Transgenic animals for producing specific isotypes of human antibodies via non-cognate switch regions

An embryonic stem (ES) cell comprising a transgene comprising

• (a) a DNA fragment comprising a DNA sequence of a human D segment gene, a human J segment gene and a human constant region gene Cμ, wherein said DNA fragment is operably linked to at least one human V segment gene, and wherein said DNA fragment further is operably linked to an additional constant region gene, said additional constant region gene comprising a human switch region, human CH1, Chinge, CH2 and CH3 exons and human membrane exons, wherein said human switch region and said human membrane exons are from the same isotype and the human CH1, Chinge, CH2 and CH3 exons are from a different isotype than said human switch region and said human membrane exons;
• or
• (b) a DNA fragment comprising a DNA sequence of a human D segment gene, a human J segment gene and a human constant region gene Cμ, wherein said DNA fragment is operably linked to at least one human V segment gene, and wherein said DNA fragment further is operably linked to an additional constant region gene, said additional constant region gene comprising:
• (1) a human switch region;
• (2) a region comprising human CH1, Chinge, CH2 and CH3 exons;
• and (3) human membrane exons, wherein said human switch region, said region comprising human CH1, Chinge, CH2 and CH3 exons, and said human membrane exons are from three different isotypes.

A transgenic non-human animal and its progeny, wherein the somatic and germ cells comprise a transgene comprising

• (a) a DNA fragment comprising a DNA sequence of a human D segment gene, a human J segment gene and a human constant region gene Cμ, wherein said DNA fragment is operably linked to at least one human V segment gene, and wherein said DNA fragment further is operably linked to an additional constant region gene, said additional constant region gene comprising a human switch region, human CH1, Chinge, CH2 and CH3 exons and human membrane exons, wherein said human switch region and said human membrane exons are from the same isotype and the human CH1, Chinge, CH2 and CH3 exons are from a different isotype than said human switch region and said human membrane exons;
• or
• (b) a DNA fragment comprising a DNA sequence of a human D segment gene, a human J segment gene and a human constant region gene Cμ, wherein said DNA fragment is operably linked to at least one human V segment gene, and wherein said DNA fragment further is operably linked to an additional constant region gene, said additional constant region gene comprising:
• (1) a human switch region;
• (2) a region comprising human CH1, Chinge, CH2 and CH3 exons;
• and (3) human membrane exons, wherein said human switch region, said region comprising human CH1, Chinge, CH2 and CH3 exons, and said human membrane exons are from three different isotypes.