EP0896584A2 - BIOLOGISCH AKTIVER EIWEISSSTOFF - KOLLAGENFRAGMENT HF-COLL-18/514cf - ZUR HEMMUNG DES WACHSTUMS VON TUMOREN UND VON GEFÄSSWUCHERUNGEN - Google Patents
BIOLOGISCH AKTIVER EIWEISSSTOFF - KOLLAGENFRAGMENT HF-COLL-18/514cf - ZUR HEMMUNG DES WACHSTUMS VON TUMOREN UND VON GEFÄSSWUCHERUNGENInfo
- Publication number
- EP0896584A2 EP0896584A2 EP97921682A EP97921682A EP0896584A2 EP 0896584 A2 EP0896584 A2 EP 0896584A2 EP 97921682 A EP97921682 A EP 97921682A EP 97921682 A EP97921682 A EP 97921682A EP 0896584 A2 EP0896584 A2 EP 0896584A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- ser
- ala
- leu
- coll
- arg
- 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.)
- Withdrawn
Links
- 206010028980 Neoplasm Diseases 0.000 title claims abstract description 10
- 239000012634 fragment Substances 0.000 title claims description 30
- 102000004169 proteins and genes Human genes 0.000 title description 10
- 108090000623 proteins and genes Proteins 0.000 title description 10
- 102000008186 Collagen Human genes 0.000 title description 4
- 108010035532 Collagen Proteins 0.000 title description 4
- 229920001436 collagen Polymers 0.000 title description 3
- 230000002401 inhibitory effect Effects 0.000 title description 3
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 32
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 26
- 239000003814 drug Substances 0.000 claims abstract description 20
- 201000010099 disease Diseases 0.000 claims abstract description 19
- 210000004369 blood Anatomy 0.000 claims abstract description 10
- 239000008280 blood Substances 0.000 claims abstract description 10
- 201000011510 cancer Diseases 0.000 claims abstract description 4
- 238000011282 treatment Methods 0.000 claims description 17
- 239000000126 substance Substances 0.000 claims description 14
- 150000001413 amino acids Chemical group 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 12
- 238000004587 chromatography analysis Methods 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 8
- 230000001225 therapeutic effect Effects 0.000 claims description 8
- 230000006444 vascular growth Effects 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 7
- 208000035475 disorder Diseases 0.000 claims description 6
- 239000000032 diagnostic agent Substances 0.000 claims description 4
- 229940039227 diagnostic agent Drugs 0.000 claims description 4
- 230000000694 effects Effects 0.000 claims description 4
- 230000004054 inflammatory process Effects 0.000 claims description 4
- 230000035755 proliferation Effects 0.000 claims description 4
- 238000002560 therapeutic procedure Methods 0.000 claims description 4
- 210000000748 cardiovascular system Anatomy 0.000 claims description 3
- 238000005516 engineering process Methods 0.000 claims description 3
- 210000000653 nervous system Anatomy 0.000 claims description 3
- 210000000056 organ Anatomy 0.000 claims description 3
- 210000002381 plasma Anatomy 0.000 claims description 3
- 238000012360 testing method Methods 0.000 claims description 3
- 208000019553 vascular disease Diseases 0.000 claims description 3
- 208000030090 Acute Disease Diseases 0.000 claims description 2
- 208000017667 Chronic Disease Diseases 0.000 claims description 2
- 206010061218 Inflammation Diseases 0.000 claims description 2
- 241001465754 Metazoa Species 0.000 claims description 2
- 208000008636 Neoplastic Processes Diseases 0.000 claims description 2
- HSRXSKHRSXRCFC-WDSKDSINSA-N Val-Ala Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](C)C(O)=O HSRXSKHRSXRCFC-WDSKDSINSA-N 0.000 claims description 2
- 239000005557 antagonist Substances 0.000 claims description 2
- 210000004204 blood vessel Anatomy 0.000 claims description 2
- 210000001185 bone marrow Anatomy 0.000 claims description 2
- 210000001175 cerebrospinal fluid Anatomy 0.000 claims description 2
- 238000003745 diagnosis Methods 0.000 claims description 2
- 230000002526 effect on cardiovascular system Effects 0.000 claims description 2
- 239000003792 electrolyte Substances 0.000 claims description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 claims description 2
- 210000000777 hematopoietic system Anatomy 0.000 claims description 2
- 210000004408 hybridoma Anatomy 0.000 claims description 2
- 210000000987 immune system Anatomy 0.000 claims description 2
- 230000003053 immunization Effects 0.000 claims description 2
- 238000003018 immunoassay Methods 0.000 claims description 2
- 230000002757 inflammatory effect Effects 0.000 claims description 2
- 239000003112 inhibitor Substances 0.000 claims description 2
- 230000005764 inhibitory process Effects 0.000 claims description 2
- 239000007791 liquid phase Substances 0.000 claims description 2
- 210000002751 lymph Anatomy 0.000 claims description 2
- 239000003550 marker Substances 0.000 claims description 2
- 230000035800 maturation Effects 0.000 claims description 2
- 238000012261 overproduction Methods 0.000 claims description 2
- 210000000697 sensory organ Anatomy 0.000 claims description 2
- 239000007790 solid phase Substances 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims description 2
- 238000003786 synthesis reaction Methods 0.000 claims description 2
- 210000001519 tissue Anatomy 0.000 claims description 2
- 210000002700 urine Anatomy 0.000 claims description 2
- 241000880493 Leptailurus serval Species 0.000 claims 1
- 239000004480 active ingredient Substances 0.000 claims 1
- 239000000654 additive Substances 0.000 claims 1
- 239000000443 aerosol Substances 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 claims 1
- 238000007796 conventional method Methods 0.000 claims 1
- 230000007812 deficiency Effects 0.000 claims 1
- 238000007918 intramuscular administration Methods 0.000 claims 1
- 238000007913 intrathecal administration Methods 0.000 claims 1
- 238000001990 intravenous administration Methods 0.000 claims 1
- 230000009885 systemic effect Effects 0.000 claims 1
- 230000000699 topical effect Effects 0.000 claims 1
- 229940079593 drug Drugs 0.000 abstract description 4
- 230000010261 cell growth Effects 0.000 abstract description 3
- 210000002889 endothelial cell Anatomy 0.000 abstract description 3
- 238000004949 mass spectrometry Methods 0.000 abstract description 3
- 239000000284 extract Substances 0.000 abstract description 2
- 238000002955 isolation Methods 0.000 abstract description 2
- 238000012163 sequencing technique Methods 0.000 abstract description 2
- 230000003915 cell function Effects 0.000 abstract 1
- 208000037824 growth disorder Diseases 0.000 abstract 1
- 239000003480 eluent Substances 0.000 description 17
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 235000018102 proteins Nutrition 0.000 description 9
- 235000001014 amino acid Nutrition 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 8
- 239000000463 material Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 238000001514 detection method Methods 0.000 description 4
- 230000004614 tumor growth Effects 0.000 description 4
- 241000283690 Bos taurus Species 0.000 description 3
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 3
- 102000003974 Fibroblast growth factor 2 Human genes 0.000 description 3
- 108090000379 Fibroblast growth factor 2 Proteins 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 229910000831 Steel Inorganic materials 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 210000001043 capillary endothelial cell Anatomy 0.000 description 3
- 238000001516 cell proliferation assay Methods 0.000 description 3
- 239000012894 fetal calf serum Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 239000010959 steel Substances 0.000 description 3
- WXTMDXOMEHJXQO-UHFFFAOYSA-N 2,5-dihydroxybenzoic acid Chemical compound OC(=O)C1=CC(O)=CC=C1O WXTMDXOMEHJXQO-UHFFFAOYSA-N 0.000 description 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- YOKVEHGYYQEQOP-QWRGUYRKSA-N Leu-Leu-Gly Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O YOKVEHGYYQEQOP-QWRGUYRKSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 230000008827 biological function Effects 0.000 description 2
- 238000005515 capillary zone electrophoresis Methods 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 239000002299 complementary DNA Substances 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000002615 hemofiltration Methods 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 238000001840 matrix-assisted laser desorption--ionisation time-of-flight mass spectrometry Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 229940126601 medicinal product Drugs 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 238000001959 radiotherapy Methods 0.000 description 2
- 238000004007 reversed phase HPLC Methods 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000003643 water by type Substances 0.000 description 2
- AFVLVVWMAFSXCK-UHFFFAOYSA-N α-cyano-4-hydroxycinnamic acid Chemical compound OC(=O)C(C#N)=CC1=CC=C(O)C=C1 AFVLVVWMAFSXCK-UHFFFAOYSA-N 0.000 description 2
- HHRAXZAYZFFRAM-CIUDSAMLSA-N Ala-Leu-Asn Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O HHRAXZAYZFFRAM-CIUDSAMLSA-N 0.000 description 1
- 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 1
- OFIYLHVAAJYRBC-HJWJTTGWSA-N Arg-Ile-Phe Chemical compound CC[C@H](C)[C@H](NC(=O)[C@@H](N)CCCNC(N)=N)C(=O)N[C@@H](Cc1ccccc1)C(O)=O OFIYLHVAAJYRBC-HJWJTTGWSA-N 0.000 description 1
- JEOCWTUOMKEEMF-RHYQMDGZSA-N Arg-Leu-Thr Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O JEOCWTUOMKEEMF-RHYQMDGZSA-N 0.000 description 1
- VLDRQOHCMKCXLY-SRVKXCTJSA-N Asn-Ser-Phe Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O VLDRQOHCMKCXLY-SRVKXCTJSA-N 0.000 description 1
- 101100505161 Caenorhabditis elegans mel-32 gene Proteins 0.000 description 1
- 229920002284 Cellulose triacetate Polymers 0.000 description 1
- 102000047200 Collagen Type XVIII Human genes 0.000 description 1
- 108010001463 Collagen Type XVIII Proteins 0.000 description 1
- BDWIZLQVVWQMTB-XKBZYTNZSA-N Cys-Glu-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CS)N)O BDWIZLQVVWQMTB-XKBZYTNZSA-N 0.000 description 1
- OTXLNICGSXPGQF-KBIXCLLPSA-N Cys-Ile-Glu Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(O)=O OTXLNICGSXPGQF-KBIXCLLPSA-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
- 108010010803 Gelatin Proteins 0.000 description 1
- IRDASPPCLZIERZ-XHNCKOQMSA-N Glu-Ala-Pro Chemical compound C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCC(=O)O)N IRDASPPCLZIERZ-XHNCKOQMSA-N 0.000 description 1
- MWMJCGBSIORNCD-AVGNSLFASA-N Glu-Leu-Leu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O MWMJCGBSIORNCD-AVGNSLFASA-N 0.000 description 1
- WXONSNSSBYQGNN-AVGNSLFASA-N Glu-Ser-Tyr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O WXONSNSSBYQGNN-AVGNSLFASA-N 0.000 description 1
- LOEANKRDMMVOGZ-YUMQZZPRSA-N Gly-Lys-Asp Chemical compound NCCCC[C@H](NC(=O)CN)C(=O)N[C@@H](CC(O)=O)C(O)=O LOEANKRDMMVOGZ-YUMQZZPRSA-N 0.000 description 1
- FGPLUIQCSKGLTI-WDSKDSINSA-N Gly-Ser-Glu Chemical compound NCC(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CCC(O)=O FGPLUIQCSKGLTI-WDSKDSINSA-N 0.000 description 1
- ZNPRMNDAFQKATM-LKTVYLICSA-N His-Ala-Tyr Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O ZNPRMNDAFQKATM-LKTVYLICSA-N 0.000 description 1
- 101000654277 Hottentotta tamulus Neurotoxin-2 Proteins 0.000 description 1
- QLRMMMQNCWBNPQ-QXEWZRGKSA-N Ile-Arg-Gly Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)NCC(=O)O)N QLRMMMQNCWBNPQ-QXEWZRGKSA-N 0.000 description 1
- UYODHPPSCXBNCS-XUXIUFHCSA-N Ile-Val-Leu Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CC(C)C UYODHPPSCXBNCS-XUXIUFHCSA-N 0.000 description 1
- 108010065920 Insulin Lispro Proteins 0.000 description 1
- 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 1
- FJUKMPUELVROGK-IHRRRGAJSA-N Leu-Arg-His Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N FJUKMPUELVROGK-IHRRRGAJSA-N 0.000 description 1
- PTRKPHUGYULXPU-KKUMJFAQSA-N Leu-Phe-Ser Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(O)=O PTRKPHUGYULXPU-KKUMJFAQSA-N 0.000 description 1
- 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 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- DSWOTZCVCBEPOU-IUCAKERBSA-N Met-Arg-Gly Chemical compound CSCC[C@H](N)C(=O)N[C@H](C(=O)NCC(O)=O)CCCNC(N)=N DSWOTZCVCBEPOU-IUCAKERBSA-N 0.000 description 1
- GMMLGMFBYCFCCX-KZVJFYERSA-N Met-Thr-Ala Chemical compound CSCC[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O GMMLGMFBYCFCCX-KZVJFYERSA-N 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 108010066427 N-valyltryptophan Proteins 0.000 description 1
- 108010047562 NGR peptide Proteins 0.000 description 1
- NJJBATPLUQHRBM-IHRRRGAJSA-N Phe-Pro-Ser Chemical compound C1C[C@H](N(C1)C(=O)[C@H](CC2=CC=CC=C2)N)C(=O)N[C@@H](CO)C(=O)O NJJBATPLUQHRBM-IHRRRGAJSA-N 0.000 description 1
- XROLYVMNVIKVEM-BQBZGAKWSA-N Pro-Asn-Gly Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC(N)=O)C(=O)NCC(O)=O XROLYVMNVIKVEM-BQBZGAKWSA-N 0.000 description 1
- CLNJSLSHKJECME-BQBZGAKWSA-N Pro-Gly-Ala Chemical compound OC(=O)[C@H](C)NC(=O)CNC(=O)[C@@H]1CCCN1 CLNJSLSHKJECME-BQBZGAKWSA-N 0.000 description 1
- MRYUJHGPZQNOAD-IHRRRGAJSA-N Pro-Leu-Lys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@@H]1CCCN1 MRYUJHGPZQNOAD-IHRRRGAJSA-N 0.000 description 1
- CNUIHOAISPKQPY-HSHDSVGOSA-N Pro-Thr-Trp Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O CNUIHOAISPKQPY-HSHDSVGOSA-N 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- ZUGXSSFMTXKHJS-ZLUOBGJFSA-N Ser-Ala-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(O)=O ZUGXSSFMTXKHJS-ZLUOBGJFSA-N 0.000 description 1
- JPIDMRXXNMIVKY-VZFHVOOUSA-N Ser-Ala-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O JPIDMRXXNMIVKY-VZFHVOOUSA-N 0.000 description 1
- COLJZWUVZIXSSS-CIUDSAMLSA-N Ser-Cys-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)O)NC(=O)[C@H](CS)NC(=O)[C@H](CO)N COLJZWUVZIXSSS-CIUDSAMLSA-N 0.000 description 1
- YMTLKLXDFCSCNX-BYPYZUCNSA-N Ser-Gly-Gly Chemical compound OC[C@H](N)C(=O)NCC(=O)NCC(O)=O YMTLKLXDFCSCNX-BYPYZUCNSA-N 0.000 description 1
- UGTZYIPOBYXWRW-SRVKXCTJSA-N Ser-Phe-Asp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(O)=O)C(O)=O UGTZYIPOBYXWRW-SRVKXCTJSA-N 0.000 description 1
- 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 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- PNHABSVRPFBUJY-UMPQAUOISA-N Trp-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=CNC2=CC=CC=C21)N)O PNHABSVRPFBUJY-UMPQAUOISA-N 0.000 description 1
- NXJZCPKZIKTYLX-XEGUGMAKSA-N Trp-Glu-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)N NXJZCPKZIKTYLX-XEGUGMAKSA-N 0.000 description 1
- XLVRTKPAIXJYOH-HOCLYGCPSA-N Trp-His-Gly Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CC3=CN=CN3)C(=O)NCC(=O)O)N XLVRTKPAIXJYOH-HOCLYGCPSA-N 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 241000002074 Utricularia minor Species 0.000 description 1
- UXBZYLSMYOATLH-DCAQKATOSA-N Val-Ala-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)C(C)C UXBZYLSMYOATLH-DCAQKATOSA-N 0.000 description 1
- NNLVGZFZQQXQNW-ADJNRHBOSA-N [(2r,3r,4s,5r,6s)-4,5-diacetyloxy-3-[(2s,3r,4s,5r,6r)-3,4,5-triacetyloxy-6-(acetyloxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6s)-4,5,6-triacetyloxy-2-(acetyloxymethyl)oxan-3-yl]oxyoxan-2-yl]methyl acetate Chemical compound O([C@@H]1O[C@@H]([C@H]([C@H](OC(C)=O)[C@H]1OC(C)=O)O[C@H]1[C@@H]([C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](COC(C)=O)O1)OC(C)=O)COC(=O)C)[C@@H]1[C@@H](COC(C)=O)O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O NNLVGZFZQQXQNW-ADJNRHBOSA-N 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 210000004404 adrenal cortex Anatomy 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 108010047857 aspartylglycine Proteins 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 244000309466 calf Species 0.000 description 1
- 238000005341 cation exchange Methods 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 238000011097 chromatography purification Methods 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000003235 crystal violet staining Methods 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 238000010353 genetic engineering Methods 0.000 description 1
- 238000001631 haemodialysis Methods 0.000 description 1
- 230000000322 hemodialysis Effects 0.000 description 1
- 239000000004 hemodialysis solution Substances 0.000 description 1
- 108010028295 histidylhistidine Proteins 0.000 description 1
- 108010085325 histidylproline Proteins 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 230000008105 immune reaction Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000003978 infusion fluid Substances 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 108010044311 leucyl-glycyl-glycine Proteins 0.000 description 1
- 238000011866 long-term treatment Methods 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
- 238000000816 matrix-assisted laser desorption--ionisation Methods 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 108010051242 phenylalanylserine Proteins 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108010031719 prolyl-serine Proteins 0.000 description 1
- 108010090894 prolylleucine Proteins 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 108010061238 threonyl-glycine Proteins 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 108010084932 tryptophyl-proline Proteins 0.000 description 1
- 238000000108 ultra-filtration Methods 0.000 description 1
- 210000002229 urogenital system 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
- C07K14/78—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin or cold insoluble globulin [CIG]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Definitions
- the present invention relates to a peptide (protein) with the ability to influence the growth of cells.
- the collagen fragment HF-C0LL-18 / 514cf, as well as fragments and / or derivatives derived from it, and a medicinal product containing the natural and synthetic peptides can be used for diagnostic or therapeutic purposes.
- the invention relates to a method for obtaining a protein in pure or partially purified form from human body fluids, which has the ability to influence the growth of cells in a surprising manner and thus to inhibit vascular and tumor growth.
- a similar substance has recently been detected in the mouse (O'Reilly et al., 1997, Cell Vol.88, page 277).
- This substance is characterized in that it can be obtained in particular from hemofiltrate or hemodialysate, which is filtered off from human blood.
- the substance is referred to as HF-COLL-18 / 514cf and can be used for the purpose of (1) the analysis of diseases, (2) for medical and commercial use as a drug.
- the substance HF-COLL-18 / 514cf was first obtained from the hemofiltrate of kidney patients after ultrafiltration on the hemodialysis machine and was classified according to its molecular mass and 60 amino acids. the N-terminus.
- a patented process (Forssmann, 1988; published application DE 36 33 707 AI) was refined, which was previously invented for the extraction of proteins from hemofiltrate.
- the fractions containing the HF-COLL-18 / 514cf can surprisingly be recognized by mass spectrometry from the molecules of a molecular weight below 20 kilodaltons obtained by this method, which are filtered off in the case of veno-venous or arterio-venous shunt connections.
- this substance could surprisingly be purified in such a way until a uniform protein substance was finally identified and its structure was clarified.
- the substance is a fragment of a protein, the protein being hitherto known only at the cDNA level (Oh et al., 1994, Genomics Vol. 19, page 494).
- the value of this invention is characterized by the fact that this substance can be purified from the hemofiltrate previously considered worthless in order to be used as an economically usable substance.
- the substance HF-COLL-18 / 514cf mentioned can be obtained by chemical synthesis and by genetic engineering production and can be used for numerous other purposes, including analysis in human blood as a pathognomonic diagnostic feature of diseases of vascular growth and growth of tumors and metastases.
- the present invention thus relates to a new peptide, the HF-COLL-18 / 514cf, its production, medicaments containing it, and preparations containing it and its use therefor, and also its natural and pharmacologically contractual 1 -
- a mean molecular weight of 18494 u daltons could be determined by mass spectrometry.
- the blood peptide HF-COLL-18 / 514cf has the amino acid sequence: Val -Ala -Leu -Asn -Ser -Pro-Leu- Ser-Gly-Gly-Met-Arg-Gly-Ile -Arg -Gly- Ala-Asp-Phe -Gln-Cys-Phe-Gln-Gln-Ala-Arg-Ala -Val -Gly-Leu-Ala-Gly- Thr- Phe- Arg- Ala- Phe - Leu - Ser -Ser- Ar Q- Leu-Gin - Asr> -Leu-Tyr- Ser -Ile - Val -Arg -Arg -Ala -Asp- Arg- Ala- Ala - Val - Pro- II e- Val -Asn-Leu-L ⁇ s -Asp- Glu-Leu-Leu- Phe-Pro-Ser-
- HF-COLL-18 / 514cf The peptide provided by the present invention, HF-COLL-18 / 514cf, is now an easily accessible drug with biological and therapeutic activity of a natural analogue of the substance found in the blood.
- the present invention provides a production method for this HF-COLL-18 / 514cf and the use of the HF-COLL-18 / 514cf as a medicament for various therapeutic and diagnostic indications.
- the HF-COLL-18 / 514cf can be used as a highly pure substance or - if sufficient for the particular use - within a partially purified peptide mixture.
- the peptide according to the invention, its derivatives and fragments can be produced by various methods, for example by prokaryotic or eukaryotic expression and, if appropriate, chromatographic purification. Furthermore, it can be isolated from human blood, for example by means of chromatographic methods known per se Finally, are HF-COLL-18 / 514cf or its derivatives or fragments can be prepared by conventional solid-phase and liquid-phase synthesis methods from the protected amino acids contained in the sequence given. After the protective groups have been removed, it can be purified using standard chromatography procedures.
- the pharmaceutical preparation according to the invention contains HF-COLL-18 / 514cf or a physiologically tolerable salt of HF-COLL-18 / 514cf.
- the form and composition of the medicinal product containing the HF-COLL-18 / 514cf depends on the mode of administration.
- the human HF-COLL-18 / 514cf can be administered parenterally, intranasally, orally, intravenously, intramuscularly, intracutaneously, intra-thecally, locally-topically and transpulmonally.
- HF-COLL-18 / '514cf is preferably made up into an injection preparation, either as a solution or as a lyophilisate for dissolution immediately before use.
- the pharmaceutical preparation can also contain auxiliaries that are due to filling technology, contribute to the solubility, stability or sterility of the drug or increase the efficiency of absorption into the body.
- auxiliaries that are due to filling technology, contribute to the solubility, stability or sterility of the drug or increase the efficiency of absorption into the body.
- the use of the lyophilized form taken with mannitol in sterile ampoules for dissolution in physiological saline and / or infusion solutions for repeated single injection and / or continuous infusion in amounts of 30 micrograms to 30 milligrams of pure HF-COLL-18 / 514cf pro Therapy unit is beneficial.
- the daily dose to be administered for HF-COLL-18 / 514cf depends on the indication and use of certain derivatives. At i.v./i.m. Injection is in the range from 100 to 1200 units ( ⁇ g) / day, with daily subcutaneous injection preferably at 300 to 2400 units ( ⁇ g) / day.
- the peptide HF-COLL-18 / 514cf according to the invention is characterized in that it is also particularly suitable for long-term JPherapy for tumor diseases or other diseases which are characterized by uncontrolled vascular growth, and does not trigger an immune reaction in the case of long-term treatment. That invented
- the preparation according to the invention is particularly suitable for combination therapy with chemotherapy or radiation therapy or in connection with chemotherapy or radiation therapy for cancer.
- the preparation according to the invention can also be used as a means of therapy and diagnosis for vascular diseases of the supporting and connective tissue, the respiratory tract, the cardiovascular system and urogenital system, the nervous system and the eye, since it can be used for the production of human-compatible antibodies are suitable for determining or influencing changes in the vascular growth in these organs.
- Such antibodies can in principle be obtained by immunizing animals with the peptide according to the invention and / or its fragments or by using hybridoma technology.
- the present invention also relates to a method for treating patients who need HF-COLL-18 / 514cf or its derivatives or fragments by administering therapeutic amounts of HF-COLL-18 / 514cf.
- Patients who suffer from excessive production of HF-COLL-18 / 514cf or its derivatives or fragments require the administration of therapeutic amounts of an antagonist / inhibitor of HF-COLL-18 / 514cf.
- the medicament according to the invention is suitable for the treatment of diseases of the human organism, in particular in connection with vascular growths, cancer diseases, diseases involving the cardiovascular and nervous systems, diseases involving the intugement and the sensory organs, in particular the eye.
- the medicament according to the invention is suitable for the treatment of acute diseases of the type mentioned above, in that it is used in a corresponding form for the treatment in the intensive care of these diseases.
- a further use of the peptide according to the invention, its fragments or the antibody according to the invention is used to diagnose diseases by producing specific antibodies against synthetic parts or the entire peptide or its derivatives and its fragments and e.g. the blood concentration of the HF-COLL-18 / 514cf is measured by immunoassays.
- a diagnostic agent containing the peptide according to the invention, its fragments or antibodies according to the invention for test systems for checking tissue, plasma, urine and cerebrospinal fluid levels of this substance are thus also the subject of the invention.
- the diagnostic agent according to the invention is particularly suitable as a marker for certain cancers and for functional disorders of blood vessels, bone marrow, lymph organs, the gastrointestinal tract, the immune system and inflammatory and neoplastic processes.
- Example 1 Isolation and characterization of circulating HF-COLL-18 / 514cf from human hemofiltrate
- Hemofiltrate which is obtained in large quantities in the treatment of kidney insufficient patients and all plasma components up to a molecular size of about 20, was used as the starting material. Contains 000 daltons.
- the hemofiltrate was obtained by means of a Sartorius hemofiltration system using cellulose triacetate filters with an exclusion size of 20,000 daltons (type SM 40042, Sartoriu ⁇ , Göttingen, FRG).
- the filtrate came from kidney insufficiency patients who were in a stable metabolic state due to long-term hemofiltration and was protected against proteolytic degradation by acidification and cooling to 4 ° C immediately after it was obtained.
- TSK SP 650 (M) Merck, Darmstadt, DE
- 2860 l of hemofiltrate were processed. 93% of the pooled extracts were successively eluted on the column material mentioned above using different buffers with different pH values. The crude fractions were then freeze-dried.
- Eluent A water with 10MM HC1
- Eluent B methanol with 10 mM HC1 gradient: 0 - 50% eluent B 28.57 min 50 - 95% eluent B 61.43 min 95% eluent B 5.71 min flow rate: 35 ml / min fractions: 50 ml or 1 , 43 min detection: 230 nm and 280 nm
- a mass spectrum was additionally measured from fraction 25 of step V using an electrospray mass spectrometer (Sciex API III, Perkin-Elmer, Langen, DE). Peaks of the eight to eleven times protonated molecule are shown.
- the average molecular mass of HF-COLL-18 / 514cf is determined here at 18494 u + 3 u, the theoretical value is 18496 u (see VIII).
- the first 60 amino acids were determined by means of automated Edman sequencing with an ABI 494 gas-phase amino acid sequencer (Applied Biosystems, Perkin-Elmer, Rothstadt, DE). No amino acid was detected at the 21st position (Xxx), as is customary for cysteine.
- Example 2 Using the method shown in Example 1, a larger amount of material of more than 0.1 mg HF-COLL-18 / 514cf was isolated from human hemofiltrate. The high-purity HF-COLL-18 / 514cf was used to determine the biological function in endothelial cell proliferation assays. For this assay, bovine capillary endothelial cells from the adrenal cortex of freshly slaughtered calves were cultured as described in the literature (Folkman et al., 1979, Proc. Natl. Acad. Sci. Vol. 76, page 5217).
- the proliferation assay was carried out as described in the literature (O'Reilly et al., 1997, Cell Vol.88, page 277).
- the bovine capillary endothelial cells were washed with PBS (phosphate buffer with sodium chloride, pH 7.4) and suspended in a 0.05% trypsin solution.
- the medium was replaced by 0.5 ml DMEM medium containing 5% FCS and 1% GPS as well as different concentrations (from 0 to 1000 ng / ml final concentration) of the isolated, high-purity HF-COLL-18 / 514cf , replaced.
- bFGF basic fibroblast growth factor
- HF-COLL-18 / 514cf added to the bovine capillary endothelial cells inhibited the proliferation of these cells stimulated with bFGF in a concentration-dependent manner.
- Half-maximal inhibition of proliferation in this assay was achieved at a concentration of 200 ng / ml HF-COLL-18 / 514cf.
- HF-COLL-18 / 514cf In order to investigate the specificity of the spectrum of activity of HF-COLL-18 / 514cf and thus other possible biological functions, proliferation assays were carried out with non-endothelial cells. In tests with fibroblast cell lines, namely NIH 3T3 cells and LMTK cells, HF-COLL-18 / 514cf showed no significant activity and therefore no antiproliferative activity.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Molecular Biology (AREA)
- Immunology (AREA)
- Toxicology (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Engineering & Computer Science (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Medicinal Preparation (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
Description
Claims
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19615710 | 1996-04-22 | ||
DE19615710A DE19615710A1 (de) | 1996-04-22 | 1996-04-22 | Verfahren zur Gewinnung und Anwendung eines biologisch aktiven Eiweisstoffes - Kollagenfragment HF-COLL-18/514cf - in partiell aufgereinigter und synthetischer Form aus Körperflüssigkeiten zur Beeinflussung des Zellwachstums und der Diagnose von Kollagenerkrankungen sowie der Osteoporose |
PCT/EP1997/002012 WO1997040073A2 (de) | 1996-04-22 | 1997-04-22 | BIOLOGISCH AKTIVER EIWEISSSTOFF - KOLLAGENFRAGMENT HF-COLL-18/514cf - ZUR HEMMUNG DES WACHSTUMS VON TUMOREN UND VON GEFÄSSWUCHERUNGEN |
Publications (1)
Publication Number | Publication Date |
---|---|
EP0896584A2 true EP0896584A2 (de) | 1999-02-17 |
Family
ID=7791888
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP97921682A Withdrawn EP0896584A2 (de) | 1996-04-22 | 1997-04-22 | BIOLOGISCH AKTIVER EIWEISSSTOFF - KOLLAGENFRAGMENT HF-COLL-18/514cf - ZUR HEMMUNG DES WACHSTUMS VON TUMOREN UND VON GEFÄSSWUCHERUNGEN |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP0896584A2 (de) |
JP (1) | JP2000511511A (de) |
AU (1) | AU2766597A (de) |
DE (1) | DE19615710A1 (de) |
WO (1) | WO1997040073A2 (de) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU3199999A (en) * | 1998-03-24 | 1999-10-18 | Children's Medical Center Corporation | Endostatin derived peptides with anti-angiogenic and anti-cancer activity |
WO2000017240A1 (de) * | 1998-09-21 | 2000-03-30 | Haemopep Pharma Gmbh | Hmw-endostatin zur hemmung des wachstums von tumoren und von gefässwucherungen und zur diagnose von gefäss- und tumorerkrankungen |
ITMI20010394A1 (it) * | 2001-02-27 | 2002-08-27 | Univ Degli Studi Milano | Peptidi ad attivita' antiangiogenica |
GB0114419D0 (en) * | 2001-06-13 | 2001-08-08 | Mars Uk Ltd | Health food |
WO2004050125A1 (ja) * | 2002-12-03 | 2004-06-17 | Koken Co.,Ltd. | 腫瘍細胞の増殖及び/又は浸潤の抑制剤 |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3633797C2 (de) * | 1986-10-03 | 1995-08-10 | Forssmann Wolf Georg | Verfahren zur Gewinnung von biologisch aktiven Eiweissen (Peptiden) aus menschlichem und tierischem Blut (bzw. anderen Körperflüssigkeiten) |
WO1993016716A1 (en) * | 1992-02-24 | 1993-09-02 | Northwestern University | Method and composition for inhibiting angiogenesis |
CN1202932A (zh) * | 1995-10-23 | 1998-12-23 | 儿童医学中心公司 | 治疗用抗血管生成的组合物和方法 |
-
1996
- 1996-04-22 DE DE19615710A patent/DE19615710A1/de not_active Withdrawn
-
1997
- 1997-04-22 WO PCT/EP1997/002012 patent/WO1997040073A2/de not_active Application Discontinuation
- 1997-04-22 AU AU27665/97A patent/AU2766597A/en not_active Abandoned
- 1997-04-22 EP EP97921682A patent/EP0896584A2/de not_active Withdrawn
- 1997-04-22 JP JP09537737A patent/JP2000511511A/ja not_active Ceased
Non-Patent Citations (1)
Title |
---|
See references of WO9740073A2 * |
Also Published As
Publication number | Publication date |
---|---|
WO1997040073A2 (de) | 1997-10-30 |
DE19615710A1 (de) | 1997-10-23 |
WO1997040073A3 (de) | 1997-12-24 |
JP2000511511A (ja) | 2000-09-05 |
AU2766597A (en) | 1997-11-12 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
DE3485945T2 (de) | Gereinigter transformierender wachstum-beta-faktor aus humanen plaketten und plazenten stammend. | |
EP0167575B1 (de) | Cardiodilatin, ein neues peptidhormon und verfahren zu seiner herstellung | |
EP0209061B1 (de) | Neue Polypeptide mit blutgerinnungshemmender Wirkung, Verfahren zu deren Herstellung bzw. Gewinnung, deren Verwendung und diese enthaltende Mittel | |
DE69736712T2 (de) | Verfahren zur milderung von neuropatischen schmerz mit prosaposin verwandten peptiden | |
DE69015671T2 (de) | Peptide und deren Benützung in der Therapie. | |
DE3100974C2 (de) | ||
EP0497915B1 (de) | hPTH-FRAGMENT-(1-37), SEINE HERSTELLUNG, DIESES ENTHALTENDE ARZNEIMITTEL UND SEINE VERWENDUNG | |
EP0158986A2 (de) | Neue Polypeptide mit blutgerinnungshemmender Wirkung, Verfahren zu deren Herstellung bzw. Gewinnung, deren Verwendung und diese enthaltende Mittel | |
DE19908041A1 (de) | Kovalent verbrückte Insulindimere | |
WO1999032620A9 (de) | Insulin-like growth factor binding protein fragmente und ihre verwendung | |
EP2217619B1 (de) | Zyklisches, cystein-freies protein | |
EP1299541B1 (de) | Verfahren zur gewinnung und anwendung neuer humaner defensine als biologisch aktive eiweisstoffe zur behandlung von infektionen und anderen erkrankungen | |
DE60124915T2 (de) | Synthetische peptide gegen neurologische krankheiten | |
DE69630583T2 (de) | Peptide, bronchodilator und den blutstrom verbesserndes mittel | |
EP0896584A2 (de) | BIOLOGISCH AKTIVER EIWEISSSTOFF - KOLLAGENFRAGMENT HF-COLL-18/514cf - ZUR HEMMUNG DES WACHSTUMS VON TUMOREN UND VON GEFÄSSWUCHERUNGEN | |
AT400444B (de) | Verfahren zur herstellung von oncostatin m | |
EP1959013A1 (de) | Humanes zirkulierendes Virus inhibierendes Peptid (VIRIP) und seine Verwendung | |
DE69029040T2 (de) | Megakaryocytopoietischer faktor | |
DE19543628A1 (de) | Humanes, im Blut zirkulierendes Peptid mit insulinotroper Wirkung (GCAP-II-(89-112), (Guanylyl Cyclase C Aktivierendes Peptid II) und seine GCAP-Analoga, insbesondere das GCAP-I-(99-115), seine Anwendung als pharmakologischer Wirkstoff und Benutzung seines Wirkungsprinzipes zur Bereitstellung neuer GC-C-abhängiger insulinotroper Wirkstoffe | |
EP1023445B1 (de) | Cadherin derived growth factor und seine verwendung | |
WO2000017240A1 (de) | Hmw-endostatin zur hemmung des wachstums von tumoren und von gefässwucherungen und zur diagnose von gefäss- und tumorerkrankungen | |
DE4244565A1 (de) | Verfahren und Anwendung des LPAP (Lymphocytoma Proliferation Activating Peptide | |
DE4309815A1 (de) | Verfahren zur Gewinnung und Anwendung des Guanylatzyklavaktivierenden Peptid I (GAP-I) | |
WO1997006258A2 (de) | cDNA-SEQUENZ UND DARAUS ABGELEITETE AMINOSÄURESEQUENZ DES VORLÄUFERPROTEINS VON HUMANEM GCAP-II/UROGUANYLIN SOWIE AMINOSÄURESEQUENZ DES IM HUMANEN BLUT ZIRKULIERENDEN FRAGMENTES | |
DE19951824A1 (de) | Humanes zirkulierendes Insulin-like Growth Factor Binding Protein-3 Fragment und seine Verwendung |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
17P | Request for examination filed |
Effective date: 19981028 |
|
AK | Designated contracting states |
Kind code of ref document: A2 Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE |
|
RAP1 | Party data changed (applicant data changed or rights of an application transferred) |
Owner name: BIOVISION GMBH & CO. KG |
|
RAP3 | Party data changed (applicant data changed or rights of an application transferred) |
Owner name: BIOVISION AG |
|
17Q | First examination report despatched |
Effective date: 20030708 |
|
19U | Interruption of proceedings before grant |
Effective date: 20060102 |
|
19W | Proceedings resumed before grant after interruption of proceedings |
Effective date: 20060703 |
|
RAP1 | Party data changed (applicant data changed or rights of an application transferred) |
Owner name: DIGILAB BIOVISION GMBH |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN |
|
18D | Application deemed to be withdrawn |
Effective date: 20061101 |