Mice that produce hybrid antibodies
A method for engineering and utilizing large DNA vectors to target, via homologous recombination, and modify, in any desirable fashion, endogenous genes and chromosomal loci in eukaryotic cells. These large DNA targeting vectors for eukaryotic cells, termed LTVECs, are derived from fragments of cloned genomic DNA larger than those typically used by other approaches intended to perform homologous targeting in eukaryotic cells. Also provided is a rapid and convenient method of detecting eukaryotic cells in which the LTVEC has correctly targeted and modified the desired endogenous gene(s) or chromosomal locus (loci) as well as the use of these cells to generate organisms bearing the genetic modification.
1. A transgenic mouse whose genome comprises 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 immunoglobulin heavy chain 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 unrearranged human immunoglobulin heavy chain V, D, and J gene segments in the mouse results in a rearranged human immunoglobulin heavy chain variable region gene linked to the mouse immunoglobulin heavy 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 and a mouse immunoglobulin heavy chain constant region encoded by the mouse immunoglobulin heavy chain constant region gene, wherein mouse V gene segments are present upstream of the unrearranged human immunoglobulin heavy chain variable region gene segments, and wherein the endogenous immunoglobulin enhancer Eμ remains intact upstream of the mouse immunoglobulin heavy chain constant region gene.
2. The mouse of claim 1 , wherein the unrearranged human immunoglobulin heavy chain V, D, and J gene segments are contained on a human genomic DNA fragment that is larger than 20 kb.
3. The mouse of claim 1 , wherein the unrearranged human immunoglobulin heavy chain V, D, and J gene segments are contained on a human genomic DNA fragment that is larger than 100 kb.