公开(公告)号：WO2011001152A1

公开(公告)日：2011-01-06

申请号：PCT/GB2010/001277

申请日：2010-07-01

Applicant: IMMUNOCORE LTD ,  JAKOBSEN, Bent Karsten ,  HARWOOD, Naomi ,  LIDDY, Nathaniel Ross

Inventor： JAKOBSEN, Bent Karsten ,  HARWOOD, Naomi ,  LIDDY, Nathaniel Ross

IPC: C07K14/705

CPC classification number: C12N15/00 ,  C07K14/705 ,  C07K14/7051 ,  C12N15/09

Abstract: A T cell receptor (TCR) having the property of binding to the gp100 YLEPGPVTA peptide-HLA-A2 complex and comprising a TCR alpha variable domain and/or a TCR beta variable domain, characterized in that: (i) said TCR is mutated relative to a TCR having the extracellular alpha and beta chain sequences SEQ ID Nos: 2 and 3 in its alpha chain variable domain amino acids 1 to 109 of SEQ ID No: 2 and/or its beta chain variable domain amino acids 1 to 112 of SEQ ID No: 3; and (ii) said alpha variable domain has at least 90% sequence identity to the amino acid sequence 1 to 109 of SEQ ID No: 2, and/or said beta variable domain has at least 90% sequence identity to the amino acid sequence 1 to 1 12 of SEQ ID No: 3; and (iii) said TCR has a binding affinity for, and/or a binding half-life for, the YLEPGPVTA-HLA-A2 complex at least double that of a reference TCR, the said reference TCR having the extracellular alpha chain sequence SEQ ID No: 45 and the extracellular beta chain sequence SEQ ID No: 46. The use of such TCRs in adoptive therapy, and fusions of such TCRs with therapeutic agents are also described.

Abstract translation: AT细胞受体（TCR）具有与gp100YLEPGPVTA肽-HLA-A2复合物结合的特性并且包含TCRα可变结构域和/或TCRβ可变结构域，其特征在于：（i）所述TCR相对于 在SEQ ID No：2的α链可变结构域氨基酸1至109和/或其SEQ ID NO：2的β链可变结构域氨基酸1至112中具有细胞外α和β链序列SEQ ID No：2和3的TCR 不：3 和（ii）所述α可变结构域与SEQ ID No：2的氨基酸序列1至109具有至少90％的序列同一性，和/或所述β可变结构域与氨基酸序列1具有至少90％的序列同一性 至SEQ ID No：3的12位; 和（iii）所述TCR与YLEPGPVTA-HLA-A2复合物的结合亲和力和/或结合半衰期至少为参考TCR的两倍，所述参考TCR具有细胞外α链序列SEQ ID 编号45和细胞外β链序列SEQ ID No：46.还描述了这种TCR在过继性治疗中的应用，以及这些TCR与治疗剂的融合。

公开(公告)号：WO2010133828A1

公开(公告)日：2010-11-25

申请号：PCT/GB2010/000988

申请日：2010-05-19

Applicant: IMMUNOCORE LTD. ,  JAKOBSEN, Bent, Karsten ,  VUIDEPOT, Annelise, Brigitte

Inventor： JAKOBSEN, Bent, Karsten ,  VUIDEPOT, Annelise, Brigitte

IPC: C07K14/705 ,  C12N15/62 ,  A61K38/17 ,  A61K38/00

CPC classification number: A61K47/6849 ,  A61K38/00 ,  A61K47/6425 ,  C07K14/7051 ,  C07K2319/33

Abstract: A bifunctional polypeptide comprising a specific binding partner for a peptide-MHC epitope, such as an antibody or a T cell receptor ("TCR"), and an immune effector, such as an antibody or a cytokine, the immune effector part being linked to the N- terminus of the peptide-MHC binding part.

Abstract translation: 包含肽-MHC表位的特异性结合配偶体例如抗体或T细胞受体（“TCR”）的双功能多肽和免疫效应物如抗体或细胞因子，所述免疫效应部分与 肽-MHC结合部分的N-末端。

公开(公告)号：WO2004050705A2

公开(公告)日：2004-06-17

申请号：PCT/GB0305104

申请日：2003-11-25

Applicant: AVIDEX LTD ,  JAKOBSEN BENT KARSTEN ,  GLICK MEIR

Inventor： JAKOBSEN BENT KARSTEN ,  GLICK MEIR

IPC: C07K14/725 ,  C07K14/705

CPC classification number: A61K51/088 ,  A61K38/00 ,  A61K47/60 ,  C07K14/7051

Abstract: A multivalent T cell receptor (TCR) complex comprising at least two TCRs, linked by a non-peptidic polymer chain or a peptidic linker sequence. Preferably the TCR complex comprises TCR heterodimers having a non-native disulfide bond between constant domain residues, said TCRs being linked via an optionally substituted, polyalkylene glycol linker. Therapeutic agents such as cytotoxic drugs may be attached to such complexes for targeted cell delivery. Such TCR complexes may be used in the diagnosis or treatment of cancer, infectious disease, or autoimmune disease.

Abstract translation: 包含至少两个TCR的多价T细胞受体（TCR）复合物，通过非肽聚合物链或肽接头序列连接。 优选地，TCR复合物包含在恒定结构域残基之间具有非天然二硫键的TCR异源二聚体，所述TCR通过任选取代的聚亚烷基二醇连接体连接。 诸如细胞毒性药物的治疗剂可以连接到这种复合物用于靶细胞递送。 这种TCR复合物可用于诊断或治疗癌症，感染性疾病或自身免疫性疾病。

公开(公告)号：WO02102840A3

公开(公告)日：2003-10-16

申请号：PCT/GB0202866

申请日：2002-06-19

Applicant: AVIDEX LTD ,  JAKOBSEN BENT KARSTEN ,  BOULTER JONATHAN MICHAEL

Inventor： JAKOBSEN BENT KARSTEN ,  BOULTER JONATHAN MICHAEL

IPC: A61K48/00 ,  A61P37/06 ,  C07K14/74 ,  C12N15/12 ,  C07K14/705 ,  A61K38/17 ,  C12N5/10

CPC classification number: C07K14/70539 ,  A61K48/00

Abstract: The present invention provides a multimers of class I Major Histocompatibility Complexes (MHCs) having a modified beta2-microglobulin whose binding to CD8 is inhibited. Such MHCs are capable of inhibiting CD8 T cell response, particularly by inducing apoptosis or anergy of the T cell. The invention also provides nucleic acids encoding such molecules, and the use of such multimers and nucleic acids in immunosuppressive therapy, in particular as inhibitors of cytotoxic T cell responses.

Abstract translation: 本发明提供具有与CD8结合的修饰的β2-微球蛋白的I类主要组织相容性复合物（MHC）的多聚体。 这样的MHC能够抑制CD8 + T细胞反应，特别是通过诱导T细胞的凋亡或无反应性。 本发明还提供了编码这种分子的核酸，以及这些多聚体和核酸在免疫抑制治疗中的用途，特别是作为细胞毒性T细胞应答的抑制剂。

公开(公告)号：WO02088740A3

公开(公告)日：2003-05-22

申请号：PCT/GB0201979

申请日：2002-04-30

Applicant: AVIDEX LTD ,  JAKOBSEN BENT KARSTEN

Inventor： JAKOBSEN BENT KARSTEN

IPC: G01N33/564 ,  G01N33/68

CPC classification number: G01N33/6878 ,  G01N33/564 ,  G01N2333/70539 ,  G01N2500/00

Abstract: The present invention provides a method for identifying an entity which binds to a peptide-Major Histocompatibility Complex (pMHC) complex. In the method, a pMHC complex is formed between a predetermined MHC and a peptide which is obtained from a protein sequence and is not known to be capable of being complexed with the predetermined MHC. The resulting pMHC is used to screen for an entity which binds to the pMHC complex.

Abstract translation: 本发明提供了鉴定结合肽 - 主要组织相容性复合物（pMHC）复合物的实体的方法。 在该方法中，在预定的MHC和从蛋白质序列获得的肽之间形成pMHC复合物，并且不知道能够与预定的MHC复合。 所得的pMHC用于筛选结合pMHC复合物的实体。

公开(公告)号：WO2002088740A2

公开(公告)日：2002-11-07

申请号：PCT/GB2002/001979

申请日：2002-04-30

Applicant: AVIDEX LIMITED ,  JAKOBSEN, Bent, Karsten

Inventor： JAKOBSEN, Bent, Karsten

IPC: G01N33/564

CPC classification number: G01N33/6878 ,  G01N33/564 ,  G01N2333/70539 ,  G01N2500/00

Abstract: The present invention provides a method for identifying an entity which binds to a peptide-Major Histocompatibility Complex (pMHC) complex. In the method, a pMHC complex is formed between a predetermined MHC and a peptide which is obtained from a protein sequence and is not known to be capable of being complexed with the predetermined MHC. The resulting pMHC is used to screen for an entity which binds to the pMHC complex.

Abstract translation: 本发明提供了鉴定结合肽 - 主要组织相容性复合物（pMHC）复合物的实体的方法。 在该方法中，在预定的MHC和从蛋白质序列获得的肽之间形成pMHC复合物，并且不知道能够与预定的MHC复合。 所得的pMHC用于筛选结合pMHC复合物的实体。

公开(公告)号：WO2013041865A1

公开(公告)日：2013-03-28

申请号：PCT/GB2012/052322

申请日：2012-09-20

Applicant: IMMUNOCORE LIMITED ,  JAKOBSEN, Bent Karsten ,  LIDDY, Nathaniel Ross ,  VUIDEPOT, Annelise Brigitte ,  MOLLOY, Peter Eamon

Inventor： JAKOBSEN, Bent Karsten ,  LIDDY, Nathaniel Ross ,  VUIDEPOT, Annelise Brigitte ,  MOLLOY, Peter Eamon

IPC: C07K14/705

CPC classification number: C07K14/7051 ,  C07K2319/30

Abstract: The present invention relates to T cell receptors (TCRs) that the property of binding to EVDPIGHLY (SEQ ID No: 1) HLA-A1 complex and comprise a TCR alpha chain variable domain and a TCR beta chain variable domain. The EVDPIGHLY peptide is derived from the MAGE-3 protein which is expressed in many tumour types, including melanomas, and other solid tumours such as Head and Neck Squamous Cell, lung, bladder, gastric, prostate, colorectal and esophageal carcimomas. Also provided are nucleic acids encoding such TCRs, cells presenting such TCRs and pharmaceutical compositions comprising such TCRs.

Abstract translation: 本发明涉及结合EVDPIGHLY（SEQ ID No：1）HLA-A1复合物并包含TCRα链可变结构域和TCRβ可变结构域的特性的T细胞受体（TCR）。 EVDPIGHLY肽衍生自MAGE-3蛋白，其在许多肿瘤类型中表达，包括黑素瘤和其他实体瘤如头颈部鳞状细胞，肺，膀胱，胃，前列腺，结肠直肠和食管癌。 还提供了编码这种TCR的核酸，呈现这种TCR的细胞和包含这种TCR的药物组合物。

公开(公告)号：WO2008037943A1

公开(公告)日：2008-04-03

申请号：PCT/GB2006/003649

申请日：2006-09-29

Applicant: MEDIGENE LIMITED ,  JAKOBSEN, Bent, Karsten ,  BOULTER, Jonathan, Michael ,  LI, Yi ,  MOLLOY, Peter, Eamon ,  DUNN, Steven, Mark

Inventor： JAKOBSEN, Bent, Karsten ,  BOULTER, Jonathan, Michael ,  LI, Yi ,  MOLLOY, Peter, Eamon ,  DUNN, Steven, Mark

IPC: C07K14/705

CPC classification number: C07K14/70503

Abstract: The present invention provides cells transformed with expressible nucleic acids encoding a TCR specific for the SLLMWITQC-HLA-A*0201 complex, said nucleic acids consisting of: (i) a sequence comprising bases 15 to 836 of SEQ ID Nos: 1, 3, 5, 7, or 9, and (ii) a sequence comprising bases 16 to 948 of SEQ ID Nos: 11, 13, 15, 17, 19, or 21 or; (a) a sequence comprising bases 15 to 836 of SEQ ID Nos: 23, 25, 27, 29 or 31 and (b) a sequence comprising bases 16 to 948 of SEQ ID Nos: 33, 35, 37, 39, 41, or 43. Such cells are useful for targeting NY-ESO + cancer cells presenting the SLLMWITQC-HLA-A*0201 complex.

Abstract translation: 本发明提供用编码针对SLLMWITQC-HLA-A * 0201复合物的TCR特异性的可表达核酸转化的细胞，所述核酸由以下组成：（i）包含SEQ ID No：1,3， 5，7或9，和（ii）包含SEQ ID NO：11,13,15,17,19或21的碱基16至948的序列; （a）包含SEQ ID No：23,25,27,29或31的碱基15至836的序列和（b）包含SEQ ID No：33,35,37,39,41， 这种细胞可用于靶向呈现SLLMWITQC-HLA-A * 0201复合物的NY-ESO +癌细胞。

公开(公告)号：WO2006129085A3

公开(公告)日：2007-02-01

申请号：PCT/GB2006001980

申请日：2006-05-31

Applicant: AVIDEX LTD ,  JAKOBSEN BENT KARSTEN ,  LIDDY NATHANIEL ROSS

Inventor： JAKOBSEN BENT KARSTEN ,  LIDDY NATHANIEL ROSS

IPC: C07K14/705 ,  C07K14/725

CPC classification number: C07K14/7051

Abstract: The present invention provides TCRs having an affinity (K D ) of less than or equal to 3µM, and/or an off-rate (k off ) of 1x10 -3 S -1 or slower, for the AAGIGILTV-HLA- A* 0201 complex.. Such TCRs are useful, either alone or associated with a therapeutic agent, for targeting cancer cells presenting that complex.

Abstract translation: 本发明提供具有小于或等于3μM的亲和力（K SUB）和/或1×10 6以下的脱离率（k off）的TCR。 对于AAGIGILTV-HLA-A * 0201复合物来说，这样的TCR可以单独使用或与治疗剂相关联，用于靶向呈递的癌细胞 那个复杂的。

公开(公告)号：WO2006037960A3

公开(公告)日：2006-08-03

申请号：PCT/GB2005003752

申请日：2005-09-29

Applicant: AVIDEX LTD ,  JAKOBSEN BENT KARSTEN ,  ANDERSEN TORBEN BENT

Inventor： JAKOBSEN BENT KARSTEN ,  ANDERSEN TORBEN BENT

IPC: C07K14/725 ,  A61K35/14 ,  A61P35/00 ,  A61P37/02 ,  C12N5/08 ,  C12N5/10 ,  C12N15/12 ,  G01N33/566

CPC classification number: C07K14/7051 ,  A61K47/6425 ,  C07K2319/00

Abstract: The present invention provides a dimeric TCR (dTCR) or single-chain TCR (scTCR) associated with selected therapeutic agents, wherein said TCR comprises a first segment constituted by an amino acid sequence corresponding to a TCR a chain variable domain sequence fused to the N terminus of an amino acid sequence corresponding to a TCR a chain constant domain extracellular sequence, a second segment constituted by an amino acid sequence corresponding to a TCR ß chain variable domain fused to the N terminus of an amino acid sequence corresponding to TCR ß chain constant domain extracellular sequence, a disulfide bond between the first and second chains, said disulfide bond being one which has no equivalent in native aß T cell receptors, and in the case of said scTCRs further comprising a linker sequence linking the C terminus of the first segment to the N terminus of the second segment, or vice versa, the length of the linker sequence and the position of the disulfide bond being such that the variable domain sequences of the first and second segments are mutually orientated substantially as in native aß T cell receptors.

Abstract translation: 本发明提供与所选择的治疗剂相关的二聚TCR（dTCR）或单链TCR（scTCR），其中所述TCR包含由对应于TCR的氨基酸序列构成的第一片段，与N融合的链可变结构域序列 对应于TCR链段恒定域细胞外序列的氨基酸序列的末端，由与对应于TCRß链常数的氨基酸序列的N末端融合的TCRß链可变结构域相对应的氨基酸序列构成的第二区段 结构域细胞外序列，第一和第二链之间的二硫键，所述二硫键是在天然αT细胞受体中不具有等同物的二硫键，并且在所述scTCR的情况下还包含连接第一链节的C末端的连接体序列 到第二段的N末端，反之亦然，接头序列的长度和二硫键的位置是这样的 在第一和第二片段的可变结构域序列基本上如在天然αT细胞受体中相互取向。