The Jackson Laboratory

University of Massachusetts

Riken Corporation

Leonard D Shultz

Dale L Greiner

Michael A Brehm

Mohit Kumar Verma

Osamu Ohara

Michael V Wiles

James Keck

Fumihiko Ishikawa

Yoriko Saito

Atsushi Hijikata

Hiroshi Kitamura

Hidetoshi Ozawa

A method of identifying anti-tumor activity of a test substance is provided along with a genetically-modified, immunodeficient mouse and methods of use, wherein the genetically-modified, immunodeficient mouse enables in vivo investigation of the interactions between the human immune system and human cancer.

Methods and models for assessing efficacy of immunotherapies

Provided herein, in some aspects, is a NOD.Cg-PrkdcIl2rg/SzJ (NOD scid gamma or NSG™) mouse comprising a nucleic acid encoding human FLT3L and an inactivated mouse Flt3 allele, methods of producing the mouse, and methods of using the mouse.

Transgenic mouse models supporting innate immune function

The present invention relates generally to genetically modified non-human animals and immunodeficient non-human animals characterized by restored complement-dependent cytotoxicity, as well as methods and compositions for assessment of therapeutic antibodies in the genetically modified immunodeficient non-human animals. In specific aspects, the present invention relates to immunodeficient non-obese diabetic (NOD), A/J, A/He, AKR, DBA/2, NZB/B1N, B10.D2/oSn and other mouse strains genetically modified to restore complement-dependent cytotoxicity which is lacking in the unmodified immunodeficient mice. In further specific aspects, the present invention relates to NOD.Cg-PrkdcIL2re/SzJ (NSG), NOD.Cg-Rag1Il2rg/SzJ (NRG) and NOD.Cg-PrkdcIl2rg/JicTac (NOG) mice genetically modified to restore complement-dependent cytotoxicity which is lacking in unmodified NSG, NRG and NOG mice. Methods for assessment of therapeutic antibodies or putative therapeutic antibodies in the genetically modified immunodeficient mice characterized by an intact complement system are provided according to specific aspects of the present invention.

Genetically modified non-human animals and methods relating to complement dependent cytotoxicity

A NOD.Cg-PrkdcH2rg/SzJ.(NOD-scid-IL2r&#x3b3;, NSG) mouse which is genetically modified such that the en NSG mouse lacks functional major histocompatibility complex I (MHC I) and lacks functional major histocompatibility complex II (MHC II) is provided according to aspects of the present, invention. According to specific aspects the genetically modified NSG mouse, is a NOD.Cg-PrkdcH2-K1H2-Ab1H2-D1H2rg/SzJ (NSG-KD)(IA)) mouse, NSG-RIP-DTR (KD)(IA) mouse, or a NOD.Cg-B2mPrKdcH2H2rg/SzJ (NSG-B2M(IA IE)) mouse. Human, immune cells and/or human: tumor cells are administered to a genetically modified immunodeficient mouse according to aspects described herein and assays of one or more test substances can be performed using the provided mice.

NSG mice lacking MHC class I and class II

The present invention relates generally to genetically modified non-human animals and immunodeficient non-human animals characterized by restored complement-dependent cytotoxicity, as well as methods and compositions for assessment of therapeutic antibodies in the genetically modified immunodeficient non-human animals. In specific aspects, the present invention relates to immunodeficient non-obese diabetic (NOD), A/J, A/He, AKR, DBA/2, NZB/BIN, B10.D2/oSn and other mouse strains genetically modified to restore complement-dependent cytotoxicity which is lacking in the unmodified immunodeficient mice. In further specific aspects, the present invention relates to NOD.Cg-PrkdcIL2rg/SzJ (NSG), NOD.Cg-Rag1IL2rg/SzJ (NRG) and NOD.Cg-PrkdcIL2rg/JicTAc (NOG) mice genetically modified to restore complement-dependent cytotoxicity which is lacking in unmodified NSG, NRG and NOG mice. Methods for assessment of therapeutic antibodies or putative therapeutic antibodies in the genetically modified immunodeficient mice characterized by an intact complement system are provided according to specific aspects of the present invention.

Described herein are immunodeficient non-human animals lacking expression of toll-like receptor 4 (TLR4) by endogenous autogeneic innate immune cells, as well as methods and compositions for engraftment of xenogeneic hematopoietic stem cells in the immunodeficient non-human animal lacking expression of toll-like receptor 4 (TLR4), thereby creating an innate immune system in the animal derived from the xenogeneic hematopoietic stem cells. Further described are immunodeficient mice lacking expression of toll-like receptor 4 by endogenous autogeneic innate immune cells, as well as methods and compositions for engraftment of xenogeneic hematopoietic stem cells in the immunodeficient mouse lacking expression of toll-like receptor 4, thereby creating an innate immune system in the animal derived from the xenogeneic hematopoietic stem cells.

Genetically modified non-human animals and methods relating to innate immune system response detection

The invention relates to a method of selectively expanding human leukemic cells in a non-adult NOD/SCID/IL2rgmouse by transplanting a substance containing a leukemic stem cell derived from a human acute myelogenous leukemia patient to the mouse. In addition, the invention relates to screening for a medicament capable of eradicating leukemic stem cell (LSC), consideration of treatment methods suitable for individual patients, identification of a differentially expressed gene and the like, using a mouse with expanded human leukemic cells.

Mouse having human leukemic stem cell and leukemic non-stem cell amplified therein, and method for production thereof

Transgenic immunodeficient non-human animals according to embodiments of the present invention are described which include in their genome a nucleic acid encoding xenogeneic Stem Cell Factor operably linked to a promoter. Administration of xenogeneic hematopoetic stem cells to the inventive transgenic animals results in engraftment of the xenogeneic hematopoetic stem cells and xenogeneic leukocytes are produced in the animals, without conditioning such as without conditioning by irradiation and without conditioning by a radiomimetic agent.

Growing community of inventors

Bar Harbor, ME, United States of America

Leonard D Shultz