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1. 发明申请

WO1995033823A1 METHODS FOR SELECTIVELY STIMULATING PROLIFERATION OF T CELLS 审中-公开
标题翻译：选择性刺激T细胞增殖的方法
公开(公告)号：WO1995033823A1
公开(公告)日：1995-12-14
申请号：PCT/US1994013782
申请日：1994-12-01
申请人： THE UNITED STATES OF AMERICA, represented by THE SECRETARY OF THE NAVY , THE REGENTS OF THE UNIVERSITY OF MICHIGAN , REPLIGEN CORPORATION , DANA-FARBER CANCER INSTITUTE
发明人： THE UNITED STATES OF AMERICA, represented by THE SECRETARY OF THE NAVY , THE REGENTS OF THE UNIVERSITY OF MICHIGAN , REPLIGEN CORPORATION , DANA-FARBER CANCER INSTITUTE , JUNE, Carl, H. , THOMPSON, Craig, B. , NABEL, Gary, J. , GRAY, Gary, S. , RENNERT, Paul, D. , FREEMAN, Gordon, J.
IPC分类号： C12N05/08
CPC分类号： C07K16/2818 , A61K2039/5158 , C07K14/705 , C07K16/2806 , C07K16/2809 , C07K16/2896 , C07K2317/34 , C12N5/0636 , C12N2501/51 , C12N2501/515 , C12N2501/599
摘要： Methods for inducing a population of T cells to proliferate by activating the population of T cells and stimulating an accessory molecule on the surface of the T cells with a ligand which binds the accessory molecule are described. T cell proliferation occurs in the absence of exogenous growth factors or accessory cells. T cell activation is accomplished by stimulating the T cell receptor (TCR)/CD3 complex or the CD2 surface protein. To induce proliferation of an activated population of T cells, an accessory molecule on the surface of the T cells, such as CD9 or CD28, is stimulated with a ligand (e.g. monoclonal antibody ES5.2D8) specific for CD9 which binds the accessory molecule. The T cell population expanded by the method of the invention can be genetically transduced and used for immunotherapy or can be used in methods of diagnosis.
摘要翻译：描述了通过激活T细胞群并用结合附属分子的配体刺激T细胞表面上的辅助分子来诱导T细胞群体增殖的方法。 T细胞增殖发生在没有外源生长因子或附属细胞的情况下。通过刺激T细胞受体（TCR）/ CD3复合物或CD2表面蛋白来完成T细胞活化。为了诱导T细胞活化群体的增殖，T细胞表面如CD9或CD28上的辅助分子被用于结合辅助分子的CD9特异性配体（例如单克隆抗体ES5.2D8）刺激。通过本发明方法扩增的T细胞群体可以被遗传转导并用于免疫治疗，或可用于诊断方法。

2. 发明申请

WO1994029436A1 METHODS FOR SELECTIVELY STIMULATING PROLIFERATION OF T CELLS 审中-公开
标题翻译：选择性刺激T细胞增殖的方法
公开(公告)号：WO1994029436A1
公开(公告)日：1994-12-22
申请号：PCT/US1994006255
申请日：1994-06-03
申请人： THE UNITED STATES OF AMERICA represented by THE SECRETARY OF THE NAVY , THE REGENTS OF THE UNIVERSITY OF MICHIGAN , REPLIGEN CORPORATION
发明人： THE UNITED STATES OF AMERICA represented by THE SECRETARY OF THE NAVY , THE REGENTS OF THE UNIVERSITY OF MICHIGAN , REPLIGEN CORPORATION , JUNE, Carl, H. , THOMPSON, Craig, B. , NABEL, Gary, J. , GRAY, Gary, S. , RENNERT, Paul, D.
IPC分类号： C12N05/08
CPC分类号： C12N5/0636 , A61K35/17 , A61K38/00 , A61K48/00 , C07K14/70532 , C07K16/2809 , C07K16/2818 , C07K16/2896 , C07K2317/34 , C07K2317/74 , C12N2501/51 , C12N2501/515 , C12N2501/599
摘要： Methods for inducing a population of T cells to proliferate by activating the population of T cells and stimulating an accessory molecule on the surface of the T cells with a ligand which binds the accessory molecule are described. T cell proliferation occurs in the absence of exogenous growth factors or accessory cells. T cell activation is accomplished by stimulating the T cell receptor (TCR)/CD3 complex or the CD2 surface protein. To induce proliferation of an activated population T cells, an accessory molecule on the surface of the T cells, such as CD28, is stimulated with a ligand which binds the accessory molecule. The T cell population expanded by the method of the invention can be genetically transduced and used for immunotherapy or can be used in methods of diagnosis.
摘要翻译：描述了通过激活T细胞群并用结合附属分子的配体刺激T细胞表面上的辅助分子来诱导T细胞群体增殖的方法。 T细胞增殖发生在没有外源生长因子或附属细胞的情况下。通过刺激T细胞受体（TCR）/ CD3复合物或CD2表面蛋白来完成T细胞活化。为了诱导活化的群体T细胞的增殖，T细胞表面上的辅助分子如CD28被与配合分子结合的配体刺激。通过本发明方法扩增的T细胞群体可以被遗传转导并用于免疫治疗，或可用于诊断方法。

3. 发明申请

WO1995003408A1 B7-2: CTL A4/CD 28 COUNTER RECEPTOR 审中-公开
标题翻译： B7-2：CTL A4 / CD 28计数器受体
公开(公告)号：WO1995003408A1
公开(公告)日：1995-02-02
申请号：PCT/US1994008423
申请日：1994-07-26
申请人： DANA-FARBER CANCER INSTITUTE , REPLIGEN CORPORATION
发明人： DANA-FARBER CANCER INSTITUTE , REPLIGEN CORPORATION , FREEMAN, Gordon, J. , NADLER, Lee, M. , GRAY, Gary, S. , GREENFIELD, Edward
IPC分类号： C12N15/12
CPC分类号： C12N15/8509 , A01K2207/15 , A01K2217/00 , A01K2217/05 , A01K2217/075 , A01K2227/105 , A01K2267/03 , A01K2267/0331 , A01K2267/0381 , A61K38/00 , C07K14/70532 , C07K16/2827 , 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 Figure 8, SEQ ID NO: 1 or Figure 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8，SEQ ID NO：1或图14，SEQ ID NO：23所示核苷酸序列的至少一部分的DNA分子。本发明的核酸序列可以整合到各种表达载体，其又指导多种宿主，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。

4. 发明申请

WO1996040915A2 NOVEL CTLA4/CD28 LIGANDS AND USES THEREFOR 审中-公开
标题翻译：新CTLA4 / CD28配对及其用途
公开(公告)号：WO1996040915A2
公开(公告)日：1996-12-19
申请号：PCT/US1996009052
申请日：1996-06-06
申请人： DANA-FARBER CANCER INSTITUTE , REPLIGEN CORPORATION
发明人： DANA-FARBER CANCER INSTITUTE , REPLIGEN CORPORATION , FREEMAN, Gordon, J. , NADLER, Lee, M. , GRAY, Gary, S.
IPC分类号： C12N15/12
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 fusion protein consisting of at least part of the B lymphocyte antigen, B7-2, fused to one or more constant domains of immunoglobulin heavy chain. Preferably, the nucleic acid is a DNA molecule comprising at least a portion of a nucleotide sequence shown in Figure 8, SEQ ID NO:1 or Figure 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，所述核酸具有编码由与免疫球蛋白重链的一个或多个恒定结构域融合的至少部分B淋巴细胞抗原B7-2组成的融合蛋白的序列。优选地，核酸是包含图8所示核苷酸序列的至少一部分的DNA分子，SEQ ID NO：1或图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。

5. 发明申请

WO1995033770A1 LIGANDS FOR INDUCTION OF ANTIGEN SPECIFIC APOPTOSIS IN T CELLS 审中-公开
标题翻译：用于诱导T细胞中抗原特异性宿主的配体
公开(公告)号：WO1995033770A1
公开(公告)日：1995-12-14
申请号：PCT/US1995006726
申请日：1995-06-02
申请人： REPLIGEN CORPORATION , DANA FARBER CANCER INSTITUTE
发明人： REPLIGEN CORPORATION , DANA FARBER CANCER INSTITUTE , GRIBBEN, John, G. , FREEMAN, Gordon, J. , NADLER, Lee, M. , RENNERT, Paul , JELLIS, Cindy, L. , GREENFIELD, Edward , GRAY, Gary, S.
IPC分类号： C07K14/705
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。

6. 发明申请

WO1996014865A1 METHODS FOR INHIBITING GRAFT VERSUS HOST DISEASE IN BONE MARROW TRANSPLANTATION 审中-公开
标题翻译：在骨髓移植中抑制维生素HOST疾病的方法
公开(公告)号：WO1996014865A1
公开(公告)日：1996-05-23
申请号：PCT/US1995014774
申请日：1995-11-09
申请人： REPLIGEN CORPORATION , DANA-FARBER CANCER INSTITUTE
发明人： REPLIGEN CORPORATION , DANA-FARBER CANCER INSTITUTE , GRIBBEN, John, G. , NADLER, Lee, M. , GRAY, Gary, S.
IPC分类号： A61K39/00
CPC分类号： C07K16/2827 , A61K38/1774
摘要： Methods for inhibiting antigen-specific T cell responses in vitro by use of an agent which inhibits a costimulatory signal in T cells, such as a CTLA4Ig fusion protein or an anti-B7-1 antibody or an anti-B7-2 are disclosed. The methods of the invention are particularly useful for inhibiting graft versus host disease which results from allogeneic bone marrow transplantation.
摘要翻译：公开了通过使用抑制T细胞如CTLA4Ig融合蛋白或抗B7-1抗体或抗B7-2的共刺激信号的试剂在体外抑制抗原特异性T细胞应答的方法。本发明的方法对于抑制由同种异体骨髓移植引起的移植物抗宿主病特别有用。

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