公开(公告)号：US07432059B2

公开(公告)日：2008-10-07

申请号：US09895837

申请日：2001-06-28

申请人： Gordon Freeman ,  Irene Chernova ,  Tatyana Chernova ,  Nelly Malenkovich ,  Clive Wood ,  Yvette Latchman ,  Arlene H. Sharpe

发明人： Gordon Freeman ,  Irene Chernova ,  Tatyana Chernova ,  Nelly Malenkovich ,  Clive Wood ,  Yvette Latchman ,  Arlene H. Sharpe

IPC分类号： G01N33/53

CPC分类号： G01N33/6854 ,  G01N33/5014 ,  G01N33/505 ,  G01N33/5052 ,  G01N33/573 ,  G01N2800/52

摘要： The invention provides isolated nucleic acids molecules, designated PD-L2 nucleic acid molecules, which encode novel B7-related molecules which are ligands for PD-1. The invention also provides antisense nucleic acid molecules, recombinant expression vectors containing PD-L2 nucleic acid molecules, host cells into which the expression vectors have been introduced, and nonhuman transgenic animals in which a PD-L2 gene has been introduced or disrupted. The invention further provides isolated PD-L2 polypeptides, fusion proteins, antigenic peptides and anti-PD-L2 antibodies. The invention still further provides methods for promoting or inhibiting the interaction between PD-L2 and PD-1. The invention further provides methods of identifying compounds that upmodulate T cell activation in the presence of a PD-1-mediated signal. Diagnostic and treatment methods utilizing compositions of the invention are also provided.

摘要翻译： 本发明提供分离的核酸分子，命名为PD-L2核酸分子，其编码作为PD-1配体的新型B7相关分子。 本发明还提供了反义核酸分子，含有PD-L2核酸分子的重组表达载体，其中引入了表达载体的宿主细胞，以及已导入或破坏了PD-L2基因的非人类转基因动物。 本发明进一步提供分离的PD-L2多肽，融合蛋白，抗原肽和抗-PD-L2抗体。 本发明还提供了促进或抑制PD-L2与PD-1之间相互作用的方法。 本发明还提供鉴定在PD-1介导的信号存在下上调T细胞活化的化合物的方法。 还提供了利用本发明组合物的诊断和治疗方法。

公开(公告)号：US07619078B2

公开(公告)日：2009-11-17

申请号：US11589275

申请日：2006-10-26

申请人： Arlene H. Sharpe ,  Francescopaolo Borriello ,  Gordon J. Freeman ,  Lee M. Nadler

发明人： Arlene H. Sharpe ,  Francescopaolo Borriello ,  Gordon J. Freeman ,  Lee M. Nadler

IPC分类号： C12N15/12 ,  C12N15/11 ,  C07K14/705

CPC分类号： C07K14/70532 ,  A01K2217/05

摘要： Novel structural forms of T cell costimulatory molecules are described. These structural forms comprise a novel structural domain or have a structural domain deleted or added. The structural forms correspond to naturally-occurring alternatively spliced forms of T cell costimulatory molecules or variants thereof which can be produced by standard recombinant DNA techniques. In one embodiment, the T cell costimulatory molecule of the invention contains a novel cytoplasmic domain. In another embodiment, the T cell costimulatory molecule of the invention contains a novel signal peptide domain or has an immunoglobulin variable region-like domain deleted. The novel structural forms of T cell costimulatory molecules can be used to identify agents which stimulate the expression of alternative forms of costimulatory molecules and to identify components of the signal transduction pathway which results in costimulation of T cells.

摘要翻译： 描述了T细胞共刺激分子的新型结构形式。 这些结构形式包括一个新的结构域或者具有缺失或添加的结构域。 结构形式对应于可以通过标准重组DNA技术产生的天然存在的可变剪接形式的T细胞共刺激分子或其变体。 在一个实施方案中，本发明的T细胞共刺激分子含有新的细胞质结构域。 在另一个实施方案中，本发明的T细胞共刺激分子含有新的信号肽结构域或具有免疫球蛋白可变区域结构域缺失。 T细胞共刺激分子的新型结构形式可用于鉴定刺激替代形式的共刺激分子表达的试剂，并鉴定导致T细胞共刺激的信号转导通路的成分。

公开(公告)号：US07722868B2

公开(公告)日：2010-05-25

申请号：US11501392

申请日：2006-08-09

申请人： Gordon J. Freeman ,  Arlene H. Sharpe ,  Janet Buhlman ,  Didier Mandelbrot

发明人： Gordon J. Freeman ,  Arlene H. Sharpe ,  Janet Buhlman ,  Didier Mandelbrot

IPC分类号： A61K39/395

CPC分类号： G01N33/6854 ,  A61K38/1709 ,  G01N33/505 ,  G01N33/6872 ,  G01N2333/70532 ,  G01N2500/02

摘要： Disclosed are methods for modulating an immune response including a method for inhibiting the interaction between a B7 polypeptide and a PD-1 ligand, the method comprising contacting an immune cell bearing a PD-1 ligand, or an immune cell bearing a B7 polypeptide, with an agent that inhibits the interaction between the PD-1 ligand and the B7 polypeptide. Such agents may be an anti-PD-1 ligand antibody or a small molecule. Also disclosed is a method for modulating an immune response comprising contacting an immune cell bearing the PD-1 ligand, or an immune cell bearing the PD-1 polypeptide, with an agent that inhibits interactions between the PD-1 ligand and the PD-1 polypeptide, without inhibiting interactions between the PD-1 ligand and a B7 polypeptide, to thereby modulate an immune response. The agent may be an anti-PD-1 ligand antibody or a small molecule.

摘要翻译： 公开了用于调节免疫应答的方法，包括抑制B7多肽和PD-1配体之间的相互作用的方法，所述方法包括使带有PD-1配体或带有B7多肽的免疫细胞的免疫细胞与 抑制PD-1配体和B7多肽之间的相互作用的试剂。 这样的试剂可以是抗PD-1配体抗体或小分子。 还公开了一种用于调节免疫应答的方法，包括将携带PD-1配体或携带PD-1多肽的免疫细胞的免疫细胞与抑制PD-1配体和PD-1之间的相互作用的试剂接触 多肽，而不抑制PD-1配体和B7多肽之间的相互作用，从而调节免疫应答。 该试剂可以是抗PD-1配体抗体或小分子。

公开(公告)号：US06608180B2

公开(公告)日：2003-08-19

申请号：US09837867

申请日：2001-04-17

申请人： Arlene H. Sharpe ,  Francescopaolo Borriello ,  Gordon J. Freeman ,  Lee M. Nadler

发明人： Arlene H. Sharpe ,  Francescopaolo Borriello ,  Gordon J. Freeman ,  Lee M. Nadler

IPC分类号： C07K1628

CPC分类号： C07K14/70532 ,  A01K2217/05

摘要： Novel structural forms of T cell costimulatory molecules are described. These structural forms comprise a novel structural domain or have a structural domain deleted or added. The structural forms correspond to naturally-occurring alternatively spliced forms of T cell costimulatory molecules or variants thereof which can be produced by standard recombinant DNA techniques. In one embodiment, the T cell costimulatory molecule of the invention contains a novel cytoplasmic domain. In another embodiment, the T cell costimulatory molecule of the invention contains a novel signal peptide domain or has an immunoglobulin variable region-like domain deleted. The novel structural forms of T cell costimulatory molecules can be used to identify agents which stimulate the expression of alternative forms of costimulatory molecules and to identify components of the signal transduction pathway which results in costimulation of T cells.

摘要翻译： 描述了T细胞共刺激分子的新型结构形式。 这些结构形式包括一个新的结构域或者具有缺失或添加的结构域。 结构形式对应于可以通过标准重组DNA技术产生的天然存在的可变剪接形式的T细胞共刺激分子或其变体。 在一个实施方案中，本发明的T细胞共刺激分子含有新的细胞质结构域。 在另一个实施方案中，本发明的T细胞共刺激分子含有新的信号肽结构域或具有免疫球蛋白可变区域结构域缺失。 T细胞共刺激分子的新型结构形式可用于鉴定刺激替代形式的共刺激分子表达的试剂，并鉴定导致T细胞共刺激的信号转导通路的成分。

公开(公告)号：US06218510B1

公开(公告)日：2001-04-17

申请号：US08205697

申请日：1994-03-02

申请人： Arlene H. Sharpe ,  Francescopaolo Borriello ,  Gordon J. Freeman ,  Lee M. Nadler

发明人： Arlene H. Sharpe ,  Francescopaolo Borriello ,  Gordon J. Freeman ,  Lee M. Nadler

IPC分类号： C07K1447

CPC分类号： C07K14/70532 ,  A01K2217/05

摘要： Structural forms of T cell costimulatory B7-1 and B7-2 molecules are described. These structural forms comprise a structural domain or have a structural domain deleted or added. The structural forms correspond to naturally-occurring alternatively spliced forms of T cell costimulatory molecules or variants thereof which can be produced by standard recombinant DNA techniques. In one embodiment, the T cell costimulatory molecule of the invention contains a cytoplasmic domain. In another embodiment, the T cell costimulatory molecule of the invention contains a signal peptide domain or has an immunoglobulin variable region-like domain deleted. The structural forms of T cell costimulatory molecules can be used to identify agents which stimulate the expression of alternative forms of costimulatory molecules and to identify components of the signal transduction pathway which results in costimulation of T cells.

摘要翻译： 描述了T细胞共刺激B7-1和B7-2分子的结构形式。 这些结构形式包括结构域或缺失或添加结构域。 结构形式对应于可以通过标准重组DNA技术产生的天然存在的可变剪接形式的T细胞共刺激分子或其变体。 在一个实施方案中，本发明的T细胞共刺激分子含有细胞质结构域。 在另一个实施方案中，本发明的T细胞共刺激分子含有信号肽结构域或具有免疫球蛋白可变区域结构域缺失。 T细胞共刺激分子的结构形式可用于鉴定刺激替代形式的共刺激分子表达的试剂，并鉴定导致T细胞共刺激的信号转导通路的成分。

公开(公告)号：US07153934B2

公开(公告)日：2006-12-26

申请号：US09962969

申请日：2001-09-24

申请人： Arlene H. Sharpe ,  Francescopaolo Borriello ,  Gordon J. Freeman ,  Lee M. Nadler

发明人： Arlene H. Sharpe ,  Francescopaolo Borriello ,  Gordon J. Freeman ,  Lee M. Nadler

IPC分类号： C07K14/435 ,  C07K14/705

CPC分类号： C07K14/70532 ,  A01K2217/05

摘要： Structural forms of T cell costimulatory polypeptides are described. These forms comprise an alternative structural domain (i.e., a structural domain having an amino acid sequence which differs from a known amino acid sequence) or have a structural domain deleted or added. The structural forms correspond to naturally-occurring alternatively spliced forms of T cell costimulatory polypeptides or variants thereof which can be produced by standard recombinant DNA techniques. In one embodiment, the T cell costimulatory polypeptide of the invention contains an alternative cytoplasmic domain. In another embodiment, the T cell costimulatory polypeptide of the invention contains an alternative signal peptide domain or has an immunoglobulin variable region-like domain deleted. The alternative structural forms of T cell costimulatory polypeptides can be used to identify agents which stimulate the expression of alternative forms of costimulatory polypeptides and to identify components of the signal transduction pathway which results in costimulation of T cells.

摘要翻译： 描述了T细胞共刺激多肽的结构形式。 这些形式包括可选择的结构域（即，具有不同于已知氨基酸序列的氨基酸序列的结构域）或具有缺失或添加的结构域。 结构形式对应于可以通过标准重组DNA技术产生的天然存在的可变剪接形式的T细胞共刺激多肽或其变体。 在一个实施方案中，本发明的T细胞共刺激多肽含有替代细胞质结构域。 在另一个实施方案中，本发明的T细胞共刺激多肽含有替代的信号肽结构域或具有免疫球蛋白可变区域结构域缺失。 T细胞共刺激多肽的替代结构形式可用于鉴定刺激替代形式的共刺激多肽的表达并鉴定导致T细胞共刺激的信号转导途径的组分的试剂。

公开(公告)号：US20170215392A1

公开(公告)日：2017-08-03

申请号：US15314251

申请日：2015-05-27

申请人： William N. HAINING ,  Arlene H. SHARPE ,  Jernej GODEC ,  Dana-Farber Cancer Institute, Inc. ,  President and Fellows of Harvard College

发明人： William N. Haining ,  Arlene H. Sharpe ,  Jernej Godec

IPC分类号： A01K67/027 ,  G01N33/50 ,  A61K49/00 ,  C12N5/0783 ,  C12N5/0781 ,  C12N15/86 ,  C12N15/11

CPC分类号： A01K67/0271 ,  A01K2207/12 ,  A01K2227/105 ,  A01K2267/025 ,  A61K35/28 ,  A61K49/0008 ,  C12N5/0635 ,  C12N5/0636 ,  C12N15/11 ,  C12N15/86 ,  C12N2310/11 ,  C12N2310/14 ,  C12N2310/141 ,  C12N2310/531 ,  C12N2740/15041 ,  C12N2740/15043 ,  C12N2840/002 ,  G01N33/505 ,  G01N33/5052 ,  G01N33/5088

摘要： The invention provides methods and compositions for perturbing gene expression in hematopoietic cell lineages in vivo.

公开(公告)号：US20130022629A1

公开(公告)日：2013-01-24

申请号：US13519621

申请日：2011-01-03

申请人： Arlene H. Sharpe ,  Manish J. Butte ,  Shinji Oyama

发明人： Arlene H. Sharpe ,  Manish J. Butte ,  Shinji Oyama

IPC分类号： A61K31/505 ,  A61K31/4439 ,  A61K31/44 ,  A61K31/433 ,  C07D239/42 ,  A61P41/00 ,  C07D211/98 ,  C07D285/135 ,  A61P31/00 ,  A61P35/00 ,  A61P37/02 ,  A61K39/00 ,  C07D417/12

CPC分类号： C07D239/42 ,  C07D213/76

摘要： Disclosed are an assay to identify modulators of the PD-1:PD-L pathway and PD-1:PD-L pathway modulators, e.g., compounds and pharmaceutical compositions thereof. Methods for treating diseases influenced by modulation of the PD-1:PD-L pathway such as, for example, autoimmune diseases, inflammatory disorders, allergies, transplant rejection, cancer, immune deficiency, and other immune system-related disorders, are also disclosed.

摘要翻译： 公开了用于鉴定PD-1：PD-L途径和PD-1：PD-L途径调节剂（例如其化合物及其药物组合物）的调节剂的测定法。 还公开了用于治疗受PD-1：PD-L途径调节影响的疾病的方法，例如自身免疫疾病，炎症性疾病，过敏反应，移植排斥反应，癌症，免疫缺陷和其他免疫系统相关疾病 。

公开(公告)号：US06294660B1

公开(公告)日：2001-09-25

申请号：US08702525

申请日：1997-02-07

申请人： Arlene H. Sharpe ,  Francescopaolo Borriello ,  Gordon J. Freeman ,  Lee M. Nadler

发明人： Arlene H. Sharpe ,  Francescopaolo Borriello ,  Gordon J. Freeman ,  Lee M. Nadler

IPC分类号： C12N1512

CPC分类号： C07K14/70532 ,  A01K2217/05

摘要： Nucleic acids encoding B7-1 and B7-2 molecules which bind CD28 or CTLA4 are described. These structural forms correspond to naturally-occurring alternatively spliced forms comprising cytoplasmic and signal peptide domains of T cell costimulatory molecules or variants thereof which can be produced by standard recombinant DNA techniques. These T cell costimulatory molecules can be used to identify agents which stimulate the express of alternative forms of costimulatory molecules and to identify components of the signal transduction pathway which results in costimulation of T cells.

摘要翻译： 描述编码结合CD28或CTLA4的B7-1和B7-2分子的核酸。 这些结构形式对应于可以通过标准重组DNA技术产生的包含T细胞共刺激分子或其变体的细胞质和信号肽结构域的天然存在的可变剪接形式。 这些T细胞共刺激分子可以用于鉴定刺激替代形式的共刺激分子的表达的试剂，并鉴定导致T细胞共刺激的信号转导通路的成分。