JP2019509021A - Ror1抗体組成物及び関連の方法 - Google Patents
Ror1抗体組成物及び関連の方法 Download PDFInfo
- Publication number
- JP2019509021A JP2019509021A JP2018537754A JP2018537754A JP2019509021A JP 2019509021 A JP2019509021 A JP 2019509021A JP 2018537754 A JP2018537754 A JP 2018537754A JP 2018537754 A JP2018537754 A JP 2018537754A JP 2019509021 A JP2019509021 A JP 2019509021A
- Authority
- JP
- Japan
- Prior art keywords
- seq
- antibody
- ror1
- nos
- binding protein
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 101001103039 Homo sapiens Inactive tyrosine-protein kinase transmembrane receptor ROR1 Proteins 0.000 title claims abstract description 123
- 238000000034 method Methods 0.000 title claims abstract description 96
- 239000000203 mixture Substances 0.000 title abstract description 28
- 101001103036 Homo sapiens Nuclear receptor ROR-alpha Proteins 0.000 title abstract description 20
- 102100039614 Nuclear receptor ROR-alpha Human genes 0.000 title abstract 2
- 102000008394 Immunoglobulin Fragments Human genes 0.000 claims abstract description 127
- 108010021625 Immunoglobulin Fragments Proteins 0.000 claims abstract description 127
- 102000049583 human ROR1 Human genes 0.000 claims abstract description 120
- 230000027455 binding Effects 0.000 claims abstract description 86
- 108010019670 Chimeric Antigen Receptors Proteins 0.000 claims abstract description 67
- 229940125644 antibody drug Drugs 0.000 claims abstract description 22
- 230000001225 therapeutic effect Effects 0.000 claims abstract description 21
- 210000004027 cell Anatomy 0.000 claims description 234
- 102000023732 binding proteins Human genes 0.000 claims description 111
- 108091008324 binding proteins Proteins 0.000 claims description 111
- 206010028980 Neoplasm Diseases 0.000 claims description 78
- 230000014509 gene expression Effects 0.000 claims description 77
- 102100035360 Cerebellar degeneration-related antigen 1 Human genes 0.000 claims description 72
- 229940049595 antibody-drug conjugate Drugs 0.000 claims description 68
- 239000000611 antibody drug conjugate Substances 0.000 claims description 59
- 108090000623 proteins and genes Proteins 0.000 claims description 59
- 102000004169 proteins and genes Human genes 0.000 claims description 40
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 37
- 239000013598 vector Substances 0.000 claims description 36
- 206010006187 Breast cancer Diseases 0.000 claims description 34
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 34
- 239000003053 toxin Substances 0.000 claims description 34
- 208000026310 Breast neoplasm Diseases 0.000 claims description 33
- 231100000765 toxin Toxicity 0.000 claims description 33
- 108700012359 toxins Proteins 0.000 claims description 33
- 201000011510 cancer Diseases 0.000 claims description 29
- 102000040430 polynucleotide Human genes 0.000 claims description 25
- 108091033319 polynucleotide Proteins 0.000 claims description 25
- 239000002157 polynucleotide Substances 0.000 claims description 25
- 231100000599 cytotoxic agent Toxicity 0.000 claims description 21
- 102000004190 Enzymes Human genes 0.000 claims description 20
- 108090000790 Enzymes Proteins 0.000 claims description 20
- 229940127089 cytotoxic agent Drugs 0.000 claims description 20
- 239000002254 cytotoxic agent Substances 0.000 claims description 20
- 201000010099 disease Diseases 0.000 claims description 20
- 101100112922 Candida albicans CDR3 gene Proteins 0.000 claims description 18
- 208000035475 disorder Diseases 0.000 claims description 17
- 108060003951 Immunoglobulin Proteins 0.000 claims description 15
- 102000018358 immunoglobulin Human genes 0.000 claims description 15
- 239000008194 pharmaceutical composition Substances 0.000 claims description 15
- 230000011664 signaling Effects 0.000 claims description 14
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 claims description 13
- 208000029742 colonic neoplasm Diseases 0.000 claims description 12
- 206010009944 Colon cancer Diseases 0.000 claims description 11
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 11
- 206010029260 Neuroblastoma Diseases 0.000 claims description 11
- 208000006265 Renal cell carcinoma Diseases 0.000 claims description 11
- 230000002147 killing effect Effects 0.000 claims description 11
- 201000005202 lung cancer Diseases 0.000 claims description 11
- 208000020816 lung neoplasm Diseases 0.000 claims description 11
- 208000025205 Mantle-Cell Lymphoma Diseases 0.000 claims description 10
- 206010039491 Sarcoma Diseases 0.000 claims description 10
- 229940045799 anthracyclines and related substance Drugs 0.000 claims description 10
- 230000002401 inhibitory effect Effects 0.000 claims description 10
- 230000003834 intracellular effect Effects 0.000 claims description 10
- 230000001404 mediated effect Effects 0.000 claims description 10
- 201000001441 melanoma Diseases 0.000 claims description 10
- 108091008874 T cell receptors Proteins 0.000 claims description 9
- 102000016266 T-Cell Antigen Receptors Human genes 0.000 claims description 9
- 239000002502 liposome Substances 0.000 claims description 9
- 239000003937 drug carrier Substances 0.000 claims description 8
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 claims description 7
- 230000021615 conjugation Effects 0.000 claims description 7
- 101000998953 Homo sapiens Immunoglobulin heavy variable 1-2 Proteins 0.000 claims description 6
- 102100036887 Immunoglobulin heavy variable 1-2 Human genes 0.000 claims description 6
- 231100000654 protein toxin Toxicity 0.000 claims description 6
- 210000004881 tumor cell Anatomy 0.000 claims description 6
- 101001008255 Homo sapiens Immunoglobulin kappa variable 1D-8 Proteins 0.000 claims description 5
- 101001047628 Homo sapiens Immunoglobulin kappa variable 2-29 Proteins 0.000 claims description 5
- 101001008321 Homo sapiens Immunoglobulin kappa variable 2D-26 Proteins 0.000 claims description 5
- 101001047619 Homo sapiens Immunoglobulin kappa variable 3-20 Proteins 0.000 claims description 5
- 101001008263 Homo sapiens Immunoglobulin kappa variable 3D-15 Proteins 0.000 claims description 5
- 102100022964 Immunoglobulin kappa variable 3-20 Human genes 0.000 claims description 5
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 claims description 4
- 230000012010 growth Effects 0.000 claims description 4
- 239000012634 fragment Substances 0.000 abstract description 33
- 239000000427 antigen Substances 0.000 abstract description 27
- 108091007433 antigens Proteins 0.000 abstract description 27
- 102000036639 antigens Human genes 0.000 abstract description 27
- 241000283973 Oryctolagus cuniculus Species 0.000 description 65
- 238000000338 in vitro Methods 0.000 description 37
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 36
- 235000018102 proteins Nutrition 0.000 description 35
- 241000699666 Mus <mouse, genus> Species 0.000 description 32
- 229920001184 polypeptide Polymers 0.000 description 26
- 102000004196 processed proteins & peptides Human genes 0.000 description 26
- 210000001744 T-lymphocyte Anatomy 0.000 description 25
- 238000011534 incubation Methods 0.000 description 25
- 238000011282 treatment Methods 0.000 description 25
- 101001103033 Homo sapiens Tyrosine-protein kinase transmembrane receptor ROR2 Proteins 0.000 description 24
- RXWNCPJZOCPEPQ-NVWDDTSBSA-N puromycin Chemical compound C1=CC(OC)=CC=C1C[C@H](N)C(=O)N[C@H]1[C@@H](O)[C@H](N2C3=NC=NC(=C3N=C2)N(C)C)O[C@@H]1CO RXWNCPJZOCPEPQ-NVWDDTSBSA-N 0.000 description 24
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 23
- 239000000872 buffer Substances 0.000 description 22
- 241000699670 Mus sp. Species 0.000 description 21
- 238000010790 dilution Methods 0.000 description 21
- 239000012895 dilution Substances 0.000 description 21
- 238000000684 flow cytometry Methods 0.000 description 21
- 230000008685 targeting Effects 0.000 description 21
- 238000002965 ELISA Methods 0.000 description 20
- 238000001514 detection method Methods 0.000 description 20
- 239000013604 expression vector Substances 0.000 description 20
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 19
- 102100039616 Tyrosine-protein kinase transmembrane receptor ROR2 Human genes 0.000 description 18
- 210000002966 serum Anatomy 0.000 description 17
- 238000012360 testing method Methods 0.000 description 17
- 230000022534 cell killing Effects 0.000 description 16
- 230000000694 effects Effects 0.000 description 16
- 239000012894 fetal calf serum Substances 0.000 description 16
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 15
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 15
- 238000001727 in vivo Methods 0.000 description 15
- 150000007523 nucleic acids Chemical group 0.000 description 15
- 239000000523 sample Substances 0.000 description 15
- 125000003275 alpha amino acid group Chemical group 0.000 description 14
- 238000004458 analytical method Methods 0.000 description 14
- 239000003814 drug Substances 0.000 description 14
- 238000005516 engineering process Methods 0.000 description 14
- 108010047041 Complementarity Determining Regions Proteins 0.000 description 13
- 229930182816 L-glutamine Natural products 0.000 description 13
- 235000001014 amino acid Nutrition 0.000 description 13
- 229910002091 carbon monoxide Inorganic materials 0.000 description 13
- 238000003384 imaging method Methods 0.000 description 13
- 238000000746 purification Methods 0.000 description 13
- 125000006850 spacer group Chemical group 0.000 description 13
- 238000001262 western blot Methods 0.000 description 13
- 229940024606 amino acid Drugs 0.000 description 12
- 150000001413 amino acids Chemical class 0.000 description 12
- 239000003153 chemical reaction reagent Substances 0.000 description 12
- 239000003795 chemical substances by application Substances 0.000 description 12
- 229950010131 puromycin Drugs 0.000 description 12
- 239000006228 supernatant Substances 0.000 description 12
- 210000001519 tissue Anatomy 0.000 description 12
- 239000004471 Glycine Substances 0.000 description 11
- 241001465754 Metazoa Species 0.000 description 11
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 11
- 210000004369 blood Anatomy 0.000 description 11
- 239000008280 blood Substances 0.000 description 11
- 108020001507 fusion proteins Proteins 0.000 description 11
- 102000037865 fusion proteins Human genes 0.000 description 11
- 239000006166 lysate Substances 0.000 description 11
- 102000039446 nucleic acids Human genes 0.000 description 11
- 108020004707 nucleic acids Proteins 0.000 description 11
- 238000012216 screening Methods 0.000 description 11
- 238000002604 ultrasonography Methods 0.000 description 11
- 241000283707 Capra Species 0.000 description 10
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 10
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 10
- 239000012472 biological sample Substances 0.000 description 10
- -1 ethylene-diamino Chemical group 0.000 description 10
- 239000001963 growth medium Substances 0.000 description 10
- 238000004020 luminiscence type Methods 0.000 description 10
- 108020004414 DNA Proteins 0.000 description 9
- 238000003556 assay Methods 0.000 description 9
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 9
- 239000000306 component Substances 0.000 description 9
- 201000010536 head and neck cancer Diseases 0.000 description 9
- 208000014829 head and neck neoplasm Diseases 0.000 description 9
- 230000003389 potentiating effect Effects 0.000 description 9
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 9
- 230000009870 specific binding Effects 0.000 description 9
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 9
- 108020004705 Codon Proteins 0.000 description 8
- 102000013463 Immunoglobulin Light Chains Human genes 0.000 description 8
- 108010065825 Immunoglobulin Light Chains Proteins 0.000 description 8
- 102220497176 Small vasohibin-binding protein_T47D_mutation Human genes 0.000 description 8
- 230000006870 function Effects 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- 102000005962 receptors Human genes 0.000 description 8
- 108020003175 receptors Proteins 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 238000002198 surface plasmon resonance spectroscopy Methods 0.000 description 8
- 108091026890 Coding region Proteins 0.000 description 7
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 7
- 102000006496 Immunoglobulin Heavy Chains Human genes 0.000 description 7
- 108010019476 Immunoglobulin Heavy Chains Proteins 0.000 description 7
- 108010076504 Protein Sorting Signals Proteins 0.000 description 7
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 7
- 239000012298 atmosphere Substances 0.000 description 7
- 229940098773 bovine serum albumin Drugs 0.000 description 7
- 238000004422 calculation algorithm Methods 0.000 description 7
- 239000000562 conjugate Substances 0.000 description 7
- 238000002784 cytotoxicity assay Methods 0.000 description 7
- 231100000263 cytotoxicity test Toxicity 0.000 description 7
- 238000010494 dissociation reaction Methods 0.000 description 7
- 230000005593 dissociations Effects 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 229910052739 hydrogen Inorganic materials 0.000 description 7
- 230000001939 inductive effect Effects 0.000 description 7
- 239000003112 inhibitor Substances 0.000 description 7
- 239000000463 material Substances 0.000 description 7
- 239000002609 medium Substances 0.000 description 7
- 239000012528 membrane Substances 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- 229940124597 therapeutic agent Drugs 0.000 description 7
- 229960000575 trastuzumab Drugs 0.000 description 7
- SLURUCSFDHKXFR-WWMWMSKMSA-N (7s,9s)-7-[[(1s,3r,4as,9s,9ar,10as)-9-methoxy-1-methyl-3,4,4a,6,7,9,9a,10a-octahydro-1h-pyrano[1,2][1,3]oxazolo[3,4-b][1,4]oxazin-3-yl]oxy]-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7h-tetracene-5,12-dione Chemical class O=C1C2=CC=CC(OC)=C2C(=O)C(C(O)=C23)=C1C(O)=C3C[C@@](O)(C(=O)CO)C[C@@H]2O[C@H]1C[C@@H]2N3CCO[C@H](OC)[C@H]3O[C@@H]2[C@H](C)O1 SLURUCSFDHKXFR-WWMWMSKMSA-N 0.000 description 6
- 241000588724 Escherichia coli Species 0.000 description 6
- 108010067060 Immunoglobulin Variable Region Proteins 0.000 description 6
- 101100038118 Mus musculus Ror1 gene Proteins 0.000 description 6
- 230000000903 blocking effect Effects 0.000 description 6
- 210000004899 c-terminal region Anatomy 0.000 description 6
- 238000010367 cloning Methods 0.000 description 6
- 231100000673 dose–response relationship Toxicity 0.000 description 6
- 238000004520 electroporation Methods 0.000 description 6
- 239000003623 enhancer Substances 0.000 description 6
- 102000049622 human ROR2 Human genes 0.000 description 6
- 230000003053 immunization Effects 0.000 description 6
- 238000003364 immunohistochemistry Methods 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- 230000035772 mutation Effects 0.000 description 6
- 238000002823 phage display Methods 0.000 description 6
- 238000013207 serial dilution Methods 0.000 description 6
- 239000000758 substrate Substances 0.000 description 6
- 229910052720 vanadium Inorganic materials 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 239000012114 Alexa Fluor 647 Substances 0.000 description 5
- 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 5
- 241000283074 Equus asinus Species 0.000 description 5
- 102000017727 Immunoglobulin Variable Region Human genes 0.000 description 5
- 108010052285 Membrane Proteins Proteins 0.000 description 5
- 108010038807 Oligopeptides Proteins 0.000 description 5
- 102000015636 Oligopeptides Human genes 0.000 description 5
- 238000002835 absorbance Methods 0.000 description 5
- 239000004480 active ingredient Substances 0.000 description 5
- 239000008186 active pharmaceutical agent Substances 0.000 description 5
- 239000013543 active substance Substances 0.000 description 5
- 125000000539 amino acid group Chemical group 0.000 description 5
- 239000004037 angiogenesis inhibitor Substances 0.000 description 5
- 229940121369 angiogenesis inhibitor Drugs 0.000 description 5
- 230000001580 bacterial effect Effects 0.000 description 5
- 238000012054 celltiter-glo Methods 0.000 description 5
- 238000005119 centrifugation Methods 0.000 description 5
- 238000003501 co-culture Methods 0.000 description 5
- 238000010276 construction Methods 0.000 description 5
- 239000002872 contrast media Substances 0.000 description 5
- 230000000875 corresponding effect Effects 0.000 description 5
- 235000018417 cysteine Nutrition 0.000 description 5
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 5
- 239000000824 cytostatic agent Substances 0.000 description 5
- 230000003013 cytotoxicity Effects 0.000 description 5
- 231100000135 cytotoxicity Toxicity 0.000 description 5
- 238000011161 development Methods 0.000 description 5
- 230000018109 developmental process Effects 0.000 description 5
- 239000012636 effector Substances 0.000 description 5
- 238000011156 evaluation Methods 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 230000010354 integration Effects 0.000 description 5
- 210000004962 mammalian cell Anatomy 0.000 description 5
- 238000005259 measurement Methods 0.000 description 5
- 239000002773 nucleotide Substances 0.000 description 5
- 125000003729 nucleotide group Chemical group 0.000 description 5
- 210000001948 pro-b lymphocyte Anatomy 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 230000002285 radioactive effect Effects 0.000 description 5
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 5
- 102000027426 receptor tyrosine kinases Human genes 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- 108090000250 sortase A Proteins 0.000 description 5
- 238000010186 staining Methods 0.000 description 5
- 230000004083 survival effect Effects 0.000 description 5
- 238000002560 therapeutic procedure Methods 0.000 description 5
- 238000012546 transfer Methods 0.000 description 5
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 4
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 4
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 4
- 238000012286 ELISA Assay Methods 0.000 description 4
- 101001018097 Homo sapiens L-selectin Proteins 0.000 description 4
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 4
- 102100033467 L-selectin Human genes 0.000 description 4
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 4
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 4
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 4
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 4
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 4
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 4
- 239000004473 Threonine Substances 0.000 description 4
- 230000004913 activation Effects 0.000 description 4
- 239000011324 bead Substances 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 201000008275 breast carcinoma Diseases 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 230000036039 immunity Effects 0.000 description 4
- 238000002649 immunization Methods 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
- 210000004698 lymphocyte Anatomy 0.000 description 4
- 239000003550 marker Substances 0.000 description 4
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 239000013642 negative control Substances 0.000 description 4
- 239000013612 plasmid Substances 0.000 description 4
- 229920000729 poly(L-lysine) polymer Polymers 0.000 description 4
- 230000010076 replication Effects 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- 241000894007 species Species 0.000 description 4
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 239000013603 viral vector Substances 0.000 description 4
- VEEGZPWAAPPXRB-BJMVGYQFSA-N (3e)-3-(1h-imidazol-5-ylmethylidene)-1h-indol-2-one Chemical compound O=C1NC2=CC=CC=C2\C1=C/C1=CN=CN1 VEEGZPWAAPPXRB-BJMVGYQFSA-N 0.000 description 3
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 3
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 3
- 102000018152 Frizzled domains Human genes 0.000 description 3
- 108050007261 Frizzled domains Proteins 0.000 description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 239000007995 HEPES buffer Substances 0.000 description 3
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 3
- 101000914514 Homo sapiens T-cell-specific surface glycoprotein CD28 Proteins 0.000 description 3
- 101000851376 Homo sapiens Tumor necrosis factor receptor superfamily member 8 Proteins 0.000 description 3
- 108010054477 Immunoglobulin Fab Fragments Proteins 0.000 description 3
- 102000001706 Immunoglobulin Fab Fragments Human genes 0.000 description 3
- 108010002350 Interleukin-2 Proteins 0.000 description 3
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 3
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 3
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 3
- 241000713666 Lentivirus Species 0.000 description 3
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 3
- 239000004472 Lysine Substances 0.000 description 3
- 238000011789 NOD SCID mouse Methods 0.000 description 3
- 108091000080 Phosphotransferase Proteins 0.000 description 3
- 108010003723 Single-Domain Antibodies Proteins 0.000 description 3
- 241000191967 Staphylococcus aureus Species 0.000 description 3
- 102100027213 T-cell-specific surface glycoprotein CD28 Human genes 0.000 description 3
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 3
- 102100036857 Tumor necrosis factor receptor superfamily member 8 Human genes 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 230000001154 acute effect Effects 0.000 description 3
- 238000001042 affinity chromatography Methods 0.000 description 3
- 235000004279 alanine Nutrition 0.000 description 3
- 125000003277 amino group Chemical group 0.000 description 3
- 238000010171 animal model Methods 0.000 description 3
- 210000003719 b-lymphocyte Anatomy 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 229910052797 bismuth Inorganic materials 0.000 description 3
- 238000004113 cell culture Methods 0.000 description 3
- 210000000170 cell membrane Anatomy 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000004186 co-expression Effects 0.000 description 3
- 231100000433 cytotoxic Toxicity 0.000 description 3
- 230000001472 cytotoxic effect Effects 0.000 description 3
- 230000006735 deficit Effects 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 210000003527 eukaryotic cell Anatomy 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 230000004927 fusion Effects 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 125000003630 glycyl group Chemical group [H]N([H])C([H])([H])C(*)=O 0.000 description 3
- 210000005260 human cell Anatomy 0.000 description 3
- 210000004408 hybridoma Anatomy 0.000 description 3
- 210000000987 immune system Anatomy 0.000 description 3
- 238000003018 immunoassay Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 238000002595 magnetic resonance imaging Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000013507 mapping Methods 0.000 description 3
- 238000002493 microarray Methods 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 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 description 3
- 238000004091 panning Methods 0.000 description 3
- 102000020233 phosphotransferase Human genes 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- 230000035755 proliferation Effects 0.000 description 3
- YUOCYTRGANSSRY-UHFFFAOYSA-N pyrrolo[2,3-i][1,2]benzodiazepine Chemical compound C1=CN=NC2=C3C=CN=C3C=CC2=C1 YUOCYTRGANSSRY-UHFFFAOYSA-N 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 230000002441 reversible effect Effects 0.000 description 3
- 239000012146 running buffer Substances 0.000 description 3
- 230000037432 silent mutation Effects 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- 238000004448 titration Methods 0.000 description 3
- 241001430294 unidentified retrovirus Species 0.000 description 3
- 239000003981 vehicle Substances 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- DIGQNXIGRZPYDK-WKSCXVIASA-N (2R)-6-amino-2-[[2-[[(2S)-2-[[2-[[(2R)-2-[[(2S)-2-[[(2R,3S)-2-[[2-[[(2S)-2-[[2-[[(2S)-2-[[(2S)-2-[[(2R)-2-[[(2S,3S)-2-[[(2R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S)-2-[[(2R)-2-[[2-[[2-[[2-[(2-amino-1-hydroxyethylidene)amino]-3-carboxy-1-hydroxypropylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1-hydroxyethylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1,3-dihydroxypropylidene]amino]-1-hydroxyethylidene]amino]-1-hydroxypropylidene]amino]-1,3-dihydroxypropylidene]amino]-1,3-dihydroxypropylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1,3-dihydroxybutylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1-hydroxypropylidene]amino]-1,3-dihydroxypropylidene]amino]-1-hydroxyethylidene]amino]-1,5-dihydroxy-5-iminopentylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1,3-dihydroxybutylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1,3-dihydroxypropylidene]amino]-1-hydroxyethylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1-hydroxyethylidene]amino]hexanoic acid Chemical compound C[C@@H]([C@@H](C(=N[C@@H](CS)C(=N[C@@H](C)C(=N[C@@H](CO)C(=NCC(=N[C@@H](CCC(=N)O)C(=NC(CS)C(=N[C@H]([C@H](C)O)C(=N[C@H](CS)C(=N[C@H](CO)C(=NCC(=N[C@H](CS)C(=NCC(=N[C@H](CCCCN)C(=O)O)O)O)O)O)O)O)O)O)O)O)O)O)O)N=C([C@H](CS)N=C([C@H](CO)N=C([C@H](CO)N=C([C@H](C)N=C(CN=C([C@H](CO)N=C([C@H](CS)N=C(CN=C(C(CS)N=C(C(CC(=O)O)N=C(CN)O)O)O)O)O)O)O)O)O)O)O)O DIGQNXIGRZPYDK-WKSCXVIASA-N 0.000 description 2
- NFGXHKASABOEEW-UHFFFAOYSA-N 1-methylethyl 11-methoxy-3,7,11-trimethyl-2,4-dodecadienoate Chemical compound COC(C)(C)CCCC(C)CC=CC(C)=CC(=O)OC(C)C NFGXHKASABOEEW-UHFFFAOYSA-N 0.000 description 2
- UZOVYGYOLBIAJR-UHFFFAOYSA-N 4-isocyanato-4'-methyldiphenylmethane Chemical compound C1=CC(C)=CC=C1CC1=CC=C(N=C=O)C=C1 UZOVYGYOLBIAJR-UHFFFAOYSA-N 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 108091007741 Chimeric antigen receptor T cells Proteins 0.000 description 2
- 101710112752 Cytotoxin Proteins 0.000 description 2
- 238000001712 DNA sequencing Methods 0.000 description 2
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 2
- 108010008655 Epstein-Barr Virus Nuclear Antigens Proteins 0.000 description 2
- 239000004606 Fillers/Extenders Substances 0.000 description 2
- 238000012413 Fluorescence activated cell sorting analysis Methods 0.000 description 2
- 102000006395 Globulins Human genes 0.000 description 2
- 108010044091 Globulins Proteins 0.000 description 2
- 102100026122 High affinity immunoglobulin gamma Fc receptor I Human genes 0.000 description 2
- 101000913074 Homo sapiens High affinity immunoglobulin gamma Fc receptor I Proteins 0.000 description 2
- 101000917826 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor II-a Proteins 0.000 description 2
- 108700005091 Immunoglobulin Genes Proteins 0.000 description 2
- 102000004877 Insulin Human genes 0.000 description 2
- 108090001061 Insulin Proteins 0.000 description 2
- 102100037850 Interferon gamma Human genes 0.000 description 2
- 108010074328 Interferon-gamma Proteins 0.000 description 2
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 2
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 2
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 2
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 2
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 2
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 2
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 2
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 2
- 102100029204 Low affinity immunoglobulin gamma Fc region receptor II-a Human genes 0.000 description 2
- 108060001084 Luciferase Proteins 0.000 description 2
- 239000005089 Luciferase Substances 0.000 description 2
- 206010025323 Lymphomas Diseases 0.000 description 2
- 206010064912 Malignant transformation Diseases 0.000 description 2
- 102000003792 Metallothionein Human genes 0.000 description 2
- 108090000157 Metallothionein Proteins 0.000 description 2
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 2
- 108091028043 Nucleic acid sequence Proteins 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 206010035603 Pleural mesothelioma Diseases 0.000 description 2
- 229920001213 Polysorbate 20 Polymers 0.000 description 2
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 2
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 2
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 2
- 108700033844 Pseudomonas aeruginosa toxA Proteins 0.000 description 2
- 102000042839 ROR family Human genes 0.000 description 2
- 108091082331 ROR family Proteins 0.000 description 2
- 239000012980 RPMI-1640 medium Substances 0.000 description 2
- 241000710961 Semliki Forest virus Species 0.000 description 2
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 2
- 108010090804 Streptavidin Proteins 0.000 description 2
- 239000006180 TBST buffer Substances 0.000 description 2
- 208000003721 Triple Negative Breast Neoplasms Diseases 0.000 description 2
- 102100022153 Tumor necrosis factor receptor superfamily member 4 Human genes 0.000 description 2
- 102100036856 Tumor necrosis factor receptor superfamily member 9 Human genes 0.000 description 2
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 2
- 241000700605 Viruses Species 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin D Natural products CC1OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)NC4C(=O)NC(C(N5CCCC5C(=O)N(C)CC(=O)N(C)C(C(C)C)C(=O)OC4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-UHFFFAOYSA-N 0.000 description 2
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 2
- 230000007815 allergy Effects 0.000 description 2
- APKFDSVGJQXUKY-INPOYWNPSA-N amphotericin B Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/C=C/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-INPOYWNPSA-N 0.000 description 2
- XCPGHVQEEXUHNC-UHFFFAOYSA-N amsacrine Chemical compound COC1=CC(NS(C)(=O)=O)=CC=C1NC1=C(C=CC=C2)C2=NC2=CC=CC=C12 XCPGHVQEEXUHNC-UHFFFAOYSA-N 0.000 description 2
- 229960001220 amsacrine Drugs 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 230000010056 antibody-dependent cellular cytotoxicity Effects 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 230000003416 augmentation Effects 0.000 description 2
- 108010044540 auristatin Proteins 0.000 description 2
- 238000012575 bio-layer interferometry Methods 0.000 description 2
- 230000000975 bioactive effect Effects 0.000 description 2
- 229960002685 biotin Drugs 0.000 description 2
- 235000020958 biotin Nutrition 0.000 description 2
- 239000011616 biotin Substances 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 229930195731 calicheamicin Natural products 0.000 description 2
- HXCHCVDVKSCDHU-LULTVBGHSA-N calicheamicin Chemical compound C1[C@H](OC)[C@@H](NCC)CO[C@H]1O[C@H]1[C@H](O[C@@H]2C\3=C(NC(=O)OC)C(=O)C[C@](C/3=C/CSSSC)(O)C#C\C=C/C#C2)O[C@H](C)[C@@H](NO[C@@H]2O[C@H](C)[C@@H](SC(=O)C=3C(=C(OC)C(O[C@H]4[C@@H]([C@H](OC)[C@@H](O)[C@H](C)O4)O)=C(I)C=3C)OC)[C@@H](O)C2)[C@@H]1O HXCHCVDVKSCDHU-LULTVBGHSA-N 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 239000006285 cell suspension Substances 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 108700010039 chimeric receptor Proteins 0.000 description 2
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 238000011260 co-administration Methods 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 230000004154 complement system Effects 0.000 description 2
- 238000010968 computed tomography angiography Methods 0.000 description 2
- 230000002596 correlated effect Effects 0.000 description 2
- 239000002619 cytotoxin Substances 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 238000002405 diagnostic procedure Methods 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 239000003534 dna topoisomerase inhibitor Substances 0.000 description 2
- 229960004679 doxorubicin Drugs 0.000 description 2
- 239000003596 drug target Substances 0.000 description 2
- 230000005014 ectopic expression Effects 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 230000013020 embryo development Effects 0.000 description 2
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 description 2
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 description 2
- 230000007705 epithelial mesenchymal transition Effects 0.000 description 2
- 229960005420 etoposide Drugs 0.000 description 2
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 2
- 239000013613 expression plasmid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- 239000007850 fluorescent dye Substances 0.000 description 2
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 2
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 2
- 239000012216 imaging agent Substances 0.000 description 2
- 238000002513 implantation Methods 0.000 description 2
- 230000001976 improved effect Effects 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000003780 insertion Methods 0.000 description 2
- 230000037431 insertion Effects 0.000 description 2
- 229940125396 insulin Drugs 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 2
- 229960000310 isoleucine Drugs 0.000 description 2
- 208000032839 leukemia Diseases 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 230000036212 malign transformation Effects 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 229910021645 metal ion Inorganic materials 0.000 description 2
- 229930182817 methionine Natural products 0.000 description 2
- 239000002062 molecular scaffold Substances 0.000 description 2
- 238000010172 mouse model Methods 0.000 description 2
- 229940126619 mouse monoclonal antibody Drugs 0.000 description 2
- 239000000346 nonvolatile oil Substances 0.000 description 2
- 238000011275 oncology therapy Methods 0.000 description 2
- 239000008188 pellet Substances 0.000 description 2
- 229940049954 penicillin Drugs 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 2
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 2
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 210000001236 prokaryotic cell Anatomy 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 2
- 239000010948 rhodium Substances 0.000 description 2
- 238000002702 ribosome display Methods 0.000 description 2
- 229960004641 rituximab Drugs 0.000 description 2
- 238000002864 sequence alignment Methods 0.000 description 2
- 238000010561 standard procedure Methods 0.000 description 2
- 229960005322 streptomycin Drugs 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000013268 sustained release Methods 0.000 description 2
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 2
- 229960001278 teniposide Drugs 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
- 229940044693 topoisomerase inhibitor Drugs 0.000 description 2
- 238000001890 transfection Methods 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- 230000005945 translocation Effects 0.000 description 2
- 208000022679 triple-negative breast carcinoma Diseases 0.000 description 2
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 2
- 241000701161 unidentified adenovirus Species 0.000 description 2
- 241001529453 unidentified herpesvirus Species 0.000 description 2
- 239000004474 valine Substances 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 2
- 229960004528 vincristine Drugs 0.000 description 2
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 2
- 238000011179 visual inspection Methods 0.000 description 2
- QWPXBEHQFHACTK-KZVYIGENSA-N (10e,12e)-86-chloro-12,14,4-trihydroxy-85,14-dimethoxy-33,2,7,10-tetramethyl-15,16-dihydro-14h-7-aza-1(6,4)-oxazina-3(2,3)-oxirana-8(1,3)-benzenacyclotetradecaphane-10,12-dien-6-one Chemical compound CN1C(=O)CC(O)C2(C)OC2C(C)C(OC(=O)N2)CC2(O)C(OC)\C=C\C=C(C)\CC2=CC(OC)=C(Cl)C1=C2 QWPXBEHQFHACTK-KZVYIGENSA-N 0.000 description 1
- DJOMZYYFFHCVSQ-UBZKRVARSA-N (1S,17S,20Z,24R,26R)-4,11,24-trihydroxy-26-[(1R)-1-hydroxyethyl]-10-methoxy-25-oxa-16-azahexacyclo[15.7.2.01,26.02,15.05,14.07,12]hexacosa-2,4,7(12),8,10,14,20-heptaen-18,22-diyne-6,13-dione Chemical compound COc1ccc2C(=O)c3c(O)cc4c(N[C@H]5C#C\C=C/C#C[C@@H](O)[C@@]44O[C@@]54[C@@H](C)O)c3C(=O)c2c1O DJOMZYYFFHCVSQ-UBZKRVARSA-N 0.000 description 1
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 1
- FDKWRPBBCBCIGA-REOHCLBHSA-N (2r)-2-azaniumyl-3-$l^{1}-selanylpropanoate Chemical compound [Se]C[C@H](N)C(O)=O FDKWRPBBCBCIGA-REOHCLBHSA-N 0.000 description 1
- MFRNYXJJRJQHNW-DEMKXPNLSA-N (2s)-2-[[(2r,3r)-3-methoxy-3-[(2s)-1-[(3r,4s,5s)-3-methoxy-5-methyl-4-[methyl-[(2s)-3-methyl-2-[[(2s)-3-methyl-2-(methylamino)butanoyl]amino]butanoyl]amino]heptanoyl]pyrrolidin-2-yl]-2-methylpropanoyl]amino]-3-phenylpropanoic acid Chemical compound CN[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N(C)[C@@H]([C@@H](C)CC)[C@H](OC)CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 MFRNYXJJRJQHNW-DEMKXPNLSA-N 0.000 description 1
- IUQKJKPHUBJDJV-UMNBWOBWSA-N (2s,4r)-2-methyl-4-[[2-[(3r)-4-methyl-3-[methyl-[(2s,3s)-3-methyl-2-[[(2r)-1-methylpiperidine-2-carbonyl]amino]pentanoyl]amino]pentyl]-1,3-thiazole-4-carbonyl]amino]-5-phenylpentanoic acid Chemical compound N([C@@H]([C@@H](C)CC)C(=O)N(C)[C@H](CCC=1SC=C(N=1)C(=O)N[C@H](C[C@H](C)C(O)=O)CC=1C=CC=CC=1)C(C)C)C(=O)[C@H]1CCCCN1C IUQKJKPHUBJDJV-UMNBWOBWSA-N 0.000 description 1
- DLKUYSQUHXBYPB-NSSHGSRYSA-N (2s,4r)-4-[[2-[(1r,3r)-1-acetyloxy-4-methyl-3-[3-methylbutanoyloxymethyl-[(2s,3s)-3-methyl-2-[[(2r)-1-methylpiperidine-2-carbonyl]amino]pentanoyl]amino]pentyl]-1,3-thiazole-4-carbonyl]amino]-2-methyl-5-(4-methylphenyl)pentanoic acid Chemical compound N([C@@H]([C@@H](C)CC)C(=O)N(COC(=O)CC(C)C)[C@H](C[C@@H](OC(C)=O)C=1SC=C(N=1)C(=O)N[C@H](C[C@H](C)C(O)=O)CC=1C=CC(C)=CC=1)C(C)C)C(=O)[C@H]1CCCCN1C DLKUYSQUHXBYPB-NSSHGSRYSA-N 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- PNDPGZBMCMUPRI-HVTJNCQCSA-N 10043-66-0 Chemical compound [131I][131I] PNDPGZBMCMUPRI-HVTJNCQCSA-N 0.000 description 1
- CVOFKRWYWCSDMA-UHFFFAOYSA-N 2-chloro-n-(2,6-diethylphenyl)-n-(methoxymethyl)acetamide;2,6-dinitro-n,n-dipropyl-4-(trifluoromethyl)aniline Chemical compound CCC1=CC=CC(CC)=C1N(COC)C(=O)CCl.CCCN(CCC)C1=C([N+]([O-])=O)C=C(C(F)(F)F)C=C1[N+]([O-])=O CVOFKRWYWCSDMA-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- CPOBTYJRKAJERX-UHFFFAOYSA-N 3-ethyl-n-[(3-ethyl-1,3-benzothiazol-2-ylidene)amino]-1,3-benzothiazol-2-imine Chemical compound S1C2=CC=CC=C2N(CC)C1=NN=C1SC2=CC=CC=C2N1CC CPOBTYJRKAJERX-UHFFFAOYSA-N 0.000 description 1
- 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 1
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- 239000012103 Alexa Fluor 488 Substances 0.000 description 1
- 101800002638 Alpha-amanitin Proteins 0.000 description 1
- 102100026882 Alpha-synuclein Human genes 0.000 description 1
- 102400000068 Angiostatin Human genes 0.000 description 1
- 108010079709 Angiostatins Proteins 0.000 description 1
- 235000002198 Annona diversifolia Nutrition 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 1
- 208000004736 B-Cell Leukemia Diseases 0.000 description 1
- 208000036170 B-Cell Marginal Zone Lymphoma Diseases 0.000 description 1
- 102100022005 B-lymphocyte antigen CD20 Human genes 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 208000011691 Burkitt lymphomas Diseases 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 1
- 241000282832 Camelidae Species 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 229940123587 Cell cycle inhibitor Drugs 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 241001429175 Colitis phage Species 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 108091035707 Consensus sequence Proteins 0.000 description 1
- 241000699802 Cricetulus griseus Species 0.000 description 1
- 108010069514 Cyclic Peptides Proteins 0.000 description 1
- 102000001189 Cyclic Peptides Human genes 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 102100039498 Cytotoxic T-lymphocyte protein 4 Human genes 0.000 description 1
- FDKWRPBBCBCIGA-UWTATZPHSA-N D-Selenocysteine Natural products [Se]C[C@@H](N)C(O)=O FDKWRPBBCBCIGA-UWTATZPHSA-N 0.000 description 1
- 101150082208 DIABLO gene Proteins 0.000 description 1
- 230000004544 DNA amplification Effects 0.000 description 1
- 108091008102 DNA aptamers Proteins 0.000 description 1
- 230000006820 DNA synthesis Effects 0.000 description 1
- 102000004163 DNA-directed RNA polymerases Human genes 0.000 description 1
- 108090000626 DNA-directed RNA polymerases Proteins 0.000 description 1
- 108010092160 Dactinomycin Proteins 0.000 description 1
- WEAHRLBPCANXCN-UHFFFAOYSA-N Daunomycin Natural products CCC1(O)CC(OC2CC(N)C(O)C(C)O2)c3cc4C(=O)c5c(OC)cccc5C(=O)c4c(O)c3C1 WEAHRLBPCANXCN-UHFFFAOYSA-N 0.000 description 1
- 241000702421 Dependoparvovirus Species 0.000 description 1
- 102100033189 Diablo IAP-binding mitochondrial protein Human genes 0.000 description 1
- 108010032363 ERRalpha estrogen-related receptor Proteins 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 108700039887 Essential Genes Proteins 0.000 description 1
- 208000010201 Exanthema Diseases 0.000 description 1
- 108010008177 Fd immunoglobulins Proteins 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 208000034951 Genetic Translocation Diseases 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 102000009127 Glutaminase Human genes 0.000 description 1
- 108010073324 Glutaminase Proteins 0.000 description 1
- 102100031181 Glyceraldehyde-3-phosphate dehydrogenase Human genes 0.000 description 1
- 108010009202 Growth Factor Receptors Proteins 0.000 description 1
- 102000009465 Growth Factor Receptors Human genes 0.000 description 1
- 208000002250 Hematologic Neoplasms Diseases 0.000 description 1
- 102100034458 Hepatitis A virus cellular receptor 2 Human genes 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000834898 Homo sapiens Alpha-synuclein Proteins 0.000 description 1
- 101000897405 Homo sapiens B-lymphocyte antigen CD20 Proteins 0.000 description 1
- 101100166600 Homo sapiens CD28 gene Proteins 0.000 description 1
- 101000889276 Homo sapiens Cytotoxic T-lymphocyte protein 4 Proteins 0.000 description 1
- 101000938351 Homo sapiens Ephrin type-A receptor 3 Proteins 0.000 description 1
- 101100334524 Homo sapiens FCGR3B gene Proteins 0.000 description 1
- 101001068133 Homo sapiens Hepatitis A virus cellular receptor 2 Proteins 0.000 description 1
- 101000961145 Homo sapiens Immunoglobulin heavy constant gamma 3 Proteins 0.000 description 1
- 101000917839 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor III-B Proteins 0.000 description 1
- 101001137987 Homo sapiens Lymphocyte activation gene 3 protein Proteins 0.000 description 1
- 101001117317 Homo sapiens Programmed cell death 1 ligand 1 Proteins 0.000 description 1
- 101000611936 Homo sapiens Programmed cell death protein 1 Proteins 0.000 description 1
- 101000652359 Homo sapiens Spermatogenesis-associated protein 2 Proteins 0.000 description 1
- 101000801234 Homo sapiens Tumor necrosis factor receptor superfamily member 18 Proteins 0.000 description 1
- 241000701044 Human gammaherpesvirus 4 Species 0.000 description 1
- GRRNUXAQVGOGFE-UHFFFAOYSA-N Hygromycin-B Natural products OC1C(NC)CC(N)C(O)C1OC1C2OC3(C(C(O)C(O)C(C(N)CO)O3)O)OC2C(O)C(CO)O1 GRRNUXAQVGOGFE-UHFFFAOYSA-N 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 description 1
- XDXDZDZNSLXDNA-UHFFFAOYSA-N Idarubicin Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XDXDZDZNSLXDNA-UHFFFAOYSA-N 0.000 description 1
- 108091008036 Immune checkpoint proteins Proteins 0.000 description 1
- 102000037982 Immune checkpoint proteins Human genes 0.000 description 1
- 102000012745 Immunoglobulin Subunits Human genes 0.000 description 1
- 108010079585 Immunoglobulin Subunits Proteins 0.000 description 1
- 102100039348 Immunoglobulin heavy constant gamma 3 Human genes 0.000 description 1
- 102100029567 Immunoglobulin kappa light chain Human genes 0.000 description 1
- 101710189008 Immunoglobulin kappa light chain Proteins 0.000 description 1
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- 239000004201 L-cysteine Substances 0.000 description 1
- 235000013878 L-cysteine Nutrition 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- 102000017578 LAG3 Human genes 0.000 description 1
- 241000282838 Lama Species 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- 102100029185 Low affinity immunoglobulin gamma Fc region receptor III-B Human genes 0.000 description 1
- 229910052765 Lutetium Inorganic materials 0.000 description 1
- 241000282567 Macaca fascicularis Species 0.000 description 1
- 229930126263 Maytansine Natural products 0.000 description 1
- QWPXBEHQFHACTK-UHFFFAOYSA-N Maytansinol Natural products CN1C(=O)CC(O)C2(C)OC2C(C)C(OC(=O)N2)CC2(O)C(OC)C=CC=C(C)CC2=CC(OC)=C(Cl)C1=C2 QWPXBEHQFHACTK-UHFFFAOYSA-N 0.000 description 1
- 102000018697 Membrane Proteins Human genes 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 102000029749 Microtubule Human genes 0.000 description 1
- 108091022875 Microtubule Proteins 0.000 description 1
- 241000713333 Mouse mammary tumor virus Species 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 1
- UGJBHEZMOKVTIM-UHFFFAOYSA-N N-formylglycine Chemical compound OC(=O)CNC=O UGJBHEZMOKVTIM-UHFFFAOYSA-N 0.000 description 1
- 108091061960 Naked DNA Proteins 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 108700026244 Open Reading Frames Proteins 0.000 description 1
- 240000007019 Oxalis corniculata Species 0.000 description 1
- 238000012408 PCR amplification Methods 0.000 description 1
- 239000002033 PVDF binder Substances 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 241001631646 Papillomaviridae Species 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 108090000279 Peptidyltransferases Proteins 0.000 description 1
- 102000011755 Phosphoglycerate Kinase Human genes 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 238000006929 Pictet-Spengler synthesis reaction Methods 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 229920002732 Polyanhydride Polymers 0.000 description 1
- 229920001710 Polyorthoester Polymers 0.000 description 1
- 229910052777 Praseodymium Inorganic materials 0.000 description 1
- 102100024216 Programmed cell death 1 ligand 1 Human genes 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 229940079156 Proteasome inhibitor Drugs 0.000 description 1
- 108020005067 RNA Splice Sites Proteins 0.000 description 1
- 108091008103 RNA aptamers Proteins 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 108020004511 Recombinant DNA Proteins 0.000 description 1
- 108020005091 Replication Origin Proteins 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- RXGJTYFDKOHJHK-UHFFFAOYSA-N S-deoxo-amaninamide Natural products CCC(C)C1NC(=O)CNC(=O)C2Cc3c(SCC(NC(=O)CNC1=O)C(=O)NC(CC(=O)N)C(=O)N4CC(O)CC4C(=O)NC(C(C)C(O)CO)C(=O)N2)[nH]c5ccccc35 RXGJTYFDKOHJHK-UHFFFAOYSA-N 0.000 description 1
- 238000011579 SCID mouse model Methods 0.000 description 1
- 206010070834 Sensitisation Diseases 0.000 description 1
- 101800001707 Spacer peptide Proteins 0.000 description 1
- 108091081024 Start codon Proteins 0.000 description 1
- 102100036832 Steroid hormone receptor ERR1 Human genes 0.000 description 1
- 229930182558 Sterol Natural products 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- 229940123237 Taxane Drugs 0.000 description 1
- 101710192266 Tegument protein VP22 Proteins 0.000 description 1
- 239000004098 Tetracycline Substances 0.000 description 1
- 101001099217 Thermotoga maritima (strain ATCC 43589 / DSM 3109 / JCM 10099 / NBRC 100826 / MSB8) Triosephosphate isomerase Proteins 0.000 description 1
- FOCVUCIESVLUNU-UHFFFAOYSA-N Thiotepa Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- 102000008579 Transposases Human genes 0.000 description 1
- 108010020764 Transposases Proteins 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- 102000044209 Tumor Suppressor Genes Human genes 0.000 description 1
- 108700025716 Tumor Suppressor Genes Proteins 0.000 description 1
- 102100033728 Tumor necrosis factor receptor superfamily member 18 Human genes 0.000 description 1
- 101710165473 Tumor necrosis factor receptor superfamily member 4 Proteins 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 241000700618 Vaccinia virus Species 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- 241001416177 Vicugna pacos Species 0.000 description 1
- 229940122803 Vinca alkaloid Drugs 0.000 description 1
- 108010087302 Viral Structural Proteins Proteins 0.000 description 1
- VWQVUPCCIRVNHF-OUBTZVSYSA-N Yttrium-90 Chemical compound [90Y] VWQVUPCCIRVNHF-OUBTZVSYSA-N 0.000 description 1
- IEDXPSOJFSVCKU-HOKPPMCLSA-N [4-[[(2S)-5-(carbamoylamino)-2-[[(2S)-2-[6-(2,5-dioxopyrrolidin-1-yl)hexanoylamino]-3-methylbutanoyl]amino]pentanoyl]amino]phenyl]methyl N-[(2S)-1-[[(2S)-1-[[(3R,4S,5S)-1-[(2S)-2-[(1R,2R)-3-[[(1S,2R)-1-hydroxy-1-phenylpropan-2-yl]amino]-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl]-3-methoxy-5-methyl-1-oxoheptan-4-yl]-methylamino]-3-methyl-1-oxobutan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]-N-methylcarbamate Chemical compound CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C)[C@@H](O)c1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OCc1ccc(NC(=O)[C@H](CCCNC(N)=O)NC(=O)[C@@H](NC(=O)CCCCCN2C(=O)CCC2=O)C(C)C)cc1)C(C)C IEDXPSOJFSVCKU-HOKPPMCLSA-N 0.000 description 1
- SWPYNTWPIAZGLT-UHFFFAOYSA-N [amino(ethoxy)phosphanyl]oxyethane Chemical compound CCOP(N)OCC SWPYNTWPIAZGLT-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 229910052767 actinium Inorganic materials 0.000 description 1
- QQINRWTZWGJFDB-UHFFFAOYSA-N actinium atom Chemical compound [Ac] QQINRWTZWGJFDB-UHFFFAOYSA-N 0.000 description 1
- RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin 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)=CC=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 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 208000009956 adenocarcinoma Diseases 0.000 description 1
- 229960005305 adenosine Drugs 0.000 description 1
- 238000004115 adherent culture Methods 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 210000000577 adipose tissue Anatomy 0.000 description 1
- 238000001261 affinity purification Methods 0.000 description 1
- 229960000548 alemtuzumab Drugs 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 108010004469 allophycocyanin Proteins 0.000 description 1
- 239000004007 alpha amanitin Substances 0.000 description 1
- CIORWBWIBBPXCG-SXZCQOKQSA-N alpha-amanitin Chemical compound O=C1N[C@@H](CC(N)=O)C(=O)N2C[C@H](O)C[C@H]2C(=O)N[C@@H]([C@@H](C)[C@@H](O)CO)C(=O)N[C@@H](C2)C(=O)NCC(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@H]1C[S@@](=O)C1=C2C2=CC=C(O)C=C2N1 CIORWBWIBBPXCG-SXZCQOKQSA-N 0.000 description 1
- CIORWBWIBBPXCG-UHFFFAOYSA-N alpha-amanitin Natural products O=C1NC(CC(N)=O)C(=O)N2CC(O)CC2C(=O)NC(C(C)C(O)CO)C(=O)NC(C2)C(=O)NCC(=O)NC(C(C)CC)C(=O)NCC(=O)NC1CS(=O)C1=C2C2=CC=C(O)C=C2N1 CIORWBWIBBPXCG-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 238000002583 angiography Methods 0.000 description 1
- 210000004102 animal cell Anatomy 0.000 description 1
- 230000003432 anti-folate effect Effects 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 229940127074 antifolate Drugs 0.000 description 1
- 230000000890 antigenic effect Effects 0.000 description 1
- 229940100197 antimetabolite Drugs 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 238000003782 apoptosis assay Methods 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- PYMYPHUHKUWMLA-WDCZJNDASA-N arabinose Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)C=O PYMYPHUHKUWMLA-WDCZJNDASA-N 0.000 description 1
- PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Natural products OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 235000009582 asparagine Nutrition 0.000 description 1
- 229960001230 asparagine Drugs 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- FZCSTZYAHCUGEM-UHFFFAOYSA-N aspergillomarasmine B Natural products OC(=O)CNC(C(O)=O)CNC(C(O)=O)CC(O)=O FZCSTZYAHCUGEM-UHFFFAOYSA-N 0.000 description 1
- 229910052789 astatine Inorganic materials 0.000 description 1
- RYXHOMYVWAEKHL-UHFFFAOYSA-N astatine atom Chemical compound [At] RYXHOMYVWAEKHL-UHFFFAOYSA-N 0.000 description 1
- 101150117004 atg18 gene Proteins 0.000 description 1
- 239000005441 aurora Substances 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 1
- 229960000686 benzalkonium chloride Drugs 0.000 description 1
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 1
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 230000001588 bifunctional effect Effects 0.000 description 1
- 230000002146 bilateral effect Effects 0.000 description 1
- 239000012148 binding buffer Substances 0.000 description 1
- 229960000106 biosimilars Drugs 0.000 description 1
- 238000001815 biotherapy Methods 0.000 description 1
- OWMVSZAMULFTJU-UHFFFAOYSA-N bis-tris Chemical compound OCCN(CCO)C(CO)(CO)CO OWMVSZAMULFTJU-UHFFFAOYSA-N 0.000 description 1
- JCXGWMGPZLAOME-UHFFFAOYSA-N bismuth atom Chemical compound [Bi] JCXGWMGPZLAOME-UHFFFAOYSA-N 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- GXJABQQUPOEUTA-RDJZCZTQSA-N bortezomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)B(O)O)NC(=O)C=1N=CC=NC=1)C1=CC=CC=C1 GXJABQQUPOEUTA-RDJZCZTQSA-N 0.000 description 1
- 229960001467 bortezomib Drugs 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 201000008274 breast adenocarcinoma Diseases 0.000 description 1
- 229960000455 brentuximab vedotin Drugs 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 229960002092 busulfan Drugs 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 238000012754 cardiac puncture Methods 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 239000013592 cell lysate Substances 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- 230000000973 chemotherapeutic effect Effects 0.000 description 1
- 229960004630 chlorambucil Drugs 0.000 description 1
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 150000001840 cholesterol esters Chemical class 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 229960002173 citrulline Drugs 0.000 description 1
- 201000010897 colon adenocarcinoma Diseases 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000007891 compressed tablet Substances 0.000 description 1
- 238000013170 computed tomography imaging Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 230000000139 costimulatory effect Effects 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 1
- 229960000640 dactinomycin Drugs 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 238000012217 deletion Methods 0.000 description 1
- 230000037430 deletion Effects 0.000 description 1
- 230000000779 depleting effect Effects 0.000 description 1
- 238000011033 desalting Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 208000002173 dizziness Diseases 0.000 description 1
- 229960003668 docetaxel Drugs 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 238000002091 elastography Methods 0.000 description 1
- 239000012149 elution buffer Substances 0.000 description 1
- 239000002158 endotoxin Substances 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 229930013356 epothilone Natural products 0.000 description 1
- 150000003883 epothilone derivatives Chemical class 0.000 description 1
- 230000003628 erosive effect Effects 0.000 description 1
- 239000003797 essential amino acid Substances 0.000 description 1
- 235000020776 essential amino acid Nutrition 0.000 description 1
- 229960000752 etoposide phosphate Drugs 0.000 description 1
- LIQODXNTTZAGID-OCBXBXKTSA-N etoposide phosphate Chemical compound COC1=C(OP(O)(O)=O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 LIQODXNTTZAGID-OCBXBXKTSA-N 0.000 description 1
- 201000005884 exanthem Diseases 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 150000005699 fluoropyrimidines Chemical class 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- 239000004052 folic acid antagonist Substances 0.000 description 1
- 239000012537 formulation buffer Substances 0.000 description 1
- 238000002825 functional assay Methods 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 230000004077 genetic alteration Effects 0.000 description 1
- 231100000118 genetic alteration Toxicity 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 238000010353 genetic engineering Methods 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 108020004445 glyceraldehyde-3-phosphate dehydrogenase Proteins 0.000 description 1
- 230000036433 growing body Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 201000005787 hematologic cancer Diseases 0.000 description 1
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 description 1
- 229940022353 herceptin Drugs 0.000 description 1
- 102000057382 human EPHA3 Human genes 0.000 description 1
- 102000053391 human F Human genes 0.000 description 1
- 108700031895 human F Proteins 0.000 description 1
- 210000000688 human artificial chromosome Anatomy 0.000 description 1
- OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine Substances NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 1
- 239000000017 hydrogel Substances 0.000 description 1
- GRRNUXAQVGOGFE-NZSRVPFOSA-N hygromycin B Chemical compound O[C@@H]1[C@@H](NC)C[C@@H](N)[C@H](O)[C@H]1O[C@H]1[C@H]2O[C@@]3([C@@H]([C@@H](O)[C@@H](O)[C@@H](C(N)CO)O3)O)O[C@H]2[C@@H](O)[C@@H](CO)O1 GRRNUXAQVGOGFE-NZSRVPFOSA-N 0.000 description 1
- 229940097277 hygromycin b Drugs 0.000 description 1
- 229960000908 idarubicin Drugs 0.000 description 1
- 229960001101 ifosfamide Drugs 0.000 description 1
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 239000012642 immune effector Substances 0.000 description 1
- 108091008915 immune receptors Proteins 0.000 description 1
- 102000027596 immune receptors Human genes 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 230000002163 immunogen Effects 0.000 description 1
- 229940121354 immunomodulator Drugs 0.000 description 1
- 230000003308 immunostimulating effect Effects 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000000126 in silico method Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- APFVFJFRJDLVQX-AHCXROLUSA-N indium-111 Chemical compound [111In] APFVFJFRJDLVQX-AHCXROLUSA-N 0.000 description 1
- 238000003331 infrared imaging Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 229940102213 injectable suspension Drugs 0.000 description 1
- 239000000138 intercalating agent Substances 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- BPHPUYQFMNQIOC-NXRLNHOXSA-N isopropyl beta-D-thiogalactopyranoside Chemical compound CC(C)S[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O BPHPUYQFMNQIOC-NXRLNHOXSA-N 0.000 description 1
- 101150066555 lacZ gene Proteins 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 239000012160 loading buffer Substances 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- WLHQHAUOOXYABV-UHFFFAOYSA-N lornoxicam Chemical compound OC=1C=2SC(Cl)=CC=2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 WLHQHAUOOXYABV-UHFFFAOYSA-N 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- OHSVLFRHMCKCQY-UHFFFAOYSA-N lutetium atom Chemical compound [Lu] OHSVLFRHMCKCQY-UHFFFAOYSA-N 0.000 description 1
- 210000002751 lymph Anatomy 0.000 description 1
- 201000011649 lymphoblastic lymphoma Diseases 0.000 description 1
- 125000005439 maleimidyl group Chemical group C1(C=CC(N1*)=O)=O 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 201000009020 malignant peripheral nerve sheath tumor Diseases 0.000 description 1
- 210000001161 mammalian embryo Anatomy 0.000 description 1
- 201000007924 marginal zone B-cell lymphoma Diseases 0.000 description 1
- 208000021937 marginal zone lymphoma Diseases 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- WKPWGQKGSOKKOO-RSFHAFMBSA-N maytansine Chemical compound CO[C@@H]([C@@]1(O)C[C@](OC(=O)N1)([C@H]([C@@H]1O[C@@]1(C)[C@@H](OC(=O)[C@H](C)N(C)C(C)=O)CC(=O)N1C)C)[H])\C=C\C=C(C)\CC2=CC(OC)=C(Cl)C1=C2 WKPWGQKGSOKKOO-RSFHAFMBSA-N 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 229960004961 mechlorethamine Drugs 0.000 description 1
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical class ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 1
- 229960001924 melphalan Drugs 0.000 description 1
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 1
- 210000003071 memory t lymphocyte Anatomy 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 238000000520 microinjection Methods 0.000 description 1
- 210000004688 microtubule Anatomy 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 229960004857 mitomycin Drugs 0.000 description 1
- 230000000394 mitotic effect Effects 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- AEMBWNDIEFEPTH-UHFFFAOYSA-N n-tert-butyl-n-ethylnitrous amide Chemical compound CCN(N=O)C(C)(C)C AEMBWNDIEFEPTH-UHFFFAOYSA-N 0.000 description 1
- 210000000822 natural killer cell Anatomy 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 229950010159 nemorubicin Drugs 0.000 description 1
- CTMCWCONSULRHO-UHQPFXKFSA-N nemorubicin Chemical compound C1CO[C@H](OC)CN1[C@@H]1[C@H](O)[C@H](C)O[C@@H](O[C@@H]2C3=C(O)C=4C(=O)C5=C(OC)C=CC=C5C(=O)C=4C(O)=C3C[C@](O)(C2)C(=O)CO)C1 CTMCWCONSULRHO-UHQPFXKFSA-N 0.000 description 1
- 238000007857 nested PCR Methods 0.000 description 1
- 208000029974 neurofibrosarcoma Diseases 0.000 description 1
- 230000004766 neurogenesis Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- CMUOJBJRZUHRMU-UHFFFAOYSA-N nitrourea Chemical compound NC(=O)N[N+]([O-])=O CMUOJBJRZUHRMU-UHFFFAOYSA-N 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000009206 nuclear medicine Methods 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 238000011580 nude mouse model Methods 0.000 description 1
- 229950005751 ocrelizumab Drugs 0.000 description 1
- 229960002450 ofatumumab Drugs 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 238000000059 patterning Methods 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 230000008855 peristalsis Effects 0.000 description 1
- 239000012466 permeate Substances 0.000 description 1
- 239000005426 pharmaceutical component Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 150000004713 phosphodiesters Chemical class 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 150000003057 platinum Chemical class 0.000 description 1
- 230000008488 polyadenylation Effects 0.000 description 1
- 229920001610 polycaprolactone Polymers 0.000 description 1
- 229920006149 polyester-amide block copolymer Polymers 0.000 description 1
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- PUDIUYLPXJFUGB-UHFFFAOYSA-N praseodymium atom Chemical compound [Pr] PUDIUYLPXJFUGB-UHFFFAOYSA-N 0.000 description 1
- 238000011533 pre-incubation Methods 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 229960004618 prednisone Drugs 0.000 description 1
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 108010060090 pretubulysin Proteins 0.000 description 1
- 238000007639 printing Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000013587 production medium Substances 0.000 description 1
- 230000005522 programmed cell death Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 239000003207 proteasome inhibitor Substances 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 230000012743 protein tagging Effects 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 206010037844 rash Diseases 0.000 description 1
- BMKDZUISNHGIBY-UHFFFAOYSA-N razoxane Chemical compound C1C(=O)NC(=O)CN1C(C)CN1CC(=O)NC(=O)C1 BMKDZUISNHGIBY-UHFFFAOYSA-N 0.000 description 1
- 229960000460 razoxane Drugs 0.000 description 1
- 238000010188 recombinant method Methods 0.000 description 1
- 108091008146 restriction endonucleases Proteins 0.000 description 1
- 238000003757 reverse transcription PCR Methods 0.000 description 1
- 229910052702 rhenium Inorganic materials 0.000 description 1
- WUAPFZMCVAUBPE-UHFFFAOYSA-N rhenium atom Chemical compound [Re] WUAPFZMCVAUBPE-UHFFFAOYSA-N 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 239000012723 sample buffer Substances 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000006152 selective media Substances 0.000 description 1
- ZKZBPNGNEQAJSX-UHFFFAOYSA-N selenocysteine Natural products [SeH]CC(N)C(O)=O ZKZBPNGNEQAJSX-UHFFFAOYSA-N 0.000 description 1
- 235000016491 selenocysteine Nutrition 0.000 description 1
- 229940055619 selenocysteine Drugs 0.000 description 1
- 230000008313 sensitization Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000012163 sequencing technique Methods 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 238000011895 specific detection Methods 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 230000010473 stable expression Effects 0.000 description 1
- 238000011146 sterile filtration Methods 0.000 description 1
- 235000003702 sterols Nutrition 0.000 description 1
- 150000003432 sterols Chemical class 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 238000004114 suspension culture Methods 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- DKPFODGZWDEEBT-QFIAKTPHSA-N taxane Chemical class C([C@]1(C)CCC[C@@H](C)[C@H]1C1)C[C@H]2[C@H](C)CC[C@@H]1C2(C)C DKPFODGZWDEEBT-QFIAKTPHSA-N 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 229910052713 technetium Inorganic materials 0.000 description 1
- GKLVYJBZJHMRIY-UHFFFAOYSA-N technetium atom Chemical compound [Tc] GKLVYJBZJHMRIY-UHFFFAOYSA-N 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- 229960001196 thiotepa Drugs 0.000 description 1
- 238000012090 tissue culture technique Methods 0.000 description 1
- 229960000303 topotecan Drugs 0.000 description 1
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 230000005030 transcription termination Effects 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- 230000026683 transduction Effects 0.000 description 1
- 239000012096 transfection reagent Substances 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 102000035160 transmembrane proteins Human genes 0.000 description 1
- 108091005703 transmembrane proteins Proteins 0.000 description 1
- 102000027257 transmembrane receptors Human genes 0.000 description 1
- 108091008578 transmembrane receptors Proteins 0.000 description 1
- 229960001612 trastuzumab emtansine Drugs 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 239000013638 trimer Substances 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 229930184737 tubulysin Natural products 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 230000005909 tumor killing Effects 0.000 description 1
- 238000013414 tumor xenograft model Methods 0.000 description 1
- 238000012285 ultrasound imaging Methods 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- 210000002845 virion Anatomy 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 239000000277 virosome Substances 0.000 description 1
- 239000011534 wash buffer Substances 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229960005502 α-amanitin Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
- A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
- A61K47/6807—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug or compound being a sugar, nucleoside, nucleotide, nucleic acid, e.g. RNA antisense
- A61K47/6809—Antibiotics, e.g. antitumor antibiotics anthracyclins, adriamycin, doxorubicin or daunomycin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
- A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
- A61K47/6811—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a protein or peptide, e.g. transferrin or bleomycin
- A61K47/6817—Toxins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
- A61K47/6849—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6889—Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6903—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being semi-solid, e.g. an ointment, a gel, a hydrogel or a solidifying gel
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- 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
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
-
- 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
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
- C07K14/70503—Immunoglobulin superfamily
- C07K14/7051—T-cell receptor (TcR)-CD3 complex
-
- 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
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/10—Transferases (2.)
- C12N9/12—Transferases (2.) transferring phosphorus containing groups, e.g. kinases (2.7)
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y207/00—Transferases transferring phosphorus-containing groups (2.7)
- C12Y207/10—Protein-tyrosine kinases (2.7.10)
- C12Y207/10001—Receptor protein-tyrosine kinase (2.7.10.1)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
- C07K2317/33—Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
- C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/01—Fusion polypeptide containing a localisation/targetting motif
- C07K2319/02—Fusion polypeptide containing a localisation/targetting motif containing a signal sequence
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/01—Fusion polypeptide containing a localisation/targetting motif
- C07K2319/03—Fusion polypeptide containing a localisation/targetting motif containing a transmembrane segment
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Immunology (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Biochemistry (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Epidemiology (AREA)
- Zoology (AREA)
- Biophysics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Cell Biology (AREA)
- Toxicology (AREA)
- Wood Science & Technology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Gastroenterology & Hepatology (AREA)
- General Engineering & Computer Science (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Biomedical Technology (AREA)
- Biotechnology (AREA)
- Microbiology (AREA)
- Peptides Or Proteins (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Description
本出願は、米国仮特許出願第62/280,843号明細書(2016年1月20日出願)に対する優先権の利益を主張する。優先出願の全開示内容は、全体として、及びあらゆる目的のために、参照により本明細書に組み込まれる。
本発明は、一部が、本発明者らによる大きなナイーブキメラウサギ/ヒトFabライブラリーの作製及びファージディスプレイを介したヒトROR1に対する結合物質の選択に基づく。受容体チロシンキナーゼオーファン受容体−1及び−2、ROR1及びROR2は、全体的な構造設計及びいくつかの機能的類似性に基づき、新たな受容体チロシンキナーゼファミリーを定義するただ2つのファミリーメンバーである。ROR1及びROR2タンパク質のいずれも、免疫グロブリンドメイン、システインリッチフリズルド(frizzled)ドメイン及びクリングル(Kringle)ドメインから構成される細胞外ドメイン(ECD)を有するI型1回膜貫通型受容体である。これらの3つの細胞外ドメインに、キナーゼドメインを含むタンパク質の細胞内部分にECDを結合する膜貫通ドメインが続く(Rabagay et al.(2012)Frontiers Oncol.2:1−8)。ヒトROR1及びROR2タンパク質は、互いに58%相同であるが、RORタンパク質の各々は、種の間で高度に保存されている。最も保存されているのは、実際に、937aa長タンパク質であるROR1タンパク質であり、これは、ヒトと全ての配列決定された非ヒト霊長類との間で98.5%超同一であり、ヒトとマウス及びウサギROR1との間でもそれぞれ96.7及び96.3%相同である(Borcherding et al.(2014)Protein Cell 5:496−502)。そのため、マウス又はウサギ免疫によって高品質の抗ROR1抗体を作製することは課題であり、許容可能な親和性を有する抗体はほんのわずかしか知られていない。例えば、国際公開第2010/124188号パンフレット(マウスモノクローナル抗体2A2)、国際公開第2012/075158号パンフレット(ウサギ抗体R11及びR12)、国際公開第2012/097313号パンフレット(マウスモノクローナル抗体D10)及び国際公開第2014/031174号パンフレット(マウスmAb99961のヒト化バージョンで、mAbD10が結合するのと同じエピトープに結合する)を参照されたい。
別に定義しない限り、本明細書で使用される全ての技術及び科学用語は、本発明が関連する技術分野の通常の技術者により一般に理解されているものと同じ意味を有する。下記の参照文献は、本発明で使用される用語の多くの一般的な定義を当業者に提供する:Academic Press Dictionary of Science and Technology,Morris(Ed.),Academic Press(1st ed., 1992); Oxford Dictionary of Biochemistry and Molecular Biology,Smith et al.(Eds.),Oxford University Press(revised ed.,2000);Encyclopaedic Dictionary of Chemistry,Kumar(Ed.),Anmol Publications Pvt.Ltd.(2002);Dictionary of Microbiology and Molecular Biology,Singleton et al.(Eds.),John Wiley & Sons (3rd ed.,2002);Dictionary of Chemistry,Hunt(Ed.),Routledge(1st ed.,1999);Dictionary of Pharmaceutical Medicine,Nahler (Ed.),Springer−Verlag Telos(1994);Dictionary of Organic Chemistry,Kumar and Anandand(Eds.),Anmol Publications Pvt.Ltd.(2002);及びa Dictionary of Biology(Oxford Paperback Reference),Martin and Hine(Eds.),Oxford University Press(4th ed.,2000)。これに加えて、本発明の実施に際して読者を補助するために、以下の定義が提供される。
一態様では、本発明は、本明細書に例示する抗ROR1抗体と同じ結合特異性で、ヒトROR1に特異的に結合する、新規の抗体、抗体ベースの結合タンパク質、その抗体フラグメント、ADC又はCARに関する(図1及び23)。本発明の抗体としては、同種抗原であるROR1に結合する能力を保持するインタクトな抗体の抗原結合部分を含有する、インタクトな抗体(例えば、本明細書に例示するIgG1抗体)、抗体フラグメント若しくは抗原結合フラグメント(例えば、本明細書に例示するFabフラグメント)、抗体ベースの結合タンパク質、ADC及びCARが挙げられる。こうした抗体フラグメントの例としては、以下のものが挙げられる:(i)Fabフラグメント、VL、VH、CL及びCH1ドメインから構成される一価フラグメント;(ii)F(ab’)2フラグメント、ヒンジ領域でのジスルフィド架橋により連結された2つのFabフラグメントを含む二価フラグメント;(iii)VH及びCH1ドメインから構成されるFdフラグメント;(iv)インタクトな抗体の単一アームのVL及びVHドメインから構成されるFvフラグメント;(v)構造的に保存されたフレームワーク領域の間で操作された鎖間ジスルフィド結合を有するジスルフィド安定化Fvs(dsFvs);(vi)VH又はVLドメインから構成される単一ドメイン抗体(dAb)(例えば、Ward et al. Nature 341:544−546,1989を参照);並びに(vii)直鎖ペプチド又は環状ペプチドなどの単離された相補性決定領域(CDR)。抗体ベースの結合タンパク質の例は、抗体の結合ドメインが、他のポリペプチド若しくはポリペプチドドメイン、例えば、別の分子スカフォールド、Fc−領域、他のポリペプチド若しくは抗体の他の機能若しくは結合ドメインと組み合わされて、追加結合特性を有する分子、例えば、二重若しくは多重特異性タンパク質又は抗体をもたらすポリペプチドである。こうしたポリペプチドは、天然に存在する抗体若しくは抗体フラグメントには通常見いだされない結合又は機能ドメインの配列を形成することができる。
本発明は、本明細書に記載の抗体、抗体ベースの結合タンパク質又はその抗体フラグメントのセグメント若しくはドメインを含むポリペプチドをコードする配列と同一又は相補的である、実質的に精製されたポリヌクレオチド(DNA若しくはRNA)を提供する。一部の実施形態では、本発明のポリヌクレオチドは、図1及び23に示す重鎖又は軽鎖ドメイン配列をコードする。適切な発明ベクターから発現されると、これらのポリヌクレオチドによりコードされたポリペプチドは、ROR1抗原結合能力を呈示することができる。さらに、本発明には、本明細書に記載の抗体の重鎖若しくは軽鎖からの少なくとも1つのCDR領域、通常、3つのCDR領域全てをコードするポリヌクレオチドも提供される。いくつかの他のポリヌクレオチドは、例示した抗体の重鎖及び/又は軽鎖の可変領域配列の全部若しくは実質的に全部をコードする。例えば、これらのポリヌクレオチドの一部は、配列番号1〜13又は130〜135のいずれか1つに示される重鎖可変領域のアミノ酸配列、及び/又は配列番号14〜26又は136〜141のいずれか1つに示される軽鎖可変領域のアミノ酸配列をコードする。コードの縮重のために、様々な核酸配列が、免疫グロブリンアミノ酸配列の各々をコードすることになる。
本明細書に開示するROR1抗体、抗体ベースの結合タンパク質、その抗体フラグメント、ADC及びCARは、様々な治療及び診断用途に使用することができる。ROR1は、様々な腫瘍の発生時に発現され、それに関与している。例えば、Rebagay et al.,Front Oncol.2,34,2012;Shabani et al.,Expert Opin.Ther.Targets 19,941−955,2015を参照されたい。例えば、ROR1は、CLL、ALL、マントル細胞リンパ腫、神経芽細胞腫、肉腫、腎細胞癌、乳癌、肺癌、結腸癌、頭部及び頚部癌、黒色腫、及びその他の癌における腫瘍細胞表面上に発現される。重要なことには、ROR1は、胚形成に発現されるが、ほとんどが誕生後停止される。ごくわずかな成体正常組織及び細胞が、ROR1を発現する。これと一致して、抗ROR1 CAR操作T細胞は、非ヒト霊長類において安全且つ活性であることがわかっており、これによって、ROR1は、癌の治療標的として認められた(Berger (2015) Cancer Immunol Res.3(2),page 2016)。従って、ROR1に対するmAbは、癌において高い治療及び診断有用性を有する。
別の態様では、本発明は、本明細書に記載の抗体、抗体フラグメント、抗体ベースの結合タンパク質、又はADCと、薬学的に許容される担体を含む医薬組成物を提供する。医薬組成物は、本明細書に記載の抗体のいずれかから調製することができる。例示的な組成物として、配列番号14(軽鎖)及び/又は配列番号1(重鎖)を有するキメラ抗体、配列番号18(軽鎖)及び/又は配列番号5(重鎖)を有するキメラ抗体、配列番号25(軽鎖)及び/又は配列番号12(重鎖)を有するキメラ抗体、並びに配列番号26(軽鎖)及び/又は配列番号13(重鎖)を有するキメラ抗体が挙げられる。本発明の医薬組成物に好適な他の抗体、抗体フラグメント、抗体ベースの結合タンパク質、又はADCとしては、配列番号14〜26若しくは136〜141に示される軽鎖配列及び/又は配列番号1〜13若しくは130〜135に示される重鎖配列を有するものが挙げられる。本発明の他の例示的な組成物は、配列番号130〜141に例示されるものと同様に、配列番号27〜104からなる群から選択される1、2、3、4、5、若しくは6つのCDRを有するヒト化抗体を含有することができる。一部の実施形態では、抗体は、図1に示される例示軽鎖又は重鎖の3つのCDR配列を含む。これらは、以下:(1)配列番号27〜29と配列番号66〜68(抗体XBR1−402)、(2)配列番号30〜32と配列番号69〜71(抗体ERR1−301)、(3)配列番号33〜35と配列番号72〜74(抗体ERR1−306)、(4)配列番号36〜38と配列番号75〜77(抗体ERR1−316)、(5)配列番号39〜41と配列番号78〜80(抗体ERR1−324)、(6)配列番号42〜44と配列番号81〜83(抗体ERR1−403)、(7)配列番号45〜47と配列番号84〜86(抗体ERR1−409)、(8)配列番号48〜50と配列番号87〜89(抗体ERR1−TOP4)、(9)配列番号51〜53と配列番号90〜92(抗体ERR1−TOP15)、(10)配列番号54〜56と配列番号93〜95(抗体ERR1−TOP22)、(11)配列番号57〜59と配列番号96〜98(抗体ERR1−TOP40)、(12)配列番号60〜62と配列番号99〜101(抗体ERR1−TOP43)、又は(13)配列番号63〜65と配列番号102〜104(抗体ERR1−TOP54)にそれぞれ示される重鎖CDR1、CDR2及びCDR3配列と、軽鎖CDR1、CDR2及びCDR3配列とを含む。一部の実施形態では、医薬組成物は、図1に例示される同じ抗体の6つのCDR配列、例えば、(a)配列番号66〜68と配列番号27〜29(抗体XBR1−402);(b)配列番号78〜80と配列番号39〜41(抗体ERR1−324);(c)配列番号99〜101と配列番号60〜62(抗体ERR1−TOP43)、又は(d)配列番号102〜104と配列番号63〜65(抗体ERR1−TOP54)を有する抗体を含む。また別の例示的な医薬組成物は、dsFvフラグメントを含み、これは、必要に応じて、また当業者には理解されるように、アミノ酸配列に1つ又は複数の修飾を含んでもよい。
細胞株:MDA−MB−231,MDA−MB−469,697,Kasumi−2、T47D、HS578T、63−12及び63−12/hROR1及び63−12/hROR2トランスフェクタント、K562及びK562/hROR1トランスフェクタント、EMT−6及びEMT−6/ROR1トランスフェクタントを、10%(v/v)熱不活性化FBS(Thermo Scientific;Logan,UT)、100U/mLペニシリン、及び100mg/mLストレプトマイシン(Invitrogen)で補充したDMEM(Invitrogen;Carlsbad,CA)中で培養した。HEK 293F細胞は、Invitrogenから購入し、接着培養を支持するために1%(v/v)熱不活性化FBS(Thermo Scientific)で補充したFreeStyle Medium中に維持するか、又は懸濁培養の場合には、FBSなしで、100U/mLペニシリン、及び100mg/mLストレプトマイシン(Invitrogen)で補充したFreeStyle Medium中に維持した。
組換えヒトROR1タンパク質の構築、発現、及び精製:ヒトROR1又はマウスROR1の様々なドメインを含有するhFc融合タンパク質の構築、発現、精製及びビオチン化が記載されている(Yang et al.,PloS One 6:e21018,2011)。hROR1−AVI−6XHIS融合タンパク質の場合、ヒトROR1(24−403)の細胞外ドメインを、プライマーpCEP4−hROR1−F及びpCEP4−hROR1−Aviタグ−R(AVIタグは、プライマーpCEP4−hROR1−Aviタグ−Rにより、ROR1のC末端に導入されたことに留意されたい)を用いてPCR増幅した後、プライマーpCEP4−シグナル−F−KpnI及びpCEP4−6HIS−R−XhoIを用いた伸長PCRにより、N及びC末端にシグナルペプチド及び6XHISタグを個別に付加した後、KpnI/XhoIを介したpCEP4へのクローニングを実施した。次に、293フェクチン(Invitrogen)を用いて、この構築物をHEK293F細胞(Invitrogen)に一過性にトランスフェクトし、Kwong and Rader,Curr Protoc Protein Sci Chapter 6:Unit 6 10,2009に記載されているように、1−mL HisTrapカラム(GE Healthcare)を用いたImmobilized Metal Ion Affinity Chromatographyによりタンパク質を精製した。精製したhROR1−AVI−6XHISの品質及び量をSDS−PAGE及びA280吸光度によりそれぞれ分析した。これに続いて、プロトコルに従ってAvidity(Aurora,Colorado)製のBirA酵素キットにより融合タンパク質をビオチン化した。手短には、10mM Tris−HCl(pH8)中40μMで2mgのROR1−AVI−6XHISを、37℃で30分のインキュベーション後、10μgのBirAを用いてビオチンの存在下、ビオチン化し、続いて、前述のように1mL HisTrapカラム(GE Healthcare)を用いて再度精製した。pCEP4−hROR1−F:5’−atcctgtttctcgtagctgctgcaactggagcacactccgcccggggcgccgccgcccag−3’(配列番号105);pCEP4−hROR1−Avi−tag−R:5’−ccactcgatcttctgggcctcgaagatgtcgttcaggccctccatcttgttcttctcctt−3’(配列番号106);pCEP4−シグナル−F−KpnI:5’gctgggtaccggcgcgccaccatggactggacttggagaatcctgtttctcgtagctgct−3’(配列番号107);pCEP4−6HIS−R−XhoI:5’−gccggcctcgagtcagtgatggtgatggtggtgctcgtgccactcgatcttctgggcctc−3’(配列番号108)。
キメラウサギ/ヒトFab及びIgG1の構築、発現及び精製:キメラウサギ/ヒトFabフォーマットのMAb XBR1−402は、大腸菌(E.coli)発現プラスミドpC3C−Hisにクローニングして、発現さ、Kwong and Rader,Curr Protoc Protein Sci Chapter 6:Unit 6 10,2009に記載されているように精製した。キメラウサギ/ヒトIgG1フォーマットのmAb XBR1−402の発現のために、以前記載されているベクターPIGG−R11を使用した(Yang et al.,PloS One 6:e21018,2011)。Fab XBR1−402のVHコード配列を、プライマー4−2_VH_F及び4−2_VH_Rを用いてPCR増幅し、ApaI/SacIを介してPIGG−R11にクローニングした。次に、XBR1−402の軽鎖コード配列を、プライマー4−2_λ_F及びLEAD−Bを用いてPCR増幅し、HindIII/XbaIを介して、対応する重鎖コード配列を有するPIGG−R11にクローニングした。Fab XBR1−402のVHコード配列のFR4の内部ApaI部位は、プライマー4−2_VH_Rにおけるサイレント突然変異によって除去されたことに留意されたい。さらに、大腸菌(E.coli)株XL1−Blueにおける選択の間に抑制されていたTAG停止コドンは、プライマー4−2_VH_Fを用いて、ネイティブVHの第1アミノ酸をコードするCAG(グルタミン)に変更した(図1)。得られたPIGG−XBR1−402プラスミドは、293フェクチン(Invitrogen)を用いて、HEK293F細胞(Invitrogen)に一過性トランスフェクトし、記載されているように(Yang et al.,PloS One 6:e21018,2011;及びYang and Rader,Methods Mol Biol 901:209−232,2012)、1mL組換えProtein A HiTrapカラム(GE Healthcare,Piscataway,NJ)を用いて、タンパク質を精製した。精製したIgG1の品質及び量をSDS−PAGE及びA280吸光度によりそれぞれ分析した。
ELISA:ELISA(図2)のために、96ウェルCostar3690プレート(Corning,Corning,NY)を25μLのコーティングバッファー(0.1 M Na2CO3、0.1M NaHCO3、pH9.6)中100ngの抗ヒトIgG1 Fcで、37℃にて1時間コーティングした。150μLの3%(w/v)BSA/TBSで、37℃にて1時間遮断してから、100ng/50μLで、37℃にて1時間のインキュベーションの後、hFc−hROR1又はhFc−mROR1を捕捉した。次に、100ng/50μLのFabを37℃の各ウェル内に塗布した。2時間後、1%(w/v)BSA/TBS中のセイヨウワサビペルオキシダーゼ(HRP)(R&D Systems,Minneapolis,MN)に結合させたマウス抗体HisタグmAbの1:1000希釈物50μLを用いて、Fabを検出した。エピトープ(図4)を決定するために、hROR1の様々なドメインを含有するhFc融合タンパク質を直接コーティングし、続いて、Fabと一緒にインキュベートした後、HRPに結合したマウス抗HisタグmAbによる検出を行った。PBSによる洗浄を繰り返してから、基質として2,2’−アジノ−ビス(3−エチルベンズチアゾリン)−6−スルホン酸(Roche)を用いて、製造者の指示に従い、比色検出を実施した。SpectraMax M5マイクロプレートリーダ(Molecular Devices;Sunnyvale,CA)及びSoftMax Proソフトウエア(Molecular Devices)を用いて、吸光度を405nmで測定した。
ストレップIIタグ付きヒトROR1−細胞外ドメインを次のように生成した:ヒトROR1(NP_005003.2)をコードするヌクレオチド配列を、シグナル配列(MNFGLRLIFLVLTLKGVQC)とN末端に融合させ、ストレップIIタグ(GWSHPQFEK)をコードする配列とC末端に融合させた。全遺伝子合成(GenScript,Piscataway,USA)により、フランキングする5’NotI及び3’HindIII部位を有する全ヌクレオチド配列を生成し、Evitria AG(Schlieren,Switzerland)により、独自の哺乳動物発現ベクターpEvi5中にアセンブルして、DNAシーケンシングにより確認した。
発現ベクター:リーダ配列としてMNFGLRLIFLVLTLKGVQCを用いた全遺伝子合成(GenScript)によって抗体可変領域コード領域を生成し、発現ベクターpCB14において、ヒトIgH−γ1及びIgL−κ又は、適用できる場合には、IgL−λ定常領域とアセンブルした。このベクター、エピソーム哺乳動物発現ベクターpCEP4(Invitrogen)の誘導体は、EBV複製起点を担持し、染色体外複製を可能にするためにEBV核抗原(EBNA−1)をコードし、元のヒグロマイシンB耐性遺伝子の代わりにプロマイシン選択マーカを含有する。
96ウェルプレートの各ウェルを、0.1M重炭酸塩コーティングバッファー(pH9.6)中2μg/mLのストレップタグ付きヒトROR1(実施例5から)100μLでコーティングした後、4℃で12時間インキュベートした。第2の96ウェルプレートも、ツイン−ストレップタグ付きヒトROR2(実施例5から)を用いて同様に調製した。
ヒト化可変領域配列(7つのhu4−2VH変異体及び4つのhu4−2VL変異体)を融合抗体(Fusion Antibodies)(Belfast,Ireland)により設計した。手短には、ウサギ可変領域内のフレームワークをヒトフレームワーク領域と交換する(独自のアルゴリズムに基づくインシリコ支援(in−silico assisted)CDR−グラフトアプローチに従って)ことによって、28の考えられる重鎖/軽鎖対を形成した。
ウェル当たり5×105個の各細胞型を96ウェルプレートに添加した。バッファー(2%(v/v)のFCSを添加したPBS)中の再懸濁物と一緒に、プレートを遠心分離(3分、1300rpm)した。2μg/mLの濃度に達するまで、2A2(mAb066)を各ウェルに添加した。次に、プレートを氷上で30分間インキュベートし、200μLのバッファーで洗浄してから、1:250の希釈率で抗ヒトIgG抗体(Fcγ特異的)PE(eBioscience 12−4998−82)で補充した200μLのバッファー中に再懸濁させた。氷上で30分のインキュベーション及び1回の洗浄後、FACSCalibur計器(BD Biosciences)を用いて細胞を分析し、FlowJo分析ソフトウエア(Tree Star,Ashland,OR)を用いてデータを分析した。
ソルターゼA酵素。黄色ブドウ球菌(Staphylococcus aureus)由来の組換え及びアフィニティ精製ソルターゼA酵素は、国際公開第2014140317A1号パンフレットに開示されているように、大腸菌(E.coli)から生成した。
XBR1−402−G5−PNUのインビトロ血清安定性を、ELISAによる血清安定性アッセイで評価した。手短には、NOD SCIDマウス(バーゼル大学病院(University Hospital of Basel,Switzerland)、Prof.Dr.med.Alfred Zippeliusからの親切な寄贈品)及びヒト血清(SRK blood donation center,Basel,Switzerlandから;男性:女性血液の50:50混合物を2000gで15分間遠心分離して、血清を取得)中100μg/mLの濃度までADCを希釈し、37℃でインキュベートした。サンプルを0、3、7及び14日目に液体窒素で瞬間凍結し、ELISA分析まで−80℃で保存した。マウス血清の場合には、ADCと結合させるために、2μg/mlの実験室内作製マウス抗PNU mAb(ヒトIgG−PNUコンジュゲートでマウスを免疫し、BSA−PNUコンジュゲートを用いてスクリーニングすることにより作製)で、又は全IgGと結合させるために、ヤギ抗ヒトFc F(ab’)2(Jackson Immunoresearch,109−006−098)でコーティングしたELISAプレート上で、ADC血清サンプルの希釈系列(希釈係数3.5、5〜0.0008μg/ml)を捕捉し、HRP結合ロバ抗ヒトIgGの1:2500希釈物(Jackson Immunoresearch,709−035−149)で検出した。ヒト血清の場合には、2μg/mlの組換えヒトROR1(ストレップタグ付き、実施例5)をELISAプレートにコーティングした後、HRP結合ロバ抗ヒトIgGの1:2500希釈物(Jackson Immunoresearch,709−035−149)又は2μg/mlのマウス抗PNU IgG(実験室内で作製)、続いて、1:5000希釈したHRP結合ヤギ抗マウスFcγ F(ab’)2(Jackson Immunoresearch,115−036−071)を、全IgG及びADCの検出のためにそれぞれ使用した。ADC及び全IgGの血清濃度は、既知濃度の同じADCのサンプルとの比較により、サンプル力価測定の最大半数値から算出した。図19に示すように、XBR1−402−G5−PNUは、いずれの血清中においても実質的に安定性を維持する。
抗ROR1 ADC XBR1−402−G5−PNU(adc262)の細胞傷害性を、野生型(WT)EMT−6及びヒトROR1を過剰発現するように操作されたEMT−6細胞(実施例2から)を用いて調べた。アイソタイプコントロールとして、Tras−G5−PNU(adc286)を含んだ。
抗ROR1 ADC XBR1−402−G5−PNU(adc409)の細胞傷害性を、ヒトROR1を過剰発現するように操作されたヒトEMT−6細胞(実施例2から)を用いて調べ、抗体Ms961ベースの抗ROR1 ADC(adc396)と比較した。アイソタイプコントロールとして、Tras−G5−PNU(adc394)を含んだ。
抗ROR1 ADC XBR1−402−G5−PNU(adc262)の細胞傷害性を、ヒト細胞株697を用いて調べ、既知抗体2A2、R11及びR12ベースの抗ROR1 ADCと比較する(図13)か、又は2A2及びR12に対する697及びKasumi−2ALL細胞を再度用いた個別の実験により調べた。
ヒト細胞株:MDA−MB−468、HS578Tを用いて、抗ROR1 ADC 2A2−G5−PNU(adc165)、XBR1−402−G5−PNU(adc135)、R12−G5−PNU(adc292)、ERR1−Top43−G5−PNU(adc204)、並びにERR1−324−G5−PNU(adc202)と2A2−G5−PNU(adc165)、ERR1−324−G5−PNU(adc202)とXBR1−402−G5−PNU(adc135)、ERR1−324−G5−PNU(adc202)とR12−G5−PNU(adc292)、及びERR1−324−G5−PNU(adc202)とERR1−Top43−G5−PNU(adc204)の50:50重量比混合物の細胞傷害性を調べた。アイソタイプコントロールとして、Ac10−G5−PNU(adc159)を含んだ。
ヒト697細胞を用いて、ヒト化抗ROR1 ADC:huXBR1−402−3−G5−PNU(adc456)、huXBR1−402−8−G5−PNU(adc457)、huXBR1−402−15−G5−PNU(adc458)、huXBR1−402−17−G5−PNU(adc459)、huXBR1−402−19−G5−PNU(adc460)及びhuXBR1−402−26−G5−PNU(adc461)の細胞傷害性を調べた。アイソタイプコントロールとして、Tras−G5−PNU(adc286)を含んだ。
下記の試験をABPRO(Burlington,MA,USA)で実施した。ケージ当たり最大5匹の動物からなるグループ毎に収容された雌CD−1マウス(試験開始時に少なくとも6週齢、Taconic Biosciences,Germantown,NY,USAから)を体重別に各々9匹ずつの2グループにランダムに分けた。1グループは、静脈内投与により、単一用量の1mg/kgのXBR1−402(mAb202)を受け、第2グループは、単一用量の1mg/kgのXBR1−402−G5−PNU(adc409)を受けた。投与後の血液サンプルを表11のプロトコルに従って各々3匹から成るサブグループから採取した。採血は、顎下静脈のランセット穿刺により実施した(約200μLを採取)が、但し、21日目の採血は例外で、心臓穿刺により実施した(約600μLを採取)。サブグループからのサンプルを各時点についてプールした。1’500gで10分間の血液遠心分離により血漿を単離し、ELISAによる実験室内分析まで滅菌クライオバイアル内に−80℃で保存した。
以下の試験をPipeline Biotech(Trige,Denmark)で実施した。XBR1−402−G5−PNU(adc288)及びヒト化hu2A2−G5−PNU(adc287;未公開PCT/欧州特許第2016/076244号明細書に基づく)の効力を、hROR1陽性697ALL細胞を注射した雌NOD−SCIDマウスにおける播種性異種移植モデルにおいて比較した。HER−2特異的抗体トラスツズマブ、Tras−G5−PNU(adc286)ベースのADCは、負のアイソタイプ適合コントロールADCとして使用した。
表13の試験プロトコルに従い、下記のマウスモデルにおいて、新規の抗ROR1抗体XBR1−402−G5−PNUベースのADC(adc262)をR12−G5−PNU(adc327)、及び既知抗体R12ベースのADC及びアイソタイプコントロールTras−G5−PNU(adc286)ADCと比較した。
ヒト患者由来異種移植(PDX)モデル(Charles River,Freiburg,Germany)の腫瘍溶解物及びコントロールとしての高度にROR1陽性の不死化細胞株(Kasumi−2)の溶解物、並びに不死化A549癌細胞からの溶解物をウエスタンブロットによるhROR1タンパク質発現についてプローブした。このために、溶解物を5×SDS−PAGEロードバッファー(250mM Tris−HCl pH6.8、10%SDS、30%グリセロール、5%μ−メルカプトエタノール)と混合し、99℃で5分間加熱することによって、溶解物を変性させた。SDS−PAGEによる分離の後、eblot transfer System(Genscript)を用いて、タンパク質をPVDF膜に転写した。次に、10%ウマ血清(Amimed,Bioconcept,Switzerland)を含有するTBST(20mM Tris−HCl、150mM NaCl、pH7.6、0.1%Tween−20)中に1:200希釈した市販のポリクローナルウサギ抗ROR1抗体4102(Cell Signaling Technology,Danvers,USA)と一緒に、膜を4℃で一晩インキュベートした。TBSTで2回洗浄した後、HRP結合抗ウサギ二次抗体(WesternSure HRP goat−anti−rabbit IgG,LiCor,Lincoln,USA)と一緒に、膜を室温で1時間インキュベートした。発光基質(SuperSignal West Femto(34094,Thermo Fisher)中で膜をインキュベートし、cDigit Western blot reader(LiCor,Lincoln,USA)を用いたイメージングにより、シグナルを明らかにした。ハウスキーピング遺伝子GAPDHの検出は、ローディングコントロールとして使用した。
下記の試験をCharles River(Oncotest GmbH,Freiburg,Germany)において実施した。
ROR1ターゲティングmAb R11及びR12について以前記載されている方法(Hudecek,M.,Lupo−Stanghellini,M.T.,Kosasih,P.L.,Sommermeyer,D.,Jensen,M.C.,Rader,C.,and Riddell,S.R.(2013)Receptor affinity and extracellular domain modifications affect tumor recognition by ROR1−specific chimeric antigen receptor T cells.Clin.Cancer Res.19,3153−3164)を用いて、XBR1−402ベースのCAR−T細胞を作製した。エクスビボ拡大一次ヒトCD8+CD62L+T細胞に、レンチウイルスにより、CD3ζ及び4−1BBシグナル伝達ドメインと短いスペーサとを含むXBR1−402又はR12由来のCARを形質導入した。形質導入したT細胞をFACSによりtEGFRを介して精製し、機能性アッセイの前日にその表現型を評価した。CD8+純度は、97%〜99%の間で変動し、tEGFR発現は、95%〜99%の間で変動した。ROR1陽性又はROR1陰性ヒト乳癌細胞との72時間の同時培養後、CFSE染色CD8+CD62L+細胞をフローサイトメトリーにより分析したところ、XBR1−402及びR12 CAR−Tの標的依存性増殖が判明した(図26;上方左側パネル)。24時間の同時培養後に採取した上清中のIFNγ及びIL2濃度をELISAにより測定した(図26;上方右側パネル)。ROR1陽性及びROR1陰性細胞との11時間の同時培養後、ルシフェラーゼベースの細胞傷害性アッセイを用いて、選択性障害性を測定した(図26;下方パネル)。
図28は、Retrogenix Cell Microarray Platformの外観を示す。一次スクリーン:精製済キメラウサギ/ヒトIgG1 XBR1−402及び精製済キメラウサギ/ヒトIgG1 XBR1−401を各々2μg/mLの濃度までプールした。4,336のヒト血漿膜タンパク質を個別に発現する固定HEK293細胞/スライドに対する結合について、プールをスクリーニングした(13スライドセット;n=2スライド/スライドセット)。トランスフェクション効率は全て、最小閾値を超えた。AlexaFluor647抗ヒトIgG Fc検出抗体を使用した。ImageQuantで蛍光(AlexaFluor647及びZsGreen1)を分析することによって、一次ヒット(重複スポット)を同定した。全ヒットをコードするベクターをシーケンシングすることにより、それらの正しいアイデンティティを確認した。確認スクリーン:全ヒットをコードするベクター、並びにコントロールベクターを新しいスライドに重複してスポットし、これらを用いて、以前と同様に、ヒトHEK293細胞をリバーストランスフェクトした。トランスフェクション効率は全て、最小閾値を超えた。同一の固定スライドを2つの試験抗体(XBR1−402及びXBR2−401)の各々で個別に処理し、さらにポジティブ及びネガティブコントロール(n=2スライド/処理)でも処理した。スライドを前述と同様に分析した(図29)。
Claims (45)
- ヒト受容体チロシンキナーゼ様オーファン受容体1(ROR1)の細胞外ドメインに対し、第2抗体のものと同じ結合特異性で、特異的に結合する抗体、抗体ベースの結合タンパク質又は抗体フラグメントであって、前記第2抗体が、(1)配列番号1と配列番号14;(2)配列番号2と配列番号15;(3)配列番号3と配列番号16;(4)配列番号4と配列番号17;(5)配列番号5と配列番号18;(6)配列番号6と配列番号19;(7)配列番号7と配列番号20;(8)配列番号8と配列番号21;(9)配列番号9と配列番号22;(10)配列番号10と配列番号23;(11)配列番号11と配列番号24;(12)配列番号12と配列番25;(13)配列番号13と配列番号26;(14)配列番号130と配列番号136;(15)配列番号131と配列番号137;(16)配列番号132と配列番号138;(17)配列番号133と配列番号139;(18)配列番号134と配列番号140;若しくは(19)配列番号135と配列番号141にそれぞれ示される、重鎖可変領域配列と軽鎖可変領域配列とを含む、抗体、抗体ベースの結合タンパク質又は抗体フラグメント。
- 重鎖可変領域配列と軽鎖可変領域配列とを含み、その一方又は両方が、(1)配列番号1と配列番号14;(2)配列番号2と配列番号15;(3)配列番号3と配列番号16;(4)配列番号4と配列番号17;(5)配列番号5と配列番号18;(6)配列番号6と配列番号19;(7)配列番号7と配列番号20;(8)配列番号8と配列番号21;(9)配列番号9と配列番号22;(10)配列番号10と配列番号23;(11)配列番号11と配列番号24;(12)配列番号12と配列番25;(13)配列番号13と配列番号26;(14)配列番号130と配列番号136;(15)配列番号131と配列番号137;(16)配列番号132と配列番号138;(17)配列番号133と配列番号139;(18)配列番号134と配列番号140;若しくは(19)配列番号135と配列番号141にそれぞれ示される重鎖可変領域配列及び軽鎖可変領域配列と少なくとも90%又は少なくとも95%同一である、請求項1に記載の抗体、抗体ベースの結合タンパク質又は抗体フラグメント。
- 重鎖可変領域配列と軽鎖可変領域配列とを含み、その一方又は両方が、(1)配列番号1と配列番号14;(2)配列番号2と配列番号15;(3)配列番号3と配列番号16;(4)配列番号4と配列番号17;(5)配列番号5と配列番号18;(6)配列番号6と配列番号19;(7)配列番号7と配列番号20;(8)配列番号8と配列番号21;(9)配列番号9と配列番号22;(10)配列番号10と配列番号23;(11)配列番号11と配列番号24;(12)配列番号12と配列番25;(13)配列番号13と配列番号26;(14)配列番号130と配列番号136;(15)配列番号131と配列番号137;(16)配列番号132と配列番号138;(17)配列番号133と配列番号139;(18)配列番号134と配列番号140;若しくは(19)配列番号135と配列番号141にそれぞれ示される重鎖可変領域配列及び軽鎖可変領域配列と同一である、請求項1に記載の抗体、抗体ベースの結合タンパク質又は抗体フラグメント。
- (1)配列番号1と配列番号14;(2)配列番号2と配列番号15;(3)配列番号3と配列番号16;(4)配列番号4と配列番号17;(5)配列番号5と配列番号18;(6)配列番号6と配列番号19;(7)配列番号7と配列番号20;(8)配列番号8と配列番号21;(9)配列番号9と配列番号22;(10)配列番号10と配列番号23;(11)配列番号11と配列番号24;(12)配列番号12と配列番25;(13)配列番号13と配列番号26;(14)配列番号130と配列番号136;(15)配列番号131と配列番号137;(16)配列番号132と配列番号138;(17)配列番号133と配列番号139;(18)配列番号134と配列番号140;若しくは(19)配列番号135と配列番号141にそれぞれ示される重鎖可変領域配列と軽鎖可変領域配列とを含む、請求項1に記載の抗体、抗体ベースの結合タンパク質又は抗体フラグメント。
- (1)配列番号27〜29と配列番号66〜68、(2)配列番号30〜32と配列番号69〜71、(3)配列番号33〜35と配列番号72〜74、(4)配列番号36〜38と配列番号75〜77、(5)配列番号39〜41と配列番号78〜80、(6)配列番号42〜44と配列番号81〜83、(7)配列番号45〜47と配列番号84〜86、(8)配列番号48〜50と配列番号87〜89、(9)配列番号51〜53と配列番号90〜92、(10)配列番号54〜56と配列番号93〜95、(11)配列番号57〜59と配列番号96〜98、(12)配列番号60〜62と配列番号99〜101、若しくは(13)配列番号63〜65と配列番号102〜104と、それぞれ少なくとも90%又は95%同一である重鎖CDR配列と軽鎖CDR配列とを含む、請求項1に記載の抗体、抗体ベースの結合タンパク質又は抗体フラグメント。
- 配列番号27〜65からなる群から選択される重鎖CDR配列を含む、請求項1に記載の抗体、抗体ベースの結合タンパク質又は抗体フラグメント。
- 配列番号66〜104からなる群から選択される軽鎖CDR配列をさらに含む、請求項6に記載の抗体、抗体ベースの結合タンパク質又は抗体フラグメント。
- 重鎖CDR1、CDR2及びCDR3配列を含み、それらは配列番号27〜29、配列番号30〜32、配列番号33〜35、配列番号36〜38、配列番号39〜41、配列番号42〜44、配列番号45〜47、配列番号48〜50、配列番号51〜53、配列番号54〜56、配列番号57〜59、配列番号60〜62、若しくは配列番号63〜65とそれぞれ同一である、請求項6に記載の抗体、抗体ベースの結合タンパク質又は抗体フラグメント。
- (1)配列番号27〜29と配列番号66〜68、(2)配列番号30〜32と配列番号69〜71、(3)配列番号33〜35と配列番号72〜74、(4)配列番号36〜38と配列番号75〜77、(5)配列番号39〜41と配列番号78〜80、(6)配列番号42〜44と配列番号81〜83、(7)配列番号45〜47と配列番号84〜86、(8)配列番号48〜50と配列番号87〜89、(9)配列番号51〜53と配列番号90〜92、(10)配列番号54〜56と配列番号93〜95、(11)配列番号57〜59と配列番号96〜98、(12)配列番号60〜62と配列番号99〜101、若しくは(13)配列番号63〜65と配列番号102〜104にそれぞれ示される、重鎖CDR1、CDR2及びCDR3配列と軽鎖CDR1、CDR2及びCDR3配列とを含む、請求項8に記載の抗体、抗体ベースの結合タンパク質又は抗体フラグメント。
- 配列番号66〜104からなる群から選択される軽鎖CDR配列を含む、請求項1に記載の抗体、抗体ベースの結合タンパク質又は抗体フラグメント。
- 配列番号27〜65からなる群から選択される重鎖CDR配列をさらに含む、請求項10に記載の抗体、抗体ベースの結合タンパク質又は抗体フラグメント。
- 軽鎖CDR1、CDR2及びCDR3配列を含み、それらは配列番号66〜68、配列番号69〜71、配列番号72〜74、配列番号75〜77、配列番号78〜80、配列番号81〜83、配列番号84〜86、配列番号87〜89、配列番号90〜92、配列番号93〜95、配列番号96〜98、配列番号99〜101、又は配列番号102〜104とそれぞれ同一である、請求項10に記載の抗体、抗体ベースの結合タンパク質又は抗体フラグメント。
- キメラ抗体又はヒト化抗体を含む、請求項1に記載の抗体、抗体ベースの結合タンパク質又は抗体フラグメント。
- (1)配列番号130〜135から選択される配列と少なくとも90%同一の免疫グロブリン重鎖可変領域配列及び/又は(2)配列番号136〜141から選択される配列と少なくとも90%同一の免疫グロブリン軽鎖可変領域配列を含む、請求項1に記載の抗体、抗体ベースの結合タンパク質又は抗体フラグメント。
- (1)配列番号130〜135から選択される配列と同一の免疫グロブリン重鎖可変領域配列及び/又は(2)配列番号136〜141から選択される配列と同一の免疫グロブリン軽鎖可変領域配列を含む、請求項14に記載の抗体、抗体ベースの結合タンパク質又は抗体フラグメント。
- (1)配列番号130と配列番号136;(2)配列番号131と配列番号137;(3)配列番号132と配列番号138;(4)配列番号133と配列番号139;(5)配列番号134と配列番号140;又は(6)配列番号135と配列番号141にそれぞれ示される重鎖可変領域配列及び軽鎖可変領域配列と同一の記載の重鎖可変領域配列と軽鎖可変領域配列とを含む、請求項14に記載の抗体、抗体ベースの結合タンパク質又は抗体フラグメント。
- 以下:IgA1、IgA2、IgD、IgE、IgG1、IgG2、IgG3、IgG4、合成IgG、IgM、F(ab)2、Fv、scFv、IgGACH2、F(ab’)2、scFv2CH3、Fab、VL、VH、scFv4、scFv3、scFv2、dsFv、Fv、scFv−Fc、(scFv)2、非枯渇IgG、ダイアボディ、及び二価抗体である、請求項1に記載の抗体、抗体ベースの結合タンパク質又は抗体フラグメント。
- 合成分子に結合した、請求項1に記載の抗体、抗体ベースの結合タンパク質又は抗体フラグメント。
- 前記合成分子が、標識、細胞傷害剤、治療用放射性同位体、又はリポソームである、請求項18に記載の抗体、抗体ベースの結合タンパク質又は抗体フラグメント。
- 前記細胞傷害剤が、低分子量毒素、又はペプチド毒素、若しくはタンパク質毒素である、請求項19に記載の抗体、抗体ベースの結合タンパク質又は抗体フラグメント。
- 請求項1に記載の抗体又は抗体フラグメントと、少なくとも1種の細胞傷害剤を含む、抗体薬物複合体(ADC)。
- 前記細胞傷害剤が、低分子量毒素、ペプチド毒素、又はタンパク質毒素である、請求項21に記載の抗体薬物複合体。
- 前記抗体又は抗体フラグメントが、ソルターゼ酵素媒介抗体結合(SMAC)を介して前記細胞傷害剤に結合される、請求項21に記載の抗体薬物複合体。
- 前記細胞傷害剤が、アントラサイクリン(PNU)毒素誘導体Gly(n)−EDA−PNUであり、ここで、nは、1〜21の任意の数である、請求項21に記載の抗体薬物複合体。
- 前記抗体又は抗体フラグメントが、キメラ又はヒト化されている、請求項21に記載の抗体薬物複合体。
- 前記抗体又は抗体フラグメントが、以下:(1)配列番号27〜29と配列番号66〜68、(2)配列番号39〜41と配列番号78〜80、又は(3)配列番号60〜62と配列番号99〜101にそれぞれ示される、重鎖CDR1、CDR2及びCDR3配列と軽鎖CDR1、CDR2及びCDR3配列とを含む、請求項21に記載の抗体薬物複合体。
- 前記抗体又は抗体フラグメントが、以下:(1)配列番号130と配列番号136;(2)配列番号131と配列番号137;(3)配列番号132と配列番号138;(4)配列番号133と配列番号139;(5)配列番号134と配列番号140;(6)配列番号135と配列番号141;(7)配列番号1と配列番号14;(8)配列番号5と配列番号18;又は(9)配列番号12と配列番号25にそれぞれ示される、重鎖可変領域配列と軽鎖可変領域配列とを含む、請求項21に記載の抗体薬物複合体。
- 膜貫通領域及び細胞内T細胞受容体(TCR)シグナル伝達ドメインと融合した、請求項1に記載の抗体又は抗体フラグメントを含むキメラ抗原受容体(CAR)。
- 前記抗体又は抗体フラグメントが、キメラ又はヒト化されている、請求項28に記載のキメラ抗原受容体。
- 前記抗体又は抗体フラグメントが、以下:(1)配列番号27〜29と配列番号66〜68にそれぞれ示される、重鎖CDR1、CDR2及びCDR3配列と軽鎖CDR1、CDR2及びCDR3配列とを含む、請求項28に記載のキメラ抗原受容体。
- 前記抗体又は抗体フラグメントが、以下:(1)配列番号130と配列番号136;(2)配列番号131と配列番号137;(3)配列番号132と配列番号138;(4)配列番号133と配列番号139;(5)配列番号134と配列番号140;(6)配列番号135と配列番号141;又は(7)配列番号1と配列番号14にそれぞれ示される、重鎖可変領域配列と軽鎖可変領域配列とを含む、請求項28に記載のキメラ抗原受容体。
- 以下:(1)治療有効量の(a)請求項1に記載の抗体、抗体ベースの結合タンパク質若しくは抗体フラグメント又は(b)請求項21に記載の抗体薬物複合体(ADC)と、(2)薬学的に許容される担体を含む医薬組成物。
- 以下:(1)請求項1に記載の抗体、抗体ベースの結合タンパク質若しくは抗体フラグメント又は(2)請求項21に記載の抗体薬物複合体(ADC)を含むキット。
- 請求項1に記載の抗体、抗体ベースの結合タンパク質若しくは抗体フラグメントの前記重鎖又は軽鎖の可変領域をコードするポリヌクレオチド。
- 配列番号34に記載のポリヌクレオチドを含むベクター。
- 被験者においてROR1を発現する細胞を殺傷するか、又はその増殖を阻害する方法であって、それを必要とする被験者に請求項32に記載の医薬組成物を投与し、それにより、前記被験者においてROR1を発現する前記細胞を殺傷するか、又はその増殖を阻害するステップを含む方法。
- 前記細胞が、腫瘍細胞である、請求項36に記載の方法。
- 前記医薬組成物が、細胞傷害剤と結合した請求項1に記載の抗体、抗体ベースの結合タンパク質又は抗体フラグメントを含む抗体薬物複合体(ADC)を含む、請求項36に記載の方法。
- 前記細胞傷害剤が、小分子量毒素、ペプチド毒素、又はタンパク質毒素である、請求項38に記載の方法。
- 被験者においてROR1の発現増大に関連する疾患又は状態を治療する方法であって、ROR1の発現増大に関連する疾患又は障害を有する被験者に請求項32に記載の医薬組成物を投与し、それによって、前記被験者におけるROR1の発現増大に関連する前記疾患又は状態を治療するステップを含む方法。
- 前記疾患又は状態が、癌である、請求項40に記載の方法。
- 前記疾患又は状態が、慢性リンパ性白血病(CLL)、急性リンパ芽球性白血病(ALL)、マントル細胞リンパ腫、神経芽細胞腫、肉腫、腎細胞癌、乳癌、肺癌、結腸癌、頭部及び頚部癌、及び黒色腫からなる群から選択される、請求項40に記載の方法。
- 前記医薬組成物が、細胞傷害剤と結合した請求項1に記載の抗体、抗体ベースの結合タンパク質又は抗体フラグメントを含む抗体薬物複合体(ADC)を含む、請求項40に記載の方法。
- 前記細胞傷害剤が、小分子量毒素、ペプチド毒素、又はタンパク質毒素である、請求項43に記載の方法。
- 前記抗体又は抗体断片が、膜貫通領域及び細胞内T細胞受容体(TCR)シグナル伝達ドメインと融合して、キメラ抗原受容体(CAR)を形成する、請求項40に記載の方法。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201662280843P | 2016-01-20 | 2016-01-20 | |
US62/280,843 | 2016-01-20 | ||
PCT/US2017/014311 WO2017127664A1 (en) | 2016-01-20 | 2017-01-20 | Ror1 antibody compositions and related methods |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2019509021A true JP2019509021A (ja) | 2019-04-04 |
JP7000660B2 JP7000660B2 (ja) | 2022-02-04 |
Family
ID=57966152
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2018537754A Active JP7000660B2 (ja) | 2016-01-20 | 2017-01-20 | Ror1抗体組成物及び関連の方法 |
Country Status (16)
Country | Link |
---|---|
US (3) | US10618959B2 (ja) |
EP (1) | EP3405496B1 (ja) |
JP (1) | JP7000660B2 (ja) |
KR (1) | KR20180101554A (ja) |
CN (1) | CN108848669B (ja) |
AU (1) | AU2017210327A1 (ja) |
BR (1) | BR112018014615A2 (ja) |
CA (1) | CA3011815A1 (ja) |
CL (1) | CL2018001971A1 (ja) |
IL (1) | IL260689B2 (ja) |
MX (1) | MX2018008926A (ja) |
PH (1) | PH12018501554A1 (ja) |
RU (1) | RU2766190C2 (ja) |
SG (1) | SG11201806120WA (ja) |
UA (1) | UA125718C2 (ja) |
WO (1) | WO2017127664A1 (ja) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2020525542A (ja) * | 2017-06-23 | 2020-08-27 | ベロスバイオ・インコーポレイテッドVelosBio Inc. | Ror1抗体免疫複合体 |
Families Citing this family (32)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA3001941A1 (en) | 2015-10-30 | 2017-05-04 | Nbe-Therapeutics Ag | Anti-ror1 antibodies |
EP3380126A4 (en) | 2015-11-25 | 2019-07-24 | LegoChem Biosciences, Inc. | ANTIBODY-MEDICINAL CONJUGATES COMPRISING BRANCHED LINKS AND RELATED METHODS |
BR112018014615A2 (pt) * | 2016-01-20 | 2018-12-11 | The Scripps Research Institute | composições de anticorpo para ror1 e métodos relacionados |
CN110573177A (zh) | 2017-04-28 | 2019-12-13 | 尤利乌斯·马克西米利安维尔茨堡大学 | 具有人源化靶向结构域的ror1特异性嵌合抗原受体(car) |
GB201710836D0 (en) | 2017-07-05 | 2017-08-16 | Ucl Business Plc | ROR1 Car T-Cells |
GB201710835D0 (en) | 2017-07-05 | 2017-08-16 | Ucl Business Plc | ROR1 Antibodies |
GB201710838D0 (en) | 2017-07-05 | 2017-08-16 | Ucl Business Plc | Bispecific antibodies |
MX2020001212A (es) * | 2017-08-07 | 2020-03-20 | Nbe Therapeutics Ag | Conjugados anticuerpo-farmaco a base de antraciclina que tienen alta tolerabilidad in vivo. |
CA3081719A1 (en) | 2017-11-03 | 2019-05-09 | Lentigen Technology, Inc. | Compositions and methods for treating cancer with anti-ror1 immunotherapy |
GB201721802D0 (en) * | 2017-12-22 | 2018-02-07 | Almac Discovery Ltd | Ror1-specific antigen binding molecules |
WO2020018964A1 (en) | 2018-07-20 | 2020-01-23 | Fred Hutchinson Cancer Research Center | Compositions and methods for controlled expression of antigen-specific receptors |
EP3636284A1 (en) * | 2018-10-11 | 2020-04-15 | NBE Therapeutics AG | Binding protein-toxin conjugates comprising anthracyclines, and use thereof in immune-oncological applications |
AU2019406453A1 (en) | 2018-12-21 | 2021-07-22 | Ose Immunotherapeutics | Bifunctional molecule directed against human PD-1 |
KR102371173B1 (ko) | 2018-12-21 | 2022-03-04 | 오제 이뮈노테라프틱스 | 인간화된 항-인간-pd-1 항체 |
CA3122914A1 (en) | 2018-12-21 | 2020-06-25 | Ose Immunotherapeutics | Bifunctional anti-pd-1/sirp.alpha. molecule |
EP3898677A1 (en) | 2018-12-21 | 2021-10-27 | OSE Immunotherapeutics | Bifunctional anti-pd-1/il-7 molecule |
US20220089758A1 (en) * | 2019-01-22 | 2022-03-24 | Revmab Biosciences Usa, Inc. | Novel anti-cd40 antibodies |
WO2020165374A1 (en) | 2019-02-14 | 2020-08-20 | Ose Immunotherapeutics | Bifunctional molecule comprising il-15ra |
CN111286512A (zh) * | 2019-06-05 | 2020-06-16 | 南京艾德免疫治疗研究院有限公司 | 靶向人源化酪氨酸激酶孤儿受体1的嵌合抗原受体及其用途 |
KR20210028544A (ko) * | 2019-09-04 | 2021-03-12 | 주식회사 레고켐 바이오사이언스 | 인간 ror1에 대한 항체를 포함하는 항체 약물 접합체 및 이의 용도 |
CN114829402A (zh) * | 2019-09-27 | 2022-07-29 | 南京艾美斐生物医药科技有限公司 | 抗ror1抗体及其制备方法与应用 |
GB202020154D0 (en) | 2020-12-18 | 2021-02-03 | Almac Discovery Ltd | ROR1-specific variant antigen binding molecules |
AU2022219517A1 (en) * | 2021-02-12 | 2023-07-13 | Boehringer Ingelheim International Gmbh | Complement c3 antigen binding proteins |
US11806405B1 (en) | 2021-07-19 | 2023-11-07 | Zeno Management, Inc. | Immunoconjugates and methods |
EP4377359A1 (en) * | 2021-09-12 | 2024-06-05 | Immunorizon Ltd. | Anti-ror1 antibodies and uses thereof |
CA3234822A1 (en) | 2021-10-28 | 2023-05-04 | Suman Kumar VODNALA | Methods for culturing cells expressing ror1-binding protein |
WO2023183950A2 (en) * | 2022-03-25 | 2023-09-28 | Board Of Regents, The University Of Texas System | Anti-ror1 antibody and chimeric antigen receptor and methods of use thereof |
KR20240016216A (ko) * | 2022-07-26 | 2024-02-06 | (주)에임드바이오 | 항-ror1 항체 및 이의 용도 |
WO2024032761A1 (en) * | 2022-08-11 | 2024-02-15 | Hansoh Bio Llc | Ligand-cytotoxicity drug conjugates and pharmaceutical uses thereof |
WO2024064952A1 (en) | 2022-09-23 | 2024-03-28 | Lyell Immunopharma, Inc. | Methods for culturing nr4a-deficient cells overexpressing c-jun |
WO2024064958A1 (en) | 2022-09-23 | 2024-03-28 | Lyell Immunopharma, Inc. | Methods for culturing nr4a-deficient cells |
WO2024077174A1 (en) | 2022-10-05 | 2024-04-11 | Lyell Immunopharma, Inc. | Methods for culturing nr4a-deficient cells |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2010124188A1 (en) * | 2009-04-23 | 2010-10-28 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Anti-human ror1 antibodies |
WO2011079902A2 (en) * | 2009-12-18 | 2011-07-07 | Biolnvent International Ab | Biological materials and uses thereof |
WO2012075158A1 (en) * | 2010-12-01 | 2012-06-07 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Chimeric rabbit/human ror1 antibodies |
JP2015532644A (ja) * | 2012-08-24 | 2015-11-12 | ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア | Ror1癌の治療および転移の阻害に使用するための抗体およびワクチン |
Family Cites Families (66)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3854480A (en) | 1969-04-01 | 1974-12-17 | Alza Corp | Drug-delivery system |
US3832253A (en) | 1973-03-21 | 1974-08-27 | Baxter Laboratories Inc | Method of making an inflatable balloon catheter |
US4458066A (en) | 1980-02-29 | 1984-07-03 | University Patents, Inc. | Process for preparing polynucleotides |
US4667014A (en) | 1983-03-07 | 1987-05-19 | Syntex (U.S.A.) Inc. | Nonapeptide and decapeptide analogs of LHRH, useful as LHRH antagonists |
US4452775A (en) | 1982-12-03 | 1984-06-05 | Syntex (U.S.A.) Inc. | Cholesterol matrix delivery system for sustained release of macromolecules |
CA1200416A (en) | 1983-05-13 | 1986-02-11 | Societe Des Produits Nestle S.A. | Food process |
US4946778A (en) | 1987-09-21 | 1990-08-07 | Genex Corporation | Single polypeptide chain binding molecules |
US5075109A (en) | 1986-10-24 | 1991-12-24 | Southern Research Institute | Method of potentiating an immune response |
JPH04167172A (ja) | 1990-10-31 | 1992-06-15 | Nec Corp | ベクトルプロセッサ |
US20030113762A1 (en) | 2001-08-17 | 2003-06-19 | Warrington Janet A. | Gleason grade 4/5 prostate cancer genes |
DK1310571T3 (da) | 2001-11-13 | 2006-06-19 | Univ Pennsylvania | Fremgangsmåde til identifikation af ukendte adeno-associerede virussekvenser (AAV-sekvenser) og et kit til fremgangsmåden |
US7462608B2 (en) | 2002-04-26 | 2008-12-09 | Gilead Sciences, Inc. | Non nucleoside reverse transcriptase inhibitors |
PT1545613E (pt) | 2002-07-31 | 2011-09-27 | Seattle Genetics Inc | Conjugados de auristatina e sua utilização para tratamento do cancro, de uma doença autoimune ou de uma doença infecciosa |
CA2563333A1 (en) | 2004-04-06 | 2005-10-27 | The Regents Of The University Of California | Orphan receptor tyrosine kinase as a target in breast cancer |
WO2008103849A2 (en) | 2007-02-21 | 2008-08-28 | The Regents Of The University Of California | Methods and compounds for lymphoma cell detection and isolation |
WO2007051077A2 (en) | 2005-10-28 | 2007-05-03 | The Regents Of The University Of California | Methods and compounds for lymphoma cell detection and isolation |
WO2007146957A2 (en) * | 2006-06-13 | 2007-12-21 | Irm Llc | Ror1 as a therapeutic target for lung cancer |
US20110008347A1 (en) | 2006-12-01 | 2011-01-13 | Agency For Science ,Technology And Research | Cancer-related protein kinases |
WO2008076868A2 (en) | 2006-12-18 | 2008-06-26 | Abbott Laboratories | Methods and compositions related to modulation of receptor tyrosine kinase orphan receptor-1 (ror-1) |
WO2008122039A2 (en) | 2007-04-02 | 2008-10-09 | The Government Of The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Selenocysteine mediated hybrid antibody molecules |
EP2240495B1 (en) | 2008-02-01 | 2015-07-15 | Genentech, Inc. | Nemorubicin metabolite and analog reagents, antibody-drug conjugates and methods |
KR100994996B1 (ko) | 2008-08-06 | 2010-11-18 | 한국과학기술연구원 | 페난트렌 노출 여부 확인용 바이오마커 및 이를 이용한확인 방법 |
RU2593720C2 (ru) * | 2008-12-19 | 2016-08-10 | Макродженикс, Инк. | Ковалентные диантитела и их применение |
WO2011054007A1 (en) | 2009-11-02 | 2011-05-05 | Oxford Biotherapeutics Ltd. | Ror1 as therapeutic and diagnostic target |
WO2011057034A2 (en) | 2009-11-05 | 2011-05-12 | Sloan Kettering Institute For Cancer Research | Catenae: serosal cancer stem cells |
AU2010328325B2 (en) | 2009-12-07 | 2015-02-05 | University Of Georgia Research Foundation, Inc. | Pyridinone hydroxycyclopentyl carboxamides: HIV integrase inhibitors with therapeutic applications |
WO2011159847A2 (en) | 2010-06-15 | 2011-12-22 | The Regents Of The University Of California | Receptor tyrosine kinase-like orphan receptor 1 (ror1) single chain fv antibody fragment conjugates and methods of use thereof |
WO2012012695A2 (en) | 2010-07-23 | 2012-01-26 | Fred Hutchinson Cancer Research Center | A method for the treatment of obesity |
US9228023B2 (en) | 2010-10-01 | 2016-01-05 | Oxford Biotherapeutics Ltd. | Anti-ROR1 antibodies and methods of use for treatment of cancer |
CA2818713C (en) | 2010-12-02 | 2019-03-26 | Nerviano Medical Sciences S.R.L. | Process for the preparation of morpholinyl anthracycline derivatives |
EP2649098B1 (en) | 2010-12-10 | 2017-11-22 | Kancera AB | Antibodies against ror1 and their uses |
GB201020995D0 (en) * | 2010-12-10 | 2011-01-26 | Bioinvent Int Ab | Biological materials and uses thereof |
DK3252076T3 (da) | 2011-01-14 | 2019-12-02 | Univ California | Diagnostisk anvendelse af antistoffer mod ror-1-protein |
US20130131139A1 (en) | 2011-11-17 | 2013-05-23 | Oregon Health & Science University | Ror1 as a gene target in acute lymphoblastic leukemia |
PT2692865E (pt) | 2012-07-30 | 2015-02-06 | Nbe Therapeutics Llc | Identificação mediada por transposição de proteínas funcionais ou de ligação específicas |
WO2014031687A1 (en) | 2012-08-20 | 2014-02-27 | Jensen, Michael | Method and compositions for cellular immunotherapy |
US10786532B2 (en) | 2012-10-02 | 2020-09-29 | Versiti Blood Research Institute Foundation, Inc. | Method of providing cellular therapy using modified natural killer cells or T lymphocytes |
EP2777714A1 (en) | 2013-03-15 | 2014-09-17 | NBE-Therapeutics LLC | Method of producing an immunoligand/payload conjugate by means of a sequence-specific transpeptidase enzyme |
EP2789630A1 (en) | 2013-04-09 | 2014-10-15 | EngMab AG | Bispecific antibodies against CD3e and ROR1 |
WO2015113110A1 (en) | 2014-01-29 | 2015-08-06 | University Of Western Sydney | A method for the purification of eye lens cells |
EP3593812A3 (en) | 2014-03-15 | 2020-05-27 | Novartis AG | Treatment of cancer using chimeric antigen receptor |
JP6788573B6 (ja) | 2014-04-10 | 2020-12-16 | シアトル チルドレンズ ホスピタル, ディービーエー シアトル チルドレンズ リサーチ インスティテュート | メトトレキサートによる選択と組み合わせたSleeping Beautyトランスポゾンによる遺伝子改変T細胞の製造 |
RU2741899C2 (ru) | 2014-04-25 | 2021-01-29 | Блубёрд Био, Инк. | Улучшенные способы производства средств адоптивной клеточной терапии |
BR112016027912A2 (pt) | 2014-05-29 | 2018-02-20 | Macrogenics, Inc. | molécula de ligação triespecífica capaz de se ligar de maneira imunoespecífica a três epítopos diferentes, composição farmacêutica, método de tratamento de câncer, método de tratamento de uma doença associada à presença de um patógeno, anticorpo anti-ror1, ou fragmento de ligação a ror1, fragmento de anticorpo biespecífico, bite ou anticorpo de cadeia simples, e método de tratamento de câncer |
CN106922148B (zh) | 2014-07-29 | 2021-10-15 | 瑟勒提斯公司 | 用于癌症免疫疗法的ror1(ntrkr1)特异性的嵌合抗原受体 |
US10544201B2 (en) | 2014-07-31 | 2020-01-28 | Cellectis | ROR1 specific multi-chain chimeric antigen receptor |
WO2016034666A1 (en) | 2014-09-04 | 2016-03-10 | Cellectis | Trophoblast glycoprotein (5t4, tpbg) specific chimeric antigen receptors for cancer immunotherapy |
CA2963696A1 (en) | 2014-10-09 | 2016-04-14 | Engmab Ag | Bispecific antibodies against cd3epsilon and ror1 for use in the treatment of ovarian cancer |
AU2015329965A1 (en) | 2014-10-09 | 2017-04-27 | Engmab Sàrl | Bispecific antibodies against CD3epsilon and ROR1 |
MX2017005344A (es) | 2014-10-27 | 2017-08-15 | Hutchinson Fred Cancer Res | Composiciones y metodos para reforzar la eficacia de inmunoterapia celular adoptiva. |
WO2016094373A1 (en) | 2014-12-08 | 2016-06-16 | George Mason University | Methods for breast cancer treatment |
WO2016094873A2 (en) | 2014-12-12 | 2016-06-16 | Emergent Product Development Seattle, Llc | Receptor tyrosine kinase-like orphan receptor 1 binding proteins and related compositions and methods |
FR3030807B1 (fr) | 2014-12-23 | 2018-02-02 | Thales | Procede non lineaire d'estimation d'un melange de signaux |
WO2016102679A1 (en) | 2014-12-23 | 2016-06-30 | Nbe-Therapeutics Ag | Binding protein drug conjugates comprising anthracycline derivatives |
WO2016142768A1 (en) | 2015-03-10 | 2016-09-15 | Eureka Therapeutics, Inc. | Ror2 antibody |
MX2017012939A (es) | 2015-04-08 | 2018-05-22 | Novartis Ag | Terapias cd20, terapias cd22 y terapias de combinacion con una celula que expresa un receptor quimerico de antigeno (car) de cd19. |
US10913798B2 (en) | 2015-04-24 | 2021-02-09 | The Regents Of The University Of California | Modulators of ROR1-ROR2 binding |
EP3297671A4 (en) | 2015-05-18 | 2019-02-06 | Eureka Therapeutics, Inc. | ANTI-ROR1 ANTIBODY |
CN108137669B (zh) | 2015-05-18 | 2023-02-17 | 优瑞科生物技术公司 | 抗ror1嵌合抗原受体 |
CA2999138C (en) | 2015-09-21 | 2024-05-21 | Aptevo Research And Development Llc | Cd3 binding polypeptides |
CA3001941A1 (en) | 2015-10-30 | 2017-05-04 | Nbe-Therapeutics Ag | Anti-ror1 antibodies |
CN106918698B (zh) | 2015-12-25 | 2019-11-22 | 广州瑞博奥生物科技有限公司 | 一种检测人受体酪氨酸激酶的磷酸化抗体芯片试剂盒 |
BR112018014615A2 (pt) | 2016-01-20 | 2018-12-11 | The Scripps Research Institute | composições de anticorpo para ror1 e métodos relacionados |
WO2017127499A1 (en) | 2016-01-22 | 2017-07-27 | Janssen Biotech, Inc. | Anti-ror1 antibodies, ror1 x cd3 bispecific antibodies, and methods of using the same |
WO2017136607A1 (en) | 2016-02-02 | 2017-08-10 | Fred Hutchinson Cancer Research Center | Anti-ror1 antibodies and uses thereof |
UY37127A (es) | 2016-02-17 | 2017-08-31 | Macrogenics Inc | Moléculas de unión a ror1, y métodos de uso de las mismas |
-
2017
- 2017-01-20 BR BR112018014615-3A patent/BR112018014615A2/pt unknown
- 2017-01-20 KR KR1020187023595A patent/KR20180101554A/ko unknown
- 2017-01-20 CA CA3011815A patent/CA3011815A1/en active Pending
- 2017-01-20 SG SG11201806120WA patent/SG11201806120WA/en unknown
- 2017-01-20 EP EP17703552.4A patent/EP3405496B1/en active Active
- 2017-01-20 RU RU2018129962A patent/RU2766190C2/ru active
- 2017-01-20 WO PCT/US2017/014311 patent/WO2017127664A1/en active Application Filing
- 2017-01-20 MX MX2018008926A patent/MX2018008926A/es unknown
- 2017-01-20 JP JP2018537754A patent/JP7000660B2/ja active Active
- 2017-01-20 CN CN201780019846.1A patent/CN108848669B/zh active Active
- 2017-01-20 UA UAA201808044A patent/UA125718C2/uk unknown
- 2017-01-20 AU AU2017210327A patent/AU2017210327A1/en active Pending
-
2018
- 2018-07-19 PH PH12018501554A patent/PH12018501554A1/en unknown
- 2018-07-19 US US16/040,244 patent/US10618959B2/en active Active
- 2018-07-19 IL IL260689A patent/IL260689B2/en unknown
- 2018-07-20 CL CL2018001971A patent/CL2018001971A1/es unknown
-
2020
- 2020-02-28 US US16/805,102 patent/US11242388B2/en active Active
-
2021
- 2021-12-28 US US17/563,273 patent/US20220153839A1/en active Pending
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2010124188A1 (en) * | 2009-04-23 | 2010-10-28 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Anti-human ror1 antibodies |
WO2011079902A2 (en) * | 2009-12-18 | 2011-07-07 | Biolnvent International Ab | Biological materials and uses thereof |
WO2012075158A1 (en) * | 2010-12-01 | 2012-06-07 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Chimeric rabbit/human ror1 antibodies |
JP2015532644A (ja) * | 2012-08-24 | 2015-11-12 | ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア | Ror1癌の治療および転移の阻害に使用するための抗体およびワクチン |
Non-Patent Citations (4)
Title |
---|
BIOCONJUGATE CHEM., 2014, VOL.25, PP.1402-1407, JPN6021002513, ISSN: 0004566801 * |
CLIN. CANCER. RES., 2013, VOL.19, PP.3153-3164, JPN6021002515, ISSN: 0004566803 * |
CLINICAL LYMPHOMA, MYELOMA & LEUKEMIA, 2015, VOL.15, S167-S169, JPN6021002512, ISSN: 0004566800 * |
LEUKEMIA, 2012, VOL.26, PP.1348-1355, JPN6021002514, ISSN: 0004566802 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2020525542A (ja) * | 2017-06-23 | 2020-08-27 | ベロスバイオ・インコーポレイテッドVelosBio Inc. | Ror1抗体免疫複合体 |
JP7245239B2 (ja) | 2017-06-23 | 2023-03-23 | ベロスバイオ・インコーポレイテッド | Ror1抗体免疫複合体 |
Also Published As
Publication number | Publication date |
---|---|
IL260689A (en) | 2022-12-01 |
WO2017127664A1 (en) | 2017-07-27 |
US11242388B2 (en) | 2022-02-08 |
US20220153839A1 (en) | 2022-05-19 |
UA125718C2 (uk) | 2022-05-25 |
SG11201806120WA (en) | 2018-08-30 |
RU2018129962A3 (ja) | 2020-06-22 |
RU2018129962A (ru) | 2020-02-20 |
KR20180101554A (ko) | 2018-09-12 |
CN108848669A (zh) | 2018-11-20 |
CN108848669B (zh) | 2022-06-07 |
BR112018014615A2 (pt) | 2018-12-11 |
RU2766190C2 (ru) | 2022-02-09 |
EP3405496B1 (en) | 2023-10-25 |
US10618959B2 (en) | 2020-04-14 |
MX2018008926A (es) | 2019-01-10 |
IL260689B2 (en) | 2023-04-01 |
JP7000660B2 (ja) | 2022-02-04 |
US20200299381A1 (en) | 2020-09-24 |
AU2017210327A1 (en) | 2018-08-09 |
US20180340026A1 (en) | 2018-11-29 |
PH12018501554A1 (en) | 2019-05-20 |
CL2018001971A1 (es) | 2018-12-21 |
EP3405496A1 (en) | 2018-11-28 |
CA3011815A1 (en) | 2017-07-27 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US11242388B2 (en) | ROR1 antibody compositions and related methods | |
US11834501B2 (en) | ROR2 antibody compositions and related methods | |
JP2019502363A (ja) | 抗ror1抗体 | |
US11306141B2 (en) | Antibody against human DLK1 and use thereof | |
WO2019030240A1 (en) | ANTIBODIES BINDING TO A LINEAR HUMAN CS1 EPITOPE | |
KR20200063155A (ko) | 다중 특이적 항체 | |
US20220372143A1 (en) | Human antibodies binding to ror2 | |
CA3105415A1 (en) | Antibodies specific to folate receptor alpha | |
JP2022529269A (ja) | ヒト化抗pd-l1抗体 | |
KR20240004860A (ko) | 디엘엘3에 대한 결합 분자 및 이의 용도 | |
JP2020508636A (ja) | IFN−γ誘導性制御性T細胞転換性抗癌(IRTCA)抗体およびその使用 | |
RU2784586C2 (ru) | Человеческие антитела, связывающиеся с ror2 | |
US11999786B2 (en) | Anti-CD48 antibodies, antibody drug conjugates, and uses thereof | |
WO2023086897A1 (en) | Siglec-6 antibodies, derivative compounds and related uses | |
AU2021446021A1 (en) | Anti-bcam antibody or antigen-binding fragment thereof | |
CN115368456A (zh) | 抗pd-1多肽及其用途 | |
CN116940595A (zh) | 抗tigit抗体及其用途 | |
IL303059A (en) | Antibodies against CD48, antibody-drug conjugates and uses thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20200109 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20210202 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20210428 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20210528 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20210810 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20211028 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20211116 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20211203 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 7000660 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |