公开(公告)号：US20140017238A1

公开(公告)日：2014-01-16

申请号：US14036514

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： C07K16/46

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：US08541646B2

公开(公告)日：2013-09-24

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 ,  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

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：US07105348B2

公开(公告)日：2006-09-12

申请号：US10076840

申请日：2002-02-15

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

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

IPC分类号： C12N15/87 ,  C12N15/00 ,  C12N15/85 ,  C07H21/02 ,  C07H21/04

CPC分类号： A01K67/0275 ,  C07K16/00 ,  C07K2317/56 ,  C12N15/902 ,  C12N15/907

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：US20210368751A1

公开(公告)日：2021-12-02

申请号：US17224524

申请日：2021-04-07

申请人： Lynn Macdonald ,  Cagan Gurer ,  Karolina A. Meagher ,  Sean Stevens ,  Andrew J. Murphy

发明人： Lynn Macdonald ,  Cagan Gurer ,  Karolina A. Meagher ,  Sean Stevens ,  Andrew J. Murphy

IPC分类号： A01K67/027 ,  C07K16/46 ,  C12N9/64

摘要： Non-human animals, tissues, cells, and genetic material are provided that comprise a modification of an endogenous non-human heavy chain immunoglobulin sequence and that comprise an ADAM6 activity functional in a rodent (e.g., a mouse), wherein the non-human animals rearrange human immunoglobulin light chain gene segments in the context of heavy chain constant regions and express immunoglobulin-like molecules comprising human immunoglobulin light chain variable domains fused to heavy chain constant domains that are cognate with human immunoglobulin light chain variable domains fused to light chain constant domains.

公开(公告)号：US20170204158A1

公开(公告)日：2017-07-20

申请号：US15463910

申请日：2017-03-20

申请人： Andrew J. Murphy ,  Nicholas J. Papadopoulos ,  Jamie M Orengo

发明人： Andrew J. Murphy ,  Nicholas J. Papadopoulos ,  Jamie M Orengo

IPC分类号： C07K14/715 ,  A61K39/395 ,  A61K45/06

CPC分类号： C07K14/7155 ,  A61K38/00 ,  A61K39/3955 ,  A61K45/06 ,  C07K2319/30 ,  C07K2319/32 ,  C07K2319/735

摘要： The present invention provides interleukin-33 (IL-33) antagonists comprising one or more IL-33-binding domains and one or more multimerizing domains and methods of using the same. According to certain embodiments of the invention, the IL-33-binding domains can comprise an IL-33-binding portion of an ST2 protein and/or an extracellular portion of an IL-1RAcP protein. The IL-33 antagonists of the invention are useful for the treatment of diseases and disorders associated with IL-33 signaling and/or IL-33 cellular expression, such as infectious diseases, inflammatory diseases, allergic diseases and fibrotic diseases.

公开(公告)号：US09035128B2

公开(公告)日：2015-05-19

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 ,  C12N5/07 ,  C12N5/0781 ,  C07K16/00 ,  C07K16/46 ,  C12N15/85 ,  C07K16/18

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.

公开(公告)号：US08883496B2

公开(公告)日：2014-11-11

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： C12N5/00 ,  A01K67/027

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性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：US20130024957A1

公开(公告)日：2013-01-24

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

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

IPC分类号： A01K67/027 ,  A61K35/14 ,  A61K35/407 ,  A61K35/12

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.

公开(公告)号：US20110307966A1

公开(公告)日：2011-12-15

申请号：US13155491

申请日：2011-06-08

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

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

IPC分类号： A01K67/027 ,  C12N15/63 ,  C12N5/10

CPC分类号： A01K67/0278 ,  A01K2217/072 ,  A01K2227/105 ,  A01K2267/0356

摘要： Genetically modified non-human animals and methods and compositions for making and using them are provided, wherein the genetic modification comprises a humanization of an extracellular loop of an endogenous NaV channel gene, in particular a humanization of the one or more extracellular pore loops of a NaV1.7 channel protein. Genetically modified non-human animals are also provided, wherein the genetic modification comprises replacement of an endogenous NaV channel gene, in particular a replacement of the endogenous NaV1.7 gene with a human NaV1.7 gene, and wherein the genetically modified non-human animals are capable of generating action potentials and communicating through the excitable cells of the genetically modified non-human animals via the expressed human or humanized NaV1.7 protein the surface of the excitable cells. Genetically modified mice are described, including mice that express the human or humanized NaV1.7 gene from the endogenous NaV1.7 locus, and wherein the mice comprise functional β-subunits.

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NaV通道基因的细胞外环的人源化，特别是一种或多种细胞外孔环的人源化 NaV1.7通道蛋白。 还提供了遗传修饰的非人动物，其中遗传修饰包括内源性NaV通道基因的替换，特别是用人NaV1.7基因替代内源性NaV1.7基因，并且其中所述遗传修饰的非人动物 动物能够通过表达的人或人源化NaV1.7蛋白质产生动力电位并通过基因修饰的非人动物的可兴奋细胞进行通信，所述可激活细胞的表面。 描述了转基因小鼠，包括从内源性NaV1.7基因座表达人或人源化NaV1.7基因的小鼠，其中小鼠包含功能性和亚基。

公开(公告)号：US20110145937A1

公开(公告)日：2011-06-16

申请号：US12965050

申请日：2010-12-10

申请人： Lynn MacDonald ,  Sean Stevens ,  Andrew J. Murphy

发明人： Lynn MacDonald ,  Sean Stevens ,  Andrew J. Murphy

IPC分类号： A01K67/027 ,  C12P21/00

CPC分类号： A01K67/0278 ,  A01K67/0275 ,  A01K67/0276 ,  A01K2217/072 ,  A01K2217/075 ,  A01K2227/105 ,  A01K2267/01 ,  C07K16/00 ,  C07K16/462 ,  C07K2317/14 ,  C07K2317/20 ,  C07K2317/21 ,  C07K2317/50 ,  C07K2317/52 ,  C12N15/8509

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 in an immunoglobulin constant region CH1 gene (optionally a deletion in a hinge region) of an IgG, IgA, IgD, and/or IgE, and wherein the mouse is capable of expressing a functional IgM. Genetically modified mice are described, including mice having a functional IgM gene and modified to have a deletion of a CH1 domain and a hinge region in a heavy chain constant domain that is not an IgM, e.g., in an IgG heavy chain constant domain. Genetically modified mice that make human variable/mouse constant chimeric heavy chain antibodies (antibodies that lack a light chain), fully mouse heavy chain antibodies, or fully human heavy chain antibodies 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，其中遗传修饰包括IgG，IgA，IgD和/或IgG的免疫球蛋白恒定区CH1基因（任选地在铰链区的缺失）中的缺失 /或IgE，并且其中所述小鼠能够表达功能性IgM。 描述了遗传修饰的小鼠，包括具有功能性IgM基因的小鼠，并且被修饰为具有不是IgM的重链恒定结构域中的CH1结构域和铰链区的缺失，例如在IgG重链恒定结构域中。 提供了使人可变/小鼠恒定的嵌合重链抗体（缺乏轻链的抗体），完全小鼠重链抗体或完全人重链抗体的转基因小鼠。