TW202402326A - 含抗體製劑 - Google Patents
含抗體製劑 Download PDFInfo
- Publication number
- TW202402326A TW202402326A TW112137276A TW112137276A TW202402326A TW 202402326 A TW202402326 A TW 202402326A TW 112137276 A TW112137276 A TW 112137276A TW 112137276 A TW112137276 A TW 112137276A TW 202402326 A TW202402326 A TW 202402326A
- Authority
- TW
- Taiwan
- Prior art keywords
- polypeptide
- antibody
- ser
- chain
- cdata
- Prior art date
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 103
- 229920001993 poloxamer 188 Polymers 0.000 claims abstract description 47
- 229940044519 poloxamer 188 Drugs 0.000 claims abstract description 46
- 229940009098 aspartate Drugs 0.000 claims abstract description 38
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 15
- 102100026735 Coagulation factor VIII Human genes 0.000 claims abstract description 9
- 101000911390 Homo sapiens Coagulation factor VIII Proteins 0.000 claims abstract description 9
- 239000007853 buffer solution Substances 0.000 claims abstract description 3
- CTKXFMQHOOWWEB-UHFFFAOYSA-N Ethylene oxide/propylene oxide copolymer Chemical compound CCCOC(C)COCCO CTKXFMQHOOWWEB-UHFFFAOYSA-N 0.000 claims abstract 8
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 98
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 95
- 229920001184 polypeptide Polymers 0.000 claims description 94
- 239000000243 solution Substances 0.000 claims description 83
- 239000000872 buffer Substances 0.000 claims description 53
- 238000000034 method Methods 0.000 claims description 43
- 230000009977 dual effect Effects 0.000 claims description 40
- 150000001413 amino acids Chemical group 0.000 claims description 39
- 230000002401 inhibitory effect Effects 0.000 claims description 23
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 claims description 14
- 229930064664 L-arginine Natural products 0.000 claims description 13
- 235000014852 L-arginine Nutrition 0.000 claims description 13
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims description 12
- 238000004220 aggregation Methods 0.000 claims description 10
- 230000002776 aggregation Effects 0.000 claims description 10
- 201000003542 Factor VIII deficiency Diseases 0.000 claims description 8
- 208000009292 Hemophilia A Diseases 0.000 claims description 8
- 230000000087 stabilizing effect Effects 0.000 claims description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 6
- IWBSOYYTRIESIC-KNIFDHDWSA-N (2s)-2-aminobutanedioic acid;(2s)-2-amino-3-(1h-imidazol-5-yl)propanoic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O.OC(=O)[C@@H](N)CC1=CN=CN1 IWBSOYYTRIESIC-KNIFDHDWSA-N 0.000 claims description 5
- 238000007920 subcutaneous administration Methods 0.000 claims description 4
- 239000004475 Arginine Substances 0.000 abstract description 33
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 abstract description 33
- 229950006925 emicizumab Drugs 0.000 abstract description 16
- 239000007788 liquid Substances 0.000 abstract description 4
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 40
- 235000009697 arginine Nutrition 0.000 description 32
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 28
- 238000012360 testing method Methods 0.000 description 24
- 235000002639 sodium chloride Nutrition 0.000 description 22
- 238000003860 storage Methods 0.000 description 22
- 229960005261 aspartic acid Drugs 0.000 description 17
- 239000012535 impurity Substances 0.000 description 17
- 238000010257 thawing Methods 0.000 description 16
- 108010054218 Factor VIII Proteins 0.000 description 14
- 102000001690 Factor VIII Human genes 0.000 description 14
- 238000007710 freezing Methods 0.000 description 14
- 230000008014 freezing Effects 0.000 description 14
- 239000011780 sodium chloride Substances 0.000 description 14
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 12
- 239000002245 particle Substances 0.000 description 12
- 108010014173 Factor X Proteins 0.000 description 11
- 229960002885 histidine Drugs 0.000 description 11
- 108010076282 Factor IX Proteins 0.000 description 10
- 229940024606 amino acid Drugs 0.000 description 10
- 235000001014 amino acid Nutrition 0.000 description 10
- 229960000301 factor viii Drugs 0.000 description 10
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 10
- 229920001213 Polysorbate 20 Polymers 0.000 description 9
- 238000004364 calculation method Methods 0.000 description 9
- 239000011521 glass Substances 0.000 description 9
- 239000000463 material Substances 0.000 description 9
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 9
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 9
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 8
- 230000002378 acidificating effect Effects 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- XKUKSGPZAADMRA-UHFFFAOYSA-N glycyl-glycyl-glycine Chemical compound NCC(=O)NCC(=O)NCC(O)=O XKUKSGPZAADMRA-UHFFFAOYSA-N 0.000 description 8
- 229940068977 polysorbate 20 Drugs 0.000 description 8
- 150000003839 salts Chemical class 0.000 description 8
- 235000003704 aspartic acid Nutrition 0.000 description 7
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 7
- MNQMTYSEKZHIDF-GCJQMDKQSA-N Asp-Thr-Ala Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O MNQMTYSEKZHIDF-GCJQMDKQSA-N 0.000 description 6
- OYTPNWYZORARHL-XHNCKOQMSA-N Gln-Ala-Pro Chemical compound C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCC(=O)N)N OYTPNWYZORARHL-XHNCKOQMSA-N 0.000 description 6
- PMGDADKJMCOXHX-UHFFFAOYSA-N L-Arginyl-L-glutamin-acetat Natural products NC(=N)NCCCC(N)C(=O)NC(CCC(N)=O)C(O)=O PMGDADKJMCOXHX-UHFFFAOYSA-N 0.000 description 6
- 108010008355 arginyl-glutamine Proteins 0.000 description 6
- 238000001514 detection method Methods 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- 238000000691 measurement method Methods 0.000 description 6
- -1 polyoxyethylene Polymers 0.000 description 6
- 108090000623 proteins and genes Proteins 0.000 description 6
- 102000013831 Coagulation factor IX Human genes 0.000 description 5
- 102100022641 Coagulation factor IX Human genes 0.000 description 5
- 241000880493 Leptailurus serval Species 0.000 description 5
- SITLTJHOQZFJGG-UHFFFAOYSA-N N-L-alpha-glutamyl-L-valine Natural products CC(C)C(C(O)=O)NC(=O)C(N)CCC(O)=O SITLTJHOQZFJGG-UHFFFAOYSA-N 0.000 description 5
- PRKWBYCXBBSLSK-GUBZILKMSA-N Pro-Ser-Val Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O PRKWBYCXBBSLSK-GUBZILKMSA-N 0.000 description 5
- YUJLIIRMIAGMCQ-CIUDSAMLSA-N Ser-Leu-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O YUJLIIRMIAGMCQ-CIUDSAMLSA-N 0.000 description 5
- 239000000427 antigen Substances 0.000 description 5
- 102000036639 antigens Human genes 0.000 description 5
- 108091007433 antigens Proteins 0.000 description 5
- 210000004027 cell Anatomy 0.000 description 5
- 229940105774 coagulation factor ix Drugs 0.000 description 5
- 229960004222 factor ix Drugs 0.000 description 5
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 4
- QNFRBNZGVVKBNJ-PEFMBERDSA-N Asp-Ile-Gln Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CC(=O)O)N QNFRBNZGVVKBNJ-PEFMBERDSA-N 0.000 description 4
- ZFBBMCKQSNJZSN-AUTRQRHGSA-N Gln-Val-Gln Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O ZFBBMCKQSNJZSN-AUTRQRHGSA-N 0.000 description 4
- 108060003951 Immunoglobulin Proteins 0.000 description 4
- FEHQLKKBVJHSEC-SZMVWBNQSA-N Leu-Glu-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CC(C)C)C(O)=O)=CNC2=C1 FEHQLKKBVJHSEC-SZMVWBNQSA-N 0.000 description 4
- PDIDTSZKKFEDMB-UWVGGRQHSA-N Lys-Pro-Gly Chemical compound [H]N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O PDIDTSZKKFEDMB-UWVGGRQHSA-N 0.000 description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 4
- 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 4
- AZWNCEBQZXELEZ-FXQIFTODSA-N Ser-Pro-Ser Chemical compound OC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O AZWNCEBQZXELEZ-FXQIFTODSA-N 0.000 description 4
- MNYNCKZAEIAONY-XGEHTFHBSA-N Thr-Val-Ser Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(O)=O MNYNCKZAEIAONY-XGEHTFHBSA-N 0.000 description 4
- MBLJBGZWLHTJBH-SZMVWBNQSA-N Trp-Val-Arg Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O)=CNC2=C1 MBLJBGZWLHTJBH-SZMVWBNQSA-N 0.000 description 4
- 239000000654 additive Substances 0.000 description 4
- 108010069020 alanyl-prolyl-glycine Proteins 0.000 description 4
- 108010086434 alanyl-seryl-glycine Proteins 0.000 description 4
- 108010092854 aspartyllysine Proteins 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- 229940105778 coagulation factor viii Drugs 0.000 description 4
- 239000013604 expression vector Substances 0.000 description 4
- 102000018358 immunoglobulin Human genes 0.000 description 4
- 235000018102 proteins Nutrition 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- 235000000346 sugar Nutrition 0.000 description 4
- 150000008163 sugars Chemical class 0.000 description 4
- 108010003137 tyrosyltyrosine Proteins 0.000 description 4
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 3
- 102100029117 Coagulation factor X Human genes 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 108010065920 Insulin Lispro Proteins 0.000 description 3
- UWKNTTJNVSYXPC-CIUDSAMLSA-N Lys-Ala-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCCN UWKNTTJNVSYXPC-CIUDSAMLSA-N 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- IHCXPSYCHXFXKT-DCAQKATOSA-N Pro-Arg-Glu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(O)=O IHCXPSYCHXFXKT-DCAQKATOSA-N 0.000 description 3
- JCLAFVNDBJMLBC-JBDRJPRFSA-N Ser-Ser-Ile Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O JCLAFVNDBJMLBC-JBDRJPRFSA-N 0.000 description 3
- BMKNXTJLHFIAAH-CIUDSAMLSA-N Ser-Ser-Leu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O BMKNXTJLHFIAAH-CIUDSAMLSA-N 0.000 description 3
- FYBFTPLPAXZBOY-KKHAAJSZSA-N Thr-Val-Asp Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O FYBFTPLPAXZBOY-KKHAAJSZSA-N 0.000 description 3
- 230000001133 acceleration Effects 0.000 description 3
- 238000005571 anion exchange chromatography Methods 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 229940105756 coagulation factor x Drugs 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 230000004927 fusion Effects 0.000 description 3
- 108010010147 glycylglutamine Proteins 0.000 description 3
- 108010037850 glycylvaline Proteins 0.000 description 3
- 238000007689 inspection Methods 0.000 description 3
- 150000002500 ions Chemical class 0.000 description 3
- 108010064235 lysylglycine Proteins 0.000 description 3
- 239000011859 microparticle Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000000178 monomer Substances 0.000 description 3
- 239000008363 phosphate buffer Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 108010005652 splenotritin Proteins 0.000 description 3
- 108010017949 tyrosyl-glycyl-glycine Proteins 0.000 description 3
- 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 2
- COEXAQSTZUWMRI-STQMWFEESA-N (2s)-1-[2-[[(2s)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]acetyl]pyrrolidine-2-carboxylic acid Chemical compound C([C@H](N)C(=O)NCC(=O)N1[C@@H](CCC1)C(O)=O)C1=CC=C(O)C=C1 COEXAQSTZUWMRI-STQMWFEESA-N 0.000 description 2
- JXYWFNAQESKDNC-BTJKTKAUSA-N (z)-4-hydroxy-4-oxobut-2-enoate;2-[(4-methoxyphenyl)methyl-pyridin-2-ylamino]ethyl-dimethylazanium Chemical compound OC(=O)\C=C/C(O)=O.C1=CC(OC)=CC=C1CN(CCN(C)C)C1=CC=CC=N1 JXYWFNAQESKDNC-BTJKTKAUSA-N 0.000 description 2
- CFKMVGJGLGKFKI-UHFFFAOYSA-N 4-chloro-m-cresol Chemical compound CC1=CC(O)=CC=C1Cl CFKMVGJGLGKFKI-UHFFFAOYSA-N 0.000 description 2
- ODHCTXKNWHHXJC-VKHMYHEASA-N 5-oxo-L-proline Chemical compound OC(=O)[C@@H]1CCC(=O)N1 ODHCTXKNWHHXJC-VKHMYHEASA-N 0.000 description 2
- YYSWCHMLFJLLBJ-ZLUOBGJFSA-N Ala-Ala-Ser Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O YYSWCHMLFJLLBJ-ZLUOBGJFSA-N 0.000 description 2
- ARHJJAAWNWOACN-FXQIFTODSA-N Ala-Ser-Val Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O ARHJJAAWNWOACN-FXQIFTODSA-N 0.000 description 2
- CREYEAPXISDKSB-FQPOAREZSA-N Ala-Thr-Tyr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O CREYEAPXISDKSB-FQPOAREZSA-N 0.000 description 2
- VKKYFICVTYKFIO-CIUDSAMLSA-N Arg-Ala-Glu Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCN=C(N)N VKKYFICVTYKFIO-CIUDSAMLSA-N 0.000 description 2
- UXJCMQFPDWCHKX-DCAQKATOSA-N Arg-Arg-Glu Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCC(O)=O)C(O)=O UXJCMQFPDWCHKX-DCAQKATOSA-N 0.000 description 2
- HJVGMOYJDDXLMI-AVGNSLFASA-N Arg-Arg-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](N)CCCNC(N)=N HJVGMOYJDDXLMI-AVGNSLFASA-N 0.000 description 2
- NABSCJGZKWSNHX-RCWTZXSCSA-N Arg-Arg-Thr Chemical compound NC(N)=NCCC[C@@H](C(=O)N[C@@H]([C@H](O)C)C(O)=O)NC(=O)[C@@H](N)CCCN=C(N)N NABSCJGZKWSNHX-RCWTZXSCSA-N 0.000 description 2
- AOHKLEBWKMKITA-IHRRRGAJSA-N Arg-Phe-Ser Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CCCN=C(N)N)N AOHKLEBWKMKITA-IHRRRGAJSA-N 0.000 description 2
- ISJWBVIYRBAXEB-CIUDSAMLSA-N Arg-Ser-Glu Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(O)=O ISJWBVIYRBAXEB-CIUDSAMLSA-N 0.000 description 2
- SLKLLQWZQHXYSV-CIUDSAMLSA-N Asn-Ala-Lys Chemical compound NC(=O)C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(O)=O SLKLLQWZQHXYSV-CIUDSAMLSA-N 0.000 description 2
- BZMWJLLUAKSIMH-FXQIFTODSA-N Asn-Glu-Glu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O BZMWJLLUAKSIMH-FXQIFTODSA-N 0.000 description 2
- MDDXKBHIMYYJLW-FXQIFTODSA-N Asn-Met-Asp Chemical compound CSCC[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)O)NC(=O)[C@H](CC(=O)N)N MDDXKBHIMYYJLW-FXQIFTODSA-N 0.000 description 2
- MKJBPDLENBUHQU-CIUDSAMLSA-N Asn-Ser-Leu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O MKJBPDLENBUHQU-CIUDSAMLSA-N 0.000 description 2
- UGXYFDQFLVCDFC-CIUDSAMLSA-N Asn-Ser-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O UGXYFDQFLVCDFC-CIUDSAMLSA-N 0.000 description 2
- JXMREEPBRANWBY-VEVYYDQMSA-N Asn-Thr-Arg Chemical compound NC(=O)C[C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O JXMREEPBRANWBY-VEVYYDQMSA-N 0.000 description 2
- JBDLMLZNDRLDIX-HJGDQZAQSA-N Asn-Thr-Leu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O JBDLMLZNDRLDIX-HJGDQZAQSA-N 0.000 description 2
- XYBJLTKSGFBLCS-QXEWZRGKSA-N Asp-Arg-Val Chemical compound NC(N)=NCCC[C@@H](C(=O)N[C@@H](C(C)C)C(O)=O)NC(=O)[C@@H](N)CC(O)=O XYBJLTKSGFBLCS-QXEWZRGKSA-N 0.000 description 2
- GISFCCXBVJKGEO-QEJZJMRPSA-N Asp-Glu-Trp Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O GISFCCXBVJKGEO-QEJZJMRPSA-N 0.000 description 2
- ODNWIBOCFGMRTP-SRVKXCTJSA-N Asp-His-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC(O)=O)CC1=CN=CN1 ODNWIBOCFGMRTP-SRVKXCTJSA-N 0.000 description 2
- AHWRSSLYSGLBGD-CIUDSAMLSA-N Asp-Pro-Glu Chemical compound OC(=O)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O AHWRSSLYSGLBGD-CIUDSAMLSA-N 0.000 description 2
- BKOIIURTQAJHAT-GUBZILKMSA-N Asp-Pro-Pro Chemical compound OC(=O)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 BKOIIURTQAJHAT-GUBZILKMSA-N 0.000 description 2
- 101100505161 Caenorhabditis elegans mel-32 gene Proteins 0.000 description 2
- OZHXXYOHPLLLMI-CIUDSAMLSA-N Cys-Lys-Ala Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O OZHXXYOHPLLLMI-CIUDSAMLSA-N 0.000 description 2
- 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 2
- 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 2
- BTSPOOHJBYJRKO-CIUDSAMLSA-N Gln-Asp-Arg Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O BTSPOOHJBYJRKO-CIUDSAMLSA-N 0.000 description 2
- FQCILXROGNOZON-YUMQZZPRSA-N Gln-Pro-Gly Chemical compound NC(=O)CC[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O FQCILXROGNOZON-YUMQZZPRSA-N 0.000 description 2
- UBRQJXFDVZNYJP-AVGNSLFASA-N Gln-Tyr-Ser Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CCC(=O)N)N)O UBRQJXFDVZNYJP-AVGNSLFASA-N 0.000 description 2
- ITYRYNUZHPNCIK-GUBZILKMSA-N Glu-Ala-Leu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(O)=O ITYRYNUZHPNCIK-GUBZILKMSA-N 0.000 description 2
- IESFZVCAVACGPH-PEFMBERDSA-N Glu-Asp-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](N)CCC(O)=O IESFZVCAVACGPH-PEFMBERDSA-N 0.000 description 2
- 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 2
- IVGJYOOGJLFKQE-AVGNSLFASA-N Glu-Leu-Lys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCC(=O)O)N IVGJYOOGJLFKQE-AVGNSLFASA-N 0.000 description 2
- ALMBZBOCGSVSAI-ACZMJKKPSA-N Glu-Ser-Asn Chemical compound C(CC(=O)O)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(=O)N)C(=O)O)N ALMBZBOCGSVSAI-ACZMJKKPSA-N 0.000 description 2
- RFTVTKBHDXCEEX-WDSKDSINSA-N Glu-Ser-Gly Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)NCC(O)=O RFTVTKBHDXCEEX-WDSKDSINSA-N 0.000 description 2
- MFYLRRCYBBJYPI-JYJNAYRXSA-N Glu-Tyr-Lys Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCC(=O)O)N)O MFYLRRCYBBJYPI-JYJNAYRXSA-N 0.000 description 2
- OGCIHJPYKVSMTE-YUMQZZPRSA-N Gly-Arg-Glu Chemical compound [H]NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(O)=O OGCIHJPYKVSMTE-YUMQZZPRSA-N 0.000 description 2
- XBWMTPAIUQIWKA-BYULHYEWSA-N Gly-Asp-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)CN XBWMTPAIUQIWKA-BYULHYEWSA-N 0.000 description 2
- BYYNJRSNDARRBX-YFKPBYRVSA-N Gly-Gln-Gly Chemical compound NCC(=O)N[C@@H](CCC(N)=O)C(=O)NCC(O)=O BYYNJRSNDARRBX-YFKPBYRVSA-N 0.000 description 2
- GNPVTZJUUBPZKW-WDSKDSINSA-N Gly-Gln-Ser Chemical compound [H]NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(O)=O GNPVTZJUUBPZKW-WDSKDSINSA-N 0.000 description 2
- XTQFHTHIAKKCTM-YFKPBYRVSA-N Gly-Glu-Gly Chemical compound NCC(=O)N[C@@H](CCC(O)=O)C(=O)NCC(O)=O XTQFHTHIAKKCTM-YFKPBYRVSA-N 0.000 description 2
- UQJNXZSSGQIPIQ-FBCQKBJTSA-N Gly-Gly-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)CNC(=O)CN UQJNXZSSGQIPIQ-FBCQKBJTSA-N 0.000 description 2
- MIIVFRCYJABHTQ-ONGXEEELSA-N Gly-Leu-Val Chemical compound [H]NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(O)=O MIIVFRCYJABHTQ-ONGXEEELSA-N 0.000 description 2
- PDUHNKAFQXQNLH-ZETCQYMHSA-N Gly-Lys-Gly Chemical compound NCCCC[C@H](NC(=O)CN)C(=O)NCC(O)=O PDUHNKAFQXQNLH-ZETCQYMHSA-N 0.000 description 2
- WNZOCXUOGVYYBJ-CDMKHQONSA-N Gly-Phe-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)NC(=O)CN)O WNZOCXUOGVYYBJ-CDMKHQONSA-N 0.000 description 2
- NVTPVQLIZCOJFK-FOHZUACHSA-N Gly-Thr-Asp Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(O)=O NVTPVQLIZCOJFK-FOHZUACHSA-N 0.000 description 2
- ZZWUYQXMIFTIIY-WEDXCCLWSA-N Gly-Thr-Leu Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O ZZWUYQXMIFTIIY-WEDXCCLWSA-N 0.000 description 2
- IROABALAWGJQGM-OALUTQOASA-N Gly-Trp-Tyr Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CC3=CC=C(C=C3)O)C(=O)O)NC(=O)CN IROABALAWGJQGM-OALUTQOASA-N 0.000 description 2
- GBYYQVBXFVDJPJ-WLTAIBSBSA-N Gly-Tyr-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)NC(=O)CN)O GBYYQVBXFVDJPJ-WLTAIBSBSA-N 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- JDAWAWXGAUZPNJ-ZPFDUUQYSA-N Ile-Glu-Arg Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N JDAWAWXGAUZPNJ-ZPFDUUQYSA-N 0.000 description 2
- HXWALXSAVBLTPK-NUTKFTJISA-N Leu-Ala-Trp Chemical compound C[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)NC(=O)[C@H](CC(C)C)N HXWALXSAVBLTPK-NUTKFTJISA-N 0.000 description 2
- PVMPDMIKUVNOBD-CIUDSAMLSA-N Leu-Asp-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O PVMPDMIKUVNOBD-CIUDSAMLSA-N 0.000 description 2
- AXZGZMGRBDQTEY-SRVKXCTJSA-N Leu-Gln-Met Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCSC)C(O)=O AXZGZMGRBDQTEY-SRVKXCTJSA-N 0.000 description 2
- CQGSYZCULZMEDE-UHFFFAOYSA-N Leu-Gln-Pro Natural products CC(C)CC(N)C(=O)NC(CCC(N)=O)C(=O)N1CCCC1C(O)=O CQGSYZCULZMEDE-UHFFFAOYSA-N 0.000 description 2
- GPICTNQYKHHHTH-GUBZILKMSA-N Leu-Gln-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(O)=O GPICTNQYKHHHTH-GUBZILKMSA-N 0.000 description 2
- KIZIOFNVSOSKJI-CIUDSAMLSA-N Leu-Ser-Cys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)O)N KIZIOFNVSOSKJI-CIUDSAMLSA-N 0.000 description 2
- SBANPBVRHYIMRR-UHFFFAOYSA-N Leu-Ser-Pro Natural products CC(C)CC(N)C(=O)NC(CO)C(=O)N1CCCC1C(O)=O SBANPBVRHYIMRR-UHFFFAOYSA-N 0.000 description 2
- AIQWYVFNBNNOLU-RHYQMDGZSA-N Leu-Thr-Val Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(O)=O AIQWYVFNBNNOLU-RHYQMDGZSA-N 0.000 description 2
- MVJRBCJCRYGCKV-GVXVVHGQSA-N Leu-Val-Gln Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O MVJRBCJCRYGCKV-GVXVVHGQSA-N 0.000 description 2
- AIMGJYMCTAABEN-GVXVVHGQSA-N Leu-Val-Glu Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O AIMGJYMCTAABEN-GVXVVHGQSA-N 0.000 description 2
- GQZMPWBZQALKJO-UWVGGRQHSA-N Lys-Gly-Arg Chemical compound [H]N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(O)=O GQZMPWBZQALKJO-UWVGGRQHSA-N 0.000 description 2
- WQDKIVRHTQYJSN-DCAQKATOSA-N Lys-Ser-Arg Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N WQDKIVRHTQYJSN-DCAQKATOSA-N 0.000 description 2
- MIFFFXHMAHFACR-KATARQTJSA-N Lys-Ser-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CCCCN MIFFFXHMAHFACR-KATARQTJSA-N 0.000 description 2
- DLCAXBGXGOVUCD-PPCPHDFISA-N Lys-Thr-Ile Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O DLCAXBGXGOVUCD-PPCPHDFISA-N 0.000 description 2
- UGCIQUYEJIEHKX-GVXVVHGQSA-N Lys-Val-Glu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O UGCIQUYEJIEHKX-GVXVVHGQSA-N 0.000 description 2
- SJDQOYTYNGZZJX-SRVKXCTJSA-N Met-Glu-Leu Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O SJDQOYTYNGZZJX-SRVKXCTJSA-N 0.000 description 2
- SPSSJSICDYYTQN-HJGDQZAQSA-N Met-Thr-Gln Chemical compound CSCC[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@H](C(O)=O)CCC(N)=O SPSSJSICDYYTQN-HJGDQZAQSA-N 0.000 description 2
- KZNQNBZMBZJQJO-UHFFFAOYSA-N N-glycyl-L-proline Natural products NCC(=O)N1CCCC1C(O)=O KZNQNBZMBZJQJO-UHFFFAOYSA-N 0.000 description 2
- 108010079364 N-glycylalanine Proteins 0.000 description 2
- 101100068676 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) gln-1 gene Proteins 0.000 description 2
- CUMXHKAOHNWRFQ-BZSNNMDCSA-N Phe-Asp-Tyr Chemical compound C([C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C1=CC=CC=C1 CUMXHKAOHNWRFQ-BZSNNMDCSA-N 0.000 description 2
- JDMKQHSHKJHAHR-UHFFFAOYSA-N Phe-Phe-Leu-Tyr Natural products C=1C=C(O)C=CC=1CC(C(O)=O)NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)CC1=CC=CC=C1 JDMKQHSHKJHAHR-UHFFFAOYSA-N 0.000 description 2
- XNMYNGDKJNOKHH-BZSNNMDCSA-N Phe-Ser-Tyr Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O XNMYNGDKJNOKHH-BZSNNMDCSA-N 0.000 description 2
- RAGOJJCBGXARPO-XVSYOHENSA-N Phe-Thr-Asp Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)[C@H]([C@H](O)C)NC(=O)[C@@H](N)CC1=CC=CC=C1 RAGOJJCBGXARPO-XVSYOHENSA-N 0.000 description 2
- FGWUALWGCZJQDJ-URLPEUOOSA-N Phe-Thr-Ile Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O FGWUALWGCZJQDJ-URLPEUOOSA-N 0.000 description 2
- KLYYKKGCPOGDPE-OEAJRASXSA-N Phe-Thr-Leu Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O KLYYKKGCPOGDPE-OEAJRASXSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- OOLOTUZJUBOMAX-GUBZILKMSA-N Pro-Ala-Val Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(O)=O OOLOTUZJUBOMAX-GUBZILKMSA-N 0.000 description 2
- TUYWCHPXKQTISF-LPEHRKFASA-N Pro-Cys-Pro Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CS)C(=O)N2CCC[C@@H]2C(=O)O TUYWCHPXKQTISF-LPEHRKFASA-N 0.000 description 2
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical group CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 description 2
- FCRMLGJMPXCAHD-FXQIFTODSA-N Ser-Arg-Asn Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(N)=O)C(O)=O FCRMLGJMPXCAHD-FXQIFTODSA-N 0.000 description 2
- QEDMOZUJTGEIBF-FXQIFTODSA-N Ser-Arg-Asp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(O)=O QEDMOZUJTGEIBF-FXQIFTODSA-N 0.000 description 2
- QFBNNYNWKYKVJO-DCAQKATOSA-N Ser-Arg-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CO)CCCN=C(N)N QFBNNYNWKYKVJO-DCAQKATOSA-N 0.000 description 2
- OYEDZGNMSBZCIM-XGEHTFHBSA-N Ser-Arg-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(O)=O OYEDZGNMSBZCIM-XGEHTFHBSA-N 0.000 description 2
- WXUBSIDKNMFAGS-IHRRRGAJSA-N Ser-Arg-Tyr Chemical compound NC(N)=NCCC[C@H](NC(=O)[C@H](CO)N)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 WXUBSIDKNMFAGS-IHRRRGAJSA-N 0.000 description 2
- ZOHGLPQGEHSLPD-FXQIFTODSA-N Ser-Gln-Glu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O ZOHGLPQGEHSLPD-FXQIFTODSA-N 0.000 description 2
- UIGMAMGZOJVTDN-WHFBIAKZSA-N Ser-Gly-Ser Chemical compound OC[C@H](N)C(=O)NCC(=O)N[C@@H](CO)C(O)=O UIGMAMGZOJVTDN-WHFBIAKZSA-N 0.000 description 2
- MQQBBLVOUUJKLH-HJPIBITLSA-N Ser-Ile-Tyr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O MQQBBLVOUUJKLH-HJPIBITLSA-N 0.000 description 2
- QYSFWUIXDFJUDW-DCAQKATOSA-N Ser-Leu-Arg Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O QYSFWUIXDFJUDW-DCAQKATOSA-N 0.000 description 2
- GJFYFGOEWLDQGW-GUBZILKMSA-N Ser-Leu-Gln Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CO)N GJFYFGOEWLDQGW-GUBZILKMSA-N 0.000 description 2
- XQJCEKXQUJQNNK-ZLUOBGJFSA-N Ser-Ser-Ser Chemical compound OC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O XQJCEKXQUJQNNK-ZLUOBGJFSA-N 0.000 description 2
- FHXGMDRKJHKLKW-QWRGUYRKSA-N Ser-Tyr-Gly Chemical compound OC[C@H](N)C(=O)N[C@H](C(=O)NCC(O)=O)CC1=CC=C(O)C=C1 FHXGMDRKJHKLKW-QWRGUYRKSA-N 0.000 description 2
- LGIMRDKGABDMBN-DCAQKATOSA-N Ser-Val-Lys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CO)N LGIMRDKGABDMBN-DCAQKATOSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- 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 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- IGROJMCBGRFRGI-YTLHQDLWSA-N Thr-Ala-Ala Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(O)=O IGROJMCBGRFRGI-YTLHQDLWSA-N 0.000 description 2
- ASJDFGOPDCVXTG-KATARQTJSA-N Thr-Cys-Leu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(C)C)C(O)=O ASJDFGOPDCVXTG-KATARQTJSA-N 0.000 description 2
- FQPDRTDDEZXCEC-SVSWQMSJSA-N Thr-Ile-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(O)=O FQPDRTDDEZXCEC-SVSWQMSJSA-N 0.000 description 2
- GXUWHVZYDAHFSV-FLBSBUHZSA-N Thr-Ile-Thr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(O)=O GXUWHVZYDAHFSV-FLBSBUHZSA-N 0.000 description 2
- KZSYAEWQMJEGRZ-RHYQMDGZSA-N Thr-Leu-Val Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(O)=O KZSYAEWQMJEGRZ-RHYQMDGZSA-N 0.000 description 2
- BIBYEFRASCNLAA-CDMKHQONSA-N Thr-Phe-Gly Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@H](C(=O)NCC(O)=O)CC1=CC=CC=C1 BIBYEFRASCNLAA-CDMKHQONSA-N 0.000 description 2
- ABCLYRRGTZNIFU-BWAGICSOSA-N Thr-Tyr-His Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CC2=CN=CN2)C(=O)O)N)O ABCLYRRGTZNIFU-BWAGICSOSA-N 0.000 description 2
- YOPQYBJJNSIQGZ-JNPHEJMOSA-N Thr-Tyr-Tyr Chemical compound C([C@H](NC(=O)[C@@H](N)[C@H](O)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C1=CC=C(O)C=C1 YOPQYBJJNSIQGZ-JNPHEJMOSA-N 0.000 description 2
- QNXZCKMXHPULME-ZNSHCXBVSA-N Thr-Val-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)O)N)O QNXZCKMXHPULME-ZNSHCXBVSA-N 0.000 description 2
- 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 2
- 239000007983 Tris buffer Substances 0.000 description 2
- SVGAWGVHFIYAEE-JSGCOSHPSA-N Trp-Gly-Gln Chemical compound C1=CC=C2C(C[C@H](N)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(O)=O)=CNC2=C1 SVGAWGVHFIYAEE-JSGCOSHPSA-N 0.000 description 2
- QOIKZODVIPOPDD-AVGNSLFASA-N Tyr-Cys-Gln Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(O)=O QOIKZODVIPOPDD-AVGNSLFASA-N 0.000 description 2
- QHEGAOPHISYNDF-XDTLVQLUSA-N Tyr-Gln-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CC1=CC=C(C=C1)O)N QHEGAOPHISYNDF-XDTLVQLUSA-N 0.000 description 2
- QUILOGWWLXMSAT-IHRRRGAJSA-N Tyr-Gln-Gln Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O QUILOGWWLXMSAT-IHRRRGAJSA-N 0.000 description 2
- HIINQLBHPIQYHN-JTQLQIEISA-N Tyr-Gly-Gly Chemical compound OC(=O)CNC(=O)CNC(=O)[C@@H](N)CC1=CC=C(O)C=C1 HIINQLBHPIQYHN-JTQLQIEISA-N 0.000 description 2
- MQGGXGKQSVEQHR-KKUMJFAQSA-N Tyr-Ser-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 MQGGXGKQSVEQHR-KKUMJFAQSA-N 0.000 description 2
- HZDQUVQEVVYDDA-ACRUOGEOSA-N Tyr-Tyr-Leu Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=C(O)C=C1 HZDQUVQEVVYDDA-ACRUOGEOSA-N 0.000 description 2
- PYXQBKJPHNCTNW-CYDGBPFRSA-N Val-Ile-Met Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCSC)C(=O)O)NC(=O)[C@H](C(C)C)N PYXQBKJPHNCTNW-CYDGBPFRSA-N 0.000 description 2
- ZXYPHBKIZLAQTL-QXEWZRGKSA-N Val-Pro-Asp Chemical compound CC(C)[C@@H](C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(=O)O)C(=O)O)N ZXYPHBKIZLAQTL-QXEWZRGKSA-N 0.000 description 2
- JQTYTBPCSOAZHI-FXQIFTODSA-N Val-Ser-Cys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)O)N JQTYTBPCSOAZHI-FXQIFTODSA-N 0.000 description 2
- HTONZBWRYUKUKC-RCWTZXSCSA-N Val-Thr-Val Chemical compound CC(C)[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(O)=O HTONZBWRYUKUKC-RCWTZXSCSA-N 0.000 description 2
- OWFGFHQMSBTKLX-UFYCRDLUSA-N Val-Tyr-Tyr Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CC2=CC=C(C=C2)O)C(=O)O)N OWFGFHQMSBTKLX-UFYCRDLUSA-N 0.000 description 2
- LLJLBRRXKZTTRD-GUBZILKMSA-N Val-Val-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(=O)O)N LLJLBRRXKZTTRD-GUBZILKMSA-N 0.000 description 2
- 239000008351 acetate buffer Substances 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 108010008685 alanyl-glutamyl-aspartic acid Proteins 0.000 description 2
- 108010087924 alanylproline Proteins 0.000 description 2
- 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 2
- KOSRFJWDECSPRO-UHFFFAOYSA-N alpha-L-glutamyl-L-glutamic acid Natural products OC(=O)CCC(N)C(=O)NC(CCC(O)=O)C(O)=O KOSRFJWDECSPRO-UHFFFAOYSA-N 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 108010069205 aspartyl-phenylalanine Proteins 0.000 description 2
- 108010068265 aspartyltyrosine Proteins 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- 238000005138 cryopreservation Methods 0.000 description 2
- 239000002577 cryoprotective agent Substances 0.000 description 2
- 230000006866 deterioration Effects 0.000 description 2
- 238000001962 electrophoresis Methods 0.000 description 2
- 108010063718 gamma-glutamylaspartic acid Proteins 0.000 description 2
- 108010078144 glutaminyl-glycine Proteins 0.000 description 2
- 108010055341 glutamyl-glutamic acid Proteins 0.000 description 2
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 2
- VPZXBVLAVMBEQI-UHFFFAOYSA-N glycyl-DL-alpha-alanine Natural products OC(=O)C(C)NC(=O)CN VPZXBVLAVMBEQI-UHFFFAOYSA-N 0.000 description 2
- XBGGUPMXALFZOT-UHFFFAOYSA-N glycyl-L-tyrosine hemihydrate Natural products NCC(=O)NC(C(O)=O)CC1=CC=C(O)C=C1 XBGGUPMXALFZOT-UHFFFAOYSA-N 0.000 description 2
- 108010000434 glycyl-alanyl-leucine Proteins 0.000 description 2
- 108010067216 glycyl-glycyl-glycine Proteins 0.000 description 2
- 108010050475 glycyl-leucyl-tyrosine Proteins 0.000 description 2
- 108010087823 glycyltyrosine Proteins 0.000 description 2
- 239000013628 high molecular weight specie Substances 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 238000004255 ion exchange chromatography Methods 0.000 description 2
- 239000007951 isotonicity adjuster Substances 0.000 description 2
- 108010044311 leucyl-glycyl-glycine Proteins 0.000 description 2
- 108010073472 leucyl-prolyl-proline Proteins 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 108010070409 phenylalanyl-glycyl-glycine Proteins 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 108010020755 prolyl-glycyl-glycine Proteins 0.000 description 2
- 108010031719 prolyl-serine Proteins 0.000 description 2
- 108010070643 prolylglutamic acid Proteins 0.000 description 2
- 108010090894 prolylleucine Proteins 0.000 description 2
- 230000001737 promoting effect Effects 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 108010048397 seryl-lysyl-leucine Proteins 0.000 description 2
- 230000035939 shock Effects 0.000 description 2
- 238000003998 size exclusion chromatography high performance liquid chromatography Methods 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 238000001179 sorption measurement Methods 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- CWERGRDVMFNCDR-UHFFFAOYSA-N thioglycolic acid Chemical compound OC(=O)CS CWERGRDVMFNCDR-UHFFFAOYSA-N 0.000 description 2
- 108010061238 threonyl-glycine Proteins 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- 108010038745 tryptophylglycine Proteins 0.000 description 2
- 108010044292 tryptophyltyrosine Proteins 0.000 description 2
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 2
- CSTRPYAGFNTOEQ-MGMRMFRLSA-N (2r)-2-[(1s)-1,2-dihydroxyethyl]-3,4-dihydroxy-2h-furan-5-one;octadecanoic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O.CCCCCCCCCCCCCCCCCC(O)=O CSTRPYAGFNTOEQ-MGMRMFRLSA-N 0.000 description 1
- DYIOSHGVFJTOAR-JGWLITMVSA-N (2r,3r,4s,5r)-6-sulfanylhexane-1,2,3,4,5-pentol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CS DYIOSHGVFJTOAR-JGWLITMVSA-N 0.000 description 1
- DIBLBAURNYJYBF-XLXZRNDBSA-N (2s)-2-[[(2s)-2-[[2-[[(2s)-6-amino-2-[[(2s)-2-amino-3-methylbutanoyl]amino]hexanoyl]amino]acetyl]amino]-3-phenylpropanoyl]amino]-3-(4-hydroxyphenyl)propanoic acid Chemical compound C([C@H](NC(=O)CNC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)C(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C1=CC=CC=C1 DIBLBAURNYJYBF-XLXZRNDBSA-N 0.000 description 1
- REYLLNRLWCBKCM-YFKPBYRVSA-N (2s)-2-acetamido-4-sulfanylbutanoic acid Chemical compound CC(=O)N[C@H](C(O)=O)CCS REYLLNRLWCBKCM-YFKPBYRVSA-N 0.000 description 1
- QZNNVYOVQUKYSC-JEDNCBNOSA-N (2s)-2-amino-3-(1h-imidazol-5-yl)propanoic acid;hydron;chloride Chemical compound Cl.OC(=O)[C@@H](N)CC1=CN=CN1 QZNNVYOVQUKYSC-JEDNCBNOSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- SPSPIUSUWPLVKD-UHFFFAOYSA-N 2,3-dibutyl-6-methylphenol Chemical compound CCCCC1=CC=C(C)C(O)=C1CCCC SPSPIUSUWPLVKD-UHFFFAOYSA-N 0.000 description 1
- QAQJMLQRFWZOBN-UHFFFAOYSA-N 2-(3,4-dihydroxy-5-oxo-2,5-dihydrofuran-2-yl)-2-hydroxyethyl hexadecanoate Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(O)C1OC(=O)C(O)=C1O QAQJMLQRFWZOBN-UHFFFAOYSA-N 0.000 description 1
- QTWJRLJHJPIABL-UHFFFAOYSA-N 2-methylphenol;3-methylphenol;4-methylphenol Chemical compound CC1=CC=C(O)C=C1.CC1=CC=CC(O)=C1.CC1=CC=CC=C1O QTWJRLJHJPIABL-UHFFFAOYSA-N 0.000 description 1
- MOMKYJPSVWEWPM-UHFFFAOYSA-N 4-(chloromethyl)-2-(4-methylphenyl)-1,3-thiazole Chemical compound C1=CC(C)=CC=C1C1=NC(CCl)=CS1 MOMKYJPSVWEWPM-UHFFFAOYSA-N 0.000 description 1
- 208000033316 Acquired hemophilia A Diseases 0.000 description 1
- WCBVQNZTOKJWJS-ACZMJKKPSA-N Ala-Cys-Glu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(O)=O)C(O)=O WCBVQNZTOKJWJS-ACZMJKKPSA-N 0.000 description 1
- MEFILNJXAVSUTO-JXUBOQSCSA-N Ala-Leu-Thr Chemical compound C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O MEFILNJXAVSUTO-JXUBOQSCSA-N 0.000 description 1
- DYJJJCHDHLEFDW-FXQIFTODSA-N Ala-Pro-Cys Chemical compound C[C@@H](C(=O)N1CCC[C@H]1C(=O)N[C@@H](CS)C(=O)O)N DYJJJCHDHLEFDW-FXQIFTODSA-N 0.000 description 1
- IORKCNUBHNIMKY-CIUDSAMLSA-N Ala-Pro-Glu Chemical compound C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O IORKCNUBHNIMKY-CIUDSAMLSA-N 0.000 description 1
- 102000013455 Amyloid beta-Peptides Human genes 0.000 description 1
- 108010090849 Amyloid beta-Peptides Proteins 0.000 description 1
- QPOARHANPULOTM-GMOBBJLQSA-N Arg-Asn-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CCCN=C(N)N)N QPOARHANPULOTM-GMOBBJLQSA-N 0.000 description 1
- JAYIQMNQDMOBFY-KKUMJFAQSA-N Arg-Glu-Tyr Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O JAYIQMNQDMOBFY-KKUMJFAQSA-N 0.000 description 1
- GOWZVQXTHUCNSQ-NHCYSSNCSA-N Arg-Glu-Val Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O GOWZVQXTHUCNSQ-NHCYSSNCSA-N 0.000 description 1
- CVXXSWQORBZAAA-SRVKXCTJSA-N Arg-Lys-Glu Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CCCN=C(N)N CVXXSWQORBZAAA-SRVKXCTJSA-N 0.000 description 1
- NPAVRDPEFVKELR-DCAQKATOSA-N Arg-Lys-Ser Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(O)=O NPAVRDPEFVKELR-DCAQKATOSA-N 0.000 description 1
- LRPZJPMQGKGHSG-XGEHTFHBSA-N Arg-Ser-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CCCN=C(N)N)N)O LRPZJPMQGKGHSG-XGEHTFHBSA-N 0.000 description 1
- UZSQXCMNUPKLCC-FJXKBIBVSA-N Arg-Thr-Gly Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(O)=O UZSQXCMNUPKLCC-FJXKBIBVSA-N 0.000 description 1
- BVLIJXXSXBUGEC-SRVKXCTJSA-N Asn-Asn-Tyr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O BVLIJXXSXBUGEC-SRVKXCTJSA-N 0.000 description 1
- OLVIPTLKNSAYRJ-YUMQZZPRSA-N Asn-Gly-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)CNC(=O)[C@H](CC(=O)N)N OLVIPTLKNSAYRJ-YUMQZZPRSA-N 0.000 description 1
- WQLJRNRLHWJIRW-KKUMJFAQSA-N Asn-His-Tyr Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)O)NC(=O)[C@H](CC2=CN=CN2)NC(=O)[C@H](CC(=O)N)N)O WQLJRNRLHWJIRW-KKUMJFAQSA-N 0.000 description 1
- NYGILGUOUOXGMJ-YUMQZZPRSA-N Asn-Lys-Gly Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)NCC(O)=O NYGILGUOUOXGMJ-YUMQZZPRSA-N 0.000 description 1
- RBOBTTLFPRSXKZ-BZSNNMDCSA-N Asn-Phe-Tyr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O RBOBTTLFPRSXKZ-BZSNNMDCSA-N 0.000 description 1
- HPBNLFLSSQDFQW-WHFBIAKZSA-N Asn-Ser-Gly Chemical compound NC(=O)C[C@H](N)C(=O)N[C@@H](CO)C(=O)NCC(O)=O HPBNLFLSSQDFQW-WHFBIAKZSA-N 0.000 description 1
- HNXWVVHIGTZTBO-LKXGYXEUSA-N Asn-Ser-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O HNXWVVHIGTZTBO-LKXGYXEUSA-N 0.000 description 1
- LGCVSPFCFXWUEY-IHPCNDPISA-N Asn-Trp-Tyr Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CC3=CC=C(C=C3)O)C(=O)O)NC(=O)[C@H](CC(=O)N)N LGCVSPFCFXWUEY-IHPCNDPISA-N 0.000 description 1
- KBQOUDLMWYWXNP-YDHLFZDLSA-N Asn-Val-Phe Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)NC(=O)[C@H](CC(=O)N)N KBQOUDLMWYWXNP-YDHLFZDLSA-N 0.000 description 1
- YNQIDCRRTWGHJD-ZLUOBGJFSA-N Asp-Asn-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CC(O)=O YNQIDCRRTWGHJD-ZLUOBGJFSA-N 0.000 description 1
- UQBGYPFHWFZMCD-ZLUOBGJFSA-N Asp-Asn-Asn Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O UQBGYPFHWFZMCD-ZLUOBGJFSA-N 0.000 description 1
- HSWYMWGDMPLTTH-FXQIFTODSA-N Asp-Glu-Gln Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O HSWYMWGDMPLTTH-FXQIFTODSA-N 0.000 description 1
- SNDBKTFJWVEVPO-WHFBIAKZSA-N Asp-Gly-Ser Chemical compound [H]N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@@H](CO)C(O)=O SNDBKTFJWVEVPO-WHFBIAKZSA-N 0.000 description 1
- WSGVTKZFVJSJOG-RCOVLWMOSA-N Asp-Gly-Val Chemical compound [H]N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@@H](C(C)C)C(O)=O WSGVTKZFVJSJOG-RCOVLWMOSA-N 0.000 description 1
- KTTCQQNRRLCIBC-GHCJXIJMSA-N Asp-Ile-Ala Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O KTTCQQNRRLCIBC-GHCJXIJMSA-N 0.000 description 1
- CYCKJEFVFNRWEZ-UGYAYLCHSA-N Asp-Ile-Asn Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(N)=O)C(O)=O CYCKJEFVFNRWEZ-UGYAYLCHSA-N 0.000 description 1
- UZFHNLYQWMGUHU-DCAQKATOSA-N Asp-Lys-Arg Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O UZFHNLYQWMGUHU-DCAQKATOSA-N 0.000 description 1
- VNXQRBXEQXLERQ-CIUDSAMLSA-N Asp-Ser-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(=O)O)N VNXQRBXEQXLERQ-CIUDSAMLSA-N 0.000 description 1
- YIDFBWRHIYOYAA-LKXGYXEUSA-N Asp-Ser-Thr Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(O)=O YIDFBWRHIYOYAA-LKXGYXEUSA-N 0.000 description 1
- YUELDQUPTAYEGM-XIRDDKMYSA-N Asp-Trp-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)NC(=O)[C@H](CC(=O)O)N YUELDQUPTAYEGM-XIRDDKMYSA-N 0.000 description 1
- SQIARYGNVQWOSB-BZSNNMDCSA-N Asp-Tyr-Phe Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O SQIARYGNVQWOSB-BZSNNMDCSA-N 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 1
- 102100021277 Beta-secretase 2 Human genes 0.000 description 1
- 101710150190 Beta-secretase 2 Proteins 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- NDUSUIGBMZCOIL-ZKWXMUAHSA-N Cys-Asn-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CS)N NDUSUIGBMZCOIL-ZKWXMUAHSA-N 0.000 description 1
- ZXCAQANTQWBICD-DCAQKATOSA-N Cys-Lys-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CS)N ZXCAQANTQWBICD-DCAQKATOSA-N 0.000 description 1
- SMEYEQDCCBHTEF-FXQIFTODSA-N Cys-Pro-Ala Chemical compound [H]N[C@@H](CS)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C)C(O)=O SMEYEQDCCBHTEF-FXQIFTODSA-N 0.000 description 1
- KSMSFCBQBQPFAD-GUBZILKMSA-N Cys-Pro-Pro Chemical compound SC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 KSMSFCBQBQPFAD-GUBZILKMSA-N 0.000 description 1
- ALTQTAKGRFLRLR-GUBZILKMSA-N Cys-Val-Val Chemical compound CC(C)[C@@H](C(=O)N[C@@H](C(C)C)C(=O)O)NC(=O)[C@H](CS)N ALTQTAKGRFLRLR-GUBZILKMSA-N 0.000 description 1
- CKLJMWTZIZZHCS-UHFFFAOYSA-N D-OH-Asp Natural products OC(=O)C(N)CC(O)=O CKLJMWTZIZZHCS-UHFFFAOYSA-N 0.000 description 1
- ZAKOWWREFLAJOT-CEFNRUSXSA-N D-alpha-tocopherylacetate Chemical compound CC(=O)OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C ZAKOWWREFLAJOT-CEFNRUSXSA-N 0.000 description 1
- CIWBSHSKHKDKBQ-DUZGATOHSA-N D-araboascorbic acid Natural products OC[C@@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-DUZGATOHSA-N 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- 239000003109 Disodium ethylene diamine tetraacetate 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
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- SHERTACNJPYHAR-ACZMJKKPSA-N Gln-Ala-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCC(N)=O SHERTACNJPYHAR-ACZMJKKPSA-N 0.000 description 1
- DHNWZLGBTPUTQQ-QEJZJMRPSA-N Gln-Asp-Trp Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CCC(=O)N)N DHNWZLGBTPUTQQ-QEJZJMRPSA-N 0.000 description 1
- LOJYQMFIIJVETK-WDSKDSINSA-N Gln-Gln Chemical compound NC(=O)CC[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(O)=O LOJYQMFIIJVETK-WDSKDSINSA-N 0.000 description 1
- KCJJFESQRXGTGC-BQBZGAKWSA-N Gln-Glu-Gly Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(O)=O KCJJFESQRXGTGC-BQBZGAKWSA-N 0.000 description 1
- FGYPOQPQTUNESW-IUCAKERBSA-N Gln-Gly-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)CNC(=O)[C@H](CCC(=O)N)N FGYPOQPQTUNESW-IUCAKERBSA-N 0.000 description 1
- AQPZYBSRDRZBAG-AVGNSLFASA-N Gln-Phe-Asn Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CCC(=O)N)N AQPZYBSRDRZBAG-AVGNSLFASA-N 0.000 description 1
- HMIXCETWRYDVMO-GUBZILKMSA-N Gln-Pro-Glu Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O HMIXCETWRYDVMO-GUBZILKMSA-N 0.000 description 1
- JILRMFFFCHUUTJ-ACZMJKKPSA-N Gln-Ser-Ser Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O JILRMFFFCHUUTJ-ACZMJKKPSA-N 0.000 description 1
- BYKZWDGMJLNFJY-XKBZYTNZSA-N Gln-Ser-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(=O)N)N)O BYKZWDGMJLNFJY-XKBZYTNZSA-N 0.000 description 1
- XKPACHRGOWQHFH-IRIUXVKKSA-N Gln-Thr-Tyr Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O XKPACHRGOWQHFH-IRIUXVKKSA-N 0.000 description 1
- FITIQFSXXBKFFM-NRPADANISA-N Gln-Val-Ser Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(O)=O FITIQFSXXBKFFM-NRPADANISA-N 0.000 description 1
- RCCDHXSRMWCOOY-GUBZILKMSA-N Glu-Arg-Gln Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(O)=O RCCDHXSRMWCOOY-GUBZILKMSA-N 0.000 description 1
- GLWXKFRTOHKGIT-ACZMJKKPSA-N Glu-Asn-Asn Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O GLWXKFRTOHKGIT-ACZMJKKPSA-N 0.000 description 1
- HUFCEIHAFNVSNR-IHRRRGAJSA-N Glu-Gln-Tyr Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 HUFCEIHAFNVSNR-IHRRRGAJSA-N 0.000 description 1
- HNVFSTLPVJWIDV-CIUDSAMLSA-N Glu-Glu-Gln Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O HNVFSTLPVJWIDV-CIUDSAMLSA-N 0.000 description 1
- YLJHCWNDBKKOEB-IHRRRGAJSA-N Glu-Glu-Phe Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O YLJHCWNDBKKOEB-IHRRRGAJSA-N 0.000 description 1
- YHOJJFFTSMWVGR-HJGDQZAQSA-N Glu-Met-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H]([C@@H](C)O)C(O)=O YHOJJFFTSMWVGR-HJGDQZAQSA-N 0.000 description 1
- AAJHGGDRKHYSDH-GUBZILKMSA-N Glu-Pro-Gln Chemical compound C1C[C@H](N(C1)C(=O)[C@H](CCC(=O)O)N)C(=O)N[C@@H](CCC(=O)N)C(=O)O AAJHGGDRKHYSDH-GUBZILKMSA-N 0.000 description 1
- NNQDRRUXFJYCCJ-NHCYSSNCSA-N Glu-Pro-Val Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(O)=O NNQDRRUXFJYCCJ-NHCYSSNCSA-N 0.000 description 1
- QOXDAWODGSIDDI-GUBZILKMSA-N Glu-Ser-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(=O)O)N QOXDAWODGSIDDI-GUBZILKMSA-N 0.000 description 1
- DMYACXMQUABZIQ-NRPADANISA-N Glu-Ser-Val Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O DMYACXMQUABZIQ-NRPADANISA-N 0.000 description 1
- ZALGPUWUVHOGAE-GVXVVHGQSA-N Glu-Val-His Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](CCC(=O)O)N ZALGPUWUVHOGAE-GVXVVHGQSA-N 0.000 description 1
- WGYHAAXZWPEBDQ-IFFSRLJSSA-N Glu-Val-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O WGYHAAXZWPEBDQ-IFFSRLJSSA-N 0.000 description 1
- 229920001503 Glucan Polymers 0.000 description 1
- 108010024636 Glutathione Proteins 0.000 description 1
- VSVZIEVNUYDAFR-YUMQZZPRSA-N Gly-Ala-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)CN VSVZIEVNUYDAFR-YUMQZZPRSA-N 0.000 description 1
- XCLCVBYNGXEVDU-WHFBIAKZSA-N Gly-Asn-Ser Chemical compound NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(O)=O XCLCVBYNGXEVDU-WHFBIAKZSA-N 0.000 description 1
- GRIRDMVMJJDZKV-RCOVLWMOSA-N Gly-Asn-Val Chemical compound [H]NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(O)=O GRIRDMVMJJDZKV-RCOVLWMOSA-N 0.000 description 1
- IXKRSKPKSLXIHN-YUMQZZPRSA-N Gly-Cys-Leu Chemical compound [H]NCC(=O)N[C@@H](CS)C(=O)N[C@@H](CC(C)C)C(O)=O IXKRSKPKSLXIHN-YUMQZZPRSA-N 0.000 description 1
- PABFFPWEJMEVEC-JGVFFNPUSA-N Gly-Gln-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCC(=O)N)NC(=O)CN)C(=O)O PABFFPWEJMEVEC-JGVFFNPUSA-N 0.000 description 1
- BIRKKBCSAIHDDF-WDSKDSINSA-N Gly-Glu-Cys Chemical compound NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CS)C(O)=O BIRKKBCSAIHDDF-WDSKDSINSA-N 0.000 description 1
- YWAQATDNEKZFFK-BYPYZUCNSA-N Gly-Gly-Ser Chemical compound NCC(=O)NCC(=O)N[C@@H](CO)C(O)=O YWAQATDNEKZFFK-BYPYZUCNSA-N 0.000 description 1
- UUYBFNKHOCJCHT-VHSXEESVSA-N Gly-Leu-Pro Chemical compound CC(C)C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)CN UUYBFNKHOCJCHT-VHSXEESVSA-N 0.000 description 1
- AFWYPMDMDYCKMD-KBPBESRZSA-N Gly-Leu-Tyr Chemical compound NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 AFWYPMDMDYCKMD-KBPBESRZSA-N 0.000 description 1
- JSLVAHYTAJJEQH-QWRGUYRKSA-N Gly-Ser-Phe Chemical compound NCC(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 JSLVAHYTAJJEQH-QWRGUYRKSA-N 0.000 description 1
- CQMFNTVQVLQRLT-JHEQGTHGSA-N Gly-Thr-Gln Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(N)=O)C(O)=O CQMFNTVQVLQRLT-JHEQGTHGSA-N 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- QZAFGJNKLMNDEM-DCAQKATOSA-N His-Asn-Arg Chemical compound NC(N)=NCCC[C@@H](C(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CC1=CN=CN1 QZAFGJNKLMNDEM-DCAQKATOSA-N 0.000 description 1
- TVMNTHXFRSXZGR-IHRRRGAJSA-N His-Lys-Val Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(O)=O TVMNTHXFRSXZGR-IHRRRGAJSA-N 0.000 description 1
- ALPXXNRQBMRCPZ-MEYUZBJRSA-N His-Thr-Phe Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O ALPXXNRQBMRCPZ-MEYUZBJRSA-N 0.000 description 1
- 102000008100 Human Serum Albumin Human genes 0.000 description 1
- 108091006905 Human Serum Albumin Proteins 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- MKWSZEHGHSLNPF-NAKRPEOUSA-N Ile-Ala-Val Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)O)N MKWSZEHGHSLNPF-NAKRPEOUSA-N 0.000 description 1
- NZGTYCMLUGYMCV-XUXIUFHCSA-N Ile-Lys-Arg Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N NZGTYCMLUGYMCV-XUXIUFHCSA-N 0.000 description 1
- FXJLRZFMKGHYJP-CFMVVWHZSA-N Ile-Tyr-Asn Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CC(=O)N)C(=O)O)N FXJLRZFMKGHYJP-CFMVVWHZSA-N 0.000 description 1
- CKLJMWTZIZZHCS-UWTATZPHSA-N L-Aspartic acid Natural products OC(=O)[C@H](N)CC(O)=O CKLJMWTZIZZHCS-UWTATZPHSA-N 0.000 description 1
- FFEARJCKVFRZRR-UHFFFAOYSA-N L-Methionine Natural products CSCCC(N)C(O)=O FFEARJCKVFRZRR-UHFFFAOYSA-N 0.000 description 1
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- 239000002211 L-ascorbic acid Substances 0.000 description 1
- 235000000069 L-ascorbic acid Nutrition 0.000 description 1
- 239000011786 L-ascorbyl-6-palmitate Substances 0.000 description 1
- 235000000072 L-ascorbyl-6-palmitate Nutrition 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
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- 229930195722 L-methionine Natural products 0.000 description 1
- 229930182821 L-proline Natural products 0.000 description 1
- OIARJGNVARWKFP-YUMQZZPRSA-N Leu-Asn-Gly Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(O)=O OIARJGNVARWKFP-YUMQZZPRSA-N 0.000 description 1
- QJUWBDPGGYVRHY-YUMQZZPRSA-N Leu-Gly-Cys Chemical compound CC(C)C[C@@H](C(=O)NCC(=O)N[C@@H](CS)C(=O)O)N QJUWBDPGGYVRHY-YUMQZZPRSA-N 0.000 description 1
- VWHGTYCRDRBSFI-ZETCQYMHSA-N Leu-Gly-Gly Chemical compound CC(C)C[C@H](N)C(=O)NCC(=O)NCC(O)=O VWHGTYCRDRBSFI-ZETCQYMHSA-N 0.000 description 1
- HYMLKESRWLZDBR-WEDXCCLWSA-N Leu-Gly-Thr Chemical compound CC(C)C[C@H](N)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(O)=O HYMLKESRWLZDBR-WEDXCCLWSA-N 0.000 description 1
- BKTXKJMNTSMJDQ-AVGNSLFASA-N Leu-His-Gln Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N BKTXKJMNTSMJDQ-AVGNSLFASA-N 0.000 description 1
- IAJFFZORSWOZPQ-SRVKXCTJSA-N Leu-Leu-Asn Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O IAJFFZORSWOZPQ-SRVKXCTJSA-N 0.000 description 1
- VCHVSKNMTXWIIP-SRVKXCTJSA-N Leu-Lys-Ser Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(O)=O VCHVSKNMTXWIIP-SRVKXCTJSA-N 0.000 description 1
- AUNMOHYWTAPQLA-XUXIUFHCSA-N Leu-Met-Ile Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O AUNMOHYWTAPQLA-XUXIUFHCSA-N 0.000 description 1
- UHNQRAFSEBGZFZ-YESZJQIVSA-N Leu-Phe-Pro Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N2CCC[C@@H]2C(=O)O)N UHNQRAFSEBGZFZ-YESZJQIVSA-N 0.000 description 1
- DPURXCQCHSQPAN-AVGNSLFASA-N Leu-Pro-Pro Chemical compound CC(C)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 DPURXCQCHSQPAN-AVGNSLFASA-N 0.000 description 1
- CHJKEDSZNSONPS-DCAQKATOSA-N Leu-Pro-Ser Chemical compound [H]N[C@@H](CC(C)C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O CHJKEDSZNSONPS-DCAQKATOSA-N 0.000 description 1
- SBANPBVRHYIMRR-GARJFASQSA-N Leu-Ser-Pro Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CO)C(=O)N1CCC[C@@H]1C(=O)O)N SBANPBVRHYIMRR-GARJFASQSA-N 0.000 description 1
- YQFZRHYZLARWDY-IHRRRGAJSA-N Leu-Val-Lys Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CCCCN YQFZRHYZLARWDY-IHRRRGAJSA-N 0.000 description 1
- MPGHETGWWWUHPY-CIUDSAMLSA-N Lys-Ala-Asp Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCCN MPGHETGWWWUHPY-CIUDSAMLSA-N 0.000 description 1
- WSXTWLJHTLRFLW-SRVKXCTJSA-N Lys-Ala-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(O)=O WSXTWLJHTLRFLW-SRVKXCTJSA-N 0.000 description 1
- NTSPQIONFJUMJV-AVGNSLFASA-N Lys-Arg-Val Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(O)=O NTSPQIONFJUMJV-AVGNSLFASA-N 0.000 description 1
- YKIRNDPUWONXQN-GUBZILKMSA-N Lys-Asn-Gln Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N YKIRNDPUWONXQN-GUBZILKMSA-N 0.000 description 1
- KWUKZRFFKPLUPE-HJGDQZAQSA-N Lys-Asp-Thr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O KWUKZRFFKPLUPE-HJGDQZAQSA-N 0.000 description 1
- VQXAVLQBQJMENB-SRVKXCTJSA-N Lys-Glu-Met Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCSC)C(O)=O VQXAVLQBQJMENB-SRVKXCTJSA-N 0.000 description 1
- XNKDCYABMBBEKN-IUCAKERBSA-N Lys-Gly-Gln Chemical compound NCCCC[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CCC(N)=O XNKDCYABMBBEKN-IUCAKERBSA-N 0.000 description 1
- PBLLTSKBTAHDNA-KBPBESRZSA-N Lys-Gly-Phe Chemical compound [H]N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O PBLLTSKBTAHDNA-KBPBESRZSA-N 0.000 description 1
- AFLBTVGQCQLOFJ-AVGNSLFASA-N Lys-Pro-Arg Chemical compound NCCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCN=C(N)N)C(O)=O AFLBTVGQCQLOFJ-AVGNSLFASA-N 0.000 description 1
- IOQWIOPSKJOEKI-SRVKXCTJSA-N Lys-Ser-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O IOQWIOPSKJOEKI-SRVKXCTJSA-N 0.000 description 1
- CAVRAQIDHUPECU-UVOCVTCTSA-N Lys-Thr-Thr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O CAVRAQIDHUPECU-UVOCVTCTSA-N 0.000 description 1
- QLFAPXUXEBAWEK-NHCYSSNCSA-N Lys-Val-Asp Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O QLFAPXUXEBAWEK-NHCYSSNCSA-N 0.000 description 1
- XABXVVSWUVCZST-GVXVVHGQSA-N Lys-Val-Gln Chemical compound NC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CCCCN XABXVVSWUVCZST-GVXVVHGQSA-N 0.000 description 1
- GILLQRYAWOMHED-DCAQKATOSA-N Lys-Val-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CCCCN GILLQRYAWOMHED-DCAQKATOSA-N 0.000 description 1
- XMBSYZWANAQXEV-UHFFFAOYSA-N N-alpha-L-glutamyl-L-phenylalanine Natural products OC(=O)CCC(N)C(=O)NC(C(O)=O)CC1=CC=CC=C1 XMBSYZWANAQXEV-UHFFFAOYSA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- HXSUFWQYLPKEHF-IHRRRGAJSA-N Phe-Asn-Arg Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N HXSUFWQYLPKEHF-IHRRRGAJSA-N 0.000 description 1
- BWTKUQPNOMMKMA-FIRPJDEBSA-N Phe-Ile-Phe Chemical compound C([C@H](N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 BWTKUQPNOMMKMA-FIRPJDEBSA-N 0.000 description 1
- SMFGCTXUBWEPKM-KBPBESRZSA-N Phe-Leu-Gly Chemical compound OC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC1=CC=CC=C1 SMFGCTXUBWEPKM-KBPBESRZSA-N 0.000 description 1
- MSHZERMPZKCODG-ACRUOGEOSA-N Phe-Leu-Phe Chemical compound C([C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 MSHZERMPZKCODG-ACRUOGEOSA-N 0.000 description 1
- WWPAHTZOWURIMR-ULQDDVLXSA-N Phe-Pro-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CC1=CC=CC=C1 WWPAHTZOWURIMR-ULQDDVLXSA-N 0.000 description 1
- IIEOLPMQYRBZCN-SRVKXCTJSA-N Phe-Ser-Cys Chemical compound N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)O IIEOLPMQYRBZCN-SRVKXCTJSA-N 0.000 description 1
- HQVPQXMCQKXARZ-FXQIFTODSA-N Pro-Cys-Ser Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CS)C(=O)N[C@@H](CO)C(=O)O HQVPQXMCQKXARZ-FXQIFTODSA-N 0.000 description 1
- UAYHMOIGIQZLFR-NHCYSSNCSA-N Pro-Gln-Val Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(O)=O UAYHMOIGIQZLFR-NHCYSSNCSA-N 0.000 description 1
- WFHYFCWBLSKEMS-KKUMJFAQSA-N Pro-Glu-Phe Chemical compound N([C@@H](CCC(=O)O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C(=O)[C@@H]1CCCN1 WFHYFCWBLSKEMS-KKUMJFAQSA-N 0.000 description 1
- LGSANCBHSMDFDY-GARJFASQSA-N Pro-Glu-Pro Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CCC(=O)O)C(=O)N2CCC[C@@H]2C(=O)O LGSANCBHSMDFDY-GARJFASQSA-N 0.000 description 1
- VPEVBAUSTBWQHN-NHCYSSNCSA-N Pro-Glu-Val Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O VPEVBAUSTBWQHN-NHCYSSNCSA-N 0.000 description 1
- FMLRRBDLBJLJIK-DCAQKATOSA-N Pro-Leu-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H]1CCCN1 FMLRRBDLBJLJIK-DCAQKATOSA-N 0.000 description 1
- ZLXKLMHAMDENIO-DCAQKATOSA-N Pro-Lys-Asp Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(O)=O ZLXKLMHAMDENIO-DCAQKATOSA-N 0.000 description 1
- ULWBBFKQBDNGOY-RWMBFGLXSA-N Pro-Lys-Pro Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CCCCN)C(=O)N2CCC[C@@H]2C(=O)O ULWBBFKQBDNGOY-RWMBFGLXSA-N 0.000 description 1
- CGSOWZUPLOKYOR-AVGNSLFASA-N Pro-Pro-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 CGSOWZUPLOKYOR-AVGNSLFASA-N 0.000 description 1
- PCWLNNZTBJTZRN-AVGNSLFASA-N Pro-Pro-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 PCWLNNZTBJTZRN-AVGNSLFASA-N 0.000 description 1
- FDMKYQQYJKYCLV-GUBZILKMSA-N Pro-Pro-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 FDMKYQQYJKYCLV-GUBZILKMSA-N 0.000 description 1
- KBUAPZAZPWNYSW-SRVKXCTJSA-N Pro-Pro-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 KBUAPZAZPWNYSW-SRVKXCTJSA-N 0.000 description 1
- OWQXAJQZLWHPBH-FXQIFTODSA-N Pro-Ser-Asn Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O OWQXAJQZLWHPBH-FXQIFTODSA-N 0.000 description 1
- GMJDSFYVTAMIBF-FXQIFTODSA-N Pro-Ser-Asp Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(O)=O GMJDSFYVTAMIBF-FXQIFTODSA-N 0.000 description 1
- SEZGGSHLMROBFX-CIUDSAMLSA-N Pro-Ser-Gln Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(O)=O SEZGGSHLMROBFX-CIUDSAMLSA-N 0.000 description 1
- BGWKULMLUIUPKY-BQBZGAKWSA-N Pro-Ser-Gly Chemical compound OC(=O)CNC(=O)[C@H](CO)NC(=O)[C@@H]1CCCN1 BGWKULMLUIUPKY-BQBZGAKWSA-N 0.000 description 1
- ODHCTXKNWHHXJC-GSVOUGTGSA-N Pyroglutamic acid Natural products OC(=O)[C@H]1CCC(=O)N1 ODHCTXKNWHHXJC-GSVOUGTGSA-N 0.000 description 1
- UEJYSALTSUZXFV-SRVKXCTJSA-N Rigin Chemical compound NCC(=O)N[C@@H](CCC(N)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCN=C(N)N)C(O)=O UEJYSALTSUZXFV-SRVKXCTJSA-N 0.000 description 1
- YQHZVYJAGWMHES-ZLUOBGJFSA-N Ser-Ala-Ser Chemical compound OC[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O YQHZVYJAGWMHES-ZLUOBGJFSA-N 0.000 description 1
- QVOGDCQNGLBNCR-FXQIFTODSA-N Ser-Arg-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(O)=O QVOGDCQNGLBNCR-FXQIFTODSA-N 0.000 description 1
- VGNYHOBZJKWRGI-CIUDSAMLSA-N Ser-Asn-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CO VGNYHOBZJKWRGI-CIUDSAMLSA-N 0.000 description 1
- UGJRQLURDVGULT-LKXGYXEUSA-N Ser-Asn-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O UGJRQLURDVGULT-LKXGYXEUSA-N 0.000 description 1
- MOVJSUIKUNCVMG-ZLUOBGJFSA-N Ser-Cys-Ser Chemical compound C([C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CO)C(=O)O)N)O MOVJSUIKUNCVMG-ZLUOBGJFSA-N 0.000 description 1
- VQBCMLMPEWPUTB-ACZMJKKPSA-N Ser-Glu-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(O)=O VQBCMLMPEWPUTB-ACZMJKKPSA-N 0.000 description 1
- GZFAWAQTEYDKII-YUMQZZPRSA-N Ser-Gly-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CO GZFAWAQTEYDKII-YUMQZZPRSA-N 0.000 description 1
- XXXAXOWMBOKTRN-XPUUQOCRSA-N Ser-Gly-Val Chemical compound [H]N[C@@H](CO)C(=O)NCC(=O)N[C@@H](C(C)C)C(O)=O XXXAXOWMBOKTRN-XPUUQOCRSA-N 0.000 description 1
- DJACUBDEDBZKLQ-KBIXCLLPSA-N Ser-Ile-Glu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(O)=O DJACUBDEDBZKLQ-KBIXCLLPSA-N 0.000 description 1
- UIPXCLNLUUAMJU-JBDRJPRFSA-N Ser-Ile-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(O)=O UIPXCLNLUUAMJU-JBDRJPRFSA-N 0.000 description 1
- GZSZPKSBVAOGIE-CIUDSAMLSA-N Ser-Lys-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O GZSZPKSBVAOGIE-CIUDSAMLSA-N 0.000 description 1
- XUDRHBPSPAPDJP-SRVKXCTJSA-N Ser-Lys-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CO XUDRHBPSPAPDJP-SRVKXCTJSA-N 0.000 description 1
- HHJFMHQYEAAOBM-ZLUOBGJFSA-N Ser-Ser-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(O)=O HHJFMHQYEAAOBM-ZLUOBGJFSA-N 0.000 description 1
- CUXJENOFJXOSOZ-BIIVOSGPSA-N Ser-Ser-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CO)NC(=O)[C@H](CO)N)C(=O)O CUXJENOFJXOSOZ-BIIVOSGPSA-N 0.000 description 1
- NADLKBTYNKUJEP-KATARQTJSA-N Ser-Thr-Leu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O NADLKBTYNKUJEP-KATARQTJSA-N 0.000 description 1
- PCJLFYBAQZQOFE-KATARQTJSA-N Ser-Thr-Lys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CO)N)O PCJLFYBAQZQOFE-KATARQTJSA-N 0.000 description 1
- RCOUFINCYASMDN-GUBZILKMSA-N Ser-Val-Met Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCSC)C(O)=O RCOUFINCYASMDN-GUBZILKMSA-N 0.000 description 1
- HSWXBJCBYSWBPT-GUBZILKMSA-N Ser-Val-Val Chemical compound CC(C)[C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)CO)C(C)C)C(O)=O HSWXBJCBYSWBPT-GUBZILKMSA-N 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- DWYAUVCQDTZIJI-VZFHVOOUSA-N Thr-Ala-Ser Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O DWYAUVCQDTZIJI-VZFHVOOUSA-N 0.000 description 1
- CEXFELBFVHLYDZ-XGEHTFHBSA-N Thr-Arg-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(O)=O CEXFELBFVHLYDZ-XGEHTFHBSA-N 0.000 description 1
- ODSAPYVQSLDRSR-LKXGYXEUSA-N Thr-Cys-Asn Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(O)=O ODSAPYVQSLDRSR-LKXGYXEUSA-N 0.000 description 1
- DSLHSTIUAPKERR-XGEHTFHBSA-N Thr-Cys-Val Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(=O)N[C@@H](C(C)C)C(O)=O DSLHSTIUAPKERR-XGEHTFHBSA-N 0.000 description 1
- VUVCRYXYUUPGSB-GLLZPBPUSA-N Thr-Gln-Glu Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N)O VUVCRYXYUUPGSB-GLLZPBPUSA-N 0.000 description 1
- GKWNLDNXMMLRMC-GLLZPBPUSA-N Thr-Glu-Gln Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N)O GKWNLDNXMMLRMC-GLLZPBPUSA-N 0.000 description 1
- FIFDDJFLNVAVMS-RHYQMDGZSA-N Thr-Leu-Met Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(O)=O FIFDDJFLNVAVMS-RHYQMDGZSA-N 0.000 description 1
- NCXVJIQMWSGRHY-KXNHARMFSA-N Thr-Leu-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N1CCC[C@@H]1C(=O)O)N)O NCXVJIQMWSGRHY-KXNHARMFSA-N 0.000 description 1
- YOOAQCZYZHGUAZ-KATARQTJSA-N Thr-Leu-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O YOOAQCZYZHGUAZ-KATARQTJSA-N 0.000 description 1
- BDGBHYCAZJPLHX-HJGDQZAQSA-N Thr-Lys-Asn Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(O)=O BDGBHYCAZJPLHX-HJGDQZAQSA-N 0.000 description 1
- JLNMFGCJODTXDH-WEDXCCLWSA-N Thr-Lys-Gly Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)NCC(O)=O JLNMFGCJODTXDH-WEDXCCLWSA-N 0.000 description 1
- DXPURPNJDFCKKO-RHYQMDGZSA-N Thr-Lys-Val Chemical compound CC(C)[C@H](NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)[C@@H](C)O)C(O)=O DXPURPNJDFCKKO-RHYQMDGZSA-N 0.000 description 1
- MROIJTGJGIDEEJ-RCWTZXSCSA-N Thr-Pro-Pro Chemical compound C[C@@H](O)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 MROIJTGJGIDEEJ-RCWTZXSCSA-N 0.000 description 1
- XHWCDRUPDNSDAZ-XKBZYTNZSA-N Thr-Ser-Glu Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N)O XHWCDRUPDNSDAZ-XKBZYTNZSA-N 0.000 description 1
- SGAOHNPSEPVAFP-ZDLURKLDSA-N Thr-Ser-Gly Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)NCC(O)=O SGAOHNPSEPVAFP-ZDLURKLDSA-N 0.000 description 1
- BEZTUFWTPVOROW-KJEVXHAQSA-N Thr-Tyr-Arg Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N)O BEZTUFWTPVOROW-KJEVXHAQSA-N 0.000 description 1
- LVRFMARKDGGZMX-IZPVPAKOSA-N Thr-Tyr-Thr Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)O)C(O)=O)CC1=CC=C(O)C=C1 LVRFMARKDGGZMX-IZPVPAKOSA-N 0.000 description 1
- OGOYMQWIWHGTGH-KZVJFYERSA-N Thr-Val-Ala Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C)C(O)=O OGOYMQWIWHGTGH-KZVJFYERSA-N 0.000 description 1
- UKINEYBQXPMOJO-UBHSHLNASA-N Trp-Asn-Ser Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CO)C(=O)O)N UKINEYBQXPMOJO-UBHSHLNASA-N 0.000 description 1
- VTHNLRXALGUDBS-BPUTZDHNSA-N Trp-Gln-Glu Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N VTHNLRXALGUDBS-BPUTZDHNSA-N 0.000 description 1
- NLWCSMOXNKBRLC-WDSOQIARSA-N Trp-Lys-Val Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(O)=O NLWCSMOXNKBRLC-WDSOQIARSA-N 0.000 description 1
- UIRVSEPRMWDVEW-RNXOBYDBSA-N Trp-Tyr-Phe Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)O)NC(=O)[C@H](CC2=CC=C(C=C2)O)NC(=O)[C@H](CC3=CNC4=CC=CC=C43)N UIRVSEPRMWDVEW-RNXOBYDBSA-N 0.000 description 1
- SSSDKJMQMZTMJP-BVSLBCMMSA-N Trp-Tyr-Val Chemical compound C([C@@H](C(=O)N[C@@H](C(C)C)C(O)=O)NC(=O)[C@@H](N)CC=1C2=CC=CC=C2NC=1)C1=CC=C(O)C=C1 SSSDKJMQMZTMJP-BVSLBCMMSA-N 0.000 description 1
- SCCKSNREWHMKOJ-SRVKXCTJSA-N Tyr-Asn-Ser Chemical compound N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(O)=O SCCKSNREWHMKOJ-SRVKXCTJSA-N 0.000 description 1
- SLCSPPCQWUHPPO-JYJNAYRXSA-N Tyr-Glu-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 SLCSPPCQWUHPPO-JYJNAYRXSA-N 0.000 description 1
- NMKJPMCEKQHRPD-IRXDYDNUSA-N Tyr-Gly-Tyr Chemical compound C([C@H](N)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C1=CC=C(O)C=C1 NMKJPMCEKQHRPD-IRXDYDNUSA-N 0.000 description 1
- BSCBBPKDVOZICB-KKUMJFAQSA-N Tyr-Leu-Asp Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O BSCBBPKDVOZICB-KKUMJFAQSA-N 0.000 description 1
- SINRIKQYQJRGDQ-MEYUZBJRSA-N Tyr-Lys-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 SINRIKQYQJRGDQ-MEYUZBJRSA-N 0.000 description 1
- WURLIFOWSMBUAR-SLFFLAALSA-N Tyr-Phe-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC2=CC=CC=C2)NC(=O)[C@H](CC3=CC=C(C=C3)O)N)C(=O)O WURLIFOWSMBUAR-SLFFLAALSA-N 0.000 description 1
- YYLHVUCSTXXKBS-IHRRRGAJSA-N Tyr-Pro-Ser Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O YYLHVUCSTXXKBS-IHRRRGAJSA-N 0.000 description 1
- GQVZBMROTPEPIF-SRVKXCTJSA-N Tyr-Ser-Asp Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(O)=O GQVZBMROTPEPIF-SRVKXCTJSA-N 0.000 description 1
- NHOVZGFNTGMYMI-KKUMJFAQSA-N Tyr-Ser-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 NHOVZGFNTGMYMI-KKUMJFAQSA-N 0.000 description 1
- RIVVDNTUSRVTQT-IRIUXVKKSA-N Tyr-Thr-Gln Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)N)O RIVVDNTUSRVTQT-IRIUXVKKSA-N 0.000 description 1
- GPLTZEMVOCZVAV-UFYCRDLUSA-N Tyr-Tyr-Arg Chemical compound C([C@H](N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O)C1=CC=C(O)C=C1 GPLTZEMVOCZVAV-UFYCRDLUSA-N 0.000 description 1
- OJCISMMNNUNNJA-BZSNNMDCSA-N Tyr-Tyr-Asp Chemical compound C([C@H](N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC(O)=O)C(O)=O)C1=CC=C(O)C=C1 OJCISMMNNUNNJA-BZSNNMDCSA-N 0.000 description 1
- QHDXUYOYTPWCSK-RCOVLWMOSA-N Val-Asp-Gly Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)NCC(=O)O)N QHDXUYOYTPWCSK-RCOVLWMOSA-N 0.000 description 1
- SCBITHMBEJNRHC-LSJOCFKGSA-N Val-Asp-Val Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](C(C)C)C(=O)O)N SCBITHMBEJNRHC-LSJOCFKGSA-N 0.000 description 1
- JXGWQYWDUOWQHA-DZKIICNBSA-N Val-Gln-Phe Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)N JXGWQYWDUOWQHA-DZKIICNBSA-N 0.000 description 1
- OQWNEUXPKHIEJO-NRPADANISA-N Val-Glu-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CO)C(=O)O)N OQWNEUXPKHIEJO-NRPADANISA-N 0.000 description 1
- RKIGNDAHUOOIMJ-BQFCYCMXSA-N Val-Glu-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)C(C)C)C(O)=O)=CNC2=C1 RKIGNDAHUOOIMJ-BQFCYCMXSA-N 0.000 description 1
- UEHRGZCNLSWGHK-DLOVCJGASA-N Val-Glu-Val Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O UEHRGZCNLSWGHK-DLOVCJGASA-N 0.000 description 1
- ZIGZPYJXIWLQFC-QTKMDUPCSA-N Val-His-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CN=CN1)NC(=O)[C@H](C(C)C)N)O ZIGZPYJXIWLQFC-QTKMDUPCSA-N 0.000 description 1
- XTDDIVQWDXMRJL-IHRRRGAJSA-N Val-Leu-His Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](C(C)C)N XTDDIVQWDXMRJL-IHRRRGAJSA-N 0.000 description 1
- SYSWVVCYSXBVJG-RHYQMDGZSA-N Val-Leu-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C(C)C)N)O SYSWVVCYSXBVJG-RHYQMDGZSA-N 0.000 description 1
- KTEZUXISLQTDDQ-NHCYSSNCSA-N Val-Lys-Asp Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(=O)O)C(=O)O)N KTEZUXISLQTDDQ-NHCYSSNCSA-N 0.000 description 1
- SBJCTAZFSZXWSR-AVGNSLFASA-N Val-Met-His Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N SBJCTAZFSZXWSR-AVGNSLFASA-N 0.000 description 1
- RYHUIHUOYRNNIE-NRPADANISA-N Val-Ser-Gln Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N RYHUIHUOYRNNIE-NRPADANISA-N 0.000 description 1
- VHIZXDZMTDVFGX-DCAQKATOSA-N Val-Ser-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](C(C)C)N VHIZXDZMTDVFGX-DCAQKATOSA-N 0.000 description 1
- TVGWMCTYUFBXAP-QTKMDUPCSA-N Val-Thr-His Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](C(C)C)N)O TVGWMCTYUFBXAP-QTKMDUPCSA-N 0.000 description 1
- GVNLOVJNNDZUHS-RHYQMDGZSA-N Val-Thr-Lys Chemical compound [H]N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(O)=O GVNLOVJNNDZUHS-RHYQMDGZSA-N 0.000 description 1
- BGTDGENDNWGMDQ-KJEVXHAQSA-N Val-Tyr-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)NC(=O)[C@H](C(C)C)N)O BGTDGENDNWGMDQ-KJEVXHAQSA-N 0.000 description 1
- ZLNYBMWGPOKSLW-LSJOCFKGSA-N Val-Val-Asp Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O ZLNYBMWGPOKSLW-LSJOCFKGSA-N 0.000 description 1
- ZHWZDZFWBXWPDW-GUBZILKMSA-N Val-Val-Cys Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CS)C(O)=O ZHWZDZFWBXWPDW-GUBZILKMSA-N 0.000 description 1
- 208000027276 Von Willebrand disease Diseases 0.000 description 1
- DFPAKSUCGFBDDF-ZQBYOMGUSA-N [14c]-nicotinamide Chemical compound N[14C](=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-ZQBYOMGUSA-N 0.000 description 1
- 230000007488 abnormal function Effects 0.000 description 1
- 229960004308 acetylcysteine Drugs 0.000 description 1
- ODHCTXKNWHHXJC-UHFFFAOYSA-N acide pyroglutamique Natural products OC(=O)C1CCC(=O)N1 ODHCTXKNWHHXJC-UHFFFAOYSA-N 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 229940087168 alpha tocopherol Drugs 0.000 description 1
- 108010050025 alpha-glutamyltryptophan Proteins 0.000 description 1
- 150000003862 amino acid derivatives Chemical class 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 210000000628 antibody-producing cell Anatomy 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 108010052670 arginyl-glutamyl-glutamic acid Proteins 0.000 description 1
- 108010009111 arginyl-glycyl-glutamic acid Proteins 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 229960001230 asparagine Drugs 0.000 description 1
- 235000009582 asparagine Nutrition 0.000 description 1
- 108010093581 aspartyl-proline Proteins 0.000 description 1
- 108010038633 aspartylglutamate Proteins 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 description 1
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 235000011148 calcium chloride Nutrition 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 229960001777 castor oil Drugs 0.000 description 1
- 238000005277 cation exchange chromatography Methods 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 229960002242 chlorocresol Drugs 0.000 description 1
- 239000003593 chromogenic compound Substances 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 238000005345 coagulation Methods 0.000 description 1
- 230000015271 coagulation Effects 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 229930003836 cresol Natural products 0.000 description 1
- 229940013361 cresol Drugs 0.000 description 1
- UFULAYFCSOUIOV-UHFFFAOYSA-N cysteamine Chemical compound NCCS UFULAYFCSOUIOV-UHFFFAOYSA-N 0.000 description 1
- ZAKOWWREFLAJOT-UHFFFAOYSA-N d-alpha-Tocopheryl acetate Natural products CC(=O)OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C ZAKOWWREFLAJOT-UHFFFAOYSA-N 0.000 description 1
- 230000006240 deamidation Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 235000019301 disodium ethylene diamine tetraacetate Nutrition 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 235000010350 erythorbic acid Nutrition 0.000 description 1
- 239000004318 erythorbic acid Substances 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- AZXVZUBIFYQWJK-KWRJMZDGSA-N ethyl (z,12r)-12-hydroxyoctadec-9-enoate Chemical compound CCCCCC[C@@H](O)C\C=C/CCCCCCCC(=O)OCC AZXVZUBIFYQWJK-KWRJMZDGSA-N 0.000 description 1
- 229960001617 ethyl hydroxybenzoate Drugs 0.000 description 1
- 235000010228 ethyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004403 ethyl p-hydroxybenzoate Substances 0.000 description 1
- 229940071106 ethylenediaminetetraacetate Drugs 0.000 description 1
- NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical compound CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-UHFFFAOYSA-N 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- FOYKKGHVWRFIBD-UHFFFAOYSA-N gamma-tocopherol acetate Natural products CC(=O)OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1 FOYKKGHVWRFIBD-UHFFFAOYSA-N 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 125000000404 glutamine group Chemical group N[C@@H](CCC(N)=O)C(=O)* 0.000 description 1
- 108010013768 glutamyl-aspartyl-proline Proteins 0.000 description 1
- 108010049041 glutamylalanine Proteins 0.000 description 1
- 229960003180 glutathione Drugs 0.000 description 1
- 235000003969 glutathione Nutrition 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 108010074027 glycyl-seryl-phenylalanine Proteins 0.000 description 1
- 108010050848 glycylleucine Proteins 0.000 description 1
- 108010015792 glycyllysine Proteins 0.000 description 1
- 108010084389 glycyltryptophan Proteins 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 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
- 229940072221 immunoglobulins Drugs 0.000 description 1
- 238000001114 immunoprecipitation Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 229940026239 isoascorbic acid Drugs 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- AGBQKNBQESQNJD-UHFFFAOYSA-M lipoate Chemical compound [O-]C(=O)CCCCC1CCSS1 AGBQKNBQESQNJD-UHFFFAOYSA-M 0.000 description 1
- 235000019136 lipoic acid Nutrition 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229960003194 meglumine Drugs 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229960003151 mercaptamine Drugs 0.000 description 1
- 229960004452 methionine Drugs 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- PJUIMOJAAPLTRJ-UHFFFAOYSA-N monothioglycerol Chemical compound OCC(O)CS PJUIMOJAAPLTRJ-UHFFFAOYSA-N 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229960003742 phenol Drugs 0.000 description 1
- 108010024654 phenylalanyl-prolyl-alanine Proteins 0.000 description 1
- 108010051242 phenylalanylserine Proteins 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000007981 phosphate-citrate buffer Substances 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229960000502 poloxamer Drugs 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 230000004481 post-translational protein modification Effects 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 229960002429 proline Drugs 0.000 description 1
- 108010077112 prolyl-proline Proteins 0.000 description 1
- 108010053725 prolylvaline Proteins 0.000 description 1
- 239000000473 propyl gallate Substances 0.000 description 1
- 235000010388 propyl gallate Nutrition 0.000 description 1
- 229940075579 propyl gallate Drugs 0.000 description 1
- 229940043131 pyroglutamate Drugs 0.000 description 1
- 238000005215 recombination Methods 0.000 description 1
- 230000006798 recombination Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000005185 salting out Methods 0.000 description 1
- 108010069117 seryl-lysyl-aspartic acid Proteins 0.000 description 1
- 108010026333 seryl-proline Proteins 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000012475 sodium chloride buffer Substances 0.000 description 1
- FQENQNTWSFEDLI-UHFFFAOYSA-J sodium diphosphate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]P([O-])(=O)OP([O-])([O-])=O FQENQNTWSFEDLI-UHFFFAOYSA-J 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 235000019983 sodium metaphosphate Nutrition 0.000 description 1
- 229940048086 sodium pyrophosphate Drugs 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 235000019818 tetrasodium diphosphate Nutrition 0.000 description 1
- 239000001577 tetrasodium phosphonato phosphate Substances 0.000 description 1
- 229960002663 thioctic acid Drugs 0.000 description 1
- YODZTKMDCQEPHD-UHFFFAOYSA-N thiodiglycol Chemical compound OCCSCCO YODZTKMDCQEPHD-UHFFFAOYSA-N 0.000 description 1
- 229950006389 thiodiglycol Drugs 0.000 description 1
- 229940035024 thioglycerol Drugs 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 229960000984 tocofersolan Drugs 0.000 description 1
- 108010080629 tryptophan-leucine Proteins 0.000 description 1
- 108010051110 tyrosyl-lysine Proteins 0.000 description 1
- 108010071635 tyrosyl-prolyl-arginine Proteins 0.000 description 1
- 238000000108 ultra-filtration Methods 0.000 description 1
- 108010052774 valyl-lysyl-glycyl-phenylalanyl-tyrosine Proteins 0.000 description 1
- 108010073969 valyllysine Proteins 0.000 description 1
- 239000013598 vector Substances 0.000 description 1
- 238000011179 visual inspection Methods 0.000 description 1
- 208000012137 von Willebrand disease (hereditary or acquired) Diseases 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 108010027345 wheylin-1 peptide Proteins 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39591—Stabilisation, fragmentation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/36—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against blood coagulation factors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0021—Intradermal administration, e.g. through microneedle arrays, needleless injectors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
- C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/51—Complete heavy chain or Fd fragment, i.e. VH + CH1
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/515—Complete light chain, i.e. VL + CL
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
- C07K2317/565—Complementarity determining region [CDR]
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Hematology (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Immunology (AREA)
- Dermatology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Diabetes (AREA)
- Inorganic Chemistry (AREA)
- Mycology (AREA)
- Microbiology (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicinal Preparation (AREA)
- Peptides Or Proteins (AREA)
Abstract
本發明係有關於取代FVIII功能之雙重專一性抗體Emicizumab(ACE910)之可抑制聚集體形成之含安定之抗體的溶液製劑,具體來說,係關於為含有20~180 mg/mL上述雙重專一性抗體、10 mM~40 mM組胺酸-天門冬胺酸鹽緩衝液、0.2~1 mg/mL Poloxamer 188及100 mM~300 mM精胺酸,pH值為4.5~6.5之上述含抗體溶液製劑。
Description
本發明係有關於含有與第IX凝血因子(FIX)及/或活性化第IX凝血因子(FIXa)以及第X凝血因子(FX)的雙方結合,以取代第VIII凝血因子(FVIII)之功能之雙重專一性抗體的製劑。
與第IX凝血因子(FIX)及/或活性化第IX凝血因子(FIXa)以及第X凝血因子(FX)雙方結合,以取代第VIII凝血因子(FVIII)之功能之雙重專一性抗體係已公開(非專利文獻1、2及專利文獻1、2、3)。藉由雙重專一性抗體Emicizumab(ACE910)取代FVIII的功能,為了改善因FVIII缺乏及功能異常所造成的凝血反應不足,以A型血友病患者作為對象進行臨床試驗。
至今持續開發大量的抗體之溶液製劑,抗體之高濃度的溶液製劑,目前已報導了使用組胺酸或精胺酸的製劑(專利文獻4)、使用組胺酸-天門冬胺酸鹽緩衝液的製劑(專利文獻5)。另一方面,已報導了含有使用作為緩衝液之組胺酸/組胺酸-HCl澱粉狀蛋白β(Aβ)之安定之液體藥學的抗體製劑(專利文獻6)。
然而,尚未報導含有上述雙重專一性抗體之溶液製劑中聚集體形成及/或電荷異性成分被抑制電荷異性的安定性溶液製劑。
[先前技術文獻]
[專利文獻]
專利文獻1:WO2005/035756
專利文獻2:WO2006/109592
專利文獻3:WO2012/067176
專利文獻4:WO2002/030463
專利文獻5:WO2011/090088
專利文獻6:WO2013/131866
[非專利文獻]
非專利文獻1:Nat Med. 2012; 18(10): 1570-74
非專利文獻2:PLoS One. 2013; 8(2): e57479
[發明所欲解決的問題]
本發明的目的為提供含有與FIX及/或FIXa與FX雙方結合,可代替FVIII之功能的雙重專一性抗體Emicizumab(ACE910)的安定性溶液製劑。
[解決問題之技術手段]
為達成上述目的而廣泛研究的結果,本發明人發現含有20~180 mg/mL上述雙重專一性抗體,10 mM~40 mM組胺酸-天門冬胺酸鹽緩衝液、0.2~1 mg/mL Poloxamer 188,100 mM~300 mM精胺酸,pH值為4.5~6.5的溶液製劑為可抑制聚集體形成之含有安定性抗體的溶液製劑,以完成本發明。
亦即,本發明提供以下內容。
[1] 一種抗體溶液製劑,包括
20~180 mg/mL第一多胜肽及第三多胜肽形成配對,第二多胜肽與第四多胜肽形成配對的雙重專一性抗體,且係由第一多胜肽為含有序列辨識號:1、2、3 (Q499的H鏈CDR)之H鏈CDR1、2、3胺基酸序列的H鏈,第二多胜肽為含有序列辨識號:4、5、6 (J327的H鏈CDR)之H鏈CDR1、2、3胺基酸序列的H鏈,第三多胜肽及第四多胜肽為含有序列辨識號:7、8、9(L404的L鏈CDR)之L鏈CDR1、2、3胺基酸序列的共通L鏈所形成的雙專一性抗體;
10 mM~40 mM之組胺酸-天門冬胺酸鹽緩衝液,
0.2~1 mg/mL之Poloxamer 188,以及
100 mM~300 mM之精胺酸,
且其pH值為4.5~6.5。
[2] 如第[1]所記載之抗體溶液製劑,其中上述雙重專一性抗體為第一多胜肽及第三多胜肽形成配對,第二多胜肽與第四多胜肽形成配對的雙重專一性抗體,且係由第一多胜肽為由序列辨識號:10之胺基酸序列所形成的H鏈,第二多胜肽為由序列辨識號:11之胺基酸序列所形成的H鏈,以及第三多胜肽與第四多胜肽為序列辨識號:12之共通L鏈所形成雙重專一性抗體。
[3] 如第[1]或[2]之抗體溶液製劑,其中Poloxamer 188的濃度為0.5 mg/mL。
[4] 如第[1]至[3]任一項之抗體溶液製劑,其中pH值為6.0。
[5] 如第[1]至[4]任一項之抗體溶液製劑,其中組胺酸-天門冬胺酸鹽緩衝溶液的濃度為20 mM。
[6] 如第[1]至[5]任一項之抗體溶液製劑,其中精胺酸濃度為150 mM。
[7] 如第[1]至[6]任一項之抗體溶液製劑,實質上不含有氯化物離子及醋酸離子。
[8] 一種抗體溶液製劑,包括:
20~180 mg/mL第一多胜肽及第三多胜肽形成配對,第二多胜肽與第四多胜肽形成配對的雙重專一性抗體,且係由第一多胜肽為由序列辨識號:10之胺基酸序列所形成的H鏈,第二多胜肽為由序列辨識號:11之胺基酸序列所形成的H鏈,以及第三多胜肽與第四多胜肽為序列辨識號:12之共通L鏈所形成的雙重專一性抗體;
20 mM之L-組胺酸-天門冬胺酸鹽緩衝液,
0.5 mg/mL之Poloxamer 188,以及
150 mM之L-精胺酸,
且其pH值為6。
[9] 如第[1]至[8]任一項之抗體溶液製劑,其係用於皮下投予。
[10] 如第[1]至[9]任一項之抗體溶液製劑,其用於治療A型血友病。
[11] 一種安定化含抗體溶液製劑中之抗體的方法,包括於溶液中添加組胺酸-天門冬胺酸鹽緩衝液、Poloxamer 188及精胺酸,其中組胺酸-天門冬胺酸鹽緩衝液濃度為10 mM~40 mM,Poloxamer 188的濃度為0.2~1 mg/mL,精胺酸的濃度為100 mM~300 mM。
[12] 一種抑制含抗體溶液製劑中抗體聚集化(形成聚集體)的方法,包括於溶液中添加組胺酸-天門冬胺酸鹽緩衝液、Poloxamer 188及精胺酸,其中組胺酸-天門冬胺酸鹽緩衝液濃度為10 mM~40 mM,Poloxamer 188的濃度為0.2~1 mg/mL,精胺酸的濃度為100 mM~300 mM。
[13] 一種減少含抗體溶液製劑中電荷異性成分的方法,包括於溶液中添加組胺酸-天門冬胺酸鹽緩衝液,其中組胺酸-天門冬胺酸鹽緩衝液的濃度為10 mM~40 mM。
[發明效果]
藉由本發明,提供安定性良好的含抗體製劑。此外,藉由本發明可提供抑制溶液狀態之製劑中之聚集體形成及/或電荷異性成分之含抗體製劑。
以下,對本發明進行詳細說明。
本發明係提供含20~180 mg/mL之與FIX及/或FIXa以及FX雙方結合,取代FVIII功能之雙重專一性抗體Emicizumab(ACE910),10 mM~40 mM組胺酸-天門冬胺酸鹽緩衝液,0.2~1 mg/mL Poloxamer 188及100 mM~300 mM精胺酸,pH值為4.5~6.5之溶液製劑。
為上述雙重專一性抗體之Emicizumab(ACE910)如下所述。
第一多胜肽及第三多胜肽形成配對,第二多胜肽及第四多胜肽形成配對之雙重專一性抗體,係為由第一多胜肽為含有序列辨識號:1、2、3(Q499的H鏈CDR)之H鏈CDR1、2、3胺基酸序列的H鏈,第二多胜肽為含有序列辨識號:4、5、6(J327的H鏈CDR)之H鏈CDR1、2、3胺基酸序列的H鏈,第三多胜肽及第四多胜肽為含有序列辨識號:7、8、9(L404的L鏈CDR)之L鏈CDR1、2、3胺基酸序列的共通L鏈所形成的雙重專一性抗體(Q499-z121/J327-z119/L404-k)。
更具體來說,上述雙重專一性抗體為第一多胜肽及第三多胜肽形成配對,第二多胜肽及第四多胜肽形成配對之雙重專一性抗體,係為由第一多胜肽為含有序列辨識號:13之H鏈可變區域胺基酸序列的H鏈,第二多胜肽為含有序列辨識號:14之H鏈可變區域胺基酸序列的H鏈,以及第三多胜肽及第四多胜肽為含有序列辨識號:15之L鏈可變區域胺基酸序列的共通L鏈所形成的雙重專一性抗體。
更具體來說,上述雙重專一性抗體為第一多胜肽及第三多胜肽形成配對,第二多胜肽及第四多胜肽形成配對之雙重專一性抗體,係為由第一多胜肽為由序列辨識號:10之胺基酸序列所形成的H鏈,第二多胜肽為由序列辨識號:11之胺基酸序列所形成的H鏈,以及第三多胜肽與第四多胜肽為序列辨識號:12之共通L鏈所形成雙重專一性抗體(Q499-z121/J327-z119/L404-k)。
此抗體可利用如WO2005/035756、WO2006/109592、WO2012/067176等所記載的方法取得。
本發明製劑中所含抗體的濃度並無特別限制,抗體濃度較佳為20 mg/mL~180 mg/mL。本發明製劑中所含抗體的濃度為,例如20 mg/mL、30 mg/mL、40 mg/mL、120 mg/mL、150 mg/mL、180 mg/mL。本發明製劑中所含抗體濃度的上限並無特別限制,通常為250 mg/mL。
本發明中所使用的抗體只要與所欲抗原結合即可,並無特別限制,可為多株抗體或單株抗體,從可穩定產生相同抗體的觀點來看,較佳為單株抗體。
此外,包含於本發明記載之胺基酸序列之胺基酸也有受到轉譯後修飾(例如,將N端麩醯胺酸利用焦麩胺酸化修飾為焦麩胺酸是業界習知的修飾)的情況,而即便此種胺基酸受到轉譯後修飾的情況,仍也包含於本發明中所使用的抗體中。
本發明中「取代FVIII的功能」係意味著辨識FIX或FIXa,及FX,並經由FIXa促進FX的活性化(經由FIXa促進FX的產生)。FXa產生促進活性,例如可藉由FIXa、FX、合成基質S-2222(FXa的合成基質)、磷脂質所形成的測定種類來進行評估。此類測定種類顯示與A型血友病病例的重症程度及臨床症狀的相關性(Rosen S, Andersson M, BLomba¨ck M et al. Clinical applications of a chromogenic substrate method for determination of FVIII activity. Thromb Haemost 1985; 54: 811-23)。
本發明中所謂「共同L鏈」係為,與2種以上不同的H鏈分別形成配對,且獲得針對分別之抗原之結合能的L鏈。於此,「不同的H鏈」意指較佳為針對不同抗原之抗體H鏈,但不限於此,可意味著胺基酸序列相互不同之H鏈。共同L鏈,例如可根據WO2006/109592所記載的方法獲得。
又,本發明中所謂「安定的含抗體製劑」係為製劑中不易生成抗體等蛋白質的聚集體及/或電荷異性成分,即溶液中不易引起不溶性聚集體、可溶液聚集體、電荷異性成分等之生成為首之劣化反應的製劑。
電荷的異性成分指藉由脫醯胺、氧化、水解等蛋白質之表面電荷與主成分不同的成分。
本發明中多胜肽通常意指具10個胺基酸以上長度的胜肽及蛋白質。此外,通常為生物來源的多胜肽,但並無特別限制,例如,也可為由人工設計序列所形成的多胜肽。另外,也可為天然多胜肽或合成多胜肽,重組多胜肽等任一種。再者,上述多胜肽的片段也包含於本發明的多胜肽。
所謂「抗體」之用語以最廣泛的意思解讀,只要具有所欲生物學活性即可,可為單株抗體、多株抗體、二聚體、多聚體、多重專一性抗體(例如,雙重專一性抗體)、抗體衍生物及抗體修飾物(Miller K et al. J Immunol. 2003, 170(9), 4854-61)。抗體可為小鼠、人類、人源化、嵌合,或其它來源,也可為人工合成。本發明說明中所述抗體可為任意種類的免疫球蛋白(例如,IgG、IgE、IgM、IgD及IgA)、類型(例如,IgG1、IgG2、IgG3、IgG4、IgA1及IgA2)或亞型。免疫球蛋白可由任何種類(例如,人類、小鼠、嵌合)來源獲得。此外,「抗體」、「免疫球蛋白」及「immunoglobulin」用語具互換性以廣義定義被使用。
「雙重專一性」抗體係指,於同一個抗體分子具含有辨識分別不同之抗原決定位的2個可變區域的抗體。雙重專一性抗體為可辨識2個以上不同抗原的抗體,亦可為可辨識同一抗原上不同之2個以上之抗原決定位的抗體。雙重專一性抗體不僅為完整的抗體,也可包含抗體衍生物。
作為抗體可使用,使用基因重組技術產生之重組型抗體。重組型抗體,可藉由從融合瘤、或產生抗體之敏感淋巴球等抗體產生細胞選殖出編碼其之DNA ,併入載體,並將此導入宿主(宿主細胞)並產生來獲得。
雙重專一性抗體不限於IgG類,例如IgG類雙重專一性抗體為可藉由融合二種產生IgG抗體之融合瘤產生的嵌合融合瘤(quadroma)所分泌(Milst ein C et al. Nature 1983, 305: 537-540)。此外,可藉由將構成目標的二種IgG L鏈及H鏈之基因,合計4種基因導入細胞中,共同表現並分泌。
本發明抗體可以該技術領域中具有通常知識者所公知的方法製造。具體來說,將編碼目標抗體DNA構築至表現載體。此時,在表現控制區域,例如增強子、啟動子的控制下,以表現方式構築至表現載體中。接著,藉由此表現載體將宿主細胞轉形,以表現抗體。此時,可使用適合的宿主及表現載體的組合。
將藉此獲得之本發明抗體由宿主細胞內或細胞外(培養基等)分離,以純化實質上高純度及均一的抗體。抗體的分離、純化可使用在一般抗體之純化中所使用的分離、純化方法,並無特別限制。例如,若適當地選擇、組合層析管柱、濾膜、超過濾、鹽析、溶劑沉澱、溶劑萃取、蒸餾、免疫沉澱、SDS-PAGE電泳、等電點電泳、透析、再結晶等,可以將抗體分離與純化。
本發明製劑中組胺酸-天門冬胺酸鹽緩衝液的較佳樣態為,在游離胺基酸狀態下添加組胺酸至水溶液等的溶液中,含有游離胺基酸狀態的天門冬胺酸,以水溶液等液體滴定的方式調整的緩衝液。此外,也可逆轉添加順序進行調整,更可直接以粉末直接滴定。
本發明人為評估含上述雙重專一性抗體樣本保存時的安定性,藉由冷凍融解試驗、熱加速試驗、長期保存試驗及冷凍保存試驗等來評估各種添加劑的效果。結果發現,與磷酸緩衝液、檸檬酸緩衝液、醋酸緩衝液相比,使用組胺酸緩衝液可抑制聚集體生成及/或電荷異性成分。
再者,藉由使用作為相對離子種類之酸性胺基酸的天門冬胺酸,亦即,藉由使用作為緩衝液的組胺酸-天門冬胺酸鹽緩衝液,可抑制聚集體生成及/或電荷異性成分。
本發明製劑中的組胺酸-天門冬胺酸鹽緩衝液的濃度(量)較佳為10~100 mM,更佳為為10~40 mM。此外,組胺酸-天門冬胺酸鹽緩衝液的濃度(量)為,例如10 mM、20 mM、40 mM。
再者,與作為含抗體製劑之安定劑被報導的氯化鈉相比,發現藉由添加精胺酸顯示更高的安定化效果(聚集體生成抑制效果、電荷異性成分抑制效果)。
本發明製劑中的精胺酸濃度(量)較佳為100 mM~300 mM。此外,精胺酸的濃度(量)為,例如100 mM、150 mM、200 mM、300 mM。
本發明製劑的溶液pH值較佳為pH 4.5~6.5,更佳為5.5~6.5,又更佳為5.5~6。此外,溶液的pH值為,例如5.5、6。
本發明製劑中所含的界面活性劑為,例如聚山梨酯20(PS20)、Pluronic F-68(波洛莎姆-188):聚氧乙烯(160) 聚氧乙烯(30)乙二醇),特別是波洛莎姆-188較佳。對於本發明製劑,波洛莎姆-188(Poloxamer 188或PX188)的添加量較佳為0.2 mg/mL~1 mg/mL。此外,本發明製劑Poloxamer-188的添加量為,例如0.2 mg/mL、0.5 mg/mL、0.8 mg/mL、1 mg/mL。
本發明所使用的組胺酸可使用單一製品或其衍生物任一種,特別較佳為L-組胺酸。本發明所使用的精胺酸可為單一製品、其衍生物、其鹽類任一種,較佳為L-精胺酸或其鹽類。此外,精胺酸的鹽類較佳為天門冬胺酸鹽或麩胺酸鹽。
本發明製劑可包括其它胺基酸。本發明中較佳所使用的胺基酸為天然胺基酸或胺基酸衍生物,較佳為L-甲硫胺酸及L-脯氨酸。
本發明製劑可含有其它醣類。本發明中較佳所使用的醣類為蔗糖、海藻糖、葡甲胺及山梨糖醇。
對於本發明製劑,胺基酸或醣類的添加量一般為1 mM~1000 mM,較佳為5 mM~500 mM,更佳為10 mM~300 mM。
本發明製劑可含有其它無機鹽類。本發明中較佳所使用的無機鹽類為鎂鹽及鈣鹽。
再者,本發明製劑作為緩衝液(緩衝劑)或安定劑的相對離子,較佳為不含有天門冬胺酸以外的陰離子。作為此製劑的一樣態,例如,可列舉出實質上不含有氯化物離子及醋酸離子的製劑。所謂「實質上不含有氯化物離子及醋酸離子」係指,例如氯化物離子及醋酸離子為5 mM以下,更佳為2 mM以下,又更佳為1 mM以下。實質上不含有安定化效果低的氯化物離子及醋酸離子,藉由使用安定化效果大的天門冬胺酸相對離子,可不提升滲透壓,而製造高安定性的含抗體製劑。
此外,本發明製劑若有需要,可添加適當的冷凍保護劑、懸浮劑、助溶劑、等張劑、保存劑、防吸著劑、稀釋劑、賦形劑、pH調整劑、止痛劑、含硫還原劑、抗氧化劑等。
冷凍保護劑為,例如,可列舉出海藻糖、蔗糖、山梨糖醇等糖類。
助溶劑為,例如,可列舉出聚氧乙烯氫化蓖麻油、聚山梨酯80、菸鹼醯胺、聚氧乙烯脫水山梨醇單月桂酸酯、聚乙二醇、蓖麻油酸乙酯等
等張劑為,例如,可列舉出氯化鈉、氯化鉀、氯化鈣等。
保存劑為,例如,可列舉出對羥基苯甲酸甲酯、對羥基苯甲酸乙酯、山梨酸、苯酚、甲酚、氯甲酚等。
防吸著劑為,例如,可列舉出人血清白蛋白、卵磷脂、葡萄糖聚糖、環氧乙烷˙環氧丙烷共聚合體、羥丙基纖維素、甲基纖維素、聚氧乙烯氫化蓖麻油、聚乙二醇等。
含硫還原劑為,例如,可列舉出N-乙醯半胱氨酸、N-乙醯基同型半胱氨酸、硫辛酸、硫二甘醇、硫代乙醇胺、硫甘油、硫代山梨醇、巰基乙酸及其鹽類、硫代硫酸鈉、穀胱甘肽、碳數1~7的硫烷烴酸等具有巰基的物質等。
抗氧化劑為,例如,可列舉出異抗壞血酸、二丁基羥基甲苯、丁基羥基茴香醚、α-生育酚、生育酚乙酸酯、L-抗壞血酸及其鹽類、L-抗壞血酸棕櫚酸酯、L-抗壞血酸硬脂酸酯酸、亞硫酸氫鈉、亞硫酸鈉、沒食子酸三戊酯、沒食子酸丙酯或乙二胺四乙酸二鈉(EDTA)、焦磷酸鈉、偏磷酸鈉等螯合劑。
本發明製劑第一實施樣態如下所述。
一種抗體溶液製劑,包括
20~180 mg/mL第一多胜肽及第三多胜肽形成配對,第二多胜肽與第四多胜肽形成配對的雙重專一性抗體,係為第一多胜肽為由序列辨識號:10之胺基酸序列所形成的H鏈,第二多胜肽為由序列辨識號:11之胺基酸序列所形成的H鏈,以及第三多胜肽與第四多胜肽為序列辨識號:12之共通L鏈所形成的雙重專一性抗體,
20 mM之組胺酸-天門冬胺酸鹽緩衝液,
0.5 mg/mL之PoLoxamer 188,以及
150 mM之L-精胺酸,
其pH值為6。
或
一種抗體溶液製劑,包括:
20~180 mg/mL之為雙重專一性抗體的Emicizumab(ACE910),
20 mM之L-組胺酸-天門冬胺酸鹽緩衝液,
0.5 mg/mL之Poloxamer 188,
150 mM之L-精胺酸,
其pH值為6。
本發明製劑另一實施樣能如下所述。
一種抗體溶液製劑,包括:
20~180 mg/mL第一多胜肽及第三多胜肽形成配對,第二多胜肽與第四多胜肽形成配對的雙重專一性抗體,係為由第一多胜肽為由序列辨識號:10之胺基酸序列所形成的H鏈,第二多胜肽為由序列辨識號:11之胺基酸序列所形成的H鏈,以及第三多胜肽與第四多胜肽為序列辨識號:12之共通L鏈所形成的雙重專一性抗體;
20 mM之L-組胺酸-天門冬胺酸鹽緩衝液
0.05 mg/mL之PS20,
150 mM之L-精胺酸,
其pH值為6。
或
一種抗體溶液製劑,包括:
20~180 mg/mL之為雙重專一性抗體的Emicizumab(ACE910),
20 mM之L-組胺酸-天門冬胺酸鹽緩衝液,
0.05 mg/mL PS20,
150 mM之L-精胺酸,
其pH值為6。
本發明含抗體製劑的投予,可以透過任何適當的路徑投予患者。例如,藥丸或持續一定時間藉由經靜脈內、肌肉、皮下注射投予之途徑患者。較佳為靜脈內投予或皮下投予。
Emicizumab(ACE910)的投予量為,例如0.001~1000 mg/kg,投予間隔至少為1日以上。
更具體來說,例如,在給投予初次用量為1 mg/kg的 Emicizumab(ACE910)後,可以每週一次的頻率投予後續用量0.3 mg/kg的Emicizumab(ACE910)。此外,例如,在投予初次用量為3 mg/kg的Emicizumab(ACE910)後,可以每週一次的頻率投予後續用量1 mg/kg的Emicizumab(ACE910)。此外,例如,在投予初次用量為3 mg/kg的Emicizumab(ACE910)後,以每週一次的頻率投予後續用量3 mg/kg的Emicizumab(ACE910)。
本發明含抗體製劑可用於由於FVIII及/或活性化第VIII凝血因子(FVIIIa)活性低下或者缺乏所發病及/或病程進展的病者,例如,A型血友病、具FVIII/FVIIIa抑制物的A型血友病、後天A型血友病、血管性血友病等,並不限於這些患者。
本發明另一實施樣態為安定化含抗體溶液製劑中抗體的方法。較佳為,安定化含抗體溶液製劑中抗體的方法,其係包括於溶液中添加組胺酸-天門冬胺酸鹽緩衝液、Poloxamer 188及精胺酸的上述方法。
此外,本發明另一實施樣態為抑制含抗體溶液製劑中抗體聚集化(形成聚集體)的方法。較佳為,抑制含抗體溶液製劑中抗體的聚集化(形成聚集體)的方法,其係包括於溶液中添加組胺酸-天門冬胺酸鹽緩衝液、Poloxamer 188及精胺酸的上述方法。
另外,上述抑制含抗體製劑中抗體聚集化(形成聚集體)的方法,包括於溶液中添加組胺酸-天門冬胺酸鹽緩衝液、Poloxamer 188及精胺酸,較佳抗體濃度為20~180 mg/mL、組胺酸-天門冬胺酸鹽緩衝液濃度為10 mM~40 mM,Poloxamer 188的濃度為0.2~1 mg/mL,精胺酸濃度為100 mM~300 mM,且pH值為4.5~6.5,更佳抗體濃度為20~180 mg/mL、組胺酸-天門冬胺酸鹽緩衝液濃度為20 mM,Poloxamer 188的濃度為0.5 mg/mL,精胺酸濃度為150 mM,且pH值為6。
本發明另一實施樣態為降低含抗體製劑中電荷異性成分的方法。較佳為,降低含抗體製劑中電荷異性成分的方法,其係包括於溶液中添加組胺酸-天門冬胺酸鹽緩衝液的上述方法。更佳為,降低含抗體製劑中電荷異性成分的方法,其係包括於溶液中添加組胺酸-天門冬胺酸鹽緩衝液,且包括將組胺酸-天門冬胺酸鹽緩衝液濃度設為10 mM~40 mM,或20 mM的上述方法。
再者,本發明另一實施樣態為降低含抗體製劑中電荷異性成分的方法,包括於溶液中添加組胺酸-天門冬胺酸鹽緩衝液、Poloxamer 188及精胺酸。更佳為,降低含抗體製劑中電荷異性成分的方法,包括於溶液中添加組胺酸-天門冬胺酸鹽緩衝液、Poloxamer 188及精胺酸,且將抗體濃度為20~180 mg/mL、組胺酸-天門冬胺酸鹽緩衝液濃度為10 mM~40 mM,Poloxamer 188的濃度為0.2~1 mg/mL,精胺酸濃度為100 mM~300 mM,且pH值為4.5~6.5較佳,更佳為抗體濃度為20~180 mg/mL、組胺酸-天門冬胺酸鹽緩衝液濃度為20 mM,Poloxamer 188的濃度為0.5 mg/mL,精胺酸濃度為150 mM,且pH值為6。
上述安定化抗體的方法、抑制抗體聚集化(形成聚集體)的方法、及降低電荷異性成分的方法中,較佳抗體為雙重專一性抗體,更佳為Emicizumab(ACE910)。
本發明說明中使用的情況,經由「…包括(comprising)」表現的樣態,包括經由「實質上由…組成(essentially consisting of)」表現的樣態、以及經由「由…組成(consisting of)」表現的樣態。
本發明說明所記載的數值,例如機器、測定條件可依業者的技術在一定範圍內進行調整,為達成本發明目的可在範圍內,如10%的程度進行調整。
本發明說明中所有引用之專利及參考文獻的內容皆可參照本發明說明獲得。
本發明以下列實施例進行示例說明,但不限於下列實施例。
[
實施例]
實施例1:組胺酸在人源化IgG4抗體ACE910之熱加速保存中所帶來之抑制聚集體效果
(1) 材料
ACE910為分別可辨識第IX凝血因子及第X凝血因子的雙重專一性抗體,為被期待藉由取代活性化第VIII凝血因子的功能來預防A型血友病出血的人源化IgG4抗體。
(2) 試驗樣本
製備含有100 mg/mL之ACE910、150 mmol/L之NaCl,pH值6,以及作為緩衝液之20 mmol/L磷酸鹽緩衝液、或20 mmol/L檸檬酸鹽緩衝液、或20 mmol/L醋酸鹽緩衝液、或20 mmol/L組胺酸緩衝液之任一個的各調劑液,並分別充填5~15 μL至玻璃瓶中。
將如此製備之含人源化抗體溶液製劑,靜置於25℃恆溫槽內8週後,作為試驗樣本。
(3) ACE910之聚集體量測定方法以及聚集體量的計算方法
樣本為藉由以使用管柱(東曹-G3000SWXL),使用50 mmol/L磷酸鹽緩衝液(pH 7.0)、300 mmol/L氯化鈉為移動相,流速0.5 mL/min進行之尺寸篩除層析法(SEC)來測定聚集體的量。
將檢測出的波峰中,面積及高度皆為最大者作為單體,單體之前所檢測出之波峰的總稱為聚集體(HMWS)。
針對所有之波峰,計算出面積,並根據以下之式計算出目標物波峰之波峰面積比率。
(4) 結果
所獲得的結果如表1所示。
表1、25℃保存後之聚集體增加量(%)
配方 | ΔHMW(%) | ||
25℃-2W | 25℃-4W | 25℃-8W | |
磷酸鹽 | 0.20 | 0.27 | 0.41 |
檸檬酸鹽 | 0.14 | 0.21 | 0.32 |
醋酸鹽 | 0.24 | 0.38 | 0.63 |
組胺酸 | 0.08 | 0.13 | 0.22 |
由表1可知,添加20 mmol/L組胺酸的樣本在25℃熱加速8週後之樣本中,獲得了高的聚集體抑制效果。
實施例2:鹽濃度及精胺酸在人源化IgG4抗體ACE910之熱加速保存及冷凍融解中所帶來之抑制聚集體效果
(1) 材料
使用實施例1中所記載之抗體。
(2) 試驗樣本
製備含有100 mg/mL之ACE910、20 mmol/L之組胺酸,pH值6,以及作為添加劑之50 mmol/L NaCl、或75 mmol/L NaCl、或150 mmol/L NaCl、或150 mmol/精胺酸之任一個的各調劑液,並分別充填5~15 μL至玻璃瓶中。
將如此製備之含人源化抗體溶液製劑,靜置於25℃恆溫槽內8週後,或重複冷凍融解(F/T)(5℃↔-20℃)10次後作為試驗樣本。
(3) ACE910之聚集體量測定方法及聚集體量的計算方法
依實施例1所記載之方法進行。
(4) 結果
所獲得的結果如表2所示。
表2、25℃保存後及冷凍融解後之聚集體增加量(%)
配方 | ΔHMW(%) | ||||
5F/T | 10F/T | 25℃-2W | 25℃-4W | 25℃-8W | |
50 mM NaCl | 1.00 | 2.07 | 0.09 | 0.16 | 0.26 |
75 mM NaCl | 0.62 | 1.43 | 0.07 | 0.13 | 0.23 |
150 mM NaCl | 0.11 | 0.28 | 0.08 | 0.13 | 0.22 |
150 mM Arg | 0.03 | 0.05 | 0.03 | 0.06 | 0.11 |
由表2可知,添加150 mmol/L精胺酸的樣本在25℃熱加速8週後之樣本及冷凍融解後之樣本中,獲得了高的聚集體抑制效果。
實施例3:天門冬胺酸在人源化IgG4抗體ACE910之冷凍融解中所帶來之抑制聚集體效果
(1) 材料
使用實施例1中所記載之抗體
(2) 試驗樣本
分別製備含有100 mg/mL之ACE910、20 mmol/L之組胺酸,pH值6,以及作為相對離子之150 mmol/L NaCl、或150 mmol/L天門冬胺酸鹽(Sodium L-Aspartic acid)之任一個的各調劑液,並分別充填5~15 μL至玻璃瓶中。
將如此製備之含人源化抗體溶液製劑重複冷凍融解(5℃↔-20℃)10次後作為試驗樣本。
(3) ACE910之聚集體量測定方法及聚集體量的計算方法
依實施例1所記載之方法進行。
(4) 結果
所獲得的結果如表3所示。
表3、冷凍融解後之聚集體增加量(%)
配方 | ΔHMW(%) | |
5F/T | 10F/T | |
NaCl | 0.11 | 0.28 |
Na 天門冬胺酸 | 0.05 | 0.13 |
由表3可知,添加天門冬胺酸的樣本在冷凍融解後之樣本中,獲得了高的聚集體抑制效果。
實施例4:pH值在人源化IgG4抗體ACE910之熱加速保存中所帶來之抑制聚集體及電荷異性成分效果
(1) 材料
使用實施例1中所記載之抗體
(2) 試驗樣本
製備含有100 mg/mL之ACE910、20 mmol/L之組胺酸-天門冬胺酸、150 mmol/L之精胺酸-天門冬胺酸,pH值4.5、或5.0、或5.5、或6.0、或6.5、或7.0、或7.5的各調劑液,並分別充填5~15 μL至玻璃瓶中。
將如此製備之含人源化抗體溶液製劑靜置於25℃恆溫槽內8週後作為試驗樣本。
(3) ACE910之聚集體量測定方法及聚集體量的計算方法
依實施例1所記載之方法進行。
(4) ACE910之電荷異性成分測定方法及計算方法
樣本為藉由以使用管柱(YMC製BioPro QA-F),使用20mmol/L Tris-HCl緩衝液(pH 7.8)作為移動相A,使用20 mmol/L Tris-HCl緩衝液(pH 7.8)、500 mmol/L氯化鈉作為移動相B,流速0.5 mL/min進行之離子交換層析法(IEC)來測定電荷異性成分量。
將檢測出的波峰中,面積及高度皆為最大者作為主峰(Main Peak),主峰之後所檢測出之波峰的總稱為酸性波峰(acidic peak)。
針對所有之波峰,計算出面積,並根據以下之式計算出目標物波峰之波峰面積比率。。
(5) 結果
所獲得的結果如表4所示。
表4、25℃保存後之聚集體增加量(%)及酸性波峰-1增加量(%)
配方 | ΔHMW(%) | Δ酸性-1(%) | ||||
25℃-2W | 25℃-4W | 25℃-8W | 25℃-2W | 25℃-4W | 25℃-8W | |
pH4.5 | 0.05 | 0.10 | 0.24 | 0.21 | 2.43 | 3.41 |
pH5.0 | 0.09 | 0.11 | 0.20 | 0.46 | 0.86 | 2.57 |
pH5.5 | 0.07 | 0.08 | 0.15 | 0.36 | 0.68 | 2.10 |
pH6.0 | 0.07 | 0.11 | 0.17 | 0.38 | 0.47 | 3.23 |
pH6.5 | 0.09 | 0.14 | 0.25 | 0.24 | 1.17 | 3.90 |
pH7.0 | 0.13 | 0.17 | 0.30 | 1.25 | 2.44 | 5.39 |
pH7.5 | 0.18 | 0.32 | 0.79 | 3.09 | 5.01 | 9.49 |
由表4可知,pH 4.5~pH 6.5,特別是pH 5.5及pH 6.0的樣本,在25℃保存後之樣本中,獲得了高的聚集體及電荷異性成分抑制效果。
實施例5:組胺酸濃度在人化源化IgG4抗體ACE910之熱加速保存中所帶來之聚集體及電荷異性成分抑制效果
(1) 材料
使用實施例1中所記載之抗體。
(2) 試驗樣本
製備含有100 mg/mL之ACE910、150 mmol/L之精胺酸,pH值6.0、5 mmol/L、或10 mmol/L、或20 mmol/L、或40 mmol/L之組胺酸-天門冬胺酸的各調劑液,並分別充填5~15 μL至玻璃瓶中。
將如此製備之含人源化抗體溶液製劑靜置於25℃恆溫槽內8週後作為試驗樣本。
(3) ACE910聚集體量測定方法及聚集體量的計算方法
依實施例1所記載之方法進行。
(4) ACE910電荷異性成分的測定方法及計算方法
依實施例4所記載之方法進行。
(5) 結果
所獲得的結果如表5所示。
表5、25℃保存後聚集體增加量(%)及酸性波峰-1增加量(%)
組胺酸濃度 | ΔHMW(%) | Δ酸性-1(%) | ||||
25℃-2W | 25℃-4W | 25℃-8W | 25℃-2W | 25℃-4W | 25℃-8W | |
5 mmol/L | 0.04 | 0.09 | 0.17 | 0.87 | 3.01 | 9.19 |
10 mmol/L | 0.02 | 0.05 | 0.14 | 0.39 | 1.50 | 7.09 |
20 mmol/L | 0.01 | 0.04 | 0.12 | 0.06 | 1.04 | 7.11 |
40 mmol/L | 0.01 | 0.02 | 0.07 | 0.52 | 1.13 | 6.74 |
由表5可知,含10 mmol/L以上之組胺酸-天門冬胺酸的樣本,在25℃保存後之樣本中,獲得了高的聚集體及電荷異性成分抑制效果。
實施例6:精胺酸濃度在人源化IgG4抗體ACE910之冷凍融解及熱加速保存及冷凍保存中所帶來之聚集體抑制效果
(1) 材料
使用實施例1中所記載之抗體。
(2) 試驗樣本
製備含有100 mg/mL之ACE910、20 mmol/L之組胺酸-天門冬胺酸、pH值6.0,75 mg/mL、或100 mmol/L、或150 mmol/L、或200 mmol/L、或300 mmol/L之精胺酸的各調劑液,並分別充填5~15 μL至玻璃瓶中。
將如此製備之含人源化抗體溶液製劑,重複冷凍融解(5℃↔-20℃)10次後,或靜置於25℃恆溫槽內8週後,或靜置於-20℃恆溫槽內6個月後,作為試驗樣本。
(3) ACE910聚集體量測定方法及聚集體量的計算方法
依實施例1所記載之方法進行。
(4) 結果
所獲得的結果如表6所示。
表6、冷凍融解及25℃保存後及-20℃保存後之聚集體增加量(%)
精胺酸濃度 | ΔHMW(%) | ||||||
5F/T | 10F/T | 25℃-2W | 25℃-4W | 25℃-8W | -20℃-3W | -20℃-6W | |
75 mmol/L | 0.10 | 0.10 | 0.02 | 0.06 | 0.17 | 0.19 | 0.53 |
100 mmol/L | 0.04 | 0.04 | 0.01 | 0.04 | 0.12 | 0.08 | 0.02 |
150 mmol/L | 0.01 | 0.01 | -0.01 | 0.01 | 0.04 | 0.00 | 0.00 |
200 mmol/L | 0.01 | 0.01 | -0.01 | 0.00 | 0.02 | 0.00 | -0.01 |
300 mmol/L | 0.00 | 0.00 | -0.02 | -0.02 | 0.00 | 0.00 | -0.01 |
由表6可知,含100 mmol/L以上之精胺酸的樣本,在冷凍融解後及25℃保存後及-20℃保存後之樣本中,獲得了高的聚集體抑制效果。
實施例7:Poloxamer 188在人化源化IgG4抗體ACE910之5℃保存中所帶來之不溶性雜質及不溶性微粒生成抑制效果
(1) 材料
使用實施例1中所記載之抗體。
(2) 試驗樣本
製備含有80 mg/mL之ACE910、20 mmol/L之組胺酸-天門冬胺酸、150 mmol/L之精胺酸,pH值6.0,作為添加劑之0 mg/mL Poloxamer 188、或0.2 mg/mL Poloxamer 188、或0.5 mg/mL Poloxamer 188、或1.0 mg/mL Poloxamer 188、或0.05 mg/mL Polysorbate20、或1.0 mg/mL Polysorbate20的各調劑液,並分別充填1.0 mL至玻璃瓶中。
將如此製備之含人源化抗體溶液製劑靜置於5℃冷藏室內5個月後,作為試驗樣本。
(3) 不溶性雜質觀察法
將樣本置於瓶用目測檢測檯的樣本檯上,回轉樣本檯後進行觀察,確認有無不溶性雜質。
(4) 不溶性微粒子測定法
使用溶液微粒子計數器(Hach Ultra Analytics, Model9703)來計數溶液中不溶性微粒子數。
(5) 結果
所獲得的結果如表7所示。
表7、5℃保存後之不溶性微粒子數(微粒子數/mL)及不溶性雜質檢出率(%)
PX188 | 0.2 mg/mL | 0.5 mg/mL | 1.0 mg/mL | |||||||||||
初始 | 1M | 3M | 5M | 初始 | 1M | 3M | 5M | 初始 | 1M | 3M | 5M | |||
溶液中不溶性微粒子數 | (微粒子數/mL) | ≧5 μm | 31 | - | 61 | 188 | 9 | - | 18 | 27 | 7 | - | 7 | 43 |
≧10 μm | 5 | - | 4 | 15 | 5 | - | 3 | 2 | 5 | - | 3 | 5 | ||
≧25 μm | 1 | - | 1 | 1 | 1 | - | 0 | 0 | 0 | - | 1 | 1 | ||
不溶性雜質檢出率(雜質樣本數/檢查樣本數) | 0/5 | 0/5 | 0/5 | 0/5 | 0/5 | 0/5 | 0/5 | 0/5 | 0/5 | 0/5 | 0/5 | 0/5 |
PS20 | 0.05 mg/mL | 1.0 mg/mL | ||||||||
初始 | 1M | 3M | 5M | 初始 | 1M | 3M | 5M | |||
溶液中不溶性微粒子數 | (微粒子數/mL) | ≧5 μm | 13 | - | 36 | 89 | 24 | - | 238 | 411 |
≧10 μm | 5 | - | 3 | 10 | 9 | - | 49 | 66 | ||
≧25 μm | 0 | - | 0 | 0 | 1 | - | 3 | 2 | ||
不溶性雜質檢出率(雜質樣本數/檢查樣本數) | 0/5 | 0/5 | 0/5 | 0/5 | 0/5 | 0/5 | 5/5 | 5/5 |
由表7可知,含0.05 mg/mL之PS20的樣本、含0.2 mg/mL之Poloxamer 188的樣本,在5℃保存後之樣本中,獲得了高的不溶性雜質及不溶性微粒抑制效果。
實施例8:Poloxamer 188在人源化IgG4抗體ACE910之震盪及冷凍融解保存中所帶來之不溶性雜質及不溶性微粒生成抑制效果
(1) 材料
使用實施例1中所記載之抗體。
(2) 試驗樣本
製備含有150 mg/mL之ACE910、20 mmol/L之組胺酸-天門冬胺酸、150 mg/mL之精胺酸-天門冬胺酸,pH值6.0,作為添加劑之0 mg/mL的Poloxamer 188、或0.2 mg/mL的Poloxamer 188、或0.5 mg/mL的Poloxamer 188、或0.8 mg/mL的Poloxamer 188的製劑,並分別充填0.9 mL至玻璃瓶中。
將如此製備之含人源化抗體溶液製劑,於室溫下使用震盪機以200 stroke/min的速度震盪24小時後,或重複冷凍融解(5℃↔-20℃)10次後,作為試驗樣本。
(3) 不溶性雜質的觀測方法
依實施例7所記載之方法進行。
(4) 不溶性雜質的偵測方法
依實施例7所記載之方法進行。
(5) 結果
所獲得的結果如表8及第1、2圖所示。
表8、震盪後及冷凍融解後之不溶性雜質的檢出率(%)
Poloxamer 188 濃度 | 不溶性雜質檢出率(%)(雜質樣本數/檢查樣本數) | |||
初始 | 震盪30分鐘 | 震盪24小時 | 冷凍融解 | |
0 mg/mL | 0%(0/10) | 50%(5/10) | 100%(10/10) | 0%(0/10) |
0.2 mg/mL | 0%(0/10) | 0%(0/10) | 0%(0/10) | 0%(0/10) |
0.5 mg/mL | 0%(0/10) | 0%(0/10) | 0%(0/10) | 0%(0/10) |
0.8 mg/mL | 0%(0/10) | 0%(0/10) | 0%(0/10) | 0%(0/10) |
由表8及第1、2圖可知,含0.2 mg/mL以上之Poloxamer 188的樣本,在震盪應力及冷凍溶解保存後之樣本,獲得了高的不溶性雜質及不溶性微粒抑制效果。
實施例9:人源化IgG4抗體ACE910濃度之在熱加速保存中及冷凍融解保存中所帶來之安定性
(1) 材料
使用實施例1中所記載之抗體。
(2) 試驗樣本
製備含有20 mmol/L之組胺酸-天門冬胺酸、150 mmol/L之精胺酸-天門冬胺酸、pH 6.0、0.5 mmol/L的Poloxamer 188,作為ACE910之20 mg/mL的ACE910、或30 mg/mL的ACE910、或40 mg/mL的ACE910、或120 mg/mL的ACE910、或150 mg/mL的ACE910、或180 mg/mL的ACE910的各調劑液,並分別充填0.65 mL至玻璃瓶中。
將如此製備之含人源化抗體溶液製劑,靜置於40℃恆溫槽內8週後,或重複冷凍融解(25℃↔-20℃)5次及10次後,作為試驗樣本。
(3) ACE910聚集體量測量方法及聚集體量的計算方法
依實施例1所記載之方法進行。
(4) ACE910電荷異性成分的測定方法及計算方法
樣本為藉由以使用管柱(Waters製TSKgeL Q-STAT),使用50 mmol/L Tris-HCl緩衝液(pH 8.0)作為移動相A,使用50 mmol/L Tris-HCl緩衝液(pH 8.0)、200 mmol/L氯化鈉作為移動相B,流速0.5 mL/min進行之陰離子交換層析法(AIEC)來測定電荷異性成分量。
將檢測出的波峰中,面積及高度皆為最大者作為主峰(Main Peak),主峰之前所檢測出之波峰總稱為鹼性波峰(basic peak),主峰之後所檢測出之波峰總稱為酸性波峰(acidic peak)。
此外,藉由以使用管柱(Thermo Scientific製ProPac WCX-10G),以9.6 mmol/L Tris、6.0 mmol/L 哌 (piperazine)、11.0 mmol/L 咪唑(imidazole)緩衝液(pH 6.0)作為移動相A,以9.6 mmol/L Tris、6.0 mmol/L 哌、11.0 mmol/L 咪唑、100 mmol/L氯化鈉緩衝液(pH 10.1)作為移動相B,流速0.5 mL/min進行之陽離子交換層析法(CIEC)來測定電荷異性成分量。
在檢測出的波峰中,面積及高度皆為最大者作為BiAb波峰,BiAb波峰之前所檢測出之波峰總稱為波峰前(Pre peak),BiAb波峰之後所檢測出之波峰總稱為波峰後(Post peak)。
針對所有之波峰,計算出面積,並根據以下之式計算出目標物
波峰之波峰面積比率。
(5) 結果
所獲得的結果如表9所示。此外,SE顯示為尺寸篩除層析法的結果,AE顯示為陰離子交換層析法的結果,CE顯示為陽離子交換層析法的結果。
表9、40℃保存後及冷凍融解後聚集體量(%)及電荷異性成分量(%)
ACE910濃度 (mg/mL) | 20 | 30 | 40 | 120 | 150 | 180 | |
SE-HPLC %HMWS | 初始 | 0.10 | 0.11 | 0.11 | 0.13 | 0.14 | 0.14 |
2週40℃ | 0.14 | 0.15 | 0.16 | 0.26 | 0.28 | 0.31 | |
4週40℃ | 0.16 | 0.17 | 0.20 | 0.34 | 0.38 | 0.44 | |
5循環F/T | 0.11 | 0.11 | 0.12 | 0.13 | 0.14 | 0.14 | |
10循環F/T | 0.11 | 0.11 | 0.11 | 0.13 | 0.13 | 0.14 | |
SE-HPLC %單體 | 初始 | 99.90 | 99.89 | 99.89 | 99.87 | 99.86 | 99.86 |
2週40℃ | 99.86 | 99.85 | 99.84 | 99.74 | 99.72 | 99.69 | |
4週40℃ | 99.84 | 99.83 | 99.80 | 99.66 | 99.62 | 99.56 | |
5循環F/T | 99.89 | 99.89 | 99.88 | 99.87 | 99.86 | 99.86 | |
10循環F/T | 99.89 | 99.89 | 99.89 | 99.87 | 99.87 | 99.86 | |
AE-HPLC %鹼性區域 | 初始 | 16.1 | 16.2 | 16.1 | 16.3 | 16.0 | 16.3 |
2週40℃ | 14.3 | 14.6 | 14.4 | 14.5 | 14.5 | 14.5 | |
4週40℃ | 12.7 | 12.8 | 12.8 | 12.8 | 12.7 | 12.7 | |
5循環F/T | 16.1 | 16.2 | 16.4 | 16.5 | 16.5 | 16.5 | |
10循環F/T | 15.9 | 16.0 | 16.2 | 16.4 | 16.5 | 16.4 | |
AE-HPLC %主要區域 | 初始 | 71.7 | 71.6 | 71.8 | 71.5 | 72.1 | 71.6 |
2週40℃ | 65.0 | 64.6 | 64.7 | 64.5 | 63.9 | 64.4 | |
4週40℃ | 58.3 | 57.8 | 57.8 | 57.2 | 57.3 | 57.5 | |
5循環F/T | 72.3 | 72.2 | 72.0 | 71.6 | 71.6 | 71.6 | |
10循環F/T | 72.7 | 72.4 | 72.1 | 71.5 | 71.6 | 71.7 | |
AE-HPLC %酸性區域 | 初始 | 12.1 | 12.2 | 12.1 | 12.2 | 11.9 | 12.1 |
2週40℃ | 20.7 | 20.8 | 20.9 | 20.9 | 21.6 | 21.1 | |
4週40℃ | 29.0 | 29.4 | 29.4 | 30.0 | 30.0 | 29.8 | |
5循環F/T | 11.6 | 11.6 | 11.6 | 11.9 | 11.9 | 12.0 | |
10循環F/T | 11.5 | 11.6 | 11.7 | 12.1 | 12.0 | 11.9 | |
CE-HPLC %波峰前(Pre-peaks) | 初始 | 3.2 | 3.2 | 3.3 | 3.3 | 3.3 | 3.3 |
2週40℃ | 3.6 | 3.8 | 3.8 | 3.7 | 3.7 | 3.7 | |
4週40℃ | 4.3 | 4.3 | 4.3 | 4.3 | 4.2 | 4.3 | |
5循環F/T | 3.4 | 3.0 | 3.2 | 3.1 | 3.0 | 3.1 | |
10循環F/T | 3.1 | 3.2 | 2.8 | 3.1 | 3.1 | 3.1 | |
CE-HPLC %BiAb | 初始 | 96.8 | 96.8 | 96.7 | 96.6 | 96.6 | 96.6 |
2週40℃ | 96.4 | 96.2 | 96.3 | 96.3 | 96.3 | 96.2 | |
4週40℃ | 95.6 | 95.7 | 95.6 | 95.7 | 95.8 | 95.8 | |
5循環F/T | 96.6 | 97.0 | 96.8 | 96.9 | 97.0 | 96.9 | |
10循環F/T | 96.8 | 96.7 | 97.2 | 96.8 | 96.9 | 96.9 | |
CE-HPLC %波峰後(Post-peaks) | 初始 | 0.0 | 0.0 | 0.0 | 0.1 | 0.1 | 0.1 |
2週40℃ | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | |
4週40℃ | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | |
5循環F/T | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | |
10循環F/T | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 |
由表9可知,比較 20mg/mL ACE910~180mg/mL ACE910的樣本,在40℃保存後及冷凍融解後具有相同且充分的安定性。
[產業利用性]
與先前的製劑相比,本發明含抗體之溶液製劑為在溶液狀態下安定性良好的製劑,且以抑制在低溫、常溫或高溫保存後及冷凍融解後之抗體分子等蛋白質的聚集體生成為特徵。此不易產生劣化反應之本發明抗體溶液製劑,例如,能夠用於經由皮下投予之A型血友病的治療。
無
第1圖顯示實施例8震盪試驗後之不溶性雜質的照片(a: 0 mg/mL Poloxamer 188,b: 0.5 mg/mL Poloxamer 188)。
第2圖顯示實施例8震盪試驗後及冷凍融解後之不溶性微粒子數(微粒子數/mL)的圖。
<![CDATA[<110> 日商中外製藥股份有限公司(CHUGAI SEIYAKU KABUSHIKI KAISHA)]]> <![CDATA[<120> 含抗體製劑]]> <![CDATA[<130> C1-A1602-TW]]> <![CDATA[<150> JP 2016-090590]]> <![CDATA[<151> 2016-04-28]]> <![CDATA[<16]]>0> 15 ]]> <br/> <br/><![CDATA[<170> PatentIn第3.5版]]> <br/> <br/><![CDATA[<210> 1]]> <br/><![CDATA[<211> 5]]> <br/><![CDATA[<212> PRT]]> <br/><![CDATA[<213> 人工序列]]> <br/> <br/><![CDATA[<220>]]> <br/><![CDATA[<223> 重鏈可變區域 CDR1]]> <br/> <br/><![CDATA[<400> 1]]> <br/> <br/><![CDATA[Tyr Tyr Asp Ile Gln 1 5 <![CDATA[<210> 2]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 重鏈可變區域 CDR2]]> <![CDATA[<400> 2]]> Ser Ile Ser Pro Ser Gly Gln Ser Thr Tyr Tyr Arg Arg Glu Val Lys 1 5 10 15 Gly <![CDATA[<210> 3]]> <![CDATA[<211> 14]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 重鏈可變區域 CDR3]]> <![CDATA[<400> 3]]> Arg Thr Gly Arg Glu Tyr Gly Gly Gly Trp Tyr Phe Asp Tyr 1 5 10 <![CDATA[<210> 4]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 重鏈可變區域 CDR1]]> <![CDATA[<400> 4]]> Asp Asn Asn Met Asp 1 5 <![CDATA[<210> 5]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 重鏈可變區域 CDR2]]> <![CDATA[<400> 5]]> Asp Ile Asn Thr Arg Ser Gly Gly Ser Ile Tyr Asn Glu Glu Phe Gln 1 5 10 15 Asp <![CDATA[<210> 6]]> <![CDATA[<211> 10]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 重鏈可變區域 CDR3]]> <![CDATA[<400> 6]]> Arg Lys Ser Tyr Gly Tyr Tyr Leu Asp Glu 1 5 10 <![CDATA[<210> 7]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 輕鏈可變區域 CDR1]]> <![CDATA[<400> 7]]> Lys Ala Ser Arg Asn Ile Glu Arg Gln Leu Ala 1 5 10 <![CDATA[<210> 8]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 輕鏈可變區域 CDR2]]> <![CDATA[<400> 8]]> Gln Ala Ser Arg Lys Glu Ser 1 5 <![CDATA[<210> 9]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 輕鏈可變區域 CDR3]]> <![CDATA[<400> 9]]> Gln Gln Tyr Ser Asp Pro Pro Leu Thr 1 5 <![CDATA[<210> 10]]> <![CDATA[<211> 448]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 重鏈]]> <![CDATA[<400> 10]]> Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Tyr 20 25 30 Asp Ile Gln Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ser Ile Ser Pro Ser Gly Gln Ser Thr Tyr Tyr Arg Arg Glu Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Thr Gly Arg Glu Tyr Gly Gly Gly Trp Tyr Phe Asp Tyr 100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly 115 120 125 Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser 130 135 140 Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 145 150 155 160 Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe 165 170 175 Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 180 185 190 Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Thr Cys Asn Val 195 200 205 Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys 210 215 220 Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly 225 230 235 240 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 245 250 255 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu 260 265 270 Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 275 280 285 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 290 295 300 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 305 310 315 320 Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu 325 330 335 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 340 345 350 Thr Leu Pro Pro Ser Gln Lys Glu Met Thr Lys Asn Gln Val Ser Leu 355 360 365 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 370 375 380 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 385 390 395 400 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 405 410 415 Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His 420 425 430 Glu Ala Leu His Asn Arg Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 435 440 445 <![CDATA[<210> 11]]> <![CDATA[<211> 444]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 重鏈]]> <![CDATA[<400> 11]]> Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Asn 20 25 30 Asn Met Asp Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Asp Ile Asn Thr Arg Ser Gly Gly Ser Ile Tyr Asn Glu Glu Phe 50 55 60 Gln Asp Arg Val Ile Met Thr Val Asp Lys Ser Thr Asp Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr His Cys 85 90 95 Ala Arg Arg Lys Ser Tyr Gly Tyr Tyr Leu Asp Glu Trp Gly Glu Gly 100 105 110 Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro 210 215 220 Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe 225 230 235 240 Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro 245 250 255 Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val 260 265 270 Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 275 280 285 Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val 290 295 300 Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys 305 310 315 320 Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser 325 330 335 Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro 340 345 350 Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val 355 360 365 Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly 370 375 380 Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp 385 390 395 400 Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp 405 410 415 Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His 420 425 430 Asn His Tyr Thr Gln Glu Ser Leu Ser Leu Ser Pro 435 440 <![CDATA[<210> 12]]> <![CDATA[<211> 214]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 輕鏈]]> <![CDATA[<400> 12]]> Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Arg Asn Ile Glu Arg Gln 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Glu Leu Leu Ile 35 40 45 Tyr Gln Ala Ser Arg Lys Glu Ser Gly Val Pro Asp Arg Phe Ser Gly 50 55 60 Ser Arg Tyr Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Asp Pro Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <![CDATA[<210> 13]]> <![CDATA[<211> 123]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 重鏈可變區域]]> <![CDATA[<400> 13]]> Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Tyr 20 25 30 Asp Ile Gln Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ser Ile Ser Pro Ser Gly Gln Ser Thr Tyr Tyr Arg Arg Glu Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Thr Gly Arg Glu Tyr Gly Gly Gly Trp Tyr Phe Asp Tyr 100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <![CDATA[<210> 14]]> <![CDATA[<211> 119]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 重鏈可變區域]]> <![CDATA[<400> 14]]> Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Asn 20 25 30 Asn Met Asp Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Asp Ile Asn Thr Arg Ser Gly Gly Ser Ile Tyr Asn Glu Glu Phe 50 55 60 Gln Asp Arg Val Ile Met Thr Val Asp Lys Ser Thr Asp Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr His Cys 85 90 95 Ala Arg Arg Lys Ser Tyr Gly Tyr Tyr Leu Asp Glu Trp Gly Glu Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <![CDATA[<210> 15]]> <![CDATA[<211> 107]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 輕鏈可變區域]]> <![CDATA[<400> 15]]> Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Arg Asn Ile Glu Arg Gln 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Glu Leu Leu Ile 35 40 45 Tyr Gln Ala Ser Arg Lys Glu Ser Gly Val Pro Asp Arg Phe Ser Gly 50 55 60 Ser Arg Tyr Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Asp Pro Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105
Claims (13)
- 一種抗體溶液製劑,包括: 一20~180 mg/mL的第一多胜肽及第三多胜肽形成配對,第二多胜肽與第四多胜肽形成配對的雙重專一性抗體,且係由第一多胜肽為含有序列辨識號:1、2、3 (Q499的H鏈CDR)之H鏈CDR1、2、3胺基酸序列的H鏈,第二多胜肽為含有序列辨識號:4、5、6 (J327的H鏈CDR)之H鏈CDR1、2、3胺基酸序列的H鏈,第三多胜肽及第四多胜肽為含有序列辨識號:7、8、9 (L404的L鏈CDR)之L鏈CDR1、2、3胺基酸序列的共通L鏈所形成的雙專一性抗體; 10 mM~40 mM組胺酸-天門冬胺酸鹽緩衝液, 0.2~1 mg/mL Poloxamer 188,以及 100 mM~300 mM L-精胺酸, 且其pH值為4.5~6.5。
- 如申請專利範圍第1項所述之抗體溶液製劑,其中該雙重專一性抗體為第一多胜肽及第三多胜肽形成配對,第二多胜肽與第四多胜肽形成配對的雙重專一性抗體,且係由第一多胜肽為由序列辨識號:10之胺基酸序列所形成的H鏈,第二多胜肽為由序列辨識號:11之胺基酸序列所形成的H鏈,以及第三多胜肽與第四多胜肽為序列辨識號:12之共通L鏈所形成之雙重專一性抗體。
- 如申請專利範圍第1或2項所述之抗體溶液製劑,其中Poloxamer 188的濃度為0.5 mg/mL。
- 如申請專利範圍第1~3項任一項所述之抗體溶液製劑,其中該pH值為6.0。
- 如申請專利範圍第1~4項任一項所述之抗體溶液製劑,其中該組胺酸-天門冬胺酸鹽緩衝溶液的濃度為20 mM。
- 如申請專利範圍第1~5項任一項所述之抗體溶液製劑,其中該L-精胺酸濃度為150 mM。
- 如申請專利範圍第1~6項任一項所述之抗體溶液製劑,其實質上不含有氯化物離子及醋酸離子。
- 一種抗體溶液製劑,包括: 一20~180 mg/mL第一多胜肽及第三多胜肽形成配對,第二多胜肽與第四多胜肽形成配對的雙重專一性抗體,且係由第一多胜肽為由序列辨識號:10之胺基酸序列所形成的H鏈,第二多胜肽為由序列辨識號:11之胺基酸序列所形成的H鏈,以及第三多胜肽與第四多胜肽為序列辨識號:12之共通L鏈所形成的雙重專一性抗體; 20 mM L-組胺酸-天門冬胺酸鹽緩衝液, 0.5 mg/mL Poloxamer 188,以及 150 mM之L-精胺酸, 且其pH值為6。
- 如申請專利範圍第1~8項任一項所述之抗體溶液製劑,其係用於皮下投予。
- 如申請專利範圍第1~9項任一項所述之抗體溶液製劑,其係用於治療A型血友病。
- 一種安定化含抗體溶液製劑中之抗體的方法,包括於溶液中添加組胺酸-天門冬胺酸鹽緩衝液、Poloxamer 188及L-精胺酸,其中該組胺酸-天門冬胺酸鹽緩衝液濃度為10 mM~40 mM,Poloxamer 188的濃度為0.2~1 mg/mL,L-精胺酸的濃度為100 mM~300 mM。
- 一種抑制含抗體溶液製劑中抗體聚集化(形成聚集體)的方法,包括於溶液中添加組胺酸-天門冬胺酸鹽緩衝液、Poloxamer 188及L-精胺酸,其中該組胺酸-天門冬胺酸鹽緩衝液濃度為10 mM~40 mM,Poloxamer 188的濃度為0.2~1 mg/mL,L-精胺酸的濃度為100 mM~300 mM。
- 一種減少含抗體溶液製劑中電荷異性成分的方法,包括於溶液中添加組胺酸-天門冬胺酸鹽緩衝液,其中該組胺酸-天門冬胺酸鹽緩衝液的濃度為10 mM~40 mM。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2016090590 | 2016-04-28 | ||
JP2016-090590 | 2016-04-28 |
Publications (1)
Publication Number | Publication Date |
---|---|
TW202402326A true TW202402326A (zh) | 2024-01-16 |
Family
ID=60160798
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
TW112137276A TW202402326A (zh) | 2016-04-28 | 2017-04-27 | 含抗體製劑 |
TW106114061A TWI820000B (zh) | 2016-04-28 | 2017-04-27 | 含抗體製劑 |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
TW106114061A TWI820000B (zh) | 2016-04-28 | 2017-04-27 | 含抗體製劑 |
Country Status (21)
Country | Link |
---|---|
US (1) | US20210189006A1 (zh) |
EP (1) | EP3449940A4 (zh) |
JP (3) | JP7320943B2 (zh) |
KR (1) | KR102456742B1 (zh) |
CN (2) | CN116059353A (zh) |
AR (1) | AR108240A1 (zh) |
AU (1) | AU2017255077B2 (zh) |
BR (1) | BR112018067792A2 (zh) |
CA (1) | CA3016301A1 (zh) |
CL (1) | CL2018003022A1 (zh) |
CR (1) | CR20180554A (zh) |
HK (1) | HK1257953A1 (zh) |
IL (1) | IL262589A (zh) |
MA (1) | MA44780A (zh) |
MX (1) | MX2018012648A (zh) |
PE (1) | PE20181889A1 (zh) |
RU (1) | RU2748046C2 (zh) |
SG (1) | SG11201807765PA (zh) |
TW (2) | TW202402326A (zh) |
UA (1) | UA126900C2 (zh) |
WO (1) | WO2017188356A1 (zh) |
Families Citing this family (20)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006106905A1 (ja) | 2005-03-31 | 2006-10-12 | Chugai Seiyaku Kabushiki Kaisha | 会合制御によるポリペプチド製造方法 |
DK2006381T3 (en) | 2006-03-31 | 2016-02-22 | Chugai Pharmaceutical Co Ltd | PROCEDURE FOR REGULATING ANTIBODIES BLOOD PHARMACOKINETICS |
DK2009101T3 (en) | 2006-03-31 | 2018-01-15 | Chugai Pharmaceutical Co Ltd | Antibody modification method for purification of a bispecific antibody |
EP3127921A1 (en) | 2007-09-26 | 2017-02-08 | Chugai Seiyaku Kabushiki Kaisha | Method of modifying isoelectric point of antibody via amino acid substition in cdr |
TWI609698B (zh) | 2010-01-20 | 2018-01-01 | Chugai Pharmaceutical Co Ltd | 穩定化的含抗體溶液製劑 |
KR101962483B1 (ko) | 2010-11-17 | 2019-03-29 | 추가이 세이야쿠 가부시키가이샤 | 혈액응고 제viii 인자의 기능을 대체하는 기능을 갖는 다중특이성 항원 결합 분자 |
BR112016006197B1 (pt) | 2013-09-27 | 2023-04-11 | Chugai Seiyaku Kabushiki Kaisha | Método para produzir um anticorpo biespecífico de polipeptídeos |
TWI700300B (zh) | 2014-09-26 | 2020-08-01 | 日商中外製藥股份有限公司 | 中和具有第viii凝血因子(fviii)機能替代活性的物質之抗體 |
TWI701435B (zh) | 2014-09-26 | 2020-08-11 | 日商中外製藥股份有限公司 | 測定fviii的反應性之方法 |
WO2016159213A1 (ja) | 2015-04-01 | 2016-10-06 | 中外製薬株式会社 | ポリペプチド異種多量体の製造方法 |
AU2016381992B2 (en) | 2015-12-28 | 2024-01-04 | Chugai Seiyaku Kabushiki Kaisha | Method for promoting efficiency of purification of Fc region-containing polypeptide |
IL265144B1 (en) | 2016-09-06 | 2024-06-01 | Chugai Pharmaceutical Co Ltd | Methods for using a bispecific antibody that recognizes coagulation factor IX and/or activated coagulation factor IX and coagulation factor X and/or activated coagulation factor X |
PE20210005A1 (es) | 2017-09-29 | 2021-01-05 | Chugai Pharmaceutical Co Ltd | Molecula de union al antigeno multiespecifica que tiene actividad de sustitucion de la funcion de cofactor del factor viii de coagulacion de sangre (fviii) y formulacion farmaceutica que contiene tal molecula como ingrediente activo |
FR3082427B1 (fr) | 2018-06-14 | 2020-09-25 | Lab Francais Du Fractionnement | Combinaison de facteur vii et d'un anticorps bispecifique anti-facteurs ix et x |
EP3849513A1 (en) * | 2018-09-11 | 2021-07-21 | Ichnos Sciences SA | Compositions comprising a bispecific antibody, bufffer and one or more stabilizing agents |
CN111665352B (zh) * | 2020-06-23 | 2024-05-17 | 广州市丹蓝生物科技有限公司 | 一种储存剂及由其制备的抗体溶液制剂及其应用 |
US20240115698A1 (en) * | 2021-02-05 | 2024-04-11 | Bio-Thera Solutions, Ltd. | Anti-il-5 antibody formulation, preparation method therefor and use thereof |
AR127269A1 (es) * | 2021-10-08 | 2024-01-03 | Chugai Pharmaceutical Co Ltd | Formulación de anticuerpo anti-hla-dq2.5 |
KR20240011866A (ko) * | 2021-12-01 | 2024-01-26 | 추가이 세이야쿠 가부시키가이샤 | 항체 함유 제제의 조제 방법 |
CN114544839A (zh) * | 2022-01-20 | 2022-05-27 | 未名生物医药有限公司 | 一种抗人神经生长因子抗体的电荷变异体检测方法 |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5530101A (en) * | 1988-12-28 | 1996-06-25 | Protein Design Labs, Inc. | Humanized immunoglobulins |
JP4340062B2 (ja) | 2000-10-12 | 2009-10-07 | ジェネンテック・インコーポレーテッド | 粘度の減少した濃縮タンパク質製剤 |
AU2003271174A1 (en) | 2003-10-10 | 2005-04-27 | Chugai Seiyaku Kabushiki Kaisha | Double specific antibodies substituting for functional protein |
JP4917024B2 (ja) | 2005-04-08 | 2012-04-18 | 中外製薬株式会社 | 血液凝固第viii因子の機能代替抗体 |
PE20091174A1 (es) * | 2007-12-27 | 2009-08-03 | Chugai Pharmaceutical Co Ltd | Formulacion liquida con contenido de alta concentracion de anticuerpo |
TWI609698B (zh) | 2010-01-20 | 2018-01-01 | Chugai Pharmaceutical Co Ltd | 穩定化的含抗體溶液製劑 |
KR101962483B1 (ko) | 2010-11-17 | 2019-03-29 | 추가이 세이야쿠 가부시키가이샤 | 혈액응고 제viii 인자의 기능을 대체하는 기능을 갖는 다중특이성 항원 결합 분자 |
CA2860543C (en) | 2012-03-08 | 2018-04-24 | F. Hoffmann-La Roche Ag | Abeta antibody formulation |
TW201625299A (zh) * | 2014-06-20 | 2016-07-16 | Chugai Pharmaceutical Co Ltd | 用於因第viii凝血因子及/或活化的第viii凝血因子的活性降低或欠缺而發病及/或進展的疾病之預防及/或治療之醫藥組成物 |
-
2017
- 2017-04-27 TW TW112137276A patent/TW202402326A/zh unknown
- 2017-04-27 MX MX2018012648A patent/MX2018012648A/es unknown
- 2017-04-27 EP EP17789638.8A patent/EP3449940A4/en active Pending
- 2017-04-27 PE PE2018001975A patent/PE20181889A1/es unknown
- 2017-04-27 MA MA044780A patent/MA44780A/fr unknown
- 2017-04-27 AU AU2017255077A patent/AU2017255077B2/en active Active
- 2017-04-27 SG SG11201807765PA patent/SG11201807765PA/en unknown
- 2017-04-27 RU RU2018141173A patent/RU2748046C2/ru active
- 2017-04-27 KR KR1020187033718A patent/KR102456742B1/ko active IP Right Grant
- 2017-04-27 CN CN202310130344.3A patent/CN116059353A/zh active Pending
- 2017-04-27 CN CN201780020233.XA patent/CN108883178B/zh active Active
- 2017-04-27 JP JP2018514687A patent/JP7320943B2/ja active Active
- 2017-04-27 TW TW106114061A patent/TWI820000B/zh active
- 2017-04-27 US US16/093,495 patent/US20210189006A1/en active Pending
- 2017-04-27 CA CA3016301A patent/CA3016301A1/en active Pending
- 2017-04-27 UA UAA201811471A patent/UA126900C2/uk unknown
- 2017-04-27 BR BR112018067792-2A patent/BR112018067792A2/pt unknown
- 2017-04-27 AR ARP170101082A patent/AR108240A1/es unknown
- 2017-04-27 CR CR20180554A patent/CR20180554A/es unknown
- 2017-04-27 WO PCT/JP2017/016658 patent/WO2017188356A1/ja active Application Filing
-
2018
- 2018-10-24 CL CL2018003022A patent/CL2018003022A1/es unknown
- 2018-10-25 IL IL262589A patent/IL262589A/en unknown
-
2019
- 2019-01-09 HK HK19100315.7A patent/HK1257953A1/zh unknown
-
2021
- 2021-12-09 JP JP2021199702A patent/JP2022037069A/ja active Pending
-
2023
- 2023-08-08 JP JP2023129455A patent/JP2023145766A/ja active Pending
Also Published As
Publication number | Publication date |
---|---|
BR112018067792A2 (pt) | 2019-02-12 |
CR20180554A (es) | 2019-01-10 |
AR108240A1 (es) | 2018-08-01 |
CA3016301A1 (en) | 2017-11-02 |
RU2018141173A (ru) | 2020-05-28 |
JP2022037069A (ja) | 2022-03-08 |
PE20181889A1 (es) | 2018-12-11 |
TW201737942A (zh) | 2017-11-01 |
RU2748046C2 (ru) | 2021-05-19 |
CN116059353A (zh) | 2023-05-05 |
RU2018141173A3 (zh) | 2020-06-11 |
MA44780A (fr) | 2019-03-06 |
AU2017255077A1 (en) | 2018-10-04 |
CL2018003022A1 (es) | 2019-01-18 |
KR20190003596A (ko) | 2019-01-09 |
KR102456742B1 (ko) | 2022-10-19 |
IL262589A (en) | 2018-12-31 |
JPWO2017188356A1 (ja) | 2019-03-07 |
WO2017188356A1 (ja) | 2017-11-02 |
EP3449940A4 (en) | 2020-01-22 |
JP7320943B2 (ja) | 2023-08-04 |
CN108883178B (zh) | 2023-03-14 |
JP2023145766A (ja) | 2023-10-11 |
CN108883178A (zh) | 2018-11-23 |
SG11201807765PA (en) | 2018-10-30 |
UA126900C2 (uk) | 2023-02-22 |
HK1257953A1 (zh) | 2019-11-01 |
MX2018012648A (es) | 2019-01-30 |
AU2017255077B2 (en) | 2024-05-16 |
TWI820000B (zh) | 2023-11-01 |
US20210189006A1 (en) | 2021-06-24 |
EP3449940A1 (en) | 2019-03-06 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
TWI820000B (zh) | 含抗體製劑 | |
AU2014229282B2 (en) | Low concentration antibody formulations | |
JP7356525B2 (ja) | ヒト抗rankl抗体の製剤及びその使用方法 | |
AU2008269086B2 (en) | Compositions of specific binding agents to hepatocyte growth factor | |
KR20170117166A (ko) | 단클론 항체를 위한 안정한 액체 제형 | |
JP7503056B6 (ja) | 抗lag3抗体および抗pd-1抗体の共-製剤 | |
JP7503056B2 (ja) | 抗lag3抗体および抗pd-1抗体の共-製剤 | |
TW201641104A (zh) | Il-17抗體之醫藥產品及穩定之液體組合物 | |
JP6954842B2 (ja) | 増強された活性を有する抗体及びその改変方法 | |
KR20220036998A (ko) | 항 cd47/pd-l1 이중특이성 항체를 포함하는 제제, 이의 제조 방법 및 용도 | |
ES2831865T3 (es) | Dominios variables únicos de inmunoglobulina para su uso en métodos de tratamiento de TTP | |
WO2020118011A1 (en) | Anti-alk2 antibodies and uses thereof | |
KR20240024941A (ko) | 항-pd1 항체의 제제 | |
US20230272106A1 (en) | Stable formulation for recombinant anti-pd-1 monoclonal antibody | |
TWI765311B (zh) | 包含抗pd-1/her2雙特異性抗體的製劑及其製備方法和用途 | |
JP2017508792A (ja) | オステオプロテゲリンはランケル・インヒビターを引き出した |