Common Light Chain Mouse

Abstract

A genetically modified mouse is provided, wherein the mouse expresses an immunoglobulin light chain repertoire characterized by a limited number of light chain variable domains. Mice are provided that express just one or a few immunoglobulin light chain variable domains from a limited repertoire in their germline. Methods for making light chain variable regions in mice, including human light chain variable regions, are provided. Methods for making human variable regions suitable for use in multispecific binding proteins, e.g., bispecific antibodies, are provided.

1 . A mouse that expresses a population of antigen-specific antibodies in response to challenge with an antigen, wherein all of the immunoglobulin light chains of the population of antigen-specific antibodies comprise a human light chain variable (V L ) region derived from the same single human V L  gene segment and the immunoglobulin heavy chains comprise a human heavy chain variable (V H ) region derived from a human V H  gene segment selected from V H 1-2, V H 1-3, V H 1-8, V H 1-18, V H 1-24, V H 1-46, V H 1-58, V H 1-69, V H 2-5, V H 2-26, V H 2-70, V H 3-7, V H 3-9, V H 3-11, V H 3-13, V H 3-15, V H 3-20, V H 3-21, V H 3-23, V H 3-30, V H 3-33, V H 3-43, V H 3-48, V H 3-53, V H 3-64, V H 3-72, V H 3-73, V H 4-31, V H 4-34, V H 4-39, V H 4-59, V H 5-51, V H 6-1. 
     
     
         2 . The mouse of  claim 1 , wherein the same single human V L  gene segment is a human Vκ1-39 gene segment. 
     
     
         3 . The mouse of  claim 1 , wherein the same single human V L  gene segment is a human Vκ3-20 gene segment. 
     
     
         4 . The mouse of  claim 1 , wherein all of the immunoglobulin light chains comprise a human light chain J (J L ) gene segment. 
     
     
         5 . The mouse of  claim 4 , wherein the human J L  gene segment is selected from a human Jκ1 and a Jκ5 gene segment. 
     
     
         6 . The mouse of  claim 1 , wherein the mouse lacks a sequence selected from a mouse immunoglobulin V L  gene segment, a mouse immunoglobulin J L  gene segment, and a combination thereof. 
     
     
         7 . The mouse of  claim 1 , wherein the human V L  region is operably linked to a human, mouse, or rat immunoglobulin light chain constant (C L ) region. 
     
     
         8 . The mouse of  claim 1 , wherein the human V L  region is expressed from an endogenous immunoglobulin light chain locus. 
     
     
         9 . The mouse of  claim 1 , wherein the human V H  region is operably linked to a human, mouse, or rat 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 of the immunoglobulin light chains of the population of antigen-specific antibodies comprise a human V L  region derived from a human Vκ1-39 gene segment and the immunoglobulin heavy chains comprise a human heavy chain variable (V H ) region derived from a human V H  gene segment selected from V H 1-18, V H 1-69, V H 2-5, V H 3-9, V H 3-13, V H 3-15, V H 3-20, V H 3-23, V H 3-30, V H 3-48, V H 3-53, V H 3-64, V H 4-31, V H 4-34, V H 4-39, V H 4-59, V H 5-51 and V H 6-1. 
     
     
         12 . The mouse of  claim 11 , wherein the human V L  region comprises a Jκ5 sequence. 
     
     
         13 . The mouse of  claim 11 , wherein the mouse lacks a mouse immunoglobulin V L  and/or J L . gene segment. 
     
     
         14 . The mouse of  claim 11 , wherein the human V L  region is operably linked to a human, rat, or mouse immunoglobulin light chain constant (C L ) region. 
     
     
         15 . The mouse of  claim 11 , wherein the human V L  region is expressed from an endogenous immunoglobulin light chain locus. 
     
     
         16 . The mouse of  claim 11 , wherein the human V H  region comprises a sequence that encodes a human J H  region selected from a human J H 1, J H 2, J H 3, J H 4, J H 5, and J H 6 gene segment. 
     
     
         17 . The mouse of  claim 11 , wherein the human V H  region is operably linked to a human, rat, or mouse 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 mouse that expresses a population of antigen-specific antibodies in response to challenge with an antigen, wherein all of the immunoglobulin light chains of the population of antigen-specific antibodies comprise a human V L  region derived from a human Vκ3-20 gene segment and the immunoglobulin heavy chains comprise a human heavy chain variable (V H ) region derived from a human V H  gene segment selected from V H 1-18, V H 1-69, V H 2-70, V H 3-11, V H 3-30, V H 3-33, V H 3-53, V H 4-39, V H 4-59, V H 5-51 and V H 6-1. 
     
     
         20 . The mouse of  claim 19 , wherein the human V L  region comprises a Jκ5 sequence. 
     
     
         21 . The mouse of  claim 19 , wherein the mouse lacks a mouse immunoglobulin V L  and/or J L  gene segment. 
     
     
         22 . The mouse of  claim 19 , wherein the human V L  region is operably linked to a human, rat, or mouse immunoglobulin light chain constant (C L ) region. 
     
     
         23 . The mouse of  claim 19 , wherein the human V L  region is expressed from an endogenous immunoglobulin light chain locus. 
     
     
         24 . The mouse of  claim 19 , wherein the human V H  region comprises a sequence that encodes a human J H  region selected from a human J H 2, J H 3, J H 4, J H 5, and J H 6 gene segment. 
     
     
         25 . The mouse of  claim 19 , wherein the human V H  region is operably linked to a human, rat, or mouse immunoglobulin heavy chain constant (C H ) region. 
     
     
         26 . The mouse of  claim 19 , wherein the human V H  region is expressed from an endogenous immunoglobulin heavy chain locus.