JPH0327320A - Human b cell differentiation factor pharmaceutical composition - Google Patents
Human b cell differentiation factor pharmaceutical compositionInfo
- Publication number
- JPH0327320A JPH0327320A JP1163088A JP16308889A JPH0327320A JP H0327320 A JPH0327320 A JP H0327320A JP 1163088 A JP1163088 A JP 1163088A JP 16308889 A JP16308889 A JP 16308889A JP H0327320 A JPH0327320 A JP H0327320A
- Authority
- JP
- Japan
- Prior art keywords
- leu
- glu
- ser
- ala
- lys
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 22
- 102000004889 Interleukin-6 Human genes 0.000 title description 6
- 108090001005 Interleukin-6 Proteins 0.000 title description 6
- 239000000203 mixture Substances 0.000 claims abstract description 21
- 239000003381 stabilizer Substances 0.000 claims abstract description 14
- 108090000623 proteins and genes Proteins 0.000 claims abstract description 12
- 210000002966 serum Anatomy 0.000 claims abstract description 12
- 102000004169 proteins and genes Human genes 0.000 claims abstract description 11
- 239000002904 solvent Substances 0.000 claims abstract description 11
- 102000009027 Albumins Human genes 0.000 claims abstract description 3
- 108010088751 Albumins Proteins 0.000 claims abstract description 3
- 102100033312 Alpha-2-macroglobulin Human genes 0.000 claims abstract description 3
- 108010015078 Pregnancy-Associated alpha 2-Macroglobulins Proteins 0.000 claims abstract description 3
- 210000003719 b-lymphocyte Anatomy 0.000 claims abstract description 3
- 150000001413 amino acids Chemical group 0.000 claims description 21
- YHKANGMVQWRMAP-DCAQKATOSA-N Ala-Leu-Arg Chemical compound C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CCCN=C(N)N YHKANGMVQWRMAP-DCAQKATOSA-N 0.000 claims description 6
- 241000282412 Homo Species 0.000 claims description 6
- GYDFRTRSSXOZCR-ACZMJKKPSA-N Ser-Ser-Glu Chemical compound OC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CCC(O)=O GYDFRTRSSXOZCR-ACZMJKKPSA-N 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 6
- XWGJDUSDTRPQRK-ZLUOBGJFSA-N Asn-Ala-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC(N)=O XWGJDUSDTRPQRK-ZLUOBGJFSA-N 0.000 claims description 5
- CQQGCWPXDHTTNF-GUBZILKMSA-N Leu-Ala-Glu Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CCC(O)=O CQQGCWPXDHTTNF-GUBZILKMSA-N 0.000 claims description 5
- BPANDPNDMJHFEV-CIUDSAMLSA-N Leu-Asp-Ala Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(O)=O BPANDPNDMJHFEV-CIUDSAMLSA-N 0.000 claims description 5
- 241001465754 Metazoa Species 0.000 claims description 5
- 108010009298 lysylglutamic acid Proteins 0.000 claims description 5
- YHBDGLZYNIARKJ-GUBZILKMSA-N Ala-Pro-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H](C)N YHBDGLZYNIARKJ-GUBZILKMSA-N 0.000 claims description 4
- 241000894006 Bacteria Species 0.000 claims description 4
- WVJHEDOLHPZLRV-CIUDSAMLSA-N Cys-Asn-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CS)N WVJHEDOLHPZLRV-CIUDSAMLSA-N 0.000 claims description 4
- VNCNWQPIQYAMAK-ACZMJKKPSA-N Glu-Ser-Ser Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O VNCNWQPIQYAMAK-ACZMJKKPSA-N 0.000 claims description 4
- ULXYQAJWJGLCNR-YUMQZZPRSA-N Leu-Asp-Gly Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(O)=O ULXYQAJWJGLCNR-YUMQZZPRSA-N 0.000 claims description 4
- URGPVYGVWLIRGT-DCAQKATOSA-N Lys-Met-Ala Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](C)C(O)=O URGPVYGVWLIRGT-DCAQKATOSA-N 0.000 claims description 4
- DBMLDOWSVHMQQN-XGEHTFHBSA-N Met-Ser-Thr Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(O)=O DBMLDOWSVHMQQN-XGEHTFHBSA-N 0.000 claims description 4
- LEIKGVHQTKHOLM-IUCAKERBSA-N Pro-Pro-Gly Chemical compound OC(=O)CNC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 LEIKGVHQTKHOLM-IUCAKERBSA-N 0.000 claims description 4
- 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 claims description 4
- 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 claims description 4
- NDXSOKGYKCGYKT-VEVYYDQMSA-N Thr-Pro-Asp Chemical compound C[C@@H](O)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(O)=O)C(O)=O NDXSOKGYKCGYKT-VEVYYDQMSA-N 0.000 claims description 4
- 108010005233 alanylglutamic acid Proteins 0.000 claims description 4
- 108010012581 phenylalanylglutamate Proteins 0.000 claims description 4
- 108010087846 prolyl-prolyl-glycine Proteins 0.000 claims description 4
- 108010069117 seryl-lysyl-aspartic acid Proteins 0.000 claims description 4
- DPLFNLDACGGBAK-KKUMJFAQSA-N Arg-Phe-Glu Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)O)NC(=O)[C@H](CCCN=C(N)N)N DPLFNLDACGGBAK-KKUMJFAQSA-N 0.000 claims description 3
- DAPLJWATMAXPPZ-CIUDSAMLSA-N Asn-Asn-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CC(N)=O DAPLJWATMAXPPZ-CIUDSAMLSA-N 0.000 claims description 3
- JLNFZLNDHONLND-GARJFASQSA-N Asn-Leu-Pro Chemical compound CC(C)C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CC(=O)N)N JLNFZLNDHONLND-GARJFASQSA-N 0.000 claims description 3
- LKVKODXGSAFOFY-VEVYYDQMSA-N Asp-Met-Thr Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H]([C@@H](C)O)C(O)=O LKVKODXGSAFOFY-VEVYYDQMSA-N 0.000 claims description 3
- ZEXHDOQQYZKOIB-ACZMJKKPSA-N Cys-Glu-Ser Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(O)=O ZEXHDOQQYZKOIB-ACZMJKKPSA-N 0.000 claims description 3
- JRHPEMVLTRADLJ-AVGNSLFASA-N Gln-Lys-Lys Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCC(=O)N)N JRHPEMVLTRADLJ-AVGNSLFASA-N 0.000 claims description 3
- XZUUUKNKNWVPHQ-JYJNAYRXSA-N Gln-Phe-Leu Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(C)C)C(O)=O XZUUUKNKNWVPHQ-JYJNAYRXSA-N 0.000 claims description 3
- IIMZHVKZBGSEKZ-SZMVWBNQSA-N Gln-Trp-Leu Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CC(C)C)C(O)=O IIMZHVKZBGSEKZ-SZMVWBNQSA-N 0.000 claims description 3
- CUPSDFQZTVVTSK-GUBZILKMSA-N Glu-Lys-Asp Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CCC(O)=O CUPSDFQZTVVTSK-GUBZILKMSA-N 0.000 claims description 3
- MTBIKIMYHUWBRX-QWRGUYRKSA-N Gly-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)CN MTBIKIMYHUWBRX-QWRGUYRKSA-N 0.000 claims description 3
- NURNJECQNNCRBK-FLBSBUHZSA-N Ile-Thr-Thr Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O NURNJECQNNCRBK-FLBSBUHZSA-N 0.000 claims description 3
- LAGPXKYZCCTSGQ-JYJNAYRXSA-N Leu-Glu-Phe Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O LAGPXKYZCCTSGQ-JYJNAYRXSA-N 0.000 claims description 3
- IEWBEPKLKUXQBU-VOAKCMCISA-N Leu-Leu-Thr Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O IEWBEPKLKUXQBU-VOAKCMCISA-N 0.000 claims description 3
- GJJQCBVRWDGLMQ-GUBZILKMSA-N Lys-Glu-Ala Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(O)=O GJJQCBVRWDGLMQ-GUBZILKMSA-N 0.000 claims description 3
- WLYPRKLMRIYGPP-JYJNAYRXSA-N Phe-Lys-Glu Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CC1=CC=CC=C1 WLYPRKLMRIYGPP-JYJNAYRXSA-N 0.000 claims description 3
- VYWNORHENYEQDW-YUMQZZPRSA-N Pro-Gly-Glu Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H]1CCCN1 VYWNORHENYEQDW-YUMQZZPRSA-N 0.000 claims description 3
- VTFXTWDFPTWNJY-RHYQMDGZSA-N Pro-Leu-Thr Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O VTFXTWDFPTWNJY-RHYQMDGZSA-N 0.000 claims description 3
- GZNYIXWOIUFLGO-ZJDVBMNYSA-N Pro-Thr-Thr Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O GZNYIXWOIUFLGO-ZJDVBMNYSA-N 0.000 claims description 3
- ZMLRZBWCXPQADC-TUAOUCFPSA-N Pro-Val-Pro Chemical compound CC(C)[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@@H]2CCCN2 ZMLRZBWCXPQADC-TUAOUCFPSA-N 0.000 claims description 3
- COAHUSQNSVFYBW-FXQIFTODSA-N Ser-Asn-Met Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCSC)C(O)=O COAHUSQNSVFYBW-FXQIFTODSA-N 0.000 claims description 3
- PPNPDKGQRFSCAC-CIUDSAMLSA-N Ser-Lys-Asp Chemical compound NCCCC[C@H](NC(=O)[C@@H](N)CO)C(=O)N[C@@H](CC(O)=O)C(O)=O PPNPDKGQRFSCAC-CIUDSAMLSA-N 0.000 claims description 3
- 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 claims description 3
- JXWGBRRVTRAZQA-ULQDDVLXSA-N Val-Tyr-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)NC(=O)[C@H](C(C)C)N JXWGBRRVTRAZQA-ULQDDVLXSA-N 0.000 claims description 3
- 108010093581 aspartyl-proline Proteins 0.000 claims description 3
- 108010092854 aspartyllysine Proteins 0.000 claims description 3
- 235000000346 sugar Nutrition 0.000 claims description 3
- 108010015385 valyl-prolyl-proline Proteins 0.000 claims description 3
- JPAWCMXVNZPJLO-IHRRRGAJSA-N Arg-Ser-Phe Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O JPAWCMXVNZPJLO-IHRRRGAJSA-N 0.000 claims description 2
- COWITDLVHMZSIW-CIUDSAMLSA-N Asn-Lys-Ser Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(O)=O COWITDLVHMZSIW-CIUDSAMLSA-N 0.000 claims description 2
- HGGIYWURFPGLIU-FXQIFTODSA-N Asn-Met-Cys Chemical compound SC[C@@H](C(O)=O)NC(=O)[C@H](CCSC)NC(=O)[C@@H](N)CC(N)=O HGGIYWURFPGLIU-FXQIFTODSA-N 0.000 claims description 2
- OETQLUYCMBARHJ-CIUDSAMLSA-N Gln-Asn-Arg Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O OETQLUYCMBARHJ-CIUDSAMLSA-N 0.000 claims description 2
- OXEMJGCAJFFREE-FXQIFTODSA-N Glu-Gln-Ala Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(O)=O OXEMJGCAJFFREE-FXQIFTODSA-N 0.000 claims description 2
- PHONAZGUEGIOEM-GLLZPBPUSA-N Glu-Glu-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O PHONAZGUEGIOEM-GLLZPBPUSA-N 0.000 claims description 2
- LWYUQLZOIORFFJ-XKBZYTNZSA-N Glu-Thr-Cys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CCC(=O)O)N)O LWYUQLZOIORFFJ-XKBZYTNZSA-N 0.000 claims description 2
- CWJQMCPYXNVMBS-STECZYCISA-N Ile-Arg-Tyr Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)O)N CWJQMCPYXNVMBS-STECZYCISA-N 0.000 claims description 2
- FADYJNXDPBKVCA-UHFFFAOYSA-N L-Phenylalanyl-L-lysin Natural products NCCCCC(C(O)=O)NC(=O)C(N)CC1=CC=CC=C1 FADYJNXDPBKVCA-UHFFFAOYSA-N 0.000 claims description 2
- YOZCKMXHBYKOMQ-IHRRRGAJSA-N Leu-Arg-Lys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCCCN)C(=O)O)N YOZCKMXHBYKOMQ-IHRRRGAJSA-N 0.000 claims description 2
- UCOCBWDBHCUPQP-DCAQKATOSA-N Leu-Arg-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(O)=O UCOCBWDBHCUPQP-DCAQKATOSA-N 0.000 claims description 2
- JWQWPTLEOFNCGX-AVGNSLFASA-N Phe-Glu-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CC1=CC=CC=C1 JWQWPTLEOFNCGX-AVGNSLFASA-N 0.000 claims description 2
- UOLGINIHBRIECN-FXQIFTODSA-N Ser-Glu-Glu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O UOLGINIHBRIECN-FXQIFTODSA-N 0.000 claims description 2
- AYCQVUUPIJHJTA-IXOXFDKPSA-N Thr-His-Leu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC(C)C)C(O)=O AYCQVUUPIJHJTA-IXOXFDKPSA-N 0.000 claims description 2
- VGNLMPBYWWNQFS-ZEILLAHLSA-N Thr-Thr-His Chemical compound C[C@H]([C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N)O VGNLMPBYWWNQFS-ZEILLAHLSA-N 0.000 claims 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 claims description 2
- 108010055341 glutamyl-glutamic acid Proteins 0.000 claims description 2
- CXRCVCURMBFFOL-FXQIFTODSA-N Ala-Ala-Pro Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O CXRCVCURMBFFOL-FXQIFTODSA-N 0.000 claims 2
- CSAHOYQKNHGDHX-ACZMJKKPSA-N Ala-Gln-Asn Chemical compound C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O CSAHOYQKNHGDHX-ACZMJKKPSA-N 0.000 claims 2
- AJBVYEYZVYPFCF-CIUDSAMLSA-N Ala-Lys-Asn Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(O)=O AJBVYEYZVYPFCF-CIUDSAMLSA-N 0.000 claims 2
- ZCUFMRIQCPNOHZ-NRPADANISA-N Ala-Val-Gln Chemical compound C[C@@H](C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N ZCUFMRIQCPNOHZ-NRPADANISA-N 0.000 claims 2
- YKBHOXLMMPZPHQ-GMOBBJLQSA-N Arg-Ile-Asp Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(O)=O)C(O)=O YKBHOXLMMPZPHQ-GMOBBJLQSA-N 0.000 claims 2
- OHLLDUNVMPPUMD-DCAQKATOSA-N Cys-Leu-Val Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](C(C)C)C(=O)O)NC(=O)[C@H](CS)N OHLLDUNVMPPUMD-DCAQKATOSA-N 0.000 claims 2
- HDXNWVLQSQFJOX-SRVKXCTJSA-N His-Arg-Gln Chemical compound C1=C(NC=N1)C[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N HDXNWVLQSQFJOX-SRVKXCTJSA-N 0.000 claims 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 claims 2
- JYXBNQOKPRQNQS-YTFOTSKYSA-N Lys-Ile-Ile Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O JYXBNQOKPRQNQS-YTFOTSKYSA-N 0.000 claims 2
- ONPDTSFZAIWMDI-AVGNSLFASA-N Lys-Leu-Gln Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O ONPDTSFZAIWMDI-AVGNSLFASA-N 0.000 claims 2
- OPEVYHFJXLCCRT-AVGNSLFASA-N Phe-Gln-Ser Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(O)=O OPEVYHFJXLCCRT-AVGNSLFASA-N 0.000 claims 2
- 108010073969 valyllysine Proteins 0.000 claims 2
- YNSUUAOAFCVINY-OSUNSFLBSA-N Arg-Thr-Ile Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O YNSUUAOAFCVINY-OSUNSFLBSA-N 0.000 claims 1
- INKFLNZBTSNFON-CIUDSAMLSA-N Gln-Ala-Arg Chemical compound NC(=O)CC[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O INKFLNZBTSNFON-CIUDSAMLSA-N 0.000 claims 1
- SOIAHPSKKUYREP-CIUDSAMLSA-N Gln-Asp-Met Chemical compound CSCC[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CCC(=O)N)N SOIAHPSKKUYREP-CIUDSAMLSA-N 0.000 claims 1
- JRCUFCXYZLPSDZ-ACZMJKKPSA-N Glu-Asp-Ser Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O JRCUFCXYZLPSDZ-ACZMJKKPSA-N 0.000 claims 1
- VFZIDQZAEBORGY-GLLZPBPUSA-N Glu-Gln-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O VFZIDQZAEBORGY-GLLZPBPUSA-N 0.000 claims 1
- UUTGYDAKPISJAO-JYJNAYRXSA-N Glu-Tyr-Leu Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(O)=O)CC1=CC=C(O)C=C1 UUTGYDAKPISJAO-JYJNAYRXSA-N 0.000 claims 1
- QRWPTXLWHHTOCO-DZKIICNBSA-N Glu-Val-Tyr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O QRWPTXLWHHTOCO-DZKIICNBSA-N 0.000 claims 1
- HAXARWKYFIIHKD-ZKWXMUAHSA-N Gly-Ile-Ser Chemical compound NCC(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(O)=O HAXARWKYFIIHKD-ZKWXMUAHSA-N 0.000 claims 1
- 101001139126 Homo sapiens Krueppel-like factor 6 Proteins 0.000 claims 1
- OUUCIIJSBIBCHB-ZPFDUUQYSA-N Ile-Leu-Asp Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O OUUCIIJSBIBCHB-ZPFDUUQYSA-N 0.000 claims 1
- YKZAMJXNJUWFIK-JBDRJPRFSA-N Ile-Ser-Ala Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(=O)O)N YKZAMJXNJUWFIK-JBDRJPRFSA-N 0.000 claims 1
- DLCXCECTCPKKCD-GUBZILKMSA-N Leu-Gln-Asn Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O DLCXCECTCPKKCD-GUBZILKMSA-N 0.000 claims 1
- LLBQJYDYOLIQAI-JYJNAYRXSA-N Leu-Glu-Tyr Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O LLBQJYDYOLIQAI-JYJNAYRXSA-N 0.000 claims 1
- KUIDCYNIEJBZBU-AJNGGQMLSA-N Leu-Ile-Leu Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(O)=O KUIDCYNIEJBZBU-AJNGGQMLSA-N 0.000 claims 1
- GKFNXYMAMKJSKD-NHCYSSNCSA-N Lys-Asp-Val Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O GKFNXYMAMKJSKD-NHCYSSNCSA-N 0.000 claims 1
- YVMQJGWLHRWMDF-MNXVOIDGSA-N Lys-Gln-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CCCCN)N YVMQJGWLHRWMDF-MNXVOIDGSA-N 0.000 claims 1
- WGLAORUKDGRINI-WDCWCFNPSA-N Lys-Glu-Thr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O WGLAORUKDGRINI-WDCWCFNPSA-N 0.000 claims 1
- 108010002311 N-glycylglutamic acid Proteins 0.000 claims 1
- GVMUJUPXFQFBBZ-GUBZILKMSA-N Ser-Lys-Glu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(O)=O GVMUJUPXFQFBBZ-GUBZILKMSA-N 0.000 claims 1
- QQWNRERCGGZOKG-WEDXCCLWSA-N Thr-Gly-Leu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CC(C)C)C(O)=O QQWNRERCGGZOKG-WEDXCCLWSA-N 0.000 claims 1
- 108010047857 aspartylglycine Proteins 0.000 claims 1
- 108010025306 histidylleucine Proteins 0.000 claims 1
- 239000002504 physiological saline solution Substances 0.000 abstract description 3
- 108010017080 Granulocyte Colony-Stimulating Factor Proteins 0.000 abstract description 2
- 102100039619 Granulocyte colony-stimulating factor Human genes 0.000 abstract description 2
- 108010002352 Interleukin-1 Proteins 0.000 abstract description 2
- 229920001491 Lentinan Polymers 0.000 abstract description 2
- 229940115286 lentinan Drugs 0.000 abstract description 2
- 229920001184 polypeptide Polymers 0.000 abstract description 2
- 108090000765 processed proteins & peptides Proteins 0.000 abstract description 2
- 102000004196 processed proteins & peptides Human genes 0.000 abstract description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 abstract 2
- 239000002671 adjuvant Substances 0.000 abstract 1
- 125000003275 alpha amino acid group Chemical group 0.000 abstract 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 abstract 1
- 239000000872 buffer Substances 0.000 abstract 1
- UQHKFADEQIVWID-UHFFFAOYSA-N cytokinin Natural products C1=NC=2C(NCC=C(CO)C)=NC=NC=2N1C1CC(O)C(CO)O1 UQHKFADEQIVWID-UHFFFAOYSA-N 0.000 abstract 1
- 239000004062 cytokinin Substances 0.000 abstract 1
- 230000000694 effects Effects 0.000 description 15
- 238000000034 method Methods 0.000 description 10
- 235000018102 proteins Nutrition 0.000 description 7
- 235000001014 amino acid Nutrition 0.000 description 6
- 241000588724 Escherichia coli Species 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 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 3
- XZFYRXDAULDNFX-UHFFFAOYSA-N N-L-cysteinyl-L-phenylalanine Natural products SCC(N)C(=O)NC(C(O)=O)CC1=CC=CC=C1 XZFYRXDAULDNFX-UHFFFAOYSA-N 0.000 description 3
- XMBSYZWANAQXEV-UHFFFAOYSA-N N-alpha-L-glutamyl-L-phenylalanine Natural products OC(=O)CCC(N)C(=O)NC(C(O)=O)CC1=CC=CC=C1 XMBSYZWANAQXEV-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 239000002158 endotoxin Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 108010073101 phenylalanylleucine Proteins 0.000 description 3
- 108010090894 prolylleucine Proteins 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- VZZUJVDCIBINIT-YDALLXLXSA-N (2s)-2-acetamido-3-(1h-indol-3-yl)propanoic acid;sodium Chemical compound [Na].C1=CC=C2C(C[C@H](NC(=O)C)C(O)=O)=CNC2=C1 VZZUJVDCIBINIT-YDALLXLXSA-N 0.000 description 2
- XAXHGSOBFPIRFG-LSJOCFKGSA-N Ala-Pro-His Chemical compound C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1cnc[nH]1)C(O)=O XAXHGSOBFPIRFG-LSJOCFKGSA-N 0.000 description 2
- HOVPGJUNRLMIOZ-CIUDSAMLSA-N Ala-Ser-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](C)N HOVPGJUNRLMIOZ-CIUDSAMLSA-N 0.000 description 2
- ZEAYJGRKRUBDOB-GARJFASQSA-N Arg-Gln-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CCCN=C(N)N)N)C(=O)O ZEAYJGRKRUBDOB-GARJFASQSA-N 0.000 description 2
- 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 2
- HUZGPXBILPMCHM-IHRRRGAJSA-N Asn-Arg-Phe Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O HUZGPXBILPMCHM-IHRRRGAJSA-N 0.000 description 2
- OAMLVOVXNKILLQ-BQBZGAKWSA-N Asp-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H](N)CC(O)=O OAMLVOVXNKILLQ-BQBZGAKWSA-N 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- JDUKCSSHWNIQQZ-IHRRRGAJSA-N Glu-Phe-Glu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCC(O)=O)C(O)=O JDUKCSSHWNIQQZ-IHRRRGAJSA-N 0.000 description 2
- SABZDFAAOJATBR-QWRGUYRKSA-N Gly-Cys-Phe Chemical compound [H]NCC(=O)N[C@@H](CS)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O SABZDFAAOJATBR-QWRGUYRKSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 102000008100 Human Serum Albumin Human genes 0.000 description 2
- 108091006905 Human Serum Albumin Proteins 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 108010002386 Interleukin-3 Proteins 0.000 description 2
- SENJXOPIZNYLHU-UHFFFAOYSA-N L-leucyl-L-arginine Natural products CC(C)CC(N)C(=O)NC(C(O)=O)CCCN=C(N)N SENJXOPIZNYLHU-UHFFFAOYSA-N 0.000 description 2
- JYOAXOMPIXKMKK-YUMQZZPRSA-N Leu-Gln Chemical compound CC(C)C[C@H]([NH3+])C(=O)N[C@H](C([O-])=O)CCC(N)=O JYOAXOMPIXKMKK-YUMQZZPRSA-N 0.000 description 2
- DAYQSYGBCUKVKT-VOAKCMCISA-N Leu-Thr-Lys Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(O)=O DAYQSYGBCUKVKT-VOAKCMCISA-N 0.000 description 2
- ILDSIMPXNFWKLH-KATARQTJSA-N Leu-Thr-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(O)=O ILDSIMPXNFWKLH-KATARQTJSA-N 0.000 description 2
- AAORVPFVUIHEAB-YUMQZZPRSA-N Lys-Asp-Gly Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(O)=O AAORVPFVUIHEAB-YUMQZZPRSA-N 0.000 description 2
- XOQMURBBIXRRCR-SRVKXCTJSA-N Lys-Lys-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CCCCN XOQMURBBIXRRCR-SRVKXCTJSA-N 0.000 description 2
- DRRXXZBXDMLGFC-IHRRRGAJSA-N Lys-Val-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CCCCN DRRXXZBXDMLGFC-IHRRRGAJSA-N 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- ONGCSGVHCSAATF-CIUDSAMLSA-N Met-Ala-Glu Chemical compound CSCC[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CCC(O)=O ONGCSGVHCSAATF-CIUDSAMLSA-N 0.000 description 2
- 108010033276 Peptide Fragments Proteins 0.000 description 2
- 102000007079 Peptide Fragments Human genes 0.000 description 2
- LCUOTSLIVGSGAU-AVGNSLFASA-N Pro-His-Arg Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O LCUOTSLIVGSGAU-AVGNSLFASA-N 0.000 description 2
- HRNQLKCLPVKZNE-CIUDSAMLSA-N Ser-Ala-Leu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(O)=O HRNQLKCLPVKZNE-CIUDSAMLSA-N 0.000 description 2
- PVDTYLHUWAEYGY-CIUDSAMLSA-N Ser-Glu-Arg Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O PVDTYLHUWAEYGY-CIUDSAMLSA-N 0.000 description 2
- JFWDJFULOLKQFY-QWRGUYRKSA-N Ser-Gly-Phe Chemical compound [H]N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O JFWDJFULOLKQFY-QWRGUYRKSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- CUTPSEKWUPZFLV-WISUUJSJSA-N Thr-Cys Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](CS)C(O)=O CUTPSEKWUPZFLV-WISUUJSJSA-N 0.000 description 2
- AAZOYLQUEQRUMZ-GSSVUCPTSA-N Thr-Thr-Asn Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@H](C(O)=O)CC(N)=O AAZOYLQUEQRUMZ-GSSVUCPTSA-N 0.000 description 2
- LYMVXFSTACVOLP-ZFWWWQNUSA-N Trp-Leu Chemical compound C1=CC=C2C(C[C@H]([NH3+])C(=O)N[C@@H](CC(C)C)C([O-])=O)=CNC2=C1 LYMVXFSTACVOLP-ZFWWWQNUSA-N 0.000 description 2
- QRVPEKJBBRYISE-XUXIUFHCSA-N Val-Lys-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C(C)C)N QRVPEKJBBRYISE-XUXIUFHCSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000012752 auxiliary agent Substances 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- -1 glycol monostearate compound Chemical class 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 229940100601 interleukin-6 Drugs 0.000 description 2
- 108010000761 leucylarginine Proteins 0.000 description 2
- 108010057821 leucylproline Proteins 0.000 description 2
- 108010054155 lysyllysine Proteins 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 239000002953 phosphate buffered saline Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 108010005652 splenotritin Proteins 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- 108010080629 tryptophan-leucine 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
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-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
- LJGHYPLBDBRCRZ-UHFFFAOYSA-N 3-(3-aminophenyl)sulfonylaniline Chemical compound NC1=CC=CC(S(=O)(=O)C=2C=C(N)C=CC=2)=C1 LJGHYPLBDBRCRZ-UHFFFAOYSA-N 0.000 description 1
- IMMKUCQIKKXKNP-DCAQKATOSA-N Ala-Arg-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@H](C)N)CCCN=C(N)N IMMKUCQIKKXKNP-DCAQKATOSA-N 0.000 description 1
- NXSFUECZFORGOG-CIUDSAMLSA-N Ala-Asn-Leu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(O)=O NXSFUECZFORGOG-CIUDSAMLSA-N 0.000 description 1
- HMRWQTHUDVXMGH-GUBZILKMSA-N Ala-Glu-Lys Chemical compound C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@H](C(O)=O)CCCCN HMRWQTHUDVXMGH-GUBZILKMSA-N 0.000 description 1
- SDZRIBWEVVRDQI-CIUDSAMLSA-N Ala-Lys-Asp Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(O)=O SDZRIBWEVVRDQI-CIUDSAMLSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- IJPNNYWHXGADJG-GUBZILKMSA-N Arg-Ala-Val Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(O)=O IJPNNYWHXGADJG-GUBZILKMSA-N 0.000 description 1
- LVMUGODRNHFGRA-AVGNSLFASA-N Arg-Leu-Arg Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O LVMUGODRNHFGRA-AVGNSLFASA-N 0.000 description 1
- XTWSWDJMIKUJDQ-RYUDHWBXSA-N Arg-Tyr Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 XTWSWDJMIKUJDQ-RYUDHWBXSA-N 0.000 description 1
- UVTGNSWSRSCPLP-UHFFFAOYSA-N Arg-Tyr Natural products NC(CCNC(=N)N)C(=O)NC(Cc1ccc(O)cc1)C(=O)O UVTGNSWSRSCPLP-UHFFFAOYSA-N 0.000 description 1
- CGWVCWFQGXOUSJ-ULQDDVLXSA-N Arg-Tyr-Leu Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(C)C)C(O)=O CGWVCWFQGXOUSJ-ULQDDVLXSA-N 0.000 description 1
- GFFRWIJAFFMQGM-NUMRIWBASA-N Asn-Glu-Thr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O GFFRWIJAFFMQGM-NUMRIWBASA-N 0.000 description 1
- PLVAAIPKSGUXDV-WHFBIAKZSA-N Asn-Gly-Cys Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CS)C(=O)O)N)C(=O)N PLVAAIPKSGUXDV-WHFBIAKZSA-N 0.000 description 1
- YVXRYLVELQYAEQ-SRVKXCTJSA-N Asn-Leu-Lys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC(=O)N)N YVXRYLVELQYAEQ-SRVKXCTJSA-N 0.000 description 1
- QDXQWFBLUVTOFL-FXQIFTODSA-N Asn-Met-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CC(=O)N)N QDXQWFBLUVTOFL-FXQIFTODSA-N 0.000 description 1
- XBQSLMACWDXWLJ-GHCJXIJMSA-N Asp-Ala-Ile Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O XBQSLMACWDXWLJ-GHCJXIJMSA-N 0.000 description 1
- PSLSTUMPZILTAH-BYULHYEWSA-N Asp-Gly-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CC(O)=O PSLSTUMPZILTAH-BYULHYEWSA-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
- RVMXMLSYBTXCAV-VEVYYDQMSA-N Asp-Pro-Thr Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)O)C(O)=O RVMXMLSYBTXCAV-VEVYYDQMSA-N 0.000 description 1
- DWBZEJHQQIURML-IMJSIDKUSA-N Asp-Ser Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CO)C(O)=O DWBZEJHQQIURML-IMJSIDKUSA-N 0.000 description 1
- 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
- XWKBWZXGNXTDKY-ZKWXMUAHSA-N Asp-Val-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CC(O)=O XWKBWZXGNXTDKY-ZKWXMUAHSA-N 0.000 description 1
- 101000798402 Bacillus licheniformis Ornithine racemase Proteins 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 241000699800 Cricetinae Species 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 108020004414 DNA Proteins 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- XQDGOJPVMSWZSO-SRVKXCTJSA-N Gln-Pro-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCC(=O)N)N XQDGOJPVMSWZSO-SRVKXCTJSA-N 0.000 description 1
- XIYWAJQIWLXXAF-XKBZYTNZSA-N Gln-Thr-Cys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CCC(=O)N)N)O XIYWAJQIWLXXAF-XKBZYTNZSA-N 0.000 description 1
- 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 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
- YYOBUPFZLKQUAX-FXQIFTODSA-N Glu-Asn-Glu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O YYOBUPFZLKQUAX-FXQIFTODSA-N 0.000 description 1
- KLJMRPIBBLTDGE-ACZMJKKPSA-N Glu-Cys-Asn Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(O)=O KLJMRPIBBLTDGE-ACZMJKKPSA-N 0.000 description 1
- QJCKNLPMTPXXEM-AUTRQRHGSA-N Glu-Glu-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CCC(O)=O QJCKNLPMTPXXEM-AUTRQRHGSA-N 0.000 description 1
- VSRCAOIHMGCIJK-SRVKXCTJSA-N Glu-Leu-Arg Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O VSRCAOIHMGCIJK-SRVKXCTJSA-N 0.000 description 1
- VMKCPNBBPGGQBJ-GUBZILKMSA-N Glu-Leu-Asn Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CCC(=O)O)N VMKCPNBBPGGQBJ-GUBZILKMSA-N 0.000 description 1
- UHPAZODVFFYEEL-QWRGUYRKSA-N Gly-Leu-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)CN UHPAZODVFFYEEL-QWRGUYRKSA-N 0.000 description 1
- BXOLYFJYQQRQDJ-MXAVVETBSA-N His-Leu-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC1=CN=CN1)N BXOLYFJYQQRQDJ-MXAVVETBSA-N 0.000 description 1
- QSPLUJGYOPZINY-ZPFDUUQYSA-N Ile-Asp-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CCCCN)C(=O)O)N QSPLUJGYOPZINY-ZPFDUUQYSA-N 0.000 description 1
- BALLIXFZYSECCF-QEWYBTABSA-N Ile-Gln-Phe Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)N BALLIXFZYSECCF-QEWYBTABSA-N 0.000 description 1
- PNDMHTTXXPUQJH-RWRJDSDZSA-N Ile-Glu-Thr Chemical compound N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H]([C@H](O)C)C(=O)O PNDMHTTXXPUQJH-RWRJDSDZSA-N 0.000 description 1
- PKGGWLOLRLOPGK-XUXIUFHCSA-N Ile-Leu-Arg Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CCCN=C(N)N PKGGWLOLRLOPGK-XUXIUFHCSA-N 0.000 description 1
- 108090000978 Interleukin-4 Proteins 0.000 description 1
- 102100026019 Interleukin-6 Human genes 0.000 description 1
- 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 1
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- JKGHDYGZRDWHGA-SRVKXCTJSA-N Leu-Asn-Leu Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(O)=O JKGHDYGZRDWHGA-SRVKXCTJSA-N 0.000 description 1
- HQUXQAMSWFIRET-AVGNSLFASA-N Leu-Glu-Lys Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@H](C(O)=O)CCCCN HQUXQAMSWFIRET-AVGNSLFASA-N 0.000 description 1
- RXGLHDWAZQECBI-SRVKXCTJSA-N Leu-Leu-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O RXGLHDWAZQECBI-SRVKXCTJSA-N 0.000 description 1
- YRRCOJOXAJNSAX-IHRRRGAJSA-N Leu-Pro-Lys Chemical compound CC(C)C[C@@H](C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(=O)O)N YRRCOJOXAJNSAX-IHRRRGAJSA-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
- FACUGMGEFUEBTI-SRVKXCTJSA-N Lys-Asn-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CCCCN FACUGMGEFUEBTI-SRVKXCTJSA-N 0.000 description 1
- OVIVOCSURJYCTM-GUBZILKMSA-N Lys-Asp-Glu Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CCC(O)=O OVIVOCSURJYCTM-GUBZILKMSA-N 0.000 description 1
- ZAENPHCEQXALHO-GUBZILKMSA-N Lys-Cys-Glu Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(O)=O)C(O)=O ZAENPHCEQXALHO-GUBZILKMSA-N 0.000 description 1
- GGNOBVSOZPHLCE-GUBZILKMSA-N Lys-Gln-Asp Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O GGNOBVSOZPHLCE-GUBZILKMSA-N 0.000 description 1
- NVGBPTNZLWRQSY-UWVGGRQHSA-N Lys-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@H](C(O)=O)CCCCN NVGBPTNZLWRQSY-UWVGGRQHSA-N 0.000 description 1
- GHKXHCMRAUYLBS-CIUDSAMLSA-N Lys-Ser-Asn Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O GHKXHCMRAUYLBS-CIUDSAMLSA-N 0.000 description 1
- PLOUVAYOMTYJRG-JXUBOQSCSA-N Lys-Thr-Ala Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O PLOUVAYOMTYJRG-JXUBOQSCSA-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
- VWPJQIHBBOJWDN-DCAQKATOSA-N Lys-Val-Ala Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C)C(O)=O VWPJQIHBBOJWDN-DCAQKATOSA-N 0.000 description 1
- CNUPMMXDISGXMU-CIUDSAMLSA-N Met-Cys-Glu Chemical compound [H]N[C@@H](CCSC)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(O)=O)C(O)=O CNUPMMXDISGXMU-CIUDSAMLSA-N 0.000 description 1
- PBOUVYGPDSARIS-IUCAKERBSA-N Met-Leu Chemical compound CSCC[C@H](N)C(=O)N[C@H](C(O)=O)CC(C)C PBOUVYGPDSARIS-IUCAKERBSA-N 0.000 description 1
- NLDXSXDCNZIQCN-ULQDDVLXSA-N Met-Phe-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CCSC)CC1=CC=CC=C1 NLDXSXDCNZIQCN-ULQDDVLXSA-N 0.000 description 1
- WEDDFMCSUNNZJR-WDSKDSINSA-N Met-Ser Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CO)C(O)=O WEDDFMCSUNNZJR-WDSKDSINSA-N 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- AUEJLPRZGVVDNU-UHFFFAOYSA-N N-L-tyrosyl-L-leucine Natural products CC(C)CC(C(O)=O)NC(=O)C(N)CC1=CC=C(O)C=C1 AUEJLPRZGVVDNU-UHFFFAOYSA-N 0.000 description 1
- KZNQNBZMBZJQJO-UHFFFAOYSA-N N-glycyl-L-proline Natural products NCC(=O)N1CCCC1C(O)=O KZNQNBZMBZJQJO-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- KIAWKQJTSGRCSA-AVGNSLFASA-N Phe-Asn-Glu Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N KIAWKQJTSGRCSA-AVGNSLFASA-N 0.000 description 1
- LXUJDHOKVUYHRC-KKUMJFAQSA-N Phe-Cys-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CS)NC(=O)[C@H](CC1=CC=CC=C1)N LXUJDHOKVUYHRC-KKUMJFAQSA-N 0.000 description 1
- LWPMGKSZPKFKJD-DZKIICNBSA-N Phe-Glu-Val Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O LWPMGKSZPKFKJD-DZKIICNBSA-N 0.000 description 1
- RFCVXVPWSPOMFJ-STQMWFEESA-N Phe-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H](N)CC1=CC=CC=C1 RFCVXVPWSPOMFJ-STQMWFEESA-N 0.000 description 1
- RSPUIENXSJYZQO-JYJNAYRXSA-N Phe-Leu-Gln Chemical compound NC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC1=CC=CC=C1 RSPUIENXSJYZQO-JYJNAYRXSA-N 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 229920001214 Polysorbate 60 Polymers 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- YFNOUBWUIIJQHF-LPEHRKFASA-N Pro-Asp-Pro Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CC(=O)O)C(=O)N2CCC[C@@H]2C(=O)O YFNOUBWUIIJQHF-LPEHRKFASA-N 0.000 description 1
- ZKQOUHVVXABNDG-IUCAKERBSA-N Pro-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1 ZKQOUHVVXABNDG-IUCAKERBSA-N 0.000 description 1
- PUQRDHNIOONJJN-AVGNSLFASA-N Pro-Lys-Met Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCSC)C(O)=O PUQRDHNIOONJJN-AVGNSLFASA-N 0.000 description 1
- FDMCIBSQRKFSTJ-RHYQMDGZSA-N Pro-Thr-Leu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O FDMCIBSQRKFSTJ-RHYQMDGZSA-N 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 108020004511 Recombinant DNA Proteins 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- SSJMZMUVNKEENT-IMJSIDKUSA-N Ser-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@@H](N)CO SSJMZMUVNKEENT-IMJSIDKUSA-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
- FIDMVVBUOCMMJG-CIUDSAMLSA-N Ser-Asn-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CO FIDMVVBUOCMMJG-CIUDSAMLSA-N 0.000 description 1
- BQWCDDAISCPDQV-XHNCKOQMSA-N Ser-Gln-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CO)N)C(=O)O BQWCDDAISCPDQV-XHNCKOQMSA-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
- LRWBCWGEUCKDTN-BJDJZHNGSA-N Ser-Lys-Ile Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O LRWBCWGEUCKDTN-BJDJZHNGSA-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
- XVWDJUROVRQKAE-KKUMJFAQSA-N Ser-Phe-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CO)CC1=CC=CC=C1 XVWDJUROVRQKAE-KKUMJFAQSA-N 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- LGNBRHZANHMZHK-NUMRIWBASA-N Thr-Glu-Asp Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CC(=O)O)C(=O)O)N)O LGNBRHZANHMZHK-NUMRIWBASA-N 0.000 description 1
- SPVHQURZJCUDQC-VOAKCMCISA-N Thr-Lys-Leu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(O)=O SPVHQURZJCUDQC-VOAKCMCISA-N 0.000 description 1
- MGJLBZFUXUGMML-VOAKCMCISA-N Thr-Lys-Lys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)O)N)O MGJLBZFUXUGMML-VOAKCMCISA-N 0.000 description 1
- WFAUDCSNCWJJAA-KXNHARMFSA-N Thr-Lys-Pro Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N1CCC[C@@H]1C(O)=O WFAUDCSNCWJJAA-KXNHARMFSA-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
- HUPLKEHTTQBXSC-YJRXYDGGSA-N Thr-Ser-Tyr Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 HUPLKEHTTQBXSC-YJRXYDGGSA-N 0.000 description 1
- DSGIVWSDDRDJIO-ZXXMMSQZSA-N Thr-Thr Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(O)=O DSGIVWSDDRDJIO-ZXXMMSQZSA-N 0.000 description 1
- BBPCSGKKPJUYRB-UVOCVTCTSA-N Thr-Thr-Leu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O BBPCSGKKPJUYRB-UVOCVTCTSA-N 0.000 description 1
- ZESGVALRVJIVLZ-VFCFLDTKSA-N Thr-Thr-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)N1CCC[C@@H]1C(=O)O)N)O ZESGVALRVJIVLZ-VFCFLDTKSA-N 0.000 description 1
- BKVICMPZWRNWOC-RHYQMDGZSA-N Thr-Val-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)[C@@H](C)O BKVICMPZWRNWOC-RHYQMDGZSA-N 0.000 description 1
- YVXIAOOYAKBAAI-SZMVWBNQSA-N Trp-Leu-Gln Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O)=CNC2=C1 YVXIAOOYAKBAAI-SZMVWBNQSA-N 0.000 description 1
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 1
- AUEJLPRZGVVDNU-STQMWFEESA-N Tyr-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 AUEJLPRZGVVDNU-STQMWFEESA-N 0.000 description 1
- KSCVLGXNQXKUAR-JYJNAYRXSA-N Tyr-Leu-Glu 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](CCC(O)=O)C(O)=O KSCVLGXNQXKUAR-JYJNAYRXSA-N 0.000 description 1
- DWAMXBFJNZIHMC-KBPBESRZSA-N Tyr-Leu-Gly Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O DWAMXBFJNZIHMC-KBPBESRZSA-N 0.000 description 1
- NSGZILIDHCIZAM-KKUMJFAQSA-N Tyr-Leu-Ser Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)N NSGZILIDHCIZAM-KKUMJFAQSA-N 0.000 description 1
- IJBTVYLICXHDRI-FXQIFTODSA-N Val-Ala-Ala Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(O)=O IJBTVYLICXHDRI-FXQIFTODSA-N 0.000 description 1
- IJBTVYLICXHDRI-UHFFFAOYSA-N Val-Ala-Ala Natural products CC(C)C(N)C(=O)NC(C)C(=O)NC(C)C(O)=O IJBTVYLICXHDRI-UHFFFAOYSA-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
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 238000007792 addition Methods 0.000 description 1
- 108010047495 alanylglycine Proteins 0.000 description 1
- 108010070944 alanylhistidine Proteins 0.000 description 1
- 108010087924 alanylproline Proteins 0.000 description 1
- 229940087168 alpha tocopherol Drugs 0.000 description 1
- 239000003945 anionic surfactant Substances 0.000 description 1
- 210000000628 antibody-producing cell Anatomy 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 108010008355 arginyl-glutamine Proteins 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 238000010322 bone marrow transplantation Methods 0.000 description 1
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229960002449 glycine Drugs 0.000 description 1
- 235000013905 glycine and its sodium salt Nutrition 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 108010092114 histidylphenylalanine Proteins 0.000 description 1
- 229920002674 hyaluronan Polymers 0.000 description 1
- 229960003160 hyaluronic acid Drugs 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 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
- 238000001155 isoelectric focusing Methods 0.000 description 1
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 description 1
- 239000008101 lactose Substances 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
- 108010034529 leucyl-lysine Proteins 0.000 description 1
- 210000003519 mature b lymphocyte Anatomy 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 229940024999 proteolytic enzymes for treatment of wounds and ulcers Drugs 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229960005480 sodium caprylate Drugs 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- BYKRNSHANADUFY-UHFFFAOYSA-M sodium octanoate Chemical compound [Na+].CCCCCCCC([O-])=O BYKRNSHANADUFY-UHFFFAOYSA-M 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- GNBVPFITFYNRCN-UHFFFAOYSA-M sodium thioglycolate Chemical compound [Na+].[O-]C(=O)CS GNBVPFITFYNRCN-UHFFFAOYSA-M 0.000 description 1
- 229940046307 sodium thioglycolate Drugs 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
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 description 1
- 235000019187 sodium-L-ascorbate Nutrition 0.000 description 1
- 239000011755 sodium-L-ascorbate Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 238000003860 storage Methods 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
- 150000008163 sugars Chemical class 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 108010061238 threonyl-glycine Proteins 0.000 description 1
- 108010071097 threonyl-lysyl-proline Proteins 0.000 description 1
- 108010072986 threonyl-seryl-lysine Proteins 0.000 description 1
- 206010043554 thrombocytopenia Diseases 0.000 description 1
- 229960000984 tocofersolan Drugs 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 108010078580 tyrosylleucine Proteins 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 238000009777 vacuum freeze-drying Methods 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Description
【発明の詳細な説明】
〔産業上の利用分野〕
本発明は医薬組成物に関する．より詳細に記すと、本発
明はヒトＢＣＤＦの治療学的に有効な量を含んで成る医
薬組成物に関する．
〔従来の技術〕
ヒト及びマウスにおいて或熟Ｂ細胞を抗体産生細胞へ分
化させる因子をＢ細胞分化因子（ＢＣＤＦ）と総称する
．
ヒトの体内においてこのような重要な作用を有するヒト
ＢＣＤＦについて、本発明者等は研究を重ね、そのＤＮ
Ａ配列、及びアξノ酸配列を決定（特開昭６３−４２６
８８ ． ６３−５６２９１ ） Ｌ、大腸菌によるヒ
トＢＣＤＦの生産に戒功している（特開昭６３−１５７
９９６ ）。DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to pharmaceutical compositions. More particularly, the present invention relates to pharmaceutical compositions comprising a therapeutically effective amount of human BCDF. [Prior Art] Factors that differentiate mature B cells into antibody-producing cells in humans and mice are collectively called B cell differentiation factors (BCDF). The present inventors have conducted repeated research on human BCDF, which has such important effects in the human body, and have determined its DNA.
A sequence and amino acid sequence determined (Japanese Patent Application Laid-Open No. 63-426
88. 63-56291) L. is devoted to the production of human BCDF by Escherichia coli (Japanese Patent Application Laid-open No. 63-157
996).
またヒト ＢＣＤＦが感染症及び癌の治療に有効な免疫
療．法則となる事（特開平１−６３５２４ ） 、骨髄
移植療法の有効な支持剤となる事（特願昭６３−３１０
５７８ ）、ワクチン効果増強剤となる事（特願昭６３
−１８３０８３）、及び血小板減少症治療剤となる事（
特願平１−６９５４）も見い出している．
これらの明細書中で製剤法についても一部言及している
。In addition, human BCDF is an effective immunotherapy for the treatment of infectious diseases and cancer. to become an effective support agent for bone marrow transplantation therapy (Japanese Patent Application No. 63-310)
578), to become a vaccine effect enhancer (patent application 1986)
-183083) and as a therapeutic agent for thrombocytopenia (
Patent application No. 1-6954) was also found. Some of the formulation methods are also mentioned in these specifications.
しかしながら、臨床的用途のためにより十分に純粋であ
り、かつより長期間にわたり安定なＢＣＤＦを含有する
製剤は未だ知られていない。However, a formulation containing BCDF that is sufficiently pure and stable for a longer period of time for clinical use is not yet known.
なおヒトＢＣＤＦをＢＳＦ−２あるいはインターロイキ
ン６ （ＩＬ−６）と呼ぶことも提唱されているが、（
Ｎａｔｕｒｅ ， ３２４ ． ７３（１９８６）
， ＥＭＢＯ．Ｊ．， ６． １２１９（１９８７））
ここでは従来よりのＢＣＤＰなる名称を用いる。また
ここで用いるヒト−ＢＣＤＰはインターフェロ０２２０
５７．４ ）とは異なる．
〔発明が解決しようとする課題〕
そこで本発明の目的は従来のものより有益な、動物又は
ヒトへの投与のために適切なヒトＢＣＤＦを安定化させ
た医薬，ｍｒｆ？．物の提供である。It has also been proposed that human BCDF be called BSF-2 or interleukin 6 (IL-6);
Nature, 324. 73 (1986)
, EMBO. J. , 6. 1219 (1987))
Here, the conventional name BCDP is used. In addition, the human BCDP used here is interfero0220
57.4). [Problems to be Solved by the Invention] Therefore, an object of the present invention is to provide a pharmaceutical stabilized with human BCDF, mrf?, suitable for administration to animals or humans, which is more useful than the conventional ones. ．． It is the provision of goods.
本発明者等は上記Ｌｉ題を解決するために鋭意研究を重
ねた結果、ヒト血清アルブミン及び安定剤を含有したリ
ン酸緩衝生理食塩水に溶解させたＢＣＤＰが十分に純粋
であり、長期間安定である事を見出し、本発明を完威し
た。すなわち、本発明はヒトＢＣＤＦの医薬組成物であ
る。As a result of extensive research to solve the above problem, the present inventors found that BCDP dissolved in phosphate buffered saline containing human serum albumin and stabilizers is sufficiently pure and stable for a long period of time. They found that this is the case, and perfected the present invention. That is, the present invention is a pharmaceutical composition of human BCDF.
本発明に係るヒト ＢＣＤＦは例えば特開昭６３−４２
６８８．６３−５６２９１及び特願昭６２−２８９００
７号公報に示されるような、下記のアミノ酸配列（１）
又は（ＩＩ）を有する．
アミノ酸配列（■）：
Ｐｒｏ Ｖａｌ Ｐｒｏ Ｐｒｏ Ｇｌｙ Ｇｌｕ Ａ
ａｐ Ｓｅｒ Ｌｙｓ Ａｓｐ ＶａｌＡｌａ Ａｌ
ａ Ｐｒｏ 旧ｓ Ａｒｇ Ｇｌｎ Ｐｒｏ
Ｌｅｕ Ｔｈｒ Ｓｅｒ ＳｅｒＧｌｕ Ａ
ｒｇ Ｉｌｅ Ａｓｐ Ｌｙｓ Ｇｌｎ Ｉｌｅ Ａｒ
ｇ Ｔｈｒ ｌｉｅ ＬｅｕＡｓｐ Ｇｌｙ ｌｉｅ
Ｓｅｒ Ａｌａ Ｌｅｕ Ａｒｇ Ｌｙｓ Ｇｌｕ Ｔ
ｈｒ ＣｙｓＡｓｎ Ｌｙｓ Ｓｅｒ Ａｓｎ Ｍｅｔ
Ｃｙｓ Ｇｌｕ Ｓｅｒ Ｓｅｒ Ｌｙｓ Ｇｌｕ＾
１ａ Ｌｅｕ Ａｌａ Ｇｌｕ Ａｓｎ Ａｓｎ Ｌｅ
ｕ Ａｓｎ Ｌｅｕ Ｐｒｏ ＬｙｓＭｅｔ Ａｌａ
Ｇｌｕ Ｌｙｓ Ａｓｐ Ｇｌｙ Ｃｙｓ Ｐｈｅ Ｇ
ｉｎ Ｓｅｒ ＧｌｙＰｈｅ Ａｓｎ Ｇｌｕ
Ｔｈｒ Ｇｌｙ Ｌｅｕ
丁ｙｒ Ｌｅｕ Ｇｌｎ
Ｇｉｎ Ａｌａ Ａｒｇ
Ｌｅｕ ｌｉｅ Ｇｉｎ
Ｌｅｕ Ａｓｐ Ａｌａ
Ａｓｎ Ａｌａ Ｓｅｒ
＾ｓｎ Ｇｉｎ Ｔｒｐ
Ｉ１ｅ Ｌｅｕ Ａｒｇ
Ｓｅｒ Ｌｅｕ Ａｒｇ
又ぱ
アミノ酸配列
Ａｌａ Ｐｒｏ Ｖａｌ
Ｖａｌ Ａ１ａ．ＡＩａ
Ｓｅｒ Ｇｌｕ Ａｒｇ
Ｌｅｕ Ａｓｐ Ｇｌｙ
Ｃｙｓ Ａｓｎ Ｌｙｓ
Ｇｌｕ Ａｌａ Ｌｅｕ
Ｌｙｓ Ｍｅｔ Ａｌａ
Ｇｌｙ Ｐｈｅ Ａｓｎ
Ｇｌｕ
Ｌｅｕ
Ａｓｎ
Ａｌａ
Ｐｈｅ
１１ｅ
Ｌｅｕ
Ｌｅｕ
Ｓｅｒ
＾１ａ
Ｔｈｒ Ｃｙｓ Ｌｅｕ
Ｇｌｕ Ｐｈｅ Ｇｌｕ
Ａｒｇ Ｐｈｅ Ｇｌｕ
Ｖａｌ Ｇｉｎ Ｍｅｔ
Ｌｅｕ Ｇｉｎ Ｌｙｓ
Ｔｈｒ Ｔｈｒ Ｐｒｏ
Ｌｅｕ Ｔｈｒ Ｌｙｓ
Ｇｌｎ Ａｓｐ Ｍｅｔ
Ｐｈｅ Ｌｙｓ Ｇｌｕ
Ｌｅｕ Ａｒｇ Ｇｉｎ
Ｖａｌ Ｌｙｓ Ｉｌｅ
Ｖａｔ Ｔｙｒ Ｌｅｕ
Ｓｅｒ Ｓｅｒ Ｇｌｕ
Ｓｅｒ Ｔｈｒ Ｌｙｓ
Ｌｙｓ Ａｌａ Ｌｙｓ
Ａｓｐ Ｐｒｏ Ｔｈｒ
Ｌｅｕ Ｇｉｎ Ａｌａ
Ｔｈｒ Ｔｈｒ Ｈｉｓ
Ｐｈｅ Ｌｅｕ Ｇｉｎ
Ｍｅｔ
ｌｉｅ
Ｇｌｕ
Ｇｌｕ
Ｖａｌ
Ａｓｎ
Ｔｈｒ
Ｇｉｎ
しｅｕ
Ｓｅｒ
（■）：
Ｐｒｏ Ｐｒｏ Ｇｌｙ
Ｐｒｏ Ｈｉｓ Ａｒｇ
ｌｉｅ Ａｓｐ Ｌｙｓ
ｌｉｅ Ｓｅｒ Ａｌａ
Ｓｅｒ Ａｓｎ Ｍｅｔ
Ａｌａ Ｇｌｕ Ａｓｎ
Ｇｌｕ Ｌｙｓ Ａｓｐ
Ｇｌｕ Ｇｆｎ Ｔｈｒ
Ｇｌｕ Ａｓｐ Ｓｅｒ
Ｇｌｎ Ｐｒｏ Ｌｅｕ
Ｇｉｎ ｌｉｅ Ａｒｇ
Ｌｅｕ Ａｒｇ Ｌｙｓ
Ｃｙｓ Ｇｌｕ Ｓｅｒ
Ａｓｎ Ｌｅｕ Ａｓｎ
Ｇｌｙ Ｃｙｓ Ｐｈｅ
Ｃｙｓ Ｌｅｕ Ｖａｌ
Ｌｙｓ Ａｓｐ
Ｔｈｒ Ｓｅｒ
Ｔｙｒ Ｉｌｅ
Ｇｌｕ Ｔｈｒ
Ｓｅｒ Ｌｙｓ
Ｌｅｕ Ｐｒｏ
Ｇｉｎ Ｓｅｒ
Ｌｙｓ Ｉｌｅ
１１ｅ Ｔｈｒ Ｃｙｓ Ｌｅｕ Ｌｅｕ Ｇｌｕ Ｐ
ｈｅ Ｇｌｅ Ｖａｌ Ｔｙｒ ＬｅｕＧｌｕ Ｔｙｒ
Ｌｅｕ Ｇｌｎ Ａｓｎ Ａｒｇ Ｐｈｅ Ｇｌｕ
Ｓｅｒ Ｓｅｒ ＧｌｕＧｌｕ Ｇｉｎ Ａｌａ Ａｒ
ｇ Ａｌａ Ｖａｌ Ｇｉｎ Ｍｅｔ Ｓｅｒ Ｔｈｒ
ＬｙｓＶａｌ Ｌｅｕ ｌｉｅ Ｇｌｎ Ｐｈｅ
Ｌｅｕ Ｇｌｎ Ｌｙｓ Ｌｙｓ Ａｌａ ＬｙｓＡ
ｓｎ Ｌｅｕ Ａｓｐ Ａｌａ ｌｉｅ Ｔｈｒ Ｔｈ
ｒ Ｐｒｏ Ａｓｐ Ｐｒｏ ＴｈｒＴｈｒ Ａｓｎ
Ａｌａ Ｓｅｒ Ｌｅｕ Ｌｅｕ Ｔｈｒ
Ｌｙｓ Ｌｅｕ Ｇｉｎ ＡｌａＧｉｎ−Ａ
ｓｎ Ｇｉｎ Ｔｒｐ Ｌｅｕ Ｇｉｎ Ａｓｐ Ｍｅ
ｔ Ｔｈｒ Ｔｈｒ ＨｉｓＬｅｕ Ｉｌｅ Ｌｅ
ｕ Ａｒｇ Ｓｅｒ Ｐｈｅ Ｌｙｓ Ｇｌ
ｕ Ｐｈｅ Ｌｅｕ ＧｉｎＳｅｒ Ｓｅｒ Ｌ
ｅｕ Ａｒｇ Ａｌａ Ｌｅｕ Ａｒｇ Ｇｉｎ Ｍｅ
ｔアミノ酸配列（１）は天然型ヒトＢＣＤＦであり、ア
ミノ酸配列（ＩＩ）は天然型ヒト ＢＣＤＰのＮ末端に
Ａｌａが１つ付加されたポリペブチド（以下ヒトＡｌａ
−ＢＣＤＦと記す）である。しかし、本発明で用いるヒ
トＢＣＯＦは必ずしも上記アミノ酸配列（Ｉ）又は（Ｕ
）で示される構造をとる必要はない。The human BCDF according to the present invention is, for example, JP-A-63-42
688.63-56291 and patent application No. 62-28900
The following amino acid sequence (1) as shown in Publication No. 7
or (II). Amino acid sequence (■): Pro Val Pro Pro Gly Glu A
ap Ser Lys Asp ValAla Al
a Pro Old s Arg Gln Pro
Leu Thr Ser Ser Glu A
rg Ile Asp Lys Gln Ile Ar
g Thr lie LeuAsp Gly lie
Ser Ala Leu Arg Lys Glu T
hr CysAsn Lys Ser Asn Met
Cys Glu Ser Ser Lys Glu＾
1a Leu Ala Glu Asn Asn Le
u Asn Leu Pro LysMet Ala
Glu Lys Asp Gly Cys Phe G
in Ser GlyPhe Asn Glu Thr Gly Leu Ding Leu Gln Gin Ala Arg Leu lie Gin Leu Asp Ala Asn Ala Ser ^sn Gin Trp I1e Leu Arg S er Leu Arg Also amino acid sequence Ala Pro Val Val A1a. AIa Ser Glu Arg Leu Asp Gly Cys Asn Lys Glu Ala Leu Lys Met Ala Gly Phe Asn Glu Leu Asn Ala Phe 11e Leu Leu Ser ^1a Thr Cys Leu Glu Phe Glu Arg Phe Glu Val Gin Met Leu Gin Lys Thr Thr Pro Leu Thr Lys Gln Asp Met Phe Lys Glu Leu Arg Gin Val Lys Ile Vat Tyr Leu Ser Ser Glu Ser Thr Lys Lys Ala Lys Asp Pro Thr Leu Gin A la Thr Thr His Phe Leu Gin Met lie Glu Glu Val Asn Thr Gin Shieu Ser (■ ): Pro Pro Gly Pro His Arg lie Asp Lys lie Ser Ala Ser Asn Met Ala Glu Asn Glu Lys Asp Glu Gfn Thr Glu Asp Ser Gln Pro Le u Gin lie Arg Leu Arg Lys Cys Glu Ser Asn Leu Asn Gly Cys Phe Cys Leu Val Lys Asp Thr Ser Tyr Ile Glu Thr Ser Lys Leu Pro Gin Ser Lys Ile 11e Thr Cys Leu Leu Glu P
he Gle Val Tyr
Leu Gln Asn Arg Phe Glu
Ser Ser GluGlu Gin Ala Ar
g Ala Val Gin Met Ser Thr
LysVal Leu lie Gln Phe
Leu Gln Lys Lys Ala LysA
sn Leu Asp Ala lie Thr Th
r Pro Asp Pro Thr Thr Asn
Ala Ser Leu Thr
Lys Leu Gin AlaGin-A
sn Gin Trp Leu Gin Asp Me
t Thr Thr HisLeu Ile Le
u Arg Ser Phe Lys Gl
u Phe Leu GinSer Ser L
eu Arg Ala Leu Arg Gin Me
The amino acid sequence (1) is natural human BCDF, and the amino acid sequence (II) is a polypeptide with one Ala added to the N-terminus of natural human BCDP (hereinafter referred to as human Ala).
-BCDF). However, the human BCOF used in the present invention does not necessarily have the above amino acid sequence (I) or (U).
) is not required.
即ち、天然型ヒト ＢＣＤＦのＮ末端及び／又はＣ末端
より１個もしくは複数個、メチオニン等のアξノ酸が付
加された構造を有するもの、天然型ヒトＢＣＤＦの構造
中の１個もしくは複数個のアミノ酸が他のアξノ酸に置
換された構造を有するものも、ヒトＢＣＤＦ活性を有す
る限り本発明のヒトＢＣＤＦとして用いることができる
。好ましくは天然型ヒトＢＣＤＦ又はヒトＡｌａ−ＢＣ
ＤＦを用いるのがよい．本発明に係るヒトＢＣＤＦの含
量は当該医薬組成物中０．０００１〜１００重量％、好
ましくは０．１〜１．０重量％である。That is, one or more amino acids such as methionine are added to the N-terminus and/or C-terminus of natural human BCDF, and one or more amino acids in the structure of natural human BCDF. A structure in which the amino acid of is substituted with another ξ-anoic acid can also be used as the human BCDF of the present invention as long as it has human BCDF activity. Preferably natural human BCDF or human Ala-BC
It is better to use DF. The content of human BCDF according to the present invention is 0.0001 to 100% by weight, preferably 0.1 to 1.0% by weight in the pharmaceutical composition.
治療学的に有効なヒト ＢＣＤＦの投与量は０．００１
ｐｇ／ｋｇ〜１０００ ｔｔ ｇ ／ ｋｇ、好まし
くは０．０１ ／／ ｇ ／ ｋｇ〜５００ μｇ／ｋ
ｇより好ましくは０． １μｇ／ｋｇ〜２５０μｇ＋〆
眩であるが、必ずしも上記に限定されるものではない。Therapeutically effective dose of human BCDF is 0.001
pg/kg ~ 1000 tt g/kg, preferably 0.01 // g/kg ~ 500 μg/k
g more preferably 0. 1 μg/kg to 250 μg+dazzle, but is not necessarily limited to the above.
更に本発明の医薬組成物にはヒトＢＣＤＦ以外に、助剤
としてレンチナンあるいはヒトＢＣＤＦ以外のサイトカ
イン、例えば、ＩＬ−３、ＩＬ−１、ＩＬ−４、ＩＬ−
５、Ｇ−ＣＳＦ ．．ＧＭ−ＣＳＦＳＭ−ＣＳＦ ＳＥ
ＰＯ及びＭｅｇ−ＣＳＰを１種類以上含有させてもよい
。Furthermore, in addition to human BCDF, the pharmaceutical composition of the present invention may contain lentinan or a cytokine other than human BCDF, such as IL-3, IL-1, IL-4, IL-
5.G-CSF. ．． GM-CSFSM-CSF SE
One or more types of PO and Meg-CSP may be contained.
これらの助剤の添加量は特に限定しないが、ヒト ＢＣ
ＥＩＦを１００とした場合にそれぞれ０．０００１〜２
０００００重量％添加すればよい。The amount of these auxiliaries added is not particularly limited, but human BC
0.0001 to 2 respectively when EIF is 100
It is sufficient to add 00000% by weight.
くり返し述べるが、ヒト ＢＣＤＦの治療学的有効量及
びこれら助剤の添加量は決して上述の値に限定されるも
のでなく、症状、患者の年令等により適宜決定すればよ
い。As stated again, the therapeutically effective amount of human BCDF and the amount of these auxiliary agents added are by no means limited to the above-mentioned values, and may be appropriately determined depending on the symptoms, age of the patient, etc.
さて、本発明に用いるヒトＢＣＤＦはヒｌ−Ｔ細胞、Ｂ
細胞、線維芽細胞等より既知の方法（ Ｐｒｏｃ．Ｎａ
ｔｌ． Ａｃａｄ． Ｓｃｌ． ＵＳＡ， ８２ ．
５４９０ （１９８５）により生産、精製したものでも
大腸菌、酵母、サル細胞（ ＣＯＳ細胞）、ハムスター
、細菌など適当な宿主にヒトＢＣＤＦをコードする遺伝
子を適当なベクターを用いて形質転換された株を培養す
ることにより生産、更には精製したヒトＢＣＤＦを用い
てもよい。Now, human BCDF used in the present invention is human T cell, B
known methods for cells, fibroblasts, etc. (Proc. Na
tl. Acad. Scl. USA, 82.
5490 (1985), the gene encoding human BCDF can be transformed into a suitable host such as Escherichia coli, yeast, monkey cells (COS cells), hamsters, or bacteria using an appropriate vector and cultured. Human BCDF produced or further purified by this method may also be used.
またヒトの血液・尿等より精製したものでも良い。It may also be purified from human blood, urine, etc.
精製法としては高速液体クロマトグラフィーゲルが過、
等電点電気泳動等を用いることができる。また特願昭６
２−２６３６３１及び特願昭６３−５３８２８に示すよ
うな方法で抗ヒトＢＣ叶抗体を用いる事もできる．
なお、これらの製造法の詳細については特開昭６１−１
１５０２４ 、特開昭６３−４２６８８、特開昭６３−
５６２９１号公報及び特開昭６３−１５７９９６を参考
にされたい。As a purification method, high performance liquid chromatography gel is used.
Isoelectric focusing or the like can be used. Also, special request in Showa 6
Anti-human BC leaf antibodies can also be used by the method shown in No. 2-263631 and Japanese Patent Application No. 63-53828. For details of these manufacturing methods, please refer to JP-A-61-1.
15024, JP-A-63-42688, JP-A-63-
Please refer to Publication No. 56291 and JP-A-63-157996.
尚、念の為に言及するが大腸菌等の原核生物から作製さ
れたものは糖鎖を有しないタイプである．さて、製造さ
れたヒトＢＣＤＦが前記のアミノ酸配列を有する事はア
ξノ酸分析並びにアξノ酸シークエンサーを用いた解析
で確認された。すなわち、ヒトＢＣＤＦそのもの及びヒ
トＢＣＤＦをアセチル化した等で切断した後、高速液体
クロマトグラフィー法等で分離したべプチドフラグメン
ト及びこれを過ギ酸酸化したものを用いて全アξノ酸配
列を同定できた。As a precaution, those produced from prokaryotes such as Escherichia coli do not have sugar chains. Now, it was confirmed by amino acid analysis and analysis using an amino acid sequencer that the produced human BCDF has the above-mentioned amino acid sequence. That is, the entire amino acid sequence can be identified using human BCDF itself, peptide fragments separated by high performance liquid chromatography after cutting human BCDF by acetylation, etc., and peptide fragments oxidized with performic acid. Ta.
本発明の特徴はヒト ＢＣＤＦ活性を有する物質を動物
又はヒトへの投与の為に安定化された医薬組成物であり
、以下にその技術を説明する。A feature of the present invention is a pharmaceutical composition in which a substance having human BCDF activity is stabilized for administration to animals or humans, and the technology thereof will be explained below.
本発明の医薬組成物は少なくとも一種以上の可溶化剤又
は安定剤等の不活性キャリアー培地中にヒト ＢＣＤＦ
を単独又はＩＬ−３等の助剤と組み合せて溶解又は分散
させたものである。The pharmaceutical composition of the present invention comprises human BCDF in an inert carrier medium such as at least one solubilizer or stabilizer.
is dissolved or dispersed alone or in combination with an auxiliary agent such as IL-3.
本発明の医薬組成物には可溶化剤または安定剤としてヒ
ト血清由来蛋白質用いると良い。例えば血清由来蛋白質
としてはアルブミンが良いが、α２マクログロプリンで
も良く、またその他の血清由あるいは蛋白分解酵素等に
よ９ヒトＢＣＤＦ分解を阻害する事等の効果を示す。Human serum-derived proteins may be used as solubilizers or stabilizers in the pharmaceutical compositions of the present invention. For example, as a serum-derived protein, albumin is preferred, but α2-macroglobulin may also be used, and other serum-derived proteins or proteolytic enzymes are also effective in inhibiting the degradation of human BCDF.
さらに安定剤として塩化ナトリウムの他にリン酸ナトリ
ウム、リン酸カリウム、カプリル酸ナトリウム、アセチ
ルトリプトファンナトリウム等の無機塩を添加してもか
まわない。これらの添加は本医薬組成物の等張性を保持
する、あるいはｐＨを安定させる事等の効果を示す。Furthermore, in addition to sodium chloride, inorganic salts such as sodium phosphate, potassium phosphate, sodium caprylate, and sodium acetyltryptophan may be added as stabilizers. These additions exhibit effects such as maintaining the isotonicity of the pharmaceutical composition or stabilizing the pH.
さらにこれら以外の可溶化剤あるいは安定剤としては、
例えば非イオン界面活性剤［（オクチルレングリコール
モノステアレート化合物（商標名Ｍａｐｅｇ ４０００
（ＭＳ）、等）、ポリオキシエチレンソルビタン脂肪酸
エステル（商標名Ｔｗｅｅｎ ２０， Ｔｓ＋ｅｅｎ８
０，ロｖｒｔａｘ ８０等）等］、陰イオン性・界面活
性剤（ラウリル硫酸ナトリウム等）天然系の界面活性剤
（レシチン等）、糖類（マンニトール，ヒアルロン酸，
デキストラン等）、高分子（ヒドロキシプ口ピルセルロ
ース，ポリビニルアルコール．ポリビニルピロリドン等
）、アξノ酸（トリプトンファン，ヒスチジン．システ
イン等）、含硫還元剤（チオグリコール酸ナトリウム、
チオ硫酸ナトリウム等）、酸化防止剤（α一トコフエロ
ール，ジブチルヒドロキシトルエン、Ｌ−アスコルビン
酸ナトリウム等）安定剤（ヘマセル、アミノ酢酸等）、
賦形剤（乳糖、マンニトール等）の一種以上を加えても
良く、前記の血清由来蛋白質及び安定剤にさらにこれら
を加えても良い。Furthermore, other solubilizers or stabilizers include:
For example, a nonionic surfactant [(octyllene glycol monostearate compound (trade name Mapeg 4000)
(MS), etc.), polyoxyethylene sorbitan fatty acid ester (trade name Tween 20, Ts+een8)
0, ro vrtax 80, etc.], anionic surfactants (sodium lauryl sulfate, etc.), natural surfactants (lecithin, etc.), sugars (mannitol, hyaluronic acid,
dextran, etc.), polymers (hydroxybutypylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, etc.), amino acids (tryptophan, histidine, cysteine, etc.), sulfur-containing reducing agents (sodium thioglycolate,
(sodium thiosulfate, etc.), antioxidants (alpha-tocopherol, dibutylhydroxytoluene, sodium L-ascorbate, etc.), stabilizers (hemacel, aminoacetic acid, etc.),
One or more excipients (lactose, mannitol, etc.) may be added, and these may be further added to the serum-derived protein and stabilizer.
前記可溶化剤あるいは安定剤の添加量はヒトＢＣＤＦを
１００とした場合にそれぞれｏ．ｏｏｏｔ〜１００００
００重量％が好ましいが、特にこの範囲に限定されるも
のではない。The amount of the solubilizer or stabilizer added is o. ooot~10000
00% by weight is preferred, but is not particularly limited to this range.
本発明の医薬組成物は液体のままでも良く、また真空凍
結乾燥等の方法で凍結乾燥形にしたものでも良い。保存
温度は３７゜Ｃ以下が望ましく、より望ましくは４゜Ｃ
または−２０℃であるが、それ以上もしくはそれ以下で
もかまわない。上記温度にて本医薬組成物中のヒト Ｂ
ＣＤＦは少なくとも６カ月以上生物活性を有し、安定で
ある。The pharmaceutical composition of the present invention may be kept as a liquid, or may be lyophilized by a method such as vacuum lyophilization. The storage temperature is preferably 37°C or lower, more preferably 4°C.
Or -20°C, but it may be higher or lower. Human B in the pharmaceutical composition at the above temperature.
CDF is biologically active and stable for at least 6 months.
本医薬組成物は、注射用蒸留水、注射用生理食塩水等に
溶解して投与すれば良い。液体形においてはそのまま投
与しても良い。The present pharmaceutical composition may be administered after being dissolved in distilled water for injection, physiological saline for injection, or the like. In liquid form, it may be administered as is.
投与方法は静脈内注射を用いても良いし、筋肉内注射、
皮下注射で用いても良い。また点滴静注等の徐放的連続
投与法を用いても良い。The administration method may be intravenous injection, intramuscular injection,
It may also be used by subcutaneous injection. Further, sustained release continuous administration methods such as intravenous drip injection may also be used.
本医薬組成物が含有するエンドトキシン量は水のエンド
トキシン適合値０．２５ＥＵ／ｍｆ及びウサギ発熱限界
ＩＯ．５ＥＵ／ｎＩ！．を下回るものである。The amount of endotoxin contained in this pharmaceutical composition is 0.25 EU/mf, which is the water endotoxin compliance value, and IO, which is the rabbit fever limit. 5EU/nI! ．． It is less than that.
エンドトキシン量は市販測定キット、例えばパイすすれ
ば良い。The amount of endotoxin can be measured using a commercially available measuring kit, such as Piss.
なお、ＢＣＤＦ活性は例えば特開昭６３−４２６８８に
示した方法により測定可能である。以下本発明を実施例
に従って説明する．
〔実施例１、ヒト ＢＣＤＰ医薬組成物の作製〕組み換
えＤＮＡ技術を用いて大腸菌で生産した後ＰＢＳ溶液、
比活性２．５Ｕ／ｎｇ）２００μｆに２０％ヒト血清ア
ルプξン液（ナトリウム３．３■／ｔａｎ，塩素３．１
■／―ｌ，カブリル酸ナトリウム２．６５９■／ｔａ
ｌ ，アセチルトリプトファンナトリウム４．２９２５
■７’ｓｌ含有）５０μｌを添加、生理食塩トＢＣＤＦ
２μｇ、ヒト血清アルブミン５００μｇ含有）を乾熱
滅菌したガラスバイアル（日電理化硝子．１５Ｘ３３ｍ
ｍ）に入れ、−８０℃にて凍結後、３ ０ｎ ｔｏｌｌ
、１０″Ｃの条件で２０時間真空凍結乾燥した。また一
部は凍結乾燥せず液体のまま保存した。In addition, BCDF activity can be measured, for example, by the method shown in JP-A No. 63-42688. The present invention will be explained below according to examples. [Example 1, Preparation of human BCDP pharmaceutical composition] Produced in Escherichia coli using recombinant DNA technology, then prepared in PBS solution,
Specific activity 2.5 U/ng) 200 μf and 20% human serum Alpine solution (sodium 3.3 μ/tan, chlorine 3.1
■/-l, sodium cabrylate 2.659■/ta
l, sodium acetyltryptophan 4.2925
■ Add 50 μl of 7'sl, physiological saline and BCDF.
2 μg, human serum albumin 500 μg) in a dry heat sterilized glass vial (Nichiden Rika Glass, 15 x 33 m)
After freezing at -80℃, 30n toll
, vacuum freeze-drying was carried out at 10''C for 20 hours. A portion was not freeze-dried and was stored as a liquid.
製造直後に上記バイアルを注射用蒸留水にて溶解し、ヒ
トＢＣ叶活性を昭６３−４２６８８の方法に従い測定し
たところ、活性は１００±０％保持されていた．また−
２０゜Ｃ， ４゜Ｃ１２０゜Ｃ及び３７゜Ｃで保存し、
１カ月後及び７カ月後に同様の方法で活性を測定したと
ころ、３７℃保存では５６±４％（１カ月後）、４０％
±５％（７カ月後）に活性は低下したが、２０℃以下で
は１００±１５％の活性を保持していた。また液体のま
まで−８０゜Ｃ、−２０℃及び４゜Ｃで保存した標品も
６カ月後でも作戒時の活性を保持していた。Immediately after production, the vial was dissolved in distilled water for injection, and the human BC activity was measured according to the method of 1988-42688, and the activity was found to be 100±0%. Also-
Store at 20°C, 4°C, 120°C and 37°C,
When the activity was measured in the same manner after 1 month and 7 months, the activity was 56 ± 4% (after 1 month) and 40% when stored at 37°C.
Although the activity decreased to ±5% (after 7 months), the activity remained at 100±15% below 20°C. In addition, specimens stored in liquid form at -80°C, -20°C, and 4°C retained their original activity even after 6 months.
〔効 果〕
本発明の、ヒトＢＣＯＦの治療学的に有効な量を含んで
戒る医薬組成物は動物又はヒトへの投与のために適切な
安定した医薬組成物として有用である。[Effects] The pharmaceutical composition of the present invention containing a therapeutically effective amount of human BCOF is useful as a stable pharmaceutical composition suitable for administration to animals or humans.
手続補正書
手続補正書
ｌ．事件の表示
平成ｌ年特許願第１８３０８８号
２．発明の名称
ヒトＢｌｌ＠分化因子医薬組成物
３．補正をする者
事件との関係 特許出願人
住所 東京都中央区京橋一丁目５１Ｆ８号ｌ．事
件の表示 平戒１年特許願第１６３０８８号２．発明の
名称 ヒトＢ細胞分化因子医薬組成物３．補正をする者
事件との関係 特許出願人
住 所 東京都中央区京橋一丁目５番８号の記載を削除
する．
５．補正により増加する発明の数 な し６．補正の
対象 明細書の特許請求の範囲及び発明の詳細な説明の
欄
７．補正の内容
（１）特許請求の範囲を別紙のとおり補正する。Procedural amendment Procedural amendment l. Case description 1999 Patent Application No. 183088 2. Name of the invention Human Bll@differentiation factor pharmaceutical composition 3. Relationship with the case of the person making the amendment Patent applicant address 1-51F8, Kyobashi, Chuo-ku, Tokyo l. Display of incident Patent Application No. 163088 2. Title of the invention Human B cell differentiation factor pharmaceutical composition 3. Relationship to the case of the person making the amendment The address of the patent applicant: 1-5-8 Kyobashi, Chuo-ku, Tokyo, will be deleted. 5. Number of inventions increased by amendment None 6. Subject of amendment Column 7 of claims and detailed description of the invention in the specification. Contents of amendment (1) The scope of claims is amended as shown in the attached sheet.
（２）明細書第７頁１２行目〜第８頁９行目の「アξノ
酸配列（■）」を以下のように訂正する。(2) "Anoic acid sequence (■)" on page 7, line 12 to page 8, line 9 of the specification is corrected as follows.
アミノ酸配列（■）：
Ａｌａ Ｐｒｏ Ｖａｌ Ｐｒｏ Ｐｒｏ Ｇｌｙ Ｇ
ｌｕ Ａｓｐ Ｓｅｒ ＬｙｓＶａｌ Ａｌａ Ａｌａ
Ｐｒｏ Ｈｉｓ Ａｒｇ Ｇｉｎ Ｐｒｏ Ｌｅｕ
ＴｈｒＳｅｒ Ｇｌｕ Ａｒｇ ｌｉｅ Ａｓｐ Ｌｙ
ｓ Ｇｌｎ ｌｉｅ Ａｒｇ ＴｙｒＬｅｕ Ａｓｐ
Ｇｌｙ Ｉｌｅ Ｓｅｒ Ａｌａ Ｌｅｕ Ａｒｇ Ｌ
ｙｓ ＧｌｕＣｙｓ Ａｓｎ Ｌｙｓ Ｓｅｒ Ａｓｎ
Ｍｅｔ Ｃｙｓ Ｇｌｕ Ｓｅｒ ＳｅｒＧｌｕ Ａ
ｌａ Ｌｅｕ Ａｌａ Ｇｌｕ Ａｓｎ Ａｓｎ Ｌｅ
ｕ Ａｓｎ ＬｅｕＬｙｓ Ｍｅｔ Ａｌａ Ｇｌｕ
Ｌｙｓ Ａｓｐ Ｇｌｙ Ｃｙｓ Ｐｈｅ ＧｌｎＧｌ
ｙ Ｐｈｅ Ａｓｎ Ｇｌｕ Ｇｉｎ Ｔｈｒ Ｃｙｓ
Ｌａｕ Ｖａｌ Ｌｙｓ１１ｅ Ｔｈｒ Ｃｙｓ Ｌ
ｅｕ Ｌｅｕ Ｇｌｕ Ｐｈｅ Ｇｌｕ Ｖａｌ Ｔｙ
ｒＧｌｕ Ｔｙｒ Ｌｅｕ Ｇｌｙ Ａｓｎ Ａｒｇ
Ｐｈｅ Ｇｌｕ Ｓｅｒ ＳｅｒＧｌｕ Ｇｌｎ Ａｌ
ａ Ａｒｇ Ａｌａ Ｖａｌ Ｇｉｎ Ｍｅｔ Ｓｅｒ
ＴｈｒＶａｌ Ｌｅｕ Ｉｌｅ Ｇｉｎ Ｐｈｅ Ｌ
ｅｕ Ｇｉｎ Ｌｙｓ Ｌｙｓ ＡｌａＡｓｎ Ｌｅｕ
Ａｓｐ Ａｌａ Ｉｌｅ Ｔｈｒ Ｔｈｒ Ｐｒｏ
Ａｓｐ ＰｒｏＴｈｒ Ａｓｎ Ａｌａ Ｓｅｒ Ｌｅ
ｕ Ｌｅｕ Ｔｈｒ Ｌｙｓ Ｌｅｕ ＧｉｎＧｉｎ
Ａｓｎ Ｇｉｎ Ｔｒｐ Ｌｅｕ Ｇｌｎ Ａｓｐ Ｍ
ｅｔ Ｔｈｒ ＴｈｒＬｅｕ Ｉｌｅ Ｌｅｕ Ａｒｇ
Ｓｅｒ Ｐｈｅ Ｌｙｓ Ｇｌｕ Ｐｈｅ ＬｅｕＳ
ｅｒ Ｓｅｒ Ｌｅｕ Ａｒｇ Ａｌａ Ｌｅｕ Ａｒ
ｇ ＧｉｎＭｅｔ＾ｓｐ
Ｓｅｒ
１１ｅ
Ｔｈｒ
Ｌｙｓ
Ｐｒｏ
Ｓｅｒ
１１ｅ
Ｌｅｕ
Ｇｌｕ
Ｌｙｓ
Ｌｙｓ
Ｔｈｒ
Ａｌａ
Ｈｉｓ
Ｇｌｎ
別紙
２．特許請求の範囲
１．動物又はヒトへの投与のために適切なヒトＢ細胞分
化因子（以下ヒト ＢＣＤＦとしるす）を安定化させた
医薬組成物。Amino acid sequence (■): Ala Pro Val Pro Pro Gly G
lu Asp Ser LysVal Ala Ala
Pro His Arg Gin Pro Leu
ThrSer Glu Arg lie Asp Ly
s Gln lie Arg TyrLeu Asp
Gly Ile Ser Ala Leu Arg L
ys GluCys Asn Lys Ser Asn
Met Cys Glu Ser Ser Glu A
la Leu Ala Glu Asn Asn Le
u Asn LeuLys Met Ala Glu
Lys Asp Gly Cys Phe GlnGl
y Phe Asn Glu Gin Thr Cys
Lau Val Lys11e Thr Cys L
eu Leu Glu Phe Glu Val Ty
rGlu Tyr Leu Gly Asn Arg
Phe Glu Ser Ser Glu Gln Al
a Arg Ala Val Gin Met Ser
ThrVal Leu Ile Gin Phe L
eu Gin Lys Lys AlaAsn Leu
Asp Ala Ile Thr Thr Pro
Asp ProThr Asn Ala Ser Le
u Leu Thr Lys Leu GinGin
Asn Gin Trp Leu Gln Asp M
et Thr ThrLeu IleLeu Arg
Ser Phe Lys Glu Phe LeuS
er Ser Leu Arg Ala Leu Ar
g GinMet^sp Ser 11e Thr Lys Pro Ser 11e Leu Glu Lys Lys Thr Ala His Gln Attachment 2. Claims 1. A pharmaceutical composition containing stabilized human B cell differentiation factor (hereinafter referred to as human BCDF) suitable for administration to animals or humans.
２．ヒトＢＣＤＦが下記のアミノ酸配列，（Ｉ）を有す
るものである請求項（１）記載の組成物．アξノ 配
（Ｉ）：
Ｐｒｏ Ｖａｌ Ｐｒｏ Ｐｒｏ Ｇｌｙ Ｇｌｕ Ａ
ｓｐ Ｓｅｒ Ｌｙｓ Ａｓｐ ＶａｌＡｌａ Ａｌａ
Ｐｒｏ Ｈｉｓ Ａｒｇ Ｇｌｎ Ｐｒｏ Ｌｅｕ
Ｔｈｒ Ｓｅｒ ＳｅｒＧｌｕ Ａｒｇ ｌｉｅ Ａｓ
ｐ Ｌｙｓ Ｇｉｎ ｌｉｅ Ａｒｇ Ｔｙｒ Ｉｃｅ
ＬｅｕＡｓｐ Ｇｌｙ ｌｉｅ Ｓｅｒ Ａｌａ Ｌ
ｅｕ Ａｒｇ Ｌｙｓ Ｇｌｕ Ｔｂｒ ＣｙｓＡｓｎ
Ｌｙｓ Ｓｅｒ Ａｓｎ Ｍｅｔ Ｃｙｓ Ｇｌｕ
Ｓｅｒ Ｓｅｒ Ｌｙｓ ＧｌｕＡｌａ Ｌｅｕ Ａｌ
ａ Ｇｌｕ Ａｓｎ Ａｓｎ Ｌｅｕ Ａｓｎ Ｌｅｕ
Ｐｒｏ ＬｙｓＭｅｔ Ａｌａ Ｇｌｕ Ｌｙｓ Ａ
ｓｐ Ｇｌｙ Ｃｙｓ Ｐｈｅ Ｇｉｎ Ｓｅｒ Ｇｌ
ｙＰｈｅＡａｎ Ｇｌｕ Ｇｌｕ Ｔｈｒ Ｃｙｓ Ｌ
ｅｕ Ｖａｌ Ｌｙｓ Ｉｌｅ ｌｉｅＴｈｒ Ｇｌｙ
Ｌｅｕ Ｌｅｕ Ｇｌｕ Ｐｈｅ Ｇｌｕ Ｖａｌ
Ｔｙｒ Ｌｅｕ Ｇｌｕ↑ｙｒ Ｌｅｕ Ｇｌｎ Ａｓ
ｎ Ａｒｇ Ｐｈｅ Ｇｌｕ Ｓｅｒ Ｓｅｒ Ｇｌｕ
ＧｌｕＧｌｎ Ａｌａ Ａｒｇ Ａｌａ Ｖａｌ Ｇ
ｌｎ Ｍｅｔ Ｓｅｒ Ｔｈｒ Ｌｙｓ ＶａｌＬｅｕ
Ｉｌｅ Ｇｌｎ Ｐｈｅ Ｌｅｕ Ｇｉｎ Ｌｙｓ
Ｌｙｓ Ａｌａ Ｌｙｓ ＡｓｎＬｅｕ Ａｓｐ Ａ
ｌａ Ｉｌｅ Ｔｈｒ Ｔｈｒ Ｐｒｏ Ａｓｐ Ｐｒ
ｏ Ｔｈｒ ＴｈｒＡｓｎ Ａｌａ Ｓｅｒ Ｌｅｕ
Ｌｅｕ Ｔｈｒ Ｌｙｓ Ｌｅｕ Ｇｉｎ Ａｌａ Ｇ
ｉｎＡｓｎ Ｇｌｎ Ｔｒｐ Ｌｅｕ Ｇｉｎ Ａｓｐ
Ｍｅｔ Ｔｈｒ Ｔｈｒ Ｈｉｓ Ｌｅｕｌｉｅ
Ｌｅｕ Ａｒｇ Ｓｅｒ Ｐｈｅ Ｌｙｓ
Ｇｌｕ Ｐｈｅ Ｌｅｕ Ｇｌｎ ＳｅｒＳｅ
ｒ Ｌｅｕ Ａｒｇ Ａｌａ Ｌｅｕ Ａｒｇ Ｇｉｎ
Ｍｅｔ３．ヒトＢＣＤＦが下記のアごノ酸配列（ＩＩ
）を有するものである請求項（１）記載の＆ｌｌ或物．
アξノ 配ＬＵＬＬ：
Ａｌａ Ｐｒｏ Ｖａｌ Ｐｒｏ Ｐｒｏ Ｇｌｙ Ｇ
ｌｕ Ａｓｐ Ｓｅｒ Ｌｙｓ ＡｓｐＶａｌ Ａｌａ
Ａｌａ Ｐｒｏ Ｈｉｓ Ａｒｇ Ｇｌｎ Ｐｒｏ
Ｌｅｕ Ｔｈｒ ＳｅｒＳｅｒ Ｇｌｕ Ａｒｇ ｌｉ
ｅ Ａｓｐ Ｌｙｓ Ｇｉｎ Ｉｌｅ Ａｒｇ Ｔｙｒ
ｌｉｅＬｅｕ Ａｓｐ Ｇｌｙ Ｉｌｅ Ｓｅｒ Ａ
ｌａ Ｌｅｕ Ａｒｇ Ｌｙｓ Ｇｌｕ ＴｈｒＣｙｓ
Ａｓｎ Ｌｙｓ Ｓｅｒ Ａｓｎ Ｍｅｔ Ｃｙｓ
Ｇｌｕ Ｓｅｒ Ｓｅｒ ＬｙｓＧｌｕ Ａｌａ
Ｌｅｕ Ａｌａ Ｇｌｕ Ａｓｎ Ａｓｎ
Ｌｅｕ Ａｓｎ Ｌｅｕ ＰｒｏＬｙｓ Ｍｅｔ
Ａｌａ Ｇｌｕ Ｌｙｓ Ａｓｐ Ｇｌｙ Ｃｙｓ
Ｐｈｅ Ｇｉｎ ＳｅｒＧｌｙ Ｐｈｅ Ａｓｎ Ｇｌ
ｕ Ｇｌｎ Ｔｈｒ Ｃｙｓ Ｌｅｕ Ｖａｌ Ｌｙｓ
ｌｉｅ１１ｅ Ｔｈｒ Ｃｙｓ Ｌｅｕ Ｌｅｕ Ｇ
ｌｕ Ｐｈｅ Ｇｌｕ Ｖａｌ Ｔｙｒ ＬｅｕＧｌｕ
Ｔｙｒ Ｌｅｕ Ｇｉｎ Ａｓｎ Ａｒｇ Ｐｈｅ
Ｇｌｕ Ｓｅｒ Ｓｅｒ ＧｌｕＧｌｕ Ｇｉｎ Ａｌ
ａ Ａｒｇ Ａｌａ Ｖａｌ Ｇｉｎ Ｍｅｔ Ｓｅｔ
Ｔｈｒ ＬｙｓＶａｌ Ｌｅｕ ｌｉｅ Ｇｉｎ
Ｐｈｅ Ｌｅｕ Ｇｉｎ Ｌｙｓ Ｌｙｓ Ａｌａ Ｌ
ｙｓＡｓｎ Ｌｅｕ Ａｓｐ Ａｌａ Ｉｌｅ Ｔｈ
ｒ Ｔｈｒ Ｐｒｏ Ａｓｐ Ｐｒｏ ＴｈｒＴｈｒ
Ａｓｎ Ａｌａ Ｓｅｒ Ｌｅｕ Ｌｅｕ Ｔｈｒ Ｌ
ｙｓ Ｌｅｕ Ｇｉｎ ＡｌａＧｉｎ ＾ｓｎ Ｇｉｎ
Ｔｒｐ Ｌｅｕ Ｇｉｎ Ａｓｐ Ｍｅｔ Ｔｈｒ
Ｔｈｒ ＨｉｓＬｅｕ ｌｉｅ Ｌｅｕ Ａｒｇ Ｓ
ｅｒ Ｐｈｅ Ｌｙｓ Ｇｌｕ Ｐｈｅ Ｌｅｕ Ｇｉ
ｎＳｅｒ Ｓｅｒ Ｌｅｕ Ａｒｇ Ａｌａ Ｌｅｕ
Ａｒｇ Ｇｉｎ Ｍｅｔ４．ヒトＢＣＤＦが！鎖を有さ
ないものである請求項（１）記載の組成物．
５．ヒトＢＣＤＰが原核生物で作られたものである請求
項（１）記載の組成物．
６．少なくとも一種の可溶化剤又は安定剤を含６、少な
くとも一種の可溶化剤又は分敗されたヒトＢＣＤＦの治
療学的に有効な量を含んで戒る請求項（１）記載の組成
物。2. The composition according to claim (1), wherein the human BCDF has the following amino acid sequence (I). Aξノ arrangement
(I): Pro Val Pro Pro Gly Glu A
sp Ser Lys Asp ValAla Ala
Pro His Arg Gln Pro Leu
Thr Ser SerGlu Arg lie As
p Lys Gin lie Arg Tyr Ice
LeuAsp Gly lie Ser Ala L
eu Arg Lys Glu Tbr CysAsn
Lys Ser Asn Met Cys Glu
Ser Ser Lys GluAla Leu Al
a Glu Asn Asn Leu Asn Leu
Pro LysMet Ala Glu Lys A
sp Gly Cys Phe Gin Ser Gl
yPheAan Glu Glu Thr Cys L
eu Val Lys Ile lieThr Gly
Leu Leu Glu Phe Glu Val
Tyr Leu Glu↑yr Leu Gln As
n Arg Phe Glu Ser Ser Glu
GluGln Ala Arg Ala Val G
ln Met Ser Thr Lys ValLeu
Ile Gln Phe Leu Gin Lys
Lys Ala Lys AsnLeu Asp A
la Ile Thr Thr Thr Pro Asp Pr
o Thr Thr Asn Ala Ser Leu
Leu Thr Lys Leu Gin Ala G
inAsn Gln Trp Leu Gin Asp
Met Thr Thr His Leulie
Leu Arg Ser Phe Lys
Glu Phe Leu Gln SerSe
r Leu Arg Ala Leu Arg Gin
Met3. Human BCDF has the following agonoic acid sequence (II
) according to claim (1).
LULL: Ala Pro Val Pro Pro Gly G
lu Asp Ser Lys AspVal Ala
Ala Pro His Arg Gln Pro
Leu Thr Ser Ser Glu Arg li
e Asp Lys Gin Ile Arg Tyr
lieLeu Asp Gly Ser A
la Leu Arg Lys Glu ThrCys
Asn Lys Ser Asn Met Cys
Glu Ser Ser LysGlu Ala
Leu Ala Glu Asn Asn
Leu Asn Leu ProLys Met
Ala Glu Lys Asp Gly Cys
Phe Gin SerGly Phe Asn Gl
u Gln Thr Cys Leu Val Lys
lie11e Thr Cys Leu Leu G
lu Phe Glu Val Tyr LeuGlu
Tyr Leu Gin Asn Arg Phe
Glu Ser Ser Glu Glu Gin Al
a Arg Ala Val Gin Met Set
Thr LysVal Leu lie Gin
Phe Leu Gin Lys Lys Ala L
ysAsn Leu Asp Ala Ile Th
r Thr Pro Asp Pro Thr Thr
Asn Ala Ser Leu Leu Thr L
ys Leu Gin AlaGin ^sn Gin
Trp Leu Gin Asp Met Thr
Thr HisLeu lieLeu Arg S
er Phe Lys Glu Phe Leu Gi
nSer Ser Leu Arg Ala Leu
Arg Gin Met4. Human BCDF! The composition according to claim (1), which has no chains. 5. The composition according to claim (1), wherein the human BCDP is produced by a prokaryote. 6. 6. The composition of claim 1, comprising at least one solubilizer or stabilizer, and a therapeutically effective amount of at least one solubilizer or cleaved human BCDF.
７．液体形又は凍結乾燥形のいずれかである請求項（１
）又は（６）記載の組成物。7. Claims (1) in either liquid form or lyophilized form
) or the composition described in (6).
８．可溶化剤又は安定剤として血清由来蛋白質を用いる
ことを特徴とする請求項（６）記載の組成物。8. The composition according to claim 6, characterized in that a serum-derived protein is used as the solubilizer or stabilizer.
９．血清由来蛋白質としてアルブξンを用いることを特
徴とする請求項（８）項記載の組成物。9. 9. The composition according to claim 8, wherein albumen is used as the serum-derived protein.
ｌＯ．血清由来蛋白質としてα，−マクログロプリンを
用いることを特徴とする請求項（８）項記載の＆ｌｌ戒
物．lO. The &lll precept according to claim (8), characterized in that α,-macroglopurin is used as the serum-derived protein.
Claims (1)
子因子（以下ヒトＢＣＤＦとしるす）を安定化させた医
薬組成物。 ２、ヒトＢＣＤＦが下記のアミノ酸配列（ I ）を有す
るものである請求項（１）記載の組成物。 ￥アミノ酸配列（ I ）￥： Ｐｒｏ Ｖａｌ Ｐｒｏ Ｐｒｏ Ｇｌｙ Ｇｌｕ Ａａｐ Ｓｅｒ Ｌｙｓ Ａｓｐ Ｖａｌ Ａｌａ Ａｌａ Ｐｒｏ Ｈｉｓ Ａｒｇ Ｇｌｎ Ｐｒｏ Ｌｅｕ Ｔｈｒ Ｓｅｒ Ｓｅｒ Ｇｌｕ Ａｒｇ Ｉｌｅ Ａｓｐ Ｌｙｓ Ｇｌｎ Ｉｌｅ Ａｒｇ Ｔｈｒ Ｉｌｅ Ｌｅｕ Ａｓｐ Ｇｌｙ Ｉｌｅ Ｓｅｒ Ａｌａ Ｌｅｕ Ａｒｇ Ｌｙｓ Ｇｌｕ Ｔｈｒ Ｃｙｓ Ａｓｎ Ｌｙｓ Ｓｅｒ Ａｓｎ Ｍｅｔ Ｃｙｓ Ｇｌｕ Ｓｅｒ Ｓｅｒ Ｌｙｓ Ｇｌｕ Ａｌａ Ｌｅｕ Ａｌａ Ｇｌｕ Ａｓｎ Ａｓｎ Ｌｅｕ Ａｓｎ Ｌｅｕ Ｐｒｏ Ｌｙｓ Ｍｅｔ Ａｌａ Ｇｌｕ Ｌｙｓ Ａｓｐ Ｇｌｙ Ｃｙｓ Ｐｈｅ Ｇｌｎ Ｓｅｒ Ｇｌｙ Ｐｈｅ Ａｓｎ Ｇｌｕ Ｇｌｕ Ｔｈｒ Ｃｙｓ Ｌｅｕ Ｖａｌ Ｌｙｓ Ｉｌｅ Ｉｌｅ Ｔｈｒ Ｇｌｙ Ｌｅｕ Ｌｅｕ Ｇｌｕ Ｐｈｅ Ｇｌｕ Ｖａｌ Ｔｙｒ Ｌｅｕ Ｇｌｕ Ｔｙｒ Ｌｅｕ Ｇｌｎ Ａｓｎ Ａｒｇ Ｐｈｅ Ｇｌｕ Ｓｅｒ Ｓｅｒ Ｇｌｕ Ｇｌｕ Ｇｌｎ Ａｌａ Ａｒｇ Ａｌａ Ｖａｌ Ｇｌｎ Ｍｅｔ Ｓｅｒ Ｔｈｒ Ｌｙｓ Ｖａｌ Ｌｅｕ Ｉｌｅ Ｇｌｎ Ｐｈｅ Ｌｅｕ Ｇｌｎ Ｌｙｓ Ｌｙｓ Ａｌａ Ｌｙｓ Ａｓｎ Ｌｅｕ Ａｓｐ Ａｌａ Ｉｌｅ Ｔｈｒ Ｔｈｒ Ｐｒｏ Ａｓｐ Ｐｒｏ Ｔｈｒ Ｔｈｒ Ａｓｎ Ａｌａ Ｓｅｒ Ｌｅｕ Ｌｅｕ Ｔｈｒ Ｌｙｓ Ｌｅｕ Ｇｌｎ Ａｌａ Ｇｌｎ Ａｓｎ Ｇｌｎ Ｔｒｐ Ｌｅｕ Ｇｉｎ Ａｓｐ Ｍｅｔ Ｔｈｒ Ｔｈｒ Ｈｉｓ Ｌｅｕ Ｉｌｅ Ｌｅｕ Ａｒｇ Ｓｅｒ Ｐｈｅ Ｌｙｓ Ｇｌｕ Ｐｈｅ Ｌｅｕ Ｇｌｎ Ｓｅｒ Ｓｅｒ Ｌｅｕ Ａｒｇ Ａｌａ Ｌｅｕ Ａｒｇ Ｇｌｎ Ｍｅｔ ３、ヒトＢＣＤＦが下記の アミノ酸配列（II）を有するものである請求項（１）記
載の組成物。 ￥アミノ酸配列（II）￥ Ａｌａ Ｐｒｏ Ｖａｌ Ｐｒｏ Ｐｒｏ Ｇｌｙ Ｇｌｕ Ａｓｐ Ｓｅｒ Ｌｙｓ Ａｓｐ Ｖａｌ Ａｌａ Ａｌａ Ｐｒｏ Ｈｉｓ Ａｒｇ Ｇｌｎ Ｐｒｏ Ｌｅｕ Ｔｈｒ Ｓｅｒ Ｓｅｒ Ｇｌｕ Ａｒｇ Ｉｌｅ Ａｓｐ Ｌｙｓ Ｇｉｎ Ｉｌｅ Ａｒｇ Ｔｙｒ Ｉｌｅ Ｌｅｕ Ａｓｐ Ｇｌｙ Ｉｌｅ Ｓｅｒ Ａｌａ Ｌｅｕ Ａｒｇ Ｌｙｓ Ｇｌｕ Ｔｈｒ Ｃｙｓ Ａｓｎ Ｌｙｓ Ｓｅｒ Ａｓｎ Ｍｅｔ Ｃｙｓ Ｇｌｕ Ｓｅｒ Ｓｅｒ Ｌｙｓ Ｇｌｕ Ａｌａ Ｌｅｕ Ａｌａ Ｇｌｕ Ａｓｎ Ａｓｎ Ｌｅｕ Ａｓｎ Ｌｅｕ Ｐｒｏ Ｌｙｓ Ｍｅｔ Ａｌａ Ｇｌｕ Ｌｙｓ Ａｓｐ Ｇｌｙ Ｃｙｓ Ｐｈｅ Ｇｌｎ Ｓｅｒ Ｇｌｙ Ｐｈｅ Ａｓｎ Ｇｌｕ Ｇｌｎ Ｔｈｒ Ｃｙｓ Ｌｅｕ Ｖａｌ Ｌｙｓ Ｉｌｅ Ｉｌｅ Ｔｈｒ Ｃｙｓ Ｌｅｕ Ｌｅｕ Ｇｌｕ Ｐｈｅ Ｇｌｅ Ｖａｌ Ｔｙｒ Ｌｅｕ Ｇｌｕ Ｔｙｒ Ｌｅｕ Ｇｌｎ Ａｓｎ Ａｒｇ Ｐｈｅ Ｇｌｕ Ｓｅｒ Ｓｅｒ Ｇｌｕ Ｇｌｕ Ｇｌｎ Ａｌａ Ａｒｇ Ａｌａ Ｖａｌ Ｇｌｎ Ｍｅｔ Ｓｅｒ Ｔｈｒ Ｌｙｓ Ｖａｌ Ｌｅｕ Ｉｌｅ Ｇｌｎ Ｐｈｅ Ｌｅｕ Ｇｌｎ Ｌｙｓ Ｌｙｓ Ａｌａ Ｌｙｓ Ａｓｎ Ｌｅｕ Ａｓｐ Ａｌａ Ｉｌｅ Ｔｈｒ Ｔｈｒ Ｐｒｏ Ａｓｐ Ｐｒｏ Ｔｈｒ Ｔｈｒ Ａｓｎ Ａｌａ Ｓｅｒ Ｌｅｕ Ｌｅｕ Ｔｈｒ Ｌｙｓ Ｌｅｕ Ｇｌｎ Ａｌａ Ｇｌｎ Ａｓｎ Ｇｌｎ Ｔｒｐ Ｌｅｕ Ｇｌｎ Ａｓｐ Ｍｅｔ Ｔｈｒ Ｔｈｒ Ｈｉｓ Ｌｅｕ Ｉｌｅ Ｌｅｕ Ａｒｇ Ｓｅｒ Ｐｈｅ Ｌｙｓ Ｇｌｕ Ｐｈｅ Ｌｅｕ Ｇｌｎ Ｓｅｒ Ｓｅｒ Ｌｅｕ Ａｒｇ Ａｌａ Ｌｅｕ Ａｒｇ Ｇｌｎ Ｍｅｔ４、ヒトＢＣＤＦ が糖鎖を有さないものである請求項（１）記載の組成物
。 ５、ヒトＢＣＤＦが原核生物で作られたものである請求
項（１）記載の組成物。 ６、少なくとも一種の可溶化剤又は安定剤を含有する不
溶性キャリヤー培地中に溶解又は分散されたヒトＢＣＤ
Ｆの治療学的に有効な量を含んで成る請求項（１）記載
の組成物。７、液体形又は凍結乾燥形のいずれかである
請求項（１）又は（６）記載の組成物。 ８、可溶化剤又は安定剤として血清由来蛋白質を用いる
ことを特徴とする請求項（６）記載の組成物。 ９、血清由来蛋白質としてアルブミンを用いることを特
徴とする請求項（８）項記載の組成物。 １０、血清由来蛋白質としてα＿２−マクログロブリン
を用いることを特徴とする請求項（８）項記載の組成物
。[Claims] 1. A pharmaceutical composition in which human B cell molecular factor (hereinafter referred to as human BCDF) suitable for administration to animals or humans is stabilized. 2. The composition according to claim (1), wherein the human BCDF has the following amino acid sequence (I). Amino acid sequence (I): Pro Val Pro Pro Gly Glu Aap Ser Lys Asp Val Ala Ala Pro His Arg Gln Pro Leu Thr Ser Ser Glu Arg Ile Asp Lys Gln Ile Arg Thr Ile Leu Asp Gly Ile Ser Ala Leu Arg Lys Glu Thr Cys Asn Lys Ser Asn Met Cys Glu Ser Ser Lys Glu Ala Leu Ala Glu Asn Asn Leu Asn Leu Pro Lys Met Ala Glu Lys Asp Gly C ys Phe Gln Ser Gly Phe Asn Glu Glu Thr Cys Leu Val Lys Ile Ile Thr Gly Leu Leu Glu Phe Glu Val Tyr Leu Glu Tyr Leu Gln Asn Arg Phe Glu Ser Ser Glu Glu Gln Ala Arg Ala Val Gln Met Ser Thr Thr Lys Val Leu I le Gln Phe Leu Gln Lys Lys Ala Lys Asn Leu Asp Ala Ile Thr Thr Thr Pro Asp Pro Thr Thr Asn Ala Ser Leu Leu Thr Lys Leu Gln Ala Gln Asn Gln Trp Leu Gin Asp Met Thr Thr His Leu Ile Leu Arg Ser Phe Lys Glu P he Leu Gln Ser Ser Leu Arg Ala Leu Arg Gln Met 3, Human BCDF contains the following amino acids The composition according to claim (1), which has sequence (II). ¥ Amino acid sequence (II) ¥ Ala Pro Val Pro Pro Gly Glu Asp Ser Lys Asp Val Ala Ala Pro His Arg Gln Pro Leu Thr Ser Ser Glu Arg Ile Asp L ys Gin Ile Arg Tyr Ile Leu Asp Gly Ile Ser Ala Leu Arg Lys Glu Thr Cys Asn Lys Ser Asn Met Cys Glu Ser Ser Lys Glu Ala Leu Ala Glu Asn Asn Leu Asn Leu Pro Lys Met Ala Glu Lys Asp Gly C ys Phe Gln Ser Gly Phe Asn Glu Gln Thr Cys Leu Val Lys Ile Ile Thr Cys Leu Leu Glu Phe Gle Val Tyr Leu Glu Tyr Leu Gln Asn Arg Phe Glu Ser Ser Glu Glu Gln Ala Arg Ala Val Gln Met Ser Thr Thr Lys Val Leu I le Gln Phe Leu Gln Lys Lys Ala Lys Asn Leu Asp Ala Ile Thr Thr Thr Pro Asp Pro Thr Thr Asn Ala Ser Leu Leu Thr Lys Leu Gln Ala Gln Asn Gln Trp Leu Gln Asp Met Thr Thr His Leu Ile Leu Arg Ser Phe Lys Glu P he Leu Gln Ser Ser Leu Arg Ala Leu Arg Gln Met4, human BCDF has a sugar chain. The composition according to claim 1, wherein the composition does not contain any of the following. 5. The composition according to claim (1), wherein the human BCDF is produced by a prokaryote. 6. Human BCD dissolved or dispersed in an insoluble carrier medium containing at least one solubilizer or stabilizer
A composition according to claim 1, comprising a therapeutically effective amount of F. 7. The composition according to claim (1) or (6), which is either in liquid form or lyophilized form. 8. The composition according to claim 6, characterized in that a serum-derived protein is used as the solubilizer or stabilizer. 9. The composition according to claim (8), wherein albumin is used as the serum-derived protein. 10. The composition according to claim (8), characterized in that α_2-macroglobulin is used as the serum-derived protein.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1163088A JPH0327320A (en) | 1989-06-26 | 1989-06-26 | Human b cell differentiation factor pharmaceutical composition |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1163088A JPH0327320A (en) | 1989-06-26 | 1989-06-26 | Human b cell differentiation factor pharmaceutical composition |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH0327320A true JPH0327320A (en) | 1991-02-05 |
Family
ID=15766958
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP1163088A Pending JPH0327320A (en) | 1989-06-26 | 1989-06-26 | Human b cell differentiation factor pharmaceutical composition |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0327320A (en) |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5578301A (en) * | 1993-12-14 | 1996-11-26 | Sandoz Ltd. | Method for using GM-CSF to reduce the acute phase response in a patient being administered IL-6 therapy |
| US5599536A (en) * | 1993-12-13 | 1997-02-04 | Sandoz Ltd. | Method for suppressing the acute phase response in a patient receiving IL-6 therapy |
| US5635176A (en) * | 1992-05-11 | 1997-06-03 | Applied Research Systems Ars Holding N.V. | Pharmaceutical compositions containing IL-6 |
| JPWO2003072123A1 (en) * | 2002-02-28 | 2005-06-16 | ニプロ株式会社 | Stabilized albumin preparation |
| US6926898B2 (en) | 2000-04-12 | 2005-08-09 | Human Genome Sciences, Inc. | Albumin fusion proteins |
| WO2006033301A1 (en) * | 2004-09-21 | 2006-03-30 | Shiseido Company, Ltd. | Specular-gloss nail enamels |
| US7045318B2 (en) | 1995-12-30 | 2006-05-16 | Delta Biotechnology Limited | Recombinant fusion proteins to growth hormone and serum albumin |
| JP2006137678A (en) * | 2004-11-10 | 2006-06-01 | Shionogi & Co Ltd | Interleukin-2 composition |
-
1989
- 1989-06-26 JP JP1163088A patent/JPH0327320A/en active Pending
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5635176A (en) * | 1992-05-11 | 1997-06-03 | Applied Research Systems Ars Holding N.V. | Pharmaceutical compositions containing IL-6 |
| US5599536A (en) * | 1993-12-13 | 1997-02-04 | Sandoz Ltd. | Method for suppressing the acute phase response in a patient receiving IL-6 therapy |
| US5578301A (en) * | 1993-12-14 | 1996-11-26 | Sandoz Ltd. | Method for using GM-CSF to reduce the acute phase response in a patient being administered IL-6 therapy |
| US7045318B2 (en) | 1995-12-30 | 2006-05-16 | Delta Biotechnology Limited | Recombinant fusion proteins to growth hormone and serum albumin |
| US6926898B2 (en) | 2000-04-12 | 2005-08-09 | Human Genome Sciences, Inc. | Albumin fusion proteins |
| JPWO2003072123A1 (en) * | 2002-02-28 | 2005-06-16 | ニプロ株式会社 | Stabilized albumin preparation |
| WO2006033301A1 (en) * | 2004-09-21 | 2006-03-30 | Shiseido Company, Ltd. | Specular-gloss nail enamels |
| JP2006137678A (en) * | 2004-11-10 | 2006-06-01 | Shionogi & Co Ltd | Interleukin-2 composition |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP2074140B1 (en) | Fibrillation-resistant insulin and insulin analogues | |
| EP1599222B1 (en) | Stabilized aqueous compositions comprising tissue factor pathway inhibitor (tfpi) or tissue factor pathway inhibitor variant | |
| CN100389821C (en) | Stabilized polypeptide-containing liquid pharmaceutical composition | |
| RU2152399C2 (en) | Complex containing human insulin analog and pharmaceutical composition based on thereof | |
| JP2763815B2 (en) | Stabilized composition containing epidermal growth factor | |
| US4931544A (en) | Succinylated interleukin-2 for pharmaceutical compositions | |
| KR102340750B1 (en) | Stabilized topical composition comprising thymosin beta 4 as an active ingredient | |
| JP3927248B2 (en) | HGF lyophilized formulation | |
| WO1990000397A1 (en) | A pharmaceutical composition for interleukin-2 containing physiologically compatible stabilizers | |
| CN101588820A (en) | Alpha-lactalbumin composition | |
| JPH04218000A (en) | Modified polypeptide | |
| JP2000510813A (en) | Formulation for IL-12 | |
| CN1165034A (en) | Pharmaceutical preparation containing human growth hormone | |
| KR20180064536A (en) | The pharmaceutical composition of IL-2 | |
| US5582822A (en) | Treatment of leukemia using interleukin 2 | |
| JP2001501619A (en) | Pharmaceutical composition containing mpl ligand | |
| JPH0327320A (en) | Human b cell differentiation factor pharmaceutical composition | |
| IE64232B1 (en) | Non-glycosylated recombining human il2 in reduced form the process for obtaining it and its use as a medicament | |
| JP2818834B2 (en) | IL-1α stabilized pharmaceutical preparation | |
| AU629549B2 (en) | Homogeneous dimeric m-csf and storage stable formulations thereof | |
| JPH02157231A (en) | Cytostatic agent | |
| JPH01500829A (en) | Succinylated interleukin-2 for pharmaceutical compositions | |
| KR20130055665A (en) | Formulations for bovine granulocyte colony stimulating factor and variants thereof | |
| JPH0378847B2 (en) | ||
| WO2002072135A1 (en) | LIQUID INTERFERON α PREPARATIONS FOR INJECTION AND METHOD OF STABILIZING THE SAME |