WO2018166468A1 - Protéine de fusion immunitaire à action prolongée de type igg et son utilisation - Google Patents
Protéine de fusion immunitaire à action prolongée de type igg et son utilisation Download PDFInfo
- Publication number
- WO2018166468A1 WO2018166468A1 PCT/CN2018/078951 CN2018078951W WO2018166468A1 WO 2018166468 A1 WO2018166468 A1 WO 2018166468A1 CN 2018078951 W CN2018078951 W CN 2018078951W WO 2018166468 A1 WO2018166468 A1 WO 2018166468A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- sequence
- amino acid
- sequence listing
- molecule
- acid sequence
- Prior art date
Links
- 108020001507 fusion proteins Proteins 0.000 title claims abstract description 69
- 102000037865 fusion proteins Human genes 0.000 title claims abstract description 69
- 108090000623 proteins and genes Proteins 0.000 claims abstract description 112
- 239000012636 effector Substances 0.000 claims abstract description 81
- 102000004169 proteins and genes Human genes 0.000 claims abstract description 40
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 24
- 230000035790 physiological processes and functions Effects 0.000 claims abstract description 4
- 230000001900 immune effect Effects 0.000 claims description 52
- 230000008685 targeting Effects 0.000 claims description 46
- 108020004414 DNA Proteins 0.000 claims description 44
- 102000053602 DNA Human genes 0.000 claims description 44
- 239000003814 drug Substances 0.000 claims description 34
- 229940079593 drug Drugs 0.000 claims description 30
- 239000013604 expression vector Substances 0.000 claims description 27
- 206010028980 Neoplasm Diseases 0.000 claims description 25
- 208000023275 Autoimmune disease Diseases 0.000 claims description 23
- 201000010099 disease Diseases 0.000 claims description 18
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 18
- 102000005962 receptors Human genes 0.000 claims description 16
- 108020003175 receptors Proteins 0.000 claims description 16
- 108010023082 activin A Proteins 0.000 claims description 15
- 206010012601 diabetes mellitus Diseases 0.000 claims description 14
- 238000002560 therapeutic procedure Methods 0.000 claims description 14
- 102000005396 glutamine synthetase Human genes 0.000 claims description 13
- 108020002326 glutamine synthetase Proteins 0.000 claims description 13
- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical group C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 claims description 11
- 238000001727 in vivo Methods 0.000 claims description 11
- 102000018997 Growth Hormone Human genes 0.000 claims description 10
- 108010051696 Growth Hormone Proteins 0.000 claims description 10
- 108060008682 Tumor Necrosis Factor Proteins 0.000 claims description 10
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 claims description 10
- 238000009261 endocrine therapy Methods 0.000 claims description 9
- 229940034984 endocrine therapy antineoplastic and immunomodulating agent Drugs 0.000 claims description 9
- 239000000122 growth hormone Substances 0.000 claims description 9
- 102100033732 Tumor necrosis factor receptor superfamily member 1A Human genes 0.000 claims description 8
- 101710187743 Tumor necrosis factor receptor superfamily member 1A Proteins 0.000 claims description 8
- 102100033733 Tumor necrosis factor receptor superfamily member 1B Human genes 0.000 claims description 8
- 101710187830 Tumor necrosis factor receptor superfamily member 1B Proteins 0.000 claims description 8
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 claims description 8
- 102000009524 Vascular Endothelial Growth Factor A Human genes 0.000 claims description 8
- 239000013598 vector Substances 0.000 claims description 8
- 102100020948 Growth hormone receptor Human genes 0.000 claims description 7
- 108010068542 Somatotropin Receptors Proteins 0.000 claims description 7
- 108091008794 FGF receptors Proteins 0.000 claims description 6
- 102000044168 Fibroblast Growth Factor Receptor Human genes 0.000 claims description 6
- 108010086246 Glucagon-Like Peptide-1 Receptor Proteins 0.000 claims description 6
- 102100032882 Glucagon-like peptide 1 receptor Human genes 0.000 claims description 6
- 102100040898 Growth/differentiation factor 11 Human genes 0.000 claims description 6
- 101710194452 Growth/differentiation factor 11 Proteins 0.000 claims description 6
- 102100040892 Growth/differentiation factor 2 Human genes 0.000 claims description 6
- 102100036922 Tumor necrosis factor ligand superfamily member 13B Human genes 0.000 claims description 6
- 238000003259 recombinant expression Methods 0.000 claims description 6
- -1 CD86 Proteins 0.000 claims description 5
- 102000008203 CTLA-4 Antigen Human genes 0.000 claims description 5
- 108010021064 CTLA-4 Antigen Proteins 0.000 claims description 5
- 102000006461 Parathyroid Hormone Receptors Human genes 0.000 claims description 5
- 108010058828 Parathyroid Hormone Receptors Proteins 0.000 claims description 5
- 102000003982 Parathyroid hormone Human genes 0.000 claims description 5
- 108090000445 Parathyroid hormone Proteins 0.000 claims description 5
- 108010053096 Vascular Endothelial Growth Factor Receptor-1 Proteins 0.000 claims description 5
- 229960001319 parathyroid hormone Drugs 0.000 claims description 5
- 239000000199 parathyroid hormone Substances 0.000 claims description 5
- 102000003973 Fibroblast growth factor 21 Human genes 0.000 claims description 4
- 108090000376 Fibroblast growth factor 21 Proteins 0.000 claims description 4
- 102100028466 Frizzled-8 Human genes 0.000 claims description 4
- 101710140933 Frizzled-8 Proteins 0.000 claims description 4
- 108010090290 Growth Differentiation Factor 2 Proteins 0.000 claims description 4
- 101001063392 Homo sapiens Lymphocyte function-associated antigen 3 Proteins 0.000 claims description 4
- 101000914484 Homo sapiens T-lymphocyte activation antigen CD80 Proteins 0.000 claims description 4
- 101000611023 Homo sapiens Tumor necrosis factor receptor superfamily member 6 Proteins 0.000 claims description 4
- 102100030984 Lymphocyte function-associated antigen 3 Human genes 0.000 claims description 4
- 102100027222 T-lymphocyte activation antigen CD80 Human genes 0.000 claims description 4
- 102100034196 Thrombopoietin receptor Human genes 0.000 claims description 4
- 102100040403 Tumor necrosis factor receptor superfamily member 6 Human genes 0.000 claims description 4
- 102000013814 Wnt Human genes 0.000 claims description 4
- 108050003627 Wnt Proteins 0.000 claims description 4
- 230000002124 endocrine Effects 0.000 claims description 4
- 102000006496 Immunoglobulin Heavy Chains Human genes 0.000 claims description 3
- 108010019476 Immunoglobulin Heavy Chains Proteins 0.000 claims description 3
- 102100031988 Tumor necrosis factor ligand superfamily member 6 Human genes 0.000 claims description 3
- 108050002568 Tumor necrosis factor ligand superfamily member 6 Proteins 0.000 claims description 3
- 210000003719 b-lymphocyte Anatomy 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 230000004936 stimulating effect Effects 0.000 claims description 3
- 108010002352 Interleukin-1 Proteins 0.000 claims description 2
- 108090000176 Interleukin-13 Proteins 0.000 claims description 2
- 108050003558 Interleukin-17 Proteins 0.000 claims description 2
- 108010065637 Interleukin-23 Proteins 0.000 claims description 2
- 108090000978 Interleukin-4 Proteins 0.000 claims description 2
- 108010002616 Interleukin-5 Proteins 0.000 claims description 2
- 108090001007 Interleukin-8 Proteins 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims description 2
- 238000003776 cleavage reaction Methods 0.000 claims description 2
- 230000007017 scission Effects 0.000 claims description 2
- 125000003275 alpha amino acid group Chemical group 0.000 claims 42
- 101000880898 Dictyostelium discoideum Probable serine/threonine-protein kinase drkA Proteins 0.000 claims 2
- 101710198884 GATA-type zinc finger protein 1 Proteins 0.000 claims 2
- 102100040918 Pro-glucagon Human genes 0.000 claims 2
- 102000016548 Vascular Endothelial Growth Factor Receptor-1 Human genes 0.000 claims 2
- 239000012190 activator Substances 0.000 claims 2
- 102000035160 transmembrane proteins Human genes 0.000 claims 2
- 108091005703 transmembrane proteins Proteins 0.000 claims 2
- 238000012338 Therapeutic targeting Methods 0.000 claims 1
- 150000001413 amino acids Chemical group 0.000 description 42
- 235000018102 proteins Nutrition 0.000 description 33
- 210000004369 blood Anatomy 0.000 description 16
- 239000008280 blood Substances 0.000 description 16
- 125000000539 amino acid group Chemical group 0.000 description 15
- 108010005794 dulaglutide Proteins 0.000 description 15
- 229960005175 dulaglutide Drugs 0.000 description 13
- 210000004027 cell Anatomy 0.000 description 11
- 108010088751 Albumins Proteins 0.000 description 10
- 102000009027 Albumins Human genes 0.000 description 10
- 108060003951 Immunoglobulin Proteins 0.000 description 9
- 238000010276 construction Methods 0.000 description 9
- 102000018358 immunoglobulin Human genes 0.000 description 9
- 102100026120 IgG receptor FcRn large subunit p51 Human genes 0.000 description 8
- 238000002474 experimental method Methods 0.000 description 8
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 7
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 7
- 101710177940 IgG receptor FcRn large subunit p51 Proteins 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 239000008103 glucose Substances 0.000 description 7
- 238000010254 subcutaneous injection Methods 0.000 description 7
- 239000007929 subcutaneous injection Substances 0.000 description 7
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 6
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 description 6
- 230000001817 pituitary effect Effects 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 101000851007 Homo sapiens Vascular endothelial growth factor receptor 2 Proteins 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 5
- 210000004899 c-terminal region Anatomy 0.000 description 5
- 239000002609 medium Substances 0.000 description 5
- 102100034136 Serine/threonine-protein kinase receptor R3 Human genes 0.000 description 4
- 101710082813 Serine/threonine-protein kinase receptor R3 Proteins 0.000 description 4
- 208000020221 Short stature Diseases 0.000 description 4
- 102100033178 Vascular endothelial growth factor receptor 1 Human genes 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 238000004364 calculation method Methods 0.000 description 4
- 238000010367 cloning Methods 0.000 description 4
- 230000029087 digestion Effects 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000012163 sequencing technique Methods 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- UZOVYGYOLBIAJR-UHFFFAOYSA-N 4-isocyanato-4'-methyldiphenylmethane Chemical compound C1=CC(C)=CC=C1CC1=CC=C(N=C=O)C=C1 UZOVYGYOLBIAJR-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 108010028006 B-Cell Activating Factor Proteins 0.000 description 3
- 108010008165 Etanercept Proteins 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 101000976075 Homo sapiens Insulin Proteins 0.000 description 3
- 102100039345 Immunoglobulin heavy constant gamma 1 Human genes 0.000 description 3
- 241000282567 Macaca fascicularis Species 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- 102000050862 Transmembrane Activator and CAML Interactor Human genes 0.000 description 3
- 101710178302 Tumor necrosis factor receptor superfamily member 13B Proteins 0.000 description 3
- HMNZFMSWFCAGGW-XPWSMXQVSA-N [3-[hydroxy(2-hydroxyethoxy)phosphoryl]oxy-2-[(e)-octadec-9-enoyl]oxypropyl] (e)-octadec-9-enoate Chemical compound CCCCCCCC\C=C\CCCCCCCC(=O)OCC(COP(O)(=O)OCCO)OC(=O)CCCCCCC\C=C\CCCCCCCC HMNZFMSWFCAGGW-XPWSMXQVSA-N 0.000 description 3
- 108010081667 aflibercept Proteins 0.000 description 3
- 229960002833 aflibercept Drugs 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 229960000403 etanercept Drugs 0.000 description 3
- 230000004927 fusion Effects 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- PBGKTOXHQIOBKM-FHFVDXKLSA-N insulin (human) Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H]1CSSC[C@H]2C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3C=CC(O)=CC=3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3NC=NC=3)NC(=O)[C@H](CO)NC(=O)CNC1=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O)=O)CSSC[C@@H](C(N2)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)[C@@H](C)CC)[C@@H](C)O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1=CN=CN1 PBGKTOXHQIOBKM-FHFVDXKLSA-N 0.000 description 3
- 230000006320 pegylation Effects 0.000 description 3
- 238000012216 screening Methods 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- 238000001356 surgical procedure Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 102100021886 Activin receptor type-2A Human genes 0.000 description 2
- 102100027647 Activin receptor type-2B Human genes 0.000 description 2
- 108010084313 CD58 Antigens Proteins 0.000 description 2
- 108010019673 Darbepoetin alfa Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- 101710204270 Growth/differentiation factor 2 Proteins 0.000 description 2
- 101000970954 Homo sapiens Activin receptor type-2A Proteins 0.000 description 2
- 101000937269 Homo sapiens Activin receptor type-2B Proteins 0.000 description 2
- 101000961156 Homo sapiens Immunoglobulin heavy constant gamma 1 Proteins 0.000 description 2
- 101000851018 Homo sapiens Vascular endothelial growth factor receptor 1 Proteins 0.000 description 2
- 102000002265 Human Growth Hormone Human genes 0.000 description 2
- 108010000521 Human Growth Hormone Proteins 0.000 description 2
- 239000000854 Human Growth Hormone Substances 0.000 description 2
- 108010057186 Insulin Glargine Proteins 0.000 description 2
- COCFEDIXXNGUNL-RFKWWTKHSA-N Insulin glargine Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H]1CSSC[C@H]2C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3C=CC(O)=CC=3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3NC=NC=3)NC(=O)[C@H](CO)NC(=O)CNC1=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(=O)NCC(O)=O)=O)CSSC[C@@H](C(N2)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)[C@@H](C)CC)[C@@H](C)O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1=CN=CN1 COCFEDIXXNGUNL-RFKWWTKHSA-N 0.000 description 2
- 108700036276 KH902 fusion Proteins 0.000 description 2
- 108091006006 PEGylated Proteins Proteins 0.000 description 2
- 102000035195 Peptidases Human genes 0.000 description 2
- 108091005804 Peptidases Proteins 0.000 description 2
- 239000004365 Protease Substances 0.000 description 2
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 2
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 2
- 108010073925 Vascular Endothelial Growth Factor B Proteins 0.000 description 2
- 102000009521 Vascular Endothelial Growth Factor B Human genes 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 229940115115 aranesp Drugs 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 230000004888 barrier function Effects 0.000 description 2
- 229950005748 conbercept Drugs 0.000 description 2
- 239000012228 culture supernatant Substances 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 230000004069 differentiation Effects 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 208000030172 endocrine system disease Diseases 0.000 description 2
- 229940088598 enzyme Drugs 0.000 description 2
- 239000013613 expression plasmid Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 229920000669 heparin Polymers 0.000 description 2
- ZFGMDIBRIDKWMY-PASTXAENSA-N heparin Chemical compound CC(O)=N[C@@H]1[C@@H](O)[C@H](O)[C@@H](COS(O)(=O)=O)O[C@@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](O[C@H]2[C@@H]([C@@H](OS(O)(=O)=O)[C@@H](O[C@@H]3[C@@H](OC(O)[C@H](OS(O)(=O)=O)[C@H]3O)C(O)=O)O[C@@H]2O)CS(O)(=O)=O)[C@H](O)[C@H]1O ZFGMDIBRIDKWMY-PASTXAENSA-N 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 239000002050 international nonproprietary name Substances 0.000 description 2
- 238000012933 kinetic analysis Methods 0.000 description 2
- 229940060975 lantus Drugs 0.000 description 2
- 210000004698 lymphocyte Anatomy 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 108010001564 pegaspargase Proteins 0.000 description 2
- 229940002988 pegasys Drugs 0.000 description 2
- 108010092853 peginterferon alfa-2a Proteins 0.000 description 2
- 108010092851 peginterferon alfa-2b Proteins 0.000 description 2
- 229940106366 pegintron Drugs 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 230000008929 regeneration Effects 0.000 description 2
- 238000011069 regeneration method Methods 0.000 description 2
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 2
- 238000007619 statistical method Methods 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 210000005239 tubule Anatomy 0.000 description 2
- 230000005747 tumor angiogenesis Effects 0.000 description 2
- PNVNVHUZROJLTJ-UHFFFAOYSA-N venlafaxine Chemical compound C1=CC(OC)=CC=C1C(CN(C)C)C1(O)CCCCC1 PNVNVHUZROJLTJ-UHFFFAOYSA-N 0.000 description 2
- SPFMQWBKVUQXJV-BTVCFUMJSA-N (2r,3s,4r,5r)-2,3,4,5,6-pentahydroxyhexanal;hydrate Chemical compound O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O SPFMQWBKVUQXJV-BTVCFUMJSA-N 0.000 description 1
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 238000012492 Biacore method Methods 0.000 description 1
- 208000031648 Body Weight Changes Diseases 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 108091026890 Coding region Proteins 0.000 description 1
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 208000017701 Endocrine disease Diseases 0.000 description 1
- 241001646716 Escherichia coli K-12 Species 0.000 description 1
- 102000015212 Fas Ligand Protein Human genes 0.000 description 1
- 108010039471 Fas Ligand Protein Proteins 0.000 description 1
- 101150050927 Fcgrt gene Proteins 0.000 description 1
- PZOHPVWRSNXCRP-QRCCJXOFSA-N GPL-1 Chemical compound C([C@@H](NC(=O)CC(O)CCCCCCCCCCCCCCCCCCCCCCCCCCCCC)C(=O)N[C@H]([C@@H](C)OC1[C@@H]([C@H](O)[C@H](O)[C@H](C)O1)O[C@H]1[C@@H]([C@H](O)[C@@H](O)[C@H](C)O1)O)C(=O)N[C@H](C)C(=O)N[C@@H](C)COC1[C@@H]([C@H](OC)[C@@H](OC)[C@H](C)O1)O)C1=CC=CC=C1 PZOHPVWRSNXCRP-QRCCJXOFSA-N 0.000 description 1
- 102400000322 Glucagon-like peptide 1 Human genes 0.000 description 1
- 101800000224 Glucagon-like peptide 1 Proteins 0.000 description 1
- 229940089838 Glucagon-like peptide 1 receptor agonist Drugs 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 101000987586 Homo sapiens Eosinophil peroxidase Proteins 0.000 description 1
- 101500025353 Homo sapiens Insulin A chain Proteins 0.000 description 1
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 1
- 101710083136 Immunoglobulin heavy constant gamma 1 Proteins 0.000 description 1
- 102000016844 Immunoglobulin-like domains Human genes 0.000 description 1
- 108050006430 Immunoglobulin-like domains Proteins 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- SXTAYKAGBXMACB-DPVSGNNYSA-N L-methionine sulfoximine Chemical compound CS(=N)(=O)CC[C@H](N)C(O)=O SXTAYKAGBXMACB-DPVSGNNYSA-N 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- 239000012515 MabSelect SuRe Substances 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- QGMRQYFBGABWDR-UHFFFAOYSA-M Pentobarbital sodium Chemical compound [Na+].CCCC(C)C1(CC)C(=O)NC(=O)[N-]C1=O QGMRQYFBGABWDR-UHFFFAOYSA-M 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 108090000873 Receptor Protein-Tyrosine Kinases Proteins 0.000 description 1
- 102000004278 Receptor Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108010071390 Serum Albumin Proteins 0.000 description 1
- 102000007562 Serum Albumin Human genes 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 102100025237 T-cell surface antigen CD2 Human genes 0.000 description 1
- 108091008605 VEGF receptors Proteins 0.000 description 1
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 1
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 1
- 229960003697 abatacept Drugs 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 108010080374 albuferon Proteins 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 230000000890 antigenic effect Effects 0.000 description 1
- 210000000436 anus Anatomy 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 238000011888 autopsy Methods 0.000 description 1
- 229960005347 belatacept Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000004579 body weight change Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 210000001151 cytotoxic T lymphocyte Anatomy 0.000 description 1
- 238000013480 data collection Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- UQLDLKMNUJERMK-UHFFFAOYSA-L di(octadecanoyloxy)lead Chemical compound [Pb+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O UQLDLKMNUJERMK-UHFFFAOYSA-L 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 239000003651 drinking water Substances 0.000 description 1
- 235000020188 drinking water Nutrition 0.000 description 1
- 238000003255 drug test Methods 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 210000000613 ear canal Anatomy 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000004313 glare Effects 0.000 description 1
- 102000034238 globular proteins Human genes 0.000 description 1
- 108091005896 globular proteins Proteins 0.000 description 1
- 230000024924 glomerular filtration Effects 0.000 description 1
- 229930182478 glucoside Natural products 0.000 description 1
- 230000013595 glycosylation Effects 0.000 description 1
- 238000006206 glycosylation reaction Methods 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 210000004349 growth plate Anatomy 0.000 description 1
- 229960001008 heparin sodium Drugs 0.000 description 1
- 239000000833 heterodimer Substances 0.000 description 1
- 101150026546 hsa gene Proteins 0.000 description 1
- 102000044890 human EPO Human genes 0.000 description 1
- 210000002758 humerus Anatomy 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 210000004283 incisor Anatomy 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- 210000003712 lysosome Anatomy 0.000 description 1
- 230000001868 lysosomic effect Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 102000035118 modified proteins Human genes 0.000 description 1
- 108091005573 modified proteins Proteins 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 108010068617 neonatal Fc receptor Proteins 0.000 description 1
- 229940071846 neulasta Drugs 0.000 description 1
- 229920001542 oligosaccharide Polymers 0.000 description 1
- 150000002482 oligosaccharides Chemical class 0.000 description 1
- 229940099216 oncaspar Drugs 0.000 description 1
- 230000036407 pain Effects 0.000 description 1
- 206010033675 panniculitis Diseases 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 108010044644 pegfilgrastim Proteins 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 229960002275 pentobarbital sodium Drugs 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 230000008884 pinocytosis Effects 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 230000004952 protein activity Effects 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- 238000012113 quantitative test Methods 0.000 description 1
- 238000002271 resection Methods 0.000 description 1
- 239000012146 running buffer Substances 0.000 description 1
- 238000003118 sandwich ELISA Methods 0.000 description 1
- 229910001961 silver nitrate Inorganic materials 0.000 description 1
- 238000002741 site-directed mutagenesis Methods 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000001632 sodium acetate Substances 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
- 230000000392 somatic effect Effects 0.000 description 1
- 210000004304 subcutaneous tissue Anatomy 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 238000010257 thawing Methods 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 239000013638 trimer Substances 0.000 description 1
- 229940013051 trulicity Drugs 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000004565 tumor cell growth Effects 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 210000001364 upper extremity Anatomy 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 239000009530 yishen Substances 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/18—Growth factors; Growth regulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/26—Glucagons
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/27—Growth hormone [GH], i.e. somatotropin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K19/00—Hybrid peptides, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/30—Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
Definitions
- Constructing mutants by constructing mutants to extend the half-life of the protein commonly used methods are: 1. Increase the degree of glycosylation of protein drugs, so as to form a protective effect on the surface of protein drugs, hinder the degradation of protein drugs by proteases, and increase protein stability. At the same time, the molecular weight of the protein drug is increased, and glomerular filtration is reduced.
- Drugs that have been successfully developed and marketed include recombinant human EPO mutants (Aranesp from Amgen) and recombinant human insulin mutants (Lantus from Aventis).
- Aranesp uses site-directed mutagenesis to increase the number of N-linked oligosaccharides from 3 to 5, increasing the molecular weight from 30 kDa to 50 kDa, and extending the half-life from 4-13 h to an average of 49 h. 2.
- the time to release the free drug is prolonged by forming a sustained release microprecipitate.
- Lantus is a mutant of recombinant human insulin expressed from E. coli K12 strain, which mutates Asp to Gly at the 21st position of the human insulin A chain; and adds two Arg at the 30th position of the B-chain carbon end.
- the isoelectric point PI of insulin changed from the original pH 4.0 to pH 6.7.
- PEGylation modified PEGylation ie polyethylene (PEG) covalently modified protein.
- PEGylated protein drugs mainly reduce the molecular weight of proteins, reduce the filtration of drugs from the renal tubules, and PEG can act as a barrier to block the antigenic determinants on the surface of protein molecules, reduce immunogenicity, reduce the clearance rate in vivo, and the barrier function of PEG can also protect proteins. It is not easily hydrolyzed by proteases. These characteristics of PEGylation are beneficial to prolong the half-life of protein drugs.
- PEGylated protein drugs such as PEGylated asparaginase (Enzon's Oncaspar), PEGylated IFN ⁇ 2b (Schering's PEGIntron), PEGylated IFN ⁇ 2a (Roche's Pegasys) and PEGylated G - CSF (Neulasta of Amgen).
- Serum albumin fusion human serum, albumin is a single-chain aglycosylated globular protein with 585 amino acid residues, molecular weight 65kDa, most therapeutic proteins and peptides generally have a short half-life. HSA has a serum half-life of up to 19 days. The results of clinical trials showed that the average half-life of Albuferon ⁇ (HSA/IFN ⁇ fusion protein) was 148 hours, which was longer than the average half-life of Pegasys (80-140 hours) and the average half-life of PEGIntron 40 hours (22-60 hours).
- Albutropin is a protein expressed by fusion of the HSA gene and the recombinant human growth hormone (rHGH) gene. In monkeys, subcutaneous injection of albutropin (0.3 mg/kg) and HGH (0.3 mg/kg) resulted in a 6-fold increase in half-life and a 8-fold slower clearance.
- a fusion protein prepared by human Fc The fusion protein prepared by albumin fusion protein and Fc mainly enhances the biological half-life of the drug through two mechanisms, one is to increase the molecular weight of the drug, so that it is not easily filtered by the renal tubule; the other is through the neonatal Fc Binding of the neonatal Fc receptor (FcRn) protects the target protein from clearance in the blood (Rath T, Baker K, Dumont JA, et al. Crit Rev Biotechnol. 2015 Jun; 35(2): 235-54).
- FcRn neonatal Fc Binding of the neonatal Fc receptor
- the FcRn receptor encoded by the fcgrt gene, also known as the Brambell receptor, is an MHC class I-like receptor molecule that forms a heterodimer with a non-covalent bond with ⁇ 2 m microglobulin.
- the binding of the FcRn receptor to albumin and immunoglobulin is strictly pH dependent, and FcRn does not bind to albumin and immunoglobulin under physiological conditions (pH 7.4).
- albumin and immunoglobulin are endocytosed into the cells through the pinocytosis pathway, in acidic lysosomes (pH 6.0-6.5), the affinity of FcRn with albumin and immunoglobulin is increased to form a complex, FcRn protection.
- Albumin and immunoglobulin are not degraded and release albumin and immunoglobulin out of the cell through the membranous circulation.
- the binding of albumin and immunoglobulin to FcRn protects them from being metabolized, extending their biological half-life.
- the present invention designs an IgG-like immunological fusion protein, which can effectively prolong the biological half-life of the protein drug (effector molecule), which is far better than the similar Fc immunofusion protein.
- Heavy chain class may be an IgG1, IgG2 and IgG4, the heavy chain comprises a constant region (C H 1, C H 2 and C H 3).
- the amino acid sequence of the linker peptide may be selected from any one of the following: AKTTPKLEEGEFSEAR (SEQ ID NO: 1); AKTTPKLEEGEFSEARV (SEQ ID NO: 2); AKTTPKLGG (SEQ ID NO: 3); SAKTTPKLGG (SEQ ID NO: 4); SAKTTP (SEQ ID NO: 5); RADAAP (sequence) 6); RADAAPTVS (sequence 7); RADAAAAGGPGS (sequence 8); RADAAAA (sequence 9); SAKTTPKLEEGEFSEARV (sequence 10); ADAAP (sequence 11); DAAPTVSIFPP (sequence 12); TVAAP (sequence 13); TVAAPSVFIFPP (sequence 14) ;QPKAAP (sequence 15); QPKAAPSVTLFPP (sequence 16); AKTTPP (sequence 17); AKTTPPSVTPLAP (se
- Mode 1 The effector molecule is respectively linked to the two heavy chains of the constant region of the IgG antibody and the N-terminus of the two light chains by the linker peptide; the molecular formula is named: (EL) 2 (EH) 2 , E is Effector molecule. E- represents an N-terminal linkage, L is a light chain, and H is a heavy chain.
- Mode 4 The effector molecule is linked to the C-terminus of two light chains of the IgG antibody constant region through the linker peptide, and no heavy chain is attached; the molecular formula is named: (LE) 2 H 2 , and E is an effector molecule.
- -E represents a C-terminal linkage, L is a light chain, and H is a heavy chain.
- Mode 5 The effector molecule is linked to the N-terminus of two heavy chains of the IgG antibody constant region through the linker peptide, and no light chain is attached; the molecular formula is named: L 2 (EH) 2 , and E is an effector molecule.
- E- represents an N-terminal linkage, L is a light chain, and H is a heavy chain.
- Mode 6 The effector molecule is linked to the N-terminus of the two heavy chains of the IgG antibody constant region and the C-terminus of the two light chains by the linker peptide, respectively.
- the molecular formula is named: (LE) 2 (EH) 2 , E is an effector molecule, -E represents a C-terminal linkage, E- represents an N-terminal linkage, L is a light chain, and H is a heavy chain.
- Mode 8 The effector molecule is respectively linked to the N-terminus and the two heavy-chain C-termini of two light chains of the IgG antibody constant region by the linker peptide; the molecular formula is named: (EL) 2 (HE) 2 , E is an effector molecule, -E represents a C-terminal linkage, E- represents an N-terminal linkage, L is a light chain, and H is a heavy chain.
- FIG. 1 See Figure 1 for a schematic diagram of the structure of the IgG-like immunological fusion protein formed by the above eight ligation methods.
- the targeting molecule for treating the autoimmune disease may be specifically selected from any one of the following: Tumor necrosis factor (TNF- ⁇ ), IL-1, IL-4, IL-5, IL-8, Molecules such as IL-13, IL-17, IL-23, CD80, CD86, CD2, CD110, CD257, and B lymphocyte stimulator (BLyS); mainly by inhibiting inflammatory mediators or by impeding lymphocyte surface receptors Somatic molecules inhibit the activation of lymphocytes.
- TNF- ⁇ Tumor necrosis factor
- IL-1 IL-1
- IL-4 IL-5
- IL-8 Molecules
- Molecules such as IL-13, IL-17, IL-23, CD80, CD86, CD2, CD110, CD257, and B lymphocyte stimulator (BLyS)
- B lymphocyte stimulator mainly by inhibiting inflammatory mediators or by impeding lymphocyte surface receptors Somatic molecules inhibit the activation of lymphocytes.
- the target molecule for tumor treatment may be specifically selected from any one of the following: vascular endothelial growth factor A (VEGF-A), Fas ligand (FasL), growth differentiation factor 2 (Growth) Differentiation molecules 2, GDF-2), Wnt, Bone morphogenetic protein 11, BMP-11, and activin A (Activin A); mainly by inhibiting tumor angiogenesis and promoting tumor cell apoptosis, Inhibition of tumor cell growth and metastasis to achieve the purpose of treating tumors.
- VEGF-A vascular endothelial growth factor A
- Fas ligand Fas ligand
- GDF-2 growth differentiation factor 2
- Wnt Wnt
- Bone morphogenetic protein 11 Bone morphogenetic protein 11
- activin A activin A
- the targeting molecule of the endocrine therapy may specifically be a molecule such as a growth hormone receptor (GHR) or a parathyroid hormone receptor (Parathyroid Hormone receptor). It exerts physiological effects through growth hormone and parathyroid hormone and its analogues for the treatment of diseases such as short stature, burns, and osteoporosis.
- GHR growth hormone receptor
- Paraathyroid Hormone receptor parathyroid Hormone receptor
- the disease may be various diseases such as diabetes, autoimmune diseases, tumors or endocrine-related diseases.
- the BY19.3L coding gene was ligated to the glutamine synthetase high-efficiency expression vector with double expression cassette by XhoI-EcoRI double digestion (see Patent Application No.: 201410441296.0); the BY19.3H coding gene was cloned by XbaI-SaII, respectively.
- the glutamine synthetase high-efficiency expression vector (the recombinant expression vector was verified and verified by sequencing) to the double expression cassette of the BY19.3L-encoded light chain gene, and the expressed IgG-like fusion protein was named BY19.3, and the molecular formula L 2 (HE) 2 .
- the high-expressing cells obtained in step 1 were cultured in serum-free CD OptiCHO, and the culture supernatant was collected at a cell viability of about 60%.
- the HiTrap MabSelect SuRe 1 ml column (GE Healthcare Life Sciences product, Cat. No: 11-0034-93) was equilibrated with a pH 7.4 PBS solution at 10 bed volumes at a flow rate of 0.5 ml/min; the culture supernatant was filtered with a 0.45 ⁇ m filter. Filtration was carried out at a flow rate of 0.5 ml/min.
- GLP-1R GLP-1R
- VEGF-A vascular endothelial growth factor
- VEGF-B TNF- ⁇
- All products of Yishen Shenzhou were diluted to a concentration of 10 ⁇ g/ml, and covalently immobilized on carboxymethyl glucoside via primary amine by amino coupling.
- Sugar-coated CM5 chip General Electric product
- fixed buffer 10 mM sodium acetate (pH 5.0) fixed amount of 1000 RU.
- Regeneration solution glycine buffer with a pH of 1.5-2.0; injection time: 30 s; flow rate: 30 ⁇ l/min.
- PBST (formulation: 0.005% by volume of Tween 20 in PBS) is Running buffer; using Kinetic Analysis Wizard mode; Dulaglutide, BY23.2, BY25 and BY19.3 are diluted to 600, 300, 150, respectively. Concentration gradients of 75, 37.5 and 18.75 nM; injection time: 2 min, dissociation time: 5 min, flow rate: 30 ⁇ l/min.
- Type II diabetes model db/db mice (Changzhou Cavans Experimental Animal Co., Ltd.), measured basal blood glucose after fasting for 3 hours, and blood glucose concentration greater than 10 mmol/L into groups; with a few points 2 groups, each group 6 Only mice.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Zoology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Epidemiology (AREA)
- Gastroenterology & Hepatology (AREA)
- Endocrinology (AREA)
- Genetics & Genomics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Diabetes (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Biophysics (AREA)
- Biotechnology (AREA)
- General Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Wood Science & Technology (AREA)
- Physics & Mathematics (AREA)
- Plant Pathology (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Emergency Medicine (AREA)
- Toxicology (AREA)
- Microbiology (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
L'invention concerne une protéine de fusion immunitaire à action prolongée de type IgG et son utilisation. La protéine de fusion immunitaire à action prolongée de type IgG est constituée d'une molécule effectrice et d'une région constante d'un anticorps IgG, et la molécule effectrice est liée à la région constante de l'anticorps IgG au moyen d'un peptide lieur ; la molécule effectrice est une protéine capable d'exercer des fonctions physiologiques dans le corps ; et la région constante de l'anticorps IgG est une structure de l'anticorps IgG avec deux régions variables de chaîne lourde et deux régions variables de chaîne légère déplacées.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201710159592.5A CN108623691B (zh) | 2017-03-17 | 2017-03-17 | IgG样长效免疫融合蛋白及其应用 |
CN201710159592.5 | 2017-03-17 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2018166468A1 true WO2018166468A1 (fr) | 2018-09-20 |
Family
ID=63522825
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CN2018/078951 WO2018166468A1 (fr) | 2017-03-17 | 2018-03-14 | Protéine de fusion immunitaire à action prolongée de type igg et son utilisation |
Country Status (2)
Country | Link |
---|---|
CN (1) | CN108623691B (fr) |
WO (1) | WO2018166468A1 (fr) |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111378044B (zh) * | 2018-12-28 | 2022-07-15 | 长春金赛药业有限责任公司 | 抗体融合蛋白、制备方法及其应用 |
CN111423512B (zh) * | 2019-01-10 | 2024-01-05 | 北京比洋生物技术有限公司 | 阻断血管内皮细胞生长且活化t细胞的多靶向融合蛋白和包含其的药物组合物 |
CN111458396B (zh) * | 2019-01-18 | 2022-07-08 | 成都康弘生物科技有限公司 | 一种蛋白的电荷异质性检测方法 |
JP2022522787A (ja) * | 2019-03-05 | 2022-04-20 | サンシャイン・レイク・ファーマ・カンパニー・リミテッド | ポリペプチド分子及びその適用 |
CN112646042A (zh) * | 2019-10-10 | 2021-04-13 | 陕西麦科奥特科技有限公司 | 活性多肽化合物 |
CN116715749B (zh) * | 2023-03-20 | 2024-04-09 | 吉林大学 | 一种与胶原具有特异结合能力vegf活性抑制蛋白及其制备方法与应用 |
CN117143242B (zh) * | 2023-10-30 | 2024-03-29 | 南京佰抗生物科技有限公司 | 抗Galectin-3蛋白的单克隆抗体组合物及应用 |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1758924A (zh) * | 2003-01-10 | 2006-04-12 | 株式会社新潟Tlo | 基因治疗用载体以及利用该基因治疗用载体在哺乳动物中或培养细胞中进行目的蛋白定量的方法 |
CN1829533A (zh) * | 2003-05-30 | 2006-09-06 | 阿莱克申药物公司 | 包含改造恒定区的抗体和融合蛋白 |
CN101426519A (zh) * | 2004-03-31 | 2009-05-06 | 森托科尔公司 | 人glp-1模拟体、组合物、方法和用途 |
CN103204944A (zh) * | 2013-03-26 | 2013-07-17 | 江苏健德生物药业有限公司 | 用于治疗糖尿病的长效免疫融合蛋白 |
CN105899532A (zh) * | 2013-08-30 | 2016-08-24 | 艾普丽尔生物有限公司 | 抗血清白蛋白的fab-效应物部分的融合构建体及其制备方法 |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ES2384055T3 (es) * | 2005-12-30 | 2012-06-28 | Merck Patent Gmbh | Variantes de la interleucina-12p40 con estabilidad mejorada |
CN104231086B (zh) * | 2013-08-27 | 2019-12-13 | 北京韩美药品有限公司 | 双功能融合蛋白及其制备方法和用途 |
-
2017
- 2017-03-17 CN CN201710159592.5A patent/CN108623691B/zh active Active
-
2018
- 2018-03-14 WO PCT/CN2018/078951 patent/WO2018166468A1/fr active Application Filing
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1758924A (zh) * | 2003-01-10 | 2006-04-12 | 株式会社新潟Tlo | 基因治疗用载体以及利用该基因治疗用载体在哺乳动物中或培养细胞中进行目的蛋白定量的方法 |
CN1829533A (zh) * | 2003-05-30 | 2006-09-06 | 阿莱克申药物公司 | 包含改造恒定区的抗体和融合蛋白 |
CN101426519A (zh) * | 2004-03-31 | 2009-05-06 | 森托科尔公司 | 人glp-1模拟体、组合物、方法和用途 |
CN103204944A (zh) * | 2013-03-26 | 2013-07-17 | 江苏健德生物药业有限公司 | 用于治疗糖尿病的长效免疫融合蛋白 |
CN105899532A (zh) * | 2013-08-30 | 2016-08-24 | 艾普丽尔生物有限公司 | 抗血清白蛋白的fab-效应物部分的融合构建体及其制备方法 |
Also Published As
Publication number | Publication date |
---|---|
CN108623691B (zh) | 2020-05-15 |
CN108623691A (zh) | 2018-10-09 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2018166468A1 (fr) | Protéine de fusion immunitaire à action prolongée de type igg et son utilisation | |
RU2711979C2 (ru) | Белковый комплекс интерлейкина 15 и его применение | |
KR102493543B1 (ko) | 자가면역 질환의 치료를 위한 조절 t 세포를 선택적으로 활성화시키는 분자 | |
JP6448368B2 (ja) | 免疫グロブリンFc変異体 | |
TWI621626B (zh) | 新穎胰島素類似物及其用途 | |
KR101281208B1 (ko) | 피브로넥틴 ed-b에 대한 항체 l19 및 인터루킨12의 융합 단백질 | |
EP2585098B1 (fr) | Domaines extracellulaires fzd8 et molécules de fusion au domaine extracellulaire fzd8 pour l'utilisation dans le traitement de l'obésité et troubles liés à l'obésité | |
KR20080022539A (ko) | 키메라 단백질 | |
AU2005248276A1 (en) | Glycosylated immunoglobulin and immunoadhesin comprising the same | |
KR20140015152A (ko) | Fc 융합 단백질의 혈청 반감기를 증가시키는 조성물들 및 방법들 | |
JP2000504210A (ja) | 半減期の長いobタンパク質誘導体 | |
US20080292628A1 (en) | Chimeric Protein | |
WO2020097946A1 (fr) | Protéine de fusion de l'interleukine-10 humaine recombinée et utilisation associée | |
US20240209049A1 (en) | Heterodimeric fc cytokines and uses thereof | |
AU2016332062A1 (en) | Treatment of bile acid disorders | |
IL293822A (en) | Cd122 with weird icd stat signal | |
CA3234552A1 (fr) | Cytokines fc heterodimeres et leurs utilisations | |
KR101791272B1 (ko) | 넓은 스펙트럼 erbb 리간드 결합 분자 및 이들을 제조하고 이용하는 방법 | |
WO2021043127A1 (fr) | Protéine chimérique | |
JP2013253079A (ja) | 生物学的に活性なヒト尿中トリプシンインヒビターのFc融合タンパク質並びにその調製および使用 | |
WO2011147320A1 (fr) | Antagoniste du facteur d'activation des lymphocytes b et son procédé de préparation et son utilisation | |
US20230272026A1 (en) | A fusion protein comprising an antigen binding domain and a cytokine trimer domain | |
WO2021031736A1 (fr) | Anticorps multifonctionnel, sa préparation et ses utilisations | |
WO2023025129A1 (fr) | Protéine de fusion gdf15 et son utilisation | |
WO2022007885A1 (fr) | Polypeptide de fusion et dimère de polypeptides, et utilisation associée |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 18767200 Country of ref document: EP Kind code of ref document: A1 |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 18767200 Country of ref document: EP Kind code of ref document: A1 |