CN109715210B - Cd80和cd86结合蛋白组合物及其用途 - Google Patents
Cd80和cd86结合蛋白组合物及其用途 Download PDFInfo
- Publication number
- CN109715210B CN109715210B CN201780057250.0A CN201780057250A CN109715210B CN 109715210 B CN109715210 B CN 109715210B CN 201780057250 A CN201780057250 A CN 201780057250A CN 109715210 B CN109715210 B CN 109715210B
- Authority
- CN
- China
- Prior art keywords
- val
- ser
- pro
- thr
- leu
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 239000000203 mixture Substances 0.000 title abstract description 28
- 101000914484 Homo sapiens T-lymphocyte activation antigen CD80 Proteins 0.000 title description 16
- 102100027222 T-lymphocyte activation antigen CD80 Human genes 0.000 title description 16
- 102000023732 binding proteins Human genes 0.000 title description 5
- 108091008324 binding proteins Proteins 0.000 title description 5
- 108010021064 CTLA-4 Antigen Proteins 0.000 claims abstract description 192
- 102000008203 CTLA-4 Antigen Human genes 0.000 claims abstract description 191
- 229940045513 CTLA4 antagonist Drugs 0.000 claims abstract description 95
- 230000001024 immunotherapeutic effect Effects 0.000 claims abstract description 21
- 230000002411 adverse Effects 0.000 claims abstract description 15
- 230000001363 autoimmune Effects 0.000 claims abstract description 13
- 230000001093 anti-cancer Effects 0.000 claims abstract description 4
- 238000002619 cancer immunotherapy Methods 0.000 claims abstract description 4
- 206010028980 Neoplasm Diseases 0.000 claims description 56
- 229960005386 ipilimumab Drugs 0.000 claims description 42
- 238000009169 immunotherapy Methods 0.000 claims description 21
- 239000008194 pharmaceutical composition Substances 0.000 claims description 17
- 201000011510 cancer Diseases 0.000 claims description 15
- 239000003814 drug Substances 0.000 claims description 11
- 108060003951 Immunoglobulin Proteins 0.000 claims description 7
- 102000018358 immunoglobulin Human genes 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 210000004899 c-terminal region Anatomy 0.000 claims description 3
- 230000027455 binding Effects 0.000 abstract description 113
- 102000004169 proteins and genes Human genes 0.000 abstract description 58
- 108090000623 proteins and genes Proteins 0.000 abstract description 57
- 230000002829 reductive effect Effects 0.000 abstract description 27
- 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 94
- 241000699670 Mus sp. Species 0.000 description 93
- 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 67
- 108020001507 fusion proteins Proteins 0.000 description 63
- 102000037865 fusion proteins Human genes 0.000 description 63
- AHWRSSLYSGLBGD-CIUDSAMLSA-N Asp-Pro-Glu Chemical compound OC(=O)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O AHWRSSLYSGLBGD-CIUDSAMLSA-N 0.000 description 56
- 235000018102 proteins Nutrition 0.000 description 55
- 108010026333 seryl-proline Proteins 0.000 description 47
- UIMCLYYSUCIUJM-UWVGGRQHSA-N Pro-Gly-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H]1CCCN1 UIMCLYYSUCIUJM-UWVGGRQHSA-N 0.000 description 45
- PEEYDECOOVQKRZ-DLOVCJGASA-N Ala-Ser-Phe Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O PEEYDECOOVQKRZ-DLOVCJGASA-N 0.000 description 43
- 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 43
- BNGDYRRHRGOPHX-IFFSRLJSSA-N Thr-Glu-Val Chemical compound CC(C)[C@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)[C@@H](C)O)C(O)=O BNGDYRRHRGOPHX-IFFSRLJSSA-N 0.000 description 43
- LGEYOIQBBIPHQN-UWJYBYFXSA-N Tyr-Ala-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 LGEYOIQBBIPHQN-UWJYBYFXSA-N 0.000 description 43
- OTJMMKPMLUNTQT-AVGNSLFASA-N Val-Leu-Arg Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)NC(=O)[C@H](C(C)C)N OTJMMKPMLUNTQT-AVGNSLFASA-N 0.000 description 43
- 235000001014 amino acid Nutrition 0.000 description 43
- 150000001413 amino acids Chemical class 0.000 description 42
- REJJNXODKSHOKA-ACZMJKKPSA-N Gln-Ala-Asp Chemical compound C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)O)NC(=O)[C@H](CCC(=O)N)N REJJNXODKSHOKA-ACZMJKKPSA-N 0.000 description 41
- NSTUFLGQJCOCDL-UWVGGRQHSA-N Gly-Leu-Arg Chemical compound NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CCCN=C(N)N NSTUFLGQJCOCDL-UWVGGRQHSA-N 0.000 description 41
- 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 41
- HVKMTOIAYDOJPL-NRPADANISA-N Ser-Gln-Val Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(O)=O HVKMTOIAYDOJPL-NRPADANISA-N 0.000 description 41
- KOPBYUSPXBQIHD-NRPADANISA-N Val-Cys-Glu Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N KOPBYUSPXBQIHD-NRPADANISA-N 0.000 description 41
- 108010061238 threonyl-glycine Proteins 0.000 description 41
- JBVSSSZFNTXJDX-YTLHQDLWSA-N Ala-Ala-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](C)N JBVSSSZFNTXJDX-YTLHQDLWSA-N 0.000 description 39
- VQUCKIAECLVLAD-SVSWQMSJSA-N Ile-Cys-Thr Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H]([C@@H](C)O)C(=O)O)N VQUCKIAECLVLAD-SVSWQMSJSA-N 0.000 description 39
- DLFAACQHIRSQGG-CIUDSAMLSA-N Leu-Asp-Asp Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O DLFAACQHIRSQGG-CIUDSAMLSA-N 0.000 description 39
- VYXIKLFLGRTANT-HRCADAONSA-N Met-Tyr-Pro Chemical compound CSCC[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N2CCC[C@@H]2C(=O)O)N VYXIKLFLGRTANT-HRCADAONSA-N 0.000 description 38
- AJNGQVUFQUVRQT-JYJNAYRXSA-N Pro-Pro-Tyr Chemical compound C([C@@H](C(=O)O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H]1NCCC1)C1=CC=C(O)C=C1 AJNGQVUFQUVRQT-JYJNAYRXSA-N 0.000 description 38
- 108010092854 aspartyllysine Proteins 0.000 description 38
- 108090000765 processed proteins & peptides Proteins 0.000 description 38
- VHEVVUZDDUCAKU-FXQIFTODSA-N Ala-Met-Asp Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(O)=O VHEVVUZDDUCAKU-FXQIFTODSA-N 0.000 description 37
- 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 37
- CQMFNTVQVLQRLT-JHEQGTHGSA-N Gly-Thr-Gln Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(N)=O)C(O)=O CQMFNTVQVLQRLT-JHEQGTHGSA-N 0.000 description 37
- LHSGPCFBGJHPCY-UHFFFAOYSA-N L-leucine-L-tyrosine Natural products CC(C)CC(N)C(=O)NC(C(O)=O)CC1=CC=C(O)C=C1 LHSGPCFBGJHPCY-UHFFFAOYSA-N 0.000 description 37
- 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 37
- TUYWCHPXKQTISF-LPEHRKFASA-N Pro-Cys-Pro Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CS)C(=O)N2CCC[C@@H]2C(=O)O TUYWCHPXKQTISF-LPEHRKFASA-N 0.000 description 37
- QQWNRERCGGZOKG-WEDXCCLWSA-N Thr-Gly-Leu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CC(C)C)C(O)=O QQWNRERCGGZOKG-WEDXCCLWSA-N 0.000 description 37
- JJNXZIPLIXIGBX-HJPIBITLSA-N Tyr-Ile-Cys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)N JJNXZIPLIXIGBX-HJPIBITLSA-N 0.000 description 37
- VKYDVKAKGDNZED-STECZYCISA-N Tyr-Val-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC1=CC=C(C=C1)O)N VKYDVKAKGDNZED-STECZYCISA-N 0.000 description 37
- 108010012058 leucyltyrosine Proteins 0.000 description 37
- ICRKQMRFXYDYMK-LAEOZQHASA-N Gln-Val-Asn Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O ICRKQMRFXYDYMK-LAEOZQHASA-N 0.000 description 35
- 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 35
- BPMRXBZYPGYPJN-WHFBIAKZSA-N Ser-Gly-Asn Chemical compound [H]N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(O)=O BPMRXBZYPGYPJN-WHFBIAKZSA-N 0.000 description 35
- 102000004196 processed proteins & peptides Human genes 0.000 description 34
- NZAFOTBEULLEQB-WDSKDSINSA-N Gly-Asn-Glu Chemical compound C(CC(=O)O)[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)CN NZAFOTBEULLEQB-WDSKDSINSA-N 0.000 description 33
- ODRREERHVHMIPT-OEAJRASXSA-N Leu-Thr-Phe 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)CC1=CC=CC=C1 ODRREERHVHMIPT-OEAJRASXSA-N 0.000 description 33
- HNERGSKJJZQGEA-JYJNAYRXSA-N Tyr-Met-Met Chemical compound CSCC[C@@H](C(=O)N[C@@H](CCSC)C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)N HNERGSKJJZQGEA-JYJNAYRXSA-N 0.000 description 33
- 229920001184 polypeptide Polymers 0.000 description 32
- 238000011282 treatment Methods 0.000 description 32
- 108010019832 glycyl-asparaginyl-glycine Proteins 0.000 description 30
- ZXCAQANTQWBICD-DCAQKATOSA-N Cys-Lys-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CS)N ZXCAQANTQWBICD-DCAQKATOSA-N 0.000 description 29
- 230000000694 effects Effects 0.000 description 29
- 241000880493 Leptailurus serval Species 0.000 description 28
- LSMDIAAALJJLRO-XQXXSGGOSA-N Ala-Thr-Glu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(O)=O)C(O)=O LSMDIAAALJJLRO-XQXXSGGOSA-N 0.000 description 27
- 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 27
- 238000002347 injection Methods 0.000 description 27
- 239000007924 injection Substances 0.000 description 27
- 125000003275 alpha amino acid group Chemical group 0.000 description 25
- 101100075830 Caenorhabditis elegans mab-5 gene Proteins 0.000 description 24
- SNDBKTFJWVEVPO-WHFBIAKZSA-N Asp-Gly-Ser Chemical compound [H]N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@@H](CO)C(O)=O SNDBKTFJWVEVPO-WHFBIAKZSA-N 0.000 description 23
- DHNWZLGBTPUTQQ-QEJZJMRPSA-N Gln-Asp-Trp Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CCC(=O)N)N DHNWZLGBTPUTQQ-QEJZJMRPSA-N 0.000 description 23
- SLQVFYWBGNNOTK-BYULHYEWSA-N Ile-Gly-Asn Chemical compound CC[C@H](C)[C@@H](C(=O)NCC(=O)N[C@@H](CC(=O)N)C(=O)O)N SLQVFYWBGNNOTK-BYULHYEWSA-N 0.000 description 23
- PVMPDMIKUVNOBD-CIUDSAMLSA-N Leu-Asp-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O PVMPDMIKUVNOBD-CIUDSAMLSA-N 0.000 description 23
- SBANPBVRHYIMRR-UHFFFAOYSA-N Leu-Ser-Pro Natural products CC(C)CC(N)C(=O)NC(CO)C(=O)N1CCCC1C(O)=O SBANPBVRHYIMRR-UHFFFAOYSA-N 0.000 description 23
- NHOVZGFNTGMYMI-KKUMJFAQSA-N Tyr-Ser-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 NHOVZGFNTGMYMI-KKUMJFAQSA-N 0.000 description 23
- XTDDIVQWDXMRJL-IHRRRGAJSA-N Val-Leu-His Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](C(C)C)N XTDDIVQWDXMRJL-IHRRRGAJSA-N 0.000 description 23
- SYSWVVCYSXBVJG-RHYQMDGZSA-N Val-Leu-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C(C)C)N)O SYSWVVCYSXBVJG-RHYQMDGZSA-N 0.000 description 23
- LLJLBRRXKZTTRD-GUBZILKMSA-N Val-Val-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(=O)O)N LLJLBRRXKZTTRD-GUBZILKMSA-N 0.000 description 23
- 108010052670 arginyl-glutamyl-glutamic acid Proteins 0.000 description 23
- 108010013768 glutamyl-aspartyl-proline Proteins 0.000 description 23
- 108010015792 glycyllysine Proteins 0.000 description 23
- 108010044311 leucyl-glycyl-glycine Proteins 0.000 description 23
- 108010073472 leucyl-prolyl-proline Proteins 0.000 description 23
- 108010052774 valyl-lysyl-glycyl-phenylalanyl-tyrosine Proteins 0.000 description 23
- 101000889276 Homo sapiens Cytotoxic T-lymphocyte protein 4 Proteins 0.000 description 22
- 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 22
- 241000699666 Mus <mouse, genus> Species 0.000 description 21
- OYJCVIGKMXUVKB-GARJFASQSA-N Ala-Leu-Pro Chemical compound C[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N1CCC[C@@H]1C(=O)O)N OYJCVIGKMXUVKB-GARJFASQSA-N 0.000 description 20
- IORKCNUBHNIMKY-CIUDSAMLSA-N Ala-Pro-Glu Chemical compound C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O IORKCNUBHNIMKY-CIUDSAMLSA-N 0.000 description 20
- VOLVNCMGXWDDQY-LPEHRKFASA-N Gln-Glu-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CCC(=O)N)N)C(=O)O VOLVNCMGXWDDQY-LPEHRKFASA-N 0.000 description 20
- IOQWIOPSKJOEKI-SRVKXCTJSA-N Lys-Ser-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O IOQWIOPSKJOEKI-SRVKXCTJSA-N 0.000 description 20
- IIEOLPMQYRBZCN-SRVKXCTJSA-N Phe-Ser-Cys Chemical compound N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)O IIEOLPMQYRBZCN-SRVKXCTJSA-N 0.000 description 20
- ZLXKLMHAMDENIO-DCAQKATOSA-N Pro-Lys-Asp Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(O)=O ZLXKLMHAMDENIO-DCAQKATOSA-N 0.000 description 20
- BDGBHYCAZJPLHX-HJGDQZAQSA-N Thr-Lys-Asn Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(O)=O BDGBHYCAZJPLHX-HJGDQZAQSA-N 0.000 description 20
- SINRIKQYQJRGDQ-MEYUZBJRSA-N Tyr-Lys-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 SINRIKQYQJRGDQ-MEYUZBJRSA-N 0.000 description 20
- QHDXUYOYTPWCSK-RCOVLWMOSA-N Val-Asp-Gly Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)NCC(=O)O)N QHDXUYOYTPWCSK-RCOVLWMOSA-N 0.000 description 20
- ZLNYBMWGPOKSLW-LSJOCFKGSA-N Val-Val-Asp Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O ZLNYBMWGPOKSLW-LSJOCFKGSA-N 0.000 description 20
- 230000000903 blocking effect Effects 0.000 description 20
- 102000043321 human CTLA4 Human genes 0.000 description 20
- 108010048397 seryl-lysyl-leucine Proteins 0.000 description 20
- 108010080629 tryptophan-leucine Proteins 0.000 description 20
- 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 19
- DIBLBAURNYJYBF-XLXZRNDBSA-N (2s)-2-[[(2s)-2-[[2-[[(2s)-6-amino-2-[[(2s)-2-amino-3-methylbutanoyl]amino]hexanoyl]amino]acetyl]amino]-3-phenylpropanoyl]amino]-3-(4-hydroxyphenyl)propanoic acid Chemical compound C([C@H](NC(=O)CNC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)C(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C1=CC=CC=C1 DIBLBAURNYJYBF-XLXZRNDBSA-N 0.000 description 19
- 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 19
- OLVIPTLKNSAYRJ-YUMQZZPRSA-N Asn-Gly-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)CNC(=O)[C@H](CC(=O)N)N OLVIPTLKNSAYRJ-YUMQZZPRSA-N 0.000 description 19
- 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 19
- PDECQIHABNQRHN-GUBZILKMSA-N Asp-Glu-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CC(O)=O PDECQIHABNQRHN-GUBZILKMSA-N 0.000 description 19
- 208000023275 Autoimmune disease Diseases 0.000 description 19
- CSMHMEATMDCQNY-DZKIICNBSA-N Gln-Val-Tyr Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O CSMHMEATMDCQNY-DZKIICNBSA-N 0.000 description 19
- ITYRYNUZHPNCIK-GUBZILKMSA-N Glu-Ala-Leu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(O)=O ITYRYNUZHPNCIK-GUBZILKMSA-N 0.000 description 19
- GLWXKFRTOHKGIT-ACZMJKKPSA-N Glu-Asn-Asn Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O GLWXKFRTOHKGIT-ACZMJKKPSA-N 0.000 description 19
- 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 19
- ALMBZBOCGSVSAI-ACZMJKKPSA-N Glu-Ser-Asn Chemical compound C(CC(=O)O)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(=O)N)C(=O)O)N ALMBZBOCGSVSAI-ACZMJKKPSA-N 0.000 description 19
- MFYLRRCYBBJYPI-JYJNAYRXSA-N Glu-Tyr-Lys Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCC(=O)O)N)O MFYLRRCYBBJYPI-JYJNAYRXSA-N 0.000 description 19
- ZALGPUWUVHOGAE-GVXVVHGQSA-N Glu-Val-His Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](CCC(=O)O)N ZALGPUWUVHOGAE-GVXVVHGQSA-N 0.000 description 19
- 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 19
- 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 19
- WMKXFMUJRCEGRP-SRVKXCTJSA-N His-Asn-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC2=CN=CN2)C(=O)O)N WMKXFMUJRCEGRP-SRVKXCTJSA-N 0.000 description 19
- 108010065920 Insulin Lispro Proteins 0.000 description 19
- VWHGTYCRDRBSFI-ZETCQYMHSA-N Leu-Gly-Gly Chemical compound CC(C)C[C@H](N)C(=O)NCC(=O)NCC(O)=O VWHGTYCRDRBSFI-ZETCQYMHSA-N 0.000 description 19
- SBANPBVRHYIMRR-GARJFASQSA-N Leu-Ser-Pro Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CO)C(=O)N1CCC[C@@H]1C(=O)O)N SBANPBVRHYIMRR-GARJFASQSA-N 0.000 description 19
- XNKDCYABMBBEKN-IUCAKERBSA-N Lys-Gly-Gln Chemical compound NCCCC[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CCC(N)=O XNKDCYABMBBEKN-IUCAKERBSA-N 0.000 description 19
- 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 19
- IEVXCWPVBYCJRZ-IXOXFDKPSA-N Lys-Thr-His Chemical compound NCCCC[C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@H](C(O)=O)CC1=CN=CN1 IEVXCWPVBYCJRZ-IXOXFDKPSA-N 0.000 description 19
- DLCAXBGXGOVUCD-PPCPHDFISA-N Lys-Thr-Ile Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O DLCAXBGXGOVUCD-PPCPHDFISA-N 0.000 description 19
- MSHZERMPZKCODG-ACRUOGEOSA-N Phe-Leu-Phe Chemical compound C([C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 MSHZERMPZKCODG-ACRUOGEOSA-N 0.000 description 19
- 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 19
- KWMUAKQOVYCQJQ-ZPFDUUQYSA-N Pro-Ile-Glu Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)O)NC(=O)[C@@H]1CCCN1 KWMUAKQOVYCQJQ-ZPFDUUQYSA-N 0.000 description 19
- PCWLNNZTBJTZRN-AVGNSLFASA-N Pro-Pro-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 PCWLNNZTBJTZRN-AVGNSLFASA-N 0.000 description 19
- KBUAPZAZPWNYSW-SRVKXCTJSA-N Pro-Pro-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 KBUAPZAZPWNYSW-SRVKXCTJSA-N 0.000 description 19
- GOMUXSCOIWIJFP-GUBZILKMSA-N Pro-Ser-Arg Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O GOMUXSCOIWIJFP-GUBZILKMSA-N 0.000 description 19
- GMJDSFYVTAMIBF-FXQIFTODSA-N Pro-Ser-Asp Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(O)=O GMJDSFYVTAMIBF-FXQIFTODSA-N 0.000 description 19
- 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 19
- 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 19
- VGNYHOBZJKWRGI-CIUDSAMLSA-N Ser-Asn-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CO VGNYHOBZJKWRGI-CIUDSAMLSA-N 0.000 description 19
- HMRAQFJFTOLDKW-GUBZILKMSA-N Ser-His-Glu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCC(O)=O)C(O)=O HMRAQFJFTOLDKW-GUBZILKMSA-N 0.000 description 19
- GZSZPKSBVAOGIE-CIUDSAMLSA-N Ser-Lys-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O GZSZPKSBVAOGIE-CIUDSAMLSA-N 0.000 description 19
- PPCZVWHJWJFTFN-ZLUOBGJFSA-N Ser-Ser-Asp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(O)=O PPCZVWHJWJFTFN-ZLUOBGJFSA-N 0.000 description 19
- 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 19
- ASJDFGOPDCVXTG-KATARQTJSA-N Thr-Cys-Leu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(C)C)C(O)=O ASJDFGOPDCVXTG-KATARQTJSA-N 0.000 description 19
- DSLHSTIUAPKERR-XGEHTFHBSA-N Thr-Cys-Val Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(=O)N[C@@H](C(C)C)C(O)=O DSLHSTIUAPKERR-XGEHTFHBSA-N 0.000 description 19
- NCXVJIQMWSGRHY-KXNHARMFSA-N Thr-Leu-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N1CCC[C@@H]1C(=O)O)N)O NCXVJIQMWSGRHY-KXNHARMFSA-N 0.000 description 19
- VUXIQSUQQYNLJP-XAVMHZPKSA-N Thr-Ser-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CO)C(=O)N1CCC[C@@H]1C(=O)O)N)O VUXIQSUQQYNLJP-XAVMHZPKSA-N 0.000 description 19
- BEZTUFWTPVOROW-KJEVXHAQSA-N Thr-Tyr-Arg Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N)O BEZTUFWTPVOROW-KJEVXHAQSA-N 0.000 description 19
- 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 19
- DQDXHYIEITXNJY-BPUTZDHNSA-N Trp-Gln-Gln 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)N)C(=O)O)N DQDXHYIEITXNJY-BPUTZDHNSA-N 0.000 description 19
- 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 19
- RIVVDNTUSRVTQT-IRIUXVKKSA-N Tyr-Thr-Gln Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)N)O RIVVDNTUSRVTQT-IRIUXVKKSA-N 0.000 description 19
- RKIGNDAHUOOIMJ-BQFCYCMXSA-N Val-Glu-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)C(C)C)C(O)=O)=CNC2=C1 RKIGNDAHUOOIMJ-BQFCYCMXSA-N 0.000 description 19
- 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 19
- SBJCTAZFSZXWSR-AVGNSLFASA-N Val-Met-His Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N SBJCTAZFSZXWSR-AVGNSLFASA-N 0.000 description 19
- 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 19
- 108010078144 glutaminyl-glycine Proteins 0.000 description 19
- 230000003993 interaction Effects 0.000 description 19
- 108010070643 prolylglutamic acid Proteins 0.000 description 19
- AUNMOHYWTAPQLA-XUXIUFHCSA-N Leu-Met-Ile Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O AUNMOHYWTAPQLA-XUXIUFHCSA-N 0.000 description 18
- 210000001744 T-lymphocyte Anatomy 0.000 description 18
- 108010003137 tyrosyltyrosine Proteins 0.000 description 17
- WWWGMQHQSAUXBU-BQBZGAKWSA-N Met-Gly-Asn Chemical compound CSCC[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CC(N)=O WWWGMQHQSAUXBU-BQBZGAKWSA-N 0.000 description 16
- DWAMXBFJNZIHMC-KBPBESRZSA-N Tyr-Leu-Gly Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O DWAMXBFJNZIHMC-KBPBESRZSA-N 0.000 description 15
- 210000004027 cell Anatomy 0.000 description 15
- XALFIVXGQUEGKV-JSGCOSHPSA-N Phe-Val-Gly Chemical compound OC(=O)CNC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CC1=CC=CC=C1 XALFIVXGQUEGKV-JSGCOSHPSA-N 0.000 description 14
- LVFZXRQQQDTBQH-IRIUXVKKSA-N Tyr-Thr-Glu Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(O)=O)C(O)=O LVFZXRQQQDTBQH-IRIUXVKKSA-N 0.000 description 14
- 230000001225 therapeutic effect Effects 0.000 description 14
- 241001529936 Murinae Species 0.000 description 13
- 230000035772 mutation Effects 0.000 description 13
- 108010021466 Mutant Proteins Proteins 0.000 description 11
- 102000008300 Mutant Proteins Human genes 0.000 description 11
- 238000002474 experimental method Methods 0.000 description 11
- 239000012634 fragment Substances 0.000 description 11
- 108010031719 prolyl-serine Proteins 0.000 description 11
- 206010039073 rheumatoid arthritis Diseases 0.000 description 11
- 108010090804 Streptavidin Proteins 0.000 description 10
- 125000000539 amino acid group Chemical group 0.000 description 10
- 201000010099 disease Diseases 0.000 description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 10
- 238000001727 in vivo Methods 0.000 description 10
- RAQMSGVCGSJKCL-FOHZUACHSA-N Asn-Gly-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CC(N)=O RAQMSGVCGSJKCL-FOHZUACHSA-N 0.000 description 9
- JJQGZGOEDSSHTE-FOHZUACHSA-N Asp-Thr-Gly Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(O)=O JJQGZGOEDSSHTE-FOHZUACHSA-N 0.000 description 9
- BQSLGJHIAGOZCD-CIUDSAMLSA-N Leu-Ala-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O BQSLGJHIAGOZCD-CIUDSAMLSA-N 0.000 description 9
- 238000002648 combination therapy Methods 0.000 description 9
- DVRDRICMWUSCBN-UKJIMTQDSA-N Ile-Gln-Val Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](C(C)C)C(=O)O)N DVRDRICMWUSCBN-UKJIMTQDSA-N 0.000 description 8
- 208000003456 Juvenile Arthritis Diseases 0.000 description 8
- 206010059176 Juvenile idiopathic arthritis Diseases 0.000 description 8
- ARNIBBOXIAWUOP-MGHWNKPDSA-N Leu-Tyr-Ile 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]([C@@H](C)CC)C(O)=O ARNIBBOXIAWUOP-MGHWNKPDSA-N 0.000 description 8
- QUCDKEKDPYISNX-HJGDQZAQSA-N Lys-Asn-Thr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O QUCDKEKDPYISNX-HJGDQZAQSA-N 0.000 description 8
- XNQMZHLAYFWSGJ-HTUGSXCWSA-N Phe-Thr-Glu Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(O)=O)C(O)=O XNQMZHLAYFWSGJ-HTUGSXCWSA-N 0.000 description 8
- FDMKYQQYJKYCLV-GUBZILKMSA-N Pro-Pro-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 FDMKYQQYJKYCLV-GUBZILKMSA-N 0.000 description 8
- HQTKVSCNCDLXSX-BQBZGAKWSA-N Ser-Arg-Gly Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O HQTKVSCNCDLXSX-BQBZGAKWSA-N 0.000 description 8
- 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 8
- DIPIPFHFLPTCLK-LOKLDPHHSA-N Thr-Gln-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N1CCC[C@@H]1C(=O)O)N)O DIPIPFHFLPTCLK-LOKLDPHHSA-N 0.000 description 8
- MDYSKHBSPXUOPV-JSGCOSHPSA-N Val-Gly-Phe Chemical compound CC(C)[C@@H](C(=O)NCC(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)N MDYSKHBSPXUOPV-JSGCOSHPSA-N 0.000 description 8
- 230000000259 anti-tumor effect Effects 0.000 description 8
- 239000000427 antigen Substances 0.000 description 8
- 108091007433 antigens Proteins 0.000 description 8
- 102000036639 antigens Human genes 0.000 description 8
- 229940079593 drug Drugs 0.000 description 8
- 230000002068 genetic effect Effects 0.000 description 8
- 108010027338 isoleucylcysteine Proteins 0.000 description 8
- 238000000034 method Methods 0.000 description 8
- 230000001988 toxicity Effects 0.000 description 8
- 231100000419 toxicity Toxicity 0.000 description 8
- 206010067484 Adverse reaction Diseases 0.000 description 7
- 108010029485 Protein Isoforms Proteins 0.000 description 7
- 102000001708 Protein Isoforms Human genes 0.000 description 7
- 230000006044 T cell activation Effects 0.000 description 7
- 230000006838 adverse reaction Effects 0.000 description 7
- 150000001875 compounds Chemical class 0.000 description 7
- 238000011161 development Methods 0.000 description 7
- 108010050848 glycylleucine Proteins 0.000 description 7
- 230000028993 immune response Effects 0.000 description 7
- 230000036039 immunity Effects 0.000 description 7
- 201000002215 juvenile rheumatoid arthritis Diseases 0.000 description 7
- 238000006467 substitution reaction Methods 0.000 description 7
- PSUXEQYPYZLNER-QXEWZRGKSA-N Arg-Val-Asn Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O PSUXEQYPYZLNER-QXEWZRGKSA-N 0.000 description 6
- UBKOVSLDWIHYSY-ACZMJKKPSA-N Asn-Glu-Ser Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(O)=O UBKOVSLDWIHYSY-ACZMJKKPSA-N 0.000 description 6
- HLYCMRDRWGSTPZ-CIUDSAMLSA-N Glu-Pro-Cys Chemical compound C1C[C@H](N(C1)C(=O)[C@H](CCC(=O)O)N)C(=O)N[C@@H](CS)C(=O)O HLYCMRDRWGSTPZ-CIUDSAMLSA-N 0.000 description 6
- HMHRTKOWRUPPNU-RCOVLWMOSA-N Gly-Ile-Gly Chemical compound NCC(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(O)=O HMHRTKOWRUPPNU-RCOVLWMOSA-N 0.000 description 6
- LLWQVJNHMYBLLK-CDMKHQONSA-N Gly-Thr-Phe Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O LLWQVJNHMYBLLK-CDMKHQONSA-N 0.000 description 6
- NPROWIBAWYMPAZ-GUDRVLHUSA-N Ile-Asp-Pro Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N1CCC[C@@H]1C(=O)O)N NPROWIBAWYMPAZ-GUDRVLHUSA-N 0.000 description 6
- WRDTXMBPHMBGIB-STECZYCISA-N Ile-Tyr-Val Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](C(C)C)C(O)=O)CC1=CC=C(O)C=C1 WRDTXMBPHMBGIB-STECZYCISA-N 0.000 description 6
- LQUIENKUVKPNIC-ULQDDVLXSA-N Leu-Met-Tyr Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O LQUIENKUVKPNIC-ULQDDVLXSA-N 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 6
- ZCXQTRXYZOSGJR-FXQIFTODSA-N Pro-Asp-Ser Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O ZCXQTRXYZOSGJR-FXQIFTODSA-N 0.000 description 6
- SBVPYBFMIGDIDX-SRVKXCTJSA-N Pro-Pro-Pro Chemical compound OC(=O)[C@@H]1CCCN1C(=O)[C@H]1N(C(=O)[C@H]2NCCC2)CCC1 SBVPYBFMIGDIDX-SRVKXCTJSA-N 0.000 description 6
- 108010076504 Protein Sorting Signals Proteins 0.000 description 6
- HZDQUVQEVVYDDA-ACRUOGEOSA-N Tyr-Tyr-Leu Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=C(O)C=C1 HZDQUVQEVVYDDA-ACRUOGEOSA-N 0.000 description 6
- 210000000612 antigen-presenting cell Anatomy 0.000 description 6
- 108010060199 cysteinylproline Proteins 0.000 description 6
- 239000003446 ligand Substances 0.000 description 6
- 210000004379 membrane Anatomy 0.000 description 6
- 239000012528 membrane Substances 0.000 description 6
- 210000003289 regulatory T cell Anatomy 0.000 description 6
- 108010020532 tyrosyl-proline Proteins 0.000 description 6
- 239000013598 vector Substances 0.000 description 6
- 230000004584 weight gain Effects 0.000 description 6
- 235000019786 weight gain Nutrition 0.000 description 6
- VYSRNGOMGHOJCK-GUBZILKMSA-N Arg-Ala-Met Chemical compound C[C@@H](C(=O)N[C@@H](CCSC)C(=O)O)NC(=O)[C@H](CCCN=C(N)N)N VYSRNGOMGHOJCK-GUBZILKMSA-N 0.000 description 5
- AOZBJZBKFHOYHL-AVGNSLFASA-N Cys-Glu-Tyr Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O AOZBJZBKFHOYHL-AVGNSLFASA-N 0.000 description 5
- JKGHMESJHRTHIC-SIUGBPQLSA-N Gln-Ile-Tyr Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)O)NC(=O)[C@H](CCC(=O)N)N JKGHMESJHRTHIC-SIUGBPQLSA-N 0.000 description 5
- DWBBKNPKDHXIAC-SRVKXCTJSA-N Glu-Leu-Met Chemical compound CSCC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCC(O)=O DWBBKNPKDHXIAC-SRVKXCTJSA-N 0.000 description 5
- MLILEEIVMRUYBX-NHCYSSNCSA-N Glu-Val-Arg Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O MLILEEIVMRUYBX-NHCYSSNCSA-N 0.000 description 5
- 101100061678 Homo sapiens CTLA4 gene Proteins 0.000 description 5
- 206010061218 Inflammation Diseases 0.000 description 5
- GRZSCTXVCDUIPO-SRVKXCTJSA-N Leu-Arg-Gln Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(O)=O GRZSCTXVCDUIPO-SRVKXCTJSA-N 0.000 description 5
- 101000859077 Mus musculus Cytotoxic T-lymphocyte protein 4 Proteins 0.000 description 5
- 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 5
- 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 5
- VXFXIBCCVLJCJT-JYJNAYRXSA-N Tyr-Pro-Pro Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(O)=O VXFXIBCCVLJCJT-JYJNAYRXSA-N 0.000 description 5
- CWSIBTLMMQLPPZ-FXQIFTODSA-N Val-Cys-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CS)NC(=O)[C@H](C(C)C)N CWSIBTLMMQLPPZ-FXQIFTODSA-N 0.000 description 5
- 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 5
- 230000004071 biological effect Effects 0.000 description 5
- 238000000338 in vitro Methods 0.000 description 5
- 230000004054 inflammatory process Effects 0.000 description 5
- 230000009984 peri-natal effect Effects 0.000 description 5
- 108010077112 prolyl-proline Proteins 0.000 description 5
- 230000000717 retained effect Effects 0.000 description 5
- 150000003839 salts Chemical group 0.000 description 5
- 230000004083 survival effect Effects 0.000 description 5
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 description 4
- SUHLZMHFRALVSY-YUMQZZPRSA-N Ala-Lys-Gly Chemical compound NCCCC[C@H](NC(=O)[C@@H](N)C)C(=O)NCC(O)=O SUHLZMHFRALVSY-YUMQZZPRSA-N 0.000 description 4
- WQLDNOCHHRISMS-NAKRPEOUSA-N Ala-Pro-Ile Chemical compound [H]N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)CC)C(O)=O WQLDNOCHHRISMS-NAKRPEOUSA-N 0.000 description 4
- YJHKTAMKPGFJCT-NRPADANISA-N Ala-Val-Glu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O YJHKTAMKPGFJCT-NRPADANISA-N 0.000 description 4
- 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 4
- OZNSCVPYWZRQPY-CIUDSAMLSA-N Arg-Asp-Glu Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O OZNSCVPYWZRQPY-CIUDSAMLSA-N 0.000 description 4
- ZUVMUOOHJYNJPP-XIRDDKMYSA-N Arg-Trp-Gln Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CCC(N)=O)C(O)=O ZUVMUOOHJYNJPP-XIRDDKMYSA-N 0.000 description 4
- 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 4
- FHETWELNCBMRMG-HJGDQZAQSA-N Asn-Leu-Thr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O FHETWELNCBMRMG-HJGDQZAQSA-N 0.000 description 4
- DPNWSMBUYCLEDG-CIUDSAMLSA-N Asp-Lys-Ser Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(O)=O DPNWSMBUYCLEDG-CIUDSAMLSA-N 0.000 description 4
- DONWIPDSZZJHHK-HJGDQZAQSA-N Asp-Lys-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC(=O)O)N)O DONWIPDSZZJHHK-HJGDQZAQSA-N 0.000 description 4
- KJJASVYBTKRYSN-FXQIFTODSA-N Cys-Pro-Asp Chemical compound C1C[C@H](N(C1)C(=O)[C@H](CS)N)C(=O)N[C@@H](CC(=O)O)C(=O)O KJJASVYBTKRYSN-FXQIFTODSA-N 0.000 description 4
- XKBASPWPBXNVLQ-WDSKDSINSA-N Gln-Gly-Asn Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(O)=O XKBASPWPBXNVLQ-WDSKDSINSA-N 0.000 description 4
- 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 4
- CKOFNWCLWRYUHK-XHNCKOQMSA-N Glu-Asp-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC(=O)O)NC(=O)[C@H](CCC(=O)O)N)C(=O)O CKOFNWCLWRYUHK-XHNCKOQMSA-N 0.000 description 4
- QDMVXRNLOPTPIE-WDCWCFNPSA-N Glu-Lys-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O QDMVXRNLOPTPIE-WDCWCFNPSA-N 0.000 description 4
- ZYRXTRTUCAVNBQ-GVXVVHGQSA-N Glu-Val-Lys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCC(=O)O)N ZYRXTRTUCAVNBQ-GVXVVHGQSA-N 0.000 description 4
- WCORRBXVISTKQL-WHFBIAKZSA-N Gly-Ser-Ser Chemical compound NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O WCORRBXVISTKQL-WHFBIAKZSA-N 0.000 description 4
- MAABHGXCIBEYQR-XVYDVKMFSA-N His-Asn-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CC1=CN=CN1)N MAABHGXCIBEYQR-XVYDVKMFSA-N 0.000 description 4
- HIAHVKLTHNOENC-HGNGGELXSA-N His-Glu-Ala Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(O)=O HIAHVKLTHNOENC-HGNGGELXSA-N 0.000 description 4
- UWSMZKRTOZEGDD-CUJWVEQBSA-N His-Thr-Ser Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(O)=O UWSMZKRTOZEGDD-CUJWVEQBSA-N 0.000 description 4
- CSTDQOOBZBAJKE-BWAGICSOSA-N His-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](CC2=CN=CN2)N)O CSTDQOOBZBAJKE-BWAGICSOSA-N 0.000 description 4
- JHNJNTMTZHEDLJ-NAKRPEOUSA-N Ile-Ser-Arg Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O JHNJNTMTZHEDLJ-NAKRPEOUSA-N 0.000 description 4
- VGSPNSSCMOHRRR-BJDJZHNGSA-N Ile-Ser-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)O)N VGSPNSSCMOHRRR-BJDJZHNGSA-N 0.000 description 4
- 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 4
- OIARJGNVARWKFP-YUMQZZPRSA-N Leu-Asn-Gly Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(O)=O OIARJGNVARWKFP-YUMQZZPRSA-N 0.000 description 4
- BTNXKBVLWJBTNR-SRVKXCTJSA-N Leu-His-Asn Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC(N)=O)C(O)=O BTNXKBVLWJBTNR-SRVKXCTJSA-N 0.000 description 4
- 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 4
- 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 4
- AIQWYVFNBNNOLU-RHYQMDGZSA-N Leu-Thr-Val Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(O)=O AIQWYVFNBNNOLU-RHYQMDGZSA-N 0.000 description 4
- 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 4
- MWVUEPNEPWMFBD-SRVKXCTJSA-N Lys-Cys-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CS)C(=O)N[C@H](C(O)=O)CCCCN MWVUEPNEPWMFBD-SRVKXCTJSA-N 0.000 description 4
- 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 4
- 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 4
- YKBSXQFZWFXFIB-VOAKCMCISA-N Lys-Thr-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@@H](CCCCN)C(O)=O YKBSXQFZWFXFIB-VOAKCMCISA-N 0.000 description 4
- JOXIIFVCSATTDH-IHPCNDPISA-N Phe-Asn-Trp Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC2=CNC3=CC=CC=C32)C(=O)O)N JOXIIFVCSATTDH-IHPCNDPISA-N 0.000 description 4
- FIRWJEJVFFGXSH-RYUDHWBXSA-N Phe-Glu-Gly Chemical compound OC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CC1=CC=CC=C1 FIRWJEJVFFGXSH-RYUDHWBXSA-N 0.000 description 4
- ZJPGOXWRFNKIQL-JYJNAYRXSA-N Phe-Pro-Pro Chemical compound C([C@H](N)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(O)=O)C1=CC=CC=C1 ZJPGOXWRFNKIQL-JYJNAYRXSA-N 0.000 description 4
- SJRQWEDYTKYHHL-SLFFLAALSA-N Phe-Tyr-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC2=CC=C(C=C2)O)NC(=O)[C@H](CC3=CC=CC=C3)N)C(=O)O SJRQWEDYTKYHHL-SLFFLAALSA-N 0.000 description 4
- UAYHMOIGIQZLFR-NHCYSSNCSA-N Pro-Gln-Val Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(O)=O UAYHMOIGIQZLFR-NHCYSSNCSA-N 0.000 description 4
- 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 4
- 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 4
- QPFJSHSJFIYDJZ-GHCJXIJMSA-N Ser-Asp-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](N)CO QPFJSHSJFIYDJZ-GHCJXIJMSA-N 0.000 description 4
- YUJLIIRMIAGMCQ-CIUDSAMLSA-N Ser-Leu-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O YUJLIIRMIAGMCQ-CIUDSAMLSA-N 0.000 description 4
- ZKOKTQPHFMRSJP-YJRXYDGGSA-N Ser-Thr-Tyr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O ZKOKTQPHFMRSJP-YJRXYDGGSA-N 0.000 description 4
- RCOUFINCYASMDN-GUBZILKMSA-N Ser-Val-Met Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCSC)C(O)=O RCOUFINCYASMDN-GUBZILKMSA-N 0.000 description 4
- YLXAMFZYJTZXFH-OLHMAJIHSA-N Thr-Asn-Asp Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC(=O)O)C(=O)O)N)O YLXAMFZYJTZXFH-OLHMAJIHSA-N 0.000 description 4
- FIFDDJFLNVAVMS-RHYQMDGZSA-N Thr-Leu-Met Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(O)=O FIFDDJFLNVAVMS-RHYQMDGZSA-N 0.000 description 4
- XKWABWFMQXMUMT-HJGDQZAQSA-N Thr-Pro-Glu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O XKWABWFMQXMUMT-HJGDQZAQSA-N 0.000 description 4
- MROIJTGJGIDEEJ-RCWTZXSCSA-N Thr-Pro-Pro Chemical compound C[C@@H](O)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 MROIJTGJGIDEEJ-RCWTZXSCSA-N 0.000 description 4
- 208000031981 Thrombocytopenic Idiopathic Purpura Diseases 0.000 description 4
- 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 4
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 4
- PWKMJDQXKCENMF-MEYUZBJRSA-N Tyr-Thr-Leu Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O PWKMJDQXKCENMF-MEYUZBJRSA-N 0.000 description 4
- UEHRGZCNLSWGHK-DLOVCJGASA-N Val-Glu-Val Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O UEHRGZCNLSWGHK-DLOVCJGASA-N 0.000 description 4
- LKUDRJSNRWVGMS-QSFUFRPTSA-N Val-Ile-Asp Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)O)NC(=O)[C@H](C(C)C)N LKUDRJSNRWVGMS-QSFUFRPTSA-N 0.000 description 4
- HJSLDXZAZGFPDK-ULQDDVLXSA-N Val-Phe-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)NC(=O)[C@H](C(C)C)N HJSLDXZAZGFPDK-ULQDDVLXSA-N 0.000 description 4
- 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 4
- KRAHMIJVUPUOTQ-DCAQKATOSA-N Val-Ser-His Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N KRAHMIJVUPUOTQ-DCAQKATOSA-N 0.000 description 4
- BZDGLJPROOOUOZ-XGEHTFHBSA-N Val-Thr-Cys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](C(C)C)N)O BZDGLJPROOOUOZ-XGEHTFHBSA-N 0.000 description 4
- MCGSCOLBFJQGHM-SCZZXKLOSA-N abacavir Chemical compound C=12N=CN([C@H]3C=C[C@@H](CO)C3)C2=NC(N)=NC=1NC1CC1 MCGSCOLBFJQGHM-SCZZXKLOSA-N 0.000 description 4
- 229960004748 abacavir Drugs 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- 108010050025 alpha-glutamyltryptophan Proteins 0.000 description 4
- 230000005875 antibody response Effects 0.000 description 4
- 108010040443 aspartyl-aspartic acid Proteins 0.000 description 4
- 108010093581 aspartyl-proline Proteins 0.000 description 4
- 201000003710 autoimmune thrombocytopenic purpura Diseases 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- 238000000684 flow cytometry Methods 0.000 description 4
- 210000002216 heart Anatomy 0.000 description 4
- 108010053037 kyotorphin Proteins 0.000 description 4
- 210000000265 leukocyte Anatomy 0.000 description 4
- 108010017391 lysylvaline Proteins 0.000 description 4
- 230000001404 mediated effect Effects 0.000 description 4
- 201000001441 melanoma Diseases 0.000 description 4
- 239000013642 negative control Substances 0.000 description 4
- 210000000056 organ Anatomy 0.000 description 4
- 230000001681 protective effect Effects 0.000 description 4
- 102000005962 receptors Human genes 0.000 description 4
- 108020003175 receptors Proteins 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 108010071097 threonyl-lysyl-proline Proteins 0.000 description 4
- 108700004896 tripeptide FEG Proteins 0.000 description 4
- 108010044292 tryptophyltyrosine Proteins 0.000 description 4
- 108010051110 tyrosyl-lysine Proteins 0.000 description 4
- 108010027345 wheylin-1 peptide Proteins 0.000 description 4
- BUDNAJYVCUHLSV-ZLUOBGJFSA-N Ala-Asp-Ser Chemical compound C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O BUDNAJYVCUHLSV-ZLUOBGJFSA-N 0.000 description 3
- NZGRHTKZFSVPAN-BIIVOSGPSA-N Ala-Ser-Pro Chemical compound C[C@@H](C(=O)N[C@@H](CO)C(=O)N1CCC[C@@H]1C(=O)O)N NZGRHTKZFSVPAN-BIIVOSGPSA-N 0.000 description 3
- CREYEAPXISDKSB-FQPOAREZSA-N Ala-Thr-Tyr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O CREYEAPXISDKSB-FQPOAREZSA-N 0.000 description 3
- JREOBWLIZLXRIS-GUBZILKMSA-N Asn-Glu-Leu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O JREOBWLIZLXRIS-GUBZILKMSA-N 0.000 description 3
- HPASIOLTWSNMFB-OLHMAJIHSA-N Asn-Thr-Asp Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(O)=O HPASIOLTWSNMFB-OLHMAJIHSA-N 0.000 description 3
- 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 3
- RYKWOUUZJFSJOH-FXQIFTODSA-N Asp-Gln-Glu Chemical compound C(CC(=O)N)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)O)NC(=O)[C@H](CC(=O)O)N RYKWOUUZJFSJOH-FXQIFTODSA-N 0.000 description 3
- DRCOAZZDQRCGGP-GHCJXIJMSA-N Asp-Ser-Ile Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O DRCOAZZDQRCGGP-GHCJXIJMSA-N 0.000 description 3
- 241000282693 Cercopithecidae Species 0.000 description 3
- 102100035360 Cerebellar degeneration-related antigen 1 Human genes 0.000 description 3
- ALNKNYKSZPSLBD-ZDLURKLDSA-N Cys-Thr-Gly Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(O)=O ALNKNYKSZPSLBD-ZDLURKLDSA-N 0.000 description 3
- 238000002965 ELISA Methods 0.000 description 3
- ZEEPYMXTJWIMSN-GUBZILKMSA-N Gln-Lys-Ser Chemical compound NCCCC[C@@H](C(=O)N[C@@H](CO)C(O)=O)NC(=O)[C@@H](N)CCC(N)=O ZEEPYMXTJWIMSN-GUBZILKMSA-N 0.000 description 3
- HUFCEIHAFNVSNR-IHRRRGAJSA-N Glu-Gln-Tyr Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 HUFCEIHAFNVSNR-IHRRRGAJSA-N 0.000 description 3
- WJZLEENECIOOSA-WDSKDSINSA-N Gly-Asn-Gln Chemical compound NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)O WJZLEENECIOOSA-WDSKDSINSA-N 0.000 description 3
- SWQALSGKVLYKDT-ZKWXMUAHSA-N Gly-Ile-Ala Chemical compound NCC(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O SWQALSGKVLYKDT-ZKWXMUAHSA-N 0.000 description 3
- SWQALSGKVLYKDT-UHFFFAOYSA-N Gly-Ile-Ala Natural products NCC(=O)NC(C(C)CC)C(=O)NC(C)C(O)=O SWQALSGKVLYKDT-UHFFFAOYSA-N 0.000 description 3
- 101710154606 Hemagglutinin Proteins 0.000 description 3
- CYHJCEKUMCNDFG-LAEOZQHASA-N Ile-Gln-Gly Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)NCC(=O)O)N CYHJCEKUMCNDFG-LAEOZQHASA-N 0.000 description 3
- KFKWRHQBZQICHA-STQMWFEESA-N L-leucyl-L-phenylalanine Natural products CC(C)C[C@H](N)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 KFKWRHQBZQICHA-STQMWFEESA-N 0.000 description 3
- CCQLQKZTXZBXTN-NHCYSSNCSA-N Leu-Gly-Ile Chemical compound [H]N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H]([C@@H](C)CC)C(O)=O CCQLQKZTXZBXTN-NHCYSSNCSA-N 0.000 description 3
- DAYQSYGBCUKVKT-VOAKCMCISA-N Leu-Thr-Lys Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(O)=O DAYQSYGBCUKVKT-VOAKCMCISA-N 0.000 description 3
- KCXUCYYZNZFGLL-SRVKXCTJSA-N Lys-Ala-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(O)=O KCXUCYYZNZFGLL-SRVKXCTJSA-N 0.000 description 3
- 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 3
- QRHWTCJBCLGYRB-FXQIFTODSA-N Met-Ala-Cys Chemical compound CSCC[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CS)C(O)=O QRHWTCJBCLGYRB-FXQIFTODSA-N 0.000 description 3
- JOYFULUKJRJCSX-IUCAKERBSA-N Met-Met-Gly Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CCSC)C(=O)NCC(O)=O JOYFULUKJRJCSX-IUCAKERBSA-N 0.000 description 3
- 101100222220 Mus musculus Ctla4 gene Proteins 0.000 description 3
- 101710093908 Outer capsid protein VP4 Proteins 0.000 description 3
- 101710135467 Outer capsid protein sigma-1 Proteins 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- AXIOGMQCDYVTNY-ACRUOGEOSA-N Phe-Phe-Leu Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)[C@@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 AXIOGMQCDYVTNY-ACRUOGEOSA-N 0.000 description 3
- CGBYDGAJHSOGFQ-LPEHRKFASA-N Pro-Ala-Pro Chemical compound C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@@H]2CCCN2 CGBYDGAJHSOGFQ-LPEHRKFASA-N 0.000 description 3
- QDDJNKWPTJHROJ-UFYCRDLUSA-N Pro-Tyr-Tyr Chemical compound C([C@@H](C(=O)O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H]1NCCC1)C1=CC=C(O)C=C1 QDDJNKWPTJHROJ-UFYCRDLUSA-N 0.000 description 3
- 101710176177 Protein A56 Proteins 0.000 description 3
- 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 3
- WPSKTVVMQCXPRO-BWBBJGPYSA-N Thr-Ser-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O WPSKTVVMQCXPRO-BWBBJGPYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- SQUMHUZLJDUROQ-YDHLFZDLSA-N Tyr-Val-Asp Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O SQUMHUZLJDUROQ-YDHLFZDLSA-N 0.000 description 3
- KISFXYYRKKNLOP-IHRRRGAJSA-N Val-Phe-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)O)N KISFXYYRKKNLOP-IHRRRGAJSA-N 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 239000005557 antagonist Substances 0.000 description 3
- 108010038633 aspartylglutamate Proteins 0.000 description 3
- 108010047857 aspartylglycine Proteins 0.000 description 3
- 230000000139 costimulatory effect Effects 0.000 description 3
- 201000001981 dermatomyositis Diseases 0.000 description 3
- 230000010437 erythropoiesis Effects 0.000 description 3
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 3
- 230000004927 fusion Effects 0.000 description 3
- 238000003209 gene knockout Methods 0.000 description 3
- 108010089804 glycyl-threonine Proteins 0.000 description 3
- 208000006454 hepatitis Diseases 0.000 description 3
- 231100000283 hepatitis Toxicity 0.000 description 3
- 231100001158 immune-related toxicity Toxicity 0.000 description 3
- 238000001802 infusion Methods 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 230000000977 initiatory effect Effects 0.000 description 3
- 238000011813 knockout mouse model Methods 0.000 description 3
- 108010044056 leucyl-phenylalanine Proteins 0.000 description 3
- 108010057821 leucylproline Proteins 0.000 description 3
- 108010003700 lysyl aspartic acid Proteins 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 210000000581 natural killer T-cell Anatomy 0.000 description 3
- 210000001672 ovary Anatomy 0.000 description 3
- 230000008506 pathogenesis Effects 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 108010048818 seryl-histidine Proteins 0.000 description 3
- 208000011580 syndromic disease Diseases 0.000 description 3
- 231100000331 toxic Toxicity 0.000 description 3
- 230000002588 toxic effect Effects 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 230000004580 weight loss Effects 0.000 description 3
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 2
- VEAPAYQQLSEKEM-GUBZILKMSA-N Ala-Met-Met Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCSC)C(O)=O VEAPAYQQLSEKEM-GUBZILKMSA-N 0.000 description 2
- DRARURMRLANNLS-GUBZILKMSA-N Ala-Met-Val Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](C(C)C)C(O)=O DRARURMRLANNLS-GUBZILKMSA-N 0.000 description 2
- KUFVXLQLDHJVOG-SHGPDSBTSA-N Ala-Thr-Thr Chemical compound C[C@H]([C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)O)NC(=O)[C@H](C)N)O KUFVXLQLDHJVOG-SHGPDSBTSA-N 0.000 description 2
- 108700028369 Alleles Proteins 0.000 description 2
- ICRHGPYYXMWHIE-LPEHRKFASA-N Arg-Ser-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CO)NC(=O)[C@H](CCCN=C(N)N)N)C(=O)O ICRHGPYYXMWHIE-LPEHRKFASA-N 0.000 description 2
- 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 2
- BCADFFUQHIMQAA-KKHAAJSZSA-N Asn-Thr-Val Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(O)=O BCADFFUQHIMQAA-KKHAAJSZSA-N 0.000 description 2
- LTCKTLYKRMCFOC-KKUMJFAQSA-N Asp-Phe-Leu Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(C)C)C(O)=O LTCKTLYKRMCFOC-KKUMJFAQSA-N 0.000 description 2
- 101100476210 Caenorhabditis elegans rnt-1 gene Proteins 0.000 description 2
- 206010008874 Chronic Fatigue Syndrome Diseases 0.000 description 2
- TVYMKYUSZSVOAG-ZLUOBGJFSA-N Cys-Ala-Ala Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(O)=O TVYMKYUSZSVOAG-ZLUOBGJFSA-N 0.000 description 2
- NXQCSPVUPLUTJH-WHFBIAKZSA-N Cys-Ser-Gly Chemical compound SC[C@H](N)C(=O)N[C@@H](CO)C(=O)NCC(O)=O NXQCSPVUPLUTJH-WHFBIAKZSA-N 0.000 description 2
- 229940123907 Disease modifying antirheumatic drug Drugs 0.000 description 2
- 208000010201 Exanthema Diseases 0.000 description 2
- 208000001640 Fibromyalgia Diseases 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- 208000007465 Giant cell arteritis Diseases 0.000 description 2
- RGRMOYQUIJVQQD-SRVKXCTJSA-N Gln-Arg-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)O)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CCC(=O)N)N RGRMOYQUIJVQQD-SRVKXCTJSA-N 0.000 description 2
- FGYPOQPQTUNESW-IUCAKERBSA-N Gln-Gly-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)CNC(=O)[C@H](CCC(=O)N)N FGYPOQPQTUNESW-IUCAKERBSA-N 0.000 description 2
- RWCBJYUPAUTWJD-NHCYSSNCSA-N Gln-Met-Val Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](C(C)C)C(O)=O RWCBJYUPAUTWJD-NHCYSSNCSA-N 0.000 description 2
- HNAUFGBKJLTWQE-IFFSRLJSSA-N Gln-Val-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CCC(=O)N)N)O HNAUFGBKJLTWQE-IFFSRLJSSA-N 0.000 description 2
- NJCALAAIGREHDR-WDCWCFNPSA-N Glu-Leu-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O NJCALAAIGREHDR-WDCWCFNPSA-N 0.000 description 2
- UJMNFCAHLYKWOZ-DCAQKATOSA-N Glu-Lys-Gln Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(N)=O)C(O)=O UJMNFCAHLYKWOZ-DCAQKATOSA-N 0.000 description 2
- WIKMTDVSCUJIPJ-CIUDSAMLSA-N Glu-Ser-Arg Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CCCN=C(N)N WIKMTDVSCUJIPJ-CIUDSAMLSA-N 0.000 description 2
- GGEJHJIXRBTJPD-BYPYZUCNSA-N Gly-Asn-Gly Chemical compound NCC(=O)N[C@@H](CC(N)=O)C(=O)NCC(O)=O GGEJHJIXRBTJPD-BYPYZUCNSA-N 0.000 description 2
- GWCJMBNBFYBQCV-XPUUQOCRSA-N Gly-Val-Ala Chemical compound NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C)C(O)=O GWCJMBNBFYBQCV-XPUUQOCRSA-N 0.000 description 2
- IZVICCORZOSGPT-JSGCOSHPSA-N Gly-Val-Tyr Chemical compound [H]NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O IZVICCORZOSGPT-JSGCOSHPSA-N 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 101001018097 Homo sapiens L-selectin Proteins 0.000 description 2
- 101000581981 Homo sapiens Neural cell adhesion molecule 1 Proteins 0.000 description 2
- 101000835093 Homo sapiens Transferrin receptor protein 1 Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 206010021067 Hypopituitarism Diseases 0.000 description 2
- 206010021245 Idiopathic thrombocytopenic purpura Diseases 0.000 description 2
- 102000008070 Interferon-gamma Human genes 0.000 description 2
- 108010074328 Interferon-gamma Proteins 0.000 description 2
- 102100033467 L-selectin Human genes 0.000 description 2
- 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 2
- 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 2
- HYIFFZAQXPUEAU-QWRGUYRKSA-N Leu-Gly-Leu Chemical compound CC(C)C[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CC(C)C HYIFFZAQXPUEAU-QWRGUYRKSA-N 0.000 description 2
- KEVYYIMVELOXCT-KBPBESRZSA-N Leu-Gly-Phe Chemical compound CC(C)C[C@H]([NH3+])C(=O)NCC(=O)N[C@H](C([O-])=O)CC1=CC=CC=C1 KEVYYIMVELOXCT-KBPBESRZSA-N 0.000 description 2
- SYRTUBLKWNDSDK-DKIMLUQUSA-N Leu-Phe-Ile Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O SYRTUBLKWNDSDK-DKIMLUQUSA-N 0.000 description 2
- AMSSKPUHBUQBOQ-SRVKXCTJSA-N Leu-Ser-Lys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)O)N AMSSKPUHBUQBOQ-SRVKXCTJSA-N 0.000 description 2
- GZRABTMNWJXFMH-UVOCVTCTSA-N Leu-Thr-Thr 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)O)C(O)=O GZRABTMNWJXFMH-UVOCVTCTSA-N 0.000 description 2
- YLMIDMSLKLRNHX-HSCHXYMDSA-N Leu-Trp-Ile Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O YLMIDMSLKLRNHX-HSCHXYMDSA-N 0.000 description 2
- JGKHAFUAPZCCDU-BZSNNMDCSA-N Leu-Tyr-Leu Chemical compound CC(C)C[C@H]([NH3+])C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C([O-])=O)CC1=CC=C(O)C=C1 JGKHAFUAPZCCDU-BZSNNMDCSA-N 0.000 description 2
- JCFYLFOCALSNLQ-GUBZILKMSA-N Lys-Ala-Gln Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(O)=O JCFYLFOCALSNLQ-GUBZILKMSA-N 0.000 description 2
- KNKHAVVBVXKOGX-JXUBOQSCSA-N Lys-Ala-Thr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O KNKHAVVBVXKOGX-JXUBOQSCSA-N 0.000 description 2
- KMSMNUFBNCHMII-IHRRRGAJSA-N Met-Leu-Lys Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CCCCN KMSMNUFBNCHMII-IHRRRGAJSA-N 0.000 description 2
- 108091007491 NSP3 Papain-like protease domains Proteins 0.000 description 2
- 102100027347 Neural cell adhesion molecule 1 Human genes 0.000 description 2
- 206010034277 Pemphigoid Diseases 0.000 description 2
- CSYVXYQDIVCQNU-QWRGUYRKSA-N Phe-Asp-Gly Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(O)=O CSYVXYQDIVCQNU-QWRGUYRKSA-N 0.000 description 2
- WFDAEEUZPZSMOG-SRVKXCTJSA-N Phe-Cys-Ser Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CS)C(=O)N[C@@H](CO)C(O)=O WFDAEEUZPZSMOG-SRVKXCTJSA-N 0.000 description 2
- IDUCUXTUHHIQIP-SOUVJXGZSA-N Phe-Gln-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CC2=CC=CC=C2)N)C(=O)O IDUCUXTUHHIQIP-SOUVJXGZSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- LCWXSALTPTZKNM-CIUDSAMLSA-N Pro-Cys-Glu Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(=O)O)C(=O)O LCWXSALTPTZKNM-CIUDSAMLSA-N 0.000 description 2
- QCARZLHECSFOGG-CIUDSAMLSA-N Pro-Glu-Cys Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CS)C(=O)O QCARZLHECSFOGG-CIUDSAMLSA-N 0.000 description 2
- BBFRBZYKHIKFBX-GMOBBJLQSA-N Pro-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]1CCCN1 BBFRBZYKHIKFBX-GMOBBJLQSA-N 0.000 description 2
- RCYUBVHMVUHEBM-RCWTZXSCSA-N Pro-Pro-Thr Chemical compound [H]N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)O)C(O)=O RCYUBVHMVUHEBM-RCWTZXSCSA-N 0.000 description 2
- RNEFESSBTOQSAC-DCAQKATOSA-N Pro-Ser-His Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC2=CN=CN2)C(=O)O RNEFESSBTOQSAC-DCAQKATOSA-N 0.000 description 2
- DYJTXTCEXMCPBF-UFYCRDLUSA-N Pro-Tyr-Phe Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CC2=CC=C(C=C2)O)C(=O)N[C@@H](CC3=CC=CC=C3)C(=O)O DYJTXTCEXMCPBF-UFYCRDLUSA-N 0.000 description 2
- 208000012322 Raynaud phenomenon Diseases 0.000 description 2
- DLPXTCTVNDTYGJ-JBDRJPRFSA-N Ser-Ile-Cys Chemical compound OC[C@H](N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CS)C(O)=O DLPXTCTVNDTYGJ-JBDRJPRFSA-N 0.000 description 2
- RWDVVSKYZBNDCO-MELADBBJSA-N Ser-Phe-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC2=CC=CC=C2)NC(=O)[C@H](CO)N)C(=O)O RWDVVSKYZBNDCO-MELADBBJSA-N 0.000 description 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
- KQNDIKOYWZTZIX-FXQIFTODSA-N Ser-Ser-Arg Chemical compound OC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CCCNC(N)=N KQNDIKOYWZTZIX-FXQIFTODSA-N 0.000 description 2
- 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 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 108091008874 T cell receptors Proteins 0.000 description 2
- 102000016266 T-Cell Antigen Receptors Human genes 0.000 description 2
- WFUAUEQXPVNAEF-ZJDVBMNYSA-N Thr-Arg-Thr Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)O)C(O)=O)CCCN=C(N)N WFUAUEQXPVNAEF-ZJDVBMNYSA-N 0.000 description 2
- HJOSVGCWOTYJFG-WDCWCFNPSA-N Thr-Glu-Lys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCCCN)C(=O)O)N)O HJOSVGCWOTYJFG-WDCWCFNPSA-N 0.000 description 2
- KBBRNEDOYWMIJP-KYNKHSRBSA-N Thr-Gly-Thr Chemical compound C[C@H]([C@@H](C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(=O)O)N)O KBBRNEDOYWMIJP-KYNKHSRBSA-N 0.000 description 2
- MEJHFIOYJHTWMK-VOAKCMCISA-N Thr-Leu-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)[C@@H](C)O MEJHFIOYJHTWMK-VOAKCMCISA-N 0.000 description 2
- KZURUCDWKDEAFZ-XVSYOHENSA-N Thr-Phe-Asn Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(=O)N)C(=O)O)N)O KZURUCDWKDEAFZ-XVSYOHENSA-N 0.000 description 2
- QJIODPFLAASXJC-JHYOHUSXSA-N Thr-Thr-Phe Chemical compound C[C@H]([C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)N)O QJIODPFLAASXJC-JHYOHUSXSA-N 0.000 description 2
- VMSSYINFMOFLJM-KJEVXHAQSA-N Thr-Tyr-Met Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CCSC)C(=O)O)N)O VMSSYINFMOFLJM-KJEVXHAQSA-N 0.000 description 2
- 102100026144 Transferrin receptor protein 1 Human genes 0.000 description 2
- KXIQQAWIPDDVOE-BPUTZDHNSA-N Trp-Pro-Cys Chemical compound O=C([C@H](CC=1C2=CC=CC=C2NC=1)N)N1CCC[C@H]1C(=O)N[C@@H](CS)C(O)=O KXIQQAWIPDDVOE-BPUTZDHNSA-N 0.000 description 2
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 2
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 2
- HVHJYXDXRIWELT-RYUDHWBXSA-N Tyr-Glu-Gly Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(O)=O HVHJYXDXRIWELT-RYUDHWBXSA-N 0.000 description 2
- FASACHWGQBNSRO-ZEWNOJEFSA-N Tyr-Phe-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)NC(=O)[C@H](CC2=CC=C(C=C2)O)N FASACHWGQBNSRO-ZEWNOJEFSA-N 0.000 description 2
- RCMWNNJFKNDKQR-UFYCRDLUSA-N Tyr-Pro-Phe Chemical compound C([C@H](N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=C(O)C=C1 RCMWNNJFKNDKQR-UFYCRDLUSA-N 0.000 description 2
- HRHYJNLMIJWGLF-BZSNNMDCSA-N Tyr-Ser-Phe Chemical compound C([C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=C(O)C=C1 HRHYJNLMIJWGLF-BZSNNMDCSA-N 0.000 description 2
- LNYOXPDEIZJDEI-NHCYSSNCSA-N Val-Asn-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](C(C)C)N LNYOXPDEIZJDEI-NHCYSSNCSA-N 0.000 description 2
- FXVDGDZRYLFQKY-WPRPVWTQSA-N Val-Gly-Met Chemical compound CSCC[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)C(C)C FXVDGDZRYLFQKY-WPRPVWTQSA-N 0.000 description 2
- IEBGHUMBJXIXHM-AVGNSLFASA-N Val-Lys-Met Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCSC)C(=O)O)N IEBGHUMBJXIXHM-AVGNSLFASA-N 0.000 description 2
- UVHFONIHVHLDDQ-IFFSRLJSSA-N Val-Thr-Glu Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)O)NC(=O)[C@H](C(C)C)N)O UVHFONIHVHLDDQ-IFFSRLJSSA-N 0.000 description 2
- 238000002679 ablation Methods 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 239000003708 ampul Substances 0.000 description 2
- 210000003484 anatomy Anatomy 0.000 description 2
- 230000005809 anti-tumor immunity Effects 0.000 description 2
- 230000008827 biological function Effects 0.000 description 2
- 210000001185 bone marrow Anatomy 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 206010009887 colitis Diseases 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 238000012217 deletion Methods 0.000 description 2
- 230000037430 deletion Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 230000009699 differential effect Effects 0.000 description 2
- 230000004069 differentiation Effects 0.000 description 2
- 108010054812 diprotin A Proteins 0.000 description 2
- 239000002988 disease modifying antirheumatic drug Substances 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 210000003162 effector t lymphocyte Anatomy 0.000 description 2
- 208000030172 endocrine system disease Diseases 0.000 description 2
- 230000002708 enhancing effect Effects 0.000 description 2
- 201000005884 exanthem Diseases 0.000 description 2
- 238000013401 experimental design Methods 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 239000000185 hemagglutinin Substances 0.000 description 2
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 2
- 238000011577 humanized mouse model Methods 0.000 description 2
- 230000005746 immune checkpoint blockade Effects 0.000 description 2
- 230000036737 immune function Effects 0.000 description 2
- 230000005847 immunogenicity Effects 0.000 description 2
- 208000033065 inborn errors of immunity Diseases 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 230000008595 infiltration Effects 0.000 description 2
- 238000001764 infiltration Methods 0.000 description 2
- 208000027866 inflammatory disease Diseases 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 238000003780 insertion Methods 0.000 description 2
- 230000037431 insertion Effects 0.000 description 2
- 229960003130 interferon gamma Drugs 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 231100001231 less toxic Toxicity 0.000 description 2
- 108010051673 leucyl-glycyl-phenylalanine Proteins 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 230000036210 malignancy Effects 0.000 description 2
- 108020004999 messenger RNA Proteins 0.000 description 2
- 108010005942 methionylglycine Proteins 0.000 description 2
- 108010085203 methionylmethionine Proteins 0.000 description 2
- 201000006417 multiple sclerosis Diseases 0.000 description 2
- 208000029766 myalgic encephalomeyelitis/chronic fatigue syndrome Diseases 0.000 description 2
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 2
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- 230000004962 physiological condition Effects 0.000 description 2
- 102000054765 polymorphisms of proteins Human genes 0.000 description 2
- 238000012809 post-inoculation Methods 0.000 description 2
- 125000002924 primary amino group Chemical class [H]N([H])* 0.000 description 2
- 208000028529 primary immunodeficiency disease Diseases 0.000 description 2
- 108010079317 prolyl-tyrosine Proteins 0.000 description 2
- 206010037844 rash Diseases 0.000 description 2
- 231100000916 relative toxicity Toxicity 0.000 description 2
- 230000001177 retroviral effect Effects 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 230000011664 signaling Effects 0.000 description 2
- 238000009097 single-agent therapy Methods 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- 206010043207 temporal arteritis Diseases 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 210000001541 thymus gland Anatomy 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 230000004614 tumor growth Effects 0.000 description 2
- 210000004291 uterus Anatomy 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- 229940055760 yervoy Drugs 0.000 description 2
- MIJDSYMOBYNHOT-UHFFFAOYSA-N 2-(ethylamino)ethanol Chemical compound CCNCCO MIJDSYMOBYNHOT-UHFFFAOYSA-N 0.000 description 1
- BFSVOASYOCHEOV-UHFFFAOYSA-N 2-diethylaminoethanol Chemical compound CCN(CC)CCO BFSVOASYOCHEOV-UHFFFAOYSA-N 0.000 description 1
- IBSREHMXUMOFBB-JFUDTMANSA-N 5u8924t11h Chemical compound O1[C@@H](C)[C@H](O)[C@@H](OC)C[C@@H]1O[C@@H]1[C@@H](OC)C[C@H](O[C@@H]2C(=C/C[C@@H]3C[C@@H](C[C@@]4(O3)C=C[C@H](C)[C@@H](C(C)C)O4)OC(=O)[C@@H]3C=C(C)[C@@H](O)[C@H]4OC\C([C@@]34O)=C/C=C/[C@@H]2C)/C)O[C@H]1C.C1=C[C@H](C)[C@@H]([C@@H](C)CC)O[C@]11O[C@H](C\C=C(C)\[C@@H](O[C@@H]2O[C@@H](C)[C@H](O[C@@H]3O[C@@H](C)[C@H](O)[C@@H](OC)C3)[C@@H](OC)C2)[C@@H](C)\C=C\C=C/2[C@]3([C@H](C(=O)O4)C=C(C)[C@@H](O)[C@H]3OC\2)O)C[C@H]4C1 IBSREHMXUMOFBB-JFUDTMANSA-N 0.000 description 1
- 239000005660 Abamectin Substances 0.000 description 1
- 208000035657 Abasia Diseases 0.000 description 1
- BLGHHPHXVJWCNK-GUBZILKMSA-N Ala-Gln-Leu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(O)=O BLGHHPHXVJWCNK-GUBZILKMSA-N 0.000 description 1
- QPBSRMDNJOTFAL-AICCOOGYSA-N Ala-Leu-Leu-Thr Chemical compound C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O QPBSRMDNJOTFAL-AICCOOGYSA-N 0.000 description 1
- 102100036475 Alanine aminotransferase 1 Human genes 0.000 description 1
- 108010082126 Alanine transaminase Proteins 0.000 description 1
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 1
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 208000003343 Antiphospholipid Syndrome Diseases 0.000 description 1
- NMTANZXPDAHUKU-ULQDDVLXSA-N Arg-Tyr-Lys Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](CCCCN)C(O)=O)CC1=CC=C(O)C=C1 NMTANZXPDAHUKU-ULQDDVLXSA-N 0.000 description 1
- NUHQMYUWLUSRJX-BIIVOSGPSA-N Asn-Ala-Pro Chemical compound C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CC(=O)N)N NUHQMYUWLUSRJX-BIIVOSGPSA-N 0.000 description 1
- VDCIPFYVCICPEC-FXQIFTODSA-N Asn-Arg-Ala Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(O)=O VDCIPFYVCICPEC-FXQIFTODSA-N 0.000 description 1
- GXMSVVBIAMWMKO-BQBZGAKWSA-N Asn-Arg-Gly Chemical compound NC(=O)C[C@H](N)C(=O)N[C@H](C(=O)NCC(O)=O)CCCN=C(N)N GXMSVVBIAMWMKO-BQBZGAKWSA-N 0.000 description 1
- 206010003827 Autoimmune hepatitis Diseases 0.000 description 1
- 208000000659 Autoimmune lymphoproliferative syndrome Diseases 0.000 description 1
- 108010074708 B7-H1 Antigen Proteins 0.000 description 1
- 102000008096 B7-H1 Antigen Human genes 0.000 description 1
- 208000023328 Basedow disease Diseases 0.000 description 1
- 208000009137 Behcet syndrome Diseases 0.000 description 1
- 208000009299 Benign Mucous Membrane Pemphigoid Diseases 0.000 description 1
- 208000008439 Biliary Liver Cirrhosis Diseases 0.000 description 1
- 206010004659 Biliary cirrhosis Diseases 0.000 description 1
- 208000031648 Body Weight Changes Diseases 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 208000031229 Cardiomyopathies Diseases 0.000 description 1
- 208000030939 Chronic inflammatory demyelinating polyneuropathy Diseases 0.000 description 1
- 108090000317 Chymotrypsin Proteins 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 108010047041 Complementarity Determining Regions Proteins 0.000 description 1
- 241000699802 Cricetulus griseus Species 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- 208000019707 Cryoglobulinemic vasculitis Diseases 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 102100039498 Cytotoxic T-lymphocyte protein 4 Human genes 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 1
- 206010058314 Dysplasia Diseases 0.000 description 1
- 108010059378 Endopeptidases Proteins 0.000 description 1
- 102000005593 Endopeptidases Human genes 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 108010008165 Etanercept Proteins 0.000 description 1
- 208000009386 Experimental Arthritis Diseases 0.000 description 1
- 108010020195 FLAG peptide Proteins 0.000 description 1
- XZWYTXMRWQJBGX-VXBMVYAYSA-N FLAG peptide Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](NC(=O)[C@@H](N)CC(O)=O)CC1=CC=C(O)C=C1 XZWYTXMRWQJBGX-VXBMVYAYSA-N 0.000 description 1
- ZBKUIQNCRIYVGH-SDDRHHMPSA-N Gln-Leu-Pro Chemical compound CC(C)C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCC(=O)N)N ZBKUIQNCRIYVGH-SDDRHHMPSA-N 0.000 description 1
- ROHVCXBMIAAASL-HJGDQZAQSA-N Gln-Met-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(=O)N)N)O ROHVCXBMIAAASL-HJGDQZAQSA-N 0.000 description 1
- VNTGPISAOMAXRK-CIUDSAMLSA-N Gln-Pro-Ser Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O VNTGPISAOMAXRK-CIUDSAMLSA-N 0.000 description 1
- WPJDPEOQUIXXOY-AVGNSLFASA-N Gln-Tyr-Asn Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CCC(=O)N)N)O WPJDPEOQUIXXOY-AVGNSLFASA-N 0.000 description 1
- RLZBLVSJDFHDBL-KBIXCLLPSA-N Glu-Ala-Ile Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O RLZBLVSJDFHDBL-KBIXCLLPSA-N 0.000 description 1
- VBOBNHSVQKKTOT-YUMQZZPRSA-N Gly-Lys-Ala Chemical compound [H]NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O VBOBNHSVQKKTOT-YUMQZZPRSA-N 0.000 description 1
- JPVGHHQGKPQYIL-KBPBESRZSA-N Gly-Phe-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)CN)CC1=CC=CC=C1 JPVGHHQGKPQYIL-KBPBESRZSA-N 0.000 description 1
- 206010072579 Granulomatosis with polyangiitis Diseases 0.000 description 1
- 208000015023 Graves' disease Diseases 0.000 description 1
- 208000030836 Hashimoto thyroiditis Diseases 0.000 description 1
- 208000035186 Hemolytic Autoimmune Anemia Diseases 0.000 description 1
- 206010019851 Hepatotoxicity Diseases 0.000 description 1
- DFHVLUKTTVTCKY-PBCZWWQYSA-N His-Asn-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CC1=CN=CN1)N)O DFHVLUKTTVTCKY-PBCZWWQYSA-N 0.000 description 1
- 108010093488 His-His-His-His-His-His Proteins 0.000 description 1
- 101100220044 Homo sapiens CD34 gene Proteins 0.000 description 1
- 201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 1
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 1
- 102000006496 Immunoglobulin Heavy Chains Human genes 0.000 description 1
- 108010019476 Immunoglobulin Heavy Chains Proteins 0.000 description 1
- 206010062016 Immunosuppression Diseases 0.000 description 1
- 108050006617 Interleukin-1 receptor Proteins 0.000 description 1
- 102000019223 Interleukin-1 receptor Human genes 0.000 description 1
- 108010002350 Interleukin-2 Proteins 0.000 description 1
- 102000000588 Interleukin-2 Human genes 0.000 description 1
- 102000010781 Interleukin-6 Receptors Human genes 0.000 description 1
- 108010038501 Interleukin-6 Receptors Proteins 0.000 description 1
- 208000012528 Juvenile dermatomyositis Diseases 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
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- RCFDOSNHHZGBOY-UHFFFAOYSA-N L-isoleucyl-L-alanine Natural products CCC(C)C(N)C(=O)NC(C)C(O)=O RCFDOSNHHZGBOY-UHFFFAOYSA-N 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- KWURTLAFFDOTEQ-GUBZILKMSA-N Leu-Cys-Glu Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N KWURTLAFFDOTEQ-GUBZILKMSA-N 0.000 description 1
- UBZGNBKMIJHOHL-BZSNNMDCSA-N Leu-Leu-Phe Chemical compound CC(C)C[C@H]([NH3+])C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C([O-])=O)CC1=CC=CC=C1 UBZGNBKMIJHOHL-BZSNNMDCSA-N 0.000 description 1
- IEWBEPKLKUXQBU-VOAKCMCISA-N Leu-Leu-Thr Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O IEWBEPKLKUXQBU-VOAKCMCISA-N 0.000 description 1
- VKVDRTGWLVZJOM-DCAQKATOSA-N Leu-Val-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(O)=O VKVDRTGWLVZJOM-DCAQKATOSA-N 0.000 description 1
- 206010067125 Liver injury Diseases 0.000 description 1
- IMAKMJCBYCSMHM-AVGNSLFASA-N Lys-Glu-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@H](C(O)=O)CCCCN IMAKMJCBYCSMHM-AVGNSLFASA-N 0.000 description 1
- 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 1
- 241000282567 Macaca fascicularis Species 0.000 description 1
- 206010064281 Malignant atrophic papulosis Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 102000018697 Membrane Proteins Human genes 0.000 description 1
- 108010052285 Membrane Proteins Proteins 0.000 description 1
- 208000027530 Meniere disease Diseases 0.000 description 1
- FXBKQTOGURNXSL-HJGDQZAQSA-N Met-Thr-Glu Chemical compound CSCC[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@H](C(O)=O)CCC(O)=O FXBKQTOGURNXSL-HJGDQZAQSA-N 0.000 description 1
- 208000003250 Mixed connective tissue disease Diseases 0.000 description 1
- 208000012192 Mucous membrane pemphigoid Diseases 0.000 description 1
- 102100038895 Myc proto-oncogene protein Human genes 0.000 description 1
- 101710135898 Myc proto-oncogene protein Proteins 0.000 description 1
- 108010038807 Oligopeptides Proteins 0.000 description 1
- 102000015636 Oligopeptides Human genes 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 201000011152 Pemphigus Diseases 0.000 description 1
- 208000031845 Pernicious anaemia Diseases 0.000 description 1
- 206010036030 Polyarthritis Diseases 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 208000007048 Polymyalgia Rheumatica Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 208000003782 Raynaud disease Diseases 0.000 description 1
- 206010039710 Scleroderma Diseases 0.000 description 1
- GZFAWAQTEYDKII-YUMQZZPRSA-N Ser-Gly-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CO GZFAWAQTEYDKII-YUMQZZPRSA-N 0.000 description 1
- NVNPWELENFJOHH-CIUDSAMLSA-N Ser-Ser-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CO)N NVNPWELENFJOHH-CIUDSAMLSA-N 0.000 description 1
- 208000021386 Sjogren Syndrome Diseases 0.000 description 1
- 201000002661 Spondylitis Diseases 0.000 description 1
- 230000006052 T cell proliferation Effects 0.000 description 1
- 210000000662 T-lymphocyte subset Anatomy 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- UKBSDLHIKIXJKH-HJGDQZAQSA-N Thr-Arg-Glu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(O)=O UKBSDLHIKIXJKH-HJGDQZAQSA-N 0.000 description 1
- WNQJTLATMXYSEL-OEAJRASXSA-N Thr-Phe-Leu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(C)C)C(O)=O WNQJTLATMXYSEL-OEAJRASXSA-N 0.000 description 1
- 101710150448 Transcriptional regulator Myc Proteins 0.000 description 1
- GFUOTIPYXKAPAH-BVSLBCMMSA-N Trp-Pro-Phe Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O GFUOTIPYXKAPAH-BVSLBCMMSA-N 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 206010053614 Type III immune complex mediated reaction Diseases 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 206010046851 Uveitis Diseases 0.000 description 1
- CPGJELLYDQEDRK-NAKRPEOUSA-N Val-Ile-Ala Chemical compound CC[C@H](C)[C@H](NC(=O)[C@@H](N)C(C)C)C(=O)N[C@@H](C)C(O)=O CPGJELLYDQEDRK-NAKRPEOUSA-N 0.000 description 1
- 206010047115 Vasculitis Diseases 0.000 description 1
- 206010047642 Vitiligo Diseases 0.000 description 1
- 229950008167 abamectin Drugs 0.000 description 1
- 229960003697 abatacept Drugs 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 238000001042 affinity chromatography Methods 0.000 description 1
- 208000004631 alopecia areata Diseases 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 238000000540 analysis of variance Methods 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 230000003367 anti-collagen effect Effects 0.000 description 1
- 230000003302 anti-idiotype Effects 0.000 description 1
- 238000011319 anticancer therapy Methods 0.000 description 1
- 230000000890 antigenic effect Effects 0.000 description 1
- 206010003230 arteritis Diseases 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 108010068265 aspartyltyrosine Proteins 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 201000000448 autoimmune hemolytic anemia Diseases 0.000 description 1
- 208000027625 autoimmune inner ear disease Diseases 0.000 description 1
- 208000036923 autoimmune primary adrenal insufficiency Diseases 0.000 description 1
- 229960005347 belatacept Drugs 0.000 description 1
- 239000012867 bioactive agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000004579 body weight change Effects 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- 208000000594 bullous pemphigoid Diseases 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 239000012830 cancer therapeutic Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 201000010415 childhood type dermatomyositis Diseases 0.000 description 1
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 1
- 201000005795 chronic inflammatory demyelinating polyneuritis Diseases 0.000 description 1
- 229960002376 chymotrypsin Drugs 0.000 description 1
- 201000010002 cicatricial pemphigoid Diseases 0.000 description 1
- 238000011281 clinical therapy Methods 0.000 description 1
- 238000011260 co-administration Methods 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 230000000875 corresponding effect Effects 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 229940111134 coxibs Drugs 0.000 description 1
- 230000009260 cross reactivity Effects 0.000 description 1
- 201000003278 cryoglobulinemia Diseases 0.000 description 1
- 238000012926 crystallographic analysis Methods 0.000 description 1
- 239000012228 culture supernatant Substances 0.000 description 1
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 230000006806 disease prevention Effects 0.000 description 1
- BFMYDTVEBKDAKJ-UHFFFAOYSA-L disodium;(2',7'-dibromo-3',6'-dioxido-3-oxospiro[2-benzofuran-1,9'-xanthene]-4'-yl)mercury;hydrate Chemical compound O.[Na+].[Na+].O1C(=O)C2=CC=CC=C2C21C1=CC(Br)=C([O-])C([Hg])=C1OC1=C2C=C(Br)C([O-])=C1 BFMYDTVEBKDAKJ-UHFFFAOYSA-L 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 229940073621 enbrel Drugs 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 210000000981 epithelium Anatomy 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 210000003527 eukaryotic cell Anatomy 0.000 description 1
- 230000003090 exacerbative effect Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- ZWJINEZUASEZBH-UHFFFAOYSA-N fenamic acid Chemical class OC(=O)C1=CC=CC=C1NC1=CC=CC=C1 ZWJINEZUASEZBH-UHFFFAOYSA-N 0.000 description 1
- 229960004887 ferric hydroxide Drugs 0.000 description 1
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 1
- 238000002523 gelfiltration Methods 0.000 description 1
- 230000030279 gene silencing Effects 0.000 description 1
- 230000013595 glycosylation Effects 0.000 description 1
- 238000006206 glycosylation reaction Methods 0.000 description 1
- 108010066198 glycyl-leucyl-phenylalanine Proteins 0.000 description 1
- 210000000777 hematopoietic system Anatomy 0.000 description 1
- 231100000753 hepatic injury Toxicity 0.000 description 1
- 231100000304 hepatotoxicity Toxicity 0.000 description 1
- 230000007686 hepatotoxicity Effects 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 238000009396 hybridization Methods 0.000 description 1
- 235000011167 hydrochloric acid Nutrition 0.000 description 1
- 238000004191 hydrophobic interaction chromatography Methods 0.000 description 1
- 229910052588 hydroxylapatite Inorganic materials 0.000 description 1
- 230000016178 immune complex formation Effects 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 230000016784 immunoglobulin production Effects 0.000 description 1
- 229940072221 immunoglobulins Drugs 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 206010022000 influenza Diseases 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 208000036971 interstitial lung disease 2 Diseases 0.000 description 1
- 210000004347 intestinal mucosa Anatomy 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 238000004255 ion exchange chromatography Methods 0.000 description 1
- IEECXTSVVFWGSE-UHFFFAOYSA-M iron(3+);oxygen(2-);hydroxide Chemical compound [OH-].[O-2].[Fe+3] IEECXTSVVFWGSE-UHFFFAOYSA-M 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 206010025135 lupus erythematosus Diseases 0.000 description 1
- 239000008176 lyophilized powder Substances 0.000 description 1
- 108010054155 lysyllysine Proteins 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 238000013507 mapping Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 210000003071 memory t lymphocyte Anatomy 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 210000002200 mouth mucosa Anatomy 0.000 description 1
- 206010028417 myasthenia gravis Diseases 0.000 description 1
- 208000029264 myotonic syndrome Diseases 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 229940035567 orencia Drugs 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 201000001976 pemphigus vulgaris Diseases 0.000 description 1
- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 108010064486 phenylalanyl-leucyl-valine Proteins 0.000 description 1
- 108010084572 phenylalanyl-valine Proteins 0.000 description 1
- 108010073101 phenylalanylleucine Proteins 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 201000006292 polyarteritis nodosa Diseases 0.000 description 1
- 208000030428 polyarticular arthritis Diseases 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920002704 polyhistidine Polymers 0.000 description 1
- 208000005987 polymyositis Diseases 0.000 description 1
- 108091033319 polynucleotide Proteins 0.000 description 1
- 102000040430 polynucleotide Human genes 0.000 description 1
- 239000002157 polynucleotide Substances 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 150000005599 propionic acid derivatives Chemical class 0.000 description 1
- 230000009993 protective function Effects 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 230000004853 protein function Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000019908 regulation of T cell activation Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000000754 repressing effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 201000003068 rheumatic fever Diseases 0.000 description 1
- 210000003079 salivary gland Anatomy 0.000 description 1
- 201000000306 sarcoidosis Diseases 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 238000002864 sequence alignment Methods 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 230000001148 spastic effect Effects 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 230000003393 splenic effect Effects 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 239000008227 sterile water for injection Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 210000001258 synovial membrane Anatomy 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000011285 therapeutic regimen Methods 0.000 description 1
- 231100000155 toxicity by organ Toxicity 0.000 description 1
- 230000007675 toxicity by organ Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 238000003146 transient transfection Methods 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 208000035408 type 1 diabetes mellitus 1 Diseases 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 239000013603 viral vector Substances 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
- C07K14/70596—Molecules with a "CD"-designation not provided for elsewhere
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/39541—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against normal tissues, cells
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
- A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
- A61K47/6811—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a protein or peptide, e.g. transferrin or bleomycin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
-
- 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
-
- 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
- C07K16/2827—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 B7 molecules, e.g. CD80, CD86
-
- 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
- A61K2039/507—Comprising a combination of two or more separate antibodies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
- C07K2317/34—Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/30—Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Immunology (AREA)
- Medicinal Chemistry (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biochemistry (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Epidemiology (AREA)
- Gastroenterology & Hepatology (AREA)
- Cell Biology (AREA)
- Zoology (AREA)
- Mycology (AREA)
- Microbiology (AREA)
- Toxicology (AREA)
- Transplantation (AREA)
- Biomedical Technology (AREA)
- Endocrinology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Peptides Or Proteins (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
本发明涉及细胞毒性T‑淋巴细胞相关抗原‑4(CTLA‑4)蛋白组合物及其在减轻与癌症免疫疗法相关的自身免疫不良事件中的用途。具体地,本公开提供一种包含CTLA‑4的突变体细胞外结构域的CTLA‑4蛋白,其中所述CTLA‑4蛋白表现出与CTLA‑4的野生型细胞外结构域相比,与抗CTLA‑4抗体的降低的结合,其中所述抗CTLA‑4抗体具有抗癌免疫治疗活性。
Description
背景技术
用抗CTLA-4抗体进行治疗已被证明是用于增强临床前模型中的抗肿瘤免疫力的有力工具(10)。用针对CTLA-4的抗体进行的单一疗法促进对各种来源的可移植肿瘤的排斥。基于有希望的临床前肿瘤模型研究,已在不同的人类恶性肿瘤中探索针对CTLA-4的抗体的临床潜力。尽管抗CTLA-4(伊匹单抗,作为Yervoy销售,在美国专利号6,984,720中公开)已证明在治疗黑素瘤中有效,但是CTLA-4的治疗和靶向与自身免疫样毒性有关。另外,抗CTLA-4 mAb诸如伊匹单抗和替西木单抗用于与抗PD-1/PD-L1抗体的组合疗法,其具有优异的治疗效果。然而,改善的治疗效果与甚至更高比率的3级和4级器官毒性相关。抑制CTLA-4的特征性副作用通常称为免疫相关不良事件(irAE),并且最常见的irAE是皮疹、肝炎、结肠炎和内分泌病,特别是垂体机能减退。因此,在保持抗CTLA-4单克隆抗体(mAb)的癌症治疗效果的同时治疗irAE的方面在医学上存在大量未满足的需求。
发明人已证明临床证明的治疗性抗人类CTLA-4 mAb和两种抗小鼠Ctla-4 mAb两者均在生理学相关条件下诱导肿瘤排斥而不阻断B7-CTLA-4相互作用。因此,甚至对于可有效阻断B7-CTLA-4相互作用的mAb,这种阻断对于肿瘤排斥也不是必需的。这些数据驳斥了抗CTLA-4 mAb通过检查点阻断赋予免疫治疗作用的假设(108)。为了支持这一观点,进一步表明由伊匹单抗和可能的其他抗CTLA-4 mAb介导的免疫治疗效果不受阻断B7-1和B7-2的影响,这对于自身免疫疾病的发病机制至关重要。
积累的数据表明,人类CTLA-4基因通过可变剪接编码两种不同的蛋白质同种型:一种具有跨膜结构域,因此所述蛋白质可能锚定在膜中,并且另一种缺乏跨膜结构域并且预测为分泌型(sCTLA-4)(128)。重要的是,遗传学研究表明,降低可溶性同种型相对丰度的CTLA-4的多态性与多种自身免疫疾病密切相关(64)。具有自身免疫倾向等位基因的受试者表达较少sCTLA-4 mRNA的事实表明sCTLA-4可能是保护性的。这一观点得到了以下支持:阿巴西普(abatacept)的广泛治疗作用(129,130),所述阿巴西普呈可溶性CTLA-4的形式,以及一项遗传研究,其中sCTLA-4同种型的选择性消融加速小鼠中I型糖尿病的发展(131)。基于这些遗传数据,发明人已认识到显示与可溶性CTLA-4具有最差结合的抗CTLA-4抗体应产生最少的irAE。实际上,基于抗体对围产期期间用抗CTLA-4抗体治疗的小鼠的体重增加的影响,发现四种抗CTLA-4 mAb之间存在强烈的相关性:伊匹单抗对sCTLA-4具有最强的结合,并且是毒性最强的抗CTLA-4,而抗体L3D10对sCTLA-4具有较弱的结合,并且毒性最小。此外,优先降低与sCTLA-4结合的人源化L3D10变体显示出与亲本抗体相比进一步改善的安全性特征。
可溶性CTLA-4分子的保护性功能进一步支持使用可溶性CTLA-4融合蛋白来减轻、减少或治疗irAE的方法。然而,由于具有抗CTLA-4 mAb诱导的irAE患者具有循环抗CTLA-4mAb,所以CTLA-4融合蛋白诸如阿巴西普不仅将通过阻止他们与细胞相关的CTLA-4分子结合而降低抗CTLA-4 mAb的治疗作用,还将变得无效,因为他们在与循环抗CTLA-4 mAb形成免疫复合物后将从循环中清除。因此,本领域需要改进的CTLA-4免疫疗法组合物和方法。
发明内容
本发明涉及人类CTLA-4蛋白和抗B7-1和抗B7-2组合物,以及他们用于免疫疗法和治疗自身免疫疾病和炎症,以及用于减少与抗CTLA-4免疫疗法相关的自身免疫副作用的用途。具体地,本发明涉及一种CTLA-4蛋白,其表现出与癌症免疫疗法中使用的抗CTLA-4抗体的降低或消除的结合,但保留结合到B7-1和B7-2的能力。
所述CTLA-4蛋白可包括一种CTLA-4蛋白,其中抗CTLA-4抗体结合表位的氨基酸进行修饰或突变,以便与CTLA-4的野生型细胞外结构域相比,减少或消除抗CTLA-4抗体与CTLA-4蛋白的结合。CTLA-4蛋白可具有抗癌免疫治疗活性。抗CTLA-4抗体可以是伊匹单抗。CTLA-4蛋白可保留其结合B7-1和B7-2中的至少一种的能力。CTLA-4蛋白可能不阻断抗CTLA-4抗体的抗癌免疫治疗作用。
CTLA-4蛋白可包含成熟人类CTLA-4的细胞外结构域、其变体或其活性片段。CTLA-4蛋白可包含选自由以下组成的组的氨基酸序列:SEQ ID NO:34、36、38、39、40和46-48、其变体以及其活性片段。CTLA-4蛋白可以是可溶的。CTLA-4蛋白可包括一种CTLA-4融合蛋白,其中人类CTLA-4的细胞外结构域附接到人类免疫球蛋白重链恒定区。CTLA-4蛋白可包含选自由以下组成的组的氨基酸序列:SEQ ID NO:17、19、21、22、23和42-44。CTLA-4蛋白可以是贝拉西普(belatacept)。
在另一个实施方案中,本发明涉及结合人类B7-1和B7-2中的至少一种的抗体组合物,以及他们用于免疫疗法和治疗自身免疫疾病和炎症,以及用于减少与抗CTLA-4免疫疗法相关的自身免疫副作用的用途。
本文还提供一种药物组合物,其包含治疗有效量的本文所述的蛋白质或抗体。药物组合物可包含生理学上可接受的载体或赋形剂。
另一方面,本文提供用于减少受试者中的一种或多种免疫功能或反应的方法,其包括向有需要的受试者施用CTLA-4蛋白或抗B7抗体组合物或其药物组合物。在一个具体实施方案中,本文提供用于预防、治疗或控制疾病的方法,其中希望抑制或减少一种或多种免疫功能或反应。所述疾病可以是自身免疫疾病,诸如类风湿性关节炎(RA)或幼年型特发性关节炎(JIA)。
本文所述的组合物还可用于减轻、最小化或治疗与免疫疗法相关的免疫相关不良反应。特别地,所述组合物可包含阻断或降低B7-1和B7-2功能而不影响抗CTLA-4抗体的癌症免疫治疗活性的分子。所述分子可以是CTLA-4蛋白、抗B7抗体或其药物组合物。所述分子可以是可在功能上阻断B7-1和B7-2中的至少一种与CD28和CTLA-4中的至少一种结合的抗体,并且可以是抗B7-1或抗B7-2。所述抗体可能够结合B7-1和B7-2两者,并且可包含与B7-1和B7-2两者反应的结合位点。
本文所述的组合物可与抗CTLA-4免疫疗法组合或在抗CTLA-4免疫疗法的背景下施用于可能患有癌症的受试者。所述组合物可预防性地用于在开始抗CTLA-4治疗之前或在出现irAE临床表现之前预防irAE。在另一个实施方案中,所述组合物治疗性地用于在开始抗CTLA-4治疗并诊断出临床症状之后治疗irAE。
附图说明
图1.人类CTLA-4序列。图1A示出人类CTLA-4蛋白的序列(NCBI登录号NP_005205;SEQ ID NO:1),其中信号肽加粗体,IgV结构域加下划线并且跨膜结构域加双下划线。图1B示出阿巴西普的序列(SEQ ID NO:2),其中CTLA-4序列加粗体示出,蛋白质的剩余部分包含IgG1 Fc区。
图2.嵌合L3D10和10D1在MC38肿瘤模型中的治疗作用。将体重大约20克的人类CTLA-4敲入小鼠用于所述研究。将1x106个MC38肿瘤细胞皮下注射到Ctla-4h/h小鼠中,并且当肿瘤直径达到0.5cm大小时,将携带肿瘤的小鼠随机分成三组,每组5或6只小鼠。然后如箭头所示,在第7、10、13和16天用100μg/注射的10D1、嵌合L3D10或对照hIgGFc处理(i.p.)小鼠。示出一式两份实验的结果(左图和右图),并且显示的数据是肿瘤大小的平均值和S.D.(左图中每组n=6,右图中每组n=5)。L3D10和10D1在此模型中具有相似的治疗作用,并且均能够诱导已建立的肿瘤的完全缓解。使用以下公式计算肿瘤的直径(d):D=√(ab),V=ab2/2,其中a是长直径,而b是短直径。通过双向重复测量ANOVA(治疗X时间)执行统计学分析。对于左图:P=10D1相对于hIgGFc:5.71e-07;L3D10相对于hIgGFc:P=5.53e-07;10D1相对于L3D10:P=0.869。
图3.嵌合L3D10和10D1与抗PD-1组合的不良反应。顶图描绘实验设计。使用体重大于4克的10天大仅雌性人类CTLA-4-敲入小鼠进行研究。它们接受指示的蛋白质或其组合。箭头指示治疗时间(100μg/小鼠/治疗)。显示的数据是重量增加%的平均值和S.D.。嵌合L3D10和10D1在成年小鼠中具有相当的癌症治疗作用(图2),但是当10D1与抗PD-1 mAb组合时,看到不同的不良反应。
图4.嵌合L3D10和10D1与抗PD-1组合的不良反应。所述图示出来自图3中概述的实验的小鼠在第42天的最终体重,所述小鼠接受对照IgG、10D1+抗PD-1或嵌合L3D10+抗PD-1(每组n=5)。在抗PD1+10D1组合中观察到显著的体重降低,这在抗PD-1+嵌合L3D10组合中未看到。
图5.嵌合L3D10和10D1与抗PD-1组合的病理学作用。组1是hIgG,组2是10D1+抗-PD1,并且组3是L3D10+抗PD1。为了进一步检查当与抗PD-1组合施用时,L3D10与10D1相比的相对毒性,研究以上图4中描述的小鼠的大体解剖结构。用10D1+PD-1处理的小鼠中的子宫/卵巢/膀胱和胸腺明显较小,而用L3D10+抗PD-1处理的小鼠中的器官与hIgG对照相当。相比之下,从用10D1处理的小鼠解剖的心脏的大小看起来更大,具有明显更白的外观。
图6.用10D1与抗PD-1组合治疗导致异常红细胞生成。鉴于图5中观察到的心脏的差异,在小鼠内研究红细胞生成,并且相对于用L3D10+抗PD-1或对照抗体(hIgG)处理的组,在用10D1+抗PD-1处理的小鼠中观察到明显的差异,所述差异是非常相似的。来自用10D1+抗PD-1处理的小鼠的骨髓具有明显更白的颜色(图6A),并且分离的血液几乎完全是白色的(图6B)。据此,当使用CD119和CD71标记物的分布分析红细胞的分化时,在10D1+抗PD-1处理的小鼠中观察到经历IV期发育的细胞数量的统计学显著降低。代表性的FACS图在图6C中示出,而概要数据在图6D中呈现。
图7.用嵌合L3D10和10D1与抗PD-1组合处理的小鼠的毒性评分。总结此组织数据并示出用10D1+抗PD-1处理的小鼠相对于用L3D10+抗PD-1处理的小鼠的高毒性评分,用L3D10+抗PD-1处理的小鼠具有仅略高于hIgG对照小鼠组的评分。
图8.L3D10和10D1显示对板固定的CTLA-4的相似结合模式。用1μg/ml的CTLA-4-His蛋白(Sino Biological,China)包被ELISA板。添加给定浓度的生物素化结合蛋白,并且使用HRP缀合的链霉抗生物素蛋白测量结合。10D1-1和10D1-2是相同抗体的两个独立材料批次。hIgG-Fc是人类Ig阴性对照。
图9.L3D10显示降低的结合可溶性CTLA-4。将给定浓度的抗人类CTLA-4 mAb在板上包被过夜,在洗涤并用牛血清白蛋白封闭后,以0.25μg/ml添加生物素化CTLA-4-Fc。在温育并洗涤之后,使用HRP标记的链霉抗生物素蛋白测量捕获的CTLA-4-Fc的量。
图10.10D1+抗-PD-1在Ctla-4h/m小鼠中没有显著毒性,如在围产期期间接受抗体治疗的小鼠的正常体重增加所证明的。小鼠在第10、13、16、19和22天腹膜内接受给定抗体或组合的治疗(100μg/小鼠/注射/抗体)。每3天至少对小鼠称重一次。
图11.与10D1相比,人源化L3D10抗体的抗肿瘤活性。在人类CTLA-4敲入小鼠中使用MC38小鼠肿瘤模型,与嵌合L3D10抗体和10D1相比,研究人源化L3D10抗体的抗肿瘤活性。图11A示出体内实验的治疗方案。从接种后第7天开始,每3天给与小鼠总计4个剂量的抗体。所有人源化抗体(每组n=6)完全根除肿瘤并且与10D1相当(图11B)。
图12.在10D1、mAb4和mAb5雌性之间针对其与抗PD-1 mAb的组合毒性的比较。在出生后第10天或第11天,用四次注射抗体(100μg/小鼠/注射,每三天一次)或对照Fc处理雌性Ctla-4h/h小鼠,如说明中所指定的。每3天对小鼠称重一次。显示的数据是30天内重量增加%的平均值和SEM。在第43天处死所有小鼠用于组织学分析。每组使用的小鼠数量在标记的括号中示出。
各种处理之间的比较的p值如下。
hIg相对于αPD1+L3D10 | P值=0.16 |
hIg相对于αPD1+hIg | P值=0.0384* |
hIg相对于αPD1+10D1 | P值=<2e-16*** |
hIg相对于αPD1+mAb4 | P值=0.16 |
hIg相对于αPD1+mAb5 | P值=0.00207** |
αPD1+L3D10相对于αPD1+hIg | P值=0.00654** |
αPD1+L3D10相对于αPD1+10D1 | P值=<2e-16*** |
αPD1+L3D10相对于αPD1+mAb4 | P值=0.492 |
αPD1+L3D10相对于αPD1+mAb5 | P值=0.000124*** |
αPD1+hIg相对于αPD1+10D1 | P值=<2e-16*** |
αPD1+hIg相对于αPD1+mAb4 | P值=0.0579 |
αPD1+hIg相对于αPD1+mAb5 | P值=0.409 |
αPD1+10D1相对于αPD1+mAb4 | P值=<2e-16*** |
αPD1+10D1相对于αPD1+mAb5 | P值=<2e-16*** |
αPD1+mAb4相对于αPD1+mAb5 | P值=0.000446*** |
图13.L3D10的人源化不影响与固定的CTLA-4的结合。如图23所述,确定人源化L3D10抗体结合固定的CTLA-4的能力。X轴指示添加到溶液中的抗CTLA-4 mAb的浓度。人源化不影响与固定的CTLA-4的结合,并且所有三种人源化抗体都显示出与亲本嵌合L3D10抗体和10D1的相似结合。当使用CTLA-4-Ig代替CTLA-4-his时,观察到相似的模式。
图14.人源化进一步降低L3D10与可溶性CTLA-4的结合。如图23所述,确定人源化L3D10抗体结合可溶性CTLA-4的能力。X轴指示包被到ELISA板上的抗CTLA-4 mAb的浓度。相对于亲本L3D10嵌合抗体,人源化进一步降低与可溶性CTLA-4的结合。当使用CTLA-4-Ig代替CTLA-4-his时,观察到相似的模式。
图15.人类、猕猴和小鼠CTLA-4细胞外结构域的比对。人类(Hm;SEQ ID NO:2的氨基酸1-124),猕猴(Mk)和小鼠(Ms)CTLA-4蛋白细胞外结构域的氨基酸序列比对,并且保守氨基酸(相对于人类序列)用短划线(-)示出。为了帮助比对,小鼠序列在突出显示的位置处具有缺失和插入(相对于人类和猴序列)。已知的B7-1Ig结合位点以粗体示出并加下划线。所述序列证明人类和猴序列是高度保守的,而小鼠序列具有许多氨基酸差异。基于此序列比对,设计11种突变体(M1-M11)人类CTLA-4Fc蛋白,其并入鼠特异性氨基酸-并入到每种突变体蛋白中的氨基酸以蓝色示出。
图16A和图16B.WT(SEQ ID NO:2)和突变体CTLA-4Fc蛋白(SEQ ID NO:7-17)的氨基酸序列组成。如图所示,设计编码WTCTLA-4Fc蛋白和并入鼠Ctla-4氨基酸的11种突变体蛋白M1-M11的DNA构建体。氨基酸序列是针对成熟蛋白质,包括IgG1 Fc部分,但不包括信号肽。已知的B7-1Ig结合位点以大写字母示出并加双下划线。突变体中被替换的鼠氨基酸残基以小写体示出。蛋白质的IgG1 Fc部分加下划线。
图17A至图17D.M11中的突变(AA103-106,YLGI>fcGm)选择性地消除与人类CTLA-4结合的抗体。显示的数据是一式两份的平均值,描绘B7-1Fc(图17A)、L3D10(图17B)、mAb4(图17C)和mAb5(图17D)结合到板包被的hCTLA-4-Fc(空心圆圈)、mCTLA-4-Fc(实心三角形)、M11(实心圆圈)和IgG1-Fc(空心三角形)的结合。
图18.L3D10、mAb4和mAb5的表位绘制成与B7-1-CTLA-4复合物的3-D结构中的B7-1结合位点相邻。B7-1结合基序和抗体表位以不同方式着色。CTLA-4上方的B7-1描绘为空间填充的条带,而CTLA-4描绘为未填充的条带。
图19.突变体CTLA-4Fc蛋白M12-M17(SEQ ID NO:18-23)的氨基酸序列组成。如图所示,设计编码并入鼠Ctla-4氨基酸的6种突变体CTLA-4Fc蛋白M12-M17的DNA构建体。氨基酸序列是针对成熟蛋白质,包括IgG1 Fc部分,但不包括信号肽。已知的B7-1Ig结合位点以大写字母示出并加双下划线。突变体中被替换的鼠氨基酸残基以小写体示出。蛋白质的IgG1 Fc部分加下划线。
图20A和图20B.鉴定保留与生物素化B7-1Fc结合的CTLA-4Fc突变体蛋白。将CTLA4-Fc融合蛋白M1-M17包被到96孔板上。将在给定浓度下的生物素化B7-1Fc与板一起温育,并且用链霉抗生物素蛋白缀合的HRP检测。显示的数据是一式两份实验的平均值。
图21A和图21B.鉴定保留与生物素化B7-1和B7-2蛋白结合的CTLA-4Fc突变体蛋白。将突变体CTLA4-Fc融合蛋白(1μg/ml)包被到96孔板上。将在给定浓度下的生物素化B7-1Fc(图21A)和B7-2Fc(图21B)与板一起温育,并且用链霉抗生物素蛋白缀合的HRP检测。显示的数据是一式两份实验的平均值。
图22A和图22B.鉴定丧失与生物素化伊匹单抗(图22A)和替西木单抗(图22B)的结合的CTLA-4Fc突变体蛋白。将突变体CTLA4-Fc融合蛋白(1μg/ml)包被到96孔板上。将在给定浓度下的生物素化抗体mAb2与板一起温育,并且用链霉抗生物素蛋白缀合的HRP检测。显示的数据是一式两份实验的平均值。
图23A和图23B.鉴定丧失与生物素化mAb4的结合的CTLA-4Fc突变体蛋白。将CTLA4-Fc融合蛋白M1-M17包被到96孔板上。将在给定浓度下的生物素化抗体mAb4与板一起温育,并且用链霉抗生物素蛋白缀合的HRP检测。显示的数据是一式两份实验的平均值。
图24A和图24B.鉴定丧失与生物素化mAb5的结合的CTLA-4Fc突变体蛋白。将CTLA4-Fc融合蛋白M1-M17包被到96孔板上。将在给定浓度下的生物素化抗体mAb5与板一起温育,并且用链霉抗生物素蛋白缀合的HRP检测。显示的数据是一式两份实验的平均值。
图25A和图25B.鉴定丧失与生物素化mAb4(图25A)和mAb5(图25B)的结合的CTLA-4Fc突变体蛋白。将突变体CTLA4-Fc融合蛋白(1μg/ml)包被到96孔板上。将在给定浓度下的生物素化抗体mAb4(图25A)或mAb5(图25B)与板一起温育,并且用链霉抗生物素蛋白缀合的HRP检测。显示的数据是一式两份实验的平均值。
图26A至图26F.伊匹单抗的治疗作用不通过阻断B7-1和/或B7-2来实现。图26A.确认抗B7 mAb的阻断活性。将表达小鼠B7-1或B7-2的CHO细胞与20mg/ml抗B7-1(上图)或抗B7-2(下图)和生物素化人类CTLA-4Fc(2mg/ml)的混合物一起温育1小时。在洗去未结合的蛋白质之后,通过PE缀合的链霉抗生物素蛋白检测细胞表面CTLA-4Fc,并通过流式细胞术测量。显示的数据是代表性FACS图,并且重复两次。图26B.实验设计图:携带MC38肿瘤的Ctla-4h/m小鼠接受抗B7-1和抗B7-2抗体(300μg/小鼠/注射,每3天一次,总计3次注射)与对照Ig或伊匹单抗的组合。接受伊匹单抗而不接受抗B7-1和抗B7-2的小鼠用作肿瘤排斥的阳性对照,并将hIg用作阴性对照。图26C和图26D.通过如图26B所示的抗体处理使B7-1和B7-2饱和。将来自如图26B所示处理的小鼠的PBL在抗B7处理后24小时处用荧光染料缀合的抗B7-1 mAb和抗B7-2 mAb染色。将来自Cd80-/-Cd86-/-小鼠的PBL用作阴性对照。图26E.基于抗体反应的消除,通过抗B7-1 mAb和抗B7-2 mAb进行的对B7的功能性阻断。在肿瘤攻击后第22天收集血清以评估抗人类IgG抗体反应。图26F.抗B7-1mAb和抗B7-2 mAb对B7-1和B7-2的饱和阻断不影响伊匹单抗的免疫治疗作用。显示的数据是随时间的肿瘤体积,并且重复两次,具有相似的结果。
图27.CTLA-4-Fc融合蛋白M11和M15针对由与抗PD-1和抗CTLA-4(伊匹单抗)的组合疗法导致的irAE保护小鼠。
图28A和图28B.CTLA4-Fc突变体M15和M17不干扰伊匹单抗的免疫治疗作用。将Ctla-4h/m杂合小鼠移植有MC38肿瘤,并且在箭头指示的时间点处用伊匹单抗与对照IgG Fc或CTLA-4突变体蛋白组合处理。图28A.肿瘤大小减小。图28B.携带肿瘤的小鼠的存活率,使用直径达到2cm的肿瘤大小作为早期移除标准。
图29A和图29B.在用人类CD34+造血干细胞重建的NSG小鼠中M15和M17-2针对伊匹单抗诱导的体重减轻的保护性作用(图29A)和M15的潜在肝毒性(图29B)。基于体重人类白细胞重建和血液中人类T细胞的%,将16只雌性人源化小鼠随机分成4组。在第0、3和6天,分别用对照人类IgG Fc(400μg/注射)、伊匹单抗(100μg/注射)+人类IgG Fc(300μg/注射)、伊匹单抗(100μg/注射)+M15(300μg/注射)或伊匹单抗(100μg/注射)+M17-2(300μg/注射)处理4组。在第18天,小鼠接受另外一次注射,其中伊匹单抗的剂量为200μg/小鼠+人类IgG Fc(300μg/注射)、伊匹单抗(100μg/注射)+M15(300μg/注射)或伊匹单抗(100μg/注射)+M17-2(300μg/注射)。使用第0天作为100%,监测小鼠30天的体重变化。图29B.在接受伊匹单抗以及M15但不接受M17-2的小鼠中观察到ALT升高。
图30A至图30F.基于第31天的脾T细胞分析,M15和M17-2在伊匹单抗诱导的T细胞活化中的差异作用。如图29所述处理小鼠,并在第31天处死用于流式细胞术。CD4和CD8 T细胞(图30A和图30D)、中枢记忆(CD44hiCD62Lhi)(图30B和图30E)和效应记忆细胞(CD44hiCD62Llo)(图30C和图30F)细胞的CD4(图30A至图30C)和CD8(图30D至图30F)频率。
图31.M15和M17对NKT细胞扩增的差异作用。如图30中详述,不同的是分析NK T细胞(CD3+CD56+)。如图29所述处理小鼠,并在第31天处死用于流式细胞术。
图32A至图32D.M15和M17-2对Treg频率(图32A和图32B)及其CTLA-4蛋白表达(图32C和图32D)的差异作用。如图29所述处理小鼠,并在第31天处死用于流式细胞术。
具体实施方式
本发明人已发现含有突变的可溶性CTLA-4融合蛋白,所述突变阻止他们与大多数抗CTLA-4 mAb结合,同时保留他们结合抗原呈递细胞(APC)上的B7-1和B7-2的能力。令人惊讶的是,这些融合蛋白在不影响抗CTLA-4的癌症治疗作用的情况下预防抗CTLA-4 mAb的自身免疫不良反应。
1.定义
本文使用的术语只用于描述特定实施方案的目的,而不意图是限制性的。如说明书和所附权利要求书中所使用,除非上下文另外明确规定之外,否则单数形式“一(a)”、“一(an)”和“所述(the)”包括复数指示物。
对于本文所列举的数值范围,明确涵盖了其间具有相同精度的每个中间数。例如,对于6-9的范围,除了6和9外还涵盖数字7和8,并且对于6.0-7.0的范围,明确涵盖了数字6.0、6.1、6.2、6.3、6.4、6.5、6.6、6.7、6.8、6,9以及7.0。
如本文所用,术语“蛋白质”、“肽”或“多肽”是指任何长度的氨基酸链,无论修饰如何(例如,磷酸化或糖基化)。氨基酸可以是天然的、合成的、或天然和合成的修饰或组合。本发明的多肽可以是重组多肽、天然多肽或合成多肽,优选地重组多肽。
如本文所用,当与多肽相关使用时,术语“部分”、“区段”和“片段”是指连续的残基序列,诸如氨基酸残基,其序列形成较大序列的子集。例如,如果将多肽经受用任何常见的内肽酶诸如胰蛋白酶或胰凝乳蛋白酶进行的处理,则由这种处理产生的寡肽将代表起始多肽的部分、区段或片段。因此,多肽的“片段”是指多肽的任何子集,其是全长蛋白质的较短多肽。通常,片段长度为五个或更多个氨基酸。
如本文所用,术语蛋白质的“可溶性部分”意指全长多肽的不包括跨膜部分或区段的任何部分的部分。例如,对于CTLA-4,可溶性部分将包括细胞外部分(具有或不具有N末端信号序列),但不包括跨膜部分的任何部分(或者,至少不足以降低溶解度)。因此,人类CTLA-4的ECD显示为SEQ ID NO:3(即,全长序列SEQ ID NO:1的氨基酸36-161),其中氨基酸1-35包含信号序列,并且不包括在成熟的细胞外并且因此可溶性的蛋白质中。
如本文所用,术语“融合蛋白”定义为使用本领域已知的方法连接在一起的一个或多个氨基酸序列。因此,连接的氨基酸序列形成一种融合蛋白。本领域已知的融合蛋白包括六组氨酸肽、血凝素“HA”标签(其对应于源自流感血凝素蛋白的表位(Wilson,I.A.等人(1984)“The Structure Of An Antigenic Determinant In A Protein,”Cell,37:767-778))和“flag”标签(Knappik,A.等人(1994)“An Improved Affinity Tag Based On TheFLAG Peptide For The Detection And Purification Of Recombinant AntibodyFragments,”Biotechniques 17(4):754-761)。
本发明的多肽(或其片段)的衍生物、类似物或同源物可以是(i)其中一个或多个氨基酸残基被保守性或非保守性氨基酸残基(优选地保守性氨基酸残基)取代并且此类取代的氨基酸残基可以是或可以不是由遗传密码编码的氨基酸残基;或者(ii)其中一个或多种氨基酸残基包括取代基团;或者(iii)其中成熟多肽与另一种化合物,诸如增加多肽半衰期的化合物(例如,聚乙二醇)融合;或者(iv)其中另外的氨基酸与成熟多肽,诸如前导序列或分泌序列或用于纯化成熟多肽或前蛋白序列的序列融合。根据本文的教义,此类衍生物和类似物被认为在本领域技术人员的范围内。
如本文所用,术语“抗体”旨在表示具有“可变区”抗原识别位点的免疫球蛋白分子。术语“可变区”旨在将免疫球蛋白的这种结构域与抗体广泛共享的结构域(诸如,抗体Fc结构域)区分开。可变区包含“高变区”,其残基负责抗原结合。高变区包含来自“互补决定区”或“CDR”的氨基酸残基(即,通常为轻链可变结构域中的大约残基24-34(L1)、50-56(L2)和89-97(L3)以及重链可变结构域中的大约残基27-35(H1)、50-65(H2)和95-102(H3);参考44)和/或来自“高变环”的那些残基(即,轻链可变结构域中的残基26-32(L1)、50-52(L2)和91-96(L3)以及重链可变结构域中的26-32(H1)、53-55(H2)和96-101(H3);参考45)。“框架区”或“FR”残基是除如本文定义的高变区残基外的那些可变结构域残基。术语抗体包括单克隆抗体、多特异性抗体、人类抗体、人源化抗体、合成抗体、嵌合抗体、骆驼抗体、单链抗体、二硫键连接的Fv(sdFv)、胞内抗体和抗独特型(抗Id)抗体(包括例如针对本发明抗体的抗Id和抗-抗Id抗体)。特别地,此类抗体包括任何类型的(例如,IgG、IgE、IgM、IgD、IgA和IgY)、类别(例如,IgG1、IgG2、IgG3、IgG4、IgA1和IgA2)或亚类的免疫球蛋白分子。
如本文所用,术语“活性片段”是指天然多肽或抗体或与天然多肽或抗体具有高序列同源性(例如,至少80%、85%、90%、95%、98%或99%氨基酸序列同一性)并且保留生物活性的多肽的一部分。“生物活性”的代表性实例包括结合B7蛋白和结合其天然受体或被特异性抗体结合的能力。例如,CTLA-4的活性片段能够结合B7.1或B7.2或结合到CTLA-4的配体。在优选的实施方案中,这种片段由CTLA-4蛋白的细胞外结构域(ECD)组成。
如本文所用,术语“分离的”意指描述感兴趣的化合物(例如,多核苷酸或多肽),其处于与化合物天然存在的环境不同的环境中,例如,诸如通过将肽浓缩到在自然界中未发现的浓度而从其天然环境中分离。“分离的”意指包括处于基本上富含感兴趣的化合物和/或其中感兴趣的化合物得以部分或基本上纯化的样品内的化合物。
“基本上相同的”可意指第一和第二氨基酸序列在1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49、50、55、60、65、70、75、80、85、90、95、100、110、120、130、140、150、160、170、180、190、200、210、220、230、240、250、260、270、280、290或300个氨基酸的区域内为至少60%、65%、70%、75%、80%、85%、90%、95%、96%、97%、98%或99%。
当提及保护动物免于疾病时,“治疗(Treatment)”或“治疗(treating)”意指预防、遏制、阻遏或完全消除疾病。预防疾病涉及在疾病发作之前向动物施用本发明的组合物。遏制疾病涉及在疾病诱发之后但在其临床表现之前向动物施用本发明的组合物。阻遏疾病涉及在疾病临床表现之后向动物施用本发明的组合物。
如本文所用,与对应野生型多肽的氨基酸序列相比,“变体”多肽含有至少一个氨基酸序列改变。如本文所用,“氨基酸序列改变”可以是例如一种或多种氨基酸的取代(可为保守取代)、缺失或插入。变体也可意指氨基酸序列基本上与具有氨基酸序列的参照蛋白相同并可保留至少一种生物活性的蛋白质。变体可以是多肽的衍生物、类似物或同源物。变体也可以是多肽的可溶性部分。氨基酸的保守性取代在本领域中被认为通常涉及微小变化,即以相似特性(例如,亲水性、带电区域的程度和分布)的不同氨基酸来替换氨基酸。这些微小变化可部分地通过考虑氨基酸的亲水指数来鉴定,如本领域中所理解的。Kyte等人,J.Mol.Biol.157:105-132(1982)。氨基酸的亲水指数是基于其疏水性和电荷的考虑。本领域已知的是相似的亲水指数的氨基酸可被取代并仍然保留蛋白质功能。一方面,亲水指数为±2的氨基酸被取代。氨基酸的亲水性还可被用来揭示会产生保留生物功能的蛋白质的取代。在肽的情形下考虑氨基酸的亲水性允许计算所述肽最大的局部平均亲水性,这是已经被报道来与抗原性和免疫原性良好关联的有用测量。美国专利号4,554,101以引用方式全部并入本文。如本领域中所理解,用亲水性值相似的氨基酸进行取代可产生保留生物活性(例如免疫原性)的肽。可利用具有在±2内的亲水性值的氨基酸彼此进行取代。氨基酸的疏水性指数和亲水性值两者均受所述氨基酸的特定侧链影响。与所述观察一致的是,与生物功能相容的氨基酸取代被理解为取决于这些氨基酸相对的相似性,并且特别是那些氨基酸的侧链,如通过疏水性、亲水性、电荷、大小以及其他特性所揭示的。
2.B7-CTLA-4相互作用和免疫疗法
T细胞最佳地介导针对抗原的免疫反应的能力需要两种不同的信号传导相互作用。首先,已排列在抗原呈递细胞(APC)表面上的抗原必须以MHC:肽复合物形式呈递给抗原特异性天然T细胞(1,2)。这种呈递通过T细胞受体(TCR)传递信号,所述T细胞受体指导T细胞启动对所呈递抗原特异的免疫反应。其次,通过APC与不同T细胞表面分子之间的相互作用介导的一系列共刺激信号首先触发T细胞的活化和增殖并最终将他们抑制(3-5)。因此,第一信号赋予免疫反应特异性,而第二信号用于确定反应的性质、量值和持续时间,同时限制对自身的免疫。这些第二信号分子中特别重要的是APC的B7.1(CD80)(6)和B7.2(CD86)(7-9)配体与T淋巴细胞的CD28和CTLA-4受体(10-12)之间的结合。
CD28(分化簇28)和细胞毒性T淋巴细胞相关抗原-4(CTLA-4)是蛋白质免疫球蛋白超家族的成员,并且参与T细胞活化的调节。CD28在原初T细胞上组成型表达,并且结合B7.1和B7.2,从而提供T细胞活化和存活所需的共刺激信号。相比之下,在T细胞活化后,CTLA-4在T细胞上上调并与CD28竞争结合到B7.1和B7.2,从而传递用于T细胞活化的抑制信号。
B7家族分子具有膜近端IgC(恒定)结构域和膜远端IgV(可变)结构域。这些配体的CD28样受体家族共享一个共同的细胞外IgV样结构域。受体-配体对的相互作用主要通过配体和受体的IgV结构域中的残基介导(Schwartz等人,Nature Immunol.,3:427-434(2002))。晶体学分析揭示,CTLA-4/B7结合界面由CDR3-来自CTLA-4的类似环的相互作用支配,其由MYPPPY基序构成(Schwartz等人,Nature,410:604-608(2001);以及Stamper等人,Nature,410:608-611(2001))。
已显示,针对CTLA-4的抗体在体外阻断CTLA-4与共刺激分子B7.1和B7.2之间的相互作用。这种阻断消除T细胞上CTLA-4介导的抑制信号,并且从而刺激可用作抗癌疗法的天然免疫反应。用抗CTLA-4抗体治疗已被证明是增强临床前模型中抗肿瘤免疫力的有力工具(10)。用针对CTLA-4的抗体进行的单一疗法促进对各种来源的可移植肿瘤的排斥。基于有希望的临床前肿瘤模型研究,已在不同的人类恶性肿瘤中探索针对CTLA-4的抗体的临床潜力。尽管抗CTLA-4(伊匹单抗,作为Yervoy销售,在美国专利号6,984,720中公开)已证明在治疗黑素瘤中有效,但是CTLA-4的治疗和靶向与自身免疫样毒性有关。抑制CTLA-4的特征性副作用通常称为免疫相关不良事件(irAE),并且最常见的irAE是皮疹、肝炎、结肠炎和内分泌病,特别是垂体机能减退。因此,希望通过减少相关的irAE来改善抗CTLA-4抗体的安全性。
本发明人意外地发现,临床证明的治疗性抗人类CTLA-4 mAb和两种抗小鼠Ctla-4mAb在生理学相关条件下诱导肿瘤排斥而不阻断B7-CTLA-4相互作用。因此,阻断CTLA-4与B7.1或B7.2的相互作用对于肿瘤排斥不是必需的,即使对于可有效阻断这些B7-CTLA-4相互作用的mAb也是如此。这些数据驳斥了抗CTLA-4 mAb通过检查点阻断赋予免疫治疗作用的假设(108)。此外,本发明人已鉴定出具有降低的免疫相关毒性的抗CTLA-4抗体L3D10,从而证明癌症免疫性和irAE可以是遗传上非偶联的。
3.可溶性CTLA-4
积累的数据表明,人类CTLA-4基因通过可变剪接编码两种不同的蛋白质同种型:一种具有跨膜结构域,因此所述蛋白质可能锚定在膜中,并且另一种缺乏跨膜结构域并且预测为分泌型(sCTLA-4,SEQ ID NO:4)(128)。重要的是,遗传学研究表明,降低可溶性同种型相对丰度的CTLA-4的多态性与多种自身免疫疾病密切相关(64)。具有自身免疫倾向等位基因的受试者表达较少sCTLA-4 mRNA的事实表明sCTLA-4可能是保护性的。这一观点得到了以下支持:阿巴西普的广泛治疗作用(129,130),所述阿巴西普呈可溶性CTLA-4的形式,以及一项遗传研究,其中sCTLA-4同种型的选择性消融加速小鼠中I型糖尿病的发展(131)。
基于这些遗传数据,发明人已认识到显示与sCTLA-4具有最差结合的抗体应与最少的irAE相关联。实际上,本发明人鉴定具有降低的免疫相关毒性的抗CTLA-4抗体L3D10,其显示相对于膜结合或固定的CTLA-4与sCTLA-4具有降低的结合。基于抗体对围产期期间用抗CTLA-4抗体治疗的小鼠的体重增加的影响,发现四种抗CTLA-4 mAb之间存在强烈的相关性:伊匹单抗对sCTLA-4具有最强的结合,并且是毒性最强的抗-CTLA-4,而L3D10对sCTLA-4具有最弱的结合,并且毒性最小。此外,L3D10抗体的人源化优先降低与sCTLA-4的结合,并且与亲本抗体相比似乎进一步改善安全性特征。
为了绘制L3D10亲本抗体和人源化变体的CTLA-4结合表位,发明人利用小鼠和人类CTLA-4蛋白质在物种之间与B7-1,但不与抗CTLA-4抗体交叉反应的事实。因此,本发明人设计许多人类CTLA-4Fc蛋白的突变体,其中来自人类CTLA-4蛋白的氨基酸簇被来自鼠Ctla-4蛋白的氨基酸(SEQ ID NO:5)替换。由于本研究中使用的抗CTLA-4抗体不与鼠Ctla-4结合,因此当抗体结合表位的关键残基被鼠氨基酸替换时,应消除抗人类CTLA-4抗体的结合。因此,本发明人已显示CTLA-4的L3D10结合位点绘制成与B7-1结合基序MYPPPY(SEQ IDNO:50)直接相邻。这与所证明的抗体在体外和在体内均阻断B7-CTLA-4相互作用的能力良好地相关。相比之下,伊匹单抗在生理条件下不阻断B7.1或B7.2与阿巴西普的结合,并且因此其还必须结合不包含MYPPPY基序的区域。然而,由于其未显示降低与sCTLA-4的结合,因此结合结构域必须不同于抗体L3D10。
内源性sCTLA-4通过细胞外IgV结构域的截短的C末端直接融合到细胞内结构域而产生,并没有居间的跨膜结构域。因此,在sCTLA-4中,MYPPPY基序的CTLA-4细胞外结构域C末端仅有12个氨基酸,而内源膜结合形式具有21个氨基酸。基于此,不受理论束缚,似乎结合多态性C末端结构域残基的抗体,诸如L3D10,更可能丧失对sCTLA-4的反应性。此外,本发明人已证明可能在此区域中对CTLA-4Fc蛋白中的这些氨基酸进行突变,使得它们不再结合抗CTLA-4抗体。
4.重组CTLA-4蛋白
CTLA-4Fc融合蛋白(阿巴西普,作为Orencia销售)是选择性共刺激调节剂,其包含与人类IgG1的Fc区融合的CTLA-4的细胞外结构域(在图1B中示出;SEQ ID NO:2),所述细胞外结构域通过与B7.1和B7.2结合而抑制T细胞(T淋巴细胞)活化,从而阻断与CD28的相互作用。在体外,阿巴西普减少T细胞增殖并抑制细胞因子TNFα(TNFα)、干扰素-γ和白细胞介素-2的产生。活化的T淋巴细胞与类风湿性关节炎(RA)的发病机制有关,并且存在于RA患者的滑膜中。在大鼠胶原诱导的关节炎模型中,阿巴西普抑制炎症,减少抗胶原抗体产生,并减少干扰素-γ的抗原特异性产生。基于此临床前活性,阿巴西普已被开发并批准用于治疗人类的RA和幼年型特发性关节炎(JIA)。
虽然能够减少免疫反应,但包含内源性CTLA-4细胞外结构域的CTLA-4Fc融合蛋白诸如阿巴西普不能减少或减轻与抗CTLA-4免疫疗法相关的免疫相关毒性,因为所述两种分子的活性正在抵消。CTLA-4融合蛋白诸如阿巴西普不仅将通过直接结合到抗体来阻止他们与内源性细胞相关的CTLA-4分子结合而降低抗CTLA-4 mAb的治疗作用,还将使自身变得无效,因为他们在与循环抗CTLA-4 mAb形成免疫复合物后将从循环中清除。
鉴于阻断和不阻断抗CTLA-4抗体两者均具有抗肿瘤作用,并且证明减少irAE的抗体与降低与sCTLA-4的结合相关,本发明人设计一组可溶性CTLA-4蛋白,其具有防止被进行测试的大多数抗CTLA-4 mAb结合的突变,同时保留其结合抗原呈递细胞上的B7-1和B7-2的能力,这对于自身免疫疾病和irAE的发病机制至关重要。由于其保留的B7结合活性,此类蛋白质可用于治疗自身免疫疾病,诸如RA和JIA。此外,此类蛋白质可与抗CTLA-4免疫疗法治疗组合使用以减少相关的irAE,同时保持免疫疗法的抗肿瘤活性完整。
a.CTLA-4蛋白
本文提供一种CTLA-4蛋白,其包含(a)成熟人类CTLA-4的细胞外结构域(SEQ IDNO:3)或小鼠CTLA-4的细胞外结构域(SEQ ID NO:6),(b)在SEQ ID NO:24-40和46-49中的一个中列出的氨基酸,(c)前述的变体,或(d)前述的活性片段。CTLA-4蛋白可以是可溶的。CTLA-4蛋白还可包含N末端信号肽。CTLA-4蛋白可保留结合人类B7.1和B7.2的能力,但缺乏结合抗CTLA-4抗体的能力。在一个具体实施方案中,CTLA-4蛋白在生理条件下不与伊匹单抗或替西木单抗结合。特别地,CTLA-4蛋白可包含SEQ ID NO:34、36、38、39、40、46、47或48中列出的氨基酸序列。CTLA-4蛋白可以是分离的。
b.CTLA-4融合蛋白
CTLA-4蛋白可在其N-末端或C-末端与另一种蛋白质融合。所述另一种蛋白质可以是哺乳动物Ig蛋白质的一部分,其可以是人或小鼠。所述部分可包含Ig蛋白的Fc区。Fc区可包含Ig蛋白的铰链区以及CH2和CH3结构域。Ig蛋白可以是人类IgG1、IgG2、IgG3、IgG4或IgA。Ig蛋白也可以是IgM,并且Fc部分可包含IgM的铰链区以及CH3和CH4结构域。在一个实施方案中,Fc区是人类IgG1,其包含SEQ ID NO:41中列出的氨基酸序列。CTLA-4蛋白可包含选自由SEQ ID NO:7-23和42-45组成的组的氨基酸序列,特别是选自由SEQ ID NO:17、19、21、22、23、42、43和44组成的组的氨基酸序列。
CTLA-4蛋白还可在其N-末端或C-末端与蛋白质标签融合,所述蛋白质标签可包括GST、His或FLAG。用于制备融合蛋白并纯化融合蛋白的方法是本领域熟知的。
5.抗B7抗体
本发明的另一个实施方案涉及一种结合人类B7-1和B7-2中的至少一种的抗B7抗体组合物。抗B7抗体可与内源性B7-1和B7-2中的一种或两种结合,并且可中和活性而不影响抗CTLA-4抗体的癌症免疫治疗活性。可将抗B7抗体人源化以使抗药物抗体最小化。抗B7抗体可以是单克隆抗体,并且可与B7-1和B7-2两者交叉反应。在又另一个实施方案中,双特异性抗体可包含两种抗体的抗原结合结构域,其分别结合到B7-1或B7-2
6.产生
可使用真核表达系统制备CTLA-4蛋白或抗B7抗体。表达系统可能需要在哺乳动物细胞(诸如,中国仓鼠卵巢(CHO)细胞)中从载体表达。所述系统也可以是病毒载体,诸如可用于感染真核细胞的复制缺陷型逆转录病毒载体。CTLA-4蛋白还可由稳定的细胞系产生,所述细胞系从已整合到细胞基因组中的载体或载体的一部分表达CTLA-4蛋白。稳定细胞系可从整合的复制缺陷型逆转录病毒载体表达CTLA-4蛋白。表达系统可以是GPExTM。
CTLA-4蛋白质或抗B7抗体可使用例如色谱方法纯化,诸如亲和色谱法、离子交换色谱法、疏水相互作用色谱法、DEAE离子交换法、凝胶过滤法和羟基磷灰石色谱法。在一些实施方案中,可将融合蛋白工程化以含有另外的含有氨基酸序列的结构域,所述氨基酸序列允许多肽被捕获到亲和基质上。例如,可使用蛋白A柱从细胞培养物上清液或细胞质提取物中分离包含免疫球蛋白结构域的Fc区的CTLA-4蛋白或抗B7抗体。另外,诸如c-myc、血凝素、多组氨酸或FlagTM(Kodak)的标签可用于辅助多肽纯化。此类标签可以插入在多肽内的任何位置,包括在羧基或氨基末端处。可使用的其他融合物包括有助于检测多肽的酶,诸如碱性磷酸酶。免疫亲和色谱也可用于纯化多肽。另外可将融合蛋白工程化以含有分泌信号(如果没有已存在的分泌信号),所述分泌信号致使融合蛋白由产生其的细胞分泌。然后可方便地从细胞培养基中分离分泌的融合蛋白。
7.药物组合物
本发明还涉及一种药物组合物,其包含治疗有效量的一种或多种以上所述的CTLA-4蛋白和抗B7抗体,以及生理学上可接受的载体或赋形剂。优选地,本发明的组合物包含预防或治疗有效量的CTLA-4蛋白或抗B7抗体以及药学上可接受的载体
在一个具体实施方案中,术语“药学上可接受的”意指由联邦监管机构或州政府批准的或者在美国药典或其他通常认可的药典上列出,以用于动物并且更具体地为用于人类。术语“载体”是指与治疗剂一起施用的稀释剂、佐剂(例如,弗氏佐剂(完全和不完全)、赋形剂或媒介物。此类药物载体可以是无菌液体,诸如水和油,包括石油、动物、植物和合成来源的那些油,诸如花生油、大豆油、矿物油、芝麻油等。当静脉内施用药物组合物时,水是优选的载体。盐水溶液和右旋糖水溶液以及甘油溶液也可用作液体载体,特别是用于可注射溶液。适合的药物赋形剂包括淀粉、葡萄糖、乳糖、蔗糖、明胶、麦芽、大米、面粉、白垩、硅胶、硬脂酸钠、单硬脂酸甘油酯、滑石、氯化钠、脱脂乳粉、甘油、丙烯、乙二醇、水、乙醇等。如果需要,组合物还可包含少量润湿剂或乳化剂或pH缓冲剂。这些组合物可采用溶液、悬浮液、乳液、片剂、丸剂、胶囊、粉末、缓释制剂等的形式。
一般来说,本发明组合物的成分可以是单独或混合在一起以单位剂型(例如以干燥冻干粉末或无水浓缩物形式)提供于指示活性剂的量的密闭容器(诸如安瓿或药囊)中。当组合物待通过输注施用时,所述组合物可用含有无菌药用级水或盐水的输注瓶来分配。当组合物是通过注射施用时,可提供注射用无菌水或盐水的安瓿以使得成分可在施用之前混合。
本发明的组合物可配制成中性或盐形式。药学上可接受的盐包括但不限于,与阴离子形成的盐,诸如衍生自盐酸、磷酸、乙酸、草酸、酒石酸等的盐;和与阳离子形成的盐,诸如衍生自钠、钾、铵、钙、氢氧化铁、异丙胺、三乙胺、2-乙氨基乙醇、组氨酸、普鲁卡因等的盐。
8.治疗方法
a.自身免疫疾病
CTLA-4蛋白或抗B7抗体或其药物组合物可用于治疗炎性或自身免疫疾病。可使用B7-H4融合多肽治疗的代表性炎性或自身免疫疾病和病症包括但不限于类风湿性关节炎(RA)、系统性红斑狼疮(SLE)、斑秃、痉挛性脊椎炎、抗磷脂综合征、自身免疫性阿狄森氏病、自身免疫性溶血性贫血、自身免疫性肝炎、自身免疫性内耳病、自身免疫性淋巴增生综合征(alps)、自身免疫性血小板减少性紫癜(ATP)、白塞病、大疱性类天疱疮、心肌病、腹腔口炎性皮炎、慢性疲劳综合征免疫缺陷综合征(CFIDS)、慢性炎症性脱髓鞘性多发性神经病、瘢痕性类天疱疮、冷凝集素病、冠状综合征、克罗恩病、德戈病、皮肌炎、幼年型皮肌炎、盘状狼疮、基本混合性冷球蛋白血症、纤维肌痛-纤维肌炎、格雷夫斯病、格林-巴利综合征、桥本氏甲状腺炎、特发性肺纤维化、特发性血小板减少性紫癜(ITP)、Iga肾病、胰岛素依赖型糖尿病(I型)、幼年关节炎、梅尼埃病、混合性结缔组织病、多发性硬化症(MS)、重症肌无力、寻常型天疱疮、恶性贫血、结节性多动脉炎、多软骨炎、多腺体综合征、风湿性多肌痛、多发性肌炎和皮肌炎、原发性无丙种球蛋白血症、原发性胆汁性肝硬化、牛皮癣、雷诺现象、瑞特氏综合征、风湿热、结节病、硬皮病、干燥综合征、全身肌强直综合征、大动脉炎、颞动脉炎/巨细胞动脉炎、溃疡性结肠炎、葡萄膜炎、血管炎、白癜风和韦格纳肉芽肿。在一个具体实施方案中,自身免疫疾病可以是类风湿性关节炎(RA)或幼年型特发性关节炎(JIA)。可将CTLA-4蛋白或抗B7抗体或其药物组合物施用给有需要的受试者。所述受试者可以是哺乳动物,诸如人类。
CTLA-4蛋白或抗B7抗体或其药物组合物可与另一种药物(诸如缓解疾病的抗风湿药(DMARD))组合。所述药物可以是非甾体抗炎药(NSAID),其可以是丙酸衍生物、乙酸衍生物、烯醇酸衍生物、灭酸衍生物或选择性Cox2抑制剂。药物也可以是皮质类固醇或甲氨蝶呤。药物可以是生物药物,其可以是TNF-α拮抗剂,诸如抗TNF-α抗体或结合到TNF-α的融合蛋白(Enbrel)、抗CD20 mAb、共刺激分子CD80和CD86的拮抗剂,诸如与两种分子结合的单克隆抗体或融合蛋白(CTLA-4Ig),或者IL-1或IL-6受体的拮抗剂。CTLA-4蛋白或抗B7抗体或其药物组合物和其他药物可一起或依次施用。
b.免疫疗法
CTLA-4蛋白或抗B7抗体或其药物组合物还可用于减轻、减少或治疗癌症患者中的与抗CTLA-4免疫疗法相关的免疫相关不良事件(irAE)。CTLA-4蛋白可预防性地施用(在irAE出现之前)或治疗性地施用(在irAE出现之后)。特别地,CTLA-4蛋白或抗B7抗体或其药物组合物可与抗CTLA-4免疫疗法组合或在抗CTLA-4免疫疗法背景下施用给受试者。所述受试者可以是癌症患者。在一个实施方案中,CTLA-4蛋白或抗B7抗体或其药物组合物预防性地用于在开始抗CTLA-4治疗之前或在出现irAE的临床表现之前预防irAE。在另一个实施方案中,CTLA-4蛋白或抗B7抗体或其药物组合物治疗性地用于在开始抗CTLA-4治疗并诊断出临床症状后治疗irAE。
c.施用方法
CTLA-4蛋白或抗B7抗体或其药物组合物可通过包括但不限于肠胃外施用(例如,皮内、肌内、腹膜内、静脉内和皮下)、硬膜外和粘膜(例如,鼻内和口腔途径)的方法施用。在一个具体实施方案中,CTLA-4蛋白或抗B7抗体或其药物组合物通过肌内、静脉内或皮下施用。组合物可通过任何方便的途径,例如通过输注或团注、通过由上皮或粘膜层(例如口腔粘膜、直肠和肠粘膜等)吸收来施用,并可与其他生物活性剂共同施用。施用可为全身性或局部的。
实施例
实施例1
嵌合L3D10抗体在引起肿瘤排斥方面具有与10D1相等的活性
在临床上,抗CTLA-4抗体伊匹单抗(mab 10D1)已显示改善癌症患者的存活率,但诱导显著的自身免疫不良反应。使用人类CTLA-4基因敲入小鼠和hu-PBL-Scid小鼠,先前已证明小鼠抗人类CTLA-4抗体减少肿瘤生长,并确定L3D10在所测试的mAb组中最有效(21)。
人类CTLA-4基因敲入小鼠(20)的可用性提供前所未有的机会来测试嵌合L3D10抗人类CTLA-4抗体与临床上使用抗-CTLA-4 mAb10D1的生物活性,所述嵌合L3D10抗人类CTLA-4抗体包含亲本L3D10可变区和人类IgG1恒定结构域(Fc区)。在此人源化小鼠模型中,编码与人类CTLA-4蛋白具有100%同一性的产物的CTLA-4基因在内源性小鼠CTLA-4基因座的控制下表达。当在人类CTLA-4敲入小鼠的MC38肿瘤模型中直接比较嵌合L3D10和10D1的抗肿瘤活性时,显然两种抗体在引起肿瘤排斥方面是相当的,而肿瘤在IgG对照组中逐渐生长。图2示出来自一式两份实验的抗体治疗关于肿瘤大小的结果。
实施例2
其他免疫治疗抗体减少自身免疫不良反应
最近的临床研究揭示,抗PD-1与抗CTLA-4 mAb之间的组合疗法进一步增加终末期黑素瘤患者的存活率。然而,55%的接受组合疗法的患者发展3级和4级免疫相关不良事件(irAE)。因此,开发毒性较小的抗体至关重要。已开发一种体内模型,其重演与在临床中观察到的抗CTLA-4和抗PD-1 mAb的组合疗法相关的irAE。在此模型中,在围产期期间用高剂量的抗PD-1和抗CTLA-4 mAb处理人类CTLA-4基因敲入小鼠(CTLA-4h/h)。我们发现,虽然幼小鼠耐受单个mAb的治疗,但与抗PD-1和10D1的组合疗法引起严重的irAE,伴有多器官炎症、贫血以及如图3所示的严重发育不良。相比之下,当与抗PD-1组合时,嵌合L3D10仅表现出轻微的irAE,如通过正常体重增加所证明的。
为了进一步检查当与抗PD-1组合施用时的嵌合L3D10与10D1相比的相对毒性,观察了施用后42天CTLA-4h/h敲入小鼠的病理学效应。如图4所示,用L3D10+抗PD-1处理的小鼠的最终体重(第42天)与用hIgG阴性对照抗体处理的小鼠相似。然而,相比之下,用10D1+抗PD-1处理的小鼠的体重要低得多。因此,当观察这些小鼠的大体解剖结构时,在用10D1+PD-1处理的小鼠中,子宫/卵巢/膀胱和胸腺明显较小(图5)。再次,用L3D10+抗PD-1处理的小鼠的器官与hIgG对照相当。相比之下,从用10D1处理的小鼠解剖的心脏的大小看起来稍微更大,具有明显更白的外观。因此,决定观察小鼠体内的红细胞生成,并且相对于用L3D10+抗PD-1或对照抗体处理的组,在用10D1+抗PD-1处理的小鼠中观察到明显的差异,所述差异是非常相似的。如图6A所示,来自用10D1+抗PD-1处理的小鼠的骨髓具有明显更白的颜色,并且分离的血液几乎完全是白色的(图6B)。据此,当我们使用CD71和CD119标记物更仔细观察经历不同血液发育阶段的细胞时。代表性的FACS图在图6C中示出,而概要数据在图6D中示出。这些数据揭示在10D1+抗PD-1处理的小鼠中经历IV期发育的细胞数量的统计上显著减少(图6D)。
为了进一步确定L3D10相对于10D1与抗PD-1组合的毒理学,在10%福尔马林中固定至少24小时后对心脏、肺、唾液腺以及肾和肝进行组织学分析。在所研究的每种组织中,用10D1+抗PD-1处理的小鼠显示出高水平的T细胞浸润。基于炎症严重程度的毒性评分总结在图7中,其示出用10D1+抗PD-1处理的小鼠相对于用L3D10+抗PD-1处理的小鼠的高毒性评分,用L3D10+抗PD-1处理的小鼠具有仅略高于hIgG对照小鼠组的评分。
实施例3
L3D10减少对可溶性CTLA-4的结合。
L3D10和10D1显示出对板固定的CTLA-4的相似结合模式(图8)。作为L3D10相对于10D1的毒性降低,特别是与10D1相关的增加的T细胞浸润/活性的可能解释,决定研究与可溶性CTLA-4的结合。选择进行研究是因为CTLA-4多态性与多种自身免疫性疾病之间的关联与可溶性CTLA-4的缺陷产生有关(67),并且sCTLA-4同种型的遗传沉默增加小鼠I型糖尿病的发病率(131)。此外,可溶性CTLA-4(阿巴西普和贝拉西普)是广泛用于免疫抑制的药物。根据这个想法,当观察与可溶性CTLA-4的相对结合时,观察到L3D10相对于10D1的结合的明显降低(图9)。
已证明抗CTLA-4 mAb在杂合Ctla-4h/m小鼠中诱导稳健的肿瘤注射,其中仅50%的CTLA-4分子可结合到抗人类CTLA-4 mAb。为了确定50%的CTLA-4的参与是否足以诱导irAE,用抗PD-1+10D1处理Ctla-4h/m小鼠。如图10所示,抗PD-1+10D1未能在Ctla-4h/m小鼠中诱导体重减轻。因此,irAE和癌症免疫性可以是遗传上非偶联的。
体内活性证明L3D10抗体保留其抗肿瘤活性,但显示出在其他免疫治疗性抗体诸如10D1的情况下观察到的降低的自身免疫不良反应,从而指示可能增强抗肿瘤活性而不加剧自身免疫不良事件。因此,自身免疫副作用不是癌症免疫的必要代价,并且可能解耦这两种活动。L3D10的表征证明其阻断CTLA-4与B7.1和B7.2的相互作用的能力比10D1更有效。进一步的表征证明L3D10和10D1以相似的结合特征结合到固定的CTLA-4。然而,L3D10表现出对可溶性CTLA-4的结合亲和力比10D1低得多。
实施例4
人源化L3D10抗CTLA-4抗体
通过产生多个杂交序列来设计人源化L3D10抗体,所述杂交序列将亲本抗体序列的选择部分与人类框架序列融合,包括将CDR序列移植到受体框架中。使用以上实施例1中描述的人类CTLA-4敲入小鼠中的同源MC38小鼠肿瘤模型评估与10D1和嵌合L3D10抗体相比的三种人源化抗体(mAb4、mAb5和mAb6)的抗肿瘤活性。图11A示出体内实验的治疗方案;从接种后第7天开始,每3天给与小鼠总计4个剂量的抗体。如图11B所示,所有人源化抗体完全根除肿瘤并且与10D1相当。使用在杂合Ctla-4h/m小鼠中的同源MC38小鼠肿瘤模型和人类CTLA-4敲入小鼠中的同源B16-F1黑素瘤小鼠肿瘤模型观察到相似的功效(数据未示出)。
为了测试人源化后是否可维持L3D10的优异安全性特征,将mAb4和mAb5与10D1进行比较,以确定它们与抗PD-1组合使用时的不良反应。如图12所示,当与抗PD-1组合使用时,mAb4和mAb5两者均比10D1毒性更低。
实施例5
人源化抗CTLA-4抗体的结合特征
为了确认人源化抗体保留其CTLA-4结合特征,观察了与固定化和板结合的CTLA-4的结合。人源化不影响与固定化CTLA-4的结合,并且所有3种人源化抗体显示出与亲本嵌合L3D10抗体的相似结合(图13)。然而,人源化进一步减少L3D10与可溶性CTLA-4的结合(图14)。
已证明嵌合L3D10具有与10D1相比1000倍更高的B7阻断活性。这提出了一个有趣的可能性,即阻断B7-CTLA-4相互作用可解释其缺乏irAE。然而,mAb4和mAb5均不在体外和在体内阻断B7-CTL-A4相互作用。mAb4和mAb5显示减少的irAE这一事实进一步支持了阻断B7-CTLA-4相互作用不是L3D10安全性改善的原因的观点。
鉴于提出的CTLA-4在预防自身免疫疾病中的作用,提出减少与可溶性CTLA-4的结合作为改善安全性特征的基本机制。为了测试这一假设,使用在围产期期间接受抗PD-1+抗CTLA-4 mAb的雌性小鼠的生长增重作为irAE的基本指标。在接受10D1和抗PD-1两者的小鼠中观察到体重增加的严重降低,而接受mAb5+抗PD-1的那些具有最低的irAE,接着是接受mAb4的小鼠,然后是接受L3D10的小鼠(数据未显示)。与sCTLA-4结合降低的严格逆相关与中心假设一致。
实施例6
L3D10和人源化抗体的表位作图
为了绘制L3D10抗体和人源化变体mAb4和mAb5的CTLA-4结合表位,利用了小鼠和人CTLA-4蛋白与B7-1但不与抗CTLA-4抗体交叉反应的事实。抗人类CTLA-4抗体不与鼠Ctla-4交叉反应的事实可能反映细胞外结构域中人类与小鼠CTLA-4之间氨基酸序列的差异。图15示出人类、猕猴和小鼠CTLA-4细胞外结构域的比对,并且突出人类与猕猴之间的序列保守性,同时示出鼠与灵长类动物序列之间的许多差异。由于MYPPPY结合基序(SEQ IDNO:50)的保守性,小鼠和人类CTLA-4蛋白与B7-1交叉反应(72)。
因此,设计11种人类CTLA-4Fc蛋白的突变体,命名为M1-M11(SEQ ID NO:7-17),其中来自人类CTLA-4蛋白的氨基酸簇被来自鼠Ctla-4蛋白的氨基酸替换。并入到11种突变体中的每一种中的氨基酸在图15中示出,并且WT和突变体CTLA-4Fc蛋白的氨基酸序列在图16A和图16B中示出。由于本研究中使用的抗CTLA-4抗体不与鼠Ctla-4结合,因此当抗体结合表位的关键残基被鼠氨基酸替换时,应消除抗人类CTLA-4抗体的结合。
基于野生型人类CTLA-4Fc序列构建编码11种CTLA-4Fc突变体蛋白的DNA载体,并且通过在HEK293中以0.01mL规模瞬时转染,接着通过一步蛋白A色谱法纯化来产生蛋白质,并且产量在表1中提供。许多突变似乎影响蛋白质表达,如其相对于WT人类CTLA-4Fc蛋白的产量所指示。
表1在HEK293细胞中瞬时产生的WT和突变体CTLA-4Fc蛋白。
蛋白质名称 | 产量(mg) |
CTLA-4Fc WT对照 | 0.72 |
突变体1 | 1.29 |
突变体2 | 0.03 |
突变体3 | 0.21 |
突变体4 | 0.11 |
突变体5 | 1.89 |
突变体6 | 0.38 |
突变体7 | 0.25 |
突变体8 | 1.61 |
突变体9 | 0.01 |
突变体10 | 0.04 |
突变体11 | 1.70 |
然后通过ELISA确定嵌合L3D10和人源化抗体mAb4和mAb5结合固定化CTLA-4Fc突变体构建体的能力,其中用CTLA-4突变体蛋白以1μg/mL包被板,并且添加生物素化抗CTLA-4抗体或B7-1Ig对照蛋白,并且使用HRP缀合的链霉抗生物素蛋白测量结合。结合测定的结果在表2-5中示出。如所预期的,所有4种结合蛋白均表现出对WT CTLA-4Fc蛋白的良好剂量依赖性结合。然而,引入到M9和M10蛋白中的突变似乎改变整体结构,并且这些突变体未能结合B7-1Fc。在M2和M4中引入的突变也部分改变CTLA-4构象,如通过相对于WT蛋白的降低的结合所指示的。与此观点一致,所有这4种突变体(M2、M4、M9和M10)以低得多的产量表达(表1)。相比之下,使用与WT CTLA-4Fc蛋白的结合和B7-1Fc蛋白的结合作为参考,M11清楚地表现为表达良好的蛋白质,有效结合B7-1Fc但不能结合两种人源化抗CTLA-4抗体。其与原始L3D10的结合也降低大约100倍(表3)。如所预期的,影响整体构象的突变也影响与抗CTLA-4抗体的结合。
由于L3D10保留与M11的显著结合,因此测试了结合是否是特异性的。用人类CTLA-4-Fc(hCTLA-4Fc)、小鼠CTLA-4-Fc(mCTLA-4-Fc)、对照IgG1-Fc或所有突变体hCTLA-4-Fc包被板并测量它们与B7-1Fc连同L3D10、mAb4和mAb5的结合。大部分数据在表6中呈现。如图17所示,生物素化B7-1同样良好地结合hCTLA-4、mCTLA-4和M11。通过缺乏与IgG1-Fc的结合证明测定的特异性。有趣的是,虽然L3D10与M11的结合比与IgG1-Fc和mCTLA-4-Fc的结合更强,但是与IgG1-Fc的显著结合表明与M11结合的嵌合抗体可能是非特异性的。相比之下,人源化抗体都不与M11、mCTLA-4和IgG1-Fc对照结合。这些数据表明,M11中引入的突变选择性地消除与CTLA-4结合的L3D10、mAb4和mAb5。
使用已知的复合结构133,在3-D结构中绘制CTLA-4表位。如图18所示,这些mAb识别的表位位于B7-1覆盖的区域内。因此,与CTLA-4结合的L3D10、mAb4和mAb5将与B7-1相互排斥。mAb4和mAb5的不良阻断是由于较低的亲合力而不是独特的结合结构域。
使用多种人类CTLA-4Fc蛋白的突变体,其中来自人类CTLA-4蛋白的氨基酸簇被来自鼠Ctla-4蛋白的氨基酸替换,清楚地证明当替换紧跟CTLA-4的已知B7-1结合结构域MYPPPY的4个氨基酸时,抗体的剂量依赖性结合在很大程度上被消除。结合表位绘制成直接与B7-1结合结构域相邻的事实与所证明的L3D10抗体在体外和在体内均阻断B7-CTLA-4相互作用的能力充分相关。
实施例7
生成融合蛋白,其显示与一种或多种癌免疫治疗性抗CTLA-4 mAb的结合降低
已经生成一组17种具有各种突变的CTLA-4-Fc融合蛋白,命名为M1-M17(SEQ IDNO:7-23),其包括实施例10中鉴定的11种蛋白质(图16)加上6种另外的突变体(图19)。对M17进行进一步的突变。新突变体称为M17-1、M17-2、M17-3和M17-4(SEQ ID NO:42-45)。生成这些突变,预期他们将消除与广谱抗CTLA-4抗体的结合,但保留与CTLA-4配体CD80(B7-1)和CD86(B7-2)的结合。作为第一步,在板上包被给定浓度的融合蛋白,并且添加生物素化B7-1Fc。如图20A和图20B所示,除了2种融合蛋白(M9和M10)之外的所有融合蛋白都保留与B7-1的结合,但在M2、M4和M7中发现B7-1结合的显著降低。由于这些蛋白质在功能上较不活跃,因此这些突变体不太可能是体内预防自身免疫不良反应的最佳选择。另外的数据证明M15、M17、M17-1和M17-2保留与CD80和CD86两者的强结合(图21)。
接下来,评估了这些突变蛋白(M1-M17和M17-1至M17-4)是否已丧失与抗CTLA4mAb的结合,这些抗CTLA4 mAb被批准临床使用或正在开发用于临床疗法。总共测试了4种mAb。对于mAb1(伊匹单抗),融合蛋白M11、M13、M15、M17、M17-1、M17-2和M17-3已丧失结合,并且因此可用于预防由此mAb诱导的自身免疫疾病(图22A)。对于由mAb2(替西木单抗)诱导的自身免疫疾病,M15、M17、M17-2和M17-3将是有效的(图22B)。对于mAb4和mAb5,M11、M12、M14和M16可能是最有效的,但M3和M17也可起作用(图23、图24和图25)。
因此,如表7中总结的,CTLA4-Fc融合蛋白M17具有用于预防由抗CTLA4抗体诱导的自身免疫疾病的广谱活性。M17-3显示出与抗CTLA4抗体的低结合但与B7-1和B7-2的低结合。然而,M17-2显示出与B7-1和B7-2的更好结合,但是对于广泛范围的抗人类CTLA-4 mAb显示出可接受的低交叉反应性。
表7
鉴定CTLA4-Fc融合蛋白,其保留与B7-1的结合,但不与抗CTLA4 mAb的结合。相对结合由“+”或“-”表示,其中“++++”是最强的结合并且“-”表示没有结合。ND=未确定。
实施例8
阻断B7-1和B7-2不阻止伊匹单抗的免疫治疗作用
用结合到B7-1/B7-2的CTLA-4-Fc突变体治疗抗CTLA-4免疫治疗相关不良反应的关键要求是阻断B7-1和B7-2不影响免疫治疗作用。由于具有Cd80(编码B7-1)和Cd86(编码B7-2)的靶向突变的小鼠不具有Treg(17)并因此表达非常少的Ctla4,因此通过使用饱和剂量的抗B7-1(1G10)和抗B7-2(GL-1)mAb测试此预测,所述抗B7-1和抗B7-2 mAb分别阻断人类CTLA-4与mB7-1和mB7-2的结合(图26A)。如图26B所示,用伊匹单抗联合对照Ig或与抗mB7-1和抗mB7-2 mAb组合治疗携带MC38肿瘤的小鼠。使用的抗mB7 mAb完全掩盖PBL中的所有B7-1和B7-2,因为它们与新抗mB7 mAb的结合降低至在具有Cd80和Cd86的靶向突变的小鼠中观察到的结果(dKO)(图26C,图26D)。使用在肿瘤攻击后第22天收集的血清评估抗B7-1和抗B7-2 mAb对B7的功能性阻断,以评估抗人类IgG抗体反应,并通过对伊匹单抗的抗体反应被消除的事实来确认(图26E)。重要的是,mB7的饱和阻断不影响伊匹单抗诱导的肿瘤排斥,因为抗mB7和对照Ig治疗的小鼠对伊匹单抗具有同等的反应性(图26F)。这些数据指示抗B7-1和抗B7-2以及不结合抗CTLA-4抗体的B7结合的CTLA-4融合蛋白可用于治疗与抗CTLA-4免疫疗法相关的irAE,同时保持保护性免疫治疗活性完整。
实施例9
使用CTLA-4融合蛋白治疗与抗CTLA-4和抗PD-1组合疗法相关的自身免疫不良反应。
与抗CTLA-4和抗PD-1的组合疗法代表最有效的癌症免疫疗法。然而,由于超过50%的接受免疫疗法的患者发展irAE,迫切需要开发治疗或预防irAE的治疗方法。如实施例8中所证明的,伊匹单抗(mAb1)的免疫治疗作用不受B7-1和B7-2的阻断的影响。这些发现促使我们测试突变体CTLA-4Fc是否可用于治疗与伊匹单抗+抗PD-1组合疗法相关的irAE。由于伊匹单抗不与CTLA-4-Fc融合蛋白M11或M15(贝拉西普)结合,因此测试了贝拉西普或M11或M15的共同施用是否可改善irAE,使用延迟生长作为irAE的读出(参见实施例2)。如图27所示,低剂量的M11(100μg/注射)或M15(200μg/注射)预防irAE。除了M11和M15之外,还可使用具有相似性质的其他蛋白质,包括M13、M16和M17。
实施例10
鉴定不干扰抗CTLA4免疫治疗活性的融合蛋白
为了确定CTLA-4-Fc融合蛋白是否干扰抗CTLA4免疫治疗作用,在第7、10、13和17天用对照IgG Fc(200μg/注射)或伊匹单抗(100μg/注射)组合对照IgGFc(100μg/注射)或CTLA4融合蛋白阿巴西普、M15或M17(100μg/注射)对携带MC38肿瘤的小鼠进行注射。肿瘤生长速率在图28A中示出,而小鼠存活至早期移除终点在图28B中示出。如所预期的,阿巴西普消除伊匹单抗的免疫治疗作用。相比之下,M15和M17不干扰伊匹单抗的治疗作用。
实施例11
用人类造血系统重建的NSG小鼠中T细胞活化的调节及其相关的不良反应
为了确定CTLA-4融合蛋白对体内人类T细胞活化和相关irAE的影响,用人类造血干细胞重建3周大的NSG小鼠并监测T细胞活化。如图29至图32所示,不同的CTLA-4 mAb似乎对T细胞表型和伊匹单抗的不良反应具有不同的作用。因此,如图29A所示,用伊匹单抗治疗可防止NSG小鼠体重增加,并且这可通过共同施用M15或M17-2来预防。有趣的是,当与伊匹单抗联合使用时,M15诱导丙氨酸转氨酶升高(图29B)。这些数据表明,当与伊匹单抗联合使用时,M15可能诱发肝损伤。重要的是,当M17-2与M15联合使用时,没有观察到这种作用。
为了理解M15与M17之间差异的免疫学基础,在第31天处死NSG小鼠并分析T细胞子集的组成。如图30所示,M17诱导更多的中枢记忆T细胞,同时减少效应T细胞。效应T细胞的减少可解释减少的不良反应,因为这是迁移到器官中而导致免疫破坏的子集。此外,由于NKT细胞是肝炎的主要介质,所以基于CD56和CD3两者的表达比较M15和M17-2对NKT细胞的影响。如图31所示,M17-2减少NKT的数量,而M15将其增强。
调节性T细胞抑制自身免疫疾病和癌症免疫性。因此,希望减少Treg以增强癌症免疫性。然而,如果减少太严重,可能诱导自身免疫疾病。与B7-CD28相互作用在小鼠中生成和维持Treg中的关键作用一致,M15和M17-2两者均显著降低了Treg的%(图32A和图32B)。然而,M15在减少Treg方面远远更有效(图32A和图32B)。此外,来自M15处理的小鼠的Treg具有显著更低的CTLA-4(图32C和图32D)。鉴于CTLA-4在体内Treg功能中的重要作用,来自M15处理的小鼠的Treg可能在功能上受损。因此,Treg的严重减少与CTLA-4蛋白水平的选择性降低相结合表明当与伊匹单抗联合使用时M15可诱导自身免疫破坏的有趣可能性。
在本说明书中提到的所有出版物和专利申请以引用的方式并入本文,其程度如同具体地和单独地指出每个单独的出版物或专利申请以引用的方式整体并入。尽管本发明结合其具体实施方案进行描述,但是应了解能够进行另外的修改,并且此申请意图覆盖大体上根据本发明的原理而对本发明进行的任何变动、使用或适应性改变,并且包括属于本发明所属领域的已知或习用实施手段并且可适用于本文所列出的基本特征的此类偏离本公开的内容。
引用的参考文献
10.Leach DR,Krummel MF,Allison JP.Enhancement of antitumor immunityby CTLA-4 blockade[see comments].Science.1996;271(5256):1734-6.
108 Guinan,E.C.et al.Transplantation of anergic histoincompatiblebone marrow allografts.N.Engl.J.Med.340,1704-1714,doi:10.1056/NEJM199906033402202(1999).
128 Magistrelli.G.et al.A soluble form of CTLA-4 generated byalternative splicing is expressed by nonstimulatcd human Tcells.Eur.J.Immunol.29,3596-3602,doi:10.1002/(SICI)1521-4141(199911)29:11<;3596::AID-IMMU3596>;3.0.CO;2-Y(1999).
64 Ueda,H.et al.Association of the T-cell regulatory gene CTLA-4 withsusceptibility to autoimmune disease.Nature 423,506-511(2003).
129 Kremer,J.M.et al.Treatment of rheumatoid arthritis by selectiveinhibition of T-cell activation with fusion protein CTLA-4Ig.N.Engl.J.Med.349,1907-1915,doi:10.1056/NEJMoa035075(2003).
130 Abrams,J.R.et al.CTLA-4Ig-mediated blockade of T-cellcostimulation in patients with psoriasis vulgaris.J.Clin.Invest.103.1243-1252,doi:10.1172/JCI5857(1999).
131 Gerold.K.D.et al.The soluble CTLA-4 splice variant protects fromtype 1 diabetes and potentiates regulatory T-cell function.Diabetes 60,1955-1963.doi:10.2337/db11-0130(2011).
132 Peach,R.J.et al.Complementarity determining region 1(CDR1)-andCDR3-analogous regions in CTLA-4 and CD28 determine the binding to B7-1.J.Exp.Med.180,2049-2058(1994).
1.Townsend ARM,Tothbard J,Gotch FM,Bahadur G,Wraith D,McMichaelAJ.The epitope of influenza nucleoprotein recognized by cytotoxic lymphocytescan be defined with short synthetic peptides.Cell.1986;44:959-68.
2.Zinkernagel RM,Doherty PC.Restriction of in vitro T cell-mediatedcytotoxicity in lymphocytic choriomeningitis within a syngeneic orsemiallogeneic system.Nature.1974;248:701-2.
3.Lafferty KJ,Prowse SJ,Simeonovic CJ,Warren HS.Immunobiology oftissue transplantation:a return to the passenger leukocyte concept.Annu RevImmunol.1983;1:143-73.
4.Liu Y,Linsley PS.Costimulation of T-cell growth.Curr OpinImmunol.1992;4(3):265-70.
5.Schwartz RH.Costimulation of T lymphocytes:the role of CD28,CTLA-4,and B7/BB1 in interleukin-2 production and immunotherapy.Cell.1992;71(7):1065-8.
6.Freernan GJ,Freedman AS,Segil JM,Lee G,Whitman JF,Nadler LM.B7,anew member of the Ig superfamily with unique expression on activated andneoplastic B cells.J Immunol.1989;143(8):2714-22.
7.Freeman GJ,Gribben JG,Boussiotis VA,Ng JW,Restivo VA,Jr.,LombardLA,et al.Cloning of B7-2:a CTLA-4 counter-receptor that costimulates human Tcell proliferation [see comments].Science.1993;262(5135):909-11.
8.Hathcock KS,Laszlo G,Dickler HB,Bradshaw J,Linsley P,HodesRJ.Identification of an alternative CTLA-4 ligand costimulatory for T cellactivation[see comments].Science.1993;262(5135):905-7.
9.Wu Y,Guo Y,Liu Y.A major costimulatory molecule on antigen-presenting cells,CTLA-4 ligand A,is distinct from B7.J Exp Med.1993;178(5):1789-93.
10.Leach DR,Krummel MF,Allison JP.Enhancement of antitumor immunityby CTLA-4 blockade[see comments].Science.1996;271(5256):1734-6.
11.Linsley PS,Brady W,Urnes M,Grosmaire LS,Damle NK,LedbetterJA.CTLA-4 is a second receptor for the B cell activation antigen B7.J ExpMed.1991;174(3):561-9.
12.Linsley PS,Clark EA,Ledbetter JA.T-cell antigen CD28 mediatesadhesion with B cells by interacting with activation antigen B7/BB-1.ProcNatl Acad Sci U S A.1990;87(13):5031-5.
21.May KF,Roychowdhury S,Bhatt D,Kocak E,Bai XF,Liu JQ,et al.Anti-human CTLA-4 monoclonal antibody promotes T cell expansion and immunity in ahu-PBL-SCID model:a new method for preclinical screening of costimulatorymonoclonal antibodies.Blood.2005;105:1114-20.PubMed PMID:15486062.
20.Lute KD,May KF,Lu P,Zhang H,Kocak E,Mosinger B,et al.Human CTLA-4-knock-in mice unravel the quantitative link between tumor immunity andautoimmunity induced by anti-CTLA-4 antibodies.Blood.2005.PubMed PMID:16037385.
49.Keler,T.et al.Activity and safety of CTLA-4 blockade combined withvaccines in cynomolgus macaques.J.Immunol.171,6251-6259(2003).
50.Wing,K.et al.CTLA-4 control over Foxp3+ regulatory T cellfunction.Science 322,271-275,doi:10.1126/science.1160062(2008).
66.Qureshi,O.S.et al.Trans-endocytosis of CD80 and CD86:a molecularbasis for the cell-extrinsic function of CTLA-4.Science 332,600-603,doi:10.1126/science.1202947(2011).
30.Walunas,T.L.,et al.,CTLA-4 can function as a negative regulator ofT cell activation.Immunity,1994.1(5):p.405-13.
31.Krummel,M.F.and J.P.Allison,CD28 and CTLA-4 have opposing effectson the response of T cells to stimulation.J Exp Med,1995.182(2):p.459-65.
52.Simpson,T.R.et al.Fc-dependent depletion of tumor-infiltratingregulatory T cells co-defines the efficacy of anti-CTLA-4 therapy againstmelanoma.J.Exp.Med.210,1695-1710,doi:10.1084/jem.20130579(2013).
55.Korman,A.J.,Peggs,K.S.&Allison,J.P.Checkpoint blockade in cancerimmunotherapy.Adv.Immunol.90,297-339,doi:10.1016/S0065-2776(06)90008-X(2006).
56.Ribas,A.et al.Tremelimumab(CP-675,206),a cytotoxic T lymphocyteassociated antigen 4 blocking monoclonal antibody in clinical development forpatients with cancer.Oncologist 12,873-883,doi:10.1634/theoncologist.12-7-873(2007).
57.Ribas,A.et al.Phase III randomized clinical trial comparingtremelimumab with standard-of-care chemotherapy in patients with advancedmelanoma.J.Clin.Oncol.31,616-622,doi:10.1200/JCO.2012.44.6112(2013).
58.Lee,K.M.et al.Molecular basis of T cell inactivation by CTLA-4[InProcess Citation].Science 282,2263-2266(1998).
59.Marengere,L.E.et al.Regulation of T cell receptor signaling bytyrosine phosphatase SYP association with CTLA-4[published errata appear inScience 1996 Dec 6;274(5293)1597 and 1997 Apr 4;276(5309):21].Science 272,1170-1173(1996).
60.Liu,Y.Is CTLA-4 a negative regulator for T-cell activation?Immunol.Today 18,569-572(1997).
61.Tivol,E.A.et al.Loss of CTLA-4 leads to massivelymphoproliferation and fatal multiorgan tissue destruction,revealing acritical negative regulatory role of CTLA-4.Immunity 3,541-547(1995).
62.Waterhouse,P.et al.Lymphoproliferative disorders with earlylethality in mice deficient in CTLA-4[see comments].Science 270,985-988(1995).
63.Bachmann,M.F.,Kohler,G.,Ecabert,B.,Mak,T.W.&Kopf,M.Cutting edge:lymphoproliferative disease in the absence of CTLA-4 is not T cellautonomous.J.Immunol.163,1128-1131(1999).
64.Bachmann,M.F.et al.Normal pathogen-specific immune responsesmounted by CTLA-4-deficient T cells:a paradigm reconsidered.Eur.J.Immunol.31,450-458(2001).
65.Nguyen,T.V.,Ke,Y.,Zhang,E.E.&Feng,G.S.Conditional deletion of Shp2tyrosine phosphatase in thymocytes suppresses both pre-TCR and TCRsignals.J.Immunol.177,5990-5996(2006).
72 Peach RJ,Bajorath J,Brady W,Leytze G,Greene J,Naemura J,etal.Complementarity determining region 1(CDR1)-and CDR3-analogous regions inCTLA-4 and CD28 determine the binding to B7-1.J Exp Med.1994;180(6):2049-58.
17.Proietto AI1,Lahoud MH,Wu L.Distinct functional capacities ofmouse thymic and splenic dendritic cell populations.Immunol Cell Biol.2008Nov-Dec;86(8):700-8.doi:10.1038/icb.2008.63.Epub 2008 Sep 9.
序列表
<110> 肿瘤免疫股份有限公司
国家儿童医疗中心儿童研究所
Liu, Yang
Devenport, Martin
Zheng, Pan
Wu, Wei
Du, Xuexiang
Liu, Mingyue
Tang, Fei
<120> CD80和CD86结合蛋白组合物及其用途
<130> 060275.0700.01PC00
<150> 62396667
<151> 2016-09-19
<160> 50
<170> PatentIn 3.5版
<210> 1
<211> 223
<212> PRT
<213> 智人
<400> 1
Met Ala Cys Leu Gly Phe Gln Arg His Lys Ala Gln Leu Asn Leu Ala
1 5 10 15
Thr Arg Thr Trp Pro Cys Thr Leu Leu Phe Phe Leu Leu Phe Ile Pro
20 25 30
Val Phe Cys Lys Ala Met His Val Ala Gln Pro Ala Val Val Leu Ala
35 40 45
Ser Ser Arg Gly Ile Ala Ser Phe Val Cys Glu Tyr Ala Ser Pro Gly
50 55 60
Lys Ala Thr Glu Val Arg Val Thr Val Leu Arg Gln Ala Asp Ser Gln
65 70 75 80
Val Thr Glu Val Cys Ala Ala Thr Tyr Met Met Gly Asn Glu Leu Thr
85 90 95
Phe Leu Asp Asp Ser Ile Cys Thr Gly Thr Ser Ser Gly Asn Gln Val
100 105 110
Asn Leu Thr Ile Gln Gly Leu Arg Ala Met Asp Thr Gly Leu Tyr Ile
115 120 125
Cys Lys Val Glu Leu Met Tyr Pro Pro Pro Tyr Tyr Leu Gly Ile Gly
130 135 140
Asn Gly Thr Gln Ile Tyr Val Ile Asp Pro Glu Pro Cys Pro Asp Ser
145 150 155 160
Asp Phe Leu Leu Trp Ile Leu Ala Ala Val Ser Ser Gly Leu Phe Phe
165 170 175
Tyr Ser Phe Leu Leu Thr Ala Val Ser Leu Ser Lys Met Leu Lys Lys
180 185 190
Arg Ser Pro Leu Thr Thr Gly Val Tyr Val Lys Met Pro Pro Thr Glu
195 200 205
Pro Glu Cys Glu Lys Gln Phe Gln Pro Tyr Phe Ile Pro Ile Asn
210 215 220
<210> 2
<211> 357
<212> PRT
<213> 智人
<400> 2
Met His Val Ala Gln Pro Ala Val Val Leu Ala Ser Ser Arg Gly Ile
1 5 10 15
Ala Ser Phe Val Cys Glu Tyr Ala Ser Pro Gly Lys Ala Thr Glu Val
20 25 30
Arg Val Thr Val Leu Arg Gln Ala Asp Ser Gln Val Thr Glu Val Cys
35 40 45
Ala Ala Thr Tyr Met Met Gly Asn Glu Leu Thr Phe Leu Asp Asp Ser
50 55 60
Ile Cys Thr Gly Thr Ser Ser Gly Asn Gln Val Asn Leu Thr Ile Gln
65 70 75 80
Gly Leu Arg Ala Met Asp Thr Gly Leu Tyr Ile Cys Lys Val Glu Leu
85 90 95
Met Tyr Pro Pro Pro Tyr Tyr Leu Gly Ile Gly Asn Gly Thr Gln Ile
100 105 110
Tyr Val Ile Asp Pro Glu Pro Cys Pro Asp Ser Asp Gln Glu Pro Lys
115 120 125
Ser Ser Asp Lys Thr His Thr Ser Pro Pro Ser Pro Ala Pro Glu Leu
130 135 140
Leu Gly Gly Ser Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
145 150 155 160
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
165 170 175
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
180 185 190
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
195 200 205
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
210 215 220
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
225 230 235 240
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
245 250 255
Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln
260 265 270
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
275 280 285
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
290 295 300
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
305 310 315 320
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
325 330 335
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
340 345 350
Leu Ser Pro Gly Lys
355
<210> 3
<211> 126
<212> PRT
<213> 智人
<400> 3
Lys Ala Met His Val Ala Gln Pro Ala Val Val Leu Ala Ser Ser Arg
1 5 10 15
Gly Ile Ala Ser Phe Val Cys Glu Tyr Ala Ser Pro Gly Lys Ala Thr
20 25 30
Glu Val Arg Val Thr Val Leu Arg Gln Ala Asp Ser Gln Val Thr Glu
35 40 45
Val Cys Ala Ala Thr Tyr Met Met Gly Asn Glu Leu Thr Phe Leu Asp
50 55 60
Asp Ser Ile Cys Thr Gly Thr Ser Ser Gly Asn Gln Val Asn Leu Thr
65 70 75 80
Ile Gln Gly Leu Arg Ala Met Asp Thr Gly Leu Tyr Ile Cys Lys Val
85 90 95
Glu Leu Met Tyr Pro Pro Pro Tyr Tyr Leu Gly Ile Gly Asn Gly Thr
100 105 110
Gln Ile Tyr Val Ile Asp Pro Glu Pro Cys Pro Asp Ser Asp
115 120 125
<210> 4
<211> 174
<212> PRT
<213> 智人
<400> 4
Met Ala Cys Leu Gly Phe Gln Arg His Lys Ala Gln Leu Asn Leu Ala
1 5 10 15
Thr Arg Thr Trp Pro Cys Thr Leu Leu Phe Phe Leu Leu Phe Ile Pro
20 25 30
Val Phe Cys Lys Ala Met His Val Ala Gln Pro Ala Val Val Leu Ala
35 40 45
Ser Ser Arg Gly Ile Ala Ser Phe Val Cys Glu Tyr Ala Ser Pro Gly
50 55 60
Lys Ala Thr Glu Val Arg Val Thr Val Leu Arg Gln Ala Asp Ser Gln
65 70 75 80
Val Thr Glu Val Cys Ala Ala Thr Tyr Met Met Gly Asn Glu Leu Thr
85 90 95
Phe Leu Asp Asp Ser Ile Cys Thr Gly Thr Ser Ser Gly Asn Gln Val
100 105 110
Asn Leu Thr Ile Gln Gly Leu Arg Ala Met Asp Thr Gly Leu Tyr Ile
115 120 125
Cys Lys Val Glu Leu Met Tyr Pro Pro Pro Tyr Tyr Leu Gly Ile Gly
130 135 140
Asn Gly Thr Gln Ile Tyr Val Ile Ala Lys Glu Lys Lys Pro Ser Tyr
145 150 155 160
Asn Arg Gly Leu Cys Glu Asn Ala Pro Asn Arg Ala Arg Met
165 170
<210> 5
<211> 223
<212> PRT
<213> 小家鼠
<400> 5
Met Ala Cys Leu Gly Leu Arg Arg Tyr Lys Ala Gln Leu Gln Leu Pro
1 5 10 15
Ser Arg Thr Trp Pro Phe Val Ala Leu Leu Thr Leu Leu Phe Ile Pro
20 25 30
Val Phe Ser Glu Ala Ile Gln Val Thr Gln Pro Ser Val Val Leu Ala
35 40 45
Ser Ser His Gly Val Ala Ser Phe Pro Cys Glu Tyr Ser Pro Ser His
50 55 60
Asn Thr Asp Glu Val Arg Val Thr Val Leu Arg Gln Thr Asn Asp Gln
65 70 75 80
Met Thr Glu Val Cys Ala Thr Thr Phe Thr Glu Lys Asn Thr Val Gly
85 90 95
Phe Leu Asp Tyr Pro Phe Cys Ser Gly Thr Phe Asn Glu Ser Arg Val
100 105 110
Asn Leu Thr Ile Gln Gly Leu Arg Ala Val Asp Thr Gly Leu Tyr Leu
115 120 125
Cys Lys Val Glu Leu Met Tyr Pro Pro Pro Tyr Phe Val Gly Met Gly
130 135 140
Asn Gly Thr Gln Ile Tyr Val Ile Asp Pro Glu Pro Cys Pro Asp Ser
145 150 155 160
Asp Phe Leu Leu Trp Ile Leu Val Ala Val Ser Leu Gly Leu Phe Phe
165 170 175
Tyr Ser Phe Leu Val Ser Ala Val Ser Leu Ser Lys Met Leu Lys Lys
180 185 190
Arg Ser Pro Leu Thr Thr Gly Val Tyr Val Lys Met Pro Pro Thr Glu
195 200 205
Pro Glu Cys Glu Lys Gln Phe Gln Pro Tyr Phe Ile Pro Ile Asn
210 215 220
<210> 6
<211> 126
<212> PRT
<213> 小家鼠
<400> 6
Glu Ala Ile Gln Val Thr Gln Pro Ser Val Val Leu Ala Ser Ser His
1 5 10 15
Gly Val Ala Ser Phe Pro Cys Glu Tyr Ser Pro Ser His Asn Thr Asp
20 25 30
Glu Val Arg Val Thr Val Leu Arg Gln Thr Asn Asp Gln Met Thr Glu
35 40 45
Val Cys Ala Thr Thr Phe Thr Glu Lys Asn Thr Val Gly Phe Leu Asp
50 55 60
Tyr Pro Phe Cys Ser Gly Thr Phe Asn Glu Ser Arg Val Asn Leu Thr
65 70 75 80
Ile Gln Gly Leu Arg Ala Val Asp Thr Gly Leu Tyr Leu Cys Lys Val
85 90 95
Glu Leu Met Tyr Pro Pro Pro Tyr Phe Val Gly Met Gly Asn Gly Thr
100 105 110
Gln Ile Tyr Val Ile Asp Pro Glu Pro Cys Pro Asp Ser Asp
115 120 125
<210> 7
<211> 357
<212> PRT
<213> 人工序列
<220>
<223> 融合蛋白
<400> 7
Ile Gln Val Thr Gln Pro Ser Val Val Leu Ala Ser Ser Arg Gly Ile
1 5 10 15
Ala Ser Phe Val Cys Glu Tyr Ala Ser Pro Gly Lys Ala Thr Glu Val
20 25 30
Arg Val Thr Val Leu Arg Gln Ala Asp Ser Gln Val Thr Glu Val Cys
35 40 45
Ala Ala Thr Tyr Met Met Gly Asn Glu Leu Thr Phe Leu Asp Asp Ser
50 55 60
Ile Cys Thr Gly Thr Ser Ser Gly Asn Gln Val Asn Leu Thr Ile Gln
65 70 75 80
Gly Leu Arg Ala Met Asp Thr Gly Leu Tyr Ile Cys Lys Val Glu Leu
85 90 95
Met Tyr Pro Pro Pro Tyr Tyr Leu Gly Ile Gly Asn Gly Thr Gln Ile
100 105 110
Tyr Val Ile Asp Pro Glu Pro Cys Pro Asp Ser Asp Gln Glu Pro Lys
115 120 125
Ser Ser Asp Lys Thr His Thr Ser Pro Pro Ser Pro Ala Pro Glu Leu
130 135 140
Leu Gly Gly Ser Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
145 150 155 160
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
165 170 175
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
180 185 190
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
195 200 205
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
210 215 220
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
225 230 235 240
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
245 250 255
Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln
260 265 270
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
275 280 285
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
290 295 300
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
305 310 315 320
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
325 330 335
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
340 345 350
Leu Ser Pro Gly Lys
355
<210> 8
<211> 357
<212> PRT
<213> 人工序列
<220>
<223> 融合蛋白
<400> 8
Met His Val Ala Gln Pro Ala Val Val Leu Ala Ser Ser His Gly Leu
1 5 10 15
Ala Ser Phe Pro Cys Glu Tyr Ala Ser Pro Gly Lys Ala Thr Glu Val
20 25 30
Arg Val Thr Val Leu Arg Gln Ala Asp Ser Gln Val Thr Glu Val Cys
35 40 45
Ala Ala Thr Tyr Met Met Gly Asn Glu Leu Thr Phe Leu Asp Asp Ser
50 55 60
Ile Cys Thr Gly Thr Ser Ser Gly Asn Gln Val Asn Leu Thr Ile Gln
65 70 75 80
Gly Leu Arg Ala Met Asp Thr Gly Leu Tyr Ile Cys Lys Val Glu Leu
85 90 95
Met Tyr Pro Pro Pro Tyr Tyr Leu Gly Ile Gly Asn Gly Thr Gln Ile
100 105 110
Tyr Val Ile Asp Pro Glu Pro Cys Pro Asp Ser Asp Gln Glu Pro Lys
115 120 125
Ser Ser Asp Lys Thr His Thr Ser Pro Pro Ser Pro Ala Pro Glu Leu
130 135 140
Leu Gly Gly Ser Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
145 150 155 160
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
165 170 175
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
180 185 190
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
195 200 205
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
210 215 220
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
225 230 235 240
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
245 250 255
Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln
260 265 270
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
275 280 285
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
290 295 300
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
305 310 315 320
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
325 330 335
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
340 345 350
Leu Ser Pro Gly Lys
355
<210> 9
<211> 358
<212> PRT
<213> 人工序列
<220>
<223> 融合蛋白
<400> 9
Met His Val Ala Gln Pro Ala Val Val Leu Ala Ser Ser Arg Gly Ile
1 5 10 15
Ala Ser Phe Val Cys Glu Tyr Ala Ser Pro Ser His Asn Thr Asp Glu
20 25 30
Val Arg Val Thr Val Leu Arg Gln Ala Asp Ser Gln Val Thr Glu Val
35 40 45
Cys Ala Ala Thr Tyr Met Met Gly Asn Glu Leu Thr Phe Leu Asp Asp
50 55 60
Ser Ile Cys Thr Gly Thr Ser Ser Gly Asn Gln Val Asn Leu Thr Ile
65 70 75 80
Gln Gly Leu Arg Ala Met Asp Thr Gly Leu Tyr Ile Cys Lys Val Glu
85 90 95
Leu Met Tyr Pro Pro Pro Tyr Tyr Leu Gly Ile Gly Asn Gly Thr Gln
100 105 110
Ile Tyr Val Ile Asp Pro Glu Pro Cys Pro Asp Ser Asp Gln Glu Pro
115 120 125
Lys Ser Ser Asp Lys Thr His Thr Ser Pro Pro Ser Pro Ala Pro Glu
130 135 140
Leu Leu Gly Gly Ser Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
145 150 155 160
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
165 170 175
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
180 185 190
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
195 200 205
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
210 215 220
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
225 230 235 240
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
245 250 255
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn
260 265 270
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
275 280 285
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
290 295 300
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
305 310 315 320
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
325 330 335
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
340 345 350
Ser Leu Ser Pro Gly Lys
355
<210> 10
<211> 357
<212> PRT
<213> 人工序列
<220>
<223> 融合蛋白
<400> 10
Met His Val Ala Gln Pro Ala Val Val Leu Ala Ser Ser Arg Gly Ile
1 5 10 15
Ala Ser Phe Val Cys Glu Tyr Ala Ser Pro Gly Lys Ala Thr Glu Val
20 25 30
Arg Val Thr Val Leu Arg Thr Asn Asp Gln Met Val Thr Glu Val Cys
35 40 45
Ala Ala Thr Tyr Met Met Gly Asn Glu Leu Thr Phe Leu Asp Asp Ser
50 55 60
Ile Cys Thr Gly Thr Ser Ser Gly Asn Gln Val Asn Leu Thr Ile Gln
65 70 75 80
Gly Leu Arg Ala Met Asp Thr Gly Leu Tyr Ile Cys Lys Val Glu Leu
85 90 95
Met Tyr Pro Pro Pro Tyr Tyr Leu Gly Ile Gly Asn Gly Thr Gln Ile
100 105 110
Tyr Val Ile Asp Pro Glu Pro Cys Pro Asp Ser Asp Gln Glu Pro Lys
115 120 125
Ser Ser Asp Lys Thr His Thr Ser Pro Pro Ser Pro Ala Pro Glu Leu
130 135 140
Leu Gly Gly Ser Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
145 150 155 160
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
165 170 175
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
180 185 190
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
195 200 205
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
210 215 220
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
225 230 235 240
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
245 250 255
Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln
260 265 270
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
275 280 285
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
290 295 300
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
305 310 315 320
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
325 330 335
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
340 345 350
Leu Ser Pro Gly Lys
355
<210> 11
<211> 357
<212> PRT
<213> 人工序列
<220>
<223> 融合蛋白
<400> 11
Met His Val Ala Gln Pro Ala Val Val Leu Ala Ser Ser Arg Gly Ile
1 5 10 15
Ala Ser Phe Val Cys Glu Tyr Ala Ser Pro Gly Lys Ala Thr Glu Val
20 25 30
Arg Val Thr Val Leu Arg Gln Ala Asp Ser Gln Val Thr Glu Val Cys
35 40 45
Ala Ala Thr Phe Thr Glu Lys Asn Thr Val Gly Phe Leu Asp Asp Ser
50 55 60
Ile Cys Thr Gly Thr Ser Ser Gly Asn Gln Val Asn Leu Thr Ile Gln
65 70 75 80
Gly Leu Arg Ala Met Asp Thr Gly Leu Tyr Ile Cys Lys Val Glu Leu
85 90 95
Met Tyr Pro Pro Pro Tyr Tyr Leu Gly Ile Gly Asn Gly Thr Gln Ile
100 105 110
Tyr Val Ile Asp Pro Glu Pro Cys Pro Asp Ser Asp Gln Glu Pro Lys
115 120 125
Ser Ser Asp Lys Thr His Thr Ser Pro Pro Ser Pro Ala Pro Glu Leu
130 135 140
Leu Gly Gly Ser Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
145 150 155 160
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
165 170 175
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
180 185 190
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
195 200 205
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
210 215 220
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
225 230 235 240
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
245 250 255
Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln
260 265 270
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
275 280 285
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
290 295 300
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
305 310 315 320
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
325 330 335
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
340 345 350
Leu Ser Pro Gly Lys
355
<210> 12
<211> 357
<212> PRT
<213> 人工序列
<220>
<223> 融合蛋白
<400> 12
Met His Val Ala Gln Pro Ala Val Val Leu Ala Ser Ser Arg Gly Ile
1 5 10 15
Ala Ser Phe Val Cys Glu Tyr Ala Ser Pro Gly Lys Ala Thr Glu Val
20 25 30
Arg Val Thr Val Leu Arg Gln Ala Asp Ser Gln Val Thr Glu Val Cys
35 40 45
Ala Thr Thr Tyr Met Met Gly Asn Glu Leu Thr Phe Leu Asp Asp Ser
50 55 60
Ile Cys Thr Gly Thr Ser Ser Gly Asn Gln Val Asn Leu Thr Ile Gln
65 70 75 80
Gly Leu Arg Ala Met Asp Thr Gly Leu Tyr Ile Cys Lys Val Glu Leu
85 90 95
Met Tyr Pro Pro Pro Tyr Tyr Leu Gly Ile Gly Asn Gly Thr Gln Ile
100 105 110
Tyr Val Ile Asp Pro Glu Pro Cys Pro Asp Ser Asp Gln Glu Pro Lys
115 120 125
Ser Ser Asp Lys Thr His Thr Ser Pro Pro Ser Pro Ala Pro Glu Leu
130 135 140
Leu Gly Gly Ser Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
145 150 155 160
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
165 170 175
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
180 185 190
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
195 200 205
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
210 215 220
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
225 230 235 240
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
245 250 255
Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln
260 265 270
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
275 280 285
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
290 295 300
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
305 310 315 320
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
325 330 335
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
340 345 350
Leu Ser Pro Gly Lys
355
<210> 13
<211> 357
<212> PRT
<213> 人工序列
<220>
<223> 融合蛋白
<400> 13
Met His Val Ala Gln Pro Ala Val Val Leu Ala Ser Ser Arg Gly Ile
1 5 10 15
Ala Ser Phe Val Cys Glu Tyr Ala Ser Pro Gly Lys Ala Thr Glu Val
20 25 30
Arg Val Thr Val Leu Arg Gln Ala Asp Ser Gln Val Thr Glu Val Cys
35 40 45
Ala Ala Thr Tyr Met Met Gly Asn Glu Leu Thr Phe Leu Asp Tyr Pro
50 55 60
Phe Cys Ser Gly Thr Ser Ser Gly Asn Gln Val Asn Leu Thr Ile Gln
65 70 75 80
Gly Leu Arg Ala Met Asp Thr Gly Leu Tyr Ile Cys Lys Val Glu Leu
85 90 95
Met Tyr Pro Pro Pro Tyr Tyr Leu Gly Ile Gly Asn Gly Thr Gln Ile
100 105 110
Tyr Val Ile Asp Pro Glu Pro Cys Pro Asp Ser Asp Gln Glu Pro Lys
115 120 125
Ser Ser Asp Lys Thr His Thr Ser Pro Pro Ser Pro Ala Pro Glu Leu
130 135 140
Leu Gly Gly Ser Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
145 150 155 160
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
165 170 175
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
180 185 190
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
195 200 205
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
210 215 220
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
225 230 235 240
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
245 250 255
Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln
260 265 270
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
275 280 285
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
290 295 300
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
305 310 315 320
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
325 330 335
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
340 345 350
Leu Ser Pro Gly Lys
355
<210> 14
<211> 357
<212> PRT
<213> 人工序列
<220>
<223> 融合蛋白
<400> 14
Met His Val Ala Gln Pro Ala Val Val Leu Ala Ser Ser Arg Gly Ile
1 5 10 15
Ala Ser Phe Val Cys Glu Tyr Ala Ser Pro Gly Lys Ala Thr Glu Val
20 25 30
Arg Val Thr Val Leu Arg Gln Ala Asp Ser Gln Val Thr Glu Val Cys
35 40 45
Ala Ala Thr Tyr Met Met Gly Asn Glu Leu Thr Phe Leu Asp Asp Ser
50 55 60
Ile Cys Thr Gly Thr Phe Asn Glu Ser Arg Val Asn Leu Thr Ile Gln
65 70 75 80
Gly Leu Arg Ala Met Asp Thr Gly Leu Tyr Ile Cys Lys Val Glu Leu
85 90 95
Met Tyr Pro Pro Pro Tyr Tyr Leu Gly Ile Gly Asn Gly Thr Gln Ile
100 105 110
Tyr Val Ile Asp Pro Glu Pro Cys Pro Asp Ser Asp Gln Glu Pro Lys
115 120 125
Ser Ser Asp Lys Thr His Thr Ser Pro Pro Ser Pro Ala Pro Glu Leu
130 135 140
Leu Gly Gly Ser Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
145 150 155 160
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
165 170 175
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
180 185 190
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
195 200 205
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
210 215 220
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
225 230 235 240
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
245 250 255
Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln
260 265 270
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
275 280 285
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
290 295 300
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
305 310 315 320
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
325 330 335
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
340 345 350
Leu Ser Pro Gly Lys
355
<210> 15
<211> 358
<212> PRT
<213> 人工序列
<220>
<223> 融合蛋白
<400> 15
Met His Val Ala Gln Pro Ala Val Val Leu Ala Ser Ser Arg Gly Ile
1 5 10 15
Ala Ser Phe Val Cys Glu Tyr Ala Ser Pro Gly Lys Ala Thr Glu Val
20 25 30
Arg Val Thr Val Leu Arg Gln Ala Asp Ser Gln Val Thr Glu Val Cys
35 40 45
Ala Ala Thr Tyr Met Met Gly Asn Glu Leu Thr Phe Leu Asp Asp Ser
50 55 60
Ile Cys Thr Gly Thr Ser Ser Gly Asn Gln Val Asn Leu Thr Ile Gln
65 70 75 80
Gly Leu Arg Ala Met Val Asp Thr Gly Leu Tyr Ile Cys Lys Val Glu
85 90 95
Leu Met Tyr Pro Pro Pro Tyr Tyr Leu Gly Ile Gly Asn Gly Thr Gln
100 105 110
Ile Tyr Val Ile Asp Pro Glu Pro Cys Pro Asp Ser Asp Gln Glu Pro
115 120 125
Lys Ser Ser Asp Lys Thr His Thr Ser Pro Pro Ser Pro Ala Pro Glu
130 135 140
Leu Leu Gly Gly Ser Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
145 150 155 160
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
165 170 175
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
180 185 190
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
195 200 205
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
210 215 220
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
225 230 235 240
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
245 250 255
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn
260 265 270
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
275 280 285
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
290 295 300
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
305 310 315 320
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
325 330 335
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
340 345 350
Ser Leu Ser Pro Gly Lys
355
<210> 16
<211> 358
<212> PRT
<213> 人工序列
<220>
<223> 融合蛋白
<400> 16
Met His Val Ala Gln Pro Ala Val Val Leu Ala Ser Ser Arg Gly Ile
1 5 10 15
Ala Ser Phe Val Cys Glu Tyr Ala Ser Pro Gly Lys Ala Thr Glu Val
20 25 30
Arg Val Thr Val Leu Arg Gln Ala Asp Ser Gln Val Thr Glu Val Cys
35 40 45
Ala Ala Thr Tyr Met Met Gly Asn Glu Leu Thr Phe Leu Asp Asp Ser
50 55 60
Ile Cys Thr Gly Thr Ser Ser Gly Asn Gln Val Asn Leu Thr Ile Gln
65 70 75 80
Gly Leu Arg Ala Met Met Asp Thr Gly Leu Tyr Leu Cys Lys Val Glu
85 90 95
Leu Met Tyr Pro Pro Pro Tyr Tyr Leu Gly Ile Gly Asn Gly Thr Gln
100 105 110
Ile Tyr Val Ile Asp Pro Glu Pro Cys Pro Asp Ser Asp Gln Glu Pro
115 120 125
Lys Ser Ser Asp Lys Thr His Thr Ser Pro Pro Ser Pro Ala Pro Glu
130 135 140
Leu Leu Gly Gly Ser Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
145 150 155 160
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
165 170 175
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
180 185 190
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
195 200 205
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
210 215 220
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
225 230 235 240
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
245 250 255
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn
260 265 270
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
275 280 285
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
290 295 300
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
305 310 315 320
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
325 330 335
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
340 345 350
Ser Leu Ser Pro Gly Lys
355
<210> 17
<211> 357
<212> PRT
<213> 人工
<220>
<223> 融合蛋白
<400> 17
Met His Val Ala Gln Pro Ala Val Val Leu Ala Ser Ser Arg Gly Ile
1 5 10 15
Ala Ser Phe Val Cys Glu Tyr Ala Ser Pro Gly Lys Ala Thr Glu Val
20 25 30
Arg Val Thr Val Leu Arg Gln Ala Asp Ser Gln Val Thr Glu Val Cys
35 40 45
Ala Ala Thr Tyr Met Met Gly Asn Glu Leu Thr Phe Leu Asp Asp Ser
50 55 60
Ile Cys Thr Gly Thr Ser Ser Gly Asn Gln Val Asn Leu Thr Ile Gln
65 70 75 80
Gly Leu Arg Ala Met Asp Thr Gly Leu Tyr Ile Cys Lys Val Glu Leu
85 90 95
Met Tyr Pro Pro Pro Tyr Phe Val Gly Met Gly Asn Gly Thr Gln Ile
100 105 110
Tyr Val Ile Asp Pro Glu Pro Cys Pro Asp Ser Asp Gln Glu Pro Lys
115 120 125
Ser Ser Asp Lys Thr His Thr Ser Pro Pro Ser Pro Ala Pro Glu Leu
130 135 140
Leu Gly Gly Ser Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
145 150 155 160
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
165 170 175
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
180 185 190
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
195 200 205
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
210 215 220
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
225 230 235 240
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
245 250 255
Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln
260 265 270
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
275 280 285
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
290 295 300
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
305 310 315 320
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
325 330 335
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
340 345 350
Leu Ser Pro Gly Lys
355
<210> 18
<211> 357
<212> PRT
<213> 人工
<220>
<223> 融合蛋白
<400> 18
Ile Gln Val Thr Gln Pro Ser Val Val Leu Ala Ser Ser Arg Gly Ile
1 5 10 15
Ala Ser Phe Val Cys Glu Tyr Ala Ser Pro Gly Lys Ala Thr Glu Val
20 25 30
Arg Val Thr Val Leu Arg Gln Ala Asp Ser Gln Val Thr Glu Val Cys
35 40 45
Ala Ala Thr Phe Thr Glu Lys Asn Thr Val Gly Phe Leu Asp Asp Ser
50 55 60
Ile Cys Thr Gly Thr Phe Asn Glu Ser Arg Val Asn Leu Thr Ile Gln
65 70 75 80
Gly Leu Arg Ala Met Asp Thr Gly Leu Tyr Ile Cys Lys Val Glu Leu
85 90 95
Met Tyr Pro Pro Pro Tyr Phe Val Gly Met Gly Asn Gly Thr Gln Ile
100 105 110
Tyr Val Ile Asp Pro Glu Pro Cys Pro Asp Ser Asp Gln Glu Pro Lys
115 120 125
Ser Ser Asp Lys Thr His Thr Ser Pro Pro Ser Pro Ala Pro Glu Leu
130 135 140
Leu Gly Gly Ser Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
145 150 155 160
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
165 170 175
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
180 185 190
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
195 200 205
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
210 215 220
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
225 230 235 240
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
245 250 255
Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln
260 265 270
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
275 280 285
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
290 295 300
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
305 310 315 320
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
325 330 335
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
340 345 350
Leu Ser Pro Gly Lys
355
<210> 19
<211> 357
<212> PRT
<213> 人工
<220>
<223> 融合蛋白
<400> 19
Met His Val Ala Gln Pro Ala Val Val Leu Ala Ser Ser Arg Gly Ile
1 5 10 15
Ala Ser Phe Val Cys Glu Tyr Ala Ser Pro Gly Lys Tyr Thr Glu Val
20 25 30
Arg Val Thr Val Leu Arg Gln Ala Asp Ser Gln Val Thr Glu Val Cys
35 40 45
Ala Ala Thr Tyr Met Met Gly Asn Glu Leu Thr Phe Leu Asp Asp Ser
50 55 60
Ile Cys Thr Gly Thr Ser Ser Gly Asn Gln Val Asn Leu Thr Ile Gln
65 70 75 80
Gly Leu Arg Ala Met Asp Thr Gly Leu Tyr Ile Cys Lys Val Glu Leu
85 90 95
Met Tyr Pro Pro Pro Tyr Phe Val Gly Met Gly Asn Gly Thr Gln Ile
100 105 110
Tyr Val Ile Asp Pro Glu Pro Cys Pro Asp Ser Asp Gln Glu Pro Lys
115 120 125
Ser Ser Asp Lys Thr His Thr Ser Pro Pro Ser Pro Ala Pro Glu Leu
130 135 140
Leu Gly Gly Ser Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
145 150 155 160
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
165 170 175
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
180 185 190
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
195 200 205
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
210 215 220
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
225 230 235 240
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
245 250 255
Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln
260 265 270
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
275 280 285
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
290 295 300
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
305 310 315 320
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
325 330 335
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
340 345 350
Leu Ser Pro Gly Lys
355
<210> 20
<211> 357
<212> PRT
<213> 人工序列
<220>
<223> 融合蛋白
<400> 20
Ile Gln Val Thr Gln Pro Ser Val Val Leu Ala Ser Ser Arg Gly Ile
1 5 10 15
Ala Ser Phe Val Cys Glu Tyr Ala Ser Pro Gly Lys Ala Thr Glu Val
20 25 30
Arg Val Thr Val Leu Arg Gln Ala Asp Ser Gln Val Thr Glu Val Cys
35 40 45
Ala Ala Thr Phe Thr Glu Lys Asn Thr Val Gly Phe Leu Asp Asp Ser
50 55 60
Ile Cys Thr Gly Thr Ser Ser Gly Asn Gln Val Asn Leu Thr Ile Gln
65 70 75 80
Gly Leu Arg Ala Met Asp Thr Gly Leu Tyr Ile Cys Lys Val Glu Leu
85 90 95
Met Tyr Pro Pro Pro Tyr Phe Val Gly Met Gly Asn Gly Thr Gln Ile
100 105 110
Tyr Val Ile Asp Pro Glu Pro Cys Pro Asp Ser Asp Gln Glu Pro Lys
115 120 125
Ser Ser Asp Lys Thr His Thr Ser Pro Pro Ser Pro Ala Pro Glu Leu
130 135 140
Leu Gly Gly Ser Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
145 150 155 160
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
165 170 175
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
180 185 190
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
195 200 205
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
210 215 220
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
225 230 235 240
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
245 250 255
Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln
260 265 270
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
275 280 285
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
290 295 300
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
305 310 315 320
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
325 330 335
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
340 345 350
Leu Ser Pro Gly Lys
355
<210> 21
<211> 357
<212> PRT
<213> 人工序列
<220>
<223> 融合蛋白
<400> 21
Met His Val Ala Gln Pro Ala Val Val Leu Ala Ser Ser Arg Gly Ile
1 5 10 15
Ala Ser Phe Val Cys Glu Tyr Ala Ser Pro Gly Lys Tyr Thr Glu Val
20 25 30
Arg Val Thr Val Leu Arg Gln Ala Asp Ser Gln Val Thr Glu Val Cys
35 40 45
Ala Ala Thr Tyr Met Met Gly Asn Glu Leu Thr Phe Leu Asp Asp Ser
50 55 60
Ile Cys Thr Gly Thr Ser Ser Gly Asn Gln Val Asn Leu Thr Ile Gln
65 70 75 80
Gly Leu Arg Ala Met Asp Thr Gly Leu Tyr Ile Cys Lys Val Glu Leu
85 90 95
Met Tyr Pro Pro Pro Tyr Tyr Glu Gly Ile Gly Asn Gly Thr Gln Ile
100 105 110
Tyr Val Ile Asp Pro Glu Pro Cys Pro Asp Ser Asp Gln Glu Pro Lys
115 120 125
Ser Ser Asp Lys Thr His Thr Ser Pro Pro Ser Pro Ala Pro Glu Leu
130 135 140
Leu Gly Gly Ser Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
145 150 155 160
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
165 170 175
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
180 185 190
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
195 200 205
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
210 215 220
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
225 230 235 240
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
245 250 255
Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln
260 265 270
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
275 280 285
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
290 295 300
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
305 310 315 320
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
325 330 335
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
340 345 350
Leu Ser Pro Gly Lys
355
<210> 22
<211> 357
<212> PRT
<213> 人工序列
<220>
<223> 融合蛋白
<400> 22
Ile Gln Val Thr Gln Pro Ser Val Val Leu Ala Ser Ser Arg Gly Ile
1 5 10 15
Ala Ser Phe Val Cys Glu Tyr Ala Ser Pro Gly Lys Ala Thr Glu Val
20 25 30
Arg Val Thr Val Leu Arg Gln Ala Asp Ser Gln Val Thr Glu Val Cys
35 40 45
Ala Ala Thr Phe Thr Glu Lys Asn Thr Val Gly Phe Leu Asp Asp Ser
50 55 60
Ile Cys Thr Gly Thr Phe Asn Glu Ser Arg Val Asn Leu Thr Ile Gln
65 70 75 80
Gly Leu Arg Ala Met Asp Thr Gly Leu Tyr Ile Cys Lys Val Glu Leu
85 90 95
Met Tyr Pro Pro Pro Tyr Phe Val Gly Met Gly Asn Gly Thr Gln Ile
100 105 110
Tyr Val Ile Asp Pro Glu Pro Cys Pro Asp Ser Asp Gln Glu Pro Lys
115 120 125
Ser Ser Asp Lys Thr His Thr Ser Pro Pro Ser Pro Ala Pro Glu Leu
130 135 140
Leu Gly Gly Ser Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
145 150 155 160
Leu Tyr Ile Thr Arg Glu Pro Glu Val Thr Cys Val Val Val Asp Val
165 170 175
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
180 185 190
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
195 200 205
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
210 215 220
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
225 230 235 240
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
245 250 255
Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln
260 265 270
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
275 280 285
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
290 295 300
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
305 310 315 320
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
325 330 335
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
340 345 350
Leu Ser Pro Gly Lys
355
<210> 23
<211> 357
<212> PRT
<213> 人工序列
<220>
<223> 融合蛋白
<400> 23
Met His Val Ala Gln Pro Ala Val Val Leu Ala Ser Ser Arg Gly Ile
1 5 10 15
Ala Ser Phe Val Cys Glu Tyr Ala Ser Pro Gly Lys Tyr Thr Glu Val
20 25 30
Arg Val Thr Val Leu Arg Gln Ala Asp Ser Gln Val Thr Glu Val Cys
35 40 45
Ala Ala Thr Tyr Met Met Gly Asn Glu Leu Thr Phe Leu Asp Asp Ser
50 55 60
Ile Cys Thr Gly Thr Ser Ser Gly Asn Gln Val Asn Leu Thr Ile Gln
65 70 75 80
Gly Leu Arg Ala Met Asp Thr Gly Leu Tyr Ile Cys Lys Val Glu Leu
85 90 95
Met Tyr Pro Pro Pro Tyr Phe Glu Gly Met Gly Asn Gly Thr Gln Ile
100 105 110
Tyr Val Ile Asp Pro Glu Pro Cys Pro Asp Ser Asp Gln Glu Pro Lys
115 120 125
Ser Ser Asp Lys Thr His Thr Ser Pro Pro Ser Pro Ala Pro Glu Leu
130 135 140
Leu Gly Gly Ser Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
145 150 155 160
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
165 170 175
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
180 185 190
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
195 200 205
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
210 215 220
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
225 230 235 240
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
245 250 255
Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln
260 265 270
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
275 280 285
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
290 295 300
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
305 310 315 320
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
325 330 335
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
340 345 350
Leu Ser Pro Gly Lys
355
<210> 24
<211> 124
<212> PRT
<213> 人工序列
<220>
<223> 突变体
<400> 24
Ile Gln Val Thr Gln Pro Ser Val Val Leu Ala Ser Ser Arg Gly Ile
1 5 10 15
Ala Ser Phe Val Cys Glu Tyr Ala Ser Pro Gly Lys Ala Thr Glu Val
20 25 30
Arg Val Thr Val Leu Arg Gln Ala Asp Ser Gln Val Thr Glu Val Cys
35 40 45
Ala Ala Thr Tyr Met Met Gly Asn Glu Leu Thr Phe Leu Asp Asp Ser
50 55 60
Ile Cys Thr Gly Thr Ser Ser Gly Asn Gln Val Asn Leu Thr Ile Gln
65 70 75 80
Gly Leu Arg Ala Met Asp Thr Gly Leu Tyr Ile Cys Lys Val Glu Leu
85 90 95
Met Tyr Pro Pro Pro Tyr Tyr Leu Gly Ile Gly Asn Gly Thr Gln Ile
100 105 110
Tyr Val Ile Asp Pro Glu Pro Cys Pro Asp Ser Asp
115 120
<210> 25
<211> 124
<212> PRT
<213> 人工序列
<220>
<223> 突变体
<400> 25
Met His Val Ala Gln Pro Ala Val Val Leu Ala Ser Ser His Gly Leu
1 5 10 15
Ala Ser Phe Pro Cys Glu Tyr Ala Ser Pro Gly Lys Ala Thr Glu Val
20 25 30
Arg Val Thr Val Leu Arg Gln Ala Asp Ser Gln Val Thr Glu Val Cys
35 40 45
Ala Ala Thr Tyr Met Met Gly Asn Glu Leu Thr Phe Leu Asp Asp Ser
50 55 60
Ile Cys Thr Gly Thr Ser Ser Gly Asn Gln Val Asn Leu Thr Ile Gln
65 70 75 80
Gly Leu Arg Ala Met Asp Thr Gly Leu Tyr Ile Cys Lys Val Glu Leu
85 90 95
Met Tyr Pro Pro Pro Tyr Tyr Leu Gly Ile Gly Asn Gly Thr Gln Ile
100 105 110
Tyr Val Ile Asp Pro Glu Pro Cys Pro Asp Ser Asp
115 120
<210> 26
<211> 125
<212> PRT
<213> 人工序列
<220>
<223> 突变体
<400> 26
Met His Val Ala Gln Pro Ala Val Val Leu Ala Ser Ser Arg Gly Ile
1 5 10 15
Ala Ser Phe Val Cys Glu Tyr Ala Ser Pro Ser His Asn Thr Asp Glu
20 25 30
Val Arg Val Thr Val Leu Arg Gln Ala Asp Ser Gln Val Thr Glu Val
35 40 45
Cys Ala Ala Thr Tyr Met Met Gly Asn Glu Leu Thr Phe Leu Asp Asp
50 55 60
Ser Ile Cys Thr Gly Thr Ser Ser Gly Asn Gln Val Asn Leu Thr Ile
65 70 75 80
Gln Gly Leu Arg Ala Met Asp Thr Gly Leu Tyr Ile Cys Lys Val Glu
85 90 95
Leu Met Tyr Pro Pro Pro Tyr Tyr Leu Gly Ile Gly Asn Gly Thr Gln
100 105 110
Ile Tyr Val Ile Asp Pro Glu Pro Cys Pro Asp Ser Asp
115 120 125
<210> 27
<211> 124
<212> PRT
<213> 人工序列
<220>
<223> 突变体
<400> 27
Met His Val Ala Gln Pro Ala Val Val Leu Ala Ser Ser Arg Gly Ile
1 5 10 15
Ala Ser Phe Val Cys Glu Tyr Ala Ser Pro Gly Lys Ala Thr Glu Val
20 25 30
Arg Val Thr Val Leu Arg Thr Asn Asp Gln Met Val Thr Glu Val Cys
35 40 45
Ala Ala Thr Tyr Met Met Gly Asn Glu Leu Thr Phe Leu Asp Asp Ser
50 55 60
Ile Cys Thr Gly Thr Ser Ser Gly Asn Gln Val Asn Leu Thr Ile Gln
65 70 75 80
Gly Leu Arg Ala Met Asp Thr Gly Leu Tyr Ile Cys Lys Val Glu Leu
85 90 95
Met Tyr Pro Pro Pro Tyr Tyr Leu Gly Ile Gly Asn Gly Thr Gln Ile
100 105 110
Tyr Val Ile Asp Pro Glu Pro Cys Pro Asp Ser Asp
115 120
<210> 28
<211> 124
<212> PRT
<213> 人工序列
<220>
<223> 突变体
<400> 28
Met His Val Ala Gln Pro Ala Val Val Leu Ala Ser Ser Arg Gly Ile
1 5 10 15
Ala Ser Phe Val Cys Glu Tyr Ala Ser Pro Gly Lys Ala Thr Glu Val
20 25 30
Arg Val Thr Val Leu Arg Gln Ala Asp Ser Gln Val Thr Glu Val Cys
35 40 45
Ala Ala Thr Phe Thr Glu Lys Asn Thr Val Gly Phe Leu Asp Asp Ser
50 55 60
Ile Cys Thr Gly Thr Ser Ser Gly Asn Gln Val Asn Leu Thr Ile Gln
65 70 75 80
Gly Leu Arg Ala Met Asp Thr Gly Leu Tyr Ile Cys Lys Val Glu Leu
85 90 95
Met Tyr Pro Pro Pro Tyr Tyr Leu Gly Ile Gly Asn Gly Thr Gln Ile
100 105 110
Tyr Val Ile Asp Pro Glu Pro Cys Pro Asp Ser Asp
115 120
<210> 29
<211> 124
<212> PRT
<213> 人工序列
<220>
<223> 突变体
<400> 29
Met His Val Ala Gln Pro Ala Val Val Leu Ala Ser Ser Arg Gly Ile
1 5 10 15
Ala Ser Phe Val Cys Glu Tyr Ala Ser Pro Gly Lys Ala Thr Glu Val
20 25 30
Arg Val Thr Val Leu Arg Gln Ala Asp Ser Gln Val Thr Glu Val Cys
35 40 45
Ala Thr Thr Tyr Met Met Gly Asn Glu Leu Thr Phe Leu Asp Asp Ser
50 55 60
Ile Cys Thr Gly Thr Ser Ser Gly Asn Gln Val Asn Leu Thr Ile Gln
65 70 75 80
Gly Leu Arg Ala Met Asp Thr Gly Leu Tyr Ile Cys Lys Val Glu Leu
85 90 95
Met Tyr Pro Pro Pro Tyr Tyr Leu Gly Ile Gly Asn Gly Thr Gln Ile
100 105 110
Tyr Val Ile Asp Pro Glu Pro Cys Pro Asp Ser Asp
115 120
<210> 30
<211> 124
<212> PRT
<213> 人工
<220>
<223> 突变体
<400> 30
Met His Val Ala Gln Pro Ala Val Val Leu Ala Ser Ser Arg Gly Ile
1 5 10 15
Ala Ser Phe Val Cys Glu Tyr Ala Ser Pro Gly Lys Ala Thr Glu Val
20 25 30
Arg Val Thr Val Leu Arg Gln Ala Asp Ser Gln Val Thr Glu Val Cys
35 40 45
Ala Ala Thr Tyr Met Met Gly Asn Glu Leu Thr Phe Leu Asp Tyr Pro
50 55 60
Phe Cys Ser Gly Thr Ser Ser Gly Asn Gln Val Asn Leu Thr Ile Gln
65 70 75 80
Gly Leu Arg Ala Met Asp Thr Gly Leu Tyr Ile Cys Lys Val Glu Leu
85 90 95
Met Tyr Pro Pro Pro Tyr Tyr Leu Gly Ile Gly Asn Gly Thr Gln Ile
100 105 110
Tyr Val Ile Asp Pro Glu Pro Cys Pro Asp Ser Asp
115 120
<210> 31
<211> 124
<212> PRT
<213> 人工序列
<220>
<223> 突变体
<400> 31
Met His Val Ala Gln Pro Ala Val Val Leu Ala Ser Ser Arg Gly Ile
1 5 10 15
Ala Ser Phe Val Cys Glu Tyr Ala Ser Pro Gly Lys Ala Thr Glu Val
20 25 30
Arg Val Thr Val Leu Arg Gln Ala Asp Ser Gln Val Thr Glu Val Cys
35 40 45
Ala Ala Thr Tyr Met Met Gly Asn Glu Leu Thr Phe Leu Asp Asp Ser
50 55 60
Ile Cys Thr Gly Thr Phe Asn Glu Ser Arg Val Asn Leu Thr Ile Gln
65 70 75 80
Gly Leu Arg Ala Met Asp Thr Gly Leu Tyr Ile Cys Lys Val Glu Leu
85 90 95
Met Tyr Pro Pro Pro Tyr Tyr Leu Gly Ile Gly Asn Gly Thr Gln Ile
100 105 110
Tyr Val Ile Asp Pro Glu Pro Cys Pro Asp Ser Asp
115 120
<210> 32
<211> 125
<212> PRT
<213> 人工序列
<220>
<223> 突变体
<400> 32
Met His Val Ala Gln Pro Ala Val Val Leu Ala Ser Ser Arg Gly Ile
1 5 10 15
Ala Ser Phe Val Cys Glu Tyr Ala Ser Pro Gly Lys Ala Thr Glu Val
20 25 30
Arg Val Thr Val Leu Arg Gln Ala Asp Ser Gln Val Thr Glu Val Cys
35 40 45
Ala Ala Thr Tyr Met Met Gly Asn Glu Leu Thr Phe Leu Asp Asp Ser
50 55 60
Ile Cys Thr Gly Thr Ser Ser Gly Asn Gln Val Asn Leu Thr Ile Gln
65 70 75 80
Gly Leu Arg Ala Met Val Asp Thr Gly Leu Tyr Ile Cys Lys Val Glu
85 90 95
Leu Met Tyr Pro Pro Pro Tyr Tyr Leu Gly Ile Gly Asn Gly Thr Gln
100 105 110
Ile Tyr Val Ile Asp Pro Glu Pro Cys Pro Asp Ser Asp
115 120 125
<210> 33
<211> 125
<212> PRT
<213> 人工
<220>
<223> 突变体
<400> 33
Met His Val Ala Gln Pro Ala Val Val Leu Ala Ser Ser Arg Gly Ile
1 5 10 15
Ala Ser Phe Val Cys Glu Tyr Ala Ser Pro Gly Lys Ala Thr Glu Val
20 25 30
Arg Val Thr Val Leu Arg Gln Ala Asp Ser Gln Val Thr Glu Val Cys
35 40 45
Ala Ala Thr Tyr Met Met Gly Asn Glu Leu Thr Phe Leu Asp Asp Ser
50 55 60
Ile Cys Thr Gly Thr Ser Ser Gly Asn Gln Val Asn Leu Thr Ile Gln
65 70 75 80
Gly Leu Arg Ala Met Met Asp Thr Gly Leu Tyr Leu Cys Lys Val Glu
85 90 95
Leu Met Tyr Pro Pro Pro Tyr Tyr Leu Gly Ile Gly Asn Gly Thr Gln
100 105 110
Ile Tyr Val Ile Asp Pro Glu Pro Cys Pro Asp Ser Asp
115 120 125
<210> 34
<211> 124
<212> PRT
<213> 人工序列
<220>
<223> 突变体
<400> 34
Met His Val Ala Gln Pro Ala Val Val Leu Ala Ser Ser Arg Gly Ile
1 5 10 15
Ala Ser Phe Val Cys Glu Tyr Ala Ser Pro Gly Lys Ala Thr Glu Val
20 25 30
Arg Val Thr Val Leu Arg Gln Ala Asp Ser Gln Val Thr Glu Val Cys
35 40 45
Ala Ala Thr Tyr Met Met Gly Asn Glu Leu Thr Phe Leu Asp Asp Ser
50 55 60
Ile Cys Thr Gly Thr Ser Ser Gly Asn Gln Val Asn Leu Thr Ile Gln
65 70 75 80
Gly Leu Arg Ala Met Asp Thr Gly Leu Tyr Ile Cys Lys Val Glu Leu
85 90 95
Met Tyr Pro Pro Pro Tyr Phe Val Gly Met Gly Asn Gly Thr Gln Ile
100 105 110
Tyr Val Ile Asp Pro Glu Pro Cys Pro Asp Ser Asp
115 120
<210> 35
<211> 124
<212> PRT
<213> 人工序列
<220>
<223> 突变体
<400> 35
Ile Gln Val Thr Gln Pro Ser Val Val Leu Ala Ser Ser Arg Gly Ile
1 5 10 15
Ala Ser Phe Val Cys Glu Tyr Ala Ser Pro Gly Lys Ala Thr Glu Val
20 25 30
Arg Val Thr Val Leu Arg Gln Ala Asp Ser Gln Val Thr Glu Val Cys
35 40 45
Ala Ala Thr Phe Thr Glu Lys Asn Thr Val Gly Phe Leu Asp Asp Ser
50 55 60
Ile Cys Thr Gly Thr Phe Asn Glu Ser Arg Val Asn Leu Thr Ile Gln
65 70 75 80
Gly Leu Arg Ala Met Asp Thr Gly Leu Tyr Ile Cys Lys Val Glu Leu
85 90 95
Met Tyr Pro Pro Pro Tyr Phe Val Gly Met Gly Asn Gly Thr Gln Ile
100 105 110
Tyr Val Ile Asp Pro Glu Pro Cys Pro Asp Ser Asp
115 120
<210> 36
<211> 124
<212> PRT
<213> 人工序列
<220>
<223> 突变体
<400> 36
Met His Val Ala Gln Pro Ala Val Val Leu Ala Ser Ser Arg Gly Ile
1 5 10 15
Ala Ser Phe Val Cys Glu Tyr Ala Ser Pro Gly Lys Tyr Thr Glu Val
20 25 30
Arg Val Thr Val Leu Arg Gln Ala Asp Ser Gln Val Thr Glu Val Cys
35 40 45
Ala Ala Thr Tyr Met Met Gly Asn Glu Leu Thr Phe Leu Asp Asp Ser
50 55 60
Ile Cys Thr Gly Thr Ser Ser Gly Asn Gln Val Asn Leu Thr Ile Gln
65 70 75 80
Gly Leu Arg Ala Met Asp Thr Gly Leu Tyr Ile Cys Lys Val Glu Leu
85 90 95
Met Tyr Pro Pro Pro Tyr Phe Val Gly Met Gly Asn Gly Thr Gln Ile
100 105 110
Tyr Val Ile Asp Pro Glu Pro Cys Pro Asp Ser Asp
115 120
<210> 37
<211> 124
<212> PRT
<213> 人工序列
<220>
<223> 突变体
<400> 37
Ile Gln Val Thr Gln Pro Ser Val Val Leu Ala Ser Ser Arg Gly Ile
1 5 10 15
Ala Ser Phe Val Cys Glu Tyr Ala Ser Pro Gly Lys Ala Thr Glu Val
20 25 30
Arg Val Thr Val Leu Arg Gln Ala Asp Ser Gln Val Thr Glu Val Cys
35 40 45
Ala Ala Thr Phe Thr Glu Lys Asn Thr Val Gly Phe Leu Asp Asp Ser
50 55 60
Ile Cys Thr Gly Thr Ser Ser Gly Asn Gln Val Asn Leu Thr Ile Gln
65 70 75 80
Gly Leu Arg Ala Met Asp Thr Gly Leu Tyr Ile Cys Lys Val Glu Leu
85 90 95
Met Tyr Pro Pro Pro Tyr Phe Val Gly Met Gly Asn Gly Thr Gln Ile
100 105 110
Tyr Val Ile Asp Pro Glu Pro Cys Pro Asp Ser Asp
115 120
<210> 38
<211> 124
<212> PRT
<213> 人工序列
<220>
<223> 突变体
<400> 38
Met His Val Ala Gln Pro Ala Val Val Leu Ala Ser Ser Arg Gly Ile
1 5 10 15
Ala Ser Phe Val Cys Glu Tyr Ala Ser Pro Gly Lys Tyr Thr Glu Val
20 25 30
Arg Val Thr Val Leu Arg Gln Ala Asp Ser Gln Val Thr Glu Val Cys
35 40 45
Ala Ala Thr Tyr Met Met Gly Asn Glu Leu Thr Phe Leu Asp Asp Ser
50 55 60
Ile Cys Thr Gly Thr Ser Ser Gly Asn Gln Val Asn Leu Thr Ile Gln
65 70 75 80
Gly Leu Arg Ala Met Asp Thr Gly Leu Tyr Ile Cys Lys Val Glu Leu
85 90 95
Met Tyr Pro Pro Pro Tyr Tyr Glu Gly Ile Gly Asn Gly Thr Gln Ile
100 105 110
Tyr Val Ile Asp Pro Glu Pro Cys Pro Asp Ser Asp
115 120
<210> 39
<211> 124
<212> PRT
<213> 人工序列
<220>
<223> 突变体
<400> 39
Ile Gln Val Thr Gln Pro Ser Val Val Leu Ala Ser Ser Arg Gly Ile
1 5 10 15
Ala Ser Phe Val Cys Glu Tyr Ala Ser Pro Gly Lys Ala Thr Glu Val
20 25 30
Arg Val Thr Val Leu Arg Gln Ala Asp Ser Gln Val Thr Glu Val Cys
35 40 45
Ala Ala Thr Phe Thr Glu Lys Asn Thr Val Gly Phe Leu Asp Asp Ser
50 55 60
Ile Cys Thr Gly Thr Phe Asn Glu Ser Arg Val Asn Leu Thr Ile Gln
65 70 75 80
Gly Leu Arg Ala Met Asp Thr Gly Leu Tyr Ile Cys Lys Val Glu Leu
85 90 95
Met Tyr Pro Pro Pro Tyr Phe Val Gly Met Gly Asn Gly Thr Gln Ile
100 105 110
Tyr Val Ile Asp Pro Glu Pro Cys Pro Asp Ser Asp
115 120
<210> 40
<211> 124
<212> PRT
<213> 人工序列
<220>
<223> 突变体
<400> 40
Met His Val Ala Gln Pro Ala Val Val Leu Ala Ser Ser Arg Gly Ile
1 5 10 15
Ala Ser Phe Val Cys Glu Tyr Ala Ser Pro Gly Lys Tyr Thr Glu Val
20 25 30
Arg Val Thr Val Leu Arg Gln Ala Asp Ser Gln Val Thr Glu Val Cys
35 40 45
Ala Ala Thr Tyr Met Met Gly Asn Glu Leu Thr Phe Leu Asp Asp Ser
50 55 60
Ile Cys Thr Gly Thr Ser Ser Gly Asn Gln Val Asn Leu Thr Ile Gln
65 70 75 80
Gly Leu Arg Ala Met Asp Thr Gly Leu Tyr Ile Cys Lys Val Glu Leu
85 90 95
Met Tyr Pro Pro Pro Tyr Phe Glu Gly Met Gly Asn Gly Thr Gln Ile
100 105 110
Tyr Val Ile Asp Pro Glu Pro Cys Pro Asp Ser Asp
115 120
<210> 41
<211> 233
<212> PRT
<213> 智人
<400> 41
Gln Glu Pro Lys Ser Ser Asp Lys Thr His Thr Ser Pro Pro Ser Pro
1 5 10 15
Ala Pro Glu Leu Leu Gly Gly Ser Ser Val Phe Leu Phe Pro Pro Lys
20 25 30
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
35 40 45
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
50 55 60
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
65 70 75 80
Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
85 90 95
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
100 105 110
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
115 120 125
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu
130 135 140
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
145 150 155 160
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
165 170 175
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
180 185 190
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
195 200 205
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
210 215 220
Lys Ser Leu Ser Leu Ser Pro Gly Lys
225 230
<210> 42
<211> 357
<212> PRT
<213> 人工序列
<220>
<223> 融合蛋白
<400> 42
Met His Val Ala Gln Pro Ala Val Val Leu Ala Ser Ser Arg Gly Ile
1 5 10 15
Ala Ser Phe Val Cys Glu Tyr Ala Ser Pro Gly Lys Tyr Thr Glu Val
20 25 30
Arg Val Thr Val Leu Arg Gln Ala Asp Ser Gln Val Thr Glu Val Cys
35 40 45
Ala Ala Thr Tyr Met Met Gly Asn Glu Leu Thr Phe Leu Asp Asp Ser
50 55 60
Ile Cys Thr Gly Thr Ser Ser Gly Asn Gln Val Asn Leu Thr Ile Gln
65 70 75 80
Gly Leu Arg Ala Met Asp Thr Gly Leu Tyr Ile Cys Lys Val Glu Leu
85 90 95
Met Tyr Pro Pro Pro Tyr Phe Val Gly Met Gly Asn Gly Thr Gln Ile
100 105 110
Tyr Val Ile Asp Pro Glu Pro Cys Pro Asp Ser Asp Gln Glu Pro Lys
115 120 125
Ser Ser Asp Lys Thr His Thr Ser Pro Pro Ser Pro Ala Pro Glu Leu
130 135 140
Leu Gly Gly Ser Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
145 150 155 160
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
165 170 175
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
180 185 190
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
195 200 205
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
210 215 220
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
225 230 235 240
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
245 250 255
Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln
260 265 270
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
275 280 285
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
290 295 300
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
305 310 315 320
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
325 330 335
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
340 345 350
Leu Ser Pro Gly Lys
355
<210> 43
<211> 357
<212> PRT
<213> 人工序列
<220>
<223> 融合蛋白
<400> 43
Met His Val Ala Gln Pro Ala Val Val Leu Ala Ser Ser Arg Gly Ile
1 5 10 15
Ala Ser Phe Val Cys Glu Tyr Ala Ser Pro Gly Lys Tyr Thr Glu Val
20 25 30
Arg Val Thr Val Leu Arg Gln Ala Asp Ser Gln Val Thr Glu Val Cys
35 40 45
Ala Ala Thr Tyr Met Met Gly Asn Glu Leu Thr Phe Leu Asp Asp Ser
50 55 60
Ile Cys Thr Gly Thr Ser Ser Gly Asn Gln Val Asn Leu Thr Ile Gln
65 70 75 80
Gly Leu Arg Ala Met Asp Thr Gly Leu Tyr Ile Cys Lys Val Glu Leu
85 90 95
Met Tyr Pro Pro Pro Tyr Phe Glu Gly Ile Gly Asn Gly Thr Gln Ile
100 105 110
Tyr Val Ile Asp Pro Glu Pro Cys Pro Asp Ser Asp Gln Glu Pro Lys
115 120 125
Ser Ser Asp Lys Thr His Thr Ser Pro Pro Ser Pro Ala Pro Glu Leu
130 135 140
Leu Gly Gly Ser Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
145 150 155 160
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
165 170 175
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
180 185 190
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
195 200 205
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
210 215 220
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
225 230 235 240
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
245 250 255
Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln
260 265 270
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
275 280 285
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
290 295 300
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
305 310 315 320
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
325 330 335
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
340 345 350
Leu Ser Pro Gly Lys
355
<210> 44
<211> 357
<212> PRT
<213> 人工序列
<220>
<223> 融合蛋白
<400> 44
Met His Val Ala Gln Pro Ala Val Val Leu Ala Ser Ser Arg Gly Ile
1 5 10 15
Ala Ser Phe Val Cys Glu Tyr Ala Ser Pro Gly Lys Tyr Thr Glu Val
20 25 30
Arg Val Thr Val Leu Arg Gln Ala Asp Ser Gln Val Thr Glu Val Cys
35 40 45
Ala Ala Thr Tyr Met Met Gly Asn Glu Leu Thr Phe Leu Asp Asp Ser
50 55 60
Ile Cys Thr Gly Thr Ser Ser Gly Asn Gln Val Asn Leu Thr Ile Gln
65 70 75 80
Gly Leu Arg Ala Met Asp Thr Gly Leu Tyr Ile Cys Lys Val Glu Leu
85 90 95
Met Tyr Pro Pro Pro Tyr Phe Asp Gly Ile Gly Asn Gly Thr Gln Ile
100 105 110
Tyr Val Ile Asp Pro Glu Pro Cys Pro Asp Ser Asp Gln Glu Pro Lys
115 120 125
Ser Ser Asp Lys Thr His Thr Ser Pro Pro Ser Pro Ala Pro Glu Leu
130 135 140
Leu Gly Gly Ser Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
145 150 155 160
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
165 170 175
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
180 185 190
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
195 200 205
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
210 215 220
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
225 230 235 240
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
245 250 255
Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln
260 265 270
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
275 280 285
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
290 295 300
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
305 310 315 320
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
325 330 335
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
340 345 350
Leu Ser Pro Gly Lys
355
<210> 45
<211> 357
<212> PRT
<213> 人工序列
<220>
<223> 融合蛋白
<400> 45
Met His Val Ala Gln Pro Ala Val Val Leu Ala Ser Ser Arg Gly Ile
1 5 10 15
Ala Ser Phe Val Cys Glu Tyr Ala Ser Pro Gly Lys Tyr Thr Glu Val
20 25 30
Arg Val Thr Val Leu Arg Gln Ala Asp Ser Gln Val Thr Glu Val Cys
35 40 45
Ala Ala Thr Tyr Met Met Gly Asn Glu Leu Thr Phe Leu Asp Asp Ser
50 55 60
Ile Cys Thr Gly Thr Ser Ser Gly Asn Gln Val Asn Leu Thr Ile Gln
65 70 75 80
Gly Leu Arg Ala Met Asp Thr Gly Leu Tyr Ile Cys Lys Val Glu Leu
85 90 95
Met Tyr Pro Pro Pro Tyr Phe Val Gly Ile Gly Asn Gly Thr Gln Ile
100 105 110
Tyr Val Ile Asp Pro Glu Pro Cys Pro Asp Ser Asp Gln Glu Pro Lys
115 120 125
Ser Ser Asp Lys Thr His Thr Ser Pro Pro Ser Pro Ala Pro Glu Leu
130 135 140
Leu Gly Gly Ser Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
145 150 155 160
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
165 170 175
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
180 185 190
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
195 200 205
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
210 215 220
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
225 230 235 240
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
245 250 255
Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln
260 265 270
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
275 280 285
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
290 295 300
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
305 310 315 320
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
325 330 335
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
340 345 350
Leu Ser Pro Gly Lys
355
<210> 46
<211> 124
<212> PRT
<213> 人工序列
<220>
<223> 突变体
<400> 46
Met His Val Ala Gln Pro Ala Val Val Leu Ala Ser Ser Arg Gly Ile
1 5 10 15
Ala Ser Phe Val Cys Glu Tyr Ala Ser Pro Gly Lys Tyr Thr Glu Val
20 25 30
Arg Val Thr Val Leu Arg Gln Ala Asp Ser Gln Val Thr Glu Val Cys
35 40 45
Ala Ala Thr Tyr Met Met Gly Asn Glu Leu Thr Phe Leu Asp Asp Ser
50 55 60
Ile Cys Thr Gly Thr Ser Ser Gly Asn Gln Val Asn Leu Thr Ile Gln
65 70 75 80
Gly Leu Arg Ala Met Asp Thr Gly Leu Tyr Ile Cys Lys Val Glu Leu
85 90 95
Met Tyr Pro Pro Pro Tyr Phe Val Gly Met Gly Asn Gly Thr Gln Ile
100 105 110
Tyr Val Ile Asp Pro Glu Pro Cys Pro Asp Ser Asp
115 120
<210> 47
<211> 124
<212> PRT
<213> 人工序列
<220>
<223> 突变体
<400> 47
Met His Val Ala Gln Pro Ala Val Val Leu Ala Ser Ser Arg Gly Ile
1 5 10 15
Ala Ser Phe Val Cys Glu Tyr Ala Ser Pro Gly Lys Tyr Thr Glu Val
20 25 30
Arg Val Thr Val Leu Arg Gln Ala Asp Ser Gln Val Thr Glu Val Cys
35 40 45
Ala Ala Thr Tyr Met Met Gly Asn Glu Leu Thr Phe Leu Asp Asp Ser
50 55 60
Ile Cys Thr Gly Thr Ser Ser Gly Asn Gln Val Asn Leu Thr Ile Gln
65 70 75 80
Gly Leu Arg Ala Met Asp Thr Gly Leu Tyr Ile Cys Lys Val Glu Leu
85 90 95
Met Tyr Pro Pro Pro Tyr Phe Glu Gly Ile Gly Asn Gly Thr Gln Ile
100 105 110
Tyr Val Ile Asp Pro Glu Pro Cys Pro Asp Ser Asp
115 120
<210> 48
<211> 124
<212> PRT
<213> 人工序列
<220>
<223> 突变体
<400> 48
Met His Val Ala Gln Pro Ala Val Val Leu Ala Ser Ser Arg Gly Ile
1 5 10 15
Ala Ser Phe Val Cys Glu Tyr Ala Ser Pro Gly Lys Tyr Thr Glu Val
20 25 30
Arg Val Thr Val Leu Arg Gln Ala Asp Ser Gln Val Thr Glu Val Cys
35 40 45
Ala Ala Thr Tyr Met Met Gly Asn Glu Leu Thr Phe Leu Asp Asp Ser
50 55 60
Ile Cys Thr Gly Thr Ser Ser Gly Asn Gln Val Asn Leu Thr Ile Gln
65 70 75 80
Gly Leu Arg Ala Met Asp Thr Gly Leu Tyr Ile Cys Lys Val Glu Leu
85 90 95
Met Tyr Pro Pro Pro Tyr Phe Asp Gly Ile Gly Asn Gly Thr Gln Ile
100 105 110
Tyr Val Ile Asp Pro Glu Pro Cys Pro Asp Ser Asp
115 120
<210> 49
<211> 124
<212> PRT
<213> 人工序列
<220>
<223> 突变体
<400> 49
Met His Val Ala Gln Pro Ala Val Val Leu Ala Ser Ser Arg Gly Ile
1 5 10 15
Ala Ser Phe Val Cys Glu Tyr Ala Ser Pro Gly Lys Tyr Thr Glu Val
20 25 30
Arg Val Thr Val Leu Arg Gln Ala Asp Ser Gln Val Thr Glu Val Cys
35 40 45
Ala Ala Thr Tyr Met Met Gly Asn Glu Leu Thr Phe Leu Asp Asp Ser
50 55 60
Ile Cys Thr Gly Thr Ser Ser Gly Asn Gln Val Asn Leu Thr Ile Gln
65 70 75 80
Gly Leu Arg Ala Met Asp Thr Gly Leu Tyr Ile Cys Lys Val Glu Leu
85 90 95
Met Tyr Pro Pro Pro Tyr Phe Val Gly Ile Gly Asn Gly Thr Gln Ile
100 105 110
Tyr Val Ile Asp Pro Glu Pro Cys Pro Asp Ser Asp
115 120
<210> 50
<211> 6
<212> PRT
<213> 智人
<400> 50
Met Tyr Pro Pro Pro Tyr
1 5
Claims (19)
1.一种CTLA-4蛋白,其包含CTLA-4的细胞外结构域,所述细胞外结构域包含SEQ IDNO:34、36、39、40和46-48中任一项中列出的序列,其中所述CTLA-4的细胞外结构域在其C端末端与选自下组的人免疫球蛋白(Ig)的Fc区融合:IgG1, IgG2, IgG3, IgG4, IgA, 和IgM。
2.如权利要求1所述的CTLA-4蛋白,其中所述CTLA-4蛋白具有结合B7-1和B7-2中的至少一种的能力。
3.如权利要求2所述的CTLA-4蛋白,其中所述CTLA-4蛋白不阻断抗CTLA-4抗体的抗癌免疫治疗作用。
4.如权利要求3所述的CTLA-4蛋白,其中所述抗CTLA-4抗体是伊匹单抗。
5.如权利要求1所述的CTLA-4蛋白,其中所述免疫球蛋白是IgG1。
6.如权利要求5所述的CTLA-4蛋白,其中所述CTLA-4蛋白的序列包括SEQ ID NO:17、19、22、23和42-44中任一项中列出的序列。
7.一种药物组合物,其包含治疗有效量的如权利要求1所述的CTLA-4蛋白和生理学上可接受的载体或赋形剂。
8.如权利要求1所述的CTLA-4蛋白在制备药物中的用途,所述药物用于治疗受试者中的与抗CTLA-4免疫疗法相关的免疫相关不良事件。
9.如权利要求8所述的用途,其中所述抗CTLA-4免疫疗法是抗CTLA-4抗体。
10.如权利要求9所述的用途,其中所述受试者患有癌症。
11.如权利要求8所述的用途,其中所述CTLA-4蛋白是如权利要求5所述的CTLA-4蛋白。
12.如权利要求11所述的用途,其中所述CTLA-4蛋白是如权利要求6所述的CTLA-4蛋白。
13.如权利要求12所述的用途,其中所述CTLA-4蛋白包含SEQ ID NO: 17中列出的序列。
14.如权利要求12所述的用途,其中所述CTLA-4蛋白包含SEQ ID NO: 23中列出的序列。
15.如权利要求1所述的CTLA-4蛋白在制备药物中的用途,所述药物用于使受试者中的与癌症免疫疗法相关的自身免疫性不良事件最小化。
16.如权利要求15所述的用途,其中所述CTLA-4蛋白是如权利要求5所述的CTLA-4蛋白。
17.如权利要求16所述的用途,其中所述CTLA-4蛋白是如权利要求6所述的CTLA-4蛋白。
18.如权利要求17所述的用途,其中所述CTLA-4蛋白包含SEQ ID NO: 17中列出的序列。
19.如权利要求17所述的用途,其中所述CTLA-4蛋白包含SEQ ID NO: 23中列出的序列。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202310565962.0A CN116942793A (zh) | 2016-09-19 | 2017-09-19 | Cd80和cd86结合蛋白组合物及其用途 |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201662396667P | 2016-09-19 | 2016-09-19 | |
US62/396,667 | 2016-09-19 | ||
PCT/US2017/052264 WO2018053506A1 (en) | 2016-09-19 | 2017-09-19 | Cd80 and cd86 binding protein compositions and uses thereof |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202310565962.0A Division CN116942793A (zh) | 2016-09-19 | 2017-09-19 | Cd80和cd86结合蛋白组合物及其用途 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN109715210A CN109715210A (zh) | 2019-05-03 |
CN109715210B true CN109715210B (zh) | 2023-05-30 |
Family
ID=61618947
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202310565962.0A Pending CN116942793A (zh) | 2016-09-19 | 2017-09-19 | Cd80和cd86结合蛋白组合物及其用途 |
CN201780057250.0A Active CN109715210B (zh) | 2016-09-19 | 2017-09-19 | Cd80和cd86结合蛋白组合物及其用途 |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202310565962.0A Pending CN116942793A (zh) | 2016-09-19 | 2017-09-19 | Cd80和cd86结合蛋白组合物及其用途 |
Country Status (5)
Country | Link |
---|---|
US (3) | US11261233B2 (zh) |
EP (1) | EP3515489A4 (zh) |
CN (2) | CN116942793A (zh) |
CA (1) | CA3036997A1 (zh) |
WO (1) | WO2018053506A1 (zh) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3920970B1 (en) | 2019-02-04 | 2022-11-23 | Assistance Publique Hôpitaux de Paris | Method for treating checkpoint inhibitors induced adverse events |
CN110063970B (zh) * | 2019-04-30 | 2024-09-03 | 上海心脉途医疗科技有限公司 | 与irAE相关的肠道菌群及irAE的治疗和预防方法 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101321783A (zh) * | 2005-07-18 | 2008-12-10 | 安姆根有限公司 | 人抗-b7rp1中和抗体 |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4554101A (en) | 1981-01-09 | 1985-11-19 | New York Blood Center, Inc. | Identification and preparation of epitopes on antigens and allergens on the basis of hydrophilicity |
FR2796067B1 (fr) | 1999-07-05 | 2001-09-07 | Rhodia Chimie Sa | Perfectionnement a l'echange et a la liberation d'une amine, de son fluorure de carbamoyle |
KR100942863B1 (ko) | 1999-08-24 | 2010-02-17 | 메다렉스, 인코포레이티드 | 인간 씨티엘에이-4 항체 및 그의 용도 |
IL152315A (en) * | 2000-05-26 | 2010-04-15 | Bristol Myers Squibb Co | Soluble mutant ALTC4 molecules and pharmaceutical preparations containing them |
WO2009100140A1 (en) | 2008-02-04 | 2009-08-13 | Medarex, Inc. | Anti-clta-4 antibodies with reduced blocking of binding of ctla-4 to b7 and uses thereof |
KR20130049775A (ko) | 2010-03-12 | 2013-05-14 | 애브비 바이오테라퓨틱스 인크. | Ctla4 단백질 및 이의 용도 |
KR101471647B1 (ko) * | 2011-10-26 | 2014-12-11 | 국립암센터 | 변이 ctla4 유전자 이입 t 세포 및 이를 포함하는 항암 면역치료용 조성물 |
CA2936611A1 (en) * | 2014-01-13 | 2015-07-16 | Pieris Pharmaceuticals Gmbh | Multi-specific polypeptide useful for localized tumor immunomodulation |
EP4374926A3 (en) * | 2015-12-15 | 2024-08-07 | OncoC4, Inc. | Chimeric and humanized anti-human ctla4 monoclonal antibodies and uses thereof |
KR20200142498A (ko) * | 2018-02-02 | 2020-12-22 | 온코이뮨, 아이앤씨. | 암 치료를 위한 더 안전하고 더 효과적인 항-ctla-4 항체를 선택하고 설계하는 방법 |
-
2017
- 2017-09-19 CA CA3036997A patent/CA3036997A1/en active Pending
- 2017-09-19 CN CN202310565962.0A patent/CN116942793A/zh active Pending
- 2017-09-19 CN CN201780057250.0A patent/CN109715210B/zh active Active
- 2017-09-19 EP EP17851784.3A patent/EP3515489A4/en active Pending
- 2017-09-19 US US16/333,888 patent/US11261233B2/en active Active
- 2017-09-19 WO PCT/US2017/052264 patent/WO2018053506A1/en unknown
-
2022
- 2022-02-22 US US17/677,795 patent/US20220259285A1/en active Pending
- 2022-02-22 US US17/677,814 patent/US20220259286A1/en active Pending
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101321783A (zh) * | 2005-07-18 | 2008-12-10 | 安姆根有限公司 | 人抗-b7rp1中和抗体 |
Also Published As
Publication number | Publication date |
---|---|
EP3515489A1 (en) | 2019-07-31 |
EP3515489A4 (en) | 2020-05-06 |
US11261233B2 (en) | 2022-03-01 |
US20220259285A1 (en) | 2022-08-18 |
US20190263889A1 (en) | 2019-08-29 |
CN116942793A (zh) | 2023-10-27 |
CA3036997A1 (en) | 2018-03-22 |
CN109715210A (zh) | 2019-05-03 |
WO2018053506A1 (en) | 2018-03-22 |
US20220259286A1 (en) | 2022-08-18 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP7286845B2 (ja) | キメラ及びヒト化抗ヒトctla4モノクローナル抗体ならびにその使用 | |
AU2017261541B2 (en) | Inhibitors of T-cell activation | |
CN112469479B (zh) | 治疗癌症和自身免疫性疾病的试剂和方法 | |
US20220259286A1 (en) | CD80 and CD86 Binding Protein Compositions and Uses Thereof | |
EP1406928B1 (en) | Ntb-a, a surface molecule involved in natural killer cells activity | |
DU et al. | CD80 and CD86 Binding Protein Compositions and Uses Thereof | |
EA038617B1 (ru) | Химерные и гуманизированные античеловеческие ctla-4 моноклональные антитела и их использование | |
OA16522A (en) | Inhibitors of T-cell activation |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
TA01 | Transfer of patent application right |
Effective date of registration: 20230317 Address after: Maryland, USA Applicant after: Onco Pharmaceuticals Applicant after: Children's Research Institute of National Children's Medical Center Address before: Maryland, USA Applicant before: ONCOIMMUNE, Inc. Applicant before: Children's Research Institute of National Children's Medical Center |
|
TA01 | Transfer of patent application right | ||
GR01 | Patent grant | ||
GR01 | Patent grant |