WO2022235061A1 - 신규 단백질 - Google Patents
신규 단백질 Download PDFInfo
- Publication number
- WO2022235061A1 WO2022235061A1 PCT/KR2022/006356 KR2022006356W WO2022235061A1 WO 2022235061 A1 WO2022235061 A1 WO 2022235061A1 KR 2022006356 W KR2022006356 W KR 2022006356W WO 2022235061 A1 WO2022235061 A1 WO 2022235061A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- protein
- cancer
- ferritin
- peptide
- binding
- Prior art date
Links
- 108090000623 proteins and genes Proteins 0.000 title claims description 51
- 102000004169 proteins and genes Human genes 0.000 title claims description 50
- 102000008857 Ferritin Human genes 0.000 claims abstract description 84
- 108050000784 Ferritin Proteins 0.000 claims abstract description 84
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 70
- 238000009739 binding Methods 0.000 claims abstract description 56
- 101000766306 Homo sapiens Serotransferrin Proteins 0.000 claims abstract description 15
- XNSAINXGIQZQOO-SRVKXCTJSA-N protirelin Chemical compound NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)[C@H]1NC(=O)CC1)CC1=CN=CN1 XNSAINXGIQZQOO-SRVKXCTJSA-N 0.000 claims abstract description 15
- 235000018102 proteins Nutrition 0.000 claims description 48
- 238000008416 Ferritin Methods 0.000 claims description 42
- 102100026144 Transferrin receptor protein 1 Human genes 0.000 claims description 36
- 239000000178 monomer Substances 0.000 claims description 36
- 239000000427 antigen Substances 0.000 claims description 29
- 102000036639 antigens Human genes 0.000 claims description 29
- 108091007433 antigens Proteins 0.000 claims description 29
- 108010033576 Transferrin Receptors Proteins 0.000 claims description 23
- -1 LIGHT Proteins 0.000 claims description 22
- 201000010099 disease Diseases 0.000 claims description 19
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 19
- 102000037982 Immune checkpoint proteins Human genes 0.000 claims description 17
- 108091008036 Immune checkpoint proteins Proteins 0.000 claims description 17
- 229940126546 immune checkpoint molecule Drugs 0.000 claims description 17
- 239000012634 fragment Substances 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 14
- 239000003446 ligand Substances 0.000 claims description 12
- 102000005962 receptors Human genes 0.000 claims description 10
- 108020003175 receptors Proteins 0.000 claims description 10
- 102100029822 B- and T-lymphocyte attenuator Human genes 0.000 claims description 8
- 101100314454 Caenorhabditis elegans tra-1 gene Proteins 0.000 claims description 8
- 102000012199 E3 ubiquitin-protein ligase Mdm2 Human genes 0.000 claims description 8
- 108050002772 E3 ubiquitin-protein ligase Mdm2 Proteins 0.000 claims description 8
- 101000864344 Homo sapiens B- and T-lymphocyte attenuator Proteins 0.000 claims description 8
- 102100034256 Mucin-1 Human genes 0.000 claims description 8
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 claims description 8
- 108010074708 B7-H1 Antigen Proteins 0.000 claims description 7
- 101001002987 Homo sapiens Ferritin heavy chain Proteins 0.000 claims description 7
- 101000633784 Homo sapiens SLAM family member 7 Proteins 0.000 claims description 7
- 102100024216 Programmed cell death 1 ligand 1 Human genes 0.000 claims description 7
- 102100029198 SLAM family member 7 Human genes 0.000 claims description 7
- 150000001413 amino acids Chemical class 0.000 claims description 7
- 102000054087 human FTH1 Human genes 0.000 claims description 7
- 101000831007 Homo sapiens T-cell immunoreceptor with Ig and ITIM domains Proteins 0.000 claims description 6
- 102100024834 T-cell immunoreceptor with Ig and ITIM domains Human genes 0.000 claims description 6
- 235000001014 amino acid Nutrition 0.000 claims description 6
- 102100040678 Programmed cell death protein 1 Human genes 0.000 claims description 5
- SSOORFWOBGFTHL-OTEJMHTDSA-N (4S)-5-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[2-[(2S)-2-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-1-[[(2S)-1-[[(2S,3S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-5-amino-1-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-6-amino-1-[[(2S)-1-[[(2S)-1-[[(2S)-5-amino-1-[[(2S)-5-carbamimidamido-1-[[(2S)-5-carbamimidamido-1-[[(1S)-4-carbamimidamido-1-carboxybutyl]amino]-1-oxopentan-2-yl]amino]-1-oxopentan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-1-oxohexan-2-yl]amino]-1-oxohexan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-1-oxohexan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-methyl-1-oxopentan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-1-oxohexan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-1-oxopropan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]carbamoyl]pyrrolidin-1-yl]-2-oxoethyl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-1-oxohexan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(1H-imidazol-4-yl)-1-oxopropan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-4-[[(2S)-2-[[(2S)-2-[[(2S)-2,6-diaminohexanoyl]amino]-3-methylbutanoyl]amino]propanoyl]amino]-5-oxopentanoic acid Chemical compound CC[C@H](C)[C@H](NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H]1CCCN1C(=O)CNC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@@H](N)CCCCN)C(C)C)C(C)C)C(C)C)C(C)C)C(C)C)C(C)C)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O SSOORFWOBGFTHL-OTEJMHTDSA-N 0.000 claims description 4
- LKKMLIBUAXYLOY-UHFFFAOYSA-N 3-Amino-1-methyl-5H-pyrido[4,3-b]indole Chemical compound N1C2=CC=CC=C2C2=C1C=C(N)N=C2C LKKMLIBUAXYLOY-UHFFFAOYSA-N 0.000 claims description 4
- 108010082808 4-1BB Ligand Proteins 0.000 claims description 4
- 102100030310 5,6-dihydroxyindole-2-carboxylic acid oxidase Human genes 0.000 claims description 4
- 101710163881 5,6-dihydroxyindole-2-carboxylic acid oxidase Proteins 0.000 claims description 4
- 102000007471 Adenosine A2A receptor Human genes 0.000 claims description 4
- 108010085277 Adenosine A2A receptor Proteins 0.000 claims description 4
- 102100021569 Apoptosis regulator Bcl-2 Human genes 0.000 claims description 4
- 102100022005 B-lymphocyte antigen CD20 Human genes 0.000 claims description 4
- 108091012583 BCL2 Proteins 0.000 claims description 4
- 102100035080 BDNF/NT-3 growth factors receptor Human genes 0.000 claims description 4
- 108091005625 BRD4 Proteins 0.000 claims description 4
- 102100021663 Baculoviral IAP repeat-containing protein 5 Human genes 0.000 claims description 4
- 101001042041 Bos taurus Isocitrate dehydrogenase [NAD] subunit beta, mitochondrial Proteins 0.000 claims description 4
- 102100029894 Bromodomain testis-specific protein Human genes 0.000 claims description 4
- 102100033640 Bromodomain-containing protein 1 Human genes 0.000 claims description 4
- 102100033641 Bromodomain-containing protein 2 Human genes 0.000 claims description 4
- 102100033642 Bromodomain-containing protein 3 Human genes 0.000 claims description 4
- 102100029895 Bromodomain-containing protein 4 Human genes 0.000 claims description 4
- 102100024217 CAMPATH-1 antigen Human genes 0.000 claims description 4
- 102100027207 CD27 antigen Human genes 0.000 claims description 4
- 102000017420 CD3 protein, epsilon/gamma/delta subunit Human genes 0.000 claims description 4
- 108050005493 CD3 protein, epsilon/gamma/delta subunit Proteins 0.000 claims description 4
- 108010029697 CD40 Ligand Proteins 0.000 claims description 4
- 102100032937 CD40 ligand Human genes 0.000 claims description 4
- 102100036008 CD48 antigen Human genes 0.000 claims description 4
- 108010065524 CD52 Antigen Proteins 0.000 claims description 4
- 101000741929 Caenorhabditis elegans Serine/threonine-protein phosphatase 2A catalytic subunit Proteins 0.000 claims description 4
- 102100025570 Cancer/testis antigen 1 Human genes 0.000 claims description 4
- 108091008815 Eph receptors Proteins 0.000 claims description 4
- 102100036725 Epithelial discoidin domain-containing receptor 1 Human genes 0.000 claims description 4
- 101710131668 Epithelial discoidin domain-containing receptor 1 Proteins 0.000 claims description 4
- 108091008794 FGF receptors Proteins 0.000 claims description 4
- 102100031351 Galectin-9 Human genes 0.000 claims description 4
- 101710121810 Galectin-9 Proteins 0.000 claims description 4
- 102100041003 Glutamate carboxypeptidase 2 Human genes 0.000 claims description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 4
- 102100034458 Hepatitis A virus cellular receptor 2 Human genes 0.000 claims description 4
- 102100035108 High affinity nerve growth factor receptor Human genes 0.000 claims description 4
- 101000897405 Homo sapiens B-lymphocyte antigen CD20 Proteins 0.000 claims description 4
- 101000596896 Homo sapiens BDNF/NT-3 growth factors receptor Proteins 0.000 claims description 4
- 101000794028 Homo sapiens Bromodomain testis-specific protein Proteins 0.000 claims description 4
- 101000871846 Homo sapiens Bromodomain-containing protein 1 Proteins 0.000 claims description 4
- 101000871850 Homo sapiens Bromodomain-containing protein 2 Proteins 0.000 claims description 4
- 101000871851 Homo sapiens Bromodomain-containing protein 3 Proteins 0.000 claims description 4
- 101000914511 Homo sapiens CD27 antigen Proteins 0.000 claims description 4
- 101000716130 Homo sapiens CD48 antigen Proteins 0.000 claims description 4
- 101000856237 Homo sapiens Cancer/testis antigen 1 Proteins 0.000 claims description 4
- 101000914324 Homo sapiens Carcinoembryonic antigen-related cell adhesion molecule 5 Proteins 0.000 claims description 4
- 101000914321 Homo sapiens Carcinoembryonic antigen-related cell adhesion molecule 7 Proteins 0.000 claims description 4
- 101000892862 Homo sapiens Glutamate carboxypeptidase 2 Proteins 0.000 claims description 4
- 101001068133 Homo sapiens Hepatitis A virus cellular receptor 2 Proteins 0.000 claims description 4
- 101000596894 Homo sapiens High affinity nerve growth factor receptor Proteins 0.000 claims description 4
- 101001019455 Homo sapiens ICOS ligand Proteins 0.000 claims description 4
- 101001034652 Homo sapiens Insulin-like growth factor 1 receptor Proteins 0.000 claims description 4
- 101000960234 Homo sapiens Isocitrate dehydrogenase [NADP] cytoplasmic Proteins 0.000 claims description 4
- 101000917858 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor III-A Proteins 0.000 claims description 4
- 101000917839 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor III-B Proteins 0.000 claims description 4
- 101001137987 Homo sapiens Lymphocyte activation gene 3 protein Proteins 0.000 claims description 4
- 101000916644 Homo sapiens Macrophage colony-stimulating factor 1 receptor Proteins 0.000 claims description 4
- 101000578784 Homo sapiens Melanoma antigen recognized by T-cells 1 Proteins 0.000 claims description 4
- 101001057156 Homo sapiens Melanoma-associated antigen C2 Proteins 0.000 claims description 4
- 101001133056 Homo sapiens Mucin-1 Proteins 0.000 claims description 4
- 101001030211 Homo sapiens Myc proto-oncogene protein Proteins 0.000 claims description 4
- 101000692455 Homo sapiens Platelet-derived growth factor receptor beta Proteins 0.000 claims description 4
- 101000617725 Homo sapiens Pregnancy-specific beta-1-glycoprotein 2 Proteins 0.000 claims description 4
- 101001136981 Homo sapiens Proteasome subunit beta type-9 Proteins 0.000 claims description 4
- 101000742054 Homo sapiens Protein phosphatase 1D Proteins 0.000 claims description 4
- 101001068027 Homo sapiens Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform Proteins 0.000 claims description 4
- 101000914514 Homo sapiens T-cell-specific surface glycoprotein CD28 Proteins 0.000 claims description 4
- 101000914484 Homo sapiens T-lymphocyte activation antigen CD80 Proteins 0.000 claims description 4
- 101000904152 Homo sapiens Transcription factor E2F1 Proteins 0.000 claims description 4
- 101000764263 Homo sapiens Tumor necrosis factor ligand superfamily member 4 Proteins 0.000 claims description 4
- 101000801234 Homo sapiens Tumor necrosis factor receptor superfamily member 18 Proteins 0.000 claims description 4
- 101000807561 Homo sapiens Tyrosine-protein kinase receptor UFO Proteins 0.000 claims description 4
- 101000666896 Homo sapiens V-type immunoglobulin domain-containing suppressor of T-cell activation Proteins 0.000 claims description 4
- 101000851018 Homo sapiens Vascular endothelial growth factor receptor 1 Proteins 0.000 claims description 4
- 101000851007 Homo sapiens Vascular endothelial growth factor receptor 2 Proteins 0.000 claims description 4
- 102100034980 ICOS ligand Human genes 0.000 claims description 4
- 102100039688 Insulin-like growth factor 1 receptor Human genes 0.000 claims description 4
- 102100039905 Isocitrate dehydrogenase [NADP] cytoplasmic Human genes 0.000 claims description 4
- 102100031413 L-dopachrome tautomerase Human genes 0.000 claims description 4
- 101710093778 L-dopachrome tautomerase Proteins 0.000 claims description 4
- 102000017578 LAG3 Human genes 0.000 claims description 4
- 102100029185 Low affinity immunoglobulin gamma Fc region receptor III-B Human genes 0.000 claims description 4
- 102100028198 Macrophage colony-stimulating factor 1 receptor Human genes 0.000 claims description 4
- 102000005727 Mammaglobin A Human genes 0.000 claims description 4
- 108010031030 Mammaglobin A Proteins 0.000 claims description 4
- 102100028389 Melanoma antigen recognized by T-cells 1 Human genes 0.000 claims description 4
- 102100027252 Melanoma-associated antigen C2 Human genes 0.000 claims description 4
- 108010008707 Mucin-1 Proteins 0.000 claims description 4
- 101100407308 Mus musculus Pdcd1lg2 gene Proteins 0.000 claims description 4
- 102100038895 Myc proto-oncogene protein Human genes 0.000 claims description 4
- 108060006580 PRAME Proteins 0.000 claims description 4
- 102000036673 PRAME Human genes 0.000 claims description 4
- 102100026547 Platelet-derived growth factor receptor beta Human genes 0.000 claims description 4
- 102100029740 Poliovirus receptor Human genes 0.000 claims description 4
- 102100022019 Pregnancy-specific beta-1-glycoprotein 2 Human genes 0.000 claims description 4
- 108700030875 Programmed Cell Death 1 Ligand 2 Proteins 0.000 claims description 4
- 102100024213 Programmed cell death 1 ligand 2 Human genes 0.000 claims description 4
- 102100035764 Proteasome subunit beta type-9 Human genes 0.000 claims description 4
- 102100038675 Protein phosphatase 1D Human genes 0.000 claims description 4
- 108010017324 STAT3 Transcription Factor Proteins 0.000 claims description 4
- 102100034464 Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform Human genes 0.000 claims description 4
- 101710173693 Short transient receptor potential channel 1 Proteins 0.000 claims description 4
- 101710173694 Short transient receptor potential channel 2 Proteins 0.000 claims description 4
- 102100024040 Signal transducer and activator of transcription 3 Human genes 0.000 claims description 4
- 108010002687 Survivin Proteins 0.000 claims description 4
- 102100027213 T-cell-specific surface glycoprotein CD28 Human genes 0.000 claims description 4
- 102100027222 T-lymphocyte activation antigen CD80 Human genes 0.000 claims description 4
- 102100024026 Transcription factor E2F1 Human genes 0.000 claims description 4
- LVTKHGUGBGNBPL-UHFFFAOYSA-N Trp-P-1 Chemical compound N1C2=CC=CC=C2C2=C1C(C)=C(N)N=C2C LVTKHGUGBGNBPL-UHFFFAOYSA-N 0.000 claims description 4
- 102100026890 Tumor necrosis factor ligand superfamily member 4 Human genes 0.000 claims description 4
- 102100032101 Tumor necrosis factor ligand superfamily member 9 Human genes 0.000 claims description 4
- 102100033728 Tumor necrosis factor receptor superfamily member 18 Human genes 0.000 claims description 4
- 108060008724 Tyrosinase Proteins 0.000 claims description 4
- 102100037236 Tyrosine-protein kinase receptor UFO Human genes 0.000 claims description 4
- 102100038282 V-type immunoglobulin domain-containing suppressor of T-cell activation Human genes 0.000 claims description 4
- 108091008605 VEGF receptors Proteins 0.000 claims description 4
- 102100033178 Vascular endothelial growth factor receptor 1 Human genes 0.000 claims description 4
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 claims description 4
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 claims description 4
- 102000052178 fibroblast growth factor receptor activity proteins Human genes 0.000 claims description 4
- IJJVMEJXYNJXOJ-UHFFFAOYSA-N fluquinconazole Chemical compound C=1C=C(Cl)C=C(Cl)C=1N1C(=O)C2=CC(F)=CC=C2N=C1N1C=NC=N1 IJJVMEJXYNJXOJ-UHFFFAOYSA-N 0.000 claims description 4
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 claims description 4
- 108010048507 poliovirus receptor Proteins 0.000 claims description 4
- 229920001481 poly(stearyl methacrylate) Polymers 0.000 claims description 4
- 102100039498 Cytotoxic T-lymphocyte protein 4 Human genes 0.000 claims description 3
- 101000834898 Homo sapiens Alpha-synuclein Proteins 0.000 claims description 3
- 101000889276 Homo sapiens Cytotoxic T-lymphocyte protein 4 Proteins 0.000 claims description 3
- 101000971538 Homo sapiens Killer cell lectin-like receptor subfamily F member 1 Proteins 0.000 claims description 3
- 101001138062 Homo sapiens Leukocyte-associated immunoglobulin-like receptor 1 Proteins 0.000 claims description 3
- 101001109503 Homo sapiens NKG2-C type II integral membrane protein Proteins 0.000 claims description 3
- 101000611936 Homo sapiens Programmed cell death protein 1 Proteins 0.000 claims description 3
- 101000652359 Homo sapiens Spermatogenesis-associated protein 2 Proteins 0.000 claims description 3
- 101000934346 Homo sapiens T-cell surface antigen CD2 Proteins 0.000 claims description 3
- 101000795169 Homo sapiens Tumor necrosis factor receptor superfamily member 13C Proteins 0.000 claims description 3
- 102100025390 Integrin beta-2 Human genes 0.000 claims description 3
- 108010064593 Intercellular Adhesion Molecule-1 Proteins 0.000 claims description 3
- 102100037877 Intercellular adhesion molecule 1 Human genes 0.000 claims description 3
- 102100021458 Killer cell lectin-like receptor subfamily F member 1 Human genes 0.000 claims description 3
- 102100020943 Leukocyte-associated immunoglobulin-like receptor 1 Human genes 0.000 claims description 3
- 108010064548 Lymphocyte Function-Associated Antigen-1 Proteins 0.000 claims description 3
- 108010061593 Member 14 Tumor Necrosis Factor Receptors Proteins 0.000 claims description 3
- 102100022683 NKG2-C type II integral membrane protein Human genes 0.000 claims description 3
- 102100025237 T-cell surface antigen CD2 Human genes 0.000 claims description 3
- 102100029690 Tumor necrosis factor receptor superfamily member 13C Human genes 0.000 claims description 3
- 102100028785 Tumor necrosis factor receptor superfamily member 14 Human genes 0.000 claims description 3
- 239000004471 Glycine Substances 0.000 claims description 2
- 101000851370 Homo sapiens Tumor necrosis factor receptor superfamily member 9 Proteins 0.000 claims description 2
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 claims description 2
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 claims description 2
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 claims description 2
- 102100036856 Tumor necrosis factor receptor superfamily member 9 Human genes 0.000 claims description 2
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 claims description 2
- 235000004279 alanine Nutrition 0.000 claims description 2
- 239000004474 valine Substances 0.000 claims description 2
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 claims 1
- 102100039094 Tyrosinase Human genes 0.000 claims 1
- 102000004196 processed proteins & peptides Human genes 0.000 abstract description 11
- 230000000694 effects Effects 0.000 abstract description 7
- 102000007238 Transferrin Receptors Human genes 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 58
- 206010028980 Neoplasm Diseases 0.000 description 55
- 201000011510 cancer Diseases 0.000 description 39
- 210000000822 natural killer cell Anatomy 0.000 description 15
- 201000009030 Carcinoma Diseases 0.000 description 14
- 238000011156 evaluation Methods 0.000 description 14
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 13
- 239000000243 solution Substances 0.000 description 13
- 108010047041 Complementarity Determining Regions Proteins 0.000 description 11
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 11
- 239000000872 buffer Substances 0.000 description 11
- 201000005202 lung cancer Diseases 0.000 description 11
- 208000020816 lung neoplasm Diseases 0.000 description 11
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 9
- 239000002105 nanoparticle Substances 0.000 description 9
- 239000008194 pharmaceutical composition Substances 0.000 description 9
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 8
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 8
- 229940079593 drug Drugs 0.000 description 8
- 239000003814 drug Substances 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- 206010041823 squamous cell carcinoma Diseases 0.000 description 8
- 241000699666 Mus <mouse, genus> Species 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 238000005119 centrifugation Methods 0.000 description 7
- UQLDLKMNUJERMK-UHFFFAOYSA-L di(octadecanoyloxy)lead Chemical compound [Pb+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O UQLDLKMNUJERMK-UHFFFAOYSA-L 0.000 description 7
- 239000006228 supernatant Substances 0.000 description 7
- 206010009944 Colon cancer Diseases 0.000 description 6
- 241000588724 Escherichia coli Species 0.000 description 6
- 101000894590 Homo sapiens Uncharacterized protein C20orf85 Proteins 0.000 description 6
- 102100021442 Uncharacterized protein C20orf85 Human genes 0.000 description 6
- 238000010586 diagram Methods 0.000 description 6
- 208000015181 infectious disease Diseases 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 230000004614 tumor growth Effects 0.000 description 6
- 229930006000 Sucrose Natural products 0.000 description 5
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 5
- 239000013604 expression vector Substances 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- PXHVJJICTQNCMI-UHFFFAOYSA-N nickel Substances [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 238000001338 self-assembly Methods 0.000 description 5
- 239000005720 sucrose Substances 0.000 description 5
- 208000003200 Adenoma Diseases 0.000 description 4
- 206010001233 Adenoma benign Diseases 0.000 description 4
- 206010008342 Cervix carcinoma Diseases 0.000 description 4
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 4
- 208000035473 Communicable disease Diseases 0.000 description 4
- 208000029523 Interstitial Lung disease Diseases 0.000 description 4
- 206010025323 Lymphomas Diseases 0.000 description 4
- 208000003445 Mouth Neoplasms Diseases 0.000 description 4
- 208000002231 Muscle Neoplasms Diseases 0.000 description 4
- 208000015634 Rectal Neoplasms Diseases 0.000 description 4
- 208000000453 Skin Neoplasms Diseases 0.000 description 4
- 206010054184 Small intestine carcinoma Diseases 0.000 description 4
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 4
- 208000009956 adenocarcinoma Diseases 0.000 description 4
- 201000009036 biliary tract cancer Diseases 0.000 description 4
- 208000020790 biliary tract neoplasm Diseases 0.000 description 4
- 239000000090 biomarker Substances 0.000 description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 4
- 201000010881 cervical cancer Diseases 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 238000012377 drug delivery Methods 0.000 description 4
- 208000027866 inflammatory disease Diseases 0.000 description 4
- 230000002757 inflammatory effect Effects 0.000 description 4
- 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 4
- 208000032839 leukemia Diseases 0.000 description 4
- 208000012987 lip and oral cavity carcinoma Diseases 0.000 description 4
- 201000002077 muscle cancer Diseases 0.000 description 4
- 108020004707 nucleic acids Proteins 0.000 description 4
- 102000039446 nucleic acids Human genes 0.000 description 4
- 150000007523 nucleic acids Chemical class 0.000 description 4
- 206010038038 rectal cancer Diseases 0.000 description 4
- 201000001275 rectum cancer Diseases 0.000 description 4
- 201000000849 skin cancer Diseases 0.000 description 4
- 208000000649 small cell carcinoma Diseases 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 229940066453 tecentriq Drugs 0.000 description 4
- 239000013598 vector Substances 0.000 description 4
- YXHLJMWYDTXDHS-IRFLANFNSA-N 7-aminoactinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=C(N)C=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 YXHLJMWYDTXDHS-IRFLANFNSA-N 0.000 description 3
- 108700012813 7-aminoactinomycin D Proteins 0.000 description 3
- 108091007499 Amphipathic helix region Proteins 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 102100030708 GTPase KRas Human genes 0.000 description 3
- 208000007465 Giant cell arteritis Diseases 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 101000584612 Homo sapiens GTPase KRas Proteins 0.000 description 3
- 101710123134 Ice-binding protein Proteins 0.000 description 3
- 101710082837 Ice-structuring protein Proteins 0.000 description 3
- 102100022807 Potassium voltage-gated channel subfamily H member 2 Human genes 0.000 description 3
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 3
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 3
- 101710107540 Type-2 ice-structuring protein Proteins 0.000 description 3
- 102000003425 Tyrosinase Human genes 0.000 description 3
- 206010047115 Vasculitis Diseases 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 238000002073 fluorescence micrograph Methods 0.000 description 3
- 230000004927 fusion Effects 0.000 description 3
- 239000001963 growth medium Substances 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 229930027917 kanamycin Natural products 0.000 description 3
- SBUJHOSQTJFQJX-NOAMYHISSA-N kanamycin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N SBUJHOSQTJFQJX-NOAMYHISSA-N 0.000 description 3
- 229960000318 kanamycin Drugs 0.000 description 3
- 229930182823 kanamycin A Natural products 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 244000005700 microbiome Species 0.000 description 3
- 210000000056 organ Anatomy 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 229920001184 polypeptide Polymers 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 108010014186 ras Proteins Proteins 0.000 description 3
- 102000016914 ras Proteins Human genes 0.000 description 3
- 239000001488 sodium phosphate Substances 0.000 description 3
- 229910000162 sodium phosphate Inorganic materials 0.000 description 3
- 206010043207 temporal arteritis Diseases 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 3
- 229960005486 vaccine Drugs 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 2
- FWBHETKCLVMNFS-UHFFFAOYSA-N 4',6-Diamino-2-phenylindol Chemical compound C1=CC(C(=N)N)=CC=C1C1=CC2=CC=C(C(N)=N)C=C2N1 FWBHETKCLVMNFS-UHFFFAOYSA-N 0.000 description 2
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 2
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 2
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 2
- 206010061424 Anal cancer Diseases 0.000 description 2
- 208000007860 Anus Neoplasms Diseases 0.000 description 2
- 102000000546 Apoferritins Human genes 0.000 description 2
- 108010002084 Apoferritins Proteins 0.000 description 2
- 206010003571 Astrocytoma Diseases 0.000 description 2
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 2
- 206010004146 Basal cell carcinoma Diseases 0.000 description 2
- 206010005003 Bladder cancer Diseases 0.000 description 2
- 206010005949 Bone cancer Diseases 0.000 description 2
- 208000018084 Bone neoplasm Diseases 0.000 description 2
- 208000003174 Brain Neoplasms Diseases 0.000 description 2
- 206010006187 Breast cancer Diseases 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- 238000011740 C57BL/6 mouse Methods 0.000 description 2
- 241000283707 Capra Species 0.000 description 2
- 206010008635 Cholestasis Diseases 0.000 description 2
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 2
- 102000007644 Colony-Stimulating Factors Human genes 0.000 description 2
- 108010071942 Colony-Stimulating Factors Proteins 0.000 description 2
- 208000002699 Digestive System Neoplasms Diseases 0.000 description 2
- 102220480600 Dimethylglycine dehydrogenase, mitochondrial_R23A_mutation Human genes 0.000 description 2
- 206010061825 Duodenal neoplasm Diseases 0.000 description 2
- 102220575187 Egl nine homolog 1_F82A_mutation Human genes 0.000 description 2
- 206010014733 Endometrial cancer Diseases 0.000 description 2
- 206010014759 Endometrial neoplasm Diseases 0.000 description 2
- 102000003951 Erythropoietin Human genes 0.000 description 2
- 108090000394 Erythropoietin Proteins 0.000 description 2
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 2
- 206010016228 Fasciitis Diseases 0.000 description 2
- 208000004057 Focal Nodular Hyperplasia Diseases 0.000 description 2
- 102000012673 Follicle Stimulating Hormone Human genes 0.000 description 2
- 108010079345 Follicle Stimulating Hormone Proteins 0.000 description 2
- 208000022072 Gallbladder Neoplasms Diseases 0.000 description 2
- 208000008999 Giant Cell Carcinoma Diseases 0.000 description 2
- 208000032612 Glial tumor Diseases 0.000 description 2
- 206010018338 Glioma Diseases 0.000 description 2
- 206010018404 Glucagonoma Diseases 0.000 description 2
- 208000002125 Hemangioendothelioma Diseases 0.000 description 2
- 206010073073 Hepatobiliary cancer Diseases 0.000 description 2
- 208000017604 Hodgkin disease Diseases 0.000 description 2
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 2
- 108010000521 Human Growth Hormone Proteins 0.000 description 2
- 102000002265 Human Growth Hormone Human genes 0.000 description 2
- 239000000854 Human Growth Hormone Substances 0.000 description 2
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 2
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 2
- 102000004877 Insulin Human genes 0.000 description 2
- 108090001061 Insulin Proteins 0.000 description 2
- 102000006992 Interferon-alpha Human genes 0.000 description 2
- 108010047761 Interferon-alpha Proteins 0.000 description 2
- 108090000467 Interferon-beta Proteins 0.000 description 2
- 108010074328 Interferon-gamma Proteins 0.000 description 2
- 102100030703 Interleukin-22 Human genes 0.000 description 2
- 208000008839 Kidney Neoplasms Diseases 0.000 description 2
- 102100020880 Kit ligand Human genes 0.000 description 2
- 206010023825 Laryngeal cancer Diseases 0.000 description 2
- 201000008197 Laryngitis Diseases 0.000 description 2
- 208000036241 Liver adenomatosis Diseases 0.000 description 2
- 102000009151 Luteinizing Hormone Human genes 0.000 description 2
- 108010073521 Luteinizing Hormone Proteins 0.000 description 2
- 102000004083 Lymphotoxin-alpha Human genes 0.000 description 2
- 108090000542 Lymphotoxin-alpha Proteins 0.000 description 2
- 206010025537 Malignant anorectal neoplasms Diseases 0.000 description 2
- 208000032271 Malignant tumor of penis Diseases 0.000 description 2
- 208000000172 Medulloblastoma Diseases 0.000 description 2
- 208000015021 Meningeal Neoplasms Diseases 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 206010057269 Mucoepidermoid carcinoma Diseases 0.000 description 2
- 208000034578 Multiple myelomas Diseases 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 2
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 2
- 206010029260 Neuroblastoma Diseases 0.000 description 2
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 2
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 2
- 201000010133 Oligodendroglioma Diseases 0.000 description 2
- 206010033128 Ovarian cancer Diseases 0.000 description 2
- 206010061535 Ovarian neoplasm Diseases 0.000 description 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 2
- 208000004091 Parotid Neoplasms Diseases 0.000 description 2
- 206010061336 Pelvic neoplasm Diseases 0.000 description 2
- 208000002471 Penile Neoplasms Diseases 0.000 description 2
- 206010034299 Penile cancer Diseases 0.000 description 2
- 208000009565 Pharyngeal Neoplasms Diseases 0.000 description 2
- 206010034811 Pharyngeal cancer Diseases 0.000 description 2
- 208000007913 Pituitary Neoplasms Diseases 0.000 description 2
- 206010035226 Plasma cell myeloma Diseases 0.000 description 2
- 208000007452 Plasmacytoma Diseases 0.000 description 2
- 206010035664 Pneumonia Diseases 0.000 description 2
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 2
- 108091000054 Prion Proteins 0.000 description 2
- 102000029797 Prion Human genes 0.000 description 2
- 101710089372 Programmed cell death protein 1 Proteins 0.000 description 2
- 206010060862 Prostate cancer Diseases 0.000 description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 2
- 206010051807 Pseudosarcoma Diseases 0.000 description 2
- 201000008183 Pulmonary blastoma Diseases 0.000 description 2
- 102220640571 Regulatory-associated protein of mTOR_Q84A_mutation Human genes 0.000 description 2
- 206010038389 Renal cancer Diseases 0.000 description 2
- 208000006265 Renal cell carcinoma Diseases 0.000 description 2
- 201000000582 Retinoblastoma Diseases 0.000 description 2
- 206010039491 Sarcoma Diseases 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- 208000032383 Soft tissue cancer Diseases 0.000 description 2
- 102000005157 Somatostatin Human genes 0.000 description 2
- 108010056088 Somatostatin Proteins 0.000 description 2
- 108010039445 Stem Cell Factor Proteins 0.000 description 2
- 208000005718 Stomach Neoplasms Diseases 0.000 description 2
- 108091008874 T cell receptors Proteins 0.000 description 2
- 102000016266 T-Cell Antigen Receptors Human genes 0.000 description 2
- 208000000389 T-cell leukemia Diseases 0.000 description 2
- 208000028530 T-cell lymphoblastic leukemia/lymphoma Diseases 0.000 description 2
- 210000001744 T-lymphocyte Anatomy 0.000 description 2
- 208000024313 Testicular Neoplasms Diseases 0.000 description 2
- 206010057644 Testis cancer Diseases 0.000 description 2
- 208000024770 Thyroid neoplasm Diseases 0.000 description 2
- 102000011923 Thyrotropin Human genes 0.000 description 2
- 108010061174 Thyrotropin Proteins 0.000 description 2
- 206010062129 Tongue neoplasm Diseases 0.000 description 2
- 108010009583 Transforming Growth Factors Proteins 0.000 description 2
- 102000009618 Transforming Growth Factors Human genes 0.000 description 2
- 208000023915 Ureteral Neoplasms Diseases 0.000 description 2
- 206010046392 Ureteric cancer Diseases 0.000 description 2
- 206010046431 Urethral cancer Diseases 0.000 description 2
- 206010046458 Urethral neoplasms Diseases 0.000 description 2
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 2
- 102220549987 Usher syndrome type-1C protein-binding protein 1_Q15A_mutation Human genes 0.000 description 2
- 208000002495 Uterine Neoplasms Diseases 0.000 description 2
- 208000009311 VIPoma Diseases 0.000 description 2
- 206010047741 Vulval cancer Diseases 0.000 description 2
- 208000004354 Vulvar Neoplasms Diseases 0.000 description 2
- 208000008383 Wilms tumor Diseases 0.000 description 2
- 208000009621 actinic keratosis Diseases 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 208000002517 adenoid cystic carcinoma Diseases 0.000 description 2
- 238000001042 affinity chromatography Methods 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 230000000890 antigenic effect Effects 0.000 description 2
- 201000011165 anus cancer Diseases 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 201000006491 bone marrow cancer Diseases 0.000 description 2
- 206010006451 bronchitis Diseases 0.000 description 2
- 208000002458 carcinoid tumor Diseases 0.000 description 2
- 229920006317 cationic polymer Polymers 0.000 description 2
- 208000006990 cholangiocarcinoma Diseases 0.000 description 2
- 231100000359 cholestasis Toxicity 0.000 description 2
- 230000007870 cholestasis Effects 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 208000009060 clear cell adenocarcinoma Diseases 0.000 description 2
- 208000029742 colonic neoplasm Diseases 0.000 description 2
- 229940047120 colony stimulating factors Drugs 0.000 description 2
- 201000010918 connective tissue cancer Diseases 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 201000003146 cystitis Diseases 0.000 description 2
- 210000000805 cytoplasm Anatomy 0.000 description 2
- 201000001981 dermatomyositis Diseases 0.000 description 2
- 238000003745 diagnosis Methods 0.000 description 2
- 208000024558 digestive system cancer Diseases 0.000 description 2
- 238000007865 diluting Methods 0.000 description 2
- 238000009509 drug development Methods 0.000 description 2
- 201000000312 duodenum cancer Diseases 0.000 description 2
- 210000000750 endocrine system Anatomy 0.000 description 2
- 210000001900 endoderm Anatomy 0.000 description 2
- 201000003908 endometrial adenocarcinoma Diseases 0.000 description 2
- 201000006828 endometrial hyperplasia Diseases 0.000 description 2
- 208000029382 endometrium adenocarcinoma Diseases 0.000 description 2
- 210000002889 endothelial cell Anatomy 0.000 description 2
- 201000010063 epididymitis Diseases 0.000 description 2
- 210000002919 epithelial cell Anatomy 0.000 description 2
- 208000010932 epithelial neoplasm Diseases 0.000 description 2
- 229940105423 erythropoietin Drugs 0.000 description 2
- 201000004101 esophageal cancer Diseases 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000000799 fluorescence microscopy Methods 0.000 description 2
- 229940028334 follicle stimulating hormone Drugs 0.000 description 2
- 230000002538 fungal effect Effects 0.000 description 2
- 201000010175 gallbladder cancer Diseases 0.000 description 2
- 206010017758 gastric cancer Diseases 0.000 description 2
- 208000015419 gastrin-producing neuroendocrine tumor Diseases 0.000 description 2
- 201000000052 gastrinoma Diseases 0.000 description 2
- 201000010231 gastrointestinal system cancer Diseases 0.000 description 2
- 238000012215 gene cloning Methods 0.000 description 2
- 208000005017 glioblastoma Diseases 0.000 description 2
- 102000034238 globular proteins Human genes 0.000 description 2
- 108091005896 globular proteins Proteins 0.000 description 2
- 239000003102 growth factor Substances 0.000 description 2
- 201000010536 head and neck cancer Diseases 0.000 description 2
- 208000014829 head and neck neoplasm Diseases 0.000 description 2
- 201000010235 heart cancer Diseases 0.000 description 2
- 208000024348 heart neoplasm Diseases 0.000 description 2
- 201000002222 hemangioblastoma Diseases 0.000 description 2
- 201000011066 hemangioma Diseases 0.000 description 2
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 2
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 2
- 201000002312 ileal neoplasm Diseases 0.000 description 2
- 230000028993 immune response Effects 0.000 description 2
- 229940125396 insulin Drugs 0.000 description 2
- 206010022498 insulinoma Diseases 0.000 description 2
- 208000020082 intraepithelial neoplasia Diseases 0.000 description 2
- 201000003856 jejunal cancer Diseases 0.000 description 2
- 201000009592 jejunal neoplasm Diseases 0.000 description 2
- 201000010982 kidney cancer Diseases 0.000 description 2
- 206010023841 laryngeal neoplasm Diseases 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 201000007270 liver cancer Diseases 0.000 description 2
- 208000014018 liver neoplasm Diseases 0.000 description 2
- 201000000014 lung giant cell carcinoma Diseases 0.000 description 2
- 229940040129 luteinizing hormone Drugs 0.000 description 2
- 230000036210 malignancy Effects 0.000 description 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 2
- 208000022006 malignant tumor of meninges Diseases 0.000 description 2
- 201000001441 melanoma Diseases 0.000 description 2
- 210000005033 mesothelial cell Anatomy 0.000 description 2
- 208000011645 metastatic carcinoma Diseases 0.000 description 2
- 206010061289 metastatic neoplasm Diseases 0.000 description 2
- 230000000813 microbial effect Effects 0.000 description 2
- 201000011682 nervous system cancer Diseases 0.000 description 2
- 239000002547 new drug Substances 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 201000000890 orbital cancer Diseases 0.000 description 2
- 201000005737 orchitis Diseases 0.000 description 2
- 201000008482 osteoarthritis Diseases 0.000 description 2
- 201000008968 osteosarcoma Diseases 0.000 description 2
- 201000002528 pancreatic cancer Diseases 0.000 description 2
- 208000008443 pancreatic carcinoma Diseases 0.000 description 2
- 208000021255 pancreatic insulinoma Diseases 0.000 description 2
- 201000005163 papillary serous adenocarcinoma Diseases 0.000 description 2
- 208000024641 papillary serous cystadenocarcinoma Diseases 0.000 description 2
- 230000003071 parasitic effect Effects 0.000 description 2
- 201000001219 parotid gland cancer Diseases 0.000 description 2
- 244000052769 pathogen Species 0.000 description 2
- 230000001717 pathogenic effect Effects 0.000 description 2
- 239000008188 pellet Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 208000010916 pituitary tumor Diseases 0.000 description 2
- OXCMYAYHXIHQOA-UHFFFAOYSA-N potassium;[2-butyl-5-chloro-3-[[4-[2-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol Chemical compound [K+].CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C2=N[N-]N=N2)C=C1 OXCMYAYHXIHQOA-UHFFFAOYSA-N 0.000 description 2
- 201000007048 respiratory system cancer Diseases 0.000 description 2
- 102200097286 rs199472825 Human genes 0.000 description 2
- 230000003248 secreting effect Effects 0.000 description 2
- 208000004548 serous cystadenocarcinoma Diseases 0.000 description 2
- 208000037968 sinus cancer Diseases 0.000 description 2
- 201000002314 small intestine cancer Diseases 0.000 description 2
- 201000000267 smooth muscle cancer Diseases 0.000 description 2
- NHXLMOGPVYXJNR-ATOGVRKGSA-N somatostatin Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CSSC[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(=O)N1)[C@@H](C)O)NC(=O)CNC(=O)[C@H](C)N)C(O)=O)=O)[C@H](O)C)C1=CC=CC=C1 NHXLMOGPVYXJNR-ATOGVRKGSA-N 0.000 description 2
- 229960000553 somatostatin Drugs 0.000 description 2
- 201000011096 spinal cancer Diseases 0.000 description 2
- 208000014618 spinal cord cancer Diseases 0.000 description 2
- 208000017572 squamous cell neoplasm Diseases 0.000 description 2
- 239000008223 sterile water Substances 0.000 description 2
- 201000011549 stomach cancer Diseases 0.000 description 2
- 201000003120 testicular cancer Diseases 0.000 description 2
- 201000002510 thyroid cancer Diseases 0.000 description 2
- 201000006134 tongue cancer Diseases 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 230000014616 translation Effects 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- 201000011294 ureter cancer Diseases 0.000 description 2
- 201000005112 urinary bladder cancer Diseases 0.000 description 2
- 206010046766 uterine cancer Diseases 0.000 description 2
- 206010046885 vaginal cancer Diseases 0.000 description 2
- 208000013139 vaginal neoplasm Diseases 0.000 description 2
- 206010055031 vascular neoplasm Diseases 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- 230000003612 virological effect Effects 0.000 description 2
- 201000005102 vulva cancer Diseases 0.000 description 2
- XSYUPRQVAHJETO-WPMUBMLPSA-N (2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-amino-3-(1h-imidazol-5-yl)propanoyl]amino]-3-(1h-imidazol-5-yl)propanoyl]amino]-3-(1h-imidazol-5-yl)propanoyl]amino]-3-(1h-imidazol-5-yl)propanoyl]amino]-3-(1h-imidazol-5-yl)propanoyl]amino]-3-(1h-imidaz Chemical compound C([C@H](N)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC=1NC=NC=1)C(O)=O)C1=CN=CN1 XSYUPRQVAHJETO-WPMUBMLPSA-N 0.000 description 1
- 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 1
- 206010069754 Acquired gene mutation Diseases 0.000 description 1
- 108010059616 Activins Proteins 0.000 description 1
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 description 1
- 208000035285 Allergic Seasonal Rhinitis Diseases 0.000 description 1
- 206010001889 Alveolitis Diseases 0.000 description 1
- 206010060937 Amniotic cavity infection Diseases 0.000 description 1
- 206010002198 Anaphylactic reaction Diseases 0.000 description 1
- 206010002556 Ankylosing Spondylitis Diseases 0.000 description 1
- 206010003011 Appendicitis Diseases 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- 208000033116 Asbestos intoxication Diseases 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 102220505885 Borealin_D124A_mutation Human genes 0.000 description 1
- 206010006448 Bronchiolitis Diseases 0.000 description 1
- 206010006458 Bronchitis chronic Diseases 0.000 description 1
- 206010006811 Bursitis Diseases 0.000 description 1
- 101100112922 Candida albicans CDR3 gene Proteins 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 206010007882 Cellulitis Diseases 0.000 description 1
- 206010008609 Cholangitis sclerosing Diseases 0.000 description 1
- 206010008617 Cholecystitis chronic Diseases 0.000 description 1
- 208000008158 Chorioamnionitis Diseases 0.000 description 1
- 102100021809 Chorionic somatomammotropin hormone 1 Human genes 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 206010010741 Conjunctivitis Diseases 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- 201000003883 Cystic fibrosis Diseases 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- XUIIKFGFIJCVMT-GFCCVEGCSA-N D-thyroxine Chemical compound IC1=CC(C[C@@H](N)C(O)=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 XUIIKFGFIJCVMT-GFCCVEGCSA-N 0.000 description 1
- 238000001712 DNA sequencing Methods 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- 206010048768 Dermatosis Diseases 0.000 description 1
- 201000003066 Diffuse Scleroderma Diseases 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 208000004145 Endometritis Diseases 0.000 description 1
- 208000004232 Enteritis Diseases 0.000 description 1
- 241000672609 Escherichia coli BL21 Species 0.000 description 1
- 102000018233 Fibroblast Growth Factor Human genes 0.000 description 1
- 108050007372 Fibroblast Growth Factor Proteins 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 208000007882 Gastritis Diseases 0.000 description 1
- 208000005577 Gastroenteritis Diseases 0.000 description 1
- 206010018364 Glomerulonephritis Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 102000006771 Gonadotropins Human genes 0.000 description 1
- 108010086677 Gonadotropins Proteins 0.000 description 1
- 208000024869 Goodpasture syndrome Diseases 0.000 description 1
- 201000005569 Gout Diseases 0.000 description 1
- 206010018634 Gouty Arthritis Diseases 0.000 description 1
- 206010072579 Granulomatosis with polyangiitis Diseases 0.000 description 1
- 208000003807 Graves Disease Diseases 0.000 description 1
- 208000015023 Graves' disease Diseases 0.000 description 1
- 208000030836 Hashimoto thyroiditis Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000599951 Homo sapiens Insulin-like growth factor I Proteins 0.000 description 1
- 101000595923 Homo sapiens Placenta growth factor Proteins 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 1
- 102100026818 Inhibin beta E chain Human genes 0.000 description 1
- 102100037852 Insulin-like growth factor I Human genes 0.000 description 1
- 102100026720 Interferon beta Human genes 0.000 description 1
- 102100037850 Interferon gamma Human genes 0.000 description 1
- 102000003996 Interferon-beta Human genes 0.000 description 1
- 102000008070 Interferon-gamma Human genes 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- 102000000589 Interleukin-1 Human genes 0.000 description 1
- 108010002352 Interleukin-1 Proteins 0.000 description 1
- 102000003814 Interleukin-10 Human genes 0.000 description 1
- 108090000174 Interleukin-10 Proteins 0.000 description 1
- 108090000177 Interleukin-11 Proteins 0.000 description 1
- 102000003815 Interleukin-11 Human genes 0.000 description 1
- 108010065805 Interleukin-12 Proteins 0.000 description 1
- 102000013462 Interleukin-12 Human genes 0.000 description 1
- 102000003812 Interleukin-15 Human genes 0.000 description 1
- 108090000172 Interleukin-15 Proteins 0.000 description 1
- 102000013691 Interleukin-17 Human genes 0.000 description 1
- 108050003558 Interleukin-17 Proteins 0.000 description 1
- 102000003810 Interleukin-18 Human genes 0.000 description 1
- 108090000171 Interleukin-18 Proteins 0.000 description 1
- 102220476524 Interleukin-18_K120A_mutation Human genes 0.000 description 1
- 102000000588 Interleukin-2 Human genes 0.000 description 1
- 108010002350 Interleukin-2 Proteins 0.000 description 1
- 102000013264 Interleukin-23 Human genes 0.000 description 1
- 108010065637 Interleukin-23 Proteins 0.000 description 1
- 102000000646 Interleukin-3 Human genes 0.000 description 1
- 108010002386 Interleukin-3 Proteins 0.000 description 1
- 102000017761 Interleukin-33 Human genes 0.000 description 1
- 108010067003 Interleukin-33 Proteins 0.000 description 1
- 102000004388 Interleukin-4 Human genes 0.000 description 1
- 108090000978 Interleukin-4 Proteins 0.000 description 1
- 102100039897 Interleukin-5 Human genes 0.000 description 1
- 108010002616 Interleukin-5 Proteins 0.000 description 1
- 108090001005 Interleukin-6 Proteins 0.000 description 1
- 102000004889 Interleukin-6 Human genes 0.000 description 1
- 102100021592 Interleukin-7 Human genes 0.000 description 1
- 108010002586 Interleukin-7 Proteins 0.000 description 1
- 108090001007 Interleukin-8 Proteins 0.000 description 1
- 102000004890 Interleukin-8 Human genes 0.000 description 1
- 108010002335 Interleukin-9 Proteins 0.000 description 1
- 102000000585 Interleukin-9 Human genes 0.000 description 1
- 102000015696 Interleukins Human genes 0.000 description 1
- 108010063738 Interleukins Proteins 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
- 239000005913 Maltodextrin Substances 0.000 description 1
- 229920002774 Maltodextrin Polymers 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 208000003250 Mixed connective tissue disease Diseases 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- 208000003926 Myelitis Diseases 0.000 description 1
- 208000009525 Myocarditis Diseases 0.000 description 1
- 206010028851 Necrosis Diseases 0.000 description 1
- 206010051606 Necrotising colitis Diseases 0.000 description 1
- 108010025020 Nerve Growth Factor Proteins 0.000 description 1
- 102000007072 Nerve Growth Factors Human genes 0.000 description 1
- 208000003435 Optic Neuritis Diseases 0.000 description 1
- 206010031149 Osteitis Diseases 0.000 description 1
- 206010031252 Osteomyelitis Diseases 0.000 description 1
- 208000005141 Otitis Diseases 0.000 description 1
- 101710160107 Outer membrane protein A Proteins 0.000 description 1
- 206010033645 Pancreatitis Diseases 0.000 description 1
- 102000003982 Parathyroid hormone Human genes 0.000 description 1
- 108090000445 Parathyroid hormone Proteins 0.000 description 1
- 206010034038 Parotitis Diseases 0.000 description 1
- 241000721454 Pemphigus Species 0.000 description 1
- 208000031845 Pernicious anaemia Diseases 0.000 description 1
- 201000007100 Pharyngitis Diseases 0.000 description 1
- 102100035194 Placenta growth factor Human genes 0.000 description 1
- 108010003044 Placental Lactogen Proteins 0.000 description 1
- 239000000381 Placental Lactogen Substances 0.000 description 1
- 208000007048 Polymyalgia Rheumatica Diseases 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- 206010036774 Proctitis Diseases 0.000 description 1
- 108010076181 Proinsulin Proteins 0.000 description 1
- 102000003946 Prolactin Human genes 0.000 description 1
- 108010057464 Prolactin Proteins 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 206010037596 Pyelonephritis Diseases 0.000 description 1
- 108090000103 Relaxin Proteins 0.000 description 1
- 102000003743 Relaxin Human genes 0.000 description 1
- 206010063837 Reperfusion injury Diseases 0.000 description 1
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- 208000007893 Salpingitis Diseases 0.000 description 1
- 206010039710 Scleroderma Diseases 0.000 description 1
- 201000010001 Silicosis Diseases 0.000 description 1
- 208000021386 Sjogren Syndrome Diseases 0.000 description 1
- 201000009594 Systemic Scleroderma Diseases 0.000 description 1
- 206010042953 Systemic sclerosis Diseases 0.000 description 1
- 208000000491 Tendinopathy Diseases 0.000 description 1
- 206010043255 Tendonitis Diseases 0.000 description 1
- 102000036693 Thrombopoietin Human genes 0.000 description 1
- 108010041111 Thrombopoietin Proteins 0.000 description 1
- 102100034195 Thrombopoietin Human genes 0.000 description 1
- 241000159243 Toxicodendron radicans Species 0.000 description 1
- 102000006747 Transforming Growth Factor alpha Human genes 0.000 description 1
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 1
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 1
- 101800004564 Transforming growth factor alpha Proteins 0.000 description 1
- 206010052779 Transplant rejections Diseases 0.000 description 1
- 206010045240 Type I hypersensitivity Diseases 0.000 description 1
- 206010053613 Type IV hypersensitivity reaction Diseases 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- COQLPRJCUIATTQ-UHFFFAOYSA-N Uranyl acetate Chemical compound O.O.O=[U]=O.CC(O)=O.CC(O)=O COQLPRJCUIATTQ-UHFFFAOYSA-N 0.000 description 1
- 208000006374 Uterine Cervicitis Diseases 0.000 description 1
- 206010046851 Uveitis Diseases 0.000 description 1
- 206010046914 Vaginal infection Diseases 0.000 description 1
- 201000008100 Vaginitis Diseases 0.000 description 1
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 1
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 1
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 1
- 108700005077 Viral Genes Proteins 0.000 description 1
- 239000000488 activin Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 208000011341 adult acute respiratory distress syndrome Diseases 0.000 description 1
- 201000000028 adult respiratory distress syndrome Diseases 0.000 description 1
- 239000011543 agarose gel Substances 0.000 description 1
- 125000003295 alanine group Chemical group N[C@@H](C)C(=O)* 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 230000001668 ameliorated effect Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 210000004102 animal cell Anatomy 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 239000012223 aqueous fraction Substances 0.000 description 1
- 208000011775 arteriosclerosis disease Diseases 0.000 description 1
- 206010003230 arteritis Diseases 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 206010003441 asbestosis Diseases 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 239000000022 bacteriostatic agent Substances 0.000 description 1
- 229910052790 beryllium Inorganic materials 0.000 description 1
- ATBAMAFKBVZNFJ-UHFFFAOYSA-N beryllium atom Chemical compound [Be] ATBAMAFKBVZNFJ-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 229920001222 biopolymer Polymers 0.000 description 1
- 208000010217 blepharitis Diseases 0.000 description 1
- 208000018339 bone inflammation disease Diseases 0.000 description 1
- 108010006025 bovine growth hormone Proteins 0.000 description 1
- 201000009267 bronchiectasis Diseases 0.000 description 1
- 239000007975 buffered saline Substances 0.000 description 1
- 230000005880 cancer cell killing Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 206010008323 cervicitis Diseases 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 208000003167 cholangitis Diseases 0.000 description 1
- 201000001352 cholecystitis Diseases 0.000 description 1
- 208000007451 chronic bronchitis Diseases 0.000 description 1
- 238000010367 cloning Methods 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 208000019258 ear infection Diseases 0.000 description 1
- 239000012149 elution buffer Substances 0.000 description 1
- 206010014599 encephalitis Diseases 0.000 description 1
- 206010014665 endocarditis Diseases 0.000 description 1
- 208000010227 enterocolitis Diseases 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 201000001155 extrinsic allergic alveolitis Diseases 0.000 description 1
- 229940126864 fibroblast growth factor Drugs 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 102000037865 fusion proteins Human genes 0.000 description 1
- 108020001507 fusion proteins Proteins 0.000 description 1
- 208000007565 gingivitis Diseases 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 239000002622 gonadotropin Substances 0.000 description 1
- 210000003714 granulocyte Anatomy 0.000 description 1
- 239000000122 growth hormone Substances 0.000 description 1
- 230000003862 health status Effects 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 238000000703 high-speed centrifugation Methods 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 208000022098 hypersensitivity pneumonitis Diseases 0.000 description 1
- 208000009326 ileitis Diseases 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 229940126533 immune checkpoint blocker Drugs 0.000 description 1
- 230000002163 immunogen Effects 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 210000003000 inclusion body Anatomy 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 239000000893 inhibin Substances 0.000 description 1
- ZPNFWUPYTFPOJU-LPYSRVMUSA-N iniprol Chemical compound C([C@H]1C(=O)NCC(=O)NCC(=O)N[C@H]2CSSC[C@H]3C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@H](C(N[C@H](C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC=4C=CC=CC=4)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC=4C=CC=CC=4)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC2=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]2N(CCC2)C(=O)[C@@H](N)CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N2[C@@H](CCC2)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N2[C@@H](CCC2)C(=O)N3)C(=O)NCC(=O)NCC(=O)N[C@@H](C)C(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H](C(=O)N1)C(C)C)[C@@H](C)O)[C@@H](C)CC)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 ZPNFWUPYTFPOJU-LPYSRVMUSA-N 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 108010044426 integrins Proteins 0.000 description 1
- 102000006495 integrins Human genes 0.000 description 1
- 229960003130 interferon gamma Drugs 0.000 description 1
- 229960001388 interferon-beta Drugs 0.000 description 1
- 229940047124 interferons Drugs 0.000 description 1
- 108010074108 interleukin-21 Proteins 0.000 description 1
- 108010074109 interleukin-22 Proteins 0.000 description 1
- 229940047122 interleukins Drugs 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 201000004614 iritis Diseases 0.000 description 1
- 208000037906 ischaemic injury Diseases 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 208000005158 lymphoid interstitial pneumonia Diseases 0.000 description 1
- 239000012139 lysis buffer Substances 0.000 description 1
- 239000006249 magnetic particle Substances 0.000 description 1
- 229940035034 maltodextrin Drugs 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 231100000350 mutagenesis Toxicity 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 206010028417 myasthenia gravis Diseases 0.000 description 1
- OHDXDNUPVVYWOV-UHFFFAOYSA-N n-methyl-1-(2-naphthalen-1-ylsulfanylphenyl)methanamine Chemical compound CNCC1=CC=CC=C1SC1=CC=CC2=CC=CC=C12 OHDXDNUPVVYWOV-UHFFFAOYSA-N 0.000 description 1
- 239000002086 nanomaterial Substances 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 208000004995 necrotizing enterocolitis Diseases 0.000 description 1
- 201000008383 nephritis Diseases 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 101150093139 ompT gene Proteins 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 230000002138 osteoinductive effect Effects 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 239000000199 parathyroid hormone Substances 0.000 description 1
- 229960001319 parathyroid hormone Drugs 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 208000008494 pericarditis Diseases 0.000 description 1
- 201000006195 perinatal necrotizing enterocolitis Diseases 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 208000001297 phlebitis Diseases 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000013612 plasmid Substances 0.000 description 1
- 208000008423 pleurisy Diseases 0.000 description 1
- 206010035653 pneumoconiosis Diseases 0.000 description 1
- 208000005987 polymyositis Diseases 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 229940097325 prolactin Drugs 0.000 description 1
- 108010087851 prorelaxin Proteins 0.000 description 1
- 201000007094 prostatitis Diseases 0.000 description 1
- 238000001742 protein purification Methods 0.000 description 1
- 239000012460 protein solution Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002096 quantum dot Substances 0.000 description 1
- 208000020029 respiratory tract infectious disease Diseases 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 201000003068 rheumatic fever Diseases 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 206010039083 rhinitis Diseases 0.000 description 1
- 102220005491 rs35932809 Human genes 0.000 description 1
- 201000000306 sarcoidosis Diseases 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 208000010157 sclerosing cholangitis Diseases 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 201000009890 sinusitis Diseases 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 230000037439 somatic mutation Effects 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 208000003265 stomatitis Diseases 0.000 description 1
- 238000012916 structural analysis Methods 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 201000004595 synovitis Diseases 0.000 description 1
- 230000033772 system development Effects 0.000 description 1
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 1
- 201000004415 tendinitis Diseases 0.000 description 1
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 1
- 229940034208 thyroxine Drugs 0.000 description 1
- XUIIKFGFIJCVMT-UHFFFAOYSA-N thyroxine-binding globulin Natural products IC1=CC(CC([NH3+])C([O-])=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 XUIIKFGFIJCVMT-UHFFFAOYSA-N 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 206010044008 tonsillitis Diseases 0.000 description 1
- 208000009174 transverse myelitis Diseases 0.000 description 1
- 230000005760 tumorsuppression Effects 0.000 description 1
- 230000005951 type IV hypersensitivity Effects 0.000 description 1
- 208000027930 type IV hypersensitivity disease Diseases 0.000 description 1
- 238000005199 ultracentrifugation Methods 0.000 description 1
- 208000000143 urethritis Diseases 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- 208000002003 vulvitis Diseases 0.000 description 1
- 208000010484 vulvovaginitis Diseases 0.000 description 1
- 239000011534 wash buffer 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
- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
-
- 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
- C12N15/09—Recombinant DNA-technology
- C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
- C12N15/70—Vectors or expression systems specially adapted for E. coli
Definitions
- the present invention relates to novel proteins.
- the drug delivery system refers to a pharmaceutical technology capable of efficiently delivering a required amount of a drug, for example, a protein, nucleic acid, or other small molecule, by minimizing the side effects of existing drugs and maximizing the efficacy and effect.
- a drug for example, a protein, nucleic acid, or other small molecule
- the above technology which reduces the cost and time required for new drug development, has recently become a field of cutting-edge technology that creates new added value in the pharmaceutical industry by combining with nanotechnology. Companies such as companies have focused their efforts on drug delivery system development along with new drug development.
- An object of the present invention is to provide a novel protein in which a foreign peptide is fused to an external surface and mutated so that the binding ability to the human transferrin receptor is reduced.
- An object of the present invention is to provide a pharmaceutical composition comprising the protein.
- the present invention provides a ferritin protein in which a foreign peptide is fused to an external surface, and a molecule capable of binding to an immune checkpoint molecule mutated to decrease binding to human transferrin receptor is fused.
- the foreign peptide may be a pharmacologically active peptide.
- the foreign peptide may include a ligand or a fragment of a ligand capable of binding to an immune checkpoint molecule, a receptor or a fragment of a receptor, an antibody or an antibody fragment comprising an antigen binding region (CDR); or a disease antigen epitope.
- CDR antigen binding region
- the immune checkpoint molecules are Her-2/neu, VISTA, 4-1BBL, Galectin-9, Adenosine A2a receptor, CD80, CD86, ICOS, ICOSL, BTLA, OX-40L, CD155, BCL2, MYC, PP2A, BRD1, BRD2 , BRD3, BRD4, BRDT, CBP, E2F1, MDM2, MDMX, PPP2CA, PPM1D, STAT3, IDH1, PD1, CTLA4, PD-L1, PD-L2, LAG3, TIM3, TIGIT, BTLA, SLAMF7, 4-1BB, OX -40, ICOS, GITR, ICAM-1, BAFFR, HVEM, LFA-1, LIGHT, NKG2C, SLAMF7, NKp80, LAIR1, 2B4, CD2, CD3, CD16, CD20, CD27, CD28, CD40L, CD48, CD52, EGFR It may be any one selected from the group consisting of
- the antigen-binding site may be any one selected from the group consisting of HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3.
- the disease antigen epitope is gp100, MART-1, Melna-A, MAGE-A3, MAGE-C2, Mammaglobin-A, proteinsase-3, mucin-1, HPV E6, LMP2, PSMA, GD2, hTERT, PAP, ERG, NA17, ALK, GM3, EPhA2, NA17-A, TRP-1, TRP-2, NY-ESO-1, CEA, CA 125, AFP, Survivin, AH1, ras, G17DT, MUC1, Her-2/neu, E75 , p53, PSA, HCG, PRAME, WT1, URLC10, VEGFR1, VEGFR2, E7, Tyrosinase peptide, B16F10, EL4, may be one selected from the group consisting of neoantigens (neoantigen) and GV1001.
- the protein of the present invention may be a spherical protein formed by self-assembly of 24 ferritin monomers fused with the foreign peptide.
- the foreign peptide may be fused to at least one of adjacent ⁇ -helices of the ferritin monomer.
- the foreign peptide may be fused to the N-terminus or C-terminus of the ferritin monomer.
- the exogenous peptide may be fused to loop A-B, loop B-C, loop C-D or loop D-E of a ferritin monomer.
- the foreign peptide may be fused between the N-terminus and the A helix or between the E helix and the C-terminus of the ferritin monomer.
- the protein of the present invention may be one in which amino acids 15, 16, 23, 82, 84, 117, 120 or 124 in the sequence of SEQ ID NO: 1 are substituted with alanine, glycine, valine or leucine.
- the ferritin protein of the present invention may have a binding affinity (K) to the transferrin receptor, satisfying Equation 1 below:
- K [P][T]/[PT]
- [P] represents the concentration of ferritin protein in the equilibrium state of the binding reaction between ferritin protein and transferrin receptor
- [T] is the equilibrium represents the concentration of the transferrin receptor in the state
- [PT] represents the concentration of the complex of the ferritin protein and the transferrin receptor in the equilibrium state
- the binding ability to the transferrin receptor may be binding to the human transferrin receptor.
- the ferritin may be a human ferritin heavy chain.
- the ferritin protein of the present invention may be present in an aqueous fraction of 40% or more in the E. coli production system.
- the protein of the present invention has a reduced binding ability to the human transferrin receptor, and thus can sufficiently exhibit activity derived from a foreign peptide.
- the protein of the present invention may be fused with a plurality of foreign peptides, and thus may exhibit more enhanced activity compared to the foreign peptide itself.
- the protein of the present invention has excellent biocompatibility and safety, and the possibility of inducing an inflammatory response or immunogenicity is very low.
- FIG. 1 is a schematic diagram of a basic vector for preparing wild type (native) human ferritin heavy chain (huHF) and mutant human ferritin heavy chain protein.
- FIG. 2 is a schematic diagram of a vector for producing huHF_Mutant1-dual and a view confirming the production of the ferritin protein.
- FIG. 3 is a schematic diagram of a vector for producing huHF_Mutant1-h_smPD1 and a diagram confirming the production of the ferritin protein.
- 4 to 6 are results of evaluation of the binding affinity of huHF_native-h_smPD1, huHF_Mutant-h_smPD1, and huHF_Mutant1-dual to human transferrin receptor, respectively.
- 9 and 10 are results of evaluation of binding capacity between NK cells and cancer cells according to huHF_mutant1-dual treatment.
- 11 is an evaluation result of cancer cell killing ability of NK cells according to huHF_mutant1-dual treatment.
- FIG. 12 is a schematic diagram of the LLC1 lung cancer animal model preparation and tumor suppression experiment.
- 13 and 14 are tumor growth inhibition evaluation results according to huHF_mutant1-dual treatment.
- 15 to 17 are avidity evaluation results for the lung cancer cell line A549 of huHF_mutant1-dual.
- 18 is an evaluation result of tumor growth inhibition in an animal model of LLC1 lung cancer when huHF_mutant1-dual or a combination thereof with an anticancer agent is used.
- the present invention relates to a ferritin protein in which a foreign peptide is fused to an external surface, and a molecule capable of binding to an immune checkpoint molecule mutated to decrease binding to human transferrin receptor is fused.
- Ferritin may be ferritin from humans, animals and microorganisms.
- Human ferritin is composed of a heavy chain (21 kDa) and a light chain (19 kDa), and exhibits the property of forming spherical nanoparticles through the self-assembly ability of the monomers constituting the ferritin.
- Ferritin can form a self-assembly having a spherical three-dimensional structure by gathering 24 monomers.
- the outer diameter is about 12 nm and the inner diameter is about 8 nm.
- the structure of the ferritin monomer is a form in which five ⁇ -helix structures, namely, A helix, B helix, C helix, D helix, and E helix, are sequentially connected, and each ⁇ -helix structure called a loop consists of a polypeptide. It contains a portion of the atypical polypeptide to which it is linked.
- the loop is a region that is not structurally broken even when a peptide or a small protein antigen is inserted into ferritin.
- a peptide-ferritin fusion protein monomer in which a peptide such as an epitope is located in a ferritin monomer can be prepared.
- the loop connecting the helix A and the helix B is A-B loop
- the loop connecting the helix B and helix C is loop B-C
- the loop connecting the helix C and helix D is C-D loop
- the loop connecting the helix D and E is D-E. called loop.
- the ferritin may be a ferritin heavy chain, specifically, a human ferritin heavy chain.
- Human ferritin heavy chain may be used interchangeably with 'huHF'.
- the ferritin protein may be a ferritin monomer. Accordingly, it may be a ferritin heavy chain monomer or a human ferritin heavy chain monomer.
- Ferritin self-assembles several of its monomers to form an organized structure or pattern.
- the ferritin protein of the present invention is a nanoscale particle.
- 24 ferritin monomers fused with a molecule capable of binding to an immune checkpoint molecule may be self-assembled to form a ferritin protein.
- the ferritin protein of the present invention may be spherical.
- the particle diameter may be 8 to 50 nm. More specifically, it may be 8 nm to 50 nm, 8 nm to 45 nm, 8 nm to 40 nm, 8 nm to 35 nm, 8 nm to 30 nm, 8 nm to 25 nm, 8 nm to 20 nm, and 8 nm to 15 nm.
- the ferritin protein of the present invention is a foreign peptide fused to an outer surface.
- the foreign peptide may be a foreign peptide to ferritin. As long as the foreign peptide is fused to the outer surface of the ferritin protein, it is not necessary that the foreign peptide is fused to all ferritin monomers constituting the ferritin protein.
- the foreign peptide when 24 ferritin monomers fused with a foreign peptide are self-assembled to form a ferritin protein, the foreign peptide may be fused to at least one ferritin monomer among the 24 ferritin monomers.
- a foreign peptide can be fused to all 24 ferritin monomers.
- One or two or more types of immune checkpoint molecules and foreign peptides may be fused to each ferritin monomer constituting the ferritin protein.
- Each ferritin monomer constituting the ferritin protein may be fused with different foreign peptides.
- the foreign peptide may be a pharmacologically active peptide. Any peptide may be used without limitation as long as it has pharmacological activity, for example, a ligand or a fragment of a ligand capable of binding to an immune checkpoint molecule, a receptor or a fragment of a receptor, an antibody or an antibody comprising an antigen binding region (CDR). snippet; or a disease antigen epitope.
- a ligand or a fragment of a ligand capable of binding to an immune checkpoint molecule for example, a ligand or a fragment of a ligand capable of binding to an immune checkpoint molecule, a receptor or a fragment of a receptor, an antibody or an antibody comprising an antigen binding region (CDR). snippet; or a disease antigen epitope.
- CDR antigen binding region
- Immune checkpoint molecules bind to T cells and inactivate them.
- Such immune checkpoint molecules include, for example, Her-2/neu, VISTA, 4-1BBL, Galectin-9, Adenosine A2a receptor, CD80, CD86, ICOS, ICOSL, BTLA, OX-40L, CD155, BCL2, MYC, PP2A, BRD1, BRD2, BRD3, BRD4, BRDT, CBP, E2F1, MDM2, MDMX, PPP2CA, PPM1D, STAT3, IDH1, PD1, CTLA4, PD-L1, PD-L2, LAG3, TIM3, TIGIT, BTLA, SLAMF7, 4- 1BB, OX-40, ICOS, GITR, ICAM-1, BAFFR, HVEM, LFA-1, LIGHT, NKG2C, SLAMF7, NKp80, LAIR1, 2B4, CD2, CD3, CD16, CD20, CD27, CD28, CD40L, CD48
- the molecule capable of binding to the immune checkpoint molecule may be a ligand or a fragment of a ligand capable of binding to the immune checkpoint molecule, a receptor or a fragment of a receptor, an antibody or an antibody fragment comprising an antigen binding region (CDR).
- CDR antigen binding region
- the antibody may be any antibody having complementarity-determining regions (CDRs), which may include all antibodies belonging to classes IgA, IGD, IgE, IgG, IgM, IgY, IgW, etc., antigen-binding fragments thereof, scFvs, and the like.
- CDRs complementarity-determining regions
- the antibody may be an antibody to a disease antigen, an antibody to an immune checkpoint molecule, an antibody to an antigen to be detected for the purpose of diagnosis, prediction, evaluation, etc., or an antibody to an antigen that is a treatment target for a disease.
- a disease antigen may be an antigen of any disease that can be prevented, treated, alleviated or ameliorated by an immune response.
- the disease antigen may be a cell surface antigen of a cancer cell, a pathogen cell, or a cell infected with a pathogen.
- a particular site that determines the antigenic specificity of a disease antigen is the disease antigen epitope.
- the disease includes all diseases that can be treated by the antibody, and may be, for example, an infectious disease, cancer, inflammatory disease, and the like.
- the infectious disease may be, for example, a viral, bacterial, fungal, parasitic or prion infection.
- Inflammatory diseases include, for example, atherosclerosis, arteriosclerosis, autoimmune disease, multiple sclerosis, systemic lupus erythematosus, polymyalgia rheumatica, gouty arthritis, degenerative arthritis, tendinitis, bursitis, psoriasis, cystic fibrosis, osteoarthritis, rheumatoid Arthritis, inflammatory arthritis, Sjogren's syndrome, giant cell arteritis, progressive systemic sclerosis (scleroderma), ankylosing spondylitis, polymyositis, dermatomyositis, pemphigus, diabetes (eg, type I), myasthenia gravis, Hashimoto's thyroiditis, Graves Disease, Goodpasture's disease, mixed connective tissue disease, sclerosing cholangitis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, pernicious anemia, inflammatory dermatos
- Cancer is, for example, brain cancer, head and neck cancer, bladder cancer, breast cancer, cervical cancer, colon cancer, colorectal cancer, endometrial cancer, esophageal cancer, leukemia, lung cancer, liver cancer, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, kidney cancer, stomach cancer, testicular cancer , uterine cancer, vascular tumor, squamous cell carcinoma, adenocarcinoma, small cell carcinoma, melanoma, glioma, neuroblastoma, sarcoma, laryngeal cancer, parotid cancer, biliary tract cancer, thyroid cancer, actinic keratosis, acute lymphocytic leukemia, acute myelogenous leukemia, adenocystic carcinoma , adenoma, adenomatous squamous cell carcinoma, anal duct cancer, anal cancer, anorectal cancer, astrocytoma, basal cell carcinoma, cholesta
- the inflammatory disease antigen may be, for example, an inflammatory cytokine, such as human growth hormone, N-methionyl human growth hormone and bovine growth hormone.
- growth hormones such as; parathyroid hormone; thyroxine; insulin (insulin); proinsulin; relaxin; prorelaxin; glycoprotein hormones such as follicle stimulating hormone (FSH), thyroid stimulating hormone (TSH), and luteinizing hormone (LH); hepatic growth factor; fibroblast growth factor; prolactin; placental lactogen; tumor necrosis factor such as tumor necrosis factor-alpha (TNF- ⁇ ) and tumor necrosis factor-beta (TNF- ⁇ ); Mullerian - inhibitory substances; mouse gonadotropin-associated peptide; inhibin; activin; vascular endothelial growth factor; integrin; human platelet production promoter (thrombopoietin, TPO); nerve growth factors such as NGF-alpha (NGF- ⁇ ); platelet-growth
- Cancer antigens are for example gp100, MART-1, Melna-A, MAGE-A3, MAGE-C2, Mammaglobin-A, proteinsase-3, mucin-1, HPV E6, LMP2, PSMA, GD2, hTERT, PAP, ERG , NA17, ALK, GM3, EPhA2, NA17-A, TRP-1, TRP-2, NY-ESO-1, CEA, CA 125, AFP, Survivin, AH1, ras, G17DT, MUC1, Her-2/neu, E75, p53, PSA, HCG, PRAME, WT1, URLC10, VEGFR1, VEGFR2, E7, Tyrosinase peptide, B16F10, EL4 may be a neoantigen (neoantigen).
- the neoantigen refers to an immunogenic peptide induced and formed by somatic mutation in tumor cells.
- the neoantigen forms a complex with MHC I, moves to the surface of tumor cells, and can be displayed as an antigenic epitope.
- T-cell receptor TCR recognizes this neoantigen-MHC I complex. may induce an immune response.
- the antibody may be, for example, an antibody against an immune checkpoint molecule on the surface of a cancer cell or T cell.
- an immune checkpoint molecule on the surface of a cancer cell or T cell.
- PD-1 Her-2/neu, VISTA, 4-1BBL, CD48, Galectin-9, Adenosine A2a receptor, CD80, CD86, ICOS, ICOSL, BTLA, OX-40L, CD155, BCL2, MYC, PP2A , BRD1, BRD2, BRD3, BRD4, BRDT, CBP, E2F1, MDM2, MDMX, PPP2CA, PPM1D, STAT3, IDH1, PD-L1, PD-L2, CD40L, LAG3, TIM3, TIGIT, BTLA, CD52, SLAMF7, 4 -1BB, OX-40, ICOS, GITR, CD27, CD28, CD16, CD3, CD20, EGFR family, AXL, CSF1R, DDR
- the antigen to be detected may be, for example, a biomarker, for example, a biomarker for diagnosing a disease, a biomarker for predicting the possibility of a disease, a biomarker for prognostic diagnosis of a specific drug, etc., but is not limited thereto.
- a CDR is a CDR that is a component of an antibody, and may be, for example, at least one selected from the group consisting of HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, for example, HCDR3.
- One or two or more CDRs may be fused to a ferritin monomer.
- the same CDRs of the same antibody may include two or more, different CDRs of the same antibody, or CDRs of different antibodies.
- the protein of the present invention may be self-assembled including a ferritin monomer fused with different CDRs.
- the different CDRs may be different CDRs from the same antibody or CDRs from different antibodies.
- Disease antigen epitopes are gp100, MART-1, Melna-A, MAGE-A3, MAGE-C2, Mammaglobin-A, proteinsase-3, mucin-1, HPV E6, LMP2, PSMA, GD2, hTERT, PAP, ERG, NA17 , ALK, GM3, EPhA2, NA17-A, TRP-1, TRP-2, NY-ESO-1, CEA, CA 125, AFP, Survivin, AH1, ras, G17DT, MUC1, Her-2/neu, E75, It may be selected from the group consisting of p53, PSA, HCG, PRAME, WT1, URLC10, VEGFR1, VEGFR2, E7, Tyrosinase peptide, B16F10, EL4, neoantigen and GV1001.
- the foreign peptide may be fused to any ferritin monomer as long as it can be exposed on the outer surface of the ferritin protein.
- the foreign peptide is fused to a position that does not interfere with self-assembly of the ferritin monomer.
- Foreign peptides can be fused inside the ferritin monomer to change the structure of the ferritin protein.
- the inner part may protrude to the outside by fusion of the foreign peptide, and on the contrary, the part that protrudes outward among each constituent part of the ferritin monomer moves to the inside by the fusion of the foreign peptide. may become involved.
- the foreign peptide is preferably fused to a position that reduces the binding ability of the ferritin protein to the human transferrin receptor or interferes with the binding ability of the human transferrin receptor.
- the foreign peptide is not limited to a specific range in its structure, molecular weight and amino acid length.
- the foreign peptide may be, for example, a ligand, antibody or fragment thereof whose amino acid length is 25aa or less. More specifically, the amino acid length is 25aa or less, 24aa or less, 23aa or less, 22aa or less, 21aa or less, 20aa or less, 19aa or less, 18aa or less, 17aa or less, 16aa or less, 15aa or less, 14aa or less, 13aa or less, 12aa or less, 11aa or less or less, 10aa or less, 9aa or less, 8aa or less, 7aa or less, 6aa or less, 5aa or less.
- the amino acid may have a length of 3aa or more, 4aa or more, 5aa or more, 6aa or more, 7aa or more, 8aa or more, 9aa or more, 10aa or more.
- the fusion site of the foreign peptide is not limited to a specific position, for example, inside the ⁇ -helix of the ferritin monomer (A helix, B helix, C helix, D helix or E helix), between adjacent ⁇ -helices, at the N-terminus, It can be fused to C-terminus, A-B loop, B-C loop, C-D loop, D-E loop, between N-terminus and A helix, between E helix and C-terminus, inside helix, etc.
- the ferritin protein of the present invention is mutated so that it does not bind well to the transferrin receptor.
- the ferritin protein of the present invention satisfies the following Equation 1 for the transferrin receptor:
- K [P][T]/[PT]
- [P] represents the concentration of ferritin protein in the equilibrium state of the binding reaction between ferritin protein and transferrin receptor
- [T] is the equilibrium represents the concentration of the transferrin receptor in the state
- [PT] represents the concentration of the complex of the ferritin protein and the transferrin receptor in the equilibrium state
- the binding force may be, for example, binding to the human transferrin receptor.
- the K value of Equation 1 is 10 nM or more, 20 nM or more, 30 nM or more, 40 nM or more, 50 nM or more, 60 nM or more, 70 nM or more, 80 nM or more, 90 nM or more, 100 nM or more, 110 nM or more, 120 nM or more, 125 nM or more, 125 nM or more, 150 nM or more, 200nM or more, 210nM or more, 220nM or more, 230nM or more, 240nM or more, 250nM or more, 260nM or more, 270nM or more, 280nM or more, 290nM or more, 300nM or more, 350nM or more, 400nM or more, 450nM or more, 500nM or more, 550nM or more, 600 nM or more, 700 nM or more, 800 nM or more, 900 nM or more, 1000 nM
- the binding force (K) to the transferrin receptor is measured in the equilibrium state of the binding reaction between the ferritin protein (A) of the present invention and the transferrin receptor.
- concentration of the ferritin protein at equilibrium ([P]), the concentration of the transferrin receptor ([T]), and the concentration of the complex of the protein of the present invention and the transferrin receptor ([PT]) can be measured by various known methods. .
- the ferritin protein of the present invention may fuse a foreign peptide to a site involved in binding to the transferrin receptor in order to lower the binding ability to the transferrin receptor.
- the foreign peptide may be fused so that the foreign peptide is located in the B-C loop and the A helix portion of the ferritin protein of the present invention.
- the ferritin protein of the present invention may be produced in a microorganism expressing a sequence encoding the protein.
- Microorganisms known in the art may be used without limitation.
- it may be E. coli, specifically BL21 (DE3), but is not limited thereto.
- the ferritin protein of the present invention has a high rate of lysis in the cytoplasm in the microbial production system. It is easy to separate/purify and utilize.
- the ferritin protein of the present invention may be prepared, for example, in an E. coli system producing the same in a state in which the water-soluble fraction ratio of the total protein is 40% or more. Specifically, it may be 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, 95% or more.
- the upper limit may be, for example, 100%, 99%, 98%, 97%, 96%, or the like.
- the above ferritin protein can be utilized for various purposes depending on the type of the foreign peptide.
- the foreign peptide when it is a pharmacologically active peptide, it may be utilized as a pharmaceutical composition utilizing such pharmacological activity.
- the foreign peptide is a ligand or a fragment of a ligand capable of binding to an immune checkpoint molecule, a receptor or a fragment of a receptor, an antibody or a fragment of an antibody comprising an antigen binding region (CDR);
- the pharmaceutical composition may be cancer, an infectious disease, an inflammatory disease, and the like.
- the present invention provides a pharmaceutical composition comprising the ferritin protein. All of the above descriptions regarding the ferritin protein apply as it is to the ferritin protein as an active ingredient of the pharmaceutical composition of the present application.
- the pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier.
- pharmaceutically acceptable carrier refers to a carrier or diluent that does not significantly stimulate the organism and does not inhibit the biological activity and properties of the administered component.
- the pharmaceutically acceptable carrier in the present invention can be used by mixing one component or one or more components among saline, sterile water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol, and these components, Other conventional additives such as antioxidants, buffers and bacteriostatic agents may be added as necessary to form an injection suitable for injection into tissues or organs.
- a target organ-specific antibody or other ligand may be used in combination with the carrier so as to act specifically on the target organ.
- composition of the present invention may further include a filler, an excipient, a disintegrant, a binder or a lubricant.
- compositions of the present invention may be formulated using methods known in the art to provide rapid, sustained or delayed release of the active ingredient after administration to a mammal.
- the pharmaceutical composition may be an injection formulation, and may be administered intravenously, but is not limited thereto.
- the term “effective amount” refers to an amount necessary to delay the onset or progression of a specific disease to be treated or to completely promote it.
- the composition may be administered in a pharmaceutically effective amount. It is apparent to those skilled in the art that a suitable total daily amount of the pharmaceutical composition can be determined by a treating physician within the scope of sound medical judgment.
- a specific pharmaceutically effective amount for a specific patient is the specific composition, including the type and extent of the response to be achieved, whether or not other agents are used if necessary, the patient's age, weight, general health status, sex It is preferable to apply differently depending on various factors including diet, administration time, administration route and secretion rate of the composition, treatment period, drugs used together or concurrently with a specific composition, and similar factors well known in the pharmaceutical field.
- the pharmaceutical composition may be accompanied by instructions associated with packaging in a form instructed by a government agency in charge of the manufacture, use and sale of drugs, if necessary, and the instructions are in the form of a composition or human or human. It indicates the approval of a private interest organization for administration to animals, and may be, for example, a label approved by the US Food and Drug Administration for the prescription of a drug.
- Cancer is, for example, brain cancer, head and neck cancer, bladder cancer, breast cancer, cervical cancer, colon cancer, colorectal cancer, endometrial cancer, esophageal cancer, leukemia, lung cancer, liver cancer, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, kidney cancer, stomach cancer, testicular cancer , uterine cancer, vascular tumor, squamous cell carcinoma, adenocarcinoma, small cell carcinoma, melanoma, glioma, neuroblastoma, sarcoma, laryngeal cancer, parotid cancer, biliary tract cancer, thyroid cancer, actinic keratosis, acute lymphocytic leukemia, acute myelogenous leukemia, adenocystic carcinoma , adenoma, adenomatous squamous cell carcinoma, anal duct cancer, anal cancer, anorectal cancer, astrocytoma, basal cell carcinoma, cholesta
- the infectious disease may be, for example, a viral, bacterial, fungal, parasitic or prion infection.
- huHF is a globular protein nanoparticle (12 nm) composed of 24 monomers, each of which is composed of a total of 5 ⁇ -helix.
- the present inventors induce mutations in the amino acid sequence that binds to the transferrin receptor of the huHF monomer through gene cloning, so that huHF_Mutant1 (Q15A, D16A, R23A, F82A, Q84A), huHF_Mutant2 (Q15A, D16A, R23A, F82A, Q84A, E117A, K120A, D124A) were obtained.
- the antibody CDR3 peptide and domain were inserted through gene cloning into the loop between the ⁇ -helix of huHF_Mutant1 and 2 (BC loop in huHF 5T to 176G; 92D/93W based on the PDB 3AJO sequence; 92D/93W) and the C-terminus to secure the delivery system. .
- E. coli strain BL21 [(fhuA2 [lon] ompT gal [dcm] ⁇ hsdS)] was transformed with the expression vector prepared above, respectively, and kanamycin-resistant transformants were selected.
- Transformed E. coli was cultured in flasks (250 mL Erlenmeyer flasks, 37 °C, 150 rpm) containing 50 mL of Luria-Bertani (LB) medium (containing 100 mg L-1 kanamycin). When the medium turbidity (OD 600) reached about 0.5-0.7, Isopropyl- ⁇ -Dthiogalactopyanosid (IPTG) (1.0 mM) was injected to induce expression of the recombinant gene.
- LB Luria-Bertani
- the cultured E. coli was centrifuged at 4,500 rpm for 10 minutes to recover the cell precipitate and suspended in 5 ml of a disruption solution (10 mM Tris-HCl buffer, pH 7.5, 10 mM EDTA). and crushed using an ultrasonic crusher (Branson Ultrasonics Corp., Danbury, CT, USA). After crushing, centrifugation was performed at 13,000 rpm for 10 minutes to separate the supernatant and insoluble aggregates. The separated supernatant was used for subsequent experiments.
- a disruption solution 10 mM Tris-HCl buffer, pH 7.5, 10 mM EDTA
- an ultrasonic crusher Branson Ultrasonics Corp., Danbury, CT, USA
- the supernatant obtained in Example 2 was purified through a three-step process. First, 1) Ni 2+ -NTA affinity chromatography using the binding of histidine and nickel fused to the recombinant protein was performed, 2) the recombinant protein was concentrated and a fluorescent substance was attached through buffer exchange, and 3) finally fluorescence was performed. In order to separate only the self-assembled protein nanoparticles to which the material is attached, sucrose gradient ultracentrifugation was performed. The detailed description of each step is as follows.
- E. coli cultured in the same manner as specified above was recovered, the cell pellet was resuspended in 5 mL lysis buffer (pH 8.0, 50 mM sodium phosphate, 300 mM NaCl, 20 mM imidazole), and a sonicator was used to disrupt cells.
- the lysed cell solution was centrifuged at 13,000 rpm for 10 minutes to separate only the supernatant, and then each recombinant protein was separated using a Ni 2+ -NTA column (Qiagen, Hilden, Germany) (washing buffer: pH 8.0, 50 mM).
- sodium phosphate, 300 mM NaCl, 80 mM imidazole / elution buffer pH 8.0, 50 mM sodium phosphate, 300 mM NaCl, 200 mM imidazole).
- BL21 competent cells were transformed with various expression vectors based on pCM (Tac promoter).
- a single colony was inoculated into LB liquid medium (50 mL) supplemented with 100 mg/L of kanamycin and cultured at 37° C. and 130 rpm in a shaking incubator.
- the turbidity/optical density at 600 nm reached 0.5
- the expression of the target protein was induced through administration of 1 mM IPTG.
- the cells in the culture medium were spun-down through centrifugation (13000 rpm, 10 minutes), and the cell pellet was collected and resuspended in 10 mM Tris-Hcl (pH 7.4) buffer. .
- Resuspended cells were ruptured using a Branson Sonifier (Branson Ultrasonics Corp., Danbury, CT). After sonication, the supernatant containing soluble protein and aggregates containing insoluble protein were separated by centrifugation (13000 rpm, 10 min). It was confirmed through SDS-PAGE analysis of the separated soluble and insoluble protein fractions ( FIGS. 2 and 3 ).
- TEM transmission electron microscope
- the binding affinity A of the prepared protein to the antigen was measured according to the following method.
- Figure 7 is a comparison of the binding force to hTfR of huHF_mutant1-dual and huHF_mutant2-dual. Referring to this, in the case of huHF_mutant2-dual, even when the concentration was increased to 10000 nM, it was not saturated, indicating that the binding force to hTfR was further reduced. can be checked If the expected saturation point is selected and the binding force Kd value is calculated, it will be about 4400 nM.
- A549 a human lung cancer cell line, was labeled with CFSE, a fluorescent substance. 10 6 cells were reacted with CFSE at a concentration of 5 ⁇ M in an incubator at 37° C. for 20 minutes, washed with PBS, and cultured for one day by diluting 10 5 cells in 2 ml culture media in a 2 ml cell plate.
- NK cells were labeled using an NK 1.1 antibody-PE antibody.
- A549 a human lung cancer cell line, was labeled with CFSE, a fluorescent substance. 10 6 cells were reacted with CFSE at a concentration of 5 ⁇ M in an incubator at 37° C. for 20 minutes, washed with PBS, and cultured for one day by diluting 10 4 cells in 200 ⁇ l culture media in a 96 well plate.
- the reaction solution was reacted in an incubator for 30 minutes, and then the ratio of cells showing both CFSE fluorescence and DAPI fluorescence was analyzed using FACS equipment (FIG. 9). Referring to this, it can be confirmed that the binding ability of NK cells to A549 cells is increased during huHF_mutant-dual treatment.
- NK cells were labeled with the NK 1.1 antibody-PE antibody.
- reaction solution was reacted in an incubator for 48 hours, and the toxicity ability according to the sample was verified with FACS equipment. The degree of cell death was analyzed with 7-AAD.
- the ratio of NK cells to cancer cells and the toxic ability of NK cells according to the sample were analyzed ( FIG. 11 ). Referring to this, it can be confirmed that the killing ability of A549 cells of NK cells is increased during huHF_mutant-dual treatment.
- Tecentriq is a monoclonal antibody that binds to PD-1 or PD-L1 used for the treatment of lung cancer, etc.
- mAb-mTIGIT is a monoclonal antibody that binds to murine TIGIT.
- a tumor model was formed by subcutaneously transplanting LLC1 into C57BL/6 by 5*10 5 each.
- the tumor size was measured and classified for each individual, and the same size was adjusted for each group.
- the sample was intravenously injected through the caudal vein every 3 days, and the tumor size was measured for each individual to compare the tumor growth inhibition efficacy (FIG. 12).
- Fig. 13 shows the tumor size by date in each experimental group
- Fig. 14 shows the tumor size on the 22nd day in each experimental group.
- target cells immunodeficiency cells, cancer cells
- the sample drug, antibody (anti-mouse PD-L1 antibody (BE0101), anti-mouse TIGIT antibody (BE0274), anti-human PD-L1 (BE0285))
- the control group 100 ⁇ l of FACS buffer (0.1%BSA + 0.01% sodium azide in PBS) was treated (3hr, room temperature).
- Fluorescence antibody (anti his tag antibody-PE(SC-8036PE), anti-IgG antibody-PE(PE goat F(ab')2 anti-rat (IgG) secondary antibody(ab7010), PE F(ab')2) -goat anti-mouse IgG (H+L) secondary antibody (12-4010-82)) was treated (2 hr, room temperature).
- FIGS. 15-17 BD Biosciences and FACS equipment were analyzed using the ratio of target cells showing PE fluorescence among live cells in each FACS column ( FIGS. 15-17 ).
- a tumor model was formed by subcutaneously transplanting LLC1 into C57BL/6 by 5*10 5 each.
- the sample was intravenously injected through the caudal vein every 3 days (in the case of the G2 group, every 6 days), and the tumor size was measured for each individual to compare the tumor growth inhibition efficacy (FIG. 18).
- Ab-1 was injected at a concentration of 30 nmol/kg, huHF_mutant-dual was 30 nmol/kg, and Vac was 10 nmol/kg.
- the huHF_mutant-dual treatment group has excellent tumor growth inhibition ability, and exhibits a more excellent effect when combined with a vaccine.
Landscapes
- Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Zoology (AREA)
- Engineering & Computer Science (AREA)
- General Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biophysics (AREA)
- Wood Science & Technology (AREA)
- Molecular Biology (AREA)
- General Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- Biomedical Technology (AREA)
- Gastroenterology & Hepatology (AREA)
- Physics & Mathematics (AREA)
- Toxicology (AREA)
- Plant Pathology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Microbiology (AREA)
- Medicinal Chemistry (AREA)
- Peptides Or Proteins (AREA)
Abstract
Description
명칭 | 서열번호 |
huHF_Native | 1 |
huHF-Mutant1 | 2 |
huHF-Mutant2 | 3 |
명칭 | 서열번호 |
huHF-αPD-L1 | 4 |
huHF αTIGIT | 5 |
huHF-h-smPD1 | 6 |
Linker1 | 7 |
Linker2 | 8 |
Linker3 | 9 |
단백질 | 발현 벡터 |
huHF_Native | NH2-NdeI-huHF-αPD-L1 HCDR3-HindIII-COOH |
huHF_Mutant1-dual | BC(92D/93W): NH2-NdeI-huHF_Mutant1-[αPD-L1 HCDR3]- huHF_Mutant1- αTIGIT HCDR3-HindIII-COOH |
huHF_Mutant2-dual | BC(92D/93W): NH2-NdeI-huHF_Mutant2-[αPD-L1 HCDR3]-huHF- αTIGIT HCDR3-HindIII-COOH |
huHF_Mutant1-h_smPD1 | NH2-NdeI-huHF_Mutant1-Linker2-h_smPD1-HindIII-COOH |
구분 | 결합력 | |
huHF-h_smPD1 |
Native | 46.8 |
Mutant | 94.2 | |
huHF_mutant1-dual | 181.9 |
Claims (14)
- 외부 표면에 외래 펩타이드가 융합되고,인간 트랜스페린 수용체에 대한 결합력이 떨어지도록 돌연변이된 페리틴 단백질.
- 청구항 1에 있어서, 상기 외래 펩타이드는 약리 활성 펩타이드인 페리틴 단백질.
- 청구항 1에 있어서, 상기 외래 펩타이드는 면역 관문 분자와 결합 가능한 리간드 또는 리간드의 단편, 수용체 또는 수용체의 단편, 항체 또는 항원 결합부위(CDR)를 포함하는 항체의 단편; 또는 질환 항원 에피토프인 단백질.
- 청구항 3에 있어서, 상기 면역 관문 분자는 Her-2/neu, VISTA, 4-1BBL, Galectin-9, Adenosine A2a receptor, CD80, CD86, ICOS, ICOSL, BTLA, OX-40L, CD155, BCL2, MYC, PP2A, BRD1, BRD2, BRD3, BRD4, BRDT, CBP, E2F1, MDM2, MDMX, PPP2CA, PPM1D, STAT3, IDH1, PD1, CTLA4, PD-L1, PD-L2, LAG3, TIM3, TIGIT, BTLA, SLAMF7, 4-1BB, OX-40, ICOS, GITR, ICAM-1, BAFFR, HVEM, LFA-1, LIGHT, NKG2C, SLAMF7, NKp80, LAIR1, 2B4, CD2, CD3, CD16, CD20, CD27, CD28, CD40L, CD48, CD52, EGFR family, AXL, CSF1R, DDR1, DDR2, EPH receptor family, FGFR family, VEGFR family, IGF1R, LTK, PDGFR family, RET, KIT, KRAS, NTRK1 및 NTRK2으로 이루어진 군에서 선택되는 어느 하나인 단백질.
- 청구항 3에 있어서, 상기 항원결합부위는 HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 및 LCDR3로 이루어진 군에서 선택되는 어느 하나인 단백질.
- 청구항 3에 있어서, 상기 질환 항원 에피토프는 gp100, MART-1, Melna-A, MAGE-A3, MAGE-C2, Mammaglobin-A, proteinsase-3, mucin-1, HPV E6, LMP2, PSMA, GD2, hTERT, PAP, ERG, NA17, ALK, GM3, EPhA2, NA17-A, TRP-1, TRP-2, NY-ESO-1, CEA, CA 125, AFP, Survivin, AH1, ras, G17DT, MUC1, Her-2/neu, E75, p53, PSA, HCG, PRAME, WT1, URLC10, VEGFR1, VEGFR2, E7, Tyrosinase 펩타이드, B16F10, EL4, 신생항원(neoantigen) 및 GV1001로 이루어진 군에서 선택되는 것인 단백질.
- 청구항 1에 있어서, 상기 외래 펩타이드는 페리틴 단량체의 인접한 α-헬릭스들 사이 중 적어도 하나에 융합되는 단백질.
- 청구항 1에 있어서, 상기 외래 펩타이드는 페리틴 단량체의 N-말단 또는 C-말단에 융합되는 단백질.
- 청구항 1에 있어서, 상기 외래 펩타이드는 페리틴 단량체의 A-B루프, B-C루프, C-D루프 또는 D-E루프에 융합된 단백질.
- 청구항 1에 있어서, 상기 외래 펩타이드는 페리틴 단량체의 N-말단과 A 헬릭스 사이 또는 E 헬릭스와 C-말단 사이에 융합된 단백질.
- 청구항 1에 있어서, 돌연변이된 상기 페리틴 단백질은 서열번호 1의 서열에서 15번, 16번, 23번, 82번, 84번, 117번, 120번 또는 124번 아미노산이 알라닌, 글라이신, 발린 또는 류신으로 치환된 것인 단백질.
- 청구항 1에 있어서, 트랜스페린 수용체에 대한 결합력(K)이 다음 수학식 1을 만족하는 단백질:[수학식 1]K ≥ 10 nM(식 중, K [P][T]/[PT]이고, 여기서 [P]는 상기 단백질과 상기 트랜스페린 수용체와의 결합 반응의 평형 상태에서의 상기 단백질의 농도를 나타내고, [T]는 상기 평형 상태에서의 상기 트랜스페린 수용체의 농도를 나타내며, [PT]는 상기 평형 상태에서의 상기 단백질과 상기 트랜스페린 수용체의 복합체의 농도를 나타냄).
- 청구항 12에 있어서, 상기 트랜스페린 수용체는 인간 트랜스페린 수용체인 단백질.
- 청구항 1에 있어서, 상기 페리틴은 인간 페리틴 중쇄인 단백질.
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP22799104.9A EP4335867A1 (en) | 2021-05-03 | 2022-05-03 | Novel protein |
JP2023568076A JP2024519578A (ja) | 2021-05-03 | 2022-05-03 | 新規タンパク質 |
CN202280032815.0A CN117242086A (zh) | 2021-05-03 | 2022-05-03 | 新型蛋白质 |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR10-2021-0057062 | 2021-05-03 | ||
KR20210057062 | 2021-05-03 | ||
KR1020220054782A KR20220150222A (ko) | 2021-05-03 | 2022-05-03 | 신규 단백질 |
KR10-2022-0054782 | 2022-05-03 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2022235061A1 true WO2022235061A1 (ko) | 2022-11-10 |
Family
ID=83932870
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/KR2022/006356 WO2022235061A1 (ko) | 2021-05-03 | 2022-05-03 | 신규 단백질 |
Country Status (2)
Country | Link |
---|---|
JP (1) | JP2024519578A (ko) |
WO (1) | WO2022235061A1 (ko) |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR20150088597A (ko) * | 2014-01-24 | 2015-08-03 | 국립대학법인 울산과학기술대학교 산학협력단 | 항원 펩타이드-페리틴 융합단백질 및 이를 포함하는 백신 조성물 |
KR20170027683A (ko) * | 2015-09-02 | 2017-03-10 | 경북대학교 산학협력단 | 인간 유래 페리틴 모노머 단편 및 이를 이용한 융합폴리펩티드 |
KR20170047120A (ko) * | 2015-10-22 | 2017-05-04 | 고려대학교 산학협력단 | 암 특이적 에피토프와 연결된 단백질 나노입자 및 이를 포함하는 암 면역치료용 조성물 |
KR20180008353A (ko) * | 2016-07-15 | 2018-01-24 | 한국과학기술연구원 | 신규 나노케이지 및 그의 용도 |
-
2022
- 2022-05-03 JP JP2023568076A patent/JP2024519578A/ja active Pending
- 2022-05-03 WO PCT/KR2022/006356 patent/WO2022235061A1/ko active Application Filing
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR20150088597A (ko) * | 2014-01-24 | 2015-08-03 | 국립대학법인 울산과학기술대학교 산학협력단 | 항원 펩타이드-페리틴 융합단백질 및 이를 포함하는 백신 조성물 |
KR20170027683A (ko) * | 2015-09-02 | 2017-03-10 | 경북대학교 산학협력단 | 인간 유래 페리틴 모노머 단편 및 이를 이용한 융합폴리펩티드 |
KR20170047120A (ko) * | 2015-10-22 | 2017-05-04 | 고려대학교 산학협력단 | 암 특이적 에피토프와 연결된 단백질 나노입자 및 이를 포함하는 암 면역치료용 조성물 |
KR20180008353A (ko) * | 2016-07-15 | 2018-01-24 | 한국과학기술연구원 | 신규 나노케이지 및 그의 용도 |
Non-Patent Citations (1)
Title |
---|
MONTEMIGLIO LINDA CELESTE, TESTI CLAUDIA, CECI PIERPAOLO, FALVO ELISABETTA, PITEA MARTINA, SAVINO CARMELINDA, ARCOVITO ALESSANDRO,: "Cryo-EM structure of the human ferritin–transferrin receptor 1 complex", NATURE COMMUNICATIONS, vol. 10, no. 1, 1 December 2019 (2019-12-01), XP093000685, DOI: 10.1038/s41467-019-09098-w * |
Also Published As
Publication number | Publication date |
---|---|
JP2024519578A (ja) | 2024-05-17 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US11840577B2 (en) | Antigen binding proteins specifically binding MAGE-A | |
CN104619350A (zh) | 结合到核受体配体多肽的抗psma抗体 | |
WO2017030370A1 (ko) | 항-코티닌 항체가 연결된 키메라 항체 수용체 및 이의 용도 | |
WO2021256724A1 (ko) | Bcma를 표적으로 하는 키메라 항원 수용체 및 이의 용도 | |
TW202112824A (zh) | 進一步與mhc分子結合的募集因子 | |
CN115103852A (zh) | Prame tcr受体和其用途 | |
Mikkelsen et al. | Carcinoembryonic antigen (CEA)-specific 4-1BB-costimulation induced by CEA-targeted 4-1BB-agonistic trimerbodies | |
WO2022235061A1 (ko) | 신규 단백질 | |
US20230132241A1 (en) | Antigen binding proteins specifically binding prame | |
US20230357428A1 (en) | Antigen binding proteins specifically binding prame | |
WO2022092974A1 (ko) | 항체 유사 단백질 및 그 용도 | |
CN112204048A (zh) | 抗cct5结合分子及其使用方法 | |
WO2022235059A1 (ko) | 폐암의 예방 또는 치료용 약학 조성물 | |
EP4335867A1 (en) | Novel protein | |
KR102561958B1 (ko) | 항체 유사 단백질 및 그 용도 | |
WO2023214623A1 (ko) | 글루타치온-s-전이효소 및 항체 결합 도메인을 포함하는 융합 단백질 및 이의 용도 | |
WO2023090780A1 (ko) | 자연살해세포-특이적 키메릭항원수용체 및 이의 용도 | |
WO2021172690A1 (ko) | 메소텔린 특이적인 키메라 항원 수용체 및 이의 용도 | |
US20240139314A1 (en) | Engineered chimeric fusion protein compositions and methods of use thereof | |
WO2021086158A1 (ko) | 질환 항원이 융합된 단백질 및 이의 용도 | |
WO2021086159A1 (ko) | 면역 관문 분자와 결합 가능한 분자가 융합된 단백질 및 이의 용도 | |
EP4386007A1 (en) | Bispecific recombinant protein and use thereof | |
WO2023195805A2 (ko) | Itgb2 매개 약물전달체 | |
WO2019066536A1 (ko) | 신규 암 치료용 조성물 | |
KR20220150221A (ko) | 폐암의 예방 또는 치료용 약학 조성물 |
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: 22799104 Country of ref document: EP Kind code of ref document: A1 |
|
WWE | Wipo information: entry into national phase |
Ref document number: 18289179 Country of ref document: US |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2023568076 Country of ref document: JP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 202280032815.0 Country of ref document: CN |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2022799104 Country of ref document: EP |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
ENP | Entry into the national phase |
Ref document number: 2022799104 Country of ref document: EP Effective date: 20231204 |