
| a) mu317 | CDR-H1, CDR-H2 및 CDR-H3 (각각 서열번호 11, 12, 13); 및 CDR-L1, CDR-L2 및 CDR-L3 (각각 서열번호 14, 15, 16); |
| b) mu326 | CDR-H1, CDR-H2 및 CDR-H3 (각각 서열번호 17, 18, 19); 및 CDR-L1, CDR-L2 및 CDR-L3 (각각 서열번호 20, 21, 22); |
| c) 317-4B6 | CDR-H1, CDR-H2 및 CDR-H3 (각각 서열번호 31, 32, 33); 및 CDR-L1, CDR-L2 및 CDR-L3 (각각 서열번호 34, 35, 36); |
| d) 326-4A3 | CDR-H1, CDR-H2 및 CDR-H3 (각각 서열번호 37, 38, 39); 및 CDR-L1, CDR-L2 및 CDR-L3 (각각 서열번호 40, 41, 42); |
| e) 317-1H | CDR-H1, CDR-H2 및 CDR-H3 (각각 서열번호 ll, 59, 13); 및 CDR-L1, CDR-L2 및 CDR-L3 (각각 서열번호 14, 15, 16); |
| f) 317-4B2 | CDR-HL, CDR-H2 및 CDR-H3 (각각 서열번호 ll, 60, 13); 및 CDR-L1, CDR-L2 및 CDR-L3 (각각 서열번호 61 , 15, 16); |
| g) 317-4B5 | CDR-Hl, CDR-H2 및 CDR-H3 (각각 서열번호 11, 60, 13); 및 CDR-L1, CDR-L2 및 CDR-L3 (각각 서열번호 61, 15, 16); |
| h) 317-4B6 | CDR-H1, CDR-H2 및 CDR-H3 (각각 서열번호 11, 32, 13); 및 CDR-L1, CDR-L2 및 CDR-L3 (각각 서열번호 61, 15, 16); |
| i) 326-1 | CDR-H1, CDR-H2 및 CDR-H3 (각각 서열번호 17, 62, 19); 및 CDR-L1, CDR-L2 및 CDR-L3 (각각 서열번호 20, 21, 22); |
| j) 326-3B1 | CDR-H1, CDR-H2 및 CDR-H3 (각각 서열번호 17, 62, 19); 및 CDR-L1, CDR-L2 및 CDR-L3 (각각 서열번호 20, 21, 22); |
| or k) 326-3G1 | CDR-H1, CDR-H2 및 CDR-H3 (각각 서열번호 17, 62, 19); 및 CDR-L1, CDR-I2 및 CDR-L3 (각각 서열번호 20, 21, 22). |
본원에 개시된 바와 같이, 일부 양태에서, 항-PD-1 항체는 표 3에 제공되는 CDR의 임의의 조합을 포함하는 중쇄 가변영역(Vh) 및 경쇄 가변영역(Vk)을 포함하는 항체이다:
| (a) | CDR-H1 (서열번호 31), CDR-H2 (서열번호 12, 32, 59 또는 60) 및 CDR-H3 (서열번호 33), CDR-L1 (서열번호 14, 34 또는 61), CDR-L2 (서열번호 35) 및 CDR-L3 (서열번호 36); 또는 |
| (b) | CDR-H1 (서열번호 37), CDR-H2 (서열번호 18, 38 또는 62) 및 CDR-H3 (서열번호 39), CDR-L1 (서열번호 40), CDR-L2 (서열번호 41) 및 CDR-L3 (서열번호 42). |
본원에 기재된 바와 같이, 항-PD-1 항체는 표 4에 제공된 서열로부터 선택된 서열을 포함하는 중쇄 가변영역(Vh) 및 경쇄 가변영역(Vk)을 포함하는 항체이다:
| a) mu317 (각각 서열번호 4 및 6); b) mu326 (각각 서열번호 8 및 10); c) 317-4B6 (각각 서열번호 24 및 26); d) 326-4A3 (각각 서열번호 28 및 30); e) 317-4B2 (각각 서열번호 43 및 44); f) 317-4B5 (각각 서열번호 45 및 46); g) 317-1 (각각 서열번호 48 및 50); h) 326-3B1 (각각 서열번호 51 및 52); i) 326-3GI (각각 서열번호 53 및 54); j) 326-1 (각각 서열번호 56 및 58); k) 317-3A1 (각각 서열번호 64 및 26); l) 317-3C1 (각각 서열번호 65 및 26); m) 317-3E1 (각각 서열번호 66 및 26); n) 317-3F1 (각각 서열번호 67 및 26); o) 317-3G1 (각각 서열번호 68 및 26); |
p) 317-3H1 (각각 서열번호 69 및 26); q) 317-311 (각각 서열번호 70 및 26); r) 317-4B 1 (각각 서열번호 71 및 26); s) 317-4B3 (각각 서열번호 72 및 26); t) 317-4B4 (각각 서열번호 73 및 26); u) 317-4A2 (각각 서열번호 74 및 26); v) 326-3 A 1 (각각 서열번호 75 및 30); w) 326-3C1 (각각 서열번호 76 및 30); x) 326-3D1 (각각 서열번호 77 및 30); y) 326-3E1 (각각 서열번호 78 및 30); z) 326-3F1 (각각 서열번호 79 및 30); aa) 326-3B N55D (각각 서열번호 80 및 30); ab) 326-4A1 (각각 서열번호 28 및 81); 또는 ac) 326-4A2 (각각 서열번호 28 및 82). |
일부 실시 양태에서, 본원에서 제공된 항-PD-1 항체는 FcγR에 대한 결합을 감소시키는 아미노산 돌연변이를 포함하는 중쇄 이펙터 또는 불변 도메인을 포함한다. 항체는 안정성이 강화된 효과기(effector) 또는 불변 도메인의 돌연변이를 하나 또는 그 이상 포함할 수 있다. 일부 실시 양태에서, 항체는 IgG4 Fc 영역을 포함한다. 일부 실시 양태에서, 항체는 FcγR에 대한 결합을 감소시키는 하나 이상의 아미노산 돌연변이를 포함하는 IgG4 Fc 영역을 포함한다. 예를 들어, 일부 실시 양태의 항체는 FcγRI, FcγRIIA, FcγRIIB, FcγRIIIA 및/또는 FcγRIIIB에 대한 결합을 감소 시키거나 제거하는 돌연변이를 포함하는 IgG4 Fc 영역을 포함한다.
일부 실시 양태에서, 항체는 228 위치에서 세린이 프롤린로 돌연변이된 IgG4 Fc 영역(EU 넘버링 시스템)을 포함한다. 일부 구체적인 예에서, 상기 돌연변이는 S228P 돌연변이로 지칭된다. 일부 실시 양태에서, 항체는 위치 233, 234, 235, 265, 309 및 409 (EU 넘버링 시스템) 중 하나 이상에서 돌연변이를 갖는 IgG4 Fc 영역을 포함한다. 예를 들어, 일부 실시 양태의 항체는 228 위치 및 하나 이상의 다른 위치에서 돌연변이된 IgG4 영역을 포함하고, 여기서 하나 이상의 다른 위치의 돌연변이는 하나 또는 그 이상의 FcγR에 대한 결합을 감소시킨다. 추가 실시 양태에서, 항체는 위치 228와 적어도 2, 적어도 3, 적어도 4, 적어도 5, 또는 적어도 6 개의 추가 위치에서 돌연변이를 갖는 IgG4 영역을 포함하며, 여기서 하나 이상의 추가 돌연변이는 하나 이상의 FcγR에 대한 결합을 감소시킨다. 일부 실시 양태에서, 항체는 위치 234 및 235에 돌연변이를 갖는 IgG4 영역을 포함한다. 일부 실시 양태에서, 항체는 위치 233, 235 및 235에서 돌연변이를 갖는 IgG4 영역을 포함한다. 일부 실시 양태에서, 항체는 위치 234, 235 및 265에서 돌연변이를 갖는 IgG4 영역을 포함한다. 일부 실시 양태에서, 항체는 위치 233, 234, 235 및 265에서 돌연변이를 갖는 IgG4 영역을 포함한다. 일부 실시 양태에서, 항체는 위치 234, 235, 265 및 409에서 돌연변이를 갖는 IgG4 영역을 포함한다. 일부 실시 양태에서, 항체는 위치 233, 234, 235, 265 및 409에서 돌연변이를 갖는 IgG4 영역을 포함한다. 일부 실시 양태에서, 항체는 위치 234, 235, 265, 309 및 409에서 돌연변이를 갖는 IgG4 영역을 포함한다. 일부 실시 양태에서, 항체는 위치 233, 234, 235, 265, 309 및 409에서 돌연변이를 갖는 IgG4 영역을 포함한다. 위치 234에서의 돌연변이는 페닐알라닌에서 발린으로의 치환 또는 페닐알라닌에서 알라닌으로의 치환일 수 있다. 위치 235에서의 돌연변이는 류신에서 알라닌으로의 치환일 수 있다. 233 위치의 돌연변이는 글루탐산이 프롤린으로의 치환 일 수 있다. 위치 265에서의 돌연변이는 아스파르트산에서 발린으로의 치환 또는 아스파르트산에서 트레오닌으로의 치환 일 수 있다. 위치 309에서의 돌연변이는 류신에서 발린으로의 치환 일 수 있다. 위치 409에서의 돌연변이는 아르기닌에서 리신, 트레오닌 또는 메티오닌 치환 일 수있다. 예시적인 IgG4 Fc 영역은 하기 표 5에 제공된다.
|
IgG4
변이체
돌연변이된 위치 |
아미노산 서열 | 서열번호 | |
| WT IgG4 | ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPSCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK | 107 | |
| 228P | ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCP P CPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK | 83 | |
| 228P233P | ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCP P CPAP P EFGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK | 91 | |
| 228P234V | ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCP P CPAPE V FGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK | 92 | |
| 228P235A | ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCP P CPAPEF A GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK | 93 | |
| 228P234V 235A |
ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCP P CPAPE VA GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK | 94 | |
| 228P234A | ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCP P CPAPE A FGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK | 95 | |
| 228P234A 235A |
ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCP P CPAPE AA GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK | 96 | |
| 228P233P 234V 235A |
ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPPVAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK | 84 | |
| 228P233P 234A 235A |
ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCP P CPAP PAA GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK | 97 | |
| 228P234V 235A 265A |
ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCP P CPAPE VA GGPSVFLFPPKPKDTLMISRTPEVTCVVV A VSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK | 98 | |
| 228P234A 235A 265A |
ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCP P CPAPE AA GGPSVFLFPPKPKDTLMISRTPEVTCVVV A VSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK | 99 | |
| 228P233P 234V 235A 265A |
ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCP P CPAP PVA GGPSVFLFPPKPKDTLMISRTPEVTCVVV A VSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK | 85 | |
| 228P233P 234A 235A 265A |
ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCP P CPAP PAA GGPSVFLFPPKPKDTLMISRTPEVTCVVV A VSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK | 100 | |
| 228P265A | ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCP P CPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVV A VSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK | 101 | |
| 228P309V | ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCP P CPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTV V HQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK | 102 | |
| 228P409K | ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCP P CPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYS K LTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK | 103 | |
| 228P309V 409K |
ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCP P CPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTV V HQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYS K LTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK | 104 | |
| 228P265A 309V 409K |
ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCP P CPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVV A VSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTV V HQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYS K LTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK | 105 | |
| 228P233P 234V 235A 265T |
ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCP P CPAP PVA GGPSVFLFPPKPKDTLMISRTPEVTCVVV T VSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK | 86 | |
| 228P233P 234V 235A 265A 409K |
ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCP P CPAP PVA GGPSVFLFPPKPKDTLMISRTPEVTCVVV A VSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYS K LTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK | 87 | |
| 228P233P 234V 235A 265A 309V 409K |
ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCP P CPAP PVA GGPSVFLFPPKPKDTLMISRTPEVTCVVV A VSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTV V HQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYS K LTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK | 88 | |
| 228P233P 234A 235A 265A 309V 409K |
ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCP P CPAP PAA GGPSVFLFPPKPKDTLMISRTPEVTCVVV A VSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTV V HQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYS K LTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK | 106 | |
본원에 개시된 바와 같이, 항-PD-1 항체는 서열번호 83-88 중 임의의 것을 포함하는 IgG4 중쇄 효과기 (effector) 또는 불변 도메인을 포함하는 항체이다.
상기 각각의 측면에 개시된 바와 같이, 항-PD-1 항체는 중쇄 가변영역 (Vh), 경쇄 가변영역 (Vk) 및 IgG4 중쇄 효과기 (effector) 또는 불변 도메인을 포함한 상기 도메인을 포함하는 F(ab) 또는 F(ab)2를 함유하는 항체이다.
본원에 개시된 바와 같이, 항-PD-1 항체는 서열번호 83-88 및 91-106에서 선택된 서열을 포함하고, 여기서 중쇄 가변영역 (Vh) 및 경쇄 가변영역 (Vk)은 표 6에 제공된 것으로부터 선택된 서열을 포하는 중쇄 가변영역 (Vh) 및 경쇄 가변영역 (Vk), 및 IgG4 중쇄 효과기 (effector) 또는 불변 도메인을 포함하는 항체이다:
| a) mu317 (각각 서열번호 4 및 6); b) mu326 (각각 서열번호 8 및 10); c) 317-4B6 (각각 서열번호 24 및 26); d) 326-4A3 (각각 서열번호 28 및 30); e) 317-4B2 (각각 서열번호 43 및 44); f) 317-4B5 (각각 서열번호 45 및 46); g) 317-1 (각각 서열번호 48 및 50); h) 326-3B1 (각각 서열번호 51 및 52); i) 326-3GI (각각 서열번호 53 및 54); j) 326-1 (각각 서열번호 56 및 58); k) 317-3A1 (각각 서열번호 64 및 26); l) 317-3C1 (각각 서열번호 65 및 26); m) 317-3E1 (각각 서열번호 66 및 26); n) 317-3F1 (각각 서열번호 67 및 26); o) 317-3G1 (각각 서열번호 68 및 26); |
p) 317-3H1 (각각 서열번호 69 및 26); q) 317-311 (각각 서열번호 70 및 26); r) 317-4B 1 (각각 서열번호 71 및 26); s) 317-4B3 (각각 서열번호 72 및 26); t) 317-4B4 (각각 서열번호 73 및 26); u) 317-4A2 (각각 서열번호 74 및 26); v) 326-3 A 1 (각각 서열번호 75 및 30); w) 326-3C1 (각각 서열번호 76 및 30); x) 326-3D1 (각각 서열번호 77 및 30); y) 326-3E1 (각각 서열번호 78 및 30); z) 326-3F1 (각각 서열번호 79 및 30); aa) 326-3B N55D (각각 서열번호 80 및 30); ab) 326-4A1 (각각 서열번호 28 및 81); 또는 ac) 326-4A2 (각각 서열번호 28 및 82). |
본원에 개시된 바와 같이, 일부 실시 양태에서, 항-PD-1 항체는 서열번호 11, 32 및 13에 따른 CDR-H1, CDR-H2 및 CDR-H3; 서열번호 61, 15 및 16에 따른 경쇄 CDR-L1, CDR-L2 및 CDR-L3; 및 서열번호 88을 포함하는 IgG4 중쇄 효과기 (effector) 또는 불변 도메인을 포함한 중쇄를 포함하는 항체이다.
본원에 개시된 바와 같이, 일부 실시 양태에서, 항-PD-1 항체는 중쇄 가변영역 (Vh) 및 경쇄 가변영역 (Vk), 및 서열번호 88을 포함하는 IgG4 중쇄 효과기 (effector) 또는 불변 도메인을 포함하는 항체로, 상기 중쇄 가변영역 (Vh) 및 경쇄 가변영역 (Vk)는 각각 서열번호 24 및 서열번호 26을 포함하는 것을 특징으로 하는 항체이다.
본원에 개시된 바와 같이, 일부 실시 양태에서, 항-PD-1 항체는 PD-1에 대한 높은 친화도 및 결합 특이성을 갖는 독창적으로 조작된 인간 IgG4 단클론 항체이고, 항체-의존성 포식작용(phagocytosis)을 제거하기 위해 T-세포 제거의 잠재적 메커니즘인 대식세포(macrophages)상의 FcγR 결합을 최소화하도록 특이적으로 조작되었다.
본원에 개시된 항-PD1 항체 및 이의 항체 단편은 WO2015/035606A1 또는 미국 특허 번호 8,735,553의 개시에 따라 제조될 수 있으며, 이의 전체 개시는 본원에 명백히 참고로 포함된다.
치료방법
본원에 개시된 치료방법에 따라서, 특정 용량의 항-PD-1 항체를 HCC 환자에게 정맥 투여하였다. 일부 실시 양태에서, HCC 환자는 이전에 PD-1 또는 PD-L1 표적화 요법으로 치료받지 않았다. 일부 실시 양태에서, HCC 환자는 이전에 다른 치료제 (예를 들어, 소라페닙(sorafenib))로 치료 받았다.
일부 실시 양태에서, 본 개시 내용은 HCC를 필요로하는 대상체를 치료하는 방법을 제공하는 것으로, 상기 방법은 대상체에게 항-PD-1 항체 또는 이의 항원 결합 단편을 투여하는 단계를 포함하며, 상기 항체는 대식세포(macrophages) 또는 다른 항원 제시 세포에서 FcγR 결합을 감소, 최소화 또는 제거하도록 조작된다. 일부 실시 양태에서, 항체는 본원에 제공된 조작된 IgG4 영역을 포함한다. 예를 들어, 일부 실시 양태에서, 항체는 서열번호 83-88 및 91-106으로 이루어진 군으로부터 선택된 아미노산 서열을 갖는 조작된 IgG4 영역을 포함한다. 일부 실시 양태에서, 항체는 각각 서열번호 11, 32 및 13에 따른 중쇄 CDR1, CDR2 및 CDR3 서열; 서열번호 61, 15 및 16에 따른 경쇄 CDR1, CDR2 및 CDR3 서열; 및 FcγR을 감소 시키도록 조작 된 IgG4 영역을 포함한다. 일부 실시 양태에서, 항체는 각각 서열번호 11, 32 및 13에 따른 중쇄 CDR1, CDR2 및 CDR3 서열을 포함하고; 서열번호 61, 15 및 16에 따른 경쇄 CDR1, CDR2 및 CDR3 서열; 및 서열 번호 83-88 및 91-106으로 이루어진 군으로부터 선택된 아미노산 서열을 갖는 IgG4 영역을 포함한다. 일부 실시 양태에서, 항체는 각각 서열번호 24 및 26에 따른 중쇄 및 경쇄 가변영역 서열, 및 감소 된 FcγR을 갖도록 조작 된 IgG4 영역을 포함한다. 일부 실시 양태에서, 항체는 각각 서열번호 24 및 26에 따른 중쇄 및 경쇄 가변영역 서열을 포함하고, 서열번호 83-88 및 91-106으로 이루어진 군으로부터 선택된 아미노산 서열을 갖는 IgG4 영역을 포함한다. 일부 실시 양태에서, 항-PD-1 항체는 Mab-1이다.
일부 실시 양태에서, 본 개시 내용은 환자에서 HCC의 치료에 사용하기 위해 본원에 제공된 항체를 제공한다. 일부 실시 양태에서, 본 개시 내용은 HCC 환자에서 면역요법에 사용하기 위해 본원에 제공된 항체를 제공한다. 일부 실시 양태에서, 본 개시 내용은 HCC의 치료를 위한 의약의 제조에 사용하기 위해 본원에 제공된 항체를 제공한다. 일부 실시 양태에서, 본 개시 내용은 HCC 환자에서 면역요법용 의약 제조에 사용하기 위해 본원에 제공된 항체를 제공한다.
일부 실시 양태에서, 본 개시 내용은 본원에 제공된 항체를 투여하는 것을 포함하는 환자에서 HCC를 치료하는 방법을 제공하며, 상기 항체의 투여는 항체를 투여받지 않은 환자에 비해 하기의 요소가 개선된다 : 전체 생존기간 (OS), 전체 반응률 (ORR), 완전 응답 비율 (CR), 부분 응답 비율 (PR), 안정 병변 (SD), 무진행생존율 (PFS), 무병생존율 (DFS), 무사건생존율 (EFS), 반응지속시간 (DoR), 종양진행시간 (TTP), 질병 통제 비율 (DCR), 임상적 이점 비율 (CBR) 또는 이들의 임의의 조합. 특정 실시 양태에서, 항체의 투여는 OS의 개선을 제공한다.
일부 실시 양태에서, OS는 임상 시험 무작위로부터 임의의 원인으로 인한 사망까지의 시간으로 정의된다. 일부 실시 양태에서, ORR은 미리 정의된 양의 종양 크기 감소 및 최소 기간 동안 환자의 백분율로 정의된다. 일부 실시 양태에서, CR은 치료에 반응하여 모든 암 징후의 소멸로 정의된다. 일부 실시 양태에서, PR은 검출 가능한 질환 (예를 들어, 종양의 크기)의 30 % 이상 감소로 정의된다. 일부 실시 양태에서, SD는 PR로서 자격을 얻기에 충분한 질병 감소 또는 진행성 질환을 자격으로하기에 충분한 질병 증가가 아닌 것으로 정의된다 (예를 들어, 검출 가능한 질환의 30 % 감소로 25 % 미만 증가 (예를 들어, 종양의 크기)). 일부 실시 양태에서, TTP는 무작위 화에서 종양 진행까지의 시간으로 정의된다. 일부 실시 양태에서, PFS는 무작위 화로부터 종양 진행까지 또는 사망이 발생할 때까지의 시간으로 정의된다. 일부 실시 양태에서, DFS는 무작위 화부터 종양의 재발까지의 시간 또는 임의의 원인으로 인한 사망으로 정의된다. 일부 실시 양태에서, EFS는 임의의 이유로 무작위에서 질환 진행, 사망 또는 치료 중단까지의 시간으로 정의된다. 일부 실시 양태에서, DoR은 종양 반응의 기록으로부터 질병 진행에 이르는 기간으로 정의된다. 일부 실시 양태에서, DCR 및 CBR 둘다는 완전한 반응, 부분 반응 또는 안정한 질환을 달성한 환자의 백분율로 정의된다.
일부 실시 양태에서, 치료 중 또는 치료 후 암 환자의 질병 반응, 진행 또는 안정성을 정의하는 공개된 규칙 세트인 RECIST v. 1.1 (고형 종양에서의 반응 평가 기준)은 본원에 제공된 항체로 치료된 환자를 평가하기 위해 사용된다.
일부 실시 양태에서, 본 개시 내용은 본원에 제공된 항체를 환자에게 투여하는 것을 포함하는 HCC로 환자를 치료하는 방법을 제공하는 것으로, 상기 방법은 적어도 약 20 % 이상, 약 25 % 이상, 약 30 % 이상, 약 35 % 이상, 약 40 % 이상, 약 45 % 이상, 약 50 % 이상, 약 55 % 이상 약 60 % 이상, 약 65 % 이상, 약 70 % 이상, 약 75 % 이상, 약 80 % 이상 또는 그 이상의 ORR 및 / 또는 CR 및 / 또는 PR 및 / 또는 DCR 및 / 또는 CBR (또는 종양 환자에 대한 다른 알려진 속도-기반 결과 측정)을 달성한다.
일부 실시 양태에서, 본 개시 내용은 본원에 제공된 항체의 투여를 포함하는 환자에서 HCC를 치료하는 방법을 제공하는 것으로, 상기 항체의 투여는 위약 치료 또는 다른 항 종양 또는 항암 요법과 관련하여 통계적으로 유의미한 치료 효과를 제공한다. 일부 실시 양태에서, 통계적으로 유의미한 효과는 독성 또는 내약성 파라미터에 대한 통계적으로 유의미한 효과와 조합된 치료 효능을 포함한다. 일부 실시 양태에서, 통계적으로 유의미한 효과는 개선 된 OS, ORR, CR, PR, SD, PFS, DFS, EFS, DoR, TTP, DCR, CBR 또는 이들의 임의의 조합을 추가로 포함한다. 일부 실시 양태에서, 본원에 제공된 방법은 소라페닙(sorafenib)과 비교하여 통계적으로 유의미한 효과를 제공한다. 일부 실시 양태에서, 본원에 제공된 방법은 본원에 제공된 항체 (예를 들어, Mab-1)의 약 200 mg IV Q3W 투여를 포함하고, 여기서 상기 방법은 약 400 mg 소라페닙(sorafenib) 경구 BID의 투여와 비교하여 통계적으로 유의미한 효과를 제공한다. 일부 실시 양태에서, 본원에 제공된 방법은 다른 PD-1 또는 PD-L1 표적화 요법과 비교하여 통계적으로 유의미한 효과를 제공한다. 용어 "통계적으로 유의미한 치료 효과" 등은 대상체에서 임상적 또는 의학적 개선을 초래하는 치료의 결과를 지칭한다. "통계적으로 유의미"하다는 것은 우연히 결과가 발생하지 않았 음을 의미한다. 통계적 유의성은 당 업계에 공지된 임의의 방법에 의해 결정될 수있다. 일반적으로 사용되는 유의미성 척도에는 귀무 가설이 참인 경우 관측된 사건이 발생할 빈도 또는 확률 인 p-값(value)이 포함된다. 얻어진 p-값이 유의미한 수준보다 작으면 귀무 가설이 기각된다. 간단한 경우, 유의미한 수준은 0.05 이하의 p-값으로 정의된다.
일부 실시 양태에서, 항-PD-1 항체는 0.5-10 mg/kg QW, 또는 Q2W, 또는 Q3W 또는 Q4W의 용량으로 투여된다. 본원의 일부 실시 양태에서, 항-PD-1 항체는 Mab-1이고, Mab-1은 0.5-10 mg/kg QW 또는 Q2W 또는 Q3W의 용량으로 투여된다. 바람직하게는, Mab-1은 0.5-5 mg/kg Q2W, 5-10 mg/kg Q2W, 또는 2-5 mg/kg Q3W의 용량으로 투여된다. 가장 바람직하게는, Mab-1은 0.5 mg/kg Q2W, 5 mg/kg Q2W, 10 mg/kg Q2W, 2 mg/kg Q3W 또는 5 mg/kg Q3W의 용량으로 비경구 투여된다.
일부 실시 양태에서, 본 개시 내용은 본원에 제공된 항-PD-1 항체를 약 50 mg, 약 75 mg, 약 100 mg, 약 125 mg, 약 150 mg, 약 175 mg, 약 200 mg, 약 225 mg, 약 250 mg, 약 300mg, 약 325mg, 약 350mg, 약 375mg, 약 400mg, 약 425mg, 약 450mg, 약 475mg 또는 약 500mg의 용량으로 투여하는 단계를 포함하는 HCC를 치료하는 방법을 제공한다. 일부 실시 양태에서, 항체는 매일, 격일로, 3 일마다, 4 일마다, 5 일마다, 6 일마다 또는 7 일마다 투여된다. 일부 실시 양태에서, 항체는 매주, 10 일마다, 2 주마다, 3 주마다, 4 주마다, 5 주마다, 6 주마다, 7 주마다, 또는 8 주마다 투여된다. 일부 구체적인 예에서, 항체는 매달 또는 격월마다 투여된다. 일부 실시 양태에서, 항체는 대상체에게 1 회 이상 투여되고, 그리고/또는 항체의 용량을 증가 시키거나 감소시키는 것은 환자의 임상 단계, 달성된 치료 효과 및 다른 환자 특성에 따라 결정된다. 특정 실시 양태에서, 항체는 대상체 QW, Q2W, Q3W 또는 Q4W 투여된다.
일부 실시 양태에서, 상기 제약 조성물의 투여 경로는 공지 된 방법, 예를 들어 서방형 시스템 또는 주입 장치를 이용한 정맥 내, 복강 내, 뇌내 (실내), 뇌 실내, 근육 내, 피하, 안구 내, 동맥 내, 문맥 내 또는 병변 내 경로를 통한다.
특정 실시 양태에서, 본 개시 내용은 본원에 제공된 항-PD-1 항체를 3 주마다 정맥 내 (IV) 약 200mg의 용량 (IV)으로 이를 필요로하는 대상체에게 HCC를 치료하는 방법을 제공한다 (Q3W).
실시예
실시예 1 진행성 간세포암종 (HCC) 환자에서 Mab-1의 임상 1A/1B상 연구
환자의 차별화(differentiation) 및 등록(enrollment) 관련 연구 설계
연구 설계의 목적은 1A상 및 1B상으로 구성된 권장 2상 용량 (RP2D) 결정 및 예비 차별화를 위해 종양을 선택함으로써 HCC 환자를 등록하는 것이다. 연구 설계는 그림 2에 자세히 설명되어 있다. 1A상에서, 10 mg/kg의 Mab-1 (임상 시험에 사용된 항체는 Mab-1 임) Q2W는 최대 투여 용량이고; 최대 허용 용량 (MTD)에 도달하지 않았다. 1B상의 모든 환자는 5 mg/kg IV 주입 Q3W로서 Mab-1을 투여 받았다. 방사선 평가는 9 주마다 이루어졌다. 여기에 제시된 결과에는 5 mg/kg Q3W로 치료된 진행성(advanced) HCC 환자가 포함된다. 최종적으로, 40 명의 HCC 환자 (n = 40)가 임상 시험에 등록되었다.
PooledHCC 인구 부분집합(subset)의 주요 자격
사전 PD-1 또는 PD-L1 치료를 받지 않은 조직학적 또는 세포학적으로 확인 된 진행/전이성(advanced/metastatic) HCC를 갖는 성인 환자 (18 세 이상)가 등록되었다.
바르셀로나 임상 간암 지표 C 또는 B를 포함하는 특정 지표는 국소영역치료(loco-regional therapy)에 다루기 힘들며/처리할 수 않고, 접근 치료요법 및 뇌증(encephalopathy)이 없는 Child-Pugh A 등급에 처리할 수 없다.
적격 환자는 B 형 간염 바이러스 (HBV) 바이러스 부하 <200 IU/mL (~ 1000 cps/mL)이어야하고, 활성 HBV 감염이있는 대상체는 치료 기간 동안 및 치료 기간 3 개월 이상 동안 및 치료 후 6개월 동안 항-HBV 억제가 있어야 한다.
치료되지 않은 활성 C 형 간염 바이러스 (HCV) 감염 환자는 연구에 허용되지 않는다.
환자 배치
대부분 HBV 양성 (n = 28 / 40) 인 진행성(advanced) HCC를 가진 40 명의 환자 가이 연구에 등록 되었다 (표 7). 해당 분석동안 총 24 명의 환자가 치료를 받았다.
|
HCC
Population
(N=40) |
||
| 평균 연령, 년 (최소, 최대) | 55.5 (28, 76) | |
| 성 | 남성/여성 | 32/8 |
| 인종 | 아시아인/백인/기타 | 35/3/2 |
| 평균 치료 기간, 일(최소, 최대) | 64 (1, 471) | |
| 이전 항암 치료 요법 수의 평균 (최소, 최대) | 2 (0, 6) | |
| 이전 항암 치료 요법, n* | 0 | 2 † |
| 1 | 16 | |
| 2 | 12 | |
| ≥3 | 10 | |
| 감염 상태, n | HBV | 28 |
| HCV | 2 | |
| HBV/HCV 공동 감염 | 6 | |
| 감염 없음 | 4 | |
| * 1 명의 환자만이 소라페닙(sorafenib)에 나이브(naive) 하였다 ;† 두 환자 모두 보조 요법으로 소라페닙을 투여 받았다. 약어 : HBV, B 형 간염 바이러스; HCV, C 형 간염 바이러스. | ||
예비(Preliminary) 항종양 활성
등록된 40 명의 진행성(advanced) HCC 환자 중 총 27 명의 환자가 평가 가능했으며, 여기서 25 명은 측정 가능한 질병 및 1 회 이상의 평가 가능한 기준선 후 종양 평가를 가졌으며 2명은 종양 평가 예정일 1 일 전에 사망 하였다.
이하의 임상 시험 및 결과에서, 모든 환자는 매 9 주마다 방사선 평가와 함께 5 mg/kg IV 주입 Q3W로서 Mab-1을 투여 받았다. 27 명의 평가 가능한 HCC 환자에서: 3 명의 환자는 적어도 부분 응답 비율 (PR)을 달성하였고 9 명의 환자는 안정 병변 (SD)을 달성 하였다. 간염 바이러스 감염 상태에 의한 종양 크기의 최상의 변화를 나타내는 부분 응답 비율 (PR) 및 안정 병변 (SD)을 포함하는 초기 질병 통제 비율 (DCR)은 도 3에 도시된 바와 같이 44 %이다.
Mab-1의 치료 기간 및 환자의 반응은 도 4에 나타내었다. 이의 최대 기간이 28 주임을 나타내었다.
상기와 같이, 3 명의 환자가 적어도 부분 반응을 달성하는 것으로 밝혀졌으며, 이는 도 5에서 부분 반응을 갖는 3 명의 환자에서 기준선 및 가장 최근의 CT 평가에 의해 확인되었다.
또한, 도 6은 HBV- 감염 HCC 환자에서 시간 경과에 따른 종양 부담의 변화가 유망하다는 것을 보여준다.
도 7은 HCC 환자의 방사선 증거에 의한 최상의 전체 반응을 보여준다. HCC 환자 중 한 명의 환자는 60 주 이상 안정 병변이 있는 것으로 나타났다.
내성 측면(Tolerability Profile)
또한, 본원에 개시된 Mab-1의 투여와 관련된 부작용 (AE)이 연구되었다.
HCC 환자 40 명 중 21 명에서 치료 관련 AEs가 발생하였다 (표 8). 이들 case 중 하나를 제외한 모든 case는 2 등급 이하였다. 가장 흔한 case는 발진 (n = 8)과 가려움증 (n = 5)이었다.
| HCC Population (N=40) | ||
| All grades | Grade ≥ 3 | |
| 치료 관련 AE (Any treatment-related AE) | 21 | 1 |
| 발진 (Rash) | 8 | 0 |
| 가려움증 (Pruritus) | 5 | 0 |
| AST 증가 ( AST increased) | 3 | 0 |
| 피로 (Fatigue) | 2 | 0 |
| 갑상선 기능 항진증 (Hypothyroidism) | 2 | 0 |
| 식욕 감퇴 (Decreased appetite) | 2 | 0 |
| 급성 간염 (Acute hepatitis)* | 1 | 1 |
| ALT 증가 (ALT increased) | 1 | 0 |
| 혈액 크레아틴 증가 (Blood creatine increased) | 1 | 0 |
| 혈액 크레아티닌 증가 (Blood creatinine increased) | 1 | 0 |
| QT 연장 (prolongation) | 1 | 0 |
| 피부 반응 (Skin reaction) | 1 | 0 |
| 오한 (Chills) | 1 | 0 |
| 열감 (Feeling hot) | 1 | 0 |
| 메스꺼움 (Nausea) | 1 | 0 |
| 구토 (Vomiting) | 1 | 0 |
| 관절통 (Arthralgia) | 1 | 0 |
| 단백뇨 ( Proteinuria ) | 1 | 0 |
| 기침 (Cough) | 1 | 0 |
| 고혈압 (Hypertension) | 1 | 0 |
| 데이터는 n으로 표시됨. 볼드체는 면역 관련 가능한 이벤트를 나타낸다. *급성 간염은 치명적 (fatal)이었다 (5 등급). |
||
2 명의 환자는 임의의 치료 응급 AE로 인해 치료를 중단하였으며, 그 중 한 명은 시험자관의 치료와 관련하여 고려된 5 AE 등급이었다. HBV와 HCC가 뇌, 간, 폐에 광범위하게 전이된 49 세의 아시아 남성은 Mab-1 의 첫 번째 및 유일한 복용 직후에 진행 (방해 의식, 복통 및 흉부 x-레이 변화)의 증거를 발견했다. 메틸프레드니솔론(methylprednisolone) 및 엔테카비르(entecavir)의 치료에도 불구하고, 환자는 연구에 들어가고 대략 5 주 후에 사망하였다. 바이러스 혈청테스트는 음성이었다; 부검은 수행되지 않았다. 사망 원인은 급성 간염에 의한 것으로 빠른 질병 진행으로 인해 혼입(독립변인 이외에 다른 변인들이 종속변인에 영향을 미치는)되었다.
이들 결과는 본원에 개시된 항체 (Mab-1)가 용인 가능함을 확인하였으며; 이의 독성 프로파일은 부작용 (AE)이 일반적으로 심각도가 낮고 관리 가능하며 가역적이라는 것을 보여준다.
이 초기 보고서에서, 절반 이상의 환자가 연구에 남아 있었다 (n=24/40); 평균 치료 기간은 64 일 (범위 : 1-471 일) 이었으며; 치료 관련 AE로 인한 치료 중단 속도는 낮았다 (n = 1 / 40). 코호트에 보고된 부작용은 연구에서 관찰된 전반적인 안전성 프로파일과 일치했으며 일반적으로 심각도가 낮고 관리 가능하며 가역적이었다. 대부분의 환자는 근본적인 바이러스 감염 (HBV+, n=28; HCV+/HBV+,n=6; HCV+,n=2)을 가졌다. "부분 반응"의 정의 (즉, 종양 부담의 적어도 30 % 감소로 정의 됨)를 충족시키는 종양 감소가 3 명의 환자에서 관찰되었고; 9 명의 환자는 안정된 질병을 앓았으며, 그 중 일부는 AFP를 상당히 감소시켰다.
실시예 2 절제 불가능한 간세포암종(HCC) 환자에서 Mab-1의 임상 2상 연구
연구 설계
임상 2상 연구는 이전에 치료된 HCC를 가진 환자에서 Mab-1의 효능, 안전성/내약성 및 약동학 (PK)을 평가하도록 설계되었다. 안전성/내약성 평가에는 면역 관련 AE를 포함한 부작용 (AE) 모니터링이 포함된다.
인구 연구(Study Population)
≥18 세인 성인 환자는 다음과 같은 경우에 등록될 것이다:
(a) 조직 학적으로 확인된 HCC;
(b) 바르셀로나 임상 간암 (BCLC) 단계 C 또는 BCLC 단계 B로, 국소 치료 처리를 받을 수 없거나 국소 치료 후에 재발하였고, 접근 치료요법을 처리할 수 없는;
(c) 절제 불가능한 HCC에 대해 적어도 한 라인(lind)의 전신 요법을 받았으며;
(d) RECIST v1.1에 정의된 바와 같이 적어도 1 개의 측정 가능한 병변을 갖고;
(e) 차일드-퍼 점수(child-Pugh score) A;
(f) 동부 종양학 협력그룹 (ECOG) 성과 상태 ≤ 1;
(g) 적절한 기관 기능.
다음과 같은 경우의 환자는 배제할 것이다:
(a) 섬유 모세포 HCC, 육종 HCC, 또는 혼합 담관암 및 HCC 조직학으로 알려진 경우;
(b) 이전에 PD-1 또는 PD-L1을 표적으로 하는 치료를 한 경우;
(c) 뇌 또는 연수막(leptomeningeal) 전이로 알고 있는 경우;
(d) 문맥의 주요 줄기 또는 하대 정맥을 포함하는 종양 혈전인 경우;
(e) 등록 전 4 주 이내에 간에 대한 국소-영역 요법을 한 경우;
(f) 간질성 폐 질환, 비-감염성 폐렴 또는 통제되지 않은 전신 질환 (예 : 당뇨병, 고혈압, 폐 섬유증, 급성 폐 질환 등)의 병력이 있는 경우;
(g) 최초 연구 약물 투여 후 28 일 또는 5 년 반감기 (둘 중 짧은 기간) 내에: 모든 화학 요법, 면역 요법 (예 : 인터루킨, 인터페론, 티 목신) 또는 모든 치료 요법; 최초 연구 약물 투여 후 14 일 이내에: 소라페닙(sorafenib), 레고라페닙(regorafenib), 또는 한약 또는 암을 제어하는데 사용되는 중국 특허 의약품을 사용한 경우;
(h) 재발 할 수 있는 활동성 자가 면역 질환 또 는자가 면역 질환의 병력이 있는 경우;
(i) 연구 약물 투여 전 14 일 이내에 코르티코 스테로이드 (프레드니손의 매일 10 mg 또는 그에 상응하는 것) 또는 다른 면역억제제로 전신 치료를 필요로하는 모든 상태.
치료
환자는 Mab-1 200 mg IV Q3W로 치료될 것이다.
실시예 3 절제 불가능한 간세포암종 (HCC) 환자의 1차 치료로서 Mab-1 대 소라페닙(sorafenib)의 효능과 안전성을 비교하기 위한 임상 3상 연구
연구 설계
진행성(advanced) HCC의 1차 치료로서 소라페닙(sorafenib)과 비교하여 Mab-1의 효능 및 안전성을 평가하기 위해 3상 연구를 설계하였다(도 8).
1차 목적은 두 치료 그룹 사이의 전체생존기간 (OS)을 비교하는 것이다. RECIST v1.1에 따라 맹검리뷰검토위원회에 의해 평가된 객관적 반응률(ORR)은 중요한 2차 목표이다. 다른 2차 목표에는 다양한 효능 평가 측면에서 Mab-1과 소라페닙(sorafenib)의 비교(무진행생존율[PFS], 반응지속시간[DoR], 종양진행시간[TTP], 질병 통제 비율[DCR] 및 임상적 이점 비율[CBR]), 건강 관련 삶의 질, 안전 및 내약성 측정이 포함된다.
인구 연구(Study Population)
≥18 세인 성인 환자는 다음과 같은 경우에 등록될 것이다 :
(a) 절제 불가능하고 조직학적으로 확인된 HCC,
(b) ECOG (동부 종양학 협력그룹; Eastern Cooperative Oncology Group) 점수 ≤1, 차일드-퍼 점수(child-Pugh score) A,
(c) 바르셀로나 임상 간암 (BCLC) C 단계 질환 또는 BCLC, 국소 치료에 적합하지 않거나 또는 치료 후 진행되었거나, 접근 치료요법에 B 단계 질환,
(d) 사전 전신요법을 받지 않음.
다음과 같은 환자를 배제할 것이다 :
(a) 섬유모세포 HCC, 육종 HCC 또는 혼합 담관암 및 HCC 조직학으로 알려진 경우,
(b) 문맥의 주요 줄기 또는 하대 정맥을 포함하는 종양 혈전의 경우,
(c) 무작위 전 28일 이내에 간에 국소 부위 요법을 받았거나 또는 이전의 면역요법법을 받았거나, 또는 무작위 배정 후 14 일 이내에 암을 조절하는 데 사용되는 한약 또는 특허 약을 받은 경우,
(d) 2등급 이상의 간성 뇌병증 (선별 또는 이전 병력)인 경우,
(e) 심장막삼출(pericardial effusion), 제어 할 수 없는 흉수(pleural effusion), 또는 선별시 임상적으로 유의 한 복수(ascites)인 경우.
치료
환자는 Mab-1 200 mg IV Q3W 또는 소라페닙(sorafenib) 400 mg을 매일 2 회 경구 (BID)투여 받는 것으로 1:1 무작위화 될 것이며, 무작위는 거대 혈관 침습의 존재, 간외(extrahepatic) 전이, ECOG 수행 상태, 병인 및 지리의 존재에 의해 계층화된다. 질병 진행, 과도한 독성 또는 다른 이유로 치료가 중단될때 까지 치료는 계속 된다.
연구 평가 및 통계 분석
(a) 종양 반응은 RECIST v1.1에 따라 1년차의 경우 9 주마다 및 2년차 이후의 경우 12 주마다 평가될 것이다.
(b) Mab-1 대 소라페닙(sorafenib)에 대한 OS의 1차 효능 종점은 비열 등성(non-inferiority)에 대해 평가될 것이다.
(c) 2차 종점(맹검리뷰검토위원회에 의해 평가된 ORR, PFS, DoR 및 TTP와 같은) 치료 비교에 대해 평가된다.
(d) 모든 시험은 단편적으로 α=0.025에서 수행된다.
(e) 부작용 (AE)을 모니터링하여 면역 관련 AEs, 신체 검사, 활력 징후 및 심전도를 포함한 안전성과 내약성 (2차 평가 변수)을 평가한다.
(f) 암 관련 삶의 질 연구 및 치료를 위한 유럽기구의 암 설문지-간세포암종 18 질문 (EORTC QLQ-HCC18) 및 암 관련 삶의 질 연구 및 치료를 위한 유럽기구 설문지 코어 30은 혼합 모델을 사용하여 두 치료 arms 사이의 건강 관련 삶의 질을 평가하는데 사용된다. 유럽인의 5차원 삶의 질도 요약될 것이다.
특정 실시 예에서 기술한 예 및 설명은 청구 범위에 의해 정의된 본 발명을 제한하는 것이 아니라 예시적인 것으로 간주되어야 한다. 쉽게 이해할 수 있는 바와 같이, 청구 범위에 제시된 바와 같이 본 발명을 벗어나지 않으면서 기술한 특징의 다양한 변형 및 조합이 이용될 수 있다. 이러한 모든 변형은 본 발명의 범위 내에 포함되도록 간주된다. 인용된 모든 참고문헌은 그 전문이 본원에 참조로 포함된다. 임의의 선행기술 간행물이 본 명세서에서 언급되는 경우, 해당 언급은 그 간행물이 임의의 국가에서 해당 기술분야의 일반적인 지식의 일부를 형성한다는 것을 인정하는 것은 아님을 이해해야 한다.
다음의 청구 범위 및 본 발명의 기술 한 설명에서, 표현 언어 또는 필요한 의미로 인해 문맥이 달리 요구되는 경우를 제외하고는, 단어 "포함하다" 또는 "포함한다" 또는 "포함하는"과 같은 변형 단어는 포괄적인 의미 즉, 언급된 특징의 존재를 특정하지만 본 발명의 다양한 실시예에서 추가 특징의 존재 또는 추가를 배제하지는 않는다는 의미로 사용된다.
식별 인용에 의해 본 명세서에 언급 된 모든 공보, 특허, 특허 출원 및 공개 된 특허 출원의 개시 내용은 그 전문이 본원에 참조로 포함된다.
SEQUENCE LISTING
<110> BeiGene Ltd.
Wang, Lai
Li, Kang
Qi, Qinzhou
Hou, Jeannie
Wu, Zhong
<120> IMMUNOTHERAPY FOR HEPATOCELLULAR CARCINOMA
<130> F18W0404TW
<150> PCT/CN2017/090397
<151> 2017-06-27
<150> US 62/524,967
<151> 2017-06-26
<160> 107
<170> PatentIn version 3.5
<210> 1
<211> 444
<212> DNA
<213> Homo sapiens
<400> 1
ccaggatggt tcttagactc cccagacagg ccctggaacc cccccacctt ctccccagcc 60
ctgctcgtgg tgaccgaagg ggacaacgcc accttcacct gcagcttctc caacacatcg 120
gagagcttcg tgctaaactg gtaccgcatg agccccagca accagacgga caagctggcc 180
gccttccccg aggaccgcag ccagcccggc caggactgcc gcttccgtgt cacacaactg 240
cccaacgggc gtgacttcca catgagcgtg gtcagggccc ggcgcaatga cagcggcacc 300
tacctctgtg gggccatctc cctggccccc aaggcgcaga tcaaagagag cctgcgggca 360
gagctcaggg tgacagagag aagggcagaa gtgcccacag cccaccccag cccctcaccc 420
aggccagccg gccagttcca aacc 444
<210> 2
<211> 148
<212> PRT
<213> Homo sapiens
<400> 2
Pro Gly Trp Phe Leu Asp Ser Pro Asp Arg Pro Trp Asn Pro Pro Thr
1 5 10 15
Phe Ser Pro Ala Leu Leu Val Val Thr Glu Gly Asp Asn Ala Thr Phe
20 25 30
Thr Cys Ser Phe Ser Asn Thr Ser Glu Ser Phe Val Leu Asn Trp Tyr
35 40 45
Arg Met Ser Pro Ser Asn Gln Thr Asp Lys Leu Ala Ala Phe Pro Glu
50 55 60
Asp Arg Ser Gln Pro Gly Gln Asp Cys Arg Phe Arg Val Thr Gln Leu
65 70 75 80
Pro Asn Gly Arg Asp Phe His Met Ser Val Val Arg Ala Arg Arg Asn
85 90 95
Asp Ser Gly Thr Tyr Leu Cys Gly Ala Ile Ser Leu Ala Pro Lys Ala
100 105 110
Gln Ile Lys Glu Ser Leu Arg Ala Glu Leu Arg Val Thr Glu Arg Arg
115 120 125
Ala Glu Val Pro Thr Ala His Pro Ser Pro Ser Pro Arg Pro Ala Gly
130 135 140
Gln Phe Gln Thr
145
<210> 3
<211> 354
<212> DNA
<213> Mus musculus
<400> 3
caggtgcagc tgaaggagtc aggacctggc ctggtggcgc cctcaaagaa cctgtccatc 60
acttgcactg tctctgggtt ttcattaacc agctatggtg tacactggat tcgccagcct 120
ccaggaaagg gactggaatg gctgggagta atatgggccg gtggaagcac aaattataat 180
tcggctctca tgtccagact gagcatcagc aaagacaact ccaggagcca agttttctta 240
agaatgaaca gtctgcaaac tgatgacaca gccatgtact actgtgccag agcctatggt 300
aactactggt acatcgatgt ctggggcgca gggaccacgg tcaccgtctc ctca 354
<210> 4
<211> 118
<212> PRT
<213> Mus musculus
<400> 4
Gln Val Gln Leu Lys Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Lys
1 5 10 15
Asn Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr
20 25 30
Gly Val His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Ala Gly Gly Ser Thr Asn Tyr Asn Ser Ala Leu Met
50 55 60
Ser Arg Leu Ser Ile Ser Lys Asp Asn Ser Arg Ser Gln Val Phe Leu
65 70 75 80
Arg Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Met Tyr Tyr Cys Ala
85 90 95
Arg Ala Tyr Gly Asn Tyr Trp Tyr Ile Asp Val Trp Gly Ala Gly Thr
100 105 110
Thr Val Thr Val Ser Ser
115
<210> 5
<211> 321
<212> DNA
<213> Mus musculus
<400> 5
gacattgtga tgacccagac tcccaaattc ctgcttgtat cagcaggaga cagggttacc 60
ataacctgca aggccagtca gagtgtgagt aatgatgtag cttggtacca acagaagcca 120
gggcagtctc ctaaactgct gataaactat gcatttcatc gcttcactgg agtccctgat 180
cgtttcactg gcagtggata tgggacggat ttcattttca ccatcagcac tgtgcaggct 240
gaagacctgg cagtttattt ctgtcaccag gcttatagtt ctccgtacac gttcggaggg 300
gggaccaagc tggaaatgaa a 321
<210> 6
<211> 107
<212> PRT
<213> Mus musculus
<400> 6
Asp Ile Val Met Thr Gln Thr Pro Lys Phe Leu Leu Val Ser Ala Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Ser Val Ser Asn Asp
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
Asn Tyr Ala Phe His Arg Phe Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Tyr Gly Thr Asp Phe Ile Phe Thr Ile Ser Thr Val Gln Ala
65 70 75 80
Glu Asp Leu Ala Val Tyr Phe Cys His Gln Ala Tyr Ser Ser Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Met Lys
100 105
<210> 7
<211> 342
<212> DNA
<213> Mus musculus
<400> 7
cagatccagt tggtgcagtc tggacctgag ctgaagaagc ctggagagac agtcaagatc 60
tcctgcaagg cttctgggta taccttcaca aactatggaa tgaactgggt gaagcaggct 120
ccaggaaagg gtttaaagtg gatgggctgg ataaacaata ataatggaga gccaacatat 180
gctgaagagt tcaagggacg gtttgccttc tctttggaaa cctctgccag cactgcctat 240
ttgcagatca acaacctcaa aaatgaggac acggctacat atttctgtgc aagagatgtt 300
atggactatt ggggtcaagg aacctcagtc accgtctcct ca 342
<210> 8
<211> 114
<212> PRT
<213> Mus musculus
<400> 8
Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys Trp Met
35 40 45
Gly Trp Ile Asn Asn Asn Asn Gly Glu Pro Thr Tyr Ala Glu Glu Phe
50 55 60
Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Leu Gln Ile Asn Asn Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys
85 90 95
Ala Arg Asp Val Met Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val
100 105 110
Ser Ser
<210> 9
<211> 330
<212> DNA
<213> Mus musculus
<400> 9
gacattgtgc tgacccaatc tccagcttct ttggctgtgt ctctagggca gagggccacc 60
atatcctgca gagccagtga aagtgttgat aattatggct atagttttat gcactggtac 120
cagcagaaac caggacagcc accccaactc ctcatctatc gtgcatccaa cctagaatct 180
gggatccctg ccaggttcag tggcagtggg tctaggacag gcttcaccct caccattaat 240
cctgtggagg ctgatgatgt tgcaacctat tactgtcagc aaagtaaaga atatccgacg 300
ttcggtggag gcaccaagct ggaagtcaaa 330
<210> 10
<211> 110
<212> PRT
<213> Mus musculus
<400> 10
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr
20 25 30
Gly Tyr Ser Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Gln Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Arg Thr Gly Phe Thr Leu Thr Ile Asn
65 70 75 80
Pro Val Glu Ala Asp Asp Val Ala Thr Tyr Tyr Cys Gln Gln Ser Lys
85 90 95
Glu Tyr Pro Thr Phe Gly Gly Gly Thr Lys Leu Glu Val Lys
100 105 110
<210> 11
<211> 10
<212> PRT
<213> Mus musculus
<400> 11
Gly Phe Ser Leu Thr Ser Tyr Gly Val His
1 5 10
<210> 12
<211> 16
<212> PRT
<213> Mus musculus
<400> 12
Val Ile Trp Ala Gly Gly Ser Thr Asn Tyr Asn Ser Ala Leu Met Ser
1 5 10 15
<210> 13
<211> 12
<212> PRT
<213> Mus musculus
<400> 13
Ala Arg Ala Tyr Gly Asn Tyr Trp Tyr Ile Asp Val
1 5 10
<210> 14
<211> 11
<212> PRT
<213> Mus musculus
<400> 14
Lys Ala Ser Gln Ser Val Ser Asn Asp Val Ala
1 5 10
<210> 15
<211> 7
<212> PRT
<213> Mus musculus
<400> 15
Tyr Ala Phe His Arg Phe Thr
1 5
<210> 16
<211> 9
<212> PRT
<213> Mus musculus
<400> 16
His Gln Ala Tyr Ser Ser Pro Tyr Thr
1 5
<210> 17
<211> 10
<212> PRT
<213> Mus musculus
<400> 17
Gly Tyr Thr Phe Thr Asn Tyr Gly Met Asn
1 5 10
<210> 18
<211> 17
<212> PRT
<213> Mus musculus
<400> 18
Trp Ile Asn Asn Asn Asn Gly Glu Pro Thr Tyr Ala Glu Glu Phe Lys
1 5 10 15
Gly
<210> 19
<211> 7
<212> PRT
<213> Mus musculus
<400> 19
Ala Arg Asp Val Met Asp Tyr
1 5
<210> 20
<211> 15
<212> PRT
<213> Mus musculus
<400> 20
Arg Ala Ser Glu Ser Val Asp Asn Tyr Gly Tyr Ser Phe Met His
1 5 10 15
<210> 21
<211> 7
<212> PRT
<213> Mus musculus
<400> 21
Arg Ala Ser Asn Leu Glu Ser
1 5
<210> 22
<211> 8
<212> PRT
<213> Mus musculus
<400> 22
Gln Gln Ser Lys Glu Tyr Pro Thr
1 5
<210> 23
<211> 354
<212> DNA
<213> Artificial Sequence
<220>
<223> 317-4B6 cDNA-Vh
<400> 23
caggtgcagc tgcaggagtc gggaccagga ctggtgaagc cttcggagac cctgtccctc 60
acctgcactg tctctgggtt ttcattaacc agctatggtg tacactggat ccggcagccc 120
ccagggaagg gactggagtg gatcggggtc atatacgccg atggaagcac aaattataat 180
ccctccctca agagtcgagt gaccatatca aaagacacct ccaagaacca ggtttccctg 240
aagctgagct ctgtgaccgc tgcggacacg gccgtgtatt actgtgcgag agcctatggt 300
aactactggt acatcgatgt ctggggccaa gggaccacgg tcaccgtctc ctca 354
<210> 24
<211> 118
<212> PRT
<213> Artificial Sequence
<220>
<223> 317-4B6 pro-Vh
<400> 24
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr
20 25 30
Gly Val His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Val Ile Tyr Ala Asp Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ala Tyr Gly Asn Tyr Trp Tyr Ile Asp Val Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser
115
<210> 25
<211> 321
<212> DNA
<213> Artificial Sequence
<220>
<223> 317-4B6 cDNA-Vk
<400> 25
gacatcgtga tgacccagtc tccagactcc ctggctgtgt ctctgggcga gagggccacc 60
atcaactgca agtccagcga gagtgtgagt aatgatgtag cttggtacca gcagaaacca 120
ggacagcctc ctaagctgct cattaactat gcatttcatc gcttcactgg ggtccctgac 180
cgattcagtg gcagcgggta tgggacagat ttcactctca ccatcagcag cctgcaggct 240
gaagatgtgg cagtttatta ctgtcaccag gcttatagtt ctccgtacac gtttggccag 300
gggaccaagc tggagatcaa a 321
<210> 26
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> 317-4B6 pro-Vk
<400> 26
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Glu Ser Val Ser Asn Asp
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile
35 40 45
Asn Tyr Ala Phe His Arg Phe Thr Gly Val Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Tyr Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala
65 70 75 80
Glu Asp Val Ala Val Tyr Tyr Cys His Gln Ala Tyr Ser Ser Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 27
<211> 342
<212> DNA
<213> Artificial Sequence
<220>
<223> 326-4A3 cDNA-Vh
<400> 27
caggtgcagc tggtgcagag cggcagcgag ctgaagaagc ccggcgccag cgtgaaggtg 60
agctgcaagg ccagcggcta caccttcacc aactacggca tgaactgggt gagacaggcc 120
cccggccagg gcctgaagtg gatgggctgg atcaacaaca acaacgccga gcccacctac 180
gcccaggact tcagaggcag attcgtgttc agcctggaca ccagcgccag caccgcctac 240
ctgcagatca gcagcctgaa gaccgaggac accgccgtgt actactgcgc cagagacgtg 300
atggactact ggggccaggg caccctggtg accgtgagca gc 342
<210> 28
<211> 114
<212> PRT
<213> Artificial Sequence
<220>
<223> 326-4A3 pro-Vh
<400> 28
Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Lys Trp Met
35 40 45
Gly Trp Ile Asn Asn Asn Asn Ala Glu Pro Thr Tyr Ala Gln Asp Phe
50 55 60
Arg Gly Arg Phe Val Phe Ser Leu Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Leu Gln Ile Ser Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Val Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
100 105 110
Ser Ser
<210> 29
<211> 330
<212> DNA
<213> Artificial Sequence
<220>
<223> 326-4A3 cDNA-Vk
<400> 29
gacattgtgc tgacccagtc tccagcctcc ttggccgtgt ctccaggaca gagggccacc 60
atcacctgca gagccagtga aagtgttgat aattatggct atagttttat gcactggtat 120
cagcagaaac caggacaacc tcctaaactc ctgatttacc gtgcatccaa cctagaatct 180
ggggtcccag ccaggttcag cggcagtggg tctgggaccg atttcaccct cacaattaat 240
cctgtggaag ctgaggatac tgcaaattat tactgtcagc aaagtaaaga atatccgacg 300
ttcggcggag ggaccaaggt ggagatcaaa 330
<210> 30
<211> 110
<212> PRT
<213> Artificial Sequence
<220>
<223> 326-4A3 pro-Vk
<400> 30
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Pro Gly
1 5 10 15
Gln Arg Ala Thr Ile Thr Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr
20 25 30
Gly Tyr Ser Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn
65 70 75 80
Pro Val Glu Ala Glu Asp Thr Ala Asn Tyr Tyr Cys Gln Gln Ser Lys
85 90 95
Glu Tyr Pro Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 31
<211> 10
<212> PRT
<213> Mus musculus
<400> 31
Gly Phe Ser Leu Thr Ser Tyr Gly Val His
1 5 10
<210> 32
<211> 16
<212> PRT
<213> Artificial Sequence
<220>
<223> 317-4B6 H-CDR2 or CDR-H2
<400> 32
Val Ile Tyr Ala Asp Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys Ser
1 5 10 15
<210> 33
<211> 12
<212> PRT
<213> Mus musculus
<400> 33
Ala Arg Ala Tyr Gly Asn Tyr Trp Tyr Ile Asp Val
1 5 10
<210> 34
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> 317-4B6 L-CDR1 or CDR-L1
<400> 34
Lys Ser Ser Glu Ser Val Ser Asn Asp Val Ala
1 5 10
<210> 35
<211> 7
<212> PRT
<213> Mus musculus
<400> 35
Tyr Ala Phe His Arg Phe Thr
1 5
<210> 36
<211> 9
<212> PRT
<213> Mus musculus
<400> 36
His Gln Ala Tyr Ser Ser Pro Tyr Thr
1 5
<210> 37
<211> 10
<212> PRT
<213> Mus musculus
<400> 37
Gly Tyr Thr Phe Thr Asn Tyr Gly Met Asn
1 5 10
<210> 38
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> 326-4A3 H-CDR2 or CDR-H2
<400> 38
Trp Ile Asn Asn Asn Asn Ala Glu Pro Thr Tyr Ala Gln Asp Phe Arg
1 5 10 15
Gly
<210> 39
<211> 7
<212> PRT
<213> Mus musculus
<400> 39
Ala Arg Asp Val Met Asp Tyr
1 5
<210> 40
<211> 15
<212> PRT
<213> Mus musculus
<400> 40
Arg Ala Ser Glu Ser Val Asp Asn Tyr Gly Tyr Ser Phe Met His
1 5 10 15
<210> 41
<211> 7
<212> PRT
<213> Mus musculus
<400> 41
Arg Ala Ser Asn Leu Glu Ser
1 5
<210> 42
<211> 8
<212> PRT
<213> Mus musculus
<400> 42
Gln Gln Ser Lys Glu Tyr Pro Thr
1 5
<210> 43
<211> 118
<212> PRT
<213> Artificial Sequence
<220>
<223> 317-4B2 pro-Vh
<400> 43
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr
20 25 30
Gly Val His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Val Ile Tyr Ala Gly Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ala Tyr Gly Asn Tyr Trp Tyr Ile Asp Val Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser
115
<210> 44
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> 317-4B2 pro-Vk
<400> 44
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Glu Ser Val Ser Asn Asp
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile
35 40 45
Asn Tyr Ala Phe His Arg Phe Thr Gly Val Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Tyr Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala
65 70 75 80
Glu Asp Val Ala Val Tyr Tyr Cys His Gln Ala Tyr Ser Ser Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 45
<211> 118
<212> PRT
<213> Artificial Sequence
<220>
<223> 317-4B5 pro-Vh
<400> 45
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr
20 25 30
Gly Val His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Val Ile Tyr Ala Gly Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ala Tyr Gly Asn Tyr Trp Tyr Ile Asp Val Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser
115
<210> 46
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> 317-4B5 pro-Vk
<400> 46
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Glu Ser Val Ser Asn Asp
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile
35 40 45
Asn Tyr Ala Phe His Arg Phe Thr Gly Val Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Tyr Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala
65 70 75 80
Glu Asp Val Ala Val Tyr Tyr Cys His Gln Ala Tyr Ser Ser Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 47
<211> 354
<212> DNA
<213> Artificial Sequence
<220>
<223> 317-1 cDNA-Vh
<400> 47
caggtgcagc tgcaggagtc gggaccagga ctggtgaagc cttcggagac cctgtccctc 60
acctgcactg tctctgggtt ttcattaacc agctatggtg tacactggat ccggcagccc 120
ccagggaagg gactggagtg gctgggggtc atatgggccg gtggaagcac aaattataat 180
ccctccctca agagtcgact gaccatatca aaagacaact ccaagagcca ggtttccctg 240
aagatgagct ctgtgaccgc tgcggacacg gccgtgtatt actgtgcgag agcctatggt 300
aactactggt acatcgatgt ctggggccaa gggaccacgg tcaccgtctc ctca 354
<210> 48
<211> 118
<212> PRT
<213> Artificial Sequence
<220>
<223> 317-1 pro-Vh
<400> 48
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr
20 25 30
Gly Val His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Ala Gly Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Leu Thr Ile Ser Lys Asp Asn Ser Lys Ser Gln Val Ser Leu
65 70 75 80
Lys Met Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ala Tyr Gly Asn Tyr Trp Tyr Ile Asp Val Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser
115
<210> 49
<211> 321
<212> DNA
<213> Artificial Sequence
<220>
<223> 317-1 cDNA-Vk
<400> 49
gacatcgtga tgacccagtc tccagactcc ctggctgtgt ctctgggcga gagggccacc 60
atcaactgca aggccagcca gagtgtgagt aatgatgtag cttggtacca gcagaaacca 120
ggacagcctc ctaagctgct cattaactat gcatttcatc gcttcactgg ggtccctgac 180
cgattcagtg gcagcgggta tgggacagat ttcactctca ccatcagcag cctgcaggct 240
gaagatgtgg cagtttatta ctgtcaccag gcttatagtt ctccgtacac gtttggcggg 300
gggaccaagc tggagatcaa a 321
<210> 50
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> 317-1 pro-Vk
<400> 50
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ala Ser Gln Ser Val Ser Asn Asp
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile
35 40 45
Asn Tyr Ala Phe His Arg Phe Thr Gly Val Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Tyr Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala
65 70 75 80
Glu Asp Val Ala Val Tyr Tyr Cys His Gln Ala Tyr Ser Ser Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 51
<211> 114
<212> PRT
<213> Artificial Sequence
<220>
<223> 326-3B1 pro-Vh
<400> 51
Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Lys Trp Met
35 40 45
Gly Trp Ile Asn Asn Asn Asn Gly Glu Pro Thr Tyr Ala Gln Asp Phe
50 55 60
Arg Gly Arg Phe Val Phe Ser Leu Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Leu Gln Ile Ser Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Val Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
100 105 110
Ser Ser
<210> 52
<211> 110
<212> PRT
<213> Artificial Sequence
<220>
<223> 326-3B1 pro-Vk
<400> 52
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Pro Gly
1 5 10 15
Gln Arg Ala Thr Ile Thr Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr
20 25 30
Gly Tyr Ser Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asn
65 70 75 80
Pro Val Glu Ala Asn Asp Thr Ala Asn Tyr Tyr Cys Gln Gln Ser Lys
85 90 95
Glu Tyr Pro Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 53
<211> 114
<212> PRT
<213> Artificial Sequence
<220>
<223> 326-3G1 pro-Vh
<400> 53
Gln Val Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Lys Trp Met
35 40 45
Gly Trp Ile Asn Asn Asn Asn Gly Glu Pro Thr Tyr Ala Gln Asp Phe
50 55 60
Arg Gly Arg Phe Val Phe Ser Leu Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Leu Gln Ile Ser Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Val Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
100 105 110
Ser Ser
<210> 54
<211> 110
<212> PRT
<213> Artificial Sequence
<220>
<223> 326-3G1 pro-Vk
<400> 54
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Pro Gly
1 5 10 15
Gln Arg Ala Thr Ile Thr Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr
20 25 30
Gly Tyr Ser Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asn
65 70 75 80
Pro Val Glu Ala Asn Asp Thr Ala Asn Tyr Tyr Cys Gln Gln Ser Lys
85 90 95
Glu Tyr Pro Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 55
<211> 342
<212> DNA
<213> Artificial Sequence
<220>
<223> 326-1 cDNA-Vh
<400> 55
caggtgcagc tggtgcagag cggcagcgag ctgaagaagc ccggcgccag cgtgaaggtg 60
agctgcaagg ccagcggcta caccttcacc aactacggca tgaactgggt gagacaggcc 120
cccggccagg gcctggagtg gatgggctgg atcaacaaca acaacggcga gcccacctac 180
gcccagggct tcagaggcag attcgtgttc agcctggaca ccagcgccag caccgcctac 240
ctgcagatca gcagcctgaa gaccgaggac accgccgtgt acttctgcgc cagagacgtg 300
atggactact ggggccaggg caccaccgtg accgtgagca gc 342
<210> 56
<211> 114
<212> PRT
<213> Artificial Sequence
<220>
<223> 326-1 pro-Vh
<400> 56
Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Asn Asn Asn Gly Glu Pro Thr Tyr Ala Gln Gly Phe
50 55 60
Arg Gly Arg Phe Val Phe Ser Leu Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Leu Gln Ile Ser Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr Phe Cys
85 90 95
Ala Arg Asp Val Met Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val
100 105 110
Ser Ser
<210> 57
<211> 330
<212> DNA
<213> Artificial Sequence
<220>
<223> 326-1 cDNA-Vk
<400> 57
gacattgtgc tgacccagtc tccagcctcc ttggccgtgt ctccaggaca gagggccacc 60
atcacctgca gagccagtga aagtgttgat aattatggct atagttttat gcactggtat 120
cagcagaaac caggacaacc tcctaaactc ctgatttacc gtgcatccaa cctagaatct 180
ggggtcccag ccaggttcag cggcagtggg tctaggaccg atttcaccct cacaattaat 240
cctgtggaag ctaatgatac tgcaaattat tactgtcagc aaagtaaaga atatccgacg 300
ttcggcggag ggaccaaggt ggagatcaaa 330
<210> 58
<211> 110
<212> PRT
<213> Artificial Sequence
<220>
<223> 326-1 pro-Vk
<400> 58
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Pro Gly
1 5 10 15
Gln Arg Ala Thr Ile Thr Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr
20 25 30
Gly Tyr Ser Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asn
65 70 75 80
Pro Val Glu Ala Asn Asp Thr Ala Asn Tyr Tyr Cys Gln Gln Ser Lys
85 90 95
Glu Tyr Pro Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 59
<211> 16
<212> PRT
<213> Artificial Sequence
<220>
<223> 317-1 H-CDR2 or CDR-H2
<400> 59
Val Ile Trp Ala Gly Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys Ser
1 5 10 15
<210> 60
<211> 16
<212> PRT
<213> Artificial Sequence
<220>
<223> 317-4B2 H-CDR2 or CDR-H2
<400> 60
Val Ile Tyr Ala Gly Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys Ser
1 5 10 15
<210> 61
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> 317-4B2 L-CDR1 or CDR-L1
<400> 61
Lys Ser Ser Glu Ser Val Ser Asn Asp Val Ala
1 5 10
<210> 62
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> 326-1 H-CDR2 or CDR-H2
<400> 62
Trp Ile Asn Asn Asn Asn Gly Glu Pro Thr Tyr Ala Gln Gly Phe Arg
1 5 10 15
Gly
<210> 63
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> 326-3G1 H-CDR2 or CDR-H2
<400> 63
Trp Ile Asn Asn Asn Asn Gly Glu Pro Thr Tyr Ala Gln Asp Phe Arg
1 5 10 15
Gly
<210> 64
<211> 118
<212> PRT
<213> Artificial Sequence
<220>
<223> 317-3A1 pro-Vh
<400> 64
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr
20 25 30
Gly Val His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Val Ile Trp Ala Gly Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ala Tyr Gly Asn Tyr Trp Tyr Ile Asp Val Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser
115
<210> 65
<211> 118
<212> PRT
<213> Artificial Sequence
<220>
<223> 317-3C1 pro-Vh
<400> 65
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr
20 25 30
Gly Val His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Ala Gly Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ala Tyr Gly Asn Tyr Trp Tyr Ile Asp Val Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser
115
<210> 66
<211> 118
<212> PRT
<213> Artificial Sequence
<220>
<223> 317-3E1 pro-Vh
<400> 66
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr
20 25 30
Gly Val His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Val Ile Trp Ala Gly Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Ser Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ala Tyr Gly Asn Tyr Trp Tyr Ile Asp Val Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser
115
<210> 67
<211> 118
<212> PRT
<213> Artificial Sequence
<220>
<223> 317-3F1 pro-Vh
<400> 67
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr
20 25 30
Gly Val His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Val Ile Trp Ala Gly Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Val Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ala Tyr Gly Asn Tyr Trp Tyr Ile Asp Val Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser
115
<210> 68
<211> 118
<212> PRT
<213> Artificial Sequence
<220>
<223> 317-3G1 pro-Vh
<400> 68
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr
20 25 30
Gly Val His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Val Ile Trp Ala Gly Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Ser Gln Val Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ala Tyr Gly Asn Tyr Trp Tyr Ile Asp Val Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser
115
<210> 69
<211> 118
<212> PRT
<213> Artificial Sequence
<220>
<223> 317-3H1 pro-Vh
<400> 69
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr
20 25 30
Gly Val His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Val Ile Trp Ala Gly Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Lys Asp Thr Ser Lys Ser Gln Val Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ala Tyr Gly Asn Tyr Trp Tyr Ile Asp Val Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser
115
<210> 70
<211> 118
<212> PRT
<213> Artificial Sequence
<220>
<223> 317-3I1 pro-Vh
<400> 70
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr
20 25 30
Gly Val His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Val Ile Trp Ala Gly Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ala Tyr Gly Asn Tyr Trp Tyr Ile Asp Val Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser
115
<210> 71
<211> 118
<212> PRT
<213> Artificial Sequence
<220>
<223> 317-4B1 pro-Vh
<400> 71
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr
20 25 30
Gly Val His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Val Ile Trp Ala Gly Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ala Tyr Gly Asn Tyr Trp Tyr Ile Asp Val Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser
115
<210> 72
<211> 118
<212> PRT
<213> Artificial Sequence
<220>
<223> 317-4B3 pro-Vh
<400> 72
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr
20 25 30
Gly Val His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Val Ile Asn Ala Gly Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ala Tyr Gly Asn Tyr Trp Tyr Ile Asp Val Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser
115
<210> 73
<211> 118
<212> PRT
<213> Artificial Sequence
<220>
<223> 317-4B4 pro-Vh
<400> 73
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr
20 25 30
Gly Val His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Val Ile Trp Ala Gly Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Ala Tyr Gly Asn Tyr Pro Tyr Ile Asp Val Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser
115
<210> 74
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> 317-4A2 pro-Vk
<400> 74
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Ser Asn Asp
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile
35 40 45
Asn Tyr Ala Phe His Arg Phe Thr Gly Val Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Tyr Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala
65 70 75 80
Glu Asp Val Ala Val Tyr Tyr Cys His Gln Ala Tyr Ser Ser Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 75
<211> 114
<212> PRT
<213> Artificial Sequence
<220>
<223> 326-3A1 pro-Vh
<400> 75
Gln Val Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Asn Asn Asn Gly Glu Pro Thr Tyr Ala Gln Gly Phe
50 55 60
Arg Gly Arg Phe Val Phe Ser Leu Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Leu Gln Ile Ser Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Val Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
100 105 110
Ser Ser
<210> 76
<211> 114
<212> PRT
<213> Artificial Sequence
<220>
<223> 326-3C1 pro-Vh
<400> 76
Gln Val Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Lys Trp Met
35 40 45
Gly Trp Ile Asn Asn Asn Asn Gly Glu Pro Thr Tyr Ala Gln Asp Phe
50 55 60
Arg Gly Arg Phe Val Phe Ser Leu Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Leu Gln Ile Ser Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Val Met Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val
100 105 110
Ser Ser
<210> 77
<211> 114
<212> PRT
<213> Artificial Sequence
<220>
<223> 326-3D1 pro-Vh
<400> 77
Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Asn Asn Asn Gly Glu Pro Thr Tyr Ala Gln Gly Phe
50 55 60
Arg Gly Arg Phe Val Phe Ser Leu Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Leu Gln Ile Ser Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Val Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
100 105 110
Ser Ser
<210> 78
<211> 114
<212> PRT
<213> Artificial Sequence
<220>
<223> 326-3E1 pro-Vh
<400> 78
Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Lys Trp Met
35 40 45
Gly Trp Ile Asn Asn Asn Asn Gly Glu Pro Thr Tyr Ala Gln Asp Phe
50 55 60
Arg Gly Arg Phe Val Phe Ser Leu Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Leu Gln Ile Ser Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Val Met Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val
100 105 110
Ser Ser
<210> 79
<211> 114
<212> PRT
<213> Artificial Sequence
<220>
<223> 326-3F1 pro-Vh
<400> 79
Gln Val Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Asn Asn Asn Gly Glu Pro Thr Tyr Ala Gln Gly Phe
50 55 60
Arg Gly Arg Phe Val Phe Ser Leu Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Leu Gln Ile Ser Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Val Met Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val
100 105 110
Ser Ser
<210> 80
<211> 114
<212> PRT
<213> Artificial Sequence
<220>
<223> 326-3B N55D pro-Vh
<400> 80
Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Lys Trp Met
35 40 45
Gly Trp Ile Asn Asn Asn Asp Gly Glu Pro Thr Tyr Ala Gln Asp Phe
50 55 60
Arg Gly Arg Phe Val Phe Ser Leu Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Leu Gln Ile Ser Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Val Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
100 105 110
Ser Ser
<210> 81
<211> 110
<212> PRT
<213> Artificial Sequence
<220>
<223> 326-4A1 pro-Vk
<400> 81
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Pro Gly
1 5 10 15
Gln Arg Ala Thr Ile Thr Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr
20 25 30
Gly Tyr Ser Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asn
65 70 75 80
Pro Val Glu Ala Glu Asp Thr Ala Asn Tyr Tyr Cys Gln Gln Ser Lys
85 90 95
Glu Tyr Pro Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 82
<211> 110
<212> PRT
<213> Artificial Sequence
<220>
<223> 326-4A2 pro-Vk
<400> 82
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Pro Gly
1 5 10 15
Gln Arg Ala Thr Ile Thr Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr
20 25 30
Gly Tyr Ser Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn
65 70 75 80
Pro Val Glu Ala Asn Asp Thr Ala Asn Tyr Tyr Cys Gln Gln Ser Lys
85 90 95
Glu Tyr Pro Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 83
<211> 327
<212> PRT
<213> Artificial Sequence
<220>
<223> huIgG4mt1 pro
<400> 83
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Glu Phe Glu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 84
<211> 327
<212> PRT
<213> Artificial Sequence
<220>
<223> huIgG4mt2 pro
<400> 84
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Pro Val Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 85
<211> 327
<212> PRT
<213> Artificial Sequence
<220>
<223> huIgG4mt6 pro
<400> 85
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Pro Val Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Ala Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 86
<211> 327
<212> PRT
<213> Artificial Sequence
<220>
<223> huIgG4mt8 pro
<400> 86
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Pro Val Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Thr Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 87
<211> 327
<212> PRT
<213> Artificial Sequence
<220>
<223> huIgG4mt9 pro
<400> 87
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Pro Val Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Ala Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 88
<211> 327
<212> PRT
<213> Artificial Sequence
<220>
<223> huIgG4mt10 pro
<400> 88
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Pro Val Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Ala Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Val His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 89
<211> 367
<212> PRT
<213> Artificial Sequence
<220>
<223> OS8 pro
<400> 89
Met Glu Arg His Trp Ile Phe Leu Leu Leu Leu Ser Val Thr Ala Gly
1 5 10 15
Val His Ser Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg
20 25 30
Pro Gly Ala Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe
35 40 45
Thr Arg Tyr Thr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu
50 55 60
Glu Trp Ile Gly Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn
65 70 75 80
Gln Lys Phe Lys Asp Lys Ala Thr Leu Thr Thr Asp Lys Ser Ser Ser
85 90 95
Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp
115 120 125
Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Gly Gly Gly Gly Ser Gly
130 135 140
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Ile Val Leu Thr Gln Ser
145 150 155 160
Pro Ala Ile Met Ser Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys
165 170 175
Ser Ala Ser Ser Ser Val Ser Tyr Met Asn Trp Tyr Gln Gln Lys Ser
180 185 190
Gly Thr Ser Pro Lys Arg Trp Ile Tyr Asp Thr Ser Lys Leu Ala Ser
195 200 205
Gly Val Pro Ala His Phe Arg Gly Ser Gly Ser Gly Thr Ser Tyr Ser
210 215 220
Leu Thr Ile Ser Gly Met Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys
225 230 235 240
Gln Gln Trp Ser Ser Asn Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu
245 250 255
Glu Ile Asn Ser Ser Val Val Pro Val Leu Gln Lys Val Asn Ser Thr
260 265 270
Thr Thr Lys Pro Val Leu Arg Thr Pro Ser Pro Val His Pro Thr Gly
275 280 285
Thr Ser Gln Pro Gln Arg Pro Glu Asp Cys Arg Pro Arg Gly Ser Val
290 295 300
Lys Gly Thr Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro
305 310 315 320
Leu Ala Gly Ile Cys Val Ala Leu Leu Leu Ser Leu Ile Ile Thr Leu
325 330 335
Ile Cys Tyr His Arg Ser Arg Lys Arg Val Cys Lys Cys Pro Arg Pro
340 345 350
Leu Val Arg Gln Glu Gly Lys Pro Arg Pro Ser Glu Lys Ile Val
355 360 365
<210> 90
<211> 304
<212> PRT
<213> Artificial Sequence
<220>
<223> P3Z pro
<400> 90
Met Gln Ile Pro Gln Ala Pro Trp Pro Val Val Trp Ala Val Leu Gln
1 5 10 15
Leu Gly Trp Arg Pro Gly Trp Phe Leu Asp Ser Pro Asp Arg Pro Trp
20 25 30
Asn Pro Pro Thr Phe Ser Pro Ala Leu Leu Val Val Thr Glu Gly Asp
35 40 45
Asn Ala Thr Phe Thr Cys Ser Phe Ser Asn Thr Ser Glu Ser Phe Val
50 55 60
Leu Asn Trp Tyr Arg Met Ser Pro Ser Asn Gln Thr Asp Lys Leu Ala
65 70 75 80
Ala Phe Pro Glu Asp Arg Ser Gln Pro Gly Gln Asp Cys Arg Phe Arg
85 90 95
Val Thr Gln Leu Pro Asn Gly Arg Asp Phe His Met Ser Val Val Arg
100 105 110
Ala Arg Arg Asn Asp Ser Gly Thr Tyr Leu Cys Gly Ala Ile Ser Leu
115 120 125
Ala Pro Lys Ala Gln Ile Lys Glu Ser Leu Arg Ala Glu Leu Arg Val
130 135 140
Thr Glu Arg Arg Ala Glu Val Pro Thr Ala His Pro Ser Pro Ser Pro
145 150 155 160
Arg Pro Ala Gly Gln Phe Gln Thr Leu Val Val Gly Val Val Gly Gly
165 170 175
Leu Leu Gly Ser Leu Val Leu Leu Val Trp Val Leu Ala Val Ile Arg
180 185 190
Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln
195 200 205
Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp
210 215 220
Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro
225 230 235 240
Gln Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys
245 250 255
Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg
260 265 270
Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala
275 280 285
Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
290 295 300
<210> 91
<211> 327
<212> PRT
<213> Artificial Sequence
<220>
<223> IgG4 Fc region 228P-233P
<400> 91
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Pro Glu Phe Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 92
<211> 327
<212> PRT
<213> Artificial Sequence
<220>
<223> IgG4 Fc region 228P-234V
<400> 92
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Glu Val Phe Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 93
<211> 327
<212> PRT
<213> Artificial Sequence
<220>
<223> IgG4 Fc region 228P-235A
<400> 93
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Glu Phe Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 94
<211> 327
<212> PRT
<213> Artificial Sequence
<220>
<223> IgG4 Fc region 228P-234V-235A
<400> 94
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Glu Val Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 95
<211> 327
<212> PRT
<213> Artificial Sequence
<220>
<223> IgG4 Fc region 228P-234A
<400> 95
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Glu Ala Phe Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 96
<211> 327
<212> PRT
<213> Artificial Sequence
<220>
<223> IgG4 Fc region 228P-234A-235A
<400> 96
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 97
<211> 327
<212> PRT
<213> Artificial Sequence
<220>
<223> IgG4 Fc region 228P-233P-234A-235A
<400> 97
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Pro Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 98
<211> 327
<212> PRT
<213> Artificial Sequence
<220>
<223> IgG4 Fc region 228P-234V-235A-265A
<400> 98
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Glu Val Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Ala Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 99
<211> 327
<212> PRT
<213> Artificial Sequence
<220>
<223> IgG4 Fc region 228P-234A-235A-265A
<400> 99
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Ala Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 100
<211> 327
<212> PRT
<213> Artificial Sequence
<220>
<223> IgG4 Fc region 228P-233P-234A-235A-265A
<400> 100
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Pro Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Ala Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 101
<211> 327
<212> PRT
<213> Artificial Sequence
<220>
<223> IgG4 Fc region 228P-265A
<400> 101
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Ala Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 102
<211> 327
<212> PRT
<213> Artificial Sequence
<220>
<223> IgG4 Fc region 228P-309V
<400> 102
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Val His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 103
<211> 327
<212> PRT
<213> Artificial Sequence
<220>
<223> IgG4 Fc region 228P-409K
<400> 103
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 104
<211> 327
<212> PRT
<213> Artificial Sequence
<220>
<223> IgG4 Fc region 228P-309V-409K
<400> 104
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Val His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 105
<211> 327
<212> PRT
<213> Artificial Sequence
<220>
<223> IgG4 Fc region 228P-265A-309V-409K
<400> 105
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Ala Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Val His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 106
<211> 327
<212> PRT
<213> Artificial Sequence
<220>
<223> IgG4 Fc region 228P-233P-234A-235A-265A-309V-409K
<400> 106
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Pro Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Ala Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Val His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 107
<211> 327
<212> PRT
<213> Homo sapiens
<400> 107
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro Ala Pro
100 105 110
Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
Claims (23)
- 치료적 유효량의 항-PD-1 항체 또는 이의 항원 결합 단편을 환자에게 투여하는 단계를 포함하는 간세포암(hepatocellular carcinoma: HCC) 환자의 면역 치료방법으로, 상기 항-PD-1 항체 또는 이의 항원 결합 단편은 항체-의존성 포식작용(phagocytosis)을 제거하기 위해 대식세포(macrophages)상의 FcγR 결합을 최소화하도록 특이적으로 조작된 것을 특징으로 하는 방법.
- 제1항에 있어서, 상기 항-PD-1 항체는 다음에 열거된 CDRs을 함유하는 중쇄 가변영역(Vh) 및 경쇄 가변영역(Vk)를 포함하는 항체인 것을 특징으로 하는 방법:
a) mu317: CDR-H1, CDR-H2 및 CDR-H3 (각각 서열번호: 11, 12, 13); 및
CDR-L1, CDR-L2 및 CDR-L3 (각각 서열번호: 14, 15, 16);
b) mu326: CDR-H1, CDR-H2 및 CDR-H3 (각각 서열번호: 17, 18, 19); 및
CDR-L1, CDR-L2 및 CDR-L3 (각각 서열번호: 20, 21, 22);
c) 317-4B6: CDR-H1, CDR-H2 및 CDR-H3 (각각 서열번호: 31, 32, 33); 및
CDR-L1 , CDR-L2 및 CDR-L3 (각각 서열번호: 34, 35, 36);
d) 326-4A3: CDR-H1, CDR-H2 및 CDR-H3 (각각 서열번호: 37, 38, 39); 및
CDR-L1, CDR--L2 및 CDR-L3 (각각 서열번호: 40, 41, 42);
e) 317-1H: CDR-H1, CDR-H2 및 CDR-H3 (각각 서열번호: l l, 59, 13); 및
CDR-L1, CDR-L2 및 CDR-L3 (각각 서열번호: 14, 15, 16);
f) 317-4B2: CDR-HL CDR-H2 및 CDR-H3 (각각 서열번호: l l, 60, 13); 및
CDR-L1 , CDR-L2 및 CDR-L3 (각각 서열번호: 61 , 15, 16);
g) 317-4B5: CDR-Hl, CDR-H2 및 CDR-H3 (각각 서열번호: 11 , 60, 13); 및
CDR-L1 , CDR-L2 및 CDR-L3 (각각 서열번호: 61 , 15, 16);
h) 317-4B6: CDR-H1, CDR-H2 및 CDR-H3 (각각 서열번호: 11, 32, 13); 및
CDR-L1, CDR-L2 및 CDR-L3 (각각 서열번호: 61, 15, 16);
i) 326-1: CDR-H1, CDR-H2 및 CDR-H3 (각각 서열번호: 17, 62, 19); 및
CDR-L1, CDR-L2 및 CDR-L3 (각각 서열번호: 20, 21, 22);
j) 326-3B1:CDR-H1, CDR-H2 및 CDR-H3 (각각 서열번호: 17, 62, 19); 및
CDR-L1, CDR-L2 및 CDR-L3 (각각 서열번호: 20, 21, 22); 또는
k) 326-3G1: CDR-H1, CDR-H2 및 CDR-H3 (각각 서열번호: 17, 62, 19); 및
CDR-L1, CDR-I 2 및 CDR-L3 (각각 서열번호: 20, 21, 22).
- 제1항에 있어서, 상기 항-PD-1 항체는 다음에 열거된 상보성 결정 영역 (CDRs)을 함유하는 중쇄 가변영역(Vh) 및 경쇄 가변영역(Vk)를 포함하는 항체인 것을 특징으로 하는 방법:
(a) CDR-H1 (서열번호 31), CDR-H2 (서열번호 12, 32, 59 또는 60) 및 CDR-H3 (서열번호 33),
CDR-L1 ( 서열번호 14, 34 또는 61), CDR-L2 (서열번호 35) 및 CDR-L3 (서열번호 36); 또는
(b) CDR-H1 (서열번호 37), CDR-H2 (서열번호 18, 38 또는 62) 및 CDR-H3 (서열번호 39),
CDR-L1 (서열번호 40), CDR-L2 (서열번호 41) 및 CDR-L3 (서열번호 42).
- 제2항 또는 제3항에 있어서, 상기 항-PD-1 항체는 다음을 포함하는 중쇄 가변영역(Vh) 및 경쇄 가변영역(Vk)를 포함하는 항체인 것을 특징으로 하는 방법:
a) mu317 (각각 서열번호: 4 및 6);
b) mu326 (각각 서열번호: 8 및 10);
c) 317-4B6 (각각 서열번호: 24 및 26);
d) 326-4A3 (각각 서열번호: 28 및 30);
e) 317-4B2 (각각 서열번호: 43 및 44);
f) 317-4B5 (각각 서열번호: 45 및 46);
g) 317-1 (각각 서열번호: 48 및 50);
h) 326-3B1 (각각 서열번호: 51 및 52);
i) 326-3GI (각각 서열번호: 53 및 54);
j) 326-1 (각각 서열번호: 56 및 58);
k) 317-3A1 (각각 서열번호: 64 및 26);
l) 317-3C1 (각각 서열번호: 65 및 26);
m) 317-3E1 (각각 서열번호: 66 및 26);
n) 317-3F1 (각각 서열번호: 67 및 26);
o) 317-3G1 (각각 서열번호: 68 및 26);
p) 317-3H1 (각각 서열번호: 69 및 26);
q) 317-311 (각각 서열번호: 70 및 26);
r) 317-4B 1 (각각 서열번호: 71 및 26);
s) 317-4B3 (각각 서열번호: 72 및 26);
t) 317-4B4 (각각 서열번호: 73 및 26);
u) 317-4A2 (각각 서열번호: 74 및 26);
v) 326-3 A 1 (각각 서열번호: 75 및 30);
w) 326-3C1 (각각 서열번호: 76 및 30);
x) 326-3D1 (각각 서열번호: 77 및 30);
y) 326-3E1 (각각 서열번호: 78 및 30);
z) 326-3F1 (각각 서열번호: 79 및 30);
aa) 326-3B N55D (각각 서열번호: 80 및 30);
ab) 326-4A1 (각각 서열번호: 28 및 81); 또는
ac) 326-4A2 (각각 서열번호: 28 및 82).
- 제2항 또는 제3항에 있어서, 상기 항-PD-1 항체는 서열번호 83-88 또는 91-106 중 임의의 서열을 포함하는 IgG4 중쇄 효과기 (effector) 또는 불변 도메인을 함유하는 항체인 것을 특징으로 하는 방법.
- 제2항 또는 제3항에 있어서, 상기 항-PD-1 항체는 제2항 내지 제5항 중 한 항의 도메인을 포함하는 F(ab) 또는 F(ab)2를 함유하는 항체인 것을 특징으로 하는 방법.
- 제1항에 있어서, 상기 항-PD-1 항체는 중쇄 가변영역 (Vh) 및 경쇄 가변영역 (Vk), 및 서열번호 87 또는 88을 포함하는 IgG4 중쇄 효과기 (effector) 또는 불변 도메인을 포함하는 항체로, 상기 중쇄 가변영역 (Vh) 및 경쇄 가변영역 (Vk)는 다음을 포함하는 것을 특징으로 하는 방법:
a) mu317 (각각 서열번호: 4 및 6);
b) mu326 (각각 서열번호: 8 및 10);
c) 317-4B6 (각각 서열번호: 24 및 26);
d) 326-4A3 (각각 서열번호: 28 및 30);
e) 317-4B2 (각각 서열번호: 43 및 44);
f) 317-4B5 (각각 서열번호: 45 및 46);
g) 317-1 (각각 서열번호: 48 및 50);
h) 326-3B1 (각각 서열번호: 51 및 52);
i) 326-3GI (각각 서열번호: 53 및 54);
j) 326-1 (각각 서열번호: 56 및 58);
k) 317-3A1 (각각 서열번호: 64 및 26);
l) 317-3C1 (각각 서열번호: 65 및 26);
m) 317-3E1 (각각 서열번호: 66 및 26);
n) 317-3F1 (각각 서열번호: 67 및 26);
o) 317-3G1 (각각 서열번호: 68 및 26);
p) 317-3H1 (각각 서열번호: 69 및 26);
q) 317-311 (각각 서열번호: 70 및 26);
r) 317-4B 1 (각각 서열번호: 71 및 26);
s) 317-4B3 (각각 서열번호: 72 및 26);
t) 317-4B4 (각각 서열번호: 73 및 26);
u) 317-4A2 (각각 서열번호: 74 및 26);
v) 326-3 A 1 (각각 서열번호: 75 및 30);
w) 326-3C1 (각각 서열번호: 76 및 30);
x) 326-3D1 (각각 서열번호: 77 및 30);
y) 326-3E1 (각각 서열번호: 78 및 30);
z) 326-3F1 (각각 서열번호: 79 및 30);
aa) 326-3B N55D (각각 서열번호: 80 및 30);
ab) 326-4A1 (각각 서열번호: 28 및 81); 또는
ac) 326-4A2 (각각 서열번호: 28 및 82).
- 제1항에 있어서, 상기 항-PD-1 항체는 중쇄 가변영역 (Vh) 및 경쇄 가변영역 (Vk), 및 서열번호 88을 포함하는 IgG4 중쇄 효과기 (effector) 또는 불변 도메인을 포함하는 항체로, 상기 중쇄 가변영역 (Vh) 및 경쇄 가변영역 (Vk)는 각각 서열번호 24 및 서열번호 26을 포함하는 것을 특징으로 하는 방법.
- 제1항 내지 제8항 중 어느 한 항에 있어서, 상기 HCC는 진행성 (advanced) HCC 및/또는 전이성 (metastatic) HCC인 것을 특징으로 하는 방법.
- 제1항 내지 제8항 중 어느 한 항에 있어서, 상기 HCC는 바이러스 감염 관련 (virus infection related) HCC인 것을 특징으로 하는 방법.
- 제10항에 있어서, 상기 HCC는 HBV 감염 HCC, HCV 감염 HCC 또는 HBV/HCV 공동 감염 HCC인 것을 특징으로 하는 방법.
- 제1항 내지 제8항 중 어느 한 항에 있어서, 상기 HCC는 진행성 HBV-감염 HCC, 전이성 HBV-감염 HCC, HCV-감염 HCC 또는 전이성 HCV-감염 HCC인 것을 특징으로 하는 방법.
- 제1항 내지 제8항 중 어느 한 항에 있어서, 상기 HCC는 진행성 HBV-감염 HCC, 또는 전이성 HBV-감염 HCC인 것을 특징으로 하는 방법.
- 제9항에 있어서, 상기 HCC는 선행의(prior) PD-1 또는 PD-L1에 의해 치료되지 않는 것을 특징으로 하는 방법.
- 제1항 내지 제14항 중 어느 한 항에 있어서, 상기 항-PD-1 항체는 0.5-10 mg/kg QW, 또는 Q2W, Q3W 또는 Q4W의 용량으로 비경구 투여되는 것을 특징으로 하는 방법.
- 제1항 내지 제14항 중 어느 한 항에 있어서, 상기 항-PD-1 항체는 0.5-10 mg/kg QW 또는 Q2W 또는 Q3W의 용량으로 투여되는 것을 특징으로 하는 방법.
- 제1항 내지 제14항 중 어느 한 항에 있어서 상기 항-PD-1 항체는 0.5-10 mg/kg Q2W 또는 Q3W의 용량으로 투여되는 것을 특징으로 하는 방법.
- 제1항 내지 제14항 중 어느 한 항에 있어서, 상기 항 PD-1 항체는 0.5-5 mg/kg Q2W, 5-10 mg/kg Q2W, 또는 2-5 mg/kg Q3W의 용량으로 비경구 투여되는 것을 특징으로 하는 방법.
- 제1항 내지 제14항 중 어느 한 항에 있어서, 상기 항 PD-1 항체는 0.5 mg/kg Q2W, 5 mg/kg Q2W, 10 mg/kg Q2W, 2 mg/kg Q3W 또는 5 mg/kg Q3W의 용량으로 비경구 투여되는 것을 특징으로 하는 방법.
- 제1항 내지 제14항 중 어느 한 항에 있어서, 상기 항-PD-1 항체는 약 200 mg의 용량으로 비경구 투여되는 것을 특징으로 하는 방법.
- 제20항에있어서, 상기 항-PD-1 항체는 Q3W로 투여되는 것을 특징으로 하는 방법.
- 제1항에있어서, 상기 HCC 환자는 < 200 IU/mL (~1000cps/mL)의 HBV 바이러스로드를 갖는 것을 특징으로 하는 방법.
- 제1항에 있어서, 상기 HCC 환자는 치료 전반에 걸쳐 3개월 이상 및 치료 이후 6 개월 동안 항-HBV 억제 상태여야 하는 활성 HBV 감염을 갖는 것을 특징으로 하는 방법.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201762524967P | 2017-06-26 | 2017-06-26 | |
| US62/524,967 | 2017-06-26 | ||
| CN2017090397 | 2017-06-27 | ||
| CNPCT/CN2017/090397 | 2017-06-27 | ||
| PCT/CN2018/092827 WO2019001417A1 (en) | 2017-06-26 | 2018-06-26 | IMMUNOTHERAPY FOR HEPATOCELLULAR CARCINOMA |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| KR20200020902A true KR20200020902A (ko) | 2020-02-26 |
Family
ID=64740368
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1020207002309A KR20200020902A (ko) | 2017-06-26 | 2018-06-26 | 간세포암(hepatocellular carcinoma: HCC)에 대한 면역 치료 |
Country Status (9)
| Country | Link |
|---|---|
| US (1) | US11597768B2 (ko) |
| EP (1) | EP3645569A4 (ko) |
| JP (2) | JP2020525411A (ko) |
| KR (1) | KR20200020902A (ko) |
| CN (1) | CN110799543A (ko) |
| AU (1) | AU2018290532A1 (ko) |
| CA (1) | CA3066518A1 (ko) |
| TW (1) | TW201906866A (ko) |
| WO (1) | WO2019001417A1 (ko) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20220023024A (ko) | 2020-08-20 | 2022-03-02 | 경상국립대학교병원 | 간세포암 환자의 생존율 예측을 위한 정보제공방법 |
| KR20230055751A (ko) | 2021-10-19 | 2023-04-26 | 가톨릭대학교 산학협력단 | 간세포암 특이적 표적 엑소좀 조성물 및 이의 용도 |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112457403B (zh) * | 2013-09-13 | 2022-11-29 | 广州百济神州生物制药有限公司 | 抗pd1抗体及其作为治疗剂与诊断剂的用途 |
| KR102130600B1 (ko) | 2014-07-03 | 2020-07-08 | 베이진 엘티디 | Pd-l1 항체와 이를 이용한 치료 및 진단 |
| CN109475536B (zh) | 2016-07-05 | 2022-05-27 | 百济神州有限公司 | 用于治疗癌症的PD-l拮抗剂和RAF抑制剂的组合 |
| KR20230162137A (ko) | 2016-08-16 | 2023-11-28 | 베이진 스위찰랜드 게엠베하 | (s)-7-(1-아크릴로일피페리딘-4-일)-2-(4-페녹시페닐)-4,5,6,7-테트라-하이드로피라졸로 [1,5-a] 피리미딘-3-카르복스아미드의 제조 및 그 용도 |
| CN118252927A (zh) | 2016-08-19 | 2024-06-28 | 百济神州有限公司 | 使用包含btk抑制剂的组合产品治疗癌症 |
| CN110461847B (zh) | 2017-01-25 | 2022-06-07 | 百济神州有限公司 | (S)-7-(1-(丁-2-炔酰基)哌啶-4-基)-2-(4-苯氧基苯基)-4,5,6,7-四氢吡唑并[1,5-a]嘧啶-3-甲酰胺的结晶形式、其制备及用途 |
| AU2018290532A1 (en) | 2017-06-26 | 2019-11-21 | Beigene, Ltd. | Immunotherapy for hepatocellular carcinoma |
| WO2019108795A1 (en) | 2017-11-29 | 2019-06-06 | Beigene Switzerland Gmbh | Treatment of indolent or aggressive b-cell lymphomas using a combination comprising btk inhibitors |
| CN111808194B (zh) * | 2020-07-13 | 2021-04-20 | 北京凯因科技股份有限公司 | 一种结合密蛋白的用于治疗癌症的人源化抗体 |
| CN116547305A (zh) * | 2020-11-11 | 2023-08-04 | 生物技术公司 | 针对程序性死亡-1蛋白的单克隆抗体及其在医学中的用途 |
Family Cites Families (231)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BE792533A (fr) | 1971-12-09 | 1973-06-08 | Int Chem & Nuclear Corp | Nouvelles pyrazolo (1,5a) pyrimidines et leur procede de preparation |
| WO1988007089A1 (en) | 1987-03-18 | 1988-09-22 | Medical Research Council | Altered antibodies |
| US5859205A (en) | 1989-12-21 | 1999-01-12 | Celltech Limited | Humanised antibodies |
| US5994514A (en) | 1991-08-14 | 1999-11-30 | Genentech, Inc. | Immunoglobulin variants |
| AU4116793A (en) | 1992-04-24 | 1993-11-29 | Board Of Regents, The University Of Texas System | Recombinant production of immunoglobulin-like domains in prokaryotic cells |
| CA2163345A1 (en) | 1993-06-16 | 1994-12-22 | Susan Adrienne Morgan | Antibodies |
| CA2143491C (en) | 1994-03-01 | 2011-02-22 | Yasumasa Ishida | A novel peptide related to human programmed cell death and dna encoding it |
| JP2778921B2 (ja) | 1994-11-18 | 1998-07-23 | 三共株式会社 | イミダゾピラゾール誘導体 |
| US6528624B1 (en) | 1998-04-02 | 2003-03-04 | Genentech, Inc. | Polypeptide variants |
| US6194551B1 (en) | 1998-04-02 | 2001-02-27 | Genentech, Inc. | Polypeptide variants |
| GB9809951D0 (en) | 1998-05-08 | 1998-07-08 | Univ Cambridge Tech | Binding molecules |
| US6737056B1 (en) | 1999-01-15 | 2004-05-18 | Genentech, Inc. | Polypeptide variants with altered effector function |
| KR20060067983A (ko) | 1999-01-15 | 2006-06-20 | 제넨테크, 인크. | 효과기 기능이 변화된 폴리펩티드 변이체 |
| IL147972A0 (en) | 1999-08-23 | 2002-09-12 | Dana Farber Cancer Inst Inc Ge | Pd-1, a receptor for b7-4 and uses therefor |
| HUP0202882A2 (en) | 1999-08-23 | 2002-12-28 | Dana Farber Cancer Inst Inc | Novel b7-4 molecules and uses therefor |
| CA2379421A1 (en) | 1999-08-27 | 2001-03-08 | Abbott Laboratories | Sulfonylphenylpyrazole compounds useful as cox-2 inhibitors |
| KR20020088406A (ko) | 1999-09-17 | 2002-11-27 | 애보트 게엠베하 운트 콤파니 카게 | 치료제로서의 피라졸로피리미딘 |
| PL358215A1 (en) | 2000-03-24 | 2004-08-09 | Micromet Ag | Multifunctional polypeptides comprising a binding site to an epitope of the nkg2d receptor complex |
| JP2003531149A (ja) | 2000-04-13 | 2003-10-21 | ザ・ロツクフエラー・ユニバーシテイ | 抗体由来の免疫応答の増強 |
| US7041298B2 (en) | 2000-09-08 | 2006-05-09 | California Institute Of Technology | Proteolysis targeting chimeric pharmaceutical |
| US20020094989A1 (en) | 2000-10-11 | 2002-07-18 | Hale Jeffrey J. | Pyrrolidine modulators of CCR5 chemokine receptor activity |
| KR20030066657A (ko) | 2000-11-15 | 2003-08-09 | 오노 야꾸힝 고교 가부시키가이샤 | Ｐｄ-1 결손 마우스 및 그 용도 |
| ATE489395T1 (de) | 2000-12-12 | 2010-12-15 | Medimmune Llc | Moleküle mit längeren halbwertszeiten, zusammensetzungen und deren verwendung |
| CA2433018A1 (en) | 2000-12-21 | 2002-06-27 | Joel C. Barrish | Thiazolyl inhibitors of tec family tyrosine kinases |
| US20030133939A1 (en) | 2001-01-17 | 2003-07-17 | Genecraft, Inc. | Binding domain-immunoglobulin fusion proteins |
| EP1366067B1 (en) | 2001-03-07 | 2012-09-26 | Merck Patent GmbH | Expression technology for proteins containing a hybrid isotype antibody moiety |
| ES2251582T3 (es) | 2001-03-09 | 2006-05-01 | Pfizer Products Inc. | Compuestos antiinflamatorios de bencimidazol. |
| AR036993A1 (es) | 2001-04-02 | 2004-10-20 | Wyeth Corp | Uso de agentes que modulan la interaccion entre pd-1 y sus ligandos en la submodulacion de respuestas inmunologicas |
| WO2003004497A1 (fr) | 2001-07-05 | 2003-01-16 | Sumitomo Pharmaceuticals Company, Limited | Compose heterocyclique |
| US7317091B2 (en) | 2002-03-01 | 2008-01-08 | Xencor, Inc. | Optimized Fc variants |
| US7662925B2 (en) | 2002-03-01 | 2010-02-16 | Xencor, Inc. | Optimized Fc variants and methods for their generation |
| DE10161767T1 (de) | 2002-07-03 | 2018-06-07 | Honjo Tasuku | Immunopotenzierende Zusammensetzungen, die einen Anti-PD-L1 Antikörper enthalten |
| CN1771231B (zh) | 2002-08-26 | 2011-05-25 | 武田药品工业株式会社 | 钙受体调节性化合物及其用途 |
| KR101050700B1 (ko) | 2002-08-26 | 2011-07-20 | 다케다 야쿠힌 고교 가부시키가이샤 | 칼슘 수용체 조절 화합물 및 이의 용도 |
| EP1578447A4 (en) | 2002-10-31 | 2009-06-03 | Genentech Inc | METHODS AND COMPOSITIONS THAT CAN INCREASE ANTIBODY PRODUCTION |
| ATE514713T1 (de) | 2002-12-23 | 2011-07-15 | Wyeth Llc | Antikörper gegen pd-1 und ihre verwendung |
| US7960512B2 (en) | 2003-01-09 | 2011-06-14 | Macrogenics, Inc. | Identification and engineering of antibodies with variant Fc regions and methods of using same |
| EP2368578A1 (en) | 2003-01-09 | 2011-09-28 | Macrogenics, Inc. | Identification and engineering of antibodies with variant Fc regions and methods of using same |
| US7563869B2 (en) | 2003-01-23 | 2009-07-21 | Ono Pharmaceutical Co., Ltd. | Substance specific to human PD-1 |
| US8084582B2 (en) | 2003-03-03 | 2011-12-27 | Xencor, Inc. | Optimized anti-CD20 monoclonal antibodies having Fc variants |
| US7405295B2 (en) | 2003-06-04 | 2008-07-29 | Cgi Pharmaceuticals, Inc. | Certain imidazo[1,2-a]pyrazin-8-ylamines and method of inhibition of Bruton's tyrosine kinase by such compounds |
| US20060183746A1 (en) | 2003-06-04 | 2006-08-17 | Currie Kevin S | Certain imidazo[1,2-a]pyrazin-8-ylamines and method of inhibition of Bruton's tyrosine kinase by such compounds |
| US7393848B2 (en) | 2003-06-30 | 2008-07-01 | Cgi Pharmaceuticals, Inc. | Certain heterocyclic substituted imidazo[1,2-A]pyrazin-8-ylamines and methods of inhibition of Bruton's tyrosine kinase by such compounds |
| CN1860118A (zh) | 2003-07-29 | 2006-11-08 | Irm责任有限公司 | 作为蛋白激酶抑制剂的化合物和组合物 |
| WO2005018572A2 (en) | 2003-08-22 | 2005-03-03 | Biogen Idec Ma Inc. | Improved antibodies having altered effector function and methods for making the same |
| US20060134105A1 (en) | 2004-10-21 | 2006-06-22 | Xencor, Inc. | IgG immunoglobulin variants with optimized effector function |
| WO2005047290A2 (en) | 2003-11-11 | 2005-05-26 | Cellular Genomics Inc. | Imidazo[1,2-a] pyrazin-8-ylamines as kinase inhibitors |
| US20050249723A1 (en) | 2003-12-22 | 2005-11-10 | Xencor, Inc. | Fc polypeptides with novel Fc ligand binding sites |
| GB0400440D0 (en) | 2004-01-09 | 2004-02-11 | Isis Innovation | Receptor modulators |
| WO2006029459A1 (en) * | 2004-09-13 | 2006-03-23 | Evogenix, Inc | Antibodies specific for hepatocellular carcinoma and other carcinomas and uses thereof |
| CA2580981C (en) | 2004-09-22 | 2013-10-22 | Kirin Beer Kabushiki Kaisha | Stabilized human igg4 antibodies |
| WO2006053121A2 (en) | 2004-11-10 | 2006-05-18 | Cgi Pharmaceuticals, Inc. | Imidazo[1 , 2-a] pyrazin-8-ylamines useful as modulators of kinase activity |
| AU2005316540A1 (en) | 2004-12-16 | 2006-06-22 | Vertex Pharmaceuticals Incorporated | Pyrid-2-ones useful as inhibitors of Tec family protein kinases for the treatment of inflammatory, proliferative and immunologically-mediated diseases |
| TW200639163A (en) | 2005-02-04 | 2006-11-16 | Genentech Inc | RAF inhibitor compounds and methods |
| TW200716551A (en) | 2005-03-10 | 2007-05-01 | Cgi Pharmaceuticals Inc | Certain substituted amides, method of making, and method of use thereof |
| NZ563193A (en) | 2005-05-09 | 2010-05-28 | Ono Pharmaceutical Co | Human monoclonal antibodies to programmed death 1(PD-1) and methods for treating cancer using anti-PD-1 antibodies alone or in combination with other immunotherapeutics |
| PT2397156T (pt) | 2005-06-08 | 2016-12-23 | The President And Fellows Of Harvard College | Métodos e composições para tratamento de infeções persistentes e cancro através da inibição da via de morte celular programada 1 (pd-1) |
| DK1907424T3 (en) | 2005-07-01 | 2015-11-09 | Squibb & Sons Llc | HUMAN MONOCLONAL ANTIBODIES TO PROGRAMMED death ligand 1 (PD-L1) |
| AU2006284900A1 (en) | 2005-08-29 | 2007-03-08 | Vertex Pharmaceuticals Incorporated | 3, 5-disubstituted pyrid-2-ones useful as inhibitors of Tec family of non-receptor tyrosine kinases |
| US7691885B2 (en) | 2005-08-29 | 2010-04-06 | Vertex Pharmaceuticals Incorporated | Pyridones useful as inhibitors of kinases |
| WO2007026720A1 (ja) | 2005-08-31 | 2007-03-08 | Taisho Pharmaceutical Co., Ltd. | 縮環ピラゾール誘導体 |
| EP1919919A1 (en) | 2005-09-01 | 2008-05-14 | Astellas Pharma Inc. | Pyridazinone derivatives used for the treatment of pain |
| RU2008127486A (ru) | 2005-12-08 | 2010-01-20 | Милленниум Фармасьютикалз, Инк. (Us) | Бициклические соединения с ингибиторной активностью в отношении киназы |
| RU2008133161A (ru) | 2006-01-13 | 2010-02-20 | Фармасайкликс, Инк. (Us) | Ингибиторы тирозин киназ и их применение |
| RU2429244C2 (ru) | 2006-03-23 | 2011-09-20 | Байоарктик Ньюросайенс Аб | Улучшенные селективные в отношении протофибрилл антитела и их применение |
| JP5271895B2 (ja) | 2006-05-15 | 2013-08-21 | メルク・シャープ・アンド・ドーム・コーポレーション | 抗糖尿病性の二環式化合物 |
| EP2865381A1 (en) | 2006-05-18 | 2015-04-29 | Pharmacyclics, Inc. | ITK inhibitors for treating blood cell malignancies |
| TWI398252B (zh) | 2006-05-26 | 2013-06-11 | Novartis Ag | 吡咯并嘧啶化合物及其用途 |
| CN101104640A (zh) | 2006-07-10 | 2008-01-16 | 苏州大学 | 抗人pd-l1单克隆抗体制备及应用 |
| AR063706A1 (es) | 2006-09-11 | 2009-02-11 | Cgi Pharmaceuticals Inc | Determinadas amidas sustituidas, el uso de las mismas para el tratamiento de enfermedades mediadas por la inhibicion de la actividad de btk y composiciones farmaceuticas que las comprenden. |
| PE20081370A1 (es) | 2006-09-11 | 2008-11-28 | Cgi Pharmaceuticals Inc | Determinadas amidas sustituidas, metodo de elaboracion y metodo de uso de las mismas |
| JP2010502751A (ja) | 2006-09-11 | 2010-01-28 | シージーアイ ファーマシューティカルズ，インコーポレイティド | キナーゼ阻害物質、およびキナーゼ阻害物質の使用および同定方法 |
| AR063946A1 (es) | 2006-09-11 | 2009-03-04 | Cgi Pharmaceuticals Inc | Determinadas pirimidinas sustituidas, el uso de las mismas para el tratamiento de enfermedades mediadas por la inhibicion de la actividad de btk y composiciones farmaceuticas que las comprenden. |
| EP2201840B1 (en) | 2006-09-22 | 2011-11-02 | Pharmacyclics, Inc. | Inhibitors of Bruton's Tyrosine Kinase |
| WO2008045627A2 (en) | 2006-10-06 | 2008-04-17 | Irm Llc | Protein kinase inhibitors and methods for using thereof |
| CA2668286C (en) | 2006-11-03 | 2014-09-16 | Pharmacyclics, Inc. | Bruton's tyrosine kinase activity probe and method of using |
| CN101730699A (zh) | 2007-03-21 | 2010-06-09 | 百时美施贵宝公司 | 可用于治疗增殖性、变应性、自身免疫性和炎症性疾病的稠合杂环化合物 |
| WO2008144253A1 (en) | 2007-05-14 | 2008-11-27 | Irm Llc | Protein kinase inhibitors and methods for using thereof |
| WO2008145142A1 (en) | 2007-05-31 | 2008-12-04 | Genmab A/S | Stable igg4 antibodies |
| EP2170959B1 (en) | 2007-06-18 | 2013-10-02 | Merck Sharp & Dohme B.V. | Antibodies to human programmed death receptor pd-1 |
| WO2009024531A1 (en) | 2007-08-17 | 2009-02-26 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Method for treating and diagnosing hematologic malignancies |
| CL2008002793A1 (es) | 2007-09-20 | 2009-09-04 | Cgi Pharmaceuticals Inc | Compuestos derivados de amidas sustituidas, inhibidores de la actividad de btk; composicion farmaceutica que los comprende; utiles en el tratamiento del cancer, trastornos oseos, enfermedades autoinmunes, entre otras |
| JO3076B1 (ar) | 2007-10-17 | 2017-03-15 | Janssen Alzheimer Immunotherap | نظم العلاج المناعي المعتمد على حالة apoe |
| AU2008314632B2 (en) | 2007-10-19 | 2015-05-28 | Celgene Avilomics Research, Inc. | Heteroaryl compounds and uses thereof |
| US7989465B2 (en) | 2007-10-19 | 2011-08-02 | Avila Therapeutics, Inc. | 4,6-disubstituted pyrimidines useful as kinase inhibitors |
| ES2499017T3 (es) | 2007-10-23 | 2014-09-26 | F. Hoffmann-La Roche Ag | Nuevos inhibidores de quinasa |
| WO2009077334A1 (en) | 2007-12-14 | 2009-06-25 | F. Hoffmann-La Roche Ag | Novel imidazo[1,2-a]pyridine and imidazo[1,2-b]pyridazine derivatives |
| DK2242749T3 (da) | 2008-02-05 | 2013-06-17 | Hoffmann La Roche | Nye pyridinoner og pyridazinoner |
| PL2250279T3 (pl) | 2008-02-08 | 2016-11-30 | Przeciwciała anty-ifnar1 o zmniejszonym powinowactwie do liganda fc | |
| US8168757B2 (en) | 2008-03-12 | 2012-05-01 | Merck Sharp & Dohme Corp. | PD-1 binding proteins |
| ES2554615T3 (es) | 2008-05-06 | 2015-12-22 | Gilead Connecticut, Inc. | Amidas sustituidas, método de preparación y utilización como inhibidores de Btk |
| US8338439B2 (en) | 2008-06-27 | 2012-12-25 | Celgene Avilomics Research, Inc. | 2,4-disubstituted pyrimidines useful as kinase inhibitors |
| SG10201510696RA (en) | 2008-06-27 | 2016-01-28 | Celgene Avilomics Res Inc | Heteroaryl compounds and uses thereof |
| CN102083819B (zh) | 2008-07-02 | 2014-07-09 | 霍夫曼-拉罗奇有限公司 | 作为激酶抑制剂的新型苯基吡嗪酮 |
| CN102066370B (zh) | 2008-07-15 | 2014-05-14 | 霍夫曼-拉罗奇有限公司 | 苯基-咪唑并吡啶类和哒嗪类 |
| EP2307025B1 (en) | 2008-07-16 | 2017-09-20 | Pharmacyclics LLC | Inhibitors of bruton's tyrosine kinase for the treatment of solid tumors |
| ES2461494T3 (es) | 2008-07-18 | 2014-05-20 | F. Hoffmann-La Roche Ag | Nuevas fenilimidazopirazinas |
| EP2323665B1 (en) | 2008-07-24 | 2013-06-19 | Bristol-Myers Squibb Company | Fused heterocyclic compounds useful as kinase modulators |
| CN102203125A (zh) | 2008-08-25 | 2011-09-28 | 安普利穆尼股份有限公司 | Pd-1拮抗剂及其使用方法 |
| NZ621143A (en) | 2008-09-05 | 2016-08-26 | Celgene Avilomics Res Inc | Algorithm for designing irreversible inhibitors |
| EP2342229A1 (en) | 2008-09-12 | 2011-07-13 | ISIS Innovation Limited | Pd-1 specific antibodies and uses thereof |
| JP5794917B2 (ja) | 2008-09-12 | 2015-10-14 | アイシス・イノベーション・リミテッドＩｓｉｓ Ｉｎｎｏｖａｔｉｏｎｌｉｍｉｔｅｄ | Ｐｄ−１特異抗体およびその使用 |
| CA2998281C (en) | 2008-09-26 | 2022-08-16 | Dana-Farber Cancer Institute, Inc. | Human anti-pd-1 antobodies and uses therefor |
| KR101050829B1 (ko) | 2008-10-02 | 2011-07-20 | 서울대학교산학협력단 | 항 ｐｄ-1 항체 또는 항 ｐｄ-ｌ1 항체를 포함하는 항암제 |
| AU2009308675A1 (en) | 2008-10-31 | 2010-05-06 | Genentech, Inc. | Pyrazolopyrimidine JAK inhibitor compounds and methods |
| US20120028981A1 (en) | 2008-11-05 | 2012-02-02 | Principia Biopharma Inc. | Kinase Knockdown Via Electrophilically Enhanced Inhibitors |
| EP2365970B1 (en) | 2008-11-12 | 2018-03-21 | Gilead Connecticut, Inc. | Pyridazinones and their use as btk inhibitors |
| KR101721707B1 (ko) | 2008-11-28 | 2017-03-30 | 에모리 유니버시티 | 감염 및 종양 치료 방법 |
| US8426428B2 (en) | 2008-12-05 | 2013-04-23 | Principia Biopharma, Inc. | EGFR kinase knockdown via electrophilically enhanced inhibitors |
| CN108997498A (zh) | 2008-12-09 | 2018-12-14 | 霍夫曼-拉罗奇有限公司 | 抗-pd-l1抗体及它们用于增强t细胞功能的用途 |
| WO2010068788A1 (en) | 2008-12-10 | 2010-06-17 | Cgi Pharmaceuticals, Inc. | Heterocyclic amides as btk inhibitors |
| WO2010068806A1 (en) | 2008-12-10 | 2010-06-17 | Cgi Pharmaceuticals, Inc. | Amide derivatives as btk inhibitors in the treatment of allergic, autoimmune and inflammatory disorders as well as cancer |
| WO2010068810A2 (en) | 2008-12-10 | 2010-06-17 | Cgi Pharmaceuticals, Inc. | Certain substituted amides, method of making, and method of use thereof |
| CN102325753B (zh) | 2008-12-19 | 2014-09-10 | 百时美施贵宝公司 | 用作激酶抑制剂的咔唑甲酰胺化合物 |
| US20100197924A1 (en) | 2008-12-22 | 2010-08-05 | Millennium Pharmaceuticals, Inc. | Preparation of aminotetralin compounds |
| EP3255047B1 (en) | 2009-01-06 | 2021-06-30 | Dana-Farber Cancer Institute, Inc. | Pyrimido-diazepinone kinase scaffold compounds and uses in treating disorders |
| JP5844159B2 (ja) | 2009-02-09 | 2016-01-13 | ユニヴェルシテ デクス−マルセイユＵｎｉｖｅｒｓｉｔｅ Ｄ’Ａｉｘ−Ｍａｒｓｅｉｌｌｅ | Ｐｄ−１抗体およびｐｄ−ｌ１抗体ならびにその使用 |
| US8299077B2 (en) | 2009-03-02 | 2012-10-30 | Roche Palo Alto Llc | Inhibitors of Bruton's tyrosine kinase |
| EP2421854B1 (en) | 2009-04-24 | 2014-07-23 | F.Hoffmann-La Roche Ag | Inhibitors of bruton's tyrosine kinase |
| EP2424368B1 (en) | 2009-04-29 | 2014-12-31 | Locus Pharmaceuticals, Inc. | Pyrrolotriazine compounds |
| JP2012529535A (ja) | 2009-06-12 | 2012-11-22 | ブリストル−マイヤーズ スクイブ カンパニー | キナーゼモジュレーターとして有用なニコチンアミド化合物 |
| AR077468A1 (es) | 2009-07-09 | 2011-08-31 | Array Biopharma Inc | Compuestos de pirazolo (1,5 -a) pirimidina sustituidos como inhibidores de trk- quinasa |
| US8846673B2 (en) | 2009-08-11 | 2014-09-30 | Bristol-Myers Squibb Company | Azaindazoles as kinase inhibitors and use thereof |
| US9493578B2 (en) | 2009-09-02 | 2016-11-15 | Xencor, Inc. | Compositions and methods for simultaneous bivalent and monovalent co-engagement of antigens |
| EP2485589A4 (en) | 2009-09-04 | 2013-02-06 | Biogen Idec Inc | HETEROARYARY INHIBITORS OF BTK |
| PL2473049T3 (pl) | 2009-09-04 | 2019-07-31 | Biogen Ma Inc. | Inhibitory kinazy tyrozynowej brutona |
| US7741330B1 (en) | 2009-10-12 | 2010-06-22 | Pharmacyclics, Inc. | Pyrazolo-pyrimidine inhibitors of Bruton's tyrosine kinase |
| JP5774595B2 (ja) | 2009-10-28 | 2015-09-09 | ヤンセン バイオテツク，インコーポレーテツド | 抗ｇｌｐ−１ｒ抗体及びそれらの使用 |
| US10053513B2 (en) | 2009-11-30 | 2018-08-21 | Janssen Biotech, Inc. | Antibody Fc mutants with ablated effector functions |
| WO2011103584A2 (en) | 2010-02-19 | 2011-08-25 | Xencor, Inc. | Novel ctla4-ig immunoadhesins |
| JP2013523098A (ja) | 2010-03-29 | 2013-06-17 | ザイムワークス，インコーポレイテッド | 強化又は抑制されたエフェクター機能を有する抗体 |
| RU2017112518A (ru) | 2010-05-07 | 2019-01-25 | Джилид Коннектикут, Инк. | Пиридоновые и азапиридоновые соединения и способы применения |
| MY189483A (en) | 2010-05-31 | 2022-02-16 | Ono Pharmaceutical Co | Purinone derivative |
| CA3113343A1 (en) | 2010-06-03 | 2011-12-08 | Pharmacyclics Llc | Use of inhibitors of bruton's tyrosine kinase (btk) in the treatment of follicular lymphoma |
| WO2011159857A1 (en) | 2010-06-16 | 2011-12-22 | Bristol-Myers Squibb Company | Carboline carboxamide compounds useful as kinase inhibitors |
| MY162132A (en) | 2010-06-23 | 2017-05-31 | Hanmi Science Co Ltd | Novel fused pyrimidine derivatives for inhibition of tyrosine kinase activity |
| US20120053189A1 (en) | 2010-06-28 | 2012-03-01 | Pharmacyclics, Inc. | Btk inhibitors for the treatment of immune mediated conditions |
| US20120100166A1 (en) | 2010-07-15 | 2012-04-26 | Zyngenia, Inc. | Ang-2 Binding Complexes and Uses Thereof |
| CN103096716B (zh) | 2010-08-10 | 2016-03-02 | 西建阿维拉米斯研究公司 | Btk抑制剂的苯磺酸盐 |
| AR082590A1 (es) | 2010-08-12 | 2012-12-19 | Hoffmann La Roche | Inhibidores de la tirosina-quinasa de bruton |
| BR112013007499A2 (pt) | 2010-09-01 | 2016-07-12 | Genentech Inc | piridazinonas - métodos de criação e usos |
| WO2012031004A1 (en) | 2010-09-01 | 2012-03-08 | Gilead Connecticut, Inc. | Pyridinones/pyrazinones, method of making, and method of use thereof |
| WO2012083370A1 (en) | 2010-12-22 | 2012-06-28 | Cephalon Australia Pty Ltd | Modified antibody with improved half-life |
| HUE041335T2 (hu) | 2011-03-29 | 2019-05-28 | Roche Glycart Ag | Antitest FC-variánsok |
| MX341076B (es) | 2011-03-31 | 2016-08-04 | Merck Sharp & Dohme | Formulaciones estables de anticuerpos para el receptor humano pd-1 de meurte programada y tratamientos relacionados. |
| CN103889962B (zh) | 2011-04-01 | 2017-05-03 | 犹他大学研究基金会 | 作为受体酪氨酸激酶btk抑制剂的取代的n‑(3‑(嘧啶‑4‑基)苯基)丙烯酰胺类似物 |
| CA2760174A1 (en) | 2011-12-01 | 2013-06-01 | Pharmascience Inc. | Protein kinase inhibitors and uses thereof |
| CN103608040B (zh) | 2011-04-20 | 2017-03-01 | 米迪缪尼有限公司 | 结合b7‑h1和pd‑1的抗体和其他分子 |
| WO2012143522A1 (en) | 2011-04-20 | 2012-10-26 | Glaxo Group Limited | Tetrahydropyrazolo [1,5 -a] pyrimidine as anti -tuberculosis compounds |
| CN103582637B (zh) | 2011-05-17 | 2015-08-12 | 弗·哈夫曼-拉罗切有限公司 | 酪氨酸激酶抑制剂 |
| WO2012158810A1 (en) | 2011-05-17 | 2012-11-22 | Principia Biopharma Inc. | Tyrosine kinase inhibitors |
| JP5974084B2 (ja) | 2011-05-17 | 2016-08-23 | プリンシピア バイオファーマ インコーポレイテッド | チロシンキナーゼ阻害剤 |
| US9376438B2 (en) | 2011-05-17 | 2016-06-28 | Principia Biopharma, Inc. | Pyrazolopyrimidine derivatives as tyrosine kinase inhibitors |
| ES2693647T3 (es) | 2011-06-06 | 2018-12-13 | Novo Nordisk A/S | Anticuerpos terapéuticos |
| DK2718270T3 (da) | 2011-06-10 | 2022-08-01 | Merck Patent Gmbh | Sammensætninger og fremgangsmåder til fremstillingen af pyrimidin- og pyridinforbindelser med btk-hæmmende aktivitet |
| ES2677367T3 (es) | 2011-06-22 | 2018-08-01 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Anticuerpos anti-Axl y usos de los mismos |
| AU2012282229B2 (en) | 2011-07-08 | 2015-05-07 | Novartis Ag | Novel pyrrolo pyrimidine derivatives |
| PE20190262A1 (es) | 2011-08-01 | 2019-02-25 | Genentech Inc | Metodos para tratar el cancer por el uso de antagonistas de union al eje pd-1 e inhibidores de mek |
| SI2785375T1 (sl) | 2011-11-28 | 2020-11-30 | Merck Patent Gmbh | Protitelesa proti PD-L1 in uporabe le-teh |
| CN117736134A (zh) | 2012-01-12 | 2024-03-22 | 耶鲁大学 | 通过e3泛素连接酶增强靶蛋白质及其他多肽降解的化合物和方法 |
| JP6226752B2 (ja) | 2012-02-09 | 2017-11-08 | 中外製薬株式会社 | 抗体のＦｃ領域改変体 |
| EP2844289B1 (en) | 2012-04-30 | 2019-07-17 | MedImmune, LLC | Molecules with reduced effector function and extended half-lives, compositions, and uses thereof |
| SG11201407190TA (en) | 2012-05-15 | 2014-12-30 | Bristol Myers Squibb Co | Cancer immunotherapy by disrupting pd-1/pd-l1 signaling |
| CN115093480A (zh) | 2012-05-31 | 2022-09-23 | 索伦托药业有限公司 | 与pd-l1结合的抗原结合蛋白 |
| CA2877516A1 (en) | 2012-07-03 | 2014-01-03 | Janssen Alzheimer Immunotherapy | C-terminal and central epitope a-beta antibodies |
| CN104994873B (zh) | 2012-10-04 | 2017-12-22 | 达纳－法伯癌症研究所公司 | 人单克隆抗‑pd‑l1抗体和使用方法 |
| US20140377269A1 (en) | 2012-12-19 | 2014-12-25 | Adimab, Llc | Multivalent antibody analogs, and methods of their preparation and use |
| AR093984A1 (es) | 2012-12-21 | 2015-07-01 | Merck Sharp & Dohme | Anticuerpos que se unen a ligando 1 de muerte programada (pd-l1) humano |
| GB201311910D0 (en) | 2013-07-03 | 2013-08-14 | Glaxosmithkline Ip Dev Ltd | Novel Compounds |
| TWI682941B (zh) | 2013-02-01 | 2020-01-21 | 美商再生元醫藥公司 | 含嵌合恆定區之抗體 |
| LT2840892T (lt) | 2013-02-20 | 2018-07-25 | Regeneron Pharmaceuticals, Inc. | Nežmogaus tipo gyvūnai su modifikuotomis imunoglobulino sunkiųjų grandinių sekomis |
| CA2904377C (en) | 2013-03-15 | 2021-07-13 | Regeneron Pharmaceuticals, Inc. | Il-33 antagonists and uses thereof |
| MX367918B (es) | 2013-04-25 | 2019-09-11 | Beigene Ltd | Compuestos heterociclicos fusionados como inhibidores de proteina quinasa. |
| CA3175360C (en) | 2013-05-31 | 2024-05-28 | Sorrento Therapeutics, Inc. | Antigen binding proteins that bind pd-1 |
| CN112457403B (zh) | 2013-09-13 | 2022-11-29 | 广州百济神州生物制药有限公司 | 抗pd1抗体及其作为治疗剂与诊断剂的用途 |
| EP3060251A4 (en) | 2013-10-25 | 2017-12-06 | Pharmacyclics LLC | Treatment using bruton's tyrosine kinase inhibitors and immunotherapy |
| JOP20200094A1 (ar) | 2014-01-24 | 2017-06-16 | Dana Farber Cancer Inst Inc | جزيئات جسم مضاد لـ pd-1 واستخداماتها |
| KR102130600B1 (ko) | 2014-07-03 | 2020-07-08 | 베이진 엘티디 | Pd-l1 항체와 이를 이용한 치료 및 진단 |
| CN106687446B (zh) | 2014-07-18 | 2020-04-28 | 百济神州(北京)生物科技有限公司 | 作为t790m/wt-egfr的选择性和不可逆的激酶抑制剂的5-氨基-4-氨甲酰基-吡唑化合物及其用途 |
| TW201618775A (zh) | 2014-08-11 | 2016-06-01 | 艾森塔製藥公司 | Ｂｔｋ抑制劑、ｐｉ３ｋ抑制劑、ｊａｋ－２抑制劑、ｐｄ－１抑制劑及／或ｐｄ－ｌ１抑制劑之治療組合物 |
| US10071164B2 (en) | 2014-08-11 | 2018-09-11 | Yale University | Estrogen-related receptor alpha based protac compounds and associated methods of use |
| US10035802B2 (en) | 2014-08-14 | 2018-07-31 | Teva Pharmaceuticals Usa, Inc. | Solid state forms of ibrutinib |
| TW201625304A (zh) | 2014-10-24 | 2016-07-16 | 美國禮來大藥廠 | 泌尿上皮癌之療法 |
| WO2016087994A1 (en) | 2014-12-05 | 2016-06-09 | Acerta Pharma B.V. | Btk inhibitors to treat solid tumors through modulation of the tumor microenvironment |
| US10485797B2 (en) | 2014-12-18 | 2019-11-26 | Principia Biopharma Inc. | Treatment of pemphigus |
| WO2016105582A1 (en) | 2014-12-24 | 2016-06-30 | Nunn Philip A | Compositions for ileo-jejunal drug delivery |
| US9139653B1 (en) | 2015-04-30 | 2015-09-22 | Kymab Limited | Anti-human OX40L antibodies and methods of treatment |
| GB201504314D0 (en) | 2015-03-13 | 2015-04-29 | Univ Dundee | Small molecules |
| KR20230175343A (ko) | 2015-03-18 | 2023-12-29 | 아비나스 오퍼레이션스, 인코포레이티드 | 타겟화된 단백질들의 향상된 분해를 위한 화합물들 및 방법들 |
| CN104777137B (zh) | 2015-03-25 | 2018-06-19 | 深圳市贝沃德克生物技术研究院有限公司 | 生物标志物检测用光谱位置调节装置 |
| ES2789500T5 (es) | 2015-05-29 | 2023-09-20 | Hoffmann La Roche | Procedimientos terapéuticos y de diagnóstico para el cáncer |
| KR102691931B1 (ko) | 2015-06-04 | 2024-08-05 | 아비나스 오퍼레이션스, 인코포레이티드 | 단백질분해의 이미드계 조절인자 및 관련된 이용 방법 |
| EP3302482A4 (en) | 2015-06-05 | 2018-12-19 | Arvinas, Inc. | Tank-binding kinase-1 protacs and associated methods of use |
| JP2018526430A (ja) | 2015-07-10 | 2018-09-13 | アルヴィナス・インコーポレイテッド | タンパク質分解のｍｄｍ２系修飾因子および関連の使用方法 |
| EP3322986A4 (en) | 2015-07-13 | 2018-09-05 | Arvinas, Inc. | Alanine-based modulators of proteolysis and associated methods of use |
| WO2017024465A1 (en) | 2015-08-10 | 2017-02-16 | Innovent Biologics (Suzhou) Co., Ltd. | Pd-1 antibodies |
| US10772962B2 (en) | 2015-08-19 | 2020-09-15 | Arvinas Operations, Inc. | Compounds and methods for the targeted degradation of bromodomain-containing proteins |
| WO2017046746A1 (en) | 2015-09-15 | 2017-03-23 | Acerta Pharma B.V. | Therapeutic combinations of a btk inhibitor and a gitr binding molecule, a 4-1bb agonist, or an ox40 agonist |
| WO2017059224A2 (en) | 2015-10-01 | 2017-04-06 | Gilead Sciences, Inc. | Combination of a btk inhibitor and a checkpoint inhibitor for treating cancers |
| JP2018531983A (ja) | 2015-11-02 | 2018-11-01 | イエール ユニバーシティ | タンパク質分解誘導キメラ化合物ならびにその調製方法および使用方法 |
| EP3445759A1 (en) | 2016-04-20 | 2019-02-27 | GlaxoSmithKline Intellectual Property Development Ltd | Conjugates comprising ripk2 inhibitors |
| WO2017197056A1 (en) | 2016-05-10 | 2017-11-16 | C4 Therapeutics, Inc. | Bromodomain targeting degronimers for target protein degradation |
| EP3455218A4 (en) | 2016-05-10 | 2019-12-18 | C4 Therapeutics, Inc. | C3 CARBON-BASED GLUTARIMIDE DEGRONIMERS FOR TARGET PROTEIN REDUCTION |
| EP3455219A4 (en) | 2016-05-10 | 2019-12-18 | C4 Therapeutics, Inc. | AMINE-LINKED C3-GLUTARIMIDE DEGRONIMERS FOR THE DEGRADATION OF TARGET PROTEINS |
| WO2017197036A1 (en) | 2016-05-10 | 2017-11-16 | C4 Therapeutics, Inc. | Spirocyclic degronimers for target protein degradation |
| WO2017201449A1 (en) | 2016-05-20 | 2017-11-23 | Genentech, Inc. | Protac antibody conjugates and methods of use |
| EP3468500A4 (en) | 2016-06-09 | 2020-03-04 | Blinkbio Inc. | THERAPEUTIC PAYLOADS BASED ON SILANOLE |
| GB201610147D0 (en) | 2016-06-10 | 2016-07-27 | Glaxosmithkline Ip Dev Ltd | Novel compounds |
| CN109475536B (zh) | 2016-07-05 | 2022-05-27 | 百济神州有限公司 | 用于治疗癌症的PD-l拮抗剂和RAF抑制剂的组合 |
| KR20230162137A (ko) | 2016-08-16 | 2023-11-28 | 베이진 스위찰랜드 게엠베하 | (s)-7-(1-아크릴로일피페리딘-4-일)-2-(4-페녹시페닐)-4,5,6,7-테트라-하이드로피라졸로 [1,5-a] 피리미딘-3-카르복스아미드의 제조 및 그 용도 |
| GB201614134D0 (en) | 2016-08-18 | 2016-10-05 | Glaxosmithkline Ip Dev Ltd | Novel compounds |
| CN118252927A (zh) | 2016-08-19 | 2024-06-28 | 百济神州有限公司 | 使用包含btk抑制剂的组合产品治疗癌症 |
| AU2017317227B2 (en) | 2016-08-26 | 2024-08-01 | Beigene, Ltd. | Anti-Tim-3 antibodies and use thereof |
| US10793632B2 (en) | 2016-08-30 | 2020-10-06 | Xencor, Inc. | Bispecific immunomodulatory antibodies that bind costimulatory and checkpoint receptors |
| EP3512842B1 (en) | 2016-09-15 | 2024-01-17 | Arvinas, Inc. | Indole derivatives as estrogen receptor degraders |
| EP3519051B1 (en) | 2016-09-27 | 2021-09-22 | Beigene, Ltd. | Treatment of cancers using combination comprising parp inhibitors |
| WO2018071606A1 (en) | 2016-10-11 | 2018-04-19 | Arvinas, Inc. | Compounds and methods for the targeted degradation of androgen receptor |
| PE20191034A1 (es) | 2016-10-14 | 2019-08-05 | Xencor Inc | Proteinas de fusion heterodimericas biespecificas que contienen proteinas de fusion fc il-15/il-15r y fragmentos de anticuerpo pd-1 |
| EP3544975B1 (en) | 2016-11-22 | 2022-01-05 | Dana-Farber Cancer Institute, Inc. | Degradation of bruton's tyrosine kinase (btk) by conjugation of btk inhibitors with e3 ligase ligand and use |
| EP3544957B1 (en) | 2016-11-22 | 2024-05-29 | Dana-Farber Cancer Institute, Inc. | Degradation of protein kinases by conjugation of protein kinase inhibitors with e3 ligase ligand and methods of use |
| CN110461847B (zh) | 2017-01-25 | 2022-06-07 | 百济神州有限公司 | (S)-7-(1-(丁-2-炔酰基)哌啶-4-基)-2-(4-苯氧基苯基)-4,5,6,7-四氢吡唑并[1,5-a]嘧啶-3-甲酰胺的结晶形式、其制备及用途 |
| WO2018193105A1 (en) | 2017-04-20 | 2018-10-25 | Adc Therapeutics Sa | Combination therapy |
| AU2018290532A1 (en) | 2017-06-26 | 2019-11-21 | Beigene, Ltd. | Immunotherapy for hepatocellular carcinoma |
| WO2019034009A1 (en) | 2017-08-12 | 2019-02-21 | Beigene, Ltd. | BTK INHIBITOR WITH ENHANCED DOUBLE SELECTIVITY |
| WO2019108795A1 (en) | 2017-11-29 | 2019-06-06 | Beigene Switzerland Gmbh | Treatment of indolent or aggressive b-cell lymphomas using a combination comprising btk inhibitors |
| EP3749366A4 (en) | 2018-02-09 | 2021-11-10 | BeiGene, Ltd. | IMMUNOTHERAPY FOR UROTHELIAL CARCINOMA |
| GB201803746D0 (en) | 2018-03-08 | 2018-04-25 | Ultrahuman Eight Ltd | PD1 binding agents |
| WO2019183226A1 (en) | 2018-03-21 | 2019-09-26 | Mei Pharma, Inc. | Combination therapy |
| CN113950327A (zh) | 2019-06-10 | 2022-01-18 | 百济神州瑞士有限责任公司 | 口服胶囊剂及其制备方法 |
| US20220249491A1 (en) | 2019-06-10 | 2022-08-11 | Beigene Switzerland Gmbh | Oral solid tablet comprising bruton's tyrosine kinase inhibitor and preparation method therefor |
| WO2021018018A1 (en) | 2019-07-26 | 2021-02-04 | Beigene, Ltd. | Degradation of bruton's tyrosine kinase (btk) by conjugation of btk inidbitors with e3 ligase ligand and methods of use |
-
2018
- 2018-06-26 AU AU2018290532A patent/AU2018290532A1/en active Pending
- 2018-06-26 CA CA3066518A patent/CA3066518A1/en active Pending
- 2018-06-26 KR KR1020207002309A patent/KR20200020902A/ko not_active Application Discontinuation
- 2018-06-26 WO PCT/CN2018/092827 patent/WO2019001417A1/en unknown
- 2018-06-26 TW TW107121942A patent/TW201906866A/zh unknown
- 2018-06-26 US US16/621,342 patent/US11597768B2/en active Active
- 2018-06-26 CN CN201880042740.8A patent/CN110799543A/zh active Pending
- 2018-06-26 JP JP2019566957A patent/JP2020525411A/ja active Pending
- 2018-06-26 EP EP18823691.3A patent/EP3645569A4/en active Pending
-
2023
- 2023-04-12 JP JP2023064789A patent/JP2023080215A/ja active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20220023024A (ko) | 2020-08-20 | 2022-03-02 | 경상국립대학교병원 | 간세포암 환자의 생존율 예측을 위한 정보제공방법 |
| KR20230055751A (ko) | 2021-10-19 | 2023-04-26 | 가톨릭대학교 산학협력단 | 간세포암 특이적 표적 엑소좀 조성물 및 이의 용도 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN110799543A (zh) | 2020-02-14 |
| CA3066518A1 (en) | 2019-01-03 |
| JP2023080215A (ja) | 2023-06-08 |
| TW201906866A (zh) | 2019-02-16 |
| EP3645569A4 (en) | 2021-03-24 |
| US20210147543A1 (en) | 2021-05-20 |
| JP2020525411A (ja) | 2020-08-27 |
| EP3645569A1 (en) | 2020-05-06 |
| WO2019001417A1 (en) | 2019-01-03 |
| AU2018290532A1 (en) | 2019-11-21 |
| US11597768B2 (en) | 2023-03-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR20200020902A (ko) | 간세포암(hepatocellular carcinoma: HCC)에 대한 면역 치료 | |
| JP2023109927A (ja) | ヒトのがんを治療するための特異的抗ｃｄ３８抗体 | |
| US20210040213A1 (en) | Immunomonotherapy for urothelial carcinoma | |
| JP6914283B2 (ja) | ヒトのがんを治療するための特異的抗ｃｄ３８抗体 | |
| KR20200130356A (ko) | 항-조직 인자 항체-약물 접합체 및 암 치료에서의 그의 용도 | |
| KR20180008571A (ko) | 다발성 골수종(mm)의 치료 | |
| US20220372161A1 (en) | Antibodies against the poliovirus receptor (pvr) and uses thereof | |
| CN114450025A (zh) | 使用包含多重酪氨酸激酶抑制剂和免疫检查点抑制剂的组合治疗癌症 | |
| JP2024527925A (ja) | 抗ｉｌｔ３抗体による急性骨髄性白血病の治療方法 | |
| KR20240038008A (ko) | 암 치료 방법 및 조성물 | |
| JP2024532744A (ja) | Ｔ１ｇｉｔアンタゴニスト、ｐｄ－１アンタゴニスト、及び（１又は複数の）化学療法剤を含む治療的組合せ | |
| CA3212604A1 (en) | Methods for treating cancer with anti-ilt3 antibodies | |
| TW202214287A (zh) | TGF-β受體的融合蛋白與多靶點酪胺酸激酶抑制劑聯合在製備治療腫瘤藥物中的用途 | |
| CN114729054A (zh) | 使用免疫检查点抑制剂抗体治疗癌症的方法和组合 | |
| KR20220097470A (ko) | 항-dll3 작용제의 투여 요법 | |
| JP7565607B2 (ja) | 肺、腎臓、または肝臓の線維症疾患の処置に使用するためのｐｓｍｐアンタゴニスト | |
| JPWO2019228514A5 (ko) | ||
| WO2024153182A1 (zh) | 抗pvrig/抗tigit双特异性抗体在治疗恶性肿瘤中的用途 | |
| CN114601924A (zh) | 抗pd-1抗体或其抗原结合片段治疗鳞状非小细胞肺癌的方法 | |
| WO2024137697A1 (en) | Combination therapies for the treatment of cancer | |
| WO2024112561A1 (en) | Methods for the treatment of myasthenia gravis | |
| TW202430575A (zh) | 抗ｐｖｒｉｇ／抗ｔｉｇｉｔ雙特異性抗體在治療惡性腫瘤中的用途 | |
| JP2024519907A (ja) | 尿路上皮癌の治療における、免疫チェックポイント阻害剤と併用での抗体薬物複合体の使用 | |
| CN118055761A (zh) | 包含tigit拮抗剂、pd-1拮抗剂和化学治疗剂的治疗组合 | |
| CN117815387A (zh) | Cdk4/6抑制剂和抗pd-l1抗体的联用药物组合物 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A201 | Request for examination | ||
| E902 | Notification of reason for refusal | ||
| E601 | Decision to refuse application |