JP2021508468A - メディトープ対応t細胞 - Google Patents
メディトープ対応t細胞 Download PDFInfo
- Publication number
- JP2021508468A JP2021508468A JP2020536020A JP2020536020A JP2021508468A JP 2021508468 A JP2021508468 A JP 2021508468A JP 2020536020 A JP2020536020 A JP 2020536020A JP 2020536020 A JP2020536020 A JP 2020536020A JP 2021508468 A JP2021508468 A JP 2021508468A
- Authority
- JP
- Japan
- Prior art keywords
- domain
- binding
- recombinant protein
- cells
- antigen
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 210000001744 T-lymphocyte Anatomy 0.000 title claims abstract description 270
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 claims abstract description 187
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 claims abstract description 187
- 210000004027 cell Anatomy 0.000 claims description 430
- 230000027455 binding Effects 0.000 claims description 364
- 238000009739 binding Methods 0.000 claims description 364
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 263
- 206010028980 Neoplasm Diseases 0.000 claims description 231
- 108091007433 antigens Proteins 0.000 claims description 226
- 102000036639 antigens Human genes 0.000 claims description 226
- 239000000427 antigen Substances 0.000 claims description 225
- 201000011510 cancer Diseases 0.000 claims description 183
- 230000003834 intracellular effect Effects 0.000 claims description 155
- 229960000575 trastuzumab Drugs 0.000 claims description 124
- 108090000623 proteins and genes Proteins 0.000 claims description 122
- 102000004169 proteins and genes Human genes 0.000 claims description 100
- 125000006850 spacer group Chemical group 0.000 claims description 92
- 230000011664 signaling Effects 0.000 claims description 85
- 238000000034 method Methods 0.000 claims description 76
- 150000007523 nucleic acids Chemical class 0.000 claims description 67
- 230000005754 cellular signaling Effects 0.000 claims description 63
- 101000914514 Homo sapiens T-cell-specific surface glycoprotein CD28 Proteins 0.000 claims description 56
- 102100027213 T-cell-specific surface glycoprotein CD28 Human genes 0.000 claims description 56
- 102000039446 nucleic acids Human genes 0.000 claims description 56
- 108020004707 nucleic acids Proteins 0.000 claims description 56
- 102100024222 B-lymphocyte antigen CD19 Human genes 0.000 claims description 46
- 101000980825 Homo sapiens B-lymphocyte antigen CD19 Proteins 0.000 claims description 45
- 238000001514 detection method Methods 0.000 claims description 42
- 208000032839 leukemia Diseases 0.000 claims description 39
- 101150029707 ERBB2 gene Proteins 0.000 claims description 37
- 238000011282 treatment Methods 0.000 claims description 35
- 206010006187 Breast cancer Diseases 0.000 claims description 28
- 208000026310 Breast neoplasm Diseases 0.000 claims description 26
- 229960004641 rituximab Drugs 0.000 claims description 24
- 201000001441 melanoma Diseases 0.000 claims description 22
- 206010033128 Ovarian cancer Diseases 0.000 claims description 21
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 21
- 125000001151 peptidyl group Chemical group 0.000 claims description 20
- 101000851370 Homo sapiens Tumor necrosis factor receptor superfamily member 9 Proteins 0.000 claims description 19
- 102100036856 Tumor necrosis factor receptor superfamily member 9 Human genes 0.000 claims description 19
- 229960005395 cetuximab Drugs 0.000 claims description 19
- 230000019491 signal transduction Effects 0.000 claims description 17
- 239000013604 expression vector Substances 0.000 claims description 16
- 210000000170 cell membrane Anatomy 0.000 claims description 14
- 208000020816 lung neoplasm Diseases 0.000 claims description 13
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 12
- 206010025323 Lymphomas Diseases 0.000 claims description 12
- 201000005202 lung cancer Diseases 0.000 claims description 12
- 206010060862 Prostate cancer Diseases 0.000 claims description 11
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 11
- 230000000139 costimulatory effect Effects 0.000 claims description 10
- 102100036011 T-cell surface glycoprotein CD4 Human genes 0.000 claims description 9
- 229960002087 pertuzumab Drugs 0.000 claims description 9
- 206010029260 Neuroblastoma Diseases 0.000 claims description 8
- 208000032612 Glial tumor Diseases 0.000 claims description 7
- 206010018338 Glioma Diseases 0.000 claims description 7
- 201000008968 osteosarcoma Diseases 0.000 claims description 7
- 241000713666 Lentivirus Species 0.000 claims description 6
- 208000000172 Medulloblastoma Diseases 0.000 claims description 6
- 210000003719 b-lymphocyte Anatomy 0.000 claims description 6
- 208000006265 Renal cell carcinoma Diseases 0.000 claims description 5
- 102100022005 B-lymphocyte antigen CD20 Human genes 0.000 claims description 3
- 208000015634 Rectal Neoplasms Diseases 0.000 claims description 3
- 230000000112 colonic effect Effects 0.000 claims description 3
- 238000000338 in vitro Methods 0.000 claims description 3
- 206010038038 rectal cancer Diseases 0.000 claims description 3
- 201000001275 rectum cancer Diseases 0.000 claims description 3
- 101000897405 Homo sapiens B-lymphocyte antigen CD20 Proteins 0.000 claims 2
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 claims 2
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 claims 2
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 claims 2
- 210000005036 nerve Anatomy 0.000 claims 2
- 208000015347 renal cell adenocarcinoma Diseases 0.000 claims 2
- 230000001225 therapeutic effect Effects 0.000 abstract description 31
- 239000000203 mixture Substances 0.000 abstract description 24
- 230000009471 action Effects 0.000 abstract description 2
- 230000009437 off-target effect Effects 0.000 abstract description 2
- 102100035360 Cerebellar degeneration-related antigen 1 Human genes 0.000 description 149
- 235000018102 proteins Nutrition 0.000 description 98
- 125000005647 linker group Chemical group 0.000 description 85
- 201000009030 Carcinoma Diseases 0.000 description 68
- 235000001014 amino acid Nutrition 0.000 description 68
- 229940024606 amino acid Drugs 0.000 description 66
- 150000001413 amino acids Chemical class 0.000 description 66
- -1 CD45RO Proteins 0.000 description 60
- 125000001424 substituent group Chemical group 0.000 description 60
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 54
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 53
- 125000000217 alkyl group Chemical group 0.000 description 50
- 125000001072 heteroaryl group Chemical group 0.000 description 50
- 125000003118 aryl group Chemical group 0.000 description 45
- 108010019670 Chimeric Antigen Receptors Proteins 0.000 description 44
- 229940022353 herceptin Drugs 0.000 description 44
- 125000004404 heteroalkyl group Chemical group 0.000 description 44
- 102000004196 processed proteins & peptides Human genes 0.000 description 41
- 230000000694 effects Effects 0.000 description 40
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 40
- 229920001184 polypeptide Polymers 0.000 description 38
- 230000014509 gene expression Effects 0.000 description 36
- 238000011534 incubation Methods 0.000 description 36
- 125000005842 heteroatom Chemical group 0.000 description 33
- 230000004913 activation Effects 0.000 description 30
- 125000000753 cycloalkyl group Chemical group 0.000 description 30
- 239000012634 fragment Substances 0.000 description 29
- 150000001875 compounds Chemical class 0.000 description 27
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 27
- 229910052757 nitrogen Inorganic materials 0.000 description 25
- 108091007741 Chimeric antigen receptor T cells Proteins 0.000 description 24
- 201000010099 disease Diseases 0.000 description 24
- 206010039491 Sarcoma Diseases 0.000 description 23
- 125000003275 alpha amino acid group Chemical group 0.000 description 23
- 229910052760 oxygen Inorganic materials 0.000 description 23
- 239000000126 substance Substances 0.000 description 23
- 229910052717 sulfur Inorganic materials 0.000 description 21
- 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 19
- 241000699670 Mus sp. Species 0.000 description 19
- 239000013598 vector Substances 0.000 description 19
- 102000001301 EGF receptor Human genes 0.000 description 18
- 108060006698 EGF receptor Proteins 0.000 description 17
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 17
- 238000004020 luminiscence type Methods 0.000 description 16
- 229910052698 phosphorus Inorganic materials 0.000 description 15
- 229910052710 silicon Inorganic materials 0.000 description 15
- 238000012360 testing method Methods 0.000 description 15
- HBZBAMXERPYTFS-SECBINFHSA-N (4S)-2-(6,7-dihydro-5H-pyrrolo[3,2-f][1,3]benzothiazol-2-yl)-4,5-dihydro-1,3-thiazole-4-carboxylic acid Chemical compound OC(=O)[C@H]1CSC(=N1)c1nc2cc3CCNc3cc2s1 HBZBAMXERPYTFS-SECBINFHSA-N 0.000 description 14
- 238000000684 flow cytometry Methods 0.000 description 14
- 210000004881 tumor cell Anatomy 0.000 description 14
- 102000017420 CD3 protein, epsilon/gamma/delta subunit Human genes 0.000 description 13
- 108050005493 CD3 protein, epsilon/gamma/delta subunit Proteins 0.000 description 13
- 108010047041 Complementarity Determining Regions Proteins 0.000 description 13
- 125000000539 amino acid group Chemical group 0.000 description 13
- 238000004422 calculation algorithm Methods 0.000 description 13
- 125000002947 alkylene group Chemical group 0.000 description 12
- 238000004458 analytical method Methods 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 12
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 11
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 11
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 11
- 230000021164 cell adhesion Effects 0.000 description 11
- 230000004083 survival effect Effects 0.000 description 11
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 10
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 10
- 230000006870 function Effects 0.000 description 10
- 239000001963 growth medium Substances 0.000 description 10
- 239000002773 nucleotide Substances 0.000 description 10
- 125000003729 nucleotide group Chemical group 0.000 description 10
- 208000024891 symptom Diseases 0.000 description 10
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 9
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 9
- 241000699666 Mus <mouse, genus> Species 0.000 description 9
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 9
- 239000004473 Threonine Substances 0.000 description 9
- 238000007792 addition Methods 0.000 description 9
- 238000003556 assay Methods 0.000 description 9
- 229910052736 halogen Inorganic materials 0.000 description 9
- 125000004474 heteroalkylene group Chemical group 0.000 description 9
- 125000005549 heteroarylene group Chemical group 0.000 description 9
- 230000003993 interaction Effects 0.000 description 9
- 210000004379 membrane Anatomy 0.000 description 9
- 239000012528 membrane Substances 0.000 description 9
- 239000013641 positive control Substances 0.000 description 9
- 239000000523 sample Substances 0.000 description 9
- 238000001890 transfection Methods 0.000 description 9
- 230000005909 tumor killing Effects 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 206010009944 Colon cancer Diseases 0.000 description 8
- 108020004414 DNA Proteins 0.000 description 8
- 108060003951 Immunoglobulin Proteins 0.000 description 8
- 208000009956 adenocarcinoma Diseases 0.000 description 8
- 239000002246 antineoplastic agent Substances 0.000 description 8
- 210000004369 blood Anatomy 0.000 description 8
- 239000008280 blood Substances 0.000 description 8
- 230000003833 cell viability Effects 0.000 description 8
- 239000003153 chemical reaction reagent Substances 0.000 description 8
- 239000003814 drug Substances 0.000 description 8
- 239000012636 effector Substances 0.000 description 8
- 230000001605 fetal effect Effects 0.000 description 8
- ZSIAUFGUXNUGDI-UHFFFAOYSA-N hexan-1-ol Chemical group CCCCCCO ZSIAUFGUXNUGDI-UHFFFAOYSA-N 0.000 description 8
- 229910052739 hydrogen Inorganic materials 0.000 description 8
- 239000001257 hydrogen Substances 0.000 description 8
- 238000003384 imaging method Methods 0.000 description 8
- 102000018358 immunoglobulin Human genes 0.000 description 8
- 108020004705 Codon Proteins 0.000 description 7
- 108010092694 L-Selectin Proteins 0.000 description 7
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 7
- 102000016551 L-selectin Human genes 0.000 description 7
- 108091028043 Nucleic acid sequence Proteins 0.000 description 7
- 102220479470 Proteasome inhibitor PI31 subunit_I83E_mutation Human genes 0.000 description 7
- 241000700605 Viruses Species 0.000 description 7
- 230000002159 abnormal effect Effects 0.000 description 7
- UCMIRNVEIXFBKS-UHFFFAOYSA-N beta-alanine Chemical compound NCCC(O)=O UCMIRNVEIXFBKS-UHFFFAOYSA-N 0.000 description 7
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- 230000001413 cellular effect Effects 0.000 description 7
- 238000012217 deletion Methods 0.000 description 7
- 230000037430 deletion Effects 0.000 description 7
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 7
- 230000002147 killing effect Effects 0.000 description 7
- 230000001404 mediated effect Effects 0.000 description 7
- 230000002085 persistent effect Effects 0.000 description 7
- 239000008194 pharmaceutical composition Substances 0.000 description 7
- 229920000642 polymer Polymers 0.000 description 7
- 108091033319 polynucleotide Chemical group 0.000 description 7
- 102000040430 polynucleotide Human genes 0.000 description 7
- 239000002157 polynucleotide Chemical group 0.000 description 7
- 102000005962 receptors Human genes 0.000 description 7
- 108020003175 receptors Proteins 0.000 description 7
- 230000009467 reduction Effects 0.000 description 7
- 208000011581 secondary neoplasm Diseases 0.000 description 7
- 241000894007 species Species 0.000 description 7
- 230000002459 sustained effect Effects 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- 208000009458 Carcinoma in Situ Diseases 0.000 description 6
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 6
- 102000004190 Enzymes Human genes 0.000 description 6
- 108090000790 Enzymes Proteins 0.000 description 6
- 101001023379 Homo sapiens Lysosome-associated membrane glycoprotein 1 Proteins 0.000 description 6
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 6
- 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 6
- 102100035133 Lysosome-associated membrane glycoprotein 1 Human genes 0.000 description 6
- 241000124008 Mammalia Species 0.000 description 6
- 206010035226 Plasma cell myeloma Diseases 0.000 description 6
- 230000006044 T cell activation Effects 0.000 description 6
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 6
- 235000004279 alanine Nutrition 0.000 description 6
- 125000000732 arylene group Chemical group 0.000 description 6
- 125000004429 atom Chemical group 0.000 description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 6
- 239000000562 conjugate Substances 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 6
- 230000008025 crystallization Effects 0.000 description 6
- 230000001186 cumulative effect Effects 0.000 description 6
- 125000002993 cycloalkylene group Chemical group 0.000 description 6
- 239000000539 dimer Substances 0.000 description 6
- 239000000975 dye Substances 0.000 description 6
- 238000005516 engineering process Methods 0.000 description 6
- 229940088598 enzyme Drugs 0.000 description 6
- 150000002367 halogens Chemical class 0.000 description 6
- 125000006588 heterocycloalkylene group Chemical group 0.000 description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 6
- 238000003780 insertion Methods 0.000 description 6
- 230000037431 insertion Effects 0.000 description 6
- 210000005075 mammary gland Anatomy 0.000 description 6
- 239000003550 marker Substances 0.000 description 6
- 238000006467 substitution reaction Methods 0.000 description 6
- 102000053602 DNA Human genes 0.000 description 5
- 241000282412 Homo Species 0.000 description 5
- 208000008839 Kidney Neoplasms Diseases 0.000 description 5
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 5
- 206010038389 Renal cancer Diseases 0.000 description 5
- 150000001412 amines Chemical class 0.000 description 5
- 230000008901 benefit Effects 0.000 description 5
- 229940127089 cytotoxic agent Drugs 0.000 description 5
- 238000010586 diagram Methods 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 208000037828 epithelial carcinoma Diseases 0.000 description 5
- 239000007850 fluorescent dye Substances 0.000 description 5
- 208000005017 glioblastoma Diseases 0.000 description 5
- 125000001188 haloalkyl group Chemical group 0.000 description 5
- 201000004933 in situ carcinoma Diseases 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 201000010982 kidney cancer Diseases 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 208000037819 metastatic cancer Diseases 0.000 description 5
- 208000011575 metastatic malignant neoplasm Diseases 0.000 description 5
- 239000000178 monomer Substances 0.000 description 5
- 230000035772 mutation Effects 0.000 description 5
- 208000025113 myeloid leukemia Diseases 0.000 description 5
- 239000013612 plasmid Substances 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- 238000010361 transduction Methods 0.000 description 5
- 230000026683 transduction Effects 0.000 description 5
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 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
- 239000012114 Alexa Fluor 647 Substances 0.000 description 4
- 206010005003 Bladder cancer Diseases 0.000 description 4
- 206010008342 Cervix carcinoma Diseases 0.000 description 4
- 102000004127 Cytokines Human genes 0.000 description 4
- 108090000695 Cytokines Proteins 0.000 description 4
- 102100025137 Early activation antigen CD69 Human genes 0.000 description 4
- 239000004471 Glycine Substances 0.000 description 4
- 101000934374 Homo sapiens Early activation antigen CD69 Proteins 0.000 description 4
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 4
- 125000002707 L-tryptophyl group Chemical group [H]C1=C([H])C([H])=C2C(C([C@](N([H])[H])(C(=O)[*])[H])([H])[H])=C([H])N([H])C2=C1[H] 0.000 description 4
- 208000034578 Multiple myelomas Diseases 0.000 description 4
- 108091005461 Nucleic proteins Proteins 0.000 description 4
- 108020004511 Recombinant DNA Proteins 0.000 description 4
- 108020004459 Small interfering RNA Proteins 0.000 description 4
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 4
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 4
- 201000010881 cervical cancer Diseases 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 230000021615 conjugation Effects 0.000 description 4
- 125000004122 cyclic group Chemical group 0.000 description 4
- 230000003247 decreasing effect Effects 0.000 description 4
- 230000029087 digestion Effects 0.000 description 4
- 230000008029 eradication Effects 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 125000001153 fluoro group Chemical group F* 0.000 description 4
- 102000037865 fusion proteins Human genes 0.000 description 4
- 108020001507 fusion proteins Proteins 0.000 description 4
- 201000010536 head and neck cancer Diseases 0.000 description 4
- 208000014829 head and neck neoplasm Diseases 0.000 description 4
- 150000003951 lactams Chemical class 0.000 description 4
- 201000007270 liver cancer Diseases 0.000 description 4
- 208000014018 liver neoplasm Diseases 0.000 description 4
- 208000003747 lymphoid leukemia Diseases 0.000 description 4
- 230000003211 malignant effect Effects 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 229910052751 metal Inorganic materials 0.000 description 4
- 239000002184 metal Substances 0.000 description 4
- 229930182817 methionine Natural products 0.000 description 4
- 239000011859 microparticle Substances 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 210000000056 organ Anatomy 0.000 description 4
- 230000001105 regulatory effect Effects 0.000 description 4
- 239000003053 toxin Substances 0.000 description 4
- 231100000765 toxin Toxicity 0.000 description 4
- 108700012359 toxins Proteins 0.000 description 4
- 238000003151 transfection method Methods 0.000 description 4
- 201000005112 urinary bladder cancer Diseases 0.000 description 4
- 230000035899 viability Effects 0.000 description 4
- 230000003442 weekly effect Effects 0.000 description 4
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 description 3
- 241000251468 Actinopterygii Species 0.000 description 3
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 3
- 108010032595 Antibody Binding Sites Proteins 0.000 description 3
- 206010003445 Ascites Diseases 0.000 description 3
- 241000283690 Bos taurus Species 0.000 description 3
- 208000003174 Brain Neoplasms Diseases 0.000 description 3
- 238000002965 ELISA Methods 0.000 description 3
- 102000018651 Epithelial Cell Adhesion Molecule Human genes 0.000 description 3
- 108010066687 Epithelial Cell Adhesion Molecule Proteins 0.000 description 3
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 3
- 101001057504 Homo sapiens Interferon-stimulated gene 20 kDa protein Proteins 0.000 description 3
- 101001055144 Homo sapiens Interleukin-2 receptor subunit alpha Proteins 0.000 description 3
- 101001018097 Homo sapiens L-selectin Proteins 0.000 description 3
- 102100026878 Interleukin-2 receptor subunit alpha Human genes 0.000 description 3
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 3
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 3
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 3
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 3
- 102100033467 L-selectin Human genes 0.000 description 3
- 208000028018 Lymphocytic leukaemia Diseases 0.000 description 3
- 206010027476 Metastases Diseases 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 3
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 3
- 102100024216 Programmed cell death 1 ligand 1 Human genes 0.000 description 3
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 3
- 101000762949 Pseudomonas aeruginosa (strain ATCC 15692 / DSM 22644 / CIP 104116 / JCM 14847 / LMG 12228 / 1C / PRS 101 / PAO1) Exotoxin A Proteins 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- 241000283984 Rodentia Species 0.000 description 3
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 3
- 208000024313 Testicular Neoplasms Diseases 0.000 description 3
- 206010057644 Testis cancer Diseases 0.000 description 3
- 208000024770 Thyroid neoplasm Diseases 0.000 description 3
- 208000003721 Triple Negative Breast Neoplasms Diseases 0.000 description 3
- 208000027418 Wounds and injury Diseases 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 230000001154 acute effect Effects 0.000 description 3
- 125000002015 acyclic group Chemical group 0.000 description 3
- 125000003342 alkenyl group Chemical group 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- 125000000304 alkynyl group Chemical group 0.000 description 3
- 229940000635 beta-alanine Drugs 0.000 description 3
- 239000012472 biological sample Substances 0.000 description 3
- 235000020958 biotin Nutrition 0.000 description 3
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 3
- 210000004899 c-terminal region Anatomy 0.000 description 3
- 150000001721 carbon Chemical group 0.000 description 3
- 230000020411 cell activation Effects 0.000 description 3
- 230000004663 cell proliferation Effects 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 230000001268 conjugating effect Effects 0.000 description 3
- 238000006352 cycloaddition reaction Methods 0.000 description 3
- 230000006378 damage Effects 0.000 description 3
- 230000003292 diminished effect Effects 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 3
- 210000003238 esophagus Anatomy 0.000 description 3
- 125000000524 functional group Chemical group 0.000 description 3
- 125000005843 halogen group Chemical group 0.000 description 3
- QNVRIHYSUZMSGM-UHFFFAOYSA-N hexan-2-ol Chemical compound CCCCC(C)O QNVRIHYSUZMSGM-UHFFFAOYSA-N 0.000 description 3
- 238000003018 immunoassay Methods 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 208000014674 injury Diseases 0.000 description 3
- 102000006495 integrins Human genes 0.000 description 3
- 108010044426 integrins Proteins 0.000 description 3
- 238000002955 isolation Methods 0.000 description 3
- 238000011005 laboratory method Methods 0.000 description 3
- 230000000670 limiting effect Effects 0.000 description 3
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 208000023356 medullary thyroid gland carcinoma Diseases 0.000 description 3
- 238000011275 oncology therapy Methods 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 201000002528 pancreatic cancer Diseases 0.000 description 3
- 208000008443 pancreatic carcinoma Diseases 0.000 description 3
- 230000036961 partial effect Effects 0.000 description 3
- 230000007170 pathology Effects 0.000 description 3
- 238000002823 phage display Methods 0.000 description 3
- 229960005190 phenylalanine Drugs 0.000 description 3
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 3
- 230000002265 prevention Effects 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 230000006798 recombination Effects 0.000 description 3
- 238000005215 recombination Methods 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 238000002864 sequence alignment Methods 0.000 description 3
- 230000037432 silent mutation Effects 0.000 description 3
- 206010041823 squamous cell carcinoma Diseases 0.000 description 3
- 230000010473 stable expression Effects 0.000 description 3
- 210000002437 synoviocyte Anatomy 0.000 description 3
- 201000003120 testicular cancer Diseases 0.000 description 3
- 229940124597 therapeutic agent Drugs 0.000 description 3
- 201000002510 thyroid cancer Diseases 0.000 description 3
- 208000022679 triple-negative breast carcinoma Diseases 0.000 description 3
- JARGNLJYKBUKSJ-KGZKBUQUSA-N (2r)-2-amino-5-[[(2r)-1-(carboxymethylamino)-3-hydroxy-1-oxopropan-2-yl]amino]-5-oxopentanoic acid;hydrobromide Chemical compound Br.OC(=O)[C@H](N)CCC(=O)N[C@H](CO)C(=O)NCC(O)=O JARGNLJYKBUKSJ-KGZKBUQUSA-N 0.000 description 2
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 2
- SKWCZPYWFRTSDD-UHFFFAOYSA-N 2,3-bis(azaniumyl)propanoate;chloride Chemical group Cl.NCC(N)C(O)=O SKWCZPYWFRTSDD-UHFFFAOYSA-N 0.000 description 2
- PFNHSEQQEPMLNI-UHFFFAOYSA-N 2-methyl-1-pentanol Chemical compound CCCC(C)CO PFNHSEQQEPMLNI-UHFFFAOYSA-N 0.000 description 2
- WFRBDWRZVBPBDO-UHFFFAOYSA-N 2-methyl-2-pentanol Chemical compound CCCC(C)(C)O WFRBDWRZVBPBDO-UHFFFAOYSA-N 0.000 description 2
- FRDAATYAJDYRNW-UHFFFAOYSA-N 3-methyl-3-pentanol Chemical compound CCC(C)(O)CC FRDAATYAJDYRNW-UHFFFAOYSA-N 0.000 description 2
- XDOLZJYETYVRKV-UHFFFAOYSA-N 7-Aminoheptanoic acid Chemical compound NCCCCCCC(O)=O XDOLZJYETYVRKV-UHFFFAOYSA-N 0.000 description 2
- 208000006468 Adrenal Cortex Neoplasms Diseases 0.000 description 2
- 208000003950 B-cell lymphoma Diseases 0.000 description 2
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 2
- 206010004146 Basal cell carcinoma Diseases 0.000 description 2
- 206010005949 Bone cancer Diseases 0.000 description 2
- 208000018084 Bone neoplasm Diseases 0.000 description 2
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 description 2
- 102100027207 CD27 antigen Human genes 0.000 description 2
- 108010021064 CTLA-4 Antigen Proteins 0.000 description 2
- 229940045513 CTLA4 antagonist Drugs 0.000 description 2
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 2
- 102000000989 Complement System Proteins Human genes 0.000 description 2
- 108010069112 Complement System Proteins Proteins 0.000 description 2
- 102100039498 Cytotoxic T-lymphocyte protein 4 Human genes 0.000 description 2
- IGXWBGJHJZYPQS-SSDOTTSWSA-N D-Luciferin Chemical compound OC(=O)[C@H]1CSC(C=2SC3=CC=C(O)C=C3N=2)=N1 IGXWBGJHJZYPQS-SSDOTTSWSA-N 0.000 description 2
- 238000000116 DAPI staining Methods 0.000 description 2
- CYCGRDQQIOGCKX-UHFFFAOYSA-N Dehydro-luciferin Natural products OC(=O)C1=CSC(C=2SC3=CC(O)=CC=C3N=2)=N1 CYCGRDQQIOGCKX-UHFFFAOYSA-N 0.000 description 2
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 208000006402 Ductal Carcinoma Diseases 0.000 description 2
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 2
- BJGNCJDXODQBOB-UHFFFAOYSA-N Fivefly Luciferin Natural products OC(=O)C1CSC(C=2SC3=CC(O)=CC=C3N=2)=N1 BJGNCJDXODQBOB-UHFFFAOYSA-N 0.000 description 2
- 102100041003 Glutamate carboxypeptidase 2 Human genes 0.000 description 2
- 102000003886 Glycoproteins Human genes 0.000 description 2
- 108090000288 Glycoproteins Proteins 0.000 description 2
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 2
- 101000914511 Homo sapiens CD27 antigen Proteins 0.000 description 2
- 101000892862 Homo sapiens Glutamate carboxypeptidase 2 Proteins 0.000 description 2
- 108010031794 IGF Type 1 Receptor Proteins 0.000 description 2
- 102000038455 IGF Type 1 Receptor Human genes 0.000 description 2
- 206010053574 Immunoblastic lymphoma Diseases 0.000 description 2
- 108010054477 Immunoglobulin Fab Fragments Proteins 0.000 description 2
- 102000001706 Immunoglobulin Fab Fragments Human genes 0.000 description 2
- 108700005091 Immunoglobulin Genes Proteins 0.000 description 2
- 108010067060 Immunoglobulin Variable Region Proteins 0.000 description 2
- 108010074328 Interferon-gamma Proteins 0.000 description 2
- 102000003777 Interleukin-1 beta Human genes 0.000 description 2
- 108090000193 Interleukin-1 beta Proteins 0.000 description 2
- 102000003816 Interleukin-13 Human genes 0.000 description 2
- 108090000176 Interleukin-13 Proteins 0.000 description 2
- 102000000588 Interleukin-2 Human genes 0.000 description 2
- 108010002350 Interleukin-2 Proteins 0.000 description 2
- 102100037792 Interleukin-6 receptor subunit alpha Human genes 0.000 description 2
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N Iron oxide Chemical compound [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 2
- LRQKBLKVPFOOQJ-YFKPBYRVSA-N L-norleucine Chemical compound CCCC[C@H]([NH3+])C([O-])=O LRQKBLKVPFOOQJ-YFKPBYRVSA-N 0.000 description 2
- 125000000773 L-serino group Chemical group [H]OC(=O)[C@@]([H])(N([H])*)C([H])([H])O[H] 0.000 description 2
- DDWFXDSYGUXRAY-UHFFFAOYSA-N Luciferin Natural products CCc1c(C)c(CC2NC(=O)C(=C2C=C)C)[nH]c1Cc3[nH]c4C(=C5/NC(CC(=O)O)C(C)C5CC(=O)O)CC(=O)c4c3C DDWFXDSYGUXRAY-UHFFFAOYSA-N 0.000 description 2
- 206010050017 Lung cancer metastatic Diseases 0.000 description 2
- 208000002030 Merkel cell carcinoma Diseases 0.000 description 2
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 2
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 2
- 206010029266 Neuroendocrine carcinoma of the skin Diseases 0.000 description 2
- 101710163270 Nuclease Proteins 0.000 description 2
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 2
- 102000057297 Pepsin A Human genes 0.000 description 2
- 108090000284 Pepsin A Proteins 0.000 description 2
- 102000035195 Peptidases Human genes 0.000 description 2
- 108091005804 Peptidases Proteins 0.000 description 2
- 108091093037 Peptide nucleic acid Proteins 0.000 description 2
- 108010076504 Protein Sorting Signals Proteins 0.000 description 2
- 108091028664 Ribonucleotide Proteins 0.000 description 2
- 208000003837 Second Primary Neoplasms Diseases 0.000 description 2
- 108010003723 Single-Domain Antibodies Proteins 0.000 description 2
- 108020004682 Single-Stranded DNA Proteins 0.000 description 2
- 208000005718 Stomach Neoplasms Diseases 0.000 description 2
- 102000009524 Vascular Endothelial Growth Factor A Human genes 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
- 208000036676 acute undifferentiated leukemia Diseases 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 150000001266 acyl halides Chemical class 0.000 description 2
- 201000002454 adrenal cortex cancer Diseases 0.000 description 2
- 150000001336 alkenes Chemical class 0.000 description 2
- 229950009106 altumomab Drugs 0.000 description 2
- 230000001093 anti-cancer Effects 0.000 description 2
- 230000000118 anti-neoplastic effect Effects 0.000 description 2
- 230000000692 anti-sense effect Effects 0.000 description 2
- 229940049595 antibody-drug conjugate Drugs 0.000 description 2
- 125000003710 aryl alkyl group Chemical group 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 229960004669 basiliximab Drugs 0.000 description 2
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 2
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229960002685 biotin Drugs 0.000 description 2
- 239000011616 biotin Substances 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 208000003362 bronchogenic carcinoma Diseases 0.000 description 2
- 208000035269 cancer or benign tumor Diseases 0.000 description 2
- 229950001178 capromab Drugs 0.000 description 2
- 230000032823 cell division Effects 0.000 description 2
- 230000010261 cell growth Effects 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 208000029742 colonic neoplasm Diseases 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 239000002872 contrast media Substances 0.000 description 2
- 208000035250 cutaneous malignant susceptibility to 1 melanoma Diseases 0.000 description 2
- 208000017763 cutaneous neuroendocrine carcinoma Diseases 0.000 description 2
- 238000004163 cytometry Methods 0.000 description 2
- 239000002254 cytotoxic agent Substances 0.000 description 2
- 231100000599 cytotoxic agent Toxicity 0.000 description 2
- 230000001472 cytotoxic effect Effects 0.000 description 2
- 230000007850 degeneration Effects 0.000 description 2
- 108700041286 delta Proteins 0.000 description 2
- 239000005547 deoxyribonucleotide Substances 0.000 description 2
- 125000002637 deoxyribonucleotide group Chemical group 0.000 description 2
- 230000004069 differentiation Effects 0.000 description 2
- 238000009792 diffusion process Methods 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 230000003467 diminishing effect Effects 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- AFOSIXZFDONLBT-UHFFFAOYSA-N divinyl sulfone Chemical class C=CS(=O)(=O)C=C AFOSIXZFDONLBT-UHFFFAOYSA-N 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 238000012377 drug delivery Methods 0.000 description 2
- 238000004520 electroporation Methods 0.000 description 2
- 210000002919 epithelial cell Anatomy 0.000 description 2
- 201000004101 esophageal cancer Diseases 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 210000003527 eukaryotic cell Anatomy 0.000 description 2
- 230000004927 fusion Effects 0.000 description 2
- UIWYJDYFSGRHKR-UHFFFAOYSA-N gadolinium atom Chemical compound [Gd] UIWYJDYFSGRHKR-UHFFFAOYSA-N 0.000 description 2
- 108010044804 gamma-glutamyl-seryl-glycine Proteins 0.000 description 2
- 206010017758 gastric cancer Diseases 0.000 description 2
- 230000002068 genetic effect Effects 0.000 description 2
- 239000003102 growth factor Substances 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 2
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 2
- ZOCHHNOQQHDWHG-UHFFFAOYSA-N hexan-3-ol Chemical compound CCCC(O)CC ZOCHHNOQQHDWHG-UHFFFAOYSA-N 0.000 description 2
- 210000005260 human cell Anatomy 0.000 description 2
- 210000004408 hybridoma Anatomy 0.000 description 2
- 150000002430 hydrocarbons Chemical group 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Substances C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 2
- 230000000984 immunochemical effect Effects 0.000 description 2
- 229940072221 immunoglobulins Drugs 0.000 description 2
- 239000002596 immunotoxin Substances 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 229960005386 ipilimumab Drugs 0.000 description 2
- 125000005956 isoquinolyl group Chemical group 0.000 description 2
- 238000002372 labelling Methods 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 230000001926 lymphatic effect Effects 0.000 description 2
- 208000025036 lymphosarcoma Diseases 0.000 description 2
- 208000025854 malignant tumor of adrenal cortex Diseases 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 230000009401 metastasis Effects 0.000 description 2
- 206010061289 metastatic neoplasm Diseases 0.000 description 2
- YACKEPLHDIMKIO-UHFFFAOYSA-N methylphosphonic acid Chemical class CP(O)(O)=O YACKEPLHDIMKIO-UHFFFAOYSA-N 0.000 description 2
- 238000010369 molecular cloning Methods 0.000 description 2
- 201000006894 monocytic leukemia Diseases 0.000 description 2
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 2
- 201000010879 mucinous adenocarcinoma Diseases 0.000 description 2
- 201000000050 myeloid neoplasm Diseases 0.000 description 2
- 239000002105 nanoparticle Substances 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 230000000683 nonmetastatic effect Effects 0.000 description 2
- VYNDHICBIRRPFP-UHFFFAOYSA-N pacific blue Chemical compound FC1=C(O)C(F)=C2OC(=O)C(C(=O)O)=CC2=C1 VYNDHICBIRRPFP-UHFFFAOYSA-N 0.000 description 2
- 229960001972 panitumumab Drugs 0.000 description 2
- 229940111202 pepsin Drugs 0.000 description 2
- 239000012466 permeate Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 210000002381 plasma Anatomy 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 210000001236 prokaryotic cell Anatomy 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 235000019833 protease Nutrition 0.000 description 2
- 108020001580 protein domains Proteins 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 description 2
- 125000000168 pyrrolyl group Chemical group 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- 230000001177 retroviral effect Effects 0.000 description 2
- 239000002336 ribonucleotide Substances 0.000 description 2
- 125000002652 ribonucleotide group Chemical group 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 125000003607 serino group Chemical group [H]N([H])[C@]([H])(C(=O)[*])C(O[H])([H])[H] 0.000 description 2
- 229950010077 sifalimumab Drugs 0.000 description 2
- 229940115586 simulect Drugs 0.000 description 2
- 238000001542 size-exclusion chromatography Methods 0.000 description 2
- 210000003491 skin Anatomy 0.000 description 2
- 201000000849 skin cancer Diseases 0.000 description 2
- 229940126586 small molecule drug Drugs 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000010186 staining Methods 0.000 description 2
- 238000010561 standard procedure Methods 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 201000011549 stomach cancer Diseases 0.000 description 2
- 125000004434 sulfur atom Chemical group 0.000 description 2
- 230000001360 synchronised effect Effects 0.000 description 2
- 101150047061 tag-72 gene Proteins 0.000 description 2
- 229950008160 tanezumab Drugs 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- CBPNZQVSJQDFBE-HGVVHKDOSA-N temsirolimus Chemical compound C1C[C@@H](OC(=O)C(C)(CO)CO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CCC2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 CBPNZQVSJQDFBE-HGVVHKDOSA-N 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- 125000003396 thiol group Chemical group [H]S* 0.000 description 2
- 125000000341 threoninyl group Chemical group [H]OC([H])(C([H])([H])[H])C([H])(N([H])[H])C(*)=O 0.000 description 2
- 210000001685 thyroid gland Anatomy 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- 125000004417 unsaturated alkyl group Chemical group 0.000 description 2
- 230000002792 vascular Effects 0.000 description 2
- 239000013603 viral vector Substances 0.000 description 2
- 230000003612 virological effect Effects 0.000 description 2
- JFVLNTLXEZDFHW-QMMMGPOBSA-N (2s)-2-amino-3-(2-bromophenyl)propanoic acid Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1Br JFVLNTLXEZDFHW-QMMMGPOBSA-N 0.000 description 1
- GDMOHOYNMWWBAU-QMMMGPOBSA-N (2s)-2-amino-3-(3-bromophenyl)propanoic acid Chemical compound OC(=O)[C@@H](N)CC1=CC=CC(Br)=C1 GDMOHOYNMWWBAU-QMMMGPOBSA-N 0.000 description 1
- PEMUHKUIQHFMTH-QMMMGPOBSA-N (2s)-2-amino-3-(4-bromophenyl)propanoic acid Chemical compound OC(=O)[C@@H](N)CC1=CC=C(Br)C=C1 PEMUHKUIQHFMTH-QMMMGPOBSA-N 0.000 description 1
- CIFCKCQAKQRJFC-REOHCLBHSA-N (2s)-2-amino-3-azidopropanoic acid Chemical group OC(=O)[C@@H](N)CN=[N+]=[N-] CIFCKCQAKQRJFC-REOHCLBHSA-N 0.000 description 1
- LOGFVTREOLYCPF-KXNHARMFSA-N (2s,3r)-2-[[(2r)-1-[(2s)-2,6-diaminohexanoyl]pyrrolidine-2-carbonyl]amino]-3-hydroxybutanoic acid Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H]1CCCN1C(=O)[C@@H](N)CCCCN LOGFVTREOLYCPF-KXNHARMFSA-N 0.000 description 1
- QGKMIGUHVLGJBR-UHFFFAOYSA-M (4z)-1-(3-methylbutyl)-4-[[1-(3-methylbutyl)quinolin-1-ium-4-yl]methylidene]quinoline;iodide Chemical compound [I-].C12=CC=CC=C2N(CCC(C)C)C=CC1=CC1=CC=[N+](CCC(C)C)C2=CC=CC=C12 QGKMIGUHVLGJBR-UHFFFAOYSA-M 0.000 description 1
- 125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 description 1
- 102000040650 (ribonucleotides)n+m Human genes 0.000 description 1
- UKAUYVFTDYCKQA-UHFFFAOYSA-N -2-Amino-4-hydroxybutanoic acid Natural products OC(=O)C(N)CCO UKAUYVFTDYCKQA-UHFFFAOYSA-N 0.000 description 1
- 125000000196 1,4-pentadienyl group Chemical group [H]C([*])=C([H])C([H])([H])C([H])=C([H])[H] 0.000 description 1
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
- 125000000530 1-propynyl group Chemical group [H]C([H])([H])C#C* 0.000 description 1
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000001462 1-pyrrolyl group Chemical group [*]N1C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- XRMVWAKMXZNZIL-UHFFFAOYSA-N 2,2-dimethyl-1-butanol Chemical compound CCC(C)(C)CO XRMVWAKMXZNZIL-UHFFFAOYSA-N 0.000 description 1
- SXSWMAUXEHKFGX-UHFFFAOYSA-N 2,3-dimethylbutan-1-ol Chemical compound CC(C)C(C)CO SXSWMAUXEHKFGX-UHFFFAOYSA-N 0.000 description 1
- IKECULIHBUCAKR-UHFFFAOYSA-N 2,3-dimethylbutan-2-ol Chemical compound CC(C)C(C)(C)O IKECULIHBUCAKR-UHFFFAOYSA-N 0.000 description 1
- QNVRIHYSUZMSGM-LURJTMIESA-N 2-Hexanol Natural products CCCC[C@H](C)O QNVRIHYSUZMSGM-LURJTMIESA-N 0.000 description 1
- RTQWWZBSTRGEAV-PKHIMPSTSA-N 2-[[(2s)-2-[bis(carboxymethyl)amino]-3-[4-(methylcarbamoylamino)phenyl]propyl]-[2-[bis(carboxymethyl)amino]propyl]amino]acetic acid Chemical compound CNC(=O)NC1=CC=C(C[C@@H](CN(CC(C)N(CC(O)=O)CC(O)=O)CC(O)=O)N(CC(O)=O)CC(O)=O)C=C1 RTQWWZBSTRGEAV-PKHIMPSTSA-N 0.000 description 1
- TZYRSLHNPKPEFV-UHFFFAOYSA-N 2-ethyl-1-butanol Chemical compound CCC(CC)CO TZYRSLHNPKPEFV-UHFFFAOYSA-N 0.000 description 1
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- ISTJMQSHILQAEC-UHFFFAOYSA-N 2-methyl-3-pentanol Chemical compound CCC(O)C(C)C ISTJMQSHILQAEC-UHFFFAOYSA-N 0.000 description 1
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- UYWWLYCGNNCLKE-UHFFFAOYSA-N 2-pyridin-4-yl-1h-benzimidazole Chemical compound N=1C2=CC=CC=C2NC=1C1=CC=NC=C1 UYWWLYCGNNCLKE-UHFFFAOYSA-N 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- DUXCSEISVMREAX-UHFFFAOYSA-N 3,3-dimethylbutan-1-ol Chemical compound CC(C)(C)CCO DUXCSEISVMREAX-UHFFFAOYSA-N 0.000 description 1
- GOLORTLGFDVFDW-UHFFFAOYSA-N 3-(1h-benzimidazol-2-yl)-7-(diethylamino)chromen-2-one Chemical compound C1=CC=C2NC(C3=CC4=CC=C(C=C4OC3=O)N(CC)CC)=NC2=C1 GOLORTLGFDVFDW-UHFFFAOYSA-N 0.000 description 1
- 125000000474 3-butynyl group Chemical group [H]C#CC([H])([H])C([H])([H])* 0.000 description 1
- BXRLWGXPSRYJDZ-UHFFFAOYSA-N 3-cyanoalanine Chemical compound OC(=O)C(N)CC#N BXRLWGXPSRYJDZ-UHFFFAOYSA-N 0.000 description 1
- ZXNBBWHRUSXUFZ-UHFFFAOYSA-N 3-methyl-2-pentanol Chemical compound CCC(C)C(C)O ZXNBBWHRUSXUFZ-UHFFFAOYSA-N 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 108010068327 4-hydroxyphenylpyruvate dioxygenase Proteins 0.000 description 1
- WVYWICLMDOOCFB-UHFFFAOYSA-N 4-methyl-2-pentanol Chemical compound CC(C)CC(C)O WVYWICLMDOOCFB-UHFFFAOYSA-N 0.000 description 1
- PCWGTDULNUVNBN-UHFFFAOYSA-N 4-methylpentan-1-ol Chemical compound CC(C)CCCO PCWGTDULNUVNBN-UHFFFAOYSA-N 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- KDDQRKBRJSGMQE-UHFFFAOYSA-N 4-thiazolyl Chemical group [C]1=CSC=N1 KDDQRKBRJSGMQE-UHFFFAOYSA-N 0.000 description 1
- CWDWFSXUQODZGW-UHFFFAOYSA-N 5-thiazolyl Chemical group [C]1=CN=CS1 CWDWFSXUQODZGW-UHFFFAOYSA-N 0.000 description 1
- 102100023990 60S ribosomal protein L17 Human genes 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 group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 101710197241 Accessory gland-specific peptide 70A Proteins 0.000 description 1
- 206010000871 Acute monocytic leukaemia Diseases 0.000 description 1
- 239000012099 Alexa Fluor family Substances 0.000 description 1
- 108700028369 Alleles Proteins 0.000 description 1
- 102100035248 Alpha-(1,3)-fucosyltransferase 4 Human genes 0.000 description 1
- 102000013455 Amyloid beta-Peptides Human genes 0.000 description 1
- 108010090849 Amyloid beta-Peptides Proteins 0.000 description 1
- 201000003076 Angiosarcoma Diseases 0.000 description 1
- 101100067974 Arabidopsis thaliana POP2 gene Proteins 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
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 1
- 102100038080 B-cell receptor CD22 Human genes 0.000 description 1
- 101710117995 B-lymphocyte antigen CD19 Proteins 0.000 description 1
- 108050001413 B-lymphocyte antigen CD20 Proteins 0.000 description 1
- 108010074708 B7-H1 Antigen Proteins 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 241000282817 Bovidae Species 0.000 description 1
- 206010055113 Breast cancer metastatic Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 206010006417 Bronchial carcinoma Diseases 0.000 description 1
- 102100036301 C-C chemokine receptor type 7 Human genes 0.000 description 1
- 108700012439 CA9 Proteins 0.000 description 1
- 102100024217 CAMPATH-1 antigen Human genes 0.000 description 1
- 101150018757 CD19 gene Proteins 0.000 description 1
- 102100032912 CD44 antigen Human genes 0.000 description 1
- 108010065524 CD52 Antigen Proteins 0.000 description 1
- 241000282832 Camelidae Species 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 102100024423 Carbonic anhydrase 9 Human genes 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 108010078791 Carrier Proteins Proteins 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 241000282994 Cervidae Species 0.000 description 1
- 206010008583 Chloroma Diseases 0.000 description 1
- 108010009685 Cholinergic Receptors Proteins 0.000 description 1
- 208000005243 Chondrosarcoma Diseases 0.000 description 1
- 208000006332 Choriocarcinoma Diseases 0.000 description 1
- 108091026890 Coding region Proteins 0.000 description 1
- 241000699800 Cricetinae Species 0.000 description 1
- 241000938605 Crocodylia Species 0.000 description 1
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 1
- 108010069514 Cyclic Peptides Proteins 0.000 description 1
- 102000001189 Cyclic Peptides Human genes 0.000 description 1
- 206010011732 Cyst Diseases 0.000 description 1
- QNAYBMKLOCPYGJ-UHFFFAOYSA-N D-alpha-Ala Natural products CC([NH3+])C([O-])=O QNAYBMKLOCPYGJ-UHFFFAOYSA-N 0.000 description 1
- 108010092160 Dactinomycin Proteins 0.000 description 1
- 241000702421 Dependoparvovirus Species 0.000 description 1
- 238000005698 Diels-Alder reaction Methods 0.000 description 1
- SHIBSTMRCDJXLN-UHFFFAOYSA-N Digoxigenin Natural products C1CC(C2C(C3(C)CCC(O)CC3CC2)CC2O)(O)C2(C)C1C1=CC(=O)OC1 SHIBSTMRCDJXLN-UHFFFAOYSA-N 0.000 description 1
- 108010053187 Diphtheria Toxin Proteins 0.000 description 1
- 102000016607 Diphtheria Toxin Human genes 0.000 description 1
- 101150039808 Egfr gene Proteins 0.000 description 1
- 208000001976 Endocrine Gland Neoplasms Diseases 0.000 description 1
- 206010014733 Endometrial cancer Diseases 0.000 description 1
- 206010014759 Endometrial neoplasm Diseases 0.000 description 1
- 206010057649 Endometrial sarcoma Diseases 0.000 description 1
- 206010014958 Eosinophilic leukaemia Diseases 0.000 description 1
- 241000206602 Eukaryota Species 0.000 description 1
- 208000006168 Ewing Sarcoma Diseases 0.000 description 1
- 208000009331 Experimental Sarcoma Diseases 0.000 description 1
- 102000009109 Fc receptors Human genes 0.000 description 1
- 108010087819 Fc receptors Proteins 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 201000008808 Fibrosarcoma Diseases 0.000 description 1
- 229910052688 Gadolinium Inorganic materials 0.000 description 1
- GYHNNYVSQQEPJS-YPZZEJLDSA-N Gallium-68 Chemical compound [68Ga] GYHNNYVSQQEPJS-YPZZEJLDSA-N 0.000 description 1
- 208000008999 Giant Cell Carcinoma Diseases 0.000 description 1
- 108010092372 Granulocyte-Macrophage Colony-Stimulating Factor Receptors Proteins 0.000 description 1
- 102000016355 Granulocyte-Macrophage Colony-Stimulating Factor Receptors Human genes 0.000 description 1
- 102000009465 Growth Factor Receptors Human genes 0.000 description 1
- 108010009202 Growth Factor Receptors Proteins 0.000 description 1
- 208000017891 HER2 positive breast carcinoma Diseases 0.000 description 1
- 239000012981 Hank's balanced salt solution Substances 0.000 description 1
- 208000001258 Hemangiosarcoma Diseases 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- 208000017604 Hodgkin disease Diseases 0.000 description 1
- 208000017662 Hodgkin disease lymphocyte depletion type stage unspecified Diseases 0.000 description 1
- 208000021519 Hodgkin lymphoma Diseases 0.000 description 1
- 101001022185 Homo sapiens Alpha-(1,3)-fucosyltransferase 4 Proteins 0.000 description 1
- 101000884305 Homo sapiens B-cell receptor CD22 Proteins 0.000 description 1
- 101000716065 Homo sapiens C-C chemokine receptor type 7 Proteins 0.000 description 1
- 101000868273 Homo sapiens CD44 antigen Proteins 0.000 description 1
- 101100118549 Homo sapiens EGFR gene Proteins 0.000 description 1
- 101001002657 Homo sapiens Interleukin-2 Proteins 0.000 description 1
- 101000868279 Homo sapiens Leukocyte surface antigen CD47 Proteins 0.000 description 1
- 101001133056 Homo sapiens Mucin-1 Proteins 0.000 description 1
- 101000934338 Homo sapiens Myeloid cell surface antigen CD33 Proteins 0.000 description 1
- 101000611183 Homo sapiens Tumor necrosis factor Proteins 0.000 description 1
- 101000851376 Homo sapiens Tumor necrosis factor receptor superfamily member 8 Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 1
- 208000037147 Hypercalcaemia Diseases 0.000 description 1
- 102000017727 Immunoglobulin Variable Region Human genes 0.000 description 1
- 108010041012 Integrin alpha4 Proteins 0.000 description 1
- 102100037850 Interferon gamma Human genes 0.000 description 1
- 102000008070 Interferon-gamma Human genes 0.000 description 1
- 102000013691 Interleukin-17 Human genes 0.000 description 1
- 102000010789 Interleukin-2 Receptors Human genes 0.000 description 1
- 108010038453 Interleukin-2 Receptors Proteins 0.000 description 1
- 102000000743 Interleukin-5 Human genes 0.000 description 1
- 108010002616 Interleukin-5 Proteins 0.000 description 1
- 102000010786 Interleukin-5 Receptors Human genes 0.000 description 1
- 108010038484 Interleukin-5 Receptors Proteins 0.000 description 1
- 102000004889 Interleukin-6 Human genes 0.000 description 1
- 108090001005 Interleukin-6 Proteins 0.000 description 1
- 108010038501 Interleukin-6 Receptors Proteins 0.000 description 1
- 208000009164 Islet Cell Adenoma Diseases 0.000 description 1
- 206010023256 Juvenile melanoma benign Diseases 0.000 description 1
- 208000007766 Kaposi sarcoma Diseases 0.000 description 1
- UKAUYVFTDYCKQA-VKHMYHEASA-N L-homoserine Chemical compound OC(=O)[C@@H](N)CCO UKAUYVFTDYCKQA-VKHMYHEASA-N 0.000 description 1
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 1
- QEFRNWWLZKMPFJ-ZXPFJRLXSA-N L-methionine (R)-S-oxide Chemical compound C[S@@](=O)CC[C@H]([NH3+])C([O-])=O QEFRNWWLZKMPFJ-ZXPFJRLXSA-N 0.000 description 1
- QEFRNWWLZKMPFJ-UHFFFAOYSA-N L-methionine sulphoxide Natural products CS(=O)CCC(N)C(O)=O QEFRNWWLZKMPFJ-UHFFFAOYSA-N 0.000 description 1
- DGYHPLMPMRKMPD-UHFFFAOYSA-N L-propargyl glycine Natural products OC(=O)C(N)CC#C DGYHPLMPMRKMPD-UHFFFAOYSA-N 0.000 description 1
- 206010023774 Large cell lung cancer Diseases 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- 206010024305 Leukaemia monocytic Diseases 0.000 description 1
- 102100032913 Leukocyte surface antigen CD47 Human genes 0.000 description 1
- 108060001084 Luciferase Proteins 0.000 description 1
- 239000005089 Luciferase Substances 0.000 description 1
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 1
- PEEHTFAAVSWFBL-UHFFFAOYSA-N Maleimide Chemical compound O=C1NC(=O)C=C1 PEEHTFAAVSWFBL-UHFFFAOYSA-N 0.000 description 1
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 description 1
- 208000007054 Medullary Carcinoma Diseases 0.000 description 1
- 238000006845 Michael addition reaction Methods 0.000 description 1
- 238000006957 Michael reaction Methods 0.000 description 1
- 229930192392 Mitomycin Natural products 0.000 description 1
- 208000035489 Monocytic Acute Leukemia Diseases 0.000 description 1
- 102100034256 Mucin-1 Human genes 0.000 description 1
- 102100023123 Mucin-16 Human genes 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- 102100025243 Myeloid cell surface antigen CD33 Human genes 0.000 description 1
- 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 1
- QPCDCPDFJACHGM-UHFFFAOYSA-N N,N-bis{2-[bis(carboxymethyl)amino]ethyl}glycine Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(=O)O)CCN(CC(O)=O)CC(O)=O QPCDCPDFJACHGM-UHFFFAOYSA-N 0.000 description 1
- 208000002454 Nasopharyngeal Carcinoma Diseases 0.000 description 1
- 206010061306 Nasopharyngeal cancer Diseases 0.000 description 1
- 108010025020 Nerve Growth Factor Proteins 0.000 description 1
- 102000015336 Nerve Growth Factor Human genes 0.000 description 1
- 206010029488 Nodular melanoma Diseases 0.000 description 1
- 238000000636 Northern blotting Methods 0.000 description 1
- 229910003849 O-Si Inorganic materials 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 229910003872 O—Si Inorganic materials 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 208000025618 Paget disease of nipple Diseases 0.000 description 1
- 208000024024 Paget disease of the nipple Diseases 0.000 description 1
- 241000282579 Pan Species 0.000 description 1
- 206010033701 Papillary thyroid cancer Diseases 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 241000276498 Pollachius virens Species 0.000 description 1
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 206010036790 Productive cough Diseases 0.000 description 1
- 101710089372 Programmed cell death protein 1 Proteins 0.000 description 1
- 102000052575 Proto-Oncogene Human genes 0.000 description 1
- 108700020978 Proto-Oncogene Proteins 0.000 description 1
- 229910001260 Pt alloy Inorganic materials 0.000 description 1
- 102000014128 RANK Ligand Human genes 0.000 description 1
- 108010025832 RANK Ligand Proteins 0.000 description 1
- 101710100968 Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 1
- 101100123851 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) HER1 gene Proteins 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- 208000000453 Skin Neoplasms Diseases 0.000 description 1
- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- 241000256248 Spodoptera Species 0.000 description 1
- 108010090804 Streptavidin Proteins 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 230000006052 T cell proliferation Effects 0.000 description 1
- 241000249096 Teschovirus Species 0.000 description 1
- DPOPAJRDYZGTIR-UHFFFAOYSA-N Tetrazine Chemical compound C1=CN=NN=N1 DPOPAJRDYZGTIR-UHFFFAOYSA-N 0.000 description 1
- RYYWUUFWQRZTIU-UHFFFAOYSA-N Thiophosphoric acid Chemical class OP(O)(S)=O RYYWUUFWQRZTIU-UHFFFAOYSA-N 0.000 description 1
- 206010052779 Transplant rejections Diseases 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 108060008683 Tumor Necrosis Factor Receptor Proteins 0.000 description 1
- 102100040247 Tumor necrosis factor Human genes 0.000 description 1
- 102100036857 Tumor necrosis factor receptor superfamily member 8 Human genes 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 208000002495 Uterine Neoplasms Diseases 0.000 description 1
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Chemical compound CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 1
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 1
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 1
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 1
- 108020005202 Viral DNA Proteins 0.000 description 1
- 208000033559 Waldenström macroglobulinemia Diseases 0.000 description 1
- 208000008383 Wilms tumor Diseases 0.000 description 1
- 241001193851 Zeta Species 0.000 description 1
- 102000034337 acetylcholine receptors Human genes 0.000 description 1
- 150000007513 acids Chemical class 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
- 239000012190 activator Substances 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 229960002964 adalimumab Drugs 0.000 description 1
- 229950009084 adecatumumab Drugs 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000003172 aldehyde group Chemical group 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 229960000548 alemtuzumab Drugs 0.000 description 1
- 238000005865 alkene metathesis reaction Methods 0.000 description 1
- 125000004450 alkenylene group Chemical group 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- 125000005237 alkyleneamino group Chemical group 0.000 description 1
- 125000005238 alkylenediamino group Chemical group 0.000 description 1
- 125000005530 alkylenedioxy group Chemical group 0.000 description 1
- 125000005529 alkyleneoxy group Chemical group 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 210000002821 alveolar epithelial cell Anatomy 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 238000004873 anchoring Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000002494 anti-cea effect Effects 0.000 description 1
- 239000000611 antibody drug conjugate Substances 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 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
- 238000002820 assay format Methods 0.000 description 1
- 230000003190 augmentative effect Effects 0.000 description 1
- 238000011888 autopsy Methods 0.000 description 1
- 229940120638 avastin Drugs 0.000 description 1
- 210000000270 basal cell Anatomy 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000002047 benzodioxolyl group Chemical group O1OC(C2=C1C=CC=C2)* 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 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
- 210000000013 bile duct Anatomy 0.000 description 1
- 239000003124 biologic agent Substances 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 238000001574 biopsy Methods 0.000 description 1
- 150000001615 biotins Chemical class 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 239000010836 blood and blood product Substances 0.000 description 1
- 210000001772 blood platelet Anatomy 0.000 description 1
- 229940125691 blood product Drugs 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 201000010983 breast ductal carcinoma Diseases 0.000 description 1
- 229960000455 brentuximab vedotin Drugs 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 229940112129 campath Drugs 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 210000004252 chorionic villi Anatomy 0.000 description 1
- 210000003764 chromatophore Anatomy 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 1
- 229940090100 cimzia Drugs 0.000 description 1
- 238000010367 cloning Methods 0.000 description 1
- 238000003501 co-culture Methods 0.000 description 1
- 238000012875 competitive assay Methods 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 238000004590 computer program Methods 0.000 description 1
- 239000000599 controlled substance Substances 0.000 description 1
- RYGMFSIKBFXOCR-IGMARMGPSA-N copper-64 Chemical compound [64Cu] RYGMFSIKBFXOCR-IGMARMGPSA-N 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 210000004748 cultured cell Anatomy 0.000 description 1
- 125000000392 cycloalkenyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 208000031513 cyst Diseases 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 229960000640 dactinomycin Drugs 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
- 229960000975 daunorubicin Drugs 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 229960001251 denosumab Drugs 0.000 description 1
- 210000003298 dental enamel Anatomy 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 125000002720 diazolyl group Chemical group 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- QONQRTHLHBTMGP-UHFFFAOYSA-N digitoxigenin Natural products CC12CCC(C3(CCC(O)CC3CC3)C)C3C11OC1CC2C1=CC(=O)OC1 QONQRTHLHBTMGP-UHFFFAOYSA-N 0.000 description 1
- SHIBSTMRCDJXLN-KCZCNTNESA-N digoxigenin Chemical compound C1([C@@H]2[C@@]3([C@@](CC2)(O)[C@H]2[C@@H]([C@@]4(C)CC[C@H](O)C[C@H]4CC2)C[C@H]3O)C)=CC(=O)OC1 SHIBSTMRCDJXLN-KCZCNTNESA-N 0.000 description 1
- HBGGXOJOCNVPFY-UHFFFAOYSA-N diisononyl phthalate Chemical compound CC(C)CCCCCCOC(=O)C1=CC=CC=C1C(=O)OCCCCCCC(C)C HBGGXOJOCNVPFY-UHFFFAOYSA-N 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 230000006806 disease prevention Effects 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- PMMYEEVYMWASQN-UHFFFAOYSA-N dl-hydroxyproline Natural products OC1C[NH2+]C(C([O-])=O)C1 PMMYEEVYMWASQN-UHFFFAOYSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- 229960001776 edrecolomab Drugs 0.000 description 1
- 230000002500 effect on skin Effects 0.000 description 1
- 210000003162 effector t lymphocyte Anatomy 0.000 description 1
- 238000007336 electrophilic substitution reaction Methods 0.000 description 1
- 230000009881 electrostatic interaction Effects 0.000 description 1
- 150000002081 enamines Chemical class 0.000 description 1
- 210000003372 endocrine gland Anatomy 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 150000002118 epoxides Chemical class 0.000 description 1
- 229940082789 erbitux Drugs 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- ZMMJGEGLRURXTF-UHFFFAOYSA-N ethidium bromide Chemical compound [Br-].C12=CC(N)=CC=C2C2=CC=C(N)C=C2[N+](CC)=C1C1=CC=CC=C1 ZMMJGEGLRURXTF-UHFFFAOYSA-N 0.000 description 1
- 229960005542 ethidium bromide Drugs 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 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 1
- 229960005420 etoposide Drugs 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 210000003499 exocrine gland Anatomy 0.000 description 1
- 210000003608 fece Anatomy 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 230000003328 fibroblastic effect Effects 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 1
- MHMNJMPURVTYEJ-UHFFFAOYSA-N fluorescein-5-isothiocyanate Chemical compound O1C(=O)C2=CC(N=C=S)=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 MHMNJMPURVTYEJ-UHFFFAOYSA-N 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- YCKRFDGAMUMZLT-BJUDXGSMSA-N fluorine-18 atom Chemical compound [18F] YCKRFDGAMUMZLT-BJUDXGSMSA-N 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- 230000003325 follicular Effects 0.000 description 1
- 238000005194 fractionation Methods 0.000 description 1
- UHBYWPGGCSDKFX-VKHMYHEASA-N gamma-carboxy-L-glutamic acid Chemical compound OC(=O)[C@@H](N)CC(C(O)=O)C(O)=O UHBYWPGGCSDKFX-VKHMYHEASA-N 0.000 description 1
- 229950004896 ganitumab Drugs 0.000 description 1
- 229960000578 gemtuzumab Drugs 0.000 description 1
- 238000001415 gene therapy Methods 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 230000013595 glycosylation Effects 0.000 description 1
- 238000006206 glycosylation reaction Methods 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 210000004565 granule cell Anatomy 0.000 description 1
- 210000003714 granulocyte Anatomy 0.000 description 1
- 208000017750 granulocytic sarcoma Diseases 0.000 description 1
- 230000003394 haemopoietic effect Effects 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 1
- 230000002008 hemorrhagic effect Effects 0.000 description 1
- 210000004024 hepatic stellate cell Anatomy 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 125000004366 heterocycloalkenyl group Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 102000055277 human IL2 Human genes 0.000 description 1
- 238000011577 humanized mouse model Methods 0.000 description 1
- 150000007857 hydrazones Chemical class 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 125000001165 hydrophobic group Chemical group 0.000 description 1
- 229960002591 hydroxyproline Drugs 0.000 description 1
- 230000000148 hypercalcaemia Effects 0.000 description 1
- 208000030915 hypercalcemia disease Diseases 0.000 description 1
- 229960001001 ibritumomab tiuxetan Drugs 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 229960001438 immunostimulant agent Drugs 0.000 description 1
- 239000003022 immunostimulating agent Substances 0.000 description 1
- 230000003308 immunostimulating effect Effects 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 230000002637 immunotoxin Effects 0.000 description 1
- 229940051026 immunotoxin Drugs 0.000 description 1
- 231100000608 immunotoxin Toxicity 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 229960000598 infliximab Drugs 0.000 description 1
- 229960003130 interferon gamma Drugs 0.000 description 1
- 108040006858 interleukin-6 receptor activity proteins Proteins 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- PWBYYTXZCUZPRD-UHFFFAOYSA-N iron platinum Chemical compound [Fe][Pt][Pt] PWBYYTXZCUZPRD-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 229960000310 isoleucine Drugs 0.000 description 1
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 238000005304 joining Methods 0.000 description 1
- 210000005067 joint tissue Anatomy 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 208000003849 large cell carcinoma Diseases 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 238000001638 lipofection Methods 0.000 description 1
- 206010024627 liposarcoma Diseases 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 229940076783 lucentis Drugs 0.000 description 1
- 210000005265 lung cell Anatomy 0.000 description 1
- 201000000014 lung giant cell carcinoma Diseases 0.000 description 1
- 201000009546 lung large cell carcinoma Diseases 0.000 description 1
- 201000005243 lung squamous cell carcinoma Diseases 0.000 description 1
- 208000037841 lung tumor Diseases 0.000 description 1
- 210000002751 lymph Anatomy 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 235000018977 lysine Nutrition 0.000 description 1
- 125000003588 lysine group Chemical class [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 230000002101 lytic effect Effects 0.000 description 1
- 201000000564 macroglobulinemia Diseases 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 230000005415 magnetization Effects 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
- 208000029559 malignant endocrine neoplasm Diseases 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 208000027202 mammary Paget disease Diseases 0.000 description 1
- 229910052748 manganese Inorganic materials 0.000 description 1
- 239000011572 manganese Substances 0.000 description 1
- 208000000516 mast-cell leukemia Diseases 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 229960004857 mitomycin Drugs 0.000 description 1
- 108091005601 modified peptides Proteins 0.000 description 1
- 238000003032 molecular docking Methods 0.000 description 1
- 125000004572 morpholin-3-yl group Chemical group N1C(COCC1)* 0.000 description 1
- 229960003816 muromonab-cd3 Drugs 0.000 description 1
- 201000005987 myeloid sarcoma Diseases 0.000 description 1
- 230000002107 myocardial effect Effects 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- QQZOPKMRPOGIEB-UHFFFAOYSA-N n-butyl methyl ketone Natural products CCCCC(C)=O QQZOPKMRPOGIEB-UHFFFAOYSA-N 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 201000011216 nasopharynx carcinoma Diseases 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 201000008026 nephroblastoma Diseases 0.000 description 1
- 229940053128 nerve growth factor Drugs 0.000 description 1
- 201000011519 neuroendocrine tumor Diseases 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 229950010203 nimotuzumab Drugs 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 201000000032 nodular malignant melanoma Diseases 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 238000001668 nucleic acid synthesis Methods 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 229960002450 ofatumumab Drugs 0.000 description 1
- 229960000470 omalizumab Drugs 0.000 description 1
- 229950007283 oregovomab Drugs 0.000 description 1
- 229940029358 orthoclone okt3 Drugs 0.000 description 1
- 210000003101 oviduct Anatomy 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- 125000004043 oxo group Chemical group O=* 0.000 description 1
- NZYXABPVYJRICY-UHFFFAOYSA-N pacific blue succinimidyl ester Chemical compound O=C1OC2=C(F)C(O)=C(F)C=C2C=C1C(=O)ON1C(=O)CCC1=O NZYXABPVYJRICY-UHFFFAOYSA-N 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 229960000402 palivizumab Drugs 0.000 description 1
- 230000009996 pancreatic endocrine effect Effects 0.000 description 1
- 210000002705 pancreatic stellate cell Anatomy 0.000 description 1
- 201000010198 papillary carcinoma Diseases 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 229940067082 pentetate Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- NMHMNPHRMNGLLB-UHFFFAOYSA-N phloretic acid Chemical compound OC(=O)CCC1=CC=C(O)C=C1 NMHMNPHRMNGLLB-UHFFFAOYSA-N 0.000 description 1
- 150000003003 phosphines Chemical class 0.000 description 1
- 150000008298 phosphoramidates Chemical class 0.000 description 1
- 150000008300 phosphoramidites Chemical class 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 125000002743 phosphorus functional group Chemical group 0.000 description 1
- BZQFBWGGLXLEPQ-REOHCLBHSA-N phosphoserine Chemical compound OC(=O)[C@@H](N)COP(O)(O)=O BZQFBWGGLXLEPQ-REOHCLBHSA-N 0.000 description 1
- DFOXKPDFWGNLJU-UHFFFAOYSA-N pinacolyl alcohol Chemical compound CC(O)C(C)(C)C DFOXKPDFWGNLJU-UHFFFAOYSA-N 0.000 description 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000004483 piperidin-3-yl group Chemical group N1CC(CCC1)* 0.000 description 1
- 208000031223 plasma cell leukemia Diseases 0.000 description 1
- 210000004180 plasmocyte Anatomy 0.000 description 1
- 229920001481 poly(stearyl methacrylate) Polymers 0.000 description 1
- 238000002264 polyacrylamide gel electrophoresis Methods 0.000 description 1
- 235000021395 porridge Nutrition 0.000 description 1
- 238000011533 pre-incubation Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 208000030266 primary brain neoplasm Diseases 0.000 description 1
- 201000003725 primary thrombocytopenia Diseases 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 230000006916 protein interaction Effects 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 239000002096 quantum dot Substances 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 229960003876 ranibizumab Drugs 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 229940116176 remicade Drugs 0.000 description 1
- 229940107685 reopro Drugs 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 206010039083 rhinitis Diseases 0.000 description 1
- PYWVYCXTNDRMGF-UHFFFAOYSA-N rhodamine B Chemical compound [Cl-].C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=CC=C1C(O)=O PYWVYCXTNDRMGF-UHFFFAOYSA-N 0.000 description 1
- XWGJFPHUCFXLBL-UHFFFAOYSA-M rongalite Chemical compound [Na+].OCS([O-])=O XWGJFPHUCFXLBL-UHFFFAOYSA-M 0.000 description 1
- 208000014212 sarcomatoid carcinoma Diseases 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 201000008157 scrotal carcinoma Diseases 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 150000007659 semicarbazones Chemical class 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 229910052814 silicon oxide Inorganic materials 0.000 description 1
- 108091069025 single-strand RNA Proteins 0.000 description 1
- 238000005549 size reduction Methods 0.000 description 1
- 201000008261 skin carcinoma Diseases 0.000 description 1
- 206010040882 skin lesion Diseases 0.000 description 1
- 231100000444 skin lesion Toxicity 0.000 description 1
- 208000000649 small cell carcinoma Diseases 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 229940055944 soliris Drugs 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
- 208000011584 spitz nevus Diseases 0.000 description 1
- 210000003802 sputum Anatomy 0.000 description 1
- 208000024794 sputum Diseases 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 1
- 125000005717 substituted cycloalkylene group Chemical group 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- RWSOTUBLDIXVET-UHFFFAOYSA-O sulfonium Chemical compound [SH3+] RWSOTUBLDIXVET-UHFFFAOYSA-O 0.000 description 1
- 125000002128 sulfonyl halide group Chemical group 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 229940036185 synagis Drugs 0.000 description 1
- 206010042863 synovial sarcoma Diseases 0.000 description 1
- 210000005222 synovial tissue Anatomy 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000009885 systemic effect Effects 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
- 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 1
- 229960001278 teniposide Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000004192 tetrahydrofuran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 150000007970 thio esters Chemical class 0.000 description 1
- 125000005309 thioalkoxy group Chemical group 0.000 description 1
- 206010043554 thrombocytopenia Diseases 0.000 description 1
- 208000030045 thyroid gland papillary carcinoma Diseases 0.000 description 1
- 229960003989 tocilizumab Drugs 0.000 description 1
- 229960005267 tositumomab Drugs 0.000 description 1
- 229950000835 tralokinumab Drugs 0.000 description 1
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 238000011830 transgenic mouse model Methods 0.000 description 1
- 230000010474 transient expression Effects 0.000 description 1
- 238000013519 translation Methods 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
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 201000007423 tubular adenocarcinoma Diseases 0.000 description 1
- 102000003298 tumor necrosis factor receptor Human genes 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 241000701161 unidentified adenovirus Species 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 206010046766 uterine cancer Diseases 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 208000008662 verrucous carcinoma Diseases 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- 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 1
- 229960004528 vincristine Drugs 0.000 description 1
- 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 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 229950004393 visilizumab Drugs 0.000 description 1
- 238000011179 visual inspection Methods 0.000 description 1
- 230000036642 wellbeing Effects 0.000 description 1
- 229940099073 xolair Drugs 0.000 description 1
- 210000005253 yeast cell Anatomy 0.000 description 1
- 229950008250 zalutumumab Drugs 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
-
- 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
- C07K16/32—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against translation products of oncogenes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/46—Cellular immunotherapy
- A61K39/461—Cellular immunotherapy characterised by the cell type used
- A61K39/4611—T-cells, e.g. tumor infiltrating lymphocytes [TIL], lymphokine-activated killer cells [LAK] or regulatory T cells [Treg]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/46—Cellular immunotherapy
- A61K39/463—Cellular immunotherapy characterised by recombinant expression
- A61K39/4631—Chimeric Antigen Receptors [CAR]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/46—Cellular immunotherapy
- A61K39/464—Cellular immunotherapy characterised by the antigen targeted or presented
- A61K39/4643—Vertebrate antigens
- A61K39/4644—Cancer antigens
- A61K39/464402—Receptors, cell surface antigens or cell surface determinants
- A61K39/464403—Receptors for growth factors
- A61K39/464406—Her-2/neu/ErbB2, Her-3/ErbB3 or Her 4/ ErbB4
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
- 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
- C07K14/70521—CD28, CD152
-
- 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
- C07K14/70596—Molecules with a "CD"-designation not provided for elsewhere
-
- 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
- C07K16/2818—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 against CD28 or CD152
-
- 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
- C07K16/2863—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for growth factors, growth regulators
-
- 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
- C07K16/2878—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 NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
-
- 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
- C07K16/2887—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against CD20
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
- C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
- C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
- C12N15/86—Viral vectors
-
- 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
- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/06—Animal cells or tissues; Human cells or tissues
- C12N5/0602—Vertebrate cells
- C12N5/0634—Cells from the blood or the immune system
- C12N5/0636—T lymphocytes
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K39/46
- A61K2239/31—Indexing codes associated with cellular immunotherapy of group A61K39/46 characterized by the route of administration
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K39/46
- A61K2239/46—Indexing codes associated with cellular immunotherapy of group A61K39/46 characterised by the cancer treated
- A61K2239/59—Reproductive system, e.g. uterus, ovaries, cervix or testes
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
- C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/52—Constant or Fc region; Isotype
- C07K2317/526—CH3 domain
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/55—Fab or Fab'
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2318/00—Antibody mimetics or scaffolds
- C07K2318/10—Immunoglobulin or domain(s) thereof as scaffolds for inserted non-Ig peptide sequences, e.g. for vaccination purposes
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/01—Fusion polypeptide containing a localisation/targetting motif
- C07K2319/033—Fusion polypeptide containing a localisation/targetting motif containing a motif for targeting to the internal surface of the plasma membrane, e.g. containing a myristoylation motif
-
- 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
- C12N2510/00—Genetically modified cells
Abstract
Description
本出願は、参照により全体において、全ての目的のために本明細書に組み込まれる、2017年12月29日に出願された、米国仮出願第62/611,924号、2018年6月4日に出願された、米国仮出願第62/680,442号に対する優先権を主張する。
048440−621001WO_Sequence_Listing_ST25というファイルに書き込まれ、2018年12月31日に、29,672バイト、マシンフォーマットをIBM−PCとし、MS Windowsオペレーションシステムにより創出された配列表が、参照により本明細書に組み込まれる。
一態様において、第1の組換えタンパク質が提供される。第1の組換えタンパク質は、(i)第1の非CDR Fab結合性ペプチドドメイン;(ii)第1の細胞内T細胞シグナル伝達ドメイン;及び(iii)第1の非CDR Fab結合性ペプチドドメインを第1の細胞内T細胞シグナル伝達ドメインに接続している第1の膜貫通ドメインを含む。複数の実施形態において、第1の組換えタンパク質は、第1の非CDR Fab結合性ペプチドドメインを第1の膜貫通ドメインに接続している第1のスペーサー領域を含む。複数の実施形態において、第1のスペーサー領域は、第1のCH3領域である。
本明細書において、本発明の多様な実施形態及び態様を示し、これらについて記載してきたが、このような実施形態が、例だけを目的として提示されていることは、当業者に明らかである。今や、本発明から逸脱しない限りにおいて、当業者は、多数の変動、変化及び代用に想到する。本明細書において記載される、本発明の実施形態に対する、多様な代替物が、本発明の実施において利用されうることを理解されたい。
(A)オキソ、ハロゲン、−CF3、−CN、−OH、−NH2、−COOH、−CONH2、−NO2、−SH、−SO2Cl、−SO3H、−SO4H、−SO2NH2、−NHNH2、−ONH2、−NHC=(O)NHNH2、−NHC=(O)NH2、−NHSO2H、−NHC=(O)H、−NHC(O)−OH、−NHOH、−OCF3、−OCHF2、非置換アルキル、非置換ヘテロアルキル、非置換シクロアルキル、非置換ヘテロシクロアルキル、非置換アリール、非置換ヘテロアリール並びに
(B)アルキル、ヘテロアルキル、シクロアルキル、ヘテロシクロアルキル、アリール、ヘテロアリールであって、
(i)オキソ、ハロゲン、−CF3、−CN、−OH、−NH2、−COOH、−CONH2、−NO2、−SH、−SO2Cl、−SO3H、−SO4H、−SO2NH2、−NHNH2、−ONH2、−NHC=(O)NHNH2、−NHC=(O)NH2、−NHSO2H、−NHC=(O)H、−NHC(O)−OH、−NHOH、−OCF3、−OCHF2、非置換アルキル、非置換ヘテロアルキル、非置換シクロアルキル、非置換ヘテロシクロアルキル、非置換アリール、非置換ヘテロアリール並びに
(ii)アルキル、ヘテロアルキル、シクロアルキル、ヘテロシクロアルキル、アリール、ヘテロアリールであって、
(a)オキソ、ハロゲン、−CF3、−CN、−OH、−NH2、−COOH、−CONH2、−NO2、−SH、−SO2Cl、−SO3H、−SO4H、−SO2NH2、−NHNH2、−ONH2、−NHC=(O)NHNH2、−NHC=(O)NH2、−NHSO2H、−NHC=(O)H、−NHC(O)−OH、−NHOH、−OCF3、−OCHF2、非置換アルキル、非置換ヘテロアルキル、非置換シクロアルキル、非置換ヘテロシクロアルキル、非置換アリール、非置換ヘテロアリール及び
(b)アルキル、ヘテロアルキル、シクロアルキル、ヘテロシクロアルキル、アリール、ヘテロアリールであって、オキソ、ハロゲン、−CF3、−CN、−OH、−NH2、−COOH、−CONH2、−NO2、−SH、−SO2Cl、−SO3H、−SO4H、−SO2NH2、−NHNH2、−ONH2、−NHC=(O)NHNH2、−NHC=(O)NH2、−NHSO2H、−NHC=(O)H、−NHC(O)−OH、−NHOH、−OCF3、−OCHF2、非置換アルキル、非置換ヘテロアルキル、非置換シクロアルキル、非置換ヘテロシクロアルキル、非置換アリールから選択された、少なくとも1つの置換基により置換された、アルキル、ヘテロアルキル、シクロアルキル、ヘテロシクロアルキル、アリール、ヘテロアリール
から選択された、少なくとも1つの置換基により置換された、アルキル、ヘテロアルキル、シクロアルキル、ヘテロシクロアルキル、アリール、ヘテロアリール
から選択された、少なくとも1つの置換基により置換された、アルキル、ヘテロアルキル、シクロアルキル、ヘテロシクロアルキル、アリール、ヘテロアリール
から選択された基を意味する。
(a)N−ヒドロキシスクシンイミドエステル、N−ヒドロキシベンズトリアゾールエステル、ハロゲン酸、アシルイミダゾール、チオエステル、p−ニトロフェニルエステル、アルキル、アルケニル、アルキニル及び芳香族エステルを含むがこれらに限定されない、カルボキシル基及びこれらの多様な誘導体;
(b)エステル、エーテル、アルデヒドなどに転換されうるヒドロキシル基;
(c)ハロゲン化物が、その後、例えば、アミン、カルボン酸アニオン、チオールアニオン、カルバニオン又はアルコキシドイオンなどの求核基により置きかえられ、これにより、新たな基の、ハロゲン原子部位における、共有結合による接合をもたらす、ハロアルキル基;
(d)例えば、マレイミド基など、ディールス−アルダー反応に参与することが可能な、ジエノフィル基;
(e)後続の誘導体化が、例えば、イミン、ヒドラゾン、セミカルバゾン若しくはオキシムなどのカルボニル誘導体の形成を介して、又はグリニャール付加若しくはアルキルリチウム付加などの機構を介して可能となるような、アルデヒド基又はケトン基;
(f)例えば、スルホンアミドを形成する、後続のアミンとの反応のための、ハロゲン化スルホニル基;
(g)ジスルフィドに転換される場合もあり、ハロゲン化アシルと反応する場合もあり、金などの金属に結合している場合もある、チオール基;
(h)例えば、アシル化、アルキル化、又は酸化されうる、アミン基又はスルフヒドリル基;
(i)例えば、シクロ付加、アシル化、マイケル付加などを経る、アルケン;
(j)例えば、アミン化合物及びヒドロキシル化合物と反応しうる、エポキシド;
(k)核酸合成において有用な、ホスホルアミダイト及び他の標準的な官能基;
(l)金属酸化ケイ素結合;
(m)例えば、リン酸ジエステル結合を形成する、反応性リン基(例えば、ホスフィン)への金属結合並びに
(n)スルホン、例えば、ビニルスルホンを含む。
本明細書において、とりわけ、T細胞により発現され、抗原結合性ドメイン(例えば、抗体、変異体又はこれらの断片)に結合し、これによりT細胞を抗原結合性ドメインにより結合している抗原を発現させる細胞(例えば、腫瘍細胞)にターゲティングすることが可能な組換えタンパク質が提示される。T細胞により発現された組換えタンパク質の抗原結合性ドメインへの結合及び抗原結合性ドメインの標的細胞により発現された抗原への結合を介して、T細胞は、活性化され、細胞傷害性となり、これにより標的細胞(例えば、がん細胞)を消失させる。本明細書において提供される組換えタンパク質は、とりわけ、養子免疫療法に、機能性を迅速に付加することを可能とし、とりわけ、多種多様な治療目的及び診断目的に有用である。例えば、その実施形態を含む本明細書において提供される組換えタンパク質は、エフェクターT細胞(例えば、自家T細胞)及び治療用抗体をそれらの作用部位に方向付け、これにより、オフターゲット効果を減殺する手段として使用されうる。本明細書において提供される組成物は、個別のCAR T細胞を創出及び最適化せずに、標的特異性を、迅速かつ効率的に変更することを可能とする。
X0−X1−X2−X3−X4−X5−X6−X7−X8−X9−X10−X11−X12(I)
のペプチド部分を含む。式(I)において、X0は、Ser又はヌルである。X1は、Ser、Cys、Gly、β−アラニン、ジアミノプロピオン酸、β−アジドアラニン又はヌルである。X2は、Gln又はヌルである。X3は、Phe、Tyr、β,β’−ジフェニル−Ala、His、Asp、2−ブロモ−L−フェニルアラニン、3−ブロモ−L−フェニルアラニン、4−ブロモ−L−フェニルアラニン、Asn、Gln、修飾Phe、水和性のカルボニル含有残基又はボロン酸含有残基である。X4は、Asp又はAsnである。X5は、Leu、β,β’−ジフェニル−Ala、Phe、Trp、Tyr、フェニルアラニン、トリプトファン又はチロシンの非天然類似体、水和性のカルボニル含有残基又はボロン酸含有残基である。X6は、Cys又はSerである。X7は、Cys、Thr又はSerである。X8は、保護Arg、Arg又はAlaである。X9は、Cys、Arg又はAlaである。X10は、Leu、Gln、Glu、β,β’−ジフェニル−Ala、Phe、Trp、Tyr;フェニルアラニン、トリプトファン又はチロシンの非天然類似体、水和性のカルボニル含有残基又はボロン酸含有残基である。X11は、Cys、Gln、Lys又はArgである。X12は、Ser、Cys、Gly、7−アミノヘプタン酸、β−アラニン、ジアミノプロピオン酸、プロパルギルグリシン、イソアスパラギン酸又はヌルである。X1とX12とは、任意選択的に、互いに接続されて、環状ペプチジル部分を形成する。
X0−X1−X2−X3−X4−X5−X6−X7−X8−X9−X10−X11−X12(I)
のペプチド部分を含む。式(I)において、X0は、Ser又はヌルである。X1は、Ser、Cys、Gly、β−アラニン又はヌルである。X2は、Gln又はヌルである。X3は、Phe、Tyr、His、Asp、Asn又はGlnである。X4は、Asp又はAsnである。X5は、Leu、Phe、Trp、Tyr、トリプトファン又はチロシンである。X6は、Cys又はSerである。X7は、Cys、Thr又はSerである。X8は、Arg又はAlaである。X9は、Cys、Arg又はAlaである。X10は、Leu、Gln、Glu、Phe、Trp、Tyr、トリプトファン又はチロシンである。X11は、Cys、Gln、Lys又はArgである。X12は、Ser、Cys、Gly又はヌルである。X1とX12とは、任意選択的に、互いに接続されて、環状ペプチジル部分を形成する。
本明細書において、その実施形態を含む本明細書において提供される組換えタンパク質をコードする核酸が提示される。したがって、一態様において、その実施形態を含む本明細書において提供される組換えタンパク質をコードする核酸が提示される。別の態様において、その実施形態を含む本明細書において提供される核酸を含む発現ベクターが提示される。複数の実施形態において、発現ベクターは、レンチウイルス又はオンコレトロウイルスである。複数の実施形態において、発現ベクターは、レンチウイルスである。複数の実施形態において、発現ベクターは、オンコレトロウイルスである。
本明細書において提供される組換えタンパク質及び核酸は、細胞の一部を形成しうる(すなわち、細胞に含まれ、かつ/又は発現される)。したがって、ある態様において、その実施形態を含む本明細書において提供される発現ベクターを含むTリンパ球が提供される。
その実施形態を含む本明細書において提供される組成物は、とりわけ、がんなどの疾患に効果的な処置をもたらすのに有用である。したがって、ある態様において、がんを処置する方法が提供される。方法は、それを必要とする対象に、有効量の、その実施形態を含む本明細書において提供されるTリンパ球及び有効量の、非CDR Fab結合性ペプチドドメインに結合することが可能な抗原結合性ドメインを投与するステップを含み、抗原結合性ドメインは、がん抗原結合性ドメインである。
クローニング:親抗Her2 scFv_IgG4op(HL−CH3)_CD28gg_op−Zeta_op−T2A−CD19t_epHIV7ベクターは、C.Brown博士より恵与された。GM−CSFr secretion signal_meditope_PASlinker17遺伝子カセットは、DNA2.0により合成し、NheI及びSbfIの制限部位を使用して、IgG4op(HL−CH3)ドメイン(それぞれ、メディトープ−CH3及びメディトープ−CD28)を伴う、又はこれを伴わないCARベクターに挿入した。クローニングされたプラスミドは、MaxiPrepキット(Qiagen)を使用して精製した。
FSC/SSC→PE−→PE−Cy7+→APC+→VioBlue+
FSC/SSC→PI−→CD19+→647+→Her2+
であった。
方法(OVCAR3)
OVCAR3−gfp−luc細胞500万個を、1日目に、マウスに、腹腔内(ip)注射した。Fabrack T細胞(群6及び7)により処置されたマウスにおいて、マウスに、4mg/kgのmemAbトラスツズマブを、3日ごとに施し(合計5回の投与)、初回のAb投与は、8日目に施した。ヒトT細胞1000万個を、9日目に、マウスにip注射した。群6において、Fabrack T細胞を、memAbと、あらかじめ混合し、洗浄した。150μlのルシフェリン(28.57mg/ml)を、マウスにip注射した後、マウスの腫瘍負荷を、発光により測定した(群1:腫瘍だけ;群2:モックT細胞;群3:Fabrack T細胞だけ;群4:モックT細胞+Ab;群5:HER2 scFv CAR;群6:Fabrack T細胞(あらかじめ混合した)+Ab;群7:Fabrack T細胞+Ab)。
マウスは、Fabrack T細胞及びmemAbを施された場合(群6及び7)、Fabrack T細胞を、memAbとあらかじめ混合したのか、しなかったのかに関わらず、腫瘍サイズの実質的な減少を示す。しかし、腫瘍は、14日目ごろに再発した。腫瘍の再発は、マウス腹水中のHER2+腫瘍細胞を示すフローサイトメトリー結果に基づく、HER2抗原の喪失と符合しなかった。腫瘍の再発は、マウスの血液中及び腹水中に、ごく少数のFabrack T細胞しか残存していないことからの、T細胞の非存続に起因しうる。腫瘍根絶に最適化するための投与スケジュールを策定中である。
MCF7−gfp−luc細胞500万個を、1日目に、マウスに、腹腔内(ip)注射した。Fabrack群において、マウスに、4mg/kgのmemAbトラスツズマブを、約4日ごとに施し、初回のAb投与を、T細胞と併せてip注射した。ヒトT細胞200万個の初回投与を、8日目に、マウスにip注射した。Fabrack T細胞200万個を、約6日ごとに、さらに施した。150μlのルシフェリン(28.57mg/ml)を、マウスにip注射した後、マウスの腫瘍負荷を、発光により測定した。
腫瘍サイズの減少は、Fabrack T細胞及びmemAbを施されたマウスにおいて、11日目及び14日目に見られた。しかし、16日目に、腫瘍の再発が見られた。22日目におけるマウス血液の解析は、Fabrack T細胞が存在し、memAbが、Fabrack T細胞に結合していることを示した。45日目におけるマウス腹水の解析は、腫瘍細胞の抗原逃避を示さなかった。腫瘍の再発は、その投与が、腫瘍上及びT細胞上のAb結合性部位を飽和させうる、Abに由来するフック効果に起因しうる。Fabrack T細胞の用量は、OVCAR3研究における1000万個と比較して、MCF7異種移植研究において、200万個であるので、Abへの結合のためのFabrack T細胞は少数であった。加えて、MCF7及びOVCAR3は、HER2の発現が低度であるので、それらのHER2は、Abにより、容易に飽和される。腫瘍根絶に最適化するための投与スケジュールを策定中である。
実施形態P1.(i)第1の非CDR Fab結合性ペプチドドメイン;(ii)第1の細胞内T細胞シグナル伝達ドメイン;及び(iii)前記第1の非CDR Fab結合性ペプチドドメインを、前記第1の細胞内T細胞シグナル伝達ドメインに接続している第1の膜貫通ドメインを含む、第1の組換えタンパク質。
実施形態1.(i)非CDR Fab結合性ペプチドドメイン;(ii)細胞内T細胞シグナル伝達ドメイン;及び(iii)前記非CDR Fab結合性ペプチドドメインを前記細胞内T細胞シグナル伝達ドメインに接続している膜貫通ドメインを含む組換えタンパク質。
CD3z;GI:623041(配列番号1)
LCYLLDGILFIYGVILTALFL
FWVLVVVGGVLACYSLLVTVAFIIFWV
MALIVLGGVAGLLLFIGLGIFF
IYIWAPLAGTCGVLLLSLVIT
IYIWAPLAGTCGVLLLSLVITLY
IYIWAPLAGTCGVLLLSLVITLYC
IISFFLALTSTALLFLLFF LTLRFSVV
VAAILGLGLVLGLLGPLAILL
FWLPIGCAAFVVVCILGCILI
PLFIPVAVMVTAFSGLAFIIWLA
RSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS
RSKRSRGGHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS(ref)
KRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL
ALYLLRRDQRLPPDAHKPPGGGSFRTPIQEEQADAHSTLAKI
CWLTKKKYSSSVHDPNGEYMFMRAVNTAKKSRLTDVTL
MFWVLVVVGGVLACYSLLVTVAFIIFWV
RSKRSRGGHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS
LEGGGEGRGSLLTCGDVEENPGPTR
GGSTSEGRGSLLTCGDVEENPGP
GSGSGSGS
SAPASSASAPSAASAPAG
SAPASSASAPSAASAPAG
PVKQLLNFDLLKLAGDVESNPGP
QCTNYALLKLAGDVESNPGP
ATNFSLLKQAGDVEENPGP
EGRGSLLTCGDVESNPGP
GGGSSGGGSG
CQFDLSTRRLQC
MLLLVTSLLLCELPHPAFLLIP
Claims (57)
- (i)非CDR Fab結合性ペプチドドメイン;
(ii)細胞内T細胞シグナル伝達ドメイン;及び
(iii)非CDR Fab結合性ペプチドドメインを細胞内T細胞シグナル伝達ドメインに接続している膜貫通ドメイン
を含む組換えタンパク質。 - 細胞内T細胞シグナル伝達ドメインが、CD3ζ細胞内T細胞シグナル伝達ドメインである、請求項1に記載の組換えタンパク質。
- 膜貫通ドメインが、CD8α膜貫通ドメイン、CD28膜貫通ドメイン、CD4膜貫通ドメイン又はCD3ゼータ膜貫通ドメインである、請求項1に記載の組換えタンパク質。
- 膜貫通ドメインが、CD28膜貫通ドメインである、請求項3に記載の組換えタンパク質。
- 非CDR Fab結合性ペプチドドメインを膜貫通ドメインに接続しているスペーサー領域をさらに含む、請求項4に記載の組換えタンパク質。
- スペーサー領域が、重鎖定常3(CH3)ドメインである、請求項5に記載の組換えタンパク質。
- 非CDR Fab結合性ペプチドドメインをスペーサー領域に接続しているペプチドリンカーをさらに含む、請求項6に記載の組換えタンパク質。
- 膜貫通ドメインを細胞内T細胞シグナル伝達ドメインに接続している細胞内共刺激シグナル伝達ドメインをさらに含む、請求項7に記載の組換えタンパク質。
- 細胞内共刺激シグナル伝達ドメインが、CD28細胞内共刺激シグナル伝達ドメイン、4−1BB細胞内共刺激シグナル伝達ドメイン、ICOS細胞内共刺激シグナル伝達ドメイン又はOX−40細胞内共刺激シグナル伝達ドメインである、請求項8に記載の組換えタンパク質。
- 細胞内共刺激シグナル伝達ドメインが、CD28細胞内共刺激シグナル伝達ドメインである、請求項9に記載の組換えタンパク質。
- 細胞内共刺激シグナル伝達ドメインが、4−1BB細胞内共刺激シグナル伝達ドメインである、請求項10に記載の組換えタンパク質。
- 細胞内T細胞シグナル伝達ドメインのC末端に結合している検出用ドメインをさらに含む、請求項11に記載の組換えタンパク質。
- 検出用ドメインが、切断型CD19タンパク質である、請求項12に記載の組換えタンパク質。
- 細胞内T細胞シグナル伝達ドメインを検出用ドメインに接続している自己切断性ペプチジル配列をさらに含む、請求項13に記載の組換えタンパク質。
- 自己切断性ペプチジルリンカー配列が、T2A配列又は2A配列である、請求項14に記載の組換えタンパク質。
- 組換えタンパク質が、細胞の一部を形成する、請求項1に記載の組換えタンパク質。
- 組換えタンパク質が、T細胞の一部を形成する、請求項1に記載の組換えタンパク質。
- 膜貫通ドメインが、T細胞の細胞膜の一部を形成する、請求項17に記載の組換えタンパク質。
- 非CDR Fab結合性ペプチドドメインが、抗原結合性ドメインに結合している、請求項1に記載の組換えタンパク質。
- 抗原結合性ドメインが、Fab、IgG又は二特異性抗体である、請求項19に記載の組換えタンパク質。
- 抗原結合性ドメインが、セツキシマブメディトープ対応ドメイン、トラスツズマブメディトープ対応ドメイン、ペルツズマブメディトープ対応ドメイン、M5Aメディトープ対応ドメイン又はリツキシマブメディトープ対応ドメインである、請求項20に記載の組換えタンパク質。
- 抗原結合性ドメインが、がん抗原に結合することが可能である、請求項19に記載の組換えタンパク質。
- 抗原結合性ドメインが、がん抗原に、非共有結合によって結合することが可能である、請求項19に記載の組換えタンパク質。
- がん抗原が、Her2、EGFR、CD19又はCD20である、請求項22に記載の組換えタンパク質。
- がん抗原が、細胞の一部を形成する、請求項22に記載の組換えタンパク質。
- 細胞が、がん細胞である、請求項25に記載の組換えタンパク質。
- がんが、卵巣がん、腎細胞癌、B細胞悪性腫瘍、白血病、リンパ腫、乳がん、結腸直腸がん、前立腺がん、神経芽細胞腫、黒色腫、髄芽腫、肺がん、骨肉腫、神経膠芽腫又は神経膠腫である、請求項26に記載の組換えタンパク質。
- 請求項1に記載の組換えタンパク質をコードする単離核酸。
- 請求項28に記載の核酸を含む発現ベクター。
- レンチウイルス又はオンコレトロウイルスである、請求項29に記載の発現ベクター。
- 請求項29に記載の発現ベクターを含むTリンパ球。
- 請求項1に記載の組換えタンパク質を含むTリンパ球。
- 請求項1に記載の組換えタンパク質を含み、膜貫通ドメインがTリンパ球の細胞膜内にある、Tリンパ球。
- Tリンパ球が、自家Tリンパ球である、請求項31に記載のTリンパ球。
- Tリンパ球が、異種Tリンパ球である、請求項31に記載のTリンパ球。
- 非CDR Fab結合性ペプチドドメインが、抗原結合性ドメインに結合している、請求項31に記載のTリンパ球。
- 抗原結合性ドメインが、Fab、IgG又は二特異性抗体である、請求項36に記載のTリンパ球。
- 抗原結合性ドメインが、がん抗原に結合している、請求項36に記載のTリンパ球。
- がん抗原が、Her2、EGFR、CD19又はCD20である、請求項38に記載のTリンパ球。
- 抗原結合性ドメインが、がん抗原結合性ドメインである、請求項36に記載のTリンパ球。
- 抗原結合性ドメインが、セツキシマブメディトープ対応ドメイン、トラスツズマブメディトープ対応ドメイン、ペルツズマブメディトープ対応ドメイン、M5Aメディトープ対応ドメイン又はリツキシマブメディトープ対応ドメインである、請求項36に記載のTリンパ球。
- がんを処置する方法であって、がんの処置を必要とする対象に、有効量の、請求項31に記載のTリンパ球及び非CDR Fab結合性ペプチドドメインに結合することが可能な抗原結合性ドメインを投与するステップを含み、抗原結合性ドメインががん抗原結合性ドメインである、方法。
- Tリンパ球及び抗原結合性ドメインが、同時に又は逐次的に投与される、請求項42に記載の方法。
- Tリンパ球が第1の時点で投与され、抗原結合性ドメインが第2の時点で投与され、第1の時点が第2の時点に先行する、請求項42に記載の方法。
- 抗原結合性ドメインが第1の時点で投与され、Tリンパ球が第2の時点で投与され、第1の時点が第2の時点に先行する、請求項42に記載の方法。
- (i)投与する前に、インビトロで非CDR Fab結合性ペプチドドメインを抗原結合性ドメインに結合させ、これによりTリンパ球−組換えタンパク質複合体を形成するステップ;及び
(ii)Tリンパ球−組換えタンパク質複合体を対象に投与し、これにより対象におけるがんを処置するステップ
を含む、請求項42に記載の方法。 - がんが、卵巣がん、腎細胞癌、B細胞悪性腫瘍、白血病、リンパ腫、乳がん、結腸直腸がん、前立腺がん、神経芽細胞腫、黒色腫、髄芽腫、肺がん、骨肉腫、神経膠芽腫又は神経膠腫である、請求項42に記載の方法。
- 抗原結合性ドメインが、セツキシマブメディトープ対応ドメイン、トラスツズマブメディトープ対応ドメイン、ペルツズマブメディトープ対応ドメイン、M5Aメディトープ対応ドメイン又はリツキシマブメディトープ対応ドメインである、請求項42に記載の方法。
- 組換えタンパク質が第1の組換えタンパク質であり、非CDR Fab結合性ペプチドドメインが第1の非CDR Fab結合性ペプチドドメインであり、細胞内T細胞シグナル伝達ドメインが第1の細胞内T細胞シグナル伝達ドメインであり、膜貫通ドメインが第1の膜貫通ドメインであり、スペーサー領域が第1のスペーサー領域であり、細胞内共刺激シグナル伝達ドメインが第1の細胞内共刺激シグナル伝達ドメインである、請求項1に記載の組換えタンパク質。
- 第1の組換えタンパク質が、第2の組換えタンパク質に非共有結合によって結合しており、第2の組換えタンパク質が、
(i)第2の非CDR Fab結合性ペプチドドメイン;
(ii)第2の細胞内T細胞シグナル伝達ドメイン;
(iii)第2の非CDR Fab結合性ペプチドドメインを第2の細胞内T細胞シグナル伝達ドメインに接続している第2の膜貫通ドメイン;及び
(iv)第2の非CDR Fab結合性ペプチドドメインを第2の膜貫通ドメインに接続しており、第1のスペーサー領域が非共有結合によって結合している、第2のスペーサー領域
を含む、請求項49に記載の組換えタンパク質。 - 第1のスペーサー領域及び第2のスペーサー領域が、第1の重鎖定常3(CH3)ドメイン及び第2の重鎖定常3(CH3)ドメインである、請求項50に記載の組換えタンパク質。
- 第1の非CDR Fab結合性ペプチドドメイン及び第2の非CDR Fab結合性ペプチドドメインが、化学的に異なる、請求項49に記載の組換えタンパク質。
- 第1の非CDR Fab結合性ペプチドドメイン及び第2の非CDR Fab結合性ペプチドドメインが、化学的に同じである、請求項49に記載の組換えタンパク質。
- 第1の非CDR Fab結合性ペプチドドメインが、第1の抗原結合性ドメインに非共有結合によって結合している、請求項49に記載の組換えタンパク質。
- 第2の非CDR Fab結合性ペプチドドメインが、第2の抗原結合性ドメインに非共有結合によって結合している、請求項50に記載の組換えタンパク質。
- 第1の抗原結合性ドメイン及び第2の抗原結合性ドメインが、化学的に異なる、又は化学的に同じである、請求項54に記載の組換えタンパク質。
- 第1の抗原結合性ドメイン及び第2の抗原結合性ドメインが、独立に、セツキシマブメディトープ対応ドメイン、トラスツズマブメディトープ対応ドメイン、ペルツズマブメディトープ対応ドメイン、M5Aメディトープ対応ドメイン又はリツキシマブメディトープ対応ドメインである、請求項54に記載の組換えタンパク質。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2023206682A JP2024028890A (ja) | 2017-12-29 | 2023-12-07 | メディトープ対応t細胞 |
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201762611924P | 2017-12-29 | 2017-12-29 | |
US62/611,924 | 2017-12-29 | ||
US201862680442P | 2018-06-04 | 2018-06-04 | |
US62/680,442 | 2018-06-04 | ||
PCT/US2018/068235 WO2019134001A1 (en) | 2017-12-29 | 2018-12-31 | Meditope-enabled t cells |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2023206682A Division JP2024028890A (ja) | 2017-12-29 | 2023-12-07 | メディトープ対応t細胞 |
Publications (1)
Publication Number | Publication Date |
---|---|
JP2021508468A true JP2021508468A (ja) | 2021-03-11 |
Family
ID=67064170
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2020536020A Pending JP2021508468A (ja) | 2017-12-29 | 2018-12-31 | メディトープ対応t細胞 |
JP2023206682A Pending JP2024028890A (ja) | 2017-12-29 | 2023-12-07 | メディトープ対応t細胞 |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2023206682A Pending JP2024028890A (ja) | 2017-12-29 | 2023-12-07 | メディトープ対応t細胞 |
Country Status (7)
Country | Link |
---|---|
US (1) | US20210061879A1 (ja) |
EP (1) | EP3731856A4 (ja) |
JP (2) | JP2021508468A (ja) |
KR (1) | KR20200115511A (ja) |
CN (1) | CN111770937A (ja) |
CA (1) | CA3087331A1 (ja) |
WO (1) | WO2019134001A1 (ja) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA3190797A1 (en) * | 2020-08-10 | 2022-02-17 | Julius-Maximilians-Universitat Wurzburg | Siglec-6-binding polypeptides |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2016187158A1 (en) * | 2015-05-15 | 2016-11-24 | City Of Hope | Chimeric antigen receptor compositions |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU2002220265A1 (en) * | 2000-11-03 | 2002-05-15 | University Of Vermont And State Agricultural College | Compositions for inhibiting grb7 |
EP3482773A1 (en) * | 2010-10-08 | 2019-05-15 | City of Hope | A monoclonal antibody framework binding interface for meditopes, meditope delivery systems and methods for their use |
WO2012075111A1 (en) * | 2010-11-30 | 2012-06-07 | Novartis Ag | Uses of anti-cd40 antibodies in combination therapy for b cell-related cancers |
SG11201401411TA (en) * | 2011-10-10 | 2014-08-28 | Hope City | Meditopes and meditope-binding antibodies and uses thereof |
AU2013221672B2 (en) * | 2012-02-13 | 2017-11-09 | Seattle Children's Hospital D/B/A Seattle Children's Research Institute | Bispecific chimeric antigen receptors and therapeutic uses thereof |
WO2015090229A1 (en) * | 2013-12-20 | 2015-06-25 | Novartis Ag | Regulatable chimeric antigen receptor |
MA40595A (fr) * | 2014-09-09 | 2021-05-26 | Unum Therapeutics | Récepteurs chimériques et utilisations de ceux-ci en thérapie immunitaire |
JP2017536091A (ja) * | 2014-10-02 | 2017-12-07 | シティ・オブ・ホープCity of Hope | 多価メディトープ、メディトープ結合性抗体およびそれらの使用 |
WO2016154621A1 (en) * | 2015-03-26 | 2016-09-29 | The California Institute For Biomedical Research | SWITCHABLE NON-scFv CHIMERIC RECEPTORS, SWITCHES, AND USES THEREOF |
US20190031780A1 (en) * | 2016-01-27 | 2019-01-31 | Siamab Therapeutics, Inc. | Compositions and methods for targeting cancer stem cells |
-
2018
- 2018-12-31 WO PCT/US2018/068235 patent/WO2019134001A1/en unknown
- 2018-12-31 JP JP2020536020A patent/JP2021508468A/ja active Pending
- 2018-12-31 CN CN201880090523.6A patent/CN111770937A/zh active Pending
- 2018-12-31 CA CA3087331A patent/CA3087331A1/en active Pending
- 2018-12-31 KR KR1020207021809A patent/KR20200115511A/ko unknown
- 2018-12-31 US US16/958,614 patent/US20210061879A1/en active Pending
- 2018-12-31 EP EP18896671.7A patent/EP3731856A4/en active Pending
-
2023
- 2023-12-07 JP JP2023206682A patent/JP2024028890A/ja active Pending
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2016187158A1 (en) * | 2015-05-15 | 2016-11-24 | City Of Hope | Chimeric antigen receptor compositions |
Non-Patent Citations (1)
Title |
---|
次世代医薬開発に向けた抗体工学の最前線, JPN6022022887, 2012, pages 31 - 32, ISSN: 0004937647 * |
Also Published As
Publication number | Publication date |
---|---|
US20210061879A1 (en) | 2021-03-04 |
EP3731856A1 (en) | 2020-11-04 |
JP2024028890A (ja) | 2024-03-05 |
CN111770937A (zh) | 2020-10-13 |
KR20200115511A (ko) | 2020-10-07 |
CA3087331A1 (en) | 2019-07-04 |
EP3731856A4 (en) | 2021-11-10 |
WO2019134001A1 (en) | 2019-07-04 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
TWI708788B (zh) | 雙特異性抗體 | |
JP2021166522A (ja) | キメラ抗原受容体組成物 | |
JP2022105085A (ja) | 改変j鎖を有する結合分子 | |
JP2023100903A (ja) | 多価メディトープ、メディトープ結合性抗体およびそれらの使用 | |
AU2018304711A1 (en) | Methods of qualitatively and/or quantitatively analyzing properties of activatable antibodies and uses thereof | |
JP2020529863A (ja) | 抗ror1抗体とその作製及び使用方法 | |
EP3502142B1 (en) | Bispecific antibody and antibody conjugate for tumour therapy and use thereof | |
JP2022507679A (ja) | Her2/pd1二重特異性抗体 | |
WO2020114479A1 (zh) | 多特异性蛋白分子 | |
US20200368364A1 (en) | Cysteine peptide-enabled antibodies | |
Hong et al. | Chemoenzymatic Synthesis of a Rhamnose‐Functionalized Bispecific Nanobody as a Bispecific Antibody Mimic for Cancer Immunotherapy | |
JP2024028890A (ja) | メディトープ対応t細胞 | |
JP6976854B2 (ja) | 機械的にかみ合った複合体 | |
TWI818916B (zh) | 抗cd147抗體、及其用途與製造方法 | |
TW201726748A (zh) | 新穎抗-mmp16抗體及使用方法 | |
JP2021509105A (ja) | EGFRvIII抗体ならびにその複合体、製造方法および使用 | |
WO2021244553A1 (zh) | 一种抗pd-l1和egfr的四价双特异性抗体 | |
Li et al. | A PD-L1xCD3 bispecific nanobody as a novel T-cell engager in treating PD-L1 overexpression melanoma | |
Moricoli et al. | Isolation of a new human scFv antibody recognizing a cell surface binding site to CEACAM1. Large yield production, purification and characterization in E. coli expression system | |
CN115698072A (zh) | 抗gpc3抗体,抗gpc3嵌合抗原受体和gpc3/cd3双特异性抗体 | |
JP7082112B2 (ja) | 抗gpr20抗体 | |
Liu et al. | A Novel Her2/VEGFR2/CD3 trispecific antibody with an optimal structural design showed improved T-cell-redirecting antitumor efficacy | |
WO2018166527A1 (zh) | 多特异性抗体、抗体偶联物和相关的药物组合物及应用 | |
JP2022504472A (ja) | Her2結合四量体ポリペプチド | |
US20220280568A1 (en) | Dual bispecific antibody compounds and uses thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20211223 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20221206 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20230228 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20230606 |
|
A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20230808 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20231207 |
|
A911 | Transfer to examiner for re-examination before appeal (zenchi) |
Free format text: JAPANESE INTERMEDIATE CODE: A911 Effective date: 20240126 |
|
A912 | Re-examination (zenchi) completed and case transferred to appeal board |
Free format text: JAPANESE INTERMEDIATE CODE: A912 Effective date: 20240308 |