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1. 发明申请

WO2018031419A1 COMPOSITIONS AND METHODS FOR ENHANCING IMMUNOGENIC CROSS-PRESENTATION OF TUMOR ANTIGENS 审中-公开
标题翻译：增强免疫原性交叉呈递肿瘤抗原的组合物和方法
公开(公告)号：WO2018031419A1
公开(公告)日：2018-02-15
申请号：PCT/US2017/045577
申请日：2017-08-04
申请人： THE BOARD OF TRUSTEES OF THE LELAND STANFORD JUNIOR UNIVERSITY
发明人： COREY, Daniel Mark , RING, Aaron Michael , MCCRACKEN, Melissa N. , WEISSMAN, Irving L.
IPC分类号： C07K14/00 , C07K14/005 , C07K14/435 , C07K14/62
CPC分类号： C07K14/47 , A61K35/17 , A61K38/1709 , A61K45/06 , C07K14/00 , C07K14/435 , C07K14/62 , C07K2319/30 , C12N15/86 , C12N2740/13043
摘要： Cell loss by apoptosis is a common feature in certain conditions, including cancer. Dying tumor cells induce immune tolerance within the tumor microenvironment largely through highly conserved homeostatic clearance programs that are designed to restore tissue homeostasis and contribute to the formation of an immunosuppressive niche. The translocation of phosphatidylserine (PS) on cellular membranes, during the initial phases of apoptosis, functions as a recognition and removal signal that limits the immunogenicity of cell death. To remove inhibitory signals in the homeostatic clearance pathway a fusion protein comprising a phosphatidylserine binding domain and an immunostimulatory domain can restore immune responses to dead tumor cells in antigen cross presentation assays and promotes recruitment and retention of tumor antigen specific immune effector cells into tumors. These effects combine to elicit anti-tumor immunity, improve responses to immune checkpoint inhibitors, and enhance the effectiveness of adoptive T cell transfers using engineered T cells.
摘要翻译：细胞凋亡引起的细胞损失是包括癌症在内的某些疾病的共同特征。死亡的肿瘤细胞主要通过高度保守的体内平衡清除程序在肿瘤微环境内诱导免疫耐受，所述清除程序旨在恢复组织稳态并有助于形成免疫抑制性生态位。细胞膜上的磷脂酰丝氨酸（PS）在细胞凋亡的初始阶段易位起到识别和去除信号的作用，该信号限制细胞死亡的免疫原性。为了去除稳态清除途径中的抑制信号，包含磷脂酰丝氨酸结合结构域和免疫刺激结构域的融合蛋白可以在抗原交叉呈递试验中恢复对死亡肿瘤细胞的免疫应答，并且促进肿瘤抗原特异性免疫效应细胞向肿瘤中的募集和保留。这些效应结合起来引发抗肿瘤免疫，改善对免疫检查点抑制剂的反应，并增强使用工程化T细胞的过继性T细胞转移的有效性。

2. 发明申请

WO2016022994A2 HIGH AFFINITY PD-1 AGENTS AND METHODS OF USE 审中-公开
标题翻译：高亲和力PD-1剂和使用方法
公开(公告)号：WO2016022994A2
公开(公告)日：2016-02-11
申请号：PCT/US2015/044356
申请日：2015-08-07
申请人： THE BOARD OF TRUSTEES OF THE LELAND STANFORD JUNIOR UNIVERSITY
发明人： RING, Aaron Michael , KRUSE, Andrew , MANGLIK, Aashish , WEISSMAN, Irving L. , MAUTE, Roy Louis , MCCRACKEN, Melissa N. , GORDON, Sydney
IPC分类号： C07K14/705 , A61K51/08
CPC分类号： C07K14/70503 , A61K35/17 , A61K38/00 , A61K45/06 , A61K48/00 , A61K51/08 , A61K51/088 , A61K51/10 , C07K14/4747 , C07K14/7051 , C07K14/70532 , C07K2319/30
摘要： High affinity PD-1 mimic polypeptides are provided, which (i) comprise at least one amino acid change relative to a wild-type PD-1 protein; and (ii) have an increased affinity for PD-L1 relative to the wild-type protein. Compositions and methods are provided for modulating the activity of immune cells in a mammal by administering a therapeutic dose of a pharmaceutical composition comprising a high affinity PD-1 mimic polypeptide, which blocks the physiological binding interaction between PD-1 and its ligand PD-L1 and/or PD-L2.
摘要翻译：提供了高亲和力PD-1模拟多肽，其（i）相对于野生型PD-1蛋白包含至少一个氨基酸改变; 和（ii）相对于野生型蛋白质具有增加的对PD-L1的亲和力。提供了用于调节哺乳动物免疫细胞活性的组合物和方法，其通过施用治疗剂量的包含高亲和力PD-1模拟多肽的药物组合物，其阻断PD-1与其配体PD-L1之间的生理结合相互作用和/或PD-L2。

3. 发明申请

WO2016191305A1 BTN3A ECTODOMAIN PROTEINS AND METHODS OF USE 审中-公开
标题翻译： BTN3A ECTODOMAIN蛋白及其使用方法
公开(公告)号：WO2016191305A1
公开(公告)日：2016-12-01
申请号：PCT/US2016/033619
申请日：2016-05-20
申请人： THE BOARD OF TRUSTEES OF THE LELAND STANFORD JUNIOR UNIVERSITY
发明人： COREY, Daniel Mark , RING, Aaron Michael , WEISSMAN, Irving L.
IPC分类号： C07K14/705 , G01N33/50 , G01N33/68
CPC分类号： A61K38/177 , A61K39/0011 , A61K2039/5154 , A61K2039/5158 , A61P35/00 , C07K14/705 , G01N33/68 , Y02A50/412
摘要： BTN3A ectodomain polypeptides are provided, which comprise a BTN3A ectodomain (e.g., a BTN3A1, BTN3A2, or BTN3A3 ectodomain) and lack a BTN3A transmembrane domain (e.g., a BTN3A1, BTN3A2, or BTN3A3 transmembrane domain). Compositions and methods are provided for activating an antigen presenting cell (APC). In some cases, the APC is activated in vivo. For example, in some cases, APC activity is stimulated (an APC is activated) in a mammal by administering a pharmaceutical composition comprising a BTN3A ectodomain polypeptide.
摘要翻译：提供BTN3A胞外域多肽，其包含BTN3A胞外域（例如BTN3A1，BTN3A2或BTN3A3胞外域），并且缺少BTN3A跨膜结构域（例如，BTN3A1，BTN3A2或BTN3A3跨膜结构域）。提供用于激活抗原呈递细胞（APC）的组合物和方法。在某些情况下，APC在体内被激活。例如，在一些情况下，通过施用包含BTN3A胞外域多肽的药物组合物，哺乳动物中APC活性被刺激（APC被激活）。

4. 发明申请

WO2016205042A1 SIRPα AGONIST ANTIBODY 审中-公开
标题翻译： SIRPα激动剂抗体
公开(公告)号：WO2016205042A1
公开(公告)日：2016-12-22
申请号：PCT/US2016/036520
申请日：2016-06-08
申请人： THE BOARD OF TRUSTEES OF THE LELAND STANFORD JUNIOR UNIVERSITY
发明人： WEISSMAN, Irving L. , GEORGE, Benson , RING, Nan Guo , RING, Aaron Michael , VOLKMER, Jens-Peter
IPC分类号： A61K39/00
CPC分类号： C07K16/42 , C07K16/2803 , C07K2317/21 , C07K2317/75
摘要： Compositions and methods are provided relating to anti-SIRPα agonist antibodies. The antibodies of the invention bind to human SIRPα, and activate signaling, thereby inhibiting processes mediated by SIRPα, including without limitation phagocytosis. Embodiments of the invention include isolated antibodies and derivatives and fragments thereof, pharmaceutical formulations comprising one or more of the anti-SIRPα agonist antibodies; and cell lines that produce these antibodies.
摘要翻译：提供了与抗SIRPα激动剂抗体有关的组合物和方法。本发明的抗体与人类SIRPα结合，激活信号传导，从而抑制由SIRPα介导的过程，包括但不限于吞噬作用。本发明的实施方案包括分离的抗体及其衍生物和片段，包含一种或多种抗SIRPα激动剂抗体的药物制剂; 和产生这些抗体的细胞系。

5. 发明申请

WO2016077249A1 COMPOSITIONS AND METHODS FOR EXPRESSING POLYPEPTIDES ON THE SURFACE OF CELLS 审中-公开
标题翻译：用于在细胞表面表达多肽的组合物和方法
公开(公告)号：WO2016077249A1
公开(公告)日：2016-05-19
申请号：PCT/US2015/059787
申请日：2015-11-09
申请人： THE BOARD OF TRUSTEES OF THE LELAND STANFORD JUNIOR UNIVERSITY
发明人： RING, Aaron Michael , KRUSE, Andrew , MANGLIK, Aashish
IPC分类号： C12N15/09
CPC分类号： C12N15/81 , C07K14/001 , C07K14/70532 , C07K14/7155 , C07K16/2818 , C07K2317/622 , C07K2319/02 , C07K2319/035 , C07K2319/70 , C07K2319/74 , C12N15/1037 , G01N33/6854 , G01N33/6863 , G01N33/6872 , G01N2333/70521 , G01N2333/70532 , G01N2333/7155
摘要： Methods and compositions are provided for displaying a protein of interest (POI) on the surface of a eukaryotic cell by fusing the POI to a signal polypeptide, a stalk polypeptide, and a surface anchor polypeptide to generate a surface accessible fusion protein. Nucleic acids are provided that include nucleotide sequences encoding a signal polypeptide, a stalk polypeptide, and a surface anchor polypeptide. In some cases, a subject nucleic acid includes and insertion site for the insertion of a POI. In some cases, a subject nucleic acid includes a nucleotide sequence that encodes a POI. In some cases a stalk polypeptide is a synthetic stalk polypeptide and various example synthetic stalk polypeptides are disclosed. In some cases, a surface anchor polypeptide is a glycosylphosphatidylinisotol (GPI) anchor domain, which can be synthetic. Kits are also provided for practicing the subject methods.
摘要翻译：提供了通过将POI融合到信号多肽，茎多肽和表面锚定多肽以产生表面可接近的融合蛋白来提供在真核细胞表面上显示感兴趣的蛋白质（POI）的方法和组合物。提供核酸，其包括编码信号多肽，茎多肽和表面锚定多肽的核苷酸序列。在一些情况下，受试者核酸包括用于插入POI的插入位点。在一些情况下，受试者核酸包括编码POI的核苷酸序列。在一些情况下，茎多肽是合成茎多肽，并且公开了各种实例的合成茎多肽。在一些情况下，表面锚定多肽是可以是合成的糖基磷脂酰肌醇（GPI）锚结构域。还提供套件来练习主题方法。

6. 发明申请

WO2016023001A1 MULTISPECIFIC HIGH AFFINITY PD-1 AGENTS AND METHODS OF USE 审中-公开
标题翻译：多重高亲属性PD-1药剂及其使用方法
公开(公告)号：WO2016023001A1
公开(公告)日：2016-02-11
申请号：PCT/US2015/044363
申请日：2015-08-07
申请人： THE BOARD OF TRUSTEES OF THE LELAND STANFORD JUNIOR UNIVERSITY
发明人： RING, Aaron Michael , KRUSE, Andrew , MANGLIK, Aashish , WEISSMAN, Irving L.
IPC分类号： C07K19/00 , A61K38/00 , C12N15/00
CPC分类号： C07K14/70596 , A61K38/00 , C07K14/70503 , C07K2319/00
摘要： Multispecific high affinity PD-1 mimic polypeptides are provided, which comprise: (a) a first region comprising an amino acid sequence of a high affinity PD-1 mimic polypeptide that is a variant of a wild-type PD1 sequence; and (b) a second region comprising an amino acid sequence of a high affinity SIRP-alpha variant that specifically binds to CD47, where the high affinity SIRP-alpha variant is CV1. Compositions and methods are provided for modulating the activity of immune cells in a mammal by administering a therapeutic dose of a pharmaceutical composition comprising a subject multispecific high affinity PD-1 mimic polypeptide, which blocks the physiological binding interaction between PD-1 and its ligand PD-L1 and/or PD-L2.
摘要翻译：提供多特异性高亲和力PD-1模拟多肽，其包含：（a）包含作为野生型PD1序列的变体的高亲和力PD-1模拟多肽的氨基酸序列的第一区域; 和（b）包含特异性结合CD47的高亲和力SIRP-α变体的氨基酸序列的第二区域，其中高亲和力SIRP-α变体是CV1。提供组合物和方法用于通过施用治疗剂量的药物组合物来调节哺乳动物中免疫细胞的活性，所述药物组合物包含受试者多特异性高亲和力PD-1模拟多肽，其阻断PD-1与其配体PD之间的生理结合相互作用 -L1和/或PD-L2。

7. 发明申请

WO2013109752A1 HIGH AFFINITY SIRP-ALPHA REAGENTS 审中-公开
标题翻译：高亲属性SIRP-ALPHA试剂
公开(公告)号：WO2013109752A1
公开(公告)日：2013-07-25
申请号：PCT/US2013/021937
申请日：2013-01-17
申请人： THE BOARD OF TRUSTEES OF THE LELAND STANFORD JUNIOR UNIVERSITY
发明人： RING, Aaron Michael , GARCIA, Kenan Christopher , WEISKOPF, Kipp Andrew , LEVIN, Aron M. , WEISSMAN, Irving L.
IPC分类号： A61K38/16
CPC分类号： C12N9/16 , A61K38/16 , C07K14/4703 , C07K16/2803 , C07K2317/52 , C07K2319/30 , C12Y301/03048 , G01N33/5005
摘要： High affinity SIRP-α reagent are provided, which (i) comprise at least one amino acid change relative to the wild-type protein; and (ii) have an increased affinity for CD47 relative to the wild-type protein. Compositions and methods are provided for modulating phagocytosis in a mammal by administering a therapeutic dose of a pharmaceutical composition comprising a high affinity SIRPα reagent, which blocks the physiological binding interaction between SIRPα and its ligand CD47.
摘要翻译：提供高亲和力SIRP-α试剂，其中（i）相对于野生型蛋白质包含至少一个氨基酸变化; 和（ii）相对于野生型蛋白质对CD47的亲和性增加。提供了通过施用治疗剂量的包含高亲和力SIRPalpha试剂的药物组合物来调节哺乳动物吞噬作用的组合物和方法，其阻止SIRPalpha及其配体CD47之间的生理结合相互作用。

8. 发明申请

WO2018026600A1 DISRUPTING FC RECEPTOR ENGAGEMENT ON MACROPHAGES ENHANCES EFFICACY OF ANTI-SIRPALPHA ANTIBODY THERAPY 审中-公开
标题翻译：破坏巨噬细胞上的FC受体参与增强抗SIRPALPHA抗体治疗的有效性
公开(公告)号：WO2018026600A1
公开(公告)日：2018-02-08
申请号：PCT/US2017/043935
申请日：2017-07-26
申请人： THE BOARD OF TRUSTEES OF THE LELAND STANFORD JUNIOR UNIVERSITY , FORTY SEVEN, INC.
发明人： LIU, Jie , RING, Aaron Michael , VOLKMER, Jens-Peter , WEISSMAN, Irving L.
IPC分类号： A61K39/395 , A61K39/00
摘要： Anti-SIRPα antibodies, including multi-specific anti-SIRPα antibodies, are provided, as are related compositions and methods. The antibodies of the disclosure bind to SIRPα and can block the interaction of CD47 on one cell with SIRPα on a phagocytic cell. The subject anti-SIRPα antibodies find use in various therapeutic methods. Embodiments of the disclosure include isolated antibodies and derivatives and fragments thereof, pharmaceutical formulations comprising one or more of the anti-SIRPα antibodies; and cell lines that produce the antibodies. Also provided are amino acid sequences of exemplary anti-SIRPα antibodies.
摘要翻译：提供抗SIRPα抗体，包括多特异性抗SIRPα抗体，以及相关组合物和方法。本公开的抗体结合SIRPα并且可以阻断一种细胞上的CD47与吞噬细胞上的SIRPα的相互作用。主题抗SIRPα抗体可用于各种治疗方法。本公开的实施方案包括分离的抗体及其衍生物和片段，包含一种或多种抗SIRPα抗体的药物制剂; 和产生抗体的细胞系。还提供了示例性抗SIRPα抗体的氨基酸序列。

9. 发明申请

WO2016179399A1 HIGH AFFINITY CD47 ANALOGS 审中-公开
标题翻译：高亲属CD47模拟
公开(公告)号：WO2016179399A1
公开(公告)日：2016-11-10
申请号：PCT/US2016/030997
申请日：2016-05-05
申请人： THE BOARD OF TRUSTEES OF THE LELAND STANFORD JUNIOR UNIVERSITY
发明人： HO, Chia Chi , GARCIA, Kenan Christopher , RING, Aaron Michael , WEISKOPF, Kipp Andrew , WEISSMAN, Irving L. , RING, Nan Guo
IPC分类号： A61K38/17 , C07K14/47 , C07K14/705 , G01N33/15
CPC分类号： C07K14/70503 , A61K38/00 , A61K38/1774 , A61K39/39558 , C07K14/70596 , C07K16/30 , C07K2319/21 , C07K2319/24 , C07K2319/30 , C07K2319/50 , G01N33/5005
摘要： High affinity CD47 reagents are provided, which (i) comprise at least one amino acid change relative to the wild-type protein; and (ii) have an increased affinity for a SIRPα relative to the wild-type protein. Compositions and methods are provided for modulating phagocytosis in a mammal by administering a therapeutic dose of a pharmaceutical composition comprising a high affinity CD47 reagent, which blocks the physiological binding interaction between SIRPα and a ligand, e.g., native CD47.
摘要翻译：提供高亲和力CD47试剂，其中（i）相对于野生型蛋白质包含至少一个氨基酸变化; 和（ii）相对于野生型蛋白质对SIRPα的亲和性增加。提供了通过施用治疗剂量的包含高亲和力CD47试剂的药物组合物来调节哺乳动物吞噬作用的组合物和方法，其阻止SIRPα和配体例如天然CD47之间的生理结合相互作用。

10. 发明申请

WO2016033201A1 ENGRAFTMENT OF STEM CELLS WITH A COMBINATION OF AN AGENT THAT TARGETS STEM CELLS AND MODULATION OF IMMUNOREGULATORY SIGNALING 审中-公开
标题翻译：具有目标干细胞和免疫调节信号调节剂的组合的干细胞的整合
公开(公告)号：WO2016033201A1
公开(公告)日：2016-03-03
申请号：PCT/US2015/046976
申请日：2015-08-26
申请人： THE BOARD OF TRUSTEES OF THE LELAND STANFORD JUNIOR UNIVERSITY
发明人： SHIZURU, Judith, A. , WEISKOPF, Kipp Andrew , RING, Aaron Michael , CHHABRA, Akanksha , SCHNORR, Peter , WEISSMAN Irving L.
IPC分类号： C12Q1/68 , A61K39/395 , C07K16/30
CPC分类号： A61K35/28 , A61K38/1709 , A61K38/1774 , A61K38/1793 , A61K39/3955 , A61K45/06 , A61K2039/505 , A61K2039/507 , C07K16/2803 , C07K16/2878 , C07K16/2896 , C07K2317/74 , C07K2317/75 , C07K2317/76 , A61K39/39558 , A61K2300/00
摘要： The present invention provides a clinically applicable method of stem cell transplantation that facilitates engraftment and reconstitutes immunocompetence of the recipient without requiring radiotherapy or chemotherapy, and without development of GVHD or graft rejection. Aspects of the present invention are based on the discovery that the depletion of the endogenous stem cell niche facilitates efficient engraftment of stem cells into that niche. In particular, the present invention combines the use of selective ablation of endogenous stem cells with a combination of antibodies specific for CD117, and agents that modulate immunoregulatory signaling pathways, e.g. agonists of immune costimulatory molecules, in combination with the administration to the recipient of exogenous stem cells, resulting in efficient, long-term engraftment, even in immunocompetent recipients.
摘要翻译：本发明提供了一种临床适用的干细胞移植方法，其有助于移植并重建受体的免疫能力，而不需要放射治疗或化学疗法，并且不发展GVHD或移植排斥反应。本发明的方面基于这样的发现：内源性干细胞生态位的消耗有助于将干细胞有效植入该生态位。特别地，本发明结合了内源性干细胞的选择性消融与CD117特异性抗体的组合的用途，以及调节免疫调节信号传导途径的试剂。免疫共刺激分子的激动剂与给予外源性干细胞受体的组合相结合，导致有效的长期植入，甚至在免疫功能受体中。

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