Mice expressing a limited immunoglobulin light chain repertoire
A genetically modified mouse is provided, wherein the mouse expresses an immunoglobulin light chain repertoire characterized by a limited number of light chain variable domains. Mice are provided that present a choice of two human light chain variable gene segments such that the immunoglobulin light chains expresses by the mouse comprise one of the two human light chain variable gene segments. Methods for making bispecific antibodies having universal light chains using mice as described herein, including human light chain variable regions, are provided. Methods for making human variable regions suitable for use in multispecific binding proteins, e.g., bispecific antibodies, and host cells are provided.
1. A mouse comprising, in its germline genome:
exactly two unrearranged human Vκ gene segments and five unrearranged human Jκ gene segments operably linked to a mouse light chain constant region at the endogenous kappa light chain loci of the mouse, wherein the exactly two unrearranged human Vκ gene segments are a human Vκ1-39 gene segment and a human Vκ3-20 gene segment; and
one or more unrearranged human V H gene segments, one or more unrearranged human D H gene segments, and one or more unrearranged human J H gene segments operably linked to a mouse heavy chain constant region at the endogenous heavy chain loci of the mouse;
wherein the unrearranged human heavy chain and kappa light chain gene segments are capable of rearranging and encoding human variable domains of an antibody, and further wherein the mouse does not comprise an endogenous Vκ gene segment that is capable of rearranging to form an immunoglobulin light chain variable region.
2. The mouse of claim 1 , wherein the mouse light chain constant region gene is a mouse Cκ region gene.
3. The mouse of claim 1 , wherein the five human Jκ gene segments are human Jκ1, Jκ2, Jκ3, Jκ4 and Jκ5.
4. The mouse of claim 1 , wherein the one or more human V H gene segments, one or more human D H gene segments, and one or more human J H gene segments are operably linked to a mouse heavy chain constant region gene.
5. The mouse of claim 1 , wherein the mouse comprises a functional λ light chain locus.
6. The mouse of claim 1 , wherein the mouse does not comprise a functional λ light chain locus.
7. An isolated cell of the mouse of claim 1 .
8. The cell of claim 7 , wherein the cell is an embryonic stem (ES) cell.
9. A mouse embryo derived from the ES cell of claim 8 .
10. The cell of claim 7 , wherein the cell is a B cell.
11. A hybridoma made with the B cell of claim 10 .
12. The mouse of claim 1 , wherein the human Vκ1-39 gene segment is a human germline Vκ1-39 gene segment and the human Vκ3-20 gene segment is a human germline Vκ3-20 gene segment.