CN114716564A - Preparation and application of chimeric antigen receptor immune cells constructed based on SECTM1 - Google Patents
Preparation and application of chimeric antigen receptor immune cells constructed based on SECTM1 Download PDFInfo
- Publication number
- CN114716564A CN114716564A CN202111566838.3A CN202111566838A CN114716564A CN 114716564 A CN114716564 A CN 114716564A CN 202111566838 A CN202111566838 A CN 202111566838A CN 114716564 A CN114716564 A CN 114716564A
- Authority
- CN
- China
- Prior art keywords
- car
- cells
- cell
- sectm1
- leu
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 108010019670 Chimeric Antigen Receptors Proteins 0.000 title claims abstract description 108
- 101000821449 Homo sapiens Secreted and transmembrane protein 1 Proteins 0.000 title claims abstract description 60
- 102100021853 Secreted and transmembrane protein 1 Human genes 0.000 title claims abstract description 60
- 210000002865 immune cell Anatomy 0.000 title claims abstract description 49
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 210000004027 cell Anatomy 0.000 claims abstract description 231
- 230000014509 gene expression Effects 0.000 claims abstract description 48
- 230000027455 binding Effects 0.000 claims abstract description 32
- 239000000203 mixture Substances 0.000 claims abstract description 29
- 102000005962 receptors Human genes 0.000 claims abstract description 25
- 108020003175 receptors Proteins 0.000 claims abstract description 25
- 238000004519 manufacturing process Methods 0.000 claims abstract description 7
- 239000013598 vector Substances 0.000 claims description 58
- 108090000623 proteins and genes Proteins 0.000 claims description 33
- 125000003275 alpha amino acid group Chemical group 0.000 claims description 30
- 238000011282 treatment Methods 0.000 claims description 30
- 150000007523 nucleic acids Chemical class 0.000 claims description 28
- 102000039446 nucleic acids Human genes 0.000 claims description 25
- 108020004707 nucleic acids Proteins 0.000 claims description 25
- 201000010099 disease Diseases 0.000 claims description 16
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 16
- 239000012634 fragment Substances 0.000 claims description 16
- 102000004169 proteins and genes Human genes 0.000 claims description 14
- 230000011664 signaling Effects 0.000 claims description 12
- 238000009472 formulation Methods 0.000 claims description 11
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 11
- 239000003446 ligand Substances 0.000 claims description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims description 10
- 108010076504 Protein Sorting Signals Proteins 0.000 claims description 7
- 230000001086 cytosolic effect Effects 0.000 claims description 5
- 239000003085 diluting agent Substances 0.000 claims description 5
- 210000000349 chromosome Anatomy 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 230000002265 prevention Effects 0.000 claims description 3
- 230000001594 aberrant effect Effects 0.000 claims description 2
- 101000914496 Homo sapiens T-cell antigen CD7 Proteins 0.000 abstract description 88
- 102100027208 T-cell antigen CD7 Human genes 0.000 abstract description 87
- 210000001744 T-lymphocyte Anatomy 0.000 abstract description 79
- 210000004881 tumor cell Anatomy 0.000 abstract description 32
- 230000002147 killing effect Effects 0.000 abstract description 31
- 241000282414 Homo sapiens Species 0.000 abstract description 30
- 238000001727 in vivo Methods 0.000 abstract description 14
- 238000005516 engineering process Methods 0.000 abstract description 7
- 230000008685 targeting Effects 0.000 abstract description 5
- 230000000903 blocking effect Effects 0.000 abstract description 4
- 210000003071 memory t lymphocyte Anatomy 0.000 abstract description 4
- 238000011109 contamination Methods 0.000 abstract description 2
- 238000010362 genome editing Methods 0.000 abstract description 2
- 238000012986 modification Methods 0.000 abstract description 2
- 230000004048 modification Effects 0.000 abstract description 2
- 238000012360 testing method Methods 0.000 abstract description 2
- 206010028980 Neoplasm Diseases 0.000 description 50
- 238000000034 method Methods 0.000 description 38
- 239000000427 antigen Substances 0.000 description 22
- 108091007433 antigens Proteins 0.000 description 22
- 102000036639 antigens Human genes 0.000 description 22
- 235000001014 amino acid Nutrition 0.000 description 16
- 201000011510 cancer Diseases 0.000 description 16
- 239000013612 plasmid Substances 0.000 description 16
- 238000001514 detection method Methods 0.000 description 15
- 150000002632 lipids Chemical class 0.000 description 15
- 102000004127 Cytokines Human genes 0.000 description 14
- 108090000695 Cytokines Proteins 0.000 description 14
- 241000700605 Viruses Species 0.000 description 13
- 230000003834 intracellular effect Effects 0.000 description 13
- 235000018102 proteins Nutrition 0.000 description 13
- 108010087924 alanylproline Proteins 0.000 description 12
- 229940024606 amino acid Drugs 0.000 description 12
- 150000001413 amino acids Chemical class 0.000 description 12
- 230000006870 function Effects 0.000 description 12
- 208000015181 infectious disease Diseases 0.000 description 12
- 108091033319 polynucleotide Proteins 0.000 description 12
- 239000002157 polynucleotide Substances 0.000 description 12
- 102000040430 polynucleotide Human genes 0.000 description 12
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 10
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 10
- 101000946843 Homo sapiens T-cell surface glycoprotein CD8 alpha chain Proteins 0.000 description 10
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 10
- 102100034922 T-cell surface glycoprotein CD8 alpha chain Human genes 0.000 description 10
- 230000000139 costimulatory effect Effects 0.000 description 10
- 239000002502 liposome Substances 0.000 description 10
- 230000015654 memory Effects 0.000 description 10
- 238000002560 therapeutic procedure Methods 0.000 description 10
- 101000914514 Homo sapiens T-cell-specific surface glycoprotein CD28 Proteins 0.000 description 9
- 101000851370 Homo sapiens Tumor necrosis factor receptor superfamily member 9 Proteins 0.000 description 9
- 108700008625 Reporter Genes Proteins 0.000 description 9
- 102100027213 T-cell-specific surface glycoprotein CD28 Human genes 0.000 description 9
- 238000000338 in vitro Methods 0.000 description 9
- 125000003729 nucleotide group Chemical group 0.000 description 9
- 229920001184 polypeptide Polymers 0.000 description 9
- 102000004196 processed proteins & peptides Human genes 0.000 description 9
- 230000001225 therapeutic effect Effects 0.000 description 9
- 241000282693 Cercopithecidae Species 0.000 description 8
- 108020004414 DNA Proteins 0.000 description 8
- 102100036856 Tumor necrosis factor receptor superfamily member 9 Human genes 0.000 description 8
- 238000003556 assay Methods 0.000 description 8
- 230000008569 process Effects 0.000 description 8
- 230000035755 proliferation Effects 0.000 description 8
- 239000006228 supernatant Substances 0.000 description 8
- 206010010144 Completed suicide Diseases 0.000 description 7
- 241000713666 Lentivirus Species 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 239000013604 expression vector Substances 0.000 description 7
- 238000001802 infusion Methods 0.000 description 7
- 210000000822 natural killer cell Anatomy 0.000 description 7
- 239000002773 nucleotide Substances 0.000 description 7
- 230000028327 secretion Effects 0.000 description 7
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 6
- 239000005089 Luciferase Substances 0.000 description 6
- 108700018351 Major Histocompatibility Complex Proteins 0.000 description 6
- 241000124008 Mammalia Species 0.000 description 6
- YBAFDPFAUTYYRW-UHFFFAOYSA-N N-L-alpha-glutamyl-L-leucine Natural products CC(C)CC(C(O)=O)NC(=O)C(N)CCC(O)=O YBAFDPFAUTYYRW-UHFFFAOYSA-N 0.000 description 6
- AJHCSUXXECOXOY-UHFFFAOYSA-N N-glycyl-L-tryptophan Natural products C1=CC=C2C(CC(NC(=O)CN)C(O)=O)=CNC2=C1 AJHCSUXXECOXOY-UHFFFAOYSA-N 0.000 description 6
- 102100036011 T-cell surface glycoprotein CD4 Human genes 0.000 description 6
- 102100022153 Tumor necrosis factor receptor superfamily member 4 Human genes 0.000 description 6
- 230000008901 benefit Effects 0.000 description 6
- 108010050475 glycyl-leucyl-tyrosine Proteins 0.000 description 6
- 230000028993 immune response Effects 0.000 description 6
- 238000002649 immunization Methods 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 230000020382 suppression by virus of host antigen processing and presentation of peptide antigen via MHC class I Effects 0.000 description 6
- 102100024222 B-lymphocyte antigen CD19 Human genes 0.000 description 5
- 101000980825 Homo sapiens B-lymphocyte antigen CD19 Proteins 0.000 description 5
- 101000611183 Homo sapiens Tumor necrosis factor Proteins 0.000 description 5
- 206010025323 Lymphomas Diseases 0.000 description 5
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 5
- WTMPKZWHRCMMMT-KZVJFYERSA-N Thr-Pro-Ala Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C)C(O)=O WTMPKZWHRCMMMT-KZVJFYERSA-N 0.000 description 5
- 230000002159 abnormal effect Effects 0.000 description 5
- 108010068380 arginylarginine Proteins 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- 210000000170 cell membrane Anatomy 0.000 description 5
- 238000011161 development Methods 0.000 description 5
- 230000018109 developmental process Effects 0.000 description 5
- 238000010586 diagram Methods 0.000 description 5
- 108010050848 glycylleucine Proteins 0.000 description 5
- 208000014951 hematologic disease Diseases 0.000 description 5
- 230000003053 immunization Effects 0.000 description 5
- 238000001990 intravenous administration Methods 0.000 description 5
- 208000032839 leukemia Diseases 0.000 description 5
- 230000007774 longterm Effects 0.000 description 5
- 210000005259 peripheral blood Anatomy 0.000 description 5
- 239000011886 peripheral blood Substances 0.000 description 5
- RXWNCPJZOCPEPQ-NVWDDTSBSA-N puromycin Chemical group C1=CC(OC)=CC=C1C[C@H](N)C(=O)N[C@H]1[C@@H](O)[C@H](N2C3=NC=NC(=C3N=C2)N(C)C)O[C@@H]1CO RXWNCPJZOCPEPQ-NVWDDTSBSA-N 0.000 description 5
- 238000006467 substitution reaction Methods 0.000 description 5
- 238000013518 transcription Methods 0.000 description 5
- 230000035897 transcription Effects 0.000 description 5
- 239000013603 viral vector Substances 0.000 description 5
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 4
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 4
- -1 CD137 Proteins 0.000 description 4
- AFWYPMDMDYCKMD-KBPBESRZSA-N Gly-Leu-Tyr Chemical compound NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 AFWYPMDMDYCKMD-KBPBESRZSA-N 0.000 description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 4
- 102000000588 Interleukin-2 Human genes 0.000 description 4
- 108010002350 Interleukin-2 Proteins 0.000 description 4
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 4
- 206010035226 Plasma cell myeloma Diseases 0.000 description 4
- 102100040247 Tumor necrosis factor Human genes 0.000 description 4
- PEVVXUGSAKEPEN-AVGNSLFASA-N Tyr-Asn-Glu Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O PEVVXUGSAKEPEN-AVGNSLFASA-N 0.000 description 4
- 125000000539 amino acid group Chemical group 0.000 description 4
- 238000013459 approach Methods 0.000 description 4
- 108010062796 arginyllysine Proteins 0.000 description 4
- 108010060035 arginylproline Proteins 0.000 description 4
- 108010069205 aspartyl-phenylalanine Proteins 0.000 description 4
- 239000007975 buffered saline Substances 0.000 description 4
- 238000002512 chemotherapy Methods 0.000 description 4
- 230000034994 death Effects 0.000 description 4
- 108010055341 glutamyl-glutamic acid Proteins 0.000 description 4
- 201000005787 hematologic cancer Diseases 0.000 description 4
- 238000009169 immunotherapy Methods 0.000 description 4
- 238000011534 incubation Methods 0.000 description 4
- 230000001939 inductive effect Effects 0.000 description 4
- 239000003550 marker Substances 0.000 description 4
- 239000000693 micelle Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 108010054624 red fluorescent protein Proteins 0.000 description 4
- 230000001177 retroviral effect Effects 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- 238000001890 transfection Methods 0.000 description 4
- 241001430294 unidentified retrovirus Species 0.000 description 4
- PPINMSZPTPRQQB-NHCYSSNCSA-N 2-[[(2s)-1-[(2s)-2-[[(2s)-2-amino-3-methylbutanoyl]amino]propanoyl]pyrrolidine-2-carbonyl]amino]acetic acid Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O PPINMSZPTPRQQB-NHCYSSNCSA-N 0.000 description 3
- NHCPCLJZRSIDHS-ZLUOBGJFSA-N Ala-Asp-Ala Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(O)=O NHCPCLJZRSIDHS-ZLUOBGJFSA-N 0.000 description 3
- WJRXVTCKASUIFF-FXQIFTODSA-N Ala-Cys-Arg Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O WJRXVTCKASUIFF-FXQIFTODSA-N 0.000 description 3
- YFWTXMRJJDNTLM-LSJOCFKGSA-N Arg-Ala-His Chemical compound C[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](CCCN=C(N)N)N YFWTXMRJJDNTLM-LSJOCFKGSA-N 0.000 description 3
- IASNWHAGGYTEKX-IUCAKERBSA-N Arg-Arg-Gly Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)NCC(O)=O IASNWHAGGYTEKX-IUCAKERBSA-N 0.000 description 3
- KMSHNDWHPWXPEC-BQBZGAKWSA-N Arg-Asp-Gly Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(O)=O KMSHNDWHPWXPEC-BQBZGAKWSA-N 0.000 description 3
- XSPKAHFVDKRGRL-DCAQKATOSA-N Arg-Pro-Glu Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O XSPKAHFVDKRGRL-DCAQKATOSA-N 0.000 description 3
- YCYXHLZRUSJITQ-SRVKXCTJSA-N Arg-Pro-Pro Chemical compound NC(=N)NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 YCYXHLZRUSJITQ-SRVKXCTJSA-N 0.000 description 3
- ACKNRKFVYUVWAC-ZPFDUUQYSA-N Asn-Ile-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC(=O)N)N ACKNRKFVYUVWAC-ZPFDUUQYSA-N 0.000 description 3
- 102100036301 C-C chemokine receptor type 7 Human genes 0.000 description 3
- 238000011357 CAR T-cell therapy Methods 0.000 description 3
- 102100027207 CD27 antigen Human genes 0.000 description 3
- 208000031637 Erythroblastic Acute Leukemia Diseases 0.000 description 3
- 208000036566 Erythroleukaemia Diseases 0.000 description 3
- KVYVOGYEMPEXBT-GUBZILKMSA-N Gln-Ala-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCC(N)=O KVYVOGYEMPEXBT-GUBZILKMSA-N 0.000 description 3
- FGYPOQPQTUNESW-IUCAKERBSA-N Gln-Gly-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)CNC(=O)[C@H](CCC(=O)N)N FGYPOQPQTUNESW-IUCAKERBSA-N 0.000 description 3
- ZFBBMCKQSNJZSN-AUTRQRHGSA-N Gln-Val-Gln Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O ZFBBMCKQSNJZSN-AUTRQRHGSA-N 0.000 description 3
- VAZZOGXDUQSVQF-NUMRIWBASA-N Glu-Asn-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CCC(=O)O)N)O VAZZOGXDUQSVQF-NUMRIWBASA-N 0.000 description 3
- BUAKRRKDHSSIKK-IHRRRGAJSA-N Glu-Glu-Tyr Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 BUAKRRKDHSSIKK-IHRRRGAJSA-N 0.000 description 3
- OAGVHWYIBZMWLA-YFKPBYRVSA-N Glu-Gly-Gly Chemical compound OC(=O)CC[C@H](N)C(=O)NCC(=O)NCC(O)=O OAGVHWYIBZMWLA-YFKPBYRVSA-N 0.000 description 3
- LRPXYSGPOBVBEH-IUCAKERBSA-N Glu-Gly-Leu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CC(C)C)C(O)=O LRPXYSGPOBVBEH-IUCAKERBSA-N 0.000 description 3
- QXUPRMQJDWJDFR-NRPADANISA-N Glu-Val-Ser Chemical compound CC(C)[C@H](NC(=O)[C@@H](N)CCC(O)=O)C(=O)N[C@@H](CO)C(O)=O QXUPRMQJDWJDFR-NRPADANISA-N 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
- UPOJUWHGMDJUQZ-IUCAKERBSA-N Gly-Arg-Arg Chemical compound NC(=N)NCCC[C@H](NC(=O)CN)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O UPOJUWHGMDJUQZ-IUCAKERBSA-N 0.000 description 3
- KTSZUNRRYXPZTK-BQBZGAKWSA-N Gly-Gln-Glu Chemical compound NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O KTSZUNRRYXPZTK-BQBZGAKWSA-N 0.000 description 3
- DHDOADIPGZTAHT-YUMQZZPRSA-N Gly-Glu-Arg Chemical compound NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@H](C(O)=O)CCCN=C(N)N DHDOADIPGZTAHT-YUMQZZPRSA-N 0.000 description 3
- OLPPXYMMIARYAL-QMMMGPOBSA-N Gly-Gly-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)CNC(=O)CN OLPPXYMMIARYAL-QMMMGPOBSA-N 0.000 description 3
- YTSVAIMKVLZUDU-YUMQZZPRSA-N Gly-Leu-Asp Chemical compound [H]NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O YTSVAIMKVLZUDU-YUMQZZPRSA-N 0.000 description 3
- ZWRDOVYMQAAISL-UWVGGRQHSA-N Gly-Met-Lys Chemical compound CSCC[C@H](NC(=O)CN)C(=O)N[C@H](C(O)=O)CCCCN ZWRDOVYMQAAISL-UWVGGRQHSA-N 0.000 description 3
- BIAKMWKJMQLZOJ-ZKWXMUAHSA-N His-Ala-Ala Chemical compound C[C@H](NC(=O)[C@H](C)NC(=O)[C@@H](N)Cc1cnc[nH]1)C(O)=O BIAKMWKJMQLZOJ-ZKWXMUAHSA-N 0.000 description 3
- 101000716065 Homo sapiens C-C chemokine receptor type 7 Proteins 0.000 description 3
- 101000914511 Homo sapiens CD27 antigen Proteins 0.000 description 3
- 101000679851 Homo sapiens Tumor necrosis factor receptor superfamily member 4 Proteins 0.000 description 3
- SITWEMZOJNKJCH-UHFFFAOYSA-N L-alanine-L-arginine Natural products CC(N)C(=O)NC(C(O)=O)CCCNC(N)=N SITWEMZOJNKJCH-UHFFFAOYSA-N 0.000 description 3
- JKGHDYGZRDWHGA-SRVKXCTJSA-N Leu-Asn-Leu Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(O)=O JKGHDYGZRDWHGA-SRVKXCTJSA-N 0.000 description 3
- FQZPTCNSNPWHLJ-AVGNSLFASA-N Leu-Gln-Lys Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(O)=O FQZPTCNSNPWHLJ-AVGNSLFASA-N 0.000 description 3
- MPSBSKHOWJQHBS-IHRRRGAJSA-N Leu-His-Met Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)N[C@@H](CCSC)C(=O)O)N MPSBSKHOWJQHBS-IHRRRGAJSA-N 0.000 description 3
- UFPLDOKWDNTTRP-ULQDDVLXSA-N Leu-Tyr-Met Chemical compound CSCC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC(C)C)CC1=CC=C(O)C=C1 UFPLDOKWDNTTRP-ULQDDVLXSA-N 0.000 description 3
- 108060001084 Luciferase Proteins 0.000 description 3
- VSRXPEHZMHSFKU-IUCAKERBSA-N Lys-Gln-Gly Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(O)=O VSRXPEHZMHSFKU-IUCAKERBSA-N 0.000 description 3
- 208000034578 Multiple myelomas Diseases 0.000 description 3
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 3
- MDHZEOMXGNBSIL-DLOVCJGASA-N Phe-Ala-Cys Chemical compound C[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)N MDHZEOMXGNBSIL-DLOVCJGASA-N 0.000 description 3
- KIAWKQJTSGRCSA-AVGNSLFASA-N Phe-Asn-Glu Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N KIAWKQJTSGRCSA-AVGNSLFASA-N 0.000 description 3
- 241000288906 Primates Species 0.000 description 3
- DZZCICYRSZASNF-FXQIFTODSA-N Pro-Ala-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1 DZZCICYRSZASNF-FXQIFTODSA-N 0.000 description 3
- LCRSGSIRKLXZMZ-BPNCWPANSA-N Pro-Ala-Tyr Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O LCRSGSIRKLXZMZ-BPNCWPANSA-N 0.000 description 3
- TYMBHHITTMGGPI-NAKRPEOUSA-N Pro-Ile-Cys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@@H]1CCCN1 TYMBHHITTMGGPI-NAKRPEOUSA-N 0.000 description 3
- JLMZKEQFMVORMA-SRVKXCTJSA-N Pro-Pro-Arg Chemical compound NC(N)=NCCC[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 JLMZKEQFMVORMA-SRVKXCTJSA-N 0.000 description 3
- CHYAYDLYYIJCKY-OSUNSFLBSA-N Pro-Thr-Ile Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O CHYAYDLYYIJCKY-OSUNSFLBSA-N 0.000 description 3
- WTWGOQRNRFHFQD-JBDRJPRFSA-N Ser-Ala-Ile Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O WTWGOQRNRFHFQD-JBDRJPRFSA-N 0.000 description 3
- BRGQQXQKPUCUJQ-KBIXCLLPSA-N Ser-Glu-Ile Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O BRGQQXQKPUCUJQ-KBIXCLLPSA-N 0.000 description 3
- XJDMUQCLVSCRSJ-VZFHVOOUSA-N Ser-Thr-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O XJDMUQCLVSCRSJ-VZFHVOOUSA-N 0.000 description 3
- LTLBNCDNXQCOLB-UBHSHLNASA-N Trp-Asp-Ser Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O)=CNC2=C1 LTLBNCDNXQCOLB-UBHSHLNASA-N 0.000 description 3
- MDDYTWOFHZFABW-SZMVWBNQSA-N Trp-Gln-Leu Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(O)=O)=CNC2=C1 MDDYTWOFHZFABW-SZMVWBNQSA-N 0.000 description 3
- 101710165473 Tumor necrosis factor receptor superfamily member 4 Proteins 0.000 description 3
- NVZVJIUDICCMHZ-BZSNNMDCSA-N Tyr-Phe-Ser Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(O)=O NVZVJIUDICCMHZ-BZSNNMDCSA-N 0.000 description 3
- YDVDTCJGBBJGRT-GUBZILKMSA-N Val-Met-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CO)C(=O)O)N YDVDTCJGBBJGRT-GUBZILKMSA-N 0.000 description 3
- LCHZBEUVGAVMKS-RHYQMDGZSA-N Val-Thr-Leu Chemical compound CC(C)C[C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)C(C)C)[C@@H](C)O)C(O)=O LCHZBEUVGAVMKS-RHYQMDGZSA-N 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 208000021841 acute erythroid leukemia Diseases 0.000 description 3
- 108010047495 alanylglycine Proteins 0.000 description 3
- KOSRFJWDECSPRO-UHFFFAOYSA-N alpha-L-glutamyl-L-glutamic acid Natural products OC(=O)CCC(N)C(=O)NC(CCC(O)=O)C(O)=O KOSRFJWDECSPRO-UHFFFAOYSA-N 0.000 description 3
- 230000000259 anti-tumor effect Effects 0.000 description 3
- 108010029539 arginyl-prolyl-proline Proteins 0.000 description 3
- 108010047857 aspartylglycine Proteins 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 230000022534 cell killing Effects 0.000 description 3
- 230000004663 cell proliferation Effects 0.000 description 3
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 3
- 238000010276 construction Methods 0.000 description 3
- 230000000875 corresponding effect Effects 0.000 description 3
- 239000012636 effector Substances 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000001476 gene delivery Methods 0.000 description 3
- 108010049041 glutamylalanine Proteins 0.000 description 3
- XBGGUPMXALFZOT-UHFFFAOYSA-N glycyl-L-tyrosine hemihydrate Natural products NCC(=O)NC(C(O)=O)CC1=CC=C(O)C=C1 XBGGUPMXALFZOT-UHFFFAOYSA-N 0.000 description 3
- XKUKSGPZAADMRA-UHFFFAOYSA-N glycyl-glycyl-glycine Natural products NCC(=O)NCC(=O)NCC(O)=O XKUKSGPZAADMRA-UHFFFAOYSA-N 0.000 description 3
- 230000036541 health Effects 0.000 description 3
- 230000001976 improved effect Effects 0.000 description 3
- 108010073472 leucyl-prolyl-proline Proteins 0.000 description 3
- 108010003700 lysyl aspartic acid Proteins 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 238000010369 molecular cloning Methods 0.000 description 3
- 230000002018 overexpression Effects 0.000 description 3
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 3
- 230000002688 persistence Effects 0.000 description 3
- 108010051242 phenylalanylserine Proteins 0.000 description 3
- 238000001959 radiotherapy Methods 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 230000010076 replication Effects 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 108010026333 seryl-proline Proteins 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000000439 tumor marker Substances 0.000 description 3
- 108010051110 tyrosyl-lysine Proteins 0.000 description 3
- 108010072644 valyl-alanyl-prolyl-glycine Proteins 0.000 description 3
- 230000009385 viral infection Effects 0.000 description 3
- 108010000998 wheylin-2 peptide Proteins 0.000 description 3
- 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 2
- YXHLJMWYDTXDHS-IRFLANFNSA-N 7-aminoactinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=C(N)C=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 YXHLJMWYDTXDHS-IRFLANFNSA-N 0.000 description 2
- 108700012813 7-aminoactinomycin D Proteins 0.000 description 2
- BLGHHPHXVJWCNK-GUBZILKMSA-N Ala-Gln-Leu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(O)=O BLGHHPHXVJWCNK-GUBZILKMSA-N 0.000 description 2
- FUSPCLTUKXQREV-ACZMJKKPSA-N Ala-Glu-Ala Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(O)=O FUSPCLTUKXQREV-ACZMJKKPSA-N 0.000 description 2
- VBRDBGCROKWTPV-XHNCKOQMSA-N Ala-Glu-Pro Chemical compound C[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N1CCC[C@@H]1C(=O)O)N VBRDBGCROKWTPV-XHNCKOQMSA-N 0.000 description 2
- YYAVDNKUWLAFCV-ACZMJKKPSA-N Ala-Ser-Gln Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(O)=O YYAVDNKUWLAFCV-ACZMJKKPSA-N 0.000 description 2
- HKRXJBBCQBAGIM-FXQIFTODSA-N Arg-Asp-Ser Chemical compound C(C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CO)C(=O)O)N)CN=C(N)N HKRXJBBCQBAGIM-FXQIFTODSA-N 0.000 description 2
- HQIZDMIGUJOSNI-IUCAKERBSA-N Arg-Gly-Arg Chemical compound N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(O)=O HQIZDMIGUJOSNI-IUCAKERBSA-N 0.000 description 2
- DNBMCNQKNOKOSD-DCAQKATOSA-N Arg-Pro-Gln Chemical compound NC(N)=NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(O)=O DNBMCNQKNOKOSD-DCAQKATOSA-N 0.000 description 2
- WOZDCBHUGJVJPL-AVGNSLFASA-N Arg-Val-Lys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCCN=C(N)N)N WOZDCBHUGJVJPL-AVGNSLFASA-N 0.000 description 2
- QQEWINYJRFBLNN-DLOVCJGASA-N Asn-Ala-Phe Chemical compound NC(=O)C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 QQEWINYJRFBLNN-DLOVCJGASA-N 0.000 description 2
- CIBWFJFMOBIFTE-CIUDSAMLSA-N Asn-Arg-Gln Chemical compound C(C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CC(=O)N)N)CN=C(N)N CIBWFJFMOBIFTE-CIUDSAMLSA-N 0.000 description 2
- GNKVBRYFXYWXAB-WDSKDSINSA-N Asn-Glu-Gly Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(O)=O GNKVBRYFXYWXAB-WDSKDSINSA-N 0.000 description 2
- SEKBHZJLARBNPB-GHCJXIJMSA-N Asn-Ile-Ser Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(O)=O SEKBHZJLARBNPB-GHCJXIJMSA-N 0.000 description 2
- YVXRYLVELQYAEQ-SRVKXCTJSA-N Asn-Leu-Lys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC(=O)N)N YVXRYLVELQYAEQ-SRVKXCTJSA-N 0.000 description 2
- RTXQQDVBACBSCW-CFMVVWHZSA-N Asp-Ile-Tyr Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O RTXQQDVBACBSCW-CFMVVWHZSA-N 0.000 description 2
- UZFHNLYQWMGUHU-DCAQKATOSA-N Asp-Lys-Arg Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O UZFHNLYQWMGUHU-DCAQKATOSA-N 0.000 description 2
- FQHBAQLBIXLWAG-DCAQKATOSA-N Asp-Lys-Met Chemical compound CSCC[C@@H](C(=O)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC(=O)O)N FQHBAQLBIXLWAG-DCAQKATOSA-N 0.000 description 2
- GIKOVDMXBAFXDF-NHCYSSNCSA-N Asp-Val-Leu Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O GIKOVDMXBAFXDF-NHCYSSNCSA-N 0.000 description 2
- 201000009030 Carcinoma Diseases 0.000 description 2
- 208000024172 Cardiovascular disease Diseases 0.000 description 2
- JTNKVWLMDHIUOG-IHRRRGAJSA-N Cys-Arg-Phe Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O JTNKVWLMDHIUOG-IHRRRGAJSA-N 0.000 description 2
- KABHAOSDMIYXTR-GUBZILKMSA-N Cys-Glu-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CS)N KABHAOSDMIYXTR-GUBZILKMSA-N 0.000 description 2
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 2
- 241000701022 Cytomegalovirus Species 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 description 2
- 241000702421 Dependoparvovirus Species 0.000 description 2
- 229920002307 Dextran Polymers 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- 238000008157 ELISA kit Methods 0.000 description 2
- 241000588724 Escherichia coli Species 0.000 description 2
- DLOHWQXXGMEZDW-CIUDSAMLSA-N Gln-Arg-Asn Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(N)=O)C(O)=O DLOHWQXXGMEZDW-CIUDSAMLSA-N 0.000 description 2
- TWHDOEYLXXQYOZ-FXQIFTODSA-N Gln-Asn-Gln Chemical compound C(CC(=O)N)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N TWHDOEYLXXQYOZ-FXQIFTODSA-N 0.000 description 2
- KUBFPYIMAGXGBT-ACZMJKKPSA-N Gln-Ser-Ala Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(O)=O KUBFPYIMAGXGBT-ACZMJKKPSA-N 0.000 description 2
- NKLRYVLERDYDBI-FXQIFTODSA-N Glu-Glu-Asp Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O NKLRYVLERDYDBI-FXQIFTODSA-N 0.000 description 2
- BUZMZDDKFCSKOT-CIUDSAMLSA-N Glu-Glu-Glu Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O BUZMZDDKFCSKOT-CIUDSAMLSA-N 0.000 description 2
- HILMIYALTUQTRC-XVKPBYJWSA-N Glu-Gly-Val Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](C(C)C)C(O)=O HILMIYALTUQTRC-XVKPBYJWSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- CLODWIOAKCSBAN-BQBZGAKWSA-N Gly-Arg-Asp Chemical compound NC(N)=NCCC[C@H](NC(=O)CN)C(=O)N[C@@H](CC(O)=O)C(O)=O CLODWIOAKCSBAN-BQBZGAKWSA-N 0.000 description 2
- QCTLGOYODITHPQ-WHFBIAKZSA-N Gly-Cys-Ser Chemical compound [H]NCC(=O)N[C@@H](CS)C(=O)N[C@@H](CO)C(O)=O QCTLGOYODITHPQ-WHFBIAKZSA-N 0.000 description 2
- CCQOOWAONKGYKQ-BYPYZUCNSA-N Gly-Gly-Ala Chemical compound OC(=O)[C@H](C)NC(=O)CNC(=O)CN CCQOOWAONKGYKQ-BYPYZUCNSA-N 0.000 description 2
- QITBQGJOXQYMOA-ZETCQYMHSA-N Gly-Gly-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)CNC(=O)CN QITBQGJOXQYMOA-ZETCQYMHSA-N 0.000 description 2
- TVTZEOHWHUVYCG-KYNKHSRBSA-N Gly-Thr-Thr Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O TVTZEOHWHUVYCG-KYNKHSRBSA-N 0.000 description 2
- 208000009329 Graft vs Host Disease Diseases 0.000 description 2
- 108010043121 Green Fluorescent Proteins Proteins 0.000 description 2
- 102000004144 Green Fluorescent Proteins Human genes 0.000 description 2
- 102100026122 High affinity immunoglobulin gamma Fc receptor I Human genes 0.000 description 2
- DCRODRAURLJOFY-XPUUQOCRSA-N His-Ala-Gly Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](C)C(=O)NCC(O)=O DCRODRAURLJOFY-XPUUQOCRSA-N 0.000 description 2
- 208000017604 Hodgkin disease Diseases 0.000 description 2
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 2
- 101000716102 Homo sapiens T-cell surface glycoprotein CD4 Proteins 0.000 description 2
- 241000725303 Human immunodeficiency virus Species 0.000 description 2
- PARSHQDZROHERM-NHCYSSNCSA-N Ile-Lys-Gly Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)O)N PARSHQDZROHERM-NHCYSSNCSA-N 0.000 description 2
- JTBFQNHKNRZJDS-SYWGBEHUSA-N Ile-Trp-Ala Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)N[C@@H](C)C(=O)O)N JTBFQNHKNRZJDS-SYWGBEHUSA-N 0.000 description 2
- 102100025390 Integrin beta-2 Human genes 0.000 description 2
- 208000031671 Large B-Cell Diffuse Lymphoma Diseases 0.000 description 2
- WUHBLPVELFTPQK-KKUMJFAQSA-N Leu-Tyr-Asn Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(N)=O)C(O)=O WUHBLPVELFTPQK-KKUMJFAQSA-N 0.000 description 2
- ARNIBBOXIAWUOP-MGHWNKPDSA-N Leu-Tyr-Ile Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O ARNIBBOXIAWUOP-MGHWNKPDSA-N 0.000 description 2
- AAKRWBIIGKPOKQ-ONGXEEELSA-N Leu-Val-Gly Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)NCC(O)=O AAKRWBIIGKPOKQ-ONGXEEELSA-N 0.000 description 2
- NCTDKZKNBDZDOL-GARJFASQSA-N Lys-Asn-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC(=O)N)NC(=O)[C@H](CCCCN)N)C(=O)O NCTDKZKNBDZDOL-GARJFASQSA-N 0.000 description 2
- UETQMSASAVBGJY-QWRGUYRKSA-N Lys-Gly-His Chemical compound NCCCC[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CC1=CNC=N1 UETQMSASAVBGJY-QWRGUYRKSA-N 0.000 description 2
- HVAUKHLDSDDROB-KKUMJFAQSA-N Lys-Lys-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(O)=O HVAUKHLDSDDROB-KKUMJFAQSA-N 0.000 description 2
- 241000829100 Macaca mulatta polyomavirus 1 Species 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 208000025205 Mantle-Cell Lymphoma Diseases 0.000 description 2
- 201000003793 Myelodysplastic syndrome Diseases 0.000 description 2
- SITLTJHOQZFJGG-UHFFFAOYSA-N N-L-alpha-glutamyl-L-valine Natural products CC(C)C(C(O)=O)NC(=O)C(N)CCC(O)=O SITLTJHOQZFJGG-UHFFFAOYSA-N 0.000 description 2
- 108010002311 N-glycylglutamic acid Proteins 0.000 description 2
- 108091028043 Nucleic acid sequence Proteins 0.000 description 2
- 208000008589 Obesity Diseases 0.000 description 2
- MJAYDXWQQUOURZ-JYJNAYRXSA-N Phe-Lys-Gln Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(N)=O)C(O)=O MJAYDXWQQUOURZ-JYJNAYRXSA-N 0.000 description 2
- WEDZFLRYSIDIRX-IHRRRGAJSA-N Phe-Ser-Arg Chemical compound NC(=N)NCCC[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC1=CC=CC=C1 WEDZFLRYSIDIRX-IHRRRGAJSA-N 0.000 description 2
- LNLNHXIQPGKRJQ-SRVKXCTJSA-N Pro-Arg-Arg Chemical compound NC(N)=NCCC[C@@H](C(O)=O)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H]1CCCN1 LNLNHXIQPGKRJQ-SRVKXCTJSA-N 0.000 description 2
- SFECXGVELZFBFJ-VEVYYDQMSA-N Pro-Asp-Thr Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O SFECXGVELZFBFJ-VEVYYDQMSA-N 0.000 description 2
- PTLOFJZJADCNCD-DCAQKATOSA-N Pro-Glu-Met Chemical compound CSCC[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@@H]1CCCN1 PTLOFJZJADCNCD-DCAQKATOSA-N 0.000 description 2
- FMLRRBDLBJLJIK-DCAQKATOSA-N Pro-Leu-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H]1CCCN1 FMLRRBDLBJLJIK-DCAQKATOSA-N 0.000 description 2
- FKYKZHOKDOPHSA-DCAQKATOSA-N Pro-Leu-Ser Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O FKYKZHOKDOPHSA-DCAQKATOSA-N 0.000 description 2
- DSGSTPRKNYHGCL-JYJNAYRXSA-N Pro-Phe-Met Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCSC)C(O)=O DSGSTPRKNYHGCL-JYJNAYRXSA-N 0.000 description 2
- JXVXYRZQIUPYSA-NHCYSSNCSA-N Pro-Val-Gln Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O JXVXYRZQIUPYSA-NHCYSSNCSA-N 0.000 description 2
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 description 2
- 101150118482 SECTM1 gene Proteins 0.000 description 2
- 206010039491 Sarcoma Diseases 0.000 description 2
- ZUDXUJSYCCNZQJ-DCAQKATOSA-N Ser-His-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CC1=CN=CN1)NC(=O)[C@H](CO)N ZUDXUJSYCCNZQJ-DCAQKATOSA-N 0.000 description 2
- BCAVNDNYOGTQMQ-AAEUAGOBSA-N Ser-Trp-Gly Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)NCC(O)=O BCAVNDNYOGTQMQ-AAEUAGOBSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- 230000006052 T cell proliferation Effects 0.000 description 2
- LYGKYFKSZTUXGZ-ZDLURKLDSA-N Thr-Cys-Gly Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(=O)NCC(O)=O LYGKYFKSZTUXGZ-ZDLURKLDSA-N 0.000 description 2
- ZSPQUTWLWGWTPS-HJGDQZAQSA-N Thr-Lys-Asp Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(O)=O ZSPQUTWLWGWTPS-HJGDQZAQSA-N 0.000 description 2
- MFMGPEKYBXFIRF-SUSMZKCASA-N Thr-Thr-Gln Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(N)=O)C(O)=O MFMGPEKYBXFIRF-SUSMZKCASA-N 0.000 description 2
- BZTSQFWJNJYZSX-JRQIVUDYSA-N Thr-Tyr-Asp Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(O)=O)C(O)=O BZTSQFWJNJYZSX-JRQIVUDYSA-N 0.000 description 2
- 102100023935 Transmembrane glycoprotein NMB Human genes 0.000 description 2
- RXEQOXHCHQJMSO-IHPCNDPISA-N Trp-His-Leu Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC(C)C)C(O)=O RXEQOXHCHQJMSO-IHPCNDPISA-N 0.000 description 2
- GMOLURHJBLOBFW-ONGXEEELSA-N Val-Gly-His Chemical compound CC(C)[C@@H](C(=O)NCC(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N GMOLURHJBLOBFW-ONGXEEELSA-N 0.000 description 2
- ZIGZPYJXIWLQFC-QTKMDUPCSA-N Val-His-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CN=CN1)NC(=O)[C@H](C(C)C)N)O ZIGZPYJXIWLQFC-QTKMDUPCSA-N 0.000 description 2
- NZYNRRGJJVSSTJ-GUBZILKMSA-N Val-Ser-Val Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O NZYNRRGJJVSSTJ-GUBZILKMSA-N 0.000 description 2
- 108010081404 acein-2 Proteins 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 230000032683 aging Effects 0.000 description 2
- 108010076324 alanyl-glycyl-glycine Proteins 0.000 description 2
- 108010005233 alanylglutamic acid Proteins 0.000 description 2
- 108010044940 alanylglutamine Proteins 0.000 description 2
- 230000000735 allogeneic effect Effects 0.000 description 2
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 230000003078 antioxidant effect Effects 0.000 description 2
- 108010093581 aspartyl-proline Proteins 0.000 description 2
- 210000003719 b-lymphocyte Anatomy 0.000 description 2
- 239000011324 bead Substances 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- 229910000389 calcium phosphate Inorganic materials 0.000 description 2
- 235000011010 calcium phosphates Nutrition 0.000 description 2
- 150000001720 carbohydrates Chemical class 0.000 description 2
- 235000014633 carbohydrates Nutrition 0.000 description 2
- 238000002659 cell therapy Methods 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 239000002738 chelating agent Substances 0.000 description 2
- 206010012818 diffuse large B-cell lymphoma Diseases 0.000 description 2
- 230000002708 enhancing effect Effects 0.000 description 2
- 238000000684 flow cytometry Methods 0.000 description 2
- 108020001507 fusion proteins Proteins 0.000 description 2
- 102000037865 fusion proteins Human genes 0.000 description 2
- 108010006664 gamma-glutamyl-glycyl-glycine Proteins 0.000 description 2
- 238000001415 gene therapy Methods 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 108010078144 glutaminyl-glycine Proteins 0.000 description 2
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 2
- VPZXBVLAVMBEQI-UHFFFAOYSA-N glycyl-DL-alpha-alanine Natural products OC(=O)C(C)NC(=O)CN VPZXBVLAVMBEQI-UHFFFAOYSA-N 0.000 description 2
- 108010084264 glycyl-glycyl-cysteine Proteins 0.000 description 2
- 108010067216 glycyl-glycyl-glycine Proteins 0.000 description 2
- 108010089804 glycyl-threonine Proteins 0.000 description 2
- 108010015792 glycyllysine Proteins 0.000 description 2
- 108010084389 glycyltryptophan Proteins 0.000 description 2
- 108010037850 glycylvaline Proteins 0.000 description 2
- 208000024908 graft versus host disease Diseases 0.000 description 2
- 239000005090 green fluorescent protein Substances 0.000 description 2
- 230000002489 hematologic effect Effects 0.000 description 2
- 208000019691 hematopoietic and lymphoid cell neoplasm Diseases 0.000 description 2
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 description 2
- 108010025306 histidylleucine Proteins 0.000 description 2
- 230000001965 increasing effect Effects 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 230000010354 integration Effects 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 description 2
- 108010034529 leucyl-lysine Proteins 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 239000012669 liquid formulation Substances 0.000 description 2
- 230000036210 malignancy Effects 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 108010034507 methionyltryptophan Proteins 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 235000020824 obesity Nutrition 0.000 description 2
- 238000004806 packaging method and process Methods 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 230000002093 peripheral effect Effects 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 230000002335 preservative effect Effects 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- 108010029020 prolylglycine Proteins 0.000 description 2
- 108010090894 prolylleucine Proteins 0.000 description 2
- 239000012474 protein marker Substances 0.000 description 2
- 229950010131 puromycin Drugs 0.000 description 2
- 102220003351 rs387906411 Human genes 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- 238000012163 sequencing technique Methods 0.000 description 2
- 108010048818 seryl-histidine Proteins 0.000 description 2
- 238000010186 staining Methods 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- 230000002459 sustained effect Effects 0.000 description 2
- 108010061238 threonyl-glycine Proteins 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- 238000013519 translation Methods 0.000 description 2
- 230000014616 translation Effects 0.000 description 2
- 108091007466 transmembrane glycoproteins Proteins 0.000 description 2
- 238000002054 transplantation Methods 0.000 description 2
- 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 2
- 230000005909 tumor killing Effects 0.000 description 2
- 210000003171 tumor-infiltrating lymphocyte Anatomy 0.000 description 2
- 241000701161 unidentified adenovirus Species 0.000 description 2
- 238000011144 upstream manufacturing Methods 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- 239000011534 wash buffer Substances 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- DIGQNXIGRZPYDK-WKSCXVIASA-N (2R)-6-amino-2-[[2-[[(2S)-2-[[2-[[(2R)-2-[[(2S)-2-[[(2R,3S)-2-[[2-[[(2S)-2-[[2-[[(2S)-2-[[(2S)-2-[[(2R)-2-[[(2S,3S)-2-[[(2R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S)-2-[[(2R)-2-[[2-[[2-[[2-[(2-amino-1-hydroxyethylidene)amino]-3-carboxy-1-hydroxypropylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1-hydroxyethylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1,3-dihydroxypropylidene]amino]-1-hydroxyethylidene]amino]-1-hydroxypropylidene]amino]-1,3-dihydroxypropylidene]amino]-1,3-dihydroxypropylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1,3-dihydroxybutylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1-hydroxypropylidene]amino]-1,3-dihydroxypropylidene]amino]-1-hydroxyethylidene]amino]-1,5-dihydroxy-5-iminopentylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1,3-dihydroxybutylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1,3-dihydroxypropylidene]amino]-1-hydroxyethylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1-hydroxyethylidene]amino]hexanoic acid Chemical compound C[C@@H]([C@@H](C(=N[C@@H](CS)C(=N[C@@H](C)C(=N[C@@H](CO)C(=NCC(=N[C@@H](CCC(=N)O)C(=NC(CS)C(=N[C@H]([C@H](C)O)C(=N[C@H](CS)C(=N[C@H](CO)C(=NCC(=N[C@H](CS)C(=NCC(=N[C@H](CCCCN)C(=O)O)O)O)O)O)O)O)O)O)O)O)O)O)O)N=C([C@H](CS)N=C([C@H](CO)N=C([C@H](CO)N=C([C@H](C)N=C(CN=C([C@H](CO)N=C([C@H](CS)N=C(CN=C(C(CS)N=C(C(CC(=O)O)N=C(CN)O)O)O)O)O)O)O)O)O)O)O)O DIGQNXIGRZPYDK-WKSCXVIASA-N 0.000 description 1
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 1
- HVCOBJNICQPDBP-UHFFFAOYSA-N 3-[3-[3,5-dihydroxy-6-methyl-4-(3,4,5-trihydroxy-6-methyloxan-2-yl)oxyoxan-2-yl]oxydecanoyloxy]decanoic acid;hydrate Chemical compound O.OC1C(OC(CC(=O)OC(CCCCCCC)CC(O)=O)CCCCCCC)OC(C)C(O)C1OC1C(O)C(O)C(O)C(C)O1 HVCOBJNICQPDBP-UHFFFAOYSA-N 0.000 description 1
- 102000007469 Actins Human genes 0.000 description 1
- 108010085238 Actins Proteins 0.000 description 1
- 206010000830 Acute leukaemia Diseases 0.000 description 1
- YYSWCHMLFJLLBJ-ZLUOBGJFSA-N Ala-Ala-Ser Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O YYSWCHMLFJLLBJ-ZLUOBGJFSA-N 0.000 description 1
- KIUYPHAMDKDICO-WHFBIAKZSA-N Ala-Asp-Gly Chemical compound C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(O)=O KIUYPHAMDKDICO-WHFBIAKZSA-N 0.000 description 1
- ZVFVBBGVOILKPO-WHFBIAKZSA-N Ala-Gly-Ala Chemical compound C[C@H](N)C(=O)NCC(=O)N[C@@H](C)C(O)=O ZVFVBBGVOILKPO-WHFBIAKZSA-N 0.000 description 1
- YHKANGMVQWRMAP-DCAQKATOSA-N Ala-Leu-Arg Chemical compound C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CCCN=C(N)N YHKANGMVQWRMAP-DCAQKATOSA-N 0.000 description 1
- AWZKCUCQJNTBAD-SRVKXCTJSA-N Ala-Leu-Lys Chemical compound C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CCCCN AWZKCUCQJNTBAD-SRVKXCTJSA-N 0.000 description 1
- BFMIRJBURUXDRG-DLOVCJGASA-N Ala-Phe-Asp Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)C)CC1=CC=CC=C1 BFMIRJBURUXDRG-DLOVCJGASA-N 0.000 description 1
- OSRZOHXQCUFIQG-FPMFFAJLSA-N Ala-Phe-Pro Chemical compound C([C@H](NC(=O)[C@@H]([NH3+])C)C(=O)N1[C@H](CCC1)C([O-])=O)C1=CC=CC=C1 OSRZOHXQCUFIQG-FPMFFAJLSA-N 0.000 description 1
- FQNILRVJOJBFFC-FXQIFTODSA-N Ala-Pro-Asp Chemical compound C[C@@H](C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(=O)O)C(=O)O)N FQNILRVJOJBFFC-FXQIFTODSA-N 0.000 description 1
- DCVYRWFAMZFSDA-ZLUOBGJFSA-N Ala-Ser-Ala Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(O)=O DCVYRWFAMZFSDA-ZLUOBGJFSA-N 0.000 description 1
- YJHKTAMKPGFJCT-NRPADANISA-N Ala-Val-Glu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O YJHKTAMKPGFJCT-NRPADANISA-N 0.000 description 1
- DHONNEYAZPNGSG-UBHSHLNASA-N Ala-Val-Phe Chemical compound C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 DHONNEYAZPNGSG-UBHSHLNASA-N 0.000 description 1
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 1
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 1
- 108010083359 Antigen Receptors Proteins 0.000 description 1
- 102000006306 Antigen Receptors Human genes 0.000 description 1
- 101100520452 Arabidopsis thaliana PMD2 gene Proteins 0.000 description 1
- MCYJBCKCAPERSE-FXQIFTODSA-N Arg-Ala-Asp Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCN=C(N)N MCYJBCKCAPERSE-FXQIFTODSA-N 0.000 description 1
- UXJCMQFPDWCHKX-DCAQKATOSA-N Arg-Arg-Glu Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCC(O)=O)C(O)=O UXJCMQFPDWCHKX-DCAQKATOSA-N 0.000 description 1
- HJVGMOYJDDXLMI-AVGNSLFASA-N Arg-Arg-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](N)CCCNC(N)=N HJVGMOYJDDXLMI-AVGNSLFASA-N 0.000 description 1
- MFAMTAVAFBPXDC-LPEHRKFASA-N Arg-Asp-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC(=O)O)NC(=O)[C@H](CCCN=C(N)N)N)C(=O)O MFAMTAVAFBPXDC-LPEHRKFASA-N 0.000 description 1
- PHHRSPBBQUFULD-UWVGGRQHSA-N Arg-Gly-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)CNC(=O)[C@H](CCCN=C(N)N)N PHHRSPBBQUFULD-UWVGGRQHSA-N 0.000 description 1
- NKNILFJYKKHBKE-WPRPVWTQSA-N Arg-Gly-Val Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](C(C)C)C(O)=O NKNILFJYKKHBKE-WPRPVWTQSA-N 0.000 description 1
- LKDHUGLXOHYINY-XUXIUFHCSA-N Arg-Ile-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCCN=C(N)N)N LKDHUGLXOHYINY-XUXIUFHCSA-N 0.000 description 1
- BTJVOUQWFXABOI-IHRRRGAJSA-N Arg-Lys-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CCCNC(N)=N BTJVOUQWFXABOI-IHRRRGAJSA-N 0.000 description 1
- VUGWHBXPMAHEGZ-SRVKXCTJSA-N Arg-Pro-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CCCN=C(N)N VUGWHBXPMAHEGZ-SRVKXCTJSA-N 0.000 description 1
- JOTRDIXZHNQYGP-DCAQKATOSA-N Arg-Ser-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CCCN=C(N)N)N JOTRDIXZHNQYGP-DCAQKATOSA-N 0.000 description 1
- QLSRIZIDQXDQHK-RCWTZXSCSA-N Arg-Val-Thr Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O QLSRIZIDQXDQHK-RCWTZXSCSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- HAJWYALLJIATCX-FXQIFTODSA-N Asn-Asn-Arg Chemical compound C(C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CC(=O)N)N)CN=C(N)N HAJWYALLJIATCX-FXQIFTODSA-N 0.000 description 1
- AYZAWXAPBAYCHO-CIUDSAMLSA-N Asn-Asn-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CC(=O)N)N AYZAWXAPBAYCHO-CIUDSAMLSA-N 0.000 description 1
- WPOLSNAQGVHROR-GUBZILKMSA-N Asn-Gln-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CC(=O)N)N WPOLSNAQGVHROR-GUBZILKMSA-N 0.000 description 1
- GJFYPBDMUGGLFR-NKWVEPMBSA-N Asn-Gly-Pro Chemical compound C1C[C@@H](N(C1)C(=O)CNC(=O)[C@H](CC(=O)N)N)C(=O)O GJFYPBDMUGGLFR-NKWVEPMBSA-N 0.000 description 1
- SUEIIIFUBHDCCS-PBCZWWQYSA-N Asn-His-Thr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O SUEIIIFUBHDCCS-PBCZWWQYSA-N 0.000 description 1
- ZJIFRAPZHAGLGR-MELADBBJSA-N Asn-Phe-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC2=CC=CC=C2)NC(=O)[C@H](CC(=O)N)N)C(=O)O ZJIFRAPZHAGLGR-MELADBBJSA-N 0.000 description 1
- XMHFCUKJRCQXGI-CIUDSAMLSA-N Asn-Pro-Gln Chemical compound C1C[C@H](N(C1)C(=O)[C@H](CC(=O)N)N)C(=O)N[C@@H](CCC(=O)N)C(=O)O XMHFCUKJRCQXGI-CIUDSAMLSA-N 0.000 description 1
- LMIWYCWRJVMAIQ-NHCYSSNCSA-N Asn-Val-Lys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC(=O)N)N LMIWYCWRJVMAIQ-NHCYSSNCSA-N 0.000 description 1
- BIVYLQMZPHDUIH-WHFBIAKZSA-N Asp-Gly-Cys Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CS)C(=O)O)N)C(=O)O BIVYLQMZPHDUIH-WHFBIAKZSA-N 0.000 description 1
- OMMIEVATLAGRCK-BYPYZUCNSA-N Asp-Gly-Gly Chemical compound OC(=O)C[C@H](N)C(=O)NCC(=O)NCC(O)=O OMMIEVATLAGRCK-BYPYZUCNSA-N 0.000 description 1
- SARSTIZOZFBDOM-FXQIFTODSA-N Asp-Met-Ala Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](C)C(O)=O SARSTIZOZFBDOM-FXQIFTODSA-N 0.000 description 1
- XMKXONRMGJXCJV-LAEOZQHASA-N Asp-Val-Glu Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O XMKXONRMGJXCJV-LAEOZQHASA-N 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 1
- 241000714230 Avian leukemia virus Species 0.000 description 1
- 208000003950 B-cell lymphoma Diseases 0.000 description 1
- 102100038080 B-cell receptor CD22 Human genes 0.000 description 1
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 1
- 206010004146 Basal cell carcinoma Diseases 0.000 description 1
- 101150013553 CD40 gene Proteins 0.000 description 1
- 102100025221 CD70 antigen Human genes 0.000 description 1
- 102100037904 CD9 antigen Human genes 0.000 description 1
- 102000000844 Cell Surface Receptors Human genes 0.000 description 1
- 108010001857 Cell Surface Receptors Proteins 0.000 description 1
- 108010035563 Chloramphenicol O-acetyltransferase Proteins 0.000 description 1
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 1
- VWFCHDSQECPREK-LURJTMIESA-N Cidofovir Chemical compound NC=1C=CN(C[C@@H](CO)OCP(O)(O)=O)C(=O)N=1 VWFCHDSQECPREK-LURJTMIESA-N 0.000 description 1
- 108091026890 Coding region Proteins 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 102000004420 Creatine Kinase Human genes 0.000 description 1
- 108010042126 Creatine kinase Proteins 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 1
- 108010036949 Cyclosporine Proteins 0.000 description 1
- DCXGXDGGXVZVMY-GHCJXIJMSA-N Cys-Asn-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CS DCXGXDGGXVZVMY-GHCJXIJMSA-N 0.000 description 1
- UPJGYXRAPJWIHD-CIUDSAMLSA-N Cys-Asn-Leu Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(O)=O UPJGYXRAPJWIHD-CIUDSAMLSA-N 0.000 description 1
- DQUWSUWXPWGTQT-DCAQKATOSA-N Cys-Pro-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CS DQUWSUWXPWGTQT-DCAQKATOSA-N 0.000 description 1
- WTXCNOPZMQRTNN-BWBBJGPYSA-N Cys-Thr-Ser Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CS)N)O WTXCNOPZMQRTNN-BWBBJGPYSA-N 0.000 description 1
- 206010050685 Cytokine storm Diseases 0.000 description 1
- 102000012410 DNA Ligases Human genes 0.000 description 1
- 108010061982 DNA Ligases Proteins 0.000 description 1
- XPOQHMRABVBWPR-UHFFFAOYSA-N Efavirenz Natural products O1C(=O)NC2=CC=C(Cl)C=C2C1(C(F)(F)F)C#CC1CC1 XPOQHMRABVBWPR-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 108700039691 Genetic Promoter Regions Proteins 0.000 description 1
- PHZYLYASFWHLHJ-FXQIFTODSA-N Gln-Asn-Glu Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O PHZYLYASFWHLHJ-FXQIFTODSA-N 0.000 description 1
- WQWMZOIPXWSZNE-WDSKDSINSA-N Gln-Asp-Gly Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(O)=O WQWMZOIPXWSZNE-WDSKDSINSA-N 0.000 description 1
- UICOTGULOUGGLC-NUMRIWBASA-N Gln-Asp-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CCC(=O)N)N)O UICOTGULOUGGLC-NUMRIWBASA-N 0.000 description 1
- NVEASDQHBRZPSU-BQBZGAKWSA-N Gln-Gln-Gly Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(O)=O NVEASDQHBRZPSU-BQBZGAKWSA-N 0.000 description 1
- SNLOOPZHAQDMJG-CIUDSAMLSA-N Gln-Glu-Glu Chemical compound NC(=O)CC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O SNLOOPZHAQDMJG-CIUDSAMLSA-N 0.000 description 1
- GNMQDOGFWYWPNM-LAEOZQHASA-N Gln-Gly-Ile Chemical compound CC[C@H](C)[C@H](NC(=O)CNC(=O)[C@@H](N)CCC(N)=O)C(O)=O GNMQDOGFWYWPNM-LAEOZQHASA-N 0.000 description 1
- JRHPEMVLTRADLJ-AVGNSLFASA-N Gln-Lys-Lys Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCC(=O)N)N JRHPEMVLTRADLJ-AVGNSLFASA-N 0.000 description 1
- MQJDLNRXBOELJW-KKUMJFAQSA-N Gln-Pro-Phe Chemical compound N[C@@H](CCC(N)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(O)=O MQJDLNRXBOELJW-KKUMJFAQSA-N 0.000 description 1
- XFHMVFKCQSHLKW-HJGDQZAQSA-N Gln-Thr-Met Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCSC)C(=O)O)NC(=O)[C@H](CCC(=O)N)N)O XFHMVFKCQSHLKW-HJGDQZAQSA-N 0.000 description 1
- STHSGOZLFLFGSS-SUSMZKCASA-N Gln-Thr-Thr Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O STHSGOZLFLFGSS-SUSMZKCASA-N 0.000 description 1
- MXOODARRORARSU-ACZMJKKPSA-N Glu-Ala-Ser Chemical compound C[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CCC(=O)O)N MXOODARRORARSU-ACZMJKKPSA-N 0.000 description 1
- KBKGRMNVKPSQIF-XDTLVQLUSA-N Glu-Ala-Tyr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O KBKGRMNVKPSQIF-XDTLVQLUSA-N 0.000 description 1
- LJLPOZGRPLORTF-CIUDSAMLSA-N Glu-Asn-Met Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCSC)C(O)=O LJLPOZGRPLORTF-CIUDSAMLSA-N 0.000 description 1
- LXAUHIRMWXQRKI-XHNCKOQMSA-N Glu-Asn-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC(=O)N)NC(=O)[C@H](CCC(=O)O)N)C(=O)O LXAUHIRMWXQRKI-XHNCKOQMSA-N 0.000 description 1
- DSPQRJXOIXHOHK-WDSKDSINSA-N Glu-Asp-Gly Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(O)=O DSPQRJXOIXHOHK-WDSKDSINSA-N 0.000 description 1
- SJPMNHCEWPTRBR-BQBZGAKWSA-N Glu-Glu-Gly Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(O)=O SJPMNHCEWPTRBR-BQBZGAKWSA-N 0.000 description 1
- PXXGVUVQWQGGIG-YUMQZZPRSA-N Glu-Gly-Arg Chemical compound OC(=O)CC[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CCCN=C(N)N PXXGVUVQWQGGIG-YUMQZZPRSA-N 0.000 description 1
- OGNJZUXUTPQVBR-BQBZGAKWSA-N Glu-Gly-Glu Chemical compound OC(=O)CC[C@H](N)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(O)=O OGNJZUXUTPQVBR-BQBZGAKWSA-N 0.000 description 1
- KRGZZKWSBGPLKL-IUCAKERBSA-N Glu-Gly-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)CNC(=O)[C@H](CCC(=O)O)N KRGZZKWSBGPLKL-IUCAKERBSA-N 0.000 description 1
- ZWQVYZXPYSYPJD-RYUDHWBXSA-N Glu-Gly-Phe Chemical compound OC(=O)CC[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 ZWQVYZXPYSYPJD-RYUDHWBXSA-N 0.000 description 1
- HPJLZFTUUJKWAJ-JHEQGTHGSA-N Glu-Gly-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(O)=O HPJLZFTUUJKWAJ-JHEQGTHGSA-N 0.000 description 1
- VGBSZQSKQRMLHD-MNXVOIDGSA-N Glu-Leu-Ile Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O VGBSZQSKQRMLHD-MNXVOIDGSA-N 0.000 description 1
- MWMJCGBSIORNCD-AVGNSLFASA-N Glu-Leu-Leu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O MWMJCGBSIORNCD-AVGNSLFASA-N 0.000 description 1
- QMOSCLNJVKSHHU-YUMQZZPRSA-N Glu-Met-Gly Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCSC)C(=O)NCC(O)=O QMOSCLNJVKSHHU-YUMQZZPRSA-N 0.000 description 1
- AAJHGGDRKHYSDH-GUBZILKMSA-N Glu-Pro-Gln Chemical compound C1C[C@H](N(C1)C(=O)[C@H](CCC(=O)O)N)C(=O)N[C@@H](CCC(=O)N)C(=O)O AAJHGGDRKHYSDH-GUBZILKMSA-N 0.000 description 1
- SWDNPSMMEWRNOH-HJGDQZAQSA-N Glu-Pro-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)O)C(O)=O SWDNPSMMEWRNOH-HJGDQZAQSA-N 0.000 description 1
- YQAQQKPWFOBSMU-WDCWCFNPSA-N Glu-Thr-Leu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O YQAQQKPWFOBSMU-WDCWCFNPSA-N 0.000 description 1
- MFVQGXGQRIXBPK-WDSKDSINSA-N Gly-Ala-Glu Chemical compound NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(O)=O MFVQGXGQRIXBPK-WDSKDSINSA-N 0.000 description 1
- VSVZIEVNUYDAFR-YUMQZZPRSA-N Gly-Ala-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)CN VSVZIEVNUYDAFR-YUMQZZPRSA-N 0.000 description 1
- JRDYDYXZKFNNRQ-XPUUQOCRSA-N Gly-Ala-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)CN JRDYDYXZKFNNRQ-XPUUQOCRSA-N 0.000 description 1
- JXYMPBCYRKWJEE-BQBZGAKWSA-N Gly-Arg-Ala Chemical compound [H]NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(O)=O JXYMPBCYRKWJEE-BQBZGAKWSA-N 0.000 description 1
- XXGQRGQPGFYECI-WDSKDSINSA-N Gly-Cys-Glu Chemical compound NCC(=O)N[C@@H](CS)C(=O)N[C@H](C(O)=O)CCC(O)=O XXGQRGQPGFYECI-WDSKDSINSA-N 0.000 description 1
- IXKRSKPKSLXIHN-YUMQZZPRSA-N Gly-Cys-Leu Chemical compound [H]NCC(=O)N[C@@H](CS)C(=O)N[C@@H](CC(C)C)C(O)=O IXKRSKPKSLXIHN-YUMQZZPRSA-N 0.000 description 1
- PDAWDNVHMUKWJR-ZETCQYMHSA-N Gly-Gly-His Chemical compound NCC(=O)NCC(=O)N[C@H](C(O)=O)CC1=CNC=N1 PDAWDNVHMUKWJR-ZETCQYMHSA-N 0.000 description 1
- VAXIVIPMCTYSHI-YUMQZZPRSA-N Gly-His-Asp Chemical compound C1=C(NC=N1)C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)O)NC(=O)CN VAXIVIPMCTYSHI-YUMQZZPRSA-N 0.000 description 1
- ALOBJFDJTMQQPW-ONGXEEELSA-N Gly-His-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CC1=CN=CN1)NC(=O)CN ALOBJFDJTMQQPW-ONGXEEELSA-N 0.000 description 1
- ULZCYBYDTUMHNF-IUCAKERBSA-N Gly-Leu-Glu Chemical compound NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O ULZCYBYDTUMHNF-IUCAKERBSA-N 0.000 description 1
- WDEHMRNSGHVNOH-VHSXEESVSA-N Gly-Lys-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCCCN)NC(=O)CN)C(=O)O WDEHMRNSGHVNOH-VHSXEESVSA-N 0.000 description 1
- WNZOCXUOGVYYBJ-CDMKHQONSA-N Gly-Phe-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)NC(=O)CN)O WNZOCXUOGVYYBJ-CDMKHQONSA-N 0.000 description 1
- NZOAFWHVAFJERA-OALUTQOASA-N Gly-Phe-Trp Chemical compound [H]NCC(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O NZOAFWHVAFJERA-OALUTQOASA-N 0.000 description 1
- HFPVRZWORNJRRC-UWVGGRQHSA-N Gly-Pro-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)CN HFPVRZWORNJRRC-UWVGGRQHSA-N 0.000 description 1
- OCPPBNKYGYSLOE-IUCAKERBSA-N Gly-Pro-Met Chemical compound CSCC[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)CN OCPPBNKYGYSLOE-IUCAKERBSA-N 0.000 description 1
- SOEGEPHNZOISMT-BYPYZUCNSA-N Gly-Ser-Gly Chemical compound NCC(=O)N[C@@H](CO)C(=O)NCC(O)=O SOEGEPHNZOISMT-BYPYZUCNSA-N 0.000 description 1
- POJJAZJHBGXEGM-YUMQZZPRSA-N Gly-Ser-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)CN POJJAZJHBGXEGM-YUMQZZPRSA-N 0.000 description 1
- ZZWUYQXMIFTIIY-WEDXCCLWSA-N Gly-Thr-Leu Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O ZZWUYQXMIFTIIY-WEDXCCLWSA-N 0.000 description 1
- CUVBTVWFVIIDOC-YEPSODPASA-N Gly-Thr-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)CN CUVBTVWFVIIDOC-YEPSODPASA-N 0.000 description 1
- BAYQNCWLXIDLHX-ONGXEEELSA-N Gly-Val-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)CN BAYQNCWLXIDLHX-ONGXEEELSA-N 0.000 description 1
- IZVICCORZOSGPT-JSGCOSHPSA-N Gly-Val-Tyr Chemical compound [H]NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O IZVICCORZOSGPT-JSGCOSHPSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 229930186217 Glycolipid Natural products 0.000 description 1
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 1
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 1
- 102000001398 Granzyme Human genes 0.000 description 1
- 108060005986 Granzyme Proteins 0.000 description 1
- 101150090209 HCST gene Proteins 0.000 description 1
- 208000002250 Hematologic Neoplasms Diseases 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- LIEIYPBMQJLASB-SRVKXCTJSA-N His-Gln-Arg Chemical compound NC(N)=NCCC[C@@H](C(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CC1=CN=CN1 LIEIYPBMQJLASB-SRVKXCTJSA-N 0.000 description 1
- STWGDDDFLUFCCA-GVXVVHGQSA-N His-Glu-Val Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O STWGDDDFLUFCCA-GVXVVHGQSA-N 0.000 description 1
- OZBDSFBWIDPVDA-BZSNNMDCSA-N His-His-Phe Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)O)NC(=O)[C@H](CC2=CN=CN2)NC(=O)[C@H](CC3=CN=CN3)N OZBDSFBWIDPVDA-BZSNNMDCSA-N 0.000 description 1
- BXOLYFJYQQRQDJ-MXAVVETBSA-N His-Leu-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC1=CN=CN1)N BXOLYFJYQQRQDJ-MXAVVETBSA-N 0.000 description 1
- UXSATKFPUVZVDK-KKUMJFAQSA-N His-Lys-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC1=CN=CN1)N UXSATKFPUVZVDK-KKUMJFAQSA-N 0.000 description 1
- YYOCMTFVGKDNQP-IHRRRGAJSA-N His-Met-Lys Chemical compound CSCC[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC1=CN=CN1)N YYOCMTFVGKDNQP-IHRRRGAJSA-N 0.000 description 1
- ZFDKSLBEWYCOCS-BZSNNMDCSA-N His-Phe-Lys Chemical compound C([C@@H](C(=O)N[C@@H](CCCCN)C(O)=O)NC(=O)[C@@H](N)CC=1NC=NC=1)C1=CC=CC=C1 ZFDKSLBEWYCOCS-BZSNNMDCSA-N 0.000 description 1
- FCPSGEVYIVXPPO-QTKMDUPCSA-N His-Thr-Arg Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O FCPSGEVYIVXPPO-QTKMDUPCSA-N 0.000 description 1
- 208000021519 Hodgkin lymphoma Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000884305 Homo sapiens B-cell receptor CD22 Proteins 0.000 description 1
- 101000934356 Homo sapiens CD70 antigen Proteins 0.000 description 1
- 101000738354 Homo sapiens CD9 antigen Proteins 0.000 description 1
- 101000913074 Homo sapiens High affinity immunoglobulin gamma Fc receptor I Proteins 0.000 description 1
- 101000935040 Homo sapiens Integrin beta-2 Proteins 0.000 description 1
- 101000777628 Homo sapiens Leukocyte antigen CD37 Proteins 0.000 description 1
- 101000917858 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor III-A Proteins 0.000 description 1
- 101000917839 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor III-B Proteins 0.000 description 1
- 101000934338 Homo sapiens Myeloid cell surface antigen CD33 Proteins 0.000 description 1
- 101001109501 Homo sapiens NKG2-D type II integral membrane protein Proteins 0.000 description 1
- 101001117317 Homo sapiens Programmed cell death 1 ligand 1 Proteins 0.000 description 1
- 101000738771 Homo sapiens Receptor-type tyrosine-protein phosphatase C Proteins 0.000 description 1
- 101000934346 Homo sapiens T-cell surface antigen CD2 Proteins 0.000 description 1
- 101000934341 Homo sapiens T-cell surface glycoprotein CD5 Proteins 0.000 description 1
- 101000914484 Homo sapiens T-lymphocyte activation antigen CD80 Proteins 0.000 description 1
- 101000831567 Homo sapiens Toll-like receptor 2 Proteins 0.000 description 1
- 101000801234 Homo sapiens Tumor necrosis factor receptor superfamily member 18 Proteins 0.000 description 1
- 101000851376 Homo sapiens Tumor necrosis factor receptor superfamily member 8 Proteins 0.000 description 1
- 108010073807 IgG Receptors Proteins 0.000 description 1
- QLRMMMQNCWBNPQ-QXEWZRGKSA-N Ile-Arg-Gly Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)NCC(=O)O)N QLRMMMQNCWBNPQ-QXEWZRGKSA-N 0.000 description 1
- IIXDMJNYALIKGP-DJFWLOJKSA-N Ile-Asn-His Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N IIXDMJNYALIKGP-DJFWLOJKSA-N 0.000 description 1
- KLBVGHCGHUNHEA-BJDJZHNGSA-N Ile-Leu-Ala Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)O)N KLBVGHCGHUNHEA-BJDJZHNGSA-N 0.000 description 1
- HPCFRQWLTRDGHT-AJNGGQMLSA-N Ile-Leu-Leu Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O HPCFRQWLTRDGHT-AJNGGQMLSA-N 0.000 description 1
- LRAUKBMYHHNADU-DKIMLUQUSA-N Ile-Phe-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)[C@@H](C)CC)CC1=CC=CC=C1 LRAUKBMYHHNADU-DKIMLUQUSA-N 0.000 description 1
- OWSWUWDMSNXTNE-GMOBBJLQSA-N Ile-Pro-Asp Chemical compound CC[C@H](C)[C@@H](C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(=O)O)C(=O)O)N OWSWUWDMSNXTNE-GMOBBJLQSA-N 0.000 description 1
- FXJLRZFMKGHYJP-CFMVVWHZSA-N Ile-Tyr-Asn Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CC(=O)N)C(=O)O)N FXJLRZFMKGHYJP-CFMVVWHZSA-N 0.000 description 1
- REXAUQBGSGDEJY-IGISWZIWSA-N Ile-Tyr-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)O)N REXAUQBGSGDEJY-IGISWZIWSA-N 0.000 description 1
- 229940076838 Immune checkpoint inhibitor Drugs 0.000 description 1
- 102000037984 Inhibitory immune checkpoint proteins Human genes 0.000 description 1
- 108091008026 Inhibitory immune checkpoint proteins Proteins 0.000 description 1
- 108010064593 Intercellular Adhesion Molecule-1 Proteins 0.000 description 1
- 102100037877 Intercellular adhesion molecule 1 Human genes 0.000 description 1
- 102000004889 Interleukin-6 Human genes 0.000 description 1
- 108090001005 Interleukin-6 Proteins 0.000 description 1
- PMGDADKJMCOXHX-UHFFFAOYSA-N L-Arginyl-L-glutamin-acetat Natural products NC(=N)NCCCC(N)C(=O)NC(CCC(N)=O)C(O)=O PMGDADKJMCOXHX-UHFFFAOYSA-N 0.000 description 1
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 1
- IBMVEYRWAWIOTN-UHFFFAOYSA-N L-Leucyl-L-Arginyl-L-Proline Natural products CC(C)CC(N)C(=O)NC(CCCN=C(N)N)C(=O)N1CCCC1C(O)=O IBMVEYRWAWIOTN-UHFFFAOYSA-N 0.000 description 1
- FADYJNXDPBKVCA-UHFFFAOYSA-N L-Phenylalanyl-L-lysin Natural products NCCCCC(C(O)=O)NC(=O)C(N)CC1=CC=CC=C1 FADYJNXDPBKVCA-UHFFFAOYSA-N 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 1
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 1
- 241000880493 Leptailurus serval Species 0.000 description 1
- WNGVUZWBXZKQES-YUMQZZPRSA-N Leu-Ala-Gly Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C)C(=O)NCC(O)=O WNGVUZWBXZKQES-YUMQZZPRSA-N 0.000 description 1
- XBBKIIGCUMBKCO-JXUBOQSCSA-N Leu-Ala-Thr Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O XBBKIIGCUMBKCO-JXUBOQSCSA-N 0.000 description 1
- MYGQXVYRZMKRDB-SRVKXCTJSA-N Leu-Asp-Lys Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CCCCN MYGQXVYRZMKRDB-SRVKXCTJSA-N 0.000 description 1
- NEEOBPIXKWSBRF-IUCAKERBSA-N Leu-Glu-Gly Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(O)=O NEEOBPIXKWSBRF-IUCAKERBSA-N 0.000 description 1
- VBZOAGIPCULURB-QWRGUYRKSA-N Leu-Gly-His Chemical compound CC(C)C[C@@H](C(=O)NCC(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N VBZOAGIPCULURB-QWRGUYRKSA-N 0.000 description 1
- JRJLGNFWYFSJHB-HOCLYGCPSA-N Leu-Gly-Trp Chemical compound [H]N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O JRJLGNFWYFSJHB-HOCLYGCPSA-N 0.000 description 1
- ORWTWZXGDBYVCP-BJDJZHNGSA-N Leu-Ile-Cys Chemical compound SC[C@@H](C(O)=O)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H](N)CC(C)C ORWTWZXGDBYVCP-BJDJZHNGSA-N 0.000 description 1
- HNDWYLYAYNBWMP-AJNGGQMLSA-N Leu-Ile-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC(C)C)N HNDWYLYAYNBWMP-AJNGGQMLSA-N 0.000 description 1
- NRFGTHFONZYFNY-MGHWNKPDSA-N Leu-Ile-Tyr Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 NRFGTHFONZYFNY-MGHWNKPDSA-N 0.000 description 1
- UCNNZELZXFXXJQ-BZSNNMDCSA-N Leu-Leu-Tyr Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 UCNNZELZXFXXJQ-BZSNNMDCSA-N 0.000 description 1
- DRWMRVFCKKXHCH-BZSNNMDCSA-N Leu-Phe-Leu Chemical compound CC(C)C[C@H]([NH3+])C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C([O-])=O)CC1=CC=CC=C1 DRWMRVFCKKXHCH-BZSNNMDCSA-N 0.000 description 1
- XXXXOVFBXRERQL-ULQDDVLXSA-N Leu-Pro-Phe Chemical compound CC(C)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 XXXXOVFBXRERQL-ULQDDVLXSA-N 0.000 description 1
- CHJKEDSZNSONPS-DCAQKATOSA-N Leu-Pro-Ser Chemical compound [H]N[C@@H](CC(C)C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O CHJKEDSZNSONPS-DCAQKATOSA-N 0.000 description 1
- IRMLZWSRWSGTOP-CIUDSAMLSA-N Leu-Ser-Ala Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(O)=O IRMLZWSRWSGTOP-CIUDSAMLSA-N 0.000 description 1
- IDGZVZJLYFTXSL-DCAQKATOSA-N Leu-Ser-Arg Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CCCN=C(N)N IDGZVZJLYFTXSL-DCAQKATOSA-N 0.000 description 1
- XOWMDXHFSBCAKQ-SRVKXCTJSA-N Leu-Ser-Leu Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CC(C)C XOWMDXHFSBCAKQ-SRVKXCTJSA-N 0.000 description 1
- SBANPBVRHYIMRR-UHFFFAOYSA-N Leu-Ser-Pro Natural products CC(C)CC(N)C(=O)NC(CO)C(=O)N1CCCC1C(O)=O SBANPBVRHYIMRR-UHFFFAOYSA-N 0.000 description 1
- ZJZNLRVCZWUONM-JXUBOQSCSA-N Leu-Thr-Ala Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O ZJZNLRVCZWUONM-JXUBOQSCSA-N 0.000 description 1
- SUYRAPCRSCCPAK-VFAJRCTISA-N Leu-Trp-Thr Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H]([C@@H](C)O)C(O)=O SUYRAPCRSCCPAK-VFAJRCTISA-N 0.000 description 1
- AXVIGSRGTMNSJU-YESZJQIVSA-N Leu-Tyr-Pro Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N2CCC[C@@H]2C(=O)O)N AXVIGSRGTMNSJU-YESZJQIVSA-N 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- 102100031586 Leukocyte antigen CD37 Human genes 0.000 description 1
- 239000000232 Lipid Bilayer Substances 0.000 description 1
- 102100029185 Low affinity immunoglobulin gamma Fc region receptor III-B Human genes 0.000 description 1
- 108010064548 Lymphocyte Function-Associated Antigen-1 Proteins 0.000 description 1
- IRNSXVOWSXSULE-DCAQKATOSA-N Lys-Ala-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCCN IRNSXVOWSXSULE-DCAQKATOSA-N 0.000 description 1
- GAOJCVKPIGHTGO-UWVGGRQHSA-N Lys-Arg-Gly Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O GAOJCVKPIGHTGO-UWVGGRQHSA-N 0.000 description 1
- FACUGMGEFUEBTI-SRVKXCTJSA-N Lys-Asn-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CCCCN FACUGMGEFUEBTI-SRVKXCTJSA-N 0.000 description 1
- KWUKZRFFKPLUPE-HJGDQZAQSA-N Lys-Asp-Thr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O KWUKZRFFKPLUPE-HJGDQZAQSA-N 0.000 description 1
- XFBBBRDEQIPGNR-KATARQTJSA-N Lys-Cys-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CS)NC(=O)[C@H](CCCCN)N)O XFBBBRDEQIPGNR-KATARQTJSA-N 0.000 description 1
- NNCDAORZCMPZPX-GUBZILKMSA-N Lys-Gln-Ser Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CO)C(=O)O)N NNCDAORZCMPZPX-GUBZILKMSA-N 0.000 description 1
- ZXEUFAVXODIPHC-GUBZILKMSA-N Lys-Glu-Asn Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O ZXEUFAVXODIPHC-GUBZILKMSA-N 0.000 description 1
- NJNRBRKHOWSGMN-SRVKXCTJSA-N Lys-Leu-Asn Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O NJNRBRKHOWSGMN-SRVKXCTJSA-N 0.000 description 1
- VMTYLUGCXIEDMV-QWRGUYRKSA-N Lys-Leu-Gly Chemical compound OC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCCCN VMTYLUGCXIEDMV-QWRGUYRKSA-N 0.000 description 1
- VUTWYNQUSJWBHO-BZSNNMDCSA-N Lys-Leu-Tyr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O VUTWYNQUSJWBHO-BZSNNMDCSA-N 0.000 description 1
- LJADEBULDNKJNK-IHRRRGAJSA-N Lys-Leu-Val Chemical compound CC(C)C[C@H](NC(=O)[C@@H](N)CCCCN)C(=O)N[C@@H](C(C)C)C(O)=O LJADEBULDNKJNK-IHRRRGAJSA-N 0.000 description 1
- ATNKHRAIZCMCCN-BZSNNMDCSA-N Lys-Lys-Phe Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCCN)N ATNKHRAIZCMCCN-BZSNNMDCSA-N 0.000 description 1
- PLDJDCJLRCYPJB-VOAKCMCISA-N Lys-Lys-Thr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O PLDJDCJLRCYPJB-VOAKCMCISA-N 0.000 description 1
- URGPVYGVWLIRGT-DCAQKATOSA-N Lys-Met-Ala Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](C)C(O)=O URGPVYGVWLIRGT-DCAQKATOSA-N 0.000 description 1
- KVNLHIXLLZBAFQ-RWMBFGLXSA-N Lys-Met-Pro Chemical compound CSCC[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCCCN)N KVNLHIXLLZBAFQ-RWMBFGLXSA-N 0.000 description 1
- BOJYMMBYBNOOGG-DCAQKATOSA-N Lys-Pro-Ala Chemical compound [H]N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C)C(O)=O BOJYMMBYBNOOGG-DCAQKATOSA-N 0.000 description 1
- MIROMRNASYKZNL-ULQDDVLXSA-N Lys-Pro-Tyr Chemical compound NCCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 MIROMRNASYKZNL-ULQDDVLXSA-N 0.000 description 1
- YCJCEMKOZOYBEF-OEAJRASXSA-N Lys-Thr-Phe Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O YCJCEMKOZOYBEF-OEAJRASXSA-N 0.000 description 1
- CAVRAQIDHUPECU-UVOCVTCTSA-N Lys-Thr-Thr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O CAVRAQIDHUPECU-UVOCVTCTSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 108010052285 Membrane Proteins Proteins 0.000 description 1
- ZEDVFJPQNNBMST-CYDGBPFRSA-N Met-Arg-Ile Chemical compound [H]N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O ZEDVFJPQNNBMST-CYDGBPFRSA-N 0.000 description 1
- HHCOOFPGNXKFGR-HJGDQZAQSA-N Met-Gln-Thr Chemical compound [H]N[C@@H](CCSC)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O HHCOOFPGNXKFGR-HJGDQZAQSA-N 0.000 description 1
- YORIKIDJCPKBON-YUMQZZPRSA-N Met-Glu-Gly Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(O)=O YORIKIDJCPKBON-YUMQZZPRSA-N 0.000 description 1
- WRLYTJVPSUBYST-AVGNSLFASA-N Met-His-Met Chemical compound CSCC[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)N[C@@H](CCSC)C(=O)O)N WRLYTJVPSUBYST-AVGNSLFASA-N 0.000 description 1
- WTHGNAAQXISJHP-AVGNSLFASA-N Met-Lys-Val Chemical compound [H]N[C@@H](CCSC)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(O)=O WTHGNAAQXISJHP-AVGNSLFASA-N 0.000 description 1
- VSJAPSMRFYUOKS-IUCAKERBSA-N Met-Pro-Gly Chemical compound CSCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O VSJAPSMRFYUOKS-IUCAKERBSA-N 0.000 description 1
- RMLLCGYYVZKKRT-CIUDSAMLSA-N Met-Ser-Glu Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CCC(O)=O RMLLCGYYVZKKRT-CIUDSAMLSA-N 0.000 description 1
- AOLKTFKKSSMRTA-WDSOQIARSA-N Met-Trp-His Chemical compound CSCC[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)N[C@@H](CC3=CN=CN3)C(=O)O)N AOLKTFKKSSMRTA-WDSOQIARSA-N 0.000 description 1
- CULGJGUDIJATIP-STQMWFEESA-N Met-Tyr-Gly Chemical compound CSCC[C@H](N)C(=O)N[C@H](C(=O)NCC(O)=O)CC1=CC=C(O)C=C1 CULGJGUDIJATIP-STQMWFEESA-N 0.000 description 1
- 102000003792 Metallothionein Human genes 0.000 description 1
- 108090000157 Metallothionein Proteins 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000713333 Mouse mammary tumor virus Species 0.000 description 1
- 241000714177 Murine leukemia virus Species 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 1
- 102100025243 Myeloid cell surface antigen CD33 Human genes 0.000 description 1
- 102000003505 Myosin Human genes 0.000 description 1
- 108060008487 Myosin Proteins 0.000 description 1
- PESQCPHRXOFIPX-UHFFFAOYSA-N N-L-methionyl-L-tyrosine Natural products CSCCC(N)C(=O)NC(C(O)=O)CC1=CC=C(O)C=C1 PESQCPHRXOFIPX-UHFFFAOYSA-N 0.000 description 1
- KZNQNBZMBZJQJO-UHFFFAOYSA-N N-glycyl-L-proline Natural products NCC(=O)N1CCCC1C(O)=O KZNQNBZMBZJQJO-UHFFFAOYSA-N 0.000 description 1
- 102100022680 NKG2-D type II integral membrane protein Human genes 0.000 description 1
- 108091034117 Oligonucleotide Proteins 0.000 description 1
- 108010038807 Oligopeptides Proteins 0.000 description 1
- 102000015636 Oligopeptides Human genes 0.000 description 1
- KHGNFPUMBJSZSM-UHFFFAOYSA-N Perforine Natural products COC1=C2CCC(O)C(CCC(C)(C)O)(OC)C2=NC2=C1C=CO2 KHGNFPUMBJSZSM-UHFFFAOYSA-N 0.000 description 1
- IUVYJBMTHARMIP-PCBIJLKTSA-N Phe-Asp-Ile Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O IUVYJBMTHARMIP-PCBIJLKTSA-N 0.000 description 1
- YTILBRIUASDGBL-BZSNNMDCSA-N Phe-Leu-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC1=CC=CC=C1 YTILBRIUASDGBL-BZSNNMDCSA-N 0.000 description 1
- BNRFQGLWLQESBG-YESZJQIVSA-N Phe-Lys-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCCCN)NC(=O)[C@H](CC2=CC=CC=C2)N)C(=O)O BNRFQGLWLQESBG-YESZJQIVSA-N 0.000 description 1
- RBRNEFJTEHPDSL-ACRUOGEOSA-N Phe-Phe-Lys Chemical compound C([C@@H](C(=O)N[C@@H](CCCCN)C(O)=O)NC(=O)[C@@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 RBRNEFJTEHPDSL-ACRUOGEOSA-N 0.000 description 1
- QARPMYDMYVLFMW-KKUMJFAQSA-N Phe-Pro-Glu Chemical compound C([C@H](N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(O)=O)C1=CC=CC=C1 QARPMYDMYVLFMW-KKUMJFAQSA-N 0.000 description 1
- ILGCZYGFYQLSDZ-KKUMJFAQSA-N Phe-Ser-His Chemical compound N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CO)C(=O)N[C@@H](Cc1cnc[nH]1)C(O)=O ILGCZYGFYQLSDZ-KKUMJFAQSA-N 0.000 description 1
- 208000009052 Precursor T-Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 1
- 208000017414 Precursor T-cell acute lymphoblastic leukemia Diseases 0.000 description 1
- FYQSMXKJYTZYRP-DCAQKATOSA-N Pro-Ala-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1 FYQSMXKJYTZYRP-DCAQKATOSA-N 0.000 description 1
- CGBYDGAJHSOGFQ-LPEHRKFASA-N Pro-Ala-Pro Chemical compound C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@@H]2CCCN2 CGBYDGAJHSOGFQ-LPEHRKFASA-N 0.000 description 1
- ICTZKEXYDDZZFP-SRVKXCTJSA-N Pro-Arg-Pro Chemical compound N([C@@H](CCCN=C(N)N)C(=O)N1[C@@H](CCC1)C(O)=O)C(=O)[C@@H]1CCCN1 ICTZKEXYDDZZFP-SRVKXCTJSA-N 0.000 description 1
- HXOLCSYHGRNXJJ-IHRRRGAJSA-N Pro-Asp-Phe Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O HXOLCSYHGRNXJJ-IHRRRGAJSA-N 0.000 description 1
- ZCXQTRXYZOSGJR-FXQIFTODSA-N Pro-Asp-Ser Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O ZCXQTRXYZOSGJR-FXQIFTODSA-N 0.000 description 1
- DIFXZGPHVCIVSQ-CIUDSAMLSA-N Pro-Gln-Ser Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(O)=O DIFXZGPHVCIVSQ-CIUDSAMLSA-N 0.000 description 1
- FRKBNXCFJBPJOL-GUBZILKMSA-N Pro-Glu-Glu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O FRKBNXCFJBPJOL-GUBZILKMSA-N 0.000 description 1
- ZUZINZIJHJFJRN-UBHSHLNASA-N Pro-Phe-Ala Chemical compound C([C@@H](C(=O)N[C@@H](C)C(O)=O)NC(=O)[C@H]1NCCC1)C1=CC=CC=C1 ZUZINZIJHJFJRN-UBHSHLNASA-N 0.000 description 1
- OWQXAJQZLWHPBH-FXQIFTODSA-N Pro-Ser-Asn Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O OWQXAJQZLWHPBH-FXQIFTODSA-N 0.000 description 1
- SXJOPONICMGFCR-DCAQKATOSA-N Pro-Ser-Lys Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)O SXJOPONICMGFCR-DCAQKATOSA-N 0.000 description 1
- XRGIDCGRSSWCKE-SRVKXCTJSA-N Pro-Val-Met Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCSC)C(O)=O XRGIDCGRSSWCKE-SRVKXCTJSA-N 0.000 description 1
- ZMLRZBWCXPQADC-TUAOUCFPSA-N Pro-Val-Pro Chemical compound CC(C)[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@@H]2CCCN2 ZMLRZBWCXPQADC-TUAOUCFPSA-N 0.000 description 1
- 102100024216 Programmed cell death 1 ligand 1 Human genes 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 102100037422 Receptor-type tyrosine-protein phosphatase C Human genes 0.000 description 1
- 108091028664 Ribonucleotide Proteins 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 241000714474 Rous sarcoma virus Species 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- QVOGDCQNGLBNCR-FXQIFTODSA-N Ser-Arg-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(O)=O QVOGDCQNGLBNCR-FXQIFTODSA-N 0.000 description 1
- XVAUJOAYHWWNQF-ZLUOBGJFSA-N Ser-Asn-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(O)=O XVAUJOAYHWWNQF-ZLUOBGJFSA-N 0.000 description 1
- BLPYXIXXCFVIIF-FXQIFTODSA-N Ser-Cys-Arg Chemical compound C(C[C@@H](C(=O)O)NC(=O)[C@H](CS)NC(=O)[C@H](CO)N)CN=C(N)N BLPYXIXXCFVIIF-FXQIFTODSA-N 0.000 description 1
- CRZRTKAVUUGKEQ-ACZMJKKPSA-N Ser-Gln-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(O)=O CRZRTKAVUUGKEQ-ACZMJKKPSA-N 0.000 description 1
- BQWCDDAISCPDQV-XHNCKOQMSA-N Ser-Gln-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CO)N)C(=O)O BQWCDDAISCPDQV-XHNCKOQMSA-N 0.000 description 1
- YRBGKVIWMNEVCZ-WDSKDSINSA-N Ser-Glu-Gly Chemical compound OC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(O)=O YRBGKVIWMNEVCZ-WDSKDSINSA-N 0.000 description 1
- GJFYFGOEWLDQGW-GUBZILKMSA-N Ser-Leu-Gln Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CO)N GJFYFGOEWLDQGW-GUBZILKMSA-N 0.000 description 1
- VMLONWHIORGALA-SRVKXCTJSA-N Ser-Leu-Leu Chemical compound CC(C)C[C@@H](C([O-])=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H]([NH3+])CO VMLONWHIORGALA-SRVKXCTJSA-N 0.000 description 1
- CRJZZXMAADSBBQ-SRVKXCTJSA-N Ser-Lys-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CO CRJZZXMAADSBBQ-SRVKXCTJSA-N 0.000 description 1
- TVPQRPNBYCRRLL-IHRRRGAJSA-N Ser-Phe-Met Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCSC)C(O)=O TVPQRPNBYCRRLL-IHRRRGAJSA-N 0.000 description 1
- RWDVVSKYZBNDCO-MELADBBJSA-N Ser-Phe-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC2=CC=CC=C2)NC(=O)[C@H](CO)N)C(=O)O RWDVVSKYZBNDCO-MELADBBJSA-N 0.000 description 1
- WNDUPCKKKGSKIQ-CIUDSAMLSA-N Ser-Pro-Gln Chemical compound OC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(O)=O WNDUPCKKKGSKIQ-CIUDSAMLSA-N 0.000 description 1
- FKYWFUYPVKLJLP-DCAQKATOSA-N Ser-Pro-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CO FKYWFUYPVKLJLP-DCAQKATOSA-N 0.000 description 1
- KKKVOZNCLALMPV-XKBZYTNZSA-N Ser-Thr-Glu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(O)=O)C(O)=O KKKVOZNCLALMPV-XKBZYTNZSA-N 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 241000700584 Simplexvirus Species 0.000 description 1
- 208000029052 T-cell acute lymphoblastic leukemia Diseases 0.000 description 1
- 102100025237 T-cell surface antigen CD2 Human genes 0.000 description 1
- 102100025244 T-cell surface glycoprotein CD5 Human genes 0.000 description 1
- 102100027222 T-lymphocyte activation antigen CD80 Human genes 0.000 description 1
- QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-N 0.000 description 1
- 239000004098 Tetracycline Substances 0.000 description 1
- CAJFZCICSVBOJK-SHGPDSBTSA-N Thr-Ala-Thr Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O CAJFZCICSVBOJK-SHGPDSBTSA-N 0.000 description 1
- WLDUCKSCDRIVLJ-NUMRIWBASA-N Thr-Gln-Asp Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CC(=O)O)C(=O)O)N)O WLDUCKSCDRIVLJ-NUMRIWBASA-N 0.000 description 1
- UHBPFYOQQPFKQR-JHEQGTHGSA-N Thr-Gln-Gly Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(O)=O UHBPFYOQQPFKQR-JHEQGTHGSA-N 0.000 description 1
- KGKWKSSSQGGYAU-SUSMZKCASA-N Thr-Gln-Thr Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H]([C@@H](C)O)C(=O)O)N)O KGKWKSSSQGGYAU-SUSMZKCASA-N 0.000 description 1
- SHOMROOOQBDGRL-JHEQGTHGSA-N Thr-Glu-Gly Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(O)=O SHOMROOOQBDGRL-JHEQGTHGSA-N 0.000 description 1
- RFKVQLIXNVEOMB-WEDXCCLWSA-N Thr-Leu-Gly Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)O)N)O RFKVQLIXNVEOMB-WEDXCCLWSA-N 0.000 description 1
- HSQXHRIRJSFDOH-URLPEUOOSA-N Thr-Phe-Ile Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O HSQXHRIRJSFDOH-URLPEUOOSA-N 0.000 description 1
- AHERARIZBPOMNU-KATARQTJSA-N Thr-Ser-Leu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O AHERARIZBPOMNU-KATARQTJSA-N 0.000 description 1
- WKGAAMOJPMBBMC-IXOXFDKPSA-N Thr-Ser-Phe Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O WKGAAMOJPMBBMC-IXOXFDKPSA-N 0.000 description 1
- COYHRQWNJDJCNA-NUJDXYNKSA-N Thr-Thr-Thr Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O COYHRQWNJDJCNA-NUJDXYNKSA-N 0.000 description 1
- XGUAUKUYQHBUNY-SWRJLBSHSA-N Thr-Trp-Glu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CCC(O)=O)C(O)=O XGUAUKUYQHBUNY-SWRJLBSHSA-N 0.000 description 1
- BEZTUFWTPVOROW-KJEVXHAQSA-N Thr-Tyr-Arg Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N)O BEZTUFWTPVOROW-KJEVXHAQSA-N 0.000 description 1
- REJRKTOJTCPDPO-IRIUXVKKSA-N Thr-Tyr-Glu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCC(O)=O)C(O)=O REJRKTOJTCPDPO-IRIUXVKKSA-N 0.000 description 1
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- 102000006601 Thymidine Kinase Human genes 0.000 description 1
- 108020004440 Thymidine kinase Proteins 0.000 description 1
- 102100024333 Toll-like receptor 2 Human genes 0.000 description 1
- 108700019146 Transgenes Proteins 0.000 description 1
- VZBWRZGNEPBRDE-HZUKXOBISA-N Trp-Ala-Pro Chemical compound C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CC2=CNC3=CC=CC=C32)N VZBWRZGNEPBRDE-HZUKXOBISA-N 0.000 description 1
- NXJZCPKZIKTYLX-XEGUGMAKSA-N Trp-Glu-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)N NXJZCPKZIKTYLX-XEGUGMAKSA-N 0.000 description 1
- PKUJMYZNJMRHEZ-XIRDDKMYSA-N Trp-Glu-Arg Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O PKUJMYZNJMRHEZ-XIRDDKMYSA-N 0.000 description 1
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 1
- 108060008683 Tumor Necrosis Factor Receptor Proteins 0.000 description 1
- 102100033728 Tumor necrosis factor receptor superfamily member 18 Human genes 0.000 description 1
- 102100040245 Tumor necrosis factor receptor superfamily member 5 Human genes 0.000 description 1
- 102100036857 Tumor necrosis factor receptor superfamily member 8 Human genes 0.000 description 1
- GAYLGYUVTDMLKC-UWJYBYFXSA-N Tyr-Asp-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 GAYLGYUVTDMLKC-UWJYBYFXSA-N 0.000 description 1
- XKDOQXAXKFQWQJ-SRVKXCTJSA-N Tyr-Cys-Asp Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(=O)O)C(=O)O)N)O XKDOQXAXKFQWQJ-SRVKXCTJSA-N 0.000 description 1
- HVHJYXDXRIWELT-RYUDHWBXSA-N Tyr-Glu-Gly Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(O)=O HVHJYXDXRIWELT-RYUDHWBXSA-N 0.000 description 1
- CDBXVDXSLPLFMD-BPNCWPANSA-N Tyr-Pro-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CC1=CC=C(O)C=C1 CDBXVDXSLPLFMD-BPNCWPANSA-N 0.000 description 1
- DDRBQONWVBDQOY-GUBZILKMSA-N Val-Ala-Arg Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O DDRBQONWVBDQOY-GUBZILKMSA-N 0.000 description 1
- BYOHPUZJVXWHAE-BYULHYEWSA-N Val-Asn-Asn Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC(=O)N)C(=O)O)N BYOHPUZJVXWHAE-BYULHYEWSA-N 0.000 description 1
- QGFPYRPIUXBYGR-YDHLFZDLSA-N Val-Asn-Phe Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)N QGFPYRPIUXBYGR-YDHLFZDLSA-N 0.000 description 1
- VLDMQVZZWDOKQF-AUTRQRHGSA-N Val-Glu-Gln Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N VLDMQVZZWDOKQF-AUTRQRHGSA-N 0.000 description 1
- QRVPEKJBBRYISE-XUXIUFHCSA-N Val-Lys-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C(C)C)N QRVPEKJBBRYISE-XUXIUFHCSA-N 0.000 description 1
- HPANGHISDXDUQY-ULQDDVLXSA-N Val-Lys-Phe Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)N HPANGHISDXDUQY-ULQDDVLXSA-N 0.000 description 1
- OFQGGTGZTOTLGH-NHCYSSNCSA-N Val-Met-Gln Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N OFQGGTGZTOTLGH-NHCYSSNCSA-N 0.000 description 1
- SDHZOOIGIUEPDY-JYJNAYRXSA-N Val-Ser-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](CO)NC(=O)[C@@H](N)C(C)C)C(O)=O)=CNC2=C1 SDHZOOIGIUEPDY-JYJNAYRXSA-N 0.000 description 1
- JAIZPWVHPQRYOU-ZJDVBMNYSA-N Val-Thr-Thr Chemical compound C[C@H]([C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)O)NC(=O)[C@H](C(C)C)N)O JAIZPWVHPQRYOU-ZJDVBMNYSA-N 0.000 description 1
- LLJLBRRXKZTTRD-GUBZILKMSA-N Val-Val-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(=O)O)N LLJLBRRXKZTTRD-GUBZILKMSA-N 0.000 description 1
- JVGDAEKKZKKZFO-RCWTZXSCSA-N Val-Val-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](C(C)C)N)O JVGDAEKKZKKZFO-RCWTZXSCSA-N 0.000 description 1
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 108091093126 WHP Posttrascriptional Response Element Proteins 0.000 description 1
- 208000033559 Waldenström macroglobulinemia Diseases 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- SAZUGELZHZOXHB-UHFFFAOYSA-N acecarbromal Chemical compound CCC(Br)(CC)C(=O)NC(=O)NC(C)=O SAZUGELZHZOXHB-UHFFFAOYSA-N 0.000 description 1
- 208000017733 acquired polycythemia vera Diseases 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 108010041407 alanylaspartic acid Proteins 0.000 description 1
- 108010011559 alanylphenylalanine Proteins 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000001414 amino alcohols Chemical class 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 238000009175 antibody therapy Methods 0.000 description 1
- 239000002246 antineoplastic agent 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
- 108010008355 arginyl-glutamine Proteins 0.000 description 1
- 108010069926 arginyl-glycyl-serine Proteins 0.000 description 1
- 239000000823 artificial membrane Substances 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
- 229960002170 azathioprine Drugs 0.000 description 1
- LMEKQMALGUDUQG-UHFFFAOYSA-N azathioprine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC=NC2=C1NC=N2 LMEKQMALGUDUQG-UHFFFAOYSA-N 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 108010005774 beta-Galactosidase Proteins 0.000 description 1
- 102000005936 beta-Galactosidase Human genes 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
- 102000023732 binding proteins Human genes 0.000 description 1
- 108091008324 binding proteins Proteins 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 238000010170 biological method Methods 0.000 description 1
- 238000001815 biotherapy Methods 0.000 description 1
- 229960002685 biotin Drugs 0.000 description 1
- 235000020958 biotin Nutrition 0.000 description 1
- 239000011616 biotin Substances 0.000 description 1
- 201000000053 blastoma Diseases 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 238000010322 bone marrow transplantation Methods 0.000 description 1
- 201000008275 breast carcinoma Diseases 0.000 description 1
- 101150058049 car gene Proteins 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000004709 cell invasion Effects 0.000 description 1
- 229940030156 cell vaccine Drugs 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 208000011654 childhood malignant neoplasm Diseases 0.000 description 1
- 208000012191 childhood neoplasm Diseases 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 208000024207 chronic leukemia Diseases 0.000 description 1
- 229960001265 ciclosporin Drugs 0.000 description 1
- 229960000724 cidofovir Drugs 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 238000010367 cloning Methods 0.000 description 1
- 238000012761 co-transfection Methods 0.000 description 1
- 238000001246 colloidal dispersion Methods 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 108091008034 costimulatory receptors Proteins 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- 229930182912 cyclosporin Natural products 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
- 229960000684 cytarabine Drugs 0.000 description 1
- 206010052015 cytokine release syndrome Diseases 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 230000001461 cytolytic effect Effects 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000012217 deletion Methods 0.000 description 1
- 230000037430 deletion Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000013024 dilution buffer Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- XPOQHMRABVBWPR-ZDUSSCGKSA-N efavirenz Chemical compound C([C@]1(C2=CC(Cl)=CC=C2NC(=O)O1)C(F)(F)F)#CC1CC1 XPOQHMRABVBWPR-ZDUSSCGKSA-N 0.000 description 1
- 229960003804 efavirenz Drugs 0.000 description 1
- 238000004520 electroporation Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 201000008184 embryoma Diseases 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 210000003527 eukaryotic cell Anatomy 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000002710 external beam radiation therapy Methods 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 229960000390 fludarabine Drugs 0.000 description 1
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 108091006047 fluorescent proteins Proteins 0.000 description 1
- 102000034287 fluorescent proteins Human genes 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 108010063718 gamma-glutamylaspartic acid Proteins 0.000 description 1
- 238000010353 genetic engineering 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
- 108010042598 glutamyl-aspartyl-glycine Proteins 0.000 description 1
- 108010027668 glycyl-alanyl-valine Proteins 0.000 description 1
- 108010078326 glycyl-glycyl-valine Proteins 0.000 description 1
- 108010020688 glycylhistidine Proteins 0.000 description 1
- 230000002709 granulomonocytic effect Effects 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 150000003278 haem Chemical class 0.000 description 1
- 201000009277 hairy cell leukemia Diseases 0.000 description 1
- 208000025750 heavy chain disease Diseases 0.000 description 1
- 210000003494 hepatocyte Anatomy 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 108010028295 histidylhistidine Proteins 0.000 description 1
- 102000057041 human TNF Human genes 0.000 description 1
- 102000050327 human TNFRSF9 Human genes 0.000 description 1
- 239000012642 immune effector Substances 0.000 description 1
- 239000012274 immune-checkpoint protein inhibitor Substances 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 230000006054 immunological memory Effects 0.000 description 1
- 239000002955 immunomodulating agent Substances 0.000 description 1
- 229940121354 immunomodulator Drugs 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 229940125721 immunosuppressive agent Drugs 0.000 description 1
- 230000001024 immunotherapeutic effect Effects 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 230000005917 in vivo anti-tumor Effects 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 230000004068 intracellular signaling Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 1
- 229960000310 isoleucine Drugs 0.000 description 1
- 108010027338 isoleucylcysteine Proteins 0.000 description 1
- 108010057821 leucylproline Proteins 0.000 description 1
- 230000021633 leukocyte mediated immunity Effects 0.000 description 1
- 238000001638 lipofection Methods 0.000 description 1
- 210000001165 lymph node Anatomy 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 208000003747 lymphoid leukemia Diseases 0.000 description 1
- 108010009298 lysylglutamic acid Proteins 0.000 description 1
- 108010054155 lysyllysine Proteins 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 108010056582 methionylglutamic acid Proteins 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 238000000520 microinjection Methods 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 210000005087 mononuclear cell Anatomy 0.000 description 1
- RTGDFNSFWBGLEC-SYZQJQIISA-N mycophenolate mofetil Chemical compound COC1=C(C)C=2COC(=O)C=2C(O)=C1C\C=C(/C)CCC(=O)OCCN1CCOCC1 RTGDFNSFWBGLEC-SYZQJQIISA-N 0.000 description 1
- 229960004866 mycophenolate mofetil Drugs 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- 239000002088 nanocapsule Substances 0.000 description 1
- 229960005027 natalizumab Drugs 0.000 description 1
- 210000000581 natural killer T-cell Anatomy 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 231100000590 oncogenic Toxicity 0.000 description 1
- 230000002246 oncogenic effect Effects 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 229930192851 perforin Natural products 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 108010073025 phenylalanylphenylalanine Proteins 0.000 description 1
- 238000000053 physical method Methods 0.000 description 1
- 208000037244 polycythemia vera Diseases 0.000 description 1
- 230000004481 post-translational protein modification Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 229960003387 progesterone Drugs 0.000 description 1
- 239000000186 progesterone Substances 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 108010031719 prolyl-serine Proteins 0.000 description 1
- 108010070643 prolylglutamic acid Proteins 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000031877 prophase Effects 0.000 description 1
- KEYDJKSQFDUAGF-YIRKRNQHSA-N prostaglandin D2 ethanolamide Chemical compound CCCCC[C@H](O)\C=C\[C@@H]1[C@@H](C\C=C/CCCC(=O)NCCO)[C@@H](O)CC1=O KEYDJKSQFDUAGF-YIRKRNQHSA-N 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000010188 recombinant method Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000003362 replicative effect Effects 0.000 description 1
- 108091008146 restriction endonucleases Proteins 0.000 description 1
- 239000002336 ribonucleotide Substances 0.000 description 1
- 125000002652 ribonucleotide group Chemical group 0.000 description 1
- 238000009666 routine test Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 201000008261 skin carcinoma Diseases 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000011272 standard treatment Methods 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 238000011476 stem cell transplantation Methods 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000012089 stop solution Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000009747 swallowing Effects 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000005026 transcription initiation Effects 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 230000002463 transducing effect Effects 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- 230000026683 transduction Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 238000011277 treatment modality Methods 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 108010084932 tryptophyl-proline Proteins 0.000 description 1
- 108010038745 tryptophylglycine Proteins 0.000 description 1
- 102000003298 tumor necrosis factor receptor Human genes 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 241001529453 unidentified herpesvirus Species 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 238000010200 validation analysis Methods 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 108010027345 wheylin-1 peptide Proteins 0.000 description 1
- 108091005957 yellow fluorescent proteins Proteins 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
- C07K14/70503—Immunoglobulin superfamily
- C07K14/7051—T-cell receptor (TcR)-CD3 complex
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/14—Blood; Artificial blood
- A61K35/17—Lymphocytes; B-cells; T-cells; Natural killer cells; Interferon-activated or cytokine-activated lymphocytes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- 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
-
- 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
- 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
- C12N2510/02—Cells for production
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Immunology (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Zoology (AREA)
- Cell Biology (AREA)
- Biomedical Technology (AREA)
- Medicinal Chemistry (AREA)
- Biotechnology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Hematology (AREA)
- Genetics & Genomics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Biochemistry (AREA)
- Wood Science & Technology (AREA)
- Developmental Biology & Embryology (AREA)
- Gastroenterology & Hepatology (AREA)
- General Engineering & Computer Science (AREA)
- Oncology (AREA)
- Virology (AREA)
- Epidemiology (AREA)
- Toxicology (AREA)
- Microbiology (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention provides a preparation method and application of a chimeric antigen receptor immune cell constructed based on SECTM 1. Specifically, the invention provides a Chimeric Antigen Receptor (CAR) based on the modification of SECTM1, said CAR comprising an extracellular binding domain capable of specifically targeting SECTM1 receptor (CD 7). The CAR immune cell has high specificity and target affinity, can effectively amplify the CAR-T cell targeting CD7 without reducing the expression of CD7 on the surface of the T cell by gene editing or CD7 blocking molecules and other technologies, and the obtained CAR-T cell is mainly a CD7 negative or low-expression T cell and contains more memory T cells, so that the CAR immune cell has longer high-efficiency killing capability in vivo. Based on the properties of the CAR-T, it is reasonable to speculate that it also eliminates tumor cell contamination during CAR-T production. The test in non-human primates shows that the composition has higher safety.
Description
Technical Field
The invention belongs to the technical field of tumor immunotherapy biomedicine, relates to a specific chimeric antigen receptor immune cell, and particularly relates to a CAR specifically targeting CD7, a modified immune response cell thereof, and a preparation method and application thereof.
Background
Cancer is currently considered to be the leading cause of death and a major obstacle to extending human life in various countries of the world. According to the World Health Organization (WHO)2019, cancer is the first or second leading cause of death among 183 countries in the population before the age of 70 years, seriously threatening the health of humans. By 2020, 1930 ten thousand new cases and 1000 cancer patients die globally, and by 2040 years estimated from the current cancer incidence, 2840 new cases of cancer (including non-melanoma skin cancer except basal cell carcinoma) will occur globally, 47% more than 2020, and overall, the incidence and mortality burden of cancer is rapidly increasing worldwide. According to the global tumor data statistics in 2020, 1,101,958 new cases, which account for 5.7% of new tumor cases, can occur when blood diseases comprise leukemia, Hodgkin lymphoma and non-Hodgkin lymphoma; 594,763 death cases account for 5.9% of cancer death cases, and blood diseases still seriously threaten human health from the statistical data.
With the development of medical technology, the life of human beings is continuously prolonged, great progress is made in the treatment of tumors, and the life cycle of cancer patients is continuously prolonged and the life quality is greatly improved by applying comprehensive treatment means such as surgery, chemotherapy, radiotherapy, biotherapy and the like at present. In addition to conventional therapeutic approaches, immunotherapy has also become a clinically important approach to cancer treatment, and more immunotherapeutic drugs are approved for clinical treatment, such as PD1, PDL1 monoclonal antibodies against immune checkpoint inhibitors, and CAR-T cell therapy. Chimeric Antigen antibody Receptor-T cell (CAR-T) T cell refers to a T cell that is genetically modified to recognize a specific Antigen of interest in an MHC non-limiting manner and to continuously activate expanded T cells. The main structure of the polypeptide comprises three types, namely an extracellular ScFv recognition structural domain which is used for recognizing and combining a target spot on a tumor cell; a hinge region and transmembrane domain, derived primarily from CD8 or CD28, anchor the CAR to the cell membrane and link the extracellular recognition domain with the intracellular signal; the endodomain, which is an activation domain, the number and length of which varies to affect the anti-tumor effect of CAR-T, is now commonly used as an activation domain plus one or more costimulatory domains, CD3 ζ being a common feature of the intracellular part of CARs, which initiates signals to drive killing of T cells, whereas costimulatory domains, mainly derived from the CD28 receptor family or TNF receptor family such as 4-1BB, OX40 or CD27, also enhance the killing effect of CAR-T by enhancing cytokine secretion or promoting proliferation and persistence. Normal T cells recognize Tumor cells by relying on T cell surface Receptor (TCR) binding to Major Histocompatibility Complex (MHC) on the surface of Tumor cells, whereas CAR-T cells recognize Tumor Associated Antigens (TAA) on the surface of Tumor cells by relying only on the structure of CAR in an MHC-independent manner, with the specificity of CAR for Antigen recognition and the killing properties of T cells.
Over the past years, with the rapid development of gene editing, immunization and other disciplines, CAR-T cell therapy has become a new and well-established therapeutic approach to the treatment of hematological disorders. CAR-T treatment of malignant tumors remains a current research hotspot, and CAR-T treatment has gone through a course of years since the first treatment of tumors with Tumor Infiltrating Lymphocytes (TILs) in 1986, through the development of the first generation CARs in 1993, until the FDA first approved CAR-T for the treatment of relapsing/refractory acute lymphoblastic leukemia in 2017. Three CAR-ts are currently used for the treatment of tumors, including kymeriah and yescata approved by the FDA at 2017 and month 8 and 10 for the treatment of relapsed/refractory acute lymphoblastic leukemia and specific types of large B-Cell Lymphoma, and Tecartus approved at month 2020 and month 7 for the treatment of adult Mantle Cell Lymphoma (MCL). CAR-T therapy is used primarily for the treatment of hematological disorders such as acute lymphoblastic leukemia, chronic lymphoblastic leukemia and multiple myeloma, the most commonly used and clinically beneficial target in hematological disorders is CD19, and CD19 CAR-T cells are designed and expanded in vitro and then injected into patients for killing CD19 positive cells. In the current CAR treatment research, CD19 has good progress in ALL, CLL and NHL, and the CR (completed response) rate of CAR-T treatment of ALL in adults reaches 83-93% and the CR rate in children reaches 67-90%; the CR rate in Diffuse Large B Cell Lymphoma (DLBCL) reaches 43-54%; the CLL reaches 21-29 percent, and has good curative effect mainly in B cell malignant tumor. Despite the high rate of complete remission, there are still some patients who relapse after CAR-T therapy targeting CD19 because of the inhibitory effect of the tumor microenvironment and the phenomenon of antigen escape.
Therefore, there is an urgent need in the art to develop new safe and effective therapeutic targets for treating diseases such as tumor and the like, and corresponding therapeutic protocols.
Disclosure of Invention
The invention aims to provide a chimeric antigen receptor immune cell taking a SECTM1 receptor as a target spot and a preparation method and an application method thereof.
In a first aspect of the invention there is provided a Chimeric Antigen Receptor (CAR), wherein the CAR comprises an extracellular binding domain, and the extracellular binding domain comprises the structure of SECTM1 or a fragment thereof based on the amino acid sequence shown in SEQ ID NO:1,
and, the extracellular binding domain is capable of specifically binding to SECTM1 receptor in the manner of a ligand receptor.
In another preferred embodiment, the extracellular binding domain has an amino acid sequence derived from SECTM 1.
In another preferred embodiment, the extracellular binding domain comprises SECTM1 protein or a fragment thereof.
In another preferred embodiment, the fragment of SECTM1 protein comprises the extracellular domain of SECTM1 protein.
In another preferred embodiment, the extracellular binding domain comprises SECTM1 protein or a fragment thereof.
In another preferred embodiment, the extracellular binding domain comprises an extracellular portion of SECTM1 protein.
In another preferred embodiment, the extracellular binding domain comprises a wild type and a mutant domain.
In another preferred embodiment, the amino acid sequence of the extracellular binding domain is as shown in positions 29-145 of the sequence shown in SEQ ID NO. 1.
In another preferred embodiment, the fragment of SECTM1 protein comprises the extracellular domain of SECTM1 protein, the amino acid sequence of the extracellular domain is corresponding to positions 29-145 of the sequence shown in SEQ ID NO. 1. In another preferred embodiment, the protein SECTM1 or fragment thereof specifically binds to SECTM1 receptors including CD 7.
In another preferred embodiment, said receptor for SECTM1 is selected from the group consisting of: CD 7.
In another preferred embodiment, the binding molecule is selected from the group consisting of: CD 7.
In another preferred embodiment, the CD7 is CD7 located on the cell membrane.
In another preferred embodiment, the CD7 is derived from a human or non-human mammal.
In another preferred embodiment, the non-human mammal comprises: rodents (e.g., rats, mice), primates (e.g., monkeys); preferably a primate.
In another preferred embodiment, the extracellular binding domain of the CAR comprises, in addition to the first extracellular domain directed to SECTM1 receptor, a second extracellular domain directed to an additional target.
In another preferred embodiment, the additional target is a tumor specific target.
In another preferred embodiment, the SECTM1 protein or fragment thereof has the amino acid sequence shown in SEQ ID NO. 1, or has the amino acid sequence from position 1 to 145, or preferably from position 29 to 145, of the sequence shown in SEQ ID NO. 1.
In another preferred embodiment, the amino acid sequence of SECTM1 protein or fragment thereof is selected from the group consisting of:
(i) 1, as shown in 29 th to 145 th positions of the sequence shown in SEQ ID NO; and
(ii) an amino acid sequence obtained by substitution, deletion, alteration or insertion of one or more amino acid residues on the basis of the sequence shown at positions 29 to 145 of the sequence shown in SEQ ID NO. 1, or addition of 1 to 30 amino acid residues, preferably 1 to 10 amino acid residues, more preferably 1 to 5 amino acid residues at the N-terminus or C-terminus thereof; and the obtained amino acid sequence has a sequence identity of more than or equal to 85 percent (preferably more than or equal to 90 percent, more preferably more than or equal to 95 percent, such as more than or equal to 96 percent, more than or equal to 97 percent, more than or equal to 98 percent or more than or equal to 99 percent) with the sequence shown in the 29 th to 145 th positions of the sequence shown in SEQ ID NO. 1; and the obtained amino acid sequence has the same or similar function as the sequence shown in (i).
In another preferred embodiment, the CAR has the structure shown in formula I below:
L-EB-H-TM-C-CD3ζ-RP (I)
in the formula (I), the compound is shown in the specification,
each "-" is independently a linker peptide or a peptide bond;
l is a null or signal peptide sequence;
EB is an extracellular binding domain that specifically binds to SECTM1 receptor;
h is a none or hinge region;
TM is a transmembrane domain;
c is a no or co-stimulatory signal molecule;
CD3 ζ is a cytoplasmic signaling sequence derived from CD3 ζ;
RP is a null or reporter protein.
In another preferred embodiment, the reporter protein RP is a fluorescent protein (e.g., green fluorescent protein, yellow fluorescent protein, red fluorescent protein).
In another preferred example, the reporter protein RP is mKate2 red fluorescent protein.
In another preferred example, the red fluorescent reporter protein RP (mKate2) further comprises a self-cleavage recognition site at its N-terminus, preferably a T2A sequence. In another preferred example, the amino acid sequence of the mKate2 red fluorescent protein is shown as SEQ ID NO. 2.
In another preferred embodiment, L is a signal peptide of a protein selected from the group consisting of: CD8, CD28, GM-CSF, CD4, CD137, SECTM1, or a combination thereof.
In another preferred embodiment, L is a signal peptide derived from CD 8.
In another preferred embodiment, the amino acid sequence of L is shown in SEQ ID NO 3.
In another preferred embodiment, said H is a hinge region of a protein selected from the group consisting of: CD8, CD28, CD137, or a combination thereof.
In another preferred embodiment, said H is a hinge region from CD 8.
In another preferred embodiment, the amino acid sequence of H is shown in SEQ ID NO. 4.
In another preferred embodiment, the TM is a transmembrane region of a protein selected from the group consisting of: CD28, CD3 epsilon, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137, CD154, or a combination thereof.
In another preferred embodiment, the TM is a CD 28-derived transmembrane region.
In another preferred embodiment, the amino acid sequence of TM is shown in SEQ ID NO. 5.
In another preferred embodiment, C is a costimulatory signal molecule for a protein selected from the group consisting of: OX40, CD2, CD7, CD27, CD28, CD30, CD40, CD70, CD134, 4-1BB (CD137), PD1, Dap10, CDS, ICAM-1, LFA-1(CD11a/CD18), ICOS (CD278), NKG2D, GITR, TLR2, or a combination thereof.
In another preferred embodiment, C is a co-stimulatory signaling molecule from 4-1 BB.
In another preferred embodiment, the amino acid sequence of C is shown in SEQ ID NO 6.
In another preferred embodiment, the amino acid sequence of the cytoplasmic signaling sequence derived from CD3 ζ is as set forth in SEQ ID NO 7.
In another preferred embodiment, the amino acid sequence of the chimeric antigen receptor CAR is shown as SEQ ID NO. 8.
In a second aspect of the invention, there is provided a nucleic acid molecule encoding a chimeric antigen receptor according to the first aspect of the invention.
In another preferred embodiment, the nucleic acid molecule has the nucleotide sequence of SEQ ID No. 9.
In a third aspect of the invention, there is provided a vector comprising a nucleic acid molecule according to the second aspect of the invention.
In another preferred embodiment, the carrier is selected from the group consisting of: DNA, RNA, plasmid, lentiviral vector, adenoviral vector, retroviral vector, transposon, or a combination thereof.
In another preferred embodiment, the vector is a lentiviral vector.
In another preferred embodiment, the carrier is selected from the group consisting of: pTomo lentivirus vector, plenti, pLVTH, pLJM1, pHCMV, pLBS.CAG, pHR, pLV and the like.
In another preferred embodiment, the vector is a pTomo lentiviral vector.
In another preferred embodiment, the vector further comprises one or more selected from the group consisting of: promoter, transcription enhancing element WPRE, long terminal repeat LTR, etc.
In another preferred embodiment, the vector comprises the nucleotide sequence shown as SEQ ID NO. 9.
In a fourth aspect of the invention there is provided a host cell comprising a vector or chromosome according to the third aspect of the invention into which has been integrated an exogenous nucleic acid molecule according to the second aspect of the invention or which expresses a CAR according to the first aspect of the invention.
In a fifth aspect of the invention there is provided an engineered immune cell comprising a vector or chromosome according to the third aspect of the invention having integrated therein an exogenous nucleic acid molecule according to the second aspect of the invention or expressing a CAR according to the first aspect of the invention.
In another preferred embodiment, the engineered immune cell is selected from the group consisting of: t cells, NK cells, NKT cells, macrophages, or a combination thereof.
In another preferred embodiment, the engineered immune cell is a chimeric antigen receptor T cell (CAR-T cell) or a chimeric antigen receptor NK cell (CAR-NK cell).
In another preferred embodiment, the engineered immune cell is a CAR-T cell.
In another preferred embodiment, the engineered immune cell is CD7 negative or low expressing CD 7.
In another preferred embodiment, the engineered immune cell is a CD7 negative T cell.
In another preferred embodiment, the engineered immune cell is a CAR-T cell having a phenotype of a memory cell.
In another preferred embodiment, the engineered immune cells are not treated with a CD7 blocking.
In a sixth aspect of the invention, there is provided a method of preparing an engineered immune cell according to the fifth aspect of the invention, comprising the steps of: transducing a nucleic acid molecule according to the second aspect of the invention or a vector according to the third aspect of the invention into an immune cell, thereby obtaining the engineered immune cell.
In another preferred embodiment, the method further comprises the step of performing functional and effective detection on the obtained engineered immune cells.
In a seventh aspect of the invention, there is provided a pharmaceutical composition comprising a CAR according to the first aspect of the invention, a nucleic acid molecule according to the second aspect of the invention, a vector according to the third aspect of the invention, a host cell according to the fourth aspect of the invention, and/or an engineered immune cell according to the fifth aspect of the invention, and a pharmaceutically acceptable carrier, diluent or excipient.
In another preferred embodiment, the formulation is a liquid formulation.
In another preferred embodiment, the formulation is in the form of an injection.
In another preferred embodiment, the concentration of said engineered immune cells in said formulation is 1 × 103-1×108Individual cells/ml, preferably 1X 104-1×107Individual cells/ml.
In an eighth aspect of the invention there is provided the use of a CAR according to the first aspect of the invention, a nucleic acid molecule according to the second aspect of the invention, a vector according to the third aspect of the invention, or a host cell according to the fourth aspect of the invention, and/or an engineered immune cell according to the fifth aspect of the invention, in the manufacture of a medicament or formulation for the prevention and/or treatment of a disease associated with aberrant expression of the SECTM1 receptor.
In another preferred embodiment, the receptor for SECTM1 includes, but is not limited to, CD 7.
In another preferred embodiment, the diseases related to the abnormal expression of SECTM1 receptor include, but are not limited to, tumor, aging, obesity, cardiovascular diseases, diabetes, neurodegenerative diseases, infectious diseases, etc.
In another preferred embodiment, the diseases related to the abnormal expression of SECTM1 receptor comprise: abnormal expression of CD7 is associated with diseases.
In another preferred embodiment, the diseases associated with the abnormal expression of CD7 include: tumor, aging, cardiovascular diseases, obesity, etc.
In another preferred embodiment, the disease is a high CD7 expressing malignancy.
In another preferred embodiment, the tumor comprises a hematological tumor.
In another preferred embodiment, the hematological tumor is selected from the group consisting of: acute Myeloid Leukemia (AML), Multiple Myeloma (MM), Chronic Lymphocytic Leukemia (CLL), Acute Lymphocytic Leukemia (ALL), lymphoma, or a combination thereof.
In another preferred embodiment, the hematologic tumor is a hematologic tumor that recurs after treatment.
In a ninth aspect of the invention, there is provided a use of the engineered immune cell according to the fifth aspect of the invention, or the pharmaceutical composition according to the seventh aspect of the invention, for the prevention and/or treatment of cancer or tumor.
In a tenth aspect of the invention, there is provided a method of treating a disease comprising administering to a subject in need thereof an effective amount of an engineered immune cell according to the fifth aspect of the invention, or a pharmaceutical composition according to the seventh aspect of the invention.
In another preferred embodiment, the disease is a disease associated with abnormal expression of the SECTM1 receptor.
In another preferred embodiment, the disease is cancer or a tumor.
In another preferred embodiment, the engineered immune cell or the CAR immune cell comprised in the pharmaceutical composition is a cell derived from the subject (autologous cell).
In another preferred embodiment, the engineered immune cell or the CAR immune cell comprised in the pharmaceutical composition is a cell derived from a healthy individual (allogeneic cell).
In another preferred embodiment, the method may be used in combination with other therapeutic methods.
In another preferred embodiment, the other treatment methods include chemotherapy, radiotherapy, targeted therapy and the like.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Drawings
FIG. 1 shows a schematic diagram of the construction of the SECTM1-CAR vector.
Wherein A is a sequence schematic diagram of SECTM1, wherein 1-28AA is a signal peptide, and 29-145AA is an extracellular domain; b is a structural schematic diagram of control group plasmids MOCK-CAR and SECTM1-CAR, wherein a signal peptide, a hinge region and a transmembrane region are all derived from a human CD8 molecule, 4-1BB is derived from human CD137, CD3 zeta is derived from human CD3, and mKate2 is a fluorescent marker and used for detecting CAR expression; c is the HindIII enzyme cutting identification of pTomo-SECTM1-CAR vector.
Figure 2 shows CAR-T cell proliferation fold and total, CD7 expression change detection, and cytokine release. A.T fold proliferation after 15 days post-infection; B. detecting the secretion level of the cell factor after 3 days of infection; C. the total number of cells was counted 15 days after infection.
FIG. 3 shows phenotypic testing 6 days after T cell infection. CD4, CD8 and memory phenotype CD45RO, CCR7 expression were examined. Among them, CD45RO + CCR7- (effector memory cells, EM), CD45RO + CCR7+ (central memory cells, CM), CD45RO-CCR7- (terminal effector memory cells, EMRA), CD45RO-CCR7+ (Naive cells, Naive).
Figure 4 shows CAR transfection efficiency assay results.
Wherein A is a cell fluorescence expression result of T cells infected by MOCK-CAR and SECTM1-CAR for 72 hours, BF is a bright field, and mKate2 is CAR fluorescence expression; and B is the flow detection fluorescence expression result.
FIG. 5 shows the difference in tumor cell CCRF-CEM and normal T cell CD7 expression and killing. A, flow detection of target cell CCRF-CEM and T cell CD7 expression; and B, killing detection after co-incubation.
FIG. 6 shows the results of CD7 expression measurements from different tumor cell lines. Wherein CCRF-CEM, MOLT4 are CD7 positive ALL tumor cells; KG-1a, Kasumi-3 are AML tumor cells positive for CD 7; k562 is a CD7 negative control cell.
FIG. 7 shows the results of in vitro assays for killing of different tumor cell lines by SECTM 1-CAR. Wherein K562 is a CD7 negative control cell line, CCRF-CEM, MOLT4 is a CD7 positive acute lymphoblastic leukemia cell line, KG-1a and Kasumi-3 are CD7 positive acute myelogenous leukemia cell lines.
Fig. 8 shows CD7 positive target cells at 2: detecting the cell factors IFN gamma and TNF alpha after killing by 1-effect target ratio.
Figure 9 shows the effect of over-expression of CD7 on cell killing. Wherein the K562 cells are erythroleukemia cell lines. A, CD7 level detection, B, killing effect detection and C, cytokine secretion detection.
FIG. 10, FIG. 10 (continuation-1), FIG. 10 (continuation-2) show signs and indications detected after infusion of SECTM1 CART cells in primate monkeys. A. Monkey T cell infection efficiency flow assay. B. Cytokine release assay. C. And (4) cell counting detection. D. Basic vital sign monitoring. E. Blood is routine.
Detailed Description
The inventor of the invention has extensively and deeply studied and screened a large number of times, and developed a chimeric antigen receptor immune cell constructed based on SECTM1 for the first time. The inventors have unexpectedly found that the use of a specific segment of the ectodomain of SECTM1 (i.e. amino acid sequence 29-145) as the extracellular binding domain of CAR not only has suitable affinity, but also that while high-expressing T cells of CD7 are killed during the preparation of CAR-T cells, CD 7-negative or low-expressing T cells (including CAR-T cells) can be successfully expanded to prepare desired CAR-T cells, and the prepared CAR-T cells are rich in memory T cells and thus can function in vivo for a longer period of time. This phenomenon in the CAR-T production process should also be effective in eliminating the inevitable contamination of tumor cells when isolating patient T cells. The present invention has been completed based on this finding.
Term(s) for
In order that the invention may be more readily understood, certain technical and scientific terms are specifically defined below. Unless otherwise defined explicitly herein, all other technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Before the present invention is described, it is to be understood that this invention is not limited to the particular methodology and experimental conditions described, as such methodologies and conditions may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. As used herein, the term "about" when used in reference to a specifically recited value means that the value may vary by no more than 1% from the recited value. For example, as used herein, the expression "about 100" includes 99 and 101 and all values in between (e.g., 99.1, 99.2, 99.3, 99.4, etc.).
As used herein, the term "optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur.
As used herein, the term "comprising" or "includes" can be open, semi-closed, and closed. In other words, the term also includes "consisting essentially of …" or "consisting of …".
"transduction," "transfection," "transformation" or terms as used herein refer to the process of delivering an exogenous polynucleotide into a host cell, transcription and translation to produce a polypeptide product, including the introduction of the exogenous polynucleotide into the host cell (e.g., E.coli) using a plasmid molecule.
"Gene expression" or "expression" refers to the process of transcription, translation and post-translational modification of a gene to produce the RNA or protein product of the gene.
"Polynucleotide" refers to a polymeric form of nucleotides of any length, including Deoxynucleotides (DNA), Ribonucleotides (RNA), hybrid sequences thereof, and the like. Polynucleotides may include modified nucleotides, such as methylated or capped nucleotides or nucleotide analogs. The term polynucleotide as used herein refers to interchangeable single-and double-stranded molecules. Unless otherwise indicated, the polynucleotides in any of the embodiments described herein include a double-stranded form and two complementary single strands that are known or predictable to make up the double-stranded form.
Conservative amino acid substitutions are known in the art. In some embodiments, the potential substituted amino acids are within one or more of the following groups: glycine, alanine; and valine, isoleucine, leucine and proline; aspartic acid, glutamic acid; asparagine, glutamine; serine, threonine lysine, arginine and histidine; and/or phenylalanine, tryptophan and tyrosine; methionine and cysteine. In addition, the invention provides non-conservative amino acid substitutions that allow amino acid substitutions from different groups.
The inclusion of all parameters, dimensions, materials and configurations described herein will be readily understood by those skilled in the art. The actual parameters, dimensions, materials and/or configurations will depend upon the specific application for which the invention is being used. It will be understood by those skilled in the art that the embodiments or claims are given by way of example only and that within the scope of equivalents or claims, the embodiments of the invention may be covered without limitation to the specifically described and claimed scope.
All definitions, as defined and used herein, should be understood to exceed dictionary definitions or definitions in documents incorporated by reference.
All references, patents, and patent applications cited herein are hereby incorporated by reference with respect to the subject matter to which they are cited, and in some cases may contain the entire document.
It should be understood that for any method described herein that includes more than one step, the order of the steps is not necessarily limited to the order described in these embodiments.
In order that the disclosure may be more readily understood, certain terms are first defined. As used in this application, each of the following terms shall have the meaning given below, unless explicitly specified otherwise herein. Other definitions are set forth throughout the application.
The term "about" can refer to a value or composition that is within an acceptable error range for the particular value or composition as determined by one of ordinary skill in the art, which will depend in part on how the value or composition is measured or determined.
The term "administering" refers to the physical introduction of the product of the invention into a subject using any of a variety of methods and delivery systems known to those skilled in the art, including intravenous, intramuscular, subcutaneous, intraperitoneal, spinal cord or other parenteral routes of administration, e.g., by injection or infusion.
CD7 molecule
The CD7 molecule is a 40kD type I transmembrane glycoprotein, a lineage specific antigen, normally found predominantly on T/NK cells and their progenitors, with only 9% of peripheral single nuclear cells (PBMCs) in peripheral blood being CD7 negative, and its primary function being to act as co-stimulatory receptors for T and B lymphocyte interactions during lymphoid development.
In addition to expression in normal T/NK cells, CD7 is also expressed on > 95% of lymphoid leukemias and lymphomas and part of peripheral blood lymphomas, and also on about 30% of AML.
The Ig superfamily molecule SECTM1 secreted by epithelial cells is the primary ligand for the CD7 molecule. The SECTM1 gene is located near the upstream 5' end of the CD7 gene, which is the only pair of molecular ligand receptors adjacent to each other in the genome, and the SECTM1 gene encodes a protein of unknown function.
The inventor unexpectedly finds that the specific segment (namely amino acid sequences at 29-145 positions) of the ectodomain of SECTM1 as the extracellular binding domain of CAR not only has proper affinity, but also has certain influence on the proliferation of CAR-T in the preparation process of CAR-T cells, but also can successfully prepare the required CAR-T cells in large quantity, and the prepared CAR-T cells have the phenotype of memory cells, so that the CAR-T cells have long-term high-efficiency killing capability and high safety on CD7 positive target cells (such as tumor cells).
Based on the fact, the invention integrates the SECTM1 specific segment into the CAR carrier by means of genetic engineering for the first time, and modifies the related immune cells, thereby realizing specific killing of cells positive to SECTM1 binding protein, and being applicable to treatment of related diseases, in particular to CD7 positive blood tumor which recurs after treatment.
Chimeric Antigen Receptors (CAR) of the invention
A Chimeric Antigen Receptor (CAR) consists of an extracellular antigen recognition region, a transmembrane region, and an intracellular costimulatory signal region.
The design of the CAR goes through the following process: the first generation CARs had only one intracellular signaling component, CD3 ζ or Fc γ RI molecule, and due to the single intracellular activation domain, it caused only transient T cell proliferation and less cytokine secretion, and did not provide long-term T cell proliferation signaling and sustained in vivo anti-tumor effects, and therefore did not achieve good clinical efficacy. The second generation CAR introduces a costimulatory molecule such as CD28, 4-1BB, OX40, ICOS on the basis of the original structure, and compared with the first generation CAR, the function is greatly improved, and the persistence of CAR-T cells and the killing capability to tumor cells are further enhanced. On the basis of the second generation CAR, a plurality of novel immune co-stimulatory molecules such as CD27 and CD134 are connected in series, and the development of the second generation CAR and the fourth generation CAR is realized.
The extracellular domain of the CAR recognizes a specific antigen and subsequently transduces the signal through the intracellular domain, causing activated proliferation of the cell, cytolytic toxicity and secretion of cytokines, which in turn clear the target cell. Autologous cells from the patient (or a heterologous donor) are first isolated, activated and genetically engineered to produce immune cells for CAR production, and then injected into the same patient. In this way, the probability of graft versus host disease is very low and antigens are recognized by immune cells in a non-MHC restricted manner.
CAR-immunocyte therapy achieves very high clinical response rate in the treatment of hematologic malignancies, which cannot be achieved by any conventional treatment means, and causes a hot tide of clinical research in the world.
Specifically, the Chimeric Antigen Receptors (CARs) of the invention include an extracellular domain, a transmembrane domain, and an intracellular domain.
The extracellular domain includes a target-specific binding member. The extracellular domain may be an ScFv based on an antibody that specifically binds to an antigen-antibody, or a native sequence or derivative thereof based on a ligand-receptor.
In the present invention, the extracellular domain of the chimeric antigen receptor is a SECTM1 protein or fragment thereof that specifically binds to the CD7 target of the CAR of the invention. More preferably, the extracellular binding domain of the chimeric antigen receptor of the present invention has the amino acid sequence from position 29 to 145 of the sequence shown in SEQ ID NO: 1.
The intracellular domain includes a costimulatory signaling region and a zeta chain moiety. The costimulatory signaling region refers to a portion of the intracellular domain that includes the costimulatory molecule. Costimulatory molecules are cell surface molecules required for efficient response of lymphocytes to antigens, rather than antigen receptors or their ligands.
A linker may be incorporated between the ectodomain and transmembrane domain of the CAR, or between the cytoplasmic domain and transmembrane domain of the CAR. As used herein, the term "linker" generally refers to any oligopeptide or polypeptide that functions to link a transmembrane domain to an extracellular domain or a cytoplasmic domain of a polypeptide chain. The linker may comprise 0-300 amino acids, preferably 2 to 100 amino acids and most preferably 3 to 50 amino acids.
The CARs of the invention, when expressed in T cells, are capable of antigen recognition based on antigen binding specificity. When it binds to its associated antigen, the tumor cells are affected, resulting in the tumor cells not growing, being forced to die or otherwise affected, and resulting in a reduction or elimination of the tumor burden in the patient. The antigen binding domain is preferably fused to an intracellular domain from one or more of the costimulatory molecule and the zeta chain. Preferably, the antigen binding domain is fused to the intracellular domain of a combination of a CD28 signaling domain, and a CD3 zeta signaling domain.
In the present invention, the extracellular binding domain of the CAR of the invention also includes sequence-based conservative variants, which refer to polypeptides formed by substituting up to 10, preferably up to 8, more preferably up to 5, and most preferably up to 3 amino acids with amino acids having similar or similar properties, as compared to the amino acid sequence at positions 29 to 145 of SEQ ID No. 1.
In the present invention, the number of amino acids to be added, deleted, modified and/or substituted is preferably not more than 40%, more preferably not more than 35%, more preferably 1 to 33%, more preferably 5 to 30%, more preferably 10 to 25%, more preferably 15 to 20% of the total number of amino acids in the original amino acid sequence.
In the present invention, the number of the amino acids to be added, deleted, modified and/or substituted is usually 1, 2, 3, 4 or 5, preferably 1 to 3, more preferably 1 to 2, and most preferably 1.
For the hinge region and transmembrane region (transmembrane domain), the CAR can be designed to include a transmembrane domain fused to the extracellular domain of the CAR. In one embodiment, a transmembrane domain that is naturally associated with one of the domains in the CAR is used. In some examples, the transmembrane domains may be selected, or modified by amino acid substitutions, to avoid binding such domains to the transmembrane domains of the same or different surface membrane proteins, thereby minimizing interaction with other members of the receptor complex.
The intracellular domains in the CAR of the invention include the 4-1BB co-stimulatory domain and the signaling domain of CD3 ζ.
In one embodiment of the invention, the CAR is a CAR that can specifically target CD 7.
Chimeric antigen receptor immune cells (CAR-immune cells)
In the present invention, there is provided a chimeric antigen receptor immune cell comprising the chimeric antigen receptor of the present invention having a specific targeting to SECTM1 receptor (preferably CD 7).
The chimeric antigen receptor immune cells of the invention may be CAR-T cells, and may also be CAR-NK cells, CAR-macrophages. Preferably, the chimeric antigen receptor immune cell of the invention is a CAR-T cell.
As used herein, the terms "CAR-T cell", "CAR-T cell of the invention" all refer to a CAR-T cell according to the fifth aspect of the invention.
CAR-T cells have the following advantages over other T cell-based therapies: (1) the action process of the CAR-T cell is not limited by MHC; (2) given that many tumor cells express the same tumor marker, the CAR gene construction for a certain tumor marker can be widely utilized once being completed; (3) the CAR can utilize a tumor protein marker and a glycolipid non-protein marker, so that the target range of the tumor marker is expanded; (4) the use of patient autologous cells reduces the risk of rejection; (5) the CAR-T cell has the function of immunological memory and can survive in vivo for a long time.
As used herein, the terms "CAR-NK cell", "CAR-NK cell of the invention" all refer to a CAR-NK cell according to the fifth aspect of the invention. The CAR-NK cells of the invention can be used for tumors with high expression of SECTM1 receptor (preferably CD 7).
Natural Killer (NK) cells are a major class of immune effector cells that protect the body from viral infection and tumor cell invasion through non-antigen specific pathways. By engineering (genetically modifying) NK cells it is possible to obtain new functions, including the ability to specifically recognize tumor antigens and having an enhanced anti-tumor cytotoxic effect.
CAR-NK cells also have the following advantages compared to CAR-T cells, for example: (1) directly kills tumor cells by releasing perforin and granzyme, but has no killing effect on normal cells of an organism; (2) they release very small amounts of cytokines and thus reduce the risk of cytokine storm; (3) is easy to be amplified in vitro and can be developed into 'existing' products. Otherwise, similar to CAR-T cell therapy.
Carrier
Nucleic acid sequences encoding the desired molecule can be obtained using recombinant methods known in the art, such as, for example, by screening libraries from cells expressing the gene, by obtaining the gene from vectors known to include the gene, or by direct isolation from cells and tissues containing the gene using standard techniques. Alternatively, the gene of interest may be produced synthetically.
The invention also provides vectors comprising the nucleic acid molecules of the invention. Vectors derived from retroviruses such as lentiviruses are suitable tools for achieving long-term gene transfer, as they allow long-term, stable integration of the transgene and its propagation in daughter cells. Lentiviral vectors have advantages over vectors derived from oncogenic retroviruses such as murine leukemia virus, in that they can transduce non-proliferating cells such as hepatocytes. They also have the advantage of low immunogenicity.
In brief summary, an expression cassette or nucleic acid sequence of the invention is typically operably linked to a promoter and incorporated into an expression vector. The vector is suitable for replication and integration into eukaryotic cells. Typical cloning vectors contain transcriptional and translational terminators, initiation sequences, and promoters that may be used to regulate the expression of the desired nucleic acid sequence.
The expression constructs of the invention may also be used for nucleic acid immunisation and gene therapy using standard gene delivery protocols. Methods of gene delivery are known in the art. See, e.g., U.S. Pat. nos. 5,399,346, 5,580,859, 5,589,466, which are incorporated herein by reference in their entirety. In another embodiment, the invention provides a gene therapy vector.
The nucleic acid can be cloned into many types of vectors. For example, the nucleic acid can be cloned into vectors including, but not limited to, plasmids, phagemids, phage derivatives, animal viruses, and cosmids. Specific vectors of interest include expression vectors, replication vectors, probe generation vectors, and sequencing vectors.
Further, the expression vector may be provided to the cell in the form of a viral vector. Viral vector technology is well known in the art and is described, for example, in Sambrook et al (2001, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory, New York) and other virology and Molecular biology manuals. Viruses that can be used as vectors include, but are not limited to, retroviruses, adenoviruses, adeno-associated viruses, herpes viruses, and lentiviruses. Generally, suitable vectors comprise an origin of replication, a promoter sequence, a convenient restriction enzyme site, and one or more selectable markers that function in at least one organism (e.g., WO 01/96584; WO 01/29058; and U.S. Pat. No. 6,326,193).
Many virus-based systems have been developed for gene transfer into mammalian cells. For example, retroviruses provide a convenient platform for gene delivery systems. The selected gene can be inserted into a vector and packaged into a retroviral particle using techniques known in the art. The recombinant virus can then be isolated and delivered to the subject cells in vivo or ex vivo. Many retroviral systems are known in the art. In some embodiments, an adenoviral vector is used. Many adenoviral vectors are known in the art. In one embodiment, a lentiviral vector is used.
Additional promoter elements, such as enhancers, may regulate the frequency of transcription initiation. Typically, these are located in the 30-110bp region upstream of the start site, although many promoters have recently been shown to also contain functional elements downstream of the start site. The spacing between promoter elements is often flexible so that promoter function is maintained when the elements are inverted or moved relative to one another. In the thymidine kinase (tk) promoter, the spacing between promoter elements can be increased by 50bp apart, and activity begins to decline. Depending on the promoter, it appears that the individual elements may function cooperatively or independently to initiate transcription.
An example of a suitable promoter is the immediate early Cytomegalovirus (CMV) promoter sequence. The promoter sequence is a strong constitutive promoter sequence capable of driving high level expression of any polynucleotide sequence operably linked thereto. Another example of a suitable promoter is elongation growth factor-1 α (EF-1 α). However, other constitutive promoter sequences may also be used, including, but not limited to, the simian virus 40(SV40) early promoter, the mouse mammary carcinoma virus (MMTV), the Human Immunodeficiency Virus (HIV) Long Terminal Repeat (LTR) promoter, the MoMuLV promoter, the avian leukemia virus promoter, the Epstein-Barr (Epstein-Barr) virus immediate early promoter, the rous sarcoma virus promoter, and human gene promoters such as, but not limited to, the actin promoter, the myosin promoter, the heme promoter, and the creatine kinase promoter. Further, the present invention should not be limited to the use of constitutive promoters. Inducible promoters are also contemplated as part of the invention. The use of an inducible promoter provides a molecular switch that is capable of turning on expression of a polynucleotide sequence operably linked to the inducible promoter when such expression is desired, or turning off expression when expression is not desired. Examples of inducible promoters include, but are not limited to, the metallothionein promoter, the glucocorticoid promoter, the progesterone promoter, and the tetracycline promoter.
To assess the expression of the CAR polypeptide or portion thereof, the expression vector introduced into the cells can also comprise either or both of a selectable marker gene or reporter gene to facilitate identification and selection of expressing cells from the population of cells sought to be transfected or infected by the viral vector. In other aspects, selectable markers may be carried on a single piece of DNA and used in a co-transfection procedure. Both the selectable marker and the reporter gene may be flanked by appropriate regulatory sequences to enable expression in a host cell. Useful selectable markers include, for example, antibiotic resistance genes, such as neo and the like.
Reporter genes are used to identify potentially transfected cells and to evaluate the functionality of regulatory sequences. Typically, the reporter gene is the following: which is not present in or expressed by the recipient organism or tissue and which encodes a polypeptide whose expression is clearly indicated by some readily detectable property, such as enzymatic activity. After the DNA has been introduced into the recipient cell, the expression of the reporter gene is assayed at an appropriate time. Suitable reporter genes may include genes encoding luciferase, β -galactosidase, chloramphenicol acetyltransferase, secreted alkaline phosphatase, or green fluorescent protein (e.g., Ui-Tei et al, 2000FEBS Letters479: 79-82). In one embodiment of the invention, the reporter gene is a gene encoding mKate2 red fluorescent protein. Suitable expression systems are well known and can be prepared using known techniques or obtained commercially. Generally, the construct with the minimum of 5 flanking regions that showed the highest level of reporter gene expression was identified as the promoter. Such promoter regions can be linked to reporter genes and used to evaluate the ability of an agent to modulate promoter-driven transcription.
Methods for introducing and expressing genes into cells are known in the art. In the context of expression vectors, the vectors can be readily introduced into host cells by any method known in the art, e.g., mammalian, bacterial, yeast, or insect cells. For example, an expression vector can be transferred into a host cell by physical, chemical, or biological means.
Physical methods for introducing polynucleotides into host cells include calcium phosphate precipitation, lipofection, particle bombardment, microinjection, electroporation, and the like. Methods for producing cells comprising vectors and/or exogenous nucleic acids are well known in the art. See, e.g., Sambrook et al (2001, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory, New York). A preferred method for introducing the polynucleotide into the host cell is calcium phosphate transfection.
Biological methods for introducing a polynucleotide of interest into a host cell include the use of DNA and RNA vectors. Viral vectors, particularly retroviral vectors, have become the most widely used method for inserting genes into mammalian, e.g., human, cells. Other viral vectors may be derived from lentiviruses, poxviruses, herpes simplex virus I, adenoviruses, adeno-associated viruses, and the like. See, for example, U.S. patent nos. 5,350,674 and 5,585,362.
Chemical means of introducing polynucleotides into host cells include colloidal dispersion systems such as macromolecular complexes, nanocapsules, microspheres, beads; and lipid-based systems including oil-in-water emulsions, micelles, mixed micelles, and liposomes. Exemplary colloidal systems for use as delivery vehicles in vitro and in vivo are liposomes (e.g., artificial membrane vesicles).
In the case of non-viral delivery systems, an exemplary delivery vehicle is a liposome. Lipid formulations are contemplated for use to introduce nucleic acids into host cells (ex vivo or in vivo). In another aspect, the nucleic acid can be associated with a lipid. The nucleic acid associated with the lipid may be encapsulated into the aqueous interior of the liposome, dispersed within the lipid bilayer of the liposome, attached to the liposome via a linker molecule associated with both the liposome and the oligonucleotide, entrapped in the liposome, complexed with the liposome, dispersed in a solution comprising the lipid, mixed with the lipid, associated with the lipid, contained as a suspension in the lipid, contained in or complexed with a micelle, or otherwise associated with the lipid. The lipid, lipid/DNA or lipid/expression vector associated with the composition is not limited to any particular structure in solution. For example, they may be present in bilayer structures, either as micelles or with a "collapsed" structure. They may also simply be dispersed in a solution, possibly forming aggregates of non-uniform size or shape. Lipids are fatty substances, which may be naturally occurring or synthetic lipids. For example, lipids include fat droplets that occur naturally in the cytoplasm as well as such compounds that contain long-chain aliphatic hydrocarbons and their derivatives such as fatty acids, alcohols, amines, amino alcohols, and aldehydes.
In a preferred embodiment of the invention, the vector is a lentiviral vector.
Preparation
The invention provides a chimeric antigen receptor CAR comprising the first aspect of the invention, a nucleic acid molecule of the second aspect of the invention, a vector of the third aspect of the invention, or a host cell of the fourth aspect of the invention or an engineered immune cell of the fifth aspect of the invention, and a pharmaceutically acceptable carrier, diluent, or carrierOr an excipient. In one embodiment, the formulation is a liquid formulation. Preferably, the formulation is an injection. Preferably, the CAR-T cells are present in the formulation at a concentration of 1X 103-1×108Individual cells/ml, more preferably 1X 104-1×107Individual cells/ml.
In one embodiment, the formulation may include buffers such as neutral buffered saline, sulfate buffered saline, and the like; carbohydrates such as glucose, mannose, sucrose or dextran, mannitol; a protein; polypeptides or amino acids such as glycine; an antioxidant; chelating agents such as EDTA or glutathione; adjuvants (e.g., aluminum hydroxide); and a preservative. The formulations of the present invention are preferably formulated for intravenous administration.
Therapeutic applications
The invention includes therapeutic applications of cells (e.g., T cells) transduced with Lentiviral Vectors (LV) encoding expression cassettes of the invention. The transduced T cells can target a marker CD7 of tumor cells, and the T cells are synergistically activated to cause immune cell immune response, so that the killing efficiency of the T cells on the tumor cells is remarkably improved.
Accordingly, the present invention also provides a method of stimulating a T cell-mediated immune response to a target cell population or tissue of a mammal comprising the steps of: administering to the mammal the CAR-cells of the invention.
In one embodiment, the invention includes a class of cell therapy in which autologous T cells (or heterologous donors) from a patient are isolated, activated, genetically engineered to produce CAR-T cells, and subsequently injected into the same patient. This approach has a very low probability of graft versus host disease, and the antigen is recognized by T cells in an MHC-unrestricted manner. Furthermore, one CAR-T can treat all cancers expressing this antigen. Unlike antibody therapy, CAR-T cells are capable of replicating in vivo, resulting in long-term persistence that can lead to sustained tumor control.
In one embodiment, the CAR-T cells of the invention can undergo robust in vivo T cell expansion and can last for an extended amount of time. In addition, the CAR-mediated immune response can be part of an adoptive immunotherapy step, wherein the CAR-modified T cell induces an immune response specific to the antigen binding domain in the CAR. For example, CAR-T cells of CD7 elicit specific immune responses against CD7 cells.
Although the data disclosed herein specifically disclose lentiviral vectors comprising SECTM1 protein or a fragment thereof, a hinge and transmembrane region, and 4-1BB and CD3 zeta signaling domains, the invention should be construed to include any number of variations on each of the construct components.
Treatable cancers include tumors that are not vascularized or have not substantially vascularized, as well as vascularized tumors. Cancers include non-solid tumors (such as hematological tumors, e.g., leukemias and lymphomas) and solid tumors. The types of cancer treated with the CARs of the invention include, but are not limited to, carcinomas, blastomas and sarcomas, and certain leukemias or lymphoid malignancies, benign and malignant tumors, such as sarcomas, carcinomas and melanomas. Adult tumors/cancers and childhood tumors/cancers are also included.
Hematologic cancers are cancers of the blood or bone marrow. Examples of hematologic (or hematological) cancers include leukemias, including acute leukemias (such as acute lymphocytic leukemia, acute myelogenous leukemia and myeloblastic, promyelocytic, granulo-monocytic, and erythroleukemia), chronic leukemias (such as chronic myelogenous (granulocytic) leukemia, chronic myelogenous leukemia, and chronic lymphocytic leukemia), polycythemia vera, lymphomas, hodgkin's disease, non-hodgkin's lymphoma (indolent and higher order forms), multiple myeloma, waldenstrom's macroglobulinemia, heavy chain disease, myelodysplastic syndrome, hairy cell leukemia, and myelodysplasia.
The CAR-modified T cells of the invention may also be used as a type of vaccine for ex vivo immunization and/or in vivo therapy of mammals. Preferably, the mammal is a human.
For ex vivo immunization, at least one of the following occurs in vitro prior to administration of the cells into a mammal: i) Expanding the cell, ii) introducing a nucleic acid encoding the CAR into the cell, and/or iii) cryopreserving the cell.
Ex vivo procedures are well known in the art and are discussed more fully below. Briefly, cells are isolated from a mammal (preferably a human) and genetically modified (i.e., transduced or transfected in vitro) with a vector expressing a CAR disclosed herein. The CAR-modified cells can be administered to a mammalian recipient to provide a therapeutic benefit. The mammalian recipient can be a human, and the CAR-modified cells can be autologous with respect to the recipient. Alternatively, the cells may be allogeneic, syngeneic (syngeneic), or xenogeneic with respect to the recipient.
In addition to using cell-based vaccines for ex vivo immunization, the present invention also provides compositions and methods for in vivo immunization to elicit an immune response against an antigen in a patient.
The invention provides a method of treating a tumor comprising administering to a subject in need thereof a therapeutically effective amount of a CAR-modified T cell of the invention.
The CAR-modified T cells of the invention can be administered alone or as a pharmaceutical composition in combination with diluents and/or with other components such as IL-2, IL-17 or other cytokines or cell populations. Briefly, a pharmaceutical composition of the invention may comprise a target cell population as described herein, in combination with one or more pharmaceutically or physiologically acceptable carriers, diluents, or excipients. Such compositions may include buffers such as neutral buffered saline, sulfate buffered saline, and the like; carbohydrates such as glucose, mannose, sucrose or dextran, mannitol; a protein; polypeptides or amino acids such as glycine; an antioxidant; chelating agents such as EDTA or glutathione; adjuvants (e.g., aluminum hydroxide); and a preservative. The compositions of the present invention are preferably formulated for intravenous administration.
The pharmaceutical compositions of the present invention may be administered in a manner suitable for the disease to be treated (or prevented). The number and frequency of administration will be determined by such factors as the condition of the patient, and the type and severity of the patient's disease-although the appropriate dosage may be determined by clinical trials.
When pointing toThe precise amount of a composition of the invention to be administered can be determined by a physician considering the age, weight, tumor size, extent of infection or metastasis, and individual differences in the condition of the patient (subject), given an "effective amount", "immunologically effective amount", "anti-tumor effective amount", "tumor-inhibiting effective amount", or "therapeutic amount". It can be generally pointed out that: pharmaceutical compositions comprising T cells described herein can be in the range of 104To 109Dosage of individual cells/kg body weight, preferably 105To 106Doses of individual cells per kg body weight (including all integer values within those ranges) are administered. The T cell composition may also be administered multiple times at these doses. Cells can be administered by using infusion techniques well known in immunotherapy (see, e.g., Rosenberg et al, New Eng.J.of Med.319:1676, 1988). Optimal dosages and treatment regimens for a particular patient can be readily determined by those skilled in the medical arts by monitoring the patient for signs of disease and adjusting the treatment accordingly.
Administration of the subject composition may be carried out in any convenient manner, including by spraying, injection, swallowing, infusion, implantation, or transplantation. The compositions described herein can be administered to a patient subcutaneously, intradermally, intratumorally, intranodal, intraspinally, intramuscularly, by intravenous (i.v.) injection, or intraperitoneally. In one embodiment, the T cell composition of the invention is administered to a patient by intradermal or subcutaneous injection. In another embodiment, the T cell composition of the invention is preferably administered by i.v. injection. The composition of T cells can be injected directly into the tumor, lymph node or site of infection.
In certain embodiments of the invention, cells activated and expanded using the methods described herein or other methods known in the art for expanding T cells to therapeutic levels are administered to a patient in conjunction with (e.g., prior to, concurrently with, or subsequent to) any number of relevant treatment modalities, including but not limited to treatment with: such as antiviral therapy, cidofovir and interleukin-2, cytarabine (also known as ARA-C) or natalizumab therapy for MS patients or efavirenz therapy for psoriasis patients or other therapy for specific tumor patients. In further embodiments, the T cells of the invention may be used in combination with: chemotherapy, radiation, immunosuppressive agents such as cyclosporine, azathioprine, methotrexate, mycophenolate mofetil, and FK506, antibodies, or other immunotherapeutic agents. In a further embodiment, the cell composition of the invention is administered to the patient in conjunction with (e.g., prior to, concurrently with, or subsequent to) bone marrow transplantation with a chemotherapeutic agent such as fludarabine, external beam radiation therapy (XRT), cyclophosphamide. For example, in one embodiment, the subject may undergo standard treatment with high-dose chemotherapy followed by peripheral blood stem cell transplantation. In some embodiments, after transplantation, the subject receives an injection of the expanded immune cells of the invention. In an additional embodiment, the expanded cells are administered before or after surgery.
The dosage of the above treatments administered to a patient will vary with the precise nature of the condition being treated and the recipient of the treatment. The proportion of doses administered to a human can be effected in accordance with accepted practice in the art. Typically, 1X 10 may be used for each treatment or each course of treatment 61 to 1010The CAR-T cells of the invention are administered to a patient, for example, by intravenous infusion.
The main advantages of the invention include:
(a) and (3) specific target spots: the CAR immune cells of the invention are only directed against malignant cells or parts of normal T cells whose cell membranes highly express CD7, and have no killing effect on other cells or tissues that do not express CD 7.
(b) The present invention utilizes the mode of action of the ligand in combination with the receptor rather than scfv in the traditional sense. Receptor/ligand binding has an affinity selected by natural evolution, and when the extracellular fragment of the ligand SECTM1 is used as an extracellular binding domain, although the suicide phenomenon of CD7 CAR-T cells is caused, a group of CAR-T cells with low expression or negative CD7 are expanded, and the cells also have the function of killing target cells.
(c) The CART cells of the invention, prepared by in vitro expansion (with partial suicide), have a phenotype that is more biased towards memory cells than the control group of CAR-T cells, which suggests a longer duration and longer duration of action in vivo.
(d) The CAR-T cell of the invention does not kill T cells negative or low-expression CD7, and can retain necessary immunity of patients when applied clinically; meanwhile, the tumor cells with higher expression of CD7 can be killed efficiently, and the problem of tumor cell pollution in the process of T cell separation and CAR-T preparation can be solved.
(e) The CAR based on the specific segment of the natural ligand receptor has higher clinical reference value for safety evaluation in primates.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are only for illustrating the present invention and are not intended to limit the scope of the present invention. The experimental procedures, without specific conditions being noted in the following examples, are generally performed according to conventional conditions, such as Sambrook et al, molecular cloning: the conditions described in the Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or according to the manufacturer's recommendations. Unless otherwise indicated, percentages and parts are percentages and parts by weight.
Reagents, plasmids, and cells in the examples of the present application are commercially available unless otherwise specified.
TABLE A sequences
Wherein the underlined part is the amino acids 29-1445 of the SECTM1 protein.
Example 1: preparation of SECTM1-CAR vector
Based on the nucleotide sequence (NM-003004.3) of SECTM1/K12, the human CD8 alpha hinge region, the human CD8 transmembrane region, the human 4-1BB intracellular region and the human CD3 zeta intracellular region gene sequence information, the corresponding nucleotide sequence was obtained by an artificial synthesis method or a PCR method. After synthesizing the CD8 signal peptide and the gene fragment of the SECTM1 extracellular region, the nucleotide sequence of the CAR molecule is double digested by XbaI (thermo) and NheI (thermo), and is inserted into a lentiviral vector pTomo into which CD8TM, 4-1BB and CD3 zeta are inserted by T4 DNA ligase (NEB) ligation, and competent Escherichia coli (Stbl3) is transformed, wherein the SECTM1 schematic diagram is shown in FIG. 1A, and the full-length CAR schematic diagram is shown in FIG. 1B.
Sequencing of the recombinant plasmid revealed that the CAR coding sequence was correctly inserted into the plasmid at the predetermined position (figure 1C).
All plasmids were extracted using a QIAGEN endotoxin-free macroextraction kit, and purified plasmids were lentivirally packaged by transfecting 293T cells with Biluo Tianipo 6000.
Example 2: virus package
Packaging in 15cm culture dish with 293T cells used for less than 20 generations, and preparing 2ml OPTIMEM dissolved plasmid mixture (core plasmid 20ug, pCMV delta R8.910ug, PMD2. G4 ug) after 293T cells are transfected with a degree of confluence of about 80% -90%; in another centrifuge tube 2ml OPTIMEM and 68ul lipo 6000. Standing at room temperature for 5min, adding the plasmid complex into the liposome complex, and standing at room temperature for 20 min. The mixture was added dropwise to 293T cells, and the medium was removed after incubation at 37 ℃ for 6 hours. The pre-warmed complete medium was added again. After collecting the virus supernatants for 48 hours and 72 hours, they were centrifuged at 3000rpm at 4 ℃ for 20 minutes, and then filtered through a 0.45um filter. The virus was concentrated by centrifugation at 25000rpm at 4 ℃ for 2.5 hours. After the concentrated virus was dissolved overnight in 30ul of virus lysis solution, the virus titer was measured by QPCR. The results show that the virus titer meets the requirements.
Example 3: CART cell preparation
Mononuclear cells were isolated from Human peripheral blood using Ficool separation, and purified CD3+ T cells were obtained from RosetteSep Human T Cell Enrichment Cocktail (Stemcell technologies). T cells were activated with CD3/CD28 magnetic beads (Life technology), and then 200U/ml IL2(PeproTech) was added to the cells, and virus infection was performed 48 hours after stimulation culture. Lentiviruses CAR-T cells were prepared by infecting T cells in the presence of lentiboost at MOI ═ 20. The medium was changed one day after infection.
The obtained CAR-T cell proliferation fold and total number results are shown in figure 2. The results show that the cell count indicates that the cell number is significantly lower on the third day after infection than in the control group (FIG. 2A), and that a significant increase in the secretion of the cytokine IFN γ can be detected (FIG. 2B), which indicates that SECTM1 CAR is indeed "suicide". Notably, unlike the ligand form of SECTM1 CAR, in this study it was observed that the proliferation fold of SECTM1 CAR was significantly lower than the control group on the first three days due to the suicide phenomenon, whereas the cell proliferation counted again on day 6 was comparable to the control group, and thereafter counted every 3 days without significant difference from the control group (fig. 3A), and the total cell count statistics showed that although T-cell prophase proliferation was affected by the suicide phenomenon, a sufficient number of T-cells could be obtained for in vivo experiments by later proliferation (fig. 2C).
The inventors have performed the detection of CD7 molecules on CAR-T cells that proliferate later, and the data indicate that the population of cells is mainly a population of CD7 negative or weakly positive T cells, while there is a report in the literature that the presence of a population of CD7 negative T cells in normal blood increases the proportion of the population of cells with age, and that the population of cells is a population of memory T cells that are biased towards CD4 positive and CD45RO positive and CD45RA negative. The inventors performed CD4, CD8 and CD45RO, CCR7 molecular assays on the resulting CD7 negative CAR-T cells, indicating that the population of CD7 negative T cells of the inventors was more positive for CD4 than the control, and also a population biased towards effector memory and central memory cell populations (fig. 3). Then having a memory phenotype for this population of CD7 negative CD7 CAR-T cells may allow this population of T cells to survive longer in vivo and thus exert a longer killing effect.
Example 4: positive rate of detecting infected CART cells by flow cytometry
And respectively centrifugally collecting the CART cells and the control group T cells after virus infection for 72 hours, washing the CART cells and the control group T cells once by PBS, discarding supernatant, re-suspending the cells by PBS containing 2% FBS, and detecting the positive rate by flow.
The results of transfection efficiency are shown in FIG. 4, in which FIG. 4A represents the results of observation under a fluorescence microscope and FIG. 4B represents the results of flow assay. The results show that, as shown in the above figure, the CAR cell is the co-expressed CAR-mKate2 fusion protein, so the expressed fusion protein is cut by T2A, and the formed mKate2 protein shows red fluorescence in the cell.
FIG. 4 shows that the CAR-T positivity of the CAR of the invention expressed on the cell membrane was around 70% when the PE-CY5 channel was flow-detected using the red fluorescent mkate2 against SECTM 1.
Example 5: differential expression and killing of tumor cell and normal T cell CD7
Target cells CCRF-CEM and normal T cells are respectively marked by two fluorescent dyes of CFSE and violet, and the density of the target cells is adjusted to be 20 ten thousand/ml respectively and 40 ten thousand/ml in total. 100ul of CFSE cells were seeded in 96-well plates, CART/NK cells were adjusted to a cell density of 80 ten thousand/ml, according to E: T of 1: 1. 2: 1. 4: 1. 8: 1 into 96-well plates, 100ul per well. The target cells and T cells were mixed well and incubated in an incubator for 24 hours. After the cells are collected, the cells are stained by 7-AAD for 10min, and then the killing effect is detected by flow.
The results are shown in fig. 5, wherein fig. 5A is the result of CD7 detection of target cells and T cells, and the results show that the CD7 abundance of tumor cells is higher than that of normal T cells; fig. 5B shows the killing results of target cells and T cells, with the target cells killing effect being higher than T cells.
Example 6: detection of expression of CD7 in target cells
2 x 10 each of the target cells6Dividing the collection into two EP tubes, adding 1ml PBS containing 2% FBS for resuspension, and adding CD7 isotype control antibody and human CD7 antibody respectively for incubation for 1h at 4 ℃; after centrifugation and supernatant discarding, the cells were washed twice with 1ml of PBS containing 2% FBS, and the positive rate of CD7 expression in the target cells was detected on a flow-type machine after 300ul of resuspension.
The results are shown in FIG. 6. The inventor selects the T-ALL tumor cells CCRF-CEM and MOLT4 which are positive for CD7 and the AML tumor cells KG-1a, Kasumi-3 and K562 which are negative for the CD7 to detect the expression of CD7, and each cell shows different expression levels of CD 7.
Example 7: construction of target cells carrying luciferase
The luciferase fragment was PCR amplified from pGL3-luciferase plasmid, and then ligated into pTomo vector by XbaI and BamHI to construct pTomo-EGFP-T2A-lucferase plasmid. IRES and puromycin fragments were amplified from pTomo and PLkO.1 plasmids, respectively. The pTomo-EGFP-T2A-luciferase-IRES-Puro plasmid is successfully constructed by three-segment connection. Lentiviral packaging and titre determination human CCRF-CEM and KG-1a cell lines were infected at MOI 100 as described above and screened with puromycin (1ug/ml) for 1 week 48 hours to give CCRF-CEM-luciferase and KG-1a-luciferase cells, respectively.
Example 8: CART cell killing
In this example, the killing ability of CART cells of the invention to different target cells was tested. Target cells employed included: target cells expressing CD 7: CCRF-CEM, MOLT4, KG-1a and Kasumi-3; target cells that do not express or do not substantially express CD 7: K562.
the method comprises the following steps: collecting each target cell, staining with CFSE, adding PBS containing 5% FBS in 3 times volume at 37 deg.C for 10min to stop staining for 5min, centrifuging to remove supernatant, washing cells twice, resuspending with T cell culture medium, and adjusting target cell density to 40 ten thousand/ml. 100ul of CFSE cells were seeded in 96-well plates with a ratio of E: T of 0.5: 1. 1: 1. 2: 1. 4: 1 into 96-well plates, 100ul per well. The target cells and T cells were mixed well and incubated in an incubator for 24 hours. Collecting cell supernatant, freezing and storing at-80 deg.C to detect cell factor release amount. After the cells are collected, the cells are stained by 7-AAD for 10min, and then the killing effect is detected by flow.
The results are shown in FIG. 7. The results show that the killing effect of SECTM1-CART cells on tumor cells expressing CD7 is gradually enhanced along with the increase of the effective target ratio (E: T), and the killing effect is positively correlated with the expression level of CD7 of target cells; has no obvious killing effect on a CD7 negative cell strain K562.
Example 9: cytokine release
In this example, cytokine release was measured in the case of co-incubation of CART cells of the invention with target cells. The cell supernatants were co-incubated in a cell killing experiment for detection.
Taking IFN γ as an example, the method is as follows: cell supernatants of CART cells of the invention of example 8 incubated with CD7 positive target cells CCRF-CEM, MOLT4, KG-1a and Ksumi-3(ET ratio 2: 1) were assayed for IFN γ according to the IFN gamma Human ELISA Kit (life technology).
The Standard was dissolved in Standard Dilution Buffer and was subjected to gradient Dilution to 1000pg/ml, 500 pg/ml, 250pg/ml, 125pg/ml, 62.5pg/ml, 31.2pg/ml, 15.6pg/ml, 0 pg/ml.
50ul of incorporation buffer, 50ul of detection sample, and 50ul of IFN γ biotin conjugated solution were added to each well, mixed well and allowed to stand at room temperature for 90 minutes.
Then the operation is carried out according to the following steps in sequence:
(1) wash the wells 4 times with 1 × Wash Buffer, each time for 1 minute.
(2) 100ul 1 × Streptavidin-HRP solution was added to each well and allowed to stand at room temperature for 45 minutes.
(3) The wells were washed 4 times with 1 × Wash Buffer, each time for 1 minute.
(4) 100ul of Stabilized chromogen was added and allowed to stand at room temperature for 30 minutes.
(5) 100ul of Stop solution was added to each well and mixed well.
(6) Absorbance at 450nm was measured.
Similarly, TNF α detection was performed with Human TNF α ELISA Kit (BD Bioscience) Kit.
The results are shown in FIG. 8. The results show that the killing effect of SECTM1-CART cells on tumor cells is accompanied by the release of IFN γ (FIG. 8A) and TNF α (FIG. 8B).
Example 10: effect of over-expression of CD7 on SECTM1-CART tumor killing
K562 is a CD7 negative erythroleukemia cell line, and SECTM1-CART has no killing effect on K562. In this example, a vector that overexpresses the CDS region of CD7 was packaged in vitro by lentivirus, K562 cells were infected with this lentivirus, and after 7 days of selection with puromycin (1ug/ml), a K562 CD7 over cell line that stably overexpresses CD7 was obtained and CD7 expression was detected by flow assay, as shown in FIG. 9A.
The killing effect of SECTM1-CAR on K562 CD7 over cells was tested by flow assay according to the in vitro killing method of example 8, and the results are shown in FIG. 9B. The results show that the K562 CD7 over cell line, which overexpresses CD7 on the cell membrane, can be effectively killed by SECTM1-CART of the invention. Simultaneously detecting the cytokine IFN gamma, the secretion of the cytokine is obviously up-regulated compared with K562 wild cells and over-expression groups (figure 9C)
Example 11: post-infusion safety validation of SECTM1C CAR-T cell monkeys
T cells isolated from monkey blood were infected in vitro at MOI 100 and the infection efficiency of T cells was examined by flow cytometry, indicating that the infection efficiency of SECTM1 CAR was around 35% (fig. 10A). Simultaneous collection of cell supernatants three days prior to infection for IFN γ, IL2, IL6, and TNF α cytokine assays, showed a different increase in cytokines of SECTM1 CAR relative to control T cells (fig. 10B), counting two days for infected T cells showed a 2 nd, day 4 SECTM1 CAR-T cells that were slightly lower than control T cells, but remained at comparable levels after day 6 (fig. 10C), indicating that: the SECTM1 CAR designed in the study can recognize monkey T cells and show suicide phenomenon and cytokine release, and can well simulate clinical process in primate monkeys.
Meanwhile, the weight, anal temperature, blood pressure, heart rate (figure 10D) and blood routine test (figure 10E) of the monkey are tested before and after CAR-T cell infusion, the changes are within the range, no serious toxic or side effect is observed, and the in vivo safety of the SECTM1 CAR is proved.
Discussion of the related Art
The CD7 molecule is a 40kD type I transmembrane glycoprotein, a lineage specific antigen, normally found predominantly on T/NK cells and their progenitors, with only 9% of peripheral single nuclear cells (PBMCs) in peripheral blood being CD7 negative, i.e. most PBMCs are CD7 positive.
Thus prior to the present invention, the art believed that CD7 did not appear to be a suitable target for CAR immune cell therapy, as CAR immune cells (such as CAR-T cells) directed against the CD7 target would also kill these CD7 positive cells.
In addition, some T cells are also CD7 positive during CAR-T cell production, and thus there is severe suicide of T cells, resulting in an inefficient production of CAR-T cells. Thus, some researchers developed CAR-T cells based on CD7 blocking technology. However, the CD7 blocking molecule is adopted to block the CART cell from expressing CD7, so that the defects of complex process and the like exist.
In the present invention, the inventors unexpectedly found that, by using a specific segment of ectodomain of SECTM1 (i.e. amino acid sequence 29-145) as the extracellular binding domain of CAR, not only has suitable affinity, but also has some effect on CAR-T proliferation during CAR-T cell preparation, the desired CAR-T cells can be successfully prepared in large quantities, and the prepared CAR-T cells contain more memory T cells, thus having longer high killing ability against target cells positive for CD7 (such as tumor cells). And because the expression abundance of the tumor cell CD7 is higher than that of a normal T cell, the CAR-T cell can preferentially eliminate the tumor cell with higher expression of CD7, so that the problem of tumor cell pollution in the processes of T cell separation and CAR-T cell preparation can be solved.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it will be appreciated that various changes or modifications may be made by those skilled in the art after reading the above teachings of the invention, and such equivalents will fall within the scope of the invention as defined in the appended claims.
Sequence listing
<110> Sichuan university Hospital in Huaxi
<120> preparation and application of chimeric antigen receptor immune cell constructed based on SECTM1
<130> P2021-1798
<160> 11
<170> PatentIn version 3.5
<210> 1
<211> 248
<212> PRT
<213> Intelligent (Homo sapiens)
<400> 1
Met Gln Thr Cys Pro Leu Ala Phe Pro Gly His Val Ser Gln Ala Leu
1 5 10 15
Gly Thr Leu Leu Phe Leu Ala Ala Ser Leu Ser Ala Gln Asn Glu Gly
20 25 30
Trp Asp Ser Pro Ile Cys Thr Glu Gly Val Val Ser Val Ser Trp Gly
35 40 45
Glu Asn Thr Val Met Ser Cys Asn Ile Ser Asn Ala Phe Ser His Val
50 55 60
Asn Ile Lys Leu Arg Ala His Gly Gln Glu Ser Ala Ile Phe Asn Glu
65 70 75 80
Val Ala Pro Gly Tyr Phe Ser Arg Asp Gly Trp Gln Leu Gln Val Gln
85 90 95
Gly Gly Val Ala Gln Leu Val Ile Lys Gly Ala Arg Asp Ser His Ala
100 105 110
Gly Leu Tyr Met Trp His Leu Val Gly His Gln Arg Asn Asn Arg Gln
115 120 125
Val Thr Leu Glu Val Ser Gly Ala Glu Pro Gln Ser Ala Pro Asp Thr
130 135 140
Gly Phe Trp Pro Val Pro Ala Val Val Thr Ala Val Phe Ile Leu Leu
145 150 155 160
Val Ala Leu Val Met Phe Ala Trp Tyr Arg Cys Arg Cys Ser Gln Gln
165 170 175
Arg Arg Glu Lys Lys Phe Phe Leu Leu Glu Pro Gln Met Lys Val Ala
180 185 190
Ala Leu Arg Ala Gly Ala Gln Gln Gly Leu Ser Arg Ala Ser Ala Glu
195 200 205
Leu Trp Thr Pro Asp Ser Glu Pro Thr Pro Arg Pro Leu Ala Leu Val
210 215 220
Phe Lys Pro Ser Pro Leu Gly Ala Leu Glu Leu Leu Ser Pro Gln Pro
225 230 235 240
Leu Phe Pro Tyr Ala Ala Asp Pro
245
<210> 2
<211> 233
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 2
Met Ser Glu Leu Ile Lys Glu Asn Met His Met Lys Leu Tyr Met Glu
1 5 10 15
Gly Thr Val Asn Asn His His Phe Lys Cys Thr Ser Glu Gly Glu Gly
20 25 30
Lys Pro Tyr Glu Gly Thr Gln Thr Met Arg Ile Lys Ala Val Glu Gly
35 40 45
Gly Pro Leu Pro Phe Ala Phe Asp Ile Leu Ala Thr Ser Phe Met Tyr
50 55 60
Gly Ser Lys Thr Phe Ile Asn His Thr Gln Gly Ile Pro Asp Phe Phe
65 70 75 80
Lys Gln Ser Phe Pro Glu Gly Phe Thr Trp Glu Arg Val Thr Thr Tyr
85 90 95
Glu Asp Gly Gly Val Leu Thr Ala Thr Gln Asp Thr Ser Leu Gln Asp
100 105 110
Gly Cys Leu Ile Tyr Asn Val Lys Ile Arg Gly Val Asn Phe Pro Ser
115 120 125
Asn Gly Pro Val Met Gln Lys Lys Thr Leu Gly Trp Glu Ala Ser Thr
130 135 140
Glu Thr Leu Tyr Pro Ala Asp Gly Gly Leu Glu Gly Arg Ala Asp Met
145 150 155 160
Ala Leu Lys Leu Val Gly Gly Gly His Leu Ile Cys Asn Leu Lys Thr
165 170 175
Thr Tyr Arg Ser Lys Lys Pro Ala Lys Asn Leu Lys Met Pro Gly Val
180 185 190
Tyr Tyr Val Asp Arg Arg Leu Glu Arg Ile Lys Glu Ala Asp Lys Glu
195 200 205
Thr Tyr Val Glu Gln His Glu Val Ala Val Ala Arg Tyr Cys Asp Leu
210 215 220
Pro Ser Lys Leu Gly His Lys Leu Asn
225 230
<210> 3
<211> 21
<212> PRT
<213> Intelligent (Homo sapiens)
<400> 3
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro
20
<210> 4
<211> 45
<212> PRT
<213> Intelligent (Homo sapiens)
<400> 4
Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala
1 5 10 15
Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly
20 25 30
Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp
35 40 45
<210> 5
<211> 24
<212> PRT
<213> Intelligent (Homo sapiens)
<400> 5
Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu
1 5 10 15
Ser Leu Val Ile Thr Leu Tyr Cys
20
<210> 6
<211> 43
<212> PRT
<213> Intelligent (Homo sapiens)
<400> 6
Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met
1 5 10 15
Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe
20 25 30
Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg
35 40
<210> 7
<211> 111
<212> PRT
<213> Intelligent (Homo sapiens)
<400> 7
Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln
1 5 10 15
Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp
20 25 30
Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro
35 40 45
Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp
50 55 60
Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg
65 70 75 80
Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr
85 90 95
Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
100 105 110
<210> 8
<211> 361
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 8
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Gln Asn Glu Gly Trp Asp Ser Pro Ile Cys Thr
20 25 30
Glu Gly Val Val Ser Val Ser Trp Gly Glu Asn Thr Val Met Ser Cys
35 40 45
Asn Ile Ser Asn Ala Phe Ser His Val Asn Ile Lys Leu Arg Ala His
50 55 60
Gly Gln Glu Ser Ala Ile Phe Asn Glu Val Ala Pro Gly Tyr Phe Ser
65 70 75 80
Arg Asp Gly Trp Gln Leu Gln Val Gln Gly Gly Val Ala Gln Leu Val
85 90 95
Ile Lys Gly Ala Arg Asp Ser His Ala Gly Leu Tyr Met Trp His Leu
100 105 110
Val Gly His Gln Arg Asn Asn Arg Gln Val Thr Leu Glu Val Ser Gly
115 120 125
Ala Glu Pro Gln Ser Ala Pro Asp Thr Gly Thr Thr Thr Pro Ala Pro
130 135 140
Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu
145 150 155 160
Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg
165 170 175
Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly
180 185 190
Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys
195 200 205
Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg
210 215 220
Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro
225 230 235 240
Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser
245 250 255
Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu
260 265 270
Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg
275 280 285
Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln
290 295 300
Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr
305 310 315 320
Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp
325 330 335
Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala
340 345 350
Leu His Met Gln Ala Leu Pro Pro Arg
355 360
<210> 9
<211> 1080
<212> DNA
<213> Artificial Sequence (Artificial Sequence)
<400> 9
atggccctgc ccgtcaccgc tctgctgctg ccccttgctc tgcttcttca tgcagcaagg 60
ccgaatgaag gctgggacag ccccatctgc acagaggggg tagtctctgt gtcttggggc 120
gagaacaccg tcatgtcctg caacatctcc aacgccttct cccatgtcaa catcaagctg 180
cgtgcccacg ggcaggagag cgccatcttc aatgaggtgg ctccaggcta cttctcccgg 240
gacggctggc agctccaggt tcagggaggc gtggcacagc tggtgatcaa aggcgcccgg 300
gactcccatg ctgggctgta catgtggcac ctcgtgggac accagagaaa taacagacaa 360
gtcacgctgg aggtttcagg tgcagaaccc cagtccgccc ccgacactgg gaccacgacg 420
ccagcgccgc gaccaccaac accggcgccc accatcgcta gccagcccct gtccctgcgc 480
ccagaggcgt gccggccagc ggcggggggc gcagtgcaca cgagggggct ggacttcgcc 540
tgtgatatct acatctgggc gcccttggcc gggacttgtg gggtccttct cctgtcactg 600
gttatcaccc tttactgcaa acggggcaga aagaaactcc tgtatatatt caaacaacca 660
tttatgagac cagtacaaac tactcaagag gaagatggct gtagctgccg atttccagaa 720
gaagaagaag gaggatgtga actgagagtg aagttcagca ggagcgcaga cgcccccgcg 780
tacaagcagg gccagaacca gctctataac gagctcaatc taggacgaag agaggagtac 840
gatgttttgg acaagagacg tggccgggac cctgagatgg ggggaaagcc gagaaggaag 900
aaccctcagg aaggcctgta caatgaactg cagaaagata agatggcgga ggcctacagt 960
gagattggga tgaaaggcga gcgccggagg ggcaaggggc acgatggcct ttaccagggt 1020
ctcagtacag ccaccaagga cacctacgac gcccttcaca tgcaggccct gccccctcgc 1080
<210> 10
<211> 615
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 10
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Gln Asn Glu Gly Trp Asp Ser Pro Ile Cys Thr
20 25 30
Glu Gly Val Val Ser Val Ser Trp Gly Glu Asn Thr Val Met Ser Cys
35 40 45
Asn Ile Ser Asn Ala Phe Ser His Val Asn Ile Lys Leu Arg Ala His
50 55 60
Gly Gln Glu Ser Ala Ile Phe Asn Glu Val Ala Pro Gly Tyr Phe Ser
65 70 75 80
Arg Asp Gly Trp Gln Leu Gln Val Gln Gly Gly Val Ala Gln Leu Val
85 90 95
Ile Lys Gly Ala Arg Asp Ser His Ala Gly Leu Tyr Met Trp His Leu
100 105 110
Val Gly His Gln Arg Asn Asn Arg Gln Val Thr Leu Glu Val Ser Gly
115 120 125
Ala Glu Pro Gln Ser Ala Pro Asp Thr Gly Thr Thr Thr Pro Ala Pro
130 135 140
Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu
145 150 155 160
Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg
165 170 175
Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly
180 185 190
Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys
195 200 205
Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg
210 215 220
Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro
225 230 235 240
Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser
245 250 255
Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu
260 265 270
Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg
275 280 285
Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln
290 295 300
Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr
305 310 315 320
Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp
325 330 335
Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala
340 345 350
Leu His Met Gln Ala Leu Pro Pro Arg Gly Ser Gly Glu Gly Arg Gly
355 360 365
Ser Leu Leu Thr Cys Gly Asp Val Glu Glu Asn Pro Gly Pro Met Ser
370 375 380
Glu Leu Ile Lys Glu Asn Met His Met Lys Leu Tyr Met Glu Gly Thr
385 390 395 400
Val Asn Asn His His Phe Lys Cys Thr Ser Glu Gly Glu Gly Lys Pro
405 410 415
Tyr Glu Gly Thr Gln Thr Met Arg Ile Lys Ala Val Glu Gly Gly Pro
420 425 430
Leu Pro Phe Ala Phe Asp Ile Leu Ala Thr Ser Phe Met Tyr Gly Ser
435 440 445
Lys Thr Phe Ile Asn His Thr Gln Gly Ile Pro Asp Phe Phe Lys Gln
450 455 460
Ser Phe Pro Glu Gly Phe Thr Trp Glu Arg Val Thr Thr Tyr Glu Asp
465 470 475 480
Gly Gly Val Leu Thr Ala Thr Gln Asp Thr Ser Leu Gln Asp Gly Cys
485 490 495
Leu Ile Tyr Asn Val Lys Ile Arg Gly Val Asn Phe Pro Ser Asn Gly
500 505 510
Pro Val Met Gln Lys Lys Thr Leu Gly Trp Glu Ala Ser Thr Glu Thr
515 520 525
Leu Tyr Pro Ala Asp Gly Gly Leu Glu Gly Arg Ala Asp Met Ala Leu
530 535 540
Lys Leu Val Gly Gly Gly His Leu Ile Cys Asn Leu Lys Thr Thr Tyr
545 550 555 560
Arg Ser Lys Lys Pro Ala Lys Asn Leu Lys Met Pro Gly Val Tyr Tyr
565 570 575
Val Asp Arg Arg Leu Glu Arg Ile Lys Glu Ala Asp Lys Glu Thr Tyr
580 585 590
Val Glu Gln His Glu Val Ala Val Ala Arg Tyr Cys Asp Leu Pro Ser
595 600 605
Lys Leu Gly His Lys Leu Asn
610 615
<210> 11
<211> 1845
<212> DNA
<213> Artificial Sequence (Artificial Sequence)
<400> 11
atggccctgc ccgtcaccgc tctgctgctg ccccttgctc tgcttcttca tgcagcaagg 60
ccgaatgaag gctgggacag ccccatctgc acagaggggg tagtctctgt gtcttggggc 120
gagaacaccg tcatgtcctg caacatctcc aacgccttct cccatgtcaa catcaagctg 180
cgtgcccacg ggcaggagag cgccatcttc aatgaggtgg ctccaggcta cttctcccgg 240
gacggctggc agctccaggt tcagggaggc gtggcacagc tggtgatcaa aggcgcccgg 300
gactcccatg ctgggctgta catgtggcac ctcgtgggac accagagaaa taacagacaa 360
gtcacgctgg aggtttcagg tgcagaaccc cagtccgccc ccgacactgg gaccacgacg 420
ccagcgccgc gaccaccaac accggcgccc accatcgcta gccagcccct gtccctgcgc 480
ccagaggcgt gccggccagc ggcggggggc gcagtgcaca cgagggggct ggacttcgcc 540
tgtgatatct acatctgggc gcccttggcc gggacttgtg gggtccttct cctgtcactg 600
gttatcaccc tttactgcaa acggggcaga aagaaactcc tgtatatatt caaacaacca 660
tttatgagac cagtacaaac tactcaagag gaagatggct gtagctgccg atttccagaa 720
gaagaagaag gaggatgtga actgagagtg aagttcagca ggagcgcaga cgcccccgcg 780
tacaagcagg gccagaacca gctctataac gagctcaatc taggacgaag agaggagtac 840
gatgttttgg acaagagacg tggccgggac cctgagatgg ggggaaagcc gagaaggaag 900
aaccctcagg aaggcctgta caatgaactg cagaaagata agatggcgga ggcctacagt 960
gagattggga tgaaaggcga gcgccggagg ggcaaggggc acgatggcct ttaccagggt 1020
ctcagtacag ccaccaagga cacctacgac gcccttcaca tgcaggccct gccccctcgc 1080
ggcagtggag agggcagagg aagtctgcta acatgcggtg acgtcgagga gaatcctggc 1140
ccaatgagcg agctgattaa ggagaacatg cacatgaagc tgtacatgga gggcaccgtg 1200
aacaaccacc acttcaagtg cacatccgag ggcgaaggca agccctacga gggcacccag 1260
accatgagaa tcaaggcggt cgagggcggc cctctcccct tcgccttcga catcctggct 1320
accagcttca tgtacggcag caaaaccttc atcaaccaca cccagggcat ccccgacttc 1380
tttaagcagt ccttccccga gggcttcaca tgggagagag tcaccacata cgaagacggg 1440
ggcgtgctga ccgctaccca ggacaccagc ctccaggacg gctgcctcat ctacaacgtc 1500
aagatcagag gggtgaactt cccatccaac ggccctgtga tgcagaagaa aacactcggc 1560
tgggaggcct ccaccgagac cctgtacccc gctgacggcg gcctggaagg cagagccgac 1620
atggccctga agctcgtggg cgggggccac ctgatctgca acttgaagac cacatacaga 1680
tccaagaaac ccgctaagaa cctcaagatg cccggcgtct actatgtgga cagaagactg 1740
gaaagaatca aggaggccga caaagagacc tacgtcgagc agcacgaggt ggctgtggcc 1800
agatactgcg acctccctag caaactgggg cacaagctta attag 1845
Claims (10)
1. A Chimeric Antigen Receptor (CAR), wherein the CAR comprises an extracellular binding domain comprising the structure of SECTM1 or a fragment thereof based on the amino acid sequence shown in SEQ ID NO:1,
and, the extracellular binding domain is capable of specifically binding to SECTM1 receptor in the manner of a ligand receptor.
2. The CAR of claim 1, wherein the extracellular binding domain comprises a SECTM1 protein or fragment thereof, wherein the SECTM1 protein or fragment thereof has the amino acid sequence set forth in SEQ ID No. 1, or the amino acid sequence from position 1 to 145 (preferably from position 29 to 145) of the sequence set forth in SEQ ID No. 1.
3. The CAR of claim 1 or 2, wherein the CAR has the structure of formula I:
L-EB-H-TM-C-CD3ζ-RP (I)
in the formula (I), the compound is shown in the specification,
each "-" is independently a linker peptide or a peptide bond;
l is a null or signal peptide sequence;
EB is an extracellular binding domain that specifically binds to SECTM1 receptor;
h is a none or hinge region;
TM is a transmembrane domain;
c is a no or co-stimulatory signaling molecule;
CD3 ζ is a cytoplasmic signaling sequence derived from CD3 ζ;
RP is a null or reporter protein.
4. A nucleic acid molecule encoding the chimeric antigen receptor of claim 1.
5. A vector comprising the nucleic acid molecule of claim 4.
6. A host cell comprising the vector or chromosome of claim 5 having integrated therein an exogenous nucleic acid molecule of claim 4 or expressing the CAR of claim 1.
7. An engineered immune cell comprising the vector or chromosome of claim 5 having integrated therein the exogenous nucleic acid molecule of claim 4 or expressing the CAR of claim 1.
8. A method of making the engineered immune cell of claim 7, comprising the steps of: transferring the nucleic acid molecule of claim 4 or the vector of claim 5 into an immune cell, thereby obtaining the engineered immune cell.
9. A pharmaceutical composition comprising the CAR of claim 1, the nucleic acid molecule of claim 4, the vector of claim 5, the host cell of claim 6, and/or the engineered immune cell of claim 7, and a pharmaceutically acceptable carrier, diluent, or excipient.
10. Use of the CAR of claim 1, the nucleic acid molecule of claim 4, the vector of claim 5, or the host cell of claim 6, and/or the engineered immune cell of claim 7, for the preparation of a medicament or formulation for the prevention and/or treatment of a disease associated with aberrant expression of SECTM1 receptor.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202111566838.3A CN114716564B (en) | 2021-12-20 | 2021-12-20 | Preparation and application of chimeric antigen receptor immune cells constructed based on SECTM1 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202111566838.3A CN114716564B (en) | 2021-12-20 | 2021-12-20 | Preparation and application of chimeric antigen receptor immune cells constructed based on SECTM1 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN114716564A true CN114716564A (en) | 2022-07-08 |
CN114716564B CN114716564B (en) | 2023-02-28 |
Family
ID=82235294
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202111566838.3A Active CN114716564B (en) | 2021-12-20 | 2021-12-20 | Preparation and application of chimeric antigen receptor immune cells constructed based on SECTM1 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN114716564B (en) |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20020141999A1 (en) * | 1999-05-28 | 2002-10-03 | Lyman Stewart D. | Ligand for CD7 and methods for use thereof |
CN108348551A (en) * | 2015-08-28 | 2018-07-31 | 宾夕法尼亚大学董事会 | Methods and compositions for cells expressing chimeric intracellular signaling molecules |
US20190192691A1 (en) * | 2016-04-11 | 2019-06-27 | Obsidian Therapeutics, Inc. | Regulated biocircuit systems |
CN110760007A (en) * | 2019-11-21 | 2020-02-07 | 博生吉医药科技(苏州)有限公司 | CD7-CAR-T cell and preparation and application thereof |
CN112601583A (en) * | 2018-03-07 | 2021-04-02 | 波赛达治疗公司 | CARTyrin compositions and methods of use |
CN113234682A (en) * | 2021-01-12 | 2021-08-10 | 上海雅科生物科技有限公司 | CD 7-targeted engineered immune cell, chimeric antigen receptor, CD7 blocking molecule and application |
-
2021
- 2021-12-20 CN CN202111566838.3A patent/CN114716564B/en active Active
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20020141999A1 (en) * | 1999-05-28 | 2002-10-03 | Lyman Stewart D. | Ligand for CD7 and methods for use thereof |
CN108348551A (en) * | 2015-08-28 | 2018-07-31 | 宾夕法尼亚大学董事会 | Methods and compositions for cells expressing chimeric intracellular signaling molecules |
US20190192691A1 (en) * | 2016-04-11 | 2019-06-27 | Obsidian Therapeutics, Inc. | Regulated biocircuit systems |
CN112601583A (en) * | 2018-03-07 | 2021-04-02 | 波赛达治疗公司 | CARTyrin compositions and methods of use |
CN110760007A (en) * | 2019-11-21 | 2020-02-07 | 博生吉医药科技(苏州)有限公司 | CD7-CAR-T cell and preparation and application thereof |
WO2021098882A1 (en) * | 2019-11-21 | 2021-05-27 | 博生吉医药科技(苏州)有限公司 | Cd7-car-t cell and preparation and application thereof |
CN113234682A (en) * | 2021-01-12 | 2021-08-10 | 上海雅科生物科技有限公司 | CD 7-targeted engineered immune cell, chimeric antigen receptor, CD7 blocking molecule and application |
Non-Patent Citations (3)
Title |
---|
NCBI: "PREDICTED: secreted and transmembrane protein 1 isoform X1 [Homo sapiens]", 《GENBANK DATABASE》 * |
STEWART D.LYMAN 等: "Identification of CD7 as a Cognate of the Human K12 (SECTM1) Protein", 《THE JOURNAL OF BIOLOGICAL CHEMISTRY》 * |
朱欣颖 等: "靶向CD7的嵌合抗原受体NK-92MI细胞对CD7阳性血液系统恶性肿瘤细胞的杀伤作用", 《中国实验血液学杂志》 * |
Also Published As
Publication number | Publication date |
---|---|
CN114716564B (en) | 2023-02-28 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2019196713A1 (en) | Bcma-targeted chimeric antigen receptor as well as preparation method therefor and application thereof | |
CN109306016B (en) | NKG2D-CAR-T cells co-expressing cytokine IL-7 and uses thereof | |
CN115925976A (en) | CD7-CAR-T cell and preparation and application thereof | |
WO2023046110A1 (en) | Engineered immune cell co-expressing ccr2b, preparation therefor and application thereof | |
CN113755448B (en) | Engineered immune cells jointly expressing CCR2b and CD40L, and preparation and application thereof | |
WO2021136040A1 (en) | Preparation and applications of chimeric antigen receptor t-cell co-expressing immunomodulatory molecule | |
CN111378625A (en) | Preparation and application of CXCL13 chemotactic CAR-T cell | |
CN107936120B (en) | CD19 targeted chimeric antigen receptor and preparation method and application thereof | |
CN113087806A (en) | Novel CAR-T cells targeting multiple tumors, and preparation and methods thereof | |
WO2024164637A1 (en) | Use of natural protein tsh as antigen-binding site in construction of car-t cells targeting tshr | |
WO2023217192A1 (en) | Preparation of chimeric antigen receptor immune cell constructed based on msln precursor protein and use thereof | |
WO2020151752A1 (en) | Engineered immune cells targeting cd20 combination | |
CN115819614B (en) | Preparation and application of chimeric antigen receptor immune cells based on IL34 | |
CN115806626B (en) | Preparation and application of chimeric antigen receptor immune cells based on CSF1 | |
CN109320602B (en) | Siglec-9 targeted chimeric antigen receptor T cell and application thereof | |
WO2022262764A1 (en) | Preparation and application of lox1-based chimeric antigen receptor immune cell | |
CN109897114B (en) | CD 47-targeted engineered immune cells with suicide gene switch | |
CN114716564B (en) | Preparation and application of chimeric antigen receptor immune cells constructed based on SECTM1 | |
CN115477705B (en) | Preparation and application of chimeric antigen receptor immune cells constructed based on granzyme B | |
WO2024179518A1 (en) | Dual-target car-t having optimized itam domain and cd28 and 4-1bb dual costimulatory molecules | |
WO2023093888A1 (en) | Preparation and use of immune cells of chimeric antigen receptor constructed on the basis of efna1 | |
WO2023083195A1 (en) | Preparation for chimeric antigen receptor immune cell constructed on basis of gas6 and use of chimeric antigen receptor immune cell | |
WO2023246908A1 (en) | Preparation and use of chimeric antigen receptor immune cell targeting csf1r | |
US20240016842A1 (en) | Preparation method and application of cd7-car-t cells | |
CN116199787A (en) | Preparation and application of chimeric antigen receptor immune cells constructed based on GFD structural domain of uPA |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |