公开(公告)号：EP4248740A3

公开(公告)日：2023-12-27

申请号：EP23175415.1

申请日：2016-04-12

申请人： Regeneron Pharmaceuticals, Inc. ,  Yale University ,  Institute for Research in Biomedicine (IRB)

发明人： HERNDLER-BRANDSTETTER, Dietmar ,  FLAVELL, Richard A. ,  FRLETA, Davor ,  GURER, Cagan ,  MANZ, Markus, Gabriel ,  MURPHY, Andrew, J. ,  PALM, Noah, W. ,  SHAN, Liang ,  STEVENS, Sean ,  STROWIG, Till ,  YANCOPOULOS, George, D. ,  DE ZOETE, Marcel

IPC分类号： A01K67/027 ,  A01K39/00 ,  A61P35/00 ,  C07K14/47 ,  C07K14/54

摘要： Genetically modified non-human animals expressing human SIRPα and human IL-15 from the non-human animal genome are provided. Also provided are methods for making non-human animals expressing human SIRPα and human IL-15 from the non-human animal genome, and methods for using non-human animals expressing human SIRPα and human IL-15 from the non-human animal genome. These animals and methods find many uses in the art, including, for example, in modeling human T cell and/or natural killer (NK) cell development and function, in modeling human pathogen infection of human T cells and/or NK cells, and in various in vivo screens.

公开(公告)号：EP3308641B1

公开(公告)日：2019-07-03

申请号：EP17184813.8

申请日：2013-11-05

申请人： Regeneron Pharmaceuticals, Inc. ,  Yale University ,  Institute for Research in Biomedicine (IRB)

发明人： FLAVELL, Richard ,  STROWIG, Till ,  MANZ, Markus G. ,  BORSOTTI, Chiara ,  DHODAPKAR, Madhav ,  MURPHY, Andrew J. ,  STEVENS, Sean ,  YANCOPOULOS, George D.

IPC分类号： A01K67/027 ,  C07K14/54 ,  C07K14/535

公开(公告)号：EP3056082A1

公开(公告)日：2016-08-17

申请号：EP16157878.6

申请日：2010-10-04

申请人： Regeneron Pharmaceuticals, Inc. ,  Yale University ,  Institute for Research in Biomedicine (IRB)

发明人： STEVENS, Sean ,  MURPHY, Andrew J. ,  FLAVELL, Richard ,  EYNON, Elizabeth ,  GALAN, Jorge ,  WILLINGER, Tim ,  MANZ, Markus, G. ,  RONGVAUX, Anthony ,  YANCOPOULOS, George D.

IPC分类号： A01K67/027 ,  C07K14/52 ,  C07K14/535 ,  C12N9/00 ,  C07K14/715 ,  C07K14/54 ,  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 yeloproliferative 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）群体衍生自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叶绿体增生性肿瘤。

公开(公告)号：EP4389764A2

公开(公告)日：2024-06-26

申请号：EP24161280.3

申请日：2013-11-05

申请人： Regeneron Pharmaceuticals, Inc. ,  Yale University ,  Institute for Research in Biomedicine (IRB)

发明人： FLAVELL, Richard ,  STROWIG, Till ,  MANZ, Markus G. ,  BORSOTTI, Chiara ,  DHODAPKAR, Madhav ,  MURPHY, Andrew J. ,  STEVENS, Sean ,  YANCOPOULOS, George D.

IPC分类号： C07K14/535

CPC分类号： C07K14/535 ,  C07K14/5403 ,  C07K14/5412 ,  A01K2217/05220130101 ,  A01K2217/07220130101 ,  A01K2217/1520130101 ,  A01K2227/10520130101 ,  C07K14/524 ,  A01K2267/0120130101 ,  A01K67/0278 ,  A61K49/0008

摘要： Genetically modified non-human animals are provided that may be used to model human hematopoietic cell development, function, or disease. The genetically modified non-human animals comprise a nucleic acid encoding human IL-6 operably linked to an IL-6 promoter. In some instances, the genetically modified non-human animal expressing human IL-6 also expresses at least one of human M-CSF, human IL-3, human GM-CSF, human SIRPa or human TPO. In some instances, the genetically modified non-human animal is immunodeficient. In some such instances, the genetically modified non-human animal is engrafted with healthy or diseased human hematopoietic cells. Also provided are methods for using the subject genetically modified non-human animals in modeling human hematopoietic cell development, function, and/or disease, as well as reagents and kits thereof that find use in making the subject genetically modified non-human animals and/or practicing the subject methods.

公开(公告)号：EP4233537A3

公开(公告)日：2023-09-13

申请号：EP23161285.4

申请日：2012-02-14

申请人： Regeneron Pharmaceuticals, Inc. ,  Yale University ,  Institute for Research in Biomedicine (IRB)

发明人： MURPHY, Andrew J. ,  STEVENS, Sean ,  RATHINAM, Chozhavendan ,  EYNON, Elizabeth ,  MANZ, Markus G. ,  FLAVELL, Richard ,  YANCOPOULOS, George D.

IPC分类号： A01K67/027

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.

公开(公告)号：EP2675271A2

公开(公告)日：2013-12-25

申请号：EP12746594.6

申请日：2012-02-14

申请人： Regeneron Pharmaceuticals, Inc. ,  Yale University ,  Institute for Research in Biomedicine (IRB)

发明人： MURPHY, Andrew J. ,  STEVENS, Sean ,  RATHINAM, Chozhavendan ,  EYNON, Elizabeth ,  MANZ, Markus G. ,  FLAVELL, Richard ,  YANCOPOULOS, George D.

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蛋白质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造血细胞的人M-CSF蛋白质的核酸序列的遗传修饰小鼠，以及用于制备这种移植小鼠的方法。 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/或活性的药剂的体内筛选中。 处于健康或疾病状态; 在体内筛选对造血细胞有毒性的药剂; 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：EP4049535A1

公开(公告)日：2022-08-31

申请号：EP21214150.1

申请日：2010-10-04

申请人： Regeneron Pharmaceuticals, Inc. ,  Yale University ,  Institute for Research in Biomedicine (IRB)

发明人： STEVENS, Sean ,  MURPHY, Andrew J. ,  FLAVELL, Richard ,  EYNON, Elizabeth ,  GALAN, Jorge ,  WILLINGER, Tim ,  MANZ, Markus, G. ,  RONGVAUX, Anthony ,  YANCOPOULOS, George D.

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

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 mll2rg 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 modelled 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 dells is described, e.g., a myeloid leukemia or a myeloproliferative neoplasia.

公开(公告)号：EP3145307B1

公开(公告)日：2019-02-06

申请号：EP15756500.3

申请日：2015-05-18

申请人： Regeneron Pharmaceuticals, Inc. ,  Yale University ,  Institute for Research in Biomedicine (IRB)

发明人： MURPHY, Andrew J. ,  STEVENS, Sean ,  FLAVELL, Richard ,  MANZ, Markus ,  SHAN, Liang

IPC分类号： A01K67/027 ,  C07K14/535 ,  C07K14/715 ,  C07K14/54 ,  C07K14/52 ,  C07K14/505 ,  C12N9/00 ,  A61K49/00 ,  G01N33/50 ,  C07K14/47

公开(公告)号：EP3417701A1

公开(公告)日：2018-12-26

申请号：EP18183928.3

申请日：2010-10-04

申请人： Regeneron Pharmaceuticals, Inc. ,  Yale University ,  Institute for Research in Biomedicine (IRB)

发明人： STEVENS, Sean ,  MURPHY, Andrew J. ,  FLAVELL, Richard ,  EYNON, Elizabeth ,  GALAN, Jorge ,  WILLINGER, Tim ,  MANZ, Markus, G. ,  RONGVAUX, Anthony ,  YANCOPOULOS, George D.

IPC分类号： A01K67/027 ,  C07K14/52 ,  C07K14/535 ,  C12N9/00 ,  C07K14/715 ,  C07K14/54 ,  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 mll2rg 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 modelled 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 dells is described, e.g., a myeloid leukemia or a myeloproliferative neoplasia.

公开(公告)号：EP3375284A1

公开(公告)日：2018-09-19

申请号：EP18166409.5

申请日：2012-02-14

申请人： Regeneron Pharmaceuticals, Inc. ,  Yale University, Inc. ,  Institute for Research in Biomedicine (IRB)

发明人： MURPHY, Andrew J. ,  STEVENS, Sean ,  RATHINAM, Chozhavendan ,  EYNON, Elizabeth ,  MANZ, Markus G. ,  FLAVELL, Richard ,  YANCOPOULOS, George D.

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.