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1. 发明申请

US20060078969A1 Regulated transcription of targeted genes and other biological events 审中-公开
公开(公告)号：US20060078969A1
公开(公告)日：2006-04-13
申请号：US11175021
申请日：2005-07-05
申请人： Gerald Crabtree , Stuart Schreiber , David Spencer , Thomas Wandless , Steffan Ho , Peter Belshaw
发明人： Gerald Crabtree , Stuart Schreiber , David Spencer , Thomas Wandless , Steffan Ho , Peter Belshaw
IPC分类号： C07K14/705 , C07H21/04 , C12P21/04
CPC分类号： C07K14/705 , A61K38/00 , A61K47/6425 , C07D498/18 , C07F5/025 , C07H19/01 , C07K7/645 , C07K14/395 , C07K14/7051 , C07K14/71 , C07K2319/00 , C07K2319/02 , C07K2319/03 , C07K2319/035 , C07K2319/09 , C07K2319/20 , C07K2319/32 , C07K2319/42 , C07K2319/43 , C07K2319/60 , C07K2319/71 , C07K2319/715 , C07K2319/81 , C07K2319/90 , C12N15/1055 , C12N15/62 , C12N15/63 , C12N15/67 , C12P15/00
摘要： Dimerization and oligomerization of proteins are general biological control mechanisms that contribute to the activation of cell membrane receptors, transcription factors, vesicle fusion proteins, and other classes of intra- and extracellular proteins. We have developed a general procedure for the regulated (inducible) dimerization or oligomerization of intracellular proteins. In principle, any two target proteins can be induced to associate by treating the cells or organisms that harbor them with cell permeable, synthetic ligands. To illustrate the practice of this invention, we have induced: (1) the intracellular aggregation of the cytoplasmic tail of the ζ chain of the T cell receptor (TCR)-CD3 complex thereby leading to signaling and transcription of a reporter gene, (2) the homodimerization of the cytoplasmic tail of the Fas receptor thereby leading to cell-specific apoptosis (programmed cell death) and (3) the heterodimerization of a DNA-binding domain (Gal4) and a transcription-activation domain (VP16) thereby leading to direct transcription of a reporter gene. Regulated intracellular protein association with our cell permeable, synthetic ligands offers new capabilities in biological research and medicine, in particular, in gene therapy. Using gene transfer techniques to introduce our artificial receptors, one can turn on or off the signaling pathways that lead to the overexpression of therapeutic proteins by administering orally active “dimerizers” or “de-dimerizers”, respectively. Since cells from different recipients can be configured to have the pathway overexpress different therapeutic proteins for use in a variety of disorders, the dimerizers have the potential to serve “universal drugs”. They can also be viewed as cell permeable, organic replacements for therapeutic antisense agents or for proteins that would otherwise require intravenous injection or intracellular expression (e.g., the LDL receptor or the CFTR protein).

2. 发明授权

US5871753A Regulated transcription of targeted genes and other biological events 失效
标题翻译：靶向基因和其他生物事件的调节转录
公开(公告)号：US5871753A
公开(公告)日：1999-02-16
申请号：US473985
申请日：1995-06-07
申请人： Gerald R. Crabtree , Stuart L. Schreiber , David M. Spencer , Thomas J. Wandless , Peter Belshaw , Steffan Ho
发明人： Gerald R. Crabtree , Stuart L. Schreiber , David M. Spencer , Thomas J. Wandless , Peter Belshaw , Steffan Ho
IPC分类号： C12N15/09 , A61K38/00 , A61K47/48 , C07D498/18 , C07F5/02 , C07H19/01 , C07K7/64 , C07K14/395 , C07K14/71 , C07K14/725 , C12N1/19 , C12N5/10 , C12N15/62 , C12N15/63 , C12P15/00 , C12P21/00 , C12R1/85 , C12R1/91 , A61K45/00 , A61K38/13 , C07D491/06 , C07K5/12
CPC分类号： C07D498/18 , A61K47/48276 , C07F5/025 , C07H19/01 , C07K14/395 , C07K14/7051 , C07K14/71 , C07K7/645 , C12N15/62 , C12N15/63 , C12P15/00 , A61K38/00 , C07K2319/00 , C07K2319/02 , C07K2319/03 , C07K2319/035 , C07K2319/09 , C07K2319/20 , C07K2319/32 , C07K2319/42 , C07K2319/43 , C07K2319/60 , C07K2319/71 , C07K2319/715 , C07K2319/81 , C07K2319/90
摘要： Methods and compositions are provided for modified cells, where a chimeric protein consisting of a ligand binding domain fused to an action domain is employed which initiates a signal which activates a biological process: transcription of at least one gene, usually a second construct introduced into the host cells; exocytosis; or an extracellular process. The second construct optimally present provides for a promoter which responds to a transcriptional activation action domain to provide for transcription, when an appropriate ligand binds to the ligand binding domain. Exemplary of the system is the use of an FKBP/CD3.zeta. or transcription factor fusion protein, using dimeric FK506 or FK520 as the ligand and a promoter responsive to NF-AT or other transcription factor requiring two molecules for transcriptional activation.
摘要翻译：为修饰的细胞提供方法和组合物，其中使用由与活性结构域融合的配体结合结构域组成的嵌合蛋白，其启动激活生物学过程的信号：至少一种基因的转录，通常是引入宿主细胞; 胞吐作用或细胞外过程。当适当的配体结合配体结合结构域时，最佳存在的第二种构建体提供响应于转录激活作用结构域以提供转录的启动子。该系统的示例是使用二聚体FK506或FK520作为配体的FKBP / CD3ζ或转录因子融合蛋白，以及对NF-AT或需要两个分子进行转录激活的其他转录因子的启动子。

3. 发明申请

US20100189716A1 TREATMENT OF HODGKINS LYMPHOMA 审中-公开
标题翻译： HODGKINS LYMPHOMA的治疗
公开(公告)号：US20100189716A1
公开(公告)日：2010-07-29
申请号：US12593281
申请日：2008-03-28
申请人： Arturo Molina , Kandasamy Hariharan , Steffan Ho
发明人： Arturo Molina , Kandasamy Hariharan , Steffan Ho
IPC分类号： A61K39/395 , C12N5/00 , A61P35/00
CPC分类号： C07K16/2827 , A61K2039/505 , C07K2317/24 , C07K2317/732 , C07K2317/76
摘要： Compositions comprising CD80 antagonists and methods using these compositions are provided for the treatment of Hodgkins lymphoma. More particularly, the disclosed CD80 antagonists may be used to induce apoptosis or lysis of Hodgkins Reed-Sternberg (HRS) cells, or to inhibit HRS cell activities that promote tumor development or progression.
摘要翻译：提供包含CD80拮抗剂的组合物和使用这些组合物的方法用于治疗霍奇金淋巴瘤。更具体地，所公开的CD80拮抗剂可以用于诱导霍奇金氏Reed-Sternberg（HRS）细胞的凋亡或裂解，或抑制促进肿瘤发展或进展的HRS细胞活性。

4. 发明申请

US20080039416A1 Methods for Treating Disease by Modulating an Osmotic Stress Pathway 审中-公开
标题翻译：通过调节渗透压力途径治疗疾病的方法
公开(公告)号：US20080039416A1
公开(公告)日：2008-02-14
申请号：US11569756
申请日：2005-06-02
申请人： Steffan Ho
发明人： Steffan Ho
IPC分类号： A61K31/7052 , A01K67/027 , A61P35/00 , A61P37/00 , C07H21/04 , C12Q1/18 , C12Q1/68 , G01N33/566 , G01N33/574
CPC分类号： G01N33/5011 , G01N33/564 , G01N33/574 , G01N2500/00
摘要： The cellular response to osmotic stress ensures that the concentration of water inside the cell is maintained within a range that is compatible with biologic function. Single cell organisms are particularly dependent on mechanisms that permit adaptation to osmotic stress because each individual cell is directly exposed to the external environment. Mammals, however, limit osmotic stress by establishing an internal aqueous environment in which intravascular water and electrolytes are subject to sensitive and dynamic, organism-based homeostatic regulation. NFAT5/TonEBP is an essential mammalian osmoregulatory transcription factor, and this invention demonstrates the unexpected yet critical significance of cell-based osmotic regulation in vivo. The invention highlights the fundamental importance of maintaining intracellular water homeostasis in the face of varying cellular metabolic activity and distinct tissue microenvironments. Methods for treating, preventing, or inhibiting human diseases using the osmotic stress pathway have been provided.
摘要翻译：细胞对渗透胁迫的反应确保细胞内水的浓度保持在与生物功能相适应的范围内。单细胞生物体特别依赖于允许适应渗透胁迫的机制，因为每个单个细胞直接暴露于外部环境。然而，哺乳动物通过建立血管内水和电解质受到敏感和动态，基于生物体的稳态调节的内部水环境来限制渗透压。 NFAT5 / TonEBP是必需的哺乳动物渗透调节转录因子，本发明证明了体内基于细胞的渗透调节的意想不到的至关重要的意义。本发明突出了维持细胞内水稳态在面对不同细胞代谢活动和不同组织微环境的根本重要性。已经提供了使用渗透胁迫途径治疗，预防或抑制人类疾病的方法。

5. 发明申请

US20090130105A1 COMPOSITIONS THAT BIND MULTIPLE EPITOPES OF IGF-1R 审中-公开
标题翻译：结合IGF-1R多重抗原决定簇的组合物
公开(公告)号：US20090130105A1
公开(公告)日：2009-05-21
申请号：US12200816
申请日：2008-08-28
申请人： Scott Glaser , Stephen Demarest , Brian Robert Miller , Kandasamy Hariharan , Steffan Ho , Jianying Dong , Alexey Alexandrovich Lugovskoy
发明人： Scott Glaser , Stephen Demarest , Brian Robert Miller , Kandasamy Hariharan , Steffan Ho , Jianying Dong , Alexey Alexandrovich Lugovskoy
IPC分类号： A61K39/395 , C07K16/00 , C07H21/00 , C12N15/63 , C12N5/10 , C12P21/00 , A61P35/00
CPC分类号： C07K16/2863 , C07K2317/34 , C07K2317/626 , C07K2317/64 , C07K2317/732 , C07K2317/77 , C07K2317/92 , C07K2319/00 , C07K2319/30
摘要： The instant invention is based, at least in part on the finding that binding molecules which bind to different epitopes within IGF-1R result in improved IGF-1 and/or IGF-2 blocking capabilities when compared to binding molecules that bind to a single IGF-1R epitope. The instant invention provides compositions that bind to multiple epitopes of IGF-1R, for example, combinations of monospecific binding molecules or multispecific binding molecules (e.g., bispecific molecules). Methods of making the subject binding molecules and methods of using the binding molecules of the invention to antagonize IGF-1R signaling are also provided.
摘要翻译：本发明至少部分地基于以下发现：当与结合单个IGF的结合分子相比时，结合IGF-1R内的不同表位的结合分子导致改善的IGF-1和/或IGF-2阻断能力 -1R表位。本发明提供了结合IGF-1R的多个表位的组合物，例如单特异性结合分子或多特异性结合分子（例如双特异性分子）的组合。还提供了制备受试者结合分子的方法和使用本发明的结合分子拮抗IGF-1R信号传导的方法。

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