Hybrid antibodies comprising human variable regions and mouse constant regions produced in a genetically modified mouse

A method of producing a human antibody, comprising:

• (a) providing a genetically modified mouse having a genome comprising human heavy chain immunoglobulin V, D, and J gene segments and human light chain immunoglobulin V and J gene segments, wherein the human heavy chain V, D, and J gene segments and human light chain V and J gene segments replace mouse endogenous heavy and light chain immunoglobulin variable region gene segments at the endogenous mouse heavy and light chain immunoglobulin variable region gene segment loci, and the human heavy chain V, D, and J gene segments and human light chain V and J gene segments are linked to the endogenous mouse heavy and light chain immunoglobulin constant region gene loci to form hybrid heavy chain locus and a hybrid light heavy chain locus, wherein the human heavy chain V, D, and J gene segments and the human light chain V and J gene segments are present in the germline of the mouse, whereby the hybrid heavy chain locus and hybrid light chain locus rearrange during B-cell development such that the mouse produces a serum containing a hybrid antibody comprising human heavy and light chain immunoglobulin variable regions and heavy and light chain immunoglobulin constant regions in response to antigenic stimulation, wherein the heavy and light chain immunoglobulin constant regions are endogenous mouse heavy and light chain constant regions;
• (b) stimulating an immune response the genetically modified mouse by administering an antigen to the genetically modified mouse;
• (c) preparing a hybridoma expressing the hybrid antibody from the genetically modified mouse stimulated with the antigen in step (b);
• (d) isolating DNA encoding the human heavy and light chain immunoglobulin variable regions of the hybrid antibody from the hybridoma of step (c);
• (e) operably linking in a cell the DNA encoding the human heavy chain immunoglobulin variable region of step (d) with the DNA encoding a human heavy chain immunoglobulin constant region and the DNA encoding the human light chain immunoglobulin variable region of step (d) with DNA encoding a human light chain immunoglobulin constant region;
• (f) growing the cell under conditions such that the cell expresses a human antibody having the human heavy and light chain variable regions of the hybrid antibody of step (d) and human heavy and light chain constant regions of step (e);
• and
• (g) recovering the antibody.