Non-human animals having an engineered immunoglobulin lambda light chain and uses thereof

A method of making a genetically modified mouse comprising the steps of:

• (a) introducing one or more DNA fragments into a first engineered immunoglobulin κ light chain locus in the genome of a mouse ES cell, wherein the one or more DNA fragments comprise:
• (i) one or more unrearranged human Vλ gene segments,
• (ii) one or more unrearranged human Jλ gene segments, and
• (iii) a single mouse Cλ gene,
• wherein the one or more unrearranged human Vλ gene segments of (i), the one or more unrearranged human Jλ gene segments of (ii), and the single mouse Cλ gene of (iii) are introduced into the genome of the mouse ES cell at the endogenous immunoglobulin κ light chain locus;
• wherein the one or more unrearranged human Vλ gene segments of (i) and the one or more unrearranged human Jλ gene segments of (ii) are in place of the one or more endogenous mouse Vκ gene segments and one or more endogenous Jκ gene segments;
• wherein the one or more unrearranged human Vλ gene segments of (i), the one or more unrearranged human Jλ gene segments of (ii), are operably linked to the single mouse Cλ gene of (iii);
• wherein the single mouse Cλ gene of (iii) is operably linked to a mouse kappa enhancer;
• wherein the genetically modified mouse lacks a mouse Cκ gene at the first engineered endogenous immunoglobulin κ light chain locus;
• and
• (b) generating a mouse using the mouse ES cell generated in (a).

A method of making a genetically modified mouse, comprising the step of:

• (a) engineering a first endogenous immunoglobulin κ light chain locus in the germline genome of the mouse to include:
• (i) one or more unrearranged human Vλ gene segments,
• (ii) one or more unrearranged human Jλ gene segments, and
• (iii) a single mouse Cλ gene,
• wherein the one or more unrearranged human Vλ gene segments of (i) and the one or more unrearranged human Jλ gene segments of (ii) are in place of the one or more endogenous mouse Vκ gene segments and one or more endogenous Jκ gene segments;
• wherein the one or more unrearranged human Vλ gene segments of (i) and the one or more unrearranged human Jλ gene segments of (ii) are operably linked to the single mouse Cλ gene of (iii);
• wherein the single mouse Cλ gene of (iii) is operably linked to a mouse kappa enhancer;
• and
• wherein the genetically modified mouse lacks a mouse Cκ gene at the first engineered endogenous immunoglobulin κ light chain locus.