WO1997040068A1 - Novel peptides suitable for use in antigen specific immunosuppressive therapy - Google Patents
Novel peptides suitable for use in antigen specific immunosuppressive therapy Download PDFInfo
- Publication number
- WO1997040068A1 WO1997040068A1 PCT/EP1997/002051 EP9702051W WO9740068A1 WO 1997040068 A1 WO1997040068 A1 WO 1997040068A1 EP 9702051 W EP9702051 W EP 9702051W WO 9740068 A1 WO9740068 A1 WO 9740068A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- seq
- peptide
- amino acid
- type
- peptides
- Prior art date
Links
- 108090000765 processed proteins & peptides Proteins 0.000 title claims abstract description 205
- 102000004196 processed proteins & peptides Human genes 0.000 title claims abstract description 92
- 239000000427 antigen Substances 0.000 title description 31
- 108091007433 antigens Proteins 0.000 title description 31
- 102000036639 antigens Human genes 0.000 title description 31
- 238000002650 immunosuppressive therapy Methods 0.000 title description 3
- 210000001744 T-lymphocyte Anatomy 0.000 claims abstract description 56
- 125000000539 amino acid group Chemical group 0.000 claims abstract description 4
- 125000003275 alpha amino acid group Chemical group 0.000 claims abstract 6
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 claims description 19
- 230000004044 response Effects 0.000 claims description 13
- 230000009696 proliferative response Effects 0.000 claims description 11
- 210000004369 blood Anatomy 0.000 claims description 6
- 239000008280 blood Substances 0.000 claims description 6
- 238000001514 detection method Methods 0.000 claims description 6
- 238000003149 assay kit Methods 0.000 claims description 5
- 238000002405 diagnostic procedure Methods 0.000 claims description 5
- 238000011534 incubation Methods 0.000 claims description 3
- 238000002955 isolation Methods 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- 238000012360 testing method Methods 0.000 claims description 2
- 230000006378 damage Effects 0.000 abstract description 10
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 9
- 230000009885 systemic effect Effects 0.000 abstract description 9
- 210000001188 articular cartilage Anatomy 0.000 abstract description 8
- 230000001900 immune effect Effects 0.000 abstract description 7
- 230000001404 mediated effect Effects 0.000 abstract description 7
- 150000001413 amino acids Chemical group 0.000 description 122
- 239000012634 fragment Substances 0.000 description 70
- 239000002253 acid Substances 0.000 description 50
- 206010039073 rheumatoid arthritis Diseases 0.000 description 28
- 150000007513 acids Chemical class 0.000 description 18
- 101001100327 Homo sapiens RNA-binding protein 45 Proteins 0.000 description 14
- 102100038823 RNA-binding protein 45 Human genes 0.000 description 14
- 210000004027 cell Anatomy 0.000 description 12
- 239000011230 binding agent Substances 0.000 description 10
- 210000000845 cartilage Anatomy 0.000 description 10
- VPZXBVLAVMBEQI-UHFFFAOYSA-N glycyl-DL-alpha-alanine Natural products OC(=O)C(C)NC(=O)CN VPZXBVLAVMBEQI-UHFFFAOYSA-N 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- 238000000034 method Methods 0.000 description 8
- 102100021277 Beta-secretase 2 Human genes 0.000 description 7
- 101710150190 Beta-secretase 2 Proteins 0.000 description 7
- 210000000987 immune system Anatomy 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 239000002671 adjuvant Substances 0.000 description 6
- 239000003550 marker Substances 0.000 description 6
- 238000002560 therapeutic procedure Methods 0.000 description 6
- AOHKLEBWKMKITA-IHRRRGAJSA-N Arg-Phe-Ser Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CCCN=C(N)N)N AOHKLEBWKMKITA-IHRRRGAJSA-N 0.000 description 5
- 208000023275 Autoimmune disease Diseases 0.000 description 5
- 102000043131 MHC class II family Human genes 0.000 description 5
- 108091054438 MHC class II family Proteins 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 238000001378 electrochemiluminescence detection Methods 0.000 description 5
- 210000005259 peripheral blood Anatomy 0.000 description 5
- 239000011886 peripheral blood Substances 0.000 description 5
- 230000020382 suppression by virus of host antigen processing and presentation of peptide antigen via MHC class I Effects 0.000 description 5
- RVLOMLVNNBWRSR-KNIFDHDWSA-N (2s)-2-aminopropanoic acid;(2s)-2,6-diaminohexanoic acid Chemical compound C[C@H](N)C(O)=O.NCCCC[C@H](N)C(O)=O RVLOMLVNNBWRSR-KNIFDHDWSA-N 0.000 description 4
- 101100512078 Caenorhabditis elegans lys-1 gene Proteins 0.000 description 4
- 101100505161 Caenorhabditis elegans mel-32 gene Proteins 0.000 description 4
- 108010058597 HLA-DR Antigens Proteins 0.000 description 4
- 102000006354 HLA-DR Antigens Human genes 0.000 description 4
- WNGVUZWBXZKQES-YUMQZZPRSA-N Leu-Ala-Gly Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C)C(=O)NCC(O)=O WNGVUZWBXZKQES-YUMQZZPRSA-N 0.000 description 4
- RXGLHDWAZQECBI-SRVKXCTJSA-N Leu-Leu-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O RXGLHDWAZQECBI-SRVKXCTJSA-N 0.000 description 4
- 108700018351 Major Histocompatibility Complex Proteins 0.000 description 4
- NSMXRFMGZYTFEX-KJEVXHAQSA-N Met-Thr-Tyr Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)O)NC(=O)[C@H](CCSC)N)O NSMXRFMGZYTFEX-KJEVXHAQSA-N 0.000 description 4
- 108010079364 N-glycylalanine Proteins 0.000 description 4
- NAIPAPCKKRCMBL-JYJNAYRXSA-N Pro-Pro-Phe Chemical compound C([C@@H](C(=O)O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H]1NCCC1)C1=CC=CC=C1 NAIPAPCKKRCMBL-JYJNAYRXSA-N 0.000 description 4
- NMCBVGFGWSIGSB-NUTKFTJISA-N Trp-Ala-Leu Chemical compound C[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)N NMCBVGFGWSIGSB-NUTKFTJISA-N 0.000 description 4
- 206010003246 arthritis Diseases 0.000 description 4
- 239000002953 phosphate buffered saline Substances 0.000 description 4
- 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 3
- NCQMBSJGJMYKCK-ZLUOBGJFSA-N Ala-Ser-Ser Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O NCQMBSJGJMYKCK-ZLUOBGJFSA-N 0.000 description 3
- IIGHQOPGMGKDMT-SRVKXCTJSA-N Cys-Asp-Phe Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CS)N IIGHQOPGMGKDMT-SRVKXCTJSA-N 0.000 description 3
- RDPOETHPAQEGDP-ACZMJKKPSA-N Glu-Asp-Ala Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(O)=O RDPOETHPAQEGDP-ACZMJKKPSA-N 0.000 description 3
- RZMXBFUSQNLEQF-QEJZJMRPSA-N Glu-Trp-Asn Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CCC(=O)O)N RZMXBFUSQNLEQF-QEJZJMRPSA-N 0.000 description 3
- GWCRIHNSVMOBEQ-BQBZGAKWSA-N Gly-Arg-Ser Chemical compound [H]NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(O)=O GWCRIHNSVMOBEQ-BQBZGAKWSA-N 0.000 description 3
- VFBZWZXKCVBTJR-SRVKXCTJSA-N His-Leu-Asp Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)O)NC(=O)[C@H](CC1=CN=CN1)N VFBZWZXKCVBTJR-SRVKXCTJSA-N 0.000 description 3
- JSQIXEHORHLQEE-MEYUZBJRSA-N His-Phe-Thr Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O JSQIXEHORHLQEE-MEYUZBJRSA-N 0.000 description 3
- 206010062016 Immunosuppression Diseases 0.000 description 3
- LZDNBBYBDGBADK-UHFFFAOYSA-N L-valyl-L-tryptophan Natural products C1=CC=C2C(CC(NC(=O)C(N)C(C)C)C(O)=O)=CNC2=C1 LZDNBBYBDGBADK-UHFFFAOYSA-N 0.000 description 3
- SUPVSFFZWVOEOI-UHFFFAOYSA-N Leu-Ala-Tyr Natural products CC(C)CC(N)C(=O)NC(C)C(=O)NC(C(O)=O)CC1=CC=C(O)C=C1 SUPVSFFZWVOEOI-UHFFFAOYSA-N 0.000 description 3
- KSZCCRIGNVSHFH-UWVGGRQHSA-N Leu-Arg-Gly Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O KSZCCRIGNVSHFH-UWVGGRQHSA-N 0.000 description 3
- DLCOFDAHNMMQPP-SRVKXCTJSA-N Leu-Asp-Leu Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O DLCOFDAHNMMQPP-SRVKXCTJSA-N 0.000 description 3
- SVBJIZVVYJYGLA-DCAQKATOSA-N Leu-Ser-Val Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O SVBJIZVVYJYGLA-DCAQKATOSA-N 0.000 description 3
- WFCKERTZVCQXKH-KBPBESRZSA-N Leu-Tyr-Gly Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)NCC(O)=O WFCKERTZVCQXKH-KBPBESRZSA-N 0.000 description 3
- MEQLGHAMAUPOSJ-DCAQKATOSA-N Lys-Ser-Val Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O MEQLGHAMAUPOSJ-DCAQKATOSA-N 0.000 description 3
- XMBSYZWANAQXEV-UHFFFAOYSA-N N-alpha-L-glutamyl-L-phenylalanine Natural products OC(=O)CCC(N)C(=O)NC(C(O)=O)CC1=CC=CC=C1 XMBSYZWANAQXEV-UHFFFAOYSA-N 0.000 description 3
- 108010066427 N-valyltryptophan Proteins 0.000 description 3
- TXKWKTWYTIAZSV-KKUMJFAQSA-N Phe-Leu-Cys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)N TXKWKTWYTIAZSV-KKUMJFAQSA-N 0.000 description 3
- XQLBWXHVZVBNJM-FXQIFTODSA-N Pro-Ala-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1 XQLBWXHVZVBNJM-FXQIFTODSA-N 0.000 description 3
- AMBLXEMWFARNNQ-DCAQKATOSA-N Pro-Asn-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@@H]1CCCN1 AMBLXEMWFARNNQ-DCAQKATOSA-N 0.000 description 3
- DMKWYMWNEKIPFC-IUCAKERBSA-N Pro-Gly-Arg Chemical compound [H]N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(O)=O DMKWYMWNEKIPFC-IUCAKERBSA-N 0.000 description 3
- 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 3
- FKYWFUYPVKLJLP-DCAQKATOSA-N Ser-Pro-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CO FKYWFUYPVKLJLP-DCAQKATOSA-N 0.000 description 3
- MECLEFZMPPOEAC-VOAKCMCISA-N Thr-Leu-Lys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)O)N)O MECLEFZMPPOEAC-VOAKCMCISA-N 0.000 description 3
- DXYWRYQRKPIGGU-BPNCWPANSA-N Tyr-Ala-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 DXYWRYQRKPIGGU-BPNCWPANSA-N 0.000 description 3
- HTHCZRWCFXMENJ-KKUMJFAQSA-N Tyr-Arg-Glu Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(O)=O HTHCZRWCFXMENJ-KKUMJFAQSA-N 0.000 description 3
- BEIGSKUPTIFYRZ-SRVKXCTJSA-N Tyr-Asp-Asp Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC(=O)O)C(=O)O)N)O BEIGSKUPTIFYRZ-SRVKXCTJSA-N 0.000 description 3
- PRONOHBTMLNXCZ-BZSNNMDCSA-N Tyr-Leu-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 PRONOHBTMLNXCZ-BZSNNMDCSA-N 0.000 description 3
- 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 3
- 108010064997 VPY tripeptide Proteins 0.000 description 3
- CELJCNRXKZPTCX-XPUUQOCRSA-N Val-Gly-Ala Chemical compound CC(C)[C@H](N)C(=O)NCC(=O)N[C@@H](C)C(O)=O CELJCNRXKZPTCX-XPUUQOCRSA-N 0.000 description 3
- QWCZXKIFPWPQHR-JYJNAYRXSA-N Val-Pro-Tyr Chemical compound CC(C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 QWCZXKIFPWPQHR-JYJNAYRXSA-N 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 108010047495 alanylglycine Proteins 0.000 description 3
- 108010043240 arginyl-leucyl-glycine Proteins 0.000 description 3
- 108010069205 aspartyl-phenylalanine Proteins 0.000 description 3
- 108010016616 cysteinylglycine Proteins 0.000 description 3
- 230000001066 destructive effect Effects 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000013604 expression vector Substances 0.000 description 3
- 108010080575 glutamyl-aspartyl-alanine Proteins 0.000 description 3
- 108010050848 glycylleucine Proteins 0.000 description 3
- 230000028993 immune response Effects 0.000 description 3
- 230000001506 immunosuppresive effect Effects 0.000 description 3
- 230000004054 inflammatory process Effects 0.000 description 3
- 230000028709 inflammatory response Effects 0.000 description 3
- 108010034529 leucyl-lysine Proteins 0.000 description 3
- 108010017391 lysylvaline Proteins 0.000 description 3
- 108010005942 methionylglycine Proteins 0.000 description 3
- 238000010647 peptide synthesis reaction Methods 0.000 description 3
- 235000018102 proteins Nutrition 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 108010061238 threonyl-glycine Proteins 0.000 description 3
- 108010015385 valyl-prolyl-proline Proteins 0.000 description 3
- 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 2
- SOBIAADAMRHGKH-CIUDSAMLSA-N Ala-Leu-Ser Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O SOBIAADAMRHGKH-CIUDSAMLSA-N 0.000 description 2
- KLALXKYLOMZDQT-ZLUOBGJFSA-N Ala-Ser-Asn Chemical compound C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CC(N)=O KLALXKYLOMZDQT-ZLUOBGJFSA-N 0.000 description 2
- SAHQGRZIQVEJPF-JXUBOQSCSA-N Ala-Thr-Lys Chemical compound C[C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@H](C(O)=O)CCCCN SAHQGRZIQVEJPF-JXUBOQSCSA-N 0.000 description 2
- IETUUAHKCHOQHP-KZVJFYERSA-N Ala-Thr-Val Chemical compound CC(C)[C@H](NC(=O)[C@@H](NC(=O)[C@H](C)N)[C@@H](C)O)C(O)=O IETUUAHKCHOQHP-KZVJFYERSA-N 0.000 description 2
- MUGAESARFRGOTQ-IGNZVWTISA-N Ala-Tyr-Tyr Chemical compound C[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CC2=CC=C(C=C2)O)C(=O)O)N MUGAESARFRGOTQ-IGNZVWTISA-N 0.000 description 2
- RYQSYXFGFOTJDJ-RHYQMDGZSA-N Arg-Thr-Leu Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O RYQSYXFGFOTJDJ-RHYQMDGZSA-N 0.000 description 2
- XHFXZQHTLJVZBN-FXQIFTODSA-N Asn-Arg-Asn Chemical compound C(C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CC(=O)N)N)CN=C(N)N XHFXZQHTLJVZBN-FXQIFTODSA-N 0.000 description 2
- PPCORQFLAZWUNO-QWRGUYRKSA-N Asn-Phe-Gly Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)NCC(=O)O)NC(=O)[C@H](CC(=O)N)N PPCORQFLAZWUNO-QWRGUYRKSA-N 0.000 description 2
- 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 2
- SVFOIXMRMLROHO-SRVKXCTJSA-N Asp-Asp-Phe Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 SVFOIXMRMLROHO-SRVKXCTJSA-N 0.000 description 2
- 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 2
- SCQIQCWLOMOEFP-DCAQKATOSA-N Asp-Leu-Arg Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O SCQIQCWLOMOEFP-DCAQKATOSA-N 0.000 description 2
- PAYPSKIBMDHZPI-CIUDSAMLSA-N Asp-Leu-Asp Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O PAYPSKIBMDHZPI-CIUDSAMLSA-N 0.000 description 2
- KRQFMDNIUOVRIF-KKUMJFAQSA-N Asp-Phe-His Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC2=CN=CN2)C(=O)O)NC(=O)[C@H](CC(=O)O)N KRQFMDNIUOVRIF-KKUMJFAQSA-N 0.000 description 2
- MGSVBZIBCCKGCY-ZLUOBGJFSA-N Asp-Ser-Ser Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O MGSVBZIBCCKGCY-ZLUOBGJFSA-N 0.000 description 2
- KCOPOPKJRHVGPE-AQZXSJQPSA-N Asp-Thr-Trp Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O KCOPOPKJRHVGPE-AQZXSJQPSA-N 0.000 description 2
- RKXVTTIQNKPCHU-KKHAAJSZSA-N Asp-Val-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CC(O)=O RKXVTTIQNKPCHU-KKHAAJSZSA-N 0.000 description 2
- 101100289888 Caenorhabditis elegans lys-5 gene Proteins 0.000 description 2
- GFMJUESGWILPEN-MELADBBJSA-N Cys-Phe-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC2=CC=CC=C2)NC(=O)[C@H](CS)N)C(=O)O GFMJUESGWILPEN-MELADBBJSA-N 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- DMYACXMQUABZIQ-NRPADANISA-N Glu-Ser-Val Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O DMYACXMQUABZIQ-NRPADANISA-N 0.000 description 2
- GPSHCSTUYOQPAI-JHEQGTHGSA-N Glu-Thr-Gly Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(O)=O GPSHCSTUYOQPAI-JHEQGTHGSA-N 0.000 description 2
- UPOJUWHGMDJUQZ-IUCAKERBSA-N Gly-Arg-Arg Chemical compound NC(=N)NCCC[C@H](NC(=O)CN)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O UPOJUWHGMDJUQZ-IUCAKERBSA-N 0.000 description 2
- UPADCCSMVOQAGF-LBPRGKRZSA-N Gly-Gly-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)CNC(=O)CN)C(O)=O)=CNC2=C1 UPADCCSMVOQAGF-LBPRGKRZSA-N 0.000 description 2
- CQIIXEHDSZUSAG-QWRGUYRKSA-N Gly-His-His Chemical compound C([C@H](NC(=O)CN)C(=O)N[C@@H](CC=1NC=NC=1)C(O)=O)C1=CN=CN1 CQIIXEHDSZUSAG-QWRGUYRKSA-N 0.000 description 2
- JSLVAHYTAJJEQH-QWRGUYRKSA-N Gly-Ser-Phe Chemical compound NCC(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 JSLVAHYTAJJEQH-QWRGUYRKSA-N 0.000 description 2
- ZZWUYQXMIFTIIY-WEDXCCLWSA-N Gly-Thr-Leu Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O ZZWUYQXMIFTIIY-WEDXCCLWSA-N 0.000 description 2
- TVTZEOHWHUVYCG-KYNKHSRBSA-N Gly-Thr-Thr Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O TVTZEOHWHUVYCG-KYNKHSRBSA-N 0.000 description 2
- IHDKKJVBLGXLEL-STQMWFEESA-N Gly-Tyr-Met Chemical compound CSCC[C@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)CN)C(O)=O IHDKKJVBLGXLEL-STQMWFEESA-N 0.000 description 2
- 108090000288 Glycoproteins Proteins 0.000 description 2
- 102000003886 Glycoproteins Human genes 0.000 description 2
- 108010029657 HLA-DRB1*04:01 antigen Proteins 0.000 description 2
- SOFSRBYHDINIRG-QTKMDUPCSA-N His-Arg-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC1=CN=CN1)N)O SOFSRBYHDINIRG-QTKMDUPCSA-N 0.000 description 2
- RAVLQPXCMRCLKT-KBPBESRZSA-N His-Gly-Phe Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)NCC(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O RAVLQPXCMRCLKT-KBPBESRZSA-N 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- HXWALXSAVBLTPK-NUTKFTJISA-N Leu-Ala-Trp Chemical compound C[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)NC(=O)[C@H](CC(C)C)N HXWALXSAVBLTPK-NUTKFTJISA-N 0.000 description 2
- STAVRDQLZOTNKJ-RHYQMDGZSA-N Leu-Arg-Thr Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(O)=O STAVRDQLZOTNKJ-RHYQMDGZSA-N 0.000 description 2
- YKNBJXOJTURHCU-DCAQKATOSA-N Leu-Asp-Arg Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CCCN=C(N)N YKNBJXOJTURHCU-DCAQKATOSA-N 0.000 description 2
- OXRLYTYUXAQTHP-YUMQZZPRSA-N Leu-Gly-Ala Chemical compound [H]N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](C)C(O)=O OXRLYTYUXAQTHP-YUMQZZPRSA-N 0.000 description 2
- AXVIGSRGTMNSJU-YESZJQIVSA-N Leu-Tyr-Pro Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N2CCC[C@@H]2C(=O)O)N AXVIGSRGTMNSJU-YESZJQIVSA-N 0.000 description 2
- HKCCVDWHHTVVPN-CIUDSAMLSA-N Lys-Asp-Ala Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(O)=O HKCCVDWHHTVVPN-CIUDSAMLSA-N 0.000 description 2
- GJJQCBVRWDGLMQ-GUBZILKMSA-N Lys-Glu-Ala Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(O)=O GJJQCBVRWDGLMQ-GUBZILKMSA-N 0.000 description 2
- VQXAVLQBQJMENB-SRVKXCTJSA-N Lys-Glu-Met Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCSC)C(O)=O VQXAVLQBQJMENB-SRVKXCTJSA-N 0.000 description 2
- LJADEBULDNKJNK-IHRRRGAJSA-N Lys-Leu-Val Chemical compound CC(C)C[C@H](NC(=O)[C@@H](N)CCCCN)C(=O)N[C@@H](C(C)C)C(O)=O LJADEBULDNKJNK-IHRRRGAJSA-N 0.000 description 2
- ZUGVARDEGWMMLK-SRVKXCTJSA-N Lys-Ser-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CCCCN ZUGVARDEGWMMLK-SRVKXCTJSA-N 0.000 description 2
- RPWTZTBIFGENIA-VOAKCMCISA-N Lys-Thr-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O RPWTZTBIFGENIA-VOAKCMCISA-N 0.000 description 2
- PZUUMQPMHBJJKE-AVGNSLFASA-N Met-Leu-Arg Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CCCNC(N)=N PZUUMQPMHBJJKE-AVGNSLFASA-N 0.000 description 2
- QZPXMHVKPHJNTR-DCAQKATOSA-N Met-Leu-Asn Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O QZPXMHVKPHJNTR-DCAQKATOSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 101100342977 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) leu-1 gene Proteins 0.000 description 2
- 101100205189 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) leu-5 gene Proteins 0.000 description 2
- 239000000020 Nitrocellulose Substances 0.000 description 2
- 101100117565 Oryza sativa subsp. japonica DRB4 gene Proteins 0.000 description 2
- CGOMLCQJEMWMCE-STQMWFEESA-N Phe-Arg-Gly Chemical compound NC(N)=NCCC[C@@H](C(=O)NCC(O)=O)NC(=O)[C@@H](N)CC1=CC=CC=C1 CGOMLCQJEMWMCE-STQMWFEESA-N 0.000 description 2
- WWPAHTZOWURIMR-ULQDDVLXSA-N Phe-Pro-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CC1=CC=CC=C1 WWPAHTZOWURIMR-ULQDDVLXSA-N 0.000 description 2
- KLYYKKGCPOGDPE-OEAJRASXSA-N Phe-Thr-Leu Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O KLYYKKGCPOGDPE-OEAJRASXSA-N 0.000 description 2
- PTDAGKJHZBGDKD-OEAJRASXSA-N Phe-Thr-Lys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)N)O PTDAGKJHZBGDKD-OEAJRASXSA-N 0.000 description 2
- JDJMFMVVJHLWDP-UNQGMJICSA-N Pro-Thr-Phe Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O JDJMFMVVJHLWDP-UNQGMJICSA-N 0.000 description 2
- NLQUOHDCLSFABG-GUBZILKMSA-N Ser-Arg-Arg Chemical compound NC(N)=NCCC[C@H](NC(=O)[C@H](CO)N)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O NLQUOHDCLSFABG-GUBZILKMSA-N 0.000 description 2
- UBRXAVQWXOWRSJ-ZLUOBGJFSA-N Ser-Asn-Asp Chemical compound C([C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)O)NC(=O)[C@H](CO)N)C(=O)N UBRXAVQWXOWRSJ-ZLUOBGJFSA-N 0.000 description 2
- KDGARKCAKHBEDB-NKWVEPMBSA-N Ser-Gly-Pro Chemical compound C1C[C@@H](N(C1)C(=O)CNC(=O)[C@H](CO)N)C(=O)O KDGARKCAKHBEDB-NKWVEPMBSA-N 0.000 description 2
- PJIQEIFXZPCWOJ-FXQIFTODSA-N Ser-Pro-Asp Chemical compound [H]N[C@@H](CO)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(O)=O)C(O)=O PJIQEIFXZPCWOJ-FXQIFTODSA-N 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 101150006914 TRP1 gene Proteins 0.000 description 2
- LVTKHGUGBGNBPL-UHFFFAOYSA-N Trp-P-1 Chemical compound N1C2=CC=CC=C2C2=C1C(C)=C(N)N=C2C LVTKHGUGBGNBPL-UHFFFAOYSA-N 0.000 description 2
- XQMGDVVKFRLQKH-BBRMVZONSA-N Trp-Val-Gly Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)NCC(O)=O)=CNC2=C1 XQMGDVVKFRLQKH-BBRMVZONSA-N 0.000 description 2
- WQOHKVRQDLNDIL-YJRXYDGGSA-N Tyr-Thr-Ser 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](CO)C(O)=O WQOHKVRQDLNDIL-YJRXYDGGSA-N 0.000 description 2
- 230000003213 activating effect Effects 0.000 description 2
- MGSKVZWGBWPBTF-UHFFFAOYSA-N aebsf Chemical compound NCCC1=CC=C(S(F)(=O)=O)C=C1 MGSKVZWGBWPBTF-UHFFFAOYSA-N 0.000 description 2
- 108010087924 alanylproline Proteins 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 210000000612 antigen-presenting cell Anatomy 0.000 description 2
- 230000002917 arthritic effect Effects 0.000 description 2
- 210000001106 artificial yeast chromosome Anatomy 0.000 description 2
- 108010077245 asparaginyl-proline Proteins 0.000 description 2
- 108010040443 aspartyl-aspartic acid Proteins 0.000 description 2
- 230000006472 autoimmune response Effects 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 239000013611 chromosomal DNA Substances 0.000 description 2
- 230000006020 chronic inflammation Effects 0.000 description 2
- 239000012997 ficoll-paque Substances 0.000 description 2
- XBGGUPMXALFZOT-UHFFFAOYSA-N glycyl-L-tyrosine hemihydrate Natural products NCC(=O)NC(C(O)=O)CC1=CC=C(O)C=C1 XBGGUPMXALFZOT-UHFFFAOYSA-N 0.000 description 2
- 108010072405 glycyl-aspartyl-glycine Proteins 0.000 description 2
- 108010074027 glycyl-seryl-phenylalanine Proteins 0.000 description 2
- 108010087823 glycyltyrosine Proteins 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 108010036413 histidylglycine Proteins 0.000 description 2
- 239000003018 immunosuppressive agent Substances 0.000 description 2
- 229940124589 immunosuppressive drug Drugs 0.000 description 2
- 238000010348 incorporation Methods 0.000 description 2
- 210000004698 lymphocyte Anatomy 0.000 description 2
- 108010064235 lysylglycine Proteins 0.000 description 2
- 108010054155 lysyllysine Proteins 0.000 description 2
- 210000005087 mononuclear cell Anatomy 0.000 description 2
- 229920001220 nitrocellulos Polymers 0.000 description 2
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000000159 protein binding assay Methods 0.000 description 2
- 108010048397 seryl-lysyl-leucine Proteins 0.000 description 2
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 2
- 239000007790 solid phase Substances 0.000 description 2
- 238000010254 subcutaneous injection Methods 0.000 description 2
- 239000007929 subcutaneous injection Substances 0.000 description 2
- 108010033670 threonyl-aspartyl-tyrosine Proteins 0.000 description 2
- 108010031491 threonyl-lysyl-glutamic acid Proteins 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 108010080629 tryptophan-leucine Proteins 0.000 description 2
- 108010073969 valyllysine Proteins 0.000 description 2
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 1
- KISWVXRQTGLFGD-UHFFFAOYSA-N 2-[[2-[[6-amino-2-[[2-[[2-[[5-amino-2-[[2-[[1-[2-[[6-amino-2-[(2,5-diamino-5-oxopentanoyl)amino]hexanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]pyrrolidine-2-carbonyl]amino]-3-hydroxypropanoyl]amino]-5-oxopentanoyl]amino]-5-(diaminomethylideneamino)p Chemical compound C1CCN(C(=O)C(CCCN=C(N)N)NC(=O)C(CCCCN)NC(=O)C(N)CCC(N)=O)C1C(=O)NC(CO)C(=O)NC(CCC(N)=O)C(=O)NC(CCCN=C(N)N)C(=O)NC(CO)C(=O)NC(CCCCN)C(=O)NC(C(=O)NC(CC(C)C)C(O)=O)CC1=CC=C(O)C=C1 KISWVXRQTGLFGD-UHFFFAOYSA-N 0.000 description 1
- BDDLHHRCDSJVKV-UHFFFAOYSA-N 7028-40-2 Chemical compound CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O BDDLHHRCDSJVKV-UHFFFAOYSA-N 0.000 description 1
- 108010042708 Acetylmuramyl-Alanyl-Isoglutamine Proteins 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 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 1
- BLIMFWGRQKRCGT-YUMQZZPRSA-N Ala-Gly-Lys Chemical compound C[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CCCCN BLIMFWGRQKRCGT-YUMQZZPRSA-N 0.000 description 1
- IPZQNYYAYVRKKK-FXQIFTODSA-N Ala-Pro-Ala Chemical compound C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C)C(O)=O IPZQNYYAYVRKKK-FXQIFTODSA-N 0.000 description 1
- AETQNIIFKCMVHP-UVBJJODRSA-N Ala-Trp-Arg Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O AETQNIIFKCMVHP-UVBJJODRSA-N 0.000 description 1
- YXXPVUOMPSZURS-ZLIFDBKOSA-N Ala-Trp-Leu Chemical compound C1=CC=C2C(C[C@@H](C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)[C@H](C)N)=CNC2=C1 YXXPVUOMPSZURS-ZLIFDBKOSA-N 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- SQKPKIJVWHAWNF-DCAQKATOSA-N Arg-Asp-Lys Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(O)=O SQKPKIJVWHAWNF-DCAQKATOSA-N 0.000 description 1
- AQPVUEJJARLJHB-BQBZGAKWSA-N Arg-Gly-Ala Chemical compound OC(=O)[C@H](C)NC(=O)CNC(=O)[C@@H](N)CCCN=C(N)N AQPVUEJJARLJHB-BQBZGAKWSA-N 0.000 description 1
- KRQSPVKUISQQFS-FJXKBIBVSA-N Arg-Gly-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCN=C(N)N KRQSPVKUISQQFS-FJXKBIBVSA-N 0.000 description 1
- YBZMTKUDWXZLIX-UWVGGRQHSA-N Arg-Leu-Gly Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O YBZMTKUDWXZLIX-UWVGGRQHSA-N 0.000 description 1
- LXMKTIZAGIBQRX-HRCADAONSA-N Arg-Phe-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC2=CC=CC=C2)NC(=O)[C@H](CCCN=C(N)N)N)C(=O)O LXMKTIZAGIBQRX-HRCADAONSA-N 0.000 description 1
- PRLPSDIHSRITSF-UNQGMJICSA-N Arg-Phe-Thr Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O PRLPSDIHSRITSF-UNQGMJICSA-N 0.000 description 1
- PBVLJOIPOGUQQP-CIUDSAMLSA-N Asp-Ala-Leu Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(O)=O PBVLJOIPOGUQQP-CIUDSAMLSA-N 0.000 description 1
- MRQQMVZUHXUPEV-IHRRRGAJSA-N Asp-Arg-Phe Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O MRQQMVZUHXUPEV-IHRRRGAJSA-N 0.000 description 1
- QCVXMEHGFUMKCO-YUMQZZPRSA-N Asp-Gly-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CC(O)=O QCVXMEHGFUMKCO-YUMQZZPRSA-N 0.000 description 1
- HSPSXROIMXIJQW-BQBZGAKWSA-N Asp-His Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(O)=O)CC1=CNC=N1 HSPSXROIMXIJQW-BQBZGAKWSA-N 0.000 description 1
- JNNVNVRBYUJYGS-CIUDSAMLSA-N Asp-Leu-Ala Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(O)=O JNNVNVRBYUJYGS-CIUDSAMLSA-N 0.000 description 1
- DWBZEJHQQIURML-IMJSIDKUSA-N Asp-Ser Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CO)C(O)=O DWBZEJHQQIURML-IMJSIDKUSA-N 0.000 description 1
- 208000032116 Autoimmune Experimental Encephalomyelitis Diseases 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 101100315624 Caenorhabditis elegans tyr-1 gene Proteins 0.000 description 1
- 206010008631 Cholera Diseases 0.000 description 1
- TULNGKSILXCZQT-IMJSIDKUSA-N Cys-Asp Chemical compound SC[C@H](N)C(=O)N[C@H](C(O)=O)CC(O)=O TULNGKSILXCZQT-IMJSIDKUSA-N 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 108020004414 DNA Proteins 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- UTKUTMJSWKKHEM-WDSKDSINSA-N Glu-Ala-Gly Chemical compound OC(=O)CNC(=O)[C@H](C)NC(=O)[C@@H](N)CCC(O)=O UTKUTMJSWKKHEM-WDSKDSINSA-N 0.000 description 1
- XMBSYZWANAQXEV-QWRGUYRKSA-N Glu-Phe Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 XMBSYZWANAQXEV-QWRGUYRKSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- LERGJIVJIIODPZ-ZANVPECISA-N Gly-Ala-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@@H](NC(=O)CN)C)C(O)=O)=CNC2=C1 LERGJIVJIIODPZ-ZANVPECISA-N 0.000 description 1
- FUESBOMYALLFNI-VKHMYHEASA-N Gly-Asn Chemical compound NCC(=O)N[C@H](C(O)=O)CC(N)=O FUESBOMYALLFNI-VKHMYHEASA-N 0.000 description 1
- YTSVAIMKVLZUDU-YUMQZZPRSA-N Gly-Leu-Asp Chemical compound [H]NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O YTSVAIMKVLZUDU-YUMQZZPRSA-N 0.000 description 1
- OQQKUTVULYLCDG-ONGXEEELSA-N Gly-Lys-Val Chemical compound CC(C)[C@H](NC(=O)[C@H](CCCCN)NC(=O)CN)C(O)=O OQQKUTVULYLCDG-ONGXEEELSA-N 0.000 description 1
- GAFKBWKVXNERFA-QWRGUYRKSA-N Gly-Phe-Asp Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)CN)CC1=CC=CC=C1 GAFKBWKVXNERFA-QWRGUYRKSA-N 0.000 description 1
- NSVOVKWEKGEOQB-LURJTMIESA-N Gly-Pro-Gly Chemical compound NCC(=O)N1CCC[C@H]1C(=O)NCC(O)=O NSVOVKWEKGEOQB-LURJTMIESA-N 0.000 description 1
- BCCRXDTUTZHDEU-VKHMYHEASA-N Gly-Ser Chemical compound NCC(=O)N[C@@H](CO)C(O)=O BCCRXDTUTZHDEU-VKHMYHEASA-N 0.000 description 1
- 102100029966 HLA class II histocompatibility antigen, DP alpha 1 chain Human genes 0.000 description 1
- 108010027412 Histocompatibility Antigens Class II Proteins 0.000 description 1
- 102000018713 Histocompatibility Antigens Class II Human genes 0.000 description 1
- 101000883515 Homo sapiens Chitinase-3-like protein 1 Proteins 0.000 description 1
- 101000864089 Homo sapiens HLA class II histocompatibility antigen, DP alpha 1 chain Proteins 0.000 description 1
- 101000930802 Homo sapiens HLA class II histocompatibility antigen, DQ alpha 1 chain Proteins 0.000 description 1
- 101000968032 Homo sapiens HLA class II histocompatibility antigen, DR beta 3 chain Proteins 0.000 description 1
- 102000015696 Interleukins Human genes 0.000 description 1
- 108010063738 Interleukins Proteins 0.000 description 1
- 206010023232 Joint swelling Diseases 0.000 description 1
- ZUKPVRWZDMRIEO-VKHMYHEASA-N L-cysteinylglycine Chemical compound SC[C@H]([NH3+])C(=O)NCC([O-])=O ZUKPVRWZDMRIEO-VKHMYHEASA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 241000880493 Leptailurus serval Species 0.000 description 1
- SUPVSFFZWVOEOI-CQDKDKBSSA-N Leu-Ala-Tyr Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 SUPVSFFZWVOEOI-CQDKDKBSSA-N 0.000 description 1
- JQSXWJXBASFONF-KKUMJFAQSA-N Leu-Asp-Phe Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O JQSXWJXBASFONF-KKUMJFAQSA-N 0.000 description 1
- OVZLLFONXILPDZ-VOAKCMCISA-N Leu-Lys-Thr Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O OVZLLFONXILPDZ-VOAKCMCISA-N 0.000 description 1
- IRMLZWSRWSGTOP-CIUDSAMLSA-N Leu-Ser-Ala Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(O)=O IRMLZWSRWSGTOP-CIUDSAMLSA-N 0.000 description 1
- AEDWWMMHUGYIFD-HJGDQZAQSA-N Leu-Thr-Asn Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(O)=O AEDWWMMHUGYIFD-HJGDQZAQSA-N 0.000 description 1
- TUIOUEWKFFVNLH-DCAQKATOSA-N Leu-Val-Cys Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CS)C(O)=O TUIOUEWKFFVNLH-DCAQKATOSA-N 0.000 description 1
- PNPYKQFJGRFYJE-GUBZILKMSA-N Lys-Ala-Glu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(O)=O PNPYKQFJGRFYJE-GUBZILKMSA-N 0.000 description 1
- UGTZHPSKYRIGRJ-YUMQZZPRSA-N Lys-Glu Chemical compound NCCCC[C@H](N)C(=O)N[C@H](C(O)=O)CCC(O)=O UGTZHPSKYRIGRJ-YUMQZZPRSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- QXOHLNCNYLGICT-YFKPBYRVSA-N Met-Gly Chemical compound CSCC[C@H](N)C(=O)NCC(O)=O QXOHLNCNYLGICT-YFKPBYRVSA-N 0.000 description 1
- UNPGTBHYKJOCCZ-DCAQKATOSA-N Met-Lys-Ala Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O UNPGTBHYKJOCCZ-DCAQKATOSA-N 0.000 description 1
- KAKJTZWHIUWTTD-VQVTYTSYSA-N Met-Thr Chemical compound CSCC[C@H]([NH3+])C(=O)N[C@@H]([C@@H](C)O)C([O-])=O KAKJTZWHIUWTTD-VQVTYTSYSA-N 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- WUGMRIBZSVSJNP-UHFFFAOYSA-N N-L-alanyl-L-tryptophan Natural products C1=CC=C2C(CC(NC(=O)C(N)C)C(O)=O)=CNC2=C1 WUGMRIBZSVSJNP-UHFFFAOYSA-N 0.000 description 1
- GHAZCVNUKKZTLG-UHFFFAOYSA-N N-ethyl-succinimide Natural products CCN1C(=O)CCC1=O GHAZCVNUKKZTLG-UHFFFAOYSA-N 0.000 description 1
- HDFGOPSGAURCEO-UHFFFAOYSA-N N-ethylmaleimide Chemical compound CCN1C(=O)C=CC1=O HDFGOPSGAURCEO-UHFFFAOYSA-N 0.000 description 1
- 108091028043 Nucleic acid sequence Proteins 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 239000002033 PVDF binder Substances 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- WSXKXSBOJXEZDV-DLOVCJGASA-N Phe-Ala-Asn Chemical compound NC(=O)C[C@@H](C([O-])=O)NC(=O)[C@H](C)NC(=O)[C@@H]([NH3+])CC1=CC=CC=C1 WSXKXSBOJXEZDV-DLOVCJGASA-N 0.000 description 1
- 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 1
- BIYWZVCPZIFGPY-QWRGUYRKSA-N Phe-Gly-Ser Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)NCC(=O)N[C@@H](CO)C(O)=O BIYWZVCPZIFGPY-QWRGUYRKSA-N 0.000 description 1
- SFKOEHXABNPLRT-KBPBESRZSA-N Phe-His-Gly Chemical compound N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1cnc[nH]1)C(=O)NCC(O)=O SFKOEHXABNPLRT-KBPBESRZSA-N 0.000 description 1
- IPFXYNKCXYGSSV-KKUMJFAQSA-N Phe-Ser-Lys Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)O)N IPFXYNKCXYGSSV-KKUMJFAQSA-N 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- UTAUEDINXUMHLG-FXQIFTODSA-N Pro-Asp-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@@H]1CCCN1 UTAUEDINXUMHLG-FXQIFTODSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- -1 Quill A. Preferably Chemical class 0.000 description 1
- 108020004511 Recombinant DNA Proteins 0.000 description 1
- 241000219061 Rheum Species 0.000 description 1
- 238000012300 Sequence Analysis Methods 0.000 description 1
- XSYJDGIDKRNWFX-SRVKXCTJSA-N Ser-Cys-Phe Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O XSYJDGIDKRNWFX-SRVKXCTJSA-N 0.000 description 1
- ZWSZBWAFDZRBNM-UBHSHLNASA-N Ser-Trp-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CO)C(O)=O ZWSZBWAFDZRBNM-UBHSHLNASA-N 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 108091008874 T cell receptors Proteins 0.000 description 1
- 102000016266 T-Cell Antigen Receptors Human genes 0.000 description 1
- SWIKDOUVROTZCW-GCJQMDKQSA-N Thr-Asn-Ala Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](C)C(=O)O)N)O SWIKDOUVROTZCW-GCJQMDKQSA-N 0.000 description 1
- WXVIGTAUZBUDPZ-DTLFHODZSA-N Thr-His Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@H](C(O)=O)CC1=CN=CN1 WXVIGTAUZBUDPZ-DTLFHODZSA-N 0.000 description 1
- BVOVIGCHYNFJBZ-JXUBOQSCSA-N Thr-Leu-Ala Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(O)=O BVOVIGCHYNFJBZ-JXUBOQSCSA-N 0.000 description 1
- IQHUITKNHOKGFC-MIMYLULJSA-N Thr-Phe Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 IQHUITKNHOKGFC-MIMYLULJSA-N 0.000 description 1
- CURFABYITJVKEW-QTKMDUPCSA-N Thr-Val-His Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N)O CURFABYITJVKEW-QTKMDUPCSA-N 0.000 description 1
- QZOSVNLXLSNHQK-UWVGGRQHSA-N Tyr-Asp Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 QZOSVNLXLSNHQK-UWVGGRQHSA-N 0.000 description 1
- FMXFHNSFABRVFZ-BZSNNMDCSA-N Tyr-Lys-Leu Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(O)=O FMXFHNSFABRVFZ-BZSNNMDCSA-N 0.000 description 1
- ZSXJENBJGRHKIG-UWVGGRQHSA-N Tyr-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 ZSXJENBJGRHKIG-UWVGGRQHSA-N 0.000 description 1
- KSGKJSFPWSMJHK-JNPHEJMOSA-N Tyr-Tyr-Thr Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O KSGKJSFPWSMJHK-JNPHEJMOSA-N 0.000 description 1
- CJDZKZFMAXGUOJ-IHRRRGAJSA-N Val-Cys-Tyr Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)O)N CJDZKZFMAXGUOJ-IHRRRGAJSA-N 0.000 description 1
- PIFJAFRUVWZRKR-QMMMGPOBSA-N Val-Gly-Gly Chemical compound CC(C)[C@H]([NH3+])C(=O)NCC(=O)NCC([O-])=O PIFJAFRUVWZRKR-QMMMGPOBSA-N 0.000 description 1
- JAKHAONCJJZVHT-DCAQKATOSA-N Val-Lys-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)O)N JAKHAONCJJZVHT-DCAQKATOSA-N 0.000 description 1
- IRAUYEAFPFPVND-UVBJJODRSA-N Val-Trp-Ala Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@@H](N)C(C)C)C(=O)N[C@@H](C)C(O)=O)=CNC2=C1 IRAUYEAFPFPVND-UVBJJODRSA-N 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 108010005233 alanylglutamic acid Proteins 0.000 description 1
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
- 229910021502 aluminium hydroxide Inorganic materials 0.000 description 1
- ILRRQNADMUWWFW-UHFFFAOYSA-K aluminium phosphate Chemical compound O1[Al]2OP1(=O)O2 ILRRQNADMUWWFW-UHFFFAOYSA-K 0.000 description 1
- 229940001007 aluminium phosphate Drugs 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000003466 anti-cipated effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000003435 antirheumatic agent Substances 0.000 description 1
- 108010047857 aspartylglycine Proteins 0.000 description 1
- 108010092854 aspartyllysine Proteins 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 230000000599 auto-anti-genic effect Effects 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 230000005784 autoimmunity Effects 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 239000012148 binding buffer Substances 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 230000008355 cartilage degradation Effects 0.000 description 1
- 239000005018 casein Substances 0.000 description 1
- BECPQYXYKAMYBN-UHFFFAOYSA-N casein, tech. Chemical compound NCCCCC(C(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(CC(C)C)N=C(O)C(CCC(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(C(C)O)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(COP(O)(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(N)CC1=CC=CC=C1 BECPQYXYKAMYBN-UHFFFAOYSA-N 0.000 description 1
- 235000021240 caseins Nutrition 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 208000037976 chronic inflammation Diseases 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 210000004748 cultured cell Anatomy 0.000 description 1
- 108010069495 cysteinyltyrosine Proteins 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 230000003828 downregulation Effects 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 201000002491 encephalomyelitis Diseases 0.000 description 1
- 210000000981 epithelium Anatomy 0.000 description 1
- 208000012997 experimental autoimmune encephalomyelitis Diseases 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000003365 glass fiber Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 102000054350 human CHI3L1 Human genes 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 229940047122 interleukins Drugs 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 238000011694 lewis rat Methods 0.000 description 1
- GZQKNULLWNGMCW-PWQABINMSA-N lipid A (E. coli) Chemical compound O1[C@H](CO)[C@@H](OP(O)(O)=O)[C@H](OC(=O)C[C@@H](CCCCCCCCCCC)OC(=O)CCCCCCCCCCCCC)[C@@H](NC(=O)C[C@@H](CCCCCCCCCCC)OC(=O)CCCCCCCCCCC)[C@@H]1OC[C@@H]1[C@@H](O)[C@H](OC(=O)C[C@H](O)CCCCCCCCCCC)[C@@H](NC(=O)C[C@H](O)CCCCCCCCCCC)[C@@H](OP(O)(O)=O)O1 GZQKNULLWNGMCW-PWQABINMSA-N 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 108010009298 lysylglutamic acid Proteins 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- CSHFHJNMIMPJST-HOTGVXAUSA-N methyl (2s)-2-[[(2s)-2-[[2-[(2-aminoacetyl)amino]acetyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoate Chemical compound NCC(=O)NCC(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(=O)OC)CC1=CC=CC=C1 CSHFHJNMIMPJST-HOTGVXAUSA-N 0.000 description 1
- 230000003278 mimic effect Effects 0.000 description 1
- BSOQXXWZTUDTEL-ZUYCGGNHSA-N muramyl dipeptide Chemical compound OC(=O)CC[C@H](C(N)=O)NC(=O)[C@H](C)NC(=O)[C@@H](C)O[C@H]1[C@H](O)[C@@H](CO)O[C@@H](O)[C@@H]1NC(C)=O BSOQXXWZTUDTEL-ZUYCGGNHSA-N 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 230000024121 nodulation Effects 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 150000007523 nucleic acids Chemical group 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 108010091212 pepstatin Proteins 0.000 description 1
- FAXGPCHRFPCXOO-LXTPJMTPSA-N pepstatin A Chemical compound OC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](C(C)C)NC(=O)[C@H](C(C)C)NC(=O)CC(C)C FAXGPCHRFPCXOO-LXTPJMTPSA-N 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 239000013612 plasmid Substances 0.000 description 1
- 102000054765 polymorphisms of proteins Human genes 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 1
- 229960004618 prednisone Drugs 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 108010090894 prolylleucine Proteins 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229930182490 saponin Natural products 0.000 description 1
- 150000007949 saponins Chemical class 0.000 description 1
- 235000017709 saponins Nutrition 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 239000013638 trimer Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
- 210000005253 yeast cell Anatomy 0.000 description 1
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
- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Definitions
- the invention relates to peptides and their use in treatment of chronic destruction of articular cartilage in autoimmune diseases, pharmaceutical compositions comprising said peptides, a diagnostic method for the detection of autoreactive T cells in a test sample and test kits to be used in said method.
- the immune system is established on a principle of discrimination between foreign antigens (non-self antigens) and autoantigens (self antigens, derived from the individuals own body) achieved by a build in tolerance against the autoantigens.
- the immune system protects individuals against foreign antigens and responds to exposure to a foreign antigen by activating specific cells such as T- and B lymphocytes and producing soluble factors like interleukins, antibodies and complement factors.
- the antigen to which the immune system responds is degraded by the antigen presenting cells (APCs) and a fragment of the antigen is expressed on the cell surface associated with a major histocompatibility complex (MHC) class II glycoprotein.
- MHC-glycoprotein-antigen-fragment complex is presented to a T cell which by virtue of its T cell receptor recognizes the antigen fragment conjointly with the MHC class II protein to which it is bound.
- the T cell becomes activated, i.e. proliferates and/or produces interleukines, resulting in the expansion of the activated lymphocytes directed to the antigen under attack (Grey et al. , Sci. Am., 2 ⁇ l:38-46, 1989) .
- Self recognition thus is intrinsic to the immune system. Under normal circumstances the immune system is tolerant to self antigens and activation of the immune response by these self antigens is avoided. When tolerance to self antigens is lost, the immune system Decomes activated against one or more self antigens, resulting m the activation of autoreactive T cells and the pro ⁇ uction of autoantibodies. This phenomenon is referred to as autoimmunity.
- the immune response in general is destructive, i.e. meant to destroy the invasive foreign antigen, autoimmune responses can cause destruction of the body's own tissue.
- T cells The contribution of T cells to autoimmune diseases nas neen established by several studies.
- EAE experimental autoimmune encephalomyelitis
- MBP myelin basic protein
- T cells In the Lewis rat, a species with high susceptibility to various autoimmune diseases, disease has been shown to be mediated by T cells.
- autoimmune diseases are also thougnt to be associated with the development of auto-aggressive T cells.
- a destructive autoimmune response has been implicated in various diseases such as rheumatoid arthritis (RA) , in which the integrity of articular cartilage is destroyed by a chronic inflammatory process.
- RA rheumatoid arthritis
- the inflammatory response resulting m the destruction of the cartilage can be treated by various drugs.
- these drugs are immunosuppressive drugs that are nonspecific and have toxic side effects.
- the disadvantages of nonspecific immunosuppression makes this a highly unfavourable therapy.
- Antigen-specific, nontoxic immunosuppression provides a very attractive alternative for nonspecific immunosuppression.
- the antigen- specific therapy involves the treatment of patients with synthetic T cell-reactive peptides which resemble or mimic the epitopes present on the autoantigen. These peptides can therefore be used to induce systemic immunological tolerance, i.e. specific T cell tolerance, both to themselves and to the autoantigen.
- systemic immunological tolerance is based on the long-observed phenomenon that animals which have been fed or have inhaled an antigen or epitope are less capable of developing a systemic immune response towards said antigen or epitope when said antigen or epitope is introduced via a systemic route.
- T cell-reactive peptides which can desensitize patients against the self antigen that is activating the T cells responsible for the inflammatory process.
- the present invention provides for such peptides.
- peptides consisting of 16 to 55 amino acid residues, said peptide comprising at least one of the ammo acid sequences LVCYYTSWS (SEQ ID NO:60), FLCTHIIYS (SEQ ID N0:61) , IIYSFANIS (SEQ ID NO:62), LKTLLSVGG (SEQ ID NO:63) , FIKSVPPFL (SEQ ID NO:60), LVCYYTSWS (SEQ ID NO:60), FLCTHIIYS (SEQ ID N0:61) , IIYSFANIS (SEQ ID NO:62), LKTLLSVGG (SEQ ID NO:63) , FIKSVPPFL (SEQ ID NO:60), LVCYYTSWS (SEQ ID NO:60), FLCTHIIYS (SEQ ID N0:61) , IIYSFANIS (SEQ ID NO:62), LKTLLSVGG (SEQ ID NO:63) , FIKSVPPFL (SEQ ID NO:60), LVCY
- the peptide according to the invention comprises at least one of the ammo acid sequences YKLVCYYTSWSQYREG (SEQ ID NO:l) , YTSWSQYREGDGSCFP (SEQ ID NO:2) ,
- LDRFLCTHIIYSFANI (SEQ ID NO:5), THIIYSFANISNDHID (SEQ ID NO:6) , PNLKTLLSVGGWNFGS (SEQ ID NO:12) , NTQSRRTFIKSVPPFL (SEQ ID NO:16), TFIKSVPPFLRTHGFD (SEQ ID NO: 17) , PPFLRTHGFDGLDLAW (SEQ ID NO: 18), HGFDGLDLAWLYPGRR (SEQ ID NO:19) , DLAWLYPGRRDKQHFT (SEQ ID NO:20) , TIDSSYDIAKISQHLD (SEQ ID NO:28) , DIAKISQHLDFISIMT (SEQ ID NO:29) , QHLDFISIMTYDFHGA (SEQ ID NO:30) , SPLFRGQEDASPDRFS (SEQ ID NO:34) , DYAVGYMLRLGAPASK (SEQ ID NO:37), MLRLGAPASKLVMGIP (SEQ ID NO
- the peptide according to the present invention comprises one of the ammo acid sequences YKLVCYYTSWSQYREG (SEQ ID NO:l), YTSWSQYREGDGSCFP (SEQ ID NO:2), LDRFLCTHIIYSFANI (SEQ ID NO:5) , THIIYSFANISNDHID (SEQ ID NO:6) , PNLKTLLSVGGWNFG ⁇ (SEQ ID NO:12) , QHLDFISIMTYDFHGA (SEQ ID NO:30) , SPLFRGQEDASPDRFS (SEQ ID NO:34) , DYAVGYMLRLGAPASK (SEQ ID NO:37) , MLRLGAPASKLVMGIP (SEQ ID NO:38) , YLKDRQLAGAMVWALD (SEQ ID NO:54) or LAGAMVWALDLDDFQG (SEQ ID NO:55) .
- the peptide according to the invention comprises one or more of the amino acid sequences YTSWSQYREGDGSCFP (SEQ ID NO:2) , SPLFRGQEDASPDRFS (SEQ ID NO:34), MLRLGAPASKLVMGIP (SEQ ID NO:38), YLKDRQLAGAMVWALD (SEQ ID NO: 54) or LAGAMVWALDLDDFQG (SEQ ID NO:55) .
- the peptides according to the invention consist of 16 to 55, preferably 16 to 35, more preferably 16 to 25, most preferably 16 ammo acid residues.
- Highly prefered peptides according to the invention are hexadecapeptides consisting of the ammo acid sequence YKLVCYYTSWSQYREG (SEQ ID NO:l) YTSWSQYREGDGSCFP (SEQ ID NO:2) ,
- LDRFLCTHIIYSFANI SEQ ID NO:5) , THIIYSFANISNDHID (SEQ ID NO:6) , PNLKTLLSVGGWNFGS (SEQ ID NO:12) , QHLDFISIMTYDFHGA (SEQ ID NO:30) , SPLFRGQEDASPDRFS (SEQ ID NO:34) , DYAVGYMLRLGAPASK (SEQ ID NO:37) , MLRLGAPASKLVMGIP (SEQ ID NO:38) , YLKDRQLAGAMVWALD (SEQ ID NO: 54) or LAGAMVWALDLDDFQG (SEQ ID NO:55) , more m pa ⁇ cular the ammo acid sequences YTSWSQYREGDGSCFP (SEQ ID NO:2) , SPLFRGQEDASPDRFS (SEQ ID NO:34), MLRLGAPASKLVMGIP (SEQ ID NO:38) , YLKDRQLAGAMVWALD (SEQ ID NO:54) or LAGAMV
- multimers of the peptides according to the invention such as for example a dimer or trimer of the peptides according to the invention.
- a multimer according to the invention can either be a homomer, consisting of a multitude of the same peptide, or a heteromer consistmg of different peptides.
- the characteristic amino acid sequences of the peptides according to the mvention can be flanked by random amino acid sequences. Prefered are flanking sequences, that have a stabilizing effect on the peptides, thus increasing their biological availability.
- HC gp-39 Human Cartilage glycoprotein 39
- HC gp-39 derived peptides were predominantly recognized by autoreactive T cells from RA patients but rarely by T cells from healthy donors, thus indicating that HC gp-39 is an autoantigen m RA.
- the arthritogemc nature of HC gp-39 was further substantiated in the Balb/c mouse.
- HC gp-39 resulted in immunological tolerance and, more importantly, m delayed and/or suppressed arthritic development.
- ammo acid sequences given m SEQ ID NO's 60-78 more specifically the sequences given in SEQ ID NO's 1, 2, 5, 6, 12, 16-20, 28-30, 34, 37-39, 46-48, 53-57 resemble MHC class II restricted T cell epitopes which are present on HC gp-39.
- the peptides according to the mvention can also oe understood to encompass fragments of the autoantigen HC gp-39 which comprise one or more of the above identified MHC Class II restricted T-cell epitopes and they are also within the scope of the mvention.
- HC gp-39 was disclosed m Hakala et al. , J.Biol .Chem. , Vol.268, No. 34, 25803 (1993) , in which it was described as a chitmase protein and suggested for use as a suitable marker for rheumatoid artnritis, any hint or suggestion towar ⁇ s tne arthritogemc nature of HC gp-39 was absent.
- the peptides according to the invention can be prepared by well known organic chemical methods for peptide synthesis such as, for example, solid-phase peptide synthesis described for instance m J. Amer. Chem. Soc. Little.:2149 (1963) and Int. J. Peptide Protem Res. 3_5_:161-214 (1990) .
- the peptides according to the invention can also be prepared by recombinant DNA techniques.
- a nucleic acid sequence coding for a peptide according to the invention or a multimer of said peptides is inserted mto an expression vector.
- Suitable expression vectors are, amongst others, plasmids, cosmids, virusses and YACs (Yeast Artificial Chromosomes) which comprise the necessary control regions for replication and expression.
- the expression vector can be brought to expression in a host cell. Suitable host cells are, for instance, bacteria, yeast cells and mammalian cells. Such techniques are well known in the art, see for instance Sambrooke et al , Molecular Clonmg:a Laboratory Manual, Cold Spring Harbor laboratory Press, Cold Spring Harbor, 1989.
- the peptides according to the invention are T-cell reactive peptides, which are recognized by and are able to stimulate activated, autoreactive T-cells. These autoreactive T cells are found m the blood of RA patients but rarely in healthy donors.
- the synthetic peptides, said peptides resembling the MHC Class II restricted T-cell epitopes present on the target autoantigen HC gp-39 are very suitable for use m a therapy to induce specific T-cell tolerance to HC gp-39 in mammals, more specifically humans, suffering from T-cell mediated cartilage destruction, such as for example arthritis, more specifically rheumatoid arthritis.
- WO 95/01995 and WO 95/02188 describe the diagnostic use of HC gp-39 as a marker for RA, the arthritogemc nature of HC gp-39 is neither disclosed nor suggested. Nowhere do they hint or suggest towards the use of fragments of HC gp-39 or T- cell reactive peptides according to the present mvention in the antigen or peptide specific therapy to induce T-cell specific tolerance to the HC gp-39 in the cartilage under attack.
- patients suffering from T-cell mediated destruction of the articular cartilage can be treated with a therapeutical composition comprising one or more peptides according to the invention and a pharmaceutical acceptable carrier.
- Administration of the pharmaceutical composition according to the invention will induce systemic immunological tolerance, in particular tolerance of the specific autoreactive T cells of these patients, to the autoantigenic proteins in the articular cartilage under attack and other self antigens which display the identified MHC Class II binding T cell epitopes characterized or mimiced by the amino acid sequences of one or more of the peptides according to the invention.
- the induced tolerance thus will lead to a reduction of the local inflamma t ory response m the articular cartilage under attack.
- Very suitable peptides to be used in a pharmaceutical composition according to the invention are the peptides having 16-55, preferably 16-35, more preferably 16-25, most preferably 16 ammo acid residues, said peptides comprising at least one of the amino acid sequences LVCYYTSWS (SEQ ID NO:60 ) , FLCTHIIYS
- LYPGRRDKQ (SEQ ID NO:66) , YDIAKISQH (SEQ ID NO:67 ) , LDFISIMTY (SEQ ID NO:68) , FISIMTYDF (SEQ ID NO:69 ) , FRG Q EDA ⁇ P (SEQ ID NO:66) , YDIAKISQH (SEQ ID NO:67 ) , LDFISIMTY (SEQ ID NO:68) , FISIMTYDF (SEQ ID NO:69 ) , FRG Q EDA ⁇ P (SEQ ID NO:66) , YDIAKISQH (SEQ ID NO:67 ) , LDFISIMTY (SEQ ID NO:68) , FISIMTYDF (SEQ ID NO:69 ) , FRG Q EDA ⁇ P (SEQ ID NO:66) , YDIAKISQH (SEQ ID NO:67 ) , LDFISIMTY (SEQ ID NO:68) , FISIMTYDF (
- LDLDDFQGS SEQ ID NO:7B
- ammo acid sequences YKLVCYYTSWSQYREG ( SEQ ID NO:l) , YTSWSQYREGDGSCFP (SEQ ID NO:2) , LDRFLCTHIIYSFANI ( SEQ ID NO:5) , THIIYSFANISNDHID (SEQ ID NO:6) , PNLKTLLSVGGWNFGS ( SEQ ID NO:12) , NTQSRRTFIKSVPPFL (SEQ ID NO:16) , TFIKSVPPFLRTHGFD (SEQ ID NO:17) , PPFLRTHGFDGLDLAW (SEQ ID NO:18 ) , HGFDGLDLAWLYPGRR (S ⁇ Q ID NO:19) , DLAWLYPGRRDKQHFT (SEQ ID NO:20 ) , TIDSSYDIAKISQHLD
- QHLDFISIMTYDFHGA (SEQ ID NO:30) , SPLFRG Q EDASPDRFS (SEQ ID NO:34), DYAVGYMLRLGAPASK (SEQ ID NO:37), MLRLGAPASKLVMGIP (SEQ ID NO:38), PASKLVMGIPTFGRSF (SEQ ID NO:39) , GTLAYYEICDFLRGAT (SEQ ID NO:46), EICDFLRGATVHRTLG (SEQ ID NO:47) , RGATVHRTLGQQVPYA (SEQ ID NO:48) , VKSKVQYLKDRQLAGA (SEQ ID NO:53) , YLKDRQLAGAMVWALD (SEQ ID NO:54), LAGAMVWALDLDDFQG (SEQ ID NO:55), WALDLDDFQGSFCGQD (SEQ ID NO:56) or DFQGSFCGQDLRFPLT (SEQ ID NO:57) .
- peptides having 16-55, preferably 16-35, more preferably 16-25, most preferably 16 ammo acid residues, said peptides comprising at least one of the ammo acid sequences YKLVCYYTSWSQYREG (SEQ ID NO:l) , YTSWSQYREGDGSCFP (SEQ ID NO:2), LDRFLCTHIIYSFANI (SEQ ID NO:5), THIIYSFANISNDHID (SEQ ID NO:6), PNLKTLLSVGGWNFGS (SEQ ID NO:12), QHLDFISIMTYDFHGA (SEQ ID NO:30) , SPLFRGQEDASPDRFS (SEQ ID NO:34), DYAVGYMLRLGAPASK (SEQ ID NO:37) , MLRLGAPASKLVMGIP (SEQ ID NO:38) , YLKDRQLAGAMVWALD (SEQ ID NO:54) or LAGAMVWALDLDDFQG
- peptides having 16-55, preferably 16-35, more preferably 16-25, most preferably 16 ammo acid residues said peptides comprising at least one of the amino acid sequences YTSWSQYREGDGSCFP (SEQ ID NO:2), SPLFRGQEDASPDRFS (SEQ ID NO:34), MLRLGAPASKLVMGIP (SEQ ID NO:38), YLKDRQLAGAMVWALD (SEQ ID NO:54) or LAGAMVWALDLDDFQG (SEQ ID NO:55) .
- hexadecapeptides consisting of the ammo acid sequence YKLVCYYTSWSQYREG (SEQ ID NO:l) YTSWSQYREGDGSCFP (SEQ ID NO:2) , LDRFLCTHIIYSFANI (SEQ ID NO:5) , THIIYSFANISNDHID (SEQ ID NO:6) , PNLKTLLSVGGWNFGS (SEQ ID NO:12), QHLDFISIMTYDFHGA (SEQ ID NO:30), SPLFRGQEDASPDRFS (SEQ ID NO:34), DYAVGYMLRLGAPASK (SEQ ID NO:37) , MLRLGAPASKLVMGIP (SEQ ID NO:38) , YLKDRQLAGAMVWALD (SEQ ID NO:54) or LAGAMVWALDLDDFQG (SEQ ID NO:55), more m paricular the ammo acid sequences YTSWSQYREGDGSCFP (SEQ ID NO:2) , LDRFLCTHI
- the peptides according to the mvention have the advantage that they have a specific effect on the autoreactive T cells thus leaving the other components of the immune system intact as compared to the nonspecific suppressive effect of immunosuppressive drugs. Treatment with the peptides according to the invention will be safe and no toxic side effects will occur.
- Systemic immunological tolerance can be attained by administering high or low doses of peptides according to the invention.
- the amount of peptide will depend on the route of administration, the time of administration, the age of the patient as well as general health conditions and diet.
- a dosage of 0.01 to 1000 ⁇ g of peptide per kg body weight preferably 0.5 to 500 ⁇ g, more preferably 0.1 to
- 100 ⁇ g of peptide can be used.
- Pharmaceutical acceptable carriers are well known to those skilled m the art and include, for example, sterile salm, lactose, sucrose, calcium phosphate, gelatin, dextrin, agar, pectin, peanut oil, olive oil, sesame oil and water.
- Other carriers may be, for example MHC class II molecules, if desired embedded in liposomes.
- the pharmaceutical composition according to the invention may comprise one or more adjuvants.
- Suitable adjuvants include, amongst others, aluminium hydroxide, aluminium phosphate, amphigen, tocophenols, monophosphenyl lipid A, muramyl dipeptide and saponins such as Quill A.
- the adjuvants to be used in the tolerance therapy accordmg to the invention are mucosal adjuvants such as the cholera toxine B- subunit or carbomers, which bind to the mucosal epithelium. The amount of adjuvant depends on the nature of the adjuvant itself.
- composition accordmg to the invention may comprise one or more stabilizers such as, for example, carbohydrates including sorbitol, mannitol, starch, sucrosedextrm and glucose, protems such as albumin or casein, and buffers like alkaline phosphates.
- stabilizers such as, for example, carbohydrates including sorbitol, mannitol, starch, sucrosedextrm and glucose, protems such as albumin or casein, and buffers like alkaline phosphates.
- Suitable administration routes are intramuscular injections, subcutaneous injections, intravenous injections or intraperitoneal injections, oral administration and nasal sprays.
- the peptides according to the invention are also very suitable for use in a diagnostic method to detect the presence of activated autoreactive T cells involved in the chronic inflammation and destruction of the articular cartilage.
- the diagnostic method according to the invention comprises the followmg steps: a) isolation of the peripheral blood mononuclear cells (PBMC) from a blood sample of an individual, b) culture said PBMC under suitable conditions, c) incubation of said PBMC culture m the presence of one or more peptides according to the invention, and d) detection of a response of T cells, for example a proliferative response, indicating the presence of activated autoreactive T cells in the individual.
- PBMC peripheral blood mononuclear cells
- the detection of a proliferative response of T cells can be detected by, for example, the incorporation of 3 H-thym ⁇ dme.
- test kits which comprise one or more peptides accordmg to the invention. These test kits are suitable for use in a diagnostic method according to the invention.
- DR4 (DRB1*0401) -positive patients diagnosed as suffering from RA according to the ARA criteria (Arnett et al . , (1988), Arthritis Rheum. 31, 315) .
- Peripheral blood samples were obtained with informed consent . There were five women and two men aged 46-79 years. Their duration of disease ranged from over 10 to over 30 years. Three out of 7 patients had at least 3 swollen joints. Four patients did not show any signs of active disease. All patients were on medication: Four patients were treated with prednisone, three patients received anti-rheumatic agents and 4 patients were treated with NSAID' s as well.
- PBMC peripheral blood mononuclear cells
- the QIA amp blood kit (QIAGEN Ine, ) was used to purify chromosomal DNA from cultured cells accordmg to the manufacturers instructions. Chromosomal DNA extracts were analysed using a DR 'low resolution' SSP kit. DR4 subtypmg was performed using the Dynal DRB1*04-SSP kit. MHC DR typing was performed at the Transplant Serology Laboratory, University Hospital, Nijmegen, The Netherlands.
- Peptides were synthesized at Eurosequence (Gronmgen, The Netherlands) . Peptides were synthesized from the C-termmus to the N-termmus on a 10 ⁇ mol scale using solid-phase FMOC chemistry. The crude peptides were partly purified by several other preparations. As indicated by the manufacturer, at least 35% of the lyophilized product contained the desired full length product. The rest contained salt and remaining solvent. The quality of the final product was checked by sequence analysis, ammo acid analysis and/or RF-HPLC. The sequences of the peptides synthesized are enlisted m Table II.
- DR4 (DRB1*0401) and DR4 (DRB1*0404) molecules were purified from the homozygous EBV-transformed human B lymphoblastoid cell lines Hulyl38IC2 and BM92 using the mAb L243, directed against a monomorphic determinant on the DR-complex (Lampson, L.A. and R.
- HLA-DR molecules (30 nM DR4 (DRB1*0401) or 15 nM DR4 (DRB1*0404) were incubated at pH5.0 with 50 nM biotinylated marker peptide (HA 309 Y ⁇ F ) and a concentration range of competitor peptide in a final volume of 25 ⁇ l binding buffer (PBS containing 0.01% NaN 3 , 0.05% NP-40, 5%
- HLA-DR-bound marker peptide was separated from free marker peptide using a 96 well vacuum dotblot apparatus (Hybri.dot, BRL) and a nitrocellulose membrane (Hybond ECL, Amersham, UK) .
- the nitrocellulose filters were blocked with 0.5% DNA blocking reagent (Boehringer) in 0.1 M maleic acid, 150 mM NaCl, pH7.5.
- the filters were washed m PBS, 0.05% Tween 20 ( Sigma) and mcubated with Streptavidin-HRPO (Southern Biotechnology) m a 1:10.000 dilution. Biotinylated peptides were detected by enhanced chemiluminescence using a Western Blot ECL kit (Amersham) . Exposure of the preflashed films (Hyperfilm- ECL, Amersham) was for 10 min. The spots were analysed by scanning the films and using Image Quant/Excel software for analysis.
- the affinity of a given peptide for binding DRB1*0401- encoded molecules was related to competition with the marker peptide. This relative binding affinity was defined as the peptide concentration at which the signal was reduced to 50%
- PBMC obtained from heparmized venous peripheral blood were isolated by standard centrifugation on a Ficoll-Paque gradient.
- Cells were cultured in four-fold at a concentration of 1,5 x 10 5 cells / well m medium supplemented with 10% heat-inactivated, autologous plasma, L-glutamme, 2-ME and antibiotics m flatbottomed microtiter plates. Cells were mcubated m medium alone or m the presence of phytohaemagglutinm (PHA) (2.5 ⁇ g/ml) to assert cell viability, or m the presence of 10 or 100 ⁇ g/ml of the HC gp-39-der ⁇ ved peptides. In several cases, sets of 2 or 3 sequential peptides were tested due to limited PBMC numbers of individual donors. Cultures were mcubated m a total volume of 210 ⁇ l for 7 days at 37 °C in a humidified atmosphere of 5% CO2 • Cultures were pulsed during the last 18 hours with
- T-cell reactivity to HC gp-39-de ⁇ ved peptides was analyzed by measuring the PBMC proliferative response in DR4 (DRB1*0401) - positive RA patients and healthy donors. Proliferative responses were tested in autologous plasma.
- Table IIIA and 11IB the results of 7 experiments are presented showing the responses of RA patients (Table IIIA) and the responses of healthy donors (Table IIIB) to 59 overlapping sequences derived from HC gp-39. Donors found to respond to both concentrations (100 and 10 ⁇ g/ml) of a peptide were ranked as responders and donors which did not respond to both concentrations tested were ranked as non-responders (NR) .
- peptide 30 means: peptide having ammo acid sequence of SEQ ID NO:30) were 40068
- petides 16-20 (residu 112-151) , 28- 29 (residu 184-205), 38-40 (residu 244-271) , 46-48 (residu 292- 319) and 53-57 (334-373) .
- RA patients Six out of 7 DR4 (DRB1*0401) -positive RA patients responded to HC gp-39-derived peptides or sets of peptides and were therefore ranked as responders. In the healthy donor group (HD) , 3 out of ⁇ donors were ranked as responders. In general, RA patients appeared to respond to many more HC gp-39 regions than healthy donors (healthy donor 230 being an exception) . For example, PBMC from RA patient 272, which were tested against individual peptides, appeared to respond to a total of 11 peptides ,L, 2, 5, 6, 30, 34, 37, 38, 40, 54 and 55 ) .
- PBMC of the o t her patients showed responses against sets of peptides overlapping these 11 sequences and identified some additonal regions containing T- cell epitopes (peptides 14-20 and 46-48 ) .
- PBMC derived from a healthy donor (230) further confirmed the presence of T-cell epitopes m peptides 1, 5, 6, 15, 30 and 37.
- peptides or sets of peptides most frequently recognized contain peptides 1/2, 5/6, 30, 37/38, 54/55) .
- Peptides 1, 2, 5, 6, 12, 15, 30, 34, 37, 38, 40, 41, 54 and 55 were all found to stimulate peripheral blood derived T-cells. As a corrollary to this finding, all of these peptides were found to bind to DR4 (DRB1*0401) with relatively high affinity (except peptides 2 and 38 which bind with intermediate relative affinity) . Peptides 3, 4, 16, 17, 18, 19, 20, 28, 29, 39, 46, 47, 48, 53, 56 and 57 were tested in sets rather than mdividualy. It is very likely that several of these peptides also contam relevant T-cell epitopes. In any case, these peptides all can bind DRB4 (DRB1*0401) with high to intermediate relative affinity (except for peptide 20 which binds with poor relative affinity) .
- Table IIIA Peptide-mduced proliferative responses of PBMC from RA patients.
- pos positive responses to both 100 and 10 microgram/ml of peptide or sets of peptides (SI ⁇ 2 were regarded positive) .
- pos positive responses to both 100 and 10 microgram/ml of peptide or sets of peptides (SI > 2 were regarded positive) .
- NR non- responder.
- R responder.
- BG mean of background counts per 5 mmutes x 10 3 measured in wells without antigen.
- AEBSF 4- (2-AmmoEthyl) -BenzeneSulfonyl Fluoride
- BSA bovine serum albumin
- DMSO Dimethyl Sulfoxide
- FACS Fluorescence Activated Cell Sorter
- HLA Human Leukocyte Antigens
- HPLC High Pressure Liquid Chormatography
- PBS Phosphate Buffered Saline
- PVDF Polyvinylidene difluoride
- MOLECULE TYPE peptide (Xl) SEQUENCE DESCRIPTION: SEQ ID NO: 4:
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Immunology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Zoology (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Animal Behavior & Ethology (AREA)
- Gastroenterology & Hepatology (AREA)
- Public Health (AREA)
- Toxicology (AREA)
- Biochemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Molecular Biology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Genetics & Genomics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biophysics (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Transplantation (AREA)
- Physical Education & Sports Medicine (AREA)
- Rheumatology (AREA)
- Epidemiology (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Description
Claims
Priority Applications (9)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PL97329618A PL329618A1 (en) | 1996-04-24 | 1997-04-22 | Novel peptides for use in an antigenm-specific immunosupressive therapy |
EP97921707A EP0920451A1 (en) | 1996-04-24 | 1997-04-22 | Novel peptides suitable for use in antigen specific immunosuppressive therapy |
AU27685/97A AU719481B2 (en) | 1996-04-24 | 1997-04-22 | Novel peptides suitable for use in antigen specific immunosuppressive therapy |
JP09537744A JP2000510106A (en) | 1996-04-24 | 1997-04-22 | Novel peptides suitable for use in antigen-specific immunosuppressive therapy |
BR9708744A BR9708744A (en) | 1996-04-24 | 1997-04-22 | Peptides consisting of 16 to 55 amino acid residues pharmaceutical composition diagnostic processes for detection of activated auto-reactive t cells and test kit |
US09/171,705 US6184204B1 (en) | 1996-04-24 | 1997-04-22 | Peptides suitable for use in antigen specific immunosuppressive therapy |
NZ332427A NZ332427A (en) | 1996-04-24 | 1997-04-22 | Peptides suitable for use in antigen specific immunosuppressive therapy |
NO984937A NO984937L (en) | 1996-04-24 | 1998-10-23 | New peptides suitable for use in antigen-specific immunosuppressive therapy |
US09/657,757 US6881824B1 (en) | 1996-04-24 | 2000-09-08 | Peptides suitable for use in antigen specific immunosuppressive therapy |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP96201106.0 | 1996-04-24 | ||
EP96201106 | 1996-04-24 |
Related Child Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09171705 A-371-Of-International | 1997-04-22 | ||
US09/657,757 Division US6881824B1 (en) | 1996-04-24 | 2000-09-08 | Peptides suitable for use in antigen specific immunosuppressive therapy |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1997040068A1 true WO1997040068A1 (en) | 1997-10-30 |
Family
ID=8223915
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP1997/002051 WO1997040068A1 (en) | 1996-04-24 | 1997-04-22 | Novel peptides suitable for use in antigen specific immunosuppressive therapy |
Country Status (20)
Country | Link |
---|---|
US (1) | US6184204B1 (en) |
EP (1) | EP0920451A1 (en) |
JP (1) | JP2000510106A (en) |
KR (1) | KR20000010561A (en) |
CN (1) | CN1216551A (en) |
AR (1) | AR006813A1 (en) |
AU (1) | AU719481B2 (en) |
BR (1) | BR9708744A (en) |
CA (1) | CA2251680A1 (en) |
CZ (1) | CZ340698A3 (en) |
HU (1) | HUP9901375A3 (en) |
IL (1) | IL120561A0 (en) |
NO (1) | NO984937L (en) |
NZ (1) | NZ332427A (en) |
PL (1) | PL329618A1 (en) |
RU (1) | RU2199548C2 (en) |
TR (1) | TR199802135T2 (en) |
TW (1) | TW575583B (en) |
WO (1) | WO1997040068A1 (en) |
ZA (1) | ZA973071B (en) |
Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000005254A2 (en) * | 1998-07-23 | 2000-02-03 | Akzo Nobel N.V. | Novel peptides for use in immunotherapy of autoimmune diseases |
WO2001029081A1 (en) * | 1999-10-18 | 2001-04-26 | Akzo Nobel N.V. | Modified peptides and peptidomimetics for use in immunotherapy |
WO2001031037A3 (en) * | 1999-10-27 | 2002-07-11 | Yeda Res & Dev | Synthetic human genes and polypeptides and their use in the treatment of autoimmune diseases |
WO2006089549A1 (en) * | 2005-02-28 | 2006-08-31 | Bio-Y A/S | Ykl-40 monoclonal antibodies |
EP1835027A1 (en) * | 2004-12-07 | 2007-09-19 | Toray Industries, Inc. | Novel cancer antigen peptide and the use thereof |
US7309703B2 (en) | 2000-08-14 | 2007-12-18 | Ortho Mcneil Pharmaceutical, Inc. | Substituted pyrazoles |
FR2908654A1 (en) * | 2006-11-20 | 2008-05-23 | Oreal | Stimulating terminal epithelial differentiation and/or proteoglycan synthesis, e.g. to combat skin aging, using chitinase family protein YKL-40 or its derivative or analog |
US20160355550A1 (en) * | 2008-10-01 | 2016-12-08 | Immatics Biotechnologies Gmbh | Novel immunotherapy against several tumors including neuronal and brain tumors |
WO2018129261A1 (en) * | 2017-01-05 | 2018-07-12 | Brown University | Methods and compositions relating to anti-chi3l1 antibody reagents |
US10766968B2 (en) | 2017-08-23 | 2020-09-08 | Brown University | Methods and compositions relating to anti-CHI3L1 antibody reagents to treat cancer |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7002985B2 (en) * | 2001-01-16 | 2006-02-21 | Motorola, Inc. | Method and apparatus for organizing and scheduling multimedia data transfers over a wireless channel |
RU2008140688A (en) * | 2008-10-15 | 2010-04-20 | Михаил Аркадьевич Шурдов (RU) | IMMUNOSUPPRESSIVE PEPTID |
CA2768246A1 (en) | 2009-06-11 | 2010-12-16 | The University Of Guelph | Serine rich peptides having antioxidative stress properties |
CA2779161A1 (en) | 2009-10-28 | 2011-05-05 | University Of Manitoba | Yellow pea seed protein-derived peptides |
CA2801237A1 (en) | 2010-05-31 | 2011-12-08 | London Health Sciences Centre Research Inc. | Rhamm binding peptides |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1995001995A1 (en) * | 1993-07-09 | 1995-01-19 | The Regents Of The University Of California | Assay for ykl-40 as a marker for degradation of mammalian connective tissue matrices |
WO1996013517A1 (en) * | 1994-10-27 | 1996-05-09 | Akzo Nobel N.V. | Novel peptides derived from autoantigen for use in immunotherapy of autoimmune diseases |
-
1997
- 1997-03-31 IL IL12056197A patent/IL120561A0/en unknown
- 1997-03-31 TW TW86104092A patent/TW575583B/en not_active IP Right Cessation
- 1997-04-10 ZA ZA973071A patent/ZA973071B/en unknown
- 1997-04-22 NZ NZ332427A patent/NZ332427A/en unknown
- 1997-04-22 AU AU27685/97A patent/AU719481B2/en not_active Ceased
- 1997-04-22 CN CN97194031A patent/CN1216551A/en active Pending
- 1997-04-22 CZ CZ983406A patent/CZ340698A3/en unknown
- 1997-04-22 JP JP09537744A patent/JP2000510106A/en not_active Ceased
- 1997-04-22 WO PCT/EP1997/002051 patent/WO1997040068A1/en not_active Application Discontinuation
- 1997-04-22 CA CA002251680A patent/CA2251680A1/en not_active Abandoned
- 1997-04-22 EP EP97921707A patent/EP0920451A1/en not_active Withdrawn
- 1997-04-22 KR KR1019980708415A patent/KR20000010561A/en not_active Application Discontinuation
- 1997-04-22 BR BR9708744A patent/BR9708744A/en not_active Application Discontinuation
- 1997-04-22 US US09/171,705 patent/US6184204B1/en not_active Expired - Fee Related
- 1997-04-22 RU RU98121402/04A patent/RU2199548C2/en not_active IP Right Cessation
- 1997-04-22 HU HU9901375A patent/HUP9901375A3/en unknown
- 1997-04-22 PL PL97329618A patent/PL329618A1/en unknown
- 1997-04-22 TR TR1998/02135T patent/TR199802135T2/en unknown
- 1997-04-24 AR ARP970101654A patent/AR006813A1/en unknown
-
1998
- 1998-10-23 NO NO984937A patent/NO984937L/en not_active Application Discontinuation
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1995001995A1 (en) * | 1993-07-09 | 1995-01-19 | The Regents Of The University Of California | Assay for ykl-40 as a marker for degradation of mammalian connective tissue matrices |
WO1996013517A1 (en) * | 1994-10-27 | 1996-05-09 | Akzo Nobel N.V. | Novel peptides derived from autoantigen for use in immunotherapy of autoimmune diseases |
Non-Patent Citations (2)
Title |
---|
B E HAKALA ET AL.: "Human cartilage gp-39, q major secretory product of articular chondrocytes and synovial cells, is a mammalian member of chitinase protein family", JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 268, no. 34, 5 December 1993 (1993-12-05), MD US, pages 25803 - 25810, XP002014036 * |
P NYIRKOS & E GOLDS: "Human synovial cells secrete a 39 kD protein similar to a bovine mammary protein expressed during the non-lactating period", BIOCHEMICAL JOURNAL, vol. 269, no. 1, 1 July 1990 (1990-07-01), LONDON, pages 265 - 268, XP002014037 * |
Cited By (28)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000005254A3 (en) * | 1998-07-23 | 2000-06-15 | Akzo Nobel Nv | Novel peptides for use in immunotherapy of autoimmune diseases |
US6964766B1 (en) | 1998-07-23 | 2005-11-15 | Akzo Nobel N.V. | Peptides for use in immunotherapy of autoimmune diseases |
WO2000005254A2 (en) * | 1998-07-23 | 2000-02-03 | Akzo Nobel N.V. | Novel peptides for use in immunotherapy of autoimmune diseases |
WO2001029081A1 (en) * | 1999-10-18 | 2001-04-26 | Akzo Nobel N.V. | Modified peptides and peptidomimetics for use in immunotherapy |
AU780238B2 (en) * | 1999-10-18 | 2005-03-10 | Akzo Nobel N.V. | Modified peptides and peptidomimetics for use in immunotherapy |
US8088389B1 (en) | 1999-10-27 | 2012-01-03 | Yeda Research And Development Co., Ltd. | Synthetic human genes and polypeptides and their use in the treatment of autoimmune diseases |
WO2001031037A3 (en) * | 1999-10-27 | 2002-07-11 | Yeda Res & Dev | Synthetic human genes and polypeptides and their use in the treatment of autoimmune diseases |
US8501189B2 (en) | 1999-10-27 | 2013-08-06 | Avraham Ben-Nun | Synthetic human genes and polypeptides and their use in the treatment of autoimmune diseases |
US7309703B2 (en) | 2000-08-14 | 2007-12-18 | Ortho Mcneil Pharmaceutical, Inc. | Substituted pyrazoles |
EP1835027A1 (en) * | 2004-12-07 | 2007-09-19 | Toray Industries, Inc. | Novel cancer antigen peptide and the use thereof |
EP1835027A4 (en) * | 2004-12-07 | 2009-09-02 | Toray Industries | Novel cancer antigen peptide and the use thereof |
US8053563B2 (en) | 2005-02-28 | 2011-11-08 | Bio-Y A/S | YKL-40 monoclonal authority |
AU2006218237B2 (en) * | 2005-02-28 | 2012-01-12 | Bio-Y A/S | YKL-40 monoclonal antibodies |
WO2006089549A1 (en) * | 2005-02-28 | 2006-08-31 | Bio-Y A/S | Ykl-40 monoclonal antibodies |
US8673301B2 (en) | 2005-02-28 | 2014-03-18 | Bio-Y A/S | YKL-40 monoclonal antibody |
US9926587B2 (en) | 2006-11-20 | 2018-03-27 | L'oreal | Cosmetic use of chitinase-type proteins |
WO2008068428A3 (en) * | 2006-11-20 | 2009-05-22 | Oreal | Cosmetic use of chitinase-type proteins<0} |
FR2908654A1 (en) * | 2006-11-20 | 2008-05-23 | Oreal | Stimulating terminal epithelial differentiation and/or proteoglycan synthesis, e.g. to combat skin aging, using chitinase family protein YKL-40 or its derivative or analog |
WO2008068428A2 (en) * | 2006-11-20 | 2008-06-12 | L'oreal | Cosmetic use of chitinase-type proteins<0} |
US20160355550A1 (en) * | 2008-10-01 | 2016-12-08 | Immatics Biotechnologies Gmbh | Novel immunotherapy against several tumors including neuronal and brain tumors |
EP3132801A1 (en) * | 2008-10-01 | 2017-02-22 | Immatics Biotechnologies GmbH | Novel immunotherapy against several tumors including neuronal and brain tumors |
US10047123B2 (en) * | 2008-10-01 | 2018-08-14 | Immatics Biotechnologies Gmbh | Immunotherapy against several tumors including neuronal and brain tumors |
WO2018129261A1 (en) * | 2017-01-05 | 2018-07-12 | Brown University | Methods and compositions relating to anti-chi3l1 antibody reagents |
US10253111B2 (en) | 2017-01-05 | 2019-04-09 | Brown University | Methods and compositions relating to anti-Chi3l1 antibody reagents |
US10752700B2 (en) | 2017-01-05 | 2020-08-25 | Brown University | Methods and compositions relating to anti-CHI3L1 antibody reagents to treat nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NFALD) or metabolic syndrome |
US11667725B2 (en) | 2017-01-05 | 2023-06-06 | Brown University | Methods and compositions relating to anti-CHI3L1 antibody reagents for the treatment of cancer |
US10766968B2 (en) | 2017-08-23 | 2020-09-08 | Brown University | Methods and compositions relating to anti-CHI3L1 antibody reagents to treat cancer |
US11667726B2 (en) | 2017-08-23 | 2023-06-06 | Brown University | Methods and compositions relating to bispecific anti-CHI3L1 antibody reagents for the treatment of cancer |
Also Published As
Publication number | Publication date |
---|---|
NO984937D0 (en) | 1998-10-23 |
JP2000510106A (en) | 2000-08-08 |
HUP9901375A2 (en) | 1999-08-30 |
US6184204B1 (en) | 2001-02-06 |
RU2199548C2 (en) | 2003-02-27 |
IL120561A0 (en) | 1997-07-13 |
AU2768597A (en) | 1997-11-12 |
HUP9901375A3 (en) | 2000-10-30 |
TW575583B (en) | 2004-02-11 |
NZ332427A (en) | 2000-03-27 |
EP0920451A1 (en) | 1999-06-09 |
BR9708744A (en) | 1999-08-03 |
TR199802135T2 (en) | 1999-01-18 |
AR006813A1 (en) | 1999-09-29 |
AU719481B2 (en) | 2000-05-11 |
CN1216551A (en) | 1999-05-12 |
CA2251680A1 (en) | 1997-10-30 |
NO984937L (en) | 1998-12-01 |
KR20000010561A (en) | 2000-02-15 |
PL329618A1 (en) | 1999-03-29 |
ZA973071B (en) | 1998-08-05 |
CZ340698A3 (en) | 1999-02-17 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US5843449A (en) | Proteins and novel peptides derived from autoantigen for use in immunotherapy of autoimmune diseases | |
EP0733065B1 (en) | Novel peptides derived from autoantigen for use in immunotherapy of autoimmune diseases | |
AU719481B2 (en) | Novel peptides suitable for use in antigen specific immunosuppressive therapy | |
AU3173199A (en) | Novel peptides for the treatment, prophylaxis, diagnosis and monitoring of autoimmune diseases | |
US20100324829A1 (en) | Method of selecting hla-dp4 ligands and the applications thereof | |
AU1881601A (en) | Fragments and antagonists of heat shock protein 60 | |
AU704942B2 (en) | Novel peptides for use in treatment of T-cell mediated cartilage destruction in autoimmune diseases | |
AU758310B2 (en) | Novel peptides for use in immunotherapy of autoimmune diseases | |
US6881824B1 (en) | Peptides suitable for use in antigen specific immunosuppressive therapy | |
US20020177554A1 (en) | Novel peptides for use in treatment of T-cell mediated cartilage destruction in autoimmune diseases | |
US20040022777A1 (en) | Fragments and antagonists of heat shock protein 60 | |
MXPA98008866A (en) | Novedosos peptidos suitable for use in antig specific immunosuppressive therapy | |
MXPA01000789A (en) | Novel peptides for use in immunotherapy of autoimmune diseases |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
WWE | Wipo information: entry into national phase |
Ref document number: 97194031.2 Country of ref document: CN |
|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AU BR CA CN CZ HU JP KR MX NO NZ PL RU SG TR US |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE |
|
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
ENP | Entry into the national phase |
Ref document number: 2251680 Country of ref document: CA Ref document number: 2251680 Country of ref document: CA Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1997921707 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1019980708415 Country of ref document: KR Ref document number: 332427 Country of ref document: NZ |
|
WWE | Wipo information: entry into national phase |
Ref document number: 09171705 Country of ref document: US Ref document number: PA/a/1998/008866 Country of ref document: MX Ref document number: PV1998-3406 Country of ref document: CZ Ref document number: 1998/02135 Country of ref document: TR |
|
WWP | Wipo information: published in national office |
Ref document number: PV1998-3406 Country of ref document: CZ |
|
WWP | Wipo information: published in national office |
Ref document number: 1997921707 Country of ref document: EP |
|
WWP | Wipo information: published in national office |
Ref document number: 1019980708415 Country of ref document: KR |
|
WWW | Wipo information: withdrawn in national office |
Ref document number: 1997921707 Country of ref document: EP |
|
WWR | Wipo information: refused in national office |
Ref document number: 1019980708415 Country of ref document: KR |
|
WWR | Wipo information: refused in national office |
Ref document number: PV1998-3406 Country of ref document: CZ |