CN116888259A - 抗c4d嵌合抗原受体调节性t细胞及其用途 - Google Patents
抗c4d嵌合抗原受体调节性t细胞及其用途 Download PDFInfo
- Publication number
- CN116888259A CN116888259A CN202280016047.XA CN202280016047A CN116888259A CN 116888259 A CN116888259 A CN 116888259A CN 202280016047 A CN202280016047 A CN 202280016047A CN 116888259 A CN116888259 A CN 116888259A
- Authority
- CN
- China
- Prior art keywords
- acid sequence
- amino acid
- sequence
- regulatory
- cell
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 210000003289 regulatory T cell Anatomy 0.000 title claims abstract description 137
- 108010019670 Chimeric Antigen Receptors Proteins 0.000 title claims description 118
- 206010052779 Transplant rejections Diseases 0.000 claims abstract description 31
- 230000000747 cardiac effect Effects 0.000 claims abstract description 17
- 238000000338 in vitro Methods 0.000 claims abstract description 13
- 230000002463 transducing effect Effects 0.000 claims abstract description 4
- 125000003275 alpha amino acid group Chemical group 0.000 claims description 125
- 150000007523 nucleic acids Chemical class 0.000 claims description 100
- 101000914514 Homo sapiens T-cell-specific surface glycoprotein CD28 Proteins 0.000 claims description 98
- 102100027213 T-cell-specific surface glycoprotein CD28 Human genes 0.000 claims description 98
- 230000001086 cytosolic effect Effects 0.000 claims description 93
- 150000001413 amino acids Chemical class 0.000 claims description 55
- 210000004027 cell Anatomy 0.000 claims description 45
- 238000000034 method Methods 0.000 claims description 45
- 239000000427 antigen Substances 0.000 claims description 42
- 102000036639 antigens Human genes 0.000 claims description 42
- 108091007433 antigens Proteins 0.000 claims description 42
- 239000013598 vector Substances 0.000 claims description 34
- 102000039446 nucleic acids Human genes 0.000 claims description 32
- 108020004707 nucleic acids Proteins 0.000 claims description 32
- 230000027455 binding Effects 0.000 claims description 28
- 108090000623 proteins and genes Proteins 0.000 claims description 22
- 102000025171 antigen binding proteins Human genes 0.000 claims description 21
- 108091000831 antigen binding proteins Proteins 0.000 claims description 21
- 102000004169 proteins and genes Human genes 0.000 claims description 21
- 210000001744 T-lymphocyte Anatomy 0.000 claims description 19
- 230000002401 inhibitory effect Effects 0.000 claims description 17
- 108010047041 Complementarity Determining Regions Proteins 0.000 claims description 16
- 230000001177 retroviral effect Effects 0.000 claims description 12
- 102000003814 Interleukin-10 Human genes 0.000 claims description 9
- 108090000174 Interleukin-10 Proteins 0.000 claims description 9
- 210000003162 effector t lymphocyte Anatomy 0.000 claims description 9
- 230000035755 proliferation Effects 0.000 claims description 9
- 108010042293 complement C4d Proteins 0.000 claims description 8
- 102100025137 Early activation antigen CD69 Human genes 0.000 claims description 7
- 101000934374 Homo sapiens Early activation antigen CD69 Proteins 0.000 claims description 7
- 210000004369 blood Anatomy 0.000 claims description 7
- 239000008280 blood Substances 0.000 claims description 7
- 230000028993 immune response Effects 0.000 claims description 7
- 230000001965 increasing effect Effects 0.000 claims description 6
- 230000001939 inductive effect Effects 0.000 claims description 5
- 101710135898 Myc proto-oncogene protein Proteins 0.000 claims description 4
- 102100038895 Myc proto-oncogene protein Human genes 0.000 claims description 4
- 101710150448 Transcriptional regulator Myc Proteins 0.000 claims description 4
- 238000012258 culturing Methods 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 3
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 claims description 2
- 210000004962 mammalian cell Anatomy 0.000 claims description 2
- 238000002054 transplantation Methods 0.000 abstract description 20
- 101001057504 Homo sapiens Interferon-stimulated gene 20 kDa protein Proteins 0.000 abstract description 12
- 101001055144 Homo sapiens Interleukin-2 receptor subunit alpha Proteins 0.000 abstract description 12
- 102100026878 Interleukin-2 receptor subunit alpha Human genes 0.000 abstract description 12
- 230000004083 survival effect Effects 0.000 abstract description 11
- 229940045513 CTLA4 antagonist Drugs 0.000 abstract description 10
- 241001430294 unidentified retrovirus Species 0.000 abstract description 8
- 230000006052 T cell proliferation Effects 0.000 abstract description 7
- 230000009870 specific binding Effects 0.000 abstract description 6
- 101001018097 Homo sapiens L-selectin Proteins 0.000 abstract description 5
- 102100033467 L-selectin Human genes 0.000 abstract description 5
- 230000008021 deposition Effects 0.000 abstract description 5
- 230000002035 prolonged effect Effects 0.000 abstract description 4
- 238000012546 transfer Methods 0.000 abstract description 4
- 201000001383 blood group incompatibility Diseases 0.000 abstract description 2
- 101710134031 CCAAT/enhancer-binding protein beta Proteins 0.000 abstract 1
- 102000008203 CTLA-4 Antigen Human genes 0.000 abstract 1
- 108010021064 CTLA-4 Antigen Proteins 0.000 abstract 1
- 102100023441 Centromere protein J Human genes 0.000 abstract 1
- 101710199286 Cytosol aminopeptidase Proteins 0.000 abstract 1
- 101710197780 E3 ubiquitin-protein ligase LAP Proteins 0.000 abstract 1
- 101000801234 Homo sapiens Tumor necrosis factor receptor superfamily member 18 Proteins 0.000 abstract 1
- 101710204480 Lysosomal acid phosphatase Proteins 0.000 abstract 1
- 101710089118 Probable cytosol aminopeptidase Proteins 0.000 abstract 1
- 102100033728 Tumor necrosis factor receptor superfamily member 18 Human genes 0.000 abstract 1
- 239000003550 marker Substances 0.000 abstract 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 82
- 108091028043 Nucleic acid sequence Proteins 0.000 description 55
- 235000001014 amino acid Nutrition 0.000 description 42
- 239000002773 nucleotide Substances 0.000 description 39
- 125000003729 nucleotide group Chemical group 0.000 description 39
- 229940024606 amino acid Drugs 0.000 description 36
- 108020004414 DNA Proteins 0.000 description 25
- 108020001507 fusion proteins Proteins 0.000 description 19
- 102000037865 fusion proteins Human genes 0.000 description 19
- 239000012634 fragment Substances 0.000 description 18
- 230000001506 immunosuppresive effect Effects 0.000 description 14
- 235000018102 proteins Nutrition 0.000 description 14
- 238000000684 flow cytometry Methods 0.000 description 12
- 108090000765 processed proteins & peptides Proteins 0.000 description 12
- 108010074328 Interferon-gamma Proteins 0.000 description 11
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 11
- 102000008070 Interferon-gamma Human genes 0.000 description 10
- 108010002350 Interleukin-2 Proteins 0.000 description 10
- 102000000588 Interleukin-2 Human genes 0.000 description 10
- XKUKSGPZAADMRA-UHFFFAOYSA-N glycyl-glycyl-glycine Natural products NCC(=O)NCC(=O)NCC(O)=O XKUKSGPZAADMRA-UHFFFAOYSA-N 0.000 description 10
- 229960003130 interferon gamma Drugs 0.000 description 10
- 102000004196 processed proteins & peptides Human genes 0.000 description 10
- 102100039498 Cytotoxic T-lymphocyte protein 4 Human genes 0.000 description 9
- 101000889276 Homo sapiens Cytotoxic T-lymphocyte protein 4 Proteins 0.000 description 9
- UIGMAMGZOJVTDN-WHFBIAKZSA-N Ser-Gly-Ser Chemical compound OC[C@H](N)C(=O)NCC(=O)N[C@@H](CO)C(O)=O UIGMAMGZOJVTDN-WHFBIAKZSA-N 0.000 description 9
- 230000004913 activation Effects 0.000 description 9
- 108010068380 arginylarginine Proteins 0.000 description 9
- 108010082286 glycyl-seryl-alanine Proteins 0.000 description 9
- 108091033319 polynucleotide Proteins 0.000 description 9
- 102000040430 polynucleotide Human genes 0.000 description 9
- 239000002157 polynucleotide Substances 0.000 description 9
- 229920001184 polypeptide Polymers 0.000 description 9
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 9
- 238000006467 substitution reaction Methods 0.000 description 9
- 108010067216 glycyl-glycyl-glycine Proteins 0.000 description 8
- 102400000401 Latency-associated peptide Human genes 0.000 description 7
- 101800001155 Latency-associated peptide Proteins 0.000 description 7
- YMTLKLXDFCSCNX-BYPYZUCNSA-N Ser-Gly-Gly Chemical compound OC[C@H](N)C(=O)NCC(=O)NCC(O)=O YMTLKLXDFCSCNX-BYPYZUCNSA-N 0.000 description 7
- QUILOGWWLXMSAT-IHRRRGAJSA-N Tyr-Gln-Gln Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O QUILOGWWLXMSAT-IHRRRGAJSA-N 0.000 description 7
- 108010008685 alanyl-glutamyl-aspartic acid Proteins 0.000 description 7
- 238000003556 assay Methods 0.000 description 7
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical group P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 108010053725 prolylvaline Proteins 0.000 description 7
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 description 7
- 229960002930 sirolimus Drugs 0.000 description 7
- 241000894007 species Species 0.000 description 7
- 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 6
- WZUVPPKBWHMQCE-UHFFFAOYSA-N Haematoxylin Chemical compound C12=CC(O)=C(O)C=C2CC2(O)C1C1=CC=C(O)C(O)=C1OC2 WZUVPPKBWHMQCE-UHFFFAOYSA-N 0.000 description 6
- 102000015696 Interleukins Human genes 0.000 description 6
- 108010063738 Interleukins Proteins 0.000 description 6
- 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 6
- 241000699670 Mus sp. Species 0.000 description 6
- 108010050848 glycylleucine Proteins 0.000 description 6
- 108010015792 glycyllysine Proteins 0.000 description 6
- 239000002953 phosphate buffered saline Substances 0.000 description 6
- 230000001105 regulatory effect Effects 0.000 description 6
- KXEVYGKATAMXJJ-ACZMJKKPSA-N Ala-Glu-Asp Chemical compound C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O KXEVYGKATAMXJJ-ACZMJKKPSA-N 0.000 description 5
- IPZQNYYAYVRKKK-FXQIFTODSA-N Ala-Pro-Ala Chemical compound C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C)C(O)=O IPZQNYYAYVRKKK-FXQIFTODSA-N 0.000 description 5
- MTDDMSUUXNQMKK-BPNCWPANSA-N Ala-Tyr-Arg Chemical compound C[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 MTDDMSUUXNQMKK-BPNCWPANSA-N 0.000 description 5
- AOHKLEBWKMKITA-IHRRRGAJSA-N Arg-Phe-Ser Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CCCN=C(N)N)N AOHKLEBWKMKITA-IHRRRGAJSA-N 0.000 description 5
- GKKUBLFXKRDMFC-BQBZGAKWSA-N Asn-Pro-Gly Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O GKKUBLFXKRDMFC-BQBZGAKWSA-N 0.000 description 5
- 238000011746 C57BL/6J (JAX™ mouse strain) Methods 0.000 description 5
- NCWOMXABNYEPLY-NRPADANISA-N Glu-Ala-Val Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(O)=O NCWOMXABNYEPLY-NRPADANISA-N 0.000 description 5
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 5
- NGRPGJGKJMUGDM-XVKPBYJWSA-N Gly-Val-Gln Chemical compound NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O NGRPGJGKJMUGDM-XVKPBYJWSA-N 0.000 description 5
- CAHCWMVNBZJVAW-NAKRPEOUSA-N Ile-Pro-Ser Chemical compound CC[C@H](C)[C@@H](C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)O)N CAHCWMVNBZJVAW-NAKRPEOUSA-N 0.000 description 5
- RKQAYOWLSFLJEE-SVSWQMSJSA-N Ile-Thr-Cys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(=O)O)N RKQAYOWLSFLJEE-SVSWQMSJSA-N 0.000 description 5
- 206010062016 Immunosuppression Diseases 0.000 description 5
- 102000004889 Interleukin-6 Human genes 0.000 description 5
- 108090001005 Interleukin-6 Proteins 0.000 description 5
- 241000880493 Leptailurus serval Species 0.000 description 5
- LCNASHSOFMRYFO-WDCWCFNPSA-N Leu-Thr-Gln Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@H](C(O)=O)CCC(N)=O LCNASHSOFMRYFO-WDCWCFNPSA-N 0.000 description 5
- MKGIILKDUGDRRO-FXQIFTODSA-N Pro-Ser-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H]1CCCN1 MKGIILKDUGDRRO-FXQIFTODSA-N 0.000 description 5
- 241000700159 Rattus Species 0.000 description 5
- BRKHVZNDAOMAHX-BIIVOSGPSA-N Ser-Ala-Pro Chemical compound C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CO)N BRKHVZNDAOMAHX-BIIVOSGPSA-N 0.000 description 5
- RHAPJNVNWDBFQI-BQBZGAKWSA-N Ser-Pro-Gly Chemical compound OC[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O RHAPJNVNWDBFQI-BQBZGAKWSA-N 0.000 description 5
- 238000000692 Student's t-test Methods 0.000 description 5
- ULHJJQYGMWONTD-HKUYNNGSSA-N Tyr-Gly-Trp Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)NCC(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O ULHJJQYGMWONTD-HKUYNNGSSA-N 0.000 description 5
- DEGUERSKQBRZMZ-FXQIFTODSA-N Val-Ser-Ala Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(O)=O DEGUERSKQBRZMZ-FXQIFTODSA-N 0.000 description 5
- 108010087924 alanylproline Proteins 0.000 description 5
- 230000000890 antigenic effect Effects 0.000 description 5
- 108010062796 arginyllysine Proteins 0.000 description 5
- 230000000139 costimulatory effect Effects 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 5
- 108010050475 glycyl-leucyl-tyrosine Proteins 0.000 description 5
- 229960000402 palivizumab Drugs 0.000 description 5
- 108010020755 prolyl-glycyl-glycine Proteins 0.000 description 5
- 108010079317 prolyl-tyrosine Proteins 0.000 description 5
- 238000003753 real-time PCR Methods 0.000 description 5
- 230000028327 secretion Effects 0.000 description 5
- 230000011664 signaling Effects 0.000 description 5
- 108010061238 threonyl-glycine Proteins 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- 238000010361 transduction Methods 0.000 description 5
- 230000026683 transduction Effects 0.000 description 5
- 238000001890 transfection Methods 0.000 description 5
- 108010073969 valyllysine Proteins 0.000 description 5
- 230000035899 viability Effects 0.000 description 5
- FWBHETKCLVMNFS-UHFFFAOYSA-N 4',6-Diamino-2-phenylindol Chemical compound C1=CC(C(=N)N)=CC=C1C1=CC2=CC=C(C(N)=N)C=C2N1 FWBHETKCLVMNFS-UHFFFAOYSA-N 0.000 description 4
- 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 4
- TTXYKSADPSNOIF-IHRRRGAJSA-N Arg-Asp-Phe Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O TTXYKSADPSNOIF-IHRRRGAJSA-N 0.000 description 4
- 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 4
- 241000287828 Gallus gallus Species 0.000 description 4
- GNPVTZJUUBPZKW-WDSKDSINSA-N Gly-Gln-Ser Chemical compound [H]NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(O)=O GNPVTZJUUBPZKW-WDSKDSINSA-N 0.000 description 4
- IRJWAYCXIYUHQE-WHFBIAKZSA-N Gly-Ser-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)CN IRJWAYCXIYUHQE-WHFBIAKZSA-N 0.000 description 4
- 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 4
- ALHULIGNEXGFRM-QWRGUYRKSA-N Phe-Cys-Gly Chemical compound OC(=O)CNC(=O)[C@H](CS)NC(=O)[C@@H](N)CC1=CC=CC=C1 ALHULIGNEXGFRM-QWRGUYRKSA-N 0.000 description 4
- 241000283984 Rodentia Species 0.000 description 4
- PYTKULIABVRXSC-BWBBJGPYSA-N Ser-Ser-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(O)=O PYTKULIABVRXSC-BWBBJGPYSA-N 0.000 description 4
- 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 4
- 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 4
- MBLJBGZWLHTJBH-SZMVWBNQSA-N Trp-Val-Arg Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O)=CNC2=C1 MBLJBGZWLHTJBH-SZMVWBNQSA-N 0.000 description 4
- 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 4
- HTONZBWRYUKUKC-RCWTZXSCSA-N Val-Thr-Val Chemical compound CC(C)[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(O)=O HTONZBWRYUKUKC-RCWTZXSCSA-N 0.000 description 4
- 125000000539 amino acid group Chemical group 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 239000011324 bead Substances 0.000 description 4
- 235000013330 chicken meat Nutrition 0.000 description 4
- 239000000975 dye Substances 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 108010044374 isoleucyl-tyrosine Proteins 0.000 description 4
- 108010073472 leucyl-prolyl-proline Proteins 0.000 description 4
- 230000000638 stimulation Effects 0.000 description 4
- 229960001967 tacrolimus Drugs 0.000 description 4
- QJJXYPPXXYFBGM-SHYZHZOCSA-N tacrolimus Natural products CO[C@H]1C[C@H](CC[C@@H]1O)C=C(C)[C@H]2OC(=O)[C@H]3CCCCN3C(=O)C(=O)[C@@]4(O)O[C@@H]([C@H](C[C@H]4C)OC)[C@@H](C[C@H](C)CC(=C[C@@H](CC=C)C(=O)C[C@H](O)[C@H]2C)C)OC QJJXYPPXXYFBGM-SHYZHZOCSA-N 0.000 description 4
- 108010000998 wheylin-2 peptide Proteins 0.000 description 4
- ISJKIHHTPAQLLW-TUFLPTIASA-N (2S)-2-[[(2S)-3-(4-hydroxyphenyl)-2-[[(2S)-1-[(2S)-pyrrolidine-2-carbonyl]pyrrolidine-2-carbonyl]amino]propanoyl]amino]-4-methylpentanoic acid Chemical compound [H]N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(C)C)C(O)=O ISJKIHHTPAQLLW-TUFLPTIASA-N 0.000 description 3
- BUOYTFVLNZIELF-UHFFFAOYSA-N 2-phenyl-1h-indole-4,6-dicarboximidamide Chemical compound N1C2=CC(C(=N)N)=CC(C(N)=N)=C2C=C1C1=CC=CC=C1 BUOYTFVLNZIELF-UHFFFAOYSA-N 0.000 description 3
- LMFXXZPPZDCPTA-ZKWXMUAHSA-N Ala-Gly-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)CNC(=O)[C@H](C)N LMFXXZPPZDCPTA-ZKWXMUAHSA-N 0.000 description 3
- DPNZTBKGAUAZQU-DLOVCJGASA-N Ala-Leu-His Chemical compound C[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N DPNZTBKGAUAZQU-DLOVCJGASA-N 0.000 description 3
- SOBIAADAMRHGKH-CIUDSAMLSA-N Ala-Leu-Ser Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O SOBIAADAMRHGKH-CIUDSAMLSA-N 0.000 description 3
- VNFSAYFQLXPHPY-CIQUZCHMSA-N Ala-Thr-Ile Chemical compound [H]N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O VNFSAYFQLXPHPY-CIQUZCHMSA-N 0.000 description 3
- OMSKGWFGWCQFBD-KZVJFYERSA-N Ala-Val-Thr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O OMSKGWFGWCQFBD-KZVJFYERSA-N 0.000 description 3
- VKKYFICVTYKFIO-CIUDSAMLSA-N Arg-Ala-Glu Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCN=C(N)N VKKYFICVTYKFIO-CIUDSAMLSA-N 0.000 description 3
- OVVUNXXROOFSIM-SDDRHHMPSA-N Arg-Arg-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CCCN=C(N)N)N)C(=O)O OVVUNXXROOFSIM-SDDRHHMPSA-N 0.000 description 3
- 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 3
- 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 3
- HGKHPCFTRQDHCU-IUCAKERBSA-N Arg-Pro-Gly Chemical compound NC(N)=NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O HGKHPCFTRQDHCU-IUCAKERBSA-N 0.000 description 3
- 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 3
- DAPLJWATMAXPPZ-CIUDSAMLSA-N Asn-Asn-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CC(N)=O DAPLJWATMAXPPZ-CIUDSAMLSA-N 0.000 description 3
- 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 3
- ZELQAFZSJOBEQS-ACZMJKKPSA-N Asp-Asn-Glu Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O ZELQAFZSJOBEQS-ACZMJKKPSA-N 0.000 description 3
- QCVXMEHGFUMKCO-YUMQZZPRSA-N Asp-Gly-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CC(O)=O QCVXMEHGFUMKCO-YUMQZZPRSA-N 0.000 description 3
- 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 3
- AHWRSSLYSGLBGD-CIUDSAMLSA-N Asp-Pro-Glu Chemical compound OC(=O)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O AHWRSSLYSGLBGD-CIUDSAMLSA-N 0.000 description 3
- JJQGZGOEDSSHTE-FOHZUACHSA-N Asp-Thr-Gly Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(O)=O JJQGZGOEDSSHTE-FOHZUACHSA-N 0.000 description 3
- WOKXEQLPBLLWHC-IHRRRGAJSA-N Asp-Tyr-Met Chemical compound CSCC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC(O)=O)CC1=CC=C(O)C=C1 WOKXEQLPBLLWHC-IHRRRGAJSA-N 0.000 description 3
- 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 3
- 102000004127 Cytokines Human genes 0.000 description 3
- 108090000695 Cytokines Proteins 0.000 description 3
- 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 3
- KCJJFESQRXGTGC-BQBZGAKWSA-N Gln-Glu-Gly Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(O)=O KCJJFESQRXGTGC-BQBZGAKWSA-N 0.000 description 3
- VMKCPNBBPGGQBJ-GUBZILKMSA-N Glu-Leu-Asn Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CCC(=O)O)N VMKCPNBBPGGQBJ-GUBZILKMSA-N 0.000 description 3
- 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 3
- DLISPGXMKZTWQG-IFFSRLJSSA-N Glu-Thr-Val Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(O)=O DLISPGXMKZTWQG-IFFSRLJSSA-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
- ADZGCWWDPFDHCY-ZETCQYMHSA-N Gly-His-Gly Chemical compound OC(=O)CNC(=O)[C@@H](NC(=O)CN)CC1=CN=CN1 ADZGCWWDPFDHCY-ZETCQYMHSA-N 0.000 description 3
- TWTPDFFBLQEBOE-IUCAKERBSA-N Gly-Leu-Gln Chemical compound [H]NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O TWTPDFFBLQEBOE-IUCAKERBSA-N 0.000 description 3
- PDUHNKAFQXQNLH-ZETCQYMHSA-N Gly-Lys-Gly Chemical compound NCCCC[C@H](NC(=O)CN)C(=O)NCC(O)=O PDUHNKAFQXQNLH-ZETCQYMHSA-N 0.000 description 3
- 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 3
- HUFUVTYGPOUCBN-MBLNEYKQSA-N Gly-Thr-Ile Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O HUFUVTYGPOUCBN-MBLNEYKQSA-N 0.000 description 3
- LJUIEESLIAZSFR-SRVKXCTJSA-N His-Leu-Cys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC1=CN=CN1)N LJUIEESLIAZSFR-SRVKXCTJSA-N 0.000 description 3
- LWWILHPVAKKLQS-QXEWZRGKSA-N Ile-Gly-Met Chemical compound CC[C@H](C)[C@@H](C(=O)NCC(=O)N[C@@H](CCSC)C(=O)O)N LWWILHPVAKKLQS-QXEWZRGKSA-N 0.000 description 3
- 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 3
- 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 3
- ILJREDZFPHTUIE-GUBZILKMSA-N Leu-Asp-Glu Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O ILJREDZFPHTUIE-GUBZILKMSA-N 0.000 description 3
- LOLUPZNNADDTAA-AVGNSLFASA-N Leu-Gln-Leu Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(O)=O LOLUPZNNADDTAA-AVGNSLFASA-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
- BABSVXFGKFLIGW-UWVGGRQHSA-N Leu-Gly-Arg Chemical compound CC(C)C[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CCCNC(N)=N BABSVXFGKFLIGW-UWVGGRQHSA-N 0.000 description 3
- 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 3
- ZDJQVSIPFLMNOX-RHYQMDGZSA-N Leu-Thr-Arg Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@H](C(O)=O)CCCN=C(N)N ZDJQVSIPFLMNOX-RHYQMDGZSA-N 0.000 description 3
- TUIOUEWKFFVNLH-DCAQKATOSA-N Leu-Val-Cys Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CS)C(O)=O TUIOUEWKFFVNLH-DCAQKATOSA-N 0.000 description 3
- 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 3
- GQZMPWBZQALKJO-UWVGGRQHSA-N Lys-Gly-Arg Chemical compound [H]N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(O)=O GQZMPWBZQALKJO-UWVGGRQHSA-N 0.000 description 3
- 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 3
- 241000124008 Mammalia Species 0.000 description 3
- DBOMZJOESVYERT-GUBZILKMSA-N Met-Asn-Met Chemical compound CSCC[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CCSC)C(=O)O)N DBOMZJOESVYERT-GUBZILKMSA-N 0.000 description 3
- YLLWCSDBVGZLOW-CIUDSAMLSA-N Met-Gln-Ala Chemical compound [H]N[C@@H](CCSC)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(O)=O YLLWCSDBVGZLOW-CIUDSAMLSA-N 0.000 description 3
- VYXIKLFLGRTANT-HRCADAONSA-N Met-Tyr-Pro Chemical compound CSCC[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N2CCC[C@@H]2C(=O)O)N VYXIKLFLGRTANT-HRCADAONSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 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 3
- 108010002311 N-glycylglutamic acid Proteins 0.000 description 3
- 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 3
- 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 3
- 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 3
- GMJDSFYVTAMIBF-FXQIFTODSA-N Pro-Ser-Asp Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(O)=O GMJDSFYVTAMIBF-FXQIFTODSA-N 0.000 description 3
- LVVBAKCGXXUHFO-ZLUOBGJFSA-N Ser-Ala-Asp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(O)=O)C(O)=O LVVBAKCGXXUHFO-ZLUOBGJFSA-N 0.000 description 3
- SRSPTFBENMJHMR-WHFBIAKZSA-N Ser-Ser-Gly Chemical compound OC[C@H](N)C(=O)N[C@@H](CO)C(=O)NCC(O)=O SRSPTFBENMJHMR-WHFBIAKZSA-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
- NADLKBTYNKUJEP-KATARQTJSA-N Ser-Thr-Leu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O NADLKBTYNKUJEP-KATARQTJSA-N 0.000 description 3
- BDMWLJLPPUCLNV-XGEHTFHBSA-N Ser-Thr-Val Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(O)=O BDMWLJLPPUCLNV-XGEHTFHBSA-N 0.000 description 3
- FQPDRTDDEZXCEC-SVSWQMSJSA-N Thr-Ile-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(O)=O FQPDRTDDEZXCEC-SVSWQMSJSA-N 0.000 description 3
- GXUWHVZYDAHFSV-FLBSBUHZSA-N Thr-Ile-Thr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(O)=O GXUWHVZYDAHFSV-FLBSBUHZSA-N 0.000 description 3
- MUAFDCVOHYAFNG-RCWTZXSCSA-N Thr-Pro-Arg Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(N)=N)C(O)=O MUAFDCVOHYAFNG-RCWTZXSCSA-N 0.000 description 3
- MXDOAJQRJBMGMO-FJXKBIBVSA-N Thr-Pro-Gly Chemical compound C[C@@H](O)[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O MXDOAJQRJBMGMO-FJXKBIBVSA-N 0.000 description 3
- 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 3
- YOPQYBJJNSIQGZ-JNPHEJMOSA-N Thr-Tyr-Tyr Chemical compound C([C@H](NC(=O)[C@@H](N)[C@H](O)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C1=CC=C(O)C=C1 YOPQYBJJNSIQGZ-JNPHEJMOSA-N 0.000 description 3
- 108060008683 Tumor Necrosis Factor Receptor Proteins 0.000 description 3
- RYSNTWVRSLCAJZ-RYUDHWBXSA-N Tyr-Gln-Gly Chemical compound OC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 RYSNTWVRSLCAJZ-RYUDHWBXSA-N 0.000 description 3
- CKHQKYHIZCRTAP-SOUVJXGZSA-N Tyr-Gln-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CC2=CC=C(C=C2)O)N)C(=O)O CKHQKYHIZCRTAP-SOUVJXGZSA-N 0.000 description 3
- QFXVAFIHVWXXBJ-AVGNSLFASA-N Tyr-Ser-Glu Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(O)=O QFXVAFIHVWXXBJ-AVGNSLFASA-N 0.000 description 3
- 239000012190 activator Substances 0.000 description 3
- 108010024078 alanyl-glycyl-serine Proteins 0.000 description 3
- 108010069020 alanyl-prolyl-glycine Proteins 0.000 description 3
- 108010008355 arginyl-glutamine Proteins 0.000 description 3
- 108010029539 arginyl-prolyl-proline Proteins 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 230000024203 complement activation Effects 0.000 description 3
- YQGOJNYOYNNSMM-UHFFFAOYSA-N eosin Chemical compound [Na+].OC(=O)C1=CC=CC=C1C1=C2C=C(Br)C(=O)C(Br)=C2OC2=C(Br)C(O)=C(Br)C=C21 YQGOJNYOYNNSMM-UHFFFAOYSA-N 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- 239000003862 glucocorticoid Substances 0.000 description 3
- 108010078144 glutaminyl-glycine Proteins 0.000 description 3
- 108010079547 glutamylmethionine Proteins 0.000 description 3
- 108020004445 glyceraldehyde-3-phosphate dehydrogenase Proteins 0.000 description 3
- VPZXBVLAVMBEQI-UHFFFAOYSA-N glycyl-DL-alpha-alanine Natural products OC(=O)C(C)NC(=O)CN VPZXBVLAVMBEQI-UHFFFAOYSA-N 0.000 description 3
- 108010001064 glycyl-glycyl-glycyl-glycine Proteins 0.000 description 3
- 230000003053 immunization Effects 0.000 description 3
- 238000002649 immunization Methods 0.000 description 3
- 238000003125 immunofluorescent labeling Methods 0.000 description 3
- 108010003700 lysyl aspartic acid Proteins 0.000 description 3
- 108010064235 lysylglycine Proteins 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 210000000056 organ Anatomy 0.000 description 3
- 108010004914 prolylarginine Proteins 0.000 description 3
- 229960004641 rituximab Drugs 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- 230000009469 supplementation Effects 0.000 description 3
- 102000003298 tumor necrosis factor receptor Human genes 0.000 description 3
- 230000003612 virological effect Effects 0.000 description 3
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 2
- NFGXHKASABOEEW-UHFFFAOYSA-N 1-methylethyl 11-methoxy-3,7,11-trimethyl-2,4-dodecadienoate Chemical compound COC(C)(C)CCCC(C)CC=CC(C)=CC(=O)OC(C)C NFGXHKASABOEEW-UHFFFAOYSA-N 0.000 description 2
- NHBKXEKEPDILRR-UHFFFAOYSA-N 2,3-bis(butanoylsulfanyl)propyl butanoate Chemical compound CCCC(=O)OCC(SC(=O)CCC)CSC(=O)CCC NHBKXEKEPDILRR-UHFFFAOYSA-N 0.000 description 2
- VDABVNMGKGUPEY-UHFFFAOYSA-N 6-carboxyfluorescein succinimidyl ester Chemical compound C=1C(O)=CC=C2C=1OC1=CC(O)=CC=C1C2(C1=C2)OC(=O)C1=CC=C2C(=O)ON1C(=O)CCC1=O VDABVNMGKGUPEY-UHFFFAOYSA-N 0.000 description 2
- QUIGLPSHIFPEOV-CIUDSAMLSA-N Ala-Lys-Ala Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O QUIGLPSHIFPEOV-CIUDSAMLSA-N 0.000 description 2
- MAEQBGQTDWDSJQ-LSJOCFKGSA-N Ala-Met-His Chemical compound C[C@@H](C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N MAEQBGQTDWDSJQ-LSJOCFKGSA-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
- IOFVWPYSRSCWHI-JXUBOQSCSA-N Ala-Thr-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](C)N IOFVWPYSRSCWHI-JXUBOQSCSA-N 0.000 description 2
- VWVPYNGMOCSSGK-GUBZILKMSA-N Arg-Arg-Asn Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(N)=O)C(O)=O VWVPYNGMOCSSGK-GUBZILKMSA-N 0.000 description 2
- 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 2
- 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 2
- PNQWAUXQDBIJDY-GUBZILKMSA-N Arg-Glu-Glu Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O PNQWAUXQDBIJDY-GUBZILKMSA-N 0.000 description 2
- 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 2
- GMFAGHNRXPSSJS-SRVKXCTJSA-N Arg-Leu-Gln Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O GMFAGHNRXPSSJS-SRVKXCTJSA-N 0.000 description 2
- GRRXPUAICOGISM-RWMBFGLXSA-N Arg-Lys-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCCCN)NC(=O)[C@H](CCCN=C(N)N)N)C(=O)O GRRXPUAICOGISM-RWMBFGLXSA-N 0.000 description 2
- 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 2
- 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 2
- KXOPYFNQLVUOAQ-FXQIFTODSA-N Arg-Ser-Ala Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(O)=O KXOPYFNQLVUOAQ-FXQIFTODSA-N 0.000 description 2
- AMIQZQAAYGYKOP-FXQIFTODSA-N Arg-Ser-Asn Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O AMIQZQAAYGYKOP-FXQIFTODSA-N 0.000 description 2
- GXMSVVBIAMWMKO-BQBZGAKWSA-N Asn-Arg-Gly Chemical compound NC(=O)C[C@H](N)C(=O)N[C@H](C(=O)NCC(O)=O)CCCN=C(N)N GXMSVVBIAMWMKO-BQBZGAKWSA-N 0.000 description 2
- QISZHYWZHJRDAO-CIUDSAMLSA-N Asn-Asp-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CC(=O)N)N QISZHYWZHJRDAO-CIUDSAMLSA-N 0.000 description 2
- JREOBWLIZLXRIS-GUBZILKMSA-N Asn-Glu-Leu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O JREOBWLIZLXRIS-GUBZILKMSA-N 0.000 description 2
- WONGRTVAMHFGBE-WDSKDSINSA-N Asn-Gly-Gln Chemical compound C(CC(=O)N)[C@@H](C(=O)O)NC(=O)CNC(=O)[C@H](CC(=O)N)N WONGRTVAMHFGBE-WDSKDSINSA-N 0.000 description 2
- WIDVAWAQBRAKTI-YUMQZZPRSA-N Asn-Leu-Gly Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O WIDVAWAQBRAKTI-YUMQZZPRSA-N 0.000 description 2
- VITDJIPIJZAVGC-VEVYYDQMSA-N Asn-Met-Thr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H]([C@@H](C)O)C(O)=O VITDJIPIJZAVGC-VEVYYDQMSA-N 0.000 description 2
- PUUPMDXIHCOPJU-HJGDQZAQSA-N Asn-Thr-Lys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC(=O)N)N)O PUUPMDXIHCOPJU-HJGDQZAQSA-N 0.000 description 2
- ZVTDYGWRRPMFCL-WFBYXXMGSA-N Asp-Ala-Trp Chemical compound C[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)NC(=O)[C@H](CC(=O)O)N ZVTDYGWRRPMFCL-WFBYXXMGSA-N 0.000 description 2
- DGKCOYGQLNWNCJ-ACZMJKKPSA-N Asp-Glu-Ser Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(O)=O DGKCOYGQLNWNCJ-ACZMJKKPSA-N 0.000 description 2
- KGHLGJAXYSVNJP-WHFBIAKZSA-N Asp-Ser-Gly Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CO)C(=O)NCC(O)=O KGHLGJAXYSVNJP-WHFBIAKZSA-N 0.000 description 2
- 241000283690 Bos taurus Species 0.000 description 2
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- 108091026890 Coding region Proteins 0.000 description 2
- 238000002965 ELISA Methods 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 108091006020 Fc-tagged proteins Proteins 0.000 description 2
- 241000282326 Felis catus Species 0.000 description 2
- OYTPNWYZORARHL-XHNCKOQMSA-N Gln-Ala-Pro Chemical compound C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCC(=O)N)N OYTPNWYZORARHL-XHNCKOQMSA-N 0.000 description 2
- 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 2
- 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 2
- DCWNCMRZIZSZBL-KKUMJFAQSA-N Gln-Pro-Tyr Chemical compound C1C[C@H](N(C1)C(=O)[C@H](CCC(=O)N)N)C(=O)N[C@@H](CC2=CC=C(C=C2)O)C(=O)O DCWNCMRZIZSZBL-KKUMJFAQSA-N 0.000 description 2
- LVCHEMOPBORRLB-DCAQKATOSA-N Glu-Gln-Lys Chemical compound NCCCC[C@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CCC(O)=O)C(O)=O LVCHEMOPBORRLB-DCAQKATOSA-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
- 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 2
- DNPCBMNFQVTHMA-DCAQKATOSA-N Glu-Leu-Gln Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O DNPCBMNFQVTHMA-DCAQKATOSA-N 0.000 description 2
- FGGKGJHCVMYGCD-UKJIMTQDSA-N Glu-Val-Ile Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O FGGKGJHCVMYGCD-UKJIMTQDSA-N 0.000 description 2
- XZRZILPOZBVTDB-GJZGRUSLSA-N Gly-Arg-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](CCCNC(N)=N)NC(=O)CN)C(O)=O)=CNC2=C1 XZRZILPOZBVTDB-GJZGRUSLSA-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
- LHYJCVCQPWRMKZ-WEDXCCLWSA-N Gly-Leu-Thr Chemical compound [H]NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O LHYJCVCQPWRMKZ-WEDXCCLWSA-N 0.000 description 2
- 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 2
- 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 2
- 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 2
- VNNRLUNBJSWZPF-ZKWXMUAHSA-N Gly-Ser-Ile Chemical compound [H]NCC(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O VNNRLUNBJSWZPF-ZKWXMUAHSA-N 0.000 description 2
- WNGHUXFWEWTKAO-YUMQZZPRSA-N Gly-Ser-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)CN WNGHUXFWEWTKAO-YUMQZZPRSA-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
- 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 2
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 2
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 2
- 102100026122 High affinity immunoglobulin gamma Fc receptor I Human genes 0.000 description 2
- PFOUFRJYHWZJKW-NKIYYHGXSA-N His-Thr-Gln Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CC1=CN=CN1)N)O PFOUFRJYHWZJKW-NKIYYHGXSA-N 0.000 description 2
- 101100166600 Homo sapiens CD28 gene Proteins 0.000 description 2
- 101000913074 Homo sapiens High affinity immunoglobulin gamma Fc receptor I Proteins 0.000 description 2
- FUOYNOXRWPJPAN-QEWYBTABSA-N Ile-Glu-Phe Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)N FUOYNOXRWPJPAN-QEWYBTABSA-N 0.000 description 2
- JLWLMGADIQFKRD-QSFUFRPTSA-N Ile-His-Ala Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](C)C(O)=O)CC1=CN=CN1 JLWLMGADIQFKRD-QSFUFRPTSA-N 0.000 description 2
- KOPIAUWNLKKELG-SIGLWIIPSA-N Ile-His-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)N[C@@H]([C@@H](C)CC)C(=O)O)N KOPIAUWNLKKELG-SIGLWIIPSA-N 0.000 description 2
- UAELWXJFLZBKQS-WHOFXGATSA-N Ile-Phe-Gly Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](Cc1ccccc1)C(=O)NCC(O)=O UAELWXJFLZBKQS-WHOFXGATSA-N 0.000 description 2
- NXRNRBOKDBIVKQ-CXTHYWKRSA-N Ile-Tyr-Tyr Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CC2=CC=C(C=C2)O)C(=O)O)N NXRNRBOKDBIVKQ-CXTHYWKRSA-N 0.000 description 2
- JZBVBOKASHNXAD-NAKRPEOUSA-N Ile-Val-Ser Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(=O)O)N JZBVBOKASHNXAD-NAKRPEOUSA-N 0.000 description 2
- 108060003951 Immunoglobulin Proteins 0.000 description 2
- 108010065920 Insulin Lispro Proteins 0.000 description 2
- 102000003777 Interleukin-1 beta Human genes 0.000 description 2
- 108090000193 Interleukin-1 beta Proteins 0.000 description 2
- TYYLDKGBCJGJGW-UHFFFAOYSA-N L-tryptophan-L-tyrosine Natural products C=1NC2=CC=CC=C2C=1CC(N)C(=O)NC(C(O)=O)CC1=CC=C(O)C=C1 TYYLDKGBCJGJGW-UHFFFAOYSA-N 0.000 description 2
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 2
- DBVWMYGBVFCRBE-CIUDSAMLSA-N Leu-Asn-Asn Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O DBVWMYGBVFCRBE-CIUDSAMLSA-N 0.000 description 2
- 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 2
- FEHQLKKBVJHSEC-SZMVWBNQSA-N Leu-Glu-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CC(C)C)C(O)=O)=CNC2=C1 FEHQLKKBVJHSEC-SZMVWBNQSA-N 0.000 description 2
- 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 2
- HRTRLSRYZZKPCO-BJDJZHNGSA-N Leu-Ile-Ser Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(O)=O HRTRLSRYZZKPCO-BJDJZHNGSA-N 0.000 description 2
- JNDYEOUZBLOVOF-AVGNSLFASA-N Leu-Leu-Gln Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O JNDYEOUZBLOVOF-AVGNSLFASA-N 0.000 description 2
- DPURXCQCHSQPAN-AVGNSLFASA-N Leu-Pro-Pro Chemical compound CC(C)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 DPURXCQCHSQPAN-AVGNSLFASA-N 0.000 description 2
- PPGBXYKMUMHFBF-KATARQTJSA-N Leu-Ser-Thr Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(O)=O PPGBXYKMUMHFBF-KATARQTJSA-N 0.000 description 2
- AIQWYVFNBNNOLU-RHYQMDGZSA-N Leu-Thr-Val Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(O)=O AIQWYVFNBNNOLU-RHYQMDGZSA-N 0.000 description 2
- 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 2
- IMAKMJCBYCSMHM-AVGNSLFASA-N Lys-Glu-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@H](C(O)=O)CCCCN IMAKMJCBYCSMHM-AVGNSLFASA-N 0.000 description 2
- LCMWVZLBCUVDAZ-IUCAKERBSA-N Lys-Gly-Glu Chemical compound [NH3+]CCCC[C@H]([NH3+])C(=O)NCC(=O)N[C@H](C([O-])=O)CCC([O-])=O LCMWVZLBCUVDAZ-IUCAKERBSA-N 0.000 description 2
- 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 2
- LUAJJLPHUXPQLH-KKUMJFAQSA-N Lys-Phe-Ser Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CCCCN)N LUAJJLPHUXPQLH-KKUMJFAQSA-N 0.000 description 2
- UZWMJZSOXGOVIN-LURJTMIESA-N Met-Gly-Gly Chemical compound CSCC[C@H](N)C(=O)NCC(=O)NCC(O)=O UZWMJZSOXGOVIN-LURJTMIESA-N 0.000 description 2
- 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 2
- 108010079364 N-glycylalanine Proteins 0.000 description 2
- 241001494479 Pecora Species 0.000 description 2
- JJHVFCUWLSKADD-ONGXEEELSA-N Phe-Gly-Ala Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)NCC(=O)N[C@@H](C)C(O)=O JJHVFCUWLSKADD-ONGXEEELSA-N 0.000 description 2
- 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 2
- VIIRRNQMMIHYHQ-XHSDSOJGSA-N Phe-Val-Pro Chemical compound CC(C)[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CC2=CC=CC=C2)N VIIRRNQMMIHYHQ-XHSDSOJGSA-N 0.000 description 2
- 108010004729 Phycoerythrin Proteins 0.000 description 2
- HFNPOYOKIPGAEI-SRVKXCTJSA-N Pro-Leu-Glu Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H]1CCCN1 HFNPOYOKIPGAEI-SRVKXCTJSA-N 0.000 description 2
- 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 2
- 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 2
- GZNYIXWOIUFLGO-ZJDVBMNYSA-N Pro-Thr-Thr Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O GZNYIXWOIUFLGO-ZJDVBMNYSA-N 0.000 description 2
- NLQUOHDCLSFABG-GUBZILKMSA-N Ser-Arg-Arg Chemical compound NC(N)=NCCC[C@H](NC(=O)[C@H](CO)N)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O NLQUOHDCLSFABG-GUBZILKMSA-N 0.000 description 2
- QEDMOZUJTGEIBF-FXQIFTODSA-N Ser-Arg-Asp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(O)=O QEDMOZUJTGEIBF-FXQIFTODSA-N 0.000 description 2
- 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 2
- HEQPKICPPDOSIN-SRVKXCTJSA-N Ser-Asp-Tyr Chemical compound OC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 HEQPKICPPDOSIN-SRVKXCTJSA-N 0.000 description 2
- HJEBZBMOTCQYDN-ACZMJKKPSA-N Ser-Glu-Asp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O HJEBZBMOTCQYDN-ACZMJKKPSA-N 0.000 description 2
- UOLGINIHBRIECN-FXQIFTODSA-N Ser-Glu-Glu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O UOLGINIHBRIECN-FXQIFTODSA-N 0.000 description 2
- 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 2
- MUARUIBTKQJKFY-WHFBIAKZSA-N Ser-Gly-Asp Chemical compound [H]N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(O)=O MUARUIBTKQJKFY-WHFBIAKZSA-N 0.000 description 2
- YMDNFPNTIPQMJP-NAKRPEOUSA-N Ser-Ile-Met Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCSC)C(O)=O YMDNFPNTIPQMJP-NAKRPEOUSA-N 0.000 description 2
- OLKICIBQRVSQMA-SRVKXCTJSA-N Ser-Ser-Tyr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O OLKICIBQRVSQMA-SRVKXCTJSA-N 0.000 description 2
- SNXUIBACCONSOH-BWBBJGPYSA-N Ser-Thr-Ser Chemical compound OC[C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@@H](CO)C(O)=O SNXUIBACCONSOH-BWBBJGPYSA-N 0.000 description 2
- BNGDYRRHRGOPHX-IFFSRLJSSA-N Thr-Glu-Val Chemical compound CC(C)[C@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)[C@@H](C)O)C(O)=O BNGDYRRHRGOPHX-IFFSRLJSSA-N 0.000 description 2
- 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 2
- BBPCSGKKPJUYRB-UVOCVTCTSA-N Thr-Thr-Leu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O BBPCSGKKPJUYRB-UVOCVTCTSA-N 0.000 description 2
- BKVICMPZWRNWOC-RHYQMDGZSA-N Thr-Val-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)[C@@H](C)O BKVICMPZWRNWOC-RHYQMDGZSA-N 0.000 description 2
- OOEUVMFKKZYSRX-LEWSCRJBSA-N Tyr-Ala-Pro Chemical compound C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CC2=CC=C(C=C2)O)N OOEUVMFKKZYSRX-LEWSCRJBSA-N 0.000 description 2
- 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 2
- FQNUWOHNGJWNLM-QWRGUYRKSA-N Tyr-Cys-Gly Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CS)C(=O)NCC(O)=O FQNUWOHNGJWNLM-QWRGUYRKSA-N 0.000 description 2
- UMSZZGTXGKHTFJ-SRVKXCTJSA-N Tyr-Ser-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 UMSZZGTXGKHTFJ-SRVKXCTJSA-N 0.000 description 2
- XXROXFHCMVXETG-UWVGGRQHSA-N Val-Gly-Val Chemical compound CC(C)[C@H](N)C(=O)NCC(=O)N[C@@H](C(C)C)C(O)=O XXROXFHCMVXETG-UWVGGRQHSA-N 0.000 description 2
- PZTZYZUTCPZWJH-FXQIFTODSA-N Val-Ser-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)O)N PZTZYZUTCPZWJH-FXQIFTODSA-N 0.000 description 2
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 2
- 108010076324 alanyl-glycyl-glycine Proteins 0.000 description 2
- 108010086434 alanyl-seryl-glycine Proteins 0.000 description 2
- 108010005233 alanylglutamic acid Proteins 0.000 description 2
- 108010047495 alanylglycine Proteins 0.000 description 2
- 108010004469 allophycocyanin Proteins 0.000 description 2
- 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 2
- 230000010056 antibody-dependent cellular cytotoxicity Effects 0.000 description 2
- 230000003915 cell function Effects 0.000 description 2
- 230000004540 complement-dependent cytotoxicity Effects 0.000 description 2
- 239000002299 complementary DNA Substances 0.000 description 2
- 238000010276 construction Methods 0.000 description 2
- 238000010494 dissociation reaction Methods 0.000 description 2
- 230000005593 dissociations Effects 0.000 description 2
- 239000013604 expression vector Substances 0.000 description 2
- 108010055341 glutamyl-glutamic acid Proteins 0.000 description 2
- 108010049041 glutamylalanine Proteins 0.000 description 2
- 102000006602 glyceraldehyde-3-phosphate dehydrogenase Human genes 0.000 description 2
- 108010089804 glycyl-threonine Proteins 0.000 description 2
- 108010092114 histidylphenylalanine Proteins 0.000 description 2
- 238000003384 imaging method Methods 0.000 description 2
- 238000003018 immunoassay Methods 0.000 description 2
- 102000018358 immunoglobulin Human genes 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 230000008595 infiltration Effects 0.000 description 2
- 238000001764 infiltration Methods 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 238000001325 log-rank test Methods 0.000 description 2
- 108020004999 messenger RNA Proteins 0.000 description 2
- 238000004806 packaging method and process Methods 0.000 description 2
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 2
- 108010051242 phenylalanylserine Proteins 0.000 description 2
- 239000013612 plasmid Substances 0.000 description 2
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 2
- 229960005205 prednisolone Drugs 0.000 description 2
- 230000000770 proinflammatory effect Effects 0.000 description 2
- 108010029020 prolylglycine Proteins 0.000 description 2
- 239000000700 radioactive tracer Substances 0.000 description 2
- 229940099538 rapamune Drugs 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 108010056030 retronectin Proteins 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- 210000000952 spleen Anatomy 0.000 description 2
- 238000010186 staining Methods 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- 230000000451 tissue damage Effects 0.000 description 2
- 231100000827 tissue damage Toxicity 0.000 description 2
- 230000002103 transcriptional effect Effects 0.000 description 2
- 108010038745 tryptophylglycine Proteins 0.000 description 2
- 108010044292 tryptophyltyrosine Proteins 0.000 description 2
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 2
- 108010003137 tyrosyltyrosine Proteins 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- HKZAAJSTFUZYTO-LURJTMIESA-N (2s)-2-[[2-[[2-[[2-[(2-aminoacetyl)amino]acetyl]amino]acetyl]amino]acetyl]amino]-3-hydroxypropanoic acid Chemical compound NCC(=O)NCC(=O)NCC(=O)NCC(=O)N[C@@H](CO)C(O)=O HKZAAJSTFUZYTO-LURJTMIESA-N 0.000 description 1
- LOGFVTREOLYCPF-KXNHARMFSA-N (2s,3r)-2-[[(2r)-1-[(2s)-2,6-diaminohexanoyl]pyrrolidine-2-carbonyl]amino]-3-hydroxybutanoic acid Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H]1CCCN1C(=O)[C@@H](N)CCCCN LOGFVTREOLYCPF-KXNHARMFSA-N 0.000 description 1
- QMOQBVOBWVNSNO-UHFFFAOYSA-N 2-[[2-[[2-[(2-azaniumylacetyl)amino]acetyl]amino]acetyl]amino]acetate Chemical compound NCC(=O)NCC(=O)NCC(=O)NCC(O)=O QMOQBVOBWVNSNO-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 108700012813 7-aminoactinomycin D Proteins 0.000 description 1
- 206010000206 ABO incompatibility Diseases 0.000 description 1
- YLTKNGYYPIWKHZ-ACZMJKKPSA-N Ala-Ala-Glu Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CCC(O)=O YLTKNGYYPIWKHZ-ACZMJKKPSA-N 0.000 description 1
- RLMISHABBKUNFO-WHFBIAKZSA-N Ala-Ala-Gly Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)NCC(O)=O RLMISHABBKUNFO-WHFBIAKZSA-N 0.000 description 1
- NXSFUECZFORGOG-CIUDSAMLSA-N Ala-Asn-Leu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(O)=O NXSFUECZFORGOG-CIUDSAMLSA-N 0.000 description 1
- 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 1
- WXERCAHAIKMTKX-ZLUOBGJFSA-N Ala-Asp-Asp Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O WXERCAHAIKMTKX-ZLUOBGJFSA-N 0.000 description 1
- IKKVASZHTMKJIR-ZKWXMUAHSA-N Ala-Asp-Val Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O IKKVASZHTMKJIR-ZKWXMUAHSA-N 0.000 description 1
- 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 1
- NJIFPLAJSVUQOZ-JBDRJPRFSA-N Ala-Cys-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CS)NC(=O)[C@H](C)N NJIFPLAJSVUQOZ-JBDRJPRFSA-N 0.000 description 1
- BGNLUHXLSAQYRQ-FXQIFTODSA-N Ala-Glu-Gln Chemical compound C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O BGNLUHXLSAQYRQ-FXQIFTODSA-N 0.000 description 1
- NBTGEURICRTMGL-WHFBIAKZSA-N Ala-Gly-Ser Chemical compound C[C@H](N)C(=O)NCC(=O)N[C@@H](CO)C(O)=O NBTGEURICRTMGL-WHFBIAKZSA-N 0.000 description 1
- CCDFBRZVTDDJNM-GUBZILKMSA-N Ala-Leu-Glu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O CCDFBRZVTDDJNM-GUBZILKMSA-N 0.000 description 1
- OYJCVIGKMXUVKB-GARJFASQSA-N Ala-Leu-Pro Chemical compound C[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N1CCC[C@@H]1C(=O)O)N OYJCVIGKMXUVKB-GARJFASQSA-N 0.000 description 1
- CHFFHQUVXHEGBY-GARJFASQSA-N Ala-Lys-Pro Chemical compound C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N1CCC[C@@H]1C(=O)O)N CHFFHQUVXHEGBY-GARJFASQSA-N 0.000 description 1
- ZBLQIYPCUWZSRZ-QEJZJMRPSA-N Ala-Phe-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@H](C)N)CC1=CC=CC=C1 ZBLQIYPCUWZSRZ-QEJZJMRPSA-N 0.000 description 1
- MAZZQZWCCYJQGZ-GUBZILKMSA-N Ala-Pro-Arg Chemical compound [H]N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(N)=N)C(O)=O MAZZQZWCCYJQGZ-GUBZILKMSA-N 0.000 description 1
- OLVCTPPSXNRGKV-GUBZILKMSA-N Ala-Pro-Pro Chemical compound C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 OLVCTPPSXNRGKV-GUBZILKMSA-N 0.000 description 1
- FFZJHQODAYHGPO-KZVJFYERSA-N Ala-Pro-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H](C)N FFZJHQODAYHGPO-KZVJFYERSA-N 0.000 description 1
- RTZCUEHYUQZIDE-WHFBIAKZSA-N Ala-Ser-Gly Chemical compound C[C@H](N)C(=O)N[C@@H](CO)C(=O)NCC(O)=O RTZCUEHYUQZIDE-WHFBIAKZSA-N 0.000 description 1
- LFFOJBOTZUWINF-ZANVPECISA-N Ala-Trp-Gly Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@@H](N)C)C(=O)NCC(O)=O)=CNC2=C1 LFFOJBOTZUWINF-ZANVPECISA-N 0.000 description 1
- BHFOJPDOQPWJRN-XDTLVQLUSA-N Ala-Tyr-Gln Chemical compound C[C@H](N)C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@@H](CCC(N)=O)C(O)=O BHFOJPDOQPWJRN-XDTLVQLUSA-N 0.000 description 1
- QRIYOHQJRDHFKF-UWJYBYFXSA-N Ala-Tyr-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)C)CC1=CC=C(O)C=C1 QRIYOHQJRDHFKF-UWJYBYFXSA-N 0.000 description 1
- XCIGOVDXZULBBV-DCAQKATOSA-N Ala-Val-Lys Chemical compound CC(C)[C@H](NC(=O)[C@H](C)N)C(=O)N[C@@H](CCCCN)C(O)=O XCIGOVDXZULBBV-DCAQKATOSA-N 0.000 description 1
- 239000012103 Alexa Fluor 488 Substances 0.000 description 1
- 239000012110 Alexa Fluor 594 Substances 0.000 description 1
- 239000012114 Alexa Fluor 647 Substances 0.000 description 1
- OTOXOKCIIQLMFH-KZVJFYERSA-N Arg-Ala-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCN=C(N)N OTOXOKCIIQLMFH-KZVJFYERSA-N 0.000 description 1
- GHNDBBVSWOWYII-LPEHRKFASA-N Arg-Asn-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC(=O)N)NC(=O)[C@H](CCCN=C(N)N)N)C(=O)O GHNDBBVSWOWYII-LPEHRKFASA-N 0.000 description 1
- PQWTZSNVWSOFFK-FXQIFTODSA-N Arg-Asp-Asn Chemical compound C(C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC(=O)N)C(=O)O)N)CN=C(N)N PQWTZSNVWSOFFK-FXQIFTODSA-N 0.000 description 1
- FEZJJKXNPSEYEV-CIUDSAMLSA-N Arg-Gln-Ala Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(O)=O FEZJJKXNPSEYEV-CIUDSAMLSA-N 0.000 description 1
- OQCWXQJLCDPRHV-UWVGGRQHSA-N Arg-Gly-Leu Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC(C)C)C(O)=O OQCWXQJLCDPRHV-UWVGGRQHSA-N 0.000 description 1
- DIIGDGJKTMLQQW-IHRRRGAJSA-N Arg-Lys-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCN=C(N)N)N DIIGDGJKTMLQQW-IHRRRGAJSA-N 0.000 description 1
- BSYKSCBTTQKOJG-GUBZILKMSA-N Arg-Pro-Ala Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C)C(O)=O BSYKSCBTTQKOJG-GUBZILKMSA-N 0.000 description 1
- 108010051330 Arg-Pro-Gly-Pro Proteins 0.000 description 1
- FRBAHXABMQXSJQ-FXQIFTODSA-N Arg-Ser-Ser Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O FRBAHXABMQXSJQ-FXQIFTODSA-N 0.000 description 1
- IZSMEUDYADKZTJ-KJEVXHAQSA-N Arg-Tyr-Thr Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O IZSMEUDYADKZTJ-KJEVXHAQSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- APHUDFFMXFYRKP-CIUDSAMLSA-N Asn-Asn-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CC(=O)N)N APHUDFFMXFYRKP-CIUDSAMLSA-N 0.000 description 1
- DDPXDCKYWDGZAL-BQBZGAKWSA-N Asn-Gly-Arg Chemical compound NC(=O)C[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CCCN=C(N)N DDPXDCKYWDGZAL-BQBZGAKWSA-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
- PBVLJOIPOGUQQP-CIUDSAMLSA-N Asp-Ala-Leu Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(O)=O PBVLJOIPOGUQQP-CIUDSAMLSA-N 0.000 description 1
- XPGVTUBABLRGHY-BIIVOSGPSA-N Asp-Ala-Pro Chemical compound C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CC(=O)O)N XPGVTUBABLRGHY-BIIVOSGPSA-N 0.000 description 1
- BLQBMRNMBAYREH-UWJYBYFXSA-N Asp-Ala-Tyr Chemical compound N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)O BLQBMRNMBAYREH-UWJYBYFXSA-N 0.000 description 1
- GWTLRDMPMJCNMH-WHFBIAKZSA-N Asp-Asn-Gly Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(O)=O GWTLRDMPMJCNMH-WHFBIAKZSA-N 0.000 description 1
- CLUMZOKVGUWUFD-CIUDSAMLSA-N Asp-Leu-Asn Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O CLUMZOKVGUWUFD-CIUDSAMLSA-N 0.000 description 1
- GYWQGGUCMDCUJE-DLOVCJGASA-N Asp-Phe-Ala Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](C)C(O)=O GYWQGGUCMDCUJE-DLOVCJGASA-N 0.000 description 1
- UAXIKORUDGGIGA-DCAQKATOSA-N Asp-Pro-Lys Chemical compound C1C[C@H](N(C1)C(=O)[C@H](CC(=O)O)N)C(=O)N[C@@H](CCCCN)C(=O)O UAXIKORUDGGIGA-DCAQKATOSA-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
- 102100022005 B-lymphocyte antigen CD20 Human genes 0.000 description 1
- 238000011725 BALB/c mouse Methods 0.000 description 1
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 1
- WMQLLTKSISGWHQ-UHFFFAOYSA-N C1CC(NC(=O)NC)CCC1CCN1CCN(C=2C(=C(Cl)C=CC=2)Cl)CC1 Chemical compound C1CC(NC(=O)NC)CCC1CCN1CCN(C=2C(=C(Cl)C=CC=2)Cl)CC1 WMQLLTKSISGWHQ-UHFFFAOYSA-N 0.000 description 1
- 102100027207 CD27 antigen Human genes 0.000 description 1
- 241000282832 Camelidae Species 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- QLCPDGRAEJSYQM-LPEHRKFASA-N Cys-Arg-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CS)N)C(=O)O QLCPDGRAEJSYQM-LPEHRKFASA-N 0.000 description 1
- YKKHFPGOZXQAGK-QWRGUYRKSA-N Cys-Gly-Tyr Chemical compound SC[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 YKKHFPGOZXQAGK-QWRGUYRKSA-N 0.000 description 1
- OZHXXYOHPLLLMI-CIUDSAMLSA-N Cys-Lys-Ala Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O OZHXXYOHPLLLMI-CIUDSAMLSA-N 0.000 description 1
- YWEHYKGJWHPGPY-XGEHTFHBSA-N Cys-Thr-Arg Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)NC(=O)[C@H](CS)N)O YWEHYKGJWHPGPY-XGEHTFHBSA-N 0.000 description 1
- 101100447432 Danio rerio gapdh-2 gene Proteins 0.000 description 1
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 241000283074 Equus asinus Species 0.000 description 1
- 241000283073 Equus caballus Species 0.000 description 1
- 102000004315 Forkhead Transcription Factors Human genes 0.000 description 1
- 108090000852 Forkhead Transcription Factors Proteins 0.000 description 1
- 108091006027 G proteins Proteins 0.000 description 1
- 102000030782 GTP binding Human genes 0.000 description 1
- 108091000058 GTP-Binding Proteins 0.000 description 1
- 101150112014 Gapdh gene Proteins 0.000 description 1
- 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 1
- KWUSGAIFNHQCBY-DCAQKATOSA-N Gln-Arg-Arg Chemical compound NC(=O)CC[C@H](N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O KWUSGAIFNHQCBY-DCAQKATOSA-N 0.000 description 1
- JFSNBQJNDMXMQF-XHNCKOQMSA-N Gln-Asp-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC(=O)O)NC(=O)[C@H](CCC(=O)N)N)C(=O)O JFSNBQJNDMXMQF-XHNCKOQMSA-N 0.000 description 1
- CLPQUWHBWXFJOX-BQBZGAKWSA-N Gln-Gly-Gln Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(O)=O CLPQUWHBWXFJOX-BQBZGAKWSA-N 0.000 description 1
- TWIAMTNJOMRDAK-GUBZILKMSA-N Gln-Lys-Asp Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(O)=O TWIAMTNJOMRDAK-GUBZILKMSA-N 0.000 description 1
- FKXCBKCOSVIGCT-AVGNSLFASA-N Gln-Lys-Leu Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(O)=O FKXCBKCOSVIGCT-AVGNSLFASA-N 0.000 description 1
- UTOQQOMEJDPDMX-ACZMJKKPSA-N Gln-Ser-Asp Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(O)=O UTOQQOMEJDPDMX-ACZMJKKPSA-N 0.000 description 1
- JILRMFFFCHUUTJ-ACZMJKKPSA-N Gln-Ser-Ser Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O JILRMFFFCHUUTJ-ACZMJKKPSA-N 0.000 description 1
- BYKZWDGMJLNFJY-XKBZYTNZSA-N Gln-Ser-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(=O)N)N)O BYKZWDGMJLNFJY-XKBZYTNZSA-N 0.000 description 1
- NHMRJKKAVMENKJ-WDCWCFNPSA-N Gln-Thr-Leu Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O NHMRJKKAVMENKJ-WDCWCFNPSA-N 0.000 description 1
- VLOLPWWCNKWRNB-LOKLDPHHSA-N Gln-Thr-Pro Chemical compound C[C@H]([C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCC(=O)N)N)O VLOLPWWCNKWRNB-LOKLDPHHSA-N 0.000 description 1
- UTKICHUQEQBDGC-ACZMJKKPSA-N Glu-Ala-Cys Chemical compound C[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CCC(=O)O)N UTKICHUQEQBDGC-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
- WOMUDRVDJMHTCV-DCAQKATOSA-N Glu-Arg-Arg Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O WOMUDRVDJMHTCV-DCAQKATOSA-N 0.000 description 1
- SBCYJMOOHUDWDA-NUMRIWBASA-N Glu-Asp-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O SBCYJMOOHUDWDA-NUMRIWBASA-N 0.000 description 1
- 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 1
- 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 1
- ITBHUUMCJJQUSC-LAEOZQHASA-N Glu-Ile-Gly Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(O)=O ITBHUUMCJJQUSC-LAEOZQHASA-N 0.000 description 1
- LHIPZASLKPYDPI-AVGNSLFASA-N Glu-Phe-Asp Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(O)=O)C(O)=O LHIPZASLKPYDPI-AVGNSLFASA-N 0.000 description 1
- HZISRJBYZAODRV-XQXXSGGOSA-N Glu-Thr-Ala Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O HZISRJBYZAODRV-XQXXSGGOSA-N 0.000 description 1
- MIWJDJAMMKHUAR-ZVZYQTTQSA-N Glu-Trp-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)NC(=O)[C@H](CCC(=O)O)N MIWJDJAMMKHUAR-ZVZYQTTQSA-N 0.000 description 1
- HHSKZJZWQFPSKN-AVGNSLFASA-N Glu-Tyr-Asp Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(O)=O)C(O)=O HHSKZJZWQFPSKN-AVGNSLFASA-N 0.000 description 1
- UGVQELHRNUDMAA-BYPYZUCNSA-N Gly-Ala-Gly Chemical compound [NH3+]CC(=O)N[C@@H](C)C(=O)NCC([O-])=O UGVQELHRNUDMAA-BYPYZUCNSA-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
- 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 1
- XUORRGAFUQIMLC-STQMWFEESA-N Gly-Arg-Tyr Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)O)NC(=O)[C@H](CCCN=C(N)N)NC(=O)CN)O XUORRGAFUQIMLC-STQMWFEESA-N 0.000 description 1
- XPJBQTCXPJNIFE-ZETCQYMHSA-N Gly-Gly-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)CNC(=O)CN XPJBQTCXPJNIFE-ZETCQYMHSA-N 0.000 description 1
- 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 1
- YWAQATDNEKZFFK-BYPYZUCNSA-N Gly-Gly-Ser Chemical compound NCC(=O)NCC(=O)N[C@@H](CO)C(O)=O YWAQATDNEKZFFK-BYPYZUCNSA-N 0.000 description 1
- UQJNXZSSGQIPIQ-FBCQKBJTSA-N Gly-Gly-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)CNC(=O)CN UQJNXZSSGQIPIQ-FBCQKBJTSA-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
- UTYGDAHJBBDPBA-BYULHYEWSA-N Gly-Ile-Asp Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)O)NC(=O)CN UTYGDAHJBBDPBA-BYULHYEWSA-N 0.000 description 1
- FCKPEGOCSVZPNC-WHOFXGATSA-N Gly-Ile-Phe Chemical compound NCC(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 FCKPEGOCSVZPNC-WHOFXGATSA-N 0.000 description 1
- HAXARWKYFIIHKD-ZKWXMUAHSA-N Gly-Ile-Ser Chemical compound NCC(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(O)=O HAXARWKYFIIHKD-ZKWXMUAHSA-N 0.000 description 1
- 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 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
- TVUWMSBGMVAHSJ-KBPBESRZSA-N Gly-Leu-Phe Chemical compound NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 TVUWMSBGMVAHSJ-KBPBESRZSA-N 0.000 description 1
- NNCSJUBVFBDDLC-YUMQZZPRSA-N Gly-Leu-Ser Chemical compound NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O NNCSJUBVFBDDLC-YUMQZZPRSA-N 0.000 description 1
- FHQRLHFYVZAQHU-IUCAKERBSA-N Gly-Lys-Gln Chemical compound [H]NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(N)=O)C(O)=O FHQRLHFYVZAQHU-IUCAKERBSA-N 0.000 description 1
- 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 1
- GGAPHLIUUTVYMX-QWRGUYRKSA-N Gly-Phe-Ser Chemical compound OC[C@@H](C([O-])=O)NC(=O)[C@@H](NC(=O)C[NH3+])CC1=CC=CC=C1 GGAPHLIUUTVYMX-QWRGUYRKSA-N 0.000 description 1
- GGLIDLCEPDHEJO-BQBZGAKWSA-N Gly-Pro-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1C(=O)CN GGLIDLCEPDHEJO-BQBZGAKWSA-N 0.000 description 1
- GLACUWHUYFBSPJ-FJXKBIBVSA-N Gly-Pro-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)CN GLACUWHUYFBSPJ-FJXKBIBVSA-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
- WCORRBXVISTKQL-WHFBIAKZSA-N Gly-Ser-Ser Chemical compound NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O WCORRBXVISTKQL-WHFBIAKZSA-N 0.000 description 1
- FKYQEVBRZSFAMJ-QWRGUYRKSA-N Gly-Ser-Tyr Chemical compound NCC(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 FKYQEVBRZSFAMJ-QWRGUYRKSA-N 0.000 description 1
- FKESCSGWBPUTPN-FOHZUACHSA-N Gly-Thr-Asn Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(O)=O FKESCSGWBPUTPN-FOHZUACHSA-N 0.000 description 1
- DBUNZBWUWCIELX-JHEQGTHGSA-N Gly-Thr-Glu Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(O)=O)C(O)=O DBUNZBWUWCIELX-JHEQGTHGSA-N 0.000 description 1
- XHVONGZZVUUORG-WEDXCCLWSA-N Gly-Thr-Lys Chemical compound NCC(=O)N[C@@H]([C@H](O)C)C(=O)N[C@H](C(O)=O)CCCCN XHVONGZZVUUORG-WEDXCCLWSA-N 0.000 description 1
- FOKISINOENBSDM-WLTAIBSBSA-N Gly-Thr-Tyr Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O FOKISINOENBSDM-WLTAIBSBSA-N 0.000 description 1
- RJVZMGQMJOQIAX-GJZGRUSLSA-N Gly-Trp-Met Chemical compound [H]NCC(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CCSC)C(O)=O RJVZMGQMJOQIAX-GJZGRUSLSA-N 0.000 description 1
- HQSKKSLNLSTONK-JTQLQIEISA-N Gly-Tyr-Gly Chemical compound OC(=O)CNC(=O)[C@@H](NC(=O)CN)CC1=CC=C(O)C=C1 HQSKKSLNLSTONK-JTQLQIEISA-N 0.000 description 1
- AFMOTCMSEBITOE-YEPSODPASA-N Gly-Val-Thr Chemical compound NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O AFMOTCMSEBITOE-YEPSODPASA-N 0.000 description 1
- 102100031181 Glyceraldehyde-3-phosphate dehydrogenase Human genes 0.000 description 1
- JBCLFWXMTIKCCB-UHFFFAOYSA-N H-Gly-Phe-OH Natural products NCC(=O)NC(C(O)=O)CC1=CC=CC=C1 JBCLFWXMTIKCCB-UHFFFAOYSA-N 0.000 description 1
- 229920000209 Hexadimethrine bromide Polymers 0.000 description 1
- LSQHWKPPOFDHHZ-YUMQZZPRSA-N His-Asp-Gly Chemical compound C1=C(NC=N1)C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)NCC(=O)O)N LSQHWKPPOFDHHZ-YUMQZZPRSA-N 0.000 description 1
- BDFCIKANUNMFGB-PMVVWTBXSA-N His-Gly-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CC1=CN=CN1 BDFCIKANUNMFGB-PMVVWTBXSA-N 0.000 description 1
- NKRWVZQTPXPNRZ-SRVKXCTJSA-N His-Met-Gln Chemical compound NC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](CCSC)NC(=O)[C@@H](N)CC1=CN=CN1 NKRWVZQTPXPNRZ-SRVKXCTJSA-N 0.000 description 1
- VDHOMPFVSABJKU-ULQDDVLXSA-N His-Phe-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)NC(=O)[C@H](CC2=CN=CN2)N VDHOMPFVSABJKU-ULQDDVLXSA-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
- 241000282412 Homo Species 0.000 description 1
- 101000897405 Homo sapiens B-lymphocyte antigen CD20 Proteins 0.000 description 1
- 101000914511 Homo sapiens CD27 antigen Proteins 0.000 description 1
- 101000851370 Homo sapiens Tumor necrosis factor receptor superfamily member 9 Proteins 0.000 description 1
- RPZFUIQVAPZLRH-GHCJXIJMSA-N Ile-Asp-Ala Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](C)C(=O)O)N RPZFUIQVAPZLRH-GHCJXIJMSA-N 0.000 description 1
- WUKLZPHVWAMZQV-UKJIMTQDSA-N Ile-Glu-Val Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](C(C)C)C(=O)O)N WUKLZPHVWAMZQV-UKJIMTQDSA-N 0.000 description 1
- APDIECQNNDGFPD-PYJNHQTQSA-N Ile-His-Val Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)N[C@@H](C(C)C)C(=O)O)N APDIECQNNDGFPD-PYJNHQTQSA-N 0.000 description 1
- UOPBQSJRBONRON-STECZYCISA-N Ile-Met-Tyr Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](CCSC)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 UOPBQSJRBONRON-STECZYCISA-N 0.000 description 1
- JHNJNTMTZHEDLJ-NAKRPEOUSA-N Ile-Ser-Arg Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O JHNJNTMTZHEDLJ-NAKRPEOUSA-N 0.000 description 1
- ZLFNNVATRMCAKN-ZKWXMUAHSA-N Ile-Ser-Gly Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)NCC(=O)O)N ZLFNNVATRMCAKN-ZKWXMUAHSA-N 0.000 description 1
- ZGKVPOSSTGHJAF-HJPIBITLSA-N Ile-Tyr-Ser Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CO)C(=O)O)N ZGKVPOSSTGHJAF-HJPIBITLSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 102100034349 Integrase Human genes 0.000 description 1
- 102000000589 Interleukin-1 Human genes 0.000 description 1
- 108010002352 Interleukin-1 Proteins 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
- UGTHTQWIQKEDEH-BQBZGAKWSA-N L-alanyl-L-prolylglycine zwitterion Chemical compound C[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O UGTHTQWIQKEDEH-BQBZGAKWSA-N 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
- 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
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-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
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 1
- IBMVEYRWAWIOTN-RWMBFGLXSA-N Leu-Arg-Pro Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1CCC[C@@H]1C(O)=O IBMVEYRWAWIOTN-RWMBFGLXSA-N 0.000 description 1
- OIARJGNVARWKFP-YUMQZZPRSA-N Leu-Asn-Gly Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(O)=O OIARJGNVARWKFP-YUMQZZPRSA-N 0.000 description 1
- 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 1
- JQSXWJXBASFONF-KKUMJFAQSA-N Leu-Asp-Phe Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O JQSXWJXBASFONF-KKUMJFAQSA-N 0.000 description 1
- CIVKXGPFXDIQBV-WDCWCFNPSA-N Leu-Gln-Thr Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O CIVKXGPFXDIQBV-WDCWCFNPSA-N 0.000 description 1
- LLBQJYDYOLIQAI-JYJNAYRXSA-N Leu-Glu-Tyr Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O LLBQJYDYOLIQAI-JYJNAYRXSA-N 0.000 description 1
- FIYMBBHGYNQFOP-IUCAKERBSA-N Leu-Gly-Gln Chemical compound CC(C)C[C@@H](C(=O)NCC(=O)N[C@@H](CCC(=O)N)C(=O)O)N FIYMBBHGYNQFOP-IUCAKERBSA-N 0.000 description 1
- OYQUOLRTJHWVSQ-SRVKXCTJSA-N Leu-His-Ser Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CO)C(O)=O OYQUOLRTJHWVSQ-SRVKXCTJSA-N 0.000 description 1
- OMHLATXVNQSALM-FQUUOJAGSA-N Leu-Ile-Pro Chemical compound CC[C@H](C)[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CC(C)C)N OMHLATXVNQSALM-FQUUOJAGSA-N 0.000 description 1
- MAXILRZVORNXBE-PMVMPFDFSA-N Leu-Phe-Trp Chemical compound C([C@H](NC(=O)[C@@H](N)CC(C)C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(O)=O)C1=CC=CC=C1 MAXILRZVORNXBE-PMVMPFDFSA-N 0.000 description 1
- WMIOEVKKYIMVKI-DCAQKATOSA-N Leu-Pro-Ala Chemical compound [H]N[C@@H](CC(C)C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C)C(O)=O WMIOEVKKYIMVKI-DCAQKATOSA-N 0.000 description 1
- KZZCOWMDDXDKSS-CIUDSAMLSA-N Leu-Ser-Asn Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O KZZCOWMDDXDKSS-CIUDSAMLSA-N 0.000 description 1
- VHTIZYYHIUHMCA-JYJNAYRXSA-N Leu-Tyr-Gln 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](CCC(N)=O)C(O)=O VHTIZYYHIUHMCA-JYJNAYRXSA-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
- UWKNTTJNVSYXPC-CIUDSAMLSA-N Lys-Ala-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCCN UWKNTTJNVSYXPC-CIUDSAMLSA-N 0.000 description 1
- GQFDWEDHOQRNLC-QWRGUYRKSA-N Lys-Gly-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN GQFDWEDHOQRNLC-QWRGUYRKSA-N 0.000 description 1
- NKKFVJRLCCUJNA-QWRGUYRKSA-N Lys-Gly-Lys Chemical compound NCCCC[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CCCCN NKKFVJRLCCUJNA-QWRGUYRKSA-N 0.000 description 1
- FHIAJWBDZVHLAH-YUMQZZPRSA-N Lys-Gly-Ser Chemical compound NCCCC[C@H](N)C(=O)NCC(=O)N[C@@H](CO)C(O)=O FHIAJWBDZVHLAH-YUMQZZPRSA-N 0.000 description 1
- WVJNGSFKBKOKRV-AJNGGQMLSA-N Lys-Leu-Ile Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O WVJNGSFKBKOKRV-AJNGGQMLSA-N 0.000 description 1
- ZJWIXBZTAAJERF-IHRRRGAJSA-N Lys-Lys-Arg Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(O)=O)CCCN=C(N)N ZJWIXBZTAAJERF-IHRRRGAJSA-N 0.000 description 1
- HKXSZKJMDBHOTG-CIUDSAMLSA-N Lys-Ser-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CCCCN HKXSZKJMDBHOTG-CIUDSAMLSA-N 0.000 description 1
- GHKXHCMRAUYLBS-CIUDSAMLSA-N Lys-Ser-Asn Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O GHKXHCMRAUYLBS-CIUDSAMLSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- AXHNAGAYRGCDLG-UWVGGRQHSA-N Met-Lys-Gly Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)NCC(O)=O AXHNAGAYRGCDLG-UWVGGRQHSA-N 0.000 description 1
- NDJSSFWDYDUQID-YTWAJWBKSA-N Met-Thr-Pro Chemical compound C[C@H]([C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCSC)N)O NDJSSFWDYDUQID-YTWAJWBKSA-N 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- WUGMRIBZSVSJNP-UHFFFAOYSA-N N-L-alanyl-L-tryptophan Natural products C1=CC=C2C(CC(NC(=O)C(N)C)C(O)=O)=CNC2=C1 WUGMRIBZSVSJNP-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 108010047562 NGR peptide Proteins 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 108091093105 Nuclear DNA Proteins 0.000 description 1
- 108091034117 Oligonucleotide Proteins 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- JEGFCFLCRSJCMA-IHRRRGAJSA-N Phe-Arg-Ser Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CO)C(=O)O)N JEGFCFLCRSJCMA-IHRRRGAJSA-N 0.000 description 1
- 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 1
- OSBADCBXAMSPQD-YESZJQIVSA-N Phe-Leu-Pro Chemical compound CC(C)C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CC2=CC=CC=C2)N OSBADCBXAMSPQD-YESZJQIVSA-N 0.000 description 1
- MMJJFXWMCMJMQA-STQMWFEESA-N Phe-Pro-Gly Chemical compound C([C@H](N)C(=O)N1[C@@H](CCC1)C(=O)NCC(O)=O)C1=CC=CC=C1 MMJJFXWMCMJMQA-STQMWFEESA-N 0.000 description 1
- XDMMOISUAHXXFD-SRVKXCTJSA-N Phe-Ser-Asp Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(O)=O XDMMOISUAHXXFD-SRVKXCTJSA-N 0.000 description 1
- GLJZDMZJHFXJQG-BZSNNMDCSA-N Phe-Ser-Phe Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O GLJZDMZJHFXJQG-BZSNNMDCSA-N 0.000 description 1
- MCIXMYKSPQUMJG-SRVKXCTJSA-N Phe-Ser-Ser Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O MCIXMYKSPQUMJG-SRVKXCTJSA-N 0.000 description 1
- 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 1
- VXCHGLYSIOOZIS-GUBZILKMSA-N Pro-Ala-Arg Chemical compound NC(N)=NCCC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1 VXCHGLYSIOOZIS-GUBZILKMSA-N 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
- 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 1
- NHDVNAKDACFHPX-GUBZILKMSA-N Pro-Arg-Ala Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(O)=O NHDVNAKDACFHPX-GUBZILKMSA-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
- UPJGUQPLYWTISV-GUBZILKMSA-N Pro-Gln-Glu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O UPJGUQPLYWTISV-GUBZILKMSA-N 0.000 description 1
- HAAQQNHQZBOWFO-LURJTMIESA-N Pro-Gly-Gly Chemical compound OC(=O)CNC(=O)CNC(=O)[C@@H]1CCCN1 HAAQQNHQZBOWFO-LURJTMIESA-N 0.000 description 1
- UIMCLYYSUCIUJM-UWVGGRQHSA-N Pro-Gly-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H]1CCCN1 UIMCLYYSUCIUJM-UWVGGRQHSA-N 0.000 description 1
- 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 1
- YYARMJSFDLIDFS-FKBYEOEOSA-N Pro-Phe-Trp Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O YYARMJSFDLIDFS-FKBYEOEOSA-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
- SNGZLPOXVRTNMB-LPEHRKFASA-N Pro-Ser-Pro Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CO)C(=O)N2CCC[C@@H]2C(=O)O SNGZLPOXVRTNMB-LPEHRKFASA-N 0.000 description 1
- 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 1
- AIOWVDNPESPXRB-YTWAJWBKSA-N Pro-Thr-Pro Chemical compound C[C@H]([C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@@H]2CCCN2)O AIOWVDNPESPXRB-YTWAJWBKSA-N 0.000 description 1
- DLZBBDSPTJBOOD-BPNCWPANSA-N Pro-Tyr-Ala Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](C)C(O)=O DLZBBDSPTJBOOD-BPNCWPANSA-N 0.000 description 1
- VDHGTOHMHHQSKG-JYJNAYRXSA-N Pro-Val-Phe Chemical compound CC(C)[C@H](NC(=O)[C@@H]1CCCN1)C(=O)N[C@@H](Cc1ccccc1)C(O)=O VDHGTOHMHHQSKG-JYJNAYRXSA-N 0.000 description 1
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 description 1
- ZUGXSSFMTXKHJS-ZLUOBGJFSA-N Ser-Ala-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(O)=O ZUGXSSFMTXKHJS-ZLUOBGJFSA-N 0.000 description 1
- HRNQLKCLPVKZNE-CIUDSAMLSA-N Ser-Ala-Leu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(O)=O HRNQLKCLPVKZNE-CIUDSAMLSA-N 0.000 description 1
- HBZBPFLJNDXRAY-FXQIFTODSA-N Ser-Ala-Val Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(O)=O HBZBPFLJNDXRAY-FXQIFTODSA-N 0.000 description 1
- WDXYVIIVDIDOSX-DCAQKATOSA-N Ser-Arg-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CO)CCCN=C(N)N WDXYVIIVDIDOSX-DCAQKATOSA-N 0.000 description 1
- HBOABDXGTMMDSE-GUBZILKMSA-N Ser-Arg-Val Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(O)=O HBOABDXGTMMDSE-GUBZILKMSA-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
- RDFQNDHEHVSONI-ZLUOBGJFSA-N Ser-Asn-Ser Chemical compound OC[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(O)=O RDFQNDHEHVSONI-ZLUOBGJFSA-N 0.000 description 1
- CNIIKZQXBBQHCX-FXQIFTODSA-N Ser-Asp-Arg Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O CNIIKZQXBBQHCX-FXQIFTODSA-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
- JFWDJFULOLKQFY-QWRGUYRKSA-N Ser-Gly-Phe Chemical compound [H]N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O JFWDJFULOLKQFY-QWRGUYRKSA-N 0.000 description 1
- SFTZWNJFZYOLBD-ZDLURKLDSA-N Ser-Gly-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CO SFTZWNJFZYOLBD-ZDLURKLDSA-N 0.000 description 1
- IXZHZUGGKLRHJD-DCAQKATOSA-N Ser-Leu-Val Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(O)=O IXZHZUGGKLRHJD-DCAQKATOSA-N 0.000 description 1
- NNFMANHDYSVNIO-DCAQKATOSA-N Ser-Lys-Arg Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O NNFMANHDYSVNIO-DCAQKATOSA-N 0.000 description 1
- HHJFMHQYEAAOBM-ZLUOBGJFSA-N Ser-Ser-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(O)=O HHJFMHQYEAAOBM-ZLUOBGJFSA-N 0.000 description 1
- KQNDIKOYWZTZIX-FXQIFTODSA-N Ser-Ser-Arg Chemical compound OC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CCCNC(N)=N KQNDIKOYWZTZIX-FXQIFTODSA-N 0.000 description 1
- XQJCEKXQUJQNNK-ZLUOBGJFSA-N Ser-Ser-Ser Chemical compound OC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O XQJCEKXQUJQNNK-ZLUOBGJFSA-N 0.000 description 1
- PIQRHJQWEPWFJG-UWJYBYFXSA-N Ser-Tyr-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](C)C(O)=O PIQRHJQWEPWFJG-UWJYBYFXSA-N 0.000 description 1
- GSCVDSBEYVGMJQ-SRVKXCTJSA-N Ser-Tyr-Asp Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)O)NC(=O)[C@H](CO)N)O GSCVDSBEYVGMJQ-SRVKXCTJSA-N 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 241000282898 Sus scrofa Species 0.000 description 1
- 230000006044 T cell activation Effects 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
- OJRNZRROAIAHDL-LKXGYXEUSA-N Thr-Asn-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(O)=O OJRNZRROAIAHDL-LKXGYXEUSA-N 0.000 description 1
- JVTHIXKSVYEWNI-JRQIVUDYSA-N Thr-Asn-Tyr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O JVTHIXKSVYEWNI-JRQIVUDYSA-N 0.000 description 1
- KBBRNEDOYWMIJP-KYNKHSRBSA-N Thr-Gly-Thr Chemical compound C[C@H]([C@@H](C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(=O)O)N)O KBBRNEDOYWMIJP-KYNKHSRBSA-N 0.000 description 1
- JQAWYCUUFIMTHE-WLTAIBSBSA-N Thr-Gly-Tyr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O JQAWYCUUFIMTHE-WLTAIBSBSA-N 0.000 description 1
- XOWKUMFHEZLKLT-CIQUZCHMSA-N Thr-Ile-Ala Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O XOWKUMFHEZLKLT-CIQUZCHMSA-N 0.000 description 1
- YOOAQCZYZHGUAZ-KATARQTJSA-N Thr-Leu-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O YOOAQCZYZHGUAZ-KATARQTJSA-N 0.000 description 1
- VRUFCJZQDACGLH-UVOCVTCTSA-N Thr-Leu-Thr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O VRUFCJZQDACGLH-UVOCVTCTSA-N 0.000 description 1
- WRQLCVIALDUQEQ-UNQGMJICSA-N Thr-Phe-Arg Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O WRQLCVIALDUQEQ-UNQGMJICSA-N 0.000 description 1
- WYLAVUAWOUVUCA-XVSYOHENSA-N Thr-Phe-Asp Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(O)=O)C(O)=O WYLAVUAWOUVUCA-XVSYOHENSA-N 0.000 description 1
- FWTFAZKJORVTIR-VZFHVOOUSA-N Thr-Ser-Ala Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(O)=O FWTFAZKJORVTIR-VZFHVOOUSA-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
- XVHAUVJXBFGUPC-RPTUDFQQSA-N Thr-Tyr-Phe 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](CC1=CC=CC=C1)C(O)=O XVHAUVJXBFGUPC-RPTUDFQQSA-N 0.000 description 1
- XGFYGMKZKFRGAI-RCWTZXSCSA-N Thr-Val-Arg Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CCCN=C(N)N XGFYGMKZKFRGAI-RCWTZXSCSA-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
- 108091023040 Transcription factor Proteins 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 1
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 1
- 108700019146 Transgenes Proteins 0.000 description 1
- 208000037280 Trisomy Diseases 0.000 description 1
- OZUJUVFWMHTWCZ-HOCLYGCPSA-N Trp-Gly-His Chemical compound N[C@@H](Cc1c[nH]c2ccccc12)C(=O)NCC(=O)N[C@@H](Cc1cnc[nH]1)C(O)=O OZUJUVFWMHTWCZ-HOCLYGCPSA-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
- 102100036856 Tumor necrosis factor receptor superfamily member 9 Human genes 0.000 description 1
- BURPTJBFWIOHEY-UWJYBYFXSA-N Tyr-Ala-Asp Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 BURPTJBFWIOHEY-UWJYBYFXSA-N 0.000 description 1
- CDRYEAWHKJSGAF-BPNCWPANSA-N Tyr-Ala-Met Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](C)C(=O)N[C@@H](CCSC)C(O)=O CDRYEAWHKJSGAF-BPNCWPANSA-N 0.000 description 1
- DKKHULUSOSWGHS-UWJYBYFXSA-N Tyr-Asn-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CC1=CC=C(C=C1)O)N DKKHULUSOSWGHS-UWJYBYFXSA-N 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
- SMLCYZYQFRTLCO-UWJYBYFXSA-N Tyr-Cys-Ala Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CS)C(=O)N[C@@H](C)C(O)=O SMLCYZYQFRTLCO-UWJYBYFXSA-N 0.000 description 1
- AZGZDDNKFFUDEH-QWRGUYRKSA-N Tyr-Gly-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CC1=CC=C(O)C=C1 AZGZDDNKFFUDEH-QWRGUYRKSA-N 0.000 description 1
- NMKJPMCEKQHRPD-IRXDYDNUSA-N Tyr-Gly-Tyr Chemical compound C([C@H](N)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C1=CC=C(O)C=C1 NMKJPMCEKQHRPD-IRXDYDNUSA-N 0.000 description 1
- 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 1
- ANHVRCNNGJMJNG-BZSNNMDCSA-N Tyr-Tyr-Cys Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CC2=CC=C(C=C2)O)C(=O)N[C@@H](CS)C(=O)O)N)O ANHVRCNNGJMJNG-BZSNNMDCSA-N 0.000 description 1
- RGJZPXFZIUUQDN-BPNCWPANSA-N Tyr-Val-Ala Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C)C(O)=O RGJZPXFZIUUQDN-BPNCWPANSA-N 0.000 description 1
- WOCYUGQDXPTQPY-FXQIFTODSA-N Val-Ala-Cys Chemical compound C[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](C(C)C)N WOCYUGQDXPTQPY-FXQIFTODSA-N 0.000 description 1
- YFOCMOVJBQDBCE-NRPADANISA-N Val-Ala-Glu Chemical compound C[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)O)NC(=O)[C@H](C(C)C)N YFOCMOVJBQDBCE-NRPADANISA-N 0.000 description 1
- JIODCDXKCJRMEH-NHCYSSNCSA-N Val-Arg-Gln Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N JIODCDXKCJRMEH-NHCYSSNCSA-N 0.000 description 1
- XIFAHCUNWWKUDE-DCAQKATOSA-N Val-Cys-Lys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CCCCN)C(=O)O)N XIFAHCUNWWKUDE-DCAQKATOSA-N 0.000 description 1
- 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 1
- MYLNLEIZWHVENT-VKOGCVSHSA-N Val-Ile-Trp Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)NC(=O)[C@H](C(C)C)N MYLNLEIZWHVENT-VKOGCVSHSA-N 0.000 description 1
- DJQIUOKSNRBTSV-CYDGBPFRSA-N Val-Ile-Val Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](C(C)C)C(=O)O)NC(=O)[C@H](C(C)C)N DJQIUOKSNRBTSV-CYDGBPFRSA-N 0.000 description 1
- LYERIXUFCYVFFX-GVXVVHGQSA-N Val-Leu-Glu Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)O)NC(=O)[C@H](C(C)C)N LYERIXUFCYVFFX-GVXVVHGQSA-N 0.000 description 1
- UMPVMAYCLYMYGA-ONGXEEELSA-N Val-Leu-Gly Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O UMPVMAYCLYMYGA-ONGXEEELSA-N 0.000 description 1
- DIOSYUIWOQCXNR-ONGXEEELSA-N Val-Lys-Gly Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)NCC(O)=O DIOSYUIWOQCXNR-ONGXEEELSA-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
- HJSLDXZAZGFPDK-ULQDDVLXSA-N Val-Phe-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)NC(=O)[C@H](C(C)C)N HJSLDXZAZGFPDK-ULQDDVLXSA-N 0.000 description 1
- AEFJNECXZCODJM-UWVGGRQHSA-N Val-Val-Gly Chemical compound CC(C)[C@H]([NH3+])C(=O)N[C@@H](C(C)C)C(=O)NCC([O-])=O AEFJNECXZCODJM-UWVGGRQHSA-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
- 241000711973 Vesicular stomatitis Indiana virus Species 0.000 description 1
- 108010003533 Viral Envelope Proteins Proteins 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 229960005305 adenosine Drugs 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 238000001042 affinity chromatography Methods 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 108010041407 alanylaspartic acid Proteins 0.000 description 1
- 108700025316 aldesleukin Proteins 0.000 description 1
- 108010050025 alpha-glutamyltryptophan Proteins 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000009833 antibody interaction Effects 0.000 description 1
- 230000009831 antigen interaction Effects 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 108010060035 arginylproline Proteins 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
- 108010038633 aspartylglutamate Proteins 0.000 description 1
- 108010047857 aspartylglycine Proteins 0.000 description 1
- 108010068265 aspartyltyrosine Proteins 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 230000008901 benefit Effects 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
- 230000037396 body weight Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000002737 cell proliferation kit Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000010367 cloning Methods 0.000 description 1
- 238000003501 co-culture Methods 0.000 description 1
- 238000004590 computer program Methods 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 108010060199 cysteinylproline Proteins 0.000 description 1
- 230000016396 cytokine production Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 210000004443 dendritic cell Anatomy 0.000 description 1
- 238000000586 desensitisation Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 230000003511 endothelial effect Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- MHMNJMPURVTYEJ-UHFFFAOYSA-N fluorescein-5-isothiocyanate Chemical compound O1C(=O)C2=CC(N=C=S)=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 MHMNJMPURVTYEJ-UHFFFAOYSA-N 0.000 description 1
- 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
- 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 1
- 108010027668 glycyl-alanyl-valine Proteins 0.000 description 1
- 108010026364 glycyl-glycyl-leucine Proteins 0.000 description 1
- 108010033719 glycyl-histidyl-glycine Proteins 0.000 description 1
- 108010066198 glycyl-leucyl-phenylalanine Proteins 0.000 description 1
- 108010010147 glycylglutamine Proteins 0.000 description 1
- 108010037850 glycylvaline Proteins 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 108010036413 histidylglycine Proteins 0.000 description 1
- 238000010562 histological examination Methods 0.000 description 1
- 230000002519 immonomodulatory effect Effects 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 108091008915 immune receptors Proteins 0.000 description 1
- 102000027596 immune receptors Human genes 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 238000010166 immunofluorescence Methods 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 229940072221 immunoglobulins Drugs 0.000 description 1
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 229940076144 interleukin-10 Drugs 0.000 description 1
- 229940100601 interleukin-6 Drugs 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 229960000310 isoleucine Drugs 0.000 description 1
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 1
- 108010057821 leucylproline Proteins 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 210000001165 lymph node Anatomy 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 108010005942 methionylglycine Proteins 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000010172 mouse model Methods 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
- 238000002559 palpation Methods 0.000 description 1
- 229920002866 paraformaldehyde Polymers 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
- 238000002616 plasmapheresis Methods 0.000 description 1
- 238000003752 polymerase chain reaction Methods 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 229940087463 proleukin Drugs 0.000 description 1
- 108010014614 prolyl-glycyl-proline Proteins 0.000 description 1
- 108010070643 prolylglutamic acid Proteins 0.000 description 1
- 108010090894 prolylleucine Proteins 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000003757 reverse transcription PCR Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000012163 sequencing technique Methods 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 208000011908 tetrasomy Diseases 0.000 description 1
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- ANRHNWWPFJCPAZ-UHFFFAOYSA-M thionine Chemical compound [Cl-].C1=CC(N)=CC2=[S+]C3=CC(N)=CC=C3N=C21 ANRHNWWPFJCPAZ-UHFFFAOYSA-M 0.000 description 1
- 230000009261 transgenic effect Effects 0.000 description 1
- 238000011282 treatment Methods 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 108700001624 vesicular stomatitis virus G Proteins 0.000 description 1
- 238000011179 visual inspection Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/001—Preparations to induce tolerance to non-self, e.g. prior to transplantation
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/46—Cellular immunotherapy
- A61K39/461—Cellular immunotherapy characterised by the cell type used
- A61K39/4611—T-cells, e.g. tumor infiltrating lymphocytes [TIL], lymphokine-activated killer cells [LAK] or regulatory T cells [Treg]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/46—Cellular immunotherapy
- A61K39/462—Cellular immunotherapy characterized by the effect or the function of the cells
- A61K39/4621—Cellular immunotherapy characterized by the effect or the function of the cells immunosuppressive or immunotolerising
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/46—Cellular immunotherapy
- A61K39/463—Cellular immunotherapy characterised by recombinant expression
- A61K39/4631—Chimeric Antigen Receptors [CAR]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/46—Cellular immunotherapy
- A61K39/464—Cellular immunotherapy characterised by the antigen targeted or presented
- A61K39/4643—Vertebrate antigens
- A61K39/46433—Antigens related to auto-immune diseases; Preparations to induce self-tolerance
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/46—Cellular immunotherapy
- A61K39/464—Cellular immunotherapy characterised by the antigen targeted or presented
- A61K39/4643—Vertebrate antigens
- A61K39/46434—Antigens related to induction of tolerance to non-self
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/46—Cellular immunotherapy
- A61K39/464—Cellular immunotherapy characterised by the antigen targeted or presented
- A61K39/4643—Vertebrate antigens
- A61K39/4644—Cancer antigens
- A61K39/464402—Receptors, cell surface antigens or cell surface determinants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
- C07K14/70503—Immunoglobulin superfamily
- C07K14/7051—T-cell receptor (TcR)-CD3 complex
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
- C07K16/2833—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against MHC-molecules, e.g. HLA-molecules
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/06—Animal cells or tissues; Human cells or tissues
- C12N5/0602—Vertebrate cells
- C12N5/0634—Cells from the blood or the immune system
- C12N5/0636—T lymphocytes
- C12N5/0637—Immunosuppressive T lymphocytes, e.g. regulatory T cells or Treg
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K39/46
- A61K2239/10—Indexing codes associated with cellular immunotherapy of group A61K39/46 characterized by the structure of the chimeric antigen receptor [CAR]
- A61K2239/11—Antigen recognition domain
- A61K2239/13—Antibody-based
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K39/46
- A61K2239/10—Indexing codes associated with cellular immunotherapy of group A61K39/46 characterized by the structure of the chimeric antigen receptor [CAR]
- A61K2239/17—Hinge-spacer domain
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K39/46
- A61K2239/10—Indexing codes associated with cellular immunotherapy of group A61K39/46 characterized by the structure of the chimeric antigen receptor [CAR]
- A61K2239/21—Transmembrane domain
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
- C07K2317/565—Complementarity determining region [CDR]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
- C07K2317/62—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising only variable region components
- C07K2317/622—Single chain antibody (scFv)
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/01—Fusion polypeptide containing a localisation/targetting motif
- C07K2319/03—Fusion polypeptide containing a localisation/targetting motif containing a transmembrane segment
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/40—Fusion polypeptide containing a tag for immunodetection, or an epitope for immunisation
- C07K2319/41—Fusion polypeptide containing a tag for immunodetection, or an epitope for immunisation containing a Myc-tag
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Immunology (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Cell Biology (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Microbiology (AREA)
- Epidemiology (AREA)
- Mycology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Genetics & Genomics (AREA)
- Biomedical Technology (AREA)
- Zoology (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- Wood Science & Technology (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biophysics (AREA)
- Hematology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Transplantation (AREA)
- General Engineering & Computer Science (AREA)
- Gastroenterology & Hepatology (AREA)
- Toxicology (AREA)
- Oncology (AREA)
- Virology (AREA)
- Developmental Biology & Embryology (AREA)
- Peptides Or Proteins (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Abstract
抗体介导的排斥(ABMR)是成功移植(包括ABO血型不相容(ABOi)移植)的主要障碍之一。C4d沉积是ABMR的标志物,并且也见于大多数ABOi同种异体移植物组织中。本文描述了抑制ABOi同种异体移植物中的ABMR的抗C4d CAR Treg。通过将CAR逆转录病毒转导到CD62L+CD4+CD25+Treg中而制备的抗C4d CAR Treg以与未转导的Treg类似的程度表达Foxp3、CD25、CTLA‑4、LAP和GITR。抗C4d CAR Treg通过与C4d特异性结合而被活化,并抑制体外T细胞增殖以及未转导的Treg。此外,抗C4d CAR Treg的过继转移显著延长了小鼠ABOi心脏同种异体移植物的存活(P<0.05)。
Description
相关申请的交叉引用
本申请要求于2021年1月20日提交的美国临时申请号63/139,617的优先权,该美国临时申请在此通过引用以其整体被并入用于所有目的。
对作为ASCII文本文件提交的“序列表”的引用
本申请包含序列表,该序列表已经以ASCII格式以电子形式提交,并在此通过引用将其整体并入。创建于2022年1月19日的所述ASCII副本被命名为107568-1292165_SL.txt并且大小为39,541字节。
背景
已开发出ABO血型不相容(ABOi)移植来克服移植中供体器官短缺的严重问题。1,2然而,抗体介导的排斥(ABMR)仍然是成功的ABOi移植的主要限制。引入由血浆置换或利妥昔单抗(rituximab)免疫吸附和强效维持免疫抑制剂诸如他克莫司(tacrolimus)和吗替麦考酚酯组成的脱敏治疗可通过抑制ABMR来改善ABOi移植的结果;然而,这种强烈的非特异性免疫抑制也会增加感染并发症。3
调节性T细胞(Treg)可促进供体特异性移植耐受,同时具有比非特异性免疫抑制少得多的不利作用。4已经显示输注Treg抑制同种异体移植物排斥。4然而,抗原特异性Treg的数量非常低,并且Treg在输注后经常失去它们的活力和活性。最近,嵌合抗原受体(CAR)T细胞被开发出,并通过特异性靶向肿瘤抗原而显示出强烈的抗肿瘤作用。5与此同时,开发了CAR Treg来增强常规Treg的抗原特异性、活力和活性。6-8CAR的胞外结构域由抗体的单链可变片段(scFv)组成,以为Treg提供抗原特异性;并且它们的胞内结构域中还具有共刺激分子,以改善Treg的活力和活性。
补体活化经常参与ABMR,并且作为抗体介导的补体活化的副产物的补体成分4d(C4d)的沉积被包括在ABMR的诊断标准中。9有趣的是,在80-90%的ABOi移植病例中观察到C4d沉积,这是ABMR或调节(accommodation)的结果,其中发生抗体结合和随后的近端补体级联的活化而没有进一步的组织损伤。10-12
为了解决本领域中的上述问题,本文描述了可有效抑制ABMR和同种异体移植物排斥的组合物和方法。
概述
本文描述了可有效抑制ABMR和同种异体移植物排斥的组合物和方法。在一个方面,组合物包含遗传修饰的调节性T细胞(Treg),所述Treg包含特异性结合补体成分4d(C4d)的抗原结合蛋白。应当理解,本文所描述的遗传修饰的调节性T细胞在自然界中并不存在。
在一些实施方案中,抗原结合蛋白包含嵌合抗原受体(CAR)。在一些实施方案中,CAR包含特异性结合C4d的scFv。
在一些实施方案中,ABP、CAR或scFv包含:轻链可变区(VL)和重链可变区(VH),所述轻链可变区(VL)包含:
包含氨基酸序列SGSSGSYG的互补决定区(CDR)1,或其中1、2、3、4或5个氨基酸相对于所述序列被取代的变体LCDR1;
包含氨基酸序列YNDKRPS的LCDR2,或其中1、2、3、4或5个氨基酸相对于所述序列被取代的变体LCDR2;
包含氨基酸序列GSEDSSYVGV的LCDR3,或其中1、2、3、4或5个氨基酸相对于所述序列被取代的变体LCDR3;
所述重链可变区(VH)包含:
包含氨基酸序列SYALE的HCDR1,或其中1、2、3、4或5个氨基酸相对于所述序列被取代的变体HCDR1;
包含氨基酸序列GISSSGSGTNYGSAVKG的HCDR2,或其中1、2、3、4或5个氨基酸相对于所述序列被取代的变体HCDR2;
包含氨基酸序列AYGYVDAYGIDA的HCDR3,或其中1、2、3、4或5个氨基酸相对于所述序列被取代的变体HCDR3。
在一些实施方案中,VL包含与LTQPSSVSANPGGTVEITCSGSSGSYGWYQQKSPGSAPVTVIYYNDKRP SDIPSRFSGSKSGSTATLTITGVQAEDEAVYFCGSEDSSYVGVFGAGTTL TVL(SEQ ID NO:2)具有至少95%同一性的氨基酸序列;并且VH包含与AVTLDESGGGLQTPGGTLSLVCKGSGFTFRSYALEWVRQAPGKGLEYV AGISSSGSGTNYGSAVKGRATISRDNGQSTVRLQLNNLRAEDTGTYYCAKSAYGYVDAYGIDAWGHGTEVIVSSTS(SEQ ID NO:4)具有至少95%同一性的氨基酸序列。
在一些实施方案中,ABP、CAR或scFv包含:轻链可变区(VL)和重链可变区(VH),所述轻链可变区(VL)包含:
包含氨基酸序列SGGGRWYG的LCDR1,或其中1、2、3、4或5个氨基酸相对于所述序列被取代的变体LCDR1;
包含氨基酸序列HANTKRPS的LCDR2,或其中1、2、3、4或5个氨基酸相对于所述序列被取代的变体LCDR2;
包含氨基酸序列GSGDSSTDSGI的LCDR3,或其中1、2、3、4或5个氨基酸相对于所述序列被取代的变体LCDR3;
所述重链可变区(VH)包含:
包含氨基酸序列DRAMH的HCDR1,或其中1、2、3、4或5个氨基酸相对于所述序列被取代的变体HCDR1;
包含氨基酸序列GIYSSGRYTGYGSAVKG的HCDR2,或其中1、2、3、4或5个氨基酸相对于所述序列被取代的变体HCDR2;
包含氨基酸序列AGSIYCGYADVACIDA的HCDR3,或其中1、2、3、4或5个氨基酸相对于所述序列被取代的变体HCDR3。
在一些实施方案中,VL包含与LTQPSSVSANPGETVKITCSGGGRWYGWYQQKSPGSAPVTLIHANTKR PSNIPSRFSGSLSGSTSTLTISGVQAEDEAVYFCGSGDSSTDSGIFGAGTT LTVL(SEQ ID NO:6)具有至少95%同一性的氨基酸序列;并且VH包含与AVTLDESGGGLQTPGGALSLVCKASGFSFSDRAMHWVRQAPGKGLEW VAGIYSSGRYTGYGSAVKGRATISRDNGQSTVRLQLNNLRAEDTGTYY CAKAGSIYCGYADVACIDAWGHGTEVIVSSTS(SEQ ID NO:8)具有至少95%同一性的氨基酸序列。
在一些实施方案中,ABP、CAR或scFv包含:轻链可变区(VL)和重链可变区(VH),所述轻链可变区(VL)包含:
包含氨基酸序列SGGGSYYG的LCDR1,或其中1、2、3、4或5个氨基酸相对于所述序列被取代的变体LCDR1;
包含氨基酸序列SNNKRPS的LCDR2,或其中1、2、3、4或5个氨基酸相对于所述序列被取代的变体LCDR2;
包含氨基酸序列GSYDSNAGI的LCDR3,或其中1、2、3、4或5个氨基酸相对于所述序列被取代的变体LCDR3;
所述重链可变区(VH)包含:
包含氨基酸序列SYAMG的HCDR1,或其中1、2、3、4或5个氨基酸相对于所述序列被取代的变体HCDR1;
包含氨基酸序列EISGSGTSTYYGPAVKG的HCDR2,或其中1、2、3、4或5个氨基酸相对于所述序列被取代的变体HCDR2;
包含氨基酸序列CTRGGGAGSYIDA的HCDR3,或其中1、2、3、4或5个氨基酸相对于所述序列被取代的变体HCDR3。
在本文所描述的任何实施方案中,CDR氨基酸序列相对于所述及的序列可包含一个或更多个保守氨基酸取代。例如,在本文所描述的任何实施方案中,CDR氨基酸序列相对于所述及的序列可包含1、2、3、4或5个保守氨基酸取代。在一些实施方案中,保守氨基酸取代基本上不降低ABP、scFv或CAR与靶抗原(诸如小鼠或人C4d)的结合亲和力。
在一些实施方案中,VL包含与LTQPSSVSANPGETVEITCSGGGSYYGWYQQKSPGSAPVTVIYSNNKRPSDIPSRFSGSKSGSTSTLTITGVQADDEAVYYCGSYDSNAGIFGAGTTLTVL具有至少95%同一性的氨基酸序列;并且VH包含与AVTLDESGGGLQTPGGALSLVCKASGFTFSSYAMGWMRQAPGKGLDFVAEISGSGTSTYYGPAVKGRATISRDNGRSTVRLQLNNLRAEDTGTYFCTRGGGAGSYIDAWGHGTEVIVSSTS具有至少95%同一性的氨基酸序列。
在一些实施方案中,ABP、CAR或scFv包含与SEQ ID NO:2或SEQ IDNO:6或LTQPSSVSANPGETVEITCSGGGSYYGWYQQKSPGSAPVTVIYSNNKRPSDIPSRFSGSKSGSTSTLTITGVQADDEAVYYCGSYDSNAGIFGAGTTLTVL具有至少80%序列同一性的轻链氨基酸序列。
在一些实施方案中,ABP、CAR或scFv包含与SEQ ID NO:4或SEQ IDNO:8或AVTLDESGGGLQTPGGALSLVCKASGFTFSSYAMGWMRQAPGKGLDFVAEISGSGTSTYYGPAVKGRATISRDNGRSTVRLQLNNLRAEDTGTYFCTRGGGAGSYIDAWGHGTEVIVSSTS具有至少80%序列同一性的重链氨基酸序列。
在一些实施方案中,scFv包含与以下具有至少80%序列同一性的氨基酸序列:
i)
ii)
或
iii)
在一些实施方案中,CAR包含前导序列。在一些实施方案中,CAR包含铰链区,诸如人CD8铰链区。在一些实施方案中,铰链区包含SEQ ID NO:10的氨基酸序列或与SEQ ID NO:10具有至少80%同一性的序列。
在一些实施方案中,CAR包含CD28跨膜结构域。在一些实施方案中,CAR包含CD28胞质结构域。在一些实施方案中,CAR包含CD28跨膜和胞质结构域。在一些实施方案中,CD28跨膜和胞质结构域包含SEQ ID NO:12的氨基酸序列或与SEQ ID NO:12具有至少80%同一性的序列。
在一些实施方案中,CAR包含CD3ζ胞质结构域。在一些实施方案中,CD3ζ胞质结构域包含SEQ ID NO:14的氨基酸序列或与SEQ ID NO:14具有至少80%同一性的序列。
在一些实施方案中,CAR包含c-myc标签。
在另一方面,提供一种调节性T细胞,所述调节性T细胞包含编码本文所描述的抗原结合蛋白、CAR或scFV的核酸。
在另一方面,提供一种载体,所述载体包含编码本文所描述的抗原结合蛋白、CAR或scFv的核酸。在一些实施方案中,载体是逆转录病毒载体。
在另一方面,提供一种细胞,所述细胞包含本文所描述的核酸或载体。在一些实施方案中,细胞是哺乳动物细胞或细胞系。在一些实施方案中,细胞是免疫细胞,诸如T细胞。在一些实施方案中,细胞是调节性T细胞。
在另一方面,描述了一种用于产生调节性T细胞的方法,所述方法包括用包含编码本文所描述的抗原结合蛋白的核酸序列的核酸或载体转染或转导调节性T细胞,以及选择表达抗原结合蛋白的Treg。在一些实施方案中,抗原结合蛋白包含嵌合抗原受体(CAR)。在一些实施方案中,CAR包含特异性结合C4d的scFv。
在另一方面,描述了一种用于诱导免疫应答的体外方法,所述方法包括使本文所描述的遗传修饰的调节性T细胞与C4d抗原接触。在一些实施方案中,使本文所描述的遗传修饰的调节性T细胞与C4d抗原接触的步骤导致抑制免疫应答的细胞表面分子和/或细胞因子的表达。在一些实施方案中,在与C4d抗原接触后,与不表达特异性结合C4d的抗原结合蛋白的对照调节性T细胞相比,调节性T细胞上调CD69表达并分泌增加水平的IL-10和IFN-γ。
在另一方面,描述了一种用于抑制T细胞增殖的体外方法,所述方法包括将本文所描述的遗传修饰的调节性T细胞与活化的效应T细胞一起培养,以及确定效应T细胞的增殖的减少。
在另一方面,描述了一种用于在受试者中抑制抗体介导的排斥(ABMR)的方法,所述方法包括向受试者施用治疗有效量的本文所描述的遗传修饰的调节性T细胞。在一些实施方案中,受试者先前已接受移植物。在一些实施方案中,受试者同时地(concurrently)接收移植物。在一些实施方案中,移植物是同种异体移植物。在一些实施方案中,同种异体移植物是ABO血型不相容(ABOi)同种异体移植物。在一些实施方案中,同种异体移植物是心脏同种异体移植物。
附图简述
图1A-图1B.抗C4d CAR的产生。图1A.通过流式细胞术分析测量抗C4d scFv克隆(SC-8-Cκ、BF-2-Cκ)和对照scFv克隆(帕利珠单抗(palivizumab)-Cκ)与小鼠C4d+Raji细胞的结合亲和力。图1B.抗C4d CAR、对照CAR和抗C4d CAR Treg的结构。CAR,嵌合抗原受体;C4d,补体成分4d;Cyt,胞质结构域;LS,前导序列;mC4d,小鼠补体成分4d;Myc,myc标签;scFv,单链可变片段;TM,跨膜结构域;Treg,调节性T细胞;VH,重链可变区;VL,轻链可变区。
图2A、图2B和图2C.抗C4d CAR Treg的生成和表型。图2A.抗C4d CAR Treg的生成方案。将分选的CD62L+CD4+CD25+Treg用含有抗C4d CAR或对照CAR的逆转录病毒转导,并且然后在IL-2和雷帕霉素(rapamycin)存在下,用抗CD3/CD28珠粒刺激。图2B.在第13天完成生成后,通过流式细胞术测量与NT Treg相比,CAR Treg中Foxp3和myc的表达以及活力(7-AAD)。图2C.与对照CAR Treg和NT Treg中Foxp3、CD25、CTLA-4、LAP和GITR的表达相比,抗C4d CAR Treg中Foxp3、CD25、CTLA-4、LAP和GITR的表达。缩写:CAR Treg,嵌合抗原受体调节性T细胞;CTLA-4,细胞毒性T淋巴细胞相关蛋白4;Foxp3,叉头框(forkhead box)P3;GITR,糖皮质激素诱导的肿瘤坏死因子受体相关蛋白;IL-2,白细胞介素-2;LAP,潜伏相关肽;NT,未转导。
图3A、图3B和图3C.抗C4d CAR Treg与C4d的特异性结合和体外免疫抑制活性。图3A.抗C4d CAR Treg与C4d的特异性结合。**,与抗C4d CAR Treg组相比,P<0.01(学生t检验(Student’s t test))。图3B.通过抗C4d CAR Treg响应与Raji细胞上C4d的结合而活化的CD69表达以及IL-10和IFN-γ的分泌。**,与抗C4d CAR Treg组相比,P<0.01(学生t检验)。图3C.抗C4d CAR Treg针对T细胞增殖的体外免疫抑制活性。将T细胞增殖通过CTV标记的T细胞的直方图展示并计算为分裂指数。**,与单独的效应T细胞相比,P<0.01;##,与NT Treg组相比,P<0.01(学生t检验)。每组N=3。条形图中的每个值指示平均值(mean)和平均值的标准误差。CAR Treg,嵌合抗原受体调节性T细胞;CTV,Cell Trace Violet;IFN-γ,干扰素-γ;IL-10,白细胞介素-10;MFI,平均荧光强度;NT,未转导;Tresp,应答T细胞。
图4A、图4B、图4C和图4D.抗C4d CAR Treg针对ABOi心脏移植中同种异体移植物排斥的免疫抑制活性。图4A.ABOi心脏移植和免疫抑制方案的总体方案。致敏的C57BL6/J小鼠在抗C4d CAR Treg、对照CAR Treg或NT Treg的过继转移后一天经历A-TG BALB/c心脏移植。通过流式细胞术分析测量抗A IgM和IgG的血清滴度。图4B.ABOi心脏移植中心脏同种异体移植物的存活率。*,与PBS组相比,P<0.01;#,与对照CAR Treg组相比,P<0.01(对数秩检验)。图4C.通过实时PCR测量心脏同种异体移植物中促炎细胞因子(IL-1β、IL-6和IFN-γ)的表达。条形图中的每个值指示平均值和平均值的标准误差。**,与PBS对照相比,P<0.01(学生t检验)。图4D.显示ABOi同种异体移植物损伤的H&E染色成像(放大倍数×200),和显示CD45.1+Myc+抗C4d CAR Treg浸润到C4d+ABOi心脏同种异体移植物组织中的IF成像合并视图(放大倍数×400)(C4d,绿色;CD45.1,红色;Myc,黄色;蓝色,DAPI)。ABOi,ABO不相容;A-TG,人血型A抗原转基因;CAR Treg,嵌合抗原受体调节性T细胞;DAPI,4,6-二脒基-2-苯基吲哚;H&E,苏木精和伊红;IF,免疫荧光染色;IL,白细胞介素;IFN-γ,干扰素-γ;NT,未转导;PCR,聚合酶链式反应;WT,野生型。
图5A显示用于在包含L细胞的培养物中通过多克隆刺激扩增调节性T细胞的代表性方案。图5B显示比较抗C4d CAR Treg细胞与对照细胞的存活曲线。数据如图4A-图4D中所描述的生成。
图6A和图6B显示用于生成抗人C4d CAR调节性T细胞(抗人C4dCAR-Treg)的代表性方案。图6A显示分离人调节性T细胞的代表性门控策略。图6B显示用对照和抗人C4d CAR转导的调节性T细胞表达的代表性标志物。
图7显示用于在包含K562细胞的培养物中通过多克隆刺激生成抗人C4d CAR调节性T细胞(抗人C4d CAR-Treg)的代表性方案。
术语
除非本文另外指明或者上下文明显矛盾,否则在描述所公开的实施方案的上下文中(尤其在所附权利要求书的上下文中)所用术语“一(a和an)”和“所述/该”以及类似指示物应当理解为涵盖单数与复数二者。除非另有说明,否则术语“包含”、“具有”、“包括”和“含有”应当理解为开放式术语(即,意指“包括但不限于”)。术语“或”应理解为意指所述及的替代方案中的任一种、两种或其任何组合。除非本文另外指明,否则本文述及的值的范围仅仅意在作为单独提及落在该范围内的每个单独值(包括该范围的端点)的简化方法,并且每个单独值都被并入本说明书中,就如同其在本文中被单独述及一样。除非本文另有指明或上下文明显矛盾,否则,本文所描述的所有方法都可按任何合适的顺序进行。除非另外要求,否则,使用本文所提供的任何和所有实例或示例性用语(例如,“诸如”)仅仅意在用于更好地阐明本公开内容的实施方案,而并不对本公开内容的范围构成限制。本说明书中的任何用语都不应当理解为表明任何未要求保护的要素对于本公开内容的实践是必不可少的。
如本文所用的,术语“调节性T细胞”(“Treg”)是指调节或抑制免疫系统中其他细胞功能的T细胞。例如,Treg抑制CD4+T细胞和CD8+T细胞的活化、增殖和细胞因子产生,并且还可抑制B细胞和树突细胞。Treg可产生具有抑制功能的可溶性信使,包括TGF-β、IL-10和腺苷。Treg通常表达细胞表面标志物CD4(T细胞共受体)和CD25,以及还有核转录因子叉头框P3(FoxP3)。参见因特网immunology.org/public-information/bitesized-immunology/cells/regulatory-t-cells-tregs。
如本文所用的,术语“抗原结合蛋白”(ABP)是指特异性结合靶抗原的蛋白,并且包括本文所描述的抗体、scFv和CAR。术语“抗原结合结构域”是指抗原结合蛋白中特异性结合靶抗原的部分。
如本文所用的,术语“抗体”是指特异性结合靶抗原的免疫球蛋白(Ig)分子或其形式片段。该术语包括单克隆抗体以及IgA、IgD、IgE、IgG和IgM同种型和亚型。该术语还包括抗原结合片段或其形式,诸如Fab(抗原结合片段)、Fv(可变结构域)、scFv(单链可变片段)、二硫键稳定的scFv(ds-scFv)、单链Fab(scFab)、二聚和多聚抗体形式如二体、三体和四体、包含连接到寡聚结构域的scFv的微型抗体(miniAb)、骆驼科重链Ab的VHH/VH和单结构域Ab(sdAb)。该术语还包括抗体或其抗原结合片段的融合蛋白,诸如scFv-轻链融合蛋白或scFv-Fc融合蛋白。该术语还包括抗体或其抗原结合片段,其包含Fc结构域以提供效应子功能,诸如抗体依赖性细胞介导的细胞毒性(ADCC)和补体依赖性细胞毒性(CDC)。
术语“人源化”是指来自非人物种的被修饰为包含人氨基酸序列的抗原结合蛋白或其抗原结合片段或形式。人源化的ABP可包含当将ABP施用于人时降低潜在免疫原性的序列。例如,人源化的ABP可包含来自非人物种的互补决定区(CDR)和来自人抗体的抗体框架或支架区。
如本文所用的,术语“特异性结合”是指与对照或非特异性抗原结合蛋白的结合相比,抗原结合蛋白与其关联(cognate)靶抗原之间的强度或结合亲和力。亲和力是指单个分子与其配体结合的强度,并且通常通过平衡解离常数(KD)来确定。KD是解离速率(koff)(ABP从其抗原解离的快速程度)与缔合速率(kon)(ABP与其抗原结合的快速程度)的比率。KD值可通过测量特定ABP或抗体/抗原相互作用的kon和koff速率且接着使用这些值的比率计算KD值来确定。特异性结合靶抗原的抗体通常具有低微摩尔(10-6)到皮摩尔(10-12)范围内的KD值。高亲和力抗体通常具有低纳摩尔范围(10-9)内的KD,而非常高亲和力的抗体可具有皮摩尔(10-12)范围内的KD。
如本文所用的,提及核酸或氨基酸序列的术语“基本相同”是指当在比较窗口或指定区域进行比较和比对以获得最大对应性时,在指定区域上具有至少约30%至至少约99.9%序列同一性(例如,至少约30%、至少约40%、至少约50%、至少约60%、至少约65%、至少约70%、至少约75%、至少约80%、至少约85%、至少约90%、至少约91%、至少约92%、至少约93%、至少约94%、至少约95%、至少约96%、至少约97%、至少约98%、至少约99%、至少约99.5%或至少约99.9%序列同一性)的两个序列,如使用序列比较算法或通过手工比对和目视检查所测量的。术语“基本相同”还包括小于100%相同的序列,例如具有30%、40%、50%、60%、65%、70%、75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、99.5%或99.9%序列同一性的序列。在一些实施方案中,当氨基酸序列具有至少约30%、至少约40%、至少约50%、至少约60%、至少约65%、至少约70%、至少约75%、至少约80%、至少约85%、至少约90%、至少约91%、至少约92%、至少约93%、至少约94%、至少约95%、至少约96%、至少约97%、至少约98%、至少约99%、至少约99.5%或至少约99.9%序列同一性时,两种蛋白(或蛋白的区域)基本相同。在一些实施方案中,当氨基酸序列具有约30%、约40%、约50%、约60%、约65%、约70%、约75%、约80%、约85%、约90%、约91%、约92%、约93%、约94%、约95%、约96%、约97%、约98%、约99%、约99.5%或约99.9%序列同一性时,两种蛋白(或蛋白的区域)基本相同。在一些实施方案中,当氨基酸序列具有大于30%的同一性但小于100%的同一性,例如具有30%、40%、50%、60%、65%、70%、75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、99.5%或99.9%序列同一性时,两种蛋白(或蛋白的区域)基本相同。在一些实施方案中,当两个核酸序列具有至少约30%、至少约40%、至少约50%、至少约60%、至少约65%、至少约70%、至少约75%、至少约80%、至少约85%、至少约90%、至少约91%、至少约92%、至少约93%、至少约94%、至少约95%、至少约96%、至少约97%、至少约98%、至少约99%、至少约99.5%或至少约99.9%序列同一性时,所述核酸序列基本相同。在一些实施方案中,当两个核酸序列具有约30%、约40%、约50%、约60%、约65%、约70%、约75%、约80%、约85%、约90%、约91%、约92%、约93%、约94%、约95%、约96%、约97%、约98%、约99%、约99.5%或约99.9%序列同一性时,所述核酸序列基本相同。在一些实施方案中,当两个核酸序列具有大于30%的同一性但小于100%的同一性,例如具有30%、40%、50%、60%、65%、70%、75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、99.5%或99.9%序列同一性时,所述核酸序列基本相同。为了确定两个氨基酸序列或两个核酸序列的同一性百分比,出于最佳比较的目的将序列进行比对(例如,可在第一和第二氨基酸或核酸序列的一个或两个中引入空位以获得最佳比对,并且出于比较目的可忽略非同源序列)。在一个实施方案中,出于比较目的比对的参考序列的长度是该参考序列长度的至少30%、至少40%、至少50%、至少60%或至少70%、80%、90%、100%。然后比较对应氨基酸位置或核苷酸位置处的氨基酸残基或核苷酸。当第一序列中的位置与第二序列中的对应位置被相同的氨基酸残基或核苷酸占据时,分子在该位置是相同的(如本文所用的,氨基酸或核酸“同一性”等同于氨基酸或核酸“同源性”)。两个序列之间的同一性百分比随所述序列共享的相同位置的数目而变化,考虑了为了所述两个序列的最佳比对而需要引入的空位数目和每个空位的长度。BLAST计算机程序可用于比对和确定核酸和氨基酸序列之间的序列同一性百分比。
“保守氨基酸取代”是其中一个氨基酸残基被具有化学性质(例如电荷或疏水性)相似的侧链(R基团)的另一氨基酸残基取代的取代。通常,保守氨基酸取代将基本上不改变蛋白的功能性质。在两个或更多个氨基酸序列因保守取代而彼此不同的情况下,可向上调整序列同一性百分比或同源性程度,以校正取代的保守性质。进行这种调整的手段是本领域技术人员熟知的(参见例如Pearson W.R.,1994,Methods in Mol Biol 25:365-89)。
以下六组各自含有彼此为保守取代的氨基酸:1)丝氨酸(S)、苏氨酸(T);2)天冬氨酸(D)、谷氨酸(E);3)天冬酰胺(N)、谷氨酰胺(Q);4)精氨酸(R)、赖氨酸(K);5)异亮氨酸(I)、亮氨酸(L)、丙氨酸(A)、缬氨酸(V)和6)苯丙氨酸(F)、酪氨酸(Y)、色氨酸(W)。
术语“受试者”是指动物,例如哺乳动物,包括但不限于人,啮齿动物,诸如小鼠或大鼠,伴侣动物,诸如狗或猫,以及家畜,诸如牛、马和绵羊。术语受试者也可与术语“患者”互换使用。
如本文所用的,术语“可操作地连接”是指核酸启动子和/或调控序列与蛋白编码序列之间的功能性连接,使得连接的启动子和/或调控序列功能性地控制蛋白编码序列的表达。
当修饰本文所描述的数值或值的范围时,术语“约”包括涵盖本领域中的正常变化和实验误差的值,并且可包括所列举的值或范围的+/-10%,诸如所列举的值或范围的+/-1%、+/-2%、+/-3%、+/-4%、+/-5%、+/-6%、+/-7%、+/-8%、+/-9%或+/-10%。
术语“互补决定区”(CDR)是指位于抗体的可变区或结构域内的结合特定抗原的氨基酸序列。CDR描述于以下文献中:Kabat et al.,J.Biol.Chem.252:6609-6616(1977);Kabat et al.,U.S.Dept.of Health and Human Services,“Sequences of proteins ofimmunological interest”(1991);Al-Lazikani,B.;Lesk,A.M.;Chothia,C.(1997)."Standard conformations for the canonical structures of immunoglobulins".Journal of Molecular Biology.273(4):927-948;和North,B.;Lehmann,A.;DunbrackJr,R.L.(2011)."ANew Clustering of Antibody CDR Loop Conformations".Journal ofMolecular Biology.406(2):228-256。如本领域充分理解的,在每个可变区(即轻链可变区(VL)和重链可变区(VH))的氨基酸序列中存在三个非连续CDR(CDR1、CDR2和CDR3)。VL中的CDR被称为LCDR1、LCDR2和LCDR3。VH中的CDR被称为HCDR1、HCDR2和HCDR3。
术语“遗传修饰的调节性T细胞”是指已用外源核酸序列或包含外源核酸序列的载体转染或转导的Treg细胞。该术语包括表达本文所描述的抗C4d ABP、抗C4d scFv或抗C4dCAR的Treg细胞。
详述
本文描述了可用于抑制ABMR和同种异体移植物排斥的组合物,以及制备和使用所述组合物的方法。在一个方面,组合物包含表达特异性结合补体成分4d(C4d)的抗原结合蛋白的遗传修饰的调节性T细胞(Treg)(抗C4d Treg)。遗传修饰的抗C4d Treg提供了以下意想不到的优点。首先,当施用于受试者时,它们有效抑制ABMR和同种异体移植物排斥。其次,它们有效抑制体外T细胞增殖以及未转导的Treg的增殖。第三,抗C4dTreg的过继转移显著延长了小鼠模型中的心脏同种异体移植物存活。因此,抗C4d Treg代表用于控制ABMR(包括与ABOi同种异体移植物相关的排斥)的有前景的治疗剂。
特异性结合补体成分4d(C4d)的调节性T细胞(Treg).
在一个方面,本文描述了可特异性结合补体成分4d(C4d)的遗传修饰的Treg。在一些实施方案中,修饰的Treg表达特异性结合C4d或其抗原性片段的抗原结合蛋白(ABP)。在一些实施方案中,修饰的Treg表达特异性结合哺乳动物C4d或其抗原性片段的抗原结合蛋白(ABP)。在一些实施方案中,修饰的Treg表达特异性结合啮齿动物(例如,大鼠或小鼠)C4d或其抗原性片段的抗原结合蛋白(ABP)。在一些实施方案中,修饰的Treg表达特异性结合人C4d或其抗原性片段的抗原结合蛋白(ABP)。在本文所描述的任何实施方案中,修饰的Treg表达特异性结合C4d-Fc融合蛋白(诸如C4d-人Fc融合蛋白)的抗原结合蛋白(ABP)。
在一些实施方案中,ABP是抗体或其抗原结合形式。在一些实施方案中,ABP是嵌合或人源化抗体或其抗原结合片段或形式。在一些实施方案中,ABP是单链可变片段(scFv)。在一些实施方案中,ABP是嵌合抗原受体(CAR)。
在一些实施方案中,CAR包含以下元件中的一种或更多种:(i)结合C4d的抗体(抗C4d抗体);(ii)铰链区;(iii)跨膜结构域;(iv)胞质结构域;和/或(v)前导序列,或它们的组合。在一些实施方案中,CAR从氨基末端开始按以下顺序包含元件:(i)前导序列;(ii)抗C4d抗体;(iii)铰链区;(iv)跨膜结构域;和(v)胞质结构域。胞质结构域含有负责T细胞活化的氨基酸序列。
在本文所描述的任何实施方案中,抗C4d抗体是特异性结合C4d的scFv。在一些实施方案中,scFv包含来自哺乳动物(诸如人或小鼠)或来自鸟纲(Aves)物种(诸如鸡)的重链和/或轻链序列。在一些实施方案中,抗C4d抗体或抗C4d scFv包含嵌合或人源化序列。在一些实施方案中,抗C4d抗体包括嵌合或人源化C4d抗体或其抗原结合片段或形式。在一些实施方案中,抗C4d抗体或scFv的轻链可变区包含与SEQ ID NO:2或SEQ ID NO:6基本相同的氨基酸序列。在一些实施方案中,抗C4d抗体或scFv的轻链可变区包含SEQ ID NO:2或SEQID NO:6。在一些实施方案中,抗C4d抗体或scFv的重链可变区包含与SEQ ID NO:4或SEQ IDNO:8基本相同的氨基酸序列。在一些实施方案中,抗C4d抗体或scFv的重链可变区包含SEQID NO:4或SEQ ID NO:8。
在一些实施方案中,抗C4d抗体或抗C4d scFv结合哺乳动物C4d,包括但不限于啮齿动物(例如,大鼠或小鼠)或人C4d或其抗原性片段。在一些实施方案中,抗C4d抗体或抗C4d scFv结合C4d-Fc融合蛋白。
在一些实施方案中,铰链区是人CD8铰链区。在一些实施方案中,铰链区包含与SEQID NO:10基本相同的氨基酸序列。在一些实施方案中,铰链区包含SEQ ID NO:10。
在一些实施方案中,跨膜结构域包括CD28跨膜结构域。在一些实施方案中,跨膜结构域包括小鼠CD28跨膜结构域。
在一些实施方案中,CAR包含胞质结构域,所述胞质结构域包含选自CD28、CD27、4-1BB或OX40的共刺激结构域。在一些实施方案中,胞质结构域包含CD28共刺激信号传导结构域。在一些实施方案中,胞质结构域包含小鼠CD28共刺激信号传导结构域。
在一些实施方案中,CAR包含CD28跨膜和/或CD28胞质结构域。在一些实施方案中,CAR包含小鼠CD28跨膜和/或小鼠CD28胞质结构域。在一些实施方案中,CD28跨膜和胞质结构域包含与SEQ ID NO:12基本相同的氨基酸序列。在一些实施方案中,CD28跨膜和胞质结构域包含SEQ ID NO:12。
在一些实施方案中,胞质结构域包括CD3ζ(CD3zeta)胞质结构域。在一些实施方案中,胞质结构域包括人CD3ζ胞质结构域。在一些实施方案中,人CD3ζ胞质结构域包含与SEQID NO:22基本相同的氨基酸序列。在一些实施方案中,人CD3ζ胞质结构域包含SEQ ID NO:22。在一些实施方案中,胞质结构域包括小鼠CD3ζ胞质结构域。在一些实施方案中,小鼠CD3ζ胞质结构域包含与SEQ ID NO:14基本相同的氨基酸序列。在一些实施方案中,小鼠CD3ζ胞质结构域包含SEQ ID NO:14。
在一些实施方案中,胞质结构域包含一个或更多个基于免疫受体酪氨酸的活化基序(ITAM)序列。
在一些实施方案中,胞质结构域包含融合蛋白,所述融合蛋白包含CD28共刺激信号传导结构域和CD3ζ胞质结构域。在一些实施方案中,胞质结构域包含融合蛋白,所述融合蛋白包含小鼠CD28共刺激信号传导结构域和人CD3ζ胞质结构域。在一些实施方案中,胞质结构域包含融合蛋白,所述融合蛋白包含小鼠CD28共刺激信号传导结构域和小鼠CD3ζ胞质结构域。
在一些实施方案中,CAR包含CD28胞外结构域、CD28跨膜结构域和/或CD28胞质结构域或其组合。在一些实施方案中,CAR包含小鼠CD28胞外结构域、小鼠CD28跨膜结构域和/或小鼠CD28胞质结构域或其组合。在一些实施方案中,CAR包含小鼠CD28胞外结构域、小鼠CD28跨膜结构域和小鼠CD28胞质结构域,所述小鼠CD28胞外结构域、小鼠CD28跨膜结构域和小鼠CD28胞质结构域具有与SEQ ID NO:20基本相同的氨基酸序列。在一些实施方案中,CAR包含CD28胞外结构域、CD28跨膜结构域和CD28胞质结构域,所述CD28胞外结构域、CD28跨膜结构域和CD28胞质结构域具有包含SEQ ID NO:20的氨基酸序列。
在一些实施方案中,CAR包含融合蛋白,所述融合蛋白包含CD28胞外结构域、CD28跨膜结构域、CD28胞质结构域和CD3ζ胞质结构域。在一些实施方案中,CAR包含融合蛋白,所述融合蛋白包含小鼠CD28胞外结构域、小鼠CD28跨膜结构域、小鼠CD28胞质结构域和/或小鼠CD3ζ胞质结构域或其组合。在一些实施方案中,CAR包含融合蛋白,所述融合蛋白包含小鼠CD28胞外结构域、小鼠CD28跨膜结构域、小鼠CD28胞质结构域和小鼠CD3ζ胞质结构域,所述小鼠CD28胞外结构域、小鼠CD28跨膜结构域、小鼠CD28胞质结构域和小鼠CD3ζ胞质结构域具有与SEQ ID NO:24基本相同的氨基酸序列。在一些实施方案中,CAR包含融合蛋白,所述融合蛋白包含CD28胞外结构域、CD28跨膜结构域、CD28胞质结构域和CD3ζ胞质结构域,所述CD28胞外结构域、CD28跨膜结构域、CD28胞质结构域和CD3ζ胞质结构域具有包含SEQ IDNO:24的氨基酸序列。
在一些实施方案中,CAR还包含氨基酸标签,诸如可用于分选和选择用CAR转染的细胞的c-myc标签。在一些实施方案中,标签位于抗C4d抗体和CAR的铰链区之间。在一些实施方案中,标签包含与SEQ ID NO:26基本相同的氨基酸序列。在一些实施方案中,标签包含SEQ ID NO:26的氨基酸序列。
在一些实施方案中,CAR包含与SEQ ID NO:16或SEQ ID NO:18基本相同的氨基酸序列。在一些实施方案中,CAR包含SEQ ID NO:16或SEQ ID NO:18的氨基酸序列。
在一些实施方案中,遗传修饰的调节性T细胞表达标志物CD62L、CD4和CD25。在一些实施方案中,遗传修饰的调节性T细胞表达抗C4dABP或CAR,并且还以与对照(例如,未转导的)或天然调节性T细胞类似的水平表达Foxp3、CD25、CTLA-4、LAP和GITR。
核酸
还描述了编码本文所描述的抗原结合蛋白的一种或更多种组分的核酸分子和/或核酸序列。在一些实施方案中,核酸分子包含编码本文所描述的CAR的一种或更多种组分的核酸序列。例如,在一些实施方案中,核酸分子包含编码以下的序列:(i)前导序列;(ii)抗C4d抗体;(iii)铰链区;(iv)跨膜结构域;和/或(v)胞质结构域。
在一些实施方案中,核酸序列编码抗C4d抗体。在一些实施方案中,核酸序列编码特异性结合C4d的抗C4d scFv。在一些实施方案中,核酸序列编码抗C4d抗体或scFv的轻链可变区。在一些实施方案中,编码抗C4d抗体或scFv的轻链可变区的核酸分子包含与SEQ IDNO:1或SEQ ID NO:5基本相同的核酸序列。在一些实施方案中,编码抗C4d抗体或scFv的轻链可变区的核酸分子包含SEQ ID NO:1或SEQ ID NO:5的核酸序列。
在一些实施方案中,核酸序列编码抗C4d抗体或scFv的重链可变区。在一些实施方案中,编码抗C4d抗体或scFv的重链可变区的核酸分子包含与SEQ ID NO:3或SEQ ID NO:7基本相同的核酸序列。在一些实施方案中,编码抗C4d抗体或scFv的重链可变区的核酸分子包含SEQ ID NO:3或SEQ ID NO:7的核酸序列。
在一些实施方案中,核酸序列编码铰链区。在一些实施方案中,核酸序列编码人CD8铰链区。在一些实施方案中,编码铰链区的核酸分子包含与SEQ ID NO:9基本相同的核酸序列。在一些实施方案中,编码铰链区的核酸分子包含SEQ ID NO:9的核酸序列。
在一些实施方案中,核酸序列编码跨膜结构域。在一些实施方案中,核酸序列编码CD28跨膜结构域。在一些实施方案中,核酸序列编码CD28跨膜和胞质结构域。在一些实施方案中,核酸序列编码小鼠CD28跨膜和胞质结构域。在一些实施方案中,编码跨膜和胞质结构域的核酸分子包含与SEQ ID NO:11基本相同的核酸序列。在一些实施方案中,编码跨膜结构域的核酸分子包含SEQ ID NO:11的核酸序列。
在一些实施方案中,核酸序列编码CD28胞外结构域、CD28跨膜结构域和/或CD28胞质结构域或其组合。在一些实施方案中,核酸序列编码小鼠CD28胞外结构域、小鼠CD28跨膜结构域和/或小鼠CD28胞质结构域或其组合。在一些实施方案中,编码小鼠CD28胞外结构域、小鼠CD28跨膜结构域和小鼠CD28胞质结构域的核酸序列包含与SEQ ID NO:19基本相同的核酸序列。在一些实施方案中,编码小鼠CD28胞外结构域、小鼠CD28跨膜结构域和小鼠CD28胞质结构域的核酸序列包含SEQ ID NO:19。
在一些实施方案中,核酸序列编码CD3ζ(CD3zeta)胞质结构域。在一些实施方案中,核酸序列编码人CD3ζ胞质结构域。在一些实施方案中,编码人CD3ζ胞质结构域的核酸序列包含与SEQ ID NO:21基本相同的核酸序列。在一些实施方案中,编码人CD3ζ胞质结构域的核酸序列包含SEQ ID NO:21。在一些实施方案中,核酸序列编码小鼠CD3ζ胞质结构域。在一些实施方案中,编码小鼠CD3ζ胞质结构域的核酸序列包含与SEQ ID NO:14基本相同的核酸序列。在一些实施方案中,编码小鼠CD3ζ胞质结构域的核酸序列包含SEQ ID NO:14。
在一些实施方案中,核酸序列编码融合蛋白,所述融合蛋白包含CD28胞外结构域、CD28跨膜结构域、CD28胞质结构域和CD3ζ胞质结构域。在一些实施方案中,核酸序列编码融合蛋白,所述融合蛋白包含小鼠CD28胞外结构域、小鼠CD28跨膜结构域、小鼠CD28胞质结构域和/或小鼠CD3ζ胞质结构域。在一些实施方案中,编码包含小鼠CD28胞外结构域、小鼠CD28跨膜结构域、小鼠CD28胞质结构域和小鼠CD3ζ胞质结构域的融合蛋白的核酸包含与SEQ ID NO:23基本相同的核酸序列。在一些实施方案中,编码包含CD28胞外结构域、CD28跨膜结构域、CD28胞质结构域和CD3ζ胞质结构域的融合蛋白的核酸包含SEQ ID NO:23的核酸序列。
在一些实施方案中,核酸编码氨基酸标签,诸如可用于分选和选择用CAR转染的细胞的c-myc标签。在一些实施方案中,编码标签的核酸序列位于编码抗C4d抗体/scFv的核酸序列和编码CAR的铰链区的核酸序列之间。在一些实施方案中,编码标签的核酸包含与SEQID NO:25基本相同的核酸序列。在一些实施方案中,编码标签的核酸包含SEQ ID NO:25的核酸序列。
在一些实施方案中,编码CAR的核酸序列包含与SEQ ID NO:15或SEQ ID NO:17基本相同的核酸序列。在一些实施方案中,编码CAR的核酸序列包含SEQ ID NO:15或SEQ IDNO:17的核酸序列。
在本文所描述的任何实施方案中,核酸或氨基酸序列可包含所述及的SEQ ID NO或由所述及的SEQ ID NO组成。
载体
在一些方面,本公开内容提供了包含本文所描述的核酸序列的载体。载体可以在宿主细胞中自我复制,或者可以整合到宿主细胞的基因组中。在一些实施方案中,载体是逆转录病毒载体。在一些实施方案中,载体包含编码结合C4d的scFv的核酸序列。在一些实施方案中,载体包含编码scFv-Cκ融合蛋白的核酸序列。
在一些实施方案中,载体包含编码本文所描述的抗C4d CAR的一个或更多个元件的一个或更多个核酸序列。在一些实施方案中,载体包含编码抗C4d抗体、氨基酸标签、铰链区、跨膜区和/或胞质区的一个或更多个核酸序列。在一些实施方案中,载体包含编码抗C4d抗体的scFv形式、c-myc标签、人CD8铰链区、小鼠CD28跨膜区和胞质区以及人CD3ζ胞质区的一个或更多个核酸序列。
在一些实施方案中,载体是包含转录和/或翻译调控元件的表达载体,所述转录和/或翻译调控元件调控可操作地连接到所述转录和/或翻译调控元件的核酸序列的RNA和/或蛋白表达。在一些实施方案中,载体包含可操作地连接到本文所描述的核酸序列的启动子序列。在一些实施方案中,启动子是组成型启动子。在一些实施方案中,启动子是诱导型启动子。
用于产生修饰的调节性T细胞的方法
在另一方面,提供了用于产生本文所描述的修饰的Treg的方法。在一些实施方案中,所述方法包括用本文所描述的核酸或载体转染或转导调节性T细胞,其中核酸或载体包含编码本文所描述的抗C4d ABP的核酸序列。在一些实施方案中,核酸或载体包含编码本文所描述的抗C4d scFv的核酸序列。在转染或转导后,可以在允许由核酸序列编码的抗原结合蛋白的表达的条件下培养Treg。然后可以例如通过用结合抗C4d ABP的组分的抗体将Treg染色并通过流式细胞术或荧光激活细胞分选(FACS)对细胞进行分选,来选择表达抗C4d ABP的Treg。在一些实施方案中,可通过检测氨基酸标签(诸如c-myc标签)的表达来选择表达抗C4d ABP的Treg。
在一些实施方案中,将修饰的Treg与抗CD3和抗CD28抗体和细胞因子IL-2一起培养。在一些实施方案中,将修饰的Treg与抗CD3和抗CD28抗体、IL-2和雷帕霉素一起培养。
用于诱导免疫应答的方法
在另一方面,描述了用于诱导免疫应答的方法。在一些实施方案中,方法包括使表达抗C4d ABP的调节性T细胞与C4d抗原接触,以及确定是否产生免疫应答。在一些实施方案中,方法为体外方法,并且包括将表达抗C4d ABP的修饰的调节性T细胞与C4d抗原一起培养。在一些实施方案中,C4d抗原是可溶性C4d抗原。在一些实施方案中,C4d抗原是可溶性C4d抗原-人Fc融合蛋白。
在一些实施方案中,免疫应答包括与不表达抗C4d ABP的对照Treg(例如,未转导的Treg(NT Treg))或表达不相关的ABP(诸如含有帕利珠单抗(palivizumab)scFv的对照CAR)的Treg相比,修饰的调节性T细胞的增加的(上调的)CD69表达、增加的IL-10表达或分泌和/或增加的IFN-γ表达或分泌。
用于抑制T细胞增殖的方法
在另一方面,提供了用于抑制T细胞增殖的体外方法。在一些实施方案中,所述方法包括将表达抗C4d ABP的修饰的Treg与活化的效应T细胞(Teff)一起培养,以及确定效应T细胞的增殖和/或活化的减少。在一些实施方案中,用荧光示踪染料(诸如羧基荧光素琥珀酰亚胺酯(CFSE))标记效应T细胞,然后开始实验,并且当细胞随着时间推移被活化和分裂时,监测子细胞中染料的稀释。在一些实施方案中,将修饰的Treg用不同的荧光示踪染料(诸如CellTrace Violet染料(CTV))标记,以从靶Teff门中排除Treg细胞并监测来自相同共培养物的Treg中的同时变化。T细胞抑制测定描述于Zappasodi,R.et al.“In vitroassays for effector T cell functions and activity of immunomodulatoryantibodies.”Methods in enzymology vol.631(2020):43-59.doi:10.1016/bs.mie.2019.08.012中。
用于抑制抗体介导的排斥(ABMR)的方法
在另一方面,提供了用于抑制抗体介导的排斥的体内方法。在一些实施方案中,所述方法包括以有效减少或预防移植器官的排斥的量向具有器官移植物的受试者施用表达抗C4d ABP的调节性T细胞。在一些实施方案中,有效量包括向受试者施用约1×106至约1×109个表达抗C4d CAR的Treg细胞。在一些实施方案中,有效量包括向受试者施用约1×106/kg至约1×109/kg(体重)的表达抗C4d CAR的Treg细胞。
在一些实施方案中,移植物是同种异体移植物。在一些实施方案中,同种异体移植物是ABO血型不相容(ABOi)同种异体移植物。在一些实施方案中,同种异体移植物是心脏同种异体移植物。
在一些实施方案中,受试者是哺乳动物,诸如但不限于啮齿动物(例如,小鼠或大鼠)、牛、绵羊、马、猪、狗、猫或非人灵长类动物。在一些实施方案中,受试者是人。
实施例
实施例1
材料和方法
动物
C57BL/6J和CD45.1+同类系C57BL/6J小鼠购自杰克逊实验室(JacksonLaboratory)(Bar Harbor,ME,USA)。人血型A抗原转基因(A-TG)BALB/c小鼠由Peter Cowan(圣文森特医院('St Vincent's Hospital),澳大利亚墨尔本大学(University ofMelbourne,Australia))和Lori West(加拿大阿尔伯塔大学(University of Alberta,Canada))慷慨提供。13
组合scFv展示噬菌体文库的生成和生物淘选
用5μg重组小鼠C4d-Fc使用三个加强免疫来免疫四只白色来亨鸡(leghornchicken)。在免疫后,如先前所描述的合成cDNA。14用C4d-Cκ缀合的磁珠进行四轮生物淘洗。15从输出滴定板中随机选择scFv克隆以用于使用C4D-Cκ包被的微量滴定板(3690;CorningLife Sciences,Corning,NY,USA)进行噬菌体酶免疫测定。16由CosmoGenetech(Seoul,Korea)使用OmpSeq引物对与C4d-Cκ反应(A405>2.0)的克隆进行测序。17
scFv-Cκ融合蛋白的表达和纯化
构建pCEP4表达载体以编码scFv-Cκ融合蛋白。还将帕利珠单抗scFv克隆到载体中作为对照。15如先前所描述的,使用FectoPRO(Polyplus,Illkirch,France)将构建体转染到人胚肾-293F细胞(Invitrogen,Carlsbad,CA,USA)中并通过亲和色谱法纯化。18
逆转录病毒载体的构建和转染
为了构建逆转录病毒载体,通过Integrated DNA Technologies(Coralville,IA,USA)合成含有抗C4d抗体的scFv片段、c-myc标签、人CD8铰链区、小鼠CD28跨膜区和胞质区以及人CD3ζ胞质区的基因的质粒。将CAR构建体克隆在pMSCV-puro逆转录病毒载体(TakaraBio,Shiga Japan)的PGK启动子下游。详细的转染和逆转录病毒包装程序描述于A.1.补充方法中。
CAR Treg的生成
用DYNABEADSTM小鼠T-活化剂CD3/CD28(Thermo Fisher Scientific,Waltham,MA,USA)和白细胞介素(IL)-2(4,000IU,PROLEUKIN,Boehringer Ingelheim Pharma,Biberach/Riss,Germany)将分选的CD62L+CD4+CD25+T细胞刺激一天(图2A)。接下来,连续两天使用retronectin(Takara Bio)用逆转录病毒转导这些细胞。在IL-2和雷帕霉素(100nM,Sigma-Aldrich,St Louis,MO,USA)存在下,用抗CD3/CD28Dynabead刺激转导的Treg两轮。作为对照,除了病毒转导之外,以相同的方式刺激未转导的Treg(NT Treg)。
用于CAR Treg的结合和活化测定
为了评估CAR Treg与C4d的结合,将NT Treg、对照CAR Treg或抗C4d CAR Treg与C4d-人Fc一起培养2h,并且然后添加抗人Fc用于流式细胞术分析。对于活化测定,将C4d+Raji细胞与三组Treg共培养48小时。19分别通过流式细胞术和酶联免疫吸附测定(Biolegend,San Diego,CA,USA)测量Treg中CD69的表达以及IL-10和干扰素-γ(IFN-γ)的分泌。
体外抑制测定
在有或没有CD45.2+CAR Treg的情况下将用CTV(CELLTRACETM Violet细胞增殖试剂盒,Thermo Fisher Scientific)标记的脾CD45.1+CD4+T细胞用抗CD3/CD28 Dynabead以4:1的比例刺激3天。将T细胞增殖表示为分裂指数。20
心脏移植和免疫抑制方案
如先前所描述的,用人血型A抗原使野生型C57BL/6J小鼠致敏。21将来自A-TGBALB/c小鼠的心脏移植到致敏的C57BL/6J小鼠中。在移植前一天将CD45.1+NT、对照CAR或抗C4d CAR Treg(1×106)转移到接受者小鼠中。每天施用泼尼松龙(prednisolone)(Yuhan,Seoul,Korea)、他克莫司(Astellas Pharma,Tokyo,Japan)和雷帕霉素(Rapamune,Pfizer Pharmaceutical Korea,Seoul,Korea)。
流式细胞术分析
用于流式细胞术分析中的抗体描述于表A.1中。添加7-氨基放线菌素D(7-AAD;BDBiosciences,San Diego,CA,USA)以将死细胞染色。使用Attune NxT流式细胞仪(ThermoFisher Scientific)进行流式细胞术。使用FlowJo软件(Tree Star,Ashland,OR,USA)分析数据。
实时聚合酶链式反应
进行对心脏同种异体移植物组织的实时聚合酶链式反应;详细信息(包括所用的对应引物)描述于表A.2和A.1.补充方法中。将IL-1β、IL-6和IFN-γ基因的mRNA水平相对于甘油醛3-磷酸脱氢酶(Gapdh)的mRNA水平归一化,并表示为与磷酸盐缓冲盐水(PBS)组相比的相对表达。
组织学分析
对心脏同种异体移植物组织进行苏木精和伊红染色。还用4,6-二脒基-2-苯基吲哚(DAPI,Sigma-Aldrich)针对C4d、Myc和CD45.1进行免疫荧光染色。详细信息(包括用于该分析中的抗体)描述于A.1.补充方法中。
统计分析
数据显示为平均值±平均值的标准误差,并通过双尾学生t检验进行分析。通过对数秩检验分析移植物存活。P<0.05被认为是统计学显著的。使用GraphPad Prism(7.0版;GraphPad Software,La Jolla,CA,USA)进行所有分析。
结果和讨论
鸡免疫后从组合scFv展示噬菌体文库中筛选抗C4d抗体
通过利用生物淘选的scFv展示噬菌体文库进行噬菌体酶免疫测定,将若干反应性克隆鉴定为候选克隆。基于其结合活性和表达水平,选择对C4d显示出良好结合亲和力的两个克隆(SC-8、BF-2)和BF-2克隆用于进行进一步研究(图1A)。
抗C4d CAR逆转录病毒载体的构建
通过将抗C4d scFv克隆到第二代CAR结构中的CD8、CD28和CD3ζ的不同区域中来生成含有抗C4d CAR的逆转录病毒载体(图1B)。还构建了含有帕利珠单抗scFv的对照CAR载体(图1B)。
抗C4d CAR Treg的生成和表型
根据图2A中的方案生成抗C4d和对照CAR Treg。两种CAR Treg都表达CAR表达(Myc+),并且显示出良好的活力(7-AAD-)且保持叉头框P3(Foxp3)表达,而NT Treg不表达Myc(图2B)。两种CAR Treg以与NT Treg类似的程度表达Foxp3、CD25、细胞毒性T淋巴细胞相关蛋白4(CTLA-4)、潜伏相关肽(LAP)和糖皮质激素诱导的肿瘤坏死因子受体相关蛋白(GITR)(图2C),表明Treg中的免疫抑制功能相关分子在抗C4d CAR Treg中得到良好保持。
通过特异性结合C4d来活化抗C4d CAR Treg
可溶性C4d-人Fc成功地结合抗C4d CAR Treg,而它不结合对照CAR Treg或NTTreg(图3A)。此外,与对照CAR Treg和NT Treg两者相比,抗C4d CAR Treg响应C4d结合而上调CD69表达,并分泌多得多的IL-10和IFN-γ(P<0.01,图3B)。这些数据显示,抗C4d CARTreg可特异性结合C4d,并通过它们与C4d的结合而被活化。
抗C4d CAR Treg的体外免疫抑制活性
所有三组Treg均抑制T细胞增殖,尽管两种CAR Treg都具有比NT Treg略强的抑制作用(p<0.05,图3C)。这些结果表明,抗C4d CAR Treg是功能活性Treg,并表现出Treg的免疫抑制活性。
抗C4d CAR Treg针对ABOi心脏移植中心脏同种异体移植物排斥的抑制活性
图4A显示抗C4d CAR Treg针对ABOi心脏移植中ABMR的体内免疫抑制活性。致敏的接受者在移植前产生高滴度的抗A IgM和IgG(图4A)。与PBS对照和对照CAR Treg相比,抗C4d CAR Treg显著延长了ABOi心脏同种异体移植物存活率(P<0.05,图4B)。当比较心脏同种异体移植物中促炎细胞因子的表达时,抗C4d CAR Treg组显示出比PBS对照组更低的IL-6表达(P<0.01,图4C);然而,抗C4d CAR Treg组和NT Treg组之间没有差异。
组织学检查显示血管周炎症和C4d沉积,表明ABMR确实发生在ABOi心脏移植中(图4D)。在免疫荧光图像中显著观察到C4d+内皮细胞周围CD45.1+Myc+抗C4d CAR Treg的浸润(图4D)。然而,CAR Treg针对组织损伤的保护作用似乎并不显著,可能是因为所有组织研究都是使用取得的移植失败后获得的终端样品进行的。
讨论
以上呈现的数据证明抗C4d CAR Treg通过与C4d的特异性结合而被活化并且有效地抑制T细胞的体外增殖。此外,抗C4d CAR Treg抑制ABOi心脏移植后的ABMR并显著延长ABOi心脏同种异体移植物的存活。
迄今为止,抗HLA-A2 CAR Treg是唯一应用于移植领域中的CAR Treg,并且已显示出对同种异体移植物排斥的良好免疫抑制作用。6-8然而,靶向供体特异性HLA的抗HLA-A2CAR Treg不能覆盖所有供体-接受者对。相比之下,抗C4d CAR Treg靶向C4d(一种众所周知的ABMR相关分子),并且可用于治疗大多数ABMR,而不管供体和接受者的HLA组合如何。抗C4d CAR Treg的一个潜在限制是它们抑制C4d阴性ABMR的能力低。22
另一方面,抗C4d CAR Treg可通过浸润C4d+ABOi同种异体移植物来预防ABOi移植中的ABMR,因为C4d沉积经由ABOi移植特有的适应机制在具有或不具有ABMR的大多数ABOi同种异体移植物中发生。10,11,21与该假设一致,本文所呈现的数据证明抗C4d CAR Treg显著延长ABOi同种异体移植物的存活。
本文所描述的数据通过提供用于ABMR和ABOi移植的靶向C4d的新型调节性T细胞,有助于CAR Treg疗法和控制移植领域中的同种异体移植物排斥。以上描述的结果使用鼠ABOi心脏移植模型首次证明抗C4dCAR Treg的表型和针对同种异体移植物排斥的免疫抑制作用。
总之,该实施例描述了通过抑制ABMR增加ABOi心脏同种异体移植物存活且因此有希望应用于人移植中的抗C4d CAR Treg。
逆转录病毒载体转染和逆转录病毒包装
将逆转录病毒构建体与含有编码印第安纳水泡性口炎病毒G蛋白(vesicularstomatitis Indiana virus G protein,VSV-G)作为病毒包膜蛋白的DNA的pMD2.G质粒(ATCC)一起转染到Phoenix GP(ATCC,Manassas,VA,USA)细胞系中。在使用Lipofectamine3000(Invitrogen,Carlsbad,CA,USA)转染后48h,收获含有VSV-G假型逆转录病毒的上清液,并直接与Phoenix Eco(ATCC)细胞系一起孵育以供用逆转录病毒感染。
用于CAR Treg的活化测定
对于活化测定,如先前所描述的,将CD20+Raji细胞与利妥昔单抗-mIgG2a(3μg/mL)一起孵育。19在将抗小鼠C5抗体(200nM,ImmunAbs,Seoul,Korea)与5% NSG小鼠血清(Chemon,Seoul,Korea)混合后,将混合物添加到利妥昔单抗预处理的Raji细胞中以将C4d沉积在Raji细胞上而不损伤细胞。接下来,将C4d+Raji细胞与NT Treg、对照CAR Treg或抗C4d CAR Treg共培养48h。分别通过流式细胞术和酶联免疫吸附测定测量Treg中CD69的表达以及白细胞介素(IL)-10和干扰素-γ(IFN-γ)的分泌。
心脏移植和免疫抑制方案
如先前所描述的,在第-21天和第-14天,用人血型A抗原使野生型C57BL/6J小鼠致敏,并且在第-7天通过流式细胞术测量抗A IgM和IgG的血清滴度。21每天施用泼尼松龙(1mg/kg/天,Yuhan,Seoul,Korea)、他克莫司(Advagraf,1mg/kg/天,Astellas Pharma,Tokyo,Japan)和雷帕霉素(Rapamune,1mg/kg/天,Pfizer Pharmaceutical Korea,Seoul,Korea)。心脏同种异体移植物排斥的发生被认为是触诊评分为0。
实时聚合酶链式反应
用Trizol试剂(Thermo Fisher Scientific,Waltham,MA,USA)将心脏同种异体移植物组织均质化,并使用Superscript II逆转录酶将RNA逆转录成cDNA。每种反应混合物包含2×SYBR Green PCR主混合物(Applied Biosystems,Foster City,CA,USA)和10pmol/μL的对应引物(表A.2)。使用QuantStudio(v.3.o;Thermo Fisher Scientific)进行实时PCR分析。
组织学分析
将心脏同种异体移植物在4%多聚甲醛中固定24h,并用苏木精和伊红将石蜡包埋的切片(4μm)染色。对于免疫荧光染色,将恒冷箱切片(4μm厚度)用兔抗小鼠C4d(1:100,多克隆,Hycult Biotech,Plymouth Meeting,PA,USA)和大鼠抗小鼠myc(1:200,克隆9E10,Abcam,Cambridge,UK)在4℃染色过夜。接下来,将切片与驴抗兔IgG-Alexa Fluor 488和山羊抗大鼠IgG-Alexa Fluor 647(Thermo Fisher Scientific)在37℃孵育2h。将抗小鼠CD45.1-Alexa Fluor 594(克隆ly-5.1,BioLegend,San Diego,CA,USA)在37℃孵育2h,并用4,6-二脒基-2-苯基吲哚(DAPI,Sigma-Aldrich,St.Louis,MO,USA)使核DNA可视化。在Leica TCS Sp8共焦激光扫描显微镜(Wetzlar,Germany)上获取图像,并使用LAS AF lite(Leica)输出。
表A.1.用于流式细胞术分析的抗体信息
APC,别藻蓝蛋白;Foxp3,叉头框P3;CTLA-4,细胞毒性T淋巴细胞相关蛋白4;Cy7,花青7;FITC,异硫氰酸荧光素;GITR,糖皮质激素诱导的肿瘤坏死因子受体相关蛋白;LAP,潜伏相关肽;PE,藻红蛋白。
表A.2.用于实时逆转录-聚合酶链式反应的引物组
/>
F,正向;GAPDH,甘油醛3-磷酸脱氢酶;IFN-γ,干扰素-γ;IL-1β,白细胞介素-1β;IL-6,白细胞介素-6;R,反向
实施例2
该实施例描述了用于生成表达抗C4d CAR的调节性T细胞的代表性方法。
小鼠抗C4d CAR Treg的生成
通过使用FACS Aria II(BD Biosciences,San Diego,CA)进行分选,从C57BL/6J小鼠的脾和淋巴结分离CD62L+CD4+CD25+T细胞。用DYNABEADSTM小鼠T-活化剂CD3/CD28(珠比细胞,1:1)和IL-2(4,000IU)将分选的Treg刺激一天。然后,使用retronectin试剂用逆转录病毒转导这些细胞,连续两天以3000rpm、32℃接种90min。在第3天使用离心机以1500rpm、3min洗涤逆转录病毒后,到第7天在IL-2和雷帕霉素(100nM)存在下通过表达CD86/CD64的L细胞和抗CD3 mAb刺激转导的Treg,到第13天对CAR Treg施加第二轮刺激(参见图5A)。作为对照,除了病毒转导之外,以相同的方式刺激未转导的Treg(NT Treg)。通过染色Myc标签,通过FACS确认CAR的转导效率。
人抗C4d CAR Treg的生成
经由Mojosort人CD4 T细胞分离试剂盒从人外周血单核细胞(PBMC)中分离出人CD4+T细胞。通过使用FACS Aria II(BD Biosciences,San Diego,CA)进行荧光辅助细胞分选来纯化CD8-CD4+CD45RA+CD127低CD25+T细胞。参见图6A。用DYNABEADSTM小鼠T-活化剂CD3/CD28(珠比细胞,1:1)和IL-2(4,000IU)将分选的Treg刺激一天。然后,使用聚凝胺(6ug/ml)试剂用逆转录病毒转导这些细胞,连续两天以25000rpm、25℃接种40min。在第3天使用离心机以1500rpm、3min洗涤逆转录病毒后,到第7天在IL-2和雷帕霉素(100nM)存在下通过表达CD86/CD64的K562细胞和抗CD3 mAb刺激转导的Treg,到第13天对CAR Treg施加第二轮刺激(参见图7)。作为对照,除了病毒转导之外,以相同的方式刺激未转导的Treg(NTTreg)。
实施例3
本实施例证实抗小鼠C4d CAR Treg增加ABOi心脏移植中的心脏同种异体移植物存活率,如上文实施例1和图4中所描述的。如图5B中所示,与PBS对照(p<0.001)、NT Treg(p<0.003)和对照CAR Treg(p<0.025)相比,抗小鼠C4d CAR Treg显著延长ABOi心脏同种异体移植物的存活率。
参考文献:
1.Koo TY,Yang J.Current progress in ABO-incompatible kidneytransplantation.Kidney Res Clin Pract.2015;34(3):170-179.
2Okumi M,Toki D,Nozaki T,et al.ABO-Incompatible Living KidneyTransplants:Evolution of Outcomes and Immunosuppressive Management.Am JTransplant.2016;16(3):886-896.
3,de Weerd AE,Betjes MGH.ABO-Incompatible Kidney Transplant Outcomes:A Meta-Analysis.Clin J Am Soc Nephrol.2018;13(8):1234-1243.
4.Tang Q,Bluestone JA.Regulatory T-cell therapy in transplantation:moving to the clinic.Cold Spring Harb Perspect Med.2013;3(11).
5.Singh AK,McGuirk JP.CAR T cells:continuation in a revolution ofimmunotherapy.Lancet Oncol.2020;21(3):e168-e178.
6.MacDonald KG,Hoeppli RE,Huang Q,et al.Alloantigen-specificregulatory T cells generated with a chimeric antigen receptor.J ClinInvest.2016;126(4):1413-1424
7.Noyan F,Zimmermann K,Hardtke-Wolenski M,et al.Prevention ofAllograft Rejection by Use of Regulatory T Cells With an MHC-SpecificChimeric Antigen Receptor.Am J Transplant.2017;17(4):917-930
8.Boardman DA,Philippeos C,Fruhwirth GO,et al.Expression of aChimeric Antigen Receptor Specific for Donor HLA Class I Enhances the Potencyof Human Regulatory T Cells in Preventing Human Skin Transplant Rejection.AmJ Transplant.2017;17(4):931-943
9.Haas M,Sis B,Racusen LC,et a1.Banff 2013meeting report:inclusion ofc4d-negative antibody-mediated rejection and antibody-associated arteriallesions.Am J Transplant.2014;14(2):272-283.
10.Garcia de Mattos Barbosa M,Cascalho M,Platt JL.Accommodation inABO-incompatible organ transplants.Xenotransplantation.2018;25(3):e12418
11.Setoguchi K,Ishida H,Shimmura H,et al.Analysis of renal transplantprotocol biopsies in ABO-incompatible kidney transplantation.Am JTransplant.2008;8(1):86-94.
12.Haas M,Rahman MH,Racusen LC,et al.C4d and C3d staining in biopsiesof ABO-and HLA-incompatible renal allografts:correlation with histologicfindings.Am J Transplant.2006;6(8):1829-1840.
13.Motyka B,Fisicaro N,Wang SI,et al.Antibody-Mediated Rejection in aBlood Group A-Transgenic Mouse Model of ABO-Incompatible Heart Transplantation.Transplantation.2016;100(6):1228-1237.
14.Lee MS,Lee JC,Choi CY,Chung J.Production and characterization ofmonoclonal antibody to botulinum neurotoxin type B light chain by phagedisplay.Hybridoma(Larchmt).2008;27(1):18-24.
15.Lee Y,Kim H,Chung J.An antibody reactive to the Gly63-Lys68epitope of NT-proBNP exhibits O-glycosylation-independent binding.Exp MolMed.2014;46:e114.
16.Barbas IIICF BD,Scott JK,Silverman GJ.Phage display-a laboratorymanual.New York:Cold Spring Harbor Laboratory Press;2001.
17.Yang W,Yoon A,Lee S,Kim S,Han J,Chung J.Next-generation sequencingenables the discovery of more diverse positive clonesfrom a phage-displayedantibodylibrary.Exp Mol Med.2017;49(3):e308.
18.Yoon S,Kim YH,Kang SH,et al.Bispecific Her2 x cotinine antibody incombination with cotinine-(histidine)2-iodine for the pre-targeting of Her2-positive breast cancer xenografts.J Cancer Res Clin Oncol.2014;140(2):227-233.
19Dechant M,Weisner W,Berger S,et al.Complement-dependent tumor celllysis triggered by combinations of epidermal growth factor receptorantibodies.Cancer Res.2008;68(13):4998-5003.
20.Brender C,Tannahill GM,Jenkins BJ,et al.Suppressor of cytokinesignaling 3regulates CD8 T-cell proliferation by inhibition of interleukins6and 27.Blood.2007;110(7):2528-2536.
21Park S,Lee J-G,Jang JY,et al.Induction of Accommodation by Anti-complement Component 5Antibody-based Immunosuppression in ABO-incompatibleHeart Transplantation.Transplantation.2019;103(9):e248-e255.
22.Orandi BJ,Alachkar N,Kraus ES,et al.Presentation and Outcomes ofC4d-Negative Antibody-Mediated Rejection After Kidney Transplantation.Am JTransplant.2016;16(1):213-220
23Wu GD,He Y,Chai NN,et al.Anti-CD20 antibody suppresses anti-HLAantibody forrnation in a HLA-A2 transgenic mouse model orsensitization.Transpl Immunol.2008;19(3-4):178-186.
应当理解,本文所描述的实施例和实施方案仅用于说明的目的,并且根据它们的各种修改或变化将被提议给本领域技术人员,并且被包括在本申请的精神和范围以及所附权利要求的范围内。本文所引用的所有出版物、Genbank登录号、专利和专利申请均在此通过引用以其整体被并入用于所有目的。
非正式的序列表:
SEQ ID NO:1.抗C4d scFv(BF-2)轻链(LC)核苷酸序列
SEQ ID NO:2.抗C4d scFv(BF-2)轻链(LC)氨基酸序列
SEQ ID NO:3.抗C4d scFv(BF-2)重链(HC)核苷酸序列
SEQ ID NO:4.抗C4d scFv(BF-2)重链(HC)氨基酸序列
SEQ ID NO:5.抗C4d scFv(SC-8)轻链(LC)核苷酸序列
SEQ ID NO:6.抗C4d scFv(SC-8)轻链(LC)氨基酸序列
SEQ ID NO:7.抗C4d scFv(SC-8)重链(HC)核苷酸序列
SEQ ID NO:8.抗C4d scFv(SC-8)重链(HC)氨基酸序列
SEQ ID NO:9.人CD8铰链核苷酸序列
SEQ ID NO:10.人CD8铰链氨基酸序列
SEQ ID NO:11.小鼠CD28跨膜和胞质核苷酸序列
SEQ ID NO:12.小鼠CD28跨膜和胞质氨基酸序列
SEQ ID NO:13.小鼠CD3ζ胞质核苷酸序列
SEQ ID NO:14.小鼠CD3ζ胞质氨基酸序列
/>
SEQ ID NO:15.抗C4d(BF-2)CAR-Treg核苷酸序列(scFv-hCD8铰链-mCD28跨膜+胞质-mCD3z)
SEQ ID NO:16.抗C4d(BF-2)CAR-Treg氨基酸序列(scFv-hCD8铰链-mCD28跨膜+胞质-mCD3z)
SEQ ID NO:17.抗C4d(SC-8)CAR-Treg核苷酸序列(scFv-hCD8铰链-mCD28跨膜+胞质-mCD3z)
/>
SEQ ID NO:18.抗C4d(SC-8)CAR-Treg氨基酸序列(scFv-hCD8铰链-mCD28跨膜+胞质-mCD3z)
SEQ ID NO:19.小鼠CD28(细胞外+跨膜+胞质)核苷酸序列
SEQ ID NO:20.小鼠CD28(细胞外+跨膜+胞质)氨基酸序列
SEQ ID NO:21.人CD3ζ胞质核苷酸序列.
SEQ ID NO:22.人CD3ζ胞质氨基酸序列
SEQ ID NO:23.小鼠CD28(胞外+跨膜+胞质)+小鼠CD3ζ核苷酸序列
SEQ ID NO:24.小鼠CD28(胞外+跨膜+胞质)+小鼠CD3ζ氨基酸序列
SEQ ID NO:25.c-myc标签核苷酸序列
SEQ ID NO:26.c-myc标签氨基酸序列
SEQ ID NO:35.N2-7 scFv核苷酸序列:
SEQ ID NO:39.N2-7轻链核苷酸序列:
SEQ ID NO:40.N2-7 scFv接头核苷酸序列:
SEQ ID NO:41.N2-7重链核苷酸序列:
SEQ ID NO:36.N2-7 scFv氨基酸序列:
SEQ ID NO:42.N2-7轻链氨基酸序列:
SEQ ID NO:43.N2-7 LCDR1氨基酸序列:
SEQ ID NO:44.N2-7 LCDR2氨基酸序列:
SEQ ID NO:45.N2-7 LCDR3氨基酸序列:
SEQ ID NO:46.N2-7 scFv接头氨基酸序列:
SEQ ID NO:47.N2-7重链氨基酸序列:
SEQ ID NO:48.N2-7 HCDR1氨基酸序列:
SEQ ID NO:49.N2-7 HCDR2氨基酸序列:
SEQ ID NO:50.N2-7 HCDR3氨基酸序列:
SEQ ID NO:37.人GM-CSF-Myc-h28z核苷酸序列.
SEQ ID NO:51.GM-CSF核苷酸序列:
SEQ ID NO:52.Myc-标签核苷酸序列:
SEQ ID NO:53.人CD28跨膜核苷酸序列:
SEQ ID NO:54.人CD3ζ核苷酸序列:
SEQ ID NO:38.人GM-CSF-Myc-h28z氨基酸序列:
SEQ ID NO:55.GM-CSF氨基酸序列:
SEQ ID NO:56.Myc-标签氨基酸序列:
SEQ ID NO:57.人CD28跨膜氨基酸序列:
SEQ ID NO:58.人CD3ζ氨基酸序列:
SEQ ID NO:59.BF-2scFv核苷酸序列:
SEQ ID NO:60.BF-2LCDR1核苷酸序列:
SEQ ID NO:61.BF-2LCDR2核苷酸序列:
SEQ ID NO:62.BF-2LCDR3核苷酸序列:
/>
SEQ ID NO:63.BF-2HCDR1核苷酸序列:
SEQ ID NO:64.BF-2HCDR2核苷酸序列:
SEQ ID NO:65.BF-2HCDR3核苷酸序列:
SEQ ID NO:66.BF-2scFv接头核苷酸序列:
SEQ ID NO:67.BF-2scFv氨基酸序列:
SEQ ID NO:68.BF-2LCDR1氨基酸序列:
SEQ ID NO:69.BF-2LCDR2氨基酸序列:
SEQ ID NO:70.BF-2LCDR3氨基酸序列:
SEQ ID NO:71.BF-2HCDR1氨基酸序列:
SEQ ID NO:72.BF-2HCDR2氨基酸序列:
SEQ ID NO:73.BF-2HCDR3氨基酸序列:
SEQ ID NO:74.BF-2scFv接头氨基酸序列:
SEQ ID NO:75.SC-8scFv核苷酸序列:
SEQ ID NO:76.SC-8LCDR1核苷酸序列:
SEQ ID NO:77.SC-8LCDR2核苷酸序列:
/>
SEQ ID NO:78.SC-8LCDR3核苷酸序列:
SEQ ID NO:79.SC-8HCDR1核苷酸序列:
SEQ ID NO:80.SC-8HCDR2核苷酸序列:
SEQ ID NO:81.SC-8HCDR3核苷酸序列:
SEQ ID NO:82.SC-8scFv接头核苷酸序列:
SEQ ID NO:83.SC-8scFv氨基酸序列:
SEQ ID NO:84.SC-8LCDR1氨基酸序列:
SEQ ID NO:85.SC-8LCDR2氨基酸序列:
SEQ ID NO:86.SC-8LCDR3氨基酸序列:
SEQ ID NO:87.SC-8HCDR1氨基酸序列:
SEQ ID NO:88.SC-8HCDR2氨基酸序列:
SEQ ID NO:89.SC-8HCDR3氨基酸序列:
SEQ ID NO:90.SC-8scFv接头氨基酸序列:
/>
序列表
<110> 首尔大学校产学协力团
首尔大学医院
财团法人峨山社会福祉财团
<120> 抗C4D嵌合抗原受体调节性T细胞及其用途
<130> 107568-1292165
<140>
<141>
<150> 63/139,617
<151> 2021-01-20
<160> 38
<170> PatentIn version 3.5
<210> 1
<211> 306
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述:合成的多核苷酸
<400> 1
ctgactcagc cgtcctcggt gtcagcaaac ccaggaggaa ccgtcgagat cacctgctcc 60
gggagtagtg gcagctatgg ctggtatcag cagaagtcac ctggcagtgc ccctgtcact 120
gtgatctatt acaacgacaa gagaccctcg gacatccctt cacgattctc cggttccaaa 180
tccggctcca cagccacatt aaccatcact ggggtccaag ccgaggacga ggctgtctat 240
ttctgtggga gtgaagacag cagctatgtt ggtgtatttg gggccgggac aaccctgacc 300
gtccta 306
<210> 2
<211> 102
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成的多肽
<400> 2
Leu Thr Gln Pro Ser Ser Val Ser Ala Asn Pro Gly Gly Thr Val Glu
1 5 10 15
Ile Thr Cys Ser Gly Ser Ser Gly Ser Tyr Gly Trp Tyr Gln Gln Lys
20 25 30
Ser Pro Gly Ser Ala Pro Val Thr Val Ile Tyr Tyr Asn Asp Lys Arg
35 40 45
Pro Ser Asp Ile Pro Ser Arg Phe Ser Gly Ser Lys Ser Gly Ser Thr
50 55 60
Ala Thr Leu Thr Ile Thr Gly Val Gln Ala Glu Asp Glu Ala Val Tyr
65 70 75 80
Phe Cys Gly Ser Glu Asp Ser Ser Tyr Val Gly Val Phe Gly Ala Gly
85 90 95
Thr Thr Leu Thr Val Leu
100
<210> 3
<211> 372
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述:合成的多核苷酸
<400> 3
gccgtgacgt tggacgagtc cgggggcggc ctccagacgc ccggaggaac gctcagcctc 60
gtctgcaagg gctccgggtt caccttcagg agttatgccc tggagtgggt gcgccaggca 120
cccggcaagg ggctggaata cgtcgcgggt attagcagca gtggcagtgg cacaaactac 180
gggtcggcgg tgaagggccg tgccaccatc tcgagggaca acgggcagag cacagtgagg 240
ctgcagctga acaacctcag ggctgaggac accggcacct actactgcgc caaaagtgct 300
tacggttatg ttgatgctta cggcatcgac gcatggggcc acgggaccga agtcatcgtc 360
tcctccacta gt 372
<210> 4
<211> 124
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成的多肽
<400> 4
Ala Val Thr Leu Asp Glu Ser Gly Gly Gly Leu Gln Thr Pro Gly Gly
1 5 10 15
Thr Leu Ser Leu Val Cys Lys Gly Ser Gly Phe Thr Phe Arg Ser Tyr
20 25 30
Ala Leu Glu Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Tyr Val
35 40 45
Ala Gly Ile Ser Ser Ser Gly Ser Gly Thr Asn Tyr Gly Ser Ala Val
50 55 60
Lys Gly Arg Ala Thr Ile Ser Arg Asp Asn Gly Gln Ser Thr Val Arg
65 70 75 80
Leu Gln Leu Asn Asn Leu Arg Ala Glu Asp Thr Gly Thr Tyr Tyr Cys
85 90 95
Ala Lys Ser Ala Tyr Gly Tyr Val Asp Ala Tyr Gly Ile Asp Ala Trp
100 105 110
Gly His Gly Thr Glu Val Ile Val Ser Ser Thr Ser
115 120
<210> 5
<211> 309
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述:合成的多核苷酸
<400> 5
ctgactcagc cgtcctcggt gtcagcaaac ccgggagaaa ccgtcaagat cacctgctcc 60
gggggtggta ggtggtatgg ctggtaccag cagaagtctc ctggcagtgc ccctgtcact 120
ctgatccatg ctaataccaa aagaccctcg aacatccctt cacgattctc cggttcccta 180
tccggctcca caagcacatt aaccatctct ggggtccaag ccgaggacga ggctgtctat 240
ttctgtggga gtggagacag cagcactgat agtggtatat ttggggccgg gacaaccctg 300
accgtccta 309
<210> 6
<211> 103
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成的多肽
<400> 6
Leu Thr Gln Pro Ser Ser Val Ser Ala Asn Pro Gly Glu Thr Val Lys
1 5 10 15
Ile Thr Cys Ser Gly Gly Gly Arg Trp Tyr Gly Trp Tyr Gln Gln Lys
20 25 30
Ser Pro Gly Ser Ala Pro Val Thr Leu Ile His Ala Asn Thr Lys Arg
35 40 45
Pro Ser Asn Ile Pro Ser Arg Phe Ser Gly Ser Leu Ser Gly Ser Thr
50 55 60
Ser Thr Leu Thr Ile Ser Gly Val Gln Ala Glu Asp Glu Ala Val Tyr
65 70 75 80
Phe Cys Gly Ser Gly Asp Ser Ser Thr Asp Ser Gly Ile Phe Gly Ala
85 90 95
Gly Thr Thr Leu Thr Val Leu
100
<210> 7
<211> 381
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述:合成的多核苷酸
<400> 7
gccgtgacgt tggacgagtc cgggggcggc ctccagacgc ccggaggagc gctcagcctc 60
gtctgcaagg cctccgggtt ctccttcagt gaccgtgcaa tgcactgggt gcgacaggca 120
cccggcaagg ggctggagtg ggtcgcgggt atttacagca gtggtagata cacaggctac 180
gggtcggcgg tgaagggccg tgccaccatc tcgagggaca acgggcagag cacagtgagg 240
ctgcagctga acaacctcag ggctgaggac accggcacct actactgcgc caaagctggt 300
agtatttact gtgggtatgc tgatgttgct tgcatcgacg cgtggggcca cgggaccgaa 360
gtcatcgtct cctccactag t 381
<210> 8
<211> 127
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成的多肽
<400> 8
Ala Val Thr Leu Asp Glu Ser Gly Gly Gly Leu Gln Thr Pro Gly Gly
1 5 10 15
Ala Leu Ser Leu Val Cys Lys Ala Ser Gly Phe Ser Phe Ser Asp Arg
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Gly Ile Tyr Ser Ser Gly Arg Tyr Thr Gly Tyr Gly Ser Ala Val
50 55 60
Lys Gly Arg Ala Thr Ile Ser Arg Asp Asn Gly Gln Ser Thr Val Arg
65 70 75 80
Leu Gln Leu Asn Asn Leu Arg Ala Glu Asp Thr Gly Thr Tyr Tyr Cys
85 90 95
Ala Lys Ala Gly Ser Ile Tyr Cys Gly Tyr Ala Asp Val Ala Cys Ile
100 105 110
Asp Ala Trp Gly His Gly Thr Glu Val Ile Val Ser Ser Thr Ser
115 120 125
<210> 9
<211> 189
<212> DNA
<213> 智人
<400> 9
tcagcgctga gcaactccat catgtacttc agccacttcg tgccggtctt cctgccagcg 60
aagcccacca cgacgccagc gccgcgacca ccaacaccgg cgcccaccat cgcgtcgcag 120
cccctgtccc tgcgcccaga ggcatgccgg ccagcggcgg ggggcgcagt gcacacgagg 180
gggctggat 189
<210> 10
<211> 63
<212> PRT
<213> 智人
<400> 10
Ser Ala Leu Ser Asn Ser Ile Met Tyr Phe Ser His Phe Val Pro Val
1 5 10 15
Phe Leu Pro Ala Lys Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr
20 25 30
Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala
35 40 45
Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp
50 55 60
<210> 11
<211> 213
<212> DNA
<213> 小鼠属的种(Mus sp.)
<400> 11
cctaagctgt tttgggcact ggtcgtggtt gctggagtcc tgttttgtta tggcttgcta 60
gtgacagtgg ctctttgtgt tatctggaca aatagtagaa ggaacagact ccttcaaagt 120
gactacatga acatgactcc ccggaggcct gggctcactc gaaagcctta ccagccctac 180
gcccctgcca gagactttgc agcgtaccgc ccc 213
<210> 12
<211> 71
<212> PRT
<213> 小鼠属的种
<400> 12
Pro Lys Leu Phe Trp Ala Leu Val Val Val Ala Gly Val Leu Phe Cys
1 5 10 15
Tyr Gly Leu Leu Val Thr Val Ala Leu Cys Val Ile Trp Thr Asn Ser
20 25 30
Arg Arg Asn Arg Leu Leu Gln Ser Asp Tyr Met Asn Met Thr Pro Arg
35 40 45
Arg Pro Gly Leu Thr Arg Lys Pro Tyr Gln Pro Tyr Ala Pro Ala Arg
50 55 60
Asp Phe Ala Ala Tyr Arg Pro
65 70
<210> 13
<211> 339
<212> DNA
<213> 小鼠属的种
<400> 13
agagtgaagt tcagcaggag cgcagacgcc cccgcgtacc agcagggcca gaaccagctc 60
tataacgagc tcaatctagg acgaagagag gagtacgatg ttttggacaa gagacgtggc 120
cgggaccctg agatgggggg aaagccgaga aggaagaacc ctcaggaagg cctgtacaat 180
gaactgcaga aagataagat ggcggaggcc tacagtgaga ttgggatgaa aggcgagcgc 240
cggaggggca aggggcacga tggcctttac cagggtctca gtacagccac caaggacacc 300
tacgacgccc ttcacatgca ggccctgccc cctcgctaa 339
<210> 14
<211> 112
<212> PRT
<213> 小鼠属的种
<400> 14
Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly
1 5 10 15
Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr
20 25 30
Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys
35 40 45
Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys
50 55 60
Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg
65 70 75 80
Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala
85 90 95
Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
100 105 110
<210> 15
<211> 1533
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述:合成的多核苷酸
<400> 15
ctgactcagc cgtcctcggt gtcagcaaac ccaggaggaa ccgtcgagat cacctgctcc 60
gggagtagtg gcagctatgg ctggtatcag cagaagtcac ctggcagtgc ccctgtcact 120
gtgatctatt acaacgacaa gagaccctcg gacatccctt cacgattctc cggttccaaa 180
tccggctcca cagccacatt aaccatcact ggggtccaag ccgaggacga ggctgtctat 240
ttctgtggga gtgaagacag cagctatgtt ggtgtatttg gggccgggac aaccctgacc 300
gtcctaggtc agtcctctag atcttccggc ggtggtggca gctccggtgg tggcggttcc 360
gccgtgacgt tggacgagtc cgggggcggc ctccagacgc ccggaggaac gctcagcctc 420
gtctgcaagg gctccgggtt caccttcagg agttatgccc tggagtgggt gcgccaggca 480
cccggcaagg ggctggaata cgtcgcgggt attagcagca gtggcagtgg cacaaactac 540
gggtcggcgg tgaagggccg tgccaccatc tcgagggaca acgggcagag cacagtgagg 600
ctgcagctga acaacctcag ggctgaggac accggcacct actactgcgc caaaagtgct 660
tacggttatg ttgatgctta cggcatcgac gcatggggcc acgggaccga agtcatcgtc 720
tcctccacta gtgcggccgc agaacaaaaa ctcatctcag aagaggatct gaatggggtc 780
accgtctctt cagcgctgag caactccatc atgtacttca gccacttcgt gccggtcttc 840
ctgccagcga agcccaccac gacgccagcg ccgcgaccac caacaccggc gcccaccatc 900
gcgtcgcagc ccctgtccct gcgcccagag gcatgccggc cagcggcggg gggcgcagtg 960
cacacgaggg ggctggatcc taagctgttt tgggcactgg tcgtggttgc tggagtcctg 1020
ttttgttatg gcttgctagt gacagtggct ctttgtgtta tctggacaaa tagtagaagg 1080
aacagactcc ttcaaagtga ctacatgaac atgactcccc ggaggcctgg gctcactcga 1140
aagccttacc agccctacgc ccctgccaga gactttgcag cgtaccgccc cctcgagaga 1200
gtgaagttca gcaggagcgc agacgccccc gcgtaccagc agggccagaa ccagctctat 1260
aacgagctca atctaggacg aagagaggag tacgatgttt tggacaagag acgtggccgg 1320
gaccctgaga tggggggaaa gccgagaagg aagaaccctc aggaaggcct gtacaatgaa 1380
ctgcagaaag ataagatggc ggaggcctac agtgagattg ggatgaaagg cgagcgccgg 1440
aggggcaagg ggcacgatgg cctttaccag ggtctcagta cagccaccaa ggacacctac 1500
gacgcccttc acatgcaggc cctgccccct cgc 1533
<210> 16
<211> 511
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成的多肽
<400> 16
Leu Thr Gln Pro Ser Ser Val Ser Ala Asn Pro Gly Gly Thr Val Glu
1 5 10 15
Ile Thr Cys Ser Gly Ser Ser Gly Ser Tyr Gly Trp Tyr Gln Gln Lys
20 25 30
Ser Pro Gly Ser Ala Pro Val Thr Val Ile Tyr Tyr Asn Asp Lys Arg
35 40 45
Pro Ser Asp Ile Pro Ser Arg Phe Ser Gly Ser Lys Ser Gly Ser Thr
50 55 60
Ala Thr Leu Thr Ile Thr Gly Val Gln Ala Glu Asp Glu Ala Val Tyr
65 70 75 80
Phe Cys Gly Ser Glu Asp Ser Ser Tyr Val Gly Val Phe Gly Ala Gly
85 90 95
Thr Thr Leu Thr Val Leu Gly Gln Ser Ser Arg Ser Ser Gly Gly Gly
100 105 110
Gly Ser Ser Gly Gly Gly Gly Ser Ala Val Thr Leu Asp Glu Ser Gly
115 120 125
Gly Gly Leu Gln Thr Pro Gly Gly Thr Leu Ser Leu Val Cys Lys Gly
130 135 140
Ser Gly Phe Thr Phe Arg Ser Tyr Ala Leu Glu Trp Val Arg Gln Ala
145 150 155 160
Pro Gly Lys Gly Leu Glu Tyr Val Ala Gly Ile Ser Ser Ser Gly Ser
165 170 175
Gly Thr Asn Tyr Gly Ser Ala Val Lys Gly Arg Ala Thr Ile Ser Arg
180 185 190
Asp Asn Gly Gln Ser Thr Val Arg Leu Gln Leu Asn Asn Leu Arg Ala
195 200 205
Glu Asp Thr Gly Thr Tyr Tyr Cys Ala Lys Ser Ala Tyr Gly Tyr Val
210 215 220
Asp Ala Tyr Gly Ile Asp Ala Trp Gly His Gly Thr Glu Val Ile Val
225 230 235 240
Ser Ser Thr Ser Ala Ala Ala Glu Gln Lys Leu Ile Ser Glu Glu Asp
245 250 255
Leu Asn Gly Val Thr Val Ser Ser Ala Leu Ser Asn Ser Ile Met Tyr
260 265 270
Phe Ser His Phe Val Pro Val Phe Leu Pro Ala Lys Pro Thr Thr Thr
275 280 285
Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro
290 295 300
Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val
305 310 315 320
His Thr Arg Gly Leu Asp Pro Lys Leu Phe Trp Ala Leu Val Val Val
325 330 335
Ala Gly Val Leu Phe Cys Tyr Gly Leu Leu Val Thr Val Ala Leu Cys
340 345 350
Val Ile Trp Thr Asn Ser Arg Arg Asn Arg Leu Leu Gln Ser Asp Tyr
355 360 365
Met Asn Met Thr Pro Arg Arg Pro Gly Leu Thr Arg Lys Pro Tyr Gln
370 375 380
Pro Tyr Ala Pro Ala Arg Asp Phe Ala Ala Tyr Arg Pro Leu Glu Arg
385 390 395 400
Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln
405 410 415
Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp
420 425 430
Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro
435 440 445
Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp
450 455 460
Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg
465 470 475 480
Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr
485 490 495
Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
500 505 510
<210> 17
<211> 1545
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述:合成的多核苷酸
<400> 17
ctgactcagc cgtcctcggt gtcagcaaac ccgggagaaa ccgtcaagat cacctgctcc 60
gggggtggta ggtggtatgg ctggtaccag cagaagtctc ctggcagtgc ccctgtcact 120
ctgatccatg ctaataccaa aagaccctcg aacatccctt cacgattctc cggttcccta 180
tccggctcca caagcacatt aaccatctct ggggtccaag ccgaggacga ggctgtctat 240
ttctgtggga gtggagacag cagcactgat agtggtatat ttggggccgg gacaaccctg 300
accgtcctag gtcagtcctc tagatcttcc ggcggtggtg gcagctccgg tggtggcggt 360
tccgccgtga cgttggacga gtccgggggc ggcctccaga cgcccggagg agcgctcagc 420
ctcgtctgca aggcctccgg gttctccttc agtgaccgtg caatgcactg ggtgcgacag 480
gcacccggca aggggctgga gtgggtcgcg ggtatttaca gcagtggtag atacacaggc 540
tacgggtcgg cggtgaaggg ccgtgccacc atctcgaggg acaacgggca gagcacagtg 600
aggctgcagc tgaacaacct cagggctgag gacaccggca cctactactg cgccaaagct 660
ggtagtattt actgtgggta tgctgatgtt gcttgcatcg acgcgtgggg ccacgggacc 720
gaagtcatcg tctcctccac tagtgcggcc gcagaacaaa aactcatctc agaagaggat 780
ctgaatgggg tcaccgtctc ttcagcgctg agcaactcca tcatgtactt cagccacttc 840
gtgccggtct tcctgccagc gaagcccacc acgacgccag cgccgcgacc accaacaccg 900
gcgcccacca tcgcgtcgca gcccctgtcc ctgcgcccag aggcatgccg gccagcggcg 960
gggggcgcag tgcacacgag ggggctggat cctaagctgt tttgggcact ggtcgtggtt 1020
gctggagtcc tgttttgtta tggcttgcta gtgacagtgg ctctttgtgt tatctggaca 1080
aatagtagaa ggaacagact ccttcaaagt gactacatga acatgactcc ccggaggcct 1140
gggctcactc gaaagcctta ccagccctac gcccctgcca gagactttgc agcgtaccgc 1200
cccctcgaga gagtgaagtt cagcaggagc gcagacgccc ccgcgtacca gcagggccag 1260
aaccagctct ataacgagct caatctagga cgaagagagg agtacgatgt tttggacaag 1320
agacgtggcc gggaccctga gatgggggga aagccgagaa ggaagaaccc tcaggaaggc 1380
ctgtacaatg aactgcagaa agataagatg gcggaggcct acagtgagat tgggatgaaa 1440
ggcgagcgcc ggaggggcaa ggggcacgat ggcctttacc agggtctcag tacagccacc 1500
aaggacacct acgacgccct tcacatgcag gccctgcccc ctcgc 1545
<210> 18
<211> 515
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成的多肽
<400> 18
Leu Thr Gln Pro Ser Ser Val Ser Ala Asn Pro Gly Glu Thr Val Lys
1 5 10 15
Ile Thr Cys Ser Gly Gly Gly Arg Trp Tyr Gly Trp Tyr Gln Gln Lys
20 25 30
Ser Pro Gly Ser Ala Pro Val Thr Leu Ile His Ala Asn Thr Lys Arg
35 40 45
Pro Ser Asn Ile Pro Ser Arg Phe Ser Gly Ser Leu Ser Gly Ser Thr
50 55 60
Ser Thr Leu Thr Ile Ser Gly Val Gln Ala Glu Asp Glu Ala Val Tyr
65 70 75 80
Phe Cys Gly Ser Gly Asp Ser Ser Thr Asp Ser Gly Ile Phe Gly Ala
85 90 95
Gly Thr Thr Leu Thr Val Leu Gly Gln Ser Ser Arg Ser Ser Gly Gly
100 105 110
Gly Gly Ser Ser Gly Gly Gly Gly Ser Ala Val Thr Leu Asp Glu Ser
115 120 125
Gly Gly Gly Leu Gln Thr Pro Gly Gly Ala Leu Ser Leu Val Cys Lys
130 135 140
Ala Ser Gly Phe Ser Phe Ser Asp Arg Ala Met His Trp Val Arg Gln
145 150 155 160
Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Gly Ile Tyr Ser Ser Gly
165 170 175
Arg Tyr Thr Gly Tyr Gly Ser Ala Val Lys Gly Arg Ala Thr Ile Ser
180 185 190
Arg Asp Asn Gly Gln Ser Thr Val Arg Leu Gln Leu Asn Asn Leu Arg
195 200 205
Ala Glu Asp Thr Gly Thr Tyr Tyr Cys Ala Lys Ala Gly Ser Ile Tyr
210 215 220
Cys Gly Tyr Ala Asp Val Ala Cys Ile Asp Ala Trp Gly His Gly Thr
225 230 235 240
Glu Val Ile Val Ser Ser Thr Ser Ala Ala Ala Glu Gln Lys Leu Ile
245 250 255
Ser Glu Glu Asp Leu Asn Gly Val Thr Val Ser Ser Ala Leu Ser Asn
260 265 270
Ser Ile Met Tyr Phe Ser His Phe Val Pro Val Phe Leu Pro Ala Lys
275 280 285
Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile
290 295 300
Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala
305 310 315 320
Gly Gly Ala Val His Thr Arg Gly Leu Asp Pro Lys Leu Phe Trp Ala
325 330 335
Leu Val Val Val Ala Gly Val Leu Phe Cys Tyr Gly Leu Leu Val Thr
340 345 350
Val Ala Leu Cys Val Ile Trp Thr Asn Ser Arg Arg Asn Arg Leu Leu
355 360 365
Gln Ser Asp Tyr Met Asn Met Thr Pro Arg Arg Pro Gly Leu Thr Arg
370 375 380
Lys Pro Tyr Gln Pro Tyr Ala Pro Ala Arg Asp Phe Ala Ala Tyr Arg
385 390 395 400
Pro Leu Glu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr
405 410 415
Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg
420 425 430
Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met
435 440 445
Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu
450 455 460
Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys
465 470 475 480
Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu
485 490 495
Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu
500 505 510
Pro Pro Arg
515
<210> 19
<211> 312
<212> DNA
<213> 小鼠属的种
<400> 19
atcgagttca tgtacccacc accctacctt gacaatgaac ggagtaacgg aactatcatt 60
cacatcaagg aaaagcatct ttgccacaca caatctagtc caaaactctt ttgggcattg 120
gtcgttgtgg ctggggtgct tttctgttat ggacttcttg tgaccgtagc actctgtgtc 180
atctggacaa atagccgccg aaaccgcggc gggcagtccg actacatgaa catgactcct 240
agacgccctg gactgactcg caaaccctat caaccttatg ctcccgctag ggacttcgca 300
gcctataggc cc 312
<210> 20
<211> 104
<212> PRT
<213> 小鼠属的种
<400> 20
Ile Glu Phe Met Tyr Pro Pro Pro Tyr Leu Asp Asn Glu Arg Ser Asn
1 5 10 15
Gly Thr Ile Ile His Ile Lys Glu Lys His Leu Cys His Thr Gln Ser
20 25 30
Ser Pro Lys Leu Phe Trp Ala Leu Val Val Val Ala Gly Val Leu Phe
35 40 45
Cys Tyr Gly Leu Leu Val Thr Val Ala Leu Cys Val Ile Trp Thr Asn
50 55 60
Ser Arg Arg Asn Arg Gly Gly Gln Ser Asp Tyr Met Asn Met Thr Pro
65 70 75 80
Arg Arg Pro Gly Leu Thr Arg Lys Pro Tyr Gln Pro Tyr Ala Pro Ala
85 90 95
Arg Asp Phe Ala Ala Tyr Arg Pro
100
<210> 21
<211> 336
<212> DNA
<213> 智人
<400> 21
agagtgaagt tcagcaggag cgcagacgcc cccgcgtacc agcagggcca gaaccagctc 60
tataacgagc tcaatctagg acgaagagag gagtacgatg ttttggacaa gagacgtggc 120
cgggaccctg agatgggggg aaagccgaga aggaagaacc ctcaggaagg cctgtacaat 180
gaactgcaga aagataagat ggcggaggcc tacagtgaga ttgggatgaa aggcgagcgc 240
cggaggggca aggggcacga tggcctttac cagggtctca gtacagccac caaggacacc 300
tacgacgccc ttcacatgca ggccctgccc cctcgc 336
<210> 22
<211> 112
<212> PRT
<213> 智人
<400> 22
Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly
1 5 10 15
Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr
20 25 30
Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys
35 40 45
Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys
50 55 60
Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg
65 70 75 80
Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala
85 90 95
Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
100 105 110
<210> 23
<211> 651
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述:合成的多核苷酸
<400> 23
atcgagttca tgtacccacc accctacctt gacaatgaac ggagtaacgg aactatcatt 60
cacatcaagg aaaagcatct ttgccacaca caatctagtc caaaactctt ttgggcattg 120
gtcgttgtgg ctggggtgct tttctgttat ggacttcttg tgaccgtagc actctgtgtc 180
atctggacaa atagccgccg aaaccgcggc gggcagtccg actacatgaa catgactcct 240
agacgccctg gactgactcg caaaccctat caaccttatg ctcccgctag ggacttcgca 300
gcctataggc ccagagccaa attttcccga tctgctgaga ctgccgccaa tctccaggac 360
ccaaatcaat tgtttaacga actgaacctt ggacggcggg aagagtttga tgttttggag 420
aagaagcgcg cacgcgaccc tgagatgggt ggcaagcagc aacgccgacg aaaccctcaa 480
gagggtgttt acaatgccct gcaaaaggac aagatggcag aggcttatag cgaaatagga 540
acaaaggggg aacggagacg aggaaaggga catgatggac tttttcaggg gctctccaca 600
gccacaaagg atacattcga cgccttgcac atgcaaaccc ttgctcctag a 651
<210> 24
<211> 217
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成的多肽
<400> 24
Ile Glu Phe Met Tyr Pro Pro Pro Tyr Leu Asp Asn Glu Arg Ser Asn
1 5 10 15
Gly Thr Ile Ile His Ile Lys Glu Lys His Leu Cys His Thr Gln Ser
20 25 30
Ser Pro Lys Leu Phe Trp Ala Leu Val Val Val Ala Gly Val Leu Phe
35 40 45
Cys Tyr Gly Leu Leu Val Thr Val Ala Leu Cys Val Ile Trp Thr Asn
50 55 60
Ser Arg Arg Asn Arg Gly Gly Gln Ser Asp Tyr Met Asn Met Thr Pro
65 70 75 80
Arg Arg Pro Gly Leu Thr Arg Lys Pro Tyr Gln Pro Tyr Ala Pro Ala
85 90 95
Arg Asp Phe Ala Ala Tyr Arg Pro Arg Ala Lys Phe Ser Arg Ser Ala
100 105 110
Glu Thr Ala Ala Asn Leu Gln Asp Pro Asn Gln Leu Phe Asn Glu Leu
115 120 125
Asn Leu Gly Arg Arg Glu Glu Phe Asp Val Leu Glu Lys Lys Arg Ala
130 135 140
Arg Asp Pro Glu Met Gly Gly Lys Gln Gln Arg Arg Arg Asn Pro Gln
145 150 155 160
Glu Gly Val Tyr Asn Ala Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr
165 170 175
Ser Glu Ile Gly Thr Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp
180 185 190
Gly Leu Phe Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Phe Asp Ala
195 200 205
Leu His Met Gln Thr Leu Ala Pro Arg
210 215
<210> 25
<211> 30
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述:合成的寡核苷酸
<400> 25
gaacaaaaac tcatctcaga agaggatctg 30
<210> 26
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成的肽
<400> 26
Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu
1 5 10
<210> 27
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述:合成的引物
<400> 27
actcattgtg gctgtggaga 20
<210> 28
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述:合成的引物
<400> 28
ttgttcatct cggagcctgt 20
<210> 29
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述:合成的引物
<400> 29
ctggggatgt ctgtagctca 20
<210> 30
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述:合成的引物
<400> 30
ctgtgaagtc tcctctccgg 20
<210> 31
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述:合成的引物
<400> 31
gattgcgggg ttgtatctgg 20
<210> 32
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述:合成的引物
<400> 32
gctttctttc agggacagcc 20
<210> 33
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述:合成的引物
<400> 33
caactcccac tcttccacct 20
<210> 34
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述:合成的引物
<400> 34
gagttgggat agggcctctc 20
<210> 35
<211> 720
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述:合成的多核苷酸
<400> 35
ctgactcagc cgtcctcggt gtcagcgaac ccgggagaaa ccgtcgagat cacctgctcc 60
gggggtggca gctactatgg ctggtaccag cagaagtctc ctggcagtgc ccctgtcact 120
gtgatctata gcaacaacaa gagaccctcg gacatccctt cacgattctc cggttccaaa 180
tccggctcca caagcacatt aaccatcact ggggtccaag ccgacgacga ggctgtctat 240
tactgtggga gctacgacag caatgctggt atatttgggg ccgggacaac cctgaccgtc 300
ctaggtcagt cctctagatc ttccggcggt ggtggcagct ccggtggtgg cggttccgcc 360
gtgacgttgg acgagtccgg gggcggcctc cagacgcccg gaggagcact cagcctcgtc 420
tgcaaggcct ccgggttcac cttcagcagt tatgccatgg gttggatgcg ccaggcaccc 480
ggcaaggggc tggacttcgt cgctgaaatt agcggcagtg gcactagcac atactacggg 540
ccggcggtga agggccgtgc caccatctcg agggacaacg ggcggagcac agtgaggctg 600
cagctgaaca acctcagggc tgaggacacc ggcacctact tctgcacgag aggtggtggt 660
gctggtagtt acatcgacgc atggggccac gggaccgaag tcatcgtctc ctccactagt 720
<210> 36
<211> 240
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成的多肽
<400> 36
Leu Thr Gln Pro Ser Ser Val Ser Ala Asn Pro Gly Glu Thr Val Glu
1 5 10 15
Ile Thr Cys Ser Gly Gly Gly Ser Tyr Tyr Gly Trp Tyr Gln Gln Lys
20 25 30
Ser Pro Gly Ser Ala Pro Val Thr Val Ile Tyr Ser Asn Asn Lys Arg
35 40 45
Pro Ser Asp Ile Pro Ser Arg Phe Ser Gly Ser Lys Ser Gly Ser Thr
50 55 60
Ser Thr Leu Thr Ile Thr Gly Val Gln Ala Asp Asp Glu Ala Val Tyr
65 70 75 80
Tyr Cys Gly Ser Tyr Asp Ser Asn Ala Gly Ile Phe Gly Ala Gly Thr
85 90 95
Thr Leu Thr Val Leu Gly Gln Ser Ser Arg Ser Ser Gly Gly Gly Gly
100 105 110
Ser Ser Gly Gly Gly Gly Ser Ala Val Thr Leu Asp Glu Ser Gly Gly
115 120 125
Gly Leu Gln Thr Pro Gly Gly Ala Leu Ser Leu Val Cys Lys Ala Ser
130 135 140
Gly Phe Thr Phe Ser Ser Tyr Ala Met Gly Trp Met Arg Gln Ala Pro
145 150 155 160
Gly Lys Gly Leu Asp Phe Val Ala Glu Ile Ser Gly Ser Gly Thr Ser
165 170 175
Thr Tyr Tyr Gly Pro Ala Val Lys Gly Arg Ala Thr Ile Ser Arg Asp
180 185 190
Asn Gly Arg Ser Thr Val Arg Leu Gln Leu Asn Asn Leu Arg Ala Glu
195 200 205
Asp Thr Gly Thr Tyr Phe Cys Thr Arg Gly Gly Gly Ala Gly Ser Tyr
210 215 220
Ile Asp Ala Trp Gly His Gly Thr Glu Val Ile Val Ser Ser Thr Ser
225 230 235 240
<210> 37
<211> 753
<212> DNA
<213> 人工序列
<220>
<223> 人工序列的描述:合成的多核苷酸
<400> 37
atgcttctcc tggtgacaag ccttctgctc tgtgagttac cacacccagc attcctcctg 60
atcccagagc agaagctgat cagcgaggag gacctgattg aagttatgta tcctcctcct 120
tacctagaca atgagaagag caatggaacc attatccatg tgaaagggaa acacctttgt 180
ccaagtcccc tatttcccgg accttctaag cccttttggg tgctggtggt ggttggggga 240
gtcctggctt gctatagctt gctagtaaca gtggccttta ttattttctg ggtgaggagt 300
aagaggagca ggctcctgca cagtgactac atgaacatga ctccccgccg ccccgggccc 360
acccgcaagc attaccagcc ctatgcccca ccacgcgact tcgcagccta tcgctccaga 420
gtgaagttca gcaggagcgc agacgccccc gcgtaccagc agggccagaa ccagctctat 480
aacgagctca atctaggacg aagagaggag tacgatgttt tggacaagag acgtggccgg 540
gaccctgaga tggggggaaa gccgagaagg aagaaccctc aggaaggcct gtacaatgaa 600
ctgcagaaag ataagatggc ggaggcctac agtgagattg ggatgaaagg cgagcgccgg 660
aggggcaagg ggcacgatgg cctttaccag ggtctcagta cagccaccaa ggacacctac 720
gacgcccttc acatgcaggc cctgccccct cgc 753
<210> 38
<211> 251
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述:合成的多肽
<400> 38
Met Leu Leu Leu Val Thr Ser Leu Leu Leu Cys Glu Leu Pro His Pro
1 5 10 15
Ala Phe Leu Leu Ile Pro Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu
20 25 30
Ile Glu Val Met Tyr Pro Pro Pro Tyr Leu Asp Asn Glu Lys Ser Asn
35 40 45
Gly Thr Ile Ile His Val Lys Gly Lys His Leu Cys Pro Ser Pro Leu
50 55 60
Phe Pro Gly Pro Ser Lys Pro Phe Trp Val Leu Val Val Val Gly Gly
65 70 75 80
Val Leu Ala Cys Tyr Ser Leu Leu Val Thr Val Ala Phe Ile Ile Phe
85 90 95
Trp Val Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met Asn
100 105 110
Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr
115 120 125
Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser Arg Val Lys Phe Ser
130 135 140
Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr
145 150 155 160
Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys
165 170 175
Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn
180 185 190
Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu
195 200 205
Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly
210 215 220
His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr
225 230 235 240
Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg
245 250
Claims (35)
1.一种遗传修饰的调节性T细胞(Treg),其包含特异性结合补体成分4d(C4d)的抗原结合蛋白(ABP)。
2.根据权利要求1所述的调节性T细胞,其中所述抗原结合蛋白包含嵌合抗原受体(CAR)。
3.根据权利要求2所述的调节性T细胞,其中所述CAR包含特异性结合C4d的scFv。
4.根据权利要求1至3中任一项所述的调节性T细胞,其中所述ABP、所述CAR或所述scFv包含:轻链可变区(VL)和重链可变区(VH),
所述轻链可变区(VL)包含:
包含氨基酸序列SGSSGSYG的互补决定区(CDR)1,或其中1、2、3、4或5个氨基酸相对于所述序列被取代的变体LCDR1;
包含氨基酸序列YNDKRPS的LCDR2,或其中1、2、3、4或5个氨基酸相对于所述序列被取代的变体LCDR2;
包含氨基酸序列GSEDSSYVGV的LCDR3,或其中1、2、3、4或5个氨基酸相对于所述序列被取代的变体LCDR3;
所述重链可变区(VH)包含:
包含氨基酸序列SYALE的HCDR1,或其中1、2、3、4或5个氨基酸相对于所述序列被取代的变体HCDR1;
包含氨基酸序列GISSSGSGTNYGSAVKG的HCDR2,或其中1、2、3、4或5个氨基酸相对于所述序列被取代的变体HCDR2;
包含氨基酸序列AYGYVDAYGIDA的HCDR3,或其中1、2、3、4或5个氨基酸相对于所述序列被取代的变体HCDR3。
5.根据权利要求4所述的调节性T细胞,其中所述VL包含与LTQPSSVSANPGGTVEITCSGSSGSYGWYQQKSPGSAPVTVIYYNDKRPSDIPSRFSGSKSGSTATLTITGVQAEDEAVYFCGSEDSSYVGVFGAGTTLTVL(SEQ ID NO:2)具有至少95%同一性的氨基酸序列;并且所述VH包含与AVTLDESGGGLQTPGGTLSLVCKGSGFTFRSYALEWVRQAPGKGLEYVAGISSSGSGTNYGSAVKGRATISRDNGQSTVRLQLNNLRAEDTGTYYCAKSAYGYVDAYGIDAWGHGTEVIVSSTS(SEQ ID NO:4)具有至少95%同一性的氨基酸序列。
6.根据权利要求1至3中任一项所述的调节性T细胞,其中所述ABP、所述CAR或所述scFv包含:轻链可变区(VL)和重链可变区(VH),
所述轻链可变区(VL)包含:
包含氨基酸序列SGGGRWYG的LCDR1,或其中1、2、3、4或5个氨基酸相对于所述序列被取代的变体LCDR1;
包含氨基酸序列HANTKRPS的LCDR2,或其中1、2、3、4或5个氨基酸相对于所述序列被取代的变体LCDR2;
包含氨基酸序列GSGDSSTDSGI的LCDR3,或其中1、2、3、4或5个氨基酸相对于所述序列被取代的变体LCDR3;
所述重链可变区(VH)包含:
包含氨基酸序列DRAMH的HCDR1,或其中1、2、3、4或5个氨基酸相对于所述序列被取代的变体HCDR1;
包含氨基酸序列GIYSSGRYTGYGSAVKG的HCDR2,或其中1、2、3、4或5个氨基酸相对于所述序列被取代的变体HCDR2;
包含氨基酸序列AGSIYCGYADVACIDA的HCDR3,或其中1、2、3、4或5个氨基酸相对于所述序列被取代的变体HCDR3。
7.根据权利要求6所述的调节性T细胞,其中所述VL包含与LTQPSSVSANPGETVKITCSGGGRWYGWYQQKSPGSAPVTLIHANTKRPSNIPSRFSGSLSGSTSTLTISGVQAEDEAVYFCGSGDSSTDSGIFGAGTTLTVL(SEQ ID NO:6)具有至少95%同一性的氨基酸序列;并且所述VH包含与AVTLDESGGGLQTPGGALSLVCKASGFSFSDRAMHWVRQAPGKGLEWVAGIYSSGRYTGYGSAVKGRATISRDNGQSTVRLQLNNLRAEDTGTYYCAKAGSIYCGYADVACIDAWGHGTEVIVSSTS(SEQ ID NO:8)具有至少95%同一性的氨基酸序列。
8.根据权利要求1至3中任一项所述的调节性T细胞,其中所述ABP、所述CAR或所述scFv包含:轻链可变区(VL)和重链可变区(VH),
所述轻链可变区(VL)包含:
包含氨基酸序列SGGGSYYG的LCDR1,或其中1、2、3、4或5个氨基酸相对于所述序列被取代的变体LCDR1;
包含氨基酸序列SNNKRPS的LCDR2,或其中1、2、3、4或5个氨基酸相对于所述序列被取代的变体LCDR2;
包含氨基酸序列GSYDSNAGI的LCDR3,或其中1、2、3、4或5个氨基酸相对于所述序列被取代的变体LCDR3;
所述重链可变区(VH)包含:
包含氨基酸序列SYAMG的HCDR1,或其中1、2、3、4或5个氨基酸相对于所述序列被取代的变体HCDR1;
包含氨基酸序列EISGSGTSTYYGPAVKG的HCDR2,或其中1、2、3、4或5个氨基酸相对于所述序列被取代的变体HCDR2;
包含氨基酸序列CTRGGGAGSYIDA的HCDR3,或其中1、2、3、4或5个氨基酸相对于所述序列被取代的变体HCDR3。
9.根据权利要求8所述的调节性T细胞,其中所述VL包含与LTQPSSVSANPGETVEITCSGGGSYYGWYQQKSPGSAPVTVIYSNNKRPSDIPSRFSGSKSGSTSTLTITGVQADDEAVYYCGSYDSNAGIFGAGTTLTVL具有至少95%同一性的氨基酸序列;并且所述VH包含与AVTLDESGGGLQTPGGALSLVCKASGFTFSSYAMGWMRQAPGKGLDFVAEISGSGTSTYYGPAVKGRATISRDNGRSTVRLQLNNLRAEDTGTYFCTRGGGAGSYIDAWGHGTEVIVSSTS具有至少95%同一性的氨基酸序列。
10.根据权利要求1至3中任一项所述的调节性T细胞,其中所述ABP、所述CAR或所述scFv包含与SEQ ID NO:2、SEQ ID NO:6或LTQPSSVSANPGETVEITCSGGGSYYGWYQQKSPGSAPVTVIYSNNKRPSDIPSRFSGSKSGSTSTLTITGVQADDEAVYYCGSYDSNAGIFGAGTTLTVL具有至少80%序列同一性的轻链氨基酸序列。
11.根据权利要求1至3所述的调节性T细胞,其中所述ABP、所述CAR或所述scFv包含与SEQ ID NO:4、SEQ ID NO:8或AVTLDESGGGLQTPGGALSLVCKASGFTFSSYAMGWMRQAPGKGLDFVAEISGSGTSTYYGPAVKGRATISRDNGRSTVRLQLNNLRAEDTGTYFCTRGGGAGSYIDAWGHGTEVIVSSTS具有至少80%序列同一性的重链氨基酸序列。
12.根据权利要求3所述的调节性T细胞,其中所述scFv包含与以下具有至少80%序列同一性的氨基酸序列:
i)LTQPSSVSANPGGTVEITCSGSSGSYGWYQQKSPGSAPVTVIYYNDKRPSDIPSRFSGSKSGSTATLTITGVQAEDEAVYFCGSEDSSYVGV FGAGTTLTVLGQSSRSSGGGGSSGGGGSAVTLDESGGGLQTPGGTLSLVCKGSGFTFRSYALEWVRQAPGKGLEYVAGISSSGSGTNYGSAVKGRATISRDNGQSTVRLQLNNLRAEDTGTYYCAKSAYGYVDAYGIDA WGHGTEVIVSSTS;
ii)LTQPSSVSANPGETVKITCSGGGRWYGWYQQKSPGSAPVTLIHANTKRPSNIPSRFSGSLSGSTSTLTISGVQAEDEAVYFCGSGDSSTDSGIFGAGTTLTVLGQSSRSSGGGGSSGGGGSAVTLDESGGGLQTPGGALSLVCKASGFSFSDRAMHWVRQAPGKGLEWVAGIYSSGRYTGYGSAVKGRATISRDNGQSTVRLQLNNLRAEDTGTYYCAKAGSIYCGYADVACIDAWGHGTEVIVSST:或
iii)LTQPSSVSANPGETVEITCSGGGSYYGWYQQKSPGSAPVTVIYSNNKRPSDIPSRFSGSKSGSTSTLTITGVQADDEAVYYCGSYDSNAGIFGAGTTLTVLGQSSRSSGGGGSSGGGGSAVTLDESGGGLQTPGGALSLVCKASGFTFSSYAMGWMRQAPGKGLDFVAEISGSGTSTYYGPAVKGRATISRDNGRSTVRLQLNNLRAEDTGTYFCTRGGGAGSYIDAWGHGTEVIVSSTS。
13.根据权利要求2至12中任一项所述的调节性T细胞,其中所述CAR包含前导序列。
14.根据权利要求2至13中任一项所述的调节性T细胞,其中所述CAR包含铰链区。
15.根据权利要求14所述的调节性T细胞,其中所述铰链区包括人CD8铰链区。
16.根据权利要求15所述的调节性T细胞,其中所述铰链区包含SEQ ID NO:10的氨基酸序列或与SEQ ID NO:10具有至少80%同一性的序列。
17.根据权利要求2至16中任一项所述的调节性T细胞,其中所述CAR包含CD28跨膜结构域。
18.根据权利要求2至17中任一项所述的调节性T细胞,其中所述CAR包含CD28跨膜和胞质结构域。
19.根据权利要求18所述的调节性T细胞,其中所述CD28跨膜和胞质结构域包含SEQ IDNO:12的氨基酸序列或与SEQ ID NO:12具有至少80%同一性的序列。
20.根据权利要求2至19中任一项所述的调节性T细胞,其中所述CAR包含CD3ζ胞质结构域。
21.根据权利要求20所述的调节性T细胞,其中所述CD3ζ胞质结构域包含SEQ ID NO:14的氨基酸序列或与SEQ ID NO:14具有至少80%同一性的序列。
22.根据权利要求2至21中任一项所述的调节性T细胞,其中所述CAR包含c-myc标签。
23.一种调节性T细胞,所述调节性T细胞包含编码根据权利要求1至22任一项中所述的抗原结合蛋白的核酸。
24.一种载体,所述载体包含编码根据权利要求1至22任一项中所述的抗原结合蛋白的核酸。
25.根据权利要求24所述的载体,其中所述载体是逆转录病毒载体。
26.一种细胞,所述细胞包含根据权利要求24所述的载体。
27.根据权利要求26所述的细胞,其中所述细胞是哺乳动物细胞或细胞系。
28.一种用于产生根据权利要求1至22中任一项所述的调节性T细胞的方法,所述方法包括用根据权利要求24或25所述的载体转染或转导调节性T细胞,以及选择表达所述抗原结合蛋白的Treg。
29.一种用于诱导免疫应答的体外方法,所述方法包括使根据权利要求1至23中任一项所述的调节性T细胞与C4d抗原接触。
30.根据权利要求29所述的方法,其中与不表达特异性结合C4d的抗原结合蛋白的对照调节性T细胞相比,所述调节性T细胞上调CD69表达并分泌增加水平的IL-10和IFN-γ。
31.一种用于抑制T细胞增殖的体外方法,所述方法包括将根据权利要求1至23中任一项所述的调节性T细胞与活化的效应T细胞一起培养,以及确定所述效应T细胞的增殖的减少。
32.一种用于在接受移植物的受试者中抑制抗体介导的排斥(ABMR)的方法,所述方法包括向受试者施用治疗有效量的根据权利要求1至23中任一项所述的调节性T细胞。
33.根据权利要求32所述的方法,其中所述移植物是同种异体移植物。
34.根据权利要求33所述的方法,其中所述同种异体移植物是ABO血型不相容(ABOi)同种异体移植物。
35.根据权利要求33所述的方法,其中所述同种异体移植物是心脏同种异体移植物。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US202163139617P | 2021-01-20 | 2021-01-20 | |
US63/139,617 | 2021-01-20 | ||
PCT/IB2022/050495 WO2022157673A1 (en) | 2021-01-20 | 2022-01-20 | Anti-c4d chimeric antigen receptor regulatory t cells and uses thereof |
Publications (1)
Publication Number | Publication Date |
---|---|
CN116888259A true CN116888259A (zh) | 2023-10-13 |
Family
ID=82548544
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202280016047.XA Pending CN116888259A (zh) | 2021-01-20 | 2022-01-20 | 抗c4d嵌合抗原受体调节性t细胞及其用途 |
Country Status (7)
Country | Link |
---|---|
US (1) | US20240082305A1 (zh) |
EP (1) | EP4281547A1 (zh) |
JP (1) | JP2024508360A (zh) |
KR (1) | KR20230171422A (zh) |
CN (1) | CN116888259A (zh) |
BR (1) | BR112023014615A2 (zh) |
WO (1) | WO2022157673A1 (zh) |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20190151414A1 (en) * | 2016-05-10 | 2019-05-23 | Annexon, Inc. | Anti-complement factor c4/c4b antibodies and uses thereof |
-
2022
- 2022-01-20 JP JP2023543331A patent/JP2024508360A/ja active Pending
- 2022-01-20 CN CN202280016047.XA patent/CN116888259A/zh active Pending
- 2022-01-20 WO PCT/IB2022/050495 patent/WO2022157673A1/en active Application Filing
- 2022-01-20 US US18/262,303 patent/US20240082305A1/en active Pending
- 2022-01-20 KR KR1020237028369A patent/KR20230171422A/ko unknown
- 2022-01-20 EP EP22742351.4A patent/EP4281547A1/en active Pending
- 2022-01-20 BR BR112023014615A patent/BR112023014615A2/pt unknown
Also Published As
Publication number | Publication date |
---|---|
BR112023014615A2 (pt) | 2023-10-03 |
US20240082305A1 (en) | 2024-03-14 |
JP2024508360A (ja) | 2024-02-27 |
KR20230171422A (ko) | 2023-12-20 |
EP4281547A1 (en) | 2023-11-29 |
WO2022157673A1 (en) | 2022-07-28 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20220251195A1 (en) | Anti-tigit antibodies and their use as therapeutics and diagnostics | |
US11634494B2 (en) | Anti HLA-G specific antibodies | |
TWI701259B (zh) | 4﹘1bb抗體及其製備方法和應用 | |
CN115141279A (zh) | 抗b7-h3的单克隆抗体及其在细胞治疗中的应用 | |
KR20170057298A (ko) | Cd19에 특이적인 항체 및 키메라 항원 수용체 | |
WO2019114235A1 (zh) | Pdl1单克隆抗体及其应用 | |
CA3094996A1 (en) | Guidance and navigation control proteins and method of making and using thereof | |
EP3498293A1 (en) | Treatment of monogenic diseases with an anti-cd45rc antibody | |
US20220064254A1 (en) | Anti-hk2 chimeric antigen receptor (car) | |
CN109970859B (zh) | Glypican-3特异性抗体及其特异性CAR-T细胞 | |
CN115947854A (zh) | 抗人cd40蛋白单克隆抗体、制备方法及其应用 | |
US20240082305A1 (en) | Anti-c4d chimeric antigen receptor regulatory t cells and uses thereof | |
CN114685659A (zh) | Cd22特异性人源化抗体及利用其的嵌合抗原受体 | |
CN115785269B (zh) | 抗pd-l1的抗体及其应用 | |
CN114213537B (zh) | Cd133抗体、嵌合抗原受体及其应用 | |
CN114213538B (zh) | Cd44抗体、嵌合抗原受体及其应用 | |
TWI835166B (zh) | 靶向pd-1和/或ox40的特異性結合蛋白及其應用 | |
CN114316049B (zh) | Cd44抗体、嵌合抗原受体及其应用 | |
CN114316050B (zh) | Cd133抗体、嵌合抗原受体及其应用 | |
WO2024077104A2 (en) | Fibroblast activation protein (fap) car-invariant natural killer t cells and uses thereof | |
CN118108845A (zh) | 一种靶向B7-H3的CAR-γδT细胞的制备方法及应用 | |
WO2024044779A2 (en) | Antibodies and chimeric antigen receptors specific for delta-like ligand 3 (dll3) | |
WO2024081544A2 (en) | Compositions and methods of treating cancer with chimeric antigen receptors targeting claudin 18.2 | |
IL295164A (en) | Antibody molecules against lilrb3 and their uses | |
IL280731A (en) | Reactive protective armor |
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 |