Mice that produce hybrid antibodies

A transgenic mouse, whose genome comprises:

• (a) unrearranged human immunoglobulin heavy chain V, D and J gene segments, wherein the unrearranged human immunoglobulin heavy chain V, D and J gene segments in situ replace endogenous mouse immunoglobulin heavy chain V, D and J gene segments, and the unrearranged human immunoglobulin heavy chain V, D and J gene segments are operably linked to an endogenous mouse heavy chain immunoglobulin constant region gene, wherein the mouse immunoglobulin heavy chain constant region gene is located at an endogenous mouse immunoglobulin heavy chain constant region locus, wherein the unrearranged human immunoglobulin heavy chain V, D and J gene segments are present in the germline of the mouse, wherein rearrangement of the human immunoglobulin heavy chain V, D and J gene segments in the mouse results in a rearranged immunoglobulin human heavy chain variable region gene linked to the mouse immunoglobulin heavy chain constant region gene;
• and
• (b) unrearranged human immunoglobulin kappa light chain V and J gene segments, wherein the unrearranged human immunoglobulin kappa light chain V and J gene segments in situ replace endogenous mouse immunoglobulin kappa light chain V and J gene segments, and the unrearranged human immunoglobulin kappa light chain V and J gene segments are operably linked to an endogenous mouse immunoglobulin kappa light chain constant region gene, wherein the mouse immunoglobulin kappa light chain constant region gene is located at an endogenous mouse immunoglobulin kappa light chain constant region locus, wherein the unrearranged human immunoglobulin kappa light chain V and J gene segments are present in the germline of the mouse, wherein rearrangement of the human immunoglobulin kappa light chain V and J gene segments in the mouse results in a rearranged human immunoglobulin kappa light chain variable region gene linked to the mouse immunoglobulin kappa light chain constant region gene;
• wherein the mouse in response to an antigen produces a hybrid antibody that comprises a human immunoglobulin heavy chain variable region encoded by the rearranged human immunoglobulin heavy chain variable region gene, a mouse immunoglobulin heavy chain constant region encoded by the mouse immunoglobulin heavy chain constant region gene, a human immunoglobulin kappa light chain variable region encoded by the rearranged human immunoglobulin kappa light chain variable region gene, and a mouse immunoglobulin kappa light chain constant region encoded by the mouse immunoglobulin kappa light chain constant region gene.