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    B7-2: a CTLA4/CD28 ligand
    1.
    发明授权
    B7-2: a CTLA4/CD28 ligand 失效
    B7-2：CTLA4 / CD28配体

    公开(公告)号：US5942607A

    公开(公告)日：1999-08-24

    申请号：US101624

    申请日：1993-07-26

    申请人： Gordon J. Freeman ,  Lee M. Nadler ,  Gary S. Gray

    发明人： Gordon J. Freeman ,  Lee M. Nadler ,  Gary S. Gray

    IPC分类号： A61K38/00 ,  C07K14/705 ,  C07K16/28 ,  C12N15/12 ,  C12N15/85 ,  C07H21/00

    CPC分类号： C12N15/8509 ,  C07K14/70532 ,  C07K16/2827 ,  A01K2217/05 ,  A01K2217/075 ,  A01K2267/03 ,  A01K2267/0381 ,  A61K38/00 ,  C07K2317/73 ,  C07K2319/30

    摘要： Isolated nucleic acids encoding novel CTLA4/CD28 ligands which costimulate T cell activation are disclosed. In one embodiment, the isolated nucleic acid has a sequence which encodes a B lymphocyte activation antigen, B7-2. Preferably, the nucleic acid is a DNA molecule comprising at least a portion of a nucleotide sequence shown in FIG. 8, SEQ ID NO: 1. The nucleic acid sequences of the invention can be integrated into various expression vectors, which in turn can direct the synthesis of the corresponding proteins or peptides in a variety of hosts, particularly eukaryotic cells, such as mammalian and insect cell culture. Also disclosed are host cells transformed to produce proteins or peptides encoded by the nucleic acid sequences of the invention and isolated proteins and peptides which comprise at least a portion of a novel B lymphocyte antigen.

    摘要翻译： 公开了分泌的编码新型CTLA4 / CD28配体的核酸，其共同刺激T细胞活化。 在一个实施方案中，分离的核酸具有编码B淋巴细胞活化抗原B7-2的序列。 优选地，核酸是包含图1所示的核苷酸序列的至少一部分的DNA分子。 8，SEQ ID NO：1。本发明的核酸序列可以整合到各种表达载体中，其又可以指导各种宿主，特别是真核细胞（例如哺乳动物和哺乳动物）中相应的蛋白质或肽的合成 昆虫细胞培养。 还公开了转化以产生由本发明的核酸序列编码的蛋白质或肽的宿主细胞和包含至少一部分新型B淋巴细胞抗原的分离的蛋白质和肽。

    Nucleic acids encoding B7-2 fusion proteins
    2.
    发明授权
    Nucleic acids encoding B7-2 fusion proteins 失效
    编码B7-2融合蛋白的核酸

    公开(公告)号：US07459544B2

    公开(公告)日：2008-12-02

    申请号：US10429079

    申请日：2003-05-02

    申请人： Gordon J. Freeman ,  Lee M. Nadler ,  Gary S. Gray

    发明人： Gordon J. Freeman ,  Lee M. Nadler ,  Gary S. Gray

    IPC分类号： C07H21/04

    CPC分类号： C07K16/2827 ,  A01K67/0276 ,  A01K2207/15 ,  A01K2217/00 ,  A01K2217/05 ,  A01K2217/075 ,  A01K2217/30 ,  A01K2227/105 ,  A01K2267/01 ,  A01K2267/03 ,  A01K2267/0325 ,  A01K2267/0331 ,  A01K2267/0381 ,  A61K38/00 ,  C07K14/70503 ,  C07K14/70532 ,  C07K2317/73 ,  C07K2319/00 ,  C07K2319/02 ,  C07K2319/30 ,  C12N15/8509

    摘要： Nucleic acids encoding novel CTLA4/CD28 ligands which costimulate T cell activation are disclosed. In one embodiment, the nucleic acid has a sequence which encodes a B lymphocyte antigen, B7-2. Preferably, the nucleic acid is a DNA molecule comprising at least a portion of a nucleotide sequence shown in FIG. 8, SEQ ID NO:1 or FIG. 14, SEQ ID NO:23. The nucleic acid sequences of the invention can be integrated into various expression vectors, which in turn direct the synthesis of the corresponding proteins or peptides in a variety of hosts, particularly eukaryotic cells, such as mammalian and insect cell culture. Also disclosed are host cells transformed to produce proteins or peptides encoded by the nucleic acid sequences of the invention and isolated proteins and peptides which comprise at least a portion of a novel B lymphocyte antigen. Proteins and peptides described herein can be administered to subjects to enhance or suppress T cell-mediated immune responses.

    摘要翻译： 公开了编码协同T细胞活化的新型CTLA4 / CD28配体的核酸。 在一个实施方案中，核酸具有编码B淋巴细胞抗原B7-2的序列。 优选地，核酸是包含图1所示的核苷酸序列的至少一部分的DNA分子。 8，SEQ ID NO：1或图3。 14，SEQ ID NO：23。 本发明的核酸序列可以整合到各种表达载体中，这又指导了多种宿主，特别是真核细胞如哺乳动物和昆虫细胞培养物中的相应蛋白质或肽的合成。 还公开了转化以产生由本发明的核酸序列编码的蛋白质或肽的宿主细胞和包含至少一部分新型B淋巴细胞抗原的分离的蛋白质和肽。 本文所述的蛋白质和肽可以施用于受试者以增强或抑制T细胞介导的免疫应答。

    Methods for inhibiting the interaction of B7-2 with its natural ligand
    3.
    发明授权
    Methods for inhibiting the interaction of B7-2 with its natural ligand 失效
    抑制B7-2与天然配体相互作用的方法

    公开(公告)号：US06824779B1

    公开(公告)日：2004-11-30

    申请号：US09425516

    申请日：1999-10-22

    申请人： Gordon J. Freeman ,  Lee M. Nadler ,  Gary S. Gray

    发明人： Gordon J. Freeman ,  Lee M. Nadler ,  Gary S. Gray

    IPC分类号： A61K39395

    CPC分类号： A01K67/0276 ,  A01K2207/15 ,  A01K2217/00 ,  A01K2217/05 ,  A01K2217/075 ,  A01K2217/30 ,  A01K2227/105 ,  A01K2267/0325 ,  A01K2267/0331 ,  A61K38/00 ,  C07K14/70503 ,  C07K14/70532 ,  C07K16/2827 ,  C07K2317/73 ,  C07K2319/00 ,  C07K2319/02 ,  C07K2319/30 ,  C12N15/8509

    摘要： The present invention relates to, inter alia, methods for inhibiting the interaction of the B-lymphocyte antigen, B7-2, with its natural ligand on the surface of an immune cell are disclosed. The methods comprise contacting the immune cell with an agent which inhibits B7-2 binding with its natural ligand, to thereby inhibit the interaction. Examples of such agents are provided, and include a soluble form of B7-2, an antibody that recognized B7-2. The method may also include contacting the immune cell with an agent that blocks the interaction of B7-1 with its natural ligand. Further, the method may include contacting the immune cell with an immunomodulating agent, for example, an antibody reactive with CD28, an antibody reactive with CTLA4, an antibody reactive with a cytokine, a CTLA4Ig fusion protein, a CD28Ig fusion protein, and an immunosuppressive drug. Both in vivo and in vitro applications of the method are disclosed.

    摘要翻译： 本发明尤其涉及用于抑制B淋巴细胞抗原B7-2与其天然配体在免疫细胞表面上的相互作用的方法。 所述方法包括使免疫细胞与抑制B7-2与其天然配体结合的试剂接触，从而抑制相互作用。 提供这些试剂的实例，并且包括可溶形式的B7-2，其是识别B7-2的抗体。 该方法还可以包括使免疫细胞与阻断B7-1与其天然配体的相互作用的试剂接触。 此外，该方法可以包括使免疫细胞与免疫调节剂接触，例如与CD28反应的抗体，与CTLA4反应的抗体，与细胞因子反应的抗体，CTLA4Ig融合蛋白，CD28Ig融合蛋白和免疫抑制 药物。 公开了该方法的体内和体外应用。

    Methods of inhibiting T cell proliferation or IL-2 accumulation with CTLA-4 specific antibodies
    5.
    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。

    Tumor cells modified to express B7-2 with increased immunogenicity and uses therefor
    6.
    发明授权
    Tumor cells modified to express B7-2 with increased immunogenicity and uses therefor 失效
    肿瘤细胞修饰以表达B7-2，增加免疫原性，并用于此

    公开(公告)号：US06723705B1

    公开(公告)日：2004-04-20

    申请号：US09206132

    申请日：1998-12-07

    申请人： Gordon J. Freeman ,  Lee M. Nadler ,  Gary S. Gray

    发明人： Gordon J. Freeman ,  Lee M. Nadler ,  Gary S. Gray

    IPC分类号： A61K3170

    CPC分类号： A01K67/0271 ,  A01K2217/05 ,  A01K2217/075 ,  A01K2267/0331 ,  A61K38/00 ,  C07K14/70532 ,  C07K16/2827 ,  C07K2319/00 ,  C07K2319/30 ,  C12N15/8509

    摘要： Tumor cells modified to express one or more T cell costimulatory molecules are disclosed. Preferred costimulatory molecules are B7-2 and B7-3. The tumor cells of the invention can be modified by transfection with nucleic acid encoding B7-2 and/or B7-3, by using an agent which induces or increases expression of B7-2 and/or B7-3 on the tumor cell or by coupling B7-2 and/or B7-3 to the tumor cell. Tumor cells modified to express B7-2 and/or B7-3 can be further modified to express B7. Tumor cells further modified to express MHC class I and/or class II molecules or in which expression of an MHC associated protein, the invariant chain, is inhibited are also disclosed. The modified tumor cells of the invention can be used in methods for treating a patient with a tumor, preventing or inhibiting metastatic spread of a tumor or preventing or inhibiting recurrence of a tumor. A method for specifically inducing a CD4+ T cell response against a tumor and a method for treating a tumor by modification of tumor cells in vivo are disclosed.

    摘要翻译： 公开了修饰以表达一种或多种T细胞共刺激分子的肿瘤细胞。 优选的共刺激分子是B7-2和B7-3。 本发明的肿瘤细胞可以通过用编码B7-2和/或B7-3的核酸转染，通过使用诱导或增加肿瘤细胞上B7-2和/或B7-3表达的试剂或通过 将B7-2和/或B7-3偶联到肿瘤细胞。 修饰以表达B7-2和/或B7-3的肿瘤细胞可进一步修饰以表达B7。 还公开了进一步修饰以表达MHC I类和/或II类分子或其中抑制MHC相关蛋白（不变链）的表达的肿瘤细胞。 本发明的修饰的肿瘤细胞可用于治疗患有肿瘤的患者，预防或抑制肿瘤的转移性扩散或预防或抑制肿瘤复发的方法。 公开了特异性诱导针对肿瘤的CD4 + T细胞应答的方法和通过体内修饰肿瘤细胞治疗肿瘤的方法。

    Fusion proteins of novel CTLA4/CD28 ligands and uses therefore
    7.
    发明授权
    Fusion proteins of novel CTLA4/CD28 ligands and uses therefore 失效
    新型CTLA4 / CD28配体的融合蛋白及其用途

    公开(公告)号：US06130316A

    公开(公告)日：2000-10-10

    申请号：US280757

    申请日：1994-07-26

    申请人： Gordon J. Freeman ,  Lee M. Nadler ,  Gary S. Gray ,  Edward Greenfield

    发明人： Gordon J. Freeman ,  Lee M. Nadler ,  Gary S. Gray ,  Edward Greenfield

    IPC分类号： A61K38/00 ,  C07K14/705 ,  C07K16/28 ,  C12N15/85 ,  C07K19/00 ,  C07H21/00

    CPC分类号： C07K16/2827 ,  C07K14/70532 ,  C12N15/8509 ,  A01K2207/15 ,  A01K2217/00 ,  A01K2217/05 ,  A01K2217/075 ,  A01K2267/01 ,  A01K2267/03 ,  A01K2267/0381 ,  A61K38/00 ,  C07K2317/73 ,  C07K2319/00 ,  C07K2319/30

    摘要： Nucleic acids encoding novel CTLA4/CD28 ligands which costimulate T cell activation are disclosed. In one embodiment, the nucleic acid has a sequence which encodes a B lymphocyte antigen, B7-2. Preferably, the nucleic acid is a DNA molecule comprising at least a portion of a nucleotide sequence shown in FIG. 8, SEQ ID NO:1 or FIG. 14, SEQ ID NO:23. The nucleic acid sequences of the invention can be integrated into various expression vectors, which in turn direct the synthesis of the corresponding proteins or peptides in a variety of hosts, particularly eukaryotic cells, such as mammalian and insect cell culture. Also disclosed are host cells transformed to produce proteins or peptides encoded by the nucleic acid sequences of the invention and isolated proteins and peptides which comprise at least a portion of a novel B lymphocyte antigen. Proteins and peptides described herein can be administered to subjects to enhance or suppress T cell-mediated immune responses.

    摘要翻译： 公开了编码协同T细胞活化的新型CTLA4 / CD28配体的核酸。 在一个实施方案中，核酸具有编码B淋巴细胞抗原B7-2的序列。 优选地，核酸是包含图1所示的核苷酸序列的至少一部分的DNA分子。 8，SEQ ID NO：1或图3。 14，SEQ ID NO：23。 本发明的核酸序列可以整合到各种表达载体中，这又指导了多种宿主，特别是真核细胞如哺乳动物和昆虫细胞培养物中的相应蛋白质或肽的合成。 还公开了转化以产生由本发明的核酸序列编码的蛋白质或肽的宿主细胞和包含至少一部分新型B淋巴细胞抗原的分离的蛋白质和肽。 本文所述的蛋白质和肽可以施用于受试者以增强或抑制T细胞介导的免疫应答。

    Methods of inhibiting T cell proliferation or IL-2 accumulation with CTLA4- specific antibodies
    8.
    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。

    Tumor cells modified to express B7-2 with increased immunogenicity and uses therefor
    10.
    发明授权
    Tumor cells modified to express B7-2 with increased immunogenicity and uses therefor 失效
    肿瘤细胞修饰以表达B7-2，增加免疫原性，并用于此

    公开(公告)号：US5861310A

    公开(公告)日：1999-01-19

    申请号：US456104

    申请日：1995-05-30

    申请人： Gordon J. Freeman ,  Lee M. Nadler ,  Gary S. Gray

    发明人： Gordon J. Freeman ,  Lee M. Nadler ,  Gary S. Gray

    IPC分类号： A01K67/027 ,  A61K38/00 ,  C07K14/705 ,  C07K16/28 ,  C12N15/85 ,  C12N5/00 ,  C12N5/08 ,  C12N5/10

    CPC分类号： C07K16/2827 ,  A01K67/0271 ,  C07K14/70532 ,  C12N15/8509 ,  A01K2217/05 ,  A01K2267/0331 ,  A01K2267/0381 ,  A61K38/00 ,  C07K2319/30

    摘要： Tumor cells modified to express one or more T cell costimulatory molecules are disclosed. Preferred costimulatory molecules are B7-2 and B7-3. The tumor cells of the invention can be modified by transfection with nucleic acid encoding B7-2 and/or B7-3, by using an agent which induces or increases expression of B7-2 and/or B7-3 on the tumor cell or by coupling B7-2 and/or B7-3 to the tumor cell. Tumor cells modified to express B7-2 and/or B7-3 can be further modified to express B7. Tumor cells further modified to express MHC class I and/or class II molecules or in which expression of an MHC associated protein, the invariant chain, is inhibited are also disclosed. The modified tumor cells of the invention can be used in methods for treating a patient with a tumor, preventing or inhibiting metastatic spread of a tumor or preventing or inhibiting recurrence of a tumor. A method for specifically inducing a CD4.sup.+ T cell response against a tumor and a method for treating a tumor by modification of tumor cells in vivo are disclosed.

    摘要翻译： 公开了修饰以表达一种或多种T细胞共刺激分子的肿瘤细胞。 优选的共刺激分子是B7-2和B7-3。 本发明的肿瘤细胞可以通过用编码B7-2和/或B7-3的核酸转染，通过使用诱导或增加肿瘤细胞上B7-2和/或B7-3表达的试剂或通过 将B7-2和/或B7-3偶联到肿瘤细胞。 修饰以表达B7-2和/或B7-3的肿瘤细胞可进一步修饰以表达B7。 还公开了进一步修饰以表达MHC I类和/或II类分子或其中抑制MHC相关蛋白（不变链）的表达的肿瘤细胞。 本发明的修饰的肿瘤细胞可用于治疗患有肿瘤的患者，预防或抑制肿瘤的转移性扩散或预防或抑制肿瘤复发的方法。 公开了特异性诱导针对肿瘤的CD4 + T细胞应答的方法和通过体内修饰肿瘤细胞治疗肿瘤的方法。