AU744907B2 - Peptides comprising a T-cell epitope specific to collagen II - Google Patents
Peptides comprising a T-cell epitope specific to collagen II Download PDFInfo
- Publication number
- AU744907B2 AU744907B2 AU58892/98A AU5889298A AU744907B2 AU 744907 B2 AU744907 B2 AU 744907B2 AU 58892/98 A AU58892/98 A AU 58892/98A AU 5889298 A AU5889298 A AU 5889298A AU 744907 B2 AU744907 B2 AU 744907B2
- Authority
- AU
- Australia
- Prior art keywords
- apg
- ppg
- sequence
- pag
- akg
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Ceased
Links
- 108090000765 processed proteins & peptides Proteins 0.000 title claims description 65
- 102000004196 processed proteins & peptides Human genes 0.000 title claims description 32
- 102000008186 Collagen Human genes 0.000 title claims description 14
- 108010035532 Collagen Proteins 0.000 title claims description 14
- 210000001744 T-lymphocyte Anatomy 0.000 title claims description 14
- 229920001436 collagen Polymers 0.000 title claims description 14
- 150000001413 amino acids Chemical class 0.000 claims description 22
- 238000000034 method Methods 0.000 claims description 19
- 239000000203 mixture Substances 0.000 claims description 12
- 230000001363 autoimmune Effects 0.000 claims description 9
- 238000002560 therapeutic procedure Methods 0.000 claims description 7
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 6
- 238000003556 assay Methods 0.000 claims description 5
- 241001465754 Metazoa Species 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 239000003085 diluting agent Substances 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 230000000638 stimulation Effects 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 2
- 238000013160 medical therapy Methods 0.000 claims description 2
- 102000007079 Peptide Fragments Human genes 0.000 claims 1
- 108010033276 Peptide Fragments Proteins 0.000 claims 1
- 230000006698 induction Effects 0.000 claims 1
- 229920001451 polypropylene glycol Polymers 0.000 description 28
- 235000001014 amino acid Nutrition 0.000 description 18
- 229940024606 amino acid Drugs 0.000 description 18
- 150000001875 compounds Chemical class 0.000 description 17
- 210000004027 cell Anatomy 0.000 description 11
- 241000699670 Mus sp. Species 0.000 description 9
- 239000001828 Gelatine Substances 0.000 description 7
- 241000699666 Mus <mouse, genus> Species 0.000 description 7
- 229920000159 gelatin Polymers 0.000 description 7
- 235000019322 gelatine Nutrition 0.000 description 7
- 239000002775 capsule Substances 0.000 description 6
- 239000003826 tablet Substances 0.000 description 6
- 238000011282 treatment Methods 0.000 description 6
- 125000000539 amino acid group Chemical group 0.000 description 5
- 210000001165 lymph node Anatomy 0.000 description 5
- 229920001223 polyethylene glycol Polymers 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 102000000503 Collagen Type II Human genes 0.000 description 4
- 108010041390 Collagen Type II Proteins 0.000 description 4
- 208000009386 Experimental Arthritis Diseases 0.000 description 4
- 238000010168 coupling process Methods 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 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 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- -1 IAG APG FPG Chemical compound 0.000 description 3
- 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 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 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 3
- 229930006000 Sucrose Natural products 0.000 description 3
- 239000002671 adjuvant Substances 0.000 description 3
- 238000001516 cell proliferation assay Methods 0.000 description 3
- 239000012634 fragment Substances 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 125000006239 protecting group Chemical group 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
- 239000011347 resin Substances 0.000 description 3
- 229920005989 resin Polymers 0.000 description 3
- 239000007790 solid phase Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 229960004793 sucrose Drugs 0.000 description 3
- 235000000346 sugar Nutrition 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
- 235000020357 syrup Nutrition 0.000 description 3
- 108090000695 Cytokines Proteins 0.000 description 2
- 102000004127 Cytokines Human genes 0.000 description 2
- 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 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 206010065159 Polychondritis Diseases 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 206010003246 arthritis Diseases 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 210000003719 b-lymphocyte Anatomy 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 210000000845 cartilage Anatomy 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 238000003745 diagnosis Methods 0.000 description 2
- 235000013681 dietary sucrose Nutrition 0.000 description 2
- MGHPNCMVUAKAIE-UHFFFAOYSA-N diphenylmethanamine Chemical compound C=1C=CC=CC=1C(N)C1=CC=CC=C1 MGHPNCMVUAKAIE-UHFFFAOYSA-N 0.000 description 2
- 239000002270 dispersing agent Substances 0.000 description 2
- 229940112141 dry powder inhaler Drugs 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- MHMNJMPURVTYEJ-UHFFFAOYSA-N fluorescein-5-isothiocyanate Chemical compound O1C(=O)C2=CC(N=C=S)=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 MHMNJMPURVTYEJ-UHFFFAOYSA-N 0.000 description 2
- 210000000987 immune system Anatomy 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- SHDMMLFAFLZUEV-UHFFFAOYSA-N n-methyl-1,1-diphenylmethanamine Chemical compound C=1C=CC=CC=1C(NC)C1=CC=CC=C1 SHDMMLFAFLZUEV-UHFFFAOYSA-N 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 239000003182 parenteral nutrition solution Substances 0.000 description 2
- 238000010647 peptide synthesis reaction Methods 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 210000000952 spleen Anatomy 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 1
- SWMBOMMGMHMOHE-MHLULTLJSA-N (2r,3r,4r,5r)-hexane-1,2,3,4,5,6-hexol;(2r,3r,4r,5s)-hexane-1,2,3,4,5,6-hexol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO SWMBOMMGMHMOHE-MHLULTLJSA-N 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- 229920000945 Amylopectin Polymers 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 125000001433 C-terminal amino-acid group Chemical group 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 206010008631 Cholera Diseases 0.000 description 1
- 208000005243 Chondrosarcoma Diseases 0.000 description 1
- 229920002261 Corn starch Polymers 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-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
- QWIZNVHXZXRPDR-UHFFFAOYSA-N D-melezitose Natural products O1C(CO)C(O)C(O)C(O)C1OC1C(O)C(CO)OC1(CO)OC1OC(CO)C(O)C(O)C1O QWIZNVHXZXRPDR-UHFFFAOYSA-N 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 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 1
- 239000004150 EU approved colour Substances 0.000 description 1
- 244000165918 Eucalyptus papuana Species 0.000 description 1
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 1
- 108010037362 Extracellular Matrix Proteins Proteins 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
- 229920000084 Gum arabic Polymers 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 102000006354 HLA-DR Antigens Human genes 0.000 description 1
- 108010058597 HLA-DR Antigens Proteins 0.000 description 1
- 101000968028 Homo sapiens HLA class II histocompatibility antigen, DRB1 beta chain Proteins 0.000 description 1
- 108090000978 Interleukin-4 Proteins 0.000 description 1
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 102000057297 Pepsin A Human genes 0.000 description 1
- 108090000284 Pepsin A Proteins 0.000 description 1
- MUPFEKGTMRGPLJ-RMMQSMQOSA-N Raffinose Natural products O(C[C@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O[C@@]2(CO)[C@H](O)[C@@H](O)[C@@H](CO)O2)O1)[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 MUPFEKGTMRGPLJ-RMMQSMQOSA-N 0.000 description 1
- 101710172711 Structural protein Proteins 0.000 description 1
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 1
- MUPFEKGTMRGPLJ-UHFFFAOYSA-N UNPD196149 Natural products OC1C(O)C(CO)OC1(CO)OC1C(O)C(O)C(O)C(COC2C(C(O)C(O)C(CO)O2)O)O1 MUPFEKGTMRGPLJ-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 1
- 150000001370 alpha-amino acid derivatives Chemical class 0.000 description 1
- 235000008206 alpha-amino acids Nutrition 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 210000000612 antigen-presenting cell Anatomy 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 125000000637 arginyl group Chemical group N[C@@H](CCCNC(N)=N)C(=O)* 0.000 description 1
- 230000002917 arthritic effect Effects 0.000 description 1
- 235000009582 asparagine Nutrition 0.000 description 1
- 229960001230 asparagine Drugs 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000003833 bile salt Substances 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000001364 causal effect Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 229960001334 corticosteroids Drugs 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 210000002744 extracellular matrix Anatomy 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 125000003630 glycyl group Chemical group [H]N([H])C([H])([H])C(*)=O 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 210000000548 hind-foot Anatomy 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 230000006058 immune tolerance Effects 0.000 description 1
- 230000002163 immunogen Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 239000000832 lactitol Substances 0.000 description 1
- VQHSOMBJVWLPSR-JVCRWLNRSA-N lactitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-JVCRWLNRSA-N 0.000 description 1
- 235000010448 lactitol Nutrition 0.000 description 1
- 229960003451 lactitol Drugs 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- VQHSOMBJVWLPSR-WUJBLJFYSA-N maltitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 description 1
- 239000000845 maltitol Substances 0.000 description 1
- 235000010449 maltitol Nutrition 0.000 description 1
- 229940035436 maltitol Drugs 0.000 description 1
- 229960001855 mannitol Drugs 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- QWIZNVHXZXRPDR-WSCXOGSTSA-N melezitose Chemical compound O([C@@]1(O[C@@H]([C@H]([C@@H]1O[C@@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)O)CO)CO)[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O QWIZNVHXZXRPDR-WSCXOGSTSA-N 0.000 description 1
- 239000011325 microbead Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 229940006093 opthalmologic coloring agent diagnostic Drugs 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 229940111202 pepsin Drugs 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000009696 proliferative response Effects 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- MUPFEKGTMRGPLJ-ZQSKZDJDSA-N raffinose 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[C@@H]2[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO)O2)O)O1 MUPFEKGTMRGPLJ-ZQSKZDJDSA-N 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 208000009169 relapsing polychondritis Diseases 0.000 description 1
- 230000003252 repetitive effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 210000004989 spleen cell Anatomy 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 235000010215 titanium dioxide Nutrition 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 229940074410 trehalose Drugs 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 210000004127 vitreous body Anatomy 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
-
- 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
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- 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
- C07K14/78—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin or cold insoluble globulin [CIG]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Molecular Biology (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (AREA)
- Transplantation (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Toxicology (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Description
WO 98/33811 PCT/SE98/00128 1 PEPTIDES COMPRISING A T-CELL EPITOPE SPECIFIC TO COLLAGEN II The present invention provides new peptides derived from collagen CII, methods for their preparation and their use in medical therapy, particularly in the treatment of rheumatoid arthritis and related autoimmune conditions Collagen molecules are some of the main structural proteins of connective tissue. They consist of three polypeptide chains forming an extended triple helical structure with a unique X-Y-Gly repetitive amino acid sequence. The extracellular matrix of cartilage is unique in containing collagens mainly of type II, but also of types IX and XI. CII has recently been cloned from the mouse and its entire sequence of 1419 amino acids determined (Metsarantam et al., 1991, J Biol Chem, 266: 16862-9).
1 Type IIcollagen is thought to be "hidden from cells of the immune system as it is only found in avascular tissues, such as the cartilage, and the vitreous body of the eye. The immune system is therefore not completely tolerant of its own type II collagen As a sequestered protein, CII has the ability, when injected in Freund's complete adjuvant, to induce tissue-specific autoimmune disease. The disease that it induces is termed collagen induced arthritis (CIA). CIA is normally induced by injection of foreign CII, which provokes the production of T cells and antibodies able to recognise the corresponding selfprotein.
Susceptibility to CIA in mice is limited to MHC types I-A and I-Ar. The binding motifs of these molecules are similar to those of human DR4 and DRI. Therefore it is believed that CII is an autoantigen in rheumatoid arthritis(RA).
No causal therapy is currently available for RA. Existing treatment methods e.g.
application of corticosteroids, are unspecific, as they suppress the immune response in T--I~__IIl n~i-i_ ;;iiLlrr;~r WO 98/33811 PCT/SE98/00128 2 general. Current research suggest an important role for autoreactive T cells in the pathogenesis of RA which has lead to the concept that tolerization of these pathogenic
T
cells by nasal/oral administration of immunogenic peptides might be of therapeutic potential.
Miyahara, H. et al Immunology 1995 86 110-115) describe the use of a fragment of type II collagen in the suppression of arthritis in mice. The fragment used (CII 607-621) does however not contain a binding motif to any of the HLA-DR molecules associated with RA in man and would therefore not be effective for use as a toleragen in human RA therapy.
WO 96/20950 purports to describe type II collagen peptides capable of binding to the human HLA DRB 1 MHC protein which it is suggested would be of use in RA therapy.
However these peptides which are present in the 273-404 region of collagen CII protein show only weak activity in relevant assays for putative toleragens for RA The peptides of the present invention are of a significantly greater therapeutic efficacy.
The present invention provides peptides which have been found to be particularly effective in inducing immune tolerance to collagen CII derived T-cell epitopes. These peptides may be used in the treatment of autoimmune conditions such as rheumatoid arthritis.
There is therefore provided according to the present invention, an isolated peptide having, or comprising, an amino acid sequence of formula A 1 -Xaa-Gly-A4-A 5 -Gly-A 7 -Xaa-Gly
(I)
wherein;
A
1 represents an amino acid residue with an aromatic or aliphatic side chain,
A
4 represents an asparagine or arginine residue or an amino acid residue with an aromatic or aliphatic side chain,
A
5 represents any naturally occurring amino acid,
A
7 represents an amino acid with a negatively charged residue, WO 98/33811 PCT/SE98/00128 3 Xaa represents any amino acid residue, and Gly represents a glycine residue.
Peptide of the present invention are preferably 9, 10 11, 12, 13, 14 or 15 amino acid peptides; and are more preferably 9 amino acid peptides.
In peptides of the present invention the following independent preferences apply;
-A
1 is F, I, L, A or P and is most preferably F
-A
4 is F, I, L, A, R, N or P and is most preferably F
-A
5 is K or R
-A
7 is E D, Q, P or N and is most preferably Q.
Preferred peptides according to the present invention include those comprising, or having, one of the following sequences: ESG SPG ENG, PPG ADG QPG, ARG NDG QPG, QPG AKG DQG, APG AKG EAG, PTG VTG PKG, AQG SRG EPG, RVG PPG ANG, PAG ASG NPG, ANG NPG PAG, TDG IPG AKG, DPG LQG PAG, SAG APG IAG, APG EKG EPG, IAG APG FPG, PQG LAG QRG, FPG PRG PPG, PKG ANG DPG, APG ASG DRG, LPG ARG LTG, DAG PQG KVG, ALG APG APG, PAG ANG EKG, KQG DRG EAG, or ARG APG EPG (SEQ IDs Nos 1 to 25 respectively); and more preferably either RVG PPG ANG (SEQ ID No 8) or ANG NPG PAG (SEQ ID No Preferred examples of peptides according to the invention also include those comprising, or having, one of the following amino acid sequences: VKG ESG SPG ENG SPG; FAG PPG ADG QPG AKG; AAG ARG NDG QPG PAG; ADG QPG AKG DQG EAG; APG AKG EAG PTG ARG; PQG PTG VTG PKG ARG; PEG AQG SRG EPG NPG; AAG RVG PPG ANG NPG; PAG ASG NPG TDG IPG; PPG I
I
WO 98/33811 PCT/SE98/00128 4 ANG NPG PAG PPG; NPG TDG IPG AKG SAG; RAG DPG LQG PAG APG; AKG SAG APG IAG APG; PAG APG EKG EPG DDG; APG IAG APG FPG PRG; PPG PQG LAG QRG IVG; APG FPG PRG PPG PQG; LAG PKG ANG DPG RPG; KQG APG ASG DRG PPG; EPG LPG ARG LTG RPG; RPG DAG PQG KVG PSG; ETG ALG APG APG s PPG; PPG PAG ANG EKG EVG; PTG KQG DRG EAG AQG; or STG ARG APG EPG ETG (SEQ IDs Nos 26 to 52 respectively); more preferably AAG RVG PPG ANG NPG (SEQ ID No 33), and most preferably PPG ANG NPG PAG PPG (SEQ ID No Preferably the peptide according to the invention comprises a 9 to 15 amino acid sequence present uninterrupted in the 701-721 region of collagen IL The invention also relates to a peptide comprising a T-cell epitope specific to collagen II which peptide comprises at least nine amino acids having the same sequence as and selected consecutively from the 110-239, 338-379 and 587-895 portions of the sequence of collagen II wherein each amino acid is optionally replaced by a functionally equivalent amino acid and wherein the peptide is of formula I as defined above.
According to the invention there is further provided a pharmaceutical composition comprising a peptide according to the invention in association with a pharmaceutically acceptable carrier or diluent. The compositions are preferably for use in providing tolerance against an autoimmune condition such as rheumatoid arthritis and relapsing polychondritis.
The invention further provides the use of a peptide according to the invention or of a composition according to the invention in the manufacture of a medicament for use in the treatment of an autoimmune condition.
According to the invention there is also provided a method of treating a human or animal suffering from an autoimmune condition such as rheumatoid arthritis and relapsing WO 98/33811 PCUSE98/00128 polychondritis, which method comprises supplying the human or animal with a therapeutically effective amount of the peptide or of the composition.
The peptides according to the invention may be prepared using methods known to the skilled man. For example by using the standard solid phase sequential coupling technique utilising an automatic peptide synthesiser (see for example: Jones, J. The Chemical Synthesis of Peptides, pp 132-156, first edition, Oxford University Press, 1991 and R.
Epton (ed) Innovation and Perspectives in Solid Phase Peptide Synthesis, SPCC Ltd, 1990). The preparation starts from the C-terminal amino acid which can be obtained 0o grafted to a methylbenzhydrylamine, benzhydrylamine or chloromethylated resin or a suitable solid support. The other amino acids are grafted step by step, after having protected the side chains thereof. In this coupling method the alpha-amino groups of the amino acids are protected with F-moc or t-Boc methodology. Protective groups for the side chains of amino acids are well known in the art. The whole protected peptide is released from the chloromethylated resin by ammoniolysis to obtain the protected amide, or from the methylbenzhydrylamine or benzhydrylamine resins by acidolysis.
Peptides according to the invention may also be prepared using solution methods, by either stepwise or fragment condensations (see for example: Jones, J. The Chemical Synthesis of Peptides, pp 115-131, first edition, Oxford University Press, 1991). An appropriately alpha aminoprotected amino acid is coupled to an appropriately alpha carboxyl protected amino acid (such protection may not be required depending on the coupling method chosen) using diimides, symmetrical or unsymmetrical anhydrides, or other coupling reagents or techniques known to those skilled in the art. These techniques may be either chemical or enzymatic. The alpha amino acid an/or alpha carboxyl protecting groups are removed and the next suitably protected amino acid or block of amino acids are coupled to extend the growing peptide. Various combinations of protecting groups and of chemical and/or enzymatic techniques and assembly strategies can be used in each synthesis.
WO 98/33811 PCT/SE98/0028 6 The peptides according to the invention are defined as comprising a T-cell epitope. In other words they are capable of activating T-cells. There are several known techniques for determining binding strength Preferably a peptide according to invention can activate the T-cells with a binding strength of at least 2 in an IFN-y release assay and/or with a stimulation index of at least 3. The IFN-y release assay can be carried out using methods known in the art or by using the methodology described in the Examples herein. Similarly the stimulation index can be determined using known proliferation assays, for example those described in "Analysis of type II collagen reactive T cells in the mouse" Andersson and Holmdahl, Eur J Immunol 20:1061-1066, 1990, preferably the assay is carried out using the methodology used in the Examples herein.
The peptides of the invention are of use in therapy without modification but alternatively the peptides may be modified, for example they may be conjugated, e.g. bound covalently, to delivery systems, for example to mucosal binding structures which include the cholera (3 toxin which assists absorption in the intestine.
The peptides of the present invention may be used in the treatment, prophlaxis or diagnosis of autoimmune conditions and the terms 'therapy' and 'treatment' as used herein should be taken also to include prophylaxis and diagnosis.
A peptide of the present invention is to be taken to be an isolated peptide in the sense that peptides of the present invention do not include peptides present in an organism. Peptides of the present invention may be either isolated from a naturally or recombinantly produced peptide or protein or may be chemically synthesised as herein described.
The compounds may be administered at a dosage from about 10 Rg to 10 mg per day either as a single dose or in divided doses 2 to 4 times per day. Thus unit doses comprise from gg to 10 mg of a compound according to the invention. The compounds may be administered intranasally in the form of solutions, suspensions, HFA aerosols and dry powder formulations, e.g. Turbuhaler formulations; or systemically, e.g. by oral WO 98/33811 PCT/SE98/00128 7 administration in the form of tablets, pills, capsules, syrups, powders or granules, or by parenteral administration in the form of sterile parenteral solutions or suspensions, or by rectal administration in the form of suppositories.
The compounds of the invention may be administered on their own or as a pharmaceutical composition comprising the compound of the invention in combination with a pharmaceutically acceptable diluent, adjuvant or carrier. Particularly preferred are compositions not containing material capable of causing an adverse, e.g. an allergic, reaction.
Dry powder formulations and pressurized HFA aerosols of the compounds of the invention may be administered by nasal inhalation. For inhalation the compound is desirably finely divided. The finely divided compound preferably has a mass median diameter of less than im, and may be suspended in a propellant mixture with the assistance of a dispersant, such as a C 8
-C
20 fatty acid or salt thereof, oleic acid), a bile salt, a phospholipid, an alkyl saccharide, a perfluorinated or polyethoxylated surfactant, or other pharmaceutically acceptable dispersant.
The compounds of the invention may also be administered by means of a dry powder inhaler. The inhaler may be a single or a multi dose inhaler, and may be a breath actuated dry powder inhaler.
One possibility is to mix the finely divided compound with a carrier substance, e.g. a mono-, di- or polysaccharide, a sugar alcohol or another polyols. Suitable carriers are sugars, e.g. lactose, glucose, raffinose, melezitose, lactitol, maltitol, trehalose, sucrose, mannitol; and starch. Alternatively the finely divided compound may be coated by another substance. The powder mixture may also be dispensed into hard gelatine capsules, each containing the desired dose of the active compound.
The pharmaceutical composition comprising the compound of the invention may conveniently be tablets, pills, capsules, syrups, powders or granules for oral administration; 1 WO 98/33811 PCT/SE98/00128 8 sterile parenteral solutions or suspensions for parenteral administration or suppositories for rectal administration.
For oral administration the active compound may be admixed with an adjuvant or a carrier, e.g. lactose, saccharose, sorbitol, mannitol, starches such as potato starch, corn starch or amylopectin, cellulose derivatives, a binder such as gelatine or polyvinylpyrrolidone, and a lubricant such as magnesium stearate, calcium stearate, polyethylene glycol, waxes, paraffin, and the like, and then compressed into tablets. If coated tablets are required, the cores, prepared as described above, may be coated with a concentrated sugar solution to which may contain e.g. gum arabic, gelatine, talcum, titanium dioxide, and the like.
Alternatively, the tablet may be coated with a suitable polymer dissolved in a readily volatile organic solvent.
For the preparation of soft gelatine capsules, the compound may be admixed with e.g. a vegetable oil or polyethylene glycol. Hard gelatine capsules may contain granules of the compound using either the above mentioned excipients for tablets, e.g. lactose, saccharose, sorbitol mannitol, starches, cellulose derivatives or gelatine. Also liquid or semisolid formulations of the drug may be filled into hard gelatine capsules.
Liquid preparations for oral application may be in the form of syrups or suspensions, for example solutions containing the compound, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol. Optionally such liquid preparations may contain colouring agents, flavouring agents, saccharine and carboxymethylcellulose as a thickening agent or other excipients known to those skilled in art.
The invention is now illustrated by the following Examples which should not be interpreted as limiting the present invention.
i WO 98/33811 PCT/SE98/00128 9 Example 1 The CII peptide chains listed in Table 1 each consisting of 15 amino acids were synthesised using an SMPS 350 automated synthesiser (Zinsser, Frankfurt/Main, Germany) using known Fmoc chemistry (see Atherton and Sheppard, Solid Phase Peptide Synthesis A Practical Approach. IRL Press, Oxford). Each peptide was then acetylated at the Nterminus and amidated at the C- terminus. The quality of the peptides was assessed by HPLC and mass spectroscopy of a sample of the peptides confirmed the expected molecular weight.
Table 1 Peptide Amino acid residues Peptde Amino acid residues 110-124 VKG ESG SPG ENG SPG 635-649 FAG PPG ADG QPG AKG 140-154 AAG ARG NDG QPG PAG 641-655 ADG QPG AKG DQG EAG 161-175 GPG FPG APG AKG EAG 665-679 PSG APG PQG PTG VTG 170-184 APG AKG EAG PTG ARG 677-691 PQGPTG VTG PKG ARG 185-199 PEG AQG SRG EPG NPG 701-715 AAG RVG PPG ANG NPG 203-217 PAG ASG NPG TDG IPG 707-721 PPG ANG NPG PAG PPG 209-223 NPG TDG IPG AKG SAG 740-754 RAG DPG LQG PAG APG 218-232 AKG SAG APG IAG APG 749-763 PAG APG EKG EPG DDG 224-238 APG IAG APG FPG PRG 770-784 PPG PQG LAG QRG IVG 230-244 APG FPG PRG PPG PQG 779-793 QPG IVG LPG QPG ERG 338-352 LAG PKG ANG DPG RPG 806-820 KQG APG ASG DRG PPG 353-367 EPG LPG ARG LTG RPG 821-835 PVG PPG LTG PAG EPG 365-379 RPG DAG PQG KVG PSG 857-871 ETG ALG APG APG PPG 593-607 PPG PAG ANG EKG EVG 881-895 PTG KQG DRG EAG AQG 614-628 STG ARG APG EPG ETG WO 98/33811 PCT/SE98/00128 The portions of the amino acid which are shown in bold were found to be the core sequences, i.e. the parts of the amino acids which were bound most strongly, by comparing the binding strengths of structurally closely related peptides.
Example 2 Mouse CII was extracted from xiphisterna by pepsin digestion using known techniques and then further purified by salt precipitation. Rat CII was purified from the Swarm chondrosarcoma again using known techniques. The collagens were dissolved in 0.1 M acetic acid. Collagen for use in restimulating primed lymph node cells was denatured by 0o incubating at 56 0 C for 30 minutes.
Example 3 To test proliferative responses and cytokine release in drained lymph node cells, male X DBA/1) Fl mice, 7-10 weeks of age, were immunised in each hind foot pad with 50 tg mouse CII or synthetic peptide emulsified in CFA (containing H37Ra, Difco, Detroit, MI). Arthritis was induced in the same mice when they were 7 to 10 weeks old, by immunising the mice at the base of the tail with 100l g of rat CII emulsified CFA as prepared in Example 2.
After 5 weeks, mice were boosted with 50.g of CII emulsified in a 1:1 ratio by weight with IFA (DIFCO, Detroit, MI). Lymph node cells drained from severely arthritic joints from these mice were then removed and pooled to test reactivity to the panel of mouse CII peptides prepared in Examples 1 in a proliferation assay in the following way.
Cytokine release was assayed from 50 p.l supernatants of primary cultures of mouse CII primed lymph node cells were restimulated in vitro with the panel of CII peptides prepared according to Example 1 using IFN-y and IL-4 minikits (Endogen, Cambridge,
MA).
The results are shown in Table 2.
WO 98/33811 PCT/SE98/00128 11 Table 2 Peptide SI IFN-y Release (ng/ml) Peptide SI IFN-y Release (ng/ml) 110-124 2.2 2.2 635-649 2.7 0.4 140-154 2.1 1.5 641-655 2.0 0.9 161-175 3.1 4.2 665-679 3.5 170-184 1.5 677-691 2.2 2.9 185-199 4.1 1.9 701-715 18.0 203-217 3.6 6.5 707-721 19.4 5.8 209-223 5.2 740-754 2.8 2.4 218-232 3.9 2.3 749-763 4.8 224-238 5.0 4.4 770-784 2.7 1.4 230-244 3.9 5.8 779-793 3.9 338-352 4.4 2.0 806-820 2.3 353-367 3.1 1.5 821-835 1.8 365-379 2.8 857-871 2.4 0.3 593-607 2.9 0.7 881-895 2.6 0.6 614-628 2.7 2.3 1 WO 98/33811 PCT/SE98/00128 12 Example 4 Lymph node cells from mice primed with mouse CII were depleted of either T cells or B cells by passage through a magnetically activated cell sorter (MACS) using superparamagnetic microbeads conjugated with monoclonal rat anti-mouse L3T4 (CD4) antibodies or rat anti-mouse B220 (CD45R) (both from Miltenyi Biotec GmbH, Bergisch Gladbach, Germany) as recommended by the manufacturer except that PBS containing 2% FCS, 5 mM EDTA, 50 gM 2-ME and 10 mM HEPES was substituted for PBS/BSA buffer.
The fractions were analysed on a FACScan flow cytometer (Becton Dickinson) using FITC-conjugated anti-mouse-CD3-e for staining T-cells and FITC-conjugated anti-mouse- K-light-chain for B cells (Pharmigen, San Diego, CA). The cells were washed three times with DMEM medium without serum after separation and then put into proliferation assays using the method described in Example 3. Enriched CD4+ T cells were mixed together with spleen cells from spleens from syngeneic mice as antigen presenting cells in a ratio of 1:2 by weight. AP cells are used in the form of a single cell suspension from spleens treated with 0.84% NH 4 C at pH 7.4 to lyse red blood cells.
Table 3 Cell Type CPM xl0 3 Unfractionated 13.6 CD4+ Enriched 21.4 CD4+ Depleted 0.3 Depleted 12.5 Enriched 0.4 V WO 98/33811 PCT/SE98/00128 13 SEQUENCE LISTING SEQUENCE ID No. 1: ESG SPG ENG SEQUENCE ID No. 2: PPG ADG QPG SEQUENCE ID No. 3: ARG NDG QPG SEQUENCE ID No. 4: QPG AKG DQG SEQUENCE ID No. 5: APG AKG EAG SEQUENCE ID No. 6: PTG VTG PKG to SEQUENCE ID No. 7: AQG SRG EPG SEQUENCE ID No. 8: RVG PPG ANG SEQUENCE ID No.
SEQUENCE ID No.
SEQUENCE ID No.
SEQUENCE ID No.
SEQUENCE ID No.
SEQUENCE ID No.
SEQUENCE ID No.
SEQUENCE ID No.
SEQUENCE ID No.
9: PAG ASG NPG 10: ANG NPG PAG 11:TDG IPG AKG 12: DPG LQG PAG 13: SAG APG IAG 14: APG EKG EPG 15: IAG APG FPG 16: PQG LAG QRG 17: FPG PRG PPG SEQUENCE ID No. 18: PKG ANG DPG SEQUENCE ID No. 19: APG ASG DRG SEQUENCE ID No. 20: LPG ARG LTG SEQUENCE ID No. 21: DAG PQG KVG SEQUENCE ID No. 22: ALG APG APG SEQUENCE ID No. 23: PAG ANG EKG SEQUENCE ID No. 24: KQG DRG EAG SEQUENCE ID No. 25: ARG APG EPG SEQUENCE ID No. 26: VKG ESG SPG ENG SPG SEQUENCE ID No. 27: FAG PPG ADG QPG AKG SEQUENCE ID No. 28: AAG ARG NDG QPG PAG -,gsian^,.^Xrr- SEQUENCE ID No. 29: ADG QPG AKG DQG EAG SEQUENCE ID No. 30: APG AKG EAG PTG ARG SEQUENCE ID No. 31: PQG PTG VTG PKG ARG SEQUENCE ID No. 32: PEG AQG SRG EPG NPG s SEQUENCE ID No. 33: AAG RVG PPG ANG NPG SEQUENCE ID No. 34: PAG ASG NPG TDG IPG SEQUENCE IED No. 35: PPG ANG NPG PAG PPG SEQUENCE ID No. 36: NPG TDG IPG AKG SAG SEQUENCE ID No. 37: RAG DPG LQG PAG APG SEQUENCE ID No. 38: AKG SAG APG LAG APG SEQUENCE ID No. 39: PAG APG EKG EPG DDG SEQUENCE ID No. 40: APG IAG APG FPG PRG SEQUENCE ID No. 41: PPG PQG LAG QRG IVG SEQUENCE ED No. 42: APG FPG PRG PPG PQG 15 SEQUENCE ID No. 43: LAG PKG ANG DPG RPG SEQUENCE ID No. 44: KQG APG ASG DRG PPG SEQUENCE ID No. 45: EPG LPG ARG LTG RPG SEQUENCE ID No. 46: RPG DAG PQG KVG PSG SEQUENCE ID No. 47: EXG ALG APG APG PPG 20 SEQUENCE IED No. 48: PPG PAG ANG EKG EVG SEQUENCE ID No. 49: PTG KQG DRG EAG AQG SEQUENCE ID No. 50: STG ARG APG EPG ETG SEQUENCE IED No. 51: AAG RVG PPG ANG NPG SEQUENCE ID No. 52: PPG ANG NPG PAG PPG With reference to the use of the word(s) "comprise" or "comprises" or "comprising" in the foregoing description and/or in the following claims, unless the context requires otherwise, those words are used on the basis and clear understanding that they are to be interpreted inclusively, rather than exclusively, and that each of those words is to be so interpreted in construing the foregoing description and/or the following claims.
Claims (6)
1. An isolated peptide having any one of the following sequences: VKG ESG SPG ENG SPG; FAG PPG ADG QPG AKG; AAG ARG NDG QPG PAG; ADG QPG AKG DQG EAG; APG AKG EAG PTG ARG; PQG PTG VTG PKG-ARG; PEG AQG SRG EPG NPG; AAG RVG PPG AN6 NPG; PAG ASG NPG TDG IPG; PPG ANG NGPGPG NPG TDG IPG AKG SAG; RAG DPG LQG PAG APG; AKG SAG APG IAG APG; PAG APG EKG EPG DDG; APG IAG APG FPG PRG; PPG PQG LAG QRG IVG; *APG FPG PRG PPG PQG; LAG PKG ANG DPG RPG; KQG APG ASG DRG PPG; EPG LPG ARG LTG RPG; R.PG DAG PQG KVG PSG; ETG AJLG APG APG PPG; PPG PAG ANG EKG EVG; PTG KQG DRG EAG AQG; or STO ARG APG EPG ETG (SEQ IDs Nos 26 to 52 respectively).
2. An isolated peptide which is a 10 to 14 amino acid peptide fragment of any one of the peptides claimed in claim 1.
3. A peptide according to claim 1 or 2 which binds to T-cells with a binding strength of at least 2 in an IFN-y release assay.
4. A peptide according to any one of the preceding claims which binds to T-cells with a stimulation index of at least 3.
5. A peptide according to any one of the preceding claims wherein the sequence of the peptide is present in the sequence of collagen II between positions 110-239, 338-379 or
587-895. :15 701-721 region of collagen II. 7. An isolated peptide according to any one of the preceding claims, for use in nmedical therapy. 20 8. A peptide according to claim 7, wherein the medical therapy comprises the induction of tolerance. 9. Use of an isolated peptide according to any one of the preceding claims, in the nmnufacture of a medicament for use in the therapy of an autoimmune condition. Use according to claim 9, wherein the autoimmune condition is rheumatoid arthritis. 11. A pharmaceutical composition comprising a peptide according to any of claims 1 to 6 in association with a pharmaceutically acceptable carrier or diluent therefor. 9 l- 6~i~C~~ 'C, 17 12.- A method of treating a human or animal suffering or liable to suffer fromn an autoimmune condition, which method comprises supplying the human or animal with a therapeutically effective amount of a peptide according to any one of claims I to 6 or of a composition according to claim 11. DATED this 18 day of January 2002 ASTRAZENECA AB, By its Patent Attorneys, E. F. WELLINGTON CO., Be eington)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SE9700301 | 1997-01-31 | ||
SE9700301A SE9700301D0 (en) | 1997-01-31 | 1997-01-31 | New compound |
PCT/SE1998/000128 WO1998033811A1 (en) | 1997-01-31 | 1998-01-29 | Peptides comprising a t-cell epitope specific to collagen ii |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
AU31421/02A Division AU3142102A (en) | 1997-01-31 | 2002-04-04 | Peptides comprising a T-cell epitope specific to collagen II |
Publications (2)
Publication Number | Publication Date |
---|---|
AU5889298A AU5889298A (en) | 1998-08-25 |
AU744907B2 true AU744907B2 (en) | 2002-03-07 |
Family
ID=20405590
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
AU58892/98A Ceased AU744907B2 (en) | 1997-01-31 | 1998-01-29 | Peptides comprising a T-cell epitope specific to collagen II |
Country Status (19)
Country | Link |
---|---|
EP (1) | EP1007547A1 (en) |
JP (1) | JP2001511143A (en) |
KR (1) | KR20000070542A (en) |
CN (1) | CN1246125A (en) |
AU (1) | AU744907B2 (en) |
BR (1) | BR9811250A (en) |
CA (1) | CA2278638A1 (en) |
EE (1) | EE9900334A (en) |
HU (1) | HUP0000836A3 (en) |
ID (1) | ID22802A (en) |
IL (1) | IL131045A0 (en) |
IS (1) | IS5138A (en) |
NO (1) | NO993684L (en) |
NZ (1) | NZ336745A (en) |
PL (1) | PL334877A1 (en) |
SE (1) | SE9700301D0 (en) |
SK (1) | SK102199A3 (en) |
TR (1) | TR199901831T2 (en) |
WO (1) | WO1998033811A1 (en) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AUPO571297A0 (en) * | 1997-03-19 | 1997-04-10 | Montech Medical Developments Pty Ltd | Method for the diagnosis of rheumatoid arthritis |
WO2003006603A2 (en) * | 2001-07-12 | 2003-01-23 | Arexis Ab | Triple polypeptide complexes |
CN1169829C (en) * | 2002-06-27 | 2004-10-06 | 北京大学人民医院 | Non-T cell conjugating peptide and its use |
WO2008130217A1 (en) * | 2006-08-08 | 2008-10-30 | Applied Nanosystems B.V. | Cyclic angiotensin analogs |
KR20170002734U (en) | 2016-01-21 | 2017-07-31 | 김인수 | The construction to automatic amputate of the wood |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1996020950A2 (en) * | 1995-01-06 | 1996-07-11 | Immulogic Pharmaceutical Corporation | Compositions and methods for treating rheumatoid arthritis |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH08151396A (en) * | 1994-11-28 | 1996-06-11 | Teijin Ltd | Hla-binding oligopeptide and immunomodulating agent containing the compound |
-
1997
- 1997-01-31 SE SE9700301A patent/SE9700301D0/en unknown
-
1998
- 1998-01-29 PL PL98334877A patent/PL334877A1/en unknown
- 1998-01-29 ID IDW990738A patent/ID22802A/en unknown
- 1998-01-29 EP EP98902337A patent/EP1007547A1/en not_active Withdrawn
- 1998-01-29 TR TR1999/01831T patent/TR199901831T2/en unknown
- 1998-01-29 NZ NZ336745A patent/NZ336745A/en unknown
- 1998-01-29 BR BR9811250-3A patent/BR9811250A/en not_active IP Right Cessation
- 1998-01-29 KR KR1019997006787A patent/KR20000070542A/en not_active Application Discontinuation
- 1998-01-29 CA CA002278638A patent/CA2278638A1/en not_active Abandoned
- 1998-01-29 WO PCT/SE1998/000128 patent/WO1998033811A1/en not_active Application Discontinuation
- 1998-01-29 EE EEP199900334A patent/EE9900334A/en unknown
- 1998-01-29 SK SK1021-99A patent/SK102199A3/en unknown
- 1998-01-29 HU HU0000836A patent/HUP0000836A3/en unknown
- 1998-01-29 JP JP53278598A patent/JP2001511143A/en active Pending
- 1998-01-29 AU AU58892/98A patent/AU744907B2/en not_active Ceased
- 1998-01-29 IL IL13104598A patent/IL131045A0/en unknown
- 1998-01-29 CN CN98802141A patent/CN1246125A/en active Pending
-
1999
- 1999-07-28 IS IS5138A patent/IS5138A/en unknown
- 1999-07-29 NO NO993684A patent/NO993684L/en not_active Application Discontinuation
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1996020950A2 (en) * | 1995-01-06 | 1996-07-11 | Immulogic Pharmaceutical Corporation | Compositions and methods for treating rheumatoid arthritis |
Non-Patent Citations (2)
Title |
---|
IMMUNOLOGY V86 1995 P110-115 H MIYAHARA ET AL * |
INT IMMUN V8 1996 P757-764, S. MATSUSHITA ET AL * |
Also Published As
Publication number | Publication date |
---|---|
EP1007547A1 (en) | 2000-06-14 |
NZ336745A (en) | 2001-09-28 |
HUP0000836A2 (en) | 2000-11-28 |
TR199901831T2 (en) | 1999-10-21 |
SK102199A3 (en) | 2000-08-14 |
HUP0000836A3 (en) | 2001-04-28 |
BR9811250A (en) | 2000-09-26 |
WO1998033811A1 (en) | 1998-08-06 |
AU5889298A (en) | 1998-08-25 |
NO993684D0 (en) | 1999-07-29 |
SE9700301D0 (en) | 1997-01-31 |
IL131045A0 (en) | 2001-01-28 |
PL334877A1 (en) | 2000-03-27 |
KR20000070542A (en) | 2000-11-25 |
JP2001511143A (en) | 2001-08-07 |
CA2278638A1 (en) | 1998-08-06 |
CN1246125A (en) | 2000-03-01 |
EE9900334A (en) | 2000-02-15 |
IS5138A (en) | 1999-07-28 |
NO993684L (en) | 1999-09-02 |
ID22802A (en) | 1999-12-09 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Schall et al. | Peptide-based approaches to treat lupus and other autoimmune diseases | |
US7456252B2 (en) | Therapeutic peptides for demyelinating conditions | |
US9175037B2 (en) | Neuromedin U derivative | |
KR20010041238A (en) | Methods for treatment of diabetes using peptide analogues of insulin | |
RU2115659C1 (en) | Derivatives of nonapeptides or their salts with pharmaceutically acceptable acids, method of their synthesis and pharmaceutical composition | |
EP1438061B1 (en) | Copolymers for suppression of autoimmune diseases, and methods of use | |
WO1993012145A1 (en) | Pva or peg conjugates of peptides for epitope-specific immunosuppression | |
WO1996012737A9 (en) | Compositions and treatment for multiple sclerosis | |
CA2203629A1 (en) | Compositions and treatment for multiple sclerosis | |
AU2002362445A1 (en) | Copolymers for suppression of autoimmune diseases, and methods of use | |
JPH10509714A (en) | Method for treating multiple sclerosis using a peptide analog at position 91 of human myelin basic protein | |
US9662370B2 (en) | Peptidyl diacylglycerides | |
AU2004255379B2 (en) | Biologically active substance of a vasoactive intestinal peptide for treating interstitial lung infections | |
AU744907B2 (en) | Peptides comprising a T-cell epitope specific to collagen II | |
KR20150105365A (en) | Peptide | |
JP4160505B2 (en) | Use of peptides containing post-translational type modifications in the concept of treatment of autoimmune diseases | |
AU3142102A (en) | Peptides comprising a T-cell epitope specific to collagen II | |
CA2614171C (en) | Copolymers for suppression of autoimmune diseases, and methods of use | |
CA2768340C (en) | Copolymers for suppression of autoimmune diseases, and methods of use | |
KR101019246B1 (en) | A pharmaceutical composition comprising a retro-inverso isomer peptide | |
CZ269199A3 (en) | Peptides containing T-cellular epitope specific for collagen, their use and pharmaceutical preparations containing such peptides | |
JP2002521387A (en) | Treatment of autoimmune diseases with Copolymer 1 and related copolymers and peptides | |
IL302604A (en) | Compositions of embedded epitope random peptides (eerp) for treatment of immune-mediated conditions, and methods of use | |
WO1997004798A1 (en) | H-y derived epitopes and uses therefor | |
Sitaraman | Myasthenia gravis: Role of cytokines in disease and design of therapy |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
TC | Change of applicant's name (sec. 104) |
Owner name: ASTRAZENECA AB Free format text: FORMER NAME: ASTRA AKTIEBOLAG |
|
FGA | Letters patent sealed or granted (standard patent) | ||
MK14 | Patent ceased section 143(a) (annual fees not paid) or expired |