Common light chain mouse

Abstract

A genetically modified mouse is provided, wherein the mouse is incapable of rearranging and expressing an endogenous mouse immunoglobulin light chain variable sequence, wherein the mouse expresses only one or two human light chain variable domains encoded by human immunoglobulin sequences operably linked to the mouse kappa (κ) constant gene at the endogenous mouse κ locus, wherein the mouse expresses a reverse chimeric antibody having a light chain variable domain derived from one of only two human light chain variable region gene segments and a mouse κ constant domain, and a human heavy chain variable domain and a mouse heavy chain constant domain, from an endogenous mouse heavy chain locus. Bispecific epitope-binding proteins that are fully human are provided, comprising two different heavy chains that associate with an identical light chain that comprises a variable domain derived from one of two different human light chain variable region gene segments.

What is claimed is: 
     
         1 . A mouse that expresses a population of antigen-specific antibodies in response to challenge with an antigen,
 wherein all immunoglobulin light chains of the population of antigen-specific antibodies comprise a human immunoglobulin light chain variable (V L ) region derived from a single rearranged human light chain variable region sequence in a germline of the mouse, wherein the single rearranged human light chain variable region sequence comprises a human germline Vκ1-39 gene segment and   wherein immunoglobulin heavy chains of the population comprise a human immunoglobulin heavy chain variable (V H ) region cognate with said V L  region wherein the V H  region comprises a sequence derived from a human V H  segment selected from V H 2-5, V H 3-23, V H 3-30, V H 4-59, and V H 5-51.   
     
     
         2 . The mouse of  claim 1 , wherein the single rearranged human light chain variable region sequence further comprises a human germline Jκ5 gene segment. 
     
     
         3 . The mouse of  claim 2 , wherein the human germline Vκ1-39 gene segment is present in rearrangement with the human germline Jκ5 gene segment in the mouse germline. 
     
     
         4 . The mouse of  claim 1 , wherein the mouse lacks a mouse immunoglobulin V L  and/or J L  segment(s). 
     
     
         5 . The mouse of  claim 1 , wherein the single rearranged human light chain variable region sequence is operably linked to a murine immunoglobulin light chain constant (C L ) region. 
     
     
         6 . The mouse of  claim 1 , wherein the human V L  region is expressed from an endogenous mouse immunoglobulin light chain locus. 
     
     
         7 . The mouse of  claim 1 , wherein the human V H  region further comprises a sequence derived from human D H 6-6, D H 3-10, D H 3-3, D H 1-7, D H 5-12, D H 6-13, D H 7-27, D H 3-22, D H 3-16 or D H 5-5 gene segment. 
     
     
         8 . The mouse of  claim 1 , wherein the human V H  region further comprises a sequence derived from human J H 1, J H 3, J H 4, or J H 5 gene segment. 
     
     
         9 . The mouse of  claim 1 , wherein the human V H  region is linked to a murine immunoglobulin heavy chain constant (C H ) region. 
     
     
         10 . The mouse of  claim 1 , wherein the human V H  region is expressed from an endogenous immunoglobulin heavy chain locus. 
     
     
         11 . A mouse that expresses a population of antigen-specific antibodies in response to challenge with an antigen,
 wherein all immunoglobulin light chains of the population of antigen-specific antibodies comprise a human immunoglobulin light chain variable (V L ) region derived from a single rearranged human light chain variable region sequence in the germline of a mouse, wherein the single rearranged human light chain variable region sequence comprises a human germline Vκ1-39 gene segment and   immunoglobulin heavy chains of the population comprise a human immunoglobulin heavy chain variable (V H ) region cognate with said V L  region wherein the V H  region is derived from a human V H /D H /J H  rearrangement selected from 2-5/6-6/1, 3-23/3-10/4, 3-23/3-3/4, 3-30/6-6/1, 3-30/6-6/3, 3-30/1-7/4, 3-30/5-12/4, 3-30/6-13/4, 3-30/6-6/4, 3-30/7-27/4, 3-30/3-22/5, 3-30/6-6/5, 3-30/7-27/5, 4-59/3-16/3, 4-59/3-22/3, 4-59/3-16/4, and 5-51/5-5/3.   
     
     
         12 . The mouse of  claim 11 , wherein the single rearranged human light chain variable region sequence further comprises a human germline Jκ5 gene segment. 
     
     
         13 . The mouse of  claim 12 , wherein the human germline Vκ1-39 gene segment is present in rearrangement with the human germline Jκ5 gene segment in the mouse germline. 
     
     
         14 . The mouse of  claim 11 , wherein the mouse lacks a mouse immunoglobulin V L  and/or J L  segment(s). 
     
     
         15 . The mouse of  claim 11 , wherein the single rearranged human light chain variable region sequence is operably linked to a murine immunoglobulin light chain constant (C L ) region. 
     
     
         16 . The mouse of  claim 11 , wherein the human V L  region is expressed from an endogenous mouse immunoglobulin light chain locus. 
     
     
         17 . The mouse of  claim 11 , wherein the human V H  region is linked to a murine immunoglobulin heavy chain constant (C H ) region. 
     
     
         18 . The mouse of  claim 11 , wherein the human V H  region is expressed from an endogenous immunoglobulin heavy chain locus. 
     
     
         19 . A method of making an antibody comprising:
 (a) immunizing a genetically modified mouse with an antigen of interest, wherein the mouse comprises in its germline
 (i) an immunoglobulin κ light chain sequence that comprises a single rearranged human light chain variable region sequence that comprises a human germline Vκ1-39 gene segment, and 
 (ii) at least one human V H , at least one human D H , and at least one human J H  gene segment, wherein the at least one human V H , D H , and J H  gene segments are at an endogenous mouse locus and are capable of rearranging to form a heavy chain variable region sequence, wherein the heavy chain variable region sequence is operably linked to a murine heavy chain constant sequence; 
   (b) allowing the mouse to develop an immune response to the antigen of interest, wherein the mouse expresses a population of antibodies in response to the antigen of interest that comprise a human heavy chain variable region (V H ) region derived from a human V H  segment selected from V H 2-5, V H 3-23, V H 3-30, V H 4-59, and V H 5-51;   (c) identifying a sequence that encodes a human V H  region that specifically binds to the antigen of interest; and   (d) employing the sequence of (c) in making an antibody wherein the antibody comprises a human light chain variable region (V L ) derived from the single rearranged human light chain variable region sequence and a human V H  region that is cognate with said V L  region.   
     
     
         20 . The method of  claim 19 , wherein the single rearranged human light chain variable region sequence further comprises a human germline Jκ5 gene segment, and wherein the human germline Vκ1-39 gene segment is present in rearrangement with the human germline Jκ5 gene segment in the mouse germline. 
     
     
         21 . The method of  claim 19 , wherein the mouse lacks a mouse immunoglobulin V L  and/or J L  segment(s). 
     
     
         22 . The method of  claim 19 , wherein the single rearranged human light chain variable region sequence is operably linked to a murine immunoglobulin light chain constant (C L ) region. 
     
     
         23 . The method of  claim 19 , wherein the human V L  region is expressed from an endogenous mouse immunoglobulin light chain locus. 
     
     
         24 . The method of  claim 19 , wherein the human V H  region further comprises a sequence derived from human D H 6-6, D H 3-10, D H 3-3, D H 1-7, D H 5-12, D H 6-13, D H 7-27, D H 3-22, D H 3-16, or D H 5-5 gene segment. 
     
     
         25 . The method of  claim 19 , wherein the human V H  region further comprises a sequence derived from human J H 1, J H 3, J H 4, or J H 5 gene segment. 
     
     
         26 . A mouse that expresses a population of antibodies
 wherein each immunoglobulin light chain of the population comprises a human immunoglobulin light chain variable (V L ) region derived from a single rearranged human light chain variable region sequence in a germline of the mouse, wherein the single rearranged human light chain variable region sequence comprises a human germline Vκ3-20 gene segment or a human germline Vκ1-39 gene segment and   wherein immunoglobulin heavy chains of the population comprise a human immunoglobulin heavy chain variable (V H ) region cognate with said V L  region wherein the V H  region comprises a sequence derived from human V H  segment 5-51.   
     
     
         27 . The mouse of  claim 26 , wherein the single rearranged human light chain variable region sequence further comprises a human germline Jκ1 or Jκ5 gene segment. 
     
     
         28 . The mouse of  claim 26 , wherein the human V H  region further comprises a sequence derived from a human J H 3, J H 5, or J H 6 gene segment. 
     
     
         29 . The mouse of  claim 26 , wherein the human V H  region further comprises a sequence derived from a human D H  5-5, D H 3-16, or D H 6-13 gene segment. 
     
     
         30 . The mouse of  claim 26  wherein the human immunoglobulin V H  region is derived from a human V H /D H /J H  gene segment rearrangement selected from 5-51/5-5/3, 5-51/6-13/5, or 5-51/3-16/6.