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1. 发明授权

US07432059B2 Methods of identifying compounds that upmodulate T cell activation in the presence of a PD-1 mediated signal 有权
标题翻译：识别在PD-1介导的信号存在下上调T细胞活化的化合物的方法
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。

2. 发明申请

US20070202100A1 PD-1, a receptor for B7-4, and uses therefor 有权
标题翻译： PD-1，B7-4的受体，并用于此
公开(公告)号：US20070202100A1
公开(公告)日：2007-08-30
申请号：US11514328
申请日：2006-08-31
申请人： Clive Wood , Gordon Freeman
发明人： Clive Wood , Gordon Freeman
IPC分类号： A61K39/395 , A61K39/00 , G01N33/53
CPC分类号： C07K14/70532 , A61K38/00 , A61K39/00 , A61K39/395 , A61K45/06 , A61K2039/55516 , C07K14/70503 , C07K16/2803 , C07K16/2827 , C07K2317/21 , C07K2317/622 , C07K2317/73 , C07K2317/74 , C07K2317/76 , C07K2319/00 , C07K2319/30 , G01N2333/70503 , G01N2500/04 , A61K2300/00
摘要： The invention identifies PD-1 as a receptor for B7-4. B7-4 can inhibit immune cell activation upon binding to an inhibitory receptor on an immune cell. Accordingly, the invention provides agents for modulating PD-1, B7-4, and the interaction between B7-4 and PD-1 in order to modulate a costimulatory or an inhibitory signal in a immune cell resulting in modulation of the immune response.
摘要翻译：本发明将PD-1鉴定为B7-4的受体。 B7-4可以在结合免疫细胞上的抑制性受体时抑制免疫细胞活化。因此，本发明提供用于调节PD-1，B7-4以及B7-4和PD-1之间的相互作用的试剂，以调节免疫细胞中的共刺激或抑制性信号，从而导致免疫应答的调节。

3. 发明授权

US09598491B2 Methods for the treatment of infections and tumors 有权
公开(公告)号：US09598491B2
公开(公告)日：2017-03-21
申请号：US12626848
申请日：2009-11-27
申请人： Rafi Ahmed , Rama Amara , Vijayakumar Velu , Kehmia Titanji , Gordon Freeman
发明人： Rafi Ahmed , Rama Amara , Vijayakumar Velu , Kehmia Titanji , Gordon Freeman
IPC分类号： C12Q1/02 , C07K16/28 , A61K31/7105 , A61K39/39 , A61K39/395 , G01N33/50 , G01N33/569 , A61K39/00
CPC分类号： G01N33/5052 , A61K31/7105 , A61K39/0011 , A61K39/12 , A61K39/39 , A61K39/39541 , A61K2039/505 , A61K2039/507 , A61K2039/55516 , C07K16/2803 , C07K16/2818 , C07K16/2827 , C07K2317/24 , C07K2317/74 , C07K2317/76 , C12N15/1138 , C12N2310/14 , C12N2760/10034 , G01N33/5088 , G01N33/56966 , G01N2333/52 , G01N2800/26 , Y02A50/41 , A61K2300/00
摘要： PD-1 antagonists are disclosed that can be used to reduce the expression or activity of PD-1 in a subject. An immune response specific to an infectious agent or to tumor cells can be enhanced using these PD-1 antagonists in conjunction with an antigen from the infectious agent or tumor. Thus, subjects with infections, such as persistent infections can be treated using PD-1 antagonists. In addition, subjects with tumors can be treated using the PD-1 antagonists. In several examples, subjects can be treated by transplanting a therapeutically effective amount of activated T cells that recognize an antigen of interest and by administering a therapeutically effective amount of a PD-1 antagonist. Methods are also disclosed for determining the efficacy of a PD-1 antagonist in a subject administered the PD-1 antagonist. In some embodiments, these methods include measuring proliferation of memory B cells in a sample from a subject administered the PD-1 antagonist.

4. 发明申请

US20050129670A1 Tumor cells modified to express B7-2 with increased immunogenicity and uses therefor 审中-公开
标题翻译：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：US20050129670A1
公开(公告)日：2005-06-16
申请号：US10767561
申请日：2004-01-28
申请人： Gordon Freeman , Lee Nadler , Gary Gray
发明人： Gordon Freeman , Lee Nadler , Gary Gray
IPC分类号： A01K67/027 , A61K38/00 , C07K14/705 , C07K16/28 , C12N15/85 , A61K48/00
CPC分类号： C12N15/8509 , A01K67/0271 , A01K2217/05 , A01K2227/105 , A01K2267/03 , A61K38/00 , C07K14/70532 , C07K16/2827 , C07K2319/00 , 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+ 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。

5. 发明授权

US5238839A Nucleic Acids Encoding proteins which induce immunological effector cell activation and chemattraction, vectors, and recombinant cells 失效
标题翻译：核酸编码诱导免疫效应细胞活化和化学吸收，载体和重组细胞的蛋白质
公开(公告)号：US5238839A
公开(公告)日：1993-08-24
申请号：US732185
申请日：1991-07-18
申请人： Harvey I. Cantor , Roberto Patarca , Joel L. Schwartz , Gordon Freeman
发明人： Harvey I. Cantor , Roberto Patarca , Joel L. Schwartz , Gordon Freeman
IPC分类号： A61K38/00 , C07K14/52 , C07K16/24
CPC分类号： C07K16/24 , C07K14/52 , A61K38/00 , C07K2317/77
摘要： The present invention relates to genes and their encoded proteins which induce immunological effector cell activation and chemattraction. The proteins of the invention attract subsets of immunological effector cells and stimulate them to express their specialized effector cell functions. Such proteins, termed Ap-1 proteins, are expressed by lymphoid cells, and bind to effector cells such as macrophages and mast cells. In particular, the ApPursuant to the provisions of 35 U.S.C. .sctn.202(c), it is hereby acknoledged that the Governament has certain rights in this invention, which was made in part with funds from the National Institutes of Health.
摘要翻译：本发明涉及诱导免疫效应细胞活化和化学诱导的基因及其编码的蛋白质。本发明的蛋白质吸引免疫效应细胞的子集并刺激它们表达其特异的效应细胞功能。称为Ap-1蛋白的蛋白质由淋巴细胞表达，并结合效应细胞如巨噬细胞和肥大细胞。特别地，Ap-1蛋白诱导巨噬细胞吞噬作用，II类主要组织相容性分子的表达，细胞毒性和迁移，并诱导造血祖细胞分化。 Ap-1分子在炎症或免疫疾病或肿瘤的治疗或诊断中可能是有价值的。

6. 发明授权

US08652465B2 Methods and compositions for the treatment of persistent infections 有权
标题翻译：用于治疗持续感染的方法和组合物
公开(公告)号：US08652465B2
公开(公告)日：2014-02-18
申请号：US11449919
申请日：2006-06-08
申请人： Gordon Freeman , Arlene Sharpe , David M. Dorfman , Rafi Ahmed , Daniel Barber , E. John Wherry
发明人： Gordon Freeman , Arlene Sharpe , David M. Dorfman , Rafi Ahmed , Daniel Barber , E. John Wherry
IPC分类号： A61K39/395 , C07K16/00
CPC分类号： C07K16/2803 , A61K31/713 , A61K38/1709 , A61K39/39 , A61K39/3955 , A61K39/39558 , A61K45/06 , A61K2039/505 , A61K2039/507 , A61K2039/55516 , A61K2039/55566 , A61K2039/572 , C07K16/2818 , C07K16/2827 , C07K2317/70 , C07K2317/73 , C07K2317/74 , C07K2317/76 , C12N15/1138 , C12N2310/14 , G01N33/5011 , G01N33/505 , G01N33/57484 , G01N33/57492 , G01N2800/26 , Y02A50/412 , Y02A50/467 , Y02A50/58
摘要： The present invention provides methods and compositions for the treatment, prevention, or reduction of persistent infections, such as chronic infections, latent infections, and slow infections and cancer. The methods and compositions of the invention are also useful for the alleviation of one or more symptoms associated with such infections and cancer.
摘要翻译：本发明提供用于治疗，预防或减少持续感染例如慢性感染，潜伏感染，慢感染和癌症的方法和组合物。本发明的方法和组合物还可用于缓解与这种感染和癌症相关的一种或多种症状。

7. 发明申请

US20100040614A1 COMPOSITIONS AND METHODS FOR THE TREATMENT OF INFECTIONS AND TUMORS 审中-公开
标题翻译：用于治疗感染和肿瘤的组合物和方法
公开(公告)号：US20100040614A1
公开(公告)日：2010-02-18
申请号：US12521302
申请日：2007-12-26
申请人： Rafi Ahmed , Rama Amara , Gordon Freeman , Arlene Sharpe
发明人： Rafi Ahmed , Rama Amara , Gordon Freeman , Arlene Sharpe
IPC分类号： A61K39/395 , A61K39/00 , A61P31/12
CPC分类号： C07K16/2827 , A61K39/12 , A61K39/395 , A61K2039/505 , A61K2039/507 , A61K2039/5158 , A61K2039/5256 , C07K16/2818 , C07K2317/64 , C12N2710/24143 , C12N2740/16011 , C12N2760/10011 , C12N2760/10034 , C12N2770/24211 , A61K2300/00
摘要： PD-1 antagonists are disclosed that can be used to reduce the expression or activity of PD-1 in a subject. An immune response specific to an infectious agent or to tumor cells can be enhanced using these PD-1 antagonists in conjunction with an antigen from the infectious agent or tumor. Thus, subjects with infections, such as persistent infections can be treated using PD-1 antagonists. In addition, subjects with tumors can be treated using the PD-1 antagonists. In several examples, subjects can be treated by transplanting a therapeutically effective amount of activated T cells that recognize an antigen of interest and by administering a therapeutically effective amount of a PD-1 antagonist.
摘要翻译：公开了可用于降低受试者中PD-1的表达或活性的PD-1拮抗剂。使用这些PD-1拮抗剂与来自感染剂或肿瘤的抗原可以增强特异于感染剂或肿瘤细胞的免疫应答。因此，可以使用PD-1拮抗剂治疗感染的受试者，例如持续感染。此外，可以使用PD-1拮抗剂治疗具有肿瘤的受试者。在几个实例中，可以通过移植治疗有效量的识别感兴趣的抗原的活化T细胞并通过施用治疗有效量的PD-1拮抗剂来治疗受试者。

8. 发明申请

US20070031811A1 METHODS OF INDUCING A T CELL MEDIATED IMMUNE RESPONSE BY ADMINISTERING ANTIGEN PRESENTING B CELLS 有权
标题翻译：通过施用抗原呈递B细胞诱导T细胞介导的免疫应答的方法
公开(公告)号：US20070031811A1
公开(公告)日：2007-02-08
申请号：US10186416
申请日：2002-07-01
申请人： Joachim Schultze , Gordon Freeman , John Gribben , Lee Nadler
发明人： Joachim Schultze , Gordon Freeman , John Gribben , Lee Nadler
IPC分类号： A01N1/02 , C12N5/08
CPC分类号： C12N5/0635 , C12N2501/04 , C12N2501/23 , C12N2501/52
摘要： We teach a strategy to obtain large quantities of desired APCs, activated B cells, which are superior in their capacity to present tumor protein antigen in a multiadministration protocol. Human B cells can be obtained from peripheral blood in large numbers. These cells can be activated in vitro by coculture with CD40L (CD40-B cells) and an immunosuppressive agent such as cyclosporin A. They can expanded up to 1×103 to 1×104 fold in 2 weeks or 1×105 to 1×106 fold in 2 months. We demonstrate these cells are most efficient APCs comparable to DCs in stimulating allogeneic CD4+ CD45RA+, CD4+ CD45RO+, and CD8+ T cells. In contrast to DCs, CD40-B cells are fully functional even in the presence of immunosuppressive cytokines such as IL-10 and TGFβ.
摘要翻译：我们教授一种策略，以获得大量所需的APC，活化的B细胞，其在多重给药方案中具有优于其呈递肿瘤蛋白抗原的能力。人B细胞可以从外周血大量获得。这些细胞可以通过与CD40L（CD40-B细胞）和免疫抑制剂如环孢菌素A共培养在体外进行活化。它们可以扩增至1×10 3至1×10 4个/ 在2个月内为1倍或1×10 5至1×10 6倍。我们证明这些细胞是最有效的APC，与刺激同种异体CD4 + CD45RA + +，+ CD4 + CD45RO + >和CD8 + T细胞。与DC相反，即使在免疫抑制性细胞因子如IL-10和TGFbeta的存在下，CD40-B细胞也是完全功能的。

9. 发明授权

US10865233B2 NKG2D-fc for immunotherapy 有权
公开(公告)号：US10865233B2
公开(公告)日：2020-12-15
申请号：US13140469
申请日：2009-12-18
申请人： Glenn Dranoff , Matthew Vanneman , Gordon Freeman
发明人： Glenn Dranoff , Matthew Vanneman , Gordon Freeman
IPC分类号： C07K14/705 , A61K38/17 , A61K45/06
CPC分类号： C07K14/70596 , A61K38/177 , A61K45/06 , C07K14/7056 , C07K2319/30
摘要： Methods for cancer immunotherapy are provided. The methods involve the use of a chimeric molecule (e.g., fusion protein) comprising an NKG2D portion and an Fc portion, which binds one or more NKG2D ligands. The methods disclosed herein are useful for the treatment of cancer that is associated with abnormal expression of one or more NKG2D ligands.

10. 发明授权

US07838220B2 T cell regulatory genes associated with immune disease 有权
标题翻译：与免疫疾病相关的T细胞调节基因
公开(公告)号：US07838220B2
公开(公告)日：2010-11-23
申请号：US10663497
申请日：2003-09-15
申请人： Jennifer Jones McIntire , Rosemarie Dekruyff , Dale T. Umetsu , Gordon Freeman
发明人： Jennifer Jones McIntire , Rosemarie Dekruyff , Dale T. Umetsu , Gordon Freeman
IPC分类号： C12Q1/68 , C12P19/34 , C07H21/04
CPC分类号： C12Q1/6883 , C07K14/70503 , C12Q2600/136 , C12Q2600/156 , C12Q2600/158 , C12Q2600/172
摘要： A genetic locus and corresponding family of proteins associated with regulation of immune development, function, and cell survival are provided. The locus comprising the TIM family is genetically associated with immune dysfunction, including atopy, autoimmunity, inflammatory bowel disease, dysplasia, and susceptibility to blood-bourne infectious diseases. Polymorphisms in the human TIM-1 gene and exposure to Hepatitis A Virus (HAV) are shown to be associated with protection from the development of atopy.
摘要翻译：提供了与调节免疫发育，功能和细胞存活相关的遗传基因座和相应的蛋白质家族。包括TIM家族的基因座在遗传上与免疫功能障碍有关，包括特应性，自身免疫，炎性肠病，发育异常和对血液传染性疾病的易感性。人TIM-1基因的多态性和甲型肝炎病毒（HAV）的暴露显示与保护免受特应性的发展有关。

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