CN114786701A - 用于治疗癌症的包括包含il-2蛋白和cd80蛋白的融合蛋白和免疫检查点抑制剂的药物组合物 - Google Patents
用于治疗癌症的包括包含il-2蛋白和cd80蛋白的融合蛋白和免疫检查点抑制剂的药物组合物 Download PDFInfo
- Publication number
- CN114786701A CN114786701A CN202080082872.0A CN202080082872A CN114786701A CN 114786701 A CN114786701 A CN 114786701A CN 202080082872 A CN202080082872 A CN 202080082872A CN 114786701 A CN114786701 A CN 114786701A
- Authority
- CN
- China
- Prior art keywords
- leu
- ser
- glu
- thr
- lys
- 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
- 108010002350 Interleukin-2 Proteins 0.000 title claims abstract description 209
- 102000000588 Interleukin-2 Human genes 0.000 title claims abstract description 209
- 108020001507 fusion proteins Proteins 0.000 title claims abstract description 177
- 102000037865 fusion proteins Human genes 0.000 title claims abstract description 177
- 206010028980 Neoplasm Diseases 0.000 title claims abstract description 153
- 201000011510 cancer Diseases 0.000 title claims abstract description 84
- 101000914484 Homo sapiens T-lymphocyte activation antigen CD80 Proteins 0.000 title claims abstract description 73
- 102100027222 T-lymphocyte activation antigen CD80 Human genes 0.000 title claims abstract description 67
- 238000011282 treatment Methods 0.000 title claims abstract description 38
- 229940076838 Immune checkpoint inhibitor Drugs 0.000 title claims abstract description 30
- 102000037984 Inhibitory immune checkpoint proteins Human genes 0.000 title claims abstract description 30
- 108091008026 Inhibitory immune checkpoint proteins Proteins 0.000 title claims abstract description 30
- 239000012274 immune-checkpoint protein inhibitor Substances 0.000 title claims abstract description 30
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 27
- 239000012634 fragment Substances 0.000 claims abstract description 56
- 239000013636 protein dimer Substances 0.000 claims abstract description 32
- 239000004480 active ingredient Substances 0.000 claims abstract description 14
- 125000003275 alpha amino acid group Chemical group 0.000 claims description 103
- 206010009944 Colon cancer Diseases 0.000 claims description 37
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 35
- 206010006187 Breast cancer Diseases 0.000 claims description 13
- 208000026310 Breast neoplasm Diseases 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 12
- 229940045513 CTLA4 antagonist Drugs 0.000 claims description 7
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 7
- 201000005202 lung cancer Diseases 0.000 claims description 7
- 208000020816 lung neoplasm Diseases 0.000 claims description 7
- 230000002265 prevention Effects 0.000 claims description 4
- 208000031261 Acute myeloid leukaemia Diseases 0.000 claims description 2
- 208000003174 Brain Neoplasms Diseases 0.000 claims description 2
- HFOBENSCBRZVSP-LKXGYXEUSA-N C[C@@H](O)[C@H](NC(=O)N[C@@H](CC(N)=O)c1nc(no1)[C@@H](N)CO)C(O)=O Chemical compound C[C@@H](O)[C@H](NC(=O)N[C@@H](CC(N)=O)c1nc(no1)[C@@H](N)CO)C(O)=O HFOBENSCBRZVSP-LKXGYXEUSA-N 0.000 claims description 2
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 2
- 206010023825 Laryngeal cancer Diseases 0.000 claims description 2
- 206010025323 Lymphomas Diseases 0.000 claims description 2
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 claims description 2
- 206010029260 Neuroblastoma Diseases 0.000 claims description 2
- 206010033128 Ovarian cancer Diseases 0.000 claims description 2
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 2
- 206010060862 Prostate cancer Diseases 0.000 claims description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 2
- 201000000582 Retinoblastoma Diseases 0.000 claims description 2
- 208000004337 Salivary Gland Neoplasms Diseases 0.000 claims description 2
- 206010061934 Salivary gland cancer Diseases 0.000 claims description 2
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 2
- 208000024770 Thyroid neoplasm Diseases 0.000 claims description 2
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 2
- 229960000548 alemtuzumab Drugs 0.000 claims description 2
- 201000010881 cervical cancer Diseases 0.000 claims description 2
- FHIVAFMUCKRCQO-UHFFFAOYSA-N diazinon Chemical compound CCOP(=S)(OCC)OC1=CC(C)=NC(C(C)C)=N1 FHIVAFMUCKRCQO-UHFFFAOYSA-N 0.000 claims description 2
- 229940056913 eftilagimod alfa Drugs 0.000 claims description 2
- 206010017758 gastric cancer Diseases 0.000 claims description 2
- 201000010536 head and neck cancer Diseases 0.000 claims description 2
- 208000014829 head and neck neoplasm Diseases 0.000 claims description 2
- 229960005386 ipilimumab Drugs 0.000 claims description 2
- 206010023841 laryngeal neoplasm Diseases 0.000 claims description 2
- 201000007270 liver cancer Diseases 0.000 claims description 2
- 208000014018 liver neoplasm Diseases 0.000 claims description 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 2
- 201000002528 pancreatic cancer Diseases 0.000 claims description 2
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 2
- 201000011549 stomach cancer Diseases 0.000 claims description 2
- 201000002510 thyroid cancer Diseases 0.000 claims description 2
- 229950007217 tremelimumab Drugs 0.000 claims description 2
- 230000000694 effects Effects 0.000 abstract description 39
- 229960002621 pembrolizumab Drugs 0.000 abstract description 20
- 210000000822 natural killer cell Anatomy 0.000 abstract description 16
- 210000002865 immune cell Anatomy 0.000 abstract description 15
- 108060003951 Immunoglobulin Proteins 0.000 abstract description 13
- 102000018358 immunoglobulin Human genes 0.000 abstract description 13
- 210000003289 regulatory T cell Anatomy 0.000 abstract description 12
- 230000002401 inhibitory effect Effects 0.000 abstract description 7
- 239000012270 PD-1 inhibitor Substances 0.000 abstract description 2
- 239000012668 PD-1-inhibitor Substances 0.000 abstract description 2
- 229940121655 pd-1 inhibitor Drugs 0.000 abstract description 2
- 210000004027 cell Anatomy 0.000 description 124
- 235000001014 amino acid Nutrition 0.000 description 113
- 241000699670 Mus sp. Species 0.000 description 103
- 229940024606 amino acid Drugs 0.000 description 87
- 150000001413 amino acids Chemical class 0.000 description 78
- 230000027455 binding Effects 0.000 description 63
- 230000004614 tumor growth Effects 0.000 description 59
- 210000001744 T-lymphocyte Anatomy 0.000 description 45
- 241000699666 Mus <mouse, genus> Species 0.000 description 40
- 230000005764 inhibitory process Effects 0.000 description 40
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 35
- 241000282414 Homo sapiens Species 0.000 description 34
- 108090000623 proteins and genes Proteins 0.000 description 34
- 238000002360 preparation method Methods 0.000 description 33
- 238000006467 substitution reaction Methods 0.000 description 33
- 108010001064 glycyl-glycyl-glycyl-glycine Proteins 0.000 description 31
- 108700004922 F42A Proteins 0.000 description 30
- 102220495631 Putative uncharacterized protein LOC645739_F42A_mutation Human genes 0.000 description 30
- 102000040430 polynucleotide Human genes 0.000 description 30
- 239000002157 polynucleotide Substances 0.000 description 30
- 108091033319 polynucleotide Proteins 0.000 description 30
- 102220596838 Non-structural maintenance of chromosomes element 1 homolog_R38A_mutation Human genes 0.000 description 29
- 238000012360 testing method Methods 0.000 description 28
- 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 27
- 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 26
- 108010031719 prolyl-serine Proteins 0.000 description 26
- 108040006849 interleukin-2 receptor activity proteins Proteins 0.000 description 25
- 230000001093 anti-cancer Effects 0.000 description 24
- 235000018102 proteins Nutrition 0.000 description 24
- 102000004169 proteins and genes Human genes 0.000 description 24
- 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 23
- 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 23
- 108010055341 glutamyl-glutamic acid Proteins 0.000 description 23
- 102100039498 Cytotoxic T-lymphocyte protein 4 Human genes 0.000 description 22
- 239000003446 ligand Substances 0.000 description 22
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 21
- 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 21
- 102100024216 Programmed cell death 1 ligand 1 Human genes 0.000 description 21
- 238000006243 chemical reaction Methods 0.000 description 21
- 239000002773 nucleotide Substances 0.000 description 21
- 125000003729 nucleotide group Chemical group 0.000 description 21
- 108010051110 tyrosyl-lysine Proteins 0.000 description 21
- 210000001266 CD8-positive T-lymphocyte Anatomy 0.000 description 20
- 239000000872 buffer Substances 0.000 description 20
- 239000013642 negative control Substances 0.000 description 20
- 102220505697 Palmitoyl-protein thioesterase 1_Y45F_mutation Human genes 0.000 description 19
- 102220610852 Thialysine N-epsilon-acetyltransferase_L72G_mutation Human genes 0.000 description 19
- 238000002347 injection Methods 0.000 description 19
- 239000007924 injection Substances 0.000 description 19
- 239000000203 mixture Substances 0.000 description 19
- 108010021064 CTLA-4 Antigen Proteins 0.000 description 18
- IHCXPSYCHXFXKT-DCAQKATOSA-N Pro-Arg-Glu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(O)=O IHCXPSYCHXFXKT-DCAQKATOSA-N 0.000 description 18
- 241001465754 Metazoa Species 0.000 description 17
- 108010013768 glutamyl-aspartyl-proline Proteins 0.000 description 17
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 17
- 210000001519 tissue Anatomy 0.000 description 17
- 238000002054 transplantation Methods 0.000 description 17
- MUSGDMDGNGXULI-DCAQKATOSA-N Glu-Glu-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CCC(O)=O MUSGDMDGNGXULI-DCAQKATOSA-N 0.000 description 16
- IVGJYOOGJLFKQE-AVGNSLFASA-N Glu-Leu-Lys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCC(=O)O)N IVGJYOOGJLFKQE-AVGNSLFASA-N 0.000 description 16
- 241000880493 Leptailurus serval Species 0.000 description 16
- VHDNDCPMHQMXIR-IHRRRGAJSA-N Phe-Met-Cys Chemical compound SC[C@@H](C(O)=O)NC(=O)[C@H](CCSC)NC(=O)[C@@H](N)CC1=CC=CC=C1 VHDNDCPMHQMXIR-IHRRRGAJSA-N 0.000 description 16
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 16
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 15
- 108010076504 Protein Sorting Signals Proteins 0.000 description 15
- NZYNRRGJJVSSTJ-GUBZILKMSA-N Val-Ser-Val Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O NZYNRRGJJVSSTJ-GUBZILKMSA-N 0.000 description 15
- 201000010099 disease Diseases 0.000 description 15
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 15
- 239000012091 fetal bovine serum Substances 0.000 description 15
- 108010034529 leucyl-lysine Proteins 0.000 description 15
- 239000000463 material Substances 0.000 description 15
- 108090000765 processed proteins & peptides Proteins 0.000 description 15
- 108010077112 prolyl-proline Proteins 0.000 description 15
- 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 14
- 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 14
- 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 14
- 238000010171 animal model Methods 0.000 description 14
- 108010052670 arginyl-glutamyl-glutamic acid Proteins 0.000 description 14
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 14
- 239000002953 phosphate buffered saline Substances 0.000 description 14
- 108010052774 valyl-lysyl-glycyl-phenylalanyl-tyrosine Proteins 0.000 description 14
- 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 13
- 238000012413 Fluorescence activated cell sorting analysis Methods 0.000 description 13
- PDQDCFBVYXEFSD-SRVKXCTJSA-N Leu-Leu-Asp Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O PDQDCFBVYXEFSD-SRVKXCTJSA-N 0.000 description 13
- 241001529936 Murinae Species 0.000 description 13
- JDMKQHSHKJHAHR-UHFFFAOYSA-N Phe-Phe-Leu-Tyr Natural products C=1C=C(O)C=CC=1CC(C(O)=O)NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)CC1=CC=CC=C1 JDMKQHSHKJHAHR-UHFFFAOYSA-N 0.000 description 13
- 102100040678 Programmed cell death protein 1 Human genes 0.000 description 13
- SYSWVVCYSXBVJG-RHYQMDGZSA-N Val-Leu-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C(C)C)N)O SYSWVVCYSXBVJG-RHYQMDGZSA-N 0.000 description 13
- 108010076324 alanyl-glycyl-glycine Proteins 0.000 description 13
- 108010049041 glutamylalanine Proteins 0.000 description 13
- 108010070643 prolylglutamic acid Proteins 0.000 description 13
- 108010015666 tryptophyl-leucyl-glutamic acid Proteins 0.000 description 13
- 108010074708 B7-H1 Antigen Proteins 0.000 description 12
- ALTQTAKGRFLRLR-GUBZILKMSA-N Cys-Val-Val Chemical compound CC(C)[C@@H](C(=O)N[C@@H](C(C)C)C(=O)O)NC(=O)[C@H](CS)N ALTQTAKGRFLRLR-GUBZILKMSA-N 0.000 description 12
- LHEZGZQRLDBSRR-WDCWCFNPSA-N Thr-Glu-Leu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O LHEZGZQRLDBSRR-WDCWCFNPSA-N 0.000 description 12
- 230000037396 body weight Effects 0.000 description 12
- 108010092114 histidylphenylalanine Proteins 0.000 description 12
- 108010090333 leucyl-lysyl-proline Proteins 0.000 description 12
- 108010054155 lysyllysine Proteins 0.000 description 12
- 238000005259 measurement Methods 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- GOVUDFOGXOONFT-VEVYYDQMSA-N Asn-Arg-Thr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(O)=O GOVUDFOGXOONFT-VEVYYDQMSA-N 0.000 description 11
- BVLIJXXSXBUGEC-SRVKXCTJSA-N Asn-Asn-Tyr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O BVLIJXXSXBUGEC-SRVKXCTJSA-N 0.000 description 11
- QNNBHTFDFFFHGC-KKUMJFAQSA-N Asn-Tyr-Lys Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC(=O)N)N)O QNNBHTFDFFFHGC-KKUMJFAQSA-N 0.000 description 11
- KAJAOGBVWCYGHZ-JTQLQIEISA-N Gly-Gly-Phe Chemical compound [NH3+]CC(=O)NCC(=O)N[C@H](C([O-])=O)CC1=CC=CC=C1 KAJAOGBVWCYGHZ-JTQLQIEISA-N 0.000 description 11
- 101000716102 Homo sapiens T-cell surface glycoprotein CD4 Proteins 0.000 description 11
- SJRQWEDYTKYHHL-SLFFLAALSA-N Phe-Tyr-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC2=CC=C(C=C2)O)NC(=O)[C@H](CC3=CC=CC=C3)N)C(=O)O SJRQWEDYTKYHHL-SLFFLAALSA-N 0.000 description 11
- LGIMRDKGABDMBN-DCAQKATOSA-N Ser-Val-Lys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CO)N LGIMRDKGABDMBN-DCAQKATOSA-N 0.000 description 11
- 102100036011 T-cell surface glycoprotein CD4 Human genes 0.000 description 11
- 108010044940 alanylglutamine Proteins 0.000 description 11
- 230000000259 anti-tumor effect Effects 0.000 description 11
- 239000003814 drug Substances 0.000 description 11
- 239000013641 positive control Substances 0.000 description 11
- 230000004083 survival effect Effects 0.000 description 11
- 108010071097 threonyl-lysyl-proline Proteins 0.000 description 11
- FNXCAFKDGBROCU-STECZYCISA-N Arg-Ile-Tyr Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 FNXCAFKDGBROCU-STECZYCISA-N 0.000 description 10
- UXHYOWXTJLBEPG-GSSVUCPTSA-N Asn-Thr-Thr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O UXHYOWXTJLBEPG-GSSVUCPTSA-N 0.000 description 10
- RFDHKPSHTXZKLL-IHRRRGAJSA-N Glu-Gln-Phe Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CCC(=O)O)N RFDHKPSHTXZKLL-IHRRRGAJSA-N 0.000 description 10
- BPCLDCNZBUYGOD-BPUTZDHNSA-N Glu-Trp-Glu Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](CCC(O)=O)N)C(=O)N[C@@H](CCC(O)=O)C(O)=O)=CNC2=C1 BPCLDCNZBUYGOD-BPUTZDHNSA-N 0.000 description 10
- MKWSZEHGHSLNPF-NAKRPEOUSA-N Ile-Ala-Val Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)O)N MKWSZEHGHSLNPF-NAKRPEOUSA-N 0.000 description 10
- MVHXGBZUJLWZOH-BJDJZHNGSA-N Leu-Ser-Ile Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O MVHXGBZUJLWZOH-BJDJZHNGSA-N 0.000 description 10
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 10
- VPEVBAUSTBWQHN-NHCYSSNCSA-N Pro-Glu-Val Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O VPEVBAUSTBWQHN-NHCYSSNCSA-N 0.000 description 10
- 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 10
- 108010047857 aspartylglycine Proteins 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 10
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 10
- 229940079593 drug Drugs 0.000 description 10
- 238000002474 experimental method Methods 0.000 description 10
- 108010025306 histidylleucine Proteins 0.000 description 10
- 108010073472 leucyl-prolyl-proline Proteins 0.000 description 10
- 108010003700 lysyl aspartic acid Proteins 0.000 description 10
- 108010064235 lysylglycine Proteins 0.000 description 10
- 239000002609 medium Substances 0.000 description 10
- 238000000746 purification Methods 0.000 description 10
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 10
- 238000003786 synthesis reaction Methods 0.000 description 10
- CQMQJWRCRQSBAF-BPUTZDHNSA-N Asn-Arg-Trp Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)O)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(=O)N)N CQMQJWRCRQSBAF-BPUTZDHNSA-N 0.000 description 9
- BKZFBJYIVSBXCO-KKUMJFAQSA-N Asn-Phe-His Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC1=CNC=N1)C(O)=O BKZFBJYIVSBXCO-KKUMJFAQSA-N 0.000 description 9
- JNCRAQVYJZGIOW-QSFUFRPTSA-N Asn-Val-Ile Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O JNCRAQVYJZGIOW-QSFUFRPTSA-N 0.000 description 9
- XDGBFDYXZCMYEX-NUMRIWBASA-N Asp-Glu-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CC(=O)O)N)O XDGBFDYXZCMYEX-NUMRIWBASA-N 0.000 description 9
- HHABWQIFXZPZCK-ACZMJKKPSA-N Cys-Gln-Ser Chemical compound C(CC(=O)N)[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CS)N HHABWQIFXZPZCK-ACZMJKKPSA-N 0.000 description 9
- XLLSMEFANRROJE-GUBZILKMSA-N Cys-Leu-Glu Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)O)NC(=O)[C@H](CS)N XLLSMEFANRROJE-GUBZILKMSA-N 0.000 description 9
- QKCZZAZNMMVICF-DCAQKATOSA-N Gln-Leu-Glu Chemical compound NC(=O)CC[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O QKCZZAZNMMVICF-DCAQKATOSA-N 0.000 description 9
- KPNWAJMEMRCLAL-GUBZILKMSA-N Gln-Ser-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(=O)N)N KPNWAJMEMRCLAL-GUBZILKMSA-N 0.000 description 9
- CAQXJMUDOLSBPF-SUSMZKCASA-N Glu-Thr-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O CAQXJMUDOLSBPF-SUSMZKCASA-N 0.000 description 9
- HVKAAUOFFTUSAA-XDTLVQLUSA-N Glu-Tyr-Ala 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](C)C(O)=O HVKAAUOFFTUSAA-XDTLVQLUSA-N 0.000 description 9
- MFYLRRCYBBJYPI-JYJNAYRXSA-N Glu-Tyr-Lys Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCC(=O)O)N)O MFYLRRCYBBJYPI-JYJNAYRXSA-N 0.000 description 9
- UROVZOUMHNXPLZ-AVGNSLFASA-N His-Leu-Gln Chemical compound NC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC1=CN=CN1 UROVZOUMHNXPLZ-AVGNSLFASA-N 0.000 description 9
- 101001117317 Homo sapiens Programmed cell death 1 ligand 1 Proteins 0.000 description 9
- WXLYNEHOGRYNFU-URLPEUOOSA-N Ile-Thr-Phe Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)N WXLYNEHOGRYNFU-URLPEUOOSA-N 0.000 description 9
- FADYJNXDPBKVCA-UHFFFAOYSA-N L-Phenylalanyl-L-lysin Natural products NCCCCC(C(O)=O)NC(=O)C(N)CC1=CC=CC=C1 FADYJNXDPBKVCA-UHFFFAOYSA-N 0.000 description 9
- CQQGCWPXDHTTNF-GUBZILKMSA-N Leu-Ala-Glu Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CCC(O)=O CQQGCWPXDHTTNF-GUBZILKMSA-N 0.000 description 9
- YQFZRHYZLARWDY-IHRRRGAJSA-N Leu-Val-Lys Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CCCCN YQFZRHYZLARWDY-IHRRRGAJSA-N 0.000 description 9
- XDGFFEZAZHRZFR-RHYQMDGZSA-N Met-Leu-Thr Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O XDGFFEZAZHRZFR-RHYQMDGZSA-N 0.000 description 9
- RMJZWERKFFNNNS-XGEHTFHBSA-N Pro-Thr-Ser Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(O)=O RMJZWERKFFNNNS-XGEHTFHBSA-N 0.000 description 9
- YMEXHZTVKDAKIY-GHCJXIJMSA-N Ser-Asn-Ile Chemical compound CC[C@H](C)[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CO)C(O)=O YMEXHZTVKDAKIY-GHCJXIJMSA-N 0.000 description 9
- RKDFEMGVMMYYNG-WDCWCFNPSA-N Thr-Gln-Leu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(O)=O RKDFEMGVMMYYNG-WDCWCFNPSA-N 0.000 description 9
- 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 9
- MGJLBZFUXUGMML-VOAKCMCISA-N Thr-Lys-Lys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)O)N)O MGJLBZFUXUGMML-VOAKCMCISA-N 0.000 description 9
- 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 9
- BTWMICVCQLKKNR-DCAQKATOSA-N Val-Leu-Ser Chemical compound CC(C)[C@H]([NH3+])C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C([O-])=O BTWMICVCQLKKNR-DCAQKATOSA-N 0.000 description 9
- RYHUIHUOYRNNIE-NRPADANISA-N Val-Ser-Gln Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N RYHUIHUOYRNNIE-NRPADANISA-N 0.000 description 9
- 108700025316 aldesleukin Proteins 0.000 description 9
- 108010077245 asparaginyl-proline Proteins 0.000 description 9
- 108010082286 glycyl-seryl-alanine Proteins 0.000 description 9
- 108010073093 leucyl-glycyl-glycyl-glycine Proteins 0.000 description 9
- 108010047926 leucyl-lysyl-tyrosine Proteins 0.000 description 9
- 238000011084 recovery Methods 0.000 description 9
- 108010048397 seryl-lysyl-leucine Proteins 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 108010031491 threonyl-lysyl-glutamic acid Proteins 0.000 description 9
- 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 8
- QFVHZQCOUORWEI-UHFFFAOYSA-N 4-[(4-anilino-5-sulfonaphthalen-1-yl)diazenyl]-5-hydroxynaphthalene-2,7-disulfonic acid Chemical compound C=12C(O)=CC(S(O)(=O)=O)=CC2=CC(S(O)(=O)=O)=CC=1N=NC(C1=CC=CC(=C11)S(O)(=O)=O)=CC=C1NC1=CC=CC=C1 QFVHZQCOUORWEI-UHFFFAOYSA-N 0.000 description 8
- BLTRAARCJYVJKV-QEJZJMRPSA-N Ala-Lys-Phe Chemical compound C[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](Cc1ccccc1)C(O)=O BLTRAARCJYVJKV-QEJZJMRPSA-N 0.000 description 8
- JEOCWTUOMKEEMF-RHYQMDGZSA-N Arg-Leu-Thr Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O JEOCWTUOMKEEMF-RHYQMDGZSA-N 0.000 description 8
- WKPXXXUSUHAXDE-SRVKXCTJSA-N Arg-Pro-Arg Chemical compound NC(N)=NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCN=C(N)N)C(O)=O WKPXXXUSUHAXDE-SRVKXCTJSA-N 0.000 description 8
- PSUXEQYPYZLNER-QXEWZRGKSA-N Arg-Val-Asn Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O PSUXEQYPYZLNER-QXEWZRGKSA-N 0.000 description 8
- SRUUBQBAVNQZGJ-LAEOZQHASA-N Asn-Gln-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CC(=O)N)N SRUUBQBAVNQZGJ-LAEOZQHASA-N 0.000 description 8
- PNHQRQTVBRDIEF-CIUDSAMLSA-N Asn-Leu-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(=O)N)N PNHQRQTVBRDIEF-CIUDSAMLSA-N 0.000 description 8
- AWXDRZJQCVHCIT-DCAQKATOSA-N Asn-Pro-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CC(N)=O AWXDRZJQCVHCIT-DCAQKATOSA-N 0.000 description 8
- HNXWVVHIGTZTBO-LKXGYXEUSA-N Asn-Ser-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O HNXWVVHIGTZTBO-LKXGYXEUSA-N 0.000 description 8
- QTKYFZCMSQLYHI-UBHSHLNASA-N Asn-Trp-Asn Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CC(N)=O)C(O)=O QTKYFZCMSQLYHI-UBHSHLNASA-N 0.000 description 8
- HRGGPWBIMIQANI-GUBZILKMSA-N Asp-Gln-Leu Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(O)=O HRGGPWBIMIQANI-GUBZILKMSA-N 0.000 description 8
- RQHLMGCXCZUOGT-ZPFDUUQYSA-N Asp-Leu-Ile Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O RQHLMGCXCZUOGT-ZPFDUUQYSA-N 0.000 description 8
- 238000011725 BALB/c mouse Methods 0.000 description 8
- NDNZRWUDUMTITL-FXQIFTODSA-N Cys-Ser-Val Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O NDNZRWUDUMTITL-FXQIFTODSA-N 0.000 description 8
- 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 8
- HPCOBEHVEHWREJ-DCAQKATOSA-N Gln-Lys-Glu Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(O)=O HPCOBEHVEHWREJ-DCAQKATOSA-N 0.000 description 8
- AQPZYBSRDRZBAG-AVGNSLFASA-N Gln-Phe-Asn Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CCC(=O)N)N AQPZYBSRDRZBAG-AVGNSLFASA-N 0.000 description 8
- RONJIBWTGKVKFY-HTUGSXCWSA-N Gln-Thr-Phe Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)NC(=O)[C@H](CCC(=O)N)N)O RONJIBWTGKVKFY-HTUGSXCWSA-N 0.000 description 8
- CKOFNWCLWRYUHK-XHNCKOQMSA-N Glu-Asp-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC(=O)O)NC(=O)[C@H](CCC(=O)O)N)C(=O)O CKOFNWCLWRYUHK-XHNCKOQMSA-N 0.000 description 8
- FKGNJUCQKXQNRA-NRPADANISA-N Glu-Cys-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H](CS)NC(=O)[C@@H](N)CCC(O)=O FKGNJUCQKXQNRA-NRPADANISA-N 0.000 description 8
- QNJNPKSWAHPYGI-JYJNAYRXSA-N Glu-Phe-Leu Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(O)=O)CC1=CC=CC=C1 QNJNPKSWAHPYGI-JYJNAYRXSA-N 0.000 description 8
- VIPDPMHGICREIS-GVXVVHGQSA-N Glu-Val-Leu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O VIPDPMHGICREIS-GVXVVHGQSA-N 0.000 description 8
- ZYRXTRTUCAVNBQ-GVXVVHGQSA-N Glu-Val-Lys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCC(=O)O)N ZYRXTRTUCAVNBQ-GVXVVHGQSA-N 0.000 description 8
- SOEATRRYCIPEHA-BQBZGAKWSA-N Gly-Glu-Glu Chemical compound [H]NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O SOEATRRYCIPEHA-BQBZGAKWSA-N 0.000 description 8
- AYBKPDHHVADEDA-YUMQZZPRSA-N Gly-His-Asn Chemical compound [H]NCC(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC(N)=O)C(O)=O AYBKPDHHVADEDA-YUMQZZPRSA-N 0.000 description 8
- DGKBSGNCMCLDSL-BYULHYEWSA-N Gly-Ile-Asn Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)CN DGKBSGNCMCLDSL-BYULHYEWSA-N 0.000 description 8
- GMTXWRIDLGTVFC-IUCAKERBSA-N Gly-Lys-Glu Chemical compound [H]NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(O)=O GMTXWRIDLGTVFC-IUCAKERBSA-N 0.000 description 8
- SYOJVRNQCXYEOV-XVKPBYJWSA-N Gly-Val-Glu Chemical compound [H]NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O SYOJVRNQCXYEOV-XVKPBYJWSA-N 0.000 description 8
- NCSIQAFSIPHVAN-IUKAMOBKSA-N Ile-Asn-Thr Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H]([C@@H](C)O)C(=O)O)N NCSIQAFSIPHVAN-IUKAMOBKSA-N 0.000 description 8
- DFJJAVZIHDFOGQ-MNXVOIDGSA-N Ile-Glu-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCCCN)C(=O)O)N DFJJAVZIHDFOGQ-MNXVOIDGSA-N 0.000 description 8
- TWYOYAKMLHWMOJ-ZPFDUUQYSA-N Ile-Leu-Asn Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O TWYOYAKMLHWMOJ-ZPFDUUQYSA-N 0.000 description 8
- JZNVOBUNTWNZPW-GHCJXIJMSA-N Ile-Ser-Asp Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(=O)O)C(=O)O)N JZNVOBUNTWNZPW-GHCJXIJMSA-N 0.000 description 8
- RQJUKVXWAKJDBW-SVSWQMSJSA-N Ile-Ser-Thr Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)O)N RQJUKVXWAKJDBW-SVSWQMSJSA-N 0.000 description 8
- BQIIHAGJIYOQBP-YFYLHZKVSA-N Ile-Trp-Pro Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)N3CCC[C@@H]3C(=O)O)N BQIIHAGJIYOQBP-YFYLHZKVSA-N 0.000 description 8
- WUFYAPWIHCUMLL-CIUDSAMLSA-N Leu-Asn-Ala Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(O)=O WUFYAPWIHCUMLL-CIUDSAMLSA-N 0.000 description 8
- 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 8
- AXZGZMGRBDQTEY-SRVKXCTJSA-N Leu-Gln-Met Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCSC)C(O)=O AXZGZMGRBDQTEY-SRVKXCTJSA-N 0.000 description 8
- HNDWYLYAYNBWMP-AJNGGQMLSA-N Leu-Ile-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC(C)C)N HNDWYLYAYNBWMP-AJNGGQMLSA-N 0.000 description 8
- 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 8
- KNKHAVVBVXKOGX-JXUBOQSCSA-N Lys-Ala-Thr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O KNKHAVVBVXKOGX-JXUBOQSCSA-N 0.000 description 8
- 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 8
- OWRUUFUVXFREBD-KKUMJFAQSA-N Lys-His-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC(C)C)C(O)=O OWRUUFUVXFREBD-KKUMJFAQSA-N 0.000 description 8
- KJIXWRWPOCKYLD-IHRRRGAJSA-N Lys-Lys-Met Chemical compound CSCC[C@@H](C(=O)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCCN)N KJIXWRWPOCKYLD-IHRRRGAJSA-N 0.000 description 8
- FWAHLGXNBLWIKB-NAKRPEOUSA-N Met-Ile-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H](N)CCSC FWAHLGXNBLWIKB-NAKRPEOUSA-N 0.000 description 8
- MGECUMGTSHYHEJ-QEWYBTABSA-N Phe-Glu-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CC1=CC=CC=C1 MGECUMGTSHYHEJ-QEWYBTABSA-N 0.000 description 8
- 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 8
- ULWBBFKQBDNGOY-RWMBFGLXSA-N Pro-Lys-Pro Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CCCCN)C(=O)N2CCC[C@@H]2C(=O)O ULWBBFKQBDNGOY-RWMBFGLXSA-N 0.000 description 8
- 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 8
- KHRLUIPIMIQFGT-AVGNSLFASA-N Pro-Val-Leu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O KHRLUIPIMIQFGT-AVGNSLFASA-N 0.000 description 8
- 101710089372 Programmed cell death protein 1 Proteins 0.000 description 8
- SRTCFKGBYBZRHA-ACZMJKKPSA-N Ser-Ala-Glu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(O)=O SRTCFKGBYBZRHA-ACZMJKKPSA-N 0.000 description 8
- XNCUYZKGQOCOQH-YUMQZZPRSA-N Ser-Leu-Gly Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O XNCUYZKGQOCOQH-YUMQZZPRSA-N 0.000 description 8
- MUJQWSAWLLRJCE-KATARQTJSA-N Ser-Leu-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O MUJQWSAWLLRJCE-KATARQTJSA-N 0.000 description 8
- 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 8
- XYFISNXATOERFZ-OSUNSFLBSA-N Thr-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@@H](C)O)N XYFISNXATOERFZ-OSUNSFLBSA-N 0.000 description 8
- 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 8
- ZESGVALRVJIVLZ-VFCFLDTKSA-N Thr-Thr-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)N1CCC[C@@H]1C(=O)O)N)O ZESGVALRVJIVLZ-VFCFLDTKSA-N 0.000 description 8
- XGFGVFMXDXALEV-XIRDDKMYSA-N Trp-Leu-Asn Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)N XGFGVFMXDXALEV-XIRDDKMYSA-N 0.000 description 8
- VPRHDRKAPYZMHL-SZMVWBNQSA-N Trp-Leu-Glu Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O)=CNC2=C1 VPRHDRKAPYZMHL-SZMVWBNQSA-N 0.000 description 8
- DXYWRYQRKPIGGU-BPNCWPANSA-N Tyr-Ala-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 DXYWRYQRKPIGGU-BPNCWPANSA-N 0.000 description 8
- QYSBJAUCUKHSLU-JYJNAYRXSA-N Tyr-Arg-Val Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(O)=O QYSBJAUCUKHSLU-JYJNAYRXSA-N 0.000 description 8
- GYBVHTWOQJMYAM-HRCADAONSA-N Tyr-Met-Pro Chemical compound CSCC[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CC2=CC=C(C=C2)O)N GYBVHTWOQJMYAM-HRCADAONSA-N 0.000 description 8
- BMGOFDMKDVVGJG-NHCYSSNCSA-N Val-Asp-Lys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CCCCN)C(=O)O)N BMGOFDMKDVVGJG-NHCYSSNCSA-N 0.000 description 8
- OACSGBOREVRSME-NHCYSSNCSA-N Val-His-Asn Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](Cc1cnc[nH]1)C(=O)N[C@@H](CC(N)=O)C(O)=O OACSGBOREVRSME-NHCYSSNCSA-N 0.000 description 8
- KNYHAWKHFQRYOX-PYJNHQTQSA-N Val-Ile-His Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](C(C)C)N KNYHAWKHFQRYOX-PYJNHQTQSA-N 0.000 description 8
- FTKXYXACXYOHND-XUXIUFHCSA-N Val-Ile-Leu Chemical compound CC(C)[C@H](N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(O)=O FTKXYXACXYOHND-XUXIUFHCSA-N 0.000 description 8
- AEMPCGRFEZTWIF-IHRRRGAJSA-N Val-Leu-Lys Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(O)=O AEMPCGRFEZTWIF-IHRRRGAJSA-N 0.000 description 8
- 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 8
- GVNLOVJNNDZUHS-RHYQMDGZSA-N Val-Thr-Lys Chemical compound [H]N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(O)=O GVNLOVJNNDZUHS-RHYQMDGZSA-N 0.000 description 8
- 229960005310 aldesleukin Drugs 0.000 description 8
- 108010038850 arginyl-isoleucyl-tyrosine Proteins 0.000 description 8
- 108010069205 aspartyl-phenylalanine Proteins 0.000 description 8
- 108010038633 aspartylglutamate Proteins 0.000 description 8
- FSXRLASFHBWESK-UHFFFAOYSA-N dipeptide phenylalanyl-tyrosine Natural products C=1C=C(O)C=CC=1CC(C(O)=O)NC(=O)C(N)CC1=CC=CC=C1 FSXRLASFHBWESK-UHFFFAOYSA-N 0.000 description 8
- XKUKSGPZAADMRA-UHFFFAOYSA-N glycyl-glycyl-glycine Chemical compound NCC(=O)NCC(=O)NCC(O)=O XKUKSGPZAADMRA-UHFFFAOYSA-N 0.000 description 8
- 108010089804 glycyl-threonine Proteins 0.000 description 8
- 108010091871 leucylmethionine Proteins 0.000 description 8
- 108010012058 leucyltyrosine Proteins 0.000 description 8
- DAEPDZWVDSPTHF-UHFFFAOYSA-M sodium pyruvate Chemical compound [Na+].CC(=O)C([O-])=O DAEPDZWVDSPTHF-UHFFFAOYSA-M 0.000 description 8
- MKZCBYZBCINNJN-DLOVCJGASA-N Ala-Asp-Phe Chemical compound C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 MKZCBYZBCINNJN-DLOVCJGASA-N 0.000 description 7
- MVBWLRJESQOQTM-ACZMJKKPSA-N Ala-Gln-Ser Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(O)=O MVBWLRJESQOQTM-ACZMJKKPSA-N 0.000 description 7
- SFNFGFDRYJKZKN-XQXXSGGOSA-N Ala-Gln-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](C)N)O SFNFGFDRYJKZKN-XQXXSGGOSA-N 0.000 description 7
- YHKANGMVQWRMAP-DCAQKATOSA-N Ala-Leu-Arg Chemical compound C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CCCN=C(N)N YHKANGMVQWRMAP-DCAQKATOSA-N 0.000 description 7
- 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 7
- OINVDEKBKBCPLX-JXUBOQSCSA-N Ala-Lys-Thr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O OINVDEKBKBCPLX-JXUBOQSCSA-N 0.000 description 7
- FFEUXEAKYRCACT-PEDHHIEDSA-N Arg-Ile-Ile Chemical compound CC[C@H](C)[C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)CCCNC(N)=N)[C@@H](C)CC)C(O)=O FFEUXEAKYRCACT-PEDHHIEDSA-N 0.000 description 7
- ZJBUILVYSXQNSW-YTWAJWBKSA-N Arg-Thr-Pro Chemical compound C[C@H]([C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCCN=C(N)N)N)O ZJBUILVYSXQNSW-YTWAJWBKSA-N 0.000 description 7
- AITGTTNYKAWKDR-CIUDSAMLSA-N Asn-His-Ser Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CO)C(O)=O AITGTTNYKAWKDR-CIUDSAMLSA-N 0.000 description 7
- WQLJRNRLHWJIRW-KKUMJFAQSA-N Asn-His-Tyr Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)O)NC(=O)[C@H](CC2=CN=CN2)NC(=O)[C@H](CC(=O)N)N)O WQLJRNRLHWJIRW-KKUMJFAQSA-N 0.000 description 7
- OLISTMZJGQUOGS-GMOBBJLQSA-N Asn-Ile-Arg Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)NC(=O)[C@H](CC(=O)N)N OLISTMZJGQUOGS-GMOBBJLQSA-N 0.000 description 7
- NYGILGUOUOXGMJ-YUMQZZPRSA-N Asn-Lys-Gly Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)NCC(O)=O NYGILGUOUOXGMJ-YUMQZZPRSA-N 0.000 description 7
- MPXTVIOEYISUQC-DHATWTDPSA-N Asn-Met-Thr-Thr Chemical compound CSCC[C@H](NC(=O)[C@@H](N)CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O MPXTVIOEYISUQC-DHATWTDPSA-N 0.000 description 7
- KBQOUDLMWYWXNP-YDHLFZDLSA-N Asn-Val-Phe Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)NC(=O)[C@H](CC(=O)N)N KBQOUDLMWYWXNP-YDHLFZDLSA-N 0.000 description 7
- NECWUSYTYSIFNC-DLOVCJGASA-N Asp-Ala-Phe Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 NECWUSYTYSIFNC-DLOVCJGASA-N 0.000 description 7
- CUQDCPXNZPDYFQ-ZLUOBGJFSA-N Asp-Ser-Asp Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(O)=O CUQDCPXNZPDYFQ-ZLUOBGJFSA-N 0.000 description 7
- QOJJMJKTMKNFEF-ZKWXMUAHSA-N Asp-Val-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CC(O)=O QOJJMJKTMKNFEF-ZKWXMUAHSA-N 0.000 description 7
- AOZBJZBKFHOYHL-AVGNSLFASA-N Cys-Glu-Tyr Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O AOZBJZBKFHOYHL-AVGNSLFASA-N 0.000 description 7
- OHLLDUNVMPPUMD-DCAQKATOSA-N Cys-Leu-Val Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](C(C)C)C(=O)O)NC(=O)[C@H](CS)N OHLLDUNVMPPUMD-DCAQKATOSA-N 0.000 description 7
- KSMSFCBQBQPFAD-GUBZILKMSA-N Cys-Pro-Pro Chemical compound SC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 KSMSFCBQBQPFAD-GUBZILKMSA-N 0.000 description 7
- UVAOVENCIONMJP-GUBZILKMSA-N Gln-Cys-Leu Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(C)C)C(O)=O UVAOVENCIONMJP-GUBZILKMSA-N 0.000 description 7
- CGVWDTRDPLOMHZ-FXQIFTODSA-N Gln-Glu-Asp Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O CGVWDTRDPLOMHZ-FXQIFTODSA-N 0.000 description 7
- 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 7
- LLRJEFPKIIBGJP-DCAQKATOSA-N Gln-Glu-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CCC(=O)N)N LLRJEFPKIIBGJP-DCAQKATOSA-N 0.000 description 7
- DOMHVQBSRJNNKD-ZPFDUUQYSA-N Gln-Met-Ile Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O DOMHVQBSRJNNKD-ZPFDUUQYSA-N 0.000 description 7
- HMIXCETWRYDVMO-GUBZILKMSA-N Gln-Pro-Glu Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O HMIXCETWRYDVMO-GUBZILKMSA-N 0.000 description 7
- FITIQFSXXBKFFM-NRPADANISA-N Gln-Val-Ser Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(O)=O FITIQFSXXBKFFM-NRPADANISA-N 0.000 description 7
- RUFHOVYUYSNDNY-ACZMJKKPSA-N Glu-Ala-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCC(O)=O RUFHOVYUYSNDNY-ACZMJKKPSA-N 0.000 description 7
- HPJLZFTUUJKWAJ-JHEQGTHGSA-N Glu-Gly-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(O)=O HPJLZFTUUJKWAJ-JHEQGTHGSA-N 0.000 description 7
- YHOJJFFTSMWVGR-HJGDQZAQSA-N Glu-Met-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H]([C@@H](C)O)C(O)=O YHOJJFFTSMWVGR-HJGDQZAQSA-N 0.000 description 7
- AAJHGGDRKHYSDH-GUBZILKMSA-N Glu-Pro-Gln Chemical compound C1C[C@H](N(C1)C(=O)[C@H](CCC(=O)O)N)C(=O)N[C@@H](CCC(=O)N)C(=O)O AAJHGGDRKHYSDH-GUBZILKMSA-N 0.000 description 7
- KIEICAOUSNYOLM-NRPADANISA-N Glu-Val-Ala Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C)C(O)=O KIEICAOUSNYOLM-NRPADANISA-N 0.000 description 7
- WGYHAAXZWPEBDQ-IFFSRLJSSA-N Glu-Val-Thr 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)O)C(O)=O WGYHAAXZWPEBDQ-IFFSRLJSSA-N 0.000 description 7
- ZRZILYKEJBMFHY-BQBZGAKWSA-N Gly-Asp-Met Chemical compound CSCC[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)CN ZRZILYKEJBMFHY-BQBZGAKWSA-N 0.000 description 7
- BUEFQXUHTUZXHR-LURJTMIESA-N Gly-Gly-Pro zwitterion Chemical compound NCC(=O)NCC(=O)N1CCC[C@H]1C(O)=O BUEFQXUHTUZXHR-LURJTMIESA-N 0.000 description 7
- OOCFXNOVSLSHAB-IUCAKERBSA-N Gly-Pro-Pro Chemical compound NCC(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 OOCFXNOVSLSHAB-IUCAKERBSA-N 0.000 description 7
- JSLVAHYTAJJEQH-QWRGUYRKSA-N Gly-Ser-Phe Chemical compound NCC(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 JSLVAHYTAJJEQH-QWRGUYRKSA-N 0.000 description 7
- 102100034458 Hepatitis A virus cellular receptor 2 Human genes 0.000 description 7
- LVXFNTIIGOQBMD-SRVKXCTJSA-N His-Leu-Ser Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O LVXFNTIIGOQBMD-SRVKXCTJSA-N 0.000 description 7
- 101000611936 Homo sapiens Programmed cell death protein 1 Proteins 0.000 description 7
- QIHJTGSVGIPHIW-QSFUFRPTSA-N Ile-Asn-Val Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](C(C)C)C(=O)O)N QIHJTGSVGIPHIW-QSFUFRPTSA-N 0.000 description 7
- IIWQTXMUALXGOV-PCBIJLKTSA-N Ile-Phe-Asp Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(=O)O)C(=O)O)N IIWQTXMUALXGOV-PCBIJLKTSA-N 0.000 description 7
- JODPUDMBQBIWCK-GHCJXIJMSA-N Ile-Ser-Asn Chemical compound [H]N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O JODPUDMBQBIWCK-GHCJXIJMSA-N 0.000 description 7
- SAEWJTCJQVZQNZ-IUKAMOBKSA-N Ile-Thr-Asn Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(=O)N)C(=O)O)N SAEWJTCJQVZQNZ-IUKAMOBKSA-N 0.000 description 7
- 102000037982 Immune checkpoint proteins Human genes 0.000 description 7
- 108091008036 Immune checkpoint proteins Proteins 0.000 description 7
- 108010038453 Interleukin-2 Receptors Proteins 0.000 description 7
- 102000010789 Interleukin-2 Receptors Human genes 0.000 description 7
- IGUOAYLTQJLPPD-DCAQKATOSA-N Leu-Asn-Arg Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(O)=O)CCCN=C(N)N IGUOAYLTQJLPPD-DCAQKATOSA-N 0.000 description 7
- BKTXKJMNTSMJDQ-AVGNSLFASA-N Leu-His-Gln Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N BKTXKJMNTSMJDQ-AVGNSLFASA-N 0.000 description 7
- KXODZBLFVFSLAI-AVGNSLFASA-N Leu-His-Glu Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC(C)C)CC1=CN=CN1 KXODZBLFVFSLAI-AVGNSLFASA-N 0.000 description 7
- UHNQRAFSEBGZFZ-YESZJQIVSA-N Leu-Phe-Pro Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N2CCC[C@@H]2C(=O)O)N UHNQRAFSEBGZFZ-YESZJQIVSA-N 0.000 description 7
- 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 7
- WSXTWLJHTLRFLW-SRVKXCTJSA-N Lys-Ala-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(O)=O WSXTWLJHTLRFLW-SRVKXCTJSA-N 0.000 description 7
- JGAMUXDWYSXYLM-SRVKXCTJSA-N Lys-Arg-Glu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(O)=O JGAMUXDWYSXYLM-SRVKXCTJSA-N 0.000 description 7
- UWHCKWNPWKTMBM-WDCWCFNPSA-N Lys-Thr-Gln Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(N)=O)C(O)=O UWHCKWNPWKTMBM-WDCWCFNPSA-N 0.000 description 7
- GILLQRYAWOMHED-DCAQKATOSA-N Lys-Val-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CCCCN GILLQRYAWOMHED-DCAQKATOSA-N 0.000 description 7
- XOFDBXYPKZUAAM-GUBZILKMSA-N Met-Met-Ser Chemical compound CSCC[C@@H](C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CO)C(=O)O)N XOFDBXYPKZUAAM-GUBZILKMSA-N 0.000 description 7
- AAERWTUHZKLDLC-IHRRRGAJSA-N Phe-Pro-Asp Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(O)=O)C(O)=O AAERWTUHZKLDLC-IHRRRGAJSA-N 0.000 description 7
- UAYHMOIGIQZLFR-NHCYSSNCSA-N Pro-Gln-Val Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(O)=O UAYHMOIGIQZLFR-NHCYSSNCSA-N 0.000 description 7
- LGSANCBHSMDFDY-GARJFASQSA-N Pro-Glu-Pro Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CCC(=O)O)C(=O)N2CCC[C@@H]2C(=O)O LGSANCBHSMDFDY-GARJFASQSA-N 0.000 description 7
- 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 7
- 239000012980 RPMI-1640 medium Substances 0.000 description 7
- UEJYSALTSUZXFV-SRVKXCTJSA-N Rigin Chemical compound NCC(=O)N[C@@H](CCC(N)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCN=C(N)N)C(O)=O UEJYSALTSUZXFV-SRVKXCTJSA-N 0.000 description 7
- HZWAHWQZPSXNCB-BPUTZDHNSA-N Ser-Arg-Trp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O HZWAHWQZPSXNCB-BPUTZDHNSA-N 0.000 description 7
- VAUMZJHYZQXZBQ-WHFBIAKZSA-N Ser-Asn-Gly Chemical compound OC[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(O)=O VAUMZJHYZQXZBQ-WHFBIAKZSA-N 0.000 description 7
- ZOHGLPQGEHSLPD-FXQIFTODSA-N Ser-Gln-Glu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O ZOHGLPQGEHSLPD-FXQIFTODSA-N 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
- QJKPECIAWNNKIT-KKUMJFAQSA-N Ser-Lys-Tyr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O QJKPECIAWNNKIT-KKUMJFAQSA-N 0.000 description 7
- OZPDGESCTGGNAD-CIUDSAMLSA-N Ser-Ser-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CO OZPDGESCTGGNAD-CIUDSAMLSA-N 0.000 description 7
- PCJLFYBAQZQOFE-KATARQTJSA-N Ser-Thr-Lys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CO)N)O PCJLFYBAQZQOFE-KATARQTJSA-N 0.000 description 7
- 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 7
- YEDSOSIKVUMIJE-DCAQKATOSA-N Ser-Val-Leu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O YEDSOSIKVUMIJE-DCAQKATOSA-N 0.000 description 7
- LAFLAXHTDVNVEL-WDCWCFNPSA-N Thr-Gln-Lys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CCCCN)C(=O)O)N)O LAFLAXHTDVNVEL-WDCWCFNPSA-N 0.000 description 7
- BDYBHQWMHYDRKJ-UNQGMJICSA-N Thr-Phe-Met Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCSC)C(=O)O)N)O BDYBHQWMHYDRKJ-UNQGMJICSA-N 0.000 description 7
- CSNBWOJOEOPYIJ-UVOCVTCTSA-N Thr-Thr-Lys Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(O)=O CSNBWOJOEOPYIJ-UVOCVTCTSA-N 0.000 description 7
- MNYNCKZAEIAONY-XGEHTFHBSA-N Thr-Val-Ser Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(O)=O MNYNCKZAEIAONY-XGEHTFHBSA-N 0.000 description 7
- YDTKYBHPRULROG-LTHWPDAASA-N Trp-Ile-Thr Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)N YDTKYBHPRULROG-LTHWPDAASA-N 0.000 description 7
- SSSDKJMQMZTMJP-BVSLBCMMSA-N Trp-Tyr-Val Chemical compound C([C@@H](C(=O)N[C@@H](C(C)C)C(O)=O)NC(=O)[C@@H](N)CC=1C2=CC=CC=C2NC=1)C1=CC=C(O)C=C1 SSSDKJMQMZTMJP-BVSLBCMMSA-N 0.000 description 7
- SLCSPPCQWUHPPO-JYJNAYRXSA-N Tyr-Glu-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 SLCSPPCQWUHPPO-JYJNAYRXSA-N 0.000 description 7
- IJUTXXAXQODRMW-KBPBESRZSA-N Tyr-Gly-His Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)NCC(=O)N[C@@H](CC2=CN=CN2)C(=O)O)N)O IJUTXXAXQODRMW-KBPBESRZSA-N 0.000 description 7
- GZUIDWDVMWZSMI-KKUMJFAQSA-N Tyr-Lys-Cys Chemical compound NCCCC[C@@H](C(=O)N[C@@H](CS)C(O)=O)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 GZUIDWDVMWZSMI-KKUMJFAQSA-N 0.000 description 7
- PWKMJDQXKCENMF-MEYUZBJRSA-N Tyr-Thr-Leu Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O PWKMJDQXKCENMF-MEYUZBJRSA-N 0.000 description 7
- BGTDGENDNWGMDQ-KJEVXHAQSA-N Val-Tyr-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)NC(=O)[C@H](C(C)C)N)O BGTDGENDNWGMDQ-KJEVXHAQSA-N 0.000 description 7
- 238000002835 absorbance Methods 0.000 description 7
- 108010087924 alanylproline Proteins 0.000 description 7
- 238000004458 analytical method Methods 0.000 description 7
- 108010060199 cysteinylproline Proteins 0.000 description 7
- 210000004443 dendritic cell Anatomy 0.000 description 7
- 238000001514 detection method Methods 0.000 description 7
- 239000000539 dimer Substances 0.000 description 7
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 7
- 108010010147 glycylglutamine Proteins 0.000 description 7
- 108010050848 glycylleucine Proteins 0.000 description 7
- 108010027338 isoleucylcysteine Proteins 0.000 description 7
- 108010078274 isoleucylvaline Proteins 0.000 description 7
- 108010057821 leucylproline Proteins 0.000 description 7
- 108010038320 lysylphenylalanine Proteins 0.000 description 7
- 108010073101 phenylalanylleucine Proteins 0.000 description 7
- 108010051242 phenylalanylserine Proteins 0.000 description 7
- 230000035755 proliferation Effects 0.000 description 7
- 229960005322 streptomycin Drugs 0.000 description 7
- 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 6
- 239000004475 Arginine Substances 0.000 description 6
- SNDBKTFJWVEVPO-WHFBIAKZSA-N Asp-Gly-Ser Chemical compound [H]N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@@H](CO)C(O)=O SNDBKTFJWVEVPO-WHFBIAKZSA-N 0.000 description 6
- DPNWSMBUYCLEDG-CIUDSAMLSA-N Asp-Lys-Ser Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(O)=O DPNWSMBUYCLEDG-CIUDSAMLSA-N 0.000 description 6
- SMEYEQDCCBHTEF-FXQIFTODSA-N Cys-Pro-Ala Chemical compound [H]N[C@@H](CS)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C)C(O)=O SMEYEQDCCBHTEF-FXQIFTODSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- DHNWZLGBTPUTQQ-QEJZJMRPSA-N Gln-Asp-Trp Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CCC(=O)N)N DHNWZLGBTPUTQQ-QEJZJMRPSA-N 0.000 description 6
- KHNJVFYHIKLUPD-SRVKXCTJSA-N Gln-Leu-Met Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCSC)C(=O)O)NC(=O)[C@H](CCC(=O)N)N KHNJVFYHIKLUPD-SRVKXCTJSA-N 0.000 description 6
- DVLZZEPUNFEUBW-AVGNSLFASA-N Glu-His-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CC1=CN=CN1)NC(=O)[C@H](CCC(=O)O)N DVLZZEPUNFEUBW-AVGNSLFASA-N 0.000 description 6
- QDMVXRNLOPTPIE-WDCWCFNPSA-N Glu-Lys-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O QDMVXRNLOPTPIE-WDCWCFNPSA-N 0.000 description 6
- HAOUOFNNJJLVNS-BQBZGAKWSA-N Gly-Pro-Ser Chemical compound NCC(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O HAOUOFNNJJLVNS-BQBZGAKWSA-N 0.000 description 6
- MAABHGXCIBEYQR-XVYDVKMFSA-N His-Asn-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CC1=CN=CN1)N MAABHGXCIBEYQR-XVYDVKMFSA-N 0.000 description 6
- HIAHVKLTHNOENC-HGNGGELXSA-N His-Glu-Ala Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(O)=O HIAHVKLTHNOENC-HGNGGELXSA-N 0.000 description 6
- 101000889276 Homo sapiens Cytotoxic T-lymphocyte protein 4 Proteins 0.000 description 6
- FFJQAEYLAQMGDL-MGHWNKPDSA-N Ile-Lys-Tyr Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 FFJQAEYLAQMGDL-MGHWNKPDSA-N 0.000 description 6
- 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 6
- 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 6
- 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 6
- PVMPDMIKUVNOBD-CIUDSAMLSA-N Leu-Asp-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O PVMPDMIKUVNOBD-CIUDSAMLSA-N 0.000 description 6
- WIDZHJTYKYBLSR-DCAQKATOSA-N Leu-Glu-Glu Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O WIDZHJTYKYBLSR-DCAQKATOSA-N 0.000 description 6
- XVZCXCTYGHPNEM-UHFFFAOYSA-N Leu-Leu-Pro Natural products CC(C)CC(N)C(=O)NC(CC(C)C)C(=O)N1CCCC1C(O)=O XVZCXCTYGHPNEM-UHFFFAOYSA-N 0.000 description 6
- ZJZNLRVCZWUONM-JXUBOQSCSA-N Leu-Thr-Ala Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O ZJZNLRVCZWUONM-JXUBOQSCSA-N 0.000 description 6
- LINKCQUOMUDLKN-KATARQTJSA-N Leu-Thr-Cys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC(C)C)N)O LINKCQUOMUDLKN-KATARQTJSA-N 0.000 description 6
- ODUQLUADRKMHOZ-JYJNAYRXSA-N Lys-Glu-Tyr Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CCCCN)N)O ODUQLUADRKMHOZ-JYJNAYRXSA-N 0.000 description 6
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 6
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 6
- TUYWCHPXKQTISF-LPEHRKFASA-N Pro-Cys-Pro Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CS)C(=O)N2CCC[C@@H]2C(=O)O TUYWCHPXKQTISF-LPEHRKFASA-N 0.000 description 6
- HWLKHNDRXWTFTN-GUBZILKMSA-N Pro-Pro-Cys Chemical compound C1C[C@H](NC1)C(=O)N2CCC[C@H]2C(=O)N[C@@H](CS)C(=O)O HWLKHNDRXWTFTN-GUBZILKMSA-N 0.000 description 6
- YUJLIIRMIAGMCQ-CIUDSAMLSA-N Ser-Leu-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O YUJLIIRMIAGMCQ-CIUDSAMLSA-N 0.000 description 6
- JCLAFVNDBJMLBC-JBDRJPRFSA-N Ser-Ser-Ile Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O JCLAFVNDBJMLBC-JBDRJPRFSA-N 0.000 description 6
- HNDMFDBQXYZSRM-IHRRRGAJSA-N Ser-Val-Phe Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O HNDMFDBQXYZSRM-IHRRRGAJSA-N 0.000 description 6
- 230000006052 T cell proliferation Effects 0.000 description 6
- MROIJTGJGIDEEJ-RCWTZXSCSA-N Thr-Pro-Pro Chemical compound C[C@@H](O)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 MROIJTGJGIDEEJ-RCWTZXSCSA-N 0.000 description 6
- GITNQBVCEQBDQC-KKUMJFAQSA-N Tyr-Lys-Asn Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(O)=O GITNQBVCEQBDQC-KKUMJFAQSA-N 0.000 description 6
- RWOKVQUCENPXGE-IHRRRGAJSA-N Tyr-Ser-Arg Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O RWOKVQUCENPXGE-IHRRRGAJSA-N 0.000 description 6
- UEHRGZCNLSWGHK-DLOVCJGASA-N Val-Glu-Val Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O UEHRGZCNLSWGHK-DLOVCJGASA-N 0.000 description 6
- XTDDIVQWDXMRJL-IHRRRGAJSA-N Val-Leu-His Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](C(C)C)N XTDDIVQWDXMRJL-IHRRRGAJSA-N 0.000 description 6
- LLJLBRRXKZTTRD-GUBZILKMSA-N Val-Val-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(=O)O)N LLJLBRRXKZTTRD-GUBZILKMSA-N 0.000 description 6
- 230000000735 allogeneic effect Effects 0.000 description 6
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 239000012153 distilled water Substances 0.000 description 6
- 108010015792 glycyllysine Proteins 0.000 description 6
- 102000054189 human CD80 Human genes 0.000 description 6
- 239000012528 membrane Substances 0.000 description 6
- 102000005962 receptors Human genes 0.000 description 6
- 108020003175 receptors Proteins 0.000 description 6
- 230000005760 tumorsuppression Effects 0.000 description 6
- WDIYWDJLXOCGRW-ACZMJKKPSA-N Ala-Asp-Glu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O WDIYWDJLXOCGRW-ACZMJKKPSA-N 0.000 description 5
- XSTZMVAYYCJTNR-DCAQKATOSA-N Ala-Met-Leu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(C)C)C(O)=O XSTZMVAYYCJTNR-DCAQKATOSA-N 0.000 description 5
- LSMDIAAALJJLRO-XQXXSGGOSA-N Ala-Thr-Glu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(O)=O)C(O)=O LSMDIAAALJJLRO-XQXXSGGOSA-N 0.000 description 5
- DHONNEYAZPNGSG-UBHSHLNASA-N Ala-Val-Phe Chemical compound C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 DHONNEYAZPNGSG-UBHSHLNASA-N 0.000 description 5
- IDDMGSKZQDEDGA-SRVKXCTJSA-N Asp-Phe-Asn Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](CC(N)=O)C(O)=O)CC1=CC=CC=C1 IDDMGSKZQDEDGA-SRVKXCTJSA-N 0.000 description 5
- 238000011740 C57BL/6 mouse Methods 0.000 description 5
- 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 5
- FGPLUIQCSKGLTI-WDSKDSINSA-N Gly-Ser-Glu Chemical compound NCC(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CCC(O)=O FGPLUIQCSKGLTI-WDSKDSINSA-N 0.000 description 5
- SKYULSWNBYAQMG-IHRRRGAJSA-N His-Leu-Arg Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O SKYULSWNBYAQMG-IHRRRGAJSA-N 0.000 description 5
- 241000282412 Homo Species 0.000 description 5
- 101001068133 Homo sapiens Hepatitis A virus cellular receptor 2 Proteins 0.000 description 5
- 101000914514 Homo sapiens T-cell-specific surface glycoprotein CD28 Proteins 0.000 description 5
- QYZYJFXHXYUZMZ-UGYAYLCHSA-N Ile-Asn-Asn Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC(=O)N)C(=O)O)N QYZYJFXHXYUZMZ-UGYAYLCHSA-N 0.000 description 5
- TWPSALMCEHCIOY-YTFOTSKYSA-N Ile-Ile-Leu Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(=O)O)N TWPSALMCEHCIOY-YTFOTSKYSA-N 0.000 description 5
- YWCJXQKATPNPOE-UKJIMTQDSA-N Ile-Val-Glu Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N YWCJXQKATPNPOE-UKJIMTQDSA-N 0.000 description 5
- UYODHPPSCXBNCS-XUXIUFHCSA-N Ile-Val-Leu Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CC(C)C UYODHPPSCXBNCS-XUXIUFHCSA-N 0.000 description 5
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 5
- 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 5
- RTIRBWJPYJYTLO-MELADBBJSA-N Leu-Lys-Pro Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N1CCC[C@@H]1C(=O)O)N RTIRBWJPYJYTLO-MELADBBJSA-N 0.000 description 5
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 5
- YVSHZSUKQHNDHD-KKUMJFAQSA-N Lys-Asn-Phe Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CCCCN)N YVSHZSUKQHNDHD-KKUMJFAQSA-N 0.000 description 5
- XMBSYZWANAQXEV-UHFFFAOYSA-N N-alpha-L-glutamyl-L-phenylalanine Natural products OC(=O)CCC(N)C(=O)NC(C(O)=O)CC1=CC=CC=C1 XMBSYZWANAQXEV-UHFFFAOYSA-N 0.000 description 5
- 229930182555 Penicillin Natural products 0.000 description 5
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 5
- FSPGBMWPNMRWDB-AVGNSLFASA-N Phe-Cys-Gln Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N FSPGBMWPNMRWDB-AVGNSLFASA-N 0.000 description 5
- SSSFPISOZOLQNP-GUBZILKMSA-N Pro-Arg-Asp Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(O)=O SSSFPISOZOLQNP-GUBZILKMSA-N 0.000 description 5
- RMODQFBNDDENCP-IHRRRGAJSA-N Pro-Lys-Leu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(O)=O RMODQFBNDDENCP-IHRRRGAJSA-N 0.000 description 5
- DWGFLKQSGRUQTI-IHRRRGAJSA-N Pro-Lys-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H]1CCCN1 DWGFLKQSGRUQTI-IHRRRGAJSA-N 0.000 description 5
- FYUIFUJFNCLUIX-XVYDVKMFSA-N Ser-His-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](C)C(O)=O FYUIFUJFNCLUIX-XVYDVKMFSA-N 0.000 description 5
- HBTCFCHYALPXME-HTFCKZLJSA-N Ser-Ile-Ile Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O HBTCFCHYALPXME-HTFCKZLJSA-N 0.000 description 5
- 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 5
- 102100027213 T-cell-specific surface glycoprotein CD28 Human genes 0.000 description 5
- ZUXQFMVPAYGPFJ-JXUBOQSCSA-N Thr-Ala-Lys Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CCCCN ZUXQFMVPAYGPFJ-JXUBOQSCSA-N 0.000 description 5
- 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 5
- GBIUHAYJGWVNLN-AEJSXWLSSA-N Val-Ser-Pro Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CO)C(=O)N1CCC[C@@H]1C(=O)O)N GBIUHAYJGWVNLN-AEJSXWLSSA-N 0.000 description 5
- GBIUHAYJGWVNLN-UHFFFAOYSA-N Val-Ser-Pro Natural products CC(C)C(N)C(=O)NC(CO)C(=O)N1CCCC1C(O)=O GBIUHAYJGWVNLN-UHFFFAOYSA-N 0.000 description 5
- ZLNYBMWGPOKSLW-LSJOCFKGSA-N Val-Val-Asp Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O ZLNYBMWGPOKSLW-LSJOCFKGSA-N 0.000 description 5
- 108010086434 alanyl-seryl-glycine Proteins 0.000 description 5
- 108010041407 alanylaspartic acid Proteins 0.000 description 5
- 239000002246 antineoplastic agent Substances 0.000 description 5
- 238000011284 combination treatment Methods 0.000 description 5
- 210000004748 cultured cell Anatomy 0.000 description 5
- 239000012636 effector Substances 0.000 description 5
- 235000013922 glutamic acid Nutrition 0.000 description 5
- 239000004220 glutamic acid Substances 0.000 description 5
- 230000013595 glycosylation Effects 0.000 description 5
- 238000006206 glycosylation reaction Methods 0.000 description 5
- 230000005965 immune activity Effects 0.000 description 5
- 230000028993 immune response Effects 0.000 description 5
- 210000002540 macrophage Anatomy 0.000 description 5
- 229960004857 mitomycin Drugs 0.000 description 5
- 229940049954 penicillin Drugs 0.000 description 5
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 5
- 108010025488 pinealon Proteins 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- 108010080629 tryptophan-leucine Proteins 0.000 description 5
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 5
- XVZCXCTYGHPNEM-IHRRRGAJSA-N (2s)-1-[(2s)-2-[[(2s)-2-amino-4-methylpentanoyl]amino]-4-methylpentanoyl]pyrrolidine-2-carboxylic acid Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N1CCC[C@H]1C(O)=O XVZCXCTYGHPNEM-IHRRRGAJSA-N 0.000 description 4
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 4
- XWTNPSHCJMZAHQ-QMMMGPOBSA-N 2-[[2-[[2-[[(2s)-2-amino-4-methylpentanoyl]amino]acetyl]amino]acetyl]amino]acetic acid Chemical compound CC(C)C[C@H](N)C(=O)NCC(=O)NCC(=O)NCC(O)=O XWTNPSHCJMZAHQ-QMMMGPOBSA-N 0.000 description 4
- SUHLZMHFRALVSY-YUMQZZPRSA-N Ala-Lys-Gly Chemical compound NCCCC[C@H](NC(=O)[C@@H](N)C)C(=O)NCC(O)=O SUHLZMHFRALVSY-YUMQZZPRSA-N 0.000 description 4
- IORKCNUBHNIMKY-CIUDSAMLSA-N Ala-Pro-Glu Chemical compound C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O IORKCNUBHNIMKY-CIUDSAMLSA-N 0.000 description 4
- 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 4
- YJHKTAMKPGFJCT-NRPADANISA-N Ala-Val-Glu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O YJHKTAMKPGFJCT-NRPADANISA-N 0.000 description 4
- OTCJMMRQBVDQRK-DCAQKATOSA-N Arg-Asp-Leu Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O OTCJMMRQBVDQRK-DCAQKATOSA-N 0.000 description 4
- ZUVMUOOHJYNJPP-XIRDDKMYSA-N Arg-Trp-Gln Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CCC(N)=O)C(O)=O ZUVMUOOHJYNJPP-XIRDDKMYSA-N 0.000 description 4
- 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 4
- SUEIIIFUBHDCCS-PBCZWWQYSA-N Asn-His-Thr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O SUEIIIFUBHDCCS-PBCZWWQYSA-N 0.000 description 4
- HPNDKUOLNRVRAY-BIIVOSGPSA-N Asn-Ser-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CO)NC(=O)[C@H](CC(=O)N)N)C(=O)O HPNDKUOLNRVRAY-BIIVOSGPSA-N 0.000 description 4
- AXXCUABIFZPKPM-BQBZGAKWSA-N Asp-Arg-Gly Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O AXXCUABIFZPKPM-BQBZGAKWSA-N 0.000 description 4
- MYLZFUMPZCPJCJ-NHCYSSNCSA-N Asp-Lys-Val Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(O)=O MYLZFUMPZCPJCJ-NHCYSSNCSA-N 0.000 description 4
- 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 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 102100029822 B- and T-lymphocyte attenuator Human genes 0.000 description 4
- 102000017420 CD3 protein, epsilon/gamma/delta subunit Human genes 0.000 description 4
- XXDLUZLKHOVPNW-IHRRRGAJSA-N Cys-Arg-Tyr Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)O)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CS)N)O XXDLUZLKHOVPNW-IHRRRGAJSA-N 0.000 description 4
- 238000008157 ELISA kit Methods 0.000 description 4
- 102100031351 Galectin-9 Human genes 0.000 description 4
- SNLOOPZHAQDMJG-CIUDSAMLSA-N Gln-Glu-Glu Chemical compound NC(=O)CC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O SNLOOPZHAQDMJG-CIUDSAMLSA-N 0.000 description 4
- YPMDZWPZFOZYFG-GUBZILKMSA-N Gln-Leu-Ser Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O YPMDZWPZFOZYFG-GUBZILKMSA-N 0.000 description 4
- JRHPEMVLTRADLJ-AVGNSLFASA-N Gln-Lys-Lys Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCC(=O)N)N JRHPEMVLTRADLJ-AVGNSLFASA-N 0.000 description 4
- NLKVNZUFDPWPNL-YUMQZZPRSA-N Glu-Arg-Gly Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O NLKVNZUFDPWPNL-YUMQZZPRSA-N 0.000 description 4
- XXCDTYBVGMPIOA-FXQIFTODSA-N Glu-Asp-Glu Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O XXCDTYBVGMPIOA-FXQIFTODSA-N 0.000 description 4
- PAQUJCSYVIBPLC-AVGNSLFASA-N Glu-Asp-Phe Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 PAQUJCSYVIBPLC-AVGNSLFASA-N 0.000 description 4
- BUZMZDDKFCSKOT-CIUDSAMLSA-N Glu-Glu-Glu Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O BUZMZDDKFCSKOT-CIUDSAMLSA-N 0.000 description 4
- QJCKNLPMTPXXEM-AUTRQRHGSA-N Glu-Glu-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CCC(O)=O QJCKNLPMTPXXEM-AUTRQRHGSA-N 0.000 description 4
- UHVIQGKBMXEVGN-WDSKDSINSA-N Glu-Gly-Asn Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(O)=O UHVIQGKBMXEVGN-WDSKDSINSA-N 0.000 description 4
- YQPFCZVKMUVZIN-AUTRQRHGSA-N Glu-Val-Gln Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O YQPFCZVKMUVZIN-AUTRQRHGSA-N 0.000 description 4
- OGCIHJPYKVSMTE-YUMQZZPRSA-N Gly-Arg-Glu Chemical compound [H]NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(O)=O OGCIHJPYKVSMTE-YUMQZZPRSA-N 0.000 description 4
- UUYBFNKHOCJCHT-VHSXEESVSA-N Gly-Leu-Pro Chemical compound CC(C)C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)CN UUYBFNKHOCJCHT-VHSXEESVSA-N 0.000 description 4
- MHXKHKWHPNETGG-QWRGUYRKSA-N Gly-Lys-Leu Chemical compound [H]NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(O)=O MHXKHKWHPNETGG-QWRGUYRKSA-N 0.000 description 4
- 239000007995 HEPES buffer Substances 0.000 description 4
- BDHUXUFYNUOUIT-SRVKXCTJSA-N His-Asp-Lys Chemical compound C1=C(NC=N1)C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CCCCN)C(=O)O)N BDHUXUFYNUOUIT-SRVKXCTJSA-N 0.000 description 4
- YAALVYQFVJNXIV-KKUMJFAQSA-N His-Leu-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC1=CN=CN1 YAALVYQFVJNXIV-KKUMJFAQSA-N 0.000 description 4
- CSTDQOOBZBAJKE-BWAGICSOSA-N His-Tyr-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)NC(=O)[C@H](CC2=CN=CN2)N)O CSTDQOOBZBAJKE-BWAGICSOSA-N 0.000 description 4
- 101000666896 Homo sapiens V-type immunoglobulin domain-containing suppressor of T-cell activation Proteins 0.000 description 4
- PFPUFNLHBXKPHY-HTFCKZLJSA-N Ile-Ile-Ser Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)O)N PFPUFNLHBXKPHY-HTFCKZLJSA-N 0.000 description 4
- RFMDODRWJZHZCR-BJDJZHNGSA-N Ile-Lys-Cys Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CS)C(O)=O RFMDODRWJZHZCR-BJDJZHNGSA-N 0.000 description 4
- VGSPNSSCMOHRRR-BJDJZHNGSA-N Ile-Ser-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)O)N VGSPNSSCMOHRRR-BJDJZHNGSA-N 0.000 description 4
- COWHUQXTSYTKQC-RWRJDSDZSA-N Ile-Thr-Glu Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N COWHUQXTSYTKQC-RWRJDSDZSA-N 0.000 description 4
- 108010065920 Insulin Lispro Proteins 0.000 description 4
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 4
- 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 4
- DLCOFDAHNMMQPP-SRVKXCTJSA-N Leu-Asp-Leu Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O DLCOFDAHNMMQPP-SRVKXCTJSA-N 0.000 description 4
- YVKSMSDXKMSIRX-GUBZILKMSA-N Leu-Glu-Asn Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O YVKSMSDXKMSIRX-GUBZILKMSA-N 0.000 description 4
- BTNXKBVLWJBTNR-SRVKXCTJSA-N Leu-His-Asn Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC(N)=O)C(O)=O BTNXKBVLWJBTNR-SRVKXCTJSA-N 0.000 description 4
- LVTJJOJKDCVZGP-QWRGUYRKSA-N Leu-Lys-Gly Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(O)=O LVTJJOJKDCVZGP-QWRGUYRKSA-N 0.000 description 4
- UCBPDSYUVAAHCD-UWVGGRQHSA-N Leu-Pro-Gly Chemical compound CC(C)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O UCBPDSYUVAAHCD-UWVGGRQHSA-N 0.000 description 4
- 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 4
- MWVUEPNEPWMFBD-SRVKXCTJSA-N Lys-Cys-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CS)C(=O)N[C@H](C(O)=O)CCCCN MWVUEPNEPWMFBD-SRVKXCTJSA-N 0.000 description 4
- OIQSIMFSVLLWBX-VOAKCMCISA-N Lys-Leu-Thr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O OIQSIMFSVLLWBX-VOAKCMCISA-N 0.000 description 4
- XOQMURBBIXRRCR-SRVKXCTJSA-N Lys-Lys-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CCCCN XOQMURBBIXRRCR-SRVKXCTJSA-N 0.000 description 4
- AFLBTVGQCQLOFJ-AVGNSLFASA-N Lys-Pro-Arg Chemical compound NCCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCN=C(N)N)C(O)=O AFLBTVGQCQLOFJ-AVGNSLFASA-N 0.000 description 4
- HYSVGEAWTGPMOA-IHRRRGAJSA-N Lys-Pro-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(C)C)C(O)=O HYSVGEAWTGPMOA-IHRRRGAJSA-N 0.000 description 4
- IOQWIOPSKJOEKI-SRVKXCTJSA-N Lys-Ser-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O IOQWIOPSKJOEKI-SRVKXCTJSA-N 0.000 description 4
- YKBSXQFZWFXFIB-VOAKCMCISA-N Lys-Thr-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@@H](CCCCN)C(O)=O YKBSXQFZWFXFIB-VOAKCMCISA-N 0.000 description 4
- XBAJINCXDBTJRH-WDSOQIARSA-N Lys-Val-Trp Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)NC(=O)[C@H](CCCCN)N XBAJINCXDBTJRH-WDSOQIARSA-N 0.000 description 4
- 241000124008 Mammalia Species 0.000 description 4
- 108010047562 NGR peptide Proteins 0.000 description 4
- UHRNIXJAGGLKHP-DLOVCJGASA-N Phe-Ala-Ser Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O UHRNIXJAGGLKHP-DLOVCJGASA-N 0.000 description 4
- JOXIIFVCSATTDH-IHPCNDPISA-N Phe-Asn-Trp Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC2=CNC3=CC=CC=C32)C(=O)O)N JOXIIFVCSATTDH-IHPCNDPISA-N 0.000 description 4
- ZJPGOXWRFNKIQL-JYJNAYRXSA-N Phe-Pro-Pro Chemical compound C([C@H](N)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(O)=O)C1=CC=CC=C1 ZJPGOXWRFNKIQL-JYJNAYRXSA-N 0.000 description 4
- IIEOLPMQYRBZCN-SRVKXCTJSA-N Phe-Ser-Cys Chemical compound N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)O IIEOLPMQYRBZCN-SRVKXCTJSA-N 0.000 description 4
- ZTVSVSFBHUVYIN-UFYCRDLUSA-N Phe-Tyr-Met Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(O)=O)NC(=O)[C@@H](N)CC=1C=CC=CC=1)C1=CC=C(O)C=C1 ZTVSVSFBHUVYIN-UFYCRDLUSA-N 0.000 description 4
- KIPIKSXPPLABPN-CIUDSAMLSA-N Pro-Glu-Asn Chemical compound NC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H]1CCCN1 KIPIKSXPPLABPN-CIUDSAMLSA-N 0.000 description 4
- QGOZJLYCGRYYRW-KKUMJFAQSA-N Pro-Glu-Tyr Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O QGOZJLYCGRYYRW-KKUMJFAQSA-N 0.000 description 4
- ZLXKLMHAMDENIO-DCAQKATOSA-N Pro-Lys-Asp Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(O)=O ZLXKLMHAMDENIO-DCAQKATOSA-N 0.000 description 4
- RFWXYTJSVDUBBZ-DCAQKATOSA-N Pro-Pro-Glu Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 RFWXYTJSVDUBBZ-DCAQKATOSA-N 0.000 description 4
- FDMKYQQYJKYCLV-GUBZILKMSA-N Pro-Pro-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 FDMKYQQYJKYCLV-GUBZILKMSA-N 0.000 description 4
- 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 4
- QPFJSHSJFIYDJZ-GHCJXIJMSA-N Ser-Asp-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](N)CO QPFJSHSJFIYDJZ-GHCJXIJMSA-N 0.000 description 4
- OJPHFSOMBZKQKQ-GUBZILKMSA-N Ser-Gln-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CO OJPHFSOMBZKQKQ-GUBZILKMSA-N 0.000 description 4
- LALNXSXEYFUUDD-GUBZILKMSA-N Ser-Glu-Leu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O LALNXSXEYFUUDD-GUBZILKMSA-N 0.000 description 4
- GZBKRJVCRMZAST-XKBZYTNZSA-N Ser-Glu-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O GZBKRJVCRMZAST-XKBZYTNZSA-N 0.000 description 4
- BPMRXBZYPGYPJN-WHFBIAKZSA-N Ser-Gly-Asn Chemical compound [H]N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(O)=O BPMRXBZYPGYPJN-WHFBIAKZSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 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 4
- BDGBHYCAZJPLHX-HJGDQZAQSA-N Thr-Lys-Asn Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(O)=O BDGBHYCAZJPLHX-HJGDQZAQSA-N 0.000 description 4
- XKWABWFMQXMUMT-HJGDQZAQSA-N Thr-Pro-Glu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O XKWABWFMQXMUMT-HJGDQZAQSA-N 0.000 description 4
- XGUAUKUYQHBUNY-SWRJLBSHSA-N Thr-Trp-Glu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CCC(O)=O)C(O)=O XGUAUKUYQHBUNY-SWRJLBSHSA-N 0.000 description 4
- REJRKTOJTCPDPO-IRIUXVKKSA-N Thr-Tyr-Glu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCC(O)=O)C(O)=O REJRKTOJTCPDPO-IRIUXVKKSA-N 0.000 description 4
- CYCGARJWIQWPQM-YJRXYDGGSA-N Thr-Tyr-Ser Chemical compound C[C@@H](O)[C@H]([NH3+])C(=O)N[C@H](C(=O)N[C@@H](CO)C([O-])=O)CC1=CC=C(O)C=C1 CYCGARJWIQWPQM-YJRXYDGGSA-N 0.000 description 4
- PTAWAMWPRFTACW-SZMVWBNQSA-N Trp-Gln-Lys Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CCCCN)C(=O)O)N PTAWAMWPRFTACW-SZMVWBNQSA-N 0.000 description 4
- UDCHKDYNMRJYMI-QEJZJMRPSA-N Trp-Glu-Ser Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(O)=O UDCHKDYNMRJYMI-QEJZJMRPSA-N 0.000 description 4
- SINRIKQYQJRGDQ-MEYUZBJRSA-N Tyr-Lys-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 SINRIKQYQJRGDQ-MEYUZBJRSA-N 0.000 description 4
- MQGGXGKQSVEQHR-KKUMJFAQSA-N Tyr-Ser-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 MQGGXGKQSVEQHR-KKUMJFAQSA-N 0.000 description 4
- NZBSVMQZQMEUHI-WZLNRYEVSA-N Tyr-Thr-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)N NZBSVMQZQMEUHI-WZLNRYEVSA-N 0.000 description 4
- 102100038929 V-set domain-containing T-cell activation inhibitor 1 Human genes 0.000 description 4
- 102100038282 V-type immunoglobulin domain-containing suppressor of T-cell activation Human genes 0.000 description 4
- VLOYGOZDPGYWFO-LAEOZQHASA-N Val-Asp-Glu Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O VLOYGOZDPGYWFO-LAEOZQHASA-N 0.000 description 4
- QHDXUYOYTPWCSK-RCOVLWMOSA-N Val-Asp-Gly Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)NCC(=O)O)N QHDXUYOYTPWCSK-RCOVLWMOSA-N 0.000 description 4
- FOADDSDHGRFUOC-DZKIICNBSA-N Val-Glu-Phe Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)N FOADDSDHGRFUOC-DZKIICNBSA-N 0.000 description 4
- CPGJELLYDQEDRK-NAKRPEOUSA-N Val-Ile-Ala Chemical compound CC[C@H](C)[C@H](NC(=O)[C@@H](N)C(C)C)C(=O)N[C@@H](C)C(O)=O CPGJELLYDQEDRK-NAKRPEOUSA-N 0.000 description 4
- 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 4
- KSFXWENSJABBFI-ZKWXMUAHSA-N Val-Ser-Asn Chemical compound [H]N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O KSFXWENSJABBFI-ZKWXMUAHSA-N 0.000 description 4
- BZDGLJPROOOUOZ-XGEHTFHBSA-N Val-Thr-Cys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](C(C)C)N)O BZDGLJPROOOUOZ-XGEHTFHBSA-N 0.000 description 4
- 239000008351 acetate buffer Substances 0.000 description 4
- 230000006978 adaptation Effects 0.000 description 4
- 235000004279 alanine Nutrition 0.000 description 4
- 108010005233 alanylglutamic acid Proteins 0.000 description 4
- 108010047495 alanylglycine Proteins 0.000 description 4
- 108010050025 alpha-glutamyltryptophan Proteins 0.000 description 4
- 125000000637 arginyl group Chemical group N[C@@H](CCCNC(N)=N)C(=O)* 0.000 description 4
- 238000005119 centrifugation Methods 0.000 description 4
- 208000029742 colonic neoplasm Diseases 0.000 description 4
- 235000018417 cysteine Nutrition 0.000 description 4
- 230000016396 cytokine production Effects 0.000 description 4
- 230000004069 differentiation Effects 0.000 description 4
- 210000003162 effector t lymphocyte Anatomy 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 108010067216 glycyl-glycyl-glycine Proteins 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 108010017391 lysylvaline Proteins 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 108010082117 matrigel Proteins 0.000 description 4
- 239000011159 matrix material Substances 0.000 description 4
- 230000007246 mechanism Effects 0.000 description 4
- 230000002062 proliferating effect Effects 0.000 description 4
- 230000004044 response Effects 0.000 description 4
- 238000001542 size-exclusion chromatography Methods 0.000 description 4
- 229940054269 sodium pyruvate Drugs 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 210000000952 spleen Anatomy 0.000 description 4
- 238000010186 staining Methods 0.000 description 4
- 238000010254 subcutaneous injection Methods 0.000 description 4
- 239000007929 subcutaneous injection Substances 0.000 description 4
- 231100000419 toxicity Toxicity 0.000 description 4
- 230000001988 toxicity Effects 0.000 description 4
- 108010044292 tryptophyltyrosine Proteins 0.000 description 4
- 239000003981 vehicle Substances 0.000 description 4
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 4
- COEXAQSTZUWMRI-STQMWFEESA-N (2s)-1-[2-[[(2s)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]acetyl]pyrrolidine-2-carboxylic acid Chemical compound C([C@H](N)C(=O)NCC(=O)N1[C@@H](CCC1)C(O)=O)C1=CC=C(O)C=C1 COEXAQSTZUWMRI-STQMWFEESA-N 0.000 description 3
- IESDGNYHXIOKRW-YXMSTPNBSA-N (2s)-2-[[(2s)-1-[(2s)-6-amino-2-[[(2s,3r)-2-amino-3-hydroxybutanoyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-5-(diaminomethylideneamino)pentanoic acid Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(N)=N)C(O)=O IESDGNYHXIOKRW-YXMSTPNBSA-N 0.000 description 3
- DIBLBAURNYJYBF-XLXZRNDBSA-N (2s)-2-[[(2s)-2-[[2-[[(2s)-6-amino-2-[[(2s)-2-amino-3-methylbutanoyl]amino]hexanoyl]amino]acetyl]amino]-3-phenylpropanoyl]amino]-3-(4-hydroxyphenyl)propanoic acid Chemical compound C([C@H](NC(=O)CNC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)C(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C1=CC=CC=C1 DIBLBAURNYJYBF-XLXZRNDBSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- PUBLUECXJRHTBK-ACZMJKKPSA-N Ala-Glu-Ser Chemical compound C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(O)=O PUBLUECXJRHTBK-ACZMJKKPSA-N 0.000 description 3
- LGCVSPFCFXWUEY-IHPCNDPISA-N Asn-Trp-Tyr Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CC3=CC=C(C=C3)O)C(=O)O)NC(=O)[C@H](CC(=O)N)N LGCVSPFCFXWUEY-IHPCNDPISA-N 0.000 description 3
- RPUYTJJZXQBWDT-SRVKXCTJSA-N Asp-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](CC(=O)O)N RPUYTJJZXQBWDT-SRVKXCTJSA-N 0.000 description 3
- BKOIIURTQAJHAT-GUBZILKMSA-N Asp-Pro-Pro Chemical compound OC(=O)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 BKOIIURTQAJHAT-GUBZILKMSA-N 0.000 description 3
- 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 3
- -1 CD86 Proteins 0.000 description 3
- 101100506090 Caenorhabditis elegans hil-2 gene Proteins 0.000 description 3
- ZXCAQANTQWBICD-DCAQKATOSA-N Cys-Lys-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CS)N ZXCAQANTQWBICD-DCAQKATOSA-N 0.000 description 3
- 101100229077 Gallus gallus GAL9 gene Proteins 0.000 description 3
- 206010060891 General symptom Diseases 0.000 description 3
- ZEEPYMXTJWIMSN-GUBZILKMSA-N Gln-Lys-Ser Chemical compound NCCCC[C@@H](C(=O)N[C@@H](CO)C(O)=O)NC(=O)[C@@H](N)CCC(N)=O ZEEPYMXTJWIMSN-GUBZILKMSA-N 0.000 description 3
- SXFPZRRVWSUYII-KBIXCLLPSA-N Gln-Ser-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(=O)N)N SXFPZRRVWSUYII-KBIXCLLPSA-N 0.000 description 3
- GLWXKFRTOHKGIT-ACZMJKKPSA-N Glu-Asn-Asn Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O GLWXKFRTOHKGIT-ACZMJKKPSA-N 0.000 description 3
- HNVFSTLPVJWIDV-CIUDSAMLSA-N Glu-Glu-Gln Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O HNVFSTLPVJWIDV-CIUDSAMLSA-N 0.000 description 3
- KASDBWKLWJKTLJ-GUBZILKMSA-N Glu-Glu-Met Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCSC)C(O)=O KASDBWKLWJKTLJ-GUBZILKMSA-N 0.000 description 3
- QOXDAWODGSIDDI-GUBZILKMSA-N Glu-Ser-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(=O)O)N QOXDAWODGSIDDI-GUBZILKMSA-N 0.000 description 3
- 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 3
- GRIRDMVMJJDZKV-RCOVLWMOSA-N Gly-Asn-Val Chemical compound [H]NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(O)=O GRIRDMVMJJDZKV-RCOVLWMOSA-N 0.000 description 3
- KQDMENMTYNBWMR-WHFBIAKZSA-N Gly-Asp-Ala Chemical compound [H]NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(O)=O KQDMENMTYNBWMR-WHFBIAKZSA-N 0.000 description 3
- PABFFPWEJMEVEC-JGVFFNPUSA-N Gly-Gln-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCC(=O)N)NC(=O)CN)C(=O)O PABFFPWEJMEVEC-JGVFFNPUSA-N 0.000 description 3
- 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 3
- IEGFSKKANYKBDU-QWHCGFSZSA-N Gly-Phe-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC2=CC=CC=C2)NC(=O)CN)C(=O)O IEGFSKKANYKBDU-QWHCGFSZSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- WMKXFMUJRCEGRP-SRVKXCTJSA-N His-Asn-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC2=CN=CN2)C(=O)O)N WMKXFMUJRCEGRP-SRVKXCTJSA-N 0.000 description 3
- XGBVLRJLHUVCNK-DCAQKATOSA-N His-Val-Ser Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(O)=O XGBVLRJLHUVCNK-DCAQKATOSA-N 0.000 description 3
- 101000864344 Homo sapiens B- and T-lymphocyte attenuator Proteins 0.000 description 3
- 101001002657 Homo sapiens Interleukin-2 Proteins 0.000 description 3
- 101001137987 Homo sapiens Lymphocyte activation gene 3 protein Proteins 0.000 description 3
- UIEZQYNXCYHMQS-BJDJZHNGSA-N Ile-Lys-Ala Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)O)N UIEZQYNXCYHMQS-BJDJZHNGSA-N 0.000 description 3
- XMYURPUVJSKTMC-KBIXCLLPSA-N Ile-Ser-Gln Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N XMYURPUVJSKTMC-KBIXCLLPSA-N 0.000 description 3
- 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 3
- 102000002698 KIR Receptors Human genes 0.000 description 3
- 108010043610 KIR Receptors Proteins 0.000 description 3
- 229930182816 L-glutamine Natural products 0.000 description 3
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 3
- IWTBYNQNAPECCS-AVGNSLFASA-N Leu-Glu-His Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@H](C(O)=O)CC1=CN=CN1 IWTBYNQNAPECCS-AVGNSLFASA-N 0.000 description 3
- QVFGXCVIXXBFHO-AVGNSLFASA-N Leu-Glu-Leu Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O QVFGXCVIXXBFHO-AVGNSLFASA-N 0.000 description 3
- ISSAURVGLGAPDK-KKUMJFAQSA-N Leu-Tyr-Asp 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(O)=O)C(O)=O ISSAURVGLGAPDK-KKUMJFAQSA-N 0.000 description 3
- XNKDCYABMBBEKN-IUCAKERBSA-N Lys-Gly-Gln Chemical compound NCCCC[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CCC(N)=O XNKDCYABMBBEKN-IUCAKERBSA-N 0.000 description 3
- 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 3
- LUTDBHBIHHREDC-IHRRRGAJSA-N Lys-Pro-Lys Chemical compound NCCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(O)=O LUTDBHBIHHREDC-IHRRRGAJSA-N 0.000 description 3
- RQILLQOQXLZTCK-KBPBESRZSA-N Lys-Tyr-Gly Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)NCC(O)=O RQILLQOQXLZTCK-KBPBESRZSA-N 0.000 description 3
- 102000018697 Membrane Proteins Human genes 0.000 description 3
- 108010052285 Membrane Proteins Proteins 0.000 description 3
- WXXNVZMWHOLNRJ-AVGNSLFASA-N Met-Pro-Lys Chemical compound CSCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(O)=O WXXNVZMWHOLNRJ-AVGNSLFASA-N 0.000 description 3
- IHRFZLQEQVHXFA-RHYQMDGZSA-N Met-Thr-Lys Chemical compound CSCC[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@H](C(O)=O)CCCCN IHRFZLQEQVHXFA-RHYQMDGZSA-N 0.000 description 3
- 101100407308 Mus musculus Pdcd1lg2 gene Proteins 0.000 description 3
- XZFYRXDAULDNFX-UHFFFAOYSA-N N-L-cysteinyl-L-phenylalanine Natural products SCC(N)C(=O)NC(C(O)=O)CC1=CC=CC=C1 XZFYRXDAULDNFX-UHFFFAOYSA-N 0.000 description 3
- KZNQNBZMBZJQJO-UHFFFAOYSA-N N-glycyl-L-proline Natural products NCC(=O)N1CCCC1C(O)=O KZNQNBZMBZJQJO-UHFFFAOYSA-N 0.000 description 3
- 241000412169 Peria Species 0.000 description 3
- CDNPIRSCAFMMBE-SRVKXCTJSA-N Phe-Asn-Ser Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(O)=O CDNPIRSCAFMMBE-SRVKXCTJSA-N 0.000 description 3
- VADLTGVIOIOKGM-BZSNNMDCSA-N Phe-His-Leu Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)[C@@H](N)CC=1C=CC=CC=1)C1=CN=CN1 VADLTGVIOIOKGM-BZSNNMDCSA-N 0.000 description 3
- MSHZERMPZKCODG-ACRUOGEOSA-N Phe-Leu-Phe Chemical compound C([C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 MSHZERMPZKCODG-ACRUOGEOSA-N 0.000 description 3
- MRWOVVNKSXXLRP-IHPCNDPISA-N Phe-Ser-Trp Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O MRWOVVNKSXXLRP-IHPCNDPISA-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
- PCWLNNZTBJTZRN-AVGNSLFASA-N Pro-Pro-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 PCWLNNZTBJTZRN-AVGNSLFASA-N 0.000 description 3
- SEZGGSHLMROBFX-CIUDSAMLSA-N Pro-Ser-Gln Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(O)=O SEZGGSHLMROBFX-CIUDSAMLSA-N 0.000 description 3
- 108700030875 Programmed Cell Death 1 Ligand 2 Proteins 0.000 description 3
- 102100024213 Programmed cell death 1 ligand 2 Human genes 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- VGNYHOBZJKWRGI-CIUDSAMLSA-N Ser-Asn-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CO VGNYHOBZJKWRGI-CIUDSAMLSA-N 0.000 description 3
- 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 3
- GZSZPKSBVAOGIE-CIUDSAMLSA-N Ser-Lys-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O GZSZPKSBVAOGIE-CIUDSAMLSA-N 0.000 description 3
- ZKOKTQPHFMRSJP-YJRXYDGGSA-N Ser-Thr-Tyr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O ZKOKTQPHFMRSJP-YJRXYDGGSA-N 0.000 description 3
- 230000006044 T cell activation Effects 0.000 description 3
- DSLHSTIUAPKERR-XGEHTFHBSA-N Thr-Cys-Val Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(=O)N[C@@H](C(C)C)C(O)=O DSLHSTIUAPKERR-XGEHTFHBSA-N 0.000 description 3
- TZJSEJOXAIWOST-RHYQMDGZSA-N Thr-Lys-Arg Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(O)=O)CCCN=C(N)N TZJSEJOXAIWOST-RHYQMDGZSA-N 0.000 description 3
- NYQIZWROIMIQSL-VEVYYDQMSA-N Thr-Pro-Asn Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(N)=O)C(O)=O NYQIZWROIMIQSL-VEVYYDQMSA-N 0.000 description 3
- QYDKSNXSBXZPFK-ZJDVBMNYSA-N Thr-Thr-Arg Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O QYDKSNXSBXZPFK-ZJDVBMNYSA-N 0.000 description 3
- BEZTUFWTPVOROW-KJEVXHAQSA-N Thr-Tyr-Arg Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N)O BEZTUFWTPVOROW-KJEVXHAQSA-N 0.000 description 3
- VTHNLRXALGUDBS-BPUTZDHNSA-N Trp-Gln-Glu Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N VTHNLRXALGUDBS-BPUTZDHNSA-N 0.000 description 3
- 102000004142 Trypsin Human genes 0.000 description 3
- 108090000631 Trypsin Proteins 0.000 description 3
- RIVVDNTUSRVTQT-IRIUXVKKSA-N Tyr-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=CC=C(C=C1)O)N)O RIVVDNTUSRVTQT-IRIUXVKKSA-N 0.000 description 3
- SQUMHUZLJDUROQ-YDHLFZDLSA-N Tyr-Val-Asp 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](CC(O)=O)C(O)=O SQUMHUZLJDUROQ-YDHLFZDLSA-N 0.000 description 3
- 108010079206 V-Set Domain-Containing T-Cell Activation Inhibitor 1 Proteins 0.000 description 3
- JXGWQYWDUOWQHA-DZKIICNBSA-N Val-Gln-Phe Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)N JXGWQYWDUOWQHA-DZKIICNBSA-N 0.000 description 3
- MLADEWAIYAPAAU-IHRRRGAJSA-N Val-Lys-His Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N MLADEWAIYAPAAU-IHRRRGAJSA-N 0.000 description 3
- KISFXYYRKKNLOP-IHRRRGAJSA-N Val-Phe-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)O)N KISFXYYRKKNLOP-IHRRRGAJSA-N 0.000 description 3
- 125000003295 alanine group Chemical group N[C@@H](C)C(=O)* 0.000 description 3
- 108010070944 alanylhistidine Proteins 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 125000000539 amino acid group Chemical group 0.000 description 3
- 230000000843 anti-fungal effect Effects 0.000 description 3
- 229940121375 antifungal agent Drugs 0.000 description 3
- 230000003542 behavioural effect Effects 0.000 description 3
- 230000003115 biocidal effect Effects 0.000 description 3
- 238000004364 calculation method Methods 0.000 description 3
- 230000003915 cell function Effects 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 238000007405 data analysis Methods 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 230000002708 enhancing effect Effects 0.000 description 3
- 239000003797 essential amino acid Substances 0.000 description 3
- 235000020776 essential amino acid Nutrition 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- 125000000291 glutamic acid group Chemical group N[C@@H](CCC(O)=O)C(=O)* 0.000 description 3
- 239000001963 growth medium Substances 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 108010053037 kyotorphin Proteins 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 229910052759 nickel Inorganic materials 0.000 description 3
- 238000001543 one-way ANOVA Methods 0.000 description 3
- 230000000638 stimulation Effects 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 239000012588 trypsin Substances 0.000 description 3
- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 3
- TZCPCKNHXULUIY-RGULYWFUSA-N 1,2-distearoyl-sn-glycero-3-phosphoserine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@H](N)C(O)=O)OC(=O)CCCCCCCCCCCCCCCCC TZCPCKNHXULUIY-RGULYWFUSA-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
- WEZNQZHACPSMEF-QEJZJMRPSA-N Ala-Phe-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)C)CC1=CC=CC=C1 WEZNQZHACPSMEF-QEJZJMRPSA-N 0.000 description 2
- NKBQZKVMKJJDLX-SRVKXCTJSA-N Arg-Glu-Leu Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O NKBQZKVMKJJDLX-SRVKXCTJSA-N 0.000 description 2
- OISWSORSLQOGFV-AVGNSLFASA-N Arg-Met-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CCSC)NC(=O)[C@@H](N)CCCN=C(N)N OISWSORSLQOGFV-AVGNSLFASA-N 0.000 description 2
- YNSUUAOAFCVINY-OSUNSFLBSA-N Arg-Thr-Ile Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O YNSUUAOAFCVINY-OSUNSFLBSA-N 0.000 description 2
- PBSQFBAJKPLRJY-BYULHYEWSA-N Asn-Gly-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)CNC(=O)[C@H](CC(=O)N)N PBSQFBAJKPLRJY-BYULHYEWSA-N 0.000 description 2
- PWAIZUBWHRHYKS-MELADBBJSA-N Asp-Phe-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC2=CC=CC=C2)NC(=O)[C@H](CC(=O)O)N)C(=O)O PWAIZUBWHRHYKS-MELADBBJSA-N 0.000 description 2
- 102100032912 CD44 antigen Human genes 0.000 description 2
- 238000002965 ELISA Methods 0.000 description 2
- DYVMTEWCGAVKSE-HJGDQZAQSA-N Gln-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](CCC(=O)N)N)O DYVMTEWCGAVKSE-HJGDQZAQSA-N 0.000 description 2
- CKRUHITYRFNUKW-WDSKDSINSA-N Glu-Asn-Gly Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(O)=O CKRUHITYRFNUKW-WDSKDSINSA-N 0.000 description 2
- BIHMNDPWRUROFZ-JYJNAYRXSA-N Glu-His-Phe Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O BIHMNDPWRUROFZ-JYJNAYRXSA-N 0.000 description 2
- HVYWQYLBVXMXSV-GUBZILKMSA-N Glu-Leu-Ala Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(O)=O HVYWQYLBVXMXSV-GUBZILKMSA-N 0.000 description 2
- IOUQWHIEQYQVFD-JYJNAYRXSA-N Glu-Leu-Tyr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O IOUQWHIEQYQVFD-JYJNAYRXSA-N 0.000 description 2
- CUPSDFQZTVVTSK-GUBZILKMSA-N Glu-Lys-Asp Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CCC(O)=O CUPSDFQZTVVTSK-GUBZILKMSA-N 0.000 description 2
- PAZQYODKOZHXGA-SRVKXCTJSA-N Glu-Pro-His Chemical compound N[C@@H](CCC(O)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1cnc[nH]1)C(O)=O PAZQYODKOZHXGA-SRVKXCTJSA-N 0.000 description 2
- FSPVILZGHUJOHS-QWRGUYRKSA-N Gly-His-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)CN)CC1=CNC=N1 FSPVILZGHUJOHS-QWRGUYRKSA-N 0.000 description 2
- 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 2
- ZWZWYGMENQVNFU-UHFFFAOYSA-N Glycerophosphorylserin Natural products OC(=O)C(N)COP(O)(=O)OCC(O)CO ZWZWYGMENQVNFU-UHFFFAOYSA-N 0.000 description 2
- 102100037907 High mobility group protein B1 Human genes 0.000 description 2
- IAYPZSHNZQHQNO-KKUMJFAQSA-N His-Ser-Phe Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC2=CN=CN2)N IAYPZSHNZQHQNO-KKUMJFAQSA-N 0.000 description 2
- 101000868273 Homo sapiens CD44 antigen Proteins 0.000 description 2
- 101001057504 Homo sapiens Interferon-stimulated gene 20 kDa protein Proteins 0.000 description 2
- 101001055144 Homo sapiens Interleukin-2 receptor subunit alpha Proteins 0.000 description 2
- DURWCDDDAWVPOP-JBDRJPRFSA-N Ile-Cys-Ser Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CO)C(=O)O)N DURWCDDDAWVPOP-JBDRJPRFSA-N 0.000 description 2
- JERJIYYCOGBAIJ-OBAATPRFSA-N Ile-Tyr-Trp 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=CNC3=CC=CC=C32)C(=O)O)N JERJIYYCOGBAIJ-OBAATPRFSA-N 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- 102100027268 Interferon-stimulated gene 20 kDa protein Human genes 0.000 description 2
- RCFDOSNHHZGBOY-UHFFFAOYSA-N L-isoleucyl-L-alanine Natural products CCC(C)C(N)C(=O)NC(C)C(O)=O RCFDOSNHHZGBOY-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
- 102000017578 LAG3 Human genes 0.000 description 2
- KIZIOFNVSOSKJI-CIUDSAMLSA-N Leu-Ser-Cys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)O)N KIZIOFNVSOSKJI-CIUDSAMLSA-N 0.000 description 2
- HWMQRQIFVGEAPH-XIRDDKMYSA-N Leu-Ser-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(C)C)C(O)=O)=CNC2=C1 HWMQRQIFVGEAPH-XIRDDKMYSA-N 0.000 description 2
- 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 2
- URHJPNHRQMQGOZ-RHYQMDGZSA-N Leu-Thr-Met Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCSC)C(O)=O URHJPNHRQMQGOZ-RHYQMDGZSA-N 0.000 description 2
- MPGHETGWWWUHPY-CIUDSAMLSA-N Lys-Ala-Asp Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCCN MPGHETGWWWUHPY-CIUDSAMLSA-N 0.000 description 2
- 108700018351 Major Histocompatibility Complex Proteins 0.000 description 2
- PTYVBBNIAQWUFV-DCAQKATOSA-N Met-Cys-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CS)NC(=O)[C@H](CCSC)N PTYVBBNIAQWUFV-DCAQKATOSA-N 0.000 description 2
- WPTDJKDGICUFCP-XUXIUFHCSA-N Met-Ile-Leu Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)O)NC(=O)[C@H](CCSC)N WPTDJKDGICUFCP-XUXIUFHCSA-N 0.000 description 2
- LXCSZPUQKMTXNW-BQBZGAKWSA-N Met-Ser-Gly Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CO)C(=O)NCC(O)=O LXCSZPUQKMTXNW-BQBZGAKWSA-N 0.000 description 2
- 108010079364 N-glycylalanine Proteins 0.000 description 2
- 244000046052 Phaseolus vulgaris Species 0.000 description 2
- IUVYJBMTHARMIP-PCBIJLKTSA-N Phe-Asp-Ile Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O IUVYJBMTHARMIP-PCBIJLKTSA-N 0.000 description 2
- IAOZOFPONWDXNT-IXOXFDKPSA-N Phe-Ser-Thr Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(O)=O IAOZOFPONWDXNT-IXOXFDKPSA-N 0.000 description 2
- 101710094000 Programmed cell death 1 ligand 1 Proteins 0.000 description 2
- 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 2
- FTVRVZNYIYWJGB-ACZMJKKPSA-N Ser-Asp-Glu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O FTVRVZNYIYWJGB-ACZMJKKPSA-N 0.000 description 2
- HDBOEVPDIDDEPC-CIUDSAMLSA-N Ser-Lys-Asn Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(O)=O HDBOEVPDIDDEPC-CIUDSAMLSA-N 0.000 description 2
- XUDRHBPSPAPDJP-SRVKXCTJSA-N Ser-Lys-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CO XUDRHBPSPAPDJP-SRVKXCTJSA-N 0.000 description 2
- 108091008874 T cell receptors Proteins 0.000 description 2
- 102000016266 T-Cell Antigen Receptors Human genes 0.000 description 2
- CJXURNZYNHCYFD-WDCWCFNPSA-N Thr-Lys-Gln Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N)O CJXURNZYNHCYFD-WDCWCFNPSA-N 0.000 description 2
- VGYVVSQFSSKZRJ-OEAJRASXSA-N Thr-Phe-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)[C@H](O)C)CC1=CC=CC=C1 VGYVVSQFSSKZRJ-OEAJRASXSA-N 0.000 description 2
- STUAPCLEDMKXKL-LKXGYXEUSA-N Thr-Ser-Asn Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O STUAPCLEDMKXKL-LKXGYXEUSA-N 0.000 description 2
- SGAOHNPSEPVAFP-ZDLURKLDSA-N Thr-Ser-Gly Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)NCC(O)=O SGAOHNPSEPVAFP-ZDLURKLDSA-N 0.000 description 2
- WPSKTVVMQCXPRO-BWBBJGPYSA-N Thr-Ser-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O WPSKTVVMQCXPRO-BWBBJGPYSA-N 0.000 description 2
- AAZOYLQUEQRUMZ-GSSVUCPTSA-N Thr-Thr-Asn Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@H](C(O)=O)CC(N)=O AAZOYLQUEQRUMZ-GSSVUCPTSA-N 0.000 description 2
- 102100028785 Tumor necrosis factor receptor superfamily member 14 Human genes 0.000 description 2
- SLLKXDSRVAOREO-KZVJFYERSA-N Val-Ala-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](C)NC(=O)[C@H](C(C)C)N)O SLLKXDSRVAOREO-KZVJFYERSA-N 0.000 description 2
- RWOGENDAOGMHLX-DCAQKATOSA-N Val-Lys-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C(C)C)N RWOGENDAOGMHLX-DCAQKATOSA-N 0.000 description 2
- IJGPOONOTBNTFS-GVXVVHGQSA-N Val-Lys-Glu Chemical compound [H]N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(O)=O IJGPOONOTBNTFS-GVXVVHGQSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 239000012491 analyte Substances 0.000 description 2
- 210000000612 antigen-presenting cell Anatomy 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 239000012131 assay buffer Substances 0.000 description 2
- 210000003719 b-lymphocyte Anatomy 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 210000000481 breast Anatomy 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 239000006285 cell suspension Substances 0.000 description 2
- 238000011260 co-administration Methods 0.000 description 2
- 201000010897 colon adenocarcinoma Diseases 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 230000000139 costimulatory effect Effects 0.000 description 2
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 2
- 150000001945 cysteines Chemical class 0.000 description 2
- 231100000433 cytotoxic Toxicity 0.000 description 2
- 210000001151 cytotoxic T lymphocyte Anatomy 0.000 description 2
- 230000001472 cytotoxic effect Effects 0.000 description 2
- 238000010494 dissociation reaction Methods 0.000 description 2
- 230000005593 dissociations Effects 0.000 description 2
- 230000029142 excretion Effects 0.000 description 2
- 230000001747 exhibiting effect Effects 0.000 description 2
- 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 2
- 238000010353 genetic engineering Methods 0.000 description 2
- VPZXBVLAVMBEQI-UHFFFAOYSA-N glycyl-DL-alpha-alanine Natural products OC(=O)C(C)NC(=O)CN VPZXBVLAVMBEQI-UHFFFAOYSA-N 0.000 description 2
- 108010077515 glycylproline Proteins 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 102000048776 human CD274 Human genes 0.000 description 2
- 102000048362 human PDCD1 Human genes 0.000 description 2
- 210000000987 immune system Anatomy 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 238000011081 inoculation Methods 0.000 description 2
- 230000009545 invasion Effects 0.000 description 2
- 125000001909 leucine group Chemical group [H]N(*)C(C(*)=O)C([H])([H])C(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 210000000265 leukocyte Anatomy 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 210000003810 lymphokine-activated killer cell Anatomy 0.000 description 2
- 108010085203 methionylmethionine Proteins 0.000 description 2
- 210000001616 monocyte Anatomy 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- 239000008188 pellet Substances 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 230000011664 signaling Effects 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- RPENMORRBUTCPR-UHFFFAOYSA-M sodium;1-hydroxy-2,5-dioxopyrrolidine-3-sulfonate Chemical compound [Na+].ON1C(=O)CC(S([O-])(=O)=O)C1=O RPENMORRBUTCPR-UHFFFAOYSA-M 0.000 description 2
- 230000009870 specific binding Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000020382 suppression by virus of host antigen processing and presentation of peptide antigen via MHC class I Effects 0.000 description 2
- 108010061238 threonyl-glycine Proteins 0.000 description 2
- 241001529453 unidentified herpesvirus Species 0.000 description 2
- 108010073969 valyllysine Proteins 0.000 description 2
- 239000011534 wash buffer Substances 0.000 description 2
- 230000003442 weekly effect Effects 0.000 description 2
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 1
- CNKBMTKICGGSCQ-ACRUOGEOSA-N (2S)-2-[[(2S)-2-[[(2S)-2,6-diamino-1-oxohexyl]amino]-1-oxo-3-phenylpropyl]amino]-3-(4-hydroxyphenyl)propanoic acid Chemical compound C([C@H](NC(=O)[C@@H](N)CCCCN)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C1=CC=CC=C1 CNKBMTKICGGSCQ-ACRUOGEOSA-N 0.000 description 1
- 230000006269 (delayed) early viral mRNA transcription Effects 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- OMMDTNGURYRDAC-NRPADANISA-N Ala-Glu-Val Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O OMMDTNGURYRDAC-NRPADANISA-N 0.000 description 1
- QHASENCZLDHBGX-ONGXEEELSA-N Ala-Gly-Phe Chemical compound C[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 QHASENCZLDHBGX-ONGXEEELSA-N 0.000 description 1
- HJGZVLLLBJLXFC-LSJOCFKGSA-N Ala-His-Val Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](C(C)C)C(O)=O HJGZVLLLBJLXFC-LSJOCFKGSA-N 0.000 description 1
- FOHXUHGZZKETFI-JBDRJPRFSA-N Ala-Ile-Cys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](C)N FOHXUHGZZKETFI-JBDRJPRFSA-N 0.000 description 1
- DEWWPUNXRNGMQN-LPEHRKFASA-N Ala-Met-Pro Chemical compound C[C@@H](C(=O)N[C@@H](CCSC)C(=O)N1CCC[C@@H]1C(=O)O)N DEWWPUNXRNGMQN-LPEHRKFASA-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
- REWSWYIDQIELBE-FXQIFTODSA-N Ala-Val-Ser Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(O)=O REWSWYIDQIELBE-FXQIFTODSA-N 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 201000004384 Alopecia Diseases 0.000 description 1
- 101100339431 Arabidopsis thaliana HMGB2 gene Proteins 0.000 description 1
- 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 1
- BHSYMWWMVRPCPA-CYDGBPFRSA-N Arg-Arg-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H](N)CCCN=C(N)N BHSYMWWMVRPCPA-CYDGBPFRSA-N 0.000 description 1
- RVDVDRUZWZIBJQ-CIUDSAMLSA-N Arg-Asn-Glu Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O RVDVDRUZWZIBJQ-CIUDSAMLSA-N 0.000 description 1
- QAXCZGMLVICQKS-SRVKXCTJSA-N Arg-Glu-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CCCN=C(N)N)N QAXCZGMLVICQKS-SRVKXCTJSA-N 0.000 description 1
- UFBURHXMKFQVLM-CIUDSAMLSA-N Arg-Glu-Ser Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(O)=O UFBURHXMKFQVLM-CIUDSAMLSA-N 0.000 description 1
- NXDXECQFKHXHAM-HJGDQZAQSA-N Arg-Glu-Thr Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O NXDXECQFKHXHAM-HJGDQZAQSA-N 0.000 description 1
- KRQSPVKUISQQFS-FJXKBIBVSA-N Arg-Gly-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCN=C(N)N KRQSPVKUISQQFS-FJXKBIBVSA-N 0.000 description 1
- OFIYLHVAAJYRBC-HJWJTTGWSA-N Arg-Ile-Phe Chemical compound CC[C@H](C)[C@H](NC(=O)[C@@H](N)CCCNC(N)=N)C(=O)N[C@@H](Cc1ccccc1)C(O)=O OFIYLHVAAJYRBC-HJWJTTGWSA-N 0.000 description 1
- HJDNZFIYILEIKR-OSUNSFLBSA-N Arg-Ile-Thr Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(O)=O HJDNZFIYILEIKR-OSUNSFLBSA-N 0.000 description 1
- LVMUGODRNHFGRA-AVGNSLFASA-N Arg-Leu-Arg Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O LVMUGODRNHFGRA-AVGNSLFASA-N 0.000 description 1
- VEAIMHJZTIDCIH-KKUMJFAQSA-N Arg-Phe-Gln Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCC(N)=O)C(O)=O VEAIMHJZTIDCIH-KKUMJFAQSA-N 0.000 description 1
- 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 1
- POZKLUIXMHIULG-FDARSICLSA-N Arg-Trp-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)NC(=O)[C@H](CCCN=C(N)N)N POZKLUIXMHIULG-FDARSICLSA-N 0.000 description 1
- BWMMKQPATDUYKB-IHRRRGAJSA-N Arg-Tyr-Asn Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](CC(N)=O)C(O)=O)CC1=CC=C(O)C=C1 BWMMKQPATDUYKB-IHRRRGAJSA-N 0.000 description 1
- RZVVKNIACROXRM-ZLUOBGJFSA-N Asn-Ala-Asp Chemical compound C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)O)NC(=O)[C@H](CC(=O)N)N RZVVKNIACROXRM-ZLUOBGJFSA-N 0.000 description 1
- CMLGVVWQQHUXOZ-GHCJXIJMSA-N Asn-Ala-Ile Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O CMLGVVWQQHUXOZ-GHCJXIJMSA-N 0.000 description 1
- 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 1
- TWVTVZUGEDBAJF-ACZMJKKPSA-N Asn-Cys-Gln Chemical compound C(CC(=O)N)[C@@H](C(=O)O)NC(=O)[C@H](CS)NC(=O)[C@H](CC(=O)N)N TWVTVZUGEDBAJF-ACZMJKKPSA-N 0.000 description 1
- CTQIOCMSIJATNX-WHFBIAKZSA-N Asn-Gly-Ala Chemical compound [H]N[C@@H](CC(N)=O)C(=O)NCC(=O)N[C@@H](C)C(O)=O CTQIOCMSIJATNX-WHFBIAKZSA-N 0.000 description 1
- PTSDPWIHOYMRGR-UGYAYLCHSA-N Asn-Ile-Asn Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(N)=O)C(O)=O PTSDPWIHOYMRGR-UGYAYLCHSA-N 0.000 description 1
- MKJBPDLENBUHQU-CIUDSAMLSA-N Asn-Ser-Leu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O MKJBPDLENBUHQU-CIUDSAMLSA-N 0.000 description 1
- SLHOOKXYTYAJGQ-XVYDVKMFSA-N Asp-Ala-His Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CC1=CNC=N1 SLHOOKXYTYAJGQ-XVYDVKMFSA-N 0.000 description 1
- HMQDRBKQMLRCCG-GMOBBJLQSA-N Asp-Arg-Ile Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O HMQDRBKQMLRCCG-GMOBBJLQSA-N 0.000 description 1
- UGKZHCBLMLSANF-CIUDSAMLSA-N Asp-Asn-Leu Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(O)=O UGKZHCBLMLSANF-CIUDSAMLSA-N 0.000 description 1
- XACXDSRQIXRMNS-OLHMAJIHSA-N Asp-Asn-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CC(=O)O)N)O XACXDSRQIXRMNS-OLHMAJIHSA-N 0.000 description 1
- HSWYMWGDMPLTTH-FXQIFTODSA-N Asp-Glu-Gln Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O HSWYMWGDMPLTTH-FXQIFTODSA-N 0.000 description 1
- VMVUDJUXJKDGNR-FXQIFTODSA-N Asp-Met-Asn Chemical compound CSCC[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CC(=O)O)N VMVUDJUXJKDGNR-FXQIFTODSA-N 0.000 description 1
- USNJAPJZSGTTPX-XVSYOHENSA-N Asp-Phe-Thr Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O USNJAPJZSGTTPX-XVSYOHENSA-N 0.000 description 1
- 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 1
- JSNWZMFSLIWAHS-HJGDQZAQSA-N Asp-Thr-Leu Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)O)NC(=O)[C@H](CC(=O)O)N)O JSNWZMFSLIWAHS-HJGDQZAQSA-N 0.000 description 1
- NAAAPCLFJPURAM-HJGDQZAQSA-N Asp-Thr-Lys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC(=O)O)N)O NAAAPCLFJPURAM-HJGDQZAQSA-N 0.000 description 1
- PDIYGFYAMZZFCW-JIOCBJNQSA-N Asp-Thr-Pro Chemical compound C[C@H]([C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CC(=O)O)N)O PDIYGFYAMZZFCW-JIOCBJNQSA-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
- 101710144268 B- and T-lymphocyte attenuator Proteins 0.000 description 1
- 108010062802 CD66 antigens Proteins 0.000 description 1
- 239000012275 CTLA-4 inhibitor Substances 0.000 description 1
- 101100510617 Caenorhabditis elegans sel-8 gene Proteins 0.000 description 1
- 102100024533 Carcinoembryonic antigen-related cell adhesion molecule 1 Human genes 0.000 description 1
- 108010072135 Cell Adhesion Molecule-1 Proteins 0.000 description 1
- 102100024649 Cell adhesion molecule 1 Human genes 0.000 description 1
- 101800004419 Cleaved form Proteins 0.000 description 1
- YFAFBAPQHGULQT-HJPIBITLSA-N Cys-Ile-Tyr Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)O)NC(=O)[C@H](CS)N YFAFBAPQHGULQT-HJPIBITLSA-N 0.000 description 1
- UIKLEGZPIOXFHJ-DLOVCJGASA-N Cys-Phe-Ala Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](C)C(O)=O UIKLEGZPIOXFHJ-DLOVCJGASA-N 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 101710121810 Galectin-9 Proteins 0.000 description 1
- ZRXBYKAOFHLTDN-GUBZILKMSA-N Gln-Cys-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)O)NC(=O)[C@H](CS)NC(=O)[C@H](CCC(=O)N)N ZRXBYKAOFHLTDN-GUBZILKMSA-N 0.000 description 1
- JXFLPKSDLDEOQK-JHEQGTHGSA-N Gln-Gly-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CCC(N)=O JXFLPKSDLDEOQK-JHEQGTHGSA-N 0.000 description 1
- LGIKBBLQVSWUGK-DCAQKATOSA-N Gln-Leu-Gln Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O LGIKBBLQVSWUGK-DCAQKATOSA-N 0.000 description 1
- KSKFIECUYMYWNS-AVGNSLFASA-N Gln-Lys-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(=O)N)N KSKFIECUYMYWNS-AVGNSLFASA-N 0.000 description 1
- XQDGOJPVMSWZSO-SRVKXCTJSA-N Gln-Pro-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCC(=O)N)N XQDGOJPVMSWZSO-SRVKXCTJSA-N 0.000 description 1
- HLRLXVPRJJITSK-IFFSRLJSSA-N Gln-Thr-Val Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(O)=O HLRLXVPRJJITSK-IFFSRLJSSA-N 0.000 description 1
- MXOODARRORARSU-ACZMJKKPSA-N Glu-Ala-Ser Chemical compound C[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CCC(=O)O)N MXOODARRORARSU-ACZMJKKPSA-N 0.000 description 1
- 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
- CGYDXNKRIMJMLV-GUBZILKMSA-N Glu-Arg-Glu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(O)=O CGYDXNKRIMJMLV-GUBZILKMSA-N 0.000 description 1
- QPRZKNOOOBWXSU-CIUDSAMLSA-N Glu-Asp-Arg Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CCCN=C(N)N QPRZKNOOOBWXSU-CIUDSAMLSA-N 0.000 description 1
- XHWLNISLUFEWNS-CIUDSAMLSA-N Glu-Gln-Gln Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O XHWLNISLUFEWNS-CIUDSAMLSA-N 0.000 description 1
- GXMXPCXXKVWOSM-KQXIARHKSA-N Glu-Ile-Pro Chemical compound CC[C@H](C)[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCC(=O)O)N GXMXPCXXKVWOSM-KQXIARHKSA-N 0.000 description 1
- GMVCSRBOSIUTFC-FXQIFTODSA-N Glu-Ser-Glu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(O)=O GMVCSRBOSIUTFC-FXQIFTODSA-N 0.000 description 1
- PMSDOVISAARGAV-FHWLQOOXSA-N Glu-Tyr-Phe Chemical compound C([C@H](NC(=O)[C@H](CCC(O)=O)N)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=C(O)C=C1 PMSDOVISAARGAV-FHWLQOOXSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- BGVYNAQWHSTTSP-BYULHYEWSA-N Gly-Asn-Ile Chemical compound [H]NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O BGVYNAQWHSTTSP-BYULHYEWSA-N 0.000 description 1
- XRTDOIOIBMAXCT-NKWVEPMBSA-N Gly-Asn-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC(=O)N)NC(=O)CN)C(=O)O XRTDOIOIBMAXCT-NKWVEPMBSA-N 0.000 description 1
- 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 1
- MIIVFRCYJABHTQ-ONGXEEELSA-N Gly-Leu-Val Chemical compound [H]NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(O)=O MIIVFRCYJABHTQ-ONGXEEELSA-N 0.000 description 1
- 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 1
- BNMRSWQOHIQTFL-JSGCOSHPSA-N Gly-Val-Phe Chemical compound NCC(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 BNMRSWQOHIQTFL-JSGCOSHPSA-N 0.000 description 1
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Natural products NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 108700010013 HMGB1 Proteins 0.000 description 1
- 101150021904 HMGB1 gene Proteins 0.000 description 1
- 108010007707 Hepatitis A Virus Cellular Receptor 2 Proteins 0.000 description 1
- 101710083479 Hepatitis A virus cellular receptor 2 homolog Proteins 0.000 description 1
- 241000709721 Hepatovirus A Species 0.000 description 1
- MDBYBTWRMOAJAY-NHCYSSNCSA-N His-Asn-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CC1=CN=CN1)N MDBYBTWRMOAJAY-NHCYSSNCSA-N 0.000 description 1
- FYVHHKMHFPMBBG-GUBZILKMSA-N His-Gln-Asp Chemical compound C1=C(NC=N1)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CC(=O)O)C(=O)O)N FYVHHKMHFPMBBG-GUBZILKMSA-N 0.000 description 1
- SDTPKSOWFXBACN-GUBZILKMSA-N His-Glu-Asp Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O SDTPKSOWFXBACN-GUBZILKMSA-N 0.000 description 1
- YADRBUZBKHHDAO-XPUUQOCRSA-N His-Gly-Ala Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)NCC(=O)N[C@@H](C)C(O)=O YADRBUZBKHHDAO-XPUUQOCRSA-N 0.000 description 1
- ORERHHPZDDEMSC-VGDYDELISA-N His-Ile-Ser Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CC1=CN=CN1)N ORERHHPZDDEMSC-VGDYDELISA-N 0.000 description 1
- XVZJRZQIHJMUBG-TUBUOCAGSA-N His-Thr-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC1=CN=CN1)N XVZJRZQIHJMUBG-TUBUOCAGSA-N 0.000 description 1
- DEMIXZCKUXVEBO-BWAGICSOSA-N His-Thr-Tyr Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)O)NC(=O)[C@H](CC2=CN=CN2)N)O DEMIXZCKUXVEBO-BWAGICSOSA-N 0.000 description 1
- 101001025337 Homo sapiens High mobility group protein B1 Proteins 0.000 description 1
- 101001078133 Homo sapiens Integrin alpha-2 Proteins 0.000 description 1
- 101001027081 Homo sapiens Killer cell immunoglobulin-like receptor 2DL1 Proteins 0.000 description 1
- 101000945371 Homo sapiens Killer cell immunoglobulin-like receptor 2DL2 Proteins 0.000 description 1
- 101000945351 Homo sapiens Killer cell immunoglobulin-like receptor 3DL1 Proteins 0.000 description 1
- 101000945490 Homo sapiens Killer cell immunoglobulin-like receptor 3DL2 Proteins 0.000 description 1
- 101000955999 Homo sapiens V-set domain-containing T-cell activation inhibitor 1 Proteins 0.000 description 1
- AQCUAZTZSPQJFF-ZKWXMUAHSA-N Ile-Ala-Gly Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](C)C(=O)NCC(O)=O AQCUAZTZSPQJFF-ZKWXMUAHSA-N 0.000 description 1
- VAXBXNPRXPHGHG-BJDJZHNGSA-N Ile-Ala-Leu Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)O)N VAXBXNPRXPHGHG-BJDJZHNGSA-N 0.000 description 1
- HLYBGMZJVDHJEO-CYDGBPFRSA-N Ile-Arg-Arg Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N HLYBGMZJVDHJEO-CYDGBPFRSA-N 0.000 description 1
- KBHYLOIVRVBBEB-JBDRJPRFSA-N Ile-Cys-Cys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CS)C(=O)O)N KBHYLOIVRVBBEB-JBDRJPRFSA-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
- KLBVGHCGHUNHEA-BJDJZHNGSA-N Ile-Leu-Ala Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)O)N KLBVGHCGHUNHEA-BJDJZHNGSA-N 0.000 description 1
- FZWVCYCYWCLQDH-NHCYSSNCSA-N Ile-Leu-Gly Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)O)N FZWVCYCYWCLQDH-NHCYSSNCSA-N 0.000 description 1
- XLXPYSDGMXTTNQ-UHFFFAOYSA-N Ile-Phe-Leu Natural products CCC(C)C(N)C(=O)NC(C(=O)NC(CC(C)C)C(O)=O)CC1=CC=CC=C1 XLXPYSDGMXTTNQ-UHFFFAOYSA-N 0.000 description 1
- XQLGNKLSPYCRMZ-HJWJTTGWSA-N Ile-Phe-Val Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](C(C)C)C(=O)O)N XQLGNKLSPYCRMZ-HJWJTTGWSA-N 0.000 description 1
- 102000016844 Immunoglobulin-like domains Human genes 0.000 description 1
- 108050006430 Immunoglobulin-like domains Proteins 0.000 description 1
- 102100025305 Integrin alpha-2 Human genes 0.000 description 1
- 102100022297 Integrin alpha-X Human genes 0.000 description 1
- 102100037363 Killer cell immunoglobulin-like receptor 2DL1 Human genes 0.000 description 1
- 102100033599 Killer cell immunoglobulin-like receptor 2DL2 Human genes 0.000 description 1
- 102100033627 Killer cell immunoglobulin-like receptor 3DL1 Human genes 0.000 description 1
- 102100034840 Killer cell immunoglobulin-like receptor 3DL2 Human genes 0.000 description 1
- PMGDADKJMCOXHX-UHFFFAOYSA-N L-Arginyl-L-glutamin-acetat Natural products NC(=N)NCCCC(N)C(=O)NC(CCC(N)=O)C(O)=O PMGDADKJMCOXHX-UHFFFAOYSA-N 0.000 description 1
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- 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
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 1
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 1
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 1
- 229940125563 LAG3 inhibitor Drugs 0.000 description 1
- 108090001090 Lectins Proteins 0.000 description 1
- 102000004856 Lectins Human genes 0.000 description 1
- MJOZZTKJZQFKDK-GUBZILKMSA-N Leu-Ala-Gln Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CCC(N)=O MJOZZTKJZQFKDK-GUBZILKMSA-N 0.000 description 1
- WNGVUZWBXZKQES-YUMQZZPRSA-N Leu-Ala-Gly Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C)C(=O)NCC(O)=O WNGVUZWBXZKQES-YUMQZZPRSA-N 0.000 description 1
- MDVZJYGNAGLPGJ-KKUMJFAQSA-N Leu-Asn-Phe Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 MDVZJYGNAGLPGJ-KKUMJFAQSA-N 0.000 description 1
- DXYBNWJZJVSZAE-GUBZILKMSA-N Leu-Gln-Cys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CS)C(=O)O)N DXYBNWJZJVSZAE-GUBZILKMSA-N 0.000 description 1
- GPICTNQYKHHHTH-GUBZILKMSA-N Leu-Gln-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(O)=O GPICTNQYKHHHTH-GUBZILKMSA-N 0.000 description 1
- WQWSMEOYXJTFRU-GUBZILKMSA-N Leu-Glu-Ser Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(O)=O WQWSMEOYXJTFRU-GUBZILKMSA-N 0.000 description 1
- HVJVUYQWFYMGJS-GVXVVHGQSA-N Leu-Glu-Val Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O HVJVUYQWFYMGJS-GVXVVHGQSA-N 0.000 description 1
- JRJLGNFWYFSJHB-HOCLYGCPSA-N Leu-Gly-Trp Chemical compound [H]N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O JRJLGNFWYFSJHB-HOCLYGCPSA-N 0.000 description 1
- LXKNSJLSGPNHSK-KKUMJFAQSA-N Leu-Leu-Lys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)O)N LXKNSJLSGPNHSK-KKUMJFAQSA-N 0.000 description 1
- ONPJGOIVICHWBW-BZSNNMDCSA-N Leu-Lys-Tyr Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 ONPJGOIVICHWBW-BZSNNMDCSA-N 0.000 description 1
- KXCMQWMNYQOAKA-SRVKXCTJSA-N Leu-Met-Gln Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N KXCMQWMNYQOAKA-SRVKXCTJSA-N 0.000 description 1
- INCJJHQRZGQLFC-KBPBESRZSA-N Leu-Phe-Gly Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)NCC(O)=O INCJJHQRZGQLFC-KBPBESRZSA-N 0.000 description 1
- HGUUMQWGYCVPKG-DCAQKATOSA-N Leu-Pro-Cys Chemical compound CC(C)C[C@@H](C(=O)N1CCC[C@H]1C(=O)N[C@@H](CS)C(=O)O)N HGUUMQWGYCVPKG-DCAQKATOSA-N 0.000 description 1
- CHJKEDSZNSONPS-DCAQKATOSA-N Leu-Pro-Ser Chemical compound [H]N[C@@H](CC(C)C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O CHJKEDSZNSONPS-DCAQKATOSA-N 0.000 description 1
- IZPVWNSAVUQBGP-CIUDSAMLSA-N Leu-Ser-Asp Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(O)=O IZPVWNSAVUQBGP-CIUDSAMLSA-N 0.000 description 1
- ADJWHHZETYAAAX-SRVKXCTJSA-N Leu-Ser-His Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N ADJWHHZETYAAAX-SRVKXCTJSA-N 0.000 description 1
- AMSSKPUHBUQBOQ-SRVKXCTJSA-N Leu-Ser-Lys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)O)N AMSSKPUHBUQBOQ-SRVKXCTJSA-N 0.000 description 1
- BRTVHXHCUSXYRI-CIUDSAMLSA-N Leu-Ser-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O BRTVHXHCUSXYRI-CIUDSAMLSA-N 0.000 description 1
- ODRREERHVHMIPT-OEAJRASXSA-N Leu-Thr-Phe 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)CC1=CC=CC=C1 ODRREERHVHMIPT-OEAJRASXSA-N 0.000 description 1
- HGLKOTPFWOMPOB-MEYUZBJRSA-N Leu-Thr-Tyr 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)CC1=CC=C(O)C=C1 HGLKOTPFWOMPOB-MEYUZBJRSA-N 0.000 description 1
- VUBIPAHVHMZHCM-KKUMJFAQSA-N Leu-Tyr-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](CO)C(O)=O)CC1=CC=C(O)C=C1 VUBIPAHVHMZHCM-KKUMJFAQSA-N 0.000 description 1
- 102100020862 Lymphocyte activation gene 3 protein Human genes 0.000 description 1
- VHNOAIFVYUQOOY-XUXIUFHCSA-N Lys-Arg-Ile Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O VHNOAIFVYUQOOY-XUXIUFHCSA-N 0.000 description 1
- DNEJSAIMVANNPA-DCAQKATOSA-N Lys-Asn-Arg Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O DNEJSAIMVANNPA-DCAQKATOSA-N 0.000 description 1
- FLCMXEFCTLXBTL-DCAQKATOSA-N Lys-Asp-Arg Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N FLCMXEFCTLXBTL-DCAQKATOSA-N 0.000 description 1
- LMVOVCYVZBBWQB-SRVKXCTJSA-N Lys-Asp-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CCCCN LMVOVCYVZBBWQB-SRVKXCTJSA-N 0.000 description 1
- SSYOBDBNBQBSQE-SRVKXCTJSA-N Lys-Cys-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(C)C)C(O)=O SSYOBDBNBQBSQE-SRVKXCTJSA-N 0.000 description 1
- KSFQPRLZAUXXPT-GARJFASQSA-N Lys-Cys-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CS)NC(=O)[C@H](CCCCN)N)C(=O)O KSFQPRLZAUXXPT-GARJFASQSA-N 0.000 description 1
- DRCILAJNUJKAHC-SRVKXCTJSA-N Lys-Glu-Arg Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O DRCILAJNUJKAHC-SRVKXCTJSA-N 0.000 description 1
- 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 1
- KNKJPYAZQUFLQK-IHRRRGAJSA-N Lys-His-Arg Chemical compound C1=C(NC=N1)C[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)NC(=O)[C@H](CCCCN)N KNKJPYAZQUFLQK-IHRRRGAJSA-N 0.000 description 1
- RBEATVHTWHTHTJ-KKUMJFAQSA-N Lys-Leu-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(O)=O RBEATVHTWHTHTJ-KKUMJFAQSA-N 0.000 description 1
- PLDJDCJLRCYPJB-VOAKCMCISA-N Lys-Lys-Thr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O PLDJDCJLRCYPJB-VOAKCMCISA-N 0.000 description 1
- KFSALEZVQJYHCE-AVGNSLFASA-N Lys-Met-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCCCN)N KFSALEZVQJYHCE-AVGNSLFASA-N 0.000 description 1
- UQJOKDAYFULYIX-AVGNSLFASA-N Lys-Pro-Pro Chemical compound NCCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 UQJOKDAYFULYIX-AVGNSLFASA-N 0.000 description 1
- MEQLGHAMAUPOSJ-DCAQKATOSA-N Lys-Ser-Val Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O MEQLGHAMAUPOSJ-DCAQKATOSA-N 0.000 description 1
- DRRXXZBXDMLGFC-IHRRRGAJSA-N Lys-Val-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CCCCN DRRXXZBXDMLGFC-IHRRRGAJSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 108091054437 MHC class I family Proteins 0.000 description 1
- 102000043129 MHC class I family Human genes 0.000 description 1
- 239000012515 MabSelect SuRe Substances 0.000 description 1
- QRHWTCJBCLGYRB-FXQIFTODSA-N Met-Ala-Cys Chemical compound CSCC[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CS)C(O)=O QRHWTCJBCLGYRB-FXQIFTODSA-N 0.000 description 1
- QXEVZBXTDTVPCP-GMOBBJLQSA-N Met-Asn-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CCSC)N QXEVZBXTDTVPCP-GMOBBJLQSA-N 0.000 description 1
- CNUPMMXDISGXMU-CIUDSAMLSA-N Met-Cys-Glu Chemical compound [H]N[C@@H](CCSC)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(O)=O)C(O)=O CNUPMMXDISGXMU-CIUDSAMLSA-N 0.000 description 1
- VOOINLQYUZOREH-SRVKXCTJSA-N Met-Gln-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CCSC)N VOOINLQYUZOREH-SRVKXCTJSA-N 0.000 description 1
- XKJUFUPCHARJKX-UWVGGRQHSA-N Met-Gly-His Chemical compound CSCC[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CC1=CNC=N1 XKJUFUPCHARJKX-UWVGGRQHSA-N 0.000 description 1
- RKIIYGUHIQJCBW-SRVKXCTJSA-N Met-His-Glu Chemical compound [H]N[C@@H](CCSC)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCC(O)=O)C(O)=O RKIIYGUHIQJCBW-SRVKXCTJSA-N 0.000 description 1
- ILKCLLLOGPDNIP-RCWTZXSCSA-N Met-Met-Thr Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CCSC)C(=O)N[C@@H]([C@@H](C)O)C(O)=O ILKCLLLOGPDNIP-RCWTZXSCSA-N 0.000 description 1
- VOAKKHOIAFKOQZ-JYJNAYRXSA-N Met-Tyr-Arg Chemical compound NC(=N)NCCC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CCSC)CC1=CC=C(O)C=C1 VOAKKHOIAFKOQZ-JYJNAYRXSA-N 0.000 description 1
- 102000005431 Molecular Chaperones Human genes 0.000 description 1
- 108010006519 Molecular Chaperones Proteins 0.000 description 1
- 108010002311 N-glycylglutamic acid Proteins 0.000 description 1
- 102100035488 Nectin-2 Human genes 0.000 description 1
- 102100035487 Nectin-3 Human genes 0.000 description 1
- 239000012271 PD-L1 inhibitor Substances 0.000 description 1
- JNRFYJZCMHHGMH-UBHSHLNASA-N Phe-Ala-Met Chemical compound CSCC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC1=CC=CC=C1 JNRFYJZCMHHGMH-UBHSHLNASA-N 0.000 description 1
- HTKNPQZCMLBOTQ-XVSYOHENSA-N Phe-Asn-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CC1=CC=CC=C1)N)O HTKNPQZCMLBOTQ-XVSYOHENSA-N 0.000 description 1
- KAGCQPSEVAETCA-JYJNAYRXSA-N Phe-Gln-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CC1=CC=CC=C1)N KAGCQPSEVAETCA-JYJNAYRXSA-N 0.000 description 1
- KLXQWABNAWDRAY-ACRUOGEOSA-N Phe-Lys-Phe Chemical compound C([C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 KLXQWABNAWDRAY-ACRUOGEOSA-N 0.000 description 1
- AXIOGMQCDYVTNY-ACRUOGEOSA-N Phe-Phe-Leu Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)[C@@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 AXIOGMQCDYVTNY-ACRUOGEOSA-N 0.000 description 1
- 208000002151 Pleural effusion Diseases 0.000 description 1
- 102100029740 Poliovirus receptor Human genes 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- OLHDPZMYUSBGDE-GUBZILKMSA-N Pro-Arg-Cys Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CS)C(=O)O OLHDPZMYUSBGDE-GUBZILKMSA-N 0.000 description 1
- XWYXZPHPYKRYPA-GMOBBJLQSA-N Pro-Asn-Ile Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O XWYXZPHPYKRYPA-GMOBBJLQSA-N 0.000 description 1
- CJZTUKSFZUSNCC-FXQIFTODSA-N Pro-Asp-Asn Chemical compound NC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H]1CCCN1 CJZTUKSFZUSNCC-FXQIFTODSA-N 0.000 description 1
- SGCZFWSQERRKBD-BQBZGAKWSA-N Pro-Asp-Gly Chemical compound OC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@@H]1CCCN1 SGCZFWSQERRKBD-BQBZGAKWSA-N 0.000 description 1
- ZCXQTRXYZOSGJR-FXQIFTODSA-N Pro-Asp-Ser Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O ZCXQTRXYZOSGJR-FXQIFTODSA-N 0.000 description 1
- FRKBNXCFJBPJOL-GUBZILKMSA-N Pro-Glu-Glu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O FRKBNXCFJBPJOL-GUBZILKMSA-N 0.000 description 1
- LXVLKXPFIDDHJG-CIUDSAMLSA-N Pro-Glu-Ser Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(O)=O LXVLKXPFIDDHJG-CIUDSAMLSA-N 0.000 description 1
- UEHYFUCOGHWASA-HJGDQZAQSA-N Pro-Glu-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H]1CCCN1 UEHYFUCOGHWASA-HJGDQZAQSA-N 0.000 description 1
- FEPSEIDIPBMIOS-QXEWZRGKSA-N Pro-Gly-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H]1CCCN1 FEPSEIDIPBMIOS-QXEWZRGKSA-N 0.000 description 1
- FKLSMYYLJHYPHH-UWVGGRQHSA-N Pro-Gly-Leu Chemical compound [H]N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](CC(C)C)C(O)=O FKLSMYYLJHYPHH-UWVGGRQHSA-N 0.000 description 1
- FHZJRBVMLGOHBX-GUBZILKMSA-N Pro-Pro-Asp Chemical compound OC(=O)C[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1)C(O)=O FHZJRBVMLGOHBX-GUBZILKMSA-N 0.000 description 1
- POQFNPILEQEODH-FXQIFTODSA-N Pro-Ser-Ala Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(O)=O POQFNPILEQEODH-FXQIFTODSA-N 0.000 description 1
- ITUDDXVFGFEKPD-NAKRPEOUSA-N Pro-Ser-Ile Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O ITUDDXVFGFEKPD-NAKRPEOUSA-N 0.000 description 1
- QKDIHFHGHBYTKB-IHRRRGAJSA-N Pro-Ser-Phe Chemical compound N([C@@H](CO)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C(=O)[C@@H]1CCCN1 QKDIHFHGHBYTKB-IHRRRGAJSA-N 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- 206010037211 Psychomotor hyperactivity Diseases 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 1
- BNFVPSRLHHPQKS-WHFBIAKZSA-N Ser-Asp-Gly Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(O)=O BNFVPSRLHHPQKS-WHFBIAKZSA-N 0.000 description 1
- OLIJLNWFEQEFDM-SRVKXCTJSA-N Ser-Asp-Phe Chemical compound OC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 OLIJLNWFEQEFDM-SRVKXCTJSA-N 0.000 description 1
- SWSRFJZZMNLMLY-ZKWXMUAHSA-N Ser-Asp-Val Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O SWSRFJZZMNLMLY-ZKWXMUAHSA-N 0.000 description 1
- RNFKSBPHLTZHLU-WHFBIAKZSA-N Ser-Cys-Gly Chemical compound C([C@@H](C(=O)N[C@@H](CS)C(=O)NCC(=O)O)N)O RNFKSBPHLTZHLU-WHFBIAKZSA-N 0.000 description 1
- XSYJDGIDKRNWFX-SRVKXCTJSA-N Ser-Cys-Phe Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O XSYJDGIDKRNWFX-SRVKXCTJSA-N 0.000 description 1
- SWIQQMYVHIXPEK-FXQIFTODSA-N Ser-Cys-Val Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)N[C@@H](C(C)C)C(O)=O SWIQQMYVHIXPEK-FXQIFTODSA-N 0.000 description 1
- ULVMNZOKDBHKKI-ACZMJKKPSA-N Ser-Gln-Asp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O ULVMNZOKDBHKKI-ACZMJKKPSA-N 0.000 description 1
- XXXAXOWMBOKTRN-XPUUQOCRSA-N Ser-Gly-Val Chemical compound [H]N[C@@H](CO)C(=O)NCC(=O)N[C@@H](C(C)C)C(O)=O XXXAXOWMBOKTRN-XPUUQOCRSA-N 0.000 description 1
- JEHPKECJCALLRW-CUJWVEQBSA-N Ser-His-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O JEHPKECJCALLRW-CUJWVEQBSA-N 0.000 description 1
- DOSZISJPMCYEHT-NAKRPEOUSA-N Ser-Ile-Val Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C(C)C)C(O)=O DOSZISJPMCYEHT-NAKRPEOUSA-N 0.000 description 1
- FUMGHWDRRFCKEP-CIUDSAMLSA-N Ser-Leu-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(O)=O FUMGHWDRRFCKEP-CIUDSAMLSA-N 0.000 description 1
- HEUVHBXOVZONPU-BJDJZHNGSA-N Ser-Leu-Ile Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O HEUVHBXOVZONPU-BJDJZHNGSA-N 0.000 description 1
- RRVFEDGUXSYWOW-BZSNNMDCSA-N Ser-Phe-Phe Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O RRVFEDGUXSYWOW-BZSNNMDCSA-N 0.000 description 1
- QPPYAWVLAVXISR-DCAQKATOSA-N Ser-Pro-His Chemical compound C1C[C@H](N(C1)C(=O)[C@H](CO)N)C(=O)N[C@@H](CC2=CN=CN2)C(=O)O QPPYAWVLAVXISR-DCAQKATOSA-N 0.000 description 1
- AZWNCEBQZXELEZ-FXQIFTODSA-N Ser-Pro-Ser Chemical compound OC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O AZWNCEBQZXELEZ-FXQIFTODSA-N 0.000 description 1
- FZXOPYUEQGDGMS-ACZMJKKPSA-N Ser-Ser-Gln Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(O)=O FZXOPYUEQGDGMS-ACZMJKKPSA-N 0.000 description 1
- FVFUOQIYDPAIJR-XIRDDKMYSA-N Ser-Trp-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)NC(=O)[C@H](CO)N FVFUOQIYDPAIJR-XIRDDKMYSA-N 0.000 description 1
- PMTWIUBUQRGCSB-FXQIFTODSA-N Ser-Val-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C)C(O)=O PMTWIUBUQRGCSB-FXQIFTODSA-N 0.000 description 1
- PCMZJFMUYWIERL-ZKWXMUAHSA-N Ser-Val-Asn Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O PCMZJFMUYWIERL-ZKWXMUAHSA-N 0.000 description 1
- BEBVVQPDSHHWQL-NRPADANISA-N Ser-Val-Glu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O BEBVVQPDSHHWQL-NRPADANISA-N 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- XYEXCEPTALHNEV-RCWTZXSCSA-N Thr-Arg-Arg Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O XYEXCEPTALHNEV-RCWTZXSCSA-N 0.000 description 1
- JMZKMSTYXHFYAK-VEVYYDQMSA-N Thr-Arg-Asn Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC(=O)N)C(=O)O)N)O JMZKMSTYXHFYAK-VEVYYDQMSA-N 0.000 description 1
- VIBXMCZWVUOZLA-OLHMAJIHSA-N Thr-Asn-Asn Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC(=O)N)C(=O)O)N)O VIBXMCZWVUOZLA-OLHMAJIHSA-N 0.000 description 1
- LOHBIDZYHQQTDM-IXOXFDKPSA-N Thr-Cys-Phe Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O LOHBIDZYHQQTDM-IXOXFDKPSA-N 0.000 description 1
- ONNSECRQFSTMCC-XKBZYTNZSA-N Thr-Glu-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(O)=O ONNSECRQFSTMCC-XKBZYTNZSA-N 0.000 description 1
- FLPZMPOZGYPBEN-PPCPHDFISA-N Thr-Leu-Ile 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)CC)C(O)=O FLPZMPOZGYPBEN-PPCPHDFISA-N 0.000 description 1
- IJVNLNRVDUTWDD-MEYUZBJRSA-N Thr-Leu-Tyr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O IJVNLNRVDUTWDD-MEYUZBJRSA-N 0.000 description 1
- KZSYAEWQMJEGRZ-RHYQMDGZSA-N Thr-Leu-Val Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(O)=O KZSYAEWQMJEGRZ-RHYQMDGZSA-N 0.000 description 1
- SCSVNSNWUTYSFO-WDCWCFNPSA-N Thr-Lys-Glu Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(O)=O SCSVNSNWUTYSFO-WDCWCFNPSA-N 0.000 description 1
- KZURUCDWKDEAFZ-XVSYOHENSA-N Thr-Phe-Asn Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(=O)N)C(=O)O)N)O KZURUCDWKDEAFZ-XVSYOHENSA-N 0.000 description 1
- UGFSAPWZBROURT-IXOXFDKPSA-N Thr-Phe-Cys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CS)C(=O)O)N)O UGFSAPWZBROURT-IXOXFDKPSA-N 0.000 description 1
- BIBYEFRASCNLAA-CDMKHQONSA-N Thr-Phe-Gly Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@H](C(=O)NCC(O)=O)CC1=CC=CC=C1 BIBYEFRASCNLAA-CDMKHQONSA-N 0.000 description 1
- KERCOYANYUPLHJ-XGEHTFHBSA-N Thr-Pro-Ser Chemical compound C[C@@H](O)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O KERCOYANYUPLHJ-XGEHTFHBSA-N 0.000 description 1
- NDZYTIMDOZMECO-SHGPDSBTSA-N Thr-Thr-Ala Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O NDZYTIMDOZMECO-SHGPDSBTSA-N 0.000 description 1
- GRIUMVXCJDKVPI-IZPVPAKOSA-N Thr-Thr-Tyr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O GRIUMVXCJDKVPI-IZPVPAKOSA-N 0.000 description 1
- 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 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
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- MJBBMTOGSOSAKJ-HJXMPXNTSA-N Trp-Ala-Ile Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O MJBBMTOGSOSAKJ-HJXMPXNTSA-N 0.000 description 1
- BXKWZPXTTSCOMX-AQZXSJQPSA-N Trp-Asn-Thr Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O BXKWZPXTTSCOMX-AQZXSJQPSA-N 0.000 description 1
- OBAMASZCXDIXSS-SZMVWBNQSA-N Trp-Glu-Lys Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCCCN)C(=O)O)N OBAMASZCXDIXSS-SZMVWBNQSA-N 0.000 description 1
- IVBJBFSWJDNQFW-XIRDDKMYSA-N Trp-Pro-Glu Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O IVBJBFSWJDNQFW-XIRDDKMYSA-N 0.000 description 1
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 1
- 108010065158 Tumor Necrosis Factor Ligand Superfamily Member 14 Proteins 0.000 description 1
- 108060008683 Tumor Necrosis Factor Receptor Proteins 0.000 description 1
- 102100024586 Tumor necrosis factor ligand superfamily member 14 Human genes 0.000 description 1
- 101710187780 Tumor necrosis factor receptor superfamily member 14 Proteins 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
- DANHCMVVXDXOHN-SRVKXCTJSA-N Tyr-Asp-Asn Chemical compound NC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 DANHCMVVXDXOHN-SRVKXCTJSA-N 0.000 description 1
- UNUZEBFXGWVAOP-DZKIICNBSA-N Tyr-Glu-Val Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O UNUZEBFXGWVAOP-DZKIICNBSA-N 0.000 description 1
- AKLNEFNQWLHIGY-QWRGUYRKSA-N Tyr-Gly-Asp Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)NCC(=O)N[C@@H](CC(=O)O)C(=O)O)N)O AKLNEFNQWLHIGY-QWRGUYRKSA-N 0.000 description 1
- ZZDYJFVIKVSUFA-WLTAIBSBSA-N Tyr-Thr-Gly Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(O)=O ZZDYJFVIKVSUFA-WLTAIBSBSA-N 0.000 description 1
- HMPMGPISLMLHSI-JBACZVJFSA-N Tyr-Trp-Gln Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CC3=CC=C(C=C3)O)N HMPMGPISLMLHSI-JBACZVJFSA-N 0.000 description 1
- CVUDMNSZAIZFAE-TUAOUCFPSA-N Val-Arg-Pro Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1CCC[C@@H]1C(=O)O)N CVUDMNSZAIZFAE-TUAOUCFPSA-N 0.000 description 1
- CVUDMNSZAIZFAE-UHFFFAOYSA-N Val-Arg-Pro Natural products NC(N)=NCCCC(NC(=O)C(N)C(C)C)C(=O)N1CCCC1C(O)=O CVUDMNSZAIZFAE-UHFFFAOYSA-N 0.000 description 1
- GXAZTLJYINLMJL-LAEOZQHASA-N Val-Asn-Gln Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N GXAZTLJYINLMJL-LAEOZQHASA-N 0.000 description 1
- NMPXRFYMZDIBRF-ZOBUZTSGSA-N Val-Asn-Trp Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)N NMPXRFYMZDIBRF-ZOBUZTSGSA-N 0.000 description 1
- ZEVNVXYRZRIRCH-GVXVVHGQSA-N Val-Gln-Lys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CCCCN)C(=O)O)N ZEVNVXYRZRIRCH-GVXVVHGQSA-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
- VIKZGAUAKQZDOF-NRPADANISA-N Val-Ser-Glu Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CCC(O)=O VIKZGAUAKQZDOF-NRPADANISA-N 0.000 description 1
- PQSNETRGCRUOGP-KKHAAJSZSA-N Val-Thr-Asn Chemical compound CC(C)[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@H](C(O)=O)CC(N)=O PQSNETRGCRUOGP-KKHAAJSZSA-N 0.000 description 1
- UQMPYVLTQCGRSK-IFFSRLJSSA-N Val-Thr-Gln Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](C(C)C)N)O UQMPYVLTQCGRSK-IFFSRLJSSA-N 0.000 description 1
- AYHNXCJKBLYVOA-KSZLIROESA-N Val-Trp-Pro Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)N3CCC[C@@H]3C(=O)O)N AYHNXCJKBLYVOA-KSZLIROESA-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
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 229960003697 abatacept Drugs 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 108010069020 alanyl-prolyl-glycine Proteins 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 231100000360 alopecia Toxicity 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 210000004102 animal cell Anatomy 0.000 description 1
- 230000005809 anti-tumor immunity Effects 0.000 description 1
- 230000005875 antibody response Effects 0.000 description 1
- 230000006907 apoptotic process Effects 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
- 108010093581 aspartyl-proline Proteins 0.000 description 1
- 108010030694 avidin-horseradish peroxidase complex Proteins 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- SQVRNKJHWKZAKO-UHFFFAOYSA-N beta-N-Acetyl-D-neuraminic acid Natural products CC(=O)NC1C(O)CC(O)(C(O)=O)OC1C(O)C(O)CO SQVRNKJHWKZAKO-UHFFFAOYSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 230000009460 calcium influx Effects 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 210000003690 classically activated macrophage Anatomy 0.000 description 1
- 201000010989 colorectal carcinoma Diseases 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 239000012228 culture supernatant Substances 0.000 description 1
- 108010016616 cysteinylglycine Proteins 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000004041 dendritic cell maturation Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 230000017188 evasion or tolerance of host immune response Effects 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 230000033581 fucosylation Effects 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 108010063718 gamma-glutamylaspartic acid Proteins 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 239000008103 glucose 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
- 125000003630 glycyl group Chemical group [H]N([H])C([H])([H])C(*)=O 0.000 description 1
- 108010077435 glycyl-phenylalanyl-glycine Proteins 0.000 description 1
- 108010079413 glycyl-prolyl-glutamic acid Proteins 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 210000002443 helper t lymphocyte Anatomy 0.000 description 1
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 230000013632 homeostatic process Effects 0.000 description 1
- 239000000710 homodimer Substances 0.000 description 1
- 102000043321 human CTLA4 Human genes 0.000 description 1
- 238000011577 humanized mouse model Methods 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 230000003832 immune regulation Effects 0.000 description 1
- 230000006058 immune tolerance Effects 0.000 description 1
- 229940072221 immunoglobulins Drugs 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 230000004068 intracellular signaling Effects 0.000 description 1
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 1
- 229960000310 isoleucine Drugs 0.000 description 1
- 108010044374 isoleucyl-tyrosine Proteins 0.000 description 1
- 239000000644 isotonic solution Substances 0.000 description 1
- 239000002523 lectin Substances 0.000 description 1
- 108010044311 leucyl-glycyl-glycine Proteins 0.000 description 1
- 230000021633 leukocyte mediated immunity Effects 0.000 description 1
- 230000008095 long lasting therapeutic effect Effects 0.000 description 1
- 210000001165 lymph node Anatomy 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 230000007087 memory ability Effects 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 229940100661 nasal inhalant Drugs 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 229940035567 orencia Drugs 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 229940121656 pd-l1 inhibitor Drugs 0.000 description 1
- 210000005105 peripheral blood lymphocyte Anatomy 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 108010073025 phenylalanylphenylalanine Proteins 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 108700042769 prolyl-leucyl-glycine Proteins 0.000 description 1
- 108010090894 prolylleucine Proteins 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 239000012562 protein A resin Substances 0.000 description 1
- 238000013102 re-test Methods 0.000 description 1
- 230000007420 reactivation Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 108010026333 seryl-proline Proteins 0.000 description 1
- SQVRNKJHWKZAKO-OQPLDHBCSA-N sialic acid Chemical compound CC(=O)N[C@@H]1[C@@H](O)C[C@@](O)(C(O)=O)OC1[C@H](O)[C@H](O)CO SQVRNKJHWKZAKO-OQPLDHBCSA-N 0.000 description 1
- 210000004988 splenocyte Anatomy 0.000 description 1
- 239000012086 standard solution Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 239000008227 sterile water for injection Substances 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 102000035160 transmembrane proteins Human genes 0.000 description 1
- 108091005703 transmembrane proteins Proteins 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 108010029384 tryptophyl-histidine Proteins 0.000 description 1
- 108010084932 tryptophyl-proline Proteins 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 102000003298 tumor necrosis factor receptor Human genes 0.000 description 1
- 230000001875 tumorinhibitory effect Effects 0.000 description 1
- 108010020532 tyrosyl-proline Proteins 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
- C07K16/249—Interferons
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
- A61K38/1774—Immunoglobulin superfamily (e.g. CD2, CD4, CD8, ICAM molecules, B7 molecules, Fc-receptors, MHC-molecules)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/20—Interleukins [IL]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/20—Interleukins [IL]
- A61K38/2013—IL-2
-
- 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
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
-
- 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
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
-
- 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
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
- A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/52—Cytokines; Lymphokines; Interferons
- C07K14/54—Interleukins [IL]
- C07K14/55—IL-2
-
- 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
- C07K14/70532—B7 molecules, e.g. CD80, CD86
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
- C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2803—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
- C07K16/2827—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 B7 molecules, e.g. CD80, CD86
-
- 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
- C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
- A61K2039/507—Comprising a combination of two or more separate antibodies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/30—Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Immunology (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Molecular Biology (AREA)
- Gastroenterology & Hepatology (AREA)
- Zoology (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Genetics & Genomics (AREA)
- Cell Biology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Microbiology (AREA)
- Mycology (AREA)
- Toxicology (AREA)
- Biomedical Technology (AREA)
- Oncology (AREA)
- Endocrinology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicinal Preparation (AREA)
Abstract
本发明提供了一种用于预防或治疗癌症的药物组合物,所述药物组合物包括作为活性成分的包含IL‑2蛋白或其变体和CD80蛋白或其片段的融合蛋白二聚体以及免疫检查点抑制剂。在一个实施方案中,包含CD80片段、免疫球蛋白的Fc结构域和IL‑2变体的所述融合蛋白可激活免疫细胞诸如自然杀伤细胞,以及控制调节性T细胞的免疫细胞调节活性。此外,所述融合蛋白和免疫检查点抑制剂诸如已知为PD‑1抑制剂的Keytruda的联合施用可有效抑制癌症。因此,本发明提供的包括作为活性成分的包含IL‑2蛋白或其变体和CD80蛋白或其片段的融合蛋白二聚体以及免疫检查点抑制剂的药物组合物可有效地用于癌症的治疗,并且具有高度的工业实用性。
Description
技术领域
本发明涉及一种用于治疗癌症的药物组合物,该药物组合物包括作为活性成分的包含IL-2蛋白或其变体和CD80蛋白或其片段的融合蛋白二聚体以及免疫检查点抑制剂。
背景技术
白细胞介素2(IL-2),也称为T细胞生长因子(TCGF),是一种球状糖蛋白,其在淋巴细胞产生、存活和体内平衡中起核心作用。IL-2的蛋白质大小为15.5kDa至16kDa,并且由133个氨基酸组成。IL-2通过与由三个不同亚基组成的IL-2受体结合介导各种免疫作用。
另外,IL-2主要由活化的T细胞合成,特别是由CD4+辅助T细胞合成。IL-2刺激T细胞的增殖和分化,并诱导细胞毒性T淋巴细胞(CTL)的产生以及外周血淋巴细胞分化成细胞毒性细胞和淋巴因子活化的杀伤细胞(LAK细胞)。
同时,CD80,也称为B7-1,为膜结合蛋白的B7家族的成员,这些膜结合蛋白通过与其配体结合、传递共刺激应答和共抑制应答而参与免疫调节。CD80是在T细胞、B细胞、树突细胞和单核细胞表面上表达的跨膜蛋白。已知CD80结合CD28、CTLA4(CD152)和PD-L1。CD80、CD86、CTLA4和CD28参与共刺激-共抑制系统。例如,它们调节T细胞的活性,并参与其增殖、分化和存活。
发明内容
技术问题
因此,作为开发安全且有效的抗癌剂的研究结果,本发明人发现在一个分子中包含IL-2蛋白或其变体和CD80蛋白或其片段的新型融合蛋白二聚体以及免疫检查点抑制剂表现出优异的抗癌作用,从而完成了本发明。
问题的解决方案
为了实现上述目的,本发明的一个方面提供一种用于治疗癌症的药物组合物,该药物组合物包括作为活性成分的包含IL-2蛋白或其变体和CD80蛋白或其片段的融合蛋白二聚体以及免疫检查点抑制剂。
发明效果
包含IL-2蛋白或其变体和CD80蛋白或其片段的融合蛋白二聚体可通过IL-2激活免疫细胞。另外,证实了当与免疫检查点抑制剂联合施用时,融合蛋白二聚体表现出协同作用。因此,本发明提供的用于治疗癌症的药物组合物,其包括作为活性成分的包含IL-2蛋白或其变体和CD80蛋白或其片段的融合蛋白二聚体以及免疫检查点抑制剂,可有效地用于癌症预防和治疗。
附图说明
图1示出了融合蛋白二聚体的示意性实施方案。
图2示出了融合蛋白二聚体在淋巴结中发挥作用的机制的示意图。
图3示出了融合蛋白二聚体在肿瘤微环境中发挥作用的机制的示意图。
图4示出了融合蛋白的结构的示意图。此处,GI101和mGI101各为融合蛋白的实施方案;GI101C1、GI101C2和mGI101C1为与融合蛋白的活性进行比较的对比例。
图5示出了融合蛋白的各种实施方案。人源蛋白和小鼠来源蛋白可组合以制备融合蛋白。CD80蛋白和IL-2蛋白可通过除Fc以外的各种接头相互结合。
图6示出了所获得的融合蛋白二聚体(GI101)的SDS-PAGE鉴定结果。
图7示出了融合蛋白(GI101)的量取决于吸光度。
图8示出了通过尺寸排阻层析法(SEC)分析所获得的融合蛋白二聚体(GI101)的结果。
图9示出了所获得的mGI101融合蛋白二聚体的SDS-PAGE鉴定结果。
图10示出了所获得的GI101C1融合蛋白二聚体的SDS-PAGE鉴定结果。
图11示出了所获得的GI101C2融合蛋白二聚体的SDS-PAGE鉴定结果。
图12示出了所获得的mGI101C1融合蛋白二聚体的SDS-PAGE鉴定结果。
图13示出了所获得的GI102-M45融合蛋白二聚体的SDS-PAGE鉴定结果。
图14示出了所获得的GI102-M61融合蛋白二聚体的SDS-PAGE鉴定结果。
图15示出了所获得的GI102-M72融合蛋白二聚体的SDS-PAGE鉴定结果。
图16示出了hCTLA4和GI101之间的结合亲和力。
图17示出了hPD-L1和GI101之间的结合亲和力。
图18示出了hPD-L1和hPD-1之间的结合亲和力。
图19示出了mCTLA4和mGI101之间的结合亲和力。
图20示出了mPD-L1和mGI101之间的结合亲和力。
图21示出了GI-101(hCD80-Fc-hIL-2v)和CTLA-4之间的结合能力的鉴定结果。经鉴定,GI-101(hCD80-Fc-hIL-2v)对CTLA-4具有高结合能力。
图22示出了GI101和IL-2Rα或IL-2Rβ之间的结合亲和力的鉴定结果。
图23示出了GI101和IL-2Rα之间的结合亲和力的鉴定结果。
图24示出了GI101和IL-2Rβ之间的结合亲和力的鉴定结果。
图25示出了IL-2Rα和GI102-M45之间的结合亲和力的鉴定结果。
图26示出了IL-2Rα和GI102-M61之间的结合亲和力的鉴定结果。
图27示出了IL-2Rα和GI102-M72之间的结合亲和力的鉴定结果。
图28示出了IL-2Rβ和GI102-M45之间的结合亲和力的鉴定结果。
图29示出了IL-2Rβ和GI102-M61之间的结合亲和力的鉴定结果。
图30示出了IL-2Rβ和GI102-M72之间的结合亲和力的鉴定结果。
图31和图32示出了当细胞以各自浓度接受GI101、GI101C1、GI101C2或IL-2处理并进行孵育时,测量细胞分泌的IFN-γ的量的结果。
图33示出了GI101、GI101C1、GI101C2和IL-2(阿地白介素)对CD8+T细胞增殖作用的鉴定结果。
图34示出了GI101作用于效应T细胞的机制的示意图。
图35示出了GI101和GI102对CD8+T细胞和CD4+T细胞增殖作用的鉴定结果。此处,(A)示出了CD8+T细胞和CD4+T细胞的比例,(B)示出了CD8+T细胞的增殖能力,以及(C)示出了CD4+/FoxP3+Treg细胞的比例。
图36和图37示出了GI101和GI101w对CD8+T细胞和NK细胞增殖作用的鉴定结果。
图38和图39示出了GI101对效应T细胞作用的鉴定结果。
图40示出了mGI101和mGI102-M61对小鼠免疫细胞作用的鉴定结果。
图41和图42示出了GI101对表达PD-L1和CTLA-4的癌细胞抑制T细胞活性作用的鉴定结果。
图43示出了在小鼠来源结直肠癌细胞移植的小鼠中,mGI101对肿瘤抑制作用(取决于其剂量)的鉴定结果。
图44示出了接受mGI101的小鼠来源结直肠癌细胞移植小鼠的存活率的鉴定结果。
图45示出了GI101在小鼠来源结直肠癌细胞移植小鼠中的肿瘤抑制作用的鉴定结果。
图46示出了在小鼠来源结直肠癌细胞移植的小鼠接受hIgG4、抗PD-1抗体或GI101治疗后,用FACS分析癌组织中的CD8+T细胞、IFN-γT细胞、CD4+T细胞和Treg细胞的结果。
图47以图表形式示出了在小鼠来源结直肠癌细胞移植的小鼠接受hIgG4、抗PD-1抗体或GI101治疗后,用FACS分析癌组织中的CD8+T细胞、IFN-γT细胞、CD4+T细胞和Treg细胞的结果。
图48示出了在小鼠来源结直肠癌细胞移植的小鼠接受hIgG4、抗PD-1抗体或GI101治疗后,用FACS分析癌组织中的巨噬细胞的结果。
图49以图表形式示出了在小鼠来源结直肠癌细胞移植的小鼠接受hIgG4、抗PD-1抗体或GI101治疗后,用FACS分析癌组织中的巨噬细胞的结果。
图50示出了在小鼠来源结直肠癌细胞移植的小鼠接受hIgG4、抗PD-1抗体或GI101治疗后,用FACS分析癌组织中的树突细胞的结果。
图51以图表形式示出了在小鼠来源结直肠癌细胞移植的小鼠接受hIgG4、抗PD-1抗体或GI101治疗后,用FACS分析癌组织中的树突细胞的结果。
图52示出了GI101在小鼠来源肺癌细胞移植小鼠中的肿瘤抑制作用的鉴定结果。
图53以图表形式示出了在小鼠来源肺癌细胞移植的小鼠接受hIgG4、抗PD-1抗体或GI101治疗后,用FACS分析癌组织中的CD8+T细胞、IFN-γT细胞、CD4+T细胞和Treg细胞的结果。
图54以图表形式示出了在小鼠来源肺癌细胞移植的小鼠接受hIgG4、抗PD-1抗体或GI101治疗后,用FACS分析癌组织中的巨噬细胞的结果。
图55以图表形式示出了在小鼠来源肺癌细胞移植的小鼠接受hIgG4、抗PD-1抗体或GI101治疗后,用FACS分析癌组织中的树突细胞的结果。
图56示出了mGI102-M61在小鼠来源结直肠癌细胞移植小鼠中的肿瘤抑制作用的鉴定结果。
图57示出了接受mGI102-M61的小鼠来源结直肠癌细胞移植小鼠的存活率的分析结果。
图58示出了mGI101在小鼠来源结直肠癌细胞移植小鼠中的肿瘤抑制作用的鉴定结果。
图59示出了mGI101对小鼠来源结直肠癌细胞移植小鼠的肿瘤抑制率。
图60显示了当GI101和Keytruda联合用于人源乳腺癌细胞移植小鼠时的肿瘤生长的曲线图。与对照组(hIgG4)相比,在GI101或Keytruda单独治疗组中肿瘤生长受到抑制。与对照组相比,GI101和Keytruda联合治疗组中的肿瘤生长受到抑制。与GI101或Keytruda单独治疗组相比,GI101和Keytruda联合治疗组中的肿瘤生长受到抑制。
图61示出了当GI-101和Keytruda联合用于人源乳腺癌细胞移植小鼠时的肿瘤生长抑制率。IgG4治疗组有2只小鼠的肿瘤生长抑制率为30%或更高,1只小鼠的肿瘤生长抑制率为50%或更高,以及1只小鼠的肿瘤生长抑制率为80%。GI101治疗组有5只小鼠的肿瘤生长抑制率为30%或更高,5只小鼠的肿瘤生长抑制率为50%或更高,以及2只小鼠的肿瘤生长抑制率为80%。Keytruda治疗组有7只小鼠的肿瘤生长抑制率为30%或更高,5只小鼠的肿瘤生长抑制率为50%或更高,以及3只小鼠的肿瘤生长抑制率为80%。GI101和Keytruda联合治疗组有8只小鼠的肿瘤生长抑制率为30%或更高,8只小鼠的肿瘤生长抑制率为50%或更高,以及6只小鼠的肿瘤生长抑制率为80%。
图62示出了当GI101和Keytruda联合用于人源乳腺癌细胞移植小鼠时每个治疗组中的个体实验动物的肿瘤生长程度。
图63示出了在人源乳腺癌细胞移植小鼠中hIgG4治疗组中的个体实验动物的肿瘤生长程度。
图64示出了在人源乳腺癌细胞移植小鼠中GI101治疗组中的个体实验动物的肿瘤生长程度。
图65示出了在人源乳腺癌细胞移植小鼠中Keytruda治疗组中的个体实验动物的肿瘤生长程度。
图66示出了在人源乳腺癌细胞移植小鼠中GI101和Keytruda联合治疗组中的个体实验动物的肿瘤生长程度。
图67示出了当mGI101和抗PD-1抗体联合施用给鼠源结直肠癌细胞移植小鼠时的肿瘤生长的曲线图。
图68示出了当mGI101和抗PD-1抗体联合施用给鼠源结直肠癌细胞移植小鼠时的肿瘤生长抑制率。
图69示出了当mGI101和抗PD-1抗体联合施用给鼠源结直肠癌细胞移植小鼠时每个治疗组中的个体实验动物的肿瘤生长程度。
图70示出了在鼠源结直肠癌细胞移植小鼠中hIgG4治疗组中的个体实验动物的肿瘤生长程度。
图71示出了在鼠源结直肠癌细胞移植小鼠中mGI101治疗组中的个体实验动物的肿瘤生长程度。
图72示出了在鼠源结直肠癌细胞移植小鼠中抗PD-1抗体治疗组中的个体实验动物的肿瘤生长程度。
图73示出了在鼠源结直肠癌细胞移植小鼠中施用mGI101和抗PD-1抗体联合治疗组中的个体实验动物的肿瘤生长程度。
图74示出了将鼠源结直肠癌细胞重新注射到实验动物后个体实验动物的肿瘤生长程度,在鼠源结直肠癌细胞移植小鼠中,mGI101和抗PD-1抗体联合治疗组的肿瘤生长完全缓解。
图75示出了当mGI101和抗PD-L1抗体联合施用给鼠源结直肠癌细胞移植小鼠时的肿瘤生长的曲线图。
图76示出了当mGI101和抗TIGIT抗体联合施用给鼠源结直肠癌细胞移植小鼠时的肿瘤生长的曲线图。
实施本发明的最佳模式
本发明的一个方面提供一种用于治疗癌症的药物组合物,所述药物组合物包括作为活性成分的包含IL-2蛋白或其变体和CD80蛋白或其片段的融合蛋白二聚体以及免疫检查点抑制剂。
免疫检查点抑制剂
如本文所用,术语“免疫检查点”是指维持自身耐受性并保护组织免受导致损伤的过度免疫应答的细胞内信号传导系统。免疫检查点蛋白为调节免疫检查点并可抑制免疫细胞的分化、增殖和活性的细胞膜蛋白。具体地,免疫检查点蛋白在活化的T细胞中表达,以起到减少T细胞增殖、细胞因子分泌和细胞毒性并抑制T细胞的过度活性的作用。已知一些免疫检查点是导致肿瘤细胞免疫逃避的主要机制之一。因此,“免疫检查点抑制剂”靶向免疫检查点蛋白以抑制或阻断免疫检查点并增加T细胞活化,从而增强抗肿瘤免疫力,并由此表现出抗癌作用。除了具有比常规细胞毒性抗癌剂更少的副作用诸如呕吐和脱发以及治疗效果更好的优点之外,已知免疫检查点抑制剂甚至在停止药物施用之后仍具有持久的治疗作用,因为,它们利用了具有优异记忆能力的免疫应答系统。
具体地,免疫检查点抑制剂可靶向CTLA-4、PD-1、PD-L1、PD-L2、B7-H4、HVEM(疱疹病毒入侵介质)、BTLA、TIM3、GAL9、LAG3、VISTA、KIR或TIGIT。
特别是,免疫检查点抑制剂可包括但不限于抗CTLA-4抗体、抗PD-1抗体、抗PD-L1抗体、抗PD-L2抗体、抗B7-H4抗体、抗HVEM抗体、抗BTLA抗体、抗TIM3抗体、抗GAL9抗体、抗LAG3抗体、抗VISTA抗体、抗KIR抗体和抗TIGIT抗体。
如本文所用,术语“细胞毒性T淋巴细胞相关抗原4(CTLA-4)”称为CD152,并且在活化的T细胞的膜表面上表达。CTLA-4结合抗原呈递细胞CD80(B7-1)和CD86(B7-2)并抑制T细胞活性。CTLA-4抑制剂可以是伊匹单抗和曲美木单抗。
如本文所用,术语“程序性细胞死亡蛋白1(PD-1)”称为CD279,并且在活化的T细胞表面上表达。PD-1与癌细胞表面的蛋白PD-L1(B7-H1)和PD-L2(B7-DC)反应,并且抑制TCR(T细胞受体)和CD28介导的T细胞活性、生长因子和细胞因子产生,以诱导负信号传导。PD-1抑制剂可以是例如帕博利珠单抗MK-3475、纳武单抗西米普利单抗JTX-4014、斯巴达珠单抗、卡瑞利珠单抗、信迪利单抗、替雷利珠单抗、特瑞普利单抗、多塔利单抗、INCMGA00012、AMP-224和AMP-514。
如本文所用,术语“程序性死亡配体1(PD-L1)”称为CD274或B7-H1,并且是存在于癌细胞表面或造血细胞上的蛋白质。存在于癌表面的PD-L1可结合存在于T细胞表面的PD-1。PD-L1抑制剂可以是例如阿特珠单抗、阿维鲁单抗德瓦鲁单抗KN035、CK-301、AUNP12、CA-170和BMS-986189。
如本文所用,术语“B7-H4”是指含V-set结构域的T细胞活化抑制剂1(VTCN1),并且在抗原呈递细胞的膜表面上表达。B7-H4结合T细胞的CD28蛋白,并抑制T细胞的活性、生长和细胞因子产生,以负调节T细胞介导的免疫应答。
如本文所用,术语“疱疹病毒入侵介质(HVEM)”称为CD270,并且也称为肿瘤坏死因子受体超家族成员14(TNFRSF14)。HVEM在包括T细胞的各种免疫细胞的膜表面上表达,并且与各种伴侣蛋白结合以调节炎症和免疫应答。当HVEM与T细胞的B淋巴细胞衰减子和T淋巴细胞衰减子(BTLA、CD272)或CD160结合时,T细胞的免疫活性受到抑制。另一方面,当HVEM结合TNFSF14(LIGHT)时,HVEM诱导树突细胞成熟、T细胞增殖和细胞因子产生,以激活炎症和免疫应答。
如本文所用,术语“T细胞膜蛋白3(TIM3)”也称为甲肝病毒细胞受体2(HAVCR2),并且在各种免疫细胞中表达。当TIM3通过与水溶性蛋白GAL9(半乳凝素9)结合而被激活时,细胞内钙内流增加,以诱导T细胞的凋亡,这继而又导致免疫耐受。另外,与GAL9一起,TIM3结合细胞粘附分子1(CEACAM1)(其为一种细胞表面蛋白),以抑制T细胞的免疫活性,并且结合高迁移率族蛋白1(HMGB1)或磷脂酰丝氨酸(PTdSer)(其为一种水溶性蛋白),以抑制免疫活性。TIM3抑制剂可以是LY3321367、MBG453和TSR-022。
如本文所用,术语“淋巴细胞活化基因3(LAG3)”称为CD223,并且结合主要组织相容性复合体(MHC)II类以抑制T细胞的增殖和活性。LAG3抑制剂可以是IMP321、瑞拉利单抗和GSK2831781。
如本文所用,术语“T细胞活化的V-结构域Ig抑制因子(VISTA)”属于B7家族(B7-H5),并且在各种免疫细胞中表达以抑制T细胞的增殖、活性和细胞因子产生。VISTA抑制剂可以是JNJ-63723283。
如本文所用,术语“杀伤细胞免疫球蛋白样受体(KIR)”是在NK细胞和T细胞中表达的膜结合蛋白,并且是具有遗传多样性和同源性的家族蛋白。其中,KIR2DL1、KIR2DL2/L3、KIR3DL1和KIR3DL2可与MHC I类结合以抑制NK细胞的细胞免疫活性。
如本文所用,术语“T细胞免疫球蛋白和ITIM结构域(TIGIT)”是在NK细胞和T细胞表面上表达的膜结合蛋白,并且可结合CD155、CD112和CD113以抑制免疫活性。
包含IL-2蛋白和CD80蛋白的融合蛋白及其二聚体
如本文所用,除非另有说明,术语“IL-2”或“白细胞介素-2”是指从任何脊椎动物来源获得的任何野生型IL-2,所述脊椎动物来源包括哺乳动物,例如灵长类(诸如人)和啮齿类(诸如小鼠和大鼠)。IL-2可从动物细胞获得,还包括从能够产生IL-2的重组细胞获得的IL-2。另外,IL-2可以是野生型IL-2或其变体。
在本说明书中,IL-2或其变体可由术语“IL-2蛋白”或“IL-2多肽”统称表达。IL-2、IL-2蛋白、IL-2多肽和IL-2变体特异性结合例如IL-2受体。这种特异性结合可通过本领域技术人员已知的方法鉴定。
IL-2的一个实施方案可具有如SEQ ID NO:35或SEQ ID NO:36所示的氨基酸序列。此处,IL-2也可以是成熟形式。具体地,成熟IL-2可能不包含信号序列,并且可具有如SEQID NO:10所示的氨基酸序列。此处,IL-2可在包含野生型IL-2的片段的概念下使用,其中,野生型IL-2的N末端或C末端的一部分被截断。
另外,IL-2片段的形式可以是从具有如SEQ ID NO:35或SEQ ID NO:36所示的氨基酸序列的蛋白质的N末端截断1个、2个、3个、4个、5个、6个、7个、8个、9个、10个、11个、12个、13个、14个、15个、16个、17个、18个、19个、20个、21个、22个、23个、24个或25个连续氨基酸。另外,IL-2片段的形式可以是从具有如SEQ ID NO:35或SEQ ID NO:36所示的氨基酸序列的蛋白质的C末端截断1个、2个、3个、4个、5个、6个、7个、8个、9个、10个、11个、12个、13个、14个、15个、16个、17个、18个、19个、20个、21个、22个、23个、24个或25个连续氨基酸。
如本文所用,术语“IL-2变体”是指其中全长IL-2或上述IL-2的片段中的氨基酸的一部分被取代的形式。即,IL-2变体可具有不同于野生型IL-2或其片段的氨基酸序列。但是,IL-2变体可具有与野生型IL-2相当或类似的活性。此处,“IL-2活性”可例如指与IL-2受体的特异性结合,该特异性结合可通过本领域技术人员已知的方法测量。
具体地,IL-2变体可通过取代野生型IL-2中的氨基酸的一部分获得。通过氨基酸取代获得的IL-2变体的一个实施方案可通过如SEQ ID NO:10所示的氨基酸序列中第38位、第42位、第45位、第61位和第72位氨基酸中的至少一个的取代来获得。
具体地,IL-2变体可通过用另一种氨基酸取代如SEQ ID NO:10所示的氨基酸序列中第38位、第42位、第45位、第61位或第72位氨基酸中的至少一个来获得。另外,当IL-2为如SEQ ID NO:35所示的氨基酸序列中的N末端的一部分被截断的形式时,与如SEQ ID NO:10所示的氨基酸序列中的氨基酸互补对应的位置处的氨基酸可被另一个氨基酸取代。例如,当IL-2具有如SEQ ID NO:35所示的氨基酸序列时,其IL-2变体可通过用另一种氨基酸取代如SEQ ID NO:35所示的氨基酸序列中第58位、第62位、第65位、第81位或第92位氨基酸中的至少一个来获得。这些氨基酸残基分别对应于如SEQ ID NO:10所示的氨基酸序列中的第38位、第42位、第45位、第61位和第72位氨基酸残基。根据一个实施方案,只要这种IL-2变体保持IL-2活性,就可取代1个、2个、3个、4个、5个、6个、7个、8个、9个或10个氨基酸。根据另一个实施方案,可取代1个至5个氨基酸。
在一个实施方案中,IL-2变体可以是其中两个氨基酸被取代的形式。具体地,IL-2变体可通过取代如SEQ ID NO:10所示的氨基酸序列中的第38位和第42位的氨基酸来获得。另外,在一个实施方案中,IL-2变体可通过取代如SEQ ID NO:10所示的氨基酸序列中的第38位和第45位的氨基酸来获得。另外,在一个实施方案中,IL-2变体可通过取代如SEQ IDNO:10所示的氨基酸序列中的第38位和第61位的氨基酸来获得。另外,在一个实施方案中,IL-2变体可通过取代如SEQ ID NO:10所示的氨基酸序列中的第38位和第72位的氨基酸来获得。另外,在一个实施方案中,IL-2变体可通过取代如SEQ ID NO:10所示的氨基酸序列中的第42位和第45位的氨基酸来获得。另外,在一个实施方案中,IL-2变体可通过取代如SEQID NO:10所示的氨基酸序列中的第42位和第61位的氨基酸来获得。另外,在一个实施方案中,IL-2变体可通过取代如SEQ ID NO:10所示的氨基酸序列中的第42位和第72位的氨基酸来获得。另外,在一个实施方案中,IL-2变体可通过取代如SEQ ID NO:10所示的氨基酸序列中的第45位和第61位的氨基酸来获得。另外,在一个实施方案中,IL-2变体可通过取代如SEQ ID NO:10所示的氨基酸序列中的第45位和第72位的氨基酸来获得。另外,在一个实施方案中,IL-2变体可通过取代如SEQ ID NO:10所示的氨基酸序列中的第61位和第72位的氨基酸来获得。
此外,IL-2变体可以是其中三个氨基酸被取代的形式。具体地,IL-2变体可通过取代如SEQ ID NO:10所示的氨基酸序列中的第38位、第42位和第45位的氨基酸来获得。另外,在一个实施方案中,IL-2变体可通过取代如SEQ ID NO:10所示的氨基酸序列中的第38位、第42位和第61位的氨基酸来获得。另外,在一个实施方案中,IL-2变体可通过取代如SEQ IDNO:10所示的氨基酸序列中的第38位、第42位和第72位的氨基酸来获得。另外,在一个实施方案中,IL-2变体可通过取代如SEQ ID NO:10所示的氨基酸序列中的第38位、第45位和第61位的氨基酸来获得。另外,在一个实施方案中,IL-2变体可通过取代如SEQ ID NO:10所示的氨基酸序列中的第38位、第45位和第72位的氨基酸来获得。另外,在一个实施方案中,IL-2变体可通过取代如SEQ ID NO:10所示的氨基酸序列中的第38位、第61位和第72位的氨基酸来获得。另外,在一个实施方案中,IL-2变体可通过取代如SEQ ID NO:10所示的氨基酸序列中的第42位、第45位和第61位的氨基酸来获得。另外,在一个实施方案中,IL-2变体可通过取代如SEQ ID NO:10所示的氨基酸序列中的第42位、第45位和第72位的氨基酸来获得。另外,在一个实施方案中,IL-2变体可通过取代如SEQ ID NO:10所示的氨基酸序列中的第45位、第61位和第72位的氨基酸来获得。
另外,IL-2变体可以是其中四个氨基酸被取代的形式。具体地,IL-2变体可通过取代如SEQ ID NO:10所示的氨基酸序列中的第38位、第42位、第45位和第61位的氨基酸来获得。另外,在一个实施方案中,IL-2变体可通过取代如SEQ ID NO:10所示的氨基酸序列中的第38位、第42位、第45位和第72位的氨基酸来获得。另外,在一个实施方案中,IL-2变体可通过取代如SEQ ID NO:10所示的氨基酸序列中的第38位、第45位、第61位和第72位的氨基酸来获得。另外,在一个实施方案中,IL-2变体可通过取代如SEQ ID NO:10所示的氨基酸序列中的第38位、第42位、第61位和第72位的氨基酸来获得。另外,在一个实施方案中,IL-2变体可通过取代如SEQ ID NO:10所示的氨基酸序列中的第42位、第45位、第61位和第72位的氨基酸来获得。
此外,IL-2变体可以是其中五个氨基酸被取代的形式。具体地,IL-2变体可通过用另一种氨基酸取代如SEQ ID NO:10所示的氨基酸序列中第38位、第42位、第45位、第61位和第72位氨基酸中的每一个来获得。
此处,通过取代引入的“另一种氨基酸”可以为选自由丙氨酸、精氨酸、天冬酰胺、天冬氨酸、半胱氨酸、谷氨酸、谷氨酰胺、组氨酸、异亮氨酸、亮氨酸、赖氨酸、甲硫氨酸、苯丙氨酸、脯氨酸、丝氨酸、苏氨酸、色氨酸、酪氨酸和缬氨酸组成的组中的任一种。然而,关于IL-2变体的氨基酸取代,在如SEQ ID NO:10所示的氨基酸序列中,第38位氨基酸不能被精氨酸取代,第42位氨基酸不能被苯丙氨酸取代,第45位氨基酸不能被酪氨酸取代,第61位氨基酸不能被谷氨酸取代,并且第72位氨基酸不能被亮氨酸取代。
关于IL-2变体的氨基酸取代,在如SEQ ID NO:10所示的氨基酸序列中,第38位氨基酸(精氨酸)可被除精氨酸以外的氨基酸取代。优选地,关于IL-2变体的氨基酸取代,在如SEQ ID NO:10所示的氨基酸序列中,第38位氨基酸(精氨酸)可被丙氨酸取代(R38A)。
关于IL-2变体的氨基酸取代,在如SEQ ID NO:10所示的氨基酸序列中,第42位氨基酸(苯丙氨酸)可被除苯丙氨酸以外的氨基酸取代。优选地,关于IL-2变体的氨基酸取代,在如SEQ ID NO:10所示的氨基酸序列中,第42位氨基酸(苯丙氨酸)可被丙氨酸取代(F42A)。
关于IL-2变体的氨基酸取代,在如SEQ ID NO:10所示的氨基酸序列中,第45位氨基酸(酪氨酸)可被除酪氨酸以外的氨基酸取代。优选地,关于IL-2变体的氨基酸取代,在如SEQ ID NO:10所示的氨基酸序列中,第45位氨基酸(酪氨酸)可被丙氨酸取代(Y45A)。
关于IL-2变体的氨基酸取代,在如SEQ ID NO:10所示的氨基酸序列中,第61位氨基酸(谷氨酸)可被除谷氨酸以外的氨基酸取代。优选地,关于IL-2变体的氨基酸取代,在如SEQ ID NO:10所示的氨基酸序列中,第61位氨基酸(谷氨酸)可被精氨酸取代(E61R)。
关于IL-2变体的氨基酸取代,在如SEQ ID NO:10所示的氨基酸序列中,第72位氨基酸(亮氨酸)可被除亮氨酸以外的氨基酸取代。优选地,关于IL-2变体的氨基酸取代,在如SEQ ID NO:10所示的氨基酸序列中,第72位氨基酸(亮氨酸)可被甘氨酸取代(L72G)。
具体地,IL-2变体可通过如SEQ ID NO:10所示的氨基酸序列中的选自由R38A、F42A、Y45A、E61R和L72G组成的组中的至少一个取代来获得。
具体地,IL-2变体可通过在选自由R38A、F42A、Y45A、E61R和L72G组成的组中的位置中的2个、3个、4个或5个位置的氨基酸取代来获得。
另外,IL-2变体可以是其中两个氨基酸被取代的形式。具体地,IL-2变体可通过取代R38A和F42A来获得。另外,在一个实施方案中,IL-2变体可通过取代R38A和Y45A来获得。另外,在一个实施方案中,IL-2变体可通过取代R38A和E61R来获得。另外,在一个实施方案中,IL-2变体可通过取代R38A和L72G来获得。另外,在一个实施方案中,IL-2变体可通过取代F42A和Y45A来获得。另外,在一个实施方案中,IL-2变体可通过取代F42A和E61R来获得。另外,在一个实施方案中,IL-2变体可通过取代F42A和L72G来获得。另外,在一个实施方案中,IL-2变体可通过取代E61R和L72G来获得。
此外,IL-2变体可以是其中三个氨基酸被取代的形式。具体地,IL-2变体可通过取代R38A、F42A和Y45A来获得。另外,在一个实施方案中,IL-2变体可通过取代R38A、F42A和E61R来获得。另外,在一个实施方案中,IL-2变体可通过取代R38A、F42A和L72G来获得。另外,在一个实施方案中,IL-2变体可通过取代R38A、Y45A和E61R来获得。另外,在一个实施方案中,IL-2变体可通过取代R38A、Y45A和L72G来获得。另外,在一个实施方案中,IL-2变体可通过取代F42A、Y45A和E61R来获得。另外,在一个实施方案中,IL-2变体可通过取代F42A、Y45A和L72G来获得。另外,在一个实施方案中,IL-2变体可通过取代F42A、E61R和L72G来获得。另外,在一个实施方案中,IL-2变体可通过取代Y45A、E61R和L72G来获得。
另外,IL-2变体可以是其中四个氨基酸被取代的形式。具体地,IL-2变体可通过取代R38A、F42A、Y45A和E61R来获得。另外,在一个实施方案中,IL-2变体可通过取代R38A、F42A、Y45A和L72G来获得。另外,在一个实施方案中,IL-2变体可通过取代R38A、F42A、E61R和L72G来获得。另外,在一个实施方案中,IL-2变体可通过取代R38A、Y45A、E61R和L72G来获得。另外,在一个实施方案中,IL-2变体可通过取代F42A、Y45A、E61R和L72G来获得。
此外,IL-2变体可通过取代R38A、F42A、Y45A、E61R和L72G来获得。
优选地,IL-2变体的一个实施方案可包含选自如SEQ ID NO:10所示的氨基酸序列中的以下取代组合(a)至(d)中的任一种:
(a)R38A/F42A
(b)R38A/F42A/Y45A
(c)R38A/F42A/E61R
(d)R38A/F42A/L72G
此处,当IL-2具有如SEQ ID NO:35所示的氨基酸序列时,氨基酸取代可存在于与如SEQ ID NO:10所示的氨基酸序列互补对应的位置处。另外,即使当IL-2为SEQ ID NO:35的氨基酸序列的片段时,氨基酸取代也可存在于与如SEQ ID NO:10所示的氨基酸序列互补对应的位置处。
具体地,IL-2变体可具有如SEQ ID NO:6、22、23或24所示的氨基酸序列。
另外,IL-2变体的特点是具有低体内毒性。此处,低体内毒性可能是由IL-2与IL-2受体α链(IL-2Rα)结合引起的副作用。已经开发了各种IL-2变体来改善由IL-2与IL-2Rα结合引起的副作用,并且此类IL-2变体可以是美国专利号5,229,109和韩国专利号1667096中公开的那些变体。特别是,本申请中描述的IL-2变体对IL-2受体α链(IL-2Rα)具有低结合能力,且因此具有比野生型IL-2更低的体内毒性。
如本文所用,术语“CD80”,也称为“B7-1”,是存在于树突细胞、活化的B细胞和单核细胞中的膜蛋白。CD80提供T细胞活化和存活必需的共刺激信号。已知CD80是存在于T细胞表面上的两种不同蛋白CD28和CTLA-4的配体。CD80由288个氨基酸组成,并且可具体具有如SEQ ID NO:11所示的氨基酸序列。另外,如本文所用,术语“CD80蛋白”是指全长CD80或CD80片段。
如本文所用,术语“CD80片段”是指CD80的裂解形式。另外,CD80片段可以是CD80的胞外结构域。CD80片段的一个实施方案可通过从作为CD80的信号序列的N末端消除第1位至第34位氨基酸来获得。具体地,CD80片段的一个实施方案可以是由SEQ ID NO:11中的第35位至第288位氨基酸组成的蛋白质。另外,CD80片段的一个实施方案可以是由SEQ ID NO:11中的第35位至第242位氨基酸组成的蛋白质。另外,CD80片段的一个实施方案可以是由SEQID NO:11中的第35位至第232位氨基酸组成的蛋白质。另外,CD80片段的一个实施方案可以是由SEQ ID NO:11中的第35位至第139位氨基酸组成的蛋白质。另外,CD80片段的一个实施方案可以是由SEQ ID NO:11中的第142位至第242位氨基酸组成的蛋白质。在一个实施方案中,CD80片段可具有SEQ ID NO:2的氨基酸序列。
另外,IL-2蛋白和CD80蛋白可通过接头或载体彼此连接。具体地,IL-2或其变体和CD80(B7-1)或其片段可通过接头或载体彼此连接。在本说明书中,接头和载体可互换使用。
接头连接两个蛋白质。接头的一个实施方案可包括1个至50个氨基酸、白蛋白或其片段、免疫球蛋白的Fc结构域等。此处,免疫球蛋白的Fc结构域是指含有免疫球蛋白的重链恒定区2(CH2)和重链恒定区3(CH3)但不含有免疫球蛋白的重链和轻链可变区以及轻链恒定区1(CH1)的蛋白质。免疫球蛋白可以是IgG、IgA、IgE、IgD或IgM,并且可以优选地是IgG4。此处,野生型免疫球蛋白G4的Fc结构域可具有如SEQ ID NO:4所示的氨基酸序列。
另外,免疫球蛋白的Fc结构域可以是Fc结构域变体以及野生型Fc结构域。另外,如本文所用,术语“Fc结构域变体”可以是指在糖基化模式方面不同于野生型Fc结构域的形式,其与野生型Fc结构域相比具有高糖基化,或与野生型Fc结构域相比具有低糖基化,或者去糖基化形式。另外,其中包括非糖基化Fc结构域。通过培养条件或宿主的遗传操纵,Fc结构域或其变体可适于具有调节数量的唾液酸、岩藻糖基化或糖基化。
另外,免疫球蛋白的Fc结构域的糖基化可通过常规方法修饰,诸如化学方法、酶方法和使用微生物的基因工程方法。另外,Fc结构域变体可以是免疫球蛋白IgG、IgA、IgE、IgD和IgM的相应Fc区的混合形式。另外,Fc结构域变体可以是其中Fc结构域的一些氨基酸被其他氨基酸取代的形式。Fc结构域变体的一个实施方案可具有如SEQ ID NO:12所示的氨基酸序列。
融合蛋白可具有这样的结构,其中使用Fc结构域作为接头(或载体),CD80蛋白和IL-2蛋白,或IL-2蛋白和CD80蛋白分别连接到接头或载体的N末端和C末端。Fc结构域的N末端或C末端和CD-80或IL-2之间的连接可任选地通过接头肽来实现。
具体地,融合蛋白可由以下结构式(I)或(II)组成:
N'-X-[接头(1)]n-Fc结构域-[接头(2)]m-Y-C'(I)
N'-Y-[接头(1)]n-Fc结构域-[接头(2)]m-X-C'(II)
此处,在结构式(I)和(II)中,
N'为融合蛋白的N末端,
C'为融合蛋白的C末端,
X为CD80蛋白,
Y为IL-2蛋白,
接头(1)和(2)为肽接头,并且
n和m各自独立地为0或1。
优选地,融合蛋白可由结构式(I)组成。IL-2蛋白如上所述。另外,CD80蛋白如上所述。根据一个实施方案,IL-2蛋白可以是与野生型IL-2相比具有1个至5个氨基酸取代的IL-2变体。CD80蛋白可以是从野生型CD80的N末端或C末端截断长达约34个连续氨基酸残基获得的片段。另选地,CD蛋白可以是具有结合T细胞表面受体CTLA-4和CD28的活性的胞外免疫球蛋白样结构域。
具体地,融合蛋白可具有如SEQ ID NO:9、26、28或30所示的氨基酸序列。根据另一个实施方案,融合蛋白包括与SEQ ID NO:9、26、28或30的氨基酸序列具有85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%序列同一性的多肽。此处,同一性是例如同源性百分比,并且可通过同源性比较软件诸如美国国家生物技术信息中心(NCBI)的BlastN软件确定。
肽接头(1)可包括在CD80蛋白和Fc结构域之间。肽接头(1)可由5个至80个连续氨基酸、20个至60个连续氨基酸、25个至50个连续氨基酸或30个至40个连续氨基酸组成。在一个实施方案中,肽接头(1)可由30个氨基酸组成。另外,肽接头(1)可含有至少一个半胱氨酸。具体地,肽接头(1)可含有1个、2个或3个半胱氨酸。另外,肽接头(1)可来源于免疫球蛋白的铰链。在一个实施方案中,肽接头(1)可以是由如SEQ ID NO:3所示的氨基酸序列组成的肽接头。
肽接头(2)可由1个至50个连续氨基酸、3个至30个连续氨基酸或5个至15个连续氨基酸组成。在一个实施方案中,肽接头(2)可以是(G4S)n(其中n是1至10的整数)。此处,在(G4S)n中,n可以是1、2、3、4、5、6、7、8、9或10。在一个实施方案中,肽接头(2)可以是由如SEQID NO:5所示的氨基酸序列组成的肽接头。
在本发明的另一方面,提供了通过结合两种融合蛋白获得的二聚体,这两种融合蛋白中的每一种包含IL-2蛋白和CD80蛋白。包含IL-2或其变体和CD80或其片段的融合蛋白如上所述。
此处,构成二聚体的融合蛋白之间的结合可通过但不限于由接头中存在的半胱氨酸形成的二硫键来实现。构成二聚体的融合蛋白可以是相同的融合蛋白,或者也可以是彼此不同的融合蛋白。优选地,二聚体可以是同源二聚体。构成二聚体的融合蛋白的一个实施方案可以是具有如SEQ ID NO:9所示的氨基酸序列的蛋白质。
本发明的药物组合物包括作为活性成分的包含IL-2蛋白质或其变体和CD80蛋白质或其片段的融合蛋白二聚体以及免疫检查点抑制剂,显示出预防或治疗癌症的功效。
所述癌症可选自由胃癌、肝癌、肺癌、结直肠癌、乳腺癌、前列腺癌、卵巢癌、胰腺癌、宫颈癌、甲状腺癌、喉癌、急性髓性白血病、脑肿瘤、成神经细胞瘤、成视网膜细胞瘤、头颈癌、唾液腺癌和淋巴瘤组成的组。
药物组合物的优选剂量根据患者的状况和体重、疾病的严重程度、药物的形式、施用途径和持续时间而变化,并且可由本领域技术人员适当地选择。在本发明的用于治疗或预防癌症的药物组合物中,活性成分可以包含在任何量(有效量)中,这取决于应用、剂型、掺合目的等,只要活性成分可表现出抗癌活性。其常规有效量将确定在基于组合物总重量的0.001重量%至20.0重量%的范围内。此处,术语“有效量”是指能够诱导抗癌作用的活性成分的量。这种有效量可在本领域技术人员的常识范围内通过实验确定。
如本文所用,术语“治疗”可用于意指治疗性和预防性治疗。此处,预防可用于意指个体的病理状况或疾病被减轻或缓和。在一个实施方案中,术语“治疗”包括用于治疗哺乳动物(包括人)的疾病的施用或任何形式的施用。另外,该术语包括抑制或减缓疾病或疾病进展;并且包括恢复或修复受损或丧失的功能使得疾病部分或完全缓解的含义;刺激低效的过程;或减轻严重疾病。
如本文所用,术语“功效”是指可由一个或多个参数确定的能力,例如,在一定时间段诸如一年、五年或十年内的存活或无病存活。另外,参数可包括抑制个体中至少一个肿瘤的大小。
药物动力学参数诸如生物利用度和基础参数诸如清除率也可影响功效。因此,“增强的功效”(例如,改善的功效)可能是由于增强的药物动力学参数和改善的功效,这可通过比较测试动物或人受试者中的清除率和肿瘤生长,或通过比较参数诸如存活、复发或无病存活来测量。
如本文所用,术语“治疗有效量”或“药学有效量”是指有效预防或治疗所述疾病的化合物或组合物的量,其足以适用于医疗的合理效益/风险比治疗疾病,并且不引起副作用。有效量的水平可根据以下因素确定,包括患者的健康状况、疾病的类型和严重程度、药物的活性、患者对药物的敏感性、施用方式、施用时间、施用途径和排泄速率、治疗持续时间、制剂或同时使用的药物,以及医学领域中公知的其他因素。在一个实施方案中,治疗有效量意指有效治疗癌症的药物的量。
此处,药物组合物可进一步包括药学上可接受的载体。药学上可接受的载体可以是任何载体,只要该载体是适于递送至患者的无毒物质。可含有蒸馏水、醇、脂肪、蜡、惰性固体作为载体。药物组合物中还可含有药学上可接受的佐剂(缓冲剂、分散剂)。
具体地,通过除了活性成分之外还包括药学上可接受的载体,可根据其施用途径使用本领域已知的常规方法将药物组合物制备成肠胃外制剂。此处,术语“药学上可接受的”意指载体的毒性不超过被应用(开处方)的受试者能够适应的程度,同时不抑制活性成分的活性。
当将药物组合物制备成肠胃外制剂时,可根据本领域已知的方法将其与合适的载体一起制成注射剂、经皮贴剂、鼻吸入剂或栓剂形式的药剂。在制成注射剂的情况下,无菌水、乙醇、多元醇诸如甘油或丙二醇或它们的混合物可用作合适的载体;并且可优选使用等渗溶液,诸如林格氏溶液,含有三乙醇胺或注射用无菌水的磷酸盐缓冲盐水(PBS)和5%葡萄糖等。药物组合物的制剂是本领域已知的,并且具体可参考Remington'sPharmaceutical Sciences(第19版,1995年)等。该文献被认为是本说明书的一部分。
药物组合物的优选剂量可以是每天0.01μg/kg至10g/kg,或0.01mg/kg至1g/kg,这取决于患者的状况、体重、性别、年龄、患者的严重程度和施用途径。该剂量可以一天一次施用或者可一天分成几次施用。该剂量不应被解释为在任何方面限制本发明的范围。
可施用(开处方)药物组合物的受试者为哺乳动物和人,其中特别优选地是人。除了活性成分之外,本申请的药物组合物可进一步包含已被安全验证并已知具有抗癌活性的任何化合物或天然提取物,以便增强或加强抗癌活性。
在本发明的又一方面,提供了一种用于治疗癌症的试剂盒,该试剂盒包括包含IL-2蛋白或其变体和CD80蛋白或其片段的融合蛋白二聚体以及免疫检查点抑制剂。
在本发明的又一方面,提供了一种用于联合施用的组合物用于预防或治疗癌症的用途,该组合物包括包含IL-2蛋白或其变体和CD80蛋白或其片段的融合蛋白二聚体以及免疫检查点抑制剂。
在本发明的又一方面,提供了一种用于联合施用的组合物用于增强对癌症的治疗作用的用途,该组合物包括包含IL-2蛋白或其变体和CD80蛋白或其片段的融合蛋白以及免疫检查点抑制剂。
在本发明的又一方面,提供了一种用于联合施用的组合物在制备用于治疗癌症的药物中的用途,该组合物包括包含IL-2蛋白或其变体和CD80蛋白或其片段的融合蛋白以及免疫检查点抑制剂。
在本发明的又一方面,提供了一种预防或治疗癌症的方法和/或增强对癌症的治疗作用的方法,该方法包括向受试者施用用于联合施用的组合物,该组合物包括包含IL-2蛋白或其变体和CD80蛋白或其片段的融合蛋白二聚体或者其中两个融合蛋白连接的融合蛋白二聚体以及免疫检查点抑制剂。
受试者可以是患有癌症的个体。另外,受试者可以为哺乳动物,优选地是人。包含IL-2蛋白或其变体和CD80蛋白或其片段的融合蛋白或者其中两个融合蛋白连接的融合蛋白二聚体如上所述。
融合蛋白或融合蛋白二聚体和NK细胞的施用途径、剂量和施用频率可根据患者的状况和副作用的存在或不存在而变化,因此融合蛋白或融合蛋白二聚体可以各种方式和量施用给受试者。本领域技术人员可在适当的范围内选择最佳的施用方法、剂量和施用频率。
由于IL-2的活性,本发明的实施方案中的融合蛋白可激活免疫细胞诸如自然杀伤细胞。因此,该融合蛋白可有效地用于癌症。特别是,经鉴定,与野生型相比,具有2个至5个氨基酸取代的IL-2变体,特别是在选自由R38A、F42A、Y45A、E61R和L72G组成的组中的2个、3个、4个或5个位置处含有氨基酸取代的IL-2变体,具有对IL-2受体α链的低结合能力,并因此表现出与常规IL-2的药理学副作用有关的改善特性。因此,当单独使用或以融合蛋白的形式使用时,这种IL-2变体可降低血管(或毛细管)渗漏综合征(VLS)的发生率,这是IL-2常规已知的问题。
实施本发明的模式
在下文中,将通过以下实施例更详细地描述本发明。然而,以下实施例仅用于说明本发明,并且本发明的范围并不限于此。
I.融合蛋白的制备
制备例1.制备hCD80-Fc-IL-2变体(2M):GI101
为了产生包含人CD80片段、Fc结构域和IL-2变体的融合蛋白,通过ThermoFisherScientific的Invitrogen GeneArt基因合成服务合成了多核苷酸。具体地,该多核苷酸包含编码融合蛋白的核苷酸序列(SEQ ID NO:8),该融合蛋白以此顺序从N末端开始包含信号肽(SEQ ID NO:1)、CD80片段(SEQ ID NO:2)、Ig铰链(SEQ ID NO:3)、Fc结构域(SEQ ID NO:4)、接头(SEQ ID NO:5)和具有两个氨基酸取代的IL-2变体(2M)(R38A、F42A)(SEQ ID NO:6)。将该多核苷酸插入到pcDNA3_4载体中。另外,将该载体导入CHO细胞(Expi-CHOTM)以表达SEQ ID NO:9的融合蛋白。在导入载体之后,在37℃、125rpm和8%CO2浓度的环境中培养7天。然后,收获培养物并从中纯化融合蛋白。将所纯化的融合蛋白命名为“GI101”。
使用含有MabSelect SuRe蛋白A树脂的层析进行纯化。在25mM Tris、25mM NaCl、pH 7.4的条件下将融合蛋白与其结合。然后,用100mM NaCl、100mM乙酸、pH 3进行洗脱。将pH 9的20%的1M Tris-HCl置于收集管中,然后收集融合蛋白。对于所收集的融合蛋白,通过透析将缓冲液与PBS缓冲液交换16小时。
然后,使用TSKgel G3000SWXL柱(TOSOH Bioscience)用尺寸排阻层析测量280nm波长处的吸光度,以获得高度浓缩的融合蛋白。此处,所分离和纯化的融合蛋白在还原(R)或非还原(NR)条件下进行SDS-PAGE,并用考马斯蓝染色以检查其纯度(图6)。经鉴定,当用NanoDrop检测时,融合蛋白的浓度为2.78mg/ml(图7)。另外,图8提供了通过使用尺寸排阻层析分析获得的结果。
制备例2.制备mCD80-Fc-IL-2变体(2M):mGI101
为了产生包含小鼠CD80、Fc结构域和IL-2变体的融合蛋白,通过ThermoFisherScientific的Invitrogen GeneArt基因合成服务合成了多核苷酸。具体地,该多核苷酸包含编码融合蛋白的核苷酸序列(SEQ ID NO:14),该融合蛋白以此顺序从N末端开始包含信号肽(SEQ ID NO:1)、mCD80(SEQ ID NO:13)、Ig铰链(SEQ ID NO:3)、Fc结构域(SEQ ID NO:4)、接头(SEQ ID NO:5)和具有两个氨基酸取代的IL-2变体(2M)(R38A、F42A)(SEQ ID NO:6)。将该多核苷酸插入到pcDNA3_4载体中。另外,将该载体导入CHO细胞(Expi-CHOTM)以表达SEQ ID NO:15的融合蛋白。在导入载体之后,在37℃、125rpm和8%CO2浓度的环境中培养7天。然后,收获培养物并从中纯化融合蛋白。将所纯化的融合蛋白命名为“mGI101”。
以与制备例1相同的方式进行融合蛋白的纯化和回收。所分离和纯化的融合蛋白在还原(R)或非还原(NR)条件下进行SDS-PAGE,并用考马斯蓝染色以检查其纯度(图9)。发现当使用NanoDrop在280nm处通过吸光度检测时,融合蛋白的浓度为1.95mg/ml。
制备例3.制备hCD80-Fc:GI101C1
为了产生包含人CD80片段和Fc结构域的融合蛋白,通过ThermoFisherScientific的Invitrogen GeneArt基因合成服务合成了多核苷酸。具体地,该多核苷酸包含编码融合蛋白的核苷酸序列(SEQ ID NO:16),该融合蛋白包含信号肽(SEQ ID NO:1)、CD80片段(SEQ ID NO:2)、Ig铰链(SEQ ID NO:3)和Fc结构域(SEQ ID NO:4)。将该多核苷酸插入到pcDNA3_4载体中。另外,将该载体导入CHO细胞(Expi-CHOTM)以表达SEQ ID NO:17的融合蛋白。在导入载体之后,在37℃、125rpm和8%CO2浓度的环境中培养7天。然后,收获培养物并从中纯化融合蛋白。将所纯化的融合蛋白命名为“GI101C1”。
以与制备例1相同的方式进行融合蛋白的纯化和回收。所分离和纯化的融合蛋白在还原(R)或非还原(NR)条件下进行SDS-PAGE,并用考马斯蓝染色以检查其纯度(图10)。观察到当使用NanoDrop在280nm处通过吸光度检测时,融合蛋白的浓度为3.61mg/ml。
制备例4.制备Fc-IL-2变体(2M):GI101C2
为了产生包含Fc结构域和IL-2变体的融合蛋白,通过ThermoFisher Scientific的Invitrogen GeneArt基因合成服务合成了多核苷酸。具体地,该多核苷酸包含编码融合蛋白的核苷酸序列(SEQ ID NO:18),该融合蛋白以此顺序从N末端开始包含信号肽(SEQ IDNO:1)、Fc结构域(SEQ ID NO:4)、接头(SEQ ID NO:5)和具有两个氨基酸取代的IL-2变体(2M)(R38A、F42A)(SEQ ID NO:6)。将该多核苷酸插入到pcDNA3_4载体中。另外,将该载体导入CHO细胞(Expi-CHOTM)以表达SEQ ID NO:19的融合蛋白。在导入载体之后,在37℃、125rpm和8%CO2浓度的环境中培养7天。然后,收获培养物并从中纯化融合蛋白。将所纯化的融合蛋白命名为“GI101C2”。
以与制备例1相同的方式进行融合蛋白的纯化和回收。所分离和纯化的融合蛋白在还原(R)或非还原(NR)条件下进行SDS-PAGE,并用考马斯蓝染色以检查其纯度(图11)。发现当使用NanoDrop在280nm处通过吸光度检测时,融合蛋白的浓度为4.79mg/ml。
制备例5.制备mCD80-Fc:mGI101C1
为了产生包含小鼠CD80和Fc结构域的融合蛋白,通过ThermoFisher Scientific的Invitrogen GeneArt基因合成服务合成了多核苷酸。具体地,该多核苷酸包含编码融合蛋白的核苷酸序列(SEQ ID NO:20),该融合蛋白以此顺序从N末端开始包含信号肽(SEQ IDNO:1)、mCD80(SEQ ID NO:13)、Ig铰链(SEQ ID NO:3)和Fc结构域(SEQ ID NO:4)。将该多核苷酸插入到pcDNA3_4载体中。另外,将该载体导入CHO细胞(Expi-CHOTM)以表达SEQ ID NO:21的融合蛋白。在导入载体之后,在37℃、125rpm和8%CO2浓度的环境中培养7天。然后,收获培养物并从中纯化融合蛋白。将所纯化的融合蛋白命名为“mGI101C1”。
以与制备例1相同的方式进行融合蛋白的纯化和回收。所分离和纯化的融合蛋白在还原(R)或非还原(NR)条件下进行SDS-PAGE,并用考马斯蓝染色以检查其纯度(图12)。观察到当使用NanoDrop在280nm处通过吸光度检测时,融合蛋白的浓度为2.49mg/ml。
制备例1至5中制备的融合蛋白汇总于下表1中。
[表1]
制备例6.制备CD80-Fc-IL-2:GI101w
为了产生包含人CD80片段、Fc结构域和人IL-2的融合蛋白,通过ThermoFisherScientific的Invitrogen GeneArt基因合成服务合成了多核苷酸。具体地,该多核苷酸包含编码融合蛋白的核苷酸序列(SEQ ID NO:31),该融合蛋白以此顺序从N末端开始包含信号肽(SEQ ID NO:1)、CD80片段(SEQ ID NO:2)、Ig铰链(SEQ ID NO:3)、Fc结构域(SEQ IDNO:4)、接头(SEQ ID NO:5)和成熟人IL-2(SEQ ID NO:10)。将该多核苷酸插入到pcDNA3_4载体中。另外,将该载体导入CHO细胞(Expi-CHOTM)以表达SEQ ID NO:32的融合蛋白。在导入载体之后,在37℃、125rpm和8%CO2浓度的环境中培养7天。然后,收获培养物并从中纯化融合蛋白。将所纯化的融合蛋白命名为“GI101w”。以与制备例1相同的方式进行融合蛋白的纯化和回收。
制备例7.制备hCD80-Fc-IL-2变体(3M):GI102-M45
为了产生包含人CD80片段、Fc结构域和具有三个氨基酸取代的IL-2变体(3M)(R38A、F42A、Y45A)(GI102-M45)的融合蛋白,通过ThermoFisher Scientific的InvitrogenGeneArt基因合成服务合成了多核苷酸。具体地,该多核苷酸包含编码融合蛋白的核苷酸序列(SEQ ID NO:25),该融合蛋白以此顺序从N末端开始包含信号肽(SEQ ID NO:1)、CD80片段(SEQ ID NO:2)、Ig铰链(SEQ ID NO:3)、Fc结构域(SEQ ID NO:4)、接头(SEQ ID NO:5)和IL-2变体(SEQ ID NO:22)。将该多核苷酸插入到pcDNA3_4载体中。另外,将该载体导入CHO细胞(Expi-CHOTM)以表达SEQ ID NO:26的融合蛋白。在导入载体之后,在37℃、125rpm和8%CO2浓度的环境中培养7天。然后,收获培养物并从中纯化融合蛋白。将所纯化的融合蛋白命名为“GI102-M45”。
以与制备例1相同的方式进行融合蛋白的纯化和回收。所分离和纯化的融合蛋白在还原(R)或非还原(NR)条件下进行SDS-PAGE,并用考马斯蓝染色以检验其纯度(图13)。
制备例8.制备hCD80-Fc-IL-2变体(3M):GI102-M61
为了产生包含人CD80片段、Fc结构域和具有三个氨基酸取代的IL-2变体(3M)(R38A、F42A、E61R)(GI102-M61)的融合蛋白,通过ThermoFisher Scientific的InvitrogenGeneArt基因合成服务合成了多核苷酸。具体地,该多核苷酸包含编码融合蛋白的核苷酸序列(SEQ ID NO:27),该融合蛋白以此顺序从N末端开始包含信号肽(SEQ ID NO:1)、CD80片段(SEQ ID NO:2)、Ig铰链(SEQ ID NO:3)、Fc结构域(SEQ ID NO:4)、接头(SEQ ID NO:5)和IL-2变体(SEQ ID NO:23)。将该多核苷酸插入到pcDNA3_4载体中。另外,将该载体导入CHO细胞(Expi-CHOTM)以表达SEQ ID NO:28的融合蛋白。在导入载体之后,在37℃、125rpm和8%CO2浓度的环境中培养7天。然后,收获培养物并从中纯化融合蛋白。将所纯化的融合蛋白命名为“GI102-M61”。
以与制备例1相同的方式进行融合蛋白的纯化和回收。所分离和纯化的融合蛋白在还原(R)或非还原(NR)条件下进行SDS-PAGE,并用考马斯蓝染色以检验其纯度(图14)。
制备例9.制备hCD80-Fc-IL-3M:GI102-M72
为了产生包含人CD80片段、Fc结构域和具有三个氨基酸取代的IL-2变体(3M)(R38A、F42A、L72G)(GI102-M72)的融合蛋白,通过ThermoFisher Scientific的InvitrogenGeneArt基因合成服务合成了多核苷酸。具体地,该多核苷酸包含编码融合蛋白的核苷酸序列(SEQ ID NO:29),该融合蛋白以此顺序从N末端开始包含信号肽(SEQ ID NO:1)、CD80片段(SEQ ID NO:2)、Ig铰链(SEQ ID NO:3)、Fc结构域(SEQ ID NO:4)、接头(SEQ ID NO:5)和IL-2变体(SEQ ID NO:24)。将该多核苷酸插入到pcDNA3_4载体中。另外,将该载体导入CHO细胞(Expi-CHOTM)以表达SEQ ID NO:30的融合蛋白。在导入载体之后,在37℃、125rpm和8%CO2浓度的环境中培养7天。然后,收获培养物并从中纯化融合蛋白。将所纯化的融合蛋白命名为“GI102-M72”。
以与制备例1相同的方式进行融合蛋白的纯化和回收。所分离和纯化的融合蛋白在还原(R)或非还原(NR)条件下进行SDS-PAGE,并用考马斯蓝染色以检验其纯度(图15)。
制备例10.制备mCD80-Fc-IL-3M:mGI102-M61
为了产生包含小鼠CD80片段、Fc结构域和具有三个氨基酸取代的IL-2变体(3M)(R38A、F42A、E61R)(GI102-M61)的融合蛋白,通过ThermoFisher Scientific的InvitrogenGeneArt基因合成服务合成了多核苷酸。具体地,该多核苷酸包含编码融合蛋白的核苷酸序列(SEQ ID NO:33),该融合蛋白以此顺序从N末端开始包含信号肽(SEQ ID NO:1)、mCD80片段(SEQ ID NO:13)、Ig铰链(SEQ ID NO:3)、Fc结构域(SEQ ID NO:4)、接头(SEQ ID NO:5)和IL-2变体(SEQ ID NO:23)。将该多核苷酸插入到pcDNA3_4载体中。另外,将该载体导入CHO细胞(Expi-CHOTM)以表达SEQ ID NO:34的融合蛋白。在导入载体之后,在37℃、125rpm和8%CO2浓度的环境中培养7天。然后,收获培养物并从中纯化融合蛋白。将所纯化的融合蛋白命名为“mGI102-M61”。
以与制备例1相同的方式进行融合蛋白的纯化和回收。
II.融合蛋白和其配体之间结合亲和力的鉴定
为了鉴定融合蛋白和其配体之间的结合亲和力,使用Octet RED 384测量该结合亲和力。
实施例1.鉴定hCTLA-4和GI101之间的结合亲和力
AR2G生物传感器(Amine Reactive 2nd gen,ForteBio,目录号:18-5092)预先在96孔微孔板(GreinerBio-One,目录号:655209)中用200μl蒸馏水水合。用10mM乙酸盐缓冲液(pH 5,AR2G试剂盒,ForteBio,目录号:18-5095)将待连接到AR2G生物传感器的配体(CTLA-4,人CTLA-4/CD152,His标签,Sino Biological,目录号:11159-H08H)稀释至5μg/ml的浓度。另外,用1X AR2G动力学缓冲液(AR2G试剂盒,ForteBio,目录号:18-5095)将待连接到配体的GI101稀释至1,000nM、500nM、250nM、125nM或62.5nM的浓度。将20mM EDC和10mM s-NHS(AR2G试剂盒,ForteBio,目录号:18-5095)在蒸馏水中混合以制备活化缓冲液。将80μl的每种试剂置于384孔微孔板(Greiner Bio-One,目录号:781209)中,并设定程序。
结果:如图16所示测量了hCTLA-4和GI101之间的结合亲和力。
实施例2.鉴定hPD-L1/GI101和hPD-L1/PD-1之间的结合亲和力
在96孔微孔板(GreinerBio-One,目录号:655209)中,将Ni-NTA(镍负载的Tris-NTA,Ni-NTA生物传感器,ForteBio,18-5101)预先用200μl的1X Ni-NTA动力学缓冲液(10×动力学缓冲液,ForteBio,18-1042)水合。用1X Ni-NTA动力学缓冲液将待连接到Ni-NTA生物传感器的配体(人PD-L1/B7-H1蛋白,His标签,Sino Biological,目录号:10084-H08H)稀释至5μg/ml的浓度。用1×Ni-NTA动力学缓冲液将待连接到配体的GI101稀释至1,000nM、500nM、250nM、125nM或62.5nM。另外,用1×Ni-NTA动力学缓冲液将待连接到配体的人PD-1/PDCD1(人PD-1/PDCD1,Fc标签,Sino Biological,目录号:10377-H02H)稀释至2,000nM、1,000nM、500nM、250nM或125nM的浓度。然后,将80μl的每种试剂置于384孔微孔板中,并设定程序。
结果:如图17所示测量了hPD-L1和GI101之间的结合亲和力。另外,如图18所示测量了hPD-L1和hPD-1之间的结合亲和力。
实施例3.鉴定mCTLA-4和mGI101之间的结合亲和力
以与实施例1相同的方式检测mCTLA-4和mGI101之间的结合亲和性。此处,所用的设备如下:生物传感器:AR2G,配体:mCTLA-4(重组小鼠CTLA-4Fc嵌合体,R&D Systems,目录号:434-CT-200),分析物:mGI101(500nM、250nM、125nM、62.5nM、31.3nM)。
结果:如图19所示测量了mCTLA-4和mGI101之间的结合亲和力。
实施例4.鉴定mPD-L1和mGI101之间的结合亲和力
以与实施例1相同的方式鉴定mPD-L1和mGI101之间的结合亲和性。此处,所用的设备如下。生物传感器:AR2G,配体:mPD-L1(重组小鼠mGI101 B7-H1/PD-L1 Fc嵌合体,R&DSystems,目录号:434-CT-200),分析物:mGI101(500nM、250nM、125nM、62.5nM、31.3nM)。
结果:如图20所示测量了mPD-L1和mGI101之间的结合亲和力。
实施例5.鉴定GI-101(hCD80-Fc-hIL-2v)与CTLA-4的结合能力
使用Octet RED 384仪器(ForteBio,Pall Life Science)在30℃和1,000rpm搅拌下进行结合动力学测量。使用Amine Reactive 2generation(AR2G)生物传感器芯片测量CTLA-4的结合能力,并且使用镍负载的Tris-NTA(Ni-NTA)生物传感器芯片测量PD-L1的结合能力。AR2G生物传感器芯片用400mM EDC和100mM Sulfo-NHS的组合活化。然后,用10mM乙酸盐缓冲液(pH 5)将人CTLA-4-His标签(Sino Biological,目录号:11159-H08H)稀释至5μg/ml,并加载到AR2G生物传感器芯片上300秒并固定。
然后,测量各种浓度的CTLA-4与GI-101(hCD80-Fc-hIL-2v)、GI-101C1(hCD80-Fc)、伊匹单抗(Bristol-Myers Squibb)和GI-101C2(Fc-hIL-2v)的结合300秒,并且还测量其解离300秒。使用Pall公司提供的Octet数据分析HT软件版本10进行结合动力学分析。结果示于图21中。
实施例6.鉴定IL-2Rα或IL-2Rβ和GI101之间的结合亲和力
使用AR2G生物传感器测量IL-2Rα的结合能力,并且使用Ni-NTA生物传感器(镍负载的Tris-NTA,Ni-NTA生物传感器,ForteBio,18-5101)测量IL-2Rβ的结合能力。
用10mM乙酸盐缓冲液(pH 5,AR2G试剂盒,ForteBio,目录号:18-5095)将待连接到AR2G生物传感器的配体(IL-2Rα-His标签,Acro,目录号:ILA-H52H9)稀释至5μg/ml的浓度。用通过混合400mM EDC和100mM Sulfo-NHS制备的缓冲液活化AR2G生物传感器,然后将稀释的配体加载到AR2G生物传感器上300秒并固定。
同时,用1×Ni-NTA动力学缓冲液将待连接到Ni-NTA生物传感器的配体(IL-2Rβ-His标签,Acro,目录号:CD2-H5221)稀释至5μg/ml的浓度。将稀释的配体加载到Ni-NTA生物传感器上600秒并固定。
然后,将各种浓度的待连接到配体的GI101、GI101w或阿地白介素(Novartis,hIL-2)加载到其上300秒。然后,测量其结合,并且还测量其解离300秒。使用Pall公司提供的Octet数据分析HT软件版本10进行结合动力学分析。结果示于图22至图24中。
结果:经鉴定,与GI101w和阿地白介素相比,GI101对IL-2受体α链IL-2Rα具有低结合能力,且对IL-2Rβ具有高结合能力。
实施例7.测量融合蛋白和配体之间的结合亲和力
为了鉴定融合蛋白和其配体之间的结合亲和力,使用Octet RED 384测量该结合亲和力。
实施例7.1.鉴定IL-2α受体和GI101-M45、GI101-M61或GI101-M72的结合亲和力
AR2G生物传感器(Amine Reactive 2nd gen,ForteBio,目录号:18-5092)预先在96孔微孔板(GreinerBio-One,目录号:655209)中用200μl蒸馏水(DW)水合。用10mM乙酸盐缓冲液(pH 5)(AR2G试剂盒,ForteBio,目录号:18-5095)将待连接到生物传感器上的配体(人IL-2Rα蛋白,His标签,Acro,ILA-H52H9)稀释至5μg/ml的浓度。用1×AR2G动力学缓冲液(AR2G试剂盒,ForteBio,目录号:18-5095)将待连接到配体的分析物(GI101-M45、GI101-M61、GI101-M72)分别稀释至500nM、250nM、125nM和62.5nM。通过将20mM EDC和10mM s-NHS(AR2G试剂盒,ForteBio,目录号:18-5095)在DW中混合来制备活化缓冲液。将80μl的每种试剂置于384孔微孔板(Greiner Bio-One,目录号:781209)中,并设定程序。
结果:IL-2α受体和GI101-M45之间的结合亲和力如图25所示。另外,IL-2α受体和GI101-M61之间的结合亲和力如图26所示,以及IL-2α受体和GI101-M72之间的结合亲和力如图27所示。
实施例7.2.鉴定GI102-M45、GI102-M61和GI102-M72与IL-2Rβ的结合亲和力
在96孔微孔板中,将Ni-NTA生物传感器预先用200μl 1×Ni-NTA动力学缓冲液(10×动力学缓冲液,ForteBio,18-1042)水合。用1×Ni-NTA动力学缓冲液将待连接到生物传感器的配体(人IL-2Rβ蛋白,His标签,Acro,CD2-H5221)稀释至2μg/ml的浓度。用1×Ni-NTA动力学缓冲液将待连接到配体的GI102-M45、GI102-M61或GI102-M72稀释至500nM、250nM、125nM或62.5nM的浓度。将80μl的每种试剂置于384孔微孔板中,并设定程序。
结果:如图28所示测量了IL-2Rβ和GI102-M45之间的结合亲和力,以及如图29所示测量了IL-2Rβ和GI102-M61之间的结合亲和力。另外,如图30所示测量了IL-2Rβ和GI102-M72之间的结合亲和力。
III.鉴定融合蛋白的免疫活性
实施例8.鉴定由融合蛋白引起的IFN-γ产生
实施例8.1.CFSE标记的PBMC的培养
通过与1μM CellTrace CFSE染料在37℃下反应20分钟,用羧基荧光素琥珀酰亚胺酯(CFSE)标记从人分离的外周血单核细胞(PBMC)。通过与具有5倍体积的染色反应溶液的培养基反应5分钟,然后在1,300rpm下离心5分钟来移除未结合到细胞上的CFSE。将CFB标记的PBMC重悬于培养基(含有10%胎牛血清(FBS)、10mM HEPES、100U/ml青霉素/链霉素、1mM丙酮酸钠、55μM 2-巯基乙醇、1mM非必需氨基酸和2mM L-谷氨酰胺的RPMI1640培养基)中,然后以1×105细胞/孔的量加入到96孔微孔板中。用5μg/ml PHA(凝集素来自菜豆,红芸豆,Sigma-Aldrich,St.Louis,MO,USA,目录号:L1668-5MG)和GI101、GI101C1、GI101C2或IL-2(阿地白介素;人重组IL-2,Novartis)进行治疗,并在37℃的5%CO2培养箱中孵育6天。
此处,GI101、GI101C1、GI101C2和IL-2的治疗浓度为1nM、10nM或100nM。通过FACS分析细胞,并使用ELISA试剂盒(Biolegend,San Diego,CA,USA,目录号:430103)测量培养基中存在的人IFN-γ。
实施例8.2.FACS分析
用FACS缓冲液(3%胎牛血清(FBS)、10mM EDTA、1M HEPES、100U/ml青霉素/链霉素、10μg/ml 1mM丙酮酸钠)洗涤通过移除上清液获得的细胞沉淀,然后,在4℃下与Fc阻断剂(Biolegend,目录号:422302)反应5分钟。之后,用APC抗CD3抗体(Biolegend,目录号:300412)和PE抗CD8a抗体(Biolegend,目录号:300908)治疗并使反应在4℃下进行20分钟。然后,用FACS缓冲液洗涤所得产物。将细胞沉淀重悬于FACS缓冲液中,然后使用BD LSRFortessa(BD Biosciences,San Diego,CA,USA)和FlowJo软件进行分析。
实施例8.3.ELISA检测人IFN-γ
使用人IFN-γELISA试剂盒(Biolegend,目录号:430103)测量分泌到培养细胞的每个样品的上清液中的人IFN-γ的量。简言之,将抗人IFNγ抗体加入到ELISA板中,并使反应在4℃下进行过夜,以使这些抗体包被在其上。然后,用添加了1%BSA的PBS溶液在室温下封闭1小时。用洗涤缓冲液(0.05%Tween-20的PBS溶液)洗涤,然后将标准溶液和各个样品适当稀释并加入其中。然后,使反应在室温下进行2小时。
在反应完成之后,洗涤该板并向其中加入第二抗体(检测抗体)。使反应在室温下进行1小时。用洗涤缓冲液洗涤,然后向其中加入抗生物素蛋白-HRP溶液。使反应在室温下进行30分钟。向其中加入底物溶液,并在室温下在黑暗中诱导显色反应20分钟。最后,加入H2SO4以终止显色反应,并用Epoch微板分光光度计(BioTek Instruments,Inc.,Winooski,VT,USA)测量450nm处的吸光度。
因此,发现与用GI101C1、GI101C2或IL-2治疗的细胞相比,用GI101治疗的细胞显示IFN-γ分泌显著增加(图31和图32)。
实施例9.鉴定GI101对CD8+T细胞增殖的作用
通过与1μM CellTrace CFSE染料在37℃下反应20分钟,用CFSE标记从人分离的外周血单核细胞(PBMC)。通过与具有5倍体积的染色反应溶液的培养基反应5分钟,然后通过在1,300rpm下离心5分钟来移除未结合到细胞上的CFSE。将CFB标记的PBMC重悬于培养基(含有10%胎牛血清(FBS)、10mM HEPES、100U/ml青霉素/链霉素、1mM丙酮酸钠、55μM 2-巯基乙醇、1mM非必需氨基酸和2mM L-谷氨酰胺的RPMI1640培养基)中,然后以1×105细胞/孔的量加入到96孔微孔板中。
然后,用1μg/ml的抗CD3ε抗体(Biolegend,目录号:L1668-5MG)和GI101、GI101C1、GI101C2或阿地白介素(Novartis)治疗,并在37℃下的5%CO2培养箱中孵育6天。此处,用浓度为100nM的GI101、GI101C1、GI101C2和IL-2治疗细胞。通过使用APC-TCRαβ和PE-CD8α抗体进行FACS分析测量未标记CFSE的CD8+T细胞的比例来检验孵育细胞的增殖程度。
结果发现,GI101在体外激活CD8+T细胞增殖的程度与野生型IL-2阿地白介素相似(图33和图34)。
实施例10.鉴定GI101和GI102对CD8+T细胞增殖的作用
人PBMC购自Allcells(Lot#3014928,USA)。使用1M CellTrace CFSE染料,将其与人PBMC在避光条件下于室温下反应20分钟。通过与1μM CellTrace CFSE染料在37℃下反应20分钟,用CFSE标记细胞。通过与具有5倍体积的染色反应溶液的培养基反应5分钟,然后在1,300rpm下离心5分钟来移除未结合到细胞上的CFSE。将CFB标记的PBMC重悬于培养基(含有10%胎牛血清(FBS)、10mM HEPES、100U/ml青霉素/链霉素、1mM丙酮酸钠、55μM 2-巯基乙醇、1mM非必需氨基酸和2mM L-谷氨酰胺的RPMI1640培养基)中,然后以1×105细胞/孔的量加入到96孔微孔板中。
然后,使CFB标记的PBMC接受1μg/ml抗CD3ε抗体(OKT3,eBioscience,USA)和GI101,GI101C1,GI101C2或阿地白介素(Novartis)的治疗,并在37℃下的5%CO2培养箱中孵育7天。此处,使细胞经受浓度为10μM的GI101、GI101C1、GI101C2和IL-2的治疗。
通过使用抗人CD4-PE抗体(Biolegend,USA)、抗人CD8-PE/Cy7抗体(Biolegend,USA)和抗人FoxP3-APC抗体(Biolegend,USA)的FACS分析测量未标记CFSE的CD8+T细胞的比例来检验孵育细胞的增殖程度。
因此,与对照组(无刺激)、抗CD3抗体单独治疗组和GI101C1治疗组相比,GI101、GI102_M61、GI101C2和阿地白介素治疗组显示CD8+T细胞比例的显著增加。另外,与阴性对照组(无刺激)和抗CD3单独治疗组相比,GI101、GI101C2和阿地白介素治疗组显示CD4+/FoxP3+Treg细胞的增殖显著增加,而GI102和GI101C1治疗组的CD4+/FoxP3+Treg细胞增殖没有显著增加(图35)。
实施例11.鉴定GI101或GI101w对CD8+T细胞和NK细胞增殖的作用
将购自Orient Bio(Korea)的7周龄C57BL/6小鼠分为3组,每组包含3只小鼠,并向其腹腔注射PBS、GI101或GI101w。此处,GI101和GI101w分别用200μl PBS制备为40.5μg,对小鼠进行腹腔注射。在注射五天之后,从每组小鼠中取出脾。从中分离细胞,并使用血细胞计数器测量细胞总数。用使用APC-CD3ε抗体(Biolegend;145-2C11)、PE-NK1.1抗体(Biolegend;PK136)和太平洋蓝-CD8α抗体(BD;53-6.7)染色的FACS分析检测脾细胞中CD8+T细胞和NK细胞的比例。由此,计算存在于脾中的CD8+T细胞和NK细胞的数量。
结果:经鉴定,与GI101w相比,GI101在体内激活了CD8+T细胞和NK细胞的增殖(图36和图37)。
实施例12.鉴定GI101对T细胞功能的作用
使用CTLA-4阻断生物测定试剂盒(Promega,目录号:JA4005)进行实验。该实验简要描述如下:将保持在液氮中的CTLA-4效应细胞在37℃恒温水浴中解冻3分钟,并将0.8mlCTLA-4效应细胞与3.2ml预热的检测缓冲液(90%RPMI+10%胎牛血清)充分混合。然后,将混合物以25μl/孔加入到96孔白细胞培养板(SPL,目录号:30196)中。然后,加入25μl各种浓度的GI101。对于阴性对照,加入25μl检测缓冲液。然后,将96孔白细胞培养板覆盖并放置在室温下直到制备完aAPC/Raji细胞。
将保持在液氮中的aAPC/Raji细胞在37℃恒温水浴中解冻3分钟,并将0.8mlaAPC/Raji细胞与3.2ml预热的检测缓冲液充分混合。然后,将25μl混合物加入到板的每孔中,并使反应在37℃的5%CO2培养箱中进行16小时。在反应完成之后,将所得物在室温下静置15分钟,然后向其中加入Bio-Glo试剂,同时小心避免产生气泡。再将Bio-Glo试剂加入到三个最外面的孔中,用作空白以校正背景信号。使反应在室温下进行10分钟,然后用Cytation 3(BioTek Instruments,Inc.,Winooski,VT,USA)进行荧光测量。通过计算RLU(GI101-背景)/RLU(无治疗背景)进行最终数据分析。
结果发现,连接到CTLA-4的GI101在效应T细胞上表达,并激活T细胞的功能而不是抑制T细胞的功能(图38和图39)。
实施例13.鉴定mGI101和mGI102对免疫细胞的作用
将购自Orient Bio(Korea)的7周龄C57BL/6小鼠分为3组,每组包含3只小鼠,并向其静脉施用PBS,3mg/kg、6mg/kg或12mg/kg的GI101,或者3mg/kg、6mg/kg或12mg/kg的mGI102(mGI102-M61)。在注射之后第1天、第3天、第5天、第7天和第14天,从每组小鼠中取出脾。然后,对于脾脏组织,使用相应抗体通过FACS分析计算效应CD8+T细胞、NK细胞和Treg细胞的数量,并且分别计算效应CD8+T细胞和NK细胞相对于Treg细胞的比例。关于在每个细胞检测中使用的抗体的信息如下:
效应CD8+T细胞:PB抗小鼠CD3ε抗体(Biolegend,#155612;KT3.1.1),FITC抗小鼠CD8α抗体(BD,#553031,53-6.7),PE/Cy7抗小鼠CD44抗体(Biolegend,#103030;IM7),APC抗小鼠CD122抗体(Biolegend,#123214;TM-β1)
NK细胞:PB抗小鼠CD3ε抗体(Biolegend,#155612;KT3.1.1),PE抗小鼠NK-1.1(Biolegend,#108708;PK136)
Treg细胞:FITC抗小鼠CD3抗体(Biolegend,#100204;17A2),PB抗小鼠CD4抗体(Biolegend,#100531;RM4-5),PE抗小鼠CD25抗体(Biolegend,#102008;PC61),APC抗小鼠Foxp3抗体(Invitrogen,#FJK-16s,17-5773-82)。
结果:与PBS施用组相比,接受mGI101或mGI102(mGI102-M61)的组在施用之后3天至14天的时间点显示CD8+T细胞和NK细胞数量的显著增加。另外,发现与PBS施用组相比,接受mGI102的组在施用之后3天至14天的时间点显示活化的CD8+T细胞/Treg细胞和NK细胞/Treg细胞的比例显著增加(图40)。
IV.鉴定融合蛋白的抗癌作用
实施例14.鉴定GI101对表达PD-L1和CTLA-4的癌细胞抑制T细胞活性的作用
表达PD-L1和CTLA-4的NCl-H292癌细胞系在含有10μg/ml丝裂霉素C(Sigma)的培养基中培养3小时,然后,用培养基洗涤以移除丝裂霉素C。之后,将5×104个细胞的丝裂霉素C治疗的NCl-H292癌细胞系与1×105细胞的人PBMC在96孔微孔板中孵育。此处,对T细胞活性进行5μg/ml PHA(Sigma)治疗。另外,将浓度为50nM的GI101C1和GI101与浓度为50nM的IgG1-Fc(Biolegend)或abatacept(=Orencia;Bristol-Myers Squibb)在4℃下反应30分钟,然后将所得物用于治疗NCl-H292癌细胞。3天之后,收集细胞培养物的上清液,并使用ELISA试剂盒(Biolegend)测定IFN-γ的量。
作为阳性对照组,使用在不存在丝裂霉素C治疗的NCl-H292癌细胞系的情况下用PHA刺激的人PBMC;作为阴性对照组,使用在存在丝裂霉素C治疗的NCl-H292癌细胞系的情况下用PHA刺激的人PBMC。以与实施例9.3相同的方式进行使用IFN-γELISA试剂盒的检测。
结果:GI101有效地激活了免疫应答,该免疫应答已被过表达PD-L1的癌细胞系抑制。另外,发现GI101抑制效应T细胞上表达的CTLA-4的信号传导(图41和图42)。
实施例15.鉴定mGI101在移植了小鼠来源结直肠癌细胞的小鼠中抗癌作用
使从Orient Bio获得的BALB/c小鼠(雌性,7周龄)进行7天的适应期。然后,将5×106个细胞的CT-26癌细胞系(ATCC,USA)与0.05ml无酚红基质胶基质(BD)混合,并通过在小鼠右背部区域以0.1ml皮下注射进行混合物的同种异体移植。在癌细胞移植之后的一定时间内,测量肿瘤体积并选择达到约28mm3的受试者,然后,基于肿瘤大小和体重将选择的小鼠均匀分组,每组包含10只小鼠。然后,使用一次性注射器(31G,1ml),将hIgG4以6mg/kg的剂量施用给阴性对照组。对于实验组,向其静脉注射3mg/kg、6mg/kg或12mg/kg剂量的mGI101。在第一次注射之后,每三天一次,共注射三次。每天测量肿瘤大小。
结果:在分别接受6mg/kg和12mg/kg剂量mGI101的组中,在一些测量时间点以及再试验结束时与阴性对照组相比,肿瘤大小受到显著抑制(图43)。此外,作为测量存活率的结果,在已接受6mg/kg剂量mGI101的组中,在一些测量时间点以及试验结束时与阴性对照组相比,观察到显著改善(图44)。
实施例16.鉴定GI101在移植了小鼠来源结直肠癌细胞的小鼠中的抗癌作用
实施例16.1.鉴定肿瘤抑制作用
使从Orient Bio获得的BALB/c小鼠(雌性,7周龄)进行7天的适应期。然后,将5×106个细胞的CT-26癌细胞系(ATCC,USA)悬浮于0.1ml PBS中,通过在小鼠右背部区域以0.1ml皮下注射进行悬浮液的同种异体移植。在癌细胞移植之后的一定时间内,测量肿瘤体积并选择达到约50mm3至200mm3的受试者,然后,基于肿瘤大小和体重将选择的小鼠均匀分组,每组包含10只小鼠。之后,使用一次性注射器(31G,1ml),不向阴性对照组施用药物,向阳性对照组静脉注射5mg/kg剂量的抗PD-1抗体或5mg/kg剂量的抗PD-1抗体和5mg/kg剂量的抗CTLA-4抗体。对于实验组,向其静脉注射0.1mg/kg或1mg/kg剂量的GI101。在第一次注射之后,每三天一次,共注射三次。每天测量肿瘤大小。
结果:在CT-26癌细胞系移植的小鼠中,与阴性对照组相比,接受0.1mg/kg或1mg/kg剂量的抗PD-1抗体、抗PD-1抗体和抗CTLA-4抗体或GI101的所有组均显示对肿瘤生长的显著抑制。特别是,与抗PD-1抗体治疗组相比,以0.1mg/kg的剂量接受GI101的实验组显示显著的肿瘤抑制作用(*p<0.05)(图45)。
实施例16.2.分析癌组织中的免疫细胞
当肿瘤体积达到平均200mm3时,将实施例16.1中的每组小鼠处死,并收集癌组织。然后,将癌组织分离至单细胞水平,以分析其中的免疫细胞,使用下列抗体对癌组织中的免疫细胞进行FACS分析。具体地,抗小鼠CD3(Biolegend,目录号:100320)、抗小鼠CD4(Biolegend,目录号:100526)、抗小鼠CD8(Biolegend,目录号:100750)、抗小鼠FoxP3(eBioscience,目录号:12-5773-82)、抗小鼠CD25(Biolegend,目录号:102049)、抗小鼠CD44(eBioscience,目录号:61-0441-82)、抗小鼠PD-1(Biolegend,目录号:135218)、抗小鼠IFN-γ(Biolegend,目录号:505832)、抗小鼠CD49b(Biolegend,目录号:108906)、抗小鼠H2(Invitrogen,目录号:A15443)、抗小鼠CD11c(Biolegend,目录号:117343)、抗小鼠CD80(eBioscience,目录号:47-4801-82)、抗小鼠CD86(Biolegend,目录号:104729)、抗小鼠F4/80(eBioscience,目录号:47-4801-82)和抗小鼠CD206(eBioscience,目录号:17-2061-80)用作抗体。
结果:与仅接受5mg/kg剂量的抗PD-1抗体的阳性对照组相比,接受0.1mg/kg剂量的GI101的实验组显示CD8+T细胞的显著增加(*p<0.05,图46和图47)。此外,与阴性对照组相比,接受GI101的所有实验组均显示T细胞中IFN-γ表达水平的显著增加(*p<0.05,图46和图47)。另外,与阴性对照组和仅接受抗PD-1抗体的阳性对照组相比,接受0.1mg/kg剂量GI101的实验组显示M1巨噬细胞的增加(图48和图49)。另外,接受GI101的所有实验组显示在巨噬细胞和树突状细胞中CD86表达水平的增加(*p<0.05,图48至图51)。
实施例17.鉴定GI101在移植了小鼠来源肺癌细胞的小鼠中的抗癌作用
17.1.鉴定肿瘤抑制作用
使从Orient Bio获得的C57BL/6小鼠(雌性,7周龄)进行7天的适应期。然后,将5×106个细胞的LLC2癌细胞系(ATCC,USA)悬浮于0.1ml PBS中,在小鼠右背部区域以0.1ml皮下注射进行悬浮液的同种异体移植。在癌细胞移植之后的一定时间内,测量肿瘤体积并选择达到约50mm3至200mm3的受试者,然后,基于肿瘤大小和体重将选择的小鼠均匀分组,每组包含10只小鼠。然后,使用一次性注射器(31G,1ml),不向阴性对照组施用药物,向阳性对照组静脉注射5mg/kg剂量的抗PD-1抗体或5mg/kg剂量的抗PD-1抗体和5mg/kg剂量的抗CTLA-4抗体。对于实验组,向其静脉注射0.1mg/kg或1mg/kg剂量的GI101。在第一次注射之后,每三天一次,共注射三次。每天测量肿瘤大小。
结果:与阴性对照组相比,所有实验组均显示显著的肿瘤抑制作用(*p<0.05)(图52)。
实施例17.2.分析癌组织中的免疫细胞
当肿瘤体积达到平均200mm3时,将实施例17.1中的每组小鼠处死,并收集癌组织。然后,以与实施例16.2相同的方式进行FACS分析,以分析癌组织的免疫细胞。
结果,与仅接受抗PD-1抗体的阳性对照组相比,接受0.1mg/kg剂量的GI101的实验组显示CD8+T细胞的显著增加(*p<0.05,图59)。此外,与阴性对照组相比,接受GI101的所有实验组均显示IFN-γ表达水平的显著增加(*p<0.05,图59)。另外,接受GI101的所有实验组显示在巨噬细胞和树突状细胞中CD86表达水平的增加(*p<0.05,图53至图55)。
实施例18.鉴定mGI102-M61在移植了小鼠来源结直肠癌细胞的小鼠中的抗癌作用
使从Orient Bio获得的BALB/c小鼠(雌性,7周龄)进行7天的适应期。然后,将5×106个细胞的CT-26癌细胞系(ATCC,USA)与0.05ml无酚红基质胶基质(BD)混合,在小鼠右背部区域以0.1ml皮下注射进行混合物的同种异体移植。在癌细胞移植之后的一定时间内,测量肿瘤体积并选择达到约28mm3的受试者,然后,基于肿瘤大小和体重将选择的小鼠均匀分组,每组包含10只小鼠。然后,使用一次性注射器(31G,1ml),将hIgG4以6mg/kg的剂量注射给阴性对照组。对于实验组,向其静脉注射3mg/kg、6mg/kg或12mg/kg剂量的mGI102-M61。在第一次注射之后,每三天一次,共注射三次。每天测量肿瘤大小。
结果:经鉴定,与阴性对照组相比,接受12mg/kg剂量mGI102-M61的实验组在一些测量时间点以及试验结束时显示肿瘤生长的显著抑制(图56)。另外,作为测量存活率的结果,经鉴定,与阴性对照组相比,接受12mg/kg剂量mGI102-M61的实验组在一些测量时间点以及试验结束时显示显著的改善(图57)。
实施例19.鉴定mGI101在移植了小鼠来源结直肠癌细胞的小鼠中的抗癌作用
使从Orient Bio获得的BALB/c小鼠(雌性,7周龄)进行7天的适应期。然后,将5×106个细胞的CT-26癌细胞系(ATCC,USA)与0.05ml无酚红基质胶基质(BD)混合,在小鼠右背部区域以0.1ml皮下注射进行混合物的同种异体移植。在癌细胞移植之后的一定时间内,测量肿瘤体积并选择达到约200mm3至250mm3的受试者,然后,基于肿瘤大小和体重将选择的小鼠均匀分组,每组包含10只小鼠。
然后,使用一次性注射器(31G,1ml),将hIgG4以4mg/kg的剂量注射给阴性对照组。对于实验组,向其静脉施用1mg/kg、4mg/kg或6mg/kg剂量的mGI101。另外,接受4.9mg/kgmCD80或2.8mg/kg Fc-IL-2v(GI101C2)的组被设定为对照组。另外,同时接受4.9mg/kgmCD80和2.8mg/kg Fc-IL-2v(GI101C2)的组被设定为对照组。
在肿瘤体积测量中,经鉴定,与阴性对照相比,接受6mg/kg剂量mGI101的组在一些测量时间点以及试验结束时显示显著的抑制作用。与接受mCD80和Fc-IL-2v(GI101C2)组合的组相比,观察到优异的肿瘤生长抑制率(图58和图59)。
总之,在对用CT-26(一种BALB/c小鼠来源结直肠癌细胞系)同种异体移植的BALB/c小鼠的肿瘤生长抑制功效试验中,证明了与mCD80和IL-2v单一制剂相比,试验物质mGI101在该试验条件下具有肿瘤抑制功效;并且经鉴定,与接受mCD80和IL-2v的组合的组相比,mGI101显示优异的抗癌功效(图58和图59)。特别是,与阴性对照组和接受mCD80和Fc-IL2v(GI101C2)的组合的组相比,接受6mg/kg剂量mGI101的组显示对肿瘤大小有显著抑制作用。
V.融合蛋白二聚体和免疫检查点抑制剂联合施用的抗癌作用的测定
实施例20.测定GI101和抗PD-1抗体联合施用在人源乳腺癌细胞移植小鼠中的抗癌作用
本测试使用通过将人PBMC异种移植到NSGb2m小鼠中制备的人源化小鼠模型评价了在移植了作为人源乳腺癌细胞的异种MDA-MB-231细胞的肿瘤模型中,单独或联合腹膜注射作为试验材料的GI101和作为阳性对照材料的Keytruda(Pembrolizumab,MSD)(一种抗PD-1抗体)之后的肿瘤生长抑制作用。
根据每个剂量添加赋形剂来稀释表2中描述的试验材料、阴性对照材料和阳性对照材料的储备溶液。
[表2]
人源乳腺癌细胞MDA-MB-231(智人,人乳腺/乳房;来源于转移部位:胸腔积液)购自韩国细胞系库(韩国)并用于本试验。混合胎牛血清(FBS,16000-044,Thermofisherscientific,U.S.A.)、青霉素-链霉素(10,000U/ml青霉素和10,000μg/ml链霉素)(15140122,Thermofisher scientific,U.S.A.))和RPMI1640(A1049101,Thermofisherscientific,U.S.A.),每100ml的成分如下表所示。
[表3]
名称 | 组合物(ml) |
FBS | 10 |
青霉素-链霉素 | 1 |
RPMI1640 | 89 |
总体积 | 100 |
将试验中使用的细胞解冻,置于烧瓶中进行细胞培养,并在37℃下的5%CO2培养箱中(MCO-170M,Panasonic,Japan)培养。使用胰蛋白酶-EDTA(目录号:25200-072,Thermofisher scientific,U.S.A.)悬浮培养的细胞。使用离心机离心(125xg,5分钟)收集悬浮的细胞,转移至新的培养基和新的烧瓶中,并传代培养。在细胞系移植当天,将培养的细胞置于离心管中,回收,然后离心(125xg,5分钟)以弃去上清液。然后,用PBS(目录号:LB001-04,Welgene Inc.,KOREA)制备细胞悬浮液(5×106个细胞/0.05ml),并储存在冰上直到接种。对于本试验,8周龄雌性NSGb2m(NOD.Cg-B2mtm1UncPrkdcscidIl2rgtm1Wjl/SzJ)小鼠购自JoongABio(Korea)并使用。在检疫和适应期结束之后的第二天测量体重,然后,将为健康动物制备的人源PBMC细胞悬浮液(5×106个细胞/0.2ml)填充到一次性注射器中,并注射到动物的尾静脉。细胞移植之后每天观察一次一般症状。
将通过向制备的MDA-MB-231细胞悬浮液(5×106个细胞/0.05ml)中加入无酚红基质胶基质(0.05ml,356237,BD,美国)制备的溶液填充到一次性注射器中,通过皮下注射(0.1ml/只)移植到移植了人PBMC的动物的右背。在细胞系移植后的植入和生长期期间每天观察一次一般症状。
在细胞移植后的一定时期之后,测量没有显示异常健康状态的小鼠的肿瘤体积,并选择32个个体,使得每组的肿瘤体积平均值达到40mm3至80mm3。基于肿瘤体积和体重,将所选择的动物尽可能均匀地分为4组(每组8只动物)。
测试组分组如表4所示。使用一次性注射器(31G,1ml)将试验材料注射给动物,并且注射频率为每周两次,共注射4次。
[表4]
在观察期期间,每天观察一次一般症状诸如外观、行为、排泄等,并鉴定死亡动物。在细胞系移植当天、每周两次和在动物处死当天测量体重。
在观察期期间,使用数显卡尺(mitutoyo,Japan)每周三次测量肿瘤的最大长度(L)和垂直宽度(W),并应用于以下方程计算肿瘤体积(TV)。
<等式1>
TV(mm3)=(W2×L)/2
<等式2>
%TGI(肿瘤生长抑制)=(1-(Ti-T0)/(Vi-V0))×100
将施用之前每个个体的肿瘤体积设定为分类时的测量值。
在肿瘤移植之后第21天、第25天、第28天和第31天,分别注射表4所示的药物,结果显示,与对照组(hIgG4)相比,在GI101或Keytruda的单独治疗组中肿瘤生长受到抑制。与对照组相比,GI101和Keytruda联合治疗组中的肿瘤生长受到抑制。与GI101或Keytruda单独治疗组相比,GI101和Keytruda联合治疗组中的肿瘤生长受到抑制(图60)。
与药物治疗第1天(肿瘤移植之后第17天)相比,在实验结束时(肿瘤移植之后第42天)计算肿瘤生长抑制率。结果:hIgG4治疗组有2只小鼠的肿瘤生长抑制率为30%或更高,1只小鼠的肿瘤生长抑制率为50%或更高,以及1只小鼠的肿瘤生长抑制率为80%或更高;GI101治疗组有5只小鼠的肿瘤生长抑制率为30%或更高,5只小鼠的肿瘤生长抑制率为50%或更高,以及2只小鼠的肿瘤生长抑制率为80%或更高;Keytruda治疗组有7只小鼠的肿瘤生长抑制率为30%或更高,5只小鼠的肿瘤生长抑制率为50%或更高,以及3只小鼠的肿瘤生长抑制率为80%或更高;GI101和Keytruda联合治疗组有8只小鼠的肿瘤生长抑制率为30%或更高,8只小鼠的肿瘤生长抑制率为50%或更高,以及6只小鼠的肿瘤生长抑制率为80%或更高(图61)。
另外,当GI101和Keytruda联合用于移植了人源乳腺癌细胞的小鼠时,每个治疗组中个体实验动物的肿瘤生长程度示于图62至图66中。
实施例21.检测mGI101和抗PD-1抗体联合施用在小鼠来源结直肠癌细胞移植小鼠中的抗癌作用
本试验评价了在将同种异体鼠结肠腺癌细胞(MC38)移植到C57BL/6小鼠的肿瘤模型中,单独或联合腹膜施用作为试验材料的mGI101和作为阳性对照材料的抗PD-1抗体之后的肿瘤生长抑制作用。
鼠结肠腺癌细胞(MC38)为鼠源结直肠癌细胞,购自Kerafast公司(USA)并用于测试。MC38细胞在含有10%胎牛血清(Gibco)和1%抗生素/抗真菌剂(Gibco)的RPMI1640培养基(Gibco)中培养。使用胰蛋白酶收获培养的细胞并悬浮于PBS中。将1×106个MC38细胞s.c.注射到C57BL/6雌性小鼠(7周龄)的右侧腹,以建立同种异体移植肿瘤模型。
基于肿瘤体积(30mm3)随机分配小鼠(每组5只)。在细胞接种之后约2天鉴定肿瘤移植物。测试组分组和施用的测试材料如表5所示。
[表5]
在试验期期间,每天观察一次临床症状诸如疾病和行为变化等,并鉴定死亡动物。在试验期之后将动物处死。MC38实体癌的大小用肿瘤3D扫描仪(TM900,Peria,belgium)测量。计算每个实验组的平均体重减轻和百分比变化,以及平均肿瘤生长抑制。与溶媒对照组相比评价抗肿瘤功效。
所有统计学计算均使用Prism 8.0(GraphPad Software Inc.,USA)进行。通过单向ANOVA(结束时间)然后通过Bonferroni多重比较试验比较肿瘤体积测量。“p”值<0.05被认为差异具有显著性。
在施用mGI101和共同施用mGI101和抗PD-1抗体之后,所有试验动物保持健康,没有显示病理学异常的征兆。图67至图73中示出了使用针对MC38肿瘤的mGI101和/或抗PD-1抗体的联合治疗的结果。与对照组相比,在药物治疗组中观察到抗癌作用,并且在16天的测试期期间,肿瘤大小有显著差异。MC38肿瘤在先前的文献中已知为对抗PD-1抗体应答的模型,并且在本试验的抗PD-1抗体施用组中也观察到其抗癌作用(p>0.01)。在mGI101(6mpk)单独施用组中也发现了与在抗PD-1抗体施用组中一样多的抗癌作用(p>0.01)。mGI101(0.6mpk)+抗PD-1(5mpk)联合施用组显示显著的抗癌作用(p>0.0001)。
每个试验组的个体肿瘤大小示于图69至图73中。根据个体肿瘤大小的结果,在抗PD-1抗体施用组中的一些动物中观察到轻微的肿瘤消退。mGI101(6mpk)单独施用组比抗PD-1抗体施用组显示了更佳的肿瘤生长抑制作用。肿瘤大小保持相同,直到第5天至第7天,但在7天后又重新生长。肿瘤大小保持相同,直到第5天至第7天,但在7天后又重新生长。联合施用组(GI101(0.6mpk)+抗PD-1抗体(5mpk))显示显著的肿瘤生长抑制作用。特别是,联合施用组中的两只小鼠显示完全应答(无肿瘤)。
将MC38细胞再注射到显示完全缓解的联合施用组的两只小鼠的左侧腹(与癌细胞的初始注射位点相对)。给这些小鼠持续施用抗PD-1抗体(5mpk,BIW)直到第32天(图74)。在两只小鼠中的一只小鼠中发现小肿瘤(>30mm3),但肿瘤大小直到第35天不再生长(图69)。在再次注射肿瘤之后,在另一只小鼠中没有发现肿瘤(图69和图74)。
总之,在MC38同种异体肿瘤模型中测试mGI101单独和与抗PD-1抗体联合的抗肿瘤功效,结果显示,联合施用组(GI101(0.6mpk)+抗PD-1(5mpk))显示最佳的抗肿瘤功效。联合施用组的两只实验动物显示完全应答,并且显示完全应答的小鼠在再次注射MC38后显示抗癌作用(表6)。
[表6]
实施例22.检测mGI101和抗PD-L1抗体联合施用在小鼠来源结直肠癌细胞移植小鼠中的抗癌作用
本试验评价了在将同种异体鼠结肠癌细胞(CT26)移植到BALB/c小鼠的肿瘤模型中,单独或联合腹膜施用作为试验材料的mGI101和作为阳性对照材料的抗PD-L1抗体(BioXcell,Cat#BE0101)之后的肿瘤生长抑制作用。
CT26细胞在含有10%胎牛血清(Gibco)和1%抗生素/抗真菌剂(Gibco)的RPMI1640培养基(Gibco)中培养。使用胰蛋白酶收获培养的细胞并悬浮于PBS中。将5×105个CT26细胞皮下注射到BALB/c雌性小鼠(7周龄)的右侧腹,以建立同种异体移植肿瘤模型。
基于肿瘤体积(50mm3至120mm3)随机分配小鼠(每组4只)。在细胞接种之后约2天鉴定肿瘤移植物。测试组分组和施用的测试材料如表7所示。
[表7]
在试验期期间,每天观察一次临床症状诸如疾病和行为变化等,并鉴定死亡动物。在试验期之后将动物处死。CT26实体癌的大小用肿瘤3D扫描仪(TM900,Peria,belgium)测量。计算每个实验组的平均体重减轻和百分比变化,以及平均肿瘤生长抑制。与溶媒对照组相比评价抗肿瘤功效。
所有统计学计算均使用Prism 8.0(GraphPad Software Inc.,USA)进行。通过单向ANOVA(结束时间),然后,通过Bonferroni多重比较试验比较肿瘤体积测量。“p”值<0.05被认为差异具有显著性。
在CT26同种异体肿瘤模型中测试mGI101单独和与抗PD-L1抗体联合的抗肿瘤功效,结果:联合施用组(mGI101(3mpk)+抗PD-L1(10mpk))显示最佳的抗肿瘤功效(图75)。
实施例23.检测mGI101和抗TIGIT抗体联合施用在小鼠来源结直肠癌细胞移植小鼠中的抗癌作用
本试验评价了在将同种异体鼠结肠癌细胞(CT26)移植到BALB/c小鼠的肿瘤模型中,单独或联合腹膜施用作为试验材料的mGI101和作为阳性对照材料的与具有如SEQ IDNO:39所示的氨基酸序列的抗TIGIT的胞外结构域(ECD)特异性结合的抗TIGIT抗体之后的肿瘤生长抑制作用。
CT26细胞在含有10%胎牛血清(Gibco)和1%抗生素/抗真菌剂(Gibco)的RPMI1640培养基(Gibco)中培养。使用胰蛋白酶收获培养的细胞并悬浮于PBS中。将5×105个CT26细胞皮下注射到BALB/c雌性小鼠(7周龄)的右侧腹,以建立同种异体移植肿瘤模型。
基于肿瘤体积(50mm3至120mm3)随机分配小鼠(每组5只)。在细胞接种之后约2天鉴定肿瘤移植物。测试组分组和施用的测试材料如表8所示。
[表8]
在试验期期间,每天观察一次临床症状诸如疾病和行为变化等,并鉴定死亡动物。在试验期之后将动物处死。CT26实体癌的大小用肿瘤3D扫描仪(TM900,Peria,belgium)测量。计算每个实验组的平均体重减轻和百分比变化,以及平均肿瘤生长抑制。与溶媒对照组相比评价抗肿瘤功效。
所有统计学计算均使用Prism 8.0(GraphPad Software Inc.,USA)进行。通过单向ANOVA(结束时间),然后,通过Bonferroni多重比较试验比较肿瘤体积测量。“p”值<0.05被认为差异具有显著性。
在CT26同种异体肿瘤模型中测试mGI101单独和与抗TIGIT抗体联合的抗肿瘤功效,结果:联合施用组(mGI101(3mpk)+抗TIGIT(20mpk))显示最佳的抗肿瘤功效(图76)。与对照组相比,在抗TIGIT抗体单独施用组中没有观察到抗肿瘤作用。然而,与mGI101单独施用组相比,抗TIGIT抗体和mGI101的联合施用显示显著更佳的抗肿瘤作用。
SEQUENCE LISTING
<110> GI 医诺微新
<120> 用于治疗癌症的包括包含IL-2蛋白和CD80蛋白的融合蛋白和免疫检查点抑制
剂
<130> P22112955WP
<150> KR 10-2019-0154632
<151> 2019-11-27
<160> 39
<170> PatentIn version 3.5
<210> 1
<211> 25
<212> PRT
<213> Artificial Sequence(人工序列)
<220>
<223> 信号肽(TPA)
<400> 1
Met Asp Ala Met Leu Arg Gly Leu Cys Cys Val Leu Leu Leu Cys Gly
1 5 10 15
Ala Val Phe Val Ser Pro Ser His Ala
20 25
<210> 2
<211> 208
<212> PRT
<213> Artificial Sequence(人工序列)
<220>
<223> CD80片段(hB7-1:35-242)
<400> 2
Val Ile His Val Thr Lys Glu Val Lys Glu Val Ala Thr Leu Ser Cys
1 5 10 15
Gly His Asn Val Ser Val Glu Glu Leu Ala Gln Thr Arg Ile Tyr Trp
20 25 30
Gln Lys Glu Lys Lys Met Val Leu Thr Met Met Ser Gly Asp Met Asn
35 40 45
Ile Trp Pro Glu Tyr Lys Asn Arg Thr Ile Phe Asp Ile Thr Asn Asn
50 55 60
Leu Ser Ile Val Ile Leu Ala Leu Arg Pro Ser Asp Glu Gly Thr Tyr
65 70 75 80
Glu Cys Val Val Leu Lys Tyr Glu Lys Asp Ala Phe Lys Arg Glu His
85 90 95
Leu Ala Glu Val Thr Leu Ser Val Lys Ala Asp Phe Pro Thr Pro Ser
100 105 110
Ile Ser Asp Phe Glu Ile Pro Thr Ser Asn Ile Arg Arg Ile Ile Cys
115 120 125
Ser Thr Ser Gly Gly Phe Pro Glu Pro His Leu Ser Trp Leu Glu Asn
130 135 140
Gly Glu Glu Leu Asn Ala Ile Asn Thr Thr Val Ser Gln Asp Pro Glu
145 150 155 160
Thr Glu Leu Tyr Ala Val Ser Ser Lys Leu Asp Phe Asn Met Thr Thr
165 170 175
Asn His Ser Phe Met Cys Leu Ile Lys Tyr Gly His Leu Arg Val Asn
180 185 190
Gln Thr Phe Asn Trp Asn Thr Thr Lys Gln Glu His Phe Pro Asp Asn
195 200 205
<210> 3
<211> 30
<212> PRT
<213> Artificial Sequence(人工序列)
<220>
<223> 铰链区
<400> 3
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
1 5 10 15
Ser Ala Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro
20 25 30
<210> 4
<211> 216
<212> PRT
<213> Artificial Sequence(人工序列)
<220>
<223> 免疫球蛋白Fc结构域
<400> 4
Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
1 5 10 15
Pro Lys Asp Gln Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
20 25 30
Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr
35 40 45
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
50 55 60
Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
65 70 75 80
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
85 90 95
Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
100 105 110
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met
115 120 125
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
130 135 140
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
145 150 155 160
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
165 170 175
Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val
180 185 190
Phe Ser Cys Ser Val Leu His Glu Ala Leu His Asn His Tyr Thr Gln
195 200 205
Lys Ser Leu Ser Leu Ser Leu Gly
210 215
<210> 5
<211> 5
<212> PRT
<213> Artificial Sequence(人工序列)
<220>
<223> 接头
<400> 5
Gly Gly Gly Gly Ser
1 5
<210> 6
<211> 133
<212> PRT
<213> Artificial Sequence(人工序列)
<220>
<223> 具有两个氨基酸取代的IL-2变体:hIL-2M
<400> 6
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Ala Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 7
<211> 617
<212> PRT
<213> Artificial Sequence(人工序列)
<220>
<223> 包含IL-2变体和CD80片段的融合蛋白
<400> 7
Met Asp Ala Met Leu Arg Gly Leu Cys Cys Val Leu Leu Leu Cys Gly
1 5 10 15
Ala Val Phe Val Ser Pro Ser His Ala Val Ile His Val Thr Lys Glu
20 25 30
Val Lys Glu Val Ala Thr Leu Ser Cys Gly His Asn Val Ser Val Glu
35 40 45
Glu Leu Ala Gln Thr Arg Ile Tyr Trp Gln Lys Glu Lys Lys Met Val
50 55 60
Leu Thr Met Met Ser Gly Asp Met Asn Ile Trp Pro Glu Tyr Lys Asn
65 70 75 80
Arg Thr Ile Phe Asp Ile Thr Asn Asn Leu Ser Ile Val Ile Leu Ala
85 90 95
Leu Arg Pro Ser Asp Glu Gly Thr Tyr Glu Cys Val Val Leu Lys Tyr
100 105 110
Glu Lys Asp Ala Phe Lys Arg Glu His Leu Ala Glu Val Thr Leu Ser
115 120 125
Val Lys Ala Asp Phe Pro Thr Pro Ser Ile Ser Asp Phe Glu Ile Pro
130 135 140
Thr Ser Asn Ile Arg Arg Ile Ile Cys Ser Thr Ser Gly Gly Phe Pro
145 150 155 160
Glu Pro His Leu Ser Trp Leu Glu Asn Gly Glu Glu Leu Asn Ala Ile
165 170 175
Asn Thr Thr Val Ser Gln Asp Pro Glu Thr Glu Leu Tyr Ala Val Ser
180 185 190
Ser Lys Leu Asp Phe Asn Met Thr Thr Asn His Ser Phe Met Cys Leu
195 200 205
Ile Lys Tyr Gly His Leu Arg Val Asn Gln Thr Phe Asn Trp Asn Thr
210 215 220
Thr Lys Gln Glu His Phe Pro Asp Asn Gly Ser Gly Gly Gly Gly Ser
225 230 235 240
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu Ser Lys Tyr Gly
245 250 255
Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser
260 265 270
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Gln Leu Met Ile Ser Arg
275 280 285
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro
290 295 300
Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
305 310 315 320
Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val
325 330 335
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
340 345 350
Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr
355 360 365
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
370 375 380
Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
385 390 395 400
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
405 410 415
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
420 425 430
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser
435 440 445
Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Leu His Glu Ala
450 455 460
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Gly
465 470 475 480
Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu
485 490 495
Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile
500 505 510
Asn Asn Tyr Lys Asn Pro Lys Leu Thr Ala Met Leu Thr Ala Lys Phe
515 520 525
Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu
530 535 540
Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys
545 550 555 560
Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile
565 570 575
Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala
580 585 590
Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe
595 600 605
Cys Gln Ser Ile Ile Ser Thr Leu Thr
610 615
<210> 8
<211> 1857
<212> DNA
<213> Artificial Sequence(人工序列)
<220>
<223> 编码融合蛋白(GI101)的核苷酸
<400> 8
atggatgcta tgctgagagg cctgtgttgc gtgctgctgc tgtgtggcgc tgtgttcgtg 60
tctccttctc acgctgtgat ccacgtgacc aaagaagtga aagaggtcgc cacactgtcc 120
tgcggccaca acgtttcagt ggaagaactg gcccagacca ggatctactg gcagaaagaa 180
aagaaaatgg tgctgaccat gatgtccggc gacatgaaca tctggcctga gtacaagaac 240
cggaccatct tcgacatcac caacaacctg tccatcgtga ttctggccct gaggccttct 300
gatgagggca cctatgagtg cgtggtgctg aagtacgaga aggacgcctt caagcgcgag 360
cacctggctg aagtgacact gtccgtgaag gccgactttc ccacaccttc catctccgac 420
ttcgagatcc ctacctccaa catccggcgg atcatctgtt ctacctctgg cggctttcct 480
gagcctcacc tgtcttggct ggaaaacggc gaggaactga acgccatcaa caccaccgtg 540
tctcaggacc ccgaaaccga gctgtacgct gtgtcctcca agctggactt caacatgacc 600
accaaccaca gcttcatgtg cctgattaag tacggccacc tgagagtgaa ccagaccttc 660
aactggaaca ccaccaagca agagcacttc cctgacaatg gatctggcgg cggaggttct 720
ggcggaggtg gaagcggagg cggaggatct gctgagtcta agtatggccc tccttgtcct 780
ccatgtcctg ctccagaagc tgctggcgga ccctctgtgt tcctgtttcc tccaaagcct 840
aaggaccagc tcatgatctc tcggacaccc gaagtgacct gcgtggtggt ggatgtgtct 900
caagaggacc ctgaggtgca gttcaattgg tacgtggacg gcgtggaagt gcacaacgcc 960
aagaccaagc ctagagagga acagttcaac tccacctaca gagtggtgtc cgtgctgacc 1020
gtgctgcacc aggattggct gaacggcaaa gagtacaagt gcaaggtgtc caacaagggc 1080
ctgccttcca gcatcgaaaa gaccatctcc aaggctaagg gccagcctag ggaaccccag 1140
gtttacaccc tgcctccaag ccaagaggaa atgaccaaga accaggtgtc cctgacctgc 1200
ctggtcaagg gcttctaccc ttccgacatt gccgtggaat gggagtccaa tggccagcct 1260
gagaacaact acaagaccac acctcctgtg ctggactccg acggctcctt ctttctgtac 1320
tctcgcctga ccgtggacaa gtctagatgg caagagggca acgtgttctc ctgctctgtg 1380
ctgcacgagg ccctgcacaa tcactacacc cagaagtccc tgtctctgtc tcttggaggt 1440
ggtggcggtt ctgcccctac cagctcctct accaagaaaa cccagctcca gttggagcat 1500
ctgctgctgg acctccagat gattctgaac gggatcaaca actataagaa ccccaagctg 1560
accgccatgc tgaccgctaa gttctacatg cccaagaagg ccaccgagct gaagcacctc 1620
cagtgcctgg aagaagaact gaagcccctg gaagaggtgc tgaatctggc ccagtccaag 1680
aacttccacc tgaggccacg ggacctgatc agcaacatca acgtgatcgt gctggaactg 1740
aagggctccg agacaacctt tatgtgcgag tacgccgacg agacagccac catcgtggaa 1800
tttctgaacc ggtggatcac cttctgccag agcatcatct ccacactgac ctgatga 1857
<210> 9
<211> 592
<212> PRT
<213> Artificial Sequence(人工序列)
<220>
<223> 融合蛋白(GI101)
<400> 9
Val Ile His Val Thr Lys Glu Val Lys Glu Val Ala Thr Leu Ser Cys
1 5 10 15
Gly His Asn Val Ser Val Glu Glu Leu Ala Gln Thr Arg Ile Tyr Trp
20 25 30
Gln Lys Glu Lys Lys Met Val Leu Thr Met Met Ser Gly Asp Met Asn
35 40 45
Ile Trp Pro Glu Tyr Lys Asn Arg Thr Ile Phe Asp Ile Thr Asn Asn
50 55 60
Leu Ser Ile Val Ile Leu Ala Leu Arg Pro Ser Asp Glu Gly Thr Tyr
65 70 75 80
Glu Cys Val Val Leu Lys Tyr Glu Lys Asp Ala Phe Lys Arg Glu His
85 90 95
Leu Ala Glu Val Thr Leu Ser Val Lys Ala Asp Phe Pro Thr Pro Ser
100 105 110
Ile Ser Asp Phe Glu Ile Pro Thr Ser Asn Ile Arg Arg Ile Ile Cys
115 120 125
Ser Thr Ser Gly Gly Phe Pro Glu Pro His Leu Ser Trp Leu Glu Asn
130 135 140
Gly Glu Glu Leu Asn Ala Ile Asn Thr Thr Val Ser Gln Asp Pro Glu
145 150 155 160
Thr Glu Leu Tyr Ala Val Ser Ser Lys Leu Asp Phe Asn Met Thr Thr
165 170 175
Asn His Ser Phe Met Cys Leu Ile Lys Tyr Gly His Leu Arg Val Asn
180 185 190
Gln Thr Phe Asn Trp Asn Thr Thr Lys Gln Glu His Phe Pro Asp Asn
195 200 205
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
210 215 220
Ser Ala Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
225 230 235 240
Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
245 250 255
Asp Gln Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
260 265 270
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
275 280 285
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
290 295 300
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
305 310 315 320
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
325 330 335
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
340 345 350
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
355 360 365
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
370 375 380
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
385 390 395 400
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
405 410 415
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
420 425 430
Cys Ser Val Leu His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
435 440 445
Leu Ser Leu Ser Leu Gly Gly Gly Gly Gly Ser Ala Pro Thr Ser Ser
450 455 460
Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu
465 470 475 480
Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr
485 490 495
Ala Met Leu Thr Ala Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu
500 505 510
Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val
515 520 525
Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu
530 535 540
Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr
545 550 555 560
Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe
565 570 575
Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr
580 585 590
<210> 10
<211> 133
<212> PRT
<213> Artificial Sequence(人工序列)
<220>
<223> 成熟人IL-2(hIL-2)
<400> 10
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 11
<211> 288
<212> PRT
<213> Artificial Sequence(人工序列)
<220>
<223> CD80蛋白
<400> 11
Met Gly His Thr Arg Arg Gln Gly Thr Ser Pro Ser Lys Cys Pro Tyr
1 5 10 15
Leu Asn Phe Phe Gln Leu Leu Val Leu Ala Gly Leu Ser His Phe Cys
20 25 30
Ser Gly Val Ile His Val Thr Lys Glu Val Lys Glu Val Ala Thr Leu
35 40 45
Ser Cys Gly His Asn Val Ser Val Glu Glu Leu Ala Gln Thr Arg Ile
50 55 60
Tyr Trp Gln Lys Glu Lys Lys Met Val Leu Thr Met Met Ser Gly Asp
65 70 75 80
Met Asn Ile Trp Pro Glu Tyr Lys Asn Arg Thr Ile Phe Asp Ile Thr
85 90 95
Asn Asn Leu Ser Ile Val Ile Leu Ala Leu Arg Pro Ser Asp Glu Gly
100 105 110
Thr Tyr Glu Cys Val Val Leu Lys Tyr Glu Lys Asp Ala Phe Lys Arg
115 120 125
Glu His Leu Ala Glu Val Thr Leu Ser Val Lys Ala Asp Phe Pro Thr
130 135 140
Pro Ser Ile Ser Asp Phe Glu Ile Pro Thr Ser Asn Ile Arg Arg Ile
145 150 155 160
Ile Cys Ser Thr Ser Gly Gly Phe Pro Glu Pro His Leu Ser Trp Leu
165 170 175
Glu Asn Gly Glu Glu Leu Asn Ala Ile Asn Thr Thr Val Ser Gln Asp
180 185 190
Pro Glu Thr Glu Leu Tyr Ala Val Ser Ser Lys Leu Asp Phe Asn Met
195 200 205
Thr Thr Asn His Ser Phe Met Cys Leu Ile Lys Tyr Gly His Leu Arg
210 215 220
Val Asn Gln Thr Phe Asn Trp Asn Thr Thr Lys Gln Glu His Phe Pro
225 230 235 240
Asp Asn Leu Leu Pro Ser Trp Ala Ile Thr Leu Ile Ser Val Asn Gly
245 250 255
Ile Phe Val Ile Cys Cys Leu Thr Tyr Cys Phe Ala Pro Arg Cys Arg
260 265 270
Glu Arg Arg Arg Asn Glu Arg Leu Arg Arg Glu Ser Val Arg Pro Val
275 280 285
<210> 12
<211> 215
<212> PRT
<213> Artificial Sequence(人工序列)
<220>
<223> Fc结构域变体
<400> 12
Ser His Thr Gln Pro Leu Gly Val Phe Leu Phe Pro Pro Lys Pro Lys
1 5 10 15
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
20 25 30
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
35 40 45
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
50 55 60
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
65 70 75 80
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
85 90 95
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
100 105 110
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
115 120 125
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
130 135 140
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
145 150 155 160
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
165 170 175
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
180 185 190
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
195 200 205
Leu Ser Leu Ser Leu Gly Lys
210 215
<210> 13
<211> 306
<212> PRT
<213> Artificial Sequence(人工序列)
<220>
<223> mCD80蛋白
<400> 13
Met Ala Cys Asn Cys Gln Leu Met Gln Asp Thr Pro Leu Leu Lys Phe
1 5 10 15
Pro Cys Pro Arg Leu Ile Leu Leu Phe Val Leu Leu Ile Arg Leu Ser
20 25 30
Gln Val Ser Ser Asp Val Asp Glu Gln Leu Ser Lys Ser Val Lys Asp
35 40 45
Lys Val Leu Leu Pro Cys Arg Tyr Asn Ser Pro His Glu Asp Glu Ser
50 55 60
Glu Asp Arg Ile Tyr Trp Gln Lys His Asp Lys Val Val Leu Ser Val
65 70 75 80
Ile Ala Gly Lys Leu Lys Val Trp Pro Glu Tyr Lys Asn Arg Thr Leu
85 90 95
Tyr Asp Asn Thr Thr Tyr Ser Leu Ile Ile Leu Gly Leu Val Leu Ser
100 105 110
Asp Arg Gly Thr Tyr Ser Cys Val Val Gln Lys Lys Glu Arg Gly Thr
115 120 125
Tyr Glu Val Lys His Leu Ala Leu Val Lys Leu Ser Ile Lys Ala Asp
130 135 140
Phe Ser Thr Pro Asn Ile Thr Glu Ser Gly Asn Pro Ser Ala Asp Thr
145 150 155 160
Lys Arg Ile Thr Cys Phe Ala Ser Gly Gly Phe Pro Lys Pro Arg Phe
165 170 175
Ser Trp Leu Glu Asn Gly Arg Glu Leu Pro Gly Ile Asn Thr Thr Ile
180 185 190
Ser Gln Asp Pro Glu Ser Glu Leu Tyr Thr Ile Ser Ser Gln Leu Asp
195 200 205
Phe Asn Thr Thr Arg Asn His Thr Ile Lys Cys Leu Ile Lys Tyr Gly
210 215 220
Asp Ala His Val Ser Glu Asp Phe Thr Trp Glu Lys Pro Pro Glu Asp
225 230 235 240
Pro Pro Asp Ser Lys Asn Thr Leu Val Leu Phe Gly Ala Gly Phe Gly
245 250 255
Ala Val Ile Thr Val Val Val Ile Val Val Ile Ile Lys Cys Phe Cys
260 265 270
Lys His Arg Ser Cys Phe Arg Arg Asn Glu Ala Ser Arg Glu Thr Asn
275 280 285
Asn Ser Leu Thr Phe Gly Pro Glu Glu Ala Leu Ala Glu Gln Thr Val
290 295 300
Phe Leu
305
<210> 14
<211> 1848
<212> DNA
<213> Artificial Sequence(人工序列)
<220>
<223> 编码融合蛋白(mGI101)的核苷酸
<400> 14
atggatgcta tgctgagagg cctgtgttgc gtgctgctgc tgtgtggcgc tgtgttcgtg 60
tctccttctc acgctgtgga cgagcagctc tccaagtccg tgaaggataa ggtcctgctg 120
ccttgccggt acaactctcc tcacgaggac gagtctgagg accggatcta ctggcagaaa 180
cacgacaagg tggtgctgtc cgtgatcgcc ggaaagctga aagtgtggcc tgagtacaag 240
aacaggaccc tgtacgacaa caccacctac agcctgatca tcctgggcct cgtgctgagc 300
gatagaggca cctattcttg cgtggtgcag aagaaagagc ggggcaccta cgaagtgaag 360
cacctggctc tggtcaagct gtccatcaag gccgacttca gcacccctaa catcaccgag 420
tctggcaacc cttccgccga caccaagaga atcacctgtt tcgcctctgg cggcttccct 480
aagcctcggt tctcttggct ggaaaacggc agagagctgc ccggcatcaa taccaccatt 540
tctcaggacc cagagtccga gctgtacacc atctccagcc agctcgactt taacaccacc 600
agaaaccaca ccatcaagtg cctgattaag tacggcgacg cccacgtgtc cgaggacttt 660
acttgggaga aacctcctga ggaccctcct gactctggat ctggcggcgg aggttctggc 720
ggaggtggaa gcggaggcgg aggatctgct gagtctaagt atggccctcc ttgtcctcca 780
tgtcctgctc cagaagctgc tggcggaccc tctgtgttcc tgtttcctcc aaagcctaag 840
gaccagctca tgatctctcg gacccctgaa gtgacctgcg tggtggtgga tgtgtctcaa 900
gaggaccctg aggtgcagtt caattggtac gtggacggcg tggaagtgca caacgccaag 960
accaagccta gagaggaaca gttcaactcc acctatagag tggtgtccgt gctgaccgtg 1020
ctgcaccagg attggctgaa cggcaaagag tacaagtgca aggtgtccaa caagggcctg 1080
ccttccagca tcgaaaagac catcagcaag gctaagggcc agcctaggga accccaggtt 1140
tacaccctgc ctccaagcca agaggaaatg accaagaacc aggtgtccct gacctgcctg 1200
gtcaagggct tctacccttc cgacattgcc gtggaatggg agtccaatgg ccagcctgag 1260
aacaactaca agaccacacc tcctgtgctg gactccgacg gctccttctt tctgtactct 1320
cgcctgaccg tggacaagtc taggtggcaa gagggcaacg tgttctcctg ctctgtgctg 1380
cacgaggctc tgcacaacca ctacacccag aagtccctgt ctctgtctct tggaggtggt 1440
ggcggttctg cccctacctc cagctctacc aagaaaaccc agctccagtt ggagcatctg 1500
ctgctggacc tccagatgat cctgaatggc atcaacaatt acaagaaccc caagctgacc 1560
gccatgctga ccgctaagtt ctacatgccc aagaaggcca ccgagctgaa gcacttgcag 1620
tgcctggaag aggaactgaa gcccctggaa gaagtgctga atctggccca gtccaagaac 1680
ttccacctga ggcctaggga cctgatctcc aacatcaacg tgatcgtgct ggaactgaaa 1740
ggctccgaga caaccttcat gtgcgagtac gccgacgaga cagccaccat cgtggaattt 1800
ctgaaccggt ggatcacctt ctgccagagc atcatctcca cactgacc 1848
<210> 15
<211> 616
<212> PRT
<213> Artificial Sequence(人工序列)
<220>
<223> 融合蛋白(mGI101)
<400> 15
Met Asp Ala Met Leu Arg Gly Leu Cys Cys Val Leu Leu Leu Cys Gly
1 5 10 15
Ala Val Phe Val Ser Pro Ser His Ala Val Asp Glu Gln Leu Ser Lys
20 25 30
Ser Val Lys Asp Lys Val Leu Leu Pro Cys Arg Tyr Asn Ser Pro His
35 40 45
Glu Asp Glu Ser Glu Asp Arg Ile Tyr Trp Gln Lys His Asp Lys Val
50 55 60
Val Leu Ser Val Ile Ala Gly Lys Leu Lys Val Trp Pro Glu Tyr Lys
65 70 75 80
Asn Arg Thr Leu Tyr Asp Asn Thr Thr Tyr Ser Leu Ile Ile Leu Gly
85 90 95
Leu Val Leu Ser Asp Arg Gly Thr Tyr Ser Cys Val Val Gln Lys Lys
100 105 110
Glu Arg Gly Thr Tyr Glu Val Lys His Leu Ala Leu Val Lys Leu Ser
115 120 125
Ile Lys Ala Asp Phe Ser Thr Pro Asn Ile Thr Glu Ser Gly Asn Pro
130 135 140
Ser Ala Asp Thr Lys Arg Ile Thr Cys Phe Ala Ser Gly Gly Phe Pro
145 150 155 160
Lys Pro Arg Phe Ser Trp Leu Glu Asn Gly Arg Glu Leu Pro Gly Ile
165 170 175
Asn Thr Thr Ile Ser Gln Asp Pro Glu Ser Glu Leu Tyr Thr Ile Ser
180 185 190
Ser Gln Leu Asp Phe Asn Thr Thr Arg Asn His Thr Ile Lys Cys Leu
195 200 205
Ile Lys Tyr Gly Asp Ala His Val Ser Glu Asp Phe Thr Trp Glu Lys
210 215 220
Pro Pro Glu Asp Pro Pro Asp Ser Gly Ser Gly Gly Gly Gly Ser Gly
225 230 235 240
Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu Ser Lys Tyr Gly Pro
245 250 255
Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val
260 265 270
Phe Leu Phe Pro Pro Lys Pro Lys Asp Gln Leu Met Ile Ser Arg Thr
275 280 285
Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu
290 295 300
Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
305 310 315 320
Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser
325 330 335
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
340 345 350
Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile
355 360 365
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
370 375 380
Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
385 390 395 400
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
405 410 415
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
420 425 430
Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg
435 440 445
Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Leu His Glu Ala Leu
450 455 460
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Gly Gly
465 470 475 480
Gly Gly Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln
485 490 495
Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn
500 505 510
Asn Tyr Lys Asn Pro Lys Leu Thr Ala Met Leu Thr Ala Lys Phe Tyr
515 520 525
Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu
530 535 540
Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn
545 550 555 560
Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val
565 570 575
Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp
580 585 590
Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys
595 600 605
Gln Ser Ile Ile Ser Thr Leu Thr
610 615
<210> 16
<211> 1437
<212> DNA
<213> Artificial Sequence(人工序列)
<220>
<223> 编码融合蛋白(GI101C1)的核苷酸
<400> 16
atggatgcta tgctgagagg cctgtgttgc gtgctgctgc tgtgtggcgc tgtgttcgtg 60
tctccttctc acgctgtgat ccacgtgacc aaagaagtga aagaggtcgc cacactgtcc 120
tgcggccaca acgtttcagt ggaagaactg gcccagacca ggatctactg gcagaaagaa 180
aagaaaatgg tgctgaccat gatgtccggc gacatgaaca tctggcctga gtacaagaac 240
cggaccatct tcgacatcac caacaacctg tccatcgtga ttctggccct gaggccttct 300
gatgagggca cctatgagtg cgtggtgctg aagtacgaga aggacgcctt caagcgcgag 360
cacctggctg aagtgacact gtccgtgaag gccgactttc ccacaccttc catctccgac 420
ttcgagatcc ctacctccaa catccggcgg atcatctgtt ctacctctgg cggctttcct 480
gagcctcacc tgtcttggct ggaaaacggc gaggaactga acgccatcaa caccaccgtg 540
tctcaggacc ccgaaaccga gctgtacgct gtgtcctcca agctggactt caacatgacc 600
accaaccaca gcttcatgtg cctgattaag tacggccacc tgagagtgaa ccagaccttc 660
aactggaaca ccaccaagca agagcacttc cctgacaatg gatctggcgg cggaggttct 720
ggcggaggtg gaagcggagg cggaggatct gctgagtcta agtatggccc tccttgtcct 780
ccatgtcctg ctccagaagc tgctggcgga ccctctgtgt tcctgtttcc tccaaagcct 840
aaggaccagc tcatgatctc tcggacaccc gaagtgacct gcgtggtggt ggatgtgtct 900
caagaggacc ctgaggtgca gttcaattgg tacgtggacg gcgtggaagt gcacaacgcc 960
aagaccaagc ctagagagga acagttcaac tccacctaca gagtggtgtc cgtgctgacc 1020
gtgctgcacc aggattggct gaacggcaaa gagtacaagt gcaaggtgtc caacaagggc 1080
ctgccttcca gcatcgaaaa gaccatctcc aaggctaagg gccagcctag ggaaccccag 1140
gtttacaccc tgcctccaag ccaagaggaa atgaccaaga accaggtgtc cctgacctgc 1200
ctggtcaagg gcttctaccc ttccgacatt gccgtggaat gggagtccaa tggccagcct 1260
gagaacaact acaagaccac acctcctgtg ctggactccg acggctcctt ctttctgtac 1320
tctcgcctga ccgtggacaa gtctaggtgg caagagggca acgtgttctc ctgctctgtg 1380
ctgcacgagg ccctgcacaa tcactacacc cagaagtccc tgtctctgtc cctgggc 1437
<210> 17
<211> 454
<212> PRT
<213> Artificial Sequence(人工序列)
<220>
<223> 融合蛋白(GI101C1)
<400> 17
Val Ile His Val Thr Lys Glu Val Lys Glu Val Ala Thr Leu Ser Cys
1 5 10 15
Gly His Asn Val Ser Val Glu Glu Leu Ala Gln Thr Arg Ile Tyr Trp
20 25 30
Gln Lys Glu Lys Lys Met Val Leu Thr Met Met Ser Gly Asp Met Asn
35 40 45
Ile Trp Pro Glu Tyr Lys Asn Arg Thr Ile Phe Asp Ile Thr Asn Asn
50 55 60
Leu Ser Ile Val Ile Leu Ala Leu Arg Pro Ser Asp Glu Gly Thr Tyr
65 70 75 80
Glu Cys Val Val Leu Lys Tyr Glu Lys Asp Ala Phe Lys Arg Glu His
85 90 95
Leu Ala Glu Val Thr Leu Ser Val Lys Ala Asp Phe Pro Thr Pro Ser
100 105 110
Ile Ser Asp Phe Glu Ile Pro Thr Ser Asn Ile Arg Arg Ile Ile Cys
115 120 125
Ser Thr Ser Gly Gly Phe Pro Glu Pro His Leu Ser Trp Leu Glu Asn
130 135 140
Gly Glu Glu Leu Asn Ala Ile Asn Thr Thr Val Ser Gln Asp Pro Glu
145 150 155 160
Thr Glu Leu Tyr Ala Val Ser Ser Lys Leu Asp Phe Asn Met Thr Thr
165 170 175
Asn His Ser Phe Met Cys Leu Ile Lys Tyr Gly His Leu Arg Val Asn
180 185 190
Gln Thr Phe Asn Trp Asn Thr Thr Lys Gln Glu His Phe Pro Asp Asn
195 200 205
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
210 215 220
Ser Ala Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
225 230 235 240
Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
245 250 255
Asp Gln Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
260 265 270
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
275 280 285
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
290 295 300
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
305 310 315 320
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
325 330 335
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
340 345 350
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
355 360 365
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
370 375 380
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
385 390 395 400
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
405 410 415
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
420 425 430
Cys Ser Val Leu His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
435 440 445
Leu Ser Leu Ser Leu Gly
450
<210> 18
<211> 1176
<212> DNA
<213> Artificial Sequence(人工序列)
<220>
<223> 编码融合蛋白(GI101C2)的核苷酸
<400> 18
atggatgcta tgctgagagg cctgtgttgc gtgctgctgc tgtgtggcgc tgtgttcgtg 60
tctccatctc acgccgctga gtctaagtac ggccctcctt gtcctccatg tcctgctcca 120
gaagctgctg gcggaccctc tgtgttcctg tttcctccaa agcctaagga ccagctcatg 180
atctctcgga cccctgaagt gacctgcgtg gtggtggatg tgtctcaaga ggaccctgag 240
gtgcagttca attggtacgt ggacggcgtg gaagtgcaca acgccaagac caagcctaga 300
gaggaacagt tcaactccac ctacagagtg gtgtccgtgc tgaccgtgct gcaccaggat 360
tggctgaacg gcaaagagta caagtgcaag gtgtccaaca agggcctgcc ttccagcatc 420
gaaaagacca tctccaaggc taagggccag cctagggaac cccaggttta caccctgcct 480
ccaagccaag aggaaatgac caagaaccag gtgtccctga cctgcctggt caagggcttc 540
tacccttccg acattgccgt ggaatgggag tccaatggcc agcctgagaa caactacaag 600
accacacctc ctgtgctgga ctccgacggc tccttctttc tgtactctcg cctgaccgtg 660
gacaagtcta ggtggcaaga gggcaacgtg ttctcctgct ctgtgctgca cgaggccctg 720
cacaatcact acacccagaa gtccctgtct ctgtctcttg gcggaggcgg aggatctgct 780
cctacctcca gctccaccaa gaaaacccag ctccagttgg agcatctgct gctggacctc 840
cagatgatcc tgaatggcat caacaattac aagaacccca agctgaccgc catgctgacc 900
gctaagttct acatgcccaa gaaggccacc gagctgaagc acctccagtg cctggaagag 960
gaactgaagc ccctggaaga agtgctgaat ctggcccagt ccaagaactt ccacctgagg 1020
cctagggacc tgatctccaa catcaacgtg atcgtgctgg aactgaaagg ctccgagaca 1080
accttcatgt gcgagtacgc cgacgagaca gccaccatcg tggaatttct gaaccggtgg 1140
atcaccttct gccagtccat catctccaca ctgacc 1176
<210> 19
<211> 367
<212> PRT
<213> Artificial Sequence(人工序列)
<220>
<223> 融合蛋白(GI101C2)
<400> 19
Ala Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu
1 5 10 15
Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
20 25 30
Gln Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
35 40 45
Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly
50 55 60
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn
65 70 75 80
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
85 90 95
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro
100 105 110
Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
115 120 125
Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn
130 135 140
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
145 150 155 160
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
165 170 175
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg
180 185 190
Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys
195 200 205
Ser Val Leu His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
210 215 220
Ser Leu Ser Leu Gly Gly Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser
225 230 235 240
Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln
245 250 255
Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Ala
260 265 270
Met Leu Thr Ala Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys
275 280 285
His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu
290 295 300
Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile
305 310 315 320
Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr
325 330 335
Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu
340 345 350
Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr
355 360 365
<210> 20
<211> 1434
<212> DNA
<213> Artificial Sequence(人工序列)
<220>
<223> 编码融合蛋白(mGI101C1)的核苷酸
<400> 20
atggatgcta tgctgagagg cctgtgttgc gtgctgctgc tgtgtggcgc tgtgttcgtg 60
tctccttctc acgctgtgga cgagcagctc tccaagtccg tgaaggataa ggtcctgctg 120
ccttgccggt acaactctcc tcacgaggac gagtctgagg accggatcta ctggcagaaa 180
cacgacaagg tggtgctgtc cgtgatcgcc ggaaagctga aagtgtggcc tgagtacaag 240
aacaggaccc tgtacgacaa caccacctac agcctgatca tcctgggcct cgtgctgagc 300
gatagaggca cctattcttg cgtggtgcag aagaaagagc ggggcaccta cgaagtgaag 360
cacctggctc tggtcaagct gtccatcaag gccgacttca gcacccctaa catcaccgag 420
tctggcaacc cttccgccga caccaagaga atcacctgtt tcgcctctgg cggcttccct 480
aagcctcggt tctcttggct ggaaaacggc agagagctgc ccggcatcaa taccaccatt 540
tctcaggacc cagagtccga gctgtacacc atctccagcc agctcgactt taacaccacc 600
agaaaccaca ccatcaagtg cctgattaag tacggcgacg cccacgtgtc cgaggacttt 660
acttgggaga aacctcctga ggaccctcct gactctggat ctggcggcgg aggttctggc 720
ggaggtggaa gcggaggcgg aggatctgct gagtctaagt atggccctcc ttgtcctcca 780
tgtcctgctc cagaagctgc tggcggaccc tctgtgttcc tgtttcctcc aaagcctaag 840
gaccagctca tgatctctcg gacccctgaa gtgacctgcg tggtggtgga tgtgtctcaa 900
gaggaccctg aggtgcagtt caattggtac gtggacggcg tggaagtgca caacgccaag 960
accaagccta gagaggaaca gttcaactcc acctatagag tggtgtccgt gctgaccgtg 1020
ctgcaccagg attggctgaa cggcaaagag tacaagtgca aggtgtccaa caagggcctg 1080
ccttccagca tcgaaaagac catcagcaag gctaagggcc agcctaggga accccaggtt 1140
tacaccctgc ctccaagcca agaggaaatg accaagaacc aggtgtccct gacctgcctg 1200
gtcaagggct tctacccttc cgacattgcc gtggaatggg agtccaatgg ccagcctgag 1260
aacaactaca agaccacacc tcctgtgctg gactccgacg gctccttctt tctgtactct 1320
cgcctgaccg tggacaagtc taggtggcaa gagggcaacg tgttctcctg ctctgtgctg 1380
cacgaggctc tgcacaacca ctacacccag aagtccctgt ctctgtccct gggc 1434
<210> 21
<211> 478
<212> PRT
<213> Artificial Sequence(人工序列)
<220>
<223> 融合蛋白(mGI101C1)
<400> 21
Met Asp Ala Met Leu Arg Gly Leu Cys Cys Val Leu Leu Leu Cys Gly
1 5 10 15
Ala Val Phe Val Ser Pro Ser His Ala Val Asp Glu Gln Leu Ser Lys
20 25 30
Ser Val Lys Asp Lys Val Leu Leu Pro Cys Arg Tyr Asn Ser Pro His
35 40 45
Glu Asp Glu Ser Glu Asp Arg Ile Tyr Trp Gln Lys His Asp Lys Val
50 55 60
Val Leu Ser Val Ile Ala Gly Lys Leu Lys Val Trp Pro Glu Tyr Lys
65 70 75 80
Asn Arg Thr Leu Tyr Asp Asn Thr Thr Tyr Ser Leu Ile Ile Leu Gly
85 90 95
Leu Val Leu Ser Asp Arg Gly Thr Tyr Ser Cys Val Val Gln Lys Lys
100 105 110
Glu Arg Gly Thr Tyr Glu Val Lys His Leu Ala Leu Val Lys Leu Ser
115 120 125
Ile Lys Ala Asp Phe Ser Thr Pro Asn Ile Thr Glu Ser Gly Asn Pro
130 135 140
Ser Ala Asp Thr Lys Arg Ile Thr Cys Phe Ala Ser Gly Gly Phe Pro
145 150 155 160
Lys Pro Arg Phe Ser Trp Leu Glu Asn Gly Arg Glu Leu Pro Gly Ile
165 170 175
Asn Thr Thr Ile Ser Gln Asp Pro Glu Ser Glu Leu Tyr Thr Ile Ser
180 185 190
Ser Gln Leu Asp Phe Asn Thr Thr Arg Asn His Thr Ile Lys Cys Leu
195 200 205
Ile Lys Tyr Gly Asp Ala His Val Ser Glu Asp Phe Thr Trp Glu Lys
210 215 220
Pro Pro Glu Asp Pro Pro Asp Ser Gly Ser Gly Gly Gly Gly Ser Gly
225 230 235 240
Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu Ser Lys Tyr Gly Pro
245 250 255
Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val
260 265 270
Phe Leu Phe Pro Pro Lys Pro Lys Asp Gln Leu Met Ile Ser Arg Thr
275 280 285
Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu
290 295 300
Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
305 310 315 320
Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser
325 330 335
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
340 345 350
Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile
355 360 365
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
370 375 380
Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
385 390 395 400
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
405 410 415
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
420 425 430
Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg
435 440 445
Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Leu His Glu Ala Leu
450 455 460
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly
465 470 475
<210> 22
<211> 133
<212> PRT
<213> Artificial Sequence(人工序列)
<220>
<223> IL-2变体:IL-2(3M, M45)
<400> 22
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Ala Met Leu Thr Ala Lys Phe Ala Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 23
<211> 133
<212> PRT
<213> Artificial Sequence(人工序列)
<220>
<223> IL-2变体:IL-2(3M, M61)
<400> 23
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Ala Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 24
<211> 133
<212> PRT
<213> Artificial Sequence(人工序列)
<220>
<223> IL-变体:IL-2(3M, M72)
<400> 24
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Ala Met Leu Thr Ala Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Gly Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 25
<211> 1851
<212> DNA
<213> Artificial Sequence(人工序列)
<220>
<223> 编码融合蛋白(GI102-M45)的核苷酸
<400> 25
atggatgcta tgctgagagg cctgtgttgc gtgctgctgc tgtgtggcgc tgtgttcgtg 60
tctccttctc acgctgtgat ccacgtgacc aaagaagtga aagaggtcgc cacactgtcc 120
tgcggccaca acgtttcagt ggaagaactg gcccagacca ggatctactg gcagaaagaa 180
aagaaaatgg tgctgaccat gatgtccggc gacatgaaca tctggcctga gtacaagaac 240
cggaccatct tcgacatcac caacaacctg tccatcgtga ttctggccct gaggccttct 300
gatgagggca cctatgagtg cgtggtgctg aagtacgaga aggacgcctt caagcgcgag 360
cacctggctg aagtgacact gtccgtgaag gccgactttc ccacaccttc catctccgac 420
ttcgagatcc ctacctccaa catccggcgg atcatctgtt ctacctctgg cggctttcct 480
gagcctcacc tgtcttggct ggaaaacggc gaggaactga acgccatcaa caccaccgtg 540
tctcaggacc ccgaaaccga gctgtacgct gtgtcctcca agctggactt caacatgacc 600
accaaccaca gcttcatgtg cctgattaag tacggccacc tgagagtgaa ccagaccttc 660
aactggaaca ccaccaagca agagcacttc cctgacaatg gatctggcgg cggaggttct 720
ggcggaggtg gaagcggagg cggaggatct gctgagtcta agtatggccc tccttgtcct 780
ccatgtcctg ctccagaagc tgctggcgga ccctctgtgt tcctgtttcc tccaaagcct 840
aaggaccagc tcatgatctc tcggacaccc gaagtgacct gcgtggtggt ggatgtgtct 900
caagaggacc ctgaggtgca gttcaattgg tacgtggacg gcgtggaagt gcacaacgcc 960
aagaccaagc ctagagagga acagttcaac tccacctaca gagtggtgtc cgtgctgacc 1020
gtgctgcacc aggattggct gaacggcaaa gagtacaagt gcaaggtgtc caacaagggc 1080
ctgccttcca gcatcgaaaa gaccatctcc aaggctaagg gccagcctag ggaaccccag 1140
gtttacaccc tgcctccaag ccaagaggaa atgaccaaga accaggtgtc cctgacctgc 1200
ctggtcaagg gcttctaccc ttccgacatt gccgtggaat gggagtccaa tggccagcct 1260
gagaacaact acaagaccac acctcctgtg ctggactccg acggctcctt ctttctgtac 1320
tctcgcctga ccgtggacaa gtctagatgg caagagggca acgtgttctc ctgctctgtg 1380
ctgcacgagg ccctgcacaa tcactacacc cagaagtccc tgtctctgtc tcttggaggt 1440
ggtggcggtt ctgcccctac cagctcctct accaagaaaa cccagctcca gttggagcat 1500
ctgctgctgg acctccagat gattctgaac gggatcaaca actataagaa ccccaagctg 1560
accgccatgc tgaccgctaa gttcgccatg cccaagaagg ccaccgagct gaagcacctc 1620
cagtgcctgg aagaagaact gaagcccctg gaagaggtgc tgaatctggc ccagtccaag 1680
aacttccacc tgaggccacg ggacctgatc agcaacatca acgtgatcgt gctggaactg 1740
aagggctccg agacaacctt tatgtgcgag tacgccgacg agacagccac catcgtggaa 1800
tttctgaacc ggtggatcac cttctgccag agcatcatct ccacactgac c 1851
<210> 26
<211> 592
<212> PRT
<213> Artificial Sequence(人工序列)
<220>
<223> 融合蛋白(GI102-M45)
<400> 26
Val Ile His Val Thr Lys Glu Val Lys Glu Val Ala Thr Leu Ser Cys
1 5 10 15
Gly His Asn Val Ser Val Glu Glu Leu Ala Gln Thr Arg Ile Tyr Trp
20 25 30
Gln Lys Glu Lys Lys Met Val Leu Thr Met Met Ser Gly Asp Met Asn
35 40 45
Ile Trp Pro Glu Tyr Lys Asn Arg Thr Ile Phe Asp Ile Thr Asn Asn
50 55 60
Leu Ser Ile Val Ile Leu Ala Leu Arg Pro Ser Asp Glu Gly Thr Tyr
65 70 75 80
Glu Cys Val Val Leu Lys Tyr Glu Lys Asp Ala Phe Lys Arg Glu His
85 90 95
Leu Ala Glu Val Thr Leu Ser Val Lys Ala Asp Phe Pro Thr Pro Ser
100 105 110
Ile Ser Asp Phe Glu Ile Pro Thr Ser Asn Ile Arg Arg Ile Ile Cys
115 120 125
Ser Thr Ser Gly Gly Phe Pro Glu Pro His Leu Ser Trp Leu Glu Asn
130 135 140
Gly Glu Glu Leu Asn Ala Ile Asn Thr Thr Val Ser Gln Asp Pro Glu
145 150 155 160
Thr Glu Leu Tyr Ala Val Ser Ser Lys Leu Asp Phe Asn Met Thr Thr
165 170 175
Asn His Ser Phe Met Cys Leu Ile Lys Tyr Gly His Leu Arg Val Asn
180 185 190
Gln Thr Phe Asn Trp Asn Thr Thr Lys Gln Glu His Phe Pro Asp Asn
195 200 205
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
210 215 220
Ser Ala Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
225 230 235 240
Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
245 250 255
Asp Gln Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
260 265 270
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
275 280 285
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
290 295 300
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
305 310 315 320
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
325 330 335
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
340 345 350
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
355 360 365
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
370 375 380
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
385 390 395 400
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
405 410 415
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
420 425 430
Cys Ser Val Leu His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
435 440 445
Leu Ser Leu Ser Leu Gly Gly Gly Gly Gly Ser Ala Pro Thr Ser Ser
450 455 460
Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu
465 470 475 480
Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr
485 490 495
Ala Met Leu Thr Ala Lys Phe Ala Met Pro Lys Lys Ala Thr Glu Leu
500 505 510
Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val
515 520 525
Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu
530 535 540
Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr
545 550 555 560
Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe
565 570 575
Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr
580 585 590
<210> 27
<211> 1851
<212> DNA
<213> Artificial Sequence(人工序列)
<220>
<223> 编码融合蛋白(GI102-M61)的核苷酸
<400> 27
atggatgcta tgctgagagg cctgtgttgc gtgctgctgc tgtgtggcgc tgtgttcgtg 60
tctccttctc acgctgtgat ccacgtgacc aaagaagtga aagaggtcgc cacactgtcc 120
tgcggccaca acgtttcagt ggaagaactg gcccagacca ggatctactg gcagaaagaa 180
aagaaaatgg tgctgaccat gatgtccggc gacatgaaca tctggcctga gtacaagaac 240
cggaccatct tcgacatcac caacaacctg tccatcgtga ttctggccct gaggccttct 300
gatgagggca cctatgagtg cgtggtgctg aagtacgaga aggacgcctt caagcgcgag 360
cacctggctg aagtgacact gtccgtgaag gccgactttc ccacaccttc catctccgac 420
ttcgagatcc ctacctccaa catccggcgg atcatctgtt ctacctctgg cggctttcct 480
gagcctcacc tgtcttggct ggaaaacggc gaggaactga acgccatcaa caccaccgtg 540
tctcaggacc ccgaaaccga gctgtacgct gtgtcctcca agctggactt caacatgacc 600
accaaccaca gcttcatgtg cctgattaag tacggccacc tgagagtgaa ccagaccttc 660
aactggaaca ccaccaagca agagcacttc cctgacaatg gatctggcgg cggaggttct 720
ggcggaggtg gaagcggagg cggaggatct gctgagtcta agtatggccc tccttgtcct 780
ccatgtcctg ctccagaagc tgctggcgga ccctctgtgt tcctgtttcc tccaaagcct 840
aaggaccagc tcatgatctc tcggacaccc gaagtgacct gcgtggtggt ggatgtgtct 900
caagaggacc ctgaggtgca gttcaattgg tacgtggacg gcgtggaagt gcacaacgcc 960
aagaccaagc ctagagagga acagttcaac tccacctaca gagtggtgtc cgtgctgacc 1020
gtgctgcacc aggattggct gaacggcaaa gagtacaagt gcaaggtgtc caacaagggc 1080
ctgccttcca gcatcgaaaa gaccatctcc aaggctaagg gccagcctag ggaaccccag 1140
gtttacaccc tgcctccaag ccaagaggaa atgaccaaga accaggtgtc cctgacctgc 1200
ctggtcaagg gcttctaccc ttccgacatt gccgtggaat gggagtccaa tggccagcct 1260
gagaacaact acaagaccac acctcctgtg ctggactccg acggctcctt ctttctgtac 1320
tctcgcctga ccgtggacaa gtctagatgg caagagggca acgtgttctc ctgctctgtg 1380
ctgcacgagg ccctgcacaa tcactacacc cagaagtccc tgtctctgtc tcttggaggt 1440
ggtggcggtt ctgcccctac cagctcctct accaagaaaa cccagctcca gttggagcat 1500
ctgctgctgg acctccagat gattctgaac gggatcaaca actataagaa ccccaagctg 1560
accgccatgc tgaccgctaa gttctacatg cccaagaagg ccaccgagct gaagcacctc 1620
cagtgcctgg aaagggaact gaagcccctg gaagaggtgc tgaatctggc ccagtccaag 1680
aacttccacc tgaggccacg ggacctgatc agcaacatca acgtgatcgt gctggaactg 1740
aagggctccg agacaacctt tatgtgcgag tacgccgacg agacagccac catcgtggaa 1800
tttctgaacc ggtggatcac cttctgccag agcatcatct ccacactgac c 1851
<210> 28
<211> 592
<212> PRT
<213> Artificial Sequence(人工序列)
<220>
<223> 融合蛋白(GI102-M61)
<400> 28
Val Ile His Val Thr Lys Glu Val Lys Glu Val Ala Thr Leu Ser Cys
1 5 10 15
Gly His Asn Val Ser Val Glu Glu Leu Ala Gln Thr Arg Ile Tyr Trp
20 25 30
Gln Lys Glu Lys Lys Met Val Leu Thr Met Met Ser Gly Asp Met Asn
35 40 45
Ile Trp Pro Glu Tyr Lys Asn Arg Thr Ile Phe Asp Ile Thr Asn Asn
50 55 60
Leu Ser Ile Val Ile Leu Ala Leu Arg Pro Ser Asp Glu Gly Thr Tyr
65 70 75 80
Glu Cys Val Val Leu Lys Tyr Glu Lys Asp Ala Phe Lys Arg Glu His
85 90 95
Leu Ala Glu Val Thr Leu Ser Val Lys Ala Asp Phe Pro Thr Pro Ser
100 105 110
Ile Ser Asp Phe Glu Ile Pro Thr Ser Asn Ile Arg Arg Ile Ile Cys
115 120 125
Ser Thr Ser Gly Gly Phe Pro Glu Pro His Leu Ser Trp Leu Glu Asn
130 135 140
Gly Glu Glu Leu Asn Ala Ile Asn Thr Thr Val Ser Gln Asp Pro Glu
145 150 155 160
Thr Glu Leu Tyr Ala Val Ser Ser Lys Leu Asp Phe Asn Met Thr Thr
165 170 175
Asn His Ser Phe Met Cys Leu Ile Lys Tyr Gly His Leu Arg Val Asn
180 185 190
Gln Thr Phe Asn Trp Asn Thr Thr Lys Gln Glu His Phe Pro Asp Asn
195 200 205
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
210 215 220
Ser Ala Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
225 230 235 240
Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
245 250 255
Asp Gln Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
260 265 270
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
275 280 285
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
290 295 300
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
305 310 315 320
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
325 330 335
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
340 345 350
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
355 360 365
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
370 375 380
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
385 390 395 400
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
405 410 415
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
420 425 430
Cys Ser Val Leu His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
435 440 445
Leu Ser Leu Ser Leu Gly Gly Gly Gly Gly Ser Ala Pro Thr Ser Ser
450 455 460
Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu
465 470 475 480
Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr
485 490 495
Ala Met Leu Thr Ala Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu
500 505 510
Lys His Leu Gln Cys Leu Glu Arg Glu Leu Lys Pro Leu Glu Glu Val
515 520 525
Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu
530 535 540
Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr
545 550 555 560
Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe
565 570 575
Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr
580 585 590
<210> 29
<211> 1857
<212> DNA
<213> Artificial Sequence(人工序列)
<220>
<223> 编码融合蛋白(GI102-M72)的核苷酸
<400> 29
atggatgcta tgctgagagg cctgtgttgc gtgctgctgc tgtgtggcgc tgtgttcgtg 60
tctccttctc acgctgtgat ccacgtgacc aaagaagtga aagaggtcgc cacactgtcc 120
tgcggccaca acgtttcagt ggaagaactg gcccagacca ggatctactg gcagaaagaa 180
aagaaaatgg tgctgaccat gatgtccggc gacatgaaca tctggcctga gtacaagaac 240
cggaccatct tcgacatcac caacaacctg tccatcgtga ttctggccct gaggccttct 300
gatgagggca cctatgagtg cgtggtgctg aagtacgaga aggacgcctt caagcgcgag 360
cacctggctg aagtgacact gtccgtgaag gccgactttc ccacaccttc catctccgac 420
ttcgagatcc ctacctccaa catccggcgg atcatctgtt ctacctctgg cggctttcct 480
gagcctcacc tgtcttggct ggaaaacggc gaggaactga acgccatcaa caccaccgtg 540
tctcaggacc ccgaaaccga gctgtacgct gtgtcctcca agctggactt caacatgacc 600
accaaccaca gcttcatgtg cctgattaag tacggccacc tgagagtgaa ccagaccttc 660
aactggaaca ccaccaagca agagcacttc cctgacaatg gatctggcgg cggaggttct 720
ggcggaggtg gaagcggagg cggaggatct gctgagtcta agtatggccc tccttgtcct 780
ccatgtcctg ctccagaagc tgctggcgga ccctctgtgt tcctgtttcc tccaaagcct 840
aaggaccagc tcatgatctc tcggacaccc gaagtgacct gcgtggtggt ggatgtgtct 900
caagaggacc ctgaggtgca gttcaattgg tacgtggacg gcgtggaagt gcacaacgcc 960
aagaccaagc ctagagagga acagttcaac tccacctaca gagtggtgtc cgtgctgacc 1020
gtgctgcacc aggattggct gaacggcaaa gagtacaagt gcaaggtgtc caacaagggc 1080
ctgccttcca gcatcgaaaa gaccatctcc aaggctaagg gccagcctag ggaaccccag 1140
gtttacaccc tgcctccaag ccaagaggaa atgaccaaga accaggtgtc cctgacctgc 1200
ctggtcaagg gcttctaccc ttccgacatt gccgtggaat gggagtccaa tggccagcct 1260
gagaacaact acaagaccac acctcctgtg ctggactccg acggctcctt ctttctgtac 1320
tctcgcctga ccgtggacaa gtctagatgg caagagggca acgtgttctc ctgctctgtg 1380
ctgcacgagg ccctgcacaa tcactacacc cagaagtccc tgtctctgtc tcttggaggt 1440
ggtggcggtt ctgcccctac cagctcctct accaagaaaa cccagctcca gttggagcat 1500
ctgctgctgg acctccagat gattctgaac gggatcaaca actataagaa ccccaagctg 1560
accgccatgc tgaccgctaa gttctacatg cccaagaagg ccaccgagct gaagcacctc 1620
cagtgcctgg aagaagaact gaagcccctg gaagaggtgc tgaatggggc ccagtccaag 1680
aacttccacc tgaggccacg ggacctgatc agcaacatca acgtgatcgt gctggaactg 1740
aagggctccg agacaacctt tatgtgcgag tacgccgacg agacagccac catcgtggaa 1800
tttctgaacc ggtggatcac cttctgccag agcatcatct ccacactgac ctgatga 1857
<210> 30
<211> 592
<212> PRT
<213> Artificial Sequence(人工序列)
<220>
<223> 融合蛋白(GI102-M72)
<400> 30
Val Ile His Val Thr Lys Glu Val Lys Glu Val Ala Thr Leu Ser Cys
1 5 10 15
Gly His Asn Val Ser Val Glu Glu Leu Ala Gln Thr Arg Ile Tyr Trp
20 25 30
Gln Lys Glu Lys Lys Met Val Leu Thr Met Met Ser Gly Asp Met Asn
35 40 45
Ile Trp Pro Glu Tyr Lys Asn Arg Thr Ile Phe Asp Ile Thr Asn Asn
50 55 60
Leu Ser Ile Val Ile Leu Ala Leu Arg Pro Ser Asp Glu Gly Thr Tyr
65 70 75 80
Glu Cys Val Val Leu Lys Tyr Glu Lys Asp Ala Phe Lys Arg Glu His
85 90 95
Leu Ala Glu Val Thr Leu Ser Val Lys Ala Asp Phe Pro Thr Pro Ser
100 105 110
Ile Ser Asp Phe Glu Ile Pro Thr Ser Asn Ile Arg Arg Ile Ile Cys
115 120 125
Ser Thr Ser Gly Gly Phe Pro Glu Pro His Leu Ser Trp Leu Glu Asn
130 135 140
Gly Glu Glu Leu Asn Ala Ile Asn Thr Thr Val Ser Gln Asp Pro Glu
145 150 155 160
Thr Glu Leu Tyr Ala Val Ser Ser Lys Leu Asp Phe Asn Met Thr Thr
165 170 175
Asn His Ser Phe Met Cys Leu Ile Lys Tyr Gly His Leu Arg Val Asn
180 185 190
Gln Thr Phe Asn Trp Asn Thr Thr Lys Gln Glu His Phe Pro Asp Asn
195 200 205
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
210 215 220
Ser Ala Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
225 230 235 240
Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
245 250 255
Asp Gln Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
260 265 270
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
275 280 285
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
290 295 300
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
305 310 315 320
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
325 330 335
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
340 345 350
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
355 360 365
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
370 375 380
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
385 390 395 400
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
405 410 415
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
420 425 430
Cys Ser Val Leu His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
435 440 445
Leu Ser Leu Ser Leu Gly Gly Gly Gly Gly Ser Ala Pro Thr Ser Ser
450 455 460
Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu
465 470 475 480
Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr
485 490 495
Ala Met Leu Thr Ala Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu
500 505 510
Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val
515 520 525
Leu Asn Gly Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu
530 535 540
Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr
545 550 555 560
Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe
565 570 575
Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr
580 585 590
<210> 31
<211> 1851
<212> DNA
<213> Artificial Sequence(人工序列)
<220>
<223> 编码融合蛋白(GI101w)的核苷酸
<400> 31
atggatgcta tgctgagagg cctgtgttgc gtgctgctgc tgtgtggcgc tgtgttcgtg 60
tctccttctc acgctgtgat ccacgtgacc aaagaagtga aagaggtcgc cacactgtcc 120
tgcggccaca acgtttcagt ggaagaactg gcccagacca ggatctactg gcagaaagaa 180
aagaaaatgg tgctgaccat gatgtccggc gacatgaaca tctggcctga gtacaagaac 240
cggaccatct tcgacatcac caacaacctg tccatcgtga ttctggccct gaggccttct 300
gatgagggca cctatgagtg cgtggtgctg aagtacgaga aggacgcctt caagcgcgag 360
cacctggctg aagtgacact gtccgtgaag gccgactttc ccacaccttc catctccgac 420
ttcgagatcc ctacctccaa catccggcgg atcatctgtt ctacctctgg cggctttcct 480
gagcctcacc tgtcttggct ggaaaacggc gaggaactga acgccatcaa caccaccgtg 540
tctcaggacc ccgaaaccga gctgtacgct gtgtcctcca agctggactt caacatgacc 600
accaaccaca gcttcatgtg cctgattaag tacggccacc tgagagtgaa ccagaccttc 660
aactggaaca ccaccaagca agagcacttc cctgacaatg gatctggcgg cggaggttct 720
ggcggaggtg gaagcggagg cggaggatct gctgagtcta agtatggccc tccttgtcct 780
ccatgtcctg ctccagaagc tgctggcgga ccctctgtgt tcctgtttcc tccaaagcct 840
aaggaccagc tcatgatctc tcggacaccc gaagtgacct gcgtggtggt ggatgtgtct 900
caagaggacc ctgaggtgca gttcaattgg tacgtggacg gcgtggaagt gcacaacgcc 960
aagaccaagc ctagagagga acagttcaac tccacctaca gagtggtgtc cgtgctgacc 1020
gtgctgcacc aggattggct gaacggcaaa gagtacaagt gcaaggtgtc caacaagggc 1080
ctgccttcca gcatcgaaaa gaccatctcc aaggctaagg gccagcctag ggaaccccag 1140
gtttacaccc tgcctccaag ccaagaggaa atgaccaaga accaggtgtc cctgacctgc 1200
ctggtcaagg gcttctaccc ttccgacatt gccgtggaat gggagtccaa tggccagcct 1260
gagaacaact acaagaccac acctcctgtg ctggactccg acggctcctt ctttctgtac 1320
tctcgcctga ccgtggacaa gtctagatgg caagagggca acgtgttctc ctgctctgtg 1380
ctgcacgagg ccctgcacaa tcactacacc cagaagtccc tgtctctgtc tcttggaggt 1440
ggtggcggtt ctgcccctac cagctcctct accaagaaaa cccagctcca gttggagcat 1500
ctgctgctgg acctccagat gattctgaac gggatcaaca actataagaa ccccaagctg 1560
acccgcatgc tgacctttaa gttctacatg cccaagaagg ccaccgagct gaagcacctc 1620
cagtgcctgg aagaagaact gaagcccctg gaagaggtgc tgaatctggc ccagtccaag 1680
aacttccacc tgaggccacg ggacctgatc agcaacatca acgtgatcgt gctggaactg 1740
aagggctccg agacaacctt tatgtgcgag tacgccgacg agacagccac catcgtggaa 1800
tttctgaacc ggtggatcac cttctgccag agcatcatct ccacactgac c 1851
<210> 32
<211> 592
<212> PRT
<213> Artificial Sequence(人工序列)
<220>
<223> 融合蛋白(GI101w)
<400> 32
Val Ile His Val Thr Lys Glu Val Lys Glu Val Ala Thr Leu Ser Cys
1 5 10 15
Gly His Asn Val Ser Val Glu Glu Leu Ala Gln Thr Arg Ile Tyr Trp
20 25 30
Gln Lys Glu Lys Lys Met Val Leu Thr Met Met Ser Gly Asp Met Asn
35 40 45
Ile Trp Pro Glu Tyr Lys Asn Arg Thr Ile Phe Asp Ile Thr Asn Asn
50 55 60
Leu Ser Ile Val Ile Leu Ala Leu Arg Pro Ser Asp Glu Gly Thr Tyr
65 70 75 80
Glu Cys Val Val Leu Lys Tyr Glu Lys Asp Ala Phe Lys Arg Glu His
85 90 95
Leu Ala Glu Val Thr Leu Ser Val Lys Ala Asp Phe Pro Thr Pro Ser
100 105 110
Ile Ser Asp Phe Glu Ile Pro Thr Ser Asn Ile Arg Arg Ile Ile Cys
115 120 125
Ser Thr Ser Gly Gly Phe Pro Glu Pro His Leu Ser Trp Leu Glu Asn
130 135 140
Gly Glu Glu Leu Asn Ala Ile Asn Thr Thr Val Ser Gln Asp Pro Glu
145 150 155 160
Thr Glu Leu Tyr Ala Val Ser Ser Lys Leu Asp Phe Asn Met Thr Thr
165 170 175
Asn His Ser Phe Met Cys Leu Ile Lys Tyr Gly His Leu Arg Val Asn
180 185 190
Gln Thr Phe Asn Trp Asn Thr Thr Lys Gln Glu His Phe Pro Asp Asn
195 200 205
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
210 215 220
Ser Ala Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
225 230 235 240
Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
245 250 255
Asp Gln Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
260 265 270
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
275 280 285
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
290 295 300
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
305 310 315 320
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
325 330 335
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
340 345 350
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
355 360 365
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
370 375 380
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
385 390 395 400
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
405 410 415
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
420 425 430
Cys Ser Val Leu His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
435 440 445
Leu Ser Leu Ser Leu Gly Gly Gly Gly Gly Ser Ala Pro Thr Ser Ser
450 455 460
Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu
465 470 475 480
Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr
485 490 495
Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu
500 505 510
Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val
515 520 525
Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu
530 535 540
Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr
545 550 555 560
Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe
565 570 575
Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr
580 585 590
<210> 33
<211> 1848
<212> DNA
<213> Artificial Sequence(人工序列)
<220>
<223> 编码融合蛋白(mGI102-M61)的核苷酸
<400> 33
atggatgcta tgctgagagg cctgtgttgc gtgctgctgc tgtgtggcgc tgtgttcgtg 60
tctccttctc acgctgtgga cgagcagctc tccaagtccg tgaaggataa ggtcctgctg 120
ccttgccggt acaactctcc tcacgaggac gagtctgagg accggatcta ctggcagaaa 180
cacgacaagg tggtgctgtc cgtgatcgcc ggaaagctga aagtgtggcc tgagtacaag 240
aacaggaccc tgtacgacaa caccacctac agcctgatca tcctgggcct cgtgctgagc 300
gatagaggca cctattcttg cgtggtgcag aagaaagagc ggggcaccta cgaagtgaag 360
cacctggctc tggtcaagct gtccatcaag gccgacttca gcacccctaa catcaccgag 420
tctggcaacc cttccgccga caccaagaga atcacctgtt tcgcctctgg cggcttccct 480
aagcctcggt tctcttggct ggaaaacggc agagagctgc ccggcatcaa taccaccatt 540
tctcaggacc cagagtccga gctgtacacc atctccagcc agctcgactt taacaccacc 600
agaaaccaca ccatcaagtg cctgattaag tacggcgacg cccacgtgtc cgaggacttt 660
acttgggaga aacctcctga ggaccctcct gactctggat ctggcggcgg aggttctggc 720
ggaggtggaa gcggaggcgg aggatctgct gagtctaagt atggccctcc ttgtcctcca 780
tgtcctgctc cagaagctgc tggcggaccc tctgtgttcc tgtttcctcc aaagcctaag 840
gaccagctca tgatctctcg gacccctgaa gtgacctgcg tggtggtgga tgtgtctcaa 900
gaggaccctg aggtgcagtt caattggtac gtggacggcg tggaagtgca caacgccaag 960
accaagccta gagaggaaca gttcaactcc acctatagag tggtgtccgt gctgaccgtg 1020
ctgcaccagg attggctgaa cggcaaagag tacaagtgca aggtgtccaa caagggcctg 1080
ccttccagca tcgaaaagac catcagcaag gctaagggcc agcctaggga accccaggtt 1140
tacaccctgc ctccaagcca agaggaaatg accaagaacc aggtgtccct gacctgcctg 1200
gtcaagggct tctacccttc cgacattgcc gtggaatggg agtccaatgg ccagcctgag 1260
aacaactaca agaccacacc tcctgtgctg gactccgacg gctccttctt tctgtactct 1320
cgcctgaccg tggacaagtc taggtggcaa gagggcaacg tgttctcctg ctctgtgctg 1380
cacgaggctc tgcacaacca ctacacccag aagtccctgt ctctgtctct tggaggtggt 1440
ggcggttctg cccctacctc cagctctacc aagaaaaccc agctccagtt ggagcatctg 1500
ctgctggacc tccagatgat cctgaatggc atcaacaatt acaagaaccc caagctgacc 1560
gccatgctga ccgctaagtt ctacatgccc aagaaggcca ccgagctgaa gcacttgcag 1620
tgcctggaaa gggaactgaa gcccctggaa gaagtgctga atctggccca gtccaagaac 1680
ttccacctga ggcctaggga cctgatctcc aacatcaacg tgatcgtgct ggaactgaaa 1740
ggctccgaga caaccttcat gtgcgagtac gccgacgaga cagccaccat cgtggaattt 1800
ctgaaccggt ggatcacctt ctgccagagc atcatctcca cactgacc 1848
<210> 34
<211> 616
<212> PRT
<213> Artificial Sequence(人工序列)
<220>
<223> 融合蛋白(mGI102-M61)
<400> 34
Met Asp Ala Met Leu Arg Gly Leu Cys Cys Val Leu Leu Leu Cys Gly
1 5 10 15
Ala Val Phe Val Ser Pro Ser His Ala Val Asp Glu Gln Leu Ser Lys
20 25 30
Ser Val Lys Asp Lys Val Leu Leu Pro Cys Arg Tyr Asn Ser Pro His
35 40 45
Glu Asp Glu Ser Glu Asp Arg Ile Tyr Trp Gln Lys His Asp Lys Val
50 55 60
Val Leu Ser Val Ile Ala Gly Lys Leu Lys Val Trp Pro Glu Tyr Lys
65 70 75 80
Asn Arg Thr Leu Tyr Asp Asn Thr Thr Tyr Ser Leu Ile Ile Leu Gly
85 90 95
Leu Val Leu Ser Asp Arg Gly Thr Tyr Ser Cys Val Val Gln Lys Lys
100 105 110
Glu Arg Gly Thr Tyr Glu Val Lys His Leu Ala Leu Val Lys Leu Ser
115 120 125
Ile Lys Ala Asp Phe Ser Thr Pro Asn Ile Thr Glu Ser Gly Asn Pro
130 135 140
Ser Ala Asp Thr Lys Arg Ile Thr Cys Phe Ala Ser Gly Gly Phe Pro
145 150 155 160
Lys Pro Arg Phe Ser Trp Leu Glu Asn Gly Arg Glu Leu Pro Gly Ile
165 170 175
Asn Thr Thr Ile Ser Gln Asp Pro Glu Ser Glu Leu Tyr Thr Ile Ser
180 185 190
Ser Gln Leu Asp Phe Asn Thr Thr Arg Asn His Thr Ile Lys Cys Leu
195 200 205
Ile Lys Tyr Gly Asp Ala His Val Ser Glu Asp Phe Thr Trp Glu Lys
210 215 220
Pro Pro Glu Asp Pro Pro Asp Ser Gly Ser Gly Gly Gly Gly Ser Gly
225 230 235 240
Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu Ser Lys Tyr Gly Pro
245 250 255
Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val
260 265 270
Phe Leu Phe Pro Pro Lys Pro Lys Asp Gln Leu Met Ile Ser Arg Thr
275 280 285
Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu
290 295 300
Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
305 310 315 320
Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser
325 330 335
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
340 345 350
Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile
355 360 365
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
370 375 380
Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
385 390 395 400
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
405 410 415
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
420 425 430
Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg
435 440 445
Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Leu His Glu Ala Leu
450 455 460
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Gly Gly
465 470 475 480
Gly Gly Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln
485 490 495
Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn
500 505 510
Asn Tyr Lys Asn Pro Lys Leu Thr Ala Met Leu Thr Ala Lys Phe Tyr
515 520 525
Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Arg
530 535 540
Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn
545 550 555 560
Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val
565 570 575
Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp
580 585 590
Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys
595 600 605
Gln Ser Ile Ile Ser Thr Leu Thr
610 615
<210> 35
<211> 153
<212> PRT
<213> Artificial Sequence(人工序列)
<220>
<223> 野生型 hIL-2
<400> 35
Met Tyr Arg Met Gln Leu Leu Ser Cys Ile Ala Leu Ser Leu Ala Leu
1 5 10 15
Val Thr Asn Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu
20 25 30
Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile
35 40 45
Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe
50 55 60
Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu
65 70 75 80
Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys
85 90 95
Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile
100 105 110
Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala
115 120 125
Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe
130 135 140
Cys Gln Ser Ile Ile Ser Thr Leu Thr
145 150
<210> 36
<211> 158
<212> PRT
<213> Artificial Sequence(人工序列)
<220>
<223> 带有信号序列的IL-2
<400> 36
Met Asp Ala Met Leu Arg Gly Leu Cys Cys Val Leu Leu Leu Cys Gly
1 5 10 15
Ala Val Phe Val Ser Pro Ser His Ala Ala Pro Thr Ser Ser Ser Thr
20 25 30
Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met
35 40 45
Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met
50 55 60
Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His
65 70 75 80
Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn
85 90 95
Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser
100 105 110
Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe
115 120 125
Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn
130 135 140
Arg Trp Ile Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr
145 150 155
<210> 37
<211> 474
<212> DNA
<213> Artificial Sequence(人工序列)
<220>
<223> 编码带有信号序列的IL-2的核苷酸序列
<400> 37
atggatgcta tgctgagagg cctgtgttgc gtgctgctgc tgtgtggcgc tgtgttcgtg 60
tctccttctc acgctgcccc taccagctcc tctaccaaga aaacccagct ccagttggag 120
catctgctgc tggacctcca gatgattctg aacgggatca acaactataa gaaccccaag 180
ctgacccgca tgctgacctt taagttctac atgcccaaga aggccaccga gctgaagcac 240
ctccagtgcc tggaagaaga actgaagccc ctggaagagg tgctgaatct ggcccagtcc 300
aagaacttcc acctgaggcc acgggacctg atcagcaaca tcaacgtgat cgtgctggaa 360
ctgaagggct ccgagacaac ctttatgtgc gagtacgccg acgagacagc caccatcgtg 420
gaatttctga accggtggat caccttctgc cagagcatca tctccacact gacc 474
<210> 38
<211> 591
<212> PRT
<213> Artificial Sequence(人工序列)
<220>
<223> 融合蛋白(mGI-101)
<400> 38
Val Asp Glu Gln Leu Ser Lys Ser Val Lys Asp Lys Val Leu Leu Pro
1 5 10 15
Cys Arg Tyr Asn Ser Pro His Glu Asp Glu Ser Glu Asp Arg Ile Tyr
20 25 30
Trp Gln Lys His Asp Lys Val Val Leu Ser Val Ile Ala Gly Lys Leu
35 40 45
Lys Val Trp Pro Glu Tyr Lys Asn Arg Thr Leu Tyr Asp Asn Thr Thr
50 55 60
Tyr Ser Leu Ile Ile Leu Gly Leu Val Leu Ser Asp Arg Gly Thr Tyr
65 70 75 80
Ser Cys Val Val Gln Lys Lys Glu Arg Gly Thr Tyr Glu Val Lys His
85 90 95
Leu Ala Leu Val Lys Leu Ser Ile Lys Ala Asp Phe Ser Thr Pro Asn
100 105 110
Ile Thr Glu Ser Gly Asn Pro Ser Ala Asp Thr Lys Arg Ile Thr Cys
115 120 125
Phe Ala Ser Gly Gly Phe Pro Lys Pro Arg Phe Ser Trp Leu Glu Asn
130 135 140
Gly Arg Glu Leu Pro Gly Ile Asn Thr Thr Ile Ser Gln Asp Pro Glu
145 150 155 160
Ser Glu Leu Tyr Thr Ile Ser Ser Gln Leu Asp Phe Asn Thr Thr Arg
165 170 175
Asn His Thr Ile Lys Cys Leu Ile Lys Tyr Gly Asp Ala His Val Ser
180 185 190
Glu Asp Phe Thr Trp Glu Lys Pro Pro Glu Asp Pro Pro Asp Ser Gly
195 200 205
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
210 215 220
Ala Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu
225 230 235 240
Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
245 250 255
Gln Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
260 265 270
Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly
275 280 285
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn
290 295 300
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
305 310 315 320
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro
325 330 335
Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
340 345 350
Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn
355 360 365
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
370 375 380
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
385 390 395 400
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg
405 410 415
Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys
420 425 430
Ser Val Leu His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
435 440 445
Ser Leu Ser Leu Gly Gly Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser
450 455 460
Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln
465 470 475 480
Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Ala
485 490 495
Met Leu Thr Ala Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys
500 505 510
His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu
515 520 525
Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile
530 535 540
Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr
545 550 555 560
Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu
565 570 575
Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr
580 585 590
<210> 39
<211> 120
<212> PRT
<213> Artificial Sequence(人工序列)
<220>
<223> 抗TIGIT的胞外结构域
<400> 39
Met Met Thr Gly Thr Ile Glu Thr Thr Gly Asn Ile Ser Ala Glu Lys
1 5 10 15
Gly Gly Ser Ile Ile Leu Gln Cys His Leu Ser Ser Thr Thr Ala Gln
20 25 30
Val Thr Gln Val Asn Trp Glu Gln Gln Asp Gln Leu Leu Ala Ile Cys
35 40 45
Asn Ala Asp Leu Gly Trp His Ile Ser Pro Ser Phe Lys Asp Arg Val
50 55 60
Ala Pro Gly Pro Gly Leu Gly Leu Thr Leu Gln Ser Leu Thr Val Asn
65 70 75 80
Asp Thr Gly Glu Tyr Phe Cys Ile Tyr His Thr Tyr Pro Asp Gly Thr
85 90 95
Tyr Thr Gly Arg Ile Phe Leu Glu Val Leu Glu Ser Ser Val Ala Glu
100 105 110
His Gly Ala Arg Phe Gln Ile Pro
115 120
Claims (10)
1.一种用于预防或治疗癌症的药物组合物,所述药物组合物包括作为活性成分的包含IL-2蛋白或其变体和CD80蛋白或其片段的融合蛋白二聚体以及免疫检查点抑制剂。
2.根据权利要求1所述的用于预防或治疗癌症的药物组合物,其中,所述IL-2蛋白或其变体和所述CD80蛋白或其片段通过接头连接。
3.根据权利要求1所述的用于预防或治疗癌症的药物组合物,其中,所述IL-2蛋白具有如SEQ ID NO:10所示的氨基酸序列。
4.根据权利要求1所述的用于预防或治疗癌症的药物组合物,其中,所述CD80具有如SEQ ID NO:11所示的氨基酸序列。
5.根据权利要求1所述的用于预防或治疗癌症的药物组合物,其中,所述融合蛋白具有如SEQ ID NO:9所示的氨基酸序列。
6.根据权利要求1所述的用于预防或治疗癌症的药物组合物,其中,所述免疫检查点抑制剂选自由抗CTLA-4抗体、抗PD-1抗体、抗PD-L1抗体、抗PD-L2抗体、抗B7-H4抗体、抗HVEM抗体、抗TIM3抗体、抗GAL9抗体、抗LAG3抗体、抗VISTA抗体、抗KIR抗体、抗BTLA抗体和抗TIGIT抗体组成的组中的任一种。
7.根据权利要求6所述的用于预防或治疗癌症的药物组合物,其中,所述抗CTLA-4抗体选自伊匹单抗和曲美木单抗中的任一种;
所述抗PD-1抗体选自由帕博利珠单抗、纳武单抗、西米普利单抗、JTX-4014、斯巴达珠单抗、卡瑞利珠单抗、信迪利单抗、替雷利珠单抗、特瑞普利单抗、多塔利单抗、INCMGA00012、AMP-224和AMP-514组成的组中的任一种;
所述抗PD-L1抗体选自由阿特珠单抗、阿维鲁单抗、德瓦鲁单抗、KN035、CK-301、AUNP12、CA-170和BMS-986189组成的组中的任一种;
所述抗TIM3抗体选自由LY3321367、MBG453和TSR-022组成的组中的任一种;
所述抗LAG3抗体选自由IMP321、瑞拉利单抗和GSK2831781组成的组中的任一种;或,
所述抗VISTA抗体为JNJ-63723283。
8.根据权利要求1所述的用于预防或治疗癌症的药物组合物,其中,所述癌症选自由胃癌、肝癌、肺癌、结直肠癌、乳腺癌、前列腺癌、卵巢癌、胰腺癌、宫颈癌、甲状腺癌、喉癌、急性髓性白血病、脑肿瘤、成神经细胞瘤、成视网膜细胞瘤、头颈癌、唾液腺癌和淋巴瘤组成的组中的任一种。
9.一种预防或治疗癌症的方法,所述方法包括:
向患有癌症的受试者施用包含IL-2蛋白或其变体和CD80蛋白或其片段的融合蛋白二聚体以及免疫检查点抑制剂。
10.一种包含IL-2蛋白或其变体和CD80蛋白或其片段的融合蛋白二聚体以及免疫检查点抑制剂在预防或治疗癌症中的用途。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR10-2019-0154632 | 2019-11-27 | ||
KR20190154632 | 2019-11-27 | ||
PCT/KR2020/017097 WO2021107689A1 (ko) | 2019-11-27 | 2020-11-27 | Il-2 단백질 및 cd80 단백질을 포함하는 융합단백질 및 면역관문 억제제를 포함하는 암 치료용 약학 조성물 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN114786701A true CN114786701A (zh) | 2022-07-22 |
Family
ID=76129744
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202080082872.0A Pending CN114786701A (zh) | 2019-11-27 | 2020-11-27 | 用于治疗癌症的包括包含il-2蛋白和cd80蛋白的融合蛋白和免疫检查点抑制剂的药物组合物 |
Country Status (15)
Country | Link |
---|---|
US (2) | US11639383B2 (zh) |
EP (1) | EP4085918A4 (zh) |
JP (1) | JP2023505067A (zh) |
KR (2) | KR102400253B1 (zh) |
CN (1) | CN114786701A (zh) |
AU (1) | AU2020392166A1 (zh) |
BR (1) | BR112022010246A2 (zh) |
CA (1) | CA3161303A1 (zh) |
CL (1) | CL2022001382A1 (zh) |
IL (1) | IL293364A (zh) |
MX (1) | MX2022006426A (zh) |
PE (1) | PE20221410A1 (zh) |
TW (1) | TWI820361B (zh) |
WO (1) | WO2021107689A1 (zh) |
ZA (1) | ZA202206994B (zh) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR102351020B1 (ko) * | 2019-11-20 | 2022-01-14 | 주식회사 지아이셀 | 자연살해세포 배양용 조성물 및 이를 이용한 자연살해세포 제조방법 |
CA3175457A1 (en) * | 2020-03-18 | 2021-09-23 | Gi Innovation, Inc. | Pharmaceutical composition for treating cancer, comprising fusion protein comprising il-2 protein and cd80 protein and anticancer drug |
KR102461837B1 (ko) * | 2022-01-13 | 2022-11-01 | ㈜지아이이노베이션 | Cd80 세포외도메인 및 항 lag3 항체 단편을 포함하는 융합 단백질 및 이의 용도 |
Family Cites Families (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5229109A (en) | 1992-04-14 | 1993-07-20 | Board Of Regents, The University Of Texas System | Low toxicity interleukin-2 analogues for use in immunotherapy |
EP3075745B1 (en) * | 2011-02-10 | 2018-09-05 | Roche Glycart AG | Mutant interleukin-2 polypeptides |
JP6800141B2 (ja) * | 2014-08-12 | 2020-12-16 | マサチューセッツ インスティテュート オブ テクノロジー | Il−2およびインテグリン結合性fc融合タンパク質による相乗的な腫瘍処置 |
WO2017024465A1 (en) | 2015-08-10 | 2017-02-16 | Innovent Biologics (Suzhou) Co., Ltd. | Pd-1 antibodies |
MA45488A (fr) | 2015-10-22 | 2018-08-29 | Juno Therapeutics Gmbh | Procédés, kits et appareil de culture de cellules |
KR102670157B1 (ko) * | 2015-10-28 | 2024-05-29 | 주식회사유한양행 | 이중 작용 단백질 및 이를 포함하는 약학적 조성물 |
KR102379464B1 (ko) * | 2016-06-20 | 2022-03-29 | 키맵 리미티드 | 항-pd-l1 항체 |
US20180009869A1 (en) * | 2016-07-08 | 2018-01-11 | AskGene Pharma, Inc. | Fusion Protein Comprising Leptin and Methods for Producing and Using the Same |
AU2018258661A1 (en) * | 2017-04-28 | 2019-10-17 | Five Prime Therapeutics, Inc. | Methods of treatment with CD80 extracellular domain polypeptides |
GB201709808D0 (en) * | 2017-06-20 | 2017-08-02 | Kymab Ltd | Antibodies |
JP2021502368A (ja) * | 2017-11-10 | 2021-01-28 | ウイスコンシン アラムナイ リサーチ ファウンデーシヨンWisconsin Alumni Research Foundation | 免疫療法に対する抗腫瘍免疫応答を促進するための標的化放射線療法(trt)の使用 |
-
2020
- 2020-11-27 CA CA3161303A patent/CA3161303A1/en active Pending
- 2020-11-27 PE PE2022000837A patent/PE20221410A1/es unknown
- 2020-11-27 JP JP2022531056A patent/JP2023505067A/ja active Pending
- 2020-11-27 CN CN202080082872.0A patent/CN114786701A/zh active Pending
- 2020-11-27 BR BR112022010246A patent/BR112022010246A2/pt unknown
- 2020-11-27 MX MX2022006426A patent/MX2022006426A/es unknown
- 2020-11-27 AU AU2020392166A patent/AU2020392166A1/en active Pending
- 2020-11-27 WO PCT/KR2020/017097 patent/WO2021107689A1/ko unknown
- 2020-11-27 IL IL293364A patent/IL293364A/en unknown
- 2020-11-27 EP EP20893963.7A patent/EP4085918A4/en active Pending
- 2020-11-27 TW TW109141896A patent/TWI820361B/zh active
- 2020-11-27 KR KR1020200162168A patent/KR102400253B1/ko active IP Right Grant
- 2020-11-27 US US17/780,364 patent/US11639383B2/en active Active
-
2022
- 2022-05-12 KR KR1020220058317A patent/KR20220066873A/ko not_active Application Discontinuation
- 2022-05-26 CL CL2022001382A patent/CL2022001382A1/es unknown
- 2022-06-23 ZA ZA2022/06994A patent/ZA202206994B/en unknown
-
2023
- 2023-03-01 US US18/176,934 patent/US20230257459A1/en active Pending
Also Published As
Publication number | Publication date |
---|---|
ZA202206994B (en) | 2023-11-29 |
IL293364A (en) | 2022-07-01 |
KR20210065887A (ko) | 2021-06-04 |
AU2020392166A1 (en) | 2022-05-26 |
EP4085918A4 (en) | 2024-01-10 |
MX2022006426A (es) | 2022-06-22 |
TW202134287A (zh) | 2021-09-16 |
EP4085918A1 (en) | 2022-11-09 |
TWI820361B (zh) | 2023-11-01 |
US11639383B2 (en) | 2023-05-02 |
US20230257459A1 (en) | 2023-08-17 |
KR20220066873A (ko) | 2022-05-24 |
CA3161303A1 (en) | 2021-06-03 |
KR102400253B9 (ko) | 2022-12-05 |
BR112022010246A2 (pt) | 2022-09-06 |
US20220403019A1 (en) | 2022-12-22 |
CL2022001382A1 (es) | 2023-02-24 |
JP2023505067A (ja) | 2023-02-08 |
KR102400253B1 (ko) | 2022-05-23 |
PE20221410A1 (es) | 2022-09-20 |
WO2021107689A1 (ko) | 2021-06-03 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP5798919B2 (ja) | Pd−1アンタゴニストの組成物および使用方法 | |
JP7085644B2 (ja) | Il-2タンパク質およびcd80タンパク質を含む融合タンパク質およびその使用 | |
CN105744955B (zh) | 用于癌症治疗的包含抗ceacam1抗体和抗pd抗体的组合物 | |
CN114786701A (zh) | 用于治疗癌症的包括包含il-2蛋白和cd80蛋白的融合蛋白和免疫检查点抑制剂的药物组合物 | |
JP7362614B2 (ja) | 癌治療のために免疫チェックポイントを調節する単一特異性および二重特異性タンパク質 | |
KR20220126679A (ko) | Il-2 단백질 및 cd80 단백질을 포함하는 융합단백질 및 항암제를 포함하는 암 치료용 약학 조성물 | |
KR20180119605A (ko) | HLA-B57 개방 이형태체(open conformer) | |
AU2021212558A1 (en) | Fusion protein comprising anti-TAA antibody, anti-PD-L1 antibody, and IL-2, and uses thereof | |
CA3233084A1 (en) | Fusion protein dimer comprising pd-1 and il-21, and use thereof | |
JP6716801B2 (ja) | 抗腫瘍剤及びその評価方法 | |
AU2020391280A1 (en) | Composition for anticancer treatment, comprising NK cells and fusion protein which comprises IL-2 protein and CD80 protein | |
RU2803148C2 (ru) | Противоопухолевое средство и способ его оценки | |
JP2020511992A (ja) | 遺伝子組換えt細胞調節分子およびその使用方法 | |
KR20220124839A (ko) | RANK 리간드(RANK ligand)에 특이적으로 결합하는 키메릭 항원 수용체 및 이의 용도 |
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 | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 40074839 Country of ref document: HK |