公开(公告)号：US08754287B2

公开(公告)日：2014-06-17

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 ,  A01K67/00 ,  C12N15/85

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。

公开(公告)号：US20140023637A1

公开(公告)日：2014-01-23

申请号：US14035432

申请日：2013-09-24

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： A01K67/027

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：US20140020125A1

公开(公告)日：2014-01-16

申请号：US14036784

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： A01K67/027 ,  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.

公开(公告)号：US08847004B2

公开(公告)日：2014-09-30

申请号：US13372787

申请日：2012-02-14

申请人： Andrew J. Murphy ,  Sean Stevens ,  Chozhavendan Rathinam ,  Elizabeth Eynon ,  Markus Manz ,  Richard Flavell ,  George D. Yancopoulos

发明人： Andrew J. Murphy ,  Sean Stevens ,  Chozhavendan Rathinam ,  Elizabeth Eynon ,  Markus Manz ,  Richard Flavell ,  George D. Yancopoulos

IPC分类号： A01K67/027

CPC分类号： A01K67/0278 ,  A01K67/027 ,  A01K67/0271 ,  A01K2207/12 ,  A01K2207/15 ,  A01K2217/072 ,  A01K2217/15 ,  A01K2227/105 ,  A01K2267/03 ,  A01K2267/0337 ,  A61K49/0008 ,  C12N15/8509 ,  C12N2015/8536 ,  G01N33/5088 ,  G01N2500/10

摘要： Genetically modified mice comprising a nucleic acid sequence encoding a human M-CSF protein are provided. Also provided are genetically modified mice comprising a nucleic acid sequence encoding a human M-CSF protein that have been engrafted with human cells such as human hematopoietic cells, and methods for making such engrafted mice. These mice find use in a number of applications, such as in modeling human immune disease and pathogen infection; in in vivo screens for agents that modulate hematopoietic cell development and/or activity, e.g. in a healthy or a diseased state; in in vivo screens for agents that are toxic to hematopoietic cells; in in vivo screens for agents that prevent against, mitigate, or reverse the toxic effects of toxic agents on hematopoietic cells; in in vivo screens of human hematopoietic cells from an individual to predict the responsiveness of an individual to a disease therapy, etc.

摘要翻译： 提供了包含编码人M-CSF蛋白的核酸序列的转基因小鼠。 还提供了包含编码人类细胞如人类造血细胞的人M-CSF蛋白质的核酸序列的遗传修饰的小鼠，以及用于制备这种移植的小鼠的方法。 这些小鼠可用于许多应用，例如建模人类免疫疾病和病原体感染; 在用于调节造血细胞发育和/或活性的试剂的体内筛选中。 处于健康或疾病状态; 在对造血细胞有毒性的药物的体内筛选中; 在体内筛选用于防止，减轻或逆转毒性剂对造血细胞的毒性作用的药剂; 在来自个体的人类造血细胞的体内筛选中以预测个体对疾病治疗的反应性等。

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：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：US20130042330A1

公开(公告)日：2013-02-14

申请号：US13372787

申请日：2012-02-14

申请人： ANDREW J. MURPHY ,  Sean Stevens ,  Chozhavendan Rathinam ,  Elizabeth Eynon ,  Markus Manz ,  Richard Flavell

发明人： ANDREW J. MURPHY ,  Sean Stevens ,  Chozhavendan Rathinam ,  Elizabeth Eynon ,  Markus Manz ,  Richard Flavell

IPC分类号： A01K67/027

CPC分类号： A01K67/0278 ,  A01K67/027 ,  A01K67/0271 ,  A01K2207/12 ,  A01K2207/15 ,  A01K2217/072 ,  A01K2217/15 ,  A01K2227/105 ,  A01K2267/03 ,  A01K2267/0337 ,  A61K49/0008 ,  C12N15/8509 ,  C12N2015/8536 ,  G01N33/5088 ,  G01N2500/10

摘要： Genetically modified mice comprising a nucleic acid sequence encoding a human M-CSF protein are provided. Also provided are genetically modified mice comprising a nucleic acid sequence encoding a human M-CSF protein that have been engrafted with human cells such as human hematopoietic cells, and methods for making such engrafted mice. These mice find use in a number of applications, such as in modeling human immune disease and pathogen infection; in in vivo screens for agents that modulate hematopoietic cell development and/or activity, e.g. in a healthy or a diseased state; in in vivo screens for agents that are toxic to hematopoietic cells; in in vivo screens for agents that prevent against, mitigate, or reverse the toxic effects of toxic agents on hematopoietic cells; in in vivo screens of human hematopoietic cells from an individual to predict the responsiveness of an individual to a disease therapy, etc.

摘要翻译： 提供了包含编码人M-CSF蛋白的核酸序列的转基因小鼠。 还提供了包含编码人类细胞如人类造血细胞的人M-CSF蛋白质的核酸序列的遗传修饰的小鼠，以及用于制备这种移植的小鼠的方法。 这些小鼠可用于许多应用，例如建模人类免疫疾病和病原体感染; 在用于调节造血细胞发育和/或活性的试剂的体内筛选中。 处于健康或疾病状态; 在对造血细胞有毒性的药物的体内筛选中; 在体内筛选用于防止，减轻或逆转毒性剂对造血细胞的毒性作用的药剂; 在来自个体的人类造血细胞的体内筛选中以预测个体对疾病治疗的反应性等。

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：US08692052B2

公开(公告)日：2014-04-08

申请号：US13617472

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： A01K67/033 ,  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 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：US20100316636A1

公开(公告)日：2010-12-16

申请号：US12780006

申请日：2010-05-14

申请人： Allen Radin ,  Sean Stevens ,  Tammy T. Huang ,  Joel H. Martin ,  Jeanette L. Fairhurst ,  Ashique Rafique ,  Eric Smith ,  Kevin J. Pobursky ,  Nicholas J. Papadopoulos ,  James P. Fandl ,  Gang Chen ,  Margaret Karow

发明人： Allen Radin ,  Sean Stevens ,  Tammy T. Huang ,  Joel H. Martin ,  Jeanette L. Fairhurst ,  Ashique Rafique ,  Eric Smith ,  Kevin J. Pobursky ,  Nicholas J. Papadopoulos ,  James P. Fandl ,  Gang Chen ,  Margaret Karow

IPC分类号： A61K39/395 ,  A61P19/02 ,  A61P29/00

CPC分类号： A61K39/3955 ,  A61K31/4706 ,  A61K31/519 ,  A61K31/655 ,  A61K38/191 ,  A61K39/39541 ,  A61K39/39558 ,  A61K45/06 ,  A61K2039/505 ,  C07K16/248 ,  C07K16/2866 ,  C07K2317/21 ,  C07K2317/56 ,  C07K2317/565 ,  C07K2317/76 ,  C07K2317/92 ,  Y10S514/885 ,  A61K2300/00

摘要： The present invention provides methods of preventing or treating rheumatoid arthritis using a fully human antibody or antigen-binding fragment thereof that specifically binds human interleukin-6 receptor (hIL-6R). The methods of the present invention may include administration of a second therapeutic agent, such as one or more of a non-steroidal anti-inflammatory drug (NSAID), a glucocorticoid, a disease-modifying anti-rheumatic drug (DMARD), or a TNF-alpha antagonist, T-cell blocker, anti-CD20 antibody, an IL-1, JAK or IL-17 antagonist, or any combination thereof.

摘要翻译： 本发明提供使用特异性结合人白细胞介素-6受体（hIL-6R）的完全人抗体或其抗原结合片段预防或治疗类风湿性关节炎的方法。 本发明的方法可以包括施用第二治疗剂，例如非甾体抗炎药（NSAID），糖皮质激素，疾病缓解性抗风湿药（DMARD）中的一种或多种，​​或 TNF-α拮抗剂，T细胞阻断剂，抗CD20抗体，IL-1，JAK或IL-17拮抗剂或其任何组合。