Human lambda light chain mice

Abstract

Genetically modified mice are provided that express human λ variable (hVλ) sequences, including mice that express hVλ sequences from an endogenous mouse λ light chain locus, mice that express hVλ sequences from an endogenous mouse κ light chain locus, and mice that express hVλ sequences from a transgene or an episome wherein the hVλ sequence is linked to a mouse constant sequence. Mice are provided that are a source of somatically mutated human λ variable sequences useful for making antigen-binding proteins. Compositions and methods for making antigen-binding proteins that comprise human λ variable sequences, including human antibodies, are provided.

1 - 20 . (canceled) 
     
     
         21 . A method of making an antibody comprising a human light chain variable domain, the method comprising:
 (a) exposing a genetically modified mouse to an antigen, wherein the genetically modified mouse has a genome that comprises:
 (i) one or more unrearranged human Vλ gene segments, 
 (ii) one or more unrearranged human Jλ gene segments, and 
 (iii) one or more human Cλ gene segments, 
 wherein the one or more unrearranged human Vλ gene segments of (i) and the one or more unrearranged human Jλ gene segments of (ii) are at an endogenous mouse λ light chain locus; 
   (b) allowing the genetically modified mouse to develop an immune response to the antigen; and   (c) isolating from the mouse of (b) an antibody specific to the antigen, wherein the antibody comprises a human light chain variable domain expressed from a rearranged human lambda light chain variable region derived from a human Vλ gene segment of the one or more unrearranged human Vλ gene segments of (i) and a human Jλ gene segment of the one or more unrearranged human Jλ gene segments of (ii).   
     
     
         22 . The method of  claim 21 , wherein the genome of the genetically modified mouse includes an endogenous lambda light chain variable region sequence. 
     
     
         23 . The method of  claim 21 , wherein the endogenous mouse λ light chain locus comprises one or more mouse Cλ gene segments. 
     
     
         24 . The method of  claim 23 , wherein the one or more mouse Cλ gene segments is one mouse Cλ gene segment. 
     
     
         25 . The method of  claim 23 , wherein the one or more unrearranged human Vλ gene segments of (i) and the one or more unrearranged human Jλ gene segments of (ii) are operably linked to the one or more human Cλ gene segments of (iii). 
     
     
         26 . The method of  claim 21 , wherein the one or more unrearranged human Vλ gene segments of (i) and the one or more unrearranged human Jλ gene segments of (ii) are operably linked to the one or more mouse Cλ gene segments. 
     
     
         27 . The method of  claim 21 , wherein the one or more human Cλ gene segments comprise at least four human Cλ gene segments. 
     
     
         28 . The method of  claim 21 , wherein the one or more unrearranged human Jλ gene segments comprise a human Jλ1 gene segment. 
     
     
         29 . The method of  claim 21 , wherein the one or more unrearranged human Jλ gene segments comprise at least two human Jλ gene segments. 
     
     
         30 . The method of  claim 21 , wherein the one or more unrearranged human Jλ gene segments comprise at least three human Jλ gene segments. 
     
     
         31 . The method of  claim 21 , wherein the one or more unrearranged human Jλ gene segments comprise at least four human Jλ gene segments. 
     
     
         32 . The method of  claim 21 , wherein the one or more unrearranged human Jλ gene segments comprise at least five human Jλ gene segments. 
     
     
         33 . The method of  claim 31 , wherein the at least four human Jλ gene segments are Jλ1, Jλ2, Jλ3 and Jλ7. 
     
     
         34 . The method of  claim 21 , wherein the one or more unrearranged human Jλ gene segments of (b) and the one or more human Cλ gene segments of (c) are present as J-C clusters. 
     
     
         35 . The method of  claim 21 , wherein the one or more unrearranged human Vλ gene segments comprise at least 12 human Vλ gene segments. 
     
     
         36 . The method of  claim 21 , wherein the one or more unrearranged human Vλ gene segments comprise at least 28 human Vλ gene segments. 
     
     
         37 . The method of  claim 21 , wherein one or more mouse enhancers are maintained at the endogenous mouse λ light chain locus. 
     
     
         38 . The method of  claim 21 , wherein the endogenous mouse λ light chain locus further comprises one or more human enhancers. 
     
     
         39 . The method of  claim 38 , wherein the one or more human enhancers are λ light chain enhancers. 
     
     
         40 . The method of  claim 21 , comprising at least two λ light chain enhancers downstream of both the one or more unrearranged human Vλ gene segments of (i) and the one or more unrearranged human Jλ gene segments of (ii). 
     
     
         41 . The method of  claim 21 , wherein the mouse produces antibodies comprising human lambda variable domains. 
     
     
         42 . The method of  claim 21 , wherein the one or more unrearranged human Vλ gene segments comprise Vλ3-1, Vλ4-3, Vλ2-8, Vλ3-9, Vλ3-10, Vλ2-11, Vλ3-12 or a combination thereof. 
     
     
         43 . The method of  claim 21 , wherein the one or more unrearranged human Vλ gene segments comprise human Vλ2-14, Vλ3-16, Vλ2-18, Vλ3-19, Vλ3-21, Vλ3-22, Vλ2-23, Vλ3-25, Vλ3-27 or a combination thereof. 
     
     
         44 . The method of  claim 21 , wherein the one or more unrearranged human Vλ gene segments comprise human Vλ1-40, Vλ7-43, Vλ1-44, Vλ5-45, Vλ7-46, Vλ1-47, Vλ9-49, Vλ1-51, Vλ5-52 or a combination thereof. 
     
     
         45 . The method of  claim 21 , wherein the human Vλ gene segment from which the rearranged human lambda light chain variable region is derived is a human Vλ3-1, Vλ4-3, Vλ2-8, Vλ3-9, Vλ3-10, Vλ2-14, Vλ3-19, Vλ2-23, Vλ3-25, Vλ1-40, Vλ7-43, Vλ1-44, Vλ5-45, Vλ7-46, Vλ9-49, Vλ1-51, Vλ1-47, or Vλ7-46. 
     
     
         46 . The method of  claim 42 , wherein the one or more human Vλ gene segments from which the rearranged human lambda light chain variable region is derived is a human Vλ3-1, Vλ4-3, Vλ2-8, Vλ3-9, or Vλ3-10. 
     
     
         47 . The method of  claim 43 , wherein the one or more human Vλ gene segments from which the rearranged human lambda light chain variable region is derived is a human Vλ2-14, Vλ3-16, Vλ2-18, Vλ3-19, Vλ3-21, Vλ3-22, Vλ2-23, Vλ3-25, or Vλ3-27. 
     
     
         48 . The method of  claim 21 , wherein the human Jλ gene segment from which the rearranged human lambda light chain variable region is derived is a human Jλ1, Jλ2, Jλ3, or Jλ7.