JPWO2020193767A5 - - Google Patents
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別の一局面は、医薬として使用するための、特にがんの処置において使用するための、本明細書記載のTCR、本明細書記載のポリペプチド、本明細書記載の多価TCR複合体、本明細書記載の核酸、本明細書記載のベクター、本明細書記載の細胞、本明細書記載の抗体、本明細書記載の組成物、または薬学的組成物に関係する。がんは、血液がんまたは固形腫瘍でありうる。がんは、肉腫、前立腺がん、子宮がん、甲状腺がん、精巣がん、腎がん、膵がん、卵巣がん、食道がん、非小細胞肺がん、非ホジキンリンパ腫、多発性骨髄腫、メラノーマ、肝細胞癌、頭頸部がん、胃がん、子宮内膜がん、結腸直腸がん、胆管癌、乳がん、膀胱がん、骨髄性白血病、および急性リンパ芽球性白血病からなる群より選択されうる。好ましくは、がんは、NSCLC、SCLC、乳がん、卵巣がんまたは結腸直腸がん、肉腫、および骨肉腫からなる群より選択される。
[本発明1001]
a)SEQ ID NO:2のアミノ酸配列を有するCDR1、SEQ ID NO:3のアミノ酸配列を有するCDR2およびSEQ ID NO:4のアミノ酸配列を有するCDR3を含む、可変TCRα領域、
SEQ ID NO:5のアミノ酸配列を有するCDR1、SEQ ID NO:6のアミノ酸配列を有するCDR2およびSEQ ID NO:7のアミノ酸配列を有するCDR3を含む、可変TCRβ領域;または
b)SEQ ID NO:12のアミノ酸配列を有するCDR1、SEQ ID NO:13のアミノ酸配列を有するCDR2およびSEQ ID NO:14のアミノ酸配列を有するCDR3を含む、可変TCRα領域、
SEQ ID NO:15のアミノ酸配列を有するCDR1、SEQ ID NO:16のアミノ酸配列を有するCDR2およびSEQ ID NO:17のアミノ酸配列を有するCDR3を含む、可変TCRβ領域;または
c)SEQ ID NO:22のアミノ酸配列を有するCDR1、SEQ ID NO:23のアミノ酸配列を有するCDR2およびSEQ ID NO:24のアミノ酸配列を有するCDR3を含む、可変TCRα領域、
SEQ ID NO:25のアミノ酸配列を有するCDR1、SEQ ID NO:26のアミノ酸配列を有するCDR2およびSEQ ID NO:27のアミノ酸配列を有するCDR3を含む、可変TCRβ領域
を含む、MAGE-A4に特異的な単離されたT細胞受容体(TCR)。
[本発明1002]
SEQ ID NO:1のアミノ酸配列またはそのフラグメントを特異的に認識する、好ましくはHLA-A2に結合した形態のSEQ ID NO:1のアミノ酸配列を特異的に認識する、より好ましくはHLA-A*02:01がコードする分子によって提示されるSEQ ID NO:1のアミノ酸配列を特異的に認識する、本発明1001の単離されたTCR。
[本発明1003]
a)SEQ ID NO:8のアミノ酸配列を有する可変TCRα領域およびSEQ ID NO:9のアミノ酸配列を有する可変TCRβ領域;または
b)SEQ ID NO:18のアミノ酸配列を有する可変TCRα領域およびSEQ ID NO:19のアミノ酸配列を有する可変TCRβ領域;または
c)SEQ ID NO:28のアミノ酸配列を有する可変TCRα領域およびSEQ ID NO:29のアミノ酸配列を有する可変TCRβ領域
を含む、前記本発明のいずれかの単離されたTCR。
[本発明1004]
SEQ ID NO:4、7、14、17、24および27のアミノ酸配列のうちの少なくとも1つを含む機能部分を含む、前記本発明のいずれかの単離されたTCR。
[本発明1005]
a)SEQ ID NO:10のアミノ酸配列を有するTCRα鎖およびSEQ ID NO:11のアミノ酸配列を有するTCRβ鎖;
b)SEQ ID NO:20のアミノ酸配列を有するTCRα鎖およびSEQ ID NO:21のアミノ酸配列を有するTCRβ鎖;または
c)SEQ ID NO:30のアミノ酸配列を有するTCRα鎖およびSEQ ID NO:31のアミノ酸配列を有するTCRβ鎖
を含む、本発明1001~1004のいずれかの単離されたTCR。
[本発明1006]
a)SEQ ID NO:87のアミノ酸配列を有するTCRα鎖およびSEQ ID NO:88のアミノ酸配列を有するTCRβ鎖;
b)SEQ ID NO:89のアミノ酸配列を有するTCRα鎖およびSEQ ID NO:90のアミノ酸配列を有するTCRβ鎖;または
c)SEQ ID NO:91のアミノ酸配列を有するTCRα鎖およびSEQ ID NO:92のアミノ酸配列を有するTCRβ鎖
を含む、本発明1001~1004のいずれかの単離されたTCR。
[本発明1007]
a)SEQ ID NO:102のアミノ酸配列を有するTCRα鎖およびSEQ ID NO:103のアミノ酸配列を有するTCRβ鎖;
b)SEQ ID NO:108のアミノ酸配列を有するTCRα鎖およびSEQ ID NO:109のアミノ酸配列を有するTCRβ鎖;または
c)SEQ ID NO:114のアミノ酸配列を有するTCRα鎖およびSEQ ID NO:115のアミノ酸配列を有するTCRβ鎖
を含む、本発明1001~1004のいずれかの単離されたTCR。
[本発明1008]
HLA-A*02:01がコードする分子によって提示されるSEQ ID NO:1のアミノ酸配列への結合によってIFN-γ分泌が誘導される、本発明1001~1007のいずれかの単離されたTCRまたは本発明1008の多価TCR複合体。
[本発明1009]
HLA-A*02:01がコードする分子によって提示されるSEQ ID NO:1のアミノ酸配列に、エフェクター細胞上に発現したTCRが結合することによって誘導されるIFN-γ分泌が、HLA-A*02:01がコードする分子によって提示されるSEQ ID NO:1のアミノ酸配列に結合した時には、HLA-A*02:01がコードする分子によって提示される無関係なペプチドへの結合と比較して、100倍超、好ましくは500倍超、より好ましくは2000倍超、高くなりうる、本発明1001~1007のいずれかの単離されたTCR。
[本発明1010]
本発明1001~1007のいずれかのTCRを少なくとも2つ含む、多価TCR複合体。
[本発明1011]
TCRα鎖とTCRβ鎖とを含み、かつSEQ ID NO:94、96、98、104、110および116のうちのいずれか1つに示されるアミノ酸配列を含む、融合タンパク質。
[本発明1012]
本発明1001~1007のいずれかのTCRまたは本発明1011の融合タンパク質をコードする、核酸。
[本発明1013]
TCRα鎖をコードする核酸配列が、SEQ ID NO:69、77、85、99、105および111のうちのいずれか1つに示される、本発明1012の核酸。
[本発明1014]
TCRβ鎖をコードする核酸配列が、SEQ ID NO:70、78、86、100、106および112のうちのいずれか1つに示される、本発明1012の核酸。
[本発明1015]
TCRが、
a)SEQ ID NO:69によってコードされるTCRα鎖およびSEQ ID NO:70によってコードされるTCRβ鎖;
b)SEQ ID NO:77によってコードされるTCRα鎖およびSEQ ID NO:78によってコードされるTCRβ鎖;
c)SEQ ID NO:85によってコードされるTCRα鎖およびSEQ ID NO:86によってコードされるTCRβ鎖;
d)SEQ ID NO:99によってコードされるTCRα鎖およびSEQ ID NO:100によってコードされるTCRβ鎖;
e)SEQ ID NO:105によってコードされるTCRα鎖およびSEQ ID NO:106によってコードされるTCRβ鎖;または
f)SEQ ID NO:111によってコードされるTCRα鎖およびSEQ ID NO:112によってコードされるTCRβ鎖
を含む、本発明1010の核酸。
[本発明1016]
融合タンパク質が、SEQ ID NO:93、95、97、101、107および113のうちのいずれか1つに示される核酸配列によってコードされる、本発明1012の核酸。
[本発明1017]
本発明1012~1016のいずれかの核酸を含む、ベクターであって、好ましくは発現ベクター、より好ましくはレトロウイルスベクター、さらに好ましくはレンチウイルスベクターである、前記ベクター。
[本発明1018]
a)SEQ ID NO:87およびSEQ ID NO:88に示すポリペプチド配列;
b)SEQ ID NO:89およびSEQ ID NO:90に示すポリペプチド配列;
c)SEQ ID NO:91およびSEQ ID NO:92に示すポリペプチド配列;
d)SEQ ID NO:102およびSEQ ID NO:103に示すポリペプチド配列;
e)SEQ ID NO:108およびSEQ ID NO:109に示すポリペプチド配列;または
f)SEQ ID NO:114およびSEQ ID NO:115に示すポリペプチド配列
をコードする核酸を含む、ベクターであって、好ましくは発現ベクター、より好ましくはレトロウイルスベクター、さらに好ましくはレンチウイルスベクターである、前記ベクター。
[本発明1019]
本発明1001~1047のいずれかのTCRを発現する、細胞。
[本発明1020]
本発明1017または1018のベクターを含む、細胞。
[本発明1021]
免疫エフェクター細胞である、本発明1019または1020の細胞。
[本発明1022]
免疫エフェクター細胞が、T細胞、ナチュラルキラー(NK)細胞またはナチュラルキラーT(NKT)細胞である、本発明1019~1021のいずれかの細胞。
[本発明1023]
本発明1001~1007のいずれかのTCRのうちのMAGE-A4に対する特異性を媒介する部分に特異的に結合する、抗体またはその抗原結合フラグメントであって、好ましくは、TCRのうちのMAGE-A4特異性を媒介する部分が、
a)SEQ ID NO:4のアルファ鎖のCDR3および/もしくはSEQ ID NO:7のベータ鎖のCDR3、または
b)SEQ ID NO:14のアルファ鎖のCDR3および/もしくはSEQ ID NO:17のベータ鎖のCDR3、または
c)SEQ ID NO:24のアルファ鎖のCDR3および/もしくはSEQ ID NO:27のベータ鎖のCDR3
を含む、前記抗体またはその抗原結合フラグメント。
[本発明1024]
本発明1001~1007のいずれかのTCR、本発明1008の多価TCR複合体、本発明1011の融合タンパク質、本発明1012~1016のいずれかの核酸、本発明1017もしくは1018のベクター、本発明1019~1022のいずれかの細胞、または本発明1023の抗体を含む、組成物。
[本発明1025]
薬学的に許容される担体と、本発明1001~1007のいずれかのTCR、本発明1008の多価TCR複合体、本発明1011の融合タンパク質、本発明1012~1016のいずれかの核酸、本発明1017もしくは1018のベクター、本発明1019~1022のいずれかの細胞、または本発明1023の抗体とを含む、薬学的組成物。
[本発明1026]
医薬として使用するための、本発明1001~1007のいずれかのTCR、本発明1008の多価TCR複合体、本発明1011の融合タンパク質、本発明1012~1016のいずれかの核酸、本発明1017もしくは1018のベクター、本発明1019~1022のいずれかの細胞、本発明1023の抗体、本発明1024の組成物、または本発明1025の薬学的組成物。
[本発明1027]
がん、好ましくは血液がんまたは固形腫瘍であるがん、より好ましくは肉腫、前立腺がん、子宮がん、甲状腺がん、精巣がん、腎がん、膵がん、卵巣がん、食道がん、非小細胞肺がん、非ホジキンリンパ腫、多発性骨髄腫、メラノーマ、肝細胞癌、頭頸部がん、胃がん、子宮内膜がん、結腸直腸がん、胆管癌、乳がん、膀胱がん、骨髄性白血病、および急性リンパ芽球性白血病からなる群より選択されるがん、最も好ましくはNSCLC、SCLC、乳がん、卵巣がんもしくは結腸直腸がん、肉腫、または骨肉腫からなる群より選択されるがんの処置において使用するための、本発明1001~1007のいずれかのTCR、本発明1008の多価TCR複合体、本発明1011の融合タンパク質、本発明1012~1016のいずれかの核酸、本発明1017もしくは1018のベクター、本発明1019~1022のいずれかの細胞、本発明1023の抗体、本発明1024の組成物、または本発明1025の薬学的組成物。
Another aspect is a TCR as described herein, a polypeptide as described herein, a multivalent TCR complex as described herein, for use as a medicament, particularly in the treatment of cancer. It relates to a nucleic acid as described herein, a vector as described herein, a cell as described herein, an antibody as described herein, a composition as described herein, or a pharmaceutical composition as described herein. Cancer can be a blood cancer or a solid tumor. Cancers include sarcoma, prostate cancer, uterine cancer, thyroid cancer, testicular cancer, kidney cancer, pancreatic cancer, ovarian cancer, esophageal cancer, non-small cell lung cancer, non-Hodgkin's lymphoma, and multiple myeloma. from the group consisting of tumor, melanoma, hepatocellular carcinoma, head and neck cancer, gastric cancer, endometrial cancer, colorectal cancer, bile duct cancer, breast cancer, bladder cancer, myeloid leukemia, and acute lymphoblastic leukemia can be selected. Preferably, the cancer is selected from the group consisting of NSCLC, SCLC, breast cancer, ovarian or colorectal cancer, sarcoma and osteosarcoma.
[Invention 1001]
a) a variable TCRα region comprising CDR1 having the amino acid sequence of SEQ ID NO:2, CDR2 having the amino acid sequence of SEQ ID NO:3 and CDR3 having the amino acid sequence of SEQ ID NO:4;
a variable TCRβ region comprising CDR1 having the amino acid sequence of SEQ ID NO:5, CDR2 having the amino acid sequence of SEQ ID NO:6 and CDR3 having the amino acid sequence of SEQ ID NO:7; or
b) a variable TCRα region comprising CDR1 having the amino acid sequence of SEQ ID NO:12, CDR2 having the amino acid sequence of SEQ ID NO:13 and CDR3 having the amino acid sequence of SEQ ID NO:14;
a variable TCRβ region comprising CDR1 having the amino acid sequence of SEQ ID NO:15, CDR2 having the amino acid sequence of SEQ ID NO:16 and CDR3 having the amino acid sequence of SEQ ID NO:17; or
c) a variable TCRα region comprising CDR1 having the amino acid sequence of SEQ ID NO:22, CDR2 having the amino acid sequence of SEQ ID NO:23 and CDR3 having the amino acid sequence of SEQ ID NO:24;
A variable TCR beta region comprising CDR1 having the amino acid sequence of SEQ ID NO:25, CDR2 having the amino acid sequence of SEQ ID NO:26 and CDR3 having the amino acid sequence of SEQ ID NO:27
An isolated T-cell receptor (TCR) specific for MAGE-A4, comprising:
[Invention 1002]
Specifically recognizes the amino acid sequence of SEQ ID NO:1 or a fragment thereof, preferably specifically recognizes the amino acid sequence of SEQ ID NO:1 in the form bound to HLA-A2, more preferably HLA-A* An isolated TCR of the invention 1001 that specifically recognizes the amino acid sequence of SEQ ID NO:1 presented by the molecule encoded by 02:01.
[Invention 1003]
a) a variable TCRα region having the amino acid sequence of SEQ ID NO:8 and a variable TCRβ region having the amino acid sequence of SEQ ID NO:9; or
b) a variable TCRα region having the amino acid sequence of SEQ ID NO:18 and a variable TCRβ region having the amino acid sequence of SEQ ID NO:19; or
c) a variable TCRα region having the amino acid sequence of SEQ ID NO:28 and a variable TCRβ region having the amino acid sequence of SEQ ID NO:29
The isolated TCR of any of the preceding inventions, comprising:
[Invention 1004]
The isolated TCR of any of the preceding inventions comprising a functional portion comprising at least one of the amino acid sequences of SEQ ID NO:4, 7, 14, 17, 24 and 27.
[Invention 1005]
a) a TCRα chain having the amino acid sequence of SEQ ID NO:10 and a TCRβ chain having the amino acid sequence of SEQ ID NO:11;
b) a TCR α chain having the amino acid sequence of SEQ ID NO:20 and a TCR β chain having the amino acid sequence of SEQ ID NO:21; or
c) a TCRα chain having the amino acid sequence of SEQ ID NO:30 and a TCRβ chain having the amino acid sequence of SEQ ID NO:31
The isolated TCR of any of the inventions 1001-1004, comprising:
[Invention 1006]
a) a TCR α chain having the amino acid sequence of SEQ ID NO:87 and a TCR β chain having the amino acid sequence of SEQ ID NO:88;
b) a TCR α chain having the amino acid sequence of SEQ ID NO:89 and a TCR β chain having the amino acid sequence of SEQ ID NO:90; or
c) a TCRα chain having the amino acid sequence of SEQ ID NO:91 and a TCRβ chain having the amino acid sequence of SEQ ID NO:92
The isolated TCR of any of the inventions 1001-1004, comprising:
[Invention 1007]
a) a TCRα chain having the amino acid sequence of SEQ ID NO:102 and a TCRβ chain having the amino acid sequence of SEQ ID NO:103;
b) a TCRα chain having the amino acid sequence of SEQ ID NO:108 and a TCRβ chain having the amino acid sequence of SEQ ID NO:109; or
c) a TCRα chain having the amino acid sequence of SEQ ID NO:114 and a TCRβ chain having the amino acid sequence of SEQ ID NO:115
The isolated TCR of any of the inventions 1001-1004, comprising:
[Invention 1008]
The isolated TCR of any of the inventions 1001-1007, wherein IFN-γ secretion is induced by binding to the amino acid sequence of SEQ ID NO:1 presented by the molecule encoding HLA-A*02:01 Or the multivalent TCR complex of the invention 1008.
[Invention 1009]
IFN-γ secretion induced by the binding of the TCR expressed on effector cells to the amino acid sequence of SEQ ID NO:1 presented by the molecule encoded by HLA-A*02:01 is induced by HLA-A*02:01. When bound to the amino acid sequence of SEQ ID NO:1 presented by the molecule encoding HLA-A*02:01, compared to binding to an irrelevant peptide presented by the molecule encoding HLA-A*02:01, The isolated TCR of any of the invention 1001-1007, which can be increased more than 100-fold, preferably more than 500-fold, more preferably more than 2000-fold.
[Invention 1010]
A multivalent TCR complex comprising at least two TCRs of any of the inventions 1001-1007.
[Invention 1011]
A fusion protein comprising a TCR α chain and a TCR β chain and comprising the amino acid sequence set forth in any one of SEQ ID NOs:94, 96, 98, 104, 110 and 116.
[Invention 1012]
A nucleic acid encoding a TCR of any of inventions 1001-1007 or a fusion protein of invention 1011.
[Invention 1013]
The nucleic acid of the invention 1012, wherein the nucleic acid sequence encoding the TCRα chain is set forth in any one of SEQ ID NOs:69, 77, 85, 99, 105 and 111.
[Invention 1014]
1012 of the invention, wherein the nucleic acid sequence encoding the TCR beta chain is set forth in any one of SEQ ID NOs:70, 78, 86, 100, 106 and 112.
[Invention 1015]
TCR is
a) a TCRα chain encoded by SEQ ID NO:69 and a TCRβ chain encoded by SEQ ID NO:70;
b) the TCRα chain encoded by SEQ ID NO:77 and the TCRβ chain encoded by SEQ ID NO:78;
c) the TCRα chain encoded by SEQ ID NO:85 and the TCRβ chain encoded by SEQ ID NO:86;
d) the TCRα chain encoded by SEQ ID NO:99 and the TCRβ chain encoded by SEQ ID NO:100;
e) a TCRα chain encoded by SEQ ID NO:105 and a TCRβ chain encoded by SEQ ID NO:106; or
f) TCRα chain encoded by SEQ ID NO:111 and TCRβ chain encoded by SEQ ID NO:112
A nucleic acid of the invention 1010 comprising:
[Invention 1016]
1013. The nucleic acid of the invention 1012, wherein the fusion protein is encoded by a nucleic acid sequence set forth in any one of SEQ ID NOs:93, 95, 97, 101, 107 and 113.
[Invention 1017]
A vector, preferably an expression vector, more preferably a retroviral vector, even more preferably a lentiviral vector, comprising the nucleic acid of any of the inventions 1012-1016.
[Invention 1018]
a) the polypeptide sequences shown in SEQ ID NO:87 and SEQ ID NO:88;
b) the polypeptide sequences shown in SEQ ID NO:89 and SEQ ID NO:90;
c) the polypeptide sequences shown in SEQ ID NO:91 and SEQ ID NO:92;
d) the polypeptide sequences shown in SEQ ID NO:102 and SEQ ID NO:103;
e) the polypeptide sequences shown in SEQ ID NO:108 and SEQ ID NO:109; or
f) the polypeptide sequences shown in SEQ ID NO:114 and SEQ ID NO:115
preferably an expression vector, more preferably a retroviral vector, even more preferably a lentiviral vector, comprising a nucleic acid encoding a
[Invention 1019]
A cell expressing the TCR of any one of inventions 1001-1047.
[Invention 1020]
A cell containing the vector of the invention 1017 or 1018.
[Invention 1021]
A cell of the invention 1019 or 1020 that is an immune effector cell.
[Invention 1022]
The cell of any of inventions 1019-1021, wherein the immune effector cells are T cells, natural killer (NK) cells or natural killer T (NKT) cells.
[Invention 1023]
An antibody or antigen-binding fragment thereof that specifically binds to a portion of the TCR of any of the inventions 1001-1007 that mediates specificity for MAGE-A4, preferably MAGE-A4 of the TCR The part that mediates the specificity is
a) the alpha chain CDR3 of SEQ ID NO:4 and/or the beta chain CDR3 of SEQ ID NO:7, or
b) the alpha chain CDR3 of SEQ ID NO:14 and/or the beta chain CDR3 of SEQ ID NO:17, or
c) CDR3 of the alpha chain of SEQ ID NO:24 and/or CDR3 of the beta chain of SEQ ID NO:27
Said antibody or antigen-binding fragment thereof.
[Invention 1024]
The TCR of any one of the inventions 1001 to 1007, the multivalent TCR complex of the invention 1008, the fusion protein of the invention 1011, the nucleic acid of any one of the inventions 1012 to 1016, the vector of the invention 1017 or 1018, the invention 1019 A composition comprising a cell of any of -1022 or an antibody of the invention 1023.
[Invention 1025]
A pharmaceutically acceptable carrier, the TCR of any one of the inventions 1001 to 1007, the multivalent TCR complex of the invention 1008, the fusion protein of the invention 1011, the nucleic acid of any one of the inventions 1012 to 1016, the invention A pharmaceutical composition comprising the vector of 1017 or 1018, the cells of any of the inventions 1019-1022, or the antibody of the invention 1023.
[Invention 1026]
a TCR of any of the inventions 1001-1007, a multivalent TCR complex of the invention 1008, a fusion protein of the invention 1011, a nucleic acid of any of the inventions 1012-1016, an invention 1017 or The vector of 1018, the cell of any of 1019-1022 of the invention, the antibody of 1023 of the invention, the composition of 1024 of the invention, or the pharmaceutical composition of 1025 of the invention.
[Invention 1027]
Cancer, preferably blood cancer or solid tumor cancer, more preferably sarcoma, prostate cancer, uterine cancer, thyroid cancer, testicular cancer, renal cancer, pancreatic cancer, ovarian cancer, esophageal cancer cancer, non-small cell lung cancer, non-Hodgkin's lymphoma, multiple myeloma, melanoma, hepatocellular carcinoma, head and neck cancer, gastric cancer, endometrial cancer, colorectal cancer, cholangiocarcinoma, breast cancer, bladder cancer, A cancer selected from the group consisting of myeloid leukemia and acute lymphoblastic leukemia, most preferably selected from the group consisting of NSCLC, SCLC, breast cancer, ovarian or colorectal cancer, sarcoma, or osteosarcoma a TCR of any of the invention 1001-1007, a multivalent TCR complex of the invention 1008, a fusion protein of the invention 1011, a nucleic acid of any of the invention 1012-1016, for use in the treatment of cancer The vector of invention 1017 or 1018, the cell of any of inventions 1019-1022, the antibody of invention 1023, the composition of invention 1024, or the pharmaceutical composition of invention 1025.
Claims (20)
SEQ ID NO:5のアミノ酸配列を有するCDR1、SEQ ID NO:6のアミノ酸配列を有するCDR2およびSEQ ID NO:7のアミノ酸配列を有するCDR3を含む、可変TCRβ領域;または
b)SEQ ID NO:12のアミノ酸配列を有するCDR1、SEQ ID NO:13のアミノ酸配列を有するCDR2およびSEQ ID NO:14のアミノ酸配列を有するCDR3を含む、可変TCRα領域、
SEQ ID NO:15のアミノ酸配列を有するCDR1、SEQ ID NO:16のアミノ酸配列を有するCDR2およびSEQ ID NO:17のアミノ酸配列を有するCDR3を含む、可変TCRβ領域;または
c)SEQ ID NO:22のアミノ酸配列を有するCDR1、SEQ ID NO:23のアミノ酸配列を有するCDR2およびSEQ ID NO:24のアミノ酸配列を有するCDR3を含む、可変TCRα領域、
SEQ ID NO:25のアミノ酸配列を有するCDR1、SEQ ID NO:26のアミノ酸配列を有するCDR2およびSEQ ID NO:27のアミノ酸配列を有するCDR3を含む、可変TCRβ領域
を含む、MAGE-A4に特異的な単離されたT細胞受容体(TCR)。 a) a variable TCRα region comprising CDR1 having the amino acid sequence of SEQ ID NO:2, CDR2 having the amino acid sequence of SEQ ID NO:3 and CDR3 having the amino acid sequence of SEQ ID NO:4;
a variable TCRβ region comprising CDR1 having the amino acid sequence of SEQ ID NO:5, CDR2 having the amino acid sequence of SEQ ID NO:6 and CDR3 having the amino acid sequence of SEQ ID NO:7; or
b) a variable TCRα region comprising CDR1 having the amino acid sequence of SEQ ID NO:12, CDR2 having the amino acid sequence of SEQ ID NO:13 and CDR3 having the amino acid sequence of SEQ ID NO:14;
a variable TCRβ region comprising CDR1 having the amino acid sequence of SEQ ID NO:15, CDR2 having the amino acid sequence of SEQ ID NO:16 and CDR3 having the amino acid sequence of SEQ ID NO:17; or
c) a variable TCRα region comprising CDR1 having the amino acid sequence of SEQ ID NO:22, CDR2 having the amino acid sequence of SEQ ID NO:23 and CDR3 having the amino acid sequence of SEQ ID NO:24;
specific for MAGE-A4, comprising a variable TCRβ region comprising CDR1 having the amino acid sequence of SEQ ID NO:25, CDR2 having the amino acid sequence of SEQ ID NO:26 and CDR3 having the amino acid sequence of SEQ ID NO:27 isolated T-cell receptors (TCRs).
(b)HLA-A2に結合した形態のSEQ ID NO:1のアミノ酸配列;および/または
(c)HLA-A*02:01がコードする分子によって提示されるSEQ ID NO:1のアミノ酸配列
を特異的に認識する、請求項1記載の単離されたTCR。 (a) the amino acid sequence of SEQ ID NO:1 or a fragment thereof ;
(b) the amino acid sequence of SEQ ID NO:1 in an HLA-A2 bound form ; and/or
2. The isolated TCR of claim 1, which specifically recognizes the amino acid sequence of SEQ ID NO:1 presented by (c) HLA-A*02:01-encoded molecules.
b)SEQ ID NO:18のアミノ酸配列を有する可変TCRα領域およびSEQ ID NO:19のアミノ酸配列を有する可変TCRβ領域;または
c)SEQ ID NO:28のアミノ酸配列を有する可変TCRα領域およびSEQ ID NO:29のアミノ酸配列を有する可変TCRβ領域
を含む、請求項1または2記載の単離されたTCR。 a) a variable TCRα region having the amino acid sequence of SEQ ID NO:8 and a variable TCRβ region having the amino acid sequence of SEQ ID NO:9; or
b) a variable TCRα region having the amino acid sequence of SEQ ID NO:18 and a variable TCRβ region having the amino acid sequence of SEQ ID NO:19; or
3. The isolated TCR of claim 1 or 2 , comprising a variable TCRα region having the amino acid sequence of SEQ ID NO:28 and a variable TCRβ region having the amino acid sequence of SEQ ID NO:29.
b)SEQ ID NO:20のアミノ酸配列を有するTCRα鎖およびSEQ ID NO:21のアミノ酸配列を有するTCRβ鎖;または
c)SEQ ID NO:30のアミノ酸配列を有するTCRα鎖およびSEQ ID NO:31のアミノ酸配列を有するTCRβ鎖
を含む、請求項1~3のいずれか一項記載の単離されたTCR。 a) a TCRα chain having the amino acid sequence of SEQ ID NO:10 and a TCRβ chain having the amino acid sequence of SEQ ID NO:11;
b) a TCR α chain having the amino acid sequence of SEQ ID NO:20 and a TCR β chain having the amino acid sequence of SEQ ID NO:21; or
c) The isolated TCR of any one of claims 1-3 , comprising a TCR α chain having the amino acid sequence of SEQ ID NO:30 and a TCR β chain having the amino acid sequence of SEQ ID NO:31.
b)SEQ ID NO:89のアミノ酸配列を有するTCRα鎖およびSEQ ID NO:90のアミノ酸配列を有するTCRβ鎖;または
c)SEQ ID NO:91のアミノ酸配列を有するTCRα鎖およびSEQ ID NO:92のアミノ酸配列を有するTCRβ鎖
を含む、請求項1~3のいずれか一項記載の単離されたTCR。 a) a TCR α chain having the amino acid sequence of SEQ ID NO:87 and a TCR β chain having the amino acid sequence of SEQ ID NO:88;
b) a TCR α chain having the amino acid sequence of SEQ ID NO:89 and a TCR β chain having the amino acid sequence of SEQ ID NO:90; or
c) The isolated TCR of any one of claims 1-3 , comprising a TCR α chain having the amino acid sequence of SEQ ID NO:91 and a TCR β chain having the amino acid sequence of SEQ ID NO:92.
b)SEQ ID NO:108のアミノ酸配列を有するTCRα鎖およびSEQ ID NO:109のアミノ酸配列を有するTCRβ鎖;または
c)SEQ ID NO:114のアミノ酸配列を有するTCRα鎖およびSEQ ID NO:115のアミノ酸配列を有するTCRβ鎖
を含む、請求項1~3のいずれか一項記載の単離されたTCR。 a) a TCRα chain having the amino acid sequence of SEQ ID NO:102 and a TCRβ chain having the amino acid sequence of SEQ ID NO:103;
b) a TCRα chain having the amino acid sequence of SEQ ID NO:108 and a TCRβ chain having the amino acid sequence of SEQ ID NO:109; or
c) The isolated TCR of any one of claims 1-3 , comprising a TCR α chain having the amino acid sequence of SEQ ID NO:114 and a TCR β chain having the amino acid sequence of SEQ ID NO:115.
a)SEQ ID NO:69によってコードされるTCRα鎖およびSEQ ID NO:70によってコードされるTCRβ鎖;
b)SEQ ID NO:77によってコードされるTCRα鎖およびSEQ ID NO:78によってコードされるTCRβ鎖;
c)SEQ ID NO:85によってコードされるTCRα鎖およびSEQ ID NO:86によってコードされるTCRβ鎖;
d)SEQ ID NO:99によってコードされるTCRα鎖およびSEQ ID NO:100によってコードされるTCRβ鎖;
e)SEQ ID NO:105によってコードされるTCRα鎖およびSEQ ID NO:106によってコードされるTCRβ鎖;または
f)SEQ ID NO:111によってコードされるTCRα鎖およびSEQ ID NO:112によってコードされるTCRβ鎖
を含む、請求項9記載の核酸。 TCR is
a) a TCRα chain encoded by SEQ ID NO:69 and a TCRβ chain encoded by SEQ ID NO:70;
b) the TCRα chain encoded by SEQ ID NO:77 and the TCRβ chain encoded by SEQ ID NO:78;
c) the TCRα chain encoded by SEQ ID NO:85 and the TCRβ chain encoded by SEQ ID NO:86;
d) the TCRα chain encoded by SEQ ID NO:99 and the TCRβ chain encoded by SEQ ID NO:100;
e) a TCRα chain encoded by SEQ ID NO:105 and a TCRβ chain encoded by SEQ ID NO:106; or
10. The nucleic acid of claim 9 , comprising f) a TCR alpha chain encoded by SEQ ID NO:111 and a TCR beta chain encoded by SEQ ID NO:112.
(b)がんが、NSCLC、SCLC、乳がん、卵巣がんもしくは結腸直腸がん、肉腫、または骨肉腫からなる群より選択される、
請求項19記載の組成物または薬学的組成物。 (a) cancer is sarcoma, prostate cancer, uterine cancer, thyroid cancer, testicular cancer, kidney cancer, pancreatic cancer, ovarian cancer, esophageal cancer, non-small cell lung cancer, non-Hodgkin's lymphoma, from multiple myeloma, melanoma, hepatocellular carcinoma, head and neck cancer, gastric cancer, endometrial cancer, colorectal cancer, cholangiocarcinoma, breast cancer, bladder cancer, myeloid leukemia, and acute lymphoblastic leukemia is selected from the group consisting of ; or
(b) the cancer is selected from the group consisting of NSCLC, SCLC, breast cancer, ovarian or colorectal cancer, sarcoma, or osteosarcoma ;
20. A composition or pharmaceutical composition according to claim 19 .
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PCT/EP2020/058779 WO2020193767A1 (en) | 2019-03-27 | 2020-03-27 | Mage a4 t cell receptors |
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CN111647069B (en) * | 2020-06-17 | 2022-06-21 | 深圳豪石生物科技有限公司 | Improved TCR and application thereof |
CN115975003B (en) * | 2021-03-09 | 2024-01-26 | 科士华(南京)生物技术有限公司 | TCR, polypeptide, expression vector, host cell, pharmaceutical composition and TCR obtaining method |
MX2023010541A (en) | 2021-03-09 | 2023-11-24 | Cdr Life Ag | Mage-a4 peptide-mhc antigen binding proteins. |
EP4091627A1 (en) | 2021-05-21 | 2022-11-23 | Max-Delbrück-Centrum für Molekulare Medizin in der Helmholtz-Gemeinschaft | Tcr constructs specific for magea4-derived epitopes |
WO2023288267A1 (en) | 2021-07-14 | 2023-01-19 | 2Seventy Bio, Inc. | Engineered t cell receptors fused to binding domains from antibodies |
CN116836261A (en) * | 2022-03-24 | 2023-10-03 | 香雪生命科学技术(广东)有限公司 | High-affinity TCR (TCR) for recognizing MAGE-A4 antigen, and sequence and application thereof |
WO2023196997A2 (en) | 2022-04-08 | 2023-10-12 | 2Seventy Bio, Inc. | Multipartite receptor and signaling complexes |
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US4703004A (en) | 1984-01-24 | 1987-10-27 | Immunex Corporation | Synthesis of protein with an identification peptide |
US4851341A (en) | 1986-12-19 | 1989-07-25 | Immunex Corporation | Immunoaffinity purification system |
WO2003020763A2 (en) | 2001-08-31 | 2003-03-13 | Avidex Limited | Soluble t cell receptor |
EP2006376A1 (en) | 2007-06-21 | 2008-12-24 | Helmholtz Zentrum München Deutsches Forschungszentrum für Gesundheit und Umwelt GmbH | Fusion protein comprising a caspase domain and a nuclear hormone receptor binding domain and methods and uses thereof |
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