Humanized transgenic animal

Abstract

Provided are a humanized transgenic non-human animal, especially a rodent, in particular a transgenic mouse containing a human interleukin 17A (IL-17A) gene, a human gene 17RA (IL-17RA) and/or a human TNF-alpha gene, and a preparation method therefor and the use thereof.

1 .- 145 . (canceled) 
     
     
         146 . A genetically-modified non-human animal whose genome comprises a sequence encoding a human IL-17A protein. 
     
     
         147 . The animal of  claim 146 , wherein the sequence encoding the human IL-17A protein is operably linked to an endogenous 5′UTR at an endogenous IL-17A gene locus. 
     
     
         148 . The animal of  claim 146 , wherein the human IL-17A protein comprises an amino acid sequence that is at least 80% identical to SEQ ID NO: 4. 
     
     
         149 . The animal of  claim 146 , wherein the human IL-17A protein comprises SEQ ID NO: 4. 
     
     
         150 . The animal of  claim 146 , wherein the human IL-17A protein consists of SEQ ID NO: 4. 
     
     
         151 . The animal of  claim 146 , wherein the animal expresses the human IL-17A protein. 
     
     
         152 . The animal of  claim 146 , wherein the animal is a rodent. 
     
     
         153 . The animal of  claim 146 , wherein the animal is a mouse. 
     
     
         154 . The animal of  claim 146 , whose genome comprises a replacement of a sequence encoding an endogenous IL-17A protein with a corresponding sequence encoding the human IL-17A protein. 
     
     
         155 . The animal of  claim 146 , wherein the animal further comprises either one or both of (a) a sequence encoding a human or humanized IL-17RA protein, and (b) a sequence encoding a human TNF-α protein. 
     
     
         156 . A method of determining in vivo effectiveness of an agent targeting human IL-17/IL-17R signaling pathway, for treating an autoimmune disease, comprising:
 a) constructing a disease model using the animal of  claim 146 ;   b) administering the agent to the animal; and   c) evaluating in vivo effectiveness of the agent targeting human IL-17/IL-17R signaling pathway.   
     
     
         157 . The method of  claim 156 , wherein the agent is an antibody against human IL-17A. 
     
     
         158 . The method of  claim 156 , wherein the autoimmune disease is encephalomyelitis or psoriasis. 
     
     
         159 . A method for making the genetically-modified non-human animal of  claim 146 , comprising:
 replacing in at least one cell of the animal, at an endogenous IL-17A gene locus, a sequence encoding a region of an endogenous IL-17A with a sequence encoding a corresponding region of human IL-17A.   
     
     
         160 . The method of  claim 159 , wherein after the replacement, the animal has one or more cells expressing a human IL-17A protein. 
     
     
         161 . A genetically-modified, non-human animal, wherein the genome of the animal comprises a replacement of a sequence encoding a region of endogenous IL-17A with a sequence encoding a corresponding region of human IL-17A at an endogenous IL-17A gene locus. 
     
     
         162 . The animal of  claim 161 , wherein the animal has one or more cells expressing a human IL-17A protein. 
     
     
         163 . A genetically-modified, non-human animal whose genome comprises a sequence encoding a human TNF-α protein at an endogenous TNF-α gene locus. 
     
     
         164 . The animal of  claim 163 , wherein the animal expresses human TNF-α protein. 
     
     
         165 . The animal of  claim 163 , wherein the human TNF-α protein comprises SEQ ID NO: 58.