Transgenic non-human animals capable of producing heterologous antibodies

A transgenic mouse having DNA segments from a human immunoglobulin heavy chain gene locus incorporated into its germline DNA to form a heavy chain immunoglobulin mini-locus such that upon antigenic stimulation the transgenic mouse develops primary response B cells expressing IgM having a mu chain encoded by a rearranged human mini-locus and secondary response B cells expressing somatically mutated IgG having a gamma chain encoded by the rearranged human mini-locus, the germline DNA of said transgenic mouse comprises:

• an unrearranged human immunoglobulin mini-locus comprising a plurality of human heavy chain V gene segments, a plurality of human heavy chain D gene segments, a plurality of human heavy chain J gene segments, a mu constant region comprised of a .mu. switch region located upstream from a .mu. coding segment, and a gamma constant region comprised of a .gamma. switch region located upstream from a human .gamma. coding segment, wherein the .gamma. constant region is in closer proximity to the .mu. constant region that in the human immunoglobulin heavy chain gene locus;
• said primary response B cells wherein after said antigenitic expressing IgM stimulation have chromosomal DNA comprised of said mu constant region and said human gamma constant and a rearranged variable region which is comprised of a VDJ rearrangement of said unrearranged human immunoglobulin minilocus, said rearranged variable region having N-region nucleotides at recombination joints between said human heavy chain V gene segments and human D gene segments and between said human D gene segments and said human heavy chain J segments, and wherein FR1, FR2, FR3, CDR1, and CDR2 portions of said rearranged variable region have DNA sequences from said human heavy chain V gene segments of said unrearranged human immunoglobulin mini-locus;
• and wherein said secondary response B cells have chromosomal DNA exhibiting a class switch recombination from said mu constant region to said gamma constant region operably linked to said rearranged variable region;
• wherein the sequence spanning the FR1, FR2, FR3, CDR1 and CDR2 portions includes a plurality of DNA sequences not identical to corresponding sequences from said unrearranged human immunoglobulin mini-locus.