Non-human mammals for the production of chimeric antibodies
First Claim
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1. An isolated non-human mammalian cell whose genome comprises a first transgene comprising an immunoglobulin heavy chain (IgH) locus, or a portion thereof, the first transgene comprising in operable linkage from 5′
- to 3′
an unrearranged DNA sequence of a human variable heavy (VH) gene segment, a diversity heavy (DH) gene segment, and a human joining heavy (JH) gene segment operably linked to a constant region gene comprising a human CH1 exon, a human Cupper hinge exon, a Cmiddle hinge exon, a mammalian non-human CH2 exon and a mammalian non-human CH3 exon, wherein the human CH1 exon is selected from the group consisting of a human mu constant region (Cμ
) CH1 exon, a human delta constant region (Cs) CH1 exon, a human gamma-1 constant region (Cγ
1) CH1 exon, a human gamma-2 constant region (Cy2) CH1 exon, a human gamma-4 constant region (Cy4) CH1 exon, a human alpha constant region (Ca) CH1 exon, and a human epsilon constant region (Cc) CH1 exon, wherein the genome further comprises a second transgene comprising a human immunoglobulin light chain (IgL) locus, or a portion thereof, wherein the IgL locus is unrearranged, and wherein said non-human mammalian cell comprises a genome encoding both a chimeric Ig heavy chain comprising a human heavy chain variable domain and a chimeric IgH constant domain and a human IgL chain.
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Abstract
The invention provides knock-in non-human cells and mammals having a genome encoding chimeric antibodies and methods of producing knock-in cells and mammals. Certain aspects of the invention include chimeric antibodies, humanized antibodies, pharmaceutical compositions and kits. Certain aspects of the invention also relate to diagnostic and treatment methods using the antibodies of the invention.
118 Citations
20 Claims
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1. An isolated non-human mammalian cell whose genome comprises a first transgene comprising an immunoglobulin heavy chain (IgH) locus, or a portion thereof, the first transgene comprising in operable linkage from 5′
- to 3′
an unrearranged DNA sequence of a human variable heavy (VH) gene segment, a diversity heavy (DH) gene segment, and a human joining heavy (JH) gene segment operably linked to a constant region gene comprising a human CH1 exon, a human Cupper hinge exon, a Cmiddle hinge exon, a mammalian non-human CH2 exon and a mammalian non-human CH3 exon, wherein the human CH1 exon is selected from the group consisting of a human mu constant region (Cμ
) CH1 exon, a human delta constant region (Cs) CH1 exon, a human gamma-1 constant region (Cγ
1) CH1 exon, a human gamma-2 constant region (Cy2) CH1 exon, a human gamma-4 constant region (Cy4) CH1 exon, a human alpha constant region (Ca) CH1 exon, and a human epsilon constant region (Cc) CH1 exon, wherein the genome further comprises a second transgene comprising a human immunoglobulin light chain (IgL) locus, or a portion thereof, wherein the IgL locus is unrearranged, and wherein said non-human mammalian cell comprises a genome encoding both a chimeric Ig heavy chain comprising a human heavy chain variable domain and a chimeric IgH constant domain and a human IgL chain. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 19, 20)
- to 3′
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17. An isolated mouse B cell whose genome comprises a first transgene comprising an immunoglobulin heavy chain (IgH) locus, or a portion thereof, comprising in operable linkage from 5′
- to 3′
a DNA sequence of a human variable heavy (VH) gene coding sequence, a diversity heavy (DH) gene coding sequence, and a human joining heavy (JH) gene sequence, operably linked to a constant region gene comprising a human CH1 exon, a human Cupper hinge exon, a mouse CH2 exon and mouse CH3 exon, wherein the human CH1 exon is selected from the group consisting of a human Cμ
CH1 exon, a human Cδ
CH1 exon, a human Cγ
1 CH1 exon, a human Cγ
2 CH1 exon, a human Cγ
4 CH1 exon, a human Cα
CH1 exon, and a human Cε
CH1 exon, and wherein the genome further comprises a second transgene comprising an immunoglobulin light chain (IgL) locus, or a portion thereof.
- to 3′
Specification