Transgenic animals for producing specific isotypes of human antibodies via non-cognate switch regions
First Claim
1. A transgenic mouse and its progeny, wherein the somatic and germ cells comprise a heavy chain transgene comprising a DNA fragment comprising a DNA sequence of a human D segment gene, a human heavy chain J segment gene and a human heavy chain constant region gene Cμ
- , wherein said DNA fragment is operably linked to at least one human heavy chain 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.
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Abstract
The present invention provides fully human antibodies in a transgenic animal of a desired isotype in response to immunization with any virtually any desired antigen. The human immunoglobulin heavy chain transgene in the foregoing animals comprises a human constant region gene segment comprising exons encoding the desired heavy chain isotype, operably linked to switch segments from a constant region of a different heavy chain isotype, i.e., a non-cognate switch region. Said additional constant region segment comprises a switch region and human constant region coding segment, wherein the constant region coding segment is operably linked to a switch region that it is not normally associated with, i.e., a non-cognate switch region. In the transgenes of the invention, the non-cognate switch region may be a switch region from a different species than the constant region coding segment. The switch region and membrane exons of the invention may comprise a human gamma-2 constant region and the secreted constant region exons are from a human gamma-1 or a human gamma-4 constant region.
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Citations
26 Claims
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1. A transgenic mouse and its progeny, wherein the somatic and germ cells comprise a heavy chain transgene comprising a DNA fragment comprising a DNA sequence of a human D segment gene, a human heavy chain J segment gene and a human heavy chain constant region gene Cμ
- , wherein said DNA fragment is operably linked to at least one human heavy chain 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.
- View Dependent Claims (2, 3, 4, 5, 6, 7, 8)
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9. A transgenic mouse and its progeny, wherein the somatic and germ cells comprise a heavy chain transgene comprising a DNA fragment comprising a DNA sequence of a human D segment gene, a human heavy chain J segment gene and a human heavy chain constant region gene Cμ
- , wherein said DNA fragment is operably linked to at least one human heavy chain 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. - View Dependent Claims (10, 11, 15, 16, 17, 18, 19, 20)
- , wherein said DNA fragment is operably linked to at least one human heavy chain 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;
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12. A transgenic mouse and its progeny, wherein the somatic and germ cells comprise a heavy chain transgene comprising a DNA fragment comprising a DNA sequence of a human D segment gene, a human heavy chain J segment gene and a human heavy chain constant region gene Cμ
- , wherein said DNA fragment is operably linked to at least one human heavy chain 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 CH1, Chinge, CH2 and CH3 exons are from the same isotype and said human membrane exons are from a different isotype than said human switch region and said human CH1, Chinge, CH2 and CH3 exons.
- View Dependent Claims (13, 14, 21, 22, 23, 24, 25, 26)
Specification