CN113797332A - 用于免疫疗法的组合物和方法 - Google Patents
用于免疫疗法的组合物和方法 Download PDFInfo
- Publication number
- CN113797332A CN113797332A CN202110793760.2A CN202110793760A CN113797332A CN 113797332 A CN113797332 A CN 113797332A CN 202110793760 A CN202110793760 A CN 202110793760A CN 113797332 A CN113797332 A CN 113797332A
- Authority
- CN
- China
- Prior art keywords
- ser
- val
- gly
- thr
- leu
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000000034 method Methods 0.000 title abstract description 27
- 239000000203 mixture Substances 0.000 title abstract description 26
- 238000009169 immunotherapy Methods 0.000 title abstract description 17
- 239000000427 antigen Substances 0.000 claims abstract description 125
- 108091007433 antigens Proteins 0.000 claims abstract description 123
- 102000036639 antigens Human genes 0.000 claims abstract description 123
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 53
- 210000001744 T-lymphocyte Anatomy 0.000 claims abstract description 42
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 30
- 230000027455 binding Effects 0.000 claims description 61
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 56
- 239000002245 particle Substances 0.000 claims description 52
- 239000003446 ligand Substances 0.000 claims description 47
- 125000003275 alpha amino acid group Chemical group 0.000 claims description 32
- 108091054438 MHC class II family Proteins 0.000 claims description 22
- 102000043131 MHC class II family Human genes 0.000 claims description 20
- 230000000890 antigenic effect Effects 0.000 claims description 16
- 102000043129 MHC class I family Human genes 0.000 claims description 7
- 108091054437 MHC class I family Proteins 0.000 claims description 7
- 102000006496 Immunoglobulin Heavy Chains Human genes 0.000 claims description 5
- 108010019476 Immunoglobulin Heavy Chains Proteins 0.000 claims description 5
- 230000002483 superagonistic effect Effects 0.000 claims description 4
- 238000001361 intraarterial administration Methods 0.000 claims description 3
- 230000002601 intratumoral effect Effects 0.000 claims description 3
- 238000001990 intravenous administration Methods 0.000 claims description 3
- 238000007920 subcutaneous administration Methods 0.000 claims description 3
- 102000013463 Immunoglobulin Light Chains Human genes 0.000 claims description 2
- 108010065825 Immunoglobulin Light Chains Proteins 0.000 claims description 2
- 101000998953 Homo sapiens Immunoglobulin heavy variable 1-2 Proteins 0.000 claims 2
- 102100036887 Immunoglobulin heavy variable 1-2 Human genes 0.000 claims 2
- 101001008255 Homo sapiens Immunoglobulin kappa variable 1D-8 Proteins 0.000 claims 1
- 101001047628 Homo sapiens Immunoglobulin kappa variable 2-29 Proteins 0.000 claims 1
- 101001008321 Homo sapiens Immunoglobulin kappa variable 2D-26 Proteins 0.000 claims 1
- 101001047619 Homo sapiens Immunoglobulin kappa variable 3-20 Proteins 0.000 claims 1
- 101001008263 Homo sapiens Immunoglobulin kappa variable 3D-15 Proteins 0.000 claims 1
- 102100022949 Immunoglobulin kappa variable 2-29 Human genes 0.000 claims 1
- 210000000612 antigen-presenting cell Anatomy 0.000 abstract description 6
- 230000001939 inductive effect Effects 0.000 abstract description 6
- 210000004027 cell Anatomy 0.000 description 35
- 102000004169 proteins and genes Human genes 0.000 description 31
- 108090000623 proteins and genes Proteins 0.000 description 31
- 235000018102 proteins Nutrition 0.000 description 30
- XKUKSGPZAADMRA-UHFFFAOYSA-N glycyl-glycyl-glycine Natural products NCC(=O)NCC(=O)NCC(O)=O XKUKSGPZAADMRA-UHFFFAOYSA-N 0.000 description 29
- 241001529936 Murinae Species 0.000 description 28
- 239000007787 solid Substances 0.000 description 25
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 22
- 239000002105 nanoparticle Substances 0.000 description 20
- 108010068265 aspartyltyrosine Proteins 0.000 description 19
- 102000004196 processed proteins & peptides Human genes 0.000 description 19
- 241000880493 Leptailurus serval Species 0.000 description 18
- 235000001014 amino acid Nutrition 0.000 description 18
- 102100035360 Cerebellar degeneration-related antigen 1 Human genes 0.000 description 17
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 17
- 108060003951 Immunoglobulin Proteins 0.000 description 17
- 210000004602 germ cell Anatomy 0.000 description 17
- 102000018358 immunoglobulin Human genes 0.000 description 17
- 229920000642 polymer Polymers 0.000 description 17
- 201000011510 cancer Diseases 0.000 description 16
- 230000004927 fusion Effects 0.000 description 16
- 125000000524 functional group Chemical group 0.000 description 15
- 108020001507 fusion proteins Proteins 0.000 description 15
- 102000037865 fusion proteins Human genes 0.000 description 15
- 108010073969 valyllysine Proteins 0.000 description 15
- HTONZBWRYUKUKC-RCWTZXSCSA-N Val-Thr-Val Chemical compound CC(C)[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(O)=O HTONZBWRYUKUKC-RCWTZXSCSA-N 0.000 description 14
- 229940024606 amino acid Drugs 0.000 description 14
- FULZDMOZUZKGQU-ONGXEEELSA-N Gly-Val-His Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)CN FULZDMOZUZKGQU-ONGXEEELSA-N 0.000 description 13
- 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 13
- 239000011324 bead Substances 0.000 description 13
- 238000002560 therapeutic procedure Methods 0.000 description 13
- 108010047041 Complementarity Determining Regions Proteins 0.000 description 12
- 108020004414 DNA Proteins 0.000 description 12
- 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 12
- 108010076324 alanyl-glycyl-glycine Proteins 0.000 description 12
- 108010077112 prolyl-proline Proteins 0.000 description 12
- -1 CD45R Proteins 0.000 description 11
- KAFOIVJDVSZUMD-UHFFFAOYSA-N Leu-Gln-Gln Natural products CC(C)CC(N)C(=O)NC(CCC(N)=O)C(=O)NC(CCC(N)=O)C(O)=O KAFOIVJDVSZUMD-UHFFFAOYSA-N 0.000 description 11
- 150000001413 amino acids Chemical class 0.000 description 11
- 108010069117 seryl-lysyl-aspartic acid Proteins 0.000 description 11
- BTYTYHBSJKQBQA-GCJQMDKQSA-N Ala-Asp-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](C)N)O BTYTYHBSJKQBQA-GCJQMDKQSA-N 0.000 description 10
- ZDILXFDENZVOTL-BPNCWPANSA-N Ala-Val-Tyr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O ZDILXFDENZVOTL-BPNCWPANSA-N 0.000 description 10
- 108700028369 Alleles Proteins 0.000 description 10
- SQKPKIJVWHAWNF-DCAQKATOSA-N Arg-Asp-Lys Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(O)=O SQKPKIJVWHAWNF-DCAQKATOSA-N 0.000 description 10
- RTFXPCYMDYBZNQ-SRVKXCTJSA-N Asn-Tyr-Asn Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(N)=O)C(O)=O RTFXPCYMDYBZNQ-SRVKXCTJSA-N 0.000 description 10
- 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 10
- UQJNXZSSGQIPIQ-FBCQKBJTSA-N Gly-Gly-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)CNC(=O)CN UQJNXZSSGQIPIQ-FBCQKBJTSA-N 0.000 description 10
- 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 10
- PDUHNKAFQXQNLH-ZETCQYMHSA-N Gly-Lys-Gly Chemical compound NCCCC[C@H](NC(=O)CN)C(=O)NCC(O)=O PDUHNKAFQXQNLH-ZETCQYMHSA-N 0.000 description 10
- ZZWUYQXMIFTIIY-WEDXCCLWSA-N Gly-Thr-Leu Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O ZZWUYQXMIFTIIY-WEDXCCLWSA-N 0.000 description 10
- DNAZKGFYFRGZIH-QWRGUYRKSA-N Gly-Tyr-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)CN)CC1=CC=C(O)C=C1 DNAZKGFYFRGZIH-QWRGUYRKSA-N 0.000 description 10
- ZVXMEWXHFBYJPI-LSJOCFKGSA-N Gly-Val-Ile Chemical compound [H]NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O ZVXMEWXHFBYJPI-LSJOCFKGSA-N 0.000 description 10
- 101000914514 Homo sapiens T-cell-specific surface glycoprotein CD28 Proteins 0.000 description 10
- 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 10
- KAFOIVJDVSZUMD-DCAQKATOSA-N Leu-Gln-Gln Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O KAFOIVJDVSZUMD-DCAQKATOSA-N 0.000 description 10
- FEHQLKKBVJHSEC-SZMVWBNQSA-N Leu-Glu-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CC(C)C)C(O)=O)=CNC2=C1 FEHQLKKBVJHSEC-SZMVWBNQSA-N 0.000 description 10
- YTJFXEDRUOQGSP-DCAQKATOSA-N Lys-Pro-Ser Chemical compound [H]N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O YTJFXEDRUOQGSP-DCAQKATOSA-N 0.000 description 10
- HRNQLKCLPVKZNE-CIUDSAMLSA-N Ser-Ala-Leu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(O)=O HRNQLKCLPVKZNE-CIUDSAMLSA-N 0.000 description 10
- KDGARKCAKHBEDB-NKWVEPMBSA-N Ser-Gly-Pro Chemical compound C1C[C@@H](N(C1)C(=O)CNC(=O)[C@H](CO)N)C(=O)O KDGARKCAKHBEDB-NKWVEPMBSA-N 0.000 description 10
- 102100027213 T-cell-specific surface glycoprotein CD28 Human genes 0.000 description 10
- 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 10
- 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 10
- CXUFDWZBHKUGKK-CABZTGNLSA-N Trp-Ala-Gly Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H](C)C(=O)NCC(O)=O)=CNC2=C1 CXUFDWZBHKUGKK-CABZTGNLSA-N 0.000 description 10
- SMLCYZYQFRTLCO-UWJYBYFXSA-N Tyr-Cys-Ala Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CS)C(=O)N[C@@H](C)C(O)=O SMLCYZYQFRTLCO-UWJYBYFXSA-N 0.000 description 10
- 108010008355 arginyl-glutamine Proteins 0.000 description 10
- 230000008901 benefit Effects 0.000 description 10
- 229920001223 polyethylene glycol Polymers 0.000 description 10
- 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 9
- 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 9
- SFTZWNJFZYOLBD-ZDLURKLDSA-N Ser-Gly-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CO SFTZWNJFZYOLBD-ZDLURKLDSA-N 0.000 description 9
- SIEBDTCABMZCLF-XGEHTFHBSA-N Ser-Val-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O SIEBDTCABMZCLF-XGEHTFHBSA-N 0.000 description 9
- DXPURPNJDFCKKO-RHYQMDGZSA-N Thr-Lys-Val Chemical compound CC(C)[C@H](NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)[C@@H](C)O)C(O)=O DXPURPNJDFCKKO-RHYQMDGZSA-N 0.000 description 9
- OQWNEUXPKHIEJO-NRPADANISA-N Val-Glu-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CO)C(=O)O)N OQWNEUXPKHIEJO-NRPADANISA-N 0.000 description 9
- 238000010168 coupling process Methods 0.000 description 9
- 238000005859 coupling reaction Methods 0.000 description 9
- 239000012634 fragment Substances 0.000 description 9
- 108010050848 glycylleucine Proteins 0.000 description 9
- 239000002609 medium Substances 0.000 description 9
- OYTPNWYZORARHL-XHNCKOQMSA-N Gln-Ala-Pro Chemical compound C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCC(=O)N)N OYTPNWYZORARHL-XHNCKOQMSA-N 0.000 description 8
- RBWKVOSARCFSQQ-FXQIFTODSA-N Gln-Gln-Ser Chemical compound NC(=O)CC[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(O)=O RBWKVOSARCFSQQ-FXQIFTODSA-N 0.000 description 8
- GGAPHLIUUTVYMX-QWRGUYRKSA-N Gly-Phe-Ser Chemical compound OC[C@@H](C([O-])=O)NC(=O)[C@@H](NC(=O)C[NH3+])CC1=CC=CC=C1 GGAPHLIUUTVYMX-QWRGUYRKSA-N 0.000 description 8
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 8
- 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 8
- 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 8
- KPJJOZUXFOLGMQ-CIUDSAMLSA-N Lys-Asp-Asn Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC(=O)N)C(=O)O)N KPJJOZUXFOLGMQ-CIUDSAMLSA-N 0.000 description 8
- 108700018351 Major Histocompatibility Complex Proteins 0.000 description 8
- 229920006022 Poly(L-lactide-co-glycolide)-b-poly(ethylene glycol) Polymers 0.000 description 8
- FPCGZYMRFFIYIH-CIUDSAMLSA-N Ser-Lys-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(O)=O FPCGZYMRFFIYIH-CIUDSAMLSA-N 0.000 description 8
- KJKQUQXDEKMPDK-FXQIFTODSA-N Ser-Met-Asp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(O)=O KJKQUQXDEKMPDK-FXQIFTODSA-N 0.000 description 8
- 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 8
- MBLJBGZWLHTJBH-SZMVWBNQSA-N Trp-Val-Arg Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O)=CNC2=C1 MBLJBGZWLHTJBH-SZMVWBNQSA-N 0.000 description 8
- NUQZCPSZHGIYTA-HKUYNNGSSA-N Tyr-Trp-Gly Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)NCC(=O)O)NC(=O)[C@H](CC3=CC=C(C=C3)O)N NUQZCPSZHGIYTA-HKUYNNGSSA-N 0.000 description 8
- RMRFSFXLFWWAJZ-HJOGWXRNSA-N Tyr-Tyr-Tyr Chemical compound C([C@H](N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C1=CC=C(O)C=C1 RMRFSFXLFWWAJZ-HJOGWXRNSA-N 0.000 description 8
- OFTXTCGQJXTNQS-XGEHTFHBSA-N Val-Thr-Ser Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](C(C)C)N)O OFTXTCGQJXTNQS-XGEHTFHBSA-N 0.000 description 8
- 108010069020 alanyl-prolyl-glycine Proteins 0.000 description 8
- 230000008878 coupling Effects 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 108010089804 glycyl-threonine Proteins 0.000 description 8
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 8
- 230000035772 mutation Effects 0.000 description 8
- 108010003137 tyrosyltyrosine Proteins 0.000 description 8
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 7
- KLALXKYLOMZDQT-ZLUOBGJFSA-N Ala-Ser-Asn Chemical compound C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CC(N)=O KLALXKYLOMZDQT-ZLUOBGJFSA-N 0.000 description 7
- 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 7
- KQBVNNAPIURMPD-PEFMBERDSA-N Asp-Ile-Glu Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(O)=O KQBVNNAPIURMPD-PEFMBERDSA-N 0.000 description 7
- SZQCDCKIGWQAQN-FXQIFTODSA-N Cys-Arg-Ala Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(O)=O SZQCDCKIGWQAQN-FXQIFTODSA-N 0.000 description 7
- 241000282326 Felis catus Species 0.000 description 7
- XZLLTYBONVKGLO-SDDRHHMPSA-N Gln-Lys-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(=O)N)N)C(=O)O XZLLTYBONVKGLO-SDDRHHMPSA-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
- AVZHGSCDKIQZPQ-CIUDSAMLSA-N Glu-Arg-Ala Chemical compound C[C@H](NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](N)CCC(O)=O)C(O)=O AVZHGSCDKIQZPQ-CIUDSAMLSA-N 0.000 description 7
- XTZDZAXYPDISRR-MNXVOIDGSA-N Glu-Ile-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCC(=O)O)N XTZDZAXYPDISRR-MNXVOIDGSA-N 0.000 description 7
- 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 7
- YGHSQRJSHKYUJY-SCZZXKLOSA-N Gly-Val-Pro Chemical compound CC(C)[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)CN YGHSQRJSHKYUJY-SCZZXKLOSA-N 0.000 description 7
- HQEPKOFULQTSFV-JURCDPSOSA-N Ile-Phe-Ala Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](C)C(=O)O)N HQEPKOFULQTSFV-JURCDPSOSA-N 0.000 description 7
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 7
- LCNASHSOFMRYFO-WDCWCFNPSA-N Leu-Thr-Gln Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@H](C(O)=O)CCC(N)=O LCNASHSOFMRYFO-WDCWCFNPSA-N 0.000 description 7
- LJBVRCDPWOJOEK-PPCPHDFISA-N Leu-Thr-Ile Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O LJBVRCDPWOJOEK-PPCPHDFISA-N 0.000 description 7
- AIRZWUMAHCDDHR-KKUMJFAQSA-N Lys-Leu-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O AIRZWUMAHCDDHR-KKUMJFAQSA-N 0.000 description 7
- OZVXDDFYCQOPFD-XQQFMLRXSA-N Lys-Val-Pro Chemical compound CC(C)[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCCCN)N OZVXDDFYCQOPFD-XQQFMLRXSA-N 0.000 description 7
- 239000004472 Lysine Substances 0.000 description 7
- 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 7
- PESQCPHRXOFIPX-UHFFFAOYSA-N N-L-methionyl-L-tyrosine Natural products CSCCC(N)C(=O)NC(C(O)=O)CC1=CC=C(O)C=C1 PESQCPHRXOFIPX-UHFFFAOYSA-N 0.000 description 7
- 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 7
- VQBCMLMPEWPUTB-ACZMJKKPSA-N Ser-Glu-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(O)=O VQBCMLMPEWPUTB-ACZMJKKPSA-N 0.000 description 7
- 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 7
- GJFYFGOEWLDQGW-GUBZILKMSA-N Ser-Leu-Gln Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CO)N GJFYFGOEWLDQGW-GUBZILKMSA-N 0.000 description 7
- 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 7
- PJIQEIFXZPCWOJ-FXQIFTODSA-N Ser-Pro-Asp Chemical compound [H]N[C@@H](CO)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(O)=O)C(O)=O PJIQEIFXZPCWOJ-FXQIFTODSA-N 0.000 description 7
- PAXANSWUSVPFNK-IUKAMOBKSA-N Thr-Ile-Asn Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H]([C@@H](C)O)N PAXANSWUSVPFNK-IUKAMOBKSA-N 0.000 description 7
- PKZIWSHDJYIPRH-JBACZVJFSA-N Trp-Tyr-Gln Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCC(N)=O)C(O)=O PKZIWSHDJYIPRH-JBACZVJFSA-N 0.000 description 7
- UPODKYBYUBTWSV-BZSNNMDCSA-N Tyr-Phe-Cys Chemical compound C([C@H](N)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CS)C(O)=O)C1=CC=C(O)C=C1 UPODKYBYUBTWSV-BZSNNMDCSA-N 0.000 description 7
- LDKDSFQSEUOCOO-RPTUDFQQSA-N Tyr-Thr-Phe 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](CC1=CC=CC=C1)C(O)=O LDKDSFQSEUOCOO-RPTUDFQQSA-N 0.000 description 7
- SMKXLHVZIFKQRB-GUBZILKMSA-N Val-Ala-Met Chemical compound C[C@@H](C(=O)N[C@@H](CCSC)C(=O)O)NC(=O)[C@H](C(C)C)N SMKXLHVZIFKQRB-GUBZILKMSA-N 0.000 description 7
- PMXBARDFIAPBGK-DZKIICNBSA-N Val-Glu-Tyr Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 PMXBARDFIAPBGK-DZKIICNBSA-N 0.000 description 7
- VHIZXDZMTDVFGX-DCAQKATOSA-N Val-Ser-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](C(C)C)N VHIZXDZMTDVFGX-DCAQKATOSA-N 0.000 description 7
- 108010064235 lysylglycine Proteins 0.000 description 7
- 108010070409 phenylalanyl-glycyl-glycine Proteins 0.000 description 7
- 108010031719 prolyl-serine Proteins 0.000 description 7
- 108010079317 prolyl-tyrosine Proteins 0.000 description 7
- 230000020382 suppression by virus of host antigen processing and presentation of peptide antigen via MHC class I Effects 0.000 description 7
- 210000001519 tissue Anatomy 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 6
- 102000008949 Histocompatibility Antigens Class I Human genes 0.000 description 6
- 108010088652 Histocompatibility Antigens Class I Proteins 0.000 description 6
- 102000018713 Histocompatibility Antigens Class II Human genes 0.000 description 6
- 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 6
- 108090001074 Nucleocapsid Proteins Proteins 0.000 description 6
- 108091000054 Prion Proteins 0.000 description 6
- QFBNNYNWKYKVJO-DCAQKATOSA-N Ser-Arg-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CO)CCCN=C(N)N QFBNNYNWKYKVJO-DCAQKATOSA-N 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 6
- 230000030741 antigen processing and presentation Effects 0.000 description 6
- 238000003556 assay Methods 0.000 description 6
- 230000021615 conjugation Effects 0.000 description 6
- 229920001577 copolymer Polymers 0.000 description 6
- 125000000151 cysteine group Chemical class N[C@@H](CS)C(=O)* 0.000 description 6
- 208000006454 hepatitis Diseases 0.000 description 6
- 231100000283 hepatitis Toxicity 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 125000003396 thiol group Chemical group [H]S* 0.000 description 6
- NFGXHKASABOEEW-UHFFFAOYSA-N 1-methylethyl 11-methoxy-3,7,11-trimethyl-2,4-dodecadienoate Chemical compound COC(C)(C)CCCC(C)CC=CC(C)=CC(=O)OC(C)C NFGXHKASABOEEW-UHFFFAOYSA-N 0.000 description 5
- KXEVYGKATAMXJJ-ACZMJKKPSA-N Ala-Glu-Asp Chemical compound C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O KXEVYGKATAMXJJ-ACZMJKKPSA-N 0.000 description 5
- 208000035473 Communicable disease Diseases 0.000 description 5
- 238000002965 ELISA Methods 0.000 description 5
- 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 5
- 101000839781 Homo sapiens Immunoglobulin heavy variable 4-59 Proteins 0.000 description 5
- 241000701044 Human gammaherpesvirus 4 Species 0.000 description 5
- 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 5
- 229940076838 Immune checkpoint inhibitor Drugs 0.000 description 5
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 5
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 5
- 102100028405 Immunoglobulin heavy variable 4-59 Human genes 0.000 description 5
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 5
- 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 5
- 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 5
- YDTUEBLEAVANFH-RCWTZXSCSA-N Pro-Val-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H]1CCCN1 YDTUEBLEAVANFH-RCWTZXSCSA-N 0.000 description 5
- 108010076504 Protein Sorting Signals Proteins 0.000 description 5
- 108010008685 alanyl-glutamyl-aspartic acid Proteins 0.000 description 5
- 108010047857 aspartylglycine Proteins 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 210000004899 c-terminal region Anatomy 0.000 description 5
- 238000000576 coating method Methods 0.000 description 5
- 238000013461 design Methods 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 108010013768 glutamyl-aspartyl-proline Proteins 0.000 description 5
- 108010049041 glutamylalanine Proteins 0.000 description 5
- 108010000434 glycyl-alanyl-leucine Proteins 0.000 description 5
- 108010050475 glycyl-leucyl-tyrosine Proteins 0.000 description 5
- 108010037850 glycylvaline Proteins 0.000 description 5
- 230000005746 immune checkpoint blockade Effects 0.000 description 5
- 239000012274 immune-checkpoint protein inhibitor Substances 0.000 description 5
- 201000001441 melanoma Diseases 0.000 description 5
- 230000004048 modification Effects 0.000 description 5
- 238000012986 modification Methods 0.000 description 5
- 108010024654 phenylalanyl-prolyl-alanine Proteins 0.000 description 5
- 229920001432 poly(L-lactide) Polymers 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 108010070643 prolylglutamic acid Proteins 0.000 description 5
- 238000010186 staining Methods 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 238000006467 substitution reaction Methods 0.000 description 5
- 108700004896 tripeptide FEG 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
- 239000013598 vector Substances 0.000 description 5
- YYSWCHMLFJLLBJ-ZLUOBGJFSA-N Ala-Ala-Ser Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O YYSWCHMLFJLLBJ-ZLUOBGJFSA-N 0.000 description 4
- BKFXFUPYETWGGA-XVSYOHENSA-N Asn-Phe-Thr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O BKFXFUPYETWGGA-XVSYOHENSA-N 0.000 description 4
- 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 4
- 208000023275 Autoimmune disease Diseases 0.000 description 4
- 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 4
- 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 4
- MKIAPEZXQDILRR-YUMQZZPRSA-N Gly-Ser-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)CN MKIAPEZXQDILRR-YUMQZZPRSA-N 0.000 description 4
- 108010027412 Histocompatibility Antigens Class II Proteins 0.000 description 4
- 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 4
- 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 4
- WRODMZBHNNPRLN-SRVKXCTJSA-N Lys-Leu-Ser Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O WRODMZBHNNPRLN-SRVKXCTJSA-N 0.000 description 4
- QLFAPXUXEBAWEK-NHCYSSNCSA-N Lys-Val-Asp Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O QLFAPXUXEBAWEK-NHCYSSNCSA-N 0.000 description 4
- 239000004698 Polyethylene Substances 0.000 description 4
- 102000029797 Prion Human genes 0.000 description 4
- 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 4
- 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 4
- HBOABDXGTMMDSE-GUBZILKMSA-N Ser-Arg-Val Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(O)=O HBOABDXGTMMDSE-GUBZILKMSA-N 0.000 description 4
- 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 4
- 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 4
- QFHRUCJIRVILCK-YJRXYDGGSA-N Tyr-Thr-Cys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)N)O QFHRUCJIRVILCK-YJRXYDGGSA-N 0.000 description 4
- 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 4
- 241000700605 Viruses Species 0.000 description 4
- 108010087924 alanylproline Proteins 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 108010052670 arginyl-glutamyl-glutamic acid Proteins 0.000 description 4
- 108010009111 arginyl-glycyl-glutamic acid Proteins 0.000 description 4
- 239000011248 coating agent Substances 0.000 description 4
- 239000013604 expression vector Substances 0.000 description 4
- XBGGUPMXALFZOT-UHFFFAOYSA-N glycyl-L-tyrosine hemihydrate Natural products NCC(=O)NC(C(O)=O)CC1=CC=C(O)C=C1 XBGGUPMXALFZOT-UHFFFAOYSA-N 0.000 description 4
- 108010087823 glycyltyrosine Proteins 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 230000003993 interaction Effects 0.000 description 4
- 235000014655 lactic acid Nutrition 0.000 description 4
- 239000004310 lactic acid Substances 0.000 description 4
- 108010017391 lysylvaline Proteins 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 239000011159 matrix material Substances 0.000 description 4
- 230000000717 retained effect Effects 0.000 description 4
- 238000001890 transfection Methods 0.000 description 4
- 108010051110 tyrosyl-lysine Proteins 0.000 description 4
- 108010052774 valyl-lysyl-glycyl-phenylalanyl-tyrosine Proteins 0.000 description 4
- SVBXIUDNTRTKHE-CIUDSAMLSA-N Ala-Arg-Glu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(O)=O SVBXIUDNTRTKHE-CIUDSAMLSA-N 0.000 description 3
- MNZHHDPWDWQJCQ-YUMQZZPRSA-N Ala-Leu-Gly Chemical compound C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O MNZHHDPWDWQJCQ-YUMQZZPRSA-N 0.000 description 3
- DPNZTBKGAUAZQU-DLOVCJGASA-N Ala-Leu-His Chemical compound C[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N DPNZTBKGAUAZQU-DLOVCJGASA-N 0.000 description 3
- 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 3
- MDNAVFBZPROEHO-UHFFFAOYSA-N Ala-Lys-Val Natural products CC(C)C(C(O)=O)NC(=O)C(NC(=O)C(C)N)CCCCN MDNAVFBZPROEHO-UHFFFAOYSA-N 0.000 description 3
- WQKAQKZRDIZYNV-VZFHVOOUSA-N Ala-Ser-Thr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(O)=O WQKAQKZRDIZYNV-VZFHVOOUSA-N 0.000 description 3
- 102100034452 Alternative prion protein Human genes 0.000 description 3
- 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 3
- 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 3
- ULBHWNVWSCJLCO-NHCYSSNCSA-N Arg-Val-Glu Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CCCN=C(N)N ULBHWNVWSCJLCO-NHCYSSNCSA-N 0.000 description 3
- 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 3
- 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 3
- JZLFYAAGGYMRIK-BYULHYEWSA-N Asn-Val-Asp Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O JZLFYAAGGYMRIK-BYULHYEWSA-N 0.000 description 3
- 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 3
- 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 3
- 241000894006 Bacteria Species 0.000 description 3
- 206010006187 Breast cancer Diseases 0.000 description 3
- 208000026310 Breast neoplasm Diseases 0.000 description 3
- 102100025570 Cancer/testis antigen 1 Human genes 0.000 description 3
- 239000004971 Cross linker Substances 0.000 description 3
- 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 3
- 102000004127 Cytokines Human genes 0.000 description 3
- 108090000695 Cytokines Proteins 0.000 description 3
- ZFBBMCKQSNJZSN-AUTRQRHGSA-N Gln-Val-Gln Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O ZFBBMCKQSNJZSN-AUTRQRHGSA-N 0.000 description 3
- ZMXZGYLINVNTKH-DZKIICNBSA-N Gln-Val-Phe Chemical compound NC(=O)CC[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 ZMXZGYLINVNTKH-DZKIICNBSA-N 0.000 description 3
- 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 3
- 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 3
- LRPXYSGPOBVBEH-IUCAKERBSA-N Glu-Gly-Leu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CC(C)C)C(O)=O LRPXYSGPOBVBEH-IUCAKERBSA-N 0.000 description 3
- RAUDKMVXNOWDLS-WDSKDSINSA-N Glu-Gly-Ser Chemical compound OC(=O)CC[C@H](N)C(=O)NCC(=O)N[C@@H](CO)C(O)=O RAUDKMVXNOWDLS-WDSKDSINSA-N 0.000 description 3
- JDUKCSSHWNIQQZ-IHRRRGAJSA-N Glu-Phe-Glu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCC(O)=O)C(O)=O JDUKCSSHWNIQQZ-IHRRRGAJSA-N 0.000 description 3
- JWNZHMSRZXXGTM-XKBZYTNZSA-N Glu-Ser-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(O)=O JWNZHMSRZXXGTM-XKBZYTNZSA-N 0.000 description 3
- 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 3
- 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 3
- 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 3
- 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 3
- TTYKEFZRLKQTHH-MELADBBJSA-N His-Lys-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCCCN)NC(=O)[C@H](CC2=CN=CN2)N)C(=O)O TTYKEFZRLKQTHH-MELADBBJSA-N 0.000 description 3
- 101000937544 Homo sapiens Beta-2-microglobulin Proteins 0.000 description 3
- 101000856237 Homo sapiens Cancer/testis antigen 1 Proteins 0.000 description 3
- 102000009490 IgG Receptors Human genes 0.000 description 3
- 108010073807 IgG Receptors Proteins 0.000 description 3
- 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 3
- 102000000588 Interleukin-2 Human genes 0.000 description 3
- 108010002350 Interleukin-2 Proteins 0.000 description 3
- PPBKJAQJAUHZKX-SRVKXCTJSA-N Leu-Cys-Leu Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CS)C(=O)N[C@H](C(O)=O)CC(C)C PPBKJAQJAUHZKX-SRVKXCTJSA-N 0.000 description 3
- HYMLKESRWLZDBR-WEDXCCLWSA-N Leu-Gly-Thr Chemical compound CC(C)C[C@H](N)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(O)=O HYMLKESRWLZDBR-WEDXCCLWSA-N 0.000 description 3
- ZDJQVSIPFLMNOX-RHYQMDGZSA-N Leu-Thr-Arg Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@H](C(O)=O)CCCN=C(N)N ZDJQVSIPFLMNOX-RHYQMDGZSA-N 0.000 description 3
- RNYLNYTYMXACRI-VFAJRCTISA-N Leu-Thr-Trp Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O RNYLNYTYMXACRI-VFAJRCTISA-N 0.000 description 3
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 3
- NTBFKPBULZGXQL-KKUMJFAQSA-N Lys-Asp-Tyr Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 NTBFKPBULZGXQL-KKUMJFAQSA-N 0.000 description 3
- RFQATBGBLDAKGI-VHSXEESVSA-N Lys-Gly-Pro Chemical compound C1C[C@@H](N(C1)C(=O)CNC(=O)[C@H](CCCCN)N)C(=O)O RFQATBGBLDAKGI-VHSXEESVSA-N 0.000 description 3
- ONPDTSFZAIWMDI-AVGNSLFASA-N Lys-Leu-Gln Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O ONPDTSFZAIWMDI-AVGNSLFASA-N 0.000 description 3
- GOVDTWNJCBRRBJ-DCAQKATOSA-N Lys-Met-Asn Chemical compound CSCC[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CCCCN)N GOVDTWNJCBRRBJ-DCAQKATOSA-N 0.000 description 3
- JYVCOTWSRGFABJ-DCAQKATOSA-N Lys-Met-Ser Chemical compound CSCC[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CCCCN)N JYVCOTWSRGFABJ-DCAQKATOSA-N 0.000 description 3
- PEEHTFAAVSWFBL-UHFFFAOYSA-N Maleimide Chemical group O=C1NC(=O)C=C1 PEEHTFAAVSWFBL-UHFFFAOYSA-N 0.000 description 3
- PNDCUTDWYVKBHX-IHRRRGAJSA-N Met-Asp-Tyr Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 PNDCUTDWYVKBHX-IHRRRGAJSA-N 0.000 description 3
- 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 3
- 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 3
- KZNQNBZMBZJQJO-UHFFFAOYSA-N N-glycyl-L-proline Natural products NCC(=O)N1CCCC1C(O)=O KZNQNBZMBZJQJO-UHFFFAOYSA-N 0.000 description 3
- QARPMYDMYVLFMW-KKUMJFAQSA-N Phe-Pro-Glu Chemical compound C([C@H](N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(O)=O)C1=CC=CC=C1 QARPMYDMYVLFMW-KKUMJFAQSA-N 0.000 description 3
- 229920001710 Polyorthoester Polymers 0.000 description 3
- 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 3
- GMJDSFYVTAMIBF-FXQIFTODSA-N Pro-Ser-Asp Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(O)=O GMJDSFYVTAMIBF-FXQIFTODSA-N 0.000 description 3
- 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 3
- 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 3
- 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 3
- 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 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
- 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 3
- RQXDSYQXBCRXBT-GUBZILKMSA-N Ser-Met-Arg Chemical compound OC[C@H](N)C(=O)N[C@@H](CCSC)C(=O)N[C@H](C(O)=O)CCCN=C(N)N RQXDSYQXBCRXBT-GUBZILKMSA-N 0.000 description 3
- SRSPTFBENMJHMR-WHFBIAKZSA-N Ser-Ser-Gly Chemical compound OC[C@H](N)C(=O)N[C@@H](CO)C(=O)NCC(O)=O SRSPTFBENMJHMR-WHFBIAKZSA-N 0.000 description 3
- 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 3
- 108091008874 T cell receptors Proteins 0.000 description 3
- 102000016266 T-Cell Antigen Receptors Human genes 0.000 description 3
- JMBRNXUOLJFURW-BEAPCOKYSA-N Thr-Phe-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N2CCC[C@@H]2C(=O)O)N)O JMBRNXUOLJFURW-BEAPCOKYSA-N 0.000 description 3
- 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 3
- 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 3
- 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 3
- 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 3
- 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 3
- 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 3
- 102000003425 Tyrosinase Human genes 0.000 description 3
- 108060008724 Tyrosinase Proteins 0.000 description 3
- 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 3
- HGJRMXOWUWVUOA-GVXVVHGQSA-N Val-Leu-Gln Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](C(C)C)N HGJRMXOWUWVUOA-GVXVVHGQSA-N 0.000 description 3
- SSYBNWFXCFNRFN-GUBZILKMSA-N Val-Pro-Ser Chemical compound CC(C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O SSYBNWFXCFNRFN-GUBZILKMSA-N 0.000 description 3
- 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 3
- 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 3
- SDHZOOIGIUEPDY-JYJNAYRXSA-N Val-Ser-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](CO)NC(=O)[C@@H](N)C(C)C)C(O)=O)=CNC2=C1 SDHZOOIGIUEPDY-JYJNAYRXSA-N 0.000 description 3
- 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 3
- 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 3
- JVGDAEKKZKKZFO-RCWTZXSCSA-N Val-Val-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](C(C)C)N)O JVGDAEKKZKKZFO-RCWTZXSCSA-N 0.000 description 3
- KOSRFJWDECSPRO-UHFFFAOYSA-N alpha-L-glutamyl-L-glutamic acid Natural products OC(=O)CCC(N)C(=O)NC(CCC(O)=O)C(O)=O KOSRFJWDECSPRO-UHFFFAOYSA-N 0.000 description 3
- 108010013835 arginine glutamate Proteins 0.000 description 3
- 210000003719 b-lymphocyte Anatomy 0.000 description 3
- 229920001400 block copolymer Polymers 0.000 description 3
- 230000010261 cell growth Effects 0.000 description 3
- 229920002678 cellulose Polymers 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 208000029742 colonic neoplasm Diseases 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 230000000139 costimulatory effect Effects 0.000 description 3
- 235000018417 cysteine Nutrition 0.000 description 3
- 238000012217 deletion Methods 0.000 description 3
- 230000037430 deletion Effects 0.000 description 3
- 210000004443 dendritic cell Anatomy 0.000 description 3
- 230000004069 differentiation Effects 0.000 description 3
- 238000006471 dimerization reaction Methods 0.000 description 3
- 108010055341 glutamyl-glutamic acid Proteins 0.000 description 3
- 108010010147 glycylglutamine Proteins 0.000 description 3
- 108010077515 glycylproline Proteins 0.000 description 3
- 230000005847 immunogenicity Effects 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 239000012678 infectious agent Substances 0.000 description 3
- 230000001788 irregular Effects 0.000 description 3
- 108010073472 leucyl-prolyl-proline Proteins 0.000 description 3
- 108010091871 leucylmethionine Proteins 0.000 description 3
- 108010057821 leucylproline Proteins 0.000 description 3
- 230000000670 limiting effect Effects 0.000 description 3
- 208000014018 liver neoplasm Diseases 0.000 description 3
- 238000011068 loading method Methods 0.000 description 3
- 201000005202 lung cancer Diseases 0.000 description 3
- 208000020816 lung neoplasm Diseases 0.000 description 3
- 125000005439 maleimidyl group Chemical group C1(C=CC(N1*)=O)=O 0.000 description 3
- 102000042567 non-coding RNA Human genes 0.000 description 3
- 108091027963 non-coding RNA Proteins 0.000 description 3
- 210000005259 peripheral blood Anatomy 0.000 description 3
- 239000011886 peripheral blood Substances 0.000 description 3
- 108010051242 phenylalanylserine Proteins 0.000 description 3
- 229920001610 polycaprolactone Polymers 0.000 description 3
- 208000017805 post-transplant lymphoproliferative disease Diseases 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 108010087846 prolyl-prolyl-glycine Proteins 0.000 description 3
- 230000000069 prophylactic effect Effects 0.000 description 3
- 102000005962 receptors Human genes 0.000 description 3
- 108020003175 receptors Proteins 0.000 description 3
- 108010071207 serylmethionine Proteins 0.000 description 3
- 239000012798 spherical particle Substances 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 210000001550 testis Anatomy 0.000 description 3
- 108010072986 threonyl-seryl-lysine Proteins 0.000 description 3
- 108010079202 tyrosyl-alanyl-cysteine Proteins 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 2
- 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 2
- GNSFRPWPOGYVLO-UHFFFAOYSA-N 3-hydroxypropyl 2-methylprop-2-enoate Chemical compound CC(=C)C(=O)OCCCO GNSFRPWPOGYVLO-UHFFFAOYSA-N 0.000 description 2
- CXRCVCURMBFFOL-FXQIFTODSA-N Ala-Ala-Pro Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O CXRCVCURMBFFOL-FXQIFTODSA-N 0.000 description 2
- KUDREHRZRIVKHS-UWJYBYFXSA-N Ala-Asp-Tyr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O KUDREHRZRIVKHS-UWJYBYFXSA-N 0.000 description 2
- MEFILNJXAVSUTO-JXUBOQSCSA-N Ala-Leu-Thr Chemical compound C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O MEFILNJXAVSUTO-JXUBOQSCSA-N 0.000 description 2
- DYJJJCHDHLEFDW-FXQIFTODSA-N Ala-Pro-Cys Chemical compound C[C@@H](C(=O)N1CCC[C@H]1C(=O)N[C@@H](CS)C(=O)O)N DYJJJCHDHLEFDW-FXQIFTODSA-N 0.000 description 2
- 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 2
- ARHJJAAWNWOACN-FXQIFTODSA-N Ala-Ser-Val Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O ARHJJAAWNWOACN-FXQIFTODSA-N 0.000 description 2
- 102100023635 Alpha-fetoprotein Human genes 0.000 description 2
- AUFHLLPVPSMEOG-YUMQZZPRSA-N Arg-Gly-Glu Chemical compound NC(N)=NCCC[C@H](N)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(O)=O AUFHLLPVPSMEOG-YUMQZZPRSA-N 0.000 description 2
- PAPSMOYMQDWIOR-AVGNSLFASA-N Arg-Lys-Val Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(O)=O PAPSMOYMQDWIOR-AVGNSLFASA-N 0.000 description 2
- XRNXPIGJPQHCPC-RCWTZXSCSA-N Arg-Thr-Val Chemical compound CC(C)[C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)CCCNC(N)=N)[C@@H](C)O)C(O)=O XRNXPIGJPQHCPC-RCWTZXSCSA-N 0.000 description 2
- XYOVHPDDWCEUDY-CIUDSAMLSA-N Asn-Ala-Leu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(O)=O XYOVHPDDWCEUDY-CIUDSAMLSA-N 0.000 description 2
- GXMSVVBIAMWMKO-BQBZGAKWSA-N Asn-Arg-Gly Chemical compound NC(=O)C[C@H](N)C(=O)N[C@H](C(=O)NCC(O)=O)CCCN=C(N)N GXMSVVBIAMWMKO-BQBZGAKWSA-N 0.000 description 2
- 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 2
- 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 2
- 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 2
- HPBNLFLSSQDFQW-WHFBIAKZSA-N Asn-Ser-Gly Chemical compound NC(=O)C[C@H](N)C(=O)N[C@@H](CO)C(=O)NCC(O)=O HPBNLFLSSQDFQW-WHFBIAKZSA-N 0.000 description 2
- 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 2
- 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 2
- 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 2
- UZFHNLYQWMGUHU-DCAQKATOSA-N Asp-Lys-Arg Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O UZFHNLYQWMGUHU-DCAQKATOSA-N 0.000 description 2
- 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 2
- AWPWHMVCSISSQK-QWRGUYRKSA-N Asp-Tyr-Gly Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)NCC(O)=O AWPWHMVCSISSQK-QWRGUYRKSA-N 0.000 description 2
- SQIARYGNVQWOSB-BZSNNMDCSA-N Asp-Tyr-Phe Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O SQIARYGNVQWOSB-BZSNNMDCSA-N 0.000 description 2
- 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 2
- 102100035526 B melanoma antigen 1 Human genes 0.000 description 2
- 102000019260 B-Cell Antigen Receptors Human genes 0.000 description 2
- 108010012919 B-Cell Antigen Receptors Proteins 0.000 description 2
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 2
- 208000023328 Basedow disease Diseases 0.000 description 2
- 101710132601 Capsid protein Proteins 0.000 description 2
- 108010022366 Carcinoembryonic Antigen Proteins 0.000 description 2
- 102100025475 Carcinoembryonic antigen-related cell adhesion molecule 5 Human genes 0.000 description 2
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 2
- 208000015943 Coeliac disease Diseases 0.000 description 2
- 206010009944 Colon cancer Diseases 0.000 description 2
- 229920000858 Cyclodextrin Polymers 0.000 description 2
- VIRYODQIWJNWNU-NRPADANISA-N Cys-Glu-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CS)N VIRYODQIWJNWNU-NRPADANISA-N 0.000 description 2
- SRIRHERUAMYIOQ-CIUDSAMLSA-N Cys-Leu-Ser Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O SRIRHERUAMYIOQ-CIUDSAMLSA-N 0.000 description 2
- 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 2
- 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 2
- 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 2
- 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 2
- 206010012468 Dermatitis herpetiformis Diseases 0.000 description 2
- 241000233866 Fungi Species 0.000 description 2
- 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 2
- 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 2
- 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 2
- IULKWYSYZSURJK-AVGNSLFASA-N Gln-Leu-Lys Chemical compound NC(=O)CC[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(O)=O IULKWYSYZSURJK-AVGNSLFASA-N 0.000 description 2
- 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 2
- UESYBOXFJWJVSB-AVGNSLFASA-N Gln-Phe-Ser Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(O)=O UESYBOXFJWJVSB-AVGNSLFASA-N 0.000 description 2
- 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 2
- WLRYGVYQFXRJDA-DCAQKATOSA-N Gln-Pro-Pro Chemical compound NC(=O)CC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 WLRYGVYQFXRJDA-DCAQKATOSA-N 0.000 description 2
- JJKKWYQVHRUSDG-GUBZILKMSA-N Glu-Ala-Lys Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(O)=O JJKKWYQVHRUSDG-GUBZILKMSA-N 0.000 description 2
- 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 2
- CLROYXHHUZELFX-FXQIFTODSA-N Glu-Gln-Asp Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O CLROYXHHUZELFX-FXQIFTODSA-N 0.000 description 2
- NKLRYVLERDYDBI-FXQIFTODSA-N Glu-Glu-Asp Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O NKLRYVLERDYDBI-FXQIFTODSA-N 0.000 description 2
- 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 2
- 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 2
- 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 2
- 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 2
- 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 2
- 102000008214 Glutamate decarboxylase Human genes 0.000 description 2
- 108091022930 Glutamate decarboxylase Proteins 0.000 description 2
- SXRSQZLOMIGNAQ-UHFFFAOYSA-N Glutaraldehyde Chemical compound O=CCCCC=O SXRSQZLOMIGNAQ-UHFFFAOYSA-N 0.000 description 2
- VSVZIEVNUYDAFR-YUMQZZPRSA-N Gly-Ala-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)CN VSVZIEVNUYDAFR-YUMQZZPRSA-N 0.000 description 2
- 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 2
- 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 2
- NNCSJUBVFBDDLC-YUMQZZPRSA-N Gly-Leu-Ser Chemical compound NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O NNCSJUBVFBDDLC-YUMQZZPRSA-N 0.000 description 2
- WNZOCXUOGVYYBJ-CDMKHQONSA-N Gly-Phe-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)NC(=O)CN)O WNZOCXUOGVYYBJ-CDMKHQONSA-N 0.000 description 2
- 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 2
- XHVONGZZVUUORG-WEDXCCLWSA-N Gly-Thr-Lys Chemical compound NCC(=O)N[C@@H]([C@H](O)C)C(=O)N[C@H](C(O)=O)CCCCN XHVONGZZVUUORG-WEDXCCLWSA-N 0.000 description 2
- 208000024869 Goodpasture syndrome Diseases 0.000 description 2
- 208000015023 Graves' disease Diseases 0.000 description 2
- 208000030836 Hashimoto thyroiditis Diseases 0.000 description 2
- 206010019695 Hepatic neoplasm Diseases 0.000 description 2
- 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 2
- 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 2
- 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 2
- 101000874316 Homo sapiens B melanoma antigen 1 Proteins 0.000 description 2
- 101000578784 Homo sapiens Melanoma antigen recognized by T-cells 1 Proteins 0.000 description 2
- 101000591210 Homo sapiens Receptor-type tyrosine-protein phosphatase-like N Proteins 0.000 description 2
- 102100034980 ICOS ligand Human genes 0.000 description 2
- 101710093458 ICOS ligand Proteins 0.000 description 2
- QQFSKBMCAKWHLG-UHFFFAOYSA-N Ile-Phe-Pro-Pro Chemical compound C1CCC(C(=O)N2C(CCC2)C(O)=O)N1C(=O)C(NC(=O)C(N)C(C)CC)CC1=CC=CC=C1 QQFSKBMCAKWHLG-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 206010061598 Immunodeficiency Diseases 0.000 description 2
- 102000037984 Inhibitory immune checkpoint proteins Human genes 0.000 description 2
- 108091008026 Inhibitory immune checkpoint proteins Proteins 0.000 description 2
- 108090001061 Insulin Proteins 0.000 description 2
- 102000004877 Insulin Human genes 0.000 description 2
- 108010065920 Insulin Lispro Proteins 0.000 description 2
- 102000015696 Interleukins Human genes 0.000 description 2
- 108010063738 Interleukins Proteins 0.000 description 2
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- JVTAAEKCZFNVCJ-REOHCLBHSA-N L-lactic acid Chemical compound C[C@H](O)C(O)=O JVTAAEKCZFNVCJ-REOHCLBHSA-N 0.000 description 2
- KSZCCRIGNVSHFH-UWVGGRQHSA-N Leu-Arg-Gly Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O KSZCCRIGNVSHFH-UWVGGRQHSA-N 0.000 description 2
- DBVWMYGBVFCRBE-CIUDSAMLSA-N Leu-Asn-Asn Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O DBVWMYGBVFCRBE-CIUDSAMLSA-N 0.000 description 2
- 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 2
- 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 2
- 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 2
- QJUWBDPGGYVRHY-YUMQZZPRSA-N Leu-Gly-Cys Chemical compound CC(C)C[C@@H](C(=O)NCC(=O)N[C@@H](CS)C(=O)O)N QJUWBDPGGYVRHY-YUMQZZPRSA-N 0.000 description 2
- APFJUBGRZGMQFF-QWRGUYRKSA-N Leu-Gly-Lys Chemical compound CC(C)C[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CCCCN APFJUBGRZGMQFF-QWRGUYRKSA-N 0.000 description 2
- 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 2
- HDHQQEDVWQGBEE-DCAQKATOSA-N Leu-Met-Ser Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CO)C(O)=O HDHQQEDVWQGBEE-DCAQKATOSA-N 0.000 description 2
- 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 2
- DPURXCQCHSQPAN-AVGNSLFASA-N Leu-Pro-Pro Chemical compound CC(C)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 DPURXCQCHSQPAN-AVGNSLFASA-N 0.000 description 2
- 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 2
- 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 2
- 206010025323 Lymphomas Diseases 0.000 description 2
- 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 2
- 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 2
- 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 2
- FGMHXLULNHTPID-KKUMJFAQSA-N Lys-His-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](CCCCN)C(O)=O)CC1=CN=CN1 FGMHXLULNHTPID-KKUMJFAQSA-N 0.000 description 2
- 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 2
- SQXZLVXQXWILKW-KKUMJFAQSA-N Lys-Ser-Phe Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O SQXZLVXQXWILKW-KKUMJFAQSA-N 0.000 description 2
- YFQSSOAGMZGXFT-MEYUZBJRSA-N Lys-Thr-Tyr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O YFQSSOAGMZGXFT-MEYUZBJRSA-N 0.000 description 2
- 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 2
- 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 2
- 102100022430 Melanocyte protein PMEL Human genes 0.000 description 2
- 102100028389 Melanoma antigen recognized by T-cells 1 Human genes 0.000 description 2
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 2
- 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 2
- 108700020796 Oncogene Proteins 0.000 description 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 2
- 201000011152 Pemphigus Diseases 0.000 description 2
- 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 2
- FIRWJEJVFFGXSH-RYUDHWBXSA-N Phe-Glu-Gly Chemical compound OC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CC1=CC=CC=C1 FIRWJEJVFFGXSH-RYUDHWBXSA-N 0.000 description 2
- 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 2
- JLLJTMHNXQTMCK-UBHSHLNASA-N Phe-Pro-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CC1=CC=CC=C1 JLLJTMHNXQTMCK-UBHSHLNASA-N 0.000 description 2
- WWPAHTZOWURIMR-ULQDDVLXSA-N Phe-Pro-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CC1=CC=CC=C1 WWPAHTZOWURIMR-ULQDDVLXSA-N 0.000 description 2
- XDMMOISUAHXXFD-SRVKXCTJSA-N Phe-Ser-Asp Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(O)=O XDMMOISUAHXXFD-SRVKXCTJSA-N 0.000 description 2
- 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 2
- 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 2
- 229920001244 Poly(D,L-lactide) Polymers 0.000 description 2
- 229920000954 Polyglycolide Polymers 0.000 description 2
- 239000004372 Polyvinyl alcohol Substances 0.000 description 2
- HQVPQXMCQKXARZ-FXQIFTODSA-N Pro-Cys-Ser Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CS)C(=O)N[C@@H](CO)C(=O)O HQVPQXMCQKXARZ-FXQIFTODSA-N 0.000 description 2
- 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 2
- FMLRRBDLBJLJIK-DCAQKATOSA-N Pro-Leu-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H]1CCCN1 FMLRRBDLBJLJIK-DCAQKATOSA-N 0.000 description 2
- 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 2
- 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 2
- 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 2
- OWQXAJQZLWHPBH-FXQIFTODSA-N Pro-Ser-Asn Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O OWQXAJQZLWHPBH-FXQIFTODSA-N 0.000 description 2
- 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 2
- 206010060862 Prostate cancer Diseases 0.000 description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 2
- 102100034091 Receptor-type tyrosine-protein phosphatase-like N Human genes 0.000 description 2
- 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 2
- QVOGDCQNGLBNCR-FXQIFTODSA-N Ser-Arg-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(O)=O QVOGDCQNGLBNCR-FXQIFTODSA-N 0.000 description 2
- 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 2
- UGJRQLURDVGULT-LKXGYXEUSA-N Ser-Asn-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O UGJRQLURDVGULT-LKXGYXEUSA-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
- 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 2
- GZFAWAQTEYDKII-YUMQZZPRSA-N Ser-Gly-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CO GZFAWAQTEYDKII-YUMQZZPRSA-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
- PPNPDKGQRFSCAC-CIUDSAMLSA-N Ser-Lys-Asp Chemical compound NCCCC[C@H](NC(=O)[C@@H](N)CO)C(=O)N[C@@H](CC(O)=O)C(O)=O PPNPDKGQRFSCAC-CIUDSAMLSA-N 0.000 description 2
- HHJFMHQYEAAOBM-ZLUOBGJFSA-N Ser-Ser-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(O)=O HHJFMHQYEAAOBM-ZLUOBGJFSA-N 0.000 description 2
- 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 2
- BMKNXTJLHFIAAH-CIUDSAMLSA-N Ser-Ser-Leu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O BMKNXTJLHFIAAH-CIUDSAMLSA-N 0.000 description 2
- 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 2
- VGQVAVQWKJLIRM-FXQIFTODSA-N Ser-Ser-Val Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O VGQVAVQWKJLIRM-FXQIFTODSA-N 0.000 description 2
- XJDMUQCLVSCRSJ-VZFHVOOUSA-N Ser-Thr-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O XJDMUQCLVSCRSJ-VZFHVOOUSA-N 0.000 description 2
- 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 2
- RCOUFINCYASMDN-GUBZILKMSA-N Ser-Val-Met Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCSC)C(O)=O RCOUFINCYASMDN-GUBZILKMSA-N 0.000 description 2
- 208000005718 Stomach Neoplasms Diseases 0.000 description 2
- 108010090804 Streptavidin Proteins 0.000 description 2
- 101800001271 Surface protein Proteins 0.000 description 2
- 230000005867 T cell response Effects 0.000 description 2
- ODSAPYVQSLDRSR-LKXGYXEUSA-N Thr-Cys-Asn Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(O)=O ODSAPYVQSLDRSR-LKXGYXEUSA-N 0.000 description 2
- 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 2
- 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 2
- CYVQBKQYQGEELV-NKIYYHGXSA-N Thr-His-Gln Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N)O CYVQBKQYQGEELV-NKIYYHGXSA-N 0.000 description 2
- FIFDDJFLNVAVMS-RHYQMDGZSA-N Thr-Leu-Met Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(O)=O FIFDDJFLNVAVMS-RHYQMDGZSA-N 0.000 description 2
- 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 2
- 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 2
- 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 2
- XHWCDRUPDNSDAZ-XKBZYTNZSA-N Thr-Ser-Glu Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N)O XHWCDRUPDNSDAZ-XKBZYTNZSA-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
- 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 2
- 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 2
- UKINEYBQXPMOJO-UBHSHLNASA-N Trp-Asn-Ser Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CO)C(=O)O)N UKINEYBQXPMOJO-UBHSHLNASA-N 0.000 description 2
- 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 2
- SVGAWGVHFIYAEE-JSGCOSHPSA-N Trp-Gly-Gln Chemical compound C1=CC=C2C(C[C@H](N)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(O)=O)=CNC2=C1 SVGAWGVHFIYAEE-JSGCOSHPSA-N 0.000 description 2
- GQHAIUPYZPTADF-FDARSICLSA-N Trp-Ile-Arg Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O)=CNC2=C1 GQHAIUPYZPTADF-FDARSICLSA-N 0.000 description 2
- 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 2
- 102100022153 Tumor necrosis factor receptor superfamily member 4 Human genes 0.000 description 2
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 2
- 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 2
- AUZADXNWQMBZOO-JYJNAYRXSA-N Tyr-Pro-Arg Chemical compound C([C@H](N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O)C1=CC=C(O)C=C1 AUZADXNWQMBZOO-JYJNAYRXSA-N 0.000 description 2
- 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 2
- 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 2
- 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 2
- 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 2
- ZQGPWORGSNRQLN-NHCYSSNCSA-N Val-Asp-His Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N ZQGPWORGSNRQLN-NHCYSSNCSA-N 0.000 description 2
- OVLIFGQSBSNGHY-KKHAAJSZSA-N Val-Asp-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](C(C)C)N)O OVLIFGQSBSNGHY-KKHAAJSZSA-N 0.000 description 2
- LHADRQBREKTRLR-DCAQKATOSA-N Val-Cys-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CS)NC(=O)[C@H](C(C)C)N LHADRQBREKTRLR-DCAQKATOSA-N 0.000 description 2
- 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 2
- OXVPMZVGCAPFIG-BQFCYCMXSA-N Val-Gln-Trp Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)N OXVPMZVGCAPFIG-BQFCYCMXSA-N 0.000 description 2
- 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 2
- ZIGZPYJXIWLQFC-QTKMDUPCSA-N Val-His-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CN=CN1)NC(=O)[C@H](C(C)C)N)O ZIGZPYJXIWLQFC-QTKMDUPCSA-N 0.000 description 2
- 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 2
- 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 2
- QPJSIBAOZBVELU-BPNCWPANSA-N Val-Tyr-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)NC(=O)[C@H](C(C)C)N QPJSIBAOZBVELU-BPNCWPANSA-N 0.000 description 2
- 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 2
- 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 2
- 208000018756 Variant Creutzfeldt-Jakob disease Diseases 0.000 description 2
- 108010067390 Viral Proteins Proteins 0.000 description 2
- 230000003213 activating effect Effects 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 238000007792 addition Methods 0.000 description 2
- 238000011374 additional therapy Methods 0.000 description 2
- 235000004279 alanine Nutrition 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 108010026331 alpha-Fetoproteins Proteins 0.000 description 2
- 108010050025 alpha-glutamyltryptophan Proteins 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 108010092854 aspartyllysine Proteins 0.000 description 2
- 102000015736 beta 2-Microglobulin Human genes 0.000 description 2
- 108010081355 beta 2-Microglobulin Proteins 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 230000017531 blood circulation Effects 0.000 description 2
- 208000005881 bovine spongiform encephalopathy Diseases 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 238000012412 chemical coupling Methods 0.000 description 2
- 230000001351 cycling effect Effects 0.000 description 2
- 210000001151 cytotoxic T lymphocyte Anatomy 0.000 description 2
- 230000007402 cytotoxic response Effects 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 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 2
- 238000009826 distribution Methods 0.000 description 2
- 239000012636 effector Substances 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 239000005038 ethylene vinyl acetate Substances 0.000 description 2
- 201000006061 fatal familial insomnia Diseases 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
- 239000012737 fresh medium Substances 0.000 description 2
- 229960002989 glutamic acid Drugs 0.000 description 2
- 235000013922 glutamic acid Nutrition 0.000 description 2
- 239000004220 glutamic acid Substances 0.000 description 2
- 108010078144 glutaminyl-glycine Proteins 0.000 description 2
- 108010015792 glycyllysine Proteins 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 239000003102 growth factor Substances 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 208000014829 head and neck neoplasm Diseases 0.000 description 2
- 102000047279 human B2M Human genes 0.000 description 2
- 230000028993 immune response Effects 0.000 description 2
- 230000002163 immunogen Effects 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 206010022000 influenza Diseases 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 244000000056 intracellular parasite Species 0.000 description 2
- 229960005386 ipilimumab Drugs 0.000 description 2
- 229920000126 latex Polymers 0.000 description 2
- 239000004816 latex Substances 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 238000013507 mapping Methods 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 239000000178 monomer Substances 0.000 description 2
- 201000006417 multiple sclerosis Diseases 0.000 description 2
- 206010028417 myasthenia gravis Diseases 0.000 description 2
- 201000005962 mycosis fungoides Diseases 0.000 description 2
- 229960003301 nivolumab Drugs 0.000 description 2
- 231100000590 oncogenic Toxicity 0.000 description 2
- 230000002246 oncogenic effect Effects 0.000 description 2
- 244000045947 parasite Species 0.000 description 2
- 230000036961 partial effect Effects 0.000 description 2
- 201000001976 pemphigus vulgaris Diseases 0.000 description 2
- 230000003285 pharmacodynamic effect Effects 0.000 description 2
- 108010073101 phenylalanylleucine Proteins 0.000 description 2
- 229920000729 poly(L-lysine) polymer Polymers 0.000 description 2
- 229920000233 poly(alkylene oxides) Polymers 0.000 description 2
- 229920001200 poly(ethylene-vinyl acetate) Polymers 0.000 description 2
- 229920000747 poly(lactic acid) Polymers 0.000 description 2
- 229920002643 polyglutamic acid Polymers 0.000 description 2
- 108091033319 polynucleotide Proteins 0.000 description 2
- 102000040430 polynucleotide Human genes 0.000 description 2
- 239000002157 polynucleotide Substances 0.000 description 2
- 239000004814 polyurethane Substances 0.000 description 2
- 229920002635 polyurethane Polymers 0.000 description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 description 2
- 229920000915 polyvinyl chloride Polymers 0.000 description 2
- 239000004800 polyvinyl chloride Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 108010053725 prolylvaline Proteins 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 description 2
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 2
- 230000006641 stabilisation Effects 0.000 description 2
- 238000011105 stabilization Methods 0.000 description 2
- 230000000087 stabilizing effect Effects 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- 108010071097 threonyl-lysyl-proline Proteins 0.000 description 2
- 230000001052 transient effect Effects 0.000 description 2
- 238000002054 transplantation Methods 0.000 description 2
- 230000032258 transport Effects 0.000 description 2
- 238000011282 treatment Methods 0.000 description 2
- 108010080629 tryptophan-leucine Proteins 0.000 description 2
- 108010071635 tyrosyl-prolyl-arginine Proteins 0.000 description 2
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 2
- 230000003612 virological effect Effects 0.000 description 2
- 108010027345 wheylin-1 peptide Proteins 0.000 description 2
- LAQPKDLYOBZWBT-NYLDSJSYSA-N (2s,4s,5r,6r)-5-acetamido-2-{[(2s,3r,4s,5s,6r)-2-{[(2r,3r,4r,5r)-5-acetamido-1,2-dihydroxy-6-oxo-4-{[(2s,3s,4r,5s,6s)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxy}hexan-3-yl]oxy}-3,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy}-4-hydroxy-6-[(1r,2r)-1,2,3-trihydrox Chemical compound O[C@H]1[C@H](O)[C@H](O)[C@H](C)O[C@H]1O[C@H]([C@@H](NC(C)=O)C=O)[C@@H]([C@H](O)CO)O[C@H]1[C@H](O)[C@@H](O[C@]2(O[C@H]([C@H](NC(C)=O)[C@@H](O)C2)[C@H](O)[C@H](O)CO)C(O)=O)[C@@H](O)[C@@H](CO)O1 LAQPKDLYOBZWBT-NYLDSJSYSA-N 0.000 description 1
- SSOORFWOBGFTHL-OTEJMHTDSA-N (4S)-5-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[2-[(2S)-2-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-1-[[(2S)-1-[[(2S,3S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-5-amino-1-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-6-amino-1-[[(2S)-1-[[(2S)-1-[[(2S)-5-amino-1-[[(2S)-5-carbamimidamido-1-[[(2S)-5-carbamimidamido-1-[[(1S)-4-carbamimidamido-1-carboxybutyl]amino]-1-oxopentan-2-yl]amino]-1-oxopentan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-1-oxohexan-2-yl]amino]-1-oxohexan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-1-oxohexan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-methyl-1-oxopentan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-1-oxohexan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-1-oxopropan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]carbamoyl]pyrrolidin-1-yl]-2-oxoethyl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-1-oxohexan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(1H-imidazol-4-yl)-1-oxopropan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-4-[[(2S)-2-[[(2S)-2-[[(2S)-2,6-diaminohexanoyl]amino]-3-methylbutanoyl]amino]propanoyl]amino]-5-oxopentanoic acid Chemical compound CC[C@H](C)[C@H](NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H]1CCCN1C(=O)CNC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@@H](N)CCCCN)C(C)C)C(C)C)C(C)C)C(C)C)C(C)C)C(C)C)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O SSOORFWOBGFTHL-OTEJMHTDSA-N 0.000 description 1
- 150000003923 2,5-pyrrolediones Chemical class 0.000 description 1
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- WEVYNIUIFUYDGI-UHFFFAOYSA-N 3-[6-[4-(trifluoromethoxy)anilino]-4-pyrimidinyl]benzamide Chemical compound NC(=O)C1=CC=CC(C=2N=CN=C(NC=3C=CC(OC(F)(F)F)=CC=3)C=2)=C1 WEVYNIUIFUYDGI-UHFFFAOYSA-N 0.000 description 1
- BHPSIKROCCEKQR-UHFFFAOYSA-N 3-sulfanylpyrrole-2,5-dione Chemical compound SC1=CC(=O)NC1=O BHPSIKROCCEKQR-UHFFFAOYSA-N 0.000 description 1
- VOUAQYXWVJDEQY-QENPJCQMSA-N 33017-11-7 Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)NCC(=O)NCC(=O)N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N1[C@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O)CCC1 VOUAQYXWVJDEQY-QENPJCQMSA-N 0.000 description 1
- 108010082808 4-1BB Ligand Proteins 0.000 description 1
- 102100038222 60 kDa heat shock protein, mitochondrial Human genes 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- 241000589291 Acinetobacter Species 0.000 description 1
- 206010069754 Acquired gene mutation Diseases 0.000 description 1
- 241000203716 Actinomycetaceae Species 0.000 description 1
- 206010000830 Acute leukaemia Diseases 0.000 description 1
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 1
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 1
- BUANFPRKJKJSRR-ACZMJKKPSA-N Ala-Ala-Gln Chemical compound C[C@H]([NH3+])C(=O)N[C@@H](C)C(=O)N[C@H](C([O-])=O)CCC(N)=O BUANFPRKJKJSRR-ACZMJKKPSA-N 0.000 description 1
- FOWHQTWRLFTELJ-FXQIFTODSA-N Ala-Asp-Met Chemical compound C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CCSC)C(=O)O)N FOWHQTWRLFTELJ-FXQIFTODSA-N 0.000 description 1
- VGPWRRFOPXVGOH-BYPYZUCNSA-N Ala-Gly-Gly Chemical compound C[C@H](N)C(=O)NCC(=O)NCC(O)=O VGPWRRFOPXVGOH-BYPYZUCNSA-N 0.000 description 1
- SUMYEVXWCAYLLJ-GUBZILKMSA-N Ala-Leu-Gln Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O SUMYEVXWCAYLLJ-GUBZILKMSA-N 0.000 description 1
- 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 1
- MDNAVFBZPROEHO-DCAQKATOSA-N Ala-Lys-Val Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(O)=O MDNAVFBZPROEHO-DCAQKATOSA-N 0.000 description 1
- BTRULDJUUVGRNE-DCAQKATOSA-N Ala-Pro-Lys Chemical compound C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(O)=O BTRULDJUUVGRNE-DCAQKATOSA-N 0.000 description 1
- XWFWAXPOLRTDFZ-FXQIFTODSA-N Ala-Pro-Ser Chemical compound C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O XWFWAXPOLRTDFZ-FXQIFTODSA-N 0.000 description 1
- JNLDTVRGXMSYJC-UVBJJODRSA-N Ala-Pro-Trp Chemical compound C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(O)=O JNLDTVRGXMSYJC-UVBJJODRSA-N 0.000 description 1
- OMCKWYSDUQBYCN-FXQIFTODSA-N Ala-Ser-Met Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCSC)C(O)=O OMCKWYSDUQBYCN-FXQIFTODSA-N 0.000 description 1
- ZJLORAAXDAJLDC-CQDKDKBSSA-N Ala-Tyr-Leu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(C)C)C(O)=O ZJLORAAXDAJLDC-CQDKDKBSSA-N 0.000 description 1
- VHAQSYHSDKERBS-XPUUQOCRSA-N Ala-Val-Gly Chemical compound C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)NCC(O)=O VHAQSYHSDKERBS-XPUUQOCRSA-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
- 102100024321 Alkaline phosphatase, placental type Human genes 0.000 description 1
- GIVATXIGCXFQQA-FXQIFTODSA-N Arg-Ala-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCN=C(N)N GIVATXIGCXFQQA-FXQIFTODSA-N 0.000 description 1
- YUIGJDNAGKJLDO-JYJNAYRXSA-N Arg-Arg-Tyr Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O YUIGJDNAGKJLDO-JYJNAYRXSA-N 0.000 description 1
- KMSHNDWHPWXPEC-BQBZGAKWSA-N Arg-Asp-Gly Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(O)=O KMSHNDWHPWXPEC-BQBZGAKWSA-N 0.000 description 1
- ZEAYJGRKRUBDOB-GARJFASQSA-N Arg-Gln-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CCCN=C(N)N)N)C(=O)O ZEAYJGRKRUBDOB-GARJFASQSA-N 0.000 description 1
- YLVGUOGAFAJMKP-JYJNAYRXSA-N Arg-Met-Tyr Chemical compound CSCC[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)O)NC(=O)[C@H](CCCN=C(N)N)N YLVGUOGAFAJMKP-JYJNAYRXSA-N 0.000 description 1
- HGKHPCFTRQDHCU-IUCAKERBSA-N Arg-Pro-Gly Chemical compound NC(N)=NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O HGKHPCFTRQDHCU-IUCAKERBSA-N 0.000 description 1
- WCZXPVPHUMYLMS-VEVYYDQMSA-N Arg-Thr-Asp Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(O)=O WCZXPVPHUMYLMS-VEVYYDQMSA-N 0.000 description 1
- QTAIIXQCOPUNBQ-QXEWZRGKSA-N Arg-Val-Asp Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O QTAIIXQCOPUNBQ-QXEWZRGKSA-N 0.000 description 1
- NVGWESORMHFISY-SRVKXCTJSA-N Asn-Asn-Phe Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O NVGWESORMHFISY-SRVKXCTJSA-N 0.000 description 1
- QPTAGIPWARILES-AVGNSLFASA-N Asn-Gln-Phe Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O QPTAGIPWARILES-AVGNSLFASA-N 0.000 description 1
- XTMZYFMTYJNABC-ZLUOBGJFSA-N Asn-Ser-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(=O)N)N XTMZYFMTYJNABC-ZLUOBGJFSA-N 0.000 description 1
- PUUPMDXIHCOPJU-HJGDQZAQSA-N Asn-Thr-Lys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC(=O)N)N)O PUUPMDXIHCOPJU-HJGDQZAQSA-N 0.000 description 1
- 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 1
- MYRLSKYSMXNLLA-LAEOZQHASA-N Asn-Val-Glu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O MYRLSKYSMXNLLA-LAEOZQHASA-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
- SVABRQFIHCSNCI-FOHZUACHSA-N Asp-Gly-Thr Chemical compound [H]N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(O)=O SVABRQFIHCSNCI-FOHZUACHSA-N 0.000 description 1
- CRNKLABLTICXDV-GUBZILKMSA-N Asp-His-Glu Chemical compound C1=C(NC=N1)C[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)O)NC(=O)[C@H](CC(=O)O)N CRNKLABLTICXDV-GUBZILKMSA-N 0.000 description 1
- LBOVBQONZJRWPV-YUMQZZPRSA-N Asp-Lys-Gly Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)NCC(O)=O LBOVBQONZJRWPV-YUMQZZPRSA-N 0.000 description 1
- QOCFFCUFZGDHTP-NUMRIWBASA-N Asp-Thr-Gln Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(N)=O)C(O)=O QOCFFCUFZGDHTP-NUMRIWBASA-N 0.000 description 1
- KNDCWFXCFKSEBM-AVGNSLFASA-N Asp-Tyr-Glu Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCC(O)=O)C(O)=O KNDCWFXCFKSEBM-AVGNSLFASA-N 0.000 description 1
- HTSSXFASOUSJQG-IHPCNDPISA-N Asp-Tyr-Trp Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O HTSSXFASOUSJQG-IHPCNDPISA-N 0.000 description 1
- 241000228212 Aspergillus Species 0.000 description 1
- 208000004736 B-Cell Leukemia Diseases 0.000 description 1
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 1
- 208000003950 B-cell lymphoma Diseases 0.000 description 1
- 102100024222 B-lymphocyte antigen CD19 Human genes 0.000 description 1
- 102100022005 B-lymphocyte antigen CD20 Human genes 0.000 description 1
- 241001112741 Bacillaceae Species 0.000 description 1
- 241000606662 Bartonellaceae Species 0.000 description 1
- 241000335423 Blastomyces Species 0.000 description 1
- 102000004506 Blood Proteins Human genes 0.000 description 1
- 108010017384 Blood Proteins Proteins 0.000 description 1
- 241000588807 Bordetella Species 0.000 description 1
- 241000589562 Brucella Species 0.000 description 1
- 108010075254 C-Peptide Proteins 0.000 description 1
- 101150011672 CCL9 gene Proteins 0.000 description 1
- 102100027207 CD27 antigen Human genes 0.000 description 1
- 102100038078 CD276 antigen Human genes 0.000 description 1
- 101710185679 CD276 antigen Proteins 0.000 description 1
- 108010029697 CD40 Ligand Proteins 0.000 description 1
- 101150013553 CD40 gene Proteins 0.000 description 1
- 102100032937 CD40 ligand Human genes 0.000 description 1
- 108010084313 CD58 Antigens Proteins 0.000 description 1
- 101100314454 Caenorhabditis elegans tra-1 gene Proteins 0.000 description 1
- 241000589876 Campylobacter Species 0.000 description 1
- 241000222120 Candida <Saccharomycetales> Species 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 102100032378 Carboxypeptidase E Human genes 0.000 description 1
- 108010058255 Carboxypeptidase H Proteins 0.000 description 1
- 102100025064 Cellular tumor antigen p53 Human genes 0.000 description 1
- 108010058432 Chaperonin 60 Proteins 0.000 description 1
- 102000019034 Chemokines Human genes 0.000 description 1
- 108010012236 Chemokines Proteins 0.000 description 1
- 241000606069 Chlamydiaceae Species 0.000 description 1
- 206010008803 Chromoblastomycosis Diseases 0.000 description 1
- 208000015116 Chromomycosis Diseases 0.000 description 1
- 241000223203 Coccidioides Species 0.000 description 1
- 108020004705 Codon Proteins 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 102000010970 Connexin Human genes 0.000 description 1
- 108050001175 Connexin Proteins 0.000 description 1
- 241000186031 Corynebacteriaceae Species 0.000 description 1
- 208000020406 Creutzfeldt Jacob disease Diseases 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- 241001337994 Cryptococcus <scale insect> Species 0.000 description 1
- WVLZTXGTNGHPBO-SRVKXCTJSA-N Cys-Leu-Leu Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O WVLZTXGTNGHPBO-SRVKXCTJSA-N 0.000 description 1
- BCFXQBXXDSEHRS-FXQIFTODSA-N Cys-Ser-Arg Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O BCFXQBXXDSEHRS-FXQIFTODSA-N 0.000 description 1
- KFYPRIGJTICABD-XGEHTFHBSA-N Cys-Thr-Val Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](C(C)C)C(=O)O)NC(=O)[C@H](CS)N)O KFYPRIGJTICABD-XGEHTFHBSA-N 0.000 description 1
- YFKWIIRWHGKSQQ-WFBYXXMGSA-N Cys-Trp-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)NC(=O)[C@H](CS)N YFKWIIRWHGKSQQ-WFBYXXMGSA-N 0.000 description 1
- VIOQRFNAZDMVLO-NRPADANISA-N Cys-Val-Glu Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O VIOQRFNAZDMVLO-NRPADANISA-N 0.000 description 1
- 206010011831 Cytomegalovirus infection Diseases 0.000 description 1
- 102000016928 DNA-directed DNA polymerase Human genes 0.000 description 1
- 108010014303 DNA-directed DNA polymerase Proteins 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 208000002699 Digestive System Neoplasms Diseases 0.000 description 1
- 208000006926 Discoid Lupus Erythematosus Diseases 0.000 description 1
- 206010061825 Duodenal neoplasm Diseases 0.000 description 1
- 206010014733 Endometrial cancer Diseases 0.000 description 1
- 206010014759 Endometrial neoplasm Diseases 0.000 description 1
- 241000588921 Enterobacteriaceae Species 0.000 description 1
- 241001480035 Epidermophyton Species 0.000 description 1
- 102100031940 Epithelial cell adhesion molecule Human genes 0.000 description 1
- 206010015108 Epstein-Barr virus infection Diseases 0.000 description 1
- 241000588698 Erwinia Species 0.000 description 1
- 101710142246 External core antigen Proteins 0.000 description 1
- 208000009849 Female Genital Neoplasms Diseases 0.000 description 1
- 241000589601 Francisella Species 0.000 description 1
- 101710177291 Gag polyprotein Proteins 0.000 description 1
- 208000032612 Glial tumor Diseases 0.000 description 1
- 206010018338 Glioma Diseases 0.000 description 1
- KJRXLVZYJJLUCV-DCAQKATOSA-N Gln-Arg-Met Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCSC)C(O)=O KJRXLVZYJJLUCV-DCAQKATOSA-N 0.000 description 1
- WLODHVXYKYHLJD-ACZMJKKPSA-N Gln-Asp-Ser Chemical compound C(CC(=O)N)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CO)C(=O)O)N WLODHVXYKYHLJD-ACZMJKKPSA-N 0.000 description 1
- SNLOOPZHAQDMJG-CIUDSAMLSA-N Gln-Glu-Glu Chemical compound NC(=O)CC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O SNLOOPZHAQDMJG-CIUDSAMLSA-N 0.000 description 1
- ZNZPKVQURDQFFS-FXQIFTODSA-N Gln-Glu-Ser Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(O)=O ZNZPKVQURDQFFS-FXQIFTODSA-N 0.000 description 1
- HWEINOMSWQSJDC-SRVKXCTJSA-N Gln-Leu-Arg Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O HWEINOMSWQSJDC-SRVKXCTJSA-N 0.000 description 1
- 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 1
- OSCLNNWLKKIQJM-WDSKDSINSA-N Gln-Ser-Gly Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)NCC(O)=O OSCLNNWLKKIQJM-WDSKDSINSA-N 0.000 description 1
- SYTFJIQPBRJSOK-NKIYYHGXSA-N Gln-Thr-His Chemical compound NC(=O)CC[C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@H](C(O)=O)CC1=CN=CN1 SYTFJIQPBRJSOK-NKIYYHGXSA-N 0.000 description 1
- BETSEXMYBWCDAE-SZMVWBNQSA-N Gln-Trp-Lys Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCC(=O)N)N BETSEXMYBWCDAE-SZMVWBNQSA-N 0.000 description 1
- 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 1
- VAIWPXWHWAPYDF-FXQIFTODSA-N Glu-Asp-Gln Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O VAIWPXWHWAPYDF-FXQIFTODSA-N 0.000 description 1
- GFLQTABMFBXRIY-GUBZILKMSA-N Glu-Gln-Arg Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O GFLQTABMFBXRIY-GUBZILKMSA-N 0.000 description 1
- 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 1
- HPJLZFTUUJKWAJ-JHEQGTHGSA-N Glu-Gly-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(O)=O HPJLZFTUUJKWAJ-JHEQGTHGSA-N 0.000 description 1
- ZSWGJYOZWBHROQ-RWRJDSDZSA-N Glu-Ile-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(O)=O ZSWGJYOZWBHROQ-RWRJDSDZSA-N 0.000 description 1
- TWYFJOHWGCCRIR-DCAQKATOSA-N Glu-Pro-Arg Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(N)=N)C(O)=O TWYFJOHWGCCRIR-DCAQKATOSA-N 0.000 description 1
- DMYACXMQUABZIQ-NRPADANISA-N Glu-Ser-Val Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O DMYACXMQUABZIQ-NRPADANISA-N 0.000 description 1
- TWYSSILQABLLME-HJGDQZAQSA-N Glu-Thr-Arg Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O TWYSSILQABLLME-HJGDQZAQSA-N 0.000 description 1
- LSYFGBRDBIQYAQ-FHWLQOOXSA-N Glu-Tyr-Tyr 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](CC1=CC=C(O)C=C1)C(O)=O LSYFGBRDBIQYAQ-FHWLQOOXSA-N 0.000 description 1
- 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 1
- 102100036255 Glucose-6-phosphatase 2 Human genes 0.000 description 1
- XCLCVBYNGXEVDU-WHFBIAKZSA-N Gly-Asn-Ser Chemical compound NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(O)=O XCLCVBYNGXEVDU-WHFBIAKZSA-N 0.000 description 1
- GZBZACMXFIPIDX-WHFBIAKZSA-N Gly-Cys-Asp Chemical compound C([C@@H](C(=O)O)NC(=O)[C@H](CS)NC(=O)CN)C(=O)O GZBZACMXFIPIDX-WHFBIAKZSA-N 0.000 description 1
- BYYNJRSNDARRBX-YFKPBYRVSA-N Gly-Gln-Gly Chemical compound NCC(=O)N[C@@H](CCC(N)=O)C(=O)NCC(O)=O BYYNJRSNDARRBX-YFKPBYRVSA-N 0.000 description 1
- MBOAPAXLTUSMQI-JHEQGTHGSA-N Gly-Glu-Thr Chemical compound [H]NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O MBOAPAXLTUSMQI-JHEQGTHGSA-N 0.000 description 1
- ULZCYBYDTUMHNF-IUCAKERBSA-N Gly-Leu-Glu Chemical compound NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O ULZCYBYDTUMHNF-IUCAKERBSA-N 0.000 description 1
- LOEANKRDMMVOGZ-YUMQZZPRSA-N Gly-Lys-Asp Chemical compound NCCCC[C@H](NC(=O)CN)C(=O)N[C@@H](CC(O)=O)C(O)=O LOEANKRDMMVOGZ-YUMQZZPRSA-N 0.000 description 1
- QAMMIGULQSIRCD-IRXDYDNUSA-N Gly-Phe-Tyr Chemical compound C([C@H](NC(=O)C[NH3+])C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C([O-])=O)C1=CC=CC=C1 QAMMIGULQSIRCD-IRXDYDNUSA-N 0.000 description 1
- JJGBXTYGTKWGAT-YUMQZZPRSA-N Gly-Pro-Glu Chemical compound NCC(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O JJGBXTYGTKWGAT-YUMQZZPRSA-N 0.000 description 1
- OHUKZZYSJBKFRR-WHFBIAKZSA-N Gly-Ser-Asp Chemical compound [H]NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(O)=O OHUKZZYSJBKFRR-WHFBIAKZSA-N 0.000 description 1
- FFJQHWKSGAWSTJ-BFHQHQDPSA-N Gly-Thr-Ala Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O FFJQHWKSGAWSTJ-BFHQHQDPSA-N 0.000 description 1
- FKESCSGWBPUTPN-FOHZUACHSA-N Gly-Thr-Asn Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(O)=O FKESCSGWBPUTPN-FOHZUACHSA-N 0.000 description 1
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Natural products NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- RVKIPWVMZANZLI-UHFFFAOYSA-N H-Lys-Trp-OH Natural products C1=CC=C2C(CC(NC(=O)C(N)CCCCN)C(O)=O)=CNC2=C1 RVKIPWVMZANZLI-UHFFFAOYSA-N 0.000 description 1
- 102000006354 HLA-DR Antigens Human genes 0.000 description 1
- 108010058597 HLA-DR Antigens Proteins 0.000 description 1
- 208000002250 Hematologic Neoplasms Diseases 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
- HVCRQRQPIIRNLY-IUCAKERBSA-N His-Gln-Gly Chemical compound C1=C(NC=N1)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)NCC(=O)O)N HVCRQRQPIIRNLY-IUCAKERBSA-N 0.000 description 1
- MVZASEMJYJPJSI-IHPCNDPISA-N His-Lys-Trp Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC3=CN=CN3)N MVZASEMJYJPJSI-IHPCNDPISA-N 0.000 description 1
- TVMNTHXFRSXZGR-IHRRRGAJSA-N His-Lys-Val Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(O)=O TVMNTHXFRSXZGR-IHRRRGAJSA-N 0.000 description 1
- CSRRMQFXMBPSIL-SIXJUCDHSA-N His-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](CC3=CN=CN3)N CSRRMQFXMBPSIL-SIXJUCDHSA-N 0.000 description 1
- 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 1
- WSXNWASHQNSMRX-GVXVVHGQSA-N His-Val-Gln Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CC1=CN=CN1)N WSXNWASHQNSMRX-GVXVVHGQSA-N 0.000 description 1
- 241000228402 Histoplasma Species 0.000 description 1
- 208000017604 Hodgkin disease Diseases 0.000 description 1
- 208000021519 Hodgkin lymphoma Diseases 0.000 description 1
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 1
- 101000980825 Homo sapiens B-lymphocyte antigen CD19 Proteins 0.000 description 1
- 101000897405 Homo sapiens B-lymphocyte antigen CD20 Proteins 0.000 description 1
- 101000914511 Homo sapiens CD27 antigen Proteins 0.000 description 1
- 101000920667 Homo sapiens Epithelial cell adhesion molecule Proteins 0.000 description 1
- 101000930907 Homo sapiens Glucose-6-phosphatase 2 Proteins 0.000 description 1
- 101000777628 Homo sapiens Leukocyte antigen CD37 Proteins 0.000 description 1
- 101000914484 Homo sapiens T-lymphocyte activation antigen CD80 Proteins 0.000 description 1
- 101001050288 Homo sapiens Transcription factor Jun Proteins 0.000 description 1
- 101000825079 Homo sapiens Transcription factor SOX-13 Proteins 0.000 description 1
- 101000764263 Homo sapiens Tumor necrosis factor ligand superfamily member 4 Proteins 0.000 description 1
- 101000801234 Homo sapiens Tumor necrosis factor receptor superfamily member 18 Proteins 0.000 description 1
- 101000679851 Homo sapiens Tumor necrosis factor receptor superfamily member 4 Proteins 0.000 description 1
- 101000851376 Homo sapiens Tumor necrosis factor receptor superfamily member 8 Proteins 0.000 description 1
- 108010048209 Human Immunodeficiency Virus Proteins Proteins 0.000 description 1
- 108090000144 Human Proteins Proteins 0.000 description 1
- 102000003839 Human Proteins Human genes 0.000 description 1
- 102000008100 Human Serum Albumin Human genes 0.000 description 1
- 108091006905 Human Serum Albumin Proteins 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- LGMUPVWZEYYUMU-YVNDNENWSA-N Ile-Glu-Gln Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N LGMUPVWZEYYUMU-YVNDNENWSA-N 0.000 description 1
- JTBFQNHKNRZJDS-SYWGBEHUSA-N Ile-Trp-Ala Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)N[C@@H](C)C(=O)O)N JTBFQNHKNRZJDS-SYWGBEHUSA-N 0.000 description 1
- 102000009786 Immunoglobulin Constant Regions Human genes 0.000 description 1
- 108010009817 Immunoglobulin Constant Regions Proteins 0.000 description 1
- 108010064593 Intercellular Adhesion Molecule-1 Proteins 0.000 description 1
- 102100037877 Intercellular adhesion molecule 1 Human genes 0.000 description 1
- 108010074328 Interferon-gamma Proteins 0.000 description 1
- 102000008070 Interferon-gamma Human genes 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- 102000003814 Interleukin-10 Human genes 0.000 description 1
- 108090000174 Interleukin-10 Proteins 0.000 description 1
- 102000013462 Interleukin-12 Human genes 0.000 description 1
- 108010065805 Interleukin-12 Proteins 0.000 description 1
- 102000003812 Interleukin-15 Human genes 0.000 description 1
- 108090000172 Interleukin-15 Proteins 0.000 description 1
- 102000010789 Interleukin-2 Receptors Human genes 0.000 description 1
- 108010038453 Interleukin-2 Receptors Proteins 0.000 description 1
- 102000004388 Interleukin-4 Human genes 0.000 description 1
- 108090000978 Interleukin-4 Proteins 0.000 description 1
- 108010002586 Interleukin-7 Proteins 0.000 description 1
- 102000000704 Interleukin-7 Human genes 0.000 description 1
- 102100027640 Islet cell autoantigen 1 Human genes 0.000 description 1
- 108050004848 Islet cell autoantigen 1 Proteins 0.000 description 1
- 102000011782 Keratins Human genes 0.000 description 1
- 108010076876 Keratins Proteins 0.000 description 1
- 208000008839 Kidney Neoplasms Diseases 0.000 description 1
- 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 1
- 241000222722 Leishmania <genus> Species 0.000 description 1
- WSGXUIQTEZDVHJ-GARJFASQSA-N Leu-Ala-Pro Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H]1C(O)=O WSGXUIQTEZDVHJ-GARJFASQSA-N 0.000 description 1
- UCOCBWDBHCUPQP-DCAQKATOSA-N Leu-Arg-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(O)=O UCOCBWDBHCUPQP-DCAQKATOSA-N 0.000 description 1
- 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 1
- HVHRPWQEQHIQJF-AVGNSLFASA-N Leu-Lys-Glu Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(O)=O HVHRPWQEQHIQJF-AVGNSLFASA-N 0.000 description 1
- VCHVSKNMTXWIIP-SRVKXCTJSA-N Leu-Lys-Ser Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(O)=O VCHVSKNMTXWIIP-SRVKXCTJSA-N 0.000 description 1
- IWMJFLJQHIDZQW-KKUMJFAQSA-N Leu-Ser-Phe Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 IWMJFLJQHIDZQW-KKUMJFAQSA-N 0.000 description 1
- QWWPYKKLXWOITQ-VOAKCMCISA-N Leu-Thr-Leu 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)CC(C)C QWWPYKKLXWOITQ-VOAKCMCISA-N 0.000 description 1
- ILDSIMPXNFWKLH-KATARQTJSA-N Leu-Thr-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(O)=O ILDSIMPXNFWKLH-KATARQTJSA-N 0.000 description 1
- QESXLSQLQHHTIX-RHYQMDGZSA-N Leu-Val-Thr Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O QESXLSQLQHHTIX-RHYQMDGZSA-N 0.000 description 1
- 102100031586 Leukocyte antigen CD37 Human genes 0.000 description 1
- 241000186781 Listeria Species 0.000 description 1
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 1
- BTSXLXFPMZXVPR-DLOVCJGASA-N Lys-Ala-His Chemical compound C[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](CCCCN)N BTSXLXFPMZXVPR-DLOVCJGASA-N 0.000 description 1
- NRQRKMYZONPCTM-CIUDSAMLSA-N Lys-Asp-Ser Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O NRQRKMYZONPCTM-CIUDSAMLSA-N 0.000 description 1
- GQFDWEDHOQRNLC-QWRGUYRKSA-N Lys-Gly-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN GQFDWEDHOQRNLC-QWRGUYRKSA-N 0.000 description 1
- NNKLKUUGESXCBS-KBPBESRZSA-N Lys-Gly-Tyr Chemical compound [H]N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O NNKLKUUGESXCBS-KBPBESRZSA-N 0.000 description 1
- 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 1
- 108010010995 MART-1 Antigen Proteins 0.000 description 1
- 102000016200 MART-1 Antigen Human genes 0.000 description 1
- 101710125418 Major capsid protein Proteins 0.000 description 1
- 241000555676 Malassezia Species 0.000 description 1
- 102000051089 Melanotransferrin Human genes 0.000 description 1
- 108700038051 Melanotransferrin Proteins 0.000 description 1
- 108010061593 Member 14 Tumor Necrosis Factor Receptors Proteins 0.000 description 1
- 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 1
- 241000192017 Micrococcaceae Species 0.000 description 1
- 241001480037 Microsporum Species 0.000 description 1
- 208000003445 Mouth Neoplasms Diseases 0.000 description 1
- 102100023123 Mucin-16 Human genes 0.000 description 1
- 241000235395 Mucor Species 0.000 description 1
- 241000186360 Mycobacteriaceae Species 0.000 description 1
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical class ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 1
- 108010087066 N2-tryptophyllysine Proteins 0.000 description 1
- 108091007491 NSP3 Papain-like protease domains Proteins 0.000 description 1
- 208000002454 Nasopharyngeal Carcinoma Diseases 0.000 description 1
- 206010061306 Nasopharyngeal cancer Diseases 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- 239000000020 Nitrocellulose Substances 0.000 description 1
- 241001655308 Nocardiaceae Species 0.000 description 1
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 1
- 241001306288 Ophrys fuciflora Species 0.000 description 1
- 208000001388 Opportunistic Infections Diseases 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 241001631646 Papillomaviridae Species 0.000 description 1
- 241000526686 Paracoccidioides brasiliensis Species 0.000 description 1
- 241001057811 Paracoccus <mealybug> Species 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 241000606752 Pasteurellaceae Species 0.000 description 1
- 206010034277 Pemphigoid Diseases 0.000 description 1
- 108010067902 Peptide Library Proteins 0.000 description 1
- 102000004590 Peripherins Human genes 0.000 description 1
- 108010003081 Peripherins Proteins 0.000 description 1
- 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 1
- WYPVCIACUMJRIB-JYJNAYRXSA-N Phe-Gln-Lys Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CCCCN)C(=O)O)N WYPVCIACUMJRIB-JYJNAYRXSA-N 0.000 description 1
- MGLBSROLWAWCKN-FCLVOEFKSA-N Phe-Phe-Thr Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O MGLBSROLWAWCKN-FCLVOEFKSA-N 0.000 description 1
- 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 1
- BELBBZDIHDAJOR-UHFFFAOYSA-N Phenolsulfonephthalein Chemical compound C1=CC(O)=CC=C1C1(C=2C=CC(O)=CC=2)C2=CC=CC=C2S(=O)(=O)O1 BELBBZDIHDAJOR-UHFFFAOYSA-N 0.000 description 1
- 229920001257 Poly(D,L-lactide-co-PEO-co-D,L-lactide) Polymers 0.000 description 1
- 229920001267 Poly(D,L-lactide-co-PPO-co-D,L-lactide) Polymers 0.000 description 1
- 229920001305 Poly(isodecyl(meth)acrylate) Polymers 0.000 description 1
- 229920002319 Poly(methyl acrylate) Polymers 0.000 description 1
- 229920001283 Polyalkylene terephthalate Polymers 0.000 description 1
- 239000004952 Polyamide Substances 0.000 description 1
- 229920002732 Polyanhydride Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 239000004743 Polypropylene Substances 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- 108700021402 PrP 27-30 Proteins 0.000 description 1
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 1
- KIZQGKLMXKGDIV-BQBZGAKWSA-N Pro-Ala-Gly Chemical compound OC(=O)CNC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1 KIZQGKLMXKGDIV-BQBZGAKWSA-N 0.000 description 1
- CGBYDGAJHSOGFQ-LPEHRKFASA-N Pro-Ala-Pro Chemical compound C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@@H]2CCCN2 CGBYDGAJHSOGFQ-LPEHRKFASA-N 0.000 description 1
- KDIIENQUNVNWHR-JYJNAYRXSA-N Pro-Arg-Phe Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O KDIIENQUNVNWHR-JYJNAYRXSA-N 0.000 description 1
- 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 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
- UIMCLYYSUCIUJM-UWVGGRQHSA-N Pro-Gly-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H]1CCCN1 UIMCLYYSUCIUJM-UWVGGRQHSA-N 0.000 description 1
- 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 1
- QKWYXRPICJEQAJ-KJEVXHAQSA-N Pro-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]2CCCN2)O QKWYXRPICJEQAJ-KJEVXHAQSA-N 0.000 description 1
- 102000007066 Prostate-Specific Antigen Human genes 0.000 description 1
- 108010072866 Prostate-Specific Antigen Proteins 0.000 description 1
- 102100035703 Prostatic acid phosphatase Human genes 0.000 description 1
- 102100027584 Protein c-Fos Human genes 0.000 description 1
- 108010071563 Proto-Oncogene Proteins c-fos Proteins 0.000 description 1
- 241000947836 Pseudomonadaceae Species 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- 241000725643 Respiratory syncytial virus Species 0.000 description 1
- 108700025701 Retinoblastoma Genes Proteins 0.000 description 1
- 241000606701 Rickettsia Species 0.000 description 1
- 238000012300 Sequence Analysis Methods 0.000 description 1
- ZUGXSSFMTXKHJS-ZLUOBGJFSA-N Ser-Ala-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(O)=O ZUGXSSFMTXKHJS-ZLUOBGJFSA-N 0.000 description 1
- SMIDBHKWSYUBRZ-ACZMJKKPSA-N Ser-Glu-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(O)=O SMIDBHKWSYUBRZ-ACZMJKKPSA-N 0.000 description 1
- 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 1
- UQFYNFTYDHUIMI-WHFBIAKZSA-N Ser-Gly-Ala Chemical compound OC(=O)[C@H](C)NC(=O)CNC(=O)[C@@H](N)CO UQFYNFTYDHUIMI-WHFBIAKZSA-N 0.000 description 1
- SNVIOQXAHVORQM-WDSKDSINSA-N Ser-Gly-Gln Chemical compound [H]N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(O)=O SNVIOQXAHVORQM-WDSKDSINSA-N 0.000 description 1
- JFWDJFULOLKQFY-QWRGUYRKSA-N Ser-Gly-Phe Chemical compound [H]N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O JFWDJFULOLKQFY-QWRGUYRKSA-N 0.000 description 1
- UBRMZSHOOIVJPW-SRVKXCTJSA-N Ser-Leu-Lys Chemical compound OC[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(O)=O UBRMZSHOOIVJPW-SRVKXCTJSA-N 0.000 description 1
- GDUZTEQRAOXYJS-SRVKXCTJSA-N Ser-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](CO)N GDUZTEQRAOXYJS-SRVKXCTJSA-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
- PYTKULIABVRXSC-BWBBJGPYSA-N Ser-Ser-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(O)=O PYTKULIABVRXSC-BWBBJGPYSA-N 0.000 description 1
- UKKROEYWYIHWBD-ZKWXMUAHSA-N Ser-Val-Asp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O UKKROEYWYIHWBD-ZKWXMUAHSA-N 0.000 description 1
- JGUWRQWULDWNCM-FXQIFTODSA-N Ser-Val-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(O)=O JGUWRQWULDWNCM-FXQIFTODSA-N 0.000 description 1
- HSWXBJCBYSWBPT-GUBZILKMSA-N Ser-Val-Val Chemical compound CC(C)[C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)CO)C(C)C)C(O)=O HSWXBJCBYSWBPT-GUBZILKMSA-N 0.000 description 1
- 108010032838 Sialoglycoproteins Proteins 0.000 description 1
- 102000007365 Sialoglycoproteins Human genes 0.000 description 1
- 241000700584 Simplexvirus Species 0.000 description 1
- 206010054184 Small intestine carcinoma Diseases 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 241000589971 Spirochaetaceae Species 0.000 description 1
- 241001149962 Sporothrix Species 0.000 description 1
- 241000187747 Streptomyces Species 0.000 description 1
- 230000006044 T cell activation Effects 0.000 description 1
- 208000031673 T-Cell Cutaneous Lymphoma Diseases 0.000 description 1
- 208000000389 T-cell leukemia Diseases 0.000 description 1
- 206010042971 T-cell lymphoma Diseases 0.000 description 1
- 102100027222 T-lymphocyte activation antigen CD80 Human genes 0.000 description 1
- 210000000173 T-lymphoid precursor cell Anatomy 0.000 description 1
- JVTHIXKSVYEWNI-JRQIVUDYSA-N Thr-Asn-Tyr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O JVTHIXKSVYEWNI-JRQIVUDYSA-N 0.000 description 1
- WLDUCKSCDRIVLJ-NUMRIWBASA-N Thr-Gln-Asp Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CC(=O)O)C(=O)O)N)O WLDUCKSCDRIVLJ-NUMRIWBASA-N 0.000 description 1
- 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 1
- XSTGOZBBXFKGHA-YJRXYDGGSA-N Thr-His-His Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)N[C@@H](CC2=CN=CN2)C(=O)O)N)O XSTGOZBBXFKGHA-YJRXYDGGSA-N 0.000 description 1
- KLCCPYZXGXHAGS-QTKMDUPCSA-N Thr-His-Met Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)N[C@@H](CCSC)C(=O)O)N)O KLCCPYZXGXHAGS-QTKMDUPCSA-N 0.000 description 1
- AMXMBCAXAZUCFA-RHYQMDGZSA-N Thr-Leu-Arg Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O AMXMBCAXAZUCFA-RHYQMDGZSA-N 0.000 description 1
- HOVLHEKTGVIKAP-WDCWCFNPSA-N Thr-Leu-Gln Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O HOVLHEKTGVIKAP-WDCWCFNPSA-N 0.000 description 1
- JWQNAFHCXKVZKZ-UVOCVTCTSA-N Thr-Lys-Thr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O JWQNAFHCXKVZKZ-UVOCVTCTSA-N 0.000 description 1
- ABWNZPOIUJMNKT-IXOXFDKPSA-N Thr-Phe-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(O)=O ABWNZPOIUJMNKT-IXOXFDKPSA-N 0.000 description 1
- IQPWNQRRAJHOKV-KATARQTJSA-N Thr-Ser-Lys Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CCCCN IQPWNQRRAJHOKV-KATARQTJSA-N 0.000 description 1
- 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 1
- SOUPNXUJAJENFU-SWRJLBSHSA-N Thr-Trp-Gln Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N)O SOUPNXUJAJENFU-SWRJLBSHSA-N 0.000 description 1
- OGOYMQWIWHGTGH-KZVJFYERSA-N Thr-Val-Ala Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C)C(O)=O OGOYMQWIWHGTGH-KZVJFYERSA-N 0.000 description 1
- QGVBFDIREUUSHX-IFFSRLJSSA-N Thr-Val-Gln Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O QGVBFDIREUUSHX-IFFSRLJSSA-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
- 102100023132 Transcription factor Jun Human genes 0.000 description 1
- 102100022435 Transcription factor SOX-13 Human genes 0.000 description 1
- 241000223238 Trichophyton Species 0.000 description 1
- BRBCKMMXKONBAA-KWBADKCTSA-N Trp-Ala-Ala Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(O)=O)=CNC2=C1 BRBCKMMXKONBAA-KWBADKCTSA-N 0.000 description 1
- AOAMKFFPFOPMLX-BVSLBCMMSA-N Trp-Arg-Phe Chemical compound C([C@H](NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)N)C(O)=O)C1=CC=CC=C1 AOAMKFFPFOPMLX-BVSLBCMMSA-N 0.000 description 1
- KIMOCKLJBXHFIN-YLVFBTJISA-N Trp-Ile-Gly Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(O)=O)=CNC2=C1 KIMOCKLJBXHFIN-YLVFBTJISA-N 0.000 description 1
- YCQXZDHDSUHUSG-FJHTZYQYSA-N Trp-Thr-Ala Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@@H](C)C(O)=O)=CNC2=C1 YCQXZDHDSUHUSG-FJHTZYQYSA-N 0.000 description 1
- 241000223104 Trypanosoma Species 0.000 description 1
- 108700025716 Tumor Suppressor Genes Proteins 0.000 description 1
- 102000044209 Tumor Suppressor Genes Human genes 0.000 description 1
- 108010040002 Tumor Suppressor Proteins Proteins 0.000 description 1
- 102000001742 Tumor Suppressor Proteins Human genes 0.000 description 1
- 102100026890 Tumor necrosis factor ligand superfamily member 4 Human genes 0.000 description 1
- 102100032101 Tumor necrosis factor ligand superfamily member 9 Human genes 0.000 description 1
- 102100028785 Tumor necrosis factor receptor superfamily member 14 Human genes 0.000 description 1
- 102100033728 Tumor necrosis factor receptor superfamily member 18 Human genes 0.000 description 1
- 101710165473 Tumor necrosis factor receptor superfamily member 4 Proteins 0.000 description 1
- 102100040245 Tumor necrosis factor receptor superfamily member 5 Human genes 0.000 description 1
- 102100036857 Tumor necrosis factor receptor superfamily member 8 Human genes 0.000 description 1
- QJBWZNTWJSZUOY-UWJYBYFXSA-N Tyr-Ala-Cys Chemical compound C[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)N QJBWZNTWJSZUOY-UWJYBYFXSA-N 0.000 description 1
- KSVMDJJCYKIXTK-IGNZVWTISA-N Tyr-Ala-Tyr Chemical compound C([C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C1=CC=C(O)C=C1 KSVMDJJCYKIXTK-IGNZVWTISA-N 0.000 description 1
- SCCKSNREWHMKOJ-SRVKXCTJSA-N Tyr-Asn-Ser Chemical compound N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(O)=O SCCKSNREWHMKOJ-SRVKXCTJSA-N 0.000 description 1
- YYZPVPJCOGGQPC-JYJNAYRXSA-N Tyr-His-Gln Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCC(N)=O)C(O)=O YYZPVPJCOGGQPC-JYJNAYRXSA-N 0.000 description 1
- USYGMBIIUDLYHJ-GVARAGBVSA-N Tyr-Ile-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 USYGMBIIUDLYHJ-GVARAGBVSA-N 0.000 description 1
- CDBXVDXSLPLFMD-BPNCWPANSA-N Tyr-Pro-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CC1=CC=C(O)C=C1 CDBXVDXSLPLFMD-BPNCWPANSA-N 0.000 description 1
- MDXLPNRXCFOBTL-BZSNNMDCSA-N Tyr-Ser-Tyr Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O MDXLPNRXCFOBTL-BZSNNMDCSA-N 0.000 description 1
- NAHUCETZGZZSEX-IHPCNDPISA-N Tyr-Trp-Asp Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)O)NC(=O)[C@H](CC3=CC=C(C=C3)O)N NAHUCETZGZZSEX-IHPCNDPISA-N 0.000 description 1
- GZWPQZDVTBZVEP-BZSNNMDCSA-N Tyr-Tyr-Asn Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(N)=O)C(O)=O GZWPQZDVTBZVEP-BZSNNMDCSA-N 0.000 description 1
- AGDDLOQMXUQPDY-BZSNNMDCSA-N Tyr-Tyr-Ser Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CO)C(O)=O AGDDLOQMXUQPDY-BZSNNMDCSA-N 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 108010064997 VPY tripeptide Proteins 0.000 description 1
- YFOCMOVJBQDBCE-NRPADANISA-N Val-Ala-Glu Chemical compound C[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)O)NC(=O)[C@H](C(C)C)N YFOCMOVJBQDBCE-NRPADANISA-N 0.000 description 1
- IVXJODPZRWHCCR-JYJNAYRXSA-N Val-Arg-Phe Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)N IVXJODPZRWHCCR-JYJNAYRXSA-N 0.000 description 1
- CGGVNFJRZJUVAE-BYULHYEWSA-N Val-Asp-Asn Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC(=O)N)C(=O)O)N CGGVNFJRZJUVAE-BYULHYEWSA-N 0.000 description 1
- MYLNLEIZWHVENT-VKOGCVSHSA-N Val-Ile-Trp Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)NC(=O)[C@H](C(C)C)N MYLNLEIZWHVENT-VKOGCVSHSA-N 0.000 description 1
- CXWJFWAZIVWBOS-XQQFMLRXSA-N Val-Lys-Pro Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N1CCC[C@@H]1C(=O)O)N CXWJFWAZIVWBOS-XQQFMLRXSA-N 0.000 description 1
- FMQGYTMERWBMSI-HJWJTTGWSA-N Val-Phe-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)NC(=O)[C@H](C(C)C)N FMQGYTMERWBMSI-HJWJTTGWSA-N 0.000 description 1
- 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 1
- 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 1
- PZTZYZUTCPZWJH-FXQIFTODSA-N Val-Ser-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)O)N PZTZYZUTCPZWJH-FXQIFTODSA-N 0.000 description 1
- 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 1
- UVHFONIHVHLDDQ-IFFSRLJSSA-N Val-Thr-Glu Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)O)NC(=O)[C@H](C(C)C)N)O UVHFONIHVHLDDQ-IFFSRLJSSA-N 0.000 description 1
- WUFHZIRMAZZWRS-OSUNSFLBSA-N Val-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](C(C)C)N WUFHZIRMAZZWRS-OSUNSFLBSA-N 0.000 description 1
- 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 1
- JSOXWWFKRJKTMT-WOPDTQHZSA-N Val-Val-Pro Chemical compound CC(C)[C@@H](C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)O)N JSOXWWFKRJKTMT-WOPDTQHZSA-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
- 241000607493 Vibrionaceae Species 0.000 description 1
- 230000001594 aberrant effect Effects 0.000 description 1
- 150000001266 acyl halides Chemical class 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 208000009956 adenocarcinoma Diseases 0.000 description 1
- 108010041407 alanylaspartic acid Proteins 0.000 description 1
- 108010005233 alanylglutamic acid Proteins 0.000 description 1
- 108010070944 alanylhistidine Proteins 0.000 description 1
- 125000003172 aldehyde group Chemical group 0.000 description 1
- 229920013820 alkyl cellulose Polymers 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 108010060035 arginylproline Proteins 0.000 description 1
- 108010040443 aspartyl-aspartic acid Proteins 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- 238000002869 basic local alignment search tool Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000001588 bifunctional effect Effects 0.000 description 1
- 238000006065 biodegradation reaction Methods 0.000 description 1
- TXFLGZOGNOOEFZ-UHFFFAOYSA-N bis(2-chloroethyl)amine Chemical class ClCCNCCCl TXFLGZOGNOOEFZ-UHFFFAOYSA-N 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 201000009613 breast lymphoma Diseases 0.000 description 1
- 208000000594 bullous pemphigoid Diseases 0.000 description 1
- DQXBYHZEEUGOBF-UHFFFAOYSA-N but-3-enoic acid;ethene Chemical compound C=C.OC(=O)CC=C DQXBYHZEEUGOBF-UHFFFAOYSA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 238000011965 cell line development Methods 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920003086 cellulose ether Polymers 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 238000010367 cloning Methods 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 238000005094 computer simulation Methods 0.000 description 1
- 230000003750 conditioning effect Effects 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 239000007771 core particle Substances 0.000 description 1
- 239000003431 cross linking reagent Substances 0.000 description 1
- 238000012926 crystallographic analysis Methods 0.000 description 1
- 238000011461 current therapy Methods 0.000 description 1
- 201000007241 cutaneous T cell lymphoma Diseases 0.000 description 1
- 208000004921 cutaneous lupus erythematosus Diseases 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 108010060199 cysteinylproline Proteins 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 230000000447 dimerizing effect Effects 0.000 description 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 201000000312 duodenum cancer Diseases 0.000 description 1
- 210000002257 embryonic structure Anatomy 0.000 description 1
- 150000002118 epoxides Chemical class 0.000 description 1
- 102000015694 estrogen receptors Human genes 0.000 description 1
- 108010038795 estrogen receptors Proteins 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 208000037957 feline spongiform encephalopathy Diseases 0.000 description 1
- 230000005714 functional activity Effects 0.000 description 1
- 230000002538 fungal effect Effects 0.000 description 1
- 229960002963 ganciclovir Drugs 0.000 description 1
- IRSCQMHQWWYFCW-UHFFFAOYSA-N ganciclovir Chemical compound O=C1NC(N)=NC2=C1N=CN2COC(CO)CO IRSCQMHQWWYFCW-UHFFFAOYSA-N 0.000 description 1
- 150000002270 gangliosides Chemical class 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 108010057083 glutamyl-aspartyl-leucine Proteins 0.000 description 1
- 125000003630 glycyl group Chemical group [H]N([H])C([H])([H])C(*)=O 0.000 description 1
- 108010081985 glycyl-cystinyl-aspartic acid Proteins 0.000 description 1
- 108010067216 glycyl-glycyl-glycine Proteins 0.000 description 1
- 108010079413 glycyl-prolyl-glutamic acid Proteins 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 201000010536 head and neck cancer Diseases 0.000 description 1
- 210000002443 helper t lymphocyte Anatomy 0.000 description 1
- 201000005787 hematologic cancer Diseases 0.000 description 1
- 230000002489 hematologic effect Effects 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229920001519 homopolymer Polymers 0.000 description 1
- 229940042795 hydrazides for tuberculosis treatment Drugs 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 150000001261 hydroxy acids Chemical class 0.000 description 1
- 229920013821 hydroxy alkyl cellulose Polymers 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000012642 immune effector Substances 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 229940121354 immunomodulator Drugs 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 229960003130 interferon gamma Drugs 0.000 description 1
- 229940047124 interferons Drugs 0.000 description 1
- 229940047122 interleukins Drugs 0.000 description 1
- 210000004153 islets of langerhan Anatomy 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001261 isocyanato group Chemical group *N=C=O 0.000 description 1
- 150000002540 isothiocyanates Chemical class 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 201000010982 kidney cancer Diseases 0.000 description 1
- 206010023497 kuru Diseases 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 201000011486 lichen planus Diseases 0.000 description 1
- 208000012987 lip and oral cavity carcinoma Diseases 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 201000004514 liver lymphoma Diseases 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 201000001037 lung lymphoma Diseases 0.000 description 1
- 210000002751 lymph Anatomy 0.000 description 1
- 210000001165 lymph node Anatomy 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 208000007282 lymphomatoid papulosis Diseases 0.000 description 1
- 108010003700 lysyl aspartic acid Proteins 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 201000004792 malaria Diseases 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 208000026037 malignant tumor of neck Diseases 0.000 description 1
- 210000004379 membrane Anatomy 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 108010056582 methionylglutamic acid Proteins 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 210000002200 mouth mucosa Anatomy 0.000 description 1
- 201000011216 nasopharynx carcinoma Diseases 0.000 description 1
- 230000009826 neoplastic cell growth Effects 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- 229920001220 nitrocellulos Polymers 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000011368 organic material Substances 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- 201000008017 ovarian lymphoma Diseases 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 229960002621 pembrolizumab Drugs 0.000 description 1
- KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical compound OI(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-N 0.000 description 1
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 1
- 210000005047 peripherin Anatomy 0.000 description 1
- 229960003531 phenolsulfonphthalein Drugs 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 108010055837 phosphocarrier protein HPr Proteins 0.000 description 1
- 108010031345 placental alkaline phosphatase Proteins 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229920000771 poly (alkylcyanoacrylate) Polymers 0.000 description 1
- 229920000111 poly(butyric acid) Polymers 0.000 description 1
- 229920001279 poly(ester amides) Polymers 0.000 description 1
- 239000005014 poly(hydroxyalkanoate) Substances 0.000 description 1
- 229920000212 poly(isobutyl acrylate) Polymers 0.000 description 1
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 description 1
- 229920001306 poly(lactide-co-caprolactone) Polymers 0.000 description 1
- 229920000184 poly(octadecyl acrylate) Polymers 0.000 description 1
- 229920002463 poly(p-dioxanone) polymer Polymers 0.000 description 1
- 229920002627 poly(phosphazenes) Polymers 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- 229920002647 polyamide Polymers 0.000 description 1
- 239000004632 polycaprolactone Substances 0.000 description 1
- 239000004417 polycarbonate Substances 0.000 description 1
- 229920000515 polycarbonate Polymers 0.000 description 1
- 229920002721 polycyanoacrylate Polymers 0.000 description 1
- 239000000622 polydioxanone Substances 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920000139 polyethylene terephthalate Polymers 0.000 description 1
- 239000005020 polyethylene terephthalate Substances 0.000 description 1
- 229920000903 polyhydroxyalkanoate Polymers 0.000 description 1
- 229920000197 polyisopropyl acrylate Polymers 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 229920000098 polyolefin Polymers 0.000 description 1
- 229920006324 polyoxymethylene Polymers 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 229920002689 polyvinyl acetate Polymers 0.000 description 1
- 239000011118 polyvinyl acetate Substances 0.000 description 1
- 229920001290 polyvinyl ester Polymers 0.000 description 1
- 229920001289 polyvinyl ether Polymers 0.000 description 1
- 229920001291 polyvinyl halide Polymers 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 230000004481 post-translational protein modification Effects 0.000 description 1
- 108010066381 preproinsulin Proteins 0.000 description 1
- 208000025638 primary cutaneous T-cell non-Hodgkin lymphoma Diseases 0.000 description 1
- 102000003998 progesterone receptors Human genes 0.000 description 1
- 108090000468 progesterone receptors Proteins 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 108010043671 prostatic acid phosphatase Proteins 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 229920005604 random copolymer Polymers 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000010322 reactivation of latent virus Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000008672 reprogramming Effects 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 208000008864 scrapie Diseases 0.000 description 1
- 238000012772 sequence design Methods 0.000 description 1
- 108010026333 seryl-proline Proteins 0.000 description 1
- 238000004088 simulation Methods 0.000 description 1
- 230000037439 somatic mutation Effects 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 125000006850 spacer group Chemical group 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 238000011476 stem cell transplantation Methods 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 231100000617 superantigen Toxicity 0.000 description 1
- 230000008093 supporting effect Effects 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 101150047061 tag-72 gene Proteins 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- YFHICDDUDORKJB-UHFFFAOYSA-N trimethylene carbonate Chemical compound O=C1OCCCO1 YFHICDDUDORKJB-UHFFFAOYSA-N 0.000 description 1
- 108010038745 tryptophylglycine Proteins 0.000 description 1
- 108010044292 tryptophyltyrosine Proteins 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 208000035408 type 1 diabetes mellitus 1 Diseases 0.000 description 1
- 108010020532 tyrosyl-proline Proteins 0.000 description 1
- 241000701161 unidentified adenovirus Species 0.000 description 1
- 241001148471 unidentified anaerobic bacterium Species 0.000 description 1
- 241000712461 unidentified influenza virus Species 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 229940005605 valeric acid Drugs 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 125000002987 valine group Chemical group [H]N([H])C([H])(C(*)=O)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 244000052613 viral pathogen Species 0.000 description 1
- 239000013603 viral vector Substances 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
Images
Classifications
-
- 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
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/001154—Enzymes
- A61K39/001156—Tyrosinase and tyrosinase related proteinases [TRP-1 or TRP-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
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/001184—Cancer testis antigens, e.g. SSX, BAGE, GAGE or SAGE
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/001184—Cancer testis antigens, e.g. SSX, BAGE, GAGE or SAGE
- A61K39/001186—MAGE
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/001184—Cancer testis antigens, e.g. SSX, BAGE, GAGE or SAGE
- A61K39/001188—NY-ESO
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/00119—Melanoma antigens
- A61K39/001191—Melan-A/MART
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/00119—Melanoma antigens
- A61K39/001192—Glycoprotein 100 [Gp100]
-
- 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
- A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
-
- 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
- A61K39/44—Antibodies bound to carriers
-
- 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
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
- A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6921—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
- A61K47/6927—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores
- A61K47/6929—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle
- A61K47/6931—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle the material constituting the nanoparticle being a polymer
- A61K47/6935—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle the material constituting the nanoparticle being a polymer the polymer being obtained otherwise than by reactions involving carbon to carbon unsaturated bonds, e.g. polyesters, polyamides or polyglycerol
- A61K47/6937—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle the material constituting the nanoparticle being a polymer the polymer being obtained otherwise than by reactions involving carbon to carbon unsaturated bonds, e.g. polyesters, polyamides or polyglycerol the polymer being PLGA, PLA or polyglycolic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- 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
- C07K14/70539—MHC-molecules, e.g. HLA-molecules
-
- 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
- C07K16/46—Hybrid immunoglobulins
- C07K16/461—Igs containing Ig-regions, -domains or -residues form different species
- C07K16/464—Igs containing CDR-residues from one specie grafted between FR-residues from another
- C07K16/465—Igs containing CDR-residues from one specie grafted between FR-residues from another with additional modified FR-residues
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/0004—Oxidoreductases (1.)
- C12N9/0071—Oxidoreductases (1.) acting on paired donors with incorporation of molecular oxygen (1.14)
-
- 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
- A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
- A61K2039/55511—Organic adjuvants
- A61K2039/55555—Liposomes; Vesicles, e.g. nanoparticles; Spheres, e.g. nanospheres; Polymers
-
- 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
- A61K2039/60—Medicinal preparations containing antigens or antibodies characteristics by the carrier linked to the antigen
- A61K2039/6031—Proteins
- A61K2039/605—MHC molecules or ligands thereof
-
- 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
- A61K2039/60—Medicinal preparations containing antigens or antibodies characteristics by the carrier linked to the antigen
- A61K2039/6093—Synthetic polymers, e.g. polyethyleneglycol [PEG], Polymers or copolymers of (D) glutamate and (D) lysine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/52—Constant or Fc region; Isotype
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
- C07K2317/565—Complementarity determining region [CDR]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/75—Agonist effect on antigen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
- C07K2317/94—Stability, e.g. half-life, pH, temperature or enzyme-resistance
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y114/00—Oxidoreductases acting on paired donors, with incorporation or reduction of molecular oxygen (1.14)
- C12Y114/18—Oxidoreductases acting on paired donors, with incorporation or reduction of molecular oxygen (1.14) with another compound as one donor, and incorporation of one atom of oxygen (1.14.18)
- C12Y114/18001—Tyrosinase (1.14.18.1)
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Immunology (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Microbiology (AREA)
- Mycology (AREA)
- Organic Chemistry (AREA)
- Oncology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Genetics & Genomics (AREA)
- Biochemistry (AREA)
- Zoology (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biophysics (AREA)
- Wood Science & Technology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nanotechnology (AREA)
- Cell Biology (AREA)
- Gastroenterology & Hepatology (AREA)
- General Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biotechnology (AREA)
- Biomedical Technology (AREA)
- Endocrinology (AREA)
- Toxicology (AREA)
- Peptides Or Proteins (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicinal Preparation (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
本发明提供用于免疫疗法的组合物和方法,其包括用于诱导抗原特异性T细胞的货架稳定的药物组合物。此类组合物用作人工抗原呈递细胞(aAPC)的组分,以向患者提供复合物用于呈递抗原(如,肿瘤抗原)和/或T细胞共刺激分子。
Description
优先权
本申请要求2013年6月24日提交的美国临时申请No.61/838,547和2014年3月6日提交的美国临时申请No.61/948,916的权益和优先权,其在此通过引用整体并入。
发明领域
本发明涉及用于免疫疗法的组合物(包括药物组合物)及方法。
背景技术
抗原呈递细胞(APC)是一种加工和呈现在其表面上与主要组织相容性复合物(MHC)蛋白复合的抗原肽的细胞。效应细胞,诸如T细胞,可使用受体诸如T细胞受体(TCR)识别这些肽-MHC(pMHC)复合物。
树突细胞(DC)是一种抗原呈递细胞的实例,其可被刺激以有效呈递抗原并支持免疫效应细胞扩增,从而激活对抗原的细胞毒反应。在一些免疫疗法中,DC是从患者收集到的并用抗原脉冲或用病毒载体转染。在输回所述患者后,这些激活的细胞呈递肿瘤抗原至效应淋巴细胞(如CD4+T细胞、CD8+T细胞和B细胞)。如果适当进行,该疗法可起始针对表达抗原(包括肿瘤抗原)细胞的细胞毒反应。
然而,DC免疫疗法,如许多免疫疗法面临显著的限制。例如,接种的癌症患者中离体可检测的强且抗原特异性T细胞反应与仅较弱的临床反应存在差异。Janikashvili N等,Personalized dendritic cell-based tumor immunotherapy.Immunotherapy 2010年1月1日;2(1):57。
仍然需要有效用于包括抗原特异性免疫疗法的免疫疗法的组合物(包括货架稳定的药物组合物)和方法。
发明概述
本发明提供用于免疫疗法的组合物和方法,其包括用于在患者中诱导抗原特异性T细胞的货架稳定的药物组合物。此类组合物用于治疗例如,癌症和传染病。在一些方面,所述组合物是人工抗原呈递细胞(aAPC),其包括在其表面上具有抗原呈递复合物和任选的T细胞共刺激信号的药学上可接受的珠粒或颗粒,以向患者提供在适当的情况下呈递一种或多种抗原(如,一种或多种肿瘤抗原)的分子复合物以激活抗原特异性T细胞。所述珠粒或颗粒经设计提供药效动力学优势,包括循环特性、生物分布和降解动力学,以及活性。此类参数包括尺寸、表面电荷、聚合物组成、配体缀合化学、配体密度等。
在一些实施方案中,T细胞共刺激信号是抗-CD28抗体或其部分,其可包含人重链氨基酸序列,包括选自IgG、IgD、IgA或IgM同种型的序列。在一些实施方案中,免疫球蛋白序列包括人IgG恒定和可变序列。框架(FW)序列可经修饰含有重要或所需的鼠科框架残基以维持一个或多个抗原结合位点的完整性。互补决定区(CDR)可基于鼠科抗体氨基酸序列(如,9.3mAb),或其它CD28结合序列,其中许多是已知的。在一些实施方案中,所述抗体重链是人IGHV4(如,IGHV4-59)种系FW的变体。在一些实施方案中,所述抗体包含轻链且所述轻链是人IGKV4-01 FW的变体。所述抗体可包含恒定区,且所述恒定区可为人IgG4或其变体。
所述共刺激分子可缀合至具有抗原呈递分子复合物的固体支撑物,以诱导抗原特异性T细胞。抗原呈递分子复合物可包括I类MHC和/或II类复合物,或其包含抗原结合槽的部分。在一些实施方案中,所述分子复合物包含一个或多个HLA氨基酸序列(如,包含HLA的胞外结构域或其抗原呈递部分),其可包含另外的序列,诸如免疫球蛋白序列,或其它二聚化序列或稳定序列。在一些实施方案中,HLA-Ig二聚化融合物提供稳定性和/或结合亲和力方面的优势。
因此,在一些实施方案中,本发明提供用于呈递抗原至T细胞的珠粒-或颗粒-缀合的分子复合物,其中所述复合物包含形成I类或II类抗原结合槽的氨基酸序列或其部分。所述抗原呈递复合物的氨基酸序列可包括与异源序列的融合物,以提供例如稳定性、亲和力和空间优势。在一些实施方案中,所述异源序列包括免疫球蛋白序列。在一些实施方案中,所述分子复合物包括融合至异源序列诸如免疫球蛋白序列的HLA(如,HLA-A2)氨基酸序列。在一些实施方案中,所述免疫球蛋白包含人重链免疫球蛋白序列(如,IGVH4),其可包括免疫球蛋白恒定序列以提供二聚体HLA,和可任选地包含可变区序列。所述可变序列如果存在可被任选地修饰以减少或消除潜在的抗原结合并且任选地无鼠科FW残基。所述HLA氨基酸序列可为HLA-A*02:01(IMGT登记号HLA00005)或其衍生物。
T细胞共刺激配体和/或抗原呈递复合物(以及本文所述的其它配体,包括靶向配体)可缀合至固体支撑物用于离体或体内抗原呈递和抗原特异性T细胞激活。在一些实施方案中,所述固体支撑物是具有用于偶联配体的表面官能团的珠粒或颗粒(如,PLGA或PLGA-PEG颗粒)。所述颗粒经设计提供药效动力学优势,包括循环特性、生物分布和降解动力学以及活性。此类参数包括尺寸、表面电荷、聚合物组成、配体缀合化学、配体密度等。
在各个实施方案中,所述药物组合物可另外包含用于呈递至T细胞且可与配体缀合的珠粒或颗粒共同配制的抗原肽。在各个实施方案中,所述药物组合物是货架稳定的,并且可以在施用前复溶的冻干形式提供,或替代地以另一种施用给患者的便利形式(如,通过肠胃外施用)提供。
本文所述的药物组合物通过向有需要的患者施用有效量的组组合物用于免疫疗法,例如,用于诱导抗原特异性细胞毒性T细胞形成的方法。具体而言,抗原呈递平台可用于治疗传染病、癌症或自身免疫性疾病患者,或者向免疫抑制患者提供预防性保护。
本发明还提供编码本文所述的氨基酸序列的多核苷酸,以及表达本文所述的氨基酸序列的宿主细胞。
本发明通过以下非限制性实例进一步说明。
本发明的细节示于以下随附的说明书和权利要求书中。尽管与本文所述那些方法和材料类似的方法和材料可用于本发明的实践或测试中,但现在描述说明性方法和材料。本发明的其它特征、目标和优势将通过说明书和权利要求书变得显而易见。除非上下文另外明确说明,否则在说明书和随附权力要求书中,单数形式还包括复数形式。除非另外定义,否则本文所用的所有技术和科学术语具有与本发明所属的领域普通技术人员通常所理解相同的含义。
附图简述
图1-3显示了抗-CD28的三条人源化可变重序列。
图4-6显示了抗-CD28的三条人源化可变轻序列。
图7显示了经修饰的恒定重序列。
图8显示了恒定κ轻序列。
图9显示了用于构建HLA融合物的人源化非CD28-结合可变区。
图10显示了人源化HLA-IgG4HC的氨基酸序列。
图11显示了轻链3(LC3或Vκ3)的氨基酸序列。
图12显示了重链1(HC1)的氨基酸序列。
图13显示了重链2(HC2)的氨基酸序列。
图14-16显示了用于在STABLEFAST-NS0细胞系中表达的表达构建体。
图17显示了人源化抗-CD28 mAb不是超激动剂。
图18显示了人源化抗-CD28克隆特异性染色人T-细胞系上的CD28。图18(A):用鼠科抗-人CD8 mAb(克隆9.3,同种型IgG2a)染色;图18(B):用人源化抗-CD28(同种型IgG4)染色。
发明详述
以下缩写可在全文中使用:BLAST-基本局部比对搜索工具,CDR-互补决定区,Cκ-κ轻链恒定区,Fc-抗体片段可结晶区,Fw-(可变区的)框架区,HLA-人白细胞抗原,MHC-主要组织相容性复合物,VH-可变重链,Vκ-可变κ轻链及V区-抗体可变区,VH或Vκ。
本发明提供用于免疫疗法的组合物和方法,其包括用于在患者中诱导抗原特异性T细胞的货架稳定的药物组合物。在一些实施方案中,所述组合物包含二聚体HLA抗原呈递复合物。在一些实施方案中,所述组合物包含人源化免疫球蛋白序列或其部分,其可用作人工抗原呈递细胞(aAPC)上配体的组分,以向患者提供二聚体分子复合物用于呈递一种或多种抗原(如,一种或多种肿瘤抗原)和任选的一种或多种共刺激信号。如下更详述的抗原呈递平台可基于人工固体支撑物,诸如药学上可接受的支撑物(包括胶乳或聚合物珠粒或颗粒)。
在一些实施方案中,所述T细胞共刺激信号是抗-CD28抗体或其部分。在一些实施方案中,所述抗-CD28抗体包含选自IgG1、IgG2、IgG3、IgG4、IgD、IgA或IgM的至少一种人免疫球蛋白同种型的序列。例如,所述抗-CD28抗体可为IgG同种型,并且可含有一种或多种IgG种系框架序列的序列。例如,所述抗-CD28可含有人IGHV4重链氨基酸序列,其可被修饰以具有一至十五个氨基酸修饰。所述修饰可包括鼠科框架残基以支持一个或多个抗原结合位点的完整性。
在一些实施方案中,互补决定区(CDR)基于鼠科抗体氨基酸序列,其可任意地包含一至十个、诸如一至五个氨基酸修饰。在一些实施方案中,一个、两个、三个或多个CDR基于小鼠9.3mAb(Tan等.J.Exp.Med.1993 177:165),其可公开获得。示例性CDR示于图1-6中。在一些实施方案中,所述抗体具有全套的重链和/或全套的轻链CDR(9.3mAb)。例如,在一些实施方案中,所述重链可变区含有一个、两个或三个以下CDR,其可各自任选地被一个、两个或三个氨基酸取代、缺失或添加修饰:CDR1(DYGVH)、CDR2(VIWAGGGTNYNSALMS)和CDR3(DKGYSYYYSMDY)。在一些实施方案中,所述轻链可变区含有一个、两个或三个以下CDR,其各自可被一个、两个或三个氨基酸取代、缺失或添加修饰:CDR1(RASESVEYYVTSLMQ)、CDR2(AASNVES)和CDR3(QQSRKVPYT)。
可替代的CDR序列、可变区或CD28-结合配体可用于各种实施方案中。可替代的配体和抗体描述于美国专利7,612,170、美国专利6,987,171和美国专利6,887,466中,例如,并且这些公开内容在此通过引用整体并入。
在一些实施方案中,所述抗体重链包含人IGHV4-59种系框架(FW)的变体,其经修饰包括5至15个鼠科FW残基。在一些实施方案中,所述抗体包含轻链氨基酸序列,并且所述轻链序列可为人IGKV4-01FW序列的变体,并且其可经修饰包括3至15个鼠科FW残基。
所述抗-CD28人重链序列可经修饰,例如,以在位置1、3、6、37、48、67、71、73、76、78、82、82a和82c(基于Kabat编号)处包含一个或多个(如,2个或更多个、3个或更多个、4个或更多个、5个或更多个或所有)鼠科Fw残基。在这些位置处的鼠科Fw残基可如9.3mAb中一样。所述轻链可经修饰以在位置3、4、49、70、85、87和80包含一个或多个(如,2个或更多个、3个或更多个、4个或更多个、5个或更多个或所有)鼠科Fw残基。所选的鼠科Fw残基可支持抗原-结合位点的完整性。人源化抗-CD28抗体维持对CD28的亲和力和9.3mAb的T细胞共刺激活性,并且为至少40%、50%、75%、80%、90%,并且在一些实施方案中,与9.3mAb相比,对于CD28结合100%或更有效。在各个实施方案中,所述抗-CD28 mAb不是超激动剂。
所述抗体可包含恒定区并且所述恒定区可为任何同种型。在一些实施方案中,所述抗体恒定区是人IgG4或其变体。在一些实施方案中,所述恒定区包含一个或多个铰链稳定突变,其可被引入至CH链中(如,S241,其可被P取代)。在一些实施方案中,所述抗体包含恒定区,并且所述恒定区包含一个或多个适于化学偶联所述抗体至固体支撑物的突变。所述一个或多个适于偶联的突变可产生氨基酸侧链官能团(如,硫醇、胺或羟基),诸如未配对的半胱氨酸(如,在S473处)。对恒定区的其它变化包括那些减少Fcγ受体结合的修饰。例如,所述CH链可在L248处修饰,如,L248E。
在一些实施方案中,所述抗体是抗体片段,诸如F(ab’)2或Fab,或者为单链抗体或其它抗原-结合抗体片段。例如,所述抗体片段可为本文所述的人源化mAb或其它抗-CD28的单链可变片段。
在一些实施方案中,所述共刺激分子是单链可变片段(scFv),其包含由抗CD28mAb诸如本文所述的抗体的VH和VL链形成的抗原结合环,或基本上由由抗CD28 mAb诸如本文所述的抗体的VH和VL链形成的抗原结合环组成。scFv抗体构建体可包含通过短肽连接子以头-头或头-尾构象连接在一起的一条或若干条(2、3、4或5)VH和VL高可变区链(每条链一起形成3-D抗原表位结合袋的部分)。此类构建体可由于其较小的尺寸经由完全合成路径方便地产生。此外,scFv可展现出较低的免疫原性潜力。
在其它实施方案中,所述共刺激配体是包含连接至共刺激分子配体或抑制配体的scFv的一个或多个HLA分子的双特异性构建体。所述抗原呈递复合物和共刺激或抑制配体可通过肽系链缀合,所述肽系链使得双特异性构建体可共价连接至纳米颗粒表面。在一些实施方案中,此类构建体产生与含有HLA的较大构建体和各自独立连接至NP表面的共刺激或抑制配体的纳米颗粒相同的活性,从而提供生产优势。
所述共刺激分子可缀合至具有抗原呈递分子复合物的固体支撑物,以诱导抗原特异性T细胞。所述抗原呈递分子复合物可包括I类和/或II类MHC复合物,或其包含抗原-结合槽的部分。在一些实施方案中,所述分子复合物包含一个或两个HLA氨基酸序列,其可含有另外的异源序列,诸如免疫球蛋白序列。可替代的异源序列包括二聚化氨基酸序列诸如c-fos和c-jun。在一些实施方案中,HLA-融合物提供在稳定性和/或结合亲和力方面另外的优势。
在各个实施方案中,所述抗原呈递复合物是MHC I类分子复合物或MHC II类分子复合物,或可替代地CD1d。所述MHC I类分子复合物可包含至少两种融合蛋白。第一融合蛋白包含第一MHC I类α链和第一免疫球蛋白重链,并且第二融合蛋白包含第二MHC I类α链和第二免疫球蛋白重链。第一和第二免疫球蛋白重链缔合以形成MHC I类分子复合物。所述MHC I类分子复合物包含第一MHC I类肽结合槽和第二MHC I类肽结合槽。所述MHC II类分子复合物可包含至少四种融合蛋白。两种第一融合蛋白包含(i)免疫球蛋白重链和(ii)MHCII类β链的胞外结构域。两种第二融合蛋白包含(i)免疫球蛋白轻链和(ii)MHC II类α链的胞外结构域。所述两种第一和两种第二融合蛋白缔合以形成MHC II类分子复合物。每个第一融合蛋白的MHC II类β链的胞外结构域和每个第二融合蛋白的MHC II类α链的胞外结构域形成MHC II类肽结合槽。抗原肽结合至肽结合槽。在各个实施方案中,所述免疫球蛋白序列是包含铰链区的部分重链序列以支持二聚化。
在一些实施方案中,所述抗原呈递复合物是经工程化含有未配对的半胱氨酸或使用天然存在的未配对半胱氨酸的合成或重组HLA单体,以用于缀合至纳米颗粒。此外,共刺激信号(或其它基于抗体的配体)可为Fab或scFv。在此类实施方案中,所述两种信号可重组在单个多功能构建体中,所述构建体包含拴系至结合所需受体的抗原结合抗体片段(如,scFv)的HLA分子。
在其它方面和实施方案中,本发明提供用于呈递抗原至T细胞的珠粒-或颗粒-缀合的分子复合物,其中所述复合物包含人源化免疫球蛋白序列或其融合至抗原呈递序列的部分,如HLA氨基酸序列。在一些实施方案中,所述免疫球蛋白序列是人重链序列(如,IGHV4框架)。所述可变区不包含针对CD28或其它人蛋白的抗原结合活性。所述HLA氨基酸序列可为HLA-A*02:01(IMGT登记号HLA00005)或其衍生物或片段,诸如具有1至10个或1至5个氨基酸取代、缺失或插入的衍生物。所述人源化免疫球蛋白序列可另外包含HLA和免疫球蛋白序列之间的连接子氨基酸序列。优选地,所述连接至缺乏免疫原性。所述分子复合物可另外包含β2微球蛋白肽。
在各个实施方案中,所述免疫球蛋白融合序列属于IgG、IgD、IgA或IgM同种型,并且可源自任何人种系框架。所述种系框架包括IGHV4(如,IGHV4-59),其可含有或可不含有相对于抗-CD28描述的一个或多个鼠科框架残基。在一些实施方案中,根据该方面,上文所述的抗-CD28抗体的重链(有或无鼠科框架残基)融合至HLA,并且在此类实施方案中,所述可变区经修饰以减少或消除CD28结合。
在一些实施方案中,所述HLA融合构建体不含可变链序列。例如,所述HLA或抗原呈递复合物可融合至铰链区上方的Ig恒定区序列以提供二聚体HLA。例如,HLA或其抗原呈递部分可缀合至每条IgG重链的CH1部分。所有IgG分子通过铰链区(上和下)中的二硫键连接在一起的两种相同的重链(恒定区和可变区)组成。例如,在一些实施方案中,HLA分子或抗原呈递复合物融合至CH1(铰链区上方的IgH链的N-端末端),从而产生由于缺乏任何VH和VL轻链序列而较小的二聚体融合蛋白。此类构建体可提供生产优势,以及展现出的免疫原性潜力较小。
在另一些实施方案中,所述抗原呈递复合物(如,HLA序列)不含有Ig融合伴侣,并且是单体。例如,在一些实施方案中,抗原呈递复合物或HLA分子(如HLA-A2等)的C-端末端含有适于定点结合至固体/半固体基质诸如合成纳米颗粒(如PLGA-PEG-马来酰亚胺嵌段共聚物,或本文所述的其它颗粒)上的官能团(如马来酰亚胺部分)的肽系链序列。所述系链序列可含有任何适当的序列,其可主要由亲水残基诸如Gly、Ser、Ala和Thr构成,诸如两个、三个、四个或五个重复的GGGSG或AAAGG,其中半胱氨酸残基掺入约5至约15个(或约5至约10个氨基酸)系链内的某处。所述半胱氨酸残基应掺入预测不形成分子内二硫键的位点处。
在一些实施方案中,所述HLA-Ig融合物或其他HLA构建体还包含用于呈递至T细胞的结合至HLA的抗原肽。所述抗原肽可包含用于酪氨酸酶、hTERT、MAGE-1、MAGE-3、gp-100、NY-ESO-1、Melan A/Mart-1、HPV 16-E7、gp75/褐色、BAGE和S-100中的一个或多个的抗原部分和/或如WO 2004/006951(其内容在此通过引用整体并入)中所述的由I类或II类复合物呈递的任一种抗原肽。所述HLA复合物可连接至固体支撑物,诸如如所述的珠粒或颗粒,用于任选地与共刺激信号一起呈递抗原至T细胞。
可与抗原呈递复合物一起提供的其它信号包括:CD80(B7-1)、CD86(B7-2)、B7-H3、4-1BBL、CD27、CD30、CD134(OX-40L)、B7h(B7RP-1)、CD40、LIGHT、(或此类分子或其活性部分的如本文所述的任选人源化的Ig融合物)、特异性结合至HVEM的抗体、特异性结合至CD40L的抗体、特异性结合至OX40的抗体、特异性结合Fas的抗体、特异性结合PD1的抗体、特异性结合至GITR的抗体及特异性结合至4-1BB的抗体。
本发明的用于抗原呈递平台的粘附分子可介导平台粘附至T细胞或至T细胞前体。用于本发明的粘附分子包括例如,ICAM-1和LFA-3。
T细胞生长因子影响T细胞的增殖和/或分化。T细胞生长因子的实例包括细胞因子(如,白介素、干扰素)和超抗原。特别有用的细胞因子包括IL-2、IL-4、IL-7、IL-10、IL-12、IL-15和γ干扰素。T细胞生长因子可封装在珠粒或颗粒中或化学缀合或吸附至所述表面。因此,在一些实施方案中,所述纳米颗粒另外包含包埋在所述颗粒的疏水性核心中的治疗化合物或蛋白/肽(如化疗剂、细胞因子或白介素诸如IL-2,趋化因子如吸引T细胞的CCL9,和/或检查点抑制分子如抗-PD1抗体或抗-PD1肽)。在一些实施方案中,此类aAPC经构建靶向特定细胞以用于刺激或抑制以及重编程。在一些实施方案中,经包埋的化合物通过降解颗粒基质释放。此类aAPC可通过限制由于脱靶相互作用导致的非所需活性,使得组合疗法更加可耐受和有效。
根据本发明的各方面表示的抗原包括肿瘤相关的抗原。肿瘤相关的抗原包括仅由所述抗原来源的肿瘤表达的独特肿瘤抗原,在许多中表达而不在正常成人组织中表达的共有肿瘤抗原(癌胚抗原、癌症/睾丸抗原),以及还由肿瘤来源于的正常组织表达的组织特异性抗原。肿瘤相关的抗原可为例如,胚胎抗原、具有异常翻译后修饰的抗原、分化抗原、突变致癌基因或肿瘤抑制子的产物、融合蛋白或致癌病毒蛋白。多种肿瘤相关的抗原是本领域已知的,并且这些中的许多是可商购获得的。癌胚和胚胎抗原包括癌性胚胎抗原和α-胎蛋白(通常仅在发育胚胎中高度表达,但通常分别由肝肿瘤和结肠肿瘤高度表达),胎盘碱性磷酸酶唾液酸化-LewisX(在腺癌中表达),CA-125和CA-19(在肠胃肿瘤、肝肿瘤和妇科肿瘤中表达),TAG-72(在结直肠肿瘤中表达),上皮糖蛋白2(在许多癌中表达),胰腺癌胚抗原、5T4(在胃癌中表达)、α胎蛋白受体(在多种肿瘤类型中表达,特别是哺乳动物肿瘤)和M2A(在生殖细胞瘤形成中表达)。
在一些实施方案中,至少一种抗原是癌症/睾丸(CT)抗原,其可包括NY-ESO-1,MAGE-A、B和C,CTAG-1,CTAG-45,GAGE和SSX,其在睾丸的生殖细胞中正常表达和不在正常成人体组织中表达。然而,多种类型的癌症细胞已显示表达CT抗原,包括黑素瘤、乳腺癌、肝癌、肺癌、卵巢癌和霍奇金氏淋巴瘤。
肿瘤相关的分化抗原包括酪氨酸酶(在黑素瘤中表达)和特定表面免疫球蛋白(在淋巴瘤中表达)。
突变致癌基因或肿瘤抑制子基因产物包括Ras和ρ53,这两者在许多肿瘤类型中表达,Her-2/neu(在乳腺癌-和妇科癌中表达)、EGF-R、雌激素受体、黄体酮受体、视网膜母细胞瘤基因产物、myc(与肺癌相关)、ras、与乳腺癌相关的p53非突变体、MAGE-1和MAGE-3(与黑素瘤、肺癌或其它癌症相关)。
其它肿瘤抗原包括在慢性髓样白血病中表达的融合蛋白诸如BCR-ABL,和在颈癌中存在的致癌病毒蛋白诸如HPV 16、E6和E7型。组织特异性肿瘤抗原包括黑素转铁蛋白和MUCl(在胰腺癌和乳腺癌中表达);CD 10(之前已知为常见急性淋巴母细胞性白血病抗原或CALLA)或表面免疫球蛋白(在B细胞白血病和淋巴瘤中表达);IL-2受体、T细胞受体、CD45R、CD4+/CD8+的α链(在T细胞白血病和淋巴瘤中表达);前列腺特异性抗原和前列腺酸磷酸酶(在前列腺癌中表达);gp100、MelanA/Mart-1、酪氨酸酶、gp75/褐色、BAGE和S-100(在黑素瘤中表达);细胞角蛋白(在各种癌中表达);及CD19、CD20和CD37(在淋巴瘤中表达)。
在一些实施方案中,所述抗原肽包括MART-1、gp100、NY-ESO-1,及由本文所述的HLA抗原呈递复合物(诸如本文所述的HLA-Ig融合复合物)呈递的MAGE-A3。
在另一些实施方案中,所述组合物包含所述肿瘤类型的多个抗原的混合物,诸如至少2、3、4、5、6、7、8、9或10个抗原(如,2至10或3-8个抗原)。
在一些实施方案中,所述抗原是自身抗原,其是生物体对其产生免疫反应的生物体自己的“自体抗原”。自身抗原参与自身免疫性疾病诸如古德帕斯彻氏综合症(Goodpasture's syndrome)、多发性硬化、格雷夫斯氏病(Graves'disease)、重症肌无力、全身性红斑狼疮、胰岛素依赖型糖尿病、风湿性关节炎、寻常性天疱疮、爱迪生氏病(Addison's disease)、疱疹样皮炎、乳糜泻和桥本氏甲状腺炎(Hashimoto'sthyroiditis)。例如,糖尿病相关的自身抗原包括胰岛素、谷氨酸脱羧酶(GAD)和其它胰岛细胞自身抗原,如ICA 512/IA-2蛋白酪氨酸磷酸酶、ICA12、ICA69、前胰岛素原或其免疫活性片段(如,胰岛素B-链、A链、C肽或其免疫活性片段)、IGRP、HSP60、羧肽酶H、外周蛋白、神经节苷脂(如,GM1-2、GM3)或其免疫活性片段。
在一些实施方案中,所述一种或多种抗原属于传染因子,诸如原生动物、细菌、真菌(单细胞和多细胞)、病毒、朊病毒、胞内寄生物、蠕虫的组分及其它可诱导免疫反应的传染因子。细菌抗原包括革兰氏阳性球菌、革兰氏阴性杆菌、革兰氏阴性细菌、厌氧细菌的抗原,诸如以下各科的有机体:放线菌科、芽胞杆菌科、巴尔通氏体科、博德特氏菌、Captophagaceae、棒状杆菌科、肠杆菌科、军团菌科、微球菌科、分支杆菌科、诺卡氏菌科、巴斯德氏菌科、假单胞菌科、螺旋体科、弧菌科以及以下各属的有机体:不动杆菌属、布鲁氏菌、弯曲菌属、丹毒丝菌属、爱文菌属、弗朗西斯氏菌属、加德纳氏菌属螺杆菌属、列文菌属、李斯特菌属、链杆菌属和吸收不良菌属。原生动物传染因子的抗原包括患疟疾的疟原虫、利什曼原虫物种、锥体虫属物种和血吸虫属物种的抗原。真菌抗原包括曲霉属、芽生菌属、假丝酵母属、球孢子菌属、隐球菌属、组织胞浆菌属、巴西副球孢子菌(Paracoccicioides)、孢子丝菌属、毛霉目的有机体、诱导着色真菌病和足分支菌病的有机体及毛癣菌属、小孢子菌属、表皮癣菌属和马拉色菌属各属的有机体的抗原。朊病毒的抗原包括引起瘙痒病、牛海绵状脑病(BSE)、猫科动物海绵状脑病、库鲁病、克鲁兹佛得-雅克病(Creutzfeldt-Jakob Disease,CJD)、格-斯二氏综合症(Gerstmann-Strassler-ScheinkerDisease,GSS)和致命性家族性失眠症(FFI)的朊病毒的唾液酸糖蛋白PrP 27-30。可从其获得抗原肽的胞内寄生物包括但不限于衣原体科、支原体科、无胆甾原体科、立克次体,及柯克斯体属和埃立克体属两属的有机体。病毒肽抗原包括但不限于腺病毒、单纯疱疹病毒、乳头瘤病毒、呼吸道合胞病毒、痘病毒、HIV、流感病毒和CMV的那些病毒肽抗原。特别有用的病毒肽抗原包括HIV蛋白诸如HIV gag蛋白(包括但不限于膜锚定(MA)蛋白、核衣壳(CA)蛋白和核壳体(NC)蛋白)、HJV聚合酶、流感病毒基质(M)蛋白和流感病毒核壳体(NP)蛋白、乙型肝炎表面抗原(HBsAg)、乙型肝炎核心蛋白(HBcAg)、戊型肝炎蛋白(HBeAg)、乙型肝炎DNA聚合酶、丙型肝炎抗原等。
抗原,包括抗原肽,可主动或被动结合至抗原呈递复合物的抗原结合槽,如美国专利6,268,411(其在此通过引用整体并入)所述。任选地,抗原肽可共价结合至肽结合槽。
如果需要,肽系链可用于连接抗原肽至肽结合槽。例如,对多种I类MHC分子的晶体学分析表明β2M的氨基端与停留于MHC肽结合槽中的抗原肽的羧基端非常靠近,相距约20.5埃。因此,使用相对短的连接子序列,长约13个氨基酸,人们可将肽栓系至β2M的氨基端。如果所述序列适当,则该肽将结合至MHC结合沟(参见美国专利6,268,411)。
所述抗体或片段和/或抗原呈递复合物可缀合至固体支撑物以用于离体或体内抗原呈递。各种固体支撑物描述于WO 2004/006951中,其内容在此通过引用整体并入。在一些实施方案中,所述固体支撑物是具有用于偶联配体的官能团的珠粒或颗粒。所述材料可为可生物降解有机材料,诸如纤维素或葡聚糖。在一些实施方案中,选择嵌段共聚物运输(traffic)至特定结构位点,并且以特定间隔生物降解,即具有较长或较短的血浆半寿期,或较长或较短的组织停留时间。
在一些实施方案中,所述珠粒或颗粒包含聚合物,诸如以下的一者或多者:含环糊精聚合物、含阳离子环糊精聚合物,聚(D,L-乳酸-共-羟基乙酸)(PLGA),聚(己内酯)(PCL),乙烯-乙酸乙烯酯聚合物(EVA),聚(乳酸)(PLA),聚(L-乳酸)(PLLA),聚(羟基乙酸)(PGA),聚(L-乳酸-共-羟基乙酸)(PLLGA),聚(D,L-丙交酯)(PDLA),聚(L-丙交酯)(PLLA),PLGA-b-聚(乙二醇)-PLGA(PLGA-bPEG-PLGA),PLLA-bPEG-PLLA,PLGA-PEG-马来酰亚胺(PLGA-PEG-mal),聚(D,L-丙交酯-共-己内酯),聚(D,L-丙交酯-共-己内酯-共-乙交酯),聚(D,L-丙交酯-共-PEO-共-D,L-丙交酯),聚(D,L-丙交酯-共-PPO-共-D,L-丙交酯),聚烷基氰基丙烯酸酯、聚氨酯、聚-L-赖氨酸(PLL),甲基丙烯酸羟丙基酯(HPMA),聚乙二醇,聚-L-谷氨酸,聚(羟基酸),聚酸酐,聚原酸酯,聚(酯酰胺),聚酰胺,聚(酯醚),聚碳酸酯,聚烯烃诸如聚乙烯和聚丙烯,聚亚烷基二醇诸如聚(乙二醇)(PEG),聚环氧烷(PEO),聚对苯二酸亚烷基酯诸如聚(对苯二甲酸乙二酯),聚乙烯醇(PVA),聚乙烯醚,聚乙烯酯诸如聚(乙酸乙烯酯),聚卤代乙烯诸如聚(氯乙烯)(PVC),聚乙烯吡咯烷酮,聚硅氧烷,聚苯乙烯(PS),聚氨酯,衍生的纤维素诸如烷基纤维素、羟烷基纤维素、纤维素醚、纤维素酯、硝基纤维素、羟丙基纤维素、羧甲基纤维素,丙烯酸的聚合物诸如聚((甲基)丙烯酸甲酯)(PMMA)、聚((甲基)丙烯酸乙酯)、聚((甲基)丙烯酸丁酯)、聚((甲基)丙烯酸异丁酯)、聚((甲基)丙烯酸己酯)、聚((甲基)丙烯酸异癸酯)、聚((甲基)丙烯酸月桂酯)、聚((甲基)丙烯酸苯酯)、聚(丙烯酸甲酯)、聚(丙烯酸异丙酯)、聚(丙烯酸异丁酯)、聚(丙烯酸十八烷基酯)(聚丙烯酸)及其共聚物和混合物,聚二噁烷酮及其共聚物,聚羟基脂肪酸酯,聚富马酸丙二酯(polypropylenefumarate)),聚氧化亚甲基,泊洛沙姆,聚(原酸酯),聚(丁酸),聚(戊酸),聚(丙交酯-共-己内酯),三亚甲基碳酸酯,聚乙烯吡咯烷酮,聚原酸酯,聚磷腈和聚磷酸酯,以及两种或多种此类聚合物的掺混物和/或嵌段共聚物。其它药学上可接受的材料,诸如胶乳,也可用作固体颗粒支撑物。
在一些实施方案中,所述抗原呈递复合物和共刺激信号缀合至在聚合物的端末端(如,背向朝向所述颗粒表面的末端)上具有表面官能团的PLGA或PLGA-PEG颗粒,诸如PLGA-PEG-马来酰亚胺颗粒(其在亲水外表面提供用于化学偶联的官能团)。在一些实施方案中,aAPC持续存于外周血液循环足够长的时间以使其经由血液/淋巴交换分布至靶组织,包括运输至淋巴结。所述壳的组成还可影响生物分布。因此,在各个实施方案中,所述颗粒具有亲水壳,其可通过PLGA-PEG共聚物的PEG实现。在各个实施方案中,所述颗粒的电荷稍微带负电,例如由于PLGA上的COOH基团的组合以及通过靶向连接至所述颗粒表面的配体导致的电荷。在一些实施方案中,所述颗粒(具有或不具有缀合的配体)具有约0至约-20mV,或在一些实施方案中,-5至-15mV或约-10mV的表面电荷。
包含PLGA-PEG共聚物的纳米颗粒描述于例如美国专利8,420,123中,其在此通过引用并入。
所述颗粒可在形状不规则与球形和/或具有不匀整或不规则表面与具有光滑表面方面不同。球形颗粒相对于不规则尺寸的颗粒具有较小的表面积。如果使用球形颗粒,则较少的试剂由于减少的表面积是必需的。换句话说,不规则成形的颗粒具有比球形颗粒显著较大的表面积,其为细胞提供每表面积缀合的蛋白含量和表面积接触。例如,不对称纳米颗粒可具有至少一个表面沿着至少一个轴的曲率半径在以下范围之一:(a)约1nm至约10nm;(b)约11nm至约100nm;(c)约101nm至约400nm;(d)约401nm至约1μm;(e)约10μm至约20μm;(f)约20μm至约100μm;和(g)约101μm至约1mm。在一些实施方案中,所述不对称纳米颗粒可具有由以下限定的不对称形状:沿着x轴的尺度(a)、沿着y轴的尺度(b),和沿着z轴的尺度(c),其中(a)、(b)或(c)的至少一个不等于至少一个其它尺度(a)、(b)或(c)。在一些实施方案中,所述不对称形状是椭球体,其可通过以下等式之一描述:a>b=c(长椭球体);a>b>c(三轴椭球体);和a=b>c(扁椭球体)。可根据本发明使用的不对称纳米颗粒描述于WO2013/086500中,其在此通过引用整体并入。
颗粒的尺寸可不同。在各个实施方案中,所述颗粒尺寸(公称直径)在0.05-50μm的范围内,或在一些实施方案中,0.05-35μm,或在一些实施方案中,0.05至10μm,及在一些实施方案中,为约0.05至约3.0、约4.0或约5.0μm。例如,在一些实施方案中,所述颗粒直径或平均直径为50至500nm。在一些实施方案中,所述颗粒的平均尺寸小于约400nm、约300nm、约200nm或约100nm,以允许更好的外周血液循环。在一些实施方案中,所述纳米颗粒的平均尺寸(如,直径或最大轴)为约100nm、约150nm或约200nm。术语“约”,当与以数字特征相关联时,意为±10%。在一些实施方案中,至少90%的颗粒在约50至约250nm、诸如约100至约150nm的范围内。所述颗粒可在尺寸方面一致或可在尺寸方面不同,其中平均颗粒尺寸优选如上文所述。在一些实施方案中,所述颗粒足够小以利用“EPR效应”(增强的渗透和滞留效应)。
本文所述的配体和分子复合物可使用任何可用的工艺化学缀合至所述珠粒。用于配体结合的官能团包括PEG-COOH、PEG-NH2、PEG-SH或连接至不同聚合物诸如聚氰基丙烯酸酯或聚己内酯的其它官能团。
例如,固体支撑物可在蛋白结合至其表面之前涂覆。一旦已经选择涂料化学,固体支撑物的表明可被激活以使特异性连接特定蛋白质分子。因此,可鉴于与各种细胞类群的最佳反应性和生物相容性来选择涂料。优选地,无论使用的涂料化学是什么,其提供适用于进一步激活化学的基质。多种此类涂料是本领域所熟知的。例如,固体支撑物可用人血清白蛋白、三(3-巯丙基)-N-甘氨酰基氨基)甲烷(美国专利6,074,884)、明胶-氨基葡聚糖(美国专利5,466,609)或氨基酸均聚物或无规共聚物涂覆。在一个实施方案中,使用包含聚(谷氨酸、赖氨酸、酪氨酸)[6:3:1]的无规氨基酸共聚物;该共聚物可从Sigma Chemical Co.以产品编号P8854获得。其为氨基酸谷氨酸、赖氨酸和酪氨酸比率为6份谷氨酸、3份赖氨酸和1份酪氨酸的线性无规聚合物。在另一个实施方案中,使用氨基酸共聚物,其包括比率为4份赖氨酸与1份酪氨酸的赖氨酸和酪氨酸。在又一个实施方案中,使用氨基酸共聚物,其包括比率为1份赖氨酸与1份丙氨酸的赖氨酸和丙氨酸。在另一个实施方案中,用合成聚合物涂覆固体支撑物,然后在合成聚合物连接至蛋白质分子之前,激活所述合成聚合物。
在一些实施方案中,分子通过吸附或通过直接化学键合(包括共价键合)直接连接至固体支撑物。参见,如,Hermanson,BlOCONJUGATE TECHNIQUES,Academic Press,NewYork,1996。分子本身可直接激活为具有多个化学官能团,包括亲核基团、离去基团或亲电子基团。激活官能团包括烷基卤和酰基卤、胺、硫氢基、醛、不饱和键、酰肼、异氰酸根、异硫氰酸根、酮及其它已知激活用于化学键合的基团。可选地,分子可通过使用小分子-偶联试剂结合至固体支撑物。偶联试剂的非限制性实例包括碳二亚胺、马来酰亚胺、N-羟基琥珀酰亚胺酯、双氯乙基胺、双功能醛诸如戊二醛、酸酐等。在其它实施方案中,分子可通过亲和力结合诸如生物素-链霉亲和素键合或偶联,如本领域熟知那样偶联至固体支撑物。例如,链霉亲和素可通过共价或非共价连接结合至固体支撑物,并且生物素化分子可使用本领域熟知的方法合成。
在一些实施方案中,所述颗粒或珠粒是聚合物,诸如PLGA-PEG、PLGA-PEG-马来酰亚胺或酯-包埋的PLGA,其中在聚合期间产生用于表面配体缀合的官能团。所述马来酰亚胺基团为形成的颗粒提供在所述颗粒外表面上的亲水"隐形"涂料(PEG),以及连接至该壳的可用于共价连接配体的官能团,所述配体具有至少一个可用的游离氢硫基(-SH)基团。例如,HLA-Ig配体和/或抗-CD28可构建在于Fc中含有S473C取代的人IgG4框架(如本文所述)上。HLA-Ig或抗-CD28的473处的该未配对半胱氨酸残基可在温和还原条件下缀合至与PEG连接的马来酰亚胺基团。温和还原条件不可能不可逆地使所述蛋白(特别是HLA-Ig分子的HLA-β-2-微球蛋白部分)变性。
在一个示例性实施方案中,所述纳米颗粒在约50nm至大到约5μm(如,平均直径或最大轴)的范围内,具有可能倾向于特定体内生物降解率的核心(PLGA)(通过调整PLGA聚合物的LA:GA比率和/或mw)、使其免受血清蛋白调理和从循环移除的亲水外壳(如“PEG刷”起作用)、用一致控制配体密度(1分子/马来酰亚胺基团的随机关系)官能化的表面,及配体朝向远离所述核心。在一些实施方案中,LA:GA比率为60%/40%至40%/60%,并且在一些实施方案中,为约50%/50%。在一些实施方案中,所述PLGA的分子量为约25K至约35K(如,约30K),并且所述PEG的分子量为约3K至约10K,诸如约5K。在一些实施方案中,所述核心颗粒的直径为约150nm或约200nm。
在一个可替代的实施方案中,所述支撑物可用含有一个或多个可用于通常通过连接子共价连接至适合的反应物的化学部分或官能团的聚合物涂覆。
激活化学允许特异性、稳定连接分子至固体支撑物表面。存在可用于连接蛋白质官能团的多种方法。例如,常见的交联剂戊二醛可用于以两步工艺连接蛋白胺基团至胺化固体支撑物编码。所得的键对水解是稳定的。其它方法包括使用含有与在蛋白上的胺反应的n-羟基-琥珀酰亚胺基(NHS)酯的交联剂、含有与含胺-、含硫氢基-或含组氨酸的蛋白反应的活性卤素的交联剂、含有与胺或硫氢基反应的环氧化物的交联剂,在马来酰亚胺基团与硫氢基之间缀合,以及通过高碘酸盐氧化侧接糖部分、然后通过还原性胺化形成蛋白醛基。
特定蛋白连接至固体支撑物表面可通过直接偶联蛋白或通过使用间接方法实现。当偶联至连接子或间隔子蛋白诸如抗-小鼠IgG或链霉亲和素时,某些蛋白将使其直接连接或缀合而其它蛋白或抗体保留更佳的功能活性。如果需要,则可使用连接子或连接蛋白。配体,诸如所述抗原呈递复合物和共刺激分子可经氨基酸取代修饰以允许化学缀合。
相同固体支撑物上具体蛋白的比率可变化以提高固体支撑物在抗原或抗体呈递中的有效性。例如,抗原呈递复合物与抗-CD28的比率可为至少约30:1、或至少约10:1、约3:1、约1:1、约0.3:1;约0.1:1,和至少约0.03:1。在一些实施方案中,所述比率为约5:1、约4:1、约3:1、约2:1、或约1:1、约1:2、约1:3、约1:4或约1:5。偶联至所述支撑物的蛋白的总量可为至少10mg/ml、至少25mg/ml、至少50mg/ml、至少100mg/ml、至少150mg/ml或大于200mg/ml。在一些实施方案中,诸如那些采用具有表面官能团(如,马来酰亚胺或酯)的PLGA或PLGA-PEG颗粒,偶联至所述颗粒的蛋白总量可为1至10μg/mg的PLGA,或在一些实施方案中,2至6μg/mg PLGA。在一些实施方案中,所述颗粒的配体密度为约103至约105个配体/μm2,或在一些实施方案中约104个配体/μm2。例如,对于尺寸在100至200nm范围内的纳米颗粒,所述纳米颗粒平均具有约100至约1500个配体,诸如约200至约1200个配体,或约400至约1000个配体,或约500至约800个配体。
在各个实施方案中,本发明提供包含聚合物珠粒或颗粒、如本文所述的抗-CD28抗体,和/或抗原呈递复合物诸如如本文所述的人源化Ig HLA融合复合物的药物组合物。所述药物组合物可另外包含用于呈递至如所述的T细胞且可与缀合珠粒或颗粒共配制的抗原肽。在各个实施方案中,所述药物组合物是货架稳定的,并且在一些实施方案中,以用于在施用前复溶的冻干形式提供,或以另一种“现成”药物制剂提供。
在一些实施方案中,本发明提供包含直径或平均直径为50至500nm的基于PLGA或PLGA-PEG的纳米颗粒和包含表面-缀合的抗-CD28抗体和抗原呈递复合物的药物组合物。所述抗-CD28抗体可为人源化抗体,如如本文所述的人源化抗体,并且可为抗体片段诸如单链可变片段。在一些实施方案中,所述抗原呈递复合物包含至少一个HLA抗原-结合槽。所述抗-CD28和HLA复合物可在相同反应中分别或一起偶联至所述颗粒。所述药物组合物可包含至少一种肽抗原,诸如肿瘤抗原(如,MART-1),并且其可与所述颗粒在无任何活性装载工艺的情况下共配制。
本文所述的药物组合物可通过向有需要的患者施用有效量的组合物用于免疫疗法,例如用于诱导抗原特异性细胞毒性T细胞形成的方法中。在一些实施方案中,所述患者是癌症患者。
本文所述的基于颗粒的抗原呈递平台可通过任何适当途径施用给患者,包括静脉内施用、动脉内施用、皮下施用、皮内施用、淋巴管内施用和肿瘤内施用。患者包括人和兽医学患者。
本发明的一些示例性实施方案描述如下。
在一些实施方案中,本发明提供包含聚合物PLGA-PEG颗粒的药物组合物,所述聚合物PLGA-PEG颗粒的尺寸在约100至200nm范围内、表面电荷为约-0至-20mV(和在一些实施方案中-5至-15mV),和每个颗粒有约100至1500个蛋白质配体。在一些实施方案中,所述蛋白质配体各自通过硫氢基-马来酰亚胺化学偶联至所述颗粒。所述配体包括抗-CD28抗体配体群体和HLA配体群体及一种或多种用于呈递至T细胞的抗原肽。所述组合物包含用于静脉内、动脉内、皮下、真皮内、淋巴管内或肿瘤内施用的药学上可接受的载体。
在一些实施方案中,所述颗粒基本上是球形或近似球形的。
在一些实施方案中,所述PLGA是约50%乳酸(LA)和50%羟基乙酸(GA)的聚合物。
在一些实施方案中,所述PLGA聚合物的分子量为约30K,并且所述PEG的分子量为约3K至约10K,诸如约5K。
在一些实施方案中,所述组合物具有每个颗粒400至1000个配体。
在一些实施方案中,所述抗-CD28抗体配体包含任选具有5至15个鼠科框架残基的人IGHV4-59种系框架,和任选具有3至15个鼠科框架残基的IGKV4-01种系框架。
在一些实施方案中,所述抗-CD28是ScFv。
在一些实施方案中,所述HLA是HLA-A*02:01,其可包含与铰链区上方的免疫球蛋白序列的融合物,足以提供二聚体HLA构建体。
在一些实施方案中,所述组合物是经冻干的。
具体而言,抗原呈递平台可用于治疗传染病、癌症或自身免疫性疾病患者,或向免疫抑制患者提供预防性保护。
可治疗的传染病包括那些由细菌、病毒、朊病毒、真菌、寄生虫、蠕虫等引起的传染病。此类疾病包括AIDS、肝炎、CMV感染和移植后淋巴增生性疾病(PTLD)。CMV,例如,是器官移植患者中存在的最常见的病毒病原体,并且是经历骨髓或外周血液干细胞移植的患者中发病率和死亡率的主要起因(Zaia,Hematol.Oncol.Clin.North Am.4,603-23,1990)。这是由于这些患者免疫受损的状况,这使得血清反应阳性患者中的潜伏性病毒重新激活或血清反应阴性个体机会性感染。当前治疗集中于使用抗病毒化合物诸如更昔洛韦,其具有缺点,其中最显著的是出现耐药性CMV。这些治疗的一种有用的替代者是预防性免疫治疗方案,其包括在启动移植程序之前产生来源于患者或适当供体的病毒特异性CTL。
PTLD发生在大比例的移植患者中,并由Epstein-Barr病毒(EBV)感染导致。EBV感染据信存在于约90%的美国成人群体中(Anagnostopoulos&Hummel,Histopathology 29,291-2)15,1996)。活跃的病毒复制和感染被免疫系统阻止,但是如在CMV的情况下,由于移植疗法而免疫受损的个体丧失控制T细胞类群,这使得病毒重新激活。这代表了对移植方案的严重妨碍。EBV还可参与多种血液学癌症和非血液学癌症中的肿瘤促进。在EBV与鼻咽癌癌之间还存在强相关性。因此,使用EBV-特异性T细胞预防性治疗为当前疗法提供了优良的替代方法。
可根据本发明肿瘤的癌症包括黑素瘤,癌如结肠癌、头颈癌、十二指肠癌、前列腺癌、乳腺癌、肺癌、卵巢癌、导管癌、结肠癌、肝癌、胰腺癌、肾癌、子宫内膜癌、胃癌、发育异常的口腔粘膜癌、息肉癌、侵入性口腔癌、非小细胞性肺癌、过渡和鳞状细胞泌尿癌等;神经恶性肿瘤,如神经母细胞瘤、神经胶质瘤等;血液学恶性肿瘤,如慢性骨髓性白血病、儿童急性白血病、非霍奇金氏淋巴瘤、慢性淋巴细胞性白血病、恶性皮肤T细胞、蕈样霉菌病、非MF皮肤T-细胞淋巴瘤、淋巴瘤样丘疹病、富T细胞皮肤淋巴性增生、大疱性类天疱疮、盘状红斑狼疮、扁平苔癣等;等。参见,如,Mackensen等,Int.J.Cancer 86,385-92,2000;Jonuleit等,Int.J.Cancer 93,243-51,2001;Lan等,J.Immunotherapy 24,66-78,2001;Meidenbauer等,J.Immunol.170(4),2161-69,2003。
在一些实施方案中,本发明提供通过施用本文所述的药物组合物以激活具有抗-肿瘤活性的T细胞来治疗癌症(包括以上鉴定的那些癌症)的方法。在一些实施方案中,所述疗法与一种或多种免疫检查点抑制剂诸如纳武单抗(Nivolumab)、Pembrolizumab和伊匹单抗(Ipilimumab)一起提供。在一些实施方案中,另外的疗法是抗-CTLA4或抗-PD1或抗-PD-L1。另外的疗法或检查点抑制可通过其常规方案分别施用,或可作为本文所述的纳米颗粒或连接至单独类群的纳米颗粒的另外配体施用。在一些实施方案中,一种或多种免疫检查点抑制剂提供为起始疗法,和使用随后开始的本文所述的纳米颗粒的疗法,例如在约1至约8周的检查点抑制疗法后或在约2至约4周的检查点抑制疗法后。在一些实施方案中,一种或多种检查点抑制剂与纳米颗粒疗法同时提供,例如在疗法开始时和约每两周,或在疗法开始时和约每两周进行一种或多种检查点抑制剂及约每四周进行纳米颗粒疗法。在一些实施方案中,所述患者对检查点抑制疗法耐受,或者仅显示了对检查点抑制疗法的部分或短暂响应,并且本文所述的aAPC增强这些患者中的肿瘤消退。在另一些实施方案中,对于通常对检查点抑制疗法耐受的癌症,本文所述的组合物扩大了成功使用针对此类癌症的检查点抑制剂。
在一些实施方案中,所述肽抗原是基于患者的个性化基础、基于对患者肿瘤的分析选择的。例如,可使用Ionov Y.,A high throughput method for identifyingpersonalized tumor-associated antigens,Oncotarget 1(2):148-155(2010)(其在此通过引用并入)所述的方法,或其它方法。在这些实施方案中,可提供所述纳米颗粒(基于“现成”),并且基于个性化基础选择和装载肿瘤抗原。
可治疗的自身免疫性疾病包括哮喘、全身性红斑狼疮、风湿性关节炎、I型糖尿病、多发性硬化、克罗恩氏病(Crohn's disease)、溃疡性结肠炎、银屑病、重症肌无力、古德帕斯彻氏综合症、格雷夫斯氏病、寻常性天疱疮、爱迪生氏病、疱疹样皮炎、乳糜泻和桥本氏甲状腺炎。
抗原特异性辅助T细胞可用于激活巨噬细胞或激活B细胞以产生可用于例如治疗传染病和癌症的特异性抗体。产生抗体的B细胞本身还可用于该目的。
本发明还提供编码本文所述的氨基酸序列的多核苷酸以及表达本文所述的氨基酸序列的宿主细胞。
本发明通过以下非限制性实例进一步说明。
实施例
实施例1:种系人源化可变区和人恒定区序列的设计
该实施例尤其表明来自小鼠抗-CD28抗体模板的种系人源化(接枝的CDR)抗体的序列设计;人恒定区序列(包括含有S241P(Kabat编号)铰链稳定突变、L248E(Kabat编号)突变以去除残余Fcγ受体结合、及适于偶联抗体的Cys残基(S473C,Kabat编号)的人IgG4)的设计;潜在不结合至CD28的变体种系人源化抗体V结构域的设计;融合HLA-A*02:01至种系人源化抗体的不含有潜在T细胞表位的N-端的连接子序列的设计。
起始抗-CD28抗体是鼠科9.3单克隆抗体(Tan等.J.Exp.Med.1993177:165)。9.3抗体V区的结构模型使用Swiss PDB产生,并分析以鉴别V区中可能对抗体结合性质必需的氨基酸。CDR内含有的所有残基(使用Kabat和Chothia定义)连同多个框架残基被认为对于结合具有潜在的重要性。抗-CD28的VH和Vκ序列含有典型的框架(Fw)残基,并且CDR 1、2和3基序与许多鼠科抗体相当。
对于人源化,人IGHV4-59种系Fw被选为重链的模板(参考由Tan等J.Immunol 2002169:1119-1125选择的IGHV3/OR16-10)。IGKV4-01种系Fw被选为轻链的模板。这些Fw都与其对应的鼠科VH和Vκ序列具有62%同源性。将所述鼠科CDR接枝至这些Fw中,并且还纳入不同数量的鼠科Fw残基以产生三种人源化VH变体和三种人源化Vκ变体(图1-6)。
对于重链Fw,Fw1残基1和3被认为对于抗原结合较重要,因为它们与结合袋相邻,而残基6被认为影响β链支持残基1和3的构象及CDR3的构象。因此这些鼠科Fw残基保留在所有变体中。
在Fw2中,残基37被认为对于维持VH与Vκ之间的界面是重要的,而残基48被认为支持CDR2的构象;因此这两个残基都保留在所有变体中。
在Fw3中,残基73、76和78直接接触CDR1,而残基71接触CDR1和CDR2两者;因此,这些残基可能为抗原结合所需(取决于CDR1和CDR2的贡献),并因此保留在所有变体中。残基71可有时通过影响残基71至78的构象而间接影响CDR1的构象,而残基82a和82c还可间接影响CDR2的构象。这些残基因此仅保留在VH1中。残基67和82在三维结构中相邻,并且相互作用以填充可影响CDR2的构象并潜在影响支持CDR 1和3的β链的空间。因此这些残基保留在变体VH1和VH2中。
对于轻链Fw,Fw1残基3与结合袋相邻,并可直接参与抗原结合,而残基4直接支持CDR3的构象。因此,这些鼠科Fw残基保留在所有变体中。
在Fw2中,残基49支持CDR2的构象,并且对于重链与轻链之间界面也是重要的,其中其直接支持重链CDR3的构象,因此保留在所有变体中。
在Fw3中,残基85和87被认为对重链和轻链的界面是重要的,并且也支持CDR3构象并因此保留在所有变体中。残基80被认为潜在具有对CDR 2和3的构象存在间接影响,并且仅保留在Vκ1中。残基70通过与轻链残基R24形成盐桥,并因此对Vκ结构域具有重要构象影响。在抗-CD28中,该盐桥不存在(因为残基70是N而非D),并引入该相互作用可以是不利的;然而在鼠科中抗体N70被糖基化(NFS),并且在人源化期间移除这个将是有益的;因此所述鼠科N保留在Vκ1和Vκ2中,但在Vκ3中改变为D。
基于人IgG4/κ的恒定区序列经设计包含铰链稳定突变(S241P)和移除残余Fcγ受体结合(L248E)的较低铰链中的突变。半胱氨酸残基还包含在Fc的C-端附近以用于化学偶联目的(S473C)。经修饰的IgG4重链恒定区序列示于图7中,连同κ轻链恒定区序列(图8)。
另外的VH结构域设计为潜在不结合至CD28,并且该序列显示于图9中。对鼠科V区序列的分析表明(从小鼠种系V区的体突变的程度说)所述VH可能是CD28结合的主要贡献者。因此仅潜在非结合人源化VH变体经设计。该变体不含有任何小鼠Fw残基以重构正确的CDR构象,并且在CDRH3中在可能对结合是重要的残基处还含有三个突变(Y100A、Y100aA、Y100bA)。
实施例2:用于融合HLA-A*02:01至人源化抗体的连接子的设计
将用于融合HLA-A*02:01(IMGT登记号HLA00005)至人源化抗-CD28抗体N-端的连接子通过iTopeTM和TCEDTM构建并并入分析以去除潜在免疫原性。
iTopeTM软件预测了34个人MHC II类等位基因的开放式结合沟内肽的氨基酸侧链与特异性结合袋之间的有利相互作用(特别是袋位置;p1、p4、p6、p7和p9)。这些等位基因代表全球存在的最常见的HLA-DR等位基因,而没有权重由于任何特定种族人群中最主要存在的那些等位基因。二十个等位基因含有‘开放’p1构型,并且十四个含有‘闭合’构型,其中位置83处的甘氨酸被缬氨酸替代。关键结合残基的位置经由电脑模拟产生重叠横跨测试蛋白质序列的一个氨基酸的9聚体肽获得。与物理MHC II类结合实验的比较已显示iTopeTM可用于以高精度成功区别结合与不结合MHC II类分子的肽。经由电脑模拟产生的MHC II类结合分析的任何限制使用TCEDTM减少,所述TCEDTM含有来源于之前在EpiScreenTM离体T细胞表位作图测定中筛选的序列的大数据库肽(>10,000条肽)序列。因此TCEDTM可用于针对不相关的抗体和蛋白序列搜索任何测试序列,以寻找与实际离体免疫原性的相关性。
使用iTopeTM对连接子序列分析是用横跨连接子序列的重叠9聚体进行的,针对34个MHC II类等位基因的每一个测试所述重叠9聚体。基于潜在‘命中’和与MHC II类分子的相互作用对每个9聚体评分。通过所述软件计算的所述肽得分在0至1之间。将产生高平均结合得分(在iTopeTM评分函数中>0.55)的非种系肽突出显示,并且如果≥50%的MHC II类结合肽(即34个等位基因中的17个)具有高结合亲和力(得分>0.6),则此类肽被定义为“混杂高亲和力”MHC II类结合肽(其被认为对于含有CD4+T细胞表位是高风险的)。其中≥50%的MHC II类结合肽(得分>0.55(但而非大部分>0.6))的肽被定义为“混杂中等亲和力”MHC II类结合肽。对所述序列的进一步分析使用TCEDTM进行。所述序列用于通过BLAST搜索询问TCEDTM以鉴定在之前EpiScreenTM研究中刺激T细胞响应的不相关蛋白的肽(T细胞表位)之间的任何高序列同一性。
由Schneck等使用的序列包含两个连接子,一个在HLA-A*02:01的N-端处以与N-端信号序列连接,和一个在C-端用于融合至抗-CD28 VH结构域(参见例如图9)。对于N-端连接子,从信号序列切割位点至连接子分析序列,并且所述序列包括HLA-A*02:01成熟蛋白的前8个氨基酸。对于C-端连接子,从HLA-A*02:01α3结构域的末端8个氨基酸至连接子序列和抗-CD28 VH结构域的多达前8个氨基酸分析序列。
结合得分>0.6(高亲和力)的肽结合至大部分的(≥17)MHC II类等位基因(定义为混杂高亲和力粘合剂)。结合得分在0.55与0.6之间的中等亲和力粘合剂结合≥17MHC II类等位基因。发现N-端连接子含有两条混杂MHC II类结合序列,一条高亲和力(在位置2处有p1锚)和一条中等亲和力(在位置4处有p1锚)。发现所述C-端连接子含有一条在位置11处具有p1锚的混杂中等亲和力MHC II类结合肽。
BLAST搜索表位的T细胞表位数据库(TCEDTM)使用如iTopeTM分析中所用相同的序列进行,以确定与之前鉴定的表位的任何同源性。所述TCEDTM用于针对大型(>10,000条肽)数据库的肽搜索任何测试序列,所述肽来源于已在EpiScreenTMT细胞表位作图测定中测试的不相关的序列。发现所述连接子序列没有一条在TCEDTM中含有任何‘命中’。
iTopeTM进一步用于评估连接子序列变化以降低其对结合至II类MHC的倾向。应注意可完全去除N-端连接子使得HLA-A*02:01的N-端直接融合至pBFKsr载体中提供的信号序列或其天然信号序列。这将确保所述融合蛋白的N-端将仅含有人种系序列并避免T细胞表位风险。发现下文推荐的连接子序列可减少MHC II类结合至本地残余水平(<5个由任何9聚体结合的等位基因),并提供适于克隆的限制位点(尽管两个序列将需要对载体修饰):
实施例3:序列和表达克隆的密码子优化
将序列工程化为具有PmeI限制位点、Kozak序列和信号肽以用于在NS0细胞中表达。翻译立即起始于Kozak序列的下游。
HLA-IgG4HC融合物的完全非翻译氨基酸序列示于图10中。
LC3(VK3)的非翻译序列示于图11中。
HC1的非翻译序列示于图12中。
HC2的非翻译序列示于图13中。
还表达了人β2微球蛋白。
实施例4:在NS0细胞中表达
基于Biacore亲和力数据和其它考虑,HC1::LC3和HC2::LC3重链和轻链组合分别被选为第一和第二mAb候选物,以用于StableFast-NS0细胞系开发。
用于STABLEFAST-NS0细胞系产生的pBFksr::HC1::LC3双顺反子表达载体的最终载体图描述于图14中。pBFksr::HC2::LC3的构建使用相同的方法进行。
亲代NS0细胞在补充无血清生长培养基中扩增。在建立健康培养物后,一千万个细胞(10×106)用45μg线性(ΔPvuI)表达载体DNA转染。使细胞在生长培养基中大量恢复24小时。在恢复后,将细胞在补充无血清选择培养基(胆固醇-)中洗涤,重新悬浮于选择性培养基中并以每孔200μL分布至40×96-孔板。对于HC1::LC3和HC2::LC3,实际分布分别为1140个细胞/孔和840个细胞/孔。将板在37℃、5%CO2下孵育1周,并以补充有选择培养基的酚红补料。在转染后两周,基于培养基颜色从红色变化为黄色,活跃地使多个孔生长。
通过ELISA筛选来自HC1::LC3转染的总共1,127个孔的人IgG表达。筛选来自HC2::LC3转染的总共612个孔。基于IgG浓度,对于HC1::LC3和HC2::LC3,分别将总共290个和101个细胞系放大到24-孔板。24小时产率测定用于选择最佳表达者以用于进一步分析。简而言之,将24-孔板以5×105个细胞接种在500μL新鲜培养基中。24小时后,上清液通过ELISA筛选。基于IgG浓度,对于HC1::LC3和HC2::LC3,分别将总共60和24个细胞系放大到6孔板。
3-天特异性产率测定用于选择最佳表达者以用于进一步分析。简而言之,将6-孔板以4×105个细胞接种在1.5mL新鲜培养基中。在3天后,对细胞计数,并且通过ELISA筛选上清液。基于IgG浓度和生长,可计算以pg/细胞/天计的平均特定产率或SPR。基于相对SPR,对于HC1::LC3和HC2::LC3,分别总共20和10个细胞系放大到T-75烧瓶。以T-75规模重复3天SPR测定以选择最终细胞系用于悬浮液适应,并放大用于mAb生产。
将针对每个mAb的五个细胞系放大至30-mL振动培养基并重新评估SPR和生长。保存(banked)所有悬浮物系。对于每个mAb表现最佳的细胞系经放大至转瓶培养基用于小规模生产。
对于HLA-IgG4融合蛋白,构建pBFksr::HLA-IgG4::LC3双顺反子表达载体以用于STABLEFAST-NS0细胞系产生。载体图示于图15中。还为三顺反子表达载体创建了含有人β2微球蛋白基因的表达盒和载体,所述三顺反子表达载体编码所有三种融合蛋白亚基(人HLA-IgG4重链融合物、a-CD28轻链[LC3]和人β2微球蛋白)。三顺反子构建体示于图16中。所有三个基因的表达在短暂HEK293培养物中通过上清液的ELISA和蛋白质印迹分析确认。
实施例5:功能表征
测试针对CD28的人源化单克隆抗体诱导刚分离的PBMC在mAb涂覆板上扩增的能力。如图17所示,人源化抗-CD28不是超激动剂。
测试人源化单克隆抗体在人T-细胞系上染色CD28的能力。结果示于图18中。图18(A)显示了用鼠科抗-人CD8 mAb(克隆9.3,同种型IgG2a)染色。黑色=未染色的细胞,红色=抗-IgG2a FITC,蓝色=抗-CD28+抗-IgG2a FITC。图18(B)显示了用人源化抗-CD28(同种型IgG4)染色。黑色=未染色的细胞,红色=抗-IgG4 PE、蓝色=抗-CD28(35ng)+抗-IgG4PE、紫色=抗CD28(1μg)+抗-IgG4 PE。用人源化抗-CD28染色可用克隆9.3mAb(未显示)阻断。
在纯化HLA-Ig之后,抗原肽装载效率通过使用构象依赖性抗-HLA mAb的ELISA检查,以捕获肽装载的蛋白(如Immunology 17.2章中当前方案所述)。与非特异性肽(即MHC错误匹配)的0%相比,预期特异性肽的可再生装载效率(即正确的MHC限制)为~90%。
通过引用并入
本文参考的所有专利和公开物在此通过引用整体并入。
序列表
<110> 耐克西缪恩公司
<120> 用于免疫疗法的组合物和方法
<130> FCT150900-99-DIV
<150> US 61/838,547
<151> 2013-06-24
<150> US 61/948,916
<151> 2014-03-06
<160> 34
<170> PatentIn version 3.5
<210> 1
<211> 360
<212> DNA
<213> 人工序列
<220>
<223> 合成序列(抗-CD28的人源化可变重序列)
<220>
<221> CDS
<222> (1)..(360)
<400> 1
gag gtg aag ctg cag cag tca gga cct ggc ctg gtg aag ccc tca gag 48
Glu Val Lys Leu Gln Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
acc ctg tcc ctc act tgt act gtc tct ggg ttt tca tta agc gac tat 96
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Asp Tyr
20 25 30
ggt gtt cat tgg gtt cgc cag gct cca gga aag gga ctg gag tgg ctg 144
Gly Val His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
gga gta ata tgg gct ggt gga ggc acg aat tat aat tcg gct ctc atg 192
Gly Val Ile Trp Ala Gly Gly Gly Thr Asn Tyr Asn Ser Ala Leu Met
50 55 60
tcc aga aag acc atc agc aaa gac aac tcc aag agc caa gtt ttc tta 240
Ser Arg Lys Thr Ile Ser Lys Asp Asn Ser Lys Ser Gln Val Phe Leu
65 70 75 80
aaa atg aac agt ctg aca gct gct gac aca gcc gtg tat tac tgt gcc 288
Lys Met Asn Ser Leu Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
aga gat aag gga tac tcc tat tac tat tct atg gac tac tgg ggc caa 336
Arg Asp Lys Gly Tyr Ser Tyr Tyr Tyr Ser Met Asp Tyr Trp Gly Gln
100 105 110
ggc acc ctg gtc acc gtc tcc tca 360
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 2
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 2
Glu Val Lys Leu Gln Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Asp Tyr
20 25 30
Gly Val His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Ala Gly Gly Gly Thr Asn Tyr Asn Ser Ala Leu Met
50 55 60
Ser Arg Lys Thr Ile Ser Lys Asp Asn Ser Lys Ser Gln Val Phe Leu
65 70 75 80
Lys Met Asn Ser Leu Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Asp Lys Gly Tyr Ser Tyr Tyr Tyr Ser Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 3
<211> 360
<212> DNA
<213> 人工序列
<220>
<223> 合成序列 (抗-CD28 VH2)
<220>
<221> CDS
<222> (1)..(360)
<400> 3
gag gtg aag ctg cag cag tca gga cct ggc ctg gtg aag ccc tca gag 48
Glu Val Lys Leu Gln Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
acc ctg tcc ctc act tgt act gtc tct ggg ttt tca tta agc gac tat 96
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Asp Tyr
20 25 30
ggt gtt cat tgg gtt cgc cag gct cca gga aag gga ctg gag tgg ctg 144
Gly Val His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
gga gta ata tgg gct ggt gga ggc acg aat tat aat tcg gct ctc atg 192
Gly Val Ile Trp Ala Gly Gly Gly Thr Asn Tyr Asn Ser Ala Leu Met
50 55 60
tcc aga aag acc atc agc aaa gac aac tcc aag agc caa gtt tcc tta 240
Ser Arg Lys Thr Ile Ser Lys Asp Asn Ser Lys Ser Gln Val Ser Leu
65 70 75 80
aaa atg agc agt gtg aca gct gct gac aca gcc gtg tat tac tgt gcc 288
Lys Met Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
aga gat aag gga tac tcc tat tac tat tct atg gac tac tgg ggc caa 336
Arg Asp Lys Gly Tyr Ser Tyr Tyr Tyr Ser Met Asp Tyr Trp Gly Gln
100 105 110
ggc acc ctg gtc acc gtc tcc tca 360
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 4
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 4
Glu Val Lys Leu Gln Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Asp Tyr
20 25 30
Gly Val His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Ala Gly Gly Gly Thr Asn Tyr Asn Ser Ala Leu Met
50 55 60
Ser Arg Lys Thr Ile Ser Lys Asp Asn Ser Lys Ser Gln Val Ser Leu
65 70 75 80
Lys Met Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Asp Lys Gly Tyr Ser Tyr Tyr Tyr Ser Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 5
<211> 360
<212> DNA
<213> 人工序列
<220>
<223> 合成序列 (抗-CD28 VH3)
<220>
<221> CDS
<222> (1)..(360)
<400> 5
gag gtg aag ctg cag cag tca gga cct ggc ctg gtg aag ccc tca gag 48
Glu Val Lys Leu Gln Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
acc ctg tcc ctc act tgt act gtc tct ggg ttt tca tta agc gac tat 96
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Asp Tyr
20 25 30
ggt gtt cat tgg gtt cgc cag gct cca gga aag gga ctg gag tgg ctg 144
Gly Val His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
gga gta ata tgg gct ggt gga ggc acg aat tat aat tcg gct ctc atg 192
Gly Val Ile Trp Ala Gly Gly Gly Thr Asn Tyr Asn Ser Ala Leu Met
50 55 60
tcc aga gtg acc atc agc aaa gac aac tcc aag agc caa gtt tcc tta 240
Ser Arg Val Thr Ile Ser Lys Asp Asn Ser Lys Ser Gln Val Ser Leu
65 70 75 80
aaa ctg agc agt gtg aca gct gct gac aca gcc gtg tat tac tgt gcc 288
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
aga gat aag gga tac tcc tat tac tat tct atg gac tac tgg ggc caa 336
Arg Asp Lys Gly Tyr Ser Tyr Tyr Tyr Ser Met Asp Tyr Trp Gly Gln
100 105 110
ggc acc ctg gtc acc gtc tcc tca 360
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 6
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 6
Glu Val Lys Leu Gln Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Asp Tyr
20 25 30
Gly Val His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Ala Gly Gly Gly Thr Asn Tyr Asn Ser Ala Leu Met
50 55 60
Ser Arg Val Thr Ile Ser Lys Asp Asn Ser Lys Ser Gln Val Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Asp Lys Gly Tyr Ser Tyr Tyr Tyr Ser Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 7
<211> 333
<212> DNA
<213> 人工序列
<220>
<223> 合成序列 (抗-CD28 VK1)
<220>
<221> CDS
<222> (1)..(333)
<400> 7
gac atc gag ctc act cag tct cca gat tct ttg gct gtg tct cta ggg 48
Asp Ile Glu Leu Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
gag aga gcc acc atc aac tgc aga gcc agt gag agt gtt gaa tat tat 96
Glu Arg Ala Thr Ile Asn Cys Arg Ala Ser Glu Ser Val Glu Tyr Tyr
20 25 30
gtc aca agt tta atg cag tgg tac cag cag aag cca gga cag cca ccc 144
Val Thr Ser Leu Met Gln Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
aaa ctc ctc atc ttt gct gca tcc aac gta gaa tct ggg gtc cct gac 192
Lys Leu Leu Ile Phe Ala Ala Ser Asn Val Glu Ser Gly Val Pro Asp
50 55 60
agg ttt agt ggc agt ggg tct ggg aca aac ttc acc ctc acc atc tct 240
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asn Phe Thr Leu Thr Ile Ser
65 70 75 80
tct ctg cag gag gag gat gtt gca atg tat ttc tgt cag caa agt agg 288
Ser Leu Gln Glu Glu Asp Val Ala Met Tyr Phe Cys Gln Gln Ser Arg
85 90 95
aag gtt cct tac acg ttc gga ggg ggg acc aag gtg gaa ata aaa 333
Lys Val Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 8
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 8
Asp Ile Glu Leu Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Arg Ala Ser Glu Ser Val Glu Tyr Tyr
20 25 30
Val Thr Ser Leu Met Gln Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Phe Ala Ala Ser Asn Val Glu Ser Gly Val Pro Asp
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asn Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Glu Glu Asp Val Ala Met Tyr Phe Cys Gln Gln Ser Arg
85 90 95
Lys Val Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 9
<211> 333
<212> DNA
<213> 人工序列
<220>
<223> 合成序列 (抗-CD28 VK2)
<220>
<221> CDS
<222> (1)..(333)
<400> 9
gac atc gag ctc act cag tct cca gat tct ttg gct gtg tct cta ggg 48
Asp Ile Glu Leu Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
gag aga gcc acc atc aac tgc aga gcc agt gag agt gtt gaa tat tat 96
Glu Arg Ala Thr Ile Asn Cys Arg Ala Ser Glu Ser Val Glu Tyr Tyr
20 25 30
gtc aca agt tta atg cag tgg tac cag cag aag cca gga cag cca ccc 144
Val Thr Ser Leu Met Gln Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
aaa ctc ctc atc ttt gct gca tcc aac gta gaa tct ggg gtc cct gac 192
Lys Leu Leu Ile Phe Ala Ala Ser Asn Val Glu Ser Gly Val Pro Asp
50 55 60
agg ttt agt ggc agt ggg tct ggg aca aac ttc acc ctc acc atc tct 240
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asn Phe Thr Leu Thr Ile Ser
65 70 75 80
tct ctg cag gcc gag gat gtt gca atg tat ttc tgt cag caa agt agg 288
Ser Leu Gln Ala Glu Asp Val Ala Met Tyr Phe Cys Gln Gln Ser Arg
85 90 95
aag gtt cct tac acg ttc gga ggg ggg acc aag gtg gaa ata aaa 333
Lys Val Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 10
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 10
Asp Ile Glu Leu Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Arg Ala Ser Glu Ser Val Glu Tyr Tyr
20 25 30
Val Thr Ser Leu Met Gln Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Phe Ala Ala Ser Asn Val Glu Ser Gly Val Pro Asp
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asn Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Ala Glu Asp Val Ala Met Tyr Phe Cys Gln Gln Ser Arg
85 90 95
Lys Val Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 11
<211> 333
<212> DNA
<213> 人工序列
<220>
<223> 合成序列 (抗-CD28 VK3)
<220>
<221> CDS
<222> (1)..(333)
<400> 11
gac atc gag ctc act cag tct cca gat tct ttg gct gtg tct cta ggg 48
Asp Ile Glu Leu Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
gag aga gcc acc atc aac tgc aga gcc agt gag agt gtt gaa tat tat 96
Glu Arg Ala Thr Ile Asn Cys Arg Ala Ser Glu Ser Val Glu Tyr Tyr
20 25 30
gtc aca agt tta atg cag tgg tac cag cag aag cca gga cag cca ccc 144
Val Thr Ser Leu Met Gln Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
aaa ctc ctc atc ttt gct gca tcc aac gta gaa tct ggg gtc cct gac 192
Lys Leu Leu Ile Phe Ala Ala Ser Asn Val Glu Ser Gly Val Pro Asp
50 55 60
agg ttt agt ggc agt ggg tct ggg aca gac ttc acc ctc acc atc tct 240
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
tct ctg cag gcc gag gat gtt gca atg tat ttc tgt cag caa agt agg 288
Ser Leu Gln Ala Glu Asp Val Ala Met Tyr Phe Cys Gln Gln Ser Arg
85 90 95
aag gtt cct tac acg ttc gga ggg ggg acc aag gtg gaa ata aaa 333
Lys Val Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 12
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 12
Asp Ile Glu Leu Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Arg Ala Ser Glu Ser Val Glu Tyr Tyr
20 25 30
Val Thr Ser Leu Met Gln Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Phe Ala Ala Ser Asn Val Glu Ser Gly Val Pro Asp
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Ala Glu Asp Val Ala Met Tyr Phe Cys Gln Gln Ser Arg
85 90 95
Lys Val Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 13
<211> 984
<212> DNA
<213> 人工序列
<220>
<223> 合成序列 (经修饰的恒定重序列)
<220>
<221> CDS
<222> (1)..(984)
<400> 13
gct tcc acc aag ggc cca tcc gtc ttc ccc ctg gcg ccc tgc tcc agg 48
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
agc acc tcc gag agc aca gcc gcc ctg ggc tgc ctg gtc aag gac tac 96
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
ttc ccc gaa ccg gtg acg gtg tcg tgg aac tca ggc gcc ctg acc agc 144
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
ggc gtg cac acc ttc ccg gct gtc cta cag tcc tca gga ctc tac tcc 192
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
ctc agc agc gtg gtg acc gtg ccc tcc agc agc ttg ggc acg aag acc 240
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
tac acc tgc aat gta gat cac aag ccc agc aac acc aag gtg gac aag 288
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
aga gtt gag tcc aaa tat ggt ccc cca tgc cca cca tgc cca gca cct 336
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
gag ttc gag ggg gga cca tca gtc ttc ctg ttc ccc cca aaa ccc aag 384
Glu Phe Glu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
gac act ctc atg atc tcc cgg acc cct gag gtc acg tgc gtg gtg gtg 432
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
gac gtg agc cag gaa gac ccc gag gtc cag ttc aac tgg tac gtg gat 480
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
ggc gtg gag gtg cat aat gcc aag aca aag ccg cgg gag gag cag ttc 528
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
aac agc acg tac cgt gtg gtc agc gtc ctc acc gtc ctg cac cag gac 576
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
tgg ctg aac ggc aag gag tac aag tgc aag gtc tcc aac aaa ggc ctc 624
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
ccg tcc tcc atc gag aaa acc atc tcc aaa gcc aaa ggg cag ccc cga 672
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
gag cca cag gtg tac acc ctg ccc cca tcc cag gag gag atg acc aag 720
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
aac cag gtc agc ctg acc tgc ctg gtc aaa ggc ttc tac ccc agc gac 768
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
atc gcc gtg gag tgg gag agc aat ggg cag ccg gag aac aac tac aag 816
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
acc acg cct ccc gtg ctg gac tcc gac ggc tcc ttc ttc ctc tac agc 864
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
agg cta acc gtg gac aag agc agg tgg cag gag ggg aat gtc ttc tca 912
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
tgc tcc gtg atg cat gag gct ctg cac aac cac tac aca cag aag agc 960
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
ctc tgc ctg tct ctg ggt aaa tga 984
Leu Cys Leu Ser Leu Gly Lys
325
<210> 14
<211> 327
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 14
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Glu Phe Glu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Cys Leu Ser Leu Gly Lys
325
<210> 15
<211> 324
<212> DNA
<213> 人工序列
<220>
<223> 合成序列 (恒定k轻序列)
<220>
<221> CDS
<222> (1)..(324)
<400> 15
cga act gtg gct gca cca tct gtc ttc atc ttc ccg cca tct gat gag 48
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
1 5 10 15
cag ttg aaa tct gga act gcc tct gtt gtg tgc ctg ctg aat aac ttc 96
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
20 25 30
tat ccc aga gag gcc aaa gta cag tgg aag gtg gat aac gcc ctc caa 144
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
35 40 45
tcg ggt aac tcc cag gag agt gtc aca gag cag gac agc aag gac agc 192
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
50 55 60
acc tac agc ctc agc agc acc ctg acg ctg agc aaa gca gac tac gag 240
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
65 70 75 80
aaa cac aaa gtc tac gcc tgc gaa gtc acc cat cag ggc ctg agc tcg 288
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
85 90 95
ccc gtc aca aag agc ttc aac agg gga gag tgt tag 324
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
100 105
<210> 16
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 16
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
1 5 10 15
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
20 25 30
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
35 40 45
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
50 55 60
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
65 70 75 80
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
85 90 95
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
100 105
<210> 17
<211> 360
<212> DNA
<213> 人工序列
<220>
<223> 合成序列 (人源化非CD28-结合可变区)
<220>
<221> CDS
<222> (1)..(360)
<400> 17
gag gtg aag ctg cag cag tca gga cct ggc ctg gtg aag ccc tca gag 48
Glu Val Lys Leu Gln Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
acc ctg tcc ctc act tgt act gtc tct ggg ttt aca ttc agc gac tat 96
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
ggt gtt cat tgg att cgc cag cct cca gga aag gga ctg gag tgg atc 144
Gly Val His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
gga gta ata tgg gct ggt gga ggc acg aat tat aat tcg gct ctc atg 192
Gly Val Ile Trp Ala Gly Gly Gly Thr Asn Tyr Asn Ser Ala Leu Met
50 55 60
tcc aga gtg acc atc agc gtg gac acc tcc aag aac caa ttt tcc tta 240
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
aaa ctg agc agt gtg aca gct gct gac aca gcc gtg tat tac tgt gcc 288
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
aga gat aag gga tac tcc gct gcc gct tct atg gac tac tgg ggc caa 336
Arg Asp Lys Gly Tyr Ser Ala Ala Ala Ser Met Asp Tyr Trp Gly Gln
100 105 110
ggc acc ctg gtc acc gtc tcc tca 360
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 18
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 18
Glu Val Lys Leu Gln Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Gly Val His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Val Ile Trp Ala Gly Gly Gly Thr Asn Tyr Asn Ser Ala Leu Met
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Asp Lys Gly Tyr Ser Ala Ala Ala Ser Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 19
<211> 733
<212> PRT
<213> 人工序列
<220>
<223> 合成序列 (人源化HLA-IgG4HC)
<400> 19
Gln Val Gln Leu Thr Arg Glu Gly Ser Gly Ser His Ser Met Arg Tyr
1 5 10 15
Phe Phe Thr Ser Val Ser Arg Pro Gly Arg Gly Glu Pro Arg Phe Ile
20 25 30
Ala Val Gly Tyr Val Asp Asp Thr Gln Phe Val Arg Phe Asp Ser Asp
35 40 45
Ala Ala Ser Gln Arg Met Glu Pro Arg Ala Pro Trp Ile Glu Gln Glu
50 55 60
Gly Pro Glu Tyr Trp Asp Gly Glu Thr Arg Lys Val Lys Ala His Ser
65 70 75 80
Gln Thr His Arg Val Asp Leu Gly Thr Leu Arg Gly Tyr Tyr Asn Gln
85 90 95
Ser Glu Ala Gly Ser His Thr Val Gln Arg Met Tyr Gly Cys Asp Val
100 105 110
Gly Ser Asp Trp Arg Phe Leu Arg Gly Tyr His Gln Tyr Ala Tyr Asp
115 120 125
Gly Lys Asp Tyr Ile Ala Leu Lys Glu Asp Leu Arg Ser Trp Thr Ala
130 135 140
Ala Asp Met Ala Ala Gln Thr Thr Lys His Lys Trp Glu Ala Ala His
145 150 155 160
Val Ala Glu Gln Leu Arg Ala Tyr Leu Glu Gly Thr Cys Val Glu Trp
165 170 175
Leu Arg Arg Tyr Leu Glu Asn Gly Lys Glu Thr Leu Gln Arg Thr Asp
180 185 190
Ala Pro Lys Thr His Met Thr His His Ala Val Ser Asp His Glu Ala
195 200 205
Thr Leu Arg Cys Trp Ala Leu Ser Phe Tyr Pro Ala Glu Ile Thr Leu
210 215 220
Thr Trp Gln Arg Asp Gly Glu Asp Gln Thr Gln Asp Thr Glu Leu Val
225 230 235 240
Glu Thr Arg Pro Ala Gly Asp Gly Thr Phe Gln Lys Trp Ala Ala Val
245 250 255
Val Val Pro Ser Gly Gln Glu Gln Arg Tyr Thr Cys His Val Gln His
260 265 270
Glu Gly Leu Pro Lys Pro Leu Thr Trp Ala Arg Glu Val Ser Glu Val
275 280 285
Lys Leu Gln Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Glu Thr Leu
290 295 300
Ser Leu Thr Cys Thr Val Ser Gly Phe Thr Phe Ser Asp Tyr Gly Val
305 310 315 320
His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile Gly Val
325 330 335
Ile Trp Ala Gly Gly Gly Thr Asn Tyr Asn Ser Ala Leu Met Ser Arg
340 345 350
Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu Lys Leu
355 360 365
Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp
370 375 380
Lys Gly Tyr Ser Ala Ala Ala Ser Met Asp Tyr Trp Gly Gln Gly Thr
385 390 395 400
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
405 410 415
Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly
420 425 430
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
435 440 445
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
450 455 460
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
465 470 475 480
Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser
485 490 495
Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys
500 505 510
Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser Val Phe Leu
515 520 525
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
530 535 540
Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln
545 550 555 560
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
565 570 575
Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu
580 585 590
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
595 600 605
Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys
610 615 620
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
625 630 635 640
Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
645 650 655
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
660 665 670
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
675 680 685
Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln
690 695 700
Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
705 710 715 720
His Tyr Thr Gln Lys Ser Leu Cys Leu Ser Leu Gly Lys
725 730
<210> 20
<211> 218
<212> PRT
<213> 人工序列
<220>
<223> 合成序列 (轻链3(LC3或Vk3))
<400> 20
Asp Ile Glu Leu Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Arg Ala Ser Glu Ser Val Glu Tyr Tyr
20 25 30
Val Thr Ser Leu Met Gln Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Phe Ala Ala Ser Asn Val Glu Ser Gly Val Pro Asp
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Ala Glu Asp Val Ala Met Tyr Phe Cys Gln Gln Ser Arg
85 90 95
Lys Val Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg
100 105 110
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
115 120 125
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
130 135 140
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
145 150 155 160
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
165 170 175
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
180 185 190
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
195 200 205
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 21
<211> 447
<212> PRT
<213> 人工序列
<220>
<223> 合成序列 (重链1(HC1))
<400> 21
Glu Val Lys Leu Gln Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Asp Tyr
20 25 30
Gly Val His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Ala Gly Gly Gly Thr Asn Tyr Asn Ser Ala Leu Met
50 55 60
Ser Arg Lys Thr Ile Ser Lys Asp Asn Ser Lys Ser Gln Val Phe Leu
65 70 75 80
Lys Met Asn Ser Leu Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Asp Lys Gly Tyr Ser Tyr Tyr Tyr Ser Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro
210 215 220
Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu
260 265 270
Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Cys Leu Ser Leu Gly Lys
435 440 445
<210> 22
<211> 447
<212> PRT
<213> 人工序列
<220>
<223> 合成序列 (重链2(HC2))
<400> 22
Glu Val Lys Leu Gln Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Asp Tyr
20 25 30
Gly Val His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Ala Gly Gly Gly Thr Asn Tyr Asn Ser Ala Leu Met
50 55 60
Ser Arg Lys Thr Ile Ser Lys Asp Asn Ser Lys Ser Gln Val Ser Leu
65 70 75 80
Lys Met Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Asp Lys Gly Tyr Ser Tyr Tyr Tyr Ser Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro
210 215 220
Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu
260 265 270
Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Cys Leu Ser Leu Gly Lys
435 440 445
<210> 23
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 23
Asp Tyr Gly Val His
1 5
<210> 24
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 24
Val Ile Trp Ala Gly Gly Gly Thr Asn Tyr Asn Ser Ala Leu Met Ser
1 5 10 15
<210> 25
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 25
Asp Lys Gly Tyr Ser Tyr Tyr Tyr Ser Met Asp Tyr
1 5 10
<210> 26
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 26
Arg Ala Ser Glu Ser Val Glu Tyr Tyr Val Thr Ser Leu Met Gln
1 5 10 15
<210> 27
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 27
Ala Ala Ser Asn Val Glu Ser
1 5
<210> 28
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 28
Gln Gln Ser Arg Lys Val Pro Tyr Thr
1 5
<210> 29
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 29
Gly Gly Gly Ser Gly
1 5
<210> 30
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成序列
<400> 30
Ala Ala Ala Gly Gly
1 5
<210> 31
<211> 51
<212> DNA
<213> 人工序列
<220>
<223> 合成序列 (N端连接子)
<220>
<221> CDS
<222> (1)..(51)
<400> 31
cag gtc caa ctg acg cgt gag ggg tcc ggc tct cac tcc atg agg tat 48
Gln Val Gln Leu Thr Arg Glu Gly Ser Gly Ser His Ser Met Arg Tyr
1 5 10 15
ttc 51
Phe
<210> 32
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 32
Gln Val Gln Leu Thr Arg Glu Gly Ser Gly Ser His Ser Met Arg Tyr
1 5 10 15
Phe
<210> 33
<211> 57
<212> DNA
<213> 人工序列
<220>
<223> 合成序列 (C端连接子)
<220>
<221> CDS
<222> (1)..(57)
<400> 33
gag ggt ttg ccc aag ccc ctc acc tgg gct cga gag gtg agc gag gtc 48
Glu Gly Leu Pro Lys Pro Leu Thr Trp Ala Arg Glu Val Ser Glu Val
1 5 10 15
aag ctg cag 57
Lys Leu Gln
<210> 34
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 34
Glu Gly Leu Pro Lys Pro Leu Thr Trp Ala Arg Glu Val Ser Glu Val
1 5 10 15
Lys Leu Gln
Claims (11)
1.一种药物组合物,包括具有抗CD28抗体和与之相连接的抗原呈递复合物配体的聚合物颗粒,其中,
所述抗CD28抗体是具有免疫球蛋白重链可变区和免疫球蛋白轻链可变区的共刺激配体,
所述免疫球蛋白重链可变区氨基酸序列为:EVKLQQSGPGLVKPSETLSLTCTVSGFSLSDYGVHWVRQAPGKGLEWLGVIWAGGGTNYNSALMSRKTISKDNSKSQVSLKMSSVTAADTAVYYCARDKGYSYYYSMDYWGQGTLVTVSS,
所述免疫球蛋白轻链可变区氨基酸序列为:DIELTQSPDSLAVSLGERATINCRASESVEYYVTSLMQWYQQKPGQPPKLLIFAASNVESGVPDRFSGSGSGTDFTLTISSLQAEDVAMYFCQQSRKVPYTFGGGTKVEIK。
2.如权利要求1所述的药物组合物,其中抗原呈递复合物包括MHC I类和/或MHC II类复合物。
3.如权利要求1或2所述的药物组合物,其中所述药物组合物与抗原肽共同配制,用于呈递给T细胞。
4.如权利要求1至3中任一项所述的药物组合物,其中所述MHC I类和/或II类复合物包括与抗原结合槽结合的肽。
5.如权利要求4所述的药物组合物,其中所述肽是肿瘤相关抗原。
6.如权利要求1至5中任一项所述的药物组合物,其中所述抗原呈递复合物包括HLA氨基酸序列。
7.如权利要求6所述的药物组合物,其中所述HLA氨基酸序列是HLA-A*02:01。
8.如权利要求1至6中任一项所述的药物组合物,所述抗CD28抗体不是超激动剂。
9.如权利要求1至8中任一项所述的药物组合物,其中所述免疫球蛋白重链氨基酸序列包括IgG4恒定区序列。
10.如权利要求1至9中任一项所述的药物组合物,其中抗原呈递复合物和共刺激配体以5:1至1:5的比例共轭。
11.如权利要求1至10中任一项所述的药物组合物,其中所述药物组合物被配制为静脉内、动脉内、皮下、皮内、淋巴内或肿瘤内施用。
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201361838547P | 2013-06-24 | 2013-06-24 | |
US61/838,547 | 2013-06-24 | ||
US201461948916P | 2014-03-06 | 2014-03-06 | |
US61/948,916 | 2014-03-06 | ||
CN201480046380.0A CN105555302B (zh) | 2013-06-24 | 2014-06-23 | 用于免疫疗法的组合物和方法 |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201480046380.0A Division CN105555302B (zh) | 2013-06-24 | 2014-06-23 | 用于免疫疗法的组合物和方法 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN113797332A true CN113797332A (zh) | 2021-12-17 |
Family
ID=52142591
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201480046380.0A Active CN105555302B (zh) | 2013-06-24 | 2014-06-23 | 用于免疫疗法的组合物和方法 |
CN202110793760.2A Pending CN113797332A (zh) | 2013-06-24 | 2014-06-23 | 用于免疫疗法的组合物和方法 |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201480046380.0A Active CN105555302B (zh) | 2013-06-24 | 2014-06-23 | 用于免疫疗法的组合物和方法 |
Country Status (13)
Country | Link |
---|---|
US (3) | US20160129133A1 (zh) |
EP (2) | EP3013361B1 (zh) |
JP (1) | JP6566938B2 (zh) |
KR (2) | KR102453188B1 (zh) |
CN (2) | CN105555302B (zh) |
AU (1) | AU2014302784B2 (zh) |
BR (1) | BR112015032277B1 (zh) |
CA (1) | CA2916465C (zh) |
ES (1) | ES2902413T3 (zh) |
IL (2) | IL243235B (zh) |
MX (1) | MX2015017959A (zh) |
SG (2) | SG11201510377SA (zh) |
WO (1) | WO2014209868A1 (zh) |
Families Citing this family (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3237003B1 (en) | 2014-12-24 | 2021-08-11 | NexImmune, Inc | Nanoparticle compositions and methods for immunotherapy |
US10136820B2 (en) * | 2015-12-21 | 2018-11-27 | Gholam A. Peyman | Method to visualize very early stage neoplasm or other lesions |
US11433260B2 (en) | 2015-12-21 | 2022-09-06 | Gholam A. Peyman | Cancer treatment methods using thermotherapy and/or enhanced immunotherapy |
WO2017216768A1 (en) | 2016-06-16 | 2017-12-21 | Association For The Advancement Of Tissue Engineering And Cell Based Technologies And Therapies - A4Tec | Dendrimer-derived artificial antigen, methods and uses thereof |
US10294454B2 (en) | 2016-08-24 | 2019-05-21 | General Electric Company | Methods and kits for cell activation |
CN111373031A (zh) * | 2017-11-10 | 2020-07-03 | 朱拉生物公司 | 基于主要组织相容性复合物的嵌合受体和其用于治疗自身免疫性疾病的用途 |
EP4021383A1 (en) * | 2019-08-29 | 2022-07-06 | Skinosive | Bioadhesive particles comprising active agents, and uses thereof |
WO2021216738A2 (en) * | 2020-04-21 | 2021-10-28 | Intima Bioscience, Inc. | Compositions and methods of generating an immune response |
KR20240045260A (ko) * | 2021-08-05 | 2024-04-05 | 이뮤노스 테라퓨틱스 아게 | Hla 융합 단백질을 포함하는 복합 치료제 |
Citations (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20020164340A1 (en) * | 2001-05-07 | 2002-11-07 | Mount Sinai School Of Medicine Of The City Of New York | Multivalent MHC class II - peptide chimeras |
WO2004006951A1 (en) * | 2002-07-12 | 2004-01-22 | The Johns Hopkins University | Reagents and methods for engaging unique clonotypic lymphocyte receptors |
CN1671416A (zh) * | 2001-07-12 | 2005-09-21 | 杰斐逊·富特 | 超人源化抗体 |
US20090017000A1 (en) * | 2006-10-04 | 2009-01-15 | Zeling Cai | Preparation of inactivated artificial antigen presenting cells and their use in cell therapies |
WO2009094273A2 (en) * | 2008-01-15 | 2009-07-30 | Yale University | Compositions and methods for adoptive and active immunotherapy |
US20100028450A1 (en) * | 2006-01-25 | 2010-02-04 | The Board Of Trustees Of The University Of Illinoi S | Tolerogenic biodegradable artificial antigen presenting system |
CN102099016A (zh) * | 2008-06-16 | 2011-06-15 | 佰恩德生物科学股份有限公司 | 载药的聚合物纳米微粒及其制备和使用方法 |
WO2012175508A1 (en) * | 2011-06-22 | 2012-12-27 | F. Hoffmann-La Roche Ag | Removal of target cells by circulating virus-specific cytotoxic t-cells using mhc class i comprising complexes |
WO2013086500A1 (en) * | 2011-12-09 | 2013-06-13 | The Johns Hopkins University | Artificial antigen presenting cells having a defined and dynamic shape |
WO2013090804A2 (en) * | 2011-12-14 | 2013-06-20 | The Johns Hopkins University | Nanoparticles with enhanced mucosal penetration or decreased inflammation |
Family Cites Families (30)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6352694B1 (en) | 1994-06-03 | 2002-03-05 | Genetics Institute, Inc. | Methods for inducing a population of T cells to proliferate using agents which recognize TCR/CD3 and ligands which stimulate an accessory molecule on the surface of the T cells |
US5466609A (en) | 1990-10-31 | 1995-11-14 | Coulter Corporation | Biodegradable gelatin-aminodextran particle coatings of and processes for making same |
DK0776339T4 (da) * | 1994-07-29 | 2010-05-25 | Sunol Molecular Corp | MHC-komplekser og anvendelser deraf |
WO1997035991A1 (en) | 1996-03-28 | 1997-10-02 | The Johns Hopkins University | Soluble divalent and multivalent heterodimeric analogs of proteins |
US6140113A (en) | 1996-03-28 | 2000-10-31 | The Johns Hopkins University | Polynucleotides encoding molecular complexes which modify immune responses |
US7973137B1 (en) | 1996-03-28 | 2011-07-05 | Johns Hopkins University | Cell compositions comprising molecular complexes that modify immune responses |
US6268411B1 (en) | 1997-09-11 | 2001-07-31 | The Johns Hopkins University | Use of multivalent chimeric peptide-loaded, MHC/ig molecules to detect, activate or suppress antigen-specific T cell-dependent immune responses |
DE19722888A1 (de) | 1997-05-28 | 1998-12-03 | Thomas Prof Dr Huenig | Human-CD28 spezifische monoklonale Antikörper zur antigenunspezifischen Aktivierung von T-Lymphozyten |
US6074884A (en) | 1997-10-09 | 2000-06-13 | Coulter International Corp. | Stable protein-nickel particles and methods of production and use thereof |
US6261606B1 (en) | 1999-09-14 | 2001-07-17 | Natural Compounds, Ltd. | Naturally extracted and synthetic hypoglycemic or hypolipidemic compositions |
JP2004513878A (ja) | 2000-06-23 | 2004-05-13 | マキシジェン, インコーポレイテッド | 新規同時刺激分子 |
EP1349569B1 (en) * | 2001-01-12 | 2007-04-18 | Becton Dickinson and Company | Intrinsically fluorescent, self-multimerizing mhc fusion proteins and complexes thereof |
JP2006525813A (ja) | 2003-05-20 | 2006-11-16 | イェシバ・ユニバーシティ | 1型糖尿病において罹患性病原性t細胞により標的とされる抗原ならびにこれの使用 |
KR100796985B1 (ko) * | 2006-06-30 | 2008-01-22 | 연세대학교 산학협력단 | 금박막이 부분 증착된 다기능성 나노입자 |
EP2842570B1 (en) | 2007-03-07 | 2020-05-06 | UTI Limited Partnership | Compositions and methods for the prevention and treatment of autoimmune conditions |
UA117446C2 (uk) * | 2007-08-29 | 2018-08-10 | Санофі-Авентіс | Гуманізоване антитіло до cxcr5 |
SI2774608T1 (sl) | 2008-06-16 | 2020-02-28 | Pfizer Inc. | Polimerni nanodelci, napolnjeni z zdravilom, ter postopki za njihovo pripravo in uporabo |
US9333163B2 (en) | 2008-10-06 | 2016-05-10 | Massachusetts Institute Of Technology | Particles with multiple functionalized surface domains |
US8343497B2 (en) | 2008-10-12 | 2013-01-01 | The Brigham And Women's Hospital, Inc. | Targeting of antigen presenting cells with immunonanotherapeutics |
DK2435568T3 (da) * | 2009-05-29 | 2014-09-08 | Morphosys Ag | Samling af syntetiske antistoffer til behandling af sygdom |
US8900590B2 (en) * | 2010-08-12 | 2014-12-02 | Theraclone Sciences, Inc. | Anti-hemagglutinin antibody compositions and methods of use thereof |
US9511151B2 (en) | 2010-11-12 | 2016-12-06 | Uti Limited Partnership | Compositions and methods for the prevention and treatment of cancer |
US20130022551A1 (en) * | 2011-07-22 | 2013-01-24 | Trustees Of Boston University | DEspR ANTAGONISTS AND AGONISTS AS THERAPEUTICS |
WO2013036585A1 (en) | 2011-09-06 | 2013-03-14 | The Trustees Of The University Of Pennsylvania | Activation and expansion of t cell subsets using biocompatible solid substrates with tunable rigidity |
WO2013093809A1 (en) * | 2011-12-23 | 2013-06-27 | Pfizer Inc. | Engineered antibody constant regions for site-specific conjugation and methods and uses therefor |
US10548957B2 (en) | 2012-09-28 | 2020-02-04 | Dana-Farber Cancer Institute, Inc. | Targeted expansion of Qa-1-peptide-specific regulatory CD8 T cells to ameliorate arthritis |
US9603948B2 (en) | 2012-10-11 | 2017-03-28 | Uti Limited Partnership | Methods and compositions for treating multiple sclerosis and related disorders |
US9550986B2 (en) | 2012-12-21 | 2017-01-24 | Abbvie Inc. | High-throughput antibody humanization |
CN105431523B (zh) | 2013-03-14 | 2020-08-21 | 约翰·霍普金斯大学 | 纳米级人工抗原呈递细胞 |
ES2730273T3 (es) | 2013-11-04 | 2019-11-11 | Uti Lp | Métodos y composiciones para inmunoterapia sostenida |
-
2014
- 2014-06-23 EP EP14816877.6A patent/EP3013361B1/en active Active
- 2014-06-23 ES ES14816877T patent/ES2902413T3/es active Active
- 2014-06-23 AU AU2014302784A patent/AU2014302784B2/en active Active
- 2014-06-23 CA CA2916465A patent/CA2916465C/en active Active
- 2014-06-23 BR BR112015032277-8A patent/BR112015032277B1/pt active IP Right Grant
- 2014-06-23 CN CN201480046380.0A patent/CN105555302B/zh active Active
- 2014-06-23 EP EP21198729.2A patent/EP3995145A1/en active Pending
- 2014-06-23 MX MX2015017959A patent/MX2015017959A/es active IP Right Grant
- 2014-06-23 US US14/900,553 patent/US20160129133A1/en not_active Abandoned
- 2014-06-23 JP JP2016521885A patent/JP6566938B2/ja active Active
- 2014-06-23 SG SG11201510377SA patent/SG11201510377SA/en unknown
- 2014-06-23 WO PCT/US2014/043629 patent/WO2014209868A1/en active Application Filing
- 2014-06-23 KR KR1020217034171A patent/KR102453188B1/ko active IP Right Grant
- 2014-06-23 SG SG10201710737VA patent/SG10201710737VA/en unknown
- 2014-06-23 KR KR1020167001637A patent/KR20160022370A/ko not_active Application Discontinuation
- 2014-06-23 CN CN202110793760.2A patent/CN113797332A/zh active Pending
-
2015
- 2015-12-20 IL IL243235A patent/IL243235B/en unknown
-
2018
- 2018-03-27 US US15/937,302 patent/US20180214564A1/en not_active Abandoned
-
2020
- 2020-03-17 US US16/821,535 patent/US11712477B2/en active Active
-
2021
- 2021-08-11 IL IL285527A patent/IL285527B2/en unknown
Patent Citations (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20020164340A1 (en) * | 2001-05-07 | 2002-11-07 | Mount Sinai School Of Medicine Of The City Of New York | Multivalent MHC class II - peptide chimeras |
CN1671416A (zh) * | 2001-07-12 | 2005-09-21 | 杰斐逊·富特 | 超人源化抗体 |
US20070003547A1 (en) * | 2001-07-12 | 2007-01-04 | Arrowsmith Technologies Llp | Super humanized antibodies |
WO2004006951A1 (en) * | 2002-07-12 | 2004-01-22 | The Johns Hopkins University | Reagents and methods for engaging unique clonotypic lymphocyte receptors |
US20100028450A1 (en) * | 2006-01-25 | 2010-02-04 | The Board Of Trustees Of The University Of Illinoi S | Tolerogenic biodegradable artificial antigen presenting system |
US20090017000A1 (en) * | 2006-10-04 | 2009-01-15 | Zeling Cai | Preparation of inactivated artificial antigen presenting cells and their use in cell therapies |
WO2009094273A2 (en) * | 2008-01-15 | 2009-07-30 | Yale University | Compositions and methods for adoptive and active immunotherapy |
CN102099016A (zh) * | 2008-06-16 | 2011-06-15 | 佰恩德生物科学股份有限公司 | 载药的聚合物纳米微粒及其制备和使用方法 |
WO2012175508A1 (en) * | 2011-06-22 | 2012-12-27 | F. Hoffmann-La Roche Ag | Removal of target cells by circulating virus-specific cytotoxic t-cells using mhc class i comprising complexes |
WO2013086500A1 (en) * | 2011-12-09 | 2013-06-13 | The Johns Hopkins University | Artificial antigen presenting cells having a defined and dynamic shape |
WO2013090804A2 (en) * | 2011-12-14 | 2013-06-20 | The Johns Hopkins University | Nanoparticles with enhanced mucosal penetration or decreased inflammation |
Also Published As
Publication number | Publication date |
---|---|
JP2016530224A (ja) | 2016-09-29 |
EP3995145A1 (en) | 2022-05-11 |
CN105555302B (zh) | 2021-07-30 |
US20200345855A1 (en) | 2020-11-05 |
SG11201510377SA (en) | 2016-01-28 |
IL285527A (en) | 2021-09-30 |
JP6566938B2 (ja) | 2019-08-28 |
ES2902413T3 (es) | 2022-03-28 |
EP3013361B1 (en) | 2021-10-06 |
IL243235B (en) | 2021-09-30 |
WO2014209868A1 (en) | 2014-12-31 |
US11712477B2 (en) | 2023-08-01 |
MX2015017959A (es) | 2018-03-01 |
KR102453188B1 (ko) | 2022-10-07 |
IL285527B2 (en) | 2023-06-01 |
CA2916465C (en) | 2023-05-23 |
AU2014302784B2 (en) | 2020-01-23 |
SG10201710737VA (en) | 2018-01-30 |
US20180214564A1 (en) | 2018-08-02 |
KR20160022370A (ko) | 2016-02-29 |
AU2014302784A1 (en) | 2016-01-21 |
US20160129133A1 (en) | 2016-05-12 |
BR112015032277B1 (pt) | 2020-12-01 |
KR20210130268A (ko) | 2021-10-29 |
EP3013361A4 (en) | 2017-05-24 |
CN105555302A (zh) | 2016-05-04 |
BR112015032277A2 (pt) | 2017-11-07 |
CA2916465A1 (en) | 2014-12-31 |
IL243235A0 (en) | 2016-03-31 |
EP3013361A1 (en) | 2016-05-04 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP7127876B2 (ja) | 免疫療法のためのナノ粒子組成物及び方法 | |
US11712477B2 (en) | Compositions and methods for immunotherapy | |
CA2971419C (en) | Nanoparticle compositions and methods for immunotherapy |
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 |