公开(公告)号：US20120083000A1

公开(公告)日：2012-04-05

申请号：US13236117

申请日：2011-09-19

申请人： Nicole M. Alessandri Haber ,  Lynn Macdonald ,  Michael L. LaCroix-Fralish ,  Andrew J. Murphy

发明人： Nicole M. Alessandri Haber ,  Lynn Macdonald ,  Michael L. LaCroix-Fralish ,  Andrew J. Murphy

IPC分类号： G01N33/567

CPC分类号： C07K14/435

摘要： Methods and compositions for using genetically modified non-human animals are provided, wherein the genetic modification comprises a humanization of the one or more extracellular pore loops of a NaV1.7 channel protein or a complete humanization of an endogenous NaV1.7 gene. Methods for using isolated DRG cultures from genetically modified non-human animals are also provided, wherein the isolated DRG express a human or chimeric NaV1.7 protein on the surface, in particular measuring primary nociceptive activation through the release of calcitonin gene-related peptide (CGRP) in isolated DRG in vitro, and wherein the isolated DRG cultures are capable of generating action potentials and communicating through an excitable signal via the expressed human or chimeric NaV1.7 protein the cell surface. In vivo and in vitro methods for characterizing NaV1.7-specific antagonists and evaluation of corresponding therapeutic potential for NaV1.7-mediated disease are also provided.

摘要翻译： 提供了使用遗传修饰的非人动物的方法和组合物，其中遗传修饰包括NaV1.7通道蛋白的一个或多个胞外孔环的人源化或内源性NaV1.7基因的完全人源化。 还提供了使用来自遗传修饰的非人动物的分离的DRG培养物的方法，其中分离的DRG在表面上表达人或嵌合的NaV1.7蛋白，特别是通过释放降钙素基因相关肽测量初级伤害感受激活（ CGRP），其中分离的DRG培养物能够产生动作电位并通过表达的人或嵌合的NaV1.7蛋白的细胞表面通过可兴奋的信号传递。 还提供了用于表征NaV1.7特异性拮抗剂的体内和体外方法以及对NaV1.7介导的疾病的相应治疗潜力的评估。

公开(公告)号：US20120073004A1

公开(公告)日：2012-03-22

申请号：US13166200

申请日：2011-06-22

申请人： Lynn MacDonald ,  Sean Stevens ,  Cagan Gurer ,  Andrew J. Murphy ,  Karolina A. Hosiawa

发明人： Lynn MacDonald ,  Sean Stevens ,  Cagan Gurer ,  Andrew J. Murphy ,  Karolina A. Hosiawa

IPC分类号： A01K67/027 ,  C12N5/10 ,  C07H21/04 ,  C07K16/46

CPC分类号： C12N5/0606 ,  A01K67/0275 ,  A01K67/0278 ,  A01K2207/15 ,  A01K2217/05 ,  A01K2217/052 ,  A01K2217/072 ,  A01K2217/15 ,  A01K2227/105 ,  A01K2267/01 ,  A01K2267/02 ,  A01K2267/0381 ,  C07K16/00 ,  C07K16/18 ,  C07K16/461 ,  C07K16/462 ,  C07K2317/10 ,  C07K2317/14 ,  C07K2317/21 ,  C07K2317/24 ,  C07K2317/50 ,  C07K2317/515 ,  C07K2317/56 ,  C07K2317/64 ,  C12N15/10 ,  C12N15/8509

摘要： Genetically modified mice are provided that express human λ variable (hVλ) sequences, including mice that express hVλ sequences from an endogenous mouse λ light chain locus, mice that express hVλ sequences from an endogenous mouse κ light chain locus, and mice that express hVλ sequences from a transgene or an episome wherein the hVλ sequence is linked to a mouse constant sequence. Mice are provided that are a source of somatically mutated human λ variable sequences useful for making antigen-binding proteins. Compositions and methods for making antigen-binding proteins that comprise human λ variable sequences, including human antibodies, are provided.

摘要翻译： 提供基因修饰的小鼠，其表达人λ变量（hVλ）序列，包括从内源小鼠λ轻链基因座表达hVλ序列的小鼠，从内源小鼠和kgr表达hVλ序列的小鼠; 轻链基因座和表达hVλ序列的小鼠，其中hVλ序列与小鼠恒定序列连接。 提供了可用于制备抗原结合蛋白的体细胞突变的人λ可变序列的来源的小鼠。 提供了包含人λ可变序列（包括人抗体）的抗原结合蛋白的组合物和方法。

公开(公告)号：US20110256556A1

公开(公告)日：2011-10-20

申请号：US13113677

申请日：2011-05-23

申请人： Lynn Macdonald ,  Naxin Tu ,  Cagan Gurer ,  Li-Hsien Wang ,  Sean Stevens ,  Andrew J. Murphy

发明人： Lynn Macdonald ,  Naxin Tu ,  Cagan Gurer ,  Li-Hsien Wang ,  Sean Stevens ,  Andrew J. Murphy

IPC分类号： G01N33/574 ,  G01N33/567 ,  C12N5/00

CPC分类号： C07K14/70535 ,  A01K67/0276 ,  A01K67/0278 ,  A01K2207/15 ,  A01K2217/072 ,  A01K2217/075 ,  A01K2217/15 ,  A01K2227/105 ,  A01K2267/0387 ,  G01N33/56977 ,  G01N2333/70535

摘要： Genetically modified non-human animals and methods and compositions for making and using them are provided, wherein the genetic modification comprises a deletion of the endogenous low affinity FcγR locus, and wherein the mouse is capable of expressing a functional FcRγ-chain. Genetically modified mice are described, including mice that express low affinity human FcγR genes from the endogenous FcγR locus, and wherein the mice comprise a functional FcRγ-chain. Genetically modified mice that express up to five low affinity human FcγR genes on accessory cells of the host immune system are provided.

摘要翻译： 提供了遗传修饰的非人动物以及用于制备和使用它们的方法和组合物，其中所述遗传修饰包括内源性低亲和力FcγR基因座的缺失，并且其中所述小鼠能够表达功能性FcRγ-链。 描述了转基因小鼠，包括从内源性FcγR基因座表达低亲和性人FcγR基因的小鼠，其中小鼠包含功能性FcRγ-链。 提供了在宿主免疫系统的辅助细胞上表达多达五个低亲和力的人FcγR基因的转基因小鼠。

公开(公告)号：US20110200982A1

公开(公告)日：2011-08-18

申请号：US12897517

申请日：2010-10-04

申请人： Sean Stevens ,  Andrew J. Murphy ,  Richard Flavell ,  Elizabeth Eynon ,  Jorge Galan ,  Tim Willinger ,  Markus Manz ,  Anthony Rongvaux

发明人： Sean Stevens ,  Andrew J. Murphy ,  Richard Flavell ,  Elizabeth Eynon ,  Jorge Galan ,  Tim Willinger ,  Markus Manz ,  Anthony Rongvaux

IPC分类号： C12Q1/68 ,  A01K67/027 ,  C12Q1/70 ,  C12Q1/02

CPC分类号： A01K67/0278 ,  A01K67/0271 ,  A01K67/0275 ,  A01K2207/12 ,  A01K2207/15 ,  A01K2217/072 ,  A01K2217/075 ,  A01K2217/15 ,  A01K2227/105 ,  A01K2267/03 ,  A01K2267/0331 ,  A01K2267/0337 ,  A01K2267/0381 ,  A01K2267/0387 ,  A61K49/00 ,  C07K14/524 ,  C07K14/535 ,  C07K14/5403 ,  C07K14/7155 ,  C12N9/00

摘要： A mouse with a humanization of the mIL-3 gene and the mGM-CSF gene, a knockout of a mRAG gene, and a knockout of a mIl2rg subunit gene; and optionally a humanization of the TPO gene is described. A RAG/Il2rg KO/hTPO knock-in mouse is described. A mouse engrafted with human hematopoietic stem cells (HSCs) that maintains a human immune cell (HIC) population derived from the HSCs and that is infectable by a human pathogen, e.g., S. typhi or M. tuberculosis is described. A mouse that models a human pathogen infection that is poorly modeled in mice is described, e.g., a mouse that models a human mycobacterial infection, wherein the mouse develops one or more granulomas comprising human immune cells. A mouse that comprises a human hematopoietic malignancy that originates from an early human hematopoietic cells is described, e.g., a myeloid leukemia or a myeloproliferative neoplasia.

摘要翻译： 具有mIL-3基因和mGM-CSF基因的人源化的小鼠，mRAG基因的敲除和mIl2rg亚基基因的敲除; 并且可选地描述了TPO基因的人源化。 描述了RAG / Il2rg KO / hTPO敲入小鼠。 描述了维持人类免疫细胞（HIC）群体的人类造血干细胞（HSCs）的小鼠，所述人类免疫细胞（HIC）群体来自HSC并且可被人类病原体例如伤寒沙门氏菌或结核分枝杆菌感染。 描述了模拟在小鼠中模拟不良的人类病原体感染的小鼠，例如模拟人类分枝杆菌感染的小鼠，其中小鼠产生包含人免疫细胞的一种或多种肉芽肿。 描述了包含源于早期人类造血细胞的人类造血恶性肿瘤的小鼠，例如骨髓性白血病或骨髓增生性肿瘤。

公开(公告)号：US07611854B2

公开(公告)日：2009-11-03

申请号：US10600003

申请日：2003-06-18

申请人： Dana M. Fowlkes ,  Jim Broach ,  John Manfredi ,  Christine Klein ,  Andrew J. Murphy ,  Jeremy Paul ,  Joshua Trueheart

发明人： Dana M. Fowlkes ,  Jim Broach ,  John Manfredi ,  Christine Klein ,  Andrew J. Murphy ,  Jeremy Paul ,  Joshua Trueheart

IPC分类号： C12N1/19 ,  G01N33/53

CPC分类号： C12N15/81 ,  C07K14/395 ,  C07K2319/02

摘要： Yeast cells are engineered to express both a surrogate of a pheromone system protein (e.g., enzymes involved in maturation of α-factor, transporters of a-factor, pheromone receptors, etc.) and a potential peptide modulator of the surrogate, in such a manner that the inhibition or activation of the surrogate affects a screenable or selectable trait of the yeast cells. Various additional features improve the signal-to-noise ratio of the screening/selection system.

摘要翻译： 酵母细胞被设计成表达信息素系统蛋白质的替代物（例如，参与α因子成熟的酶，α-因子的转运蛋白，信息素受体等）和代理的潜在的肽调节剂，在这样的 替代物的抑制或活化影响酵母细胞的可筛选或选择性状的方式。 各种附加功能提高了筛选/选择系统的信噪比。

公开(公告)号：US20090055943A1

公开(公告)日：2009-02-26

申请号：US11809473

申请日：2007-06-01

申请人： Aris N. Economides ,  Andrew J. Murphy ,  David M. Valenzuela ,  David Frendewey ,  George D. Yancopoulos

发明人： Aris N. Economides ,  Andrew J. Murphy ,  David M. Valenzuela ,  David Frendewey ,  George D. Yancopoulos

IPC分类号： A01K67/027 ,  C12Q1/68

CPC分类号： C12N15/85 ,  A01K67/0275 ,  A01K2217/05 ,  A01K2227/105 ,  C12N5/0606 ,  C12N15/79 ,  C12N15/907 ,  C12N2510/00 ,  C12N2810/10 ,  C12Q1/6827

摘要： A method for engineering and utilizing large DNA vectors to target, via homologous recombination, and modify, in any desirable fashion, endogenous genes and chromosomal loci in eukaryotic cells. These large DNA targeting vectors for eukaryotic cells, termed LTVECs, are derived from fragments of cloned genomic DNA larger than those typically used by other approaches intended to perform homologous targeting in eukaryotic cells. Also provided is a rapid and convenient method of detecting eukaryotic cells in which the LTVEC has correctly targeted and modified the desired endogenous gene(s) or chromosomal locus (loci) as well as the use of these cells to generate organisms bearing the genetic modification.

公开(公告)号：US06596541B2

公开(公告)日：2003-07-22

申请号：US09784859

申请日：2001-02-16

申请人： Andrew J. Murphy ,  George D. Yancopoulos

发明人： Andrew J. Murphy ,  George D. Yancopoulos

IPC分类号： C12N1587

CPC分类号： C12P21/00 ,  A01K67/0275 ,  A01K67/0278 ,  A01K2207/15 ,  A01K2217/05 ,  A01K2227/105 ,  A01K2267/01 ,  C07K16/00 ,  C07K16/28 ,  C07K16/462 ,  C07K2317/10 ,  C07K2317/21 ,  C07K2317/24 ,  C07K2317/51 ,  C07K2317/515 ,  C07K2317/56 ,  C12N15/67 ,  C12N15/85 ,  C12N15/8509 ,  C12N15/902 ,  C12N15/907 ,  C12N2800/204

摘要： A method for engineering and utilizing large DNA vectors to target, via homologous recombination, and modify, in any desirable fashion, endogenous genes and chromosomal loci in eukaryotic cells. These large DNA targeting vectors for eukaryotic cells, termed LTVECs, are derived from fragments of cloned genomic DNA larger than those typically used by other approaches intended to perform homologous targeting in eukaryotic cells. Also provided is a rapid and convenient method of detecting eukaryotic cells in which the LTVEC has correctly targeted and modified the desired endogenous gene(s) or chromosomal locus (loci) as well as the use of these cells to generate organisms bearing the genetic modification.

公开(公告)号：US10143186B2

公开(公告)日：2018-12-04

申请号：US13022759

申请日：2011-02-08

申请人： John McWhirter ,  Lynn Macdonald ,  Sean Stevens ,  David R. Buckler ,  Andrew J. Murphy

发明人： John McWhirter ,  Lynn Macdonald ,  Sean Stevens ,  David R. Buckler ,  Andrew J. Murphy

IPC分类号： A01K67/027 ,  C07K16/46 ,  C07K16/00 ,  C07K16/28 ,  C12N15/85 ,  C12N15/90 ,  C07K16/22

摘要： A genetically modified mouse is provided, wherein the mouse is incapable of rearranging and expressing an endogenous mouse immunoglobulin light chain variable sequence, wherein the mouse expresses only one or two human light chain variable domains encoded by human immunoglobulin sequences operably linked to the mouse kappa (κ) constant gene at the endogenous mouse κ locus, wherein the mouse expresses a reverse chimeric antibody having a light chain variable domain derived from one of only two human light chain variable region gene segments and a mouse κ constant domain, and a human heavy chain variable domain and a mouse heavy chain constant domain, from an endogenous mouse heavy chain locus. Bispecific epitope-binding proteins that are fully human are provided, comprising two different heavy chains that associate with an identical light chain that comprises a variable domain derived from one of two different human light chain variable region gene segments.

公开(公告)号：US09301509B2

公开(公告)日：2016-04-05

申请号：US13617448

申请日：2012-09-14

申请人： Sean Stevens ,  Andrew J. Murphy ,  Richard Flavell ,  Elizabeth Eynon ,  Jorge Galan ,  Tim Willinger ,  Markus Manz ,  Anthony Rongvaux ,  George D. Yancopoulos

发明人： Sean Stevens ,  Andrew J. Murphy ,  Richard Flavell ,  Elizabeth Eynon ,  Jorge Galan ,  Tim Willinger ,  Markus Manz ,  Anthony Rongvaux ,  George D. Yancopoulos

IPC分类号： A01K67/027 ,  G01N33/00 ,  C07K14/52 ,  C07K14/535 ,  C07K14/54 ,  C07K14/715 ,  C12N9/00 ,  A61K49/00

CPC分类号： A01K67/0278 ,  A01K67/0271 ,  A01K67/0275 ,  A01K2207/12 ,  A01K2207/15 ,  A01K2217/072 ,  A01K2217/075 ,  A01K2217/15 ,  A01K2227/105 ,  A01K2267/03 ,  A01K2267/0331 ,  A01K2267/0337 ,  A01K2267/0381 ,  A01K2267/0387 ,  A61K49/00 ,  C07K14/524 ,  C07K14/535 ,  C07K14/5403 ,  C07K14/7155 ,  C12N9/00

摘要： A mouse with a humanization of the mIL-3 gene and the mGM-CSF gene, a knockout of a mRAG gene, and a knockout of a mII2rg subunit gene; and optionally a humanization of the TPO gene is described. A RAG/II2rg KO/hTPO knock-in mouse is described. A mouse engrafted with human hematopoietic stem cells (HSCs) that maintains a human immune cell (HIC) population derived from the HSCs and that is infectable by a human pathogen, e.g., S. typhi or M. tuberculosis is described. A mouse that models a human pathogen infection that is poorly modeled in mice is described, e.g., a mouse that models a human mycobacterial infection, wherein the mouse develops one or more granulomas comprising human immune cells. A mouse that comprises a human hematopoietic malignancy that originates from an early human hematopoietic cells is described, e.g., a myeloid leukemia or a myeloproliferative neoplasia.

摘要翻译： 具有mIL-3基因和mGM-CSF基因的人源化的小鼠，mRAG基因的敲除和mII2rg亚基基因的敲除; 并且可选地描述了TPO基因的人源化。 描述了RAG / II2rg KO / hTPO敲入小鼠。 描述了维持人类免疫细胞（HIC）群体的人类造血干细胞（HSCs）的小鼠，所述人类免疫细胞（HIC）群体来自HSC并且可被人类病原体例如伤寒沙门氏菌或结核分枝杆菌感染。 描述了模拟在小鼠中模拟不良的人类病原体感染的小鼠，例如模拟人类分枝杆菌感染的小鼠，其中小鼠产生包含人免疫细胞的一种或多种肉芽肿。 描述了包含源于早期人类造血细胞的人类造血恶性肿瘤的小鼠，例如骨髓性白血病或骨髓增生性肿瘤。

公开(公告)号：US20140013457A1

公开(公告)日：2014-01-09

申请号：US14036518

申请日：2013-09-25

申请人： Andrew J. Murphy ,  George D. Yancopoulos ,  Margaret Karow ,  Lynn Macdonald ,  Sean Stevens

发明人： Andrew J. Murphy ,  George D. Yancopoulos ,  Margaret Karow ,  Lynn Macdonald ,  Sean Stevens

IPC分类号： C12N15/85

CPC分类号： C12P21/00 ,  A01K67/0275 ,  A01K67/0278 ,  A01K2207/15 ,  A01K2217/05 ,  A01K2227/105 ,  A01K2267/01 ,  C07K16/00 ,  C07K16/28 ,  C07K16/462 ,  C07K2317/10 ,  C07K2317/21 ,  C07K2317/24 ,  C07K2317/51 ,  C07K2317/515 ,  C07K2317/56 ,  C12N15/67 ,  C12N15/85 ,  C12N15/8509 ,  C12N15/902 ,  C12N15/907 ,  C12N2800/204

摘要： A method for engineering and utilizing large DNA vectors to target, via homologous recombination, and modify, in any desirable fashion, endogenous genes and chromosomal loci in eukaryotic cells. These large DNA targeting vectors for eukaryotic cells, termed LTVECs, are derived from fragments of cloned genomic DNA larger than those typically used by other approaches intended to perform homologous targeting in eukaryotic cells. Also provided is a rapid and convenient method of detecting eukaryotic cells in which the LTVEC has correctly targeted and modified the desired endogenous gene(s) or chromosomal locus (loci) as well as the use of these cells to generate organisms bearing the genetic modification.