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    CTLA4-immunoglobulin fusion proteins having modified effector functions and uses therefor
    1.
    发明授权
    CTLA4-immunoglobulin fusion proteins having modified effector functions and uses therefor 失效
    具有修饰的效应子功能的CTLA4-免疫球蛋白融合蛋白及其用途

    公开(公告)号：US06750334B1

    公开(公告)日：2004-06-15

    申请号：US08595590

    申请日：1996-02-02

    申请人： Gary S. Gray ,  Jerry Carson ,  Kashi Javaherian ,  Cindy L. Jellis ,  Paul D. Rennert ,  Sandra Silver

    发明人： Gary S. Gray ,  Jerry Carson ,  Kashi Javaherian ,  Cindy L. Jellis ,  Paul D. Rennert ,  Sandra Silver

    IPC分类号： C07H2104

    CPC分类号： C07K14/70503 ,  A61K38/00 ,  A61K2039/5154 ,  C07K2319/00

    摘要： CTLA4-immunoglobulin fusion proteins having modified immunoglobulin constant region-mediated effector functions, and nucleic acids encoding the fusion proteins, are described. The CTLA4-immunoglobulin fusion proteins comprise two components: a first peptide having a CTLA4 activity and a second peptide comprising an immunoglobulin constant region which is modified to reduce at least one constant region-mediated biological effector function relative to a CTLA4-IgG1 fusion protein. The nucleic acids of the invention can be integrated into various expression vectors, which in turn can direct the synthesis of the corresponding proteins in a variety of hosts, particularly eukaryotic cells. The CTLA4-immunoglobulin fusion proteins described herein can be administered to a subject to inhibit an interaction between a CTLA4 ligand (e.g., B7-1 and/or B7-2) on an antigen presenting cell and a receptor for the CTLA4 ligand (e.g., CD28 and/or CTLA4) on the surface of T cells to thereby suppress an immune response in the subject, for example to inhibit transplantation rejection, graft versus host disease or autoimmune responses.

    摘要翻译： 描述了具有修饰的免疫球蛋白恒定区介导的效应子功能的CTLA4-免疫球蛋白融合蛋白，以及编码融合蛋白的核酸。 CTLA4免疫球蛋白融合蛋白包含两个组分：具有CTLA4活性的第一肽和包含免疫球蛋白恒定区的第二个肽，其被修饰以相对于CTLA4-IgG1融合蛋白减少至少一个恒定区介导的生物效应子功能。 本发明的核酸可以整合到各种表达载体中，这又可以指导各种宿主，特别是真核细胞中相应的蛋白质的合成。 本文所述的CTLA4-免疫球蛋白融合蛋白可以施用于受试者以抑制抗原呈递细胞上的CTLA4配体（例如B7-1和/或B7-2）与CTLA4配体的受体（例如， CD28和/或CTLA4），从而抑制受试者的免疫应答，例如抑制移植排斥反应，移植物抗宿主病或自身免疫应答。

    CTLA4-C&ggr;4 fusion proteins
    2.
    发明授权
    CTLA4-C&ggr;4 fusion proteins 失效
    CTLA4-Cgamma4融合蛋白

    公开(公告)号：US06444792B1

    公开(公告)日：2002-09-03

    申请号：US09227595

    申请日：1999-01-08

    申请人： Gary S. Gray ,  Jerry Carson ,  Kashi Javaherian ,  Paul D. Rennert ,  Sandra Silver

    发明人： Gary S. Gray ,  Jerry Carson ,  Kashi Javaherian ,  Paul D. Rennert ,  Sandra Silver

    IPC分类号： A61K39395

    CPC分类号： C07K14/70503 ,  A61K38/00 ,  A61K2039/5154 ,  C07K2319/00

    摘要： CTLA4-immunoglobulin fusion proteins having modified immunoglobulin constant region-mediated effector functions, and nucleic acids encoding the fusion proteins, are described. The CTLA4-immunoglobulin fusion proteins comprise two components: a first peptide having a CTLA4 activity and a second peptide comprising an immunoglobulin constant region which is modified to reduce at least one constant region-mediated biological effector function relative to a CTLA4-IgG1 fusion protein. The nucleic acids of the invention can be integrated into various expression vectors, which in turn can direct the synthesis of the corresponding proteins in a variety of hosts, particularly eukaryotic cells. The CTLA4-immunoglobulin fusion proteins described herein can be administered to a subject to inhibit an interaction between a CTLA4 ligand (e.g., B7-1 and/or B7-2) on an antigen presenting cell and a receptor for the CTLA4 ligand (e.g., CD28 and/or CTLA4) on the surface of T cells to thereby suppress an immune response in the subject, for example to inhibit transplantation rejection, graft versus host disease or autoimmune responses.

    摘要翻译： 描述了具有修饰的免疫球蛋白恒定区介导的效应子功能的CTLA4-免疫球蛋白融合蛋白，以及编码融合蛋白的核酸。 CTLA4免疫球蛋白融合蛋白包含两个组分：具有CTLA4活性的第一肽和包含免疫球蛋白恒定区的第二个肽，其被修饰以相对于CTLA4-IgG1融合蛋白减少至少一个恒定区介导的生物效应子功能。 本发明的核酸可以整合到各种表达载体中，这又可以指导各种宿主，特别是真核细胞中相应的蛋白质的合成。 本文所述的CTLA4-免疫球蛋白融合蛋白可以施用于受试者以抑制抗原呈递细胞上的CTLA4配体（例如B7-1和/或B7-2）与CTLA4配体的受体（例如， CD28和/或CTLA4），从而抑制受试者的免疫应答，例如抑制移植排斥反应，移植物抗宿主病或自身免疫应答。

    Methods of inhibiting T cell proliferation or IL-2 accumulation with CTLA-4 specific antibodies
    3.
    发明授权
    Methods of inhibiting T cell proliferation or IL-2 accumulation with CTLA-4 specific antibodies 失效
    用CTLA-4特异性抗体抑制T细胞增殖或IL-2积累的方法

    公开(公告)号：US07592007B2

    公开(公告)日：2009-09-22

    申请号：US10732847

    申请日：2003-12-09

    申请人： John G. Gribben ,  Gordon J. Freeman ,  Lee M. Nadler ,  Paul Rennert ,  Cindy L. Jellis ,  Edward Greenfield ,  Gary S. Gray

    发明人： John G. Gribben ,  Gordon J. Freeman ,  Lee M. Nadler ,  Paul Rennert ,  Cindy L. Jellis ,  Edward Greenfield ,  Gary S. Gray

    IPC分类号： A61K39/395 ,  C07K16/28

    CPC分类号： C07K14/70521 ,  A61K38/00 ,  C07K14/70532 ,  C07K16/2818 ,  C07K2317/34

    摘要： Isolated ligands which bind a molecule expressed on the surface of T cells and induce antigen specific apoptosis in activated T cells are disclosed. Preferably, the T cell surface molecule is CTLA4 and the ligand is a monoclonal anti-CTLA4 antibody that binds to an epitope of CTLA4 distinct from the binding sites of B7-1 and B7-2. Upon binding of the antibody to CTLA4 on an activated T cell, in the presence of an antigenic signal, antigen specific apoptosis is induced. The invention also describes a novel natural CTLA4 ligand, distinct from B7-1 and B7-2, which mediates induction of apoptosis. Pharmaceutical compositions of anti-CTLA4 antibodies or other isolated CTLA4 ligands which can be administered to subjects to induce T cell apoptosis, thereby clonally deleting antigen specific T cells, such as alloreactive T cells in transplantation situations or autoreactive T cells in autoimmune disorders, are also disclosed. Methods for inducing T cell apoptosis in vitro with an anti-CTLA4 antibody or other ligand of the invention together with an antigen specific signal are also disclosed, e.g., for use in purging alloreactive T cells from donor bone marrow prior to bone marrow transplantation to inhibit graft versus host disease.

    摘要翻译： 公开了结合在T细胞表面上表达并在活化的T细胞中诱导抗原特异性凋亡的分子的分离的配体。 优选地，T细胞表面分子是CTLA4，并且配体是结合与B7-1和B7-2的结合位点不同的CTLA4的表位的单克隆抗CTLA4抗体。 当抗体与CTLA4在活化的T细胞上结合时，在抗原信号存在下，诱导抗原特异性凋亡。 本发明还描述了一种与介导细胞凋亡诱导的B7-1和B7-2不同的新型天然CTLA4配体。 抗CTLA4抗体或其他分离的CTLA4配体的药物组合物也可以被给予受试者诱导T细胞凋亡，从而克隆地删除抗原特异性T细胞，例如移植情况下的同种异体反应性T细胞或自身免疫性疾病中的自身反应性T细胞， 披露 还公开了用本发明的抗CTLA4抗体或其他配体与抗原特异性信号一起体外诱导T细胞凋亡的方法，例如用于在骨髓移植之前从供体骨髓中清除同种异体反应性T细胞以抑制 移植物抗宿主病。

    Methods of inhibiting T cell proliferation or IL-2 accumulation with CTLA4- specific antibodies
    4.
    发明授权
    Methods of inhibiting T cell proliferation or IL-2 accumulation with CTLA4- specific antibodies 失效
    用CTLA4特异性抗体抑制T细胞增殖或IL-2积累的方法

    公开(公告)号：US06719972B1

    公开(公告)日：2004-04-13

    申请号：US08253783

    申请日：1994-06-03

    申请人： John G. Gribben ,  Gordon J. Freeman ,  Lee M. Nadler ,  Paul Rennert ,  Cindy L. Jellis ,  Edward Greenfield ,  Gary S. Gray

    发明人： John G. Gribben ,  Gordon J. Freeman ,  Lee M. Nadler ,  Paul Rennert ,  Cindy L. Jellis ,  Edward Greenfield ,  Gary S. Gray

    IPC分类号： A61K39395

    CPC分类号： C07K14/70521 ,  A61K38/00 ,  C07K14/70532 ,  C07K16/2818 ,  C07K2317/34

    摘要： Isolated ligands which bind a molecule expressed on the surface of T cells and induce antigen specific apoptosis in activated T cells are disclosed. Preferably, the T cell surface molecule is CTLA4 and the ligand is a monoclonal anti-CTLA4 antibody that binds to an epitope of CTLA4 distinct from the binding sites of B7-1 and B7-2. Upon binding of the antibody to CTLA4 on an activated T cell, in the presence of an antigenic signal, antigen specific apoptosis is induced. The invention also describes a novel natural CTLA4 ligand, distinct from B7-1 and B7-2, which mediates induction of apoptosis. Pharmaceutical compositions of anti-CTLA4 antibodies or other isolated CTLA4 ligands which can be administered to subjects to induce T cell apoptosis, thereby clonally deleting antigen specific. T cells, such as alloreactive T cells in transplantation situations or autoreactive T cells in autoimmune disorders, are also disclosed. Methods for inducing T cell apoptosis in vitro with an anti-CTLA4 antibody or other ligand of the invention together with an antigen specific signal are also disclosed, e.g., for use in purging alloreactive T cells from donor bone marrow prior to bone marrow transplantation to inhibit graft versus host disease.

    摘要翻译： 公开了结合在T细胞表面上表达并在活化的T细胞中诱导抗原特异性凋亡的分子的分离的配体。 优选地，T细胞表面分子是CTLA4，并且配体是结合与B7-1和B7-2的结合位点不同的CTLA4的表位的单克隆抗CTLA4抗体。 当抗体与CTLA4在活化的T细胞上结合时，在抗原信号存在下，诱导抗原特异性凋亡。 本发明还描述了一种与介导细胞凋亡诱导的B7-1和B7-2不同的新型天然CTLA4配体。 抗CTLA4抗体或其他分离的CTLA4配体的药物组合物，其可以施用于受试者以诱导T细胞凋亡，从而克隆地删除抗原特异性。 还公开了T细胞，例如移植情况中的同种异体反应性T细胞或自身免疫性疾病中的自身反应性T细胞。 还公开了用本发明的抗CTLA4抗体或其他配体与抗原特异性信号一起体外诱导T细胞凋亡的方法，例如用于在骨髓移植之前从供体骨髓中清除同种异体反应性T细胞以抑制 移植物抗宿主病。