US 11,778,995 B2
Genetically modified non-human animals and methods of use thereof
Richard Flavell, Guilford, CT (US); Till Strowig, Braunschweig (DE); Markus G. Manz, Zollikon (CH); Chiara Borsotti, Bronxville, NY (US); Madhav Dhodapkar, New Haven, CT (US); Andrew J. Murphy, Croton-on-Hudson, NY (US); Sean Stevens, San Diego, CA (US); and George D. Yancopoulos, Yorktown Heights, NY (US)
Assigned to Regeneron Pharmaceuticals, Inc., Tarrytown, NY (US); Yale University, New Haven, CT (US); and Institute for Research in Biomedicine (IRB), Bellinzona (CH)
Filed by Regeneron Pharmaceuticals, Inc., Tarrytown, NY (US); Yale University, New Haven, CT (US); and Institute for Research In Biomedicine (IRB), Bellinzona (CH)
Filed on Aug. 21, 2020, as Appl. No. 17/140.
Application 15/804,989 is a division of application No. 14/072,626, filed on Nov. 5, 2013, granted, now 9,901,082, issued on Feb. 27, 2018.
Application 17/000,140 is a continuation of application No. 15/804,989, filed on Nov. 6, 2017, granted, now 10,785,968.
Claims priority of provisional application 61/722,437, filed on Nov. 5, 2012.
Prior Publication US 2021/0100228 A1, Apr. 8, 2021
Int. Cl. A01K 67/027 (2006.01); C07K 14/535 (2006.01); C07K 14/54 (2006.01); C07K 14/52 (2006.01); A61K 49/00 (2006.01)
CPC A01K 67/0278 (2013.01) [A01K 67/0276 (2013.01); A01K 2207/15 (2013.01); A01K 2217/052 (2013.01); A01K 2217/072 (2013.01); A01K 2217/075 (2013.01); A01K 2217/15 (2013.01); A01K 2227/105 (2013.01); A01K 2267/01 (2013.01); A61K 49/0008 (2013.01); C07K 14/524 (2013.01); C07K 14/535 (2013.01); C07K 14/5403 (2013.01); C07K 14/5412 (2013.01)] 11 Claims
 
1. A method of screening a candidate agent for the ability to treat a hematopoietic cancer, the method comprising,
contacting a first genetically modified, immunodeficient mouse with a candidate agent, wherein the first genetically modified, immunodeficient mouse is a Rag-2−/−IL-2rgnull mouse comprising
a genome comprising a nucleic acid encoding human IL-6, wherein the nucleic acid encoding human IL-6 replaces the endogenous mouse IL-6 gene at the endogenous mouse IL-6 gene locus, and wherein the nucleic acid encoding human IL-6 is operably linked to the endogenous mouse IL-6 promoter, and
an engraftment of human hematopoietic cancer cells; and
comparing the viability and/or proliferative rate of human hematopoietic cancer cells in the contacted first genetically modified, immunodeficient mouse to the viability and/or proliferative rate of human hematopoietic cancer cells in a second genetically modified, immunodeficient mouse not contacted with the candidate agent, wherein the second genetically modified, immunodeficient mouse is a Rag-2−/−IL-2rgnull mouse comprising
a genome comprising a nucleic acid encoding human IL-6, wherein the nucleic acid encoding human IL-6 replaces the endogenous mouse IL-6 gene at the endogenous mouse IL-6 gene locus, and wherein the nucleic acid encoding human IL-6 is operably linked to the endogenous mouse IL-6 promoter, and
an engraftment of human hematopoietic cancer cells,
wherein a decrease in the viability and/or rate of proliferation of the human hematopoietic cancer cells in the contacted first genetically modified,
immunodeficient mouse is indicative of the ability of the candidate agent to treat the hematopoietic cancer.