Method of making antibodies using a human lambda light chain mouse

摘要

Genetically modified mice are provided that express human λ variable (hVλ) sequences, including mice that express hVλ sequences from an endogenous mouse λ light chain locus, mice that express hVλ sequences from an endogenous mouse κ light chain locus, and mice that express hVλ sequences from a transgene or an episome wherein the hVλ sequence is linked to a mouse constant sequence. Mice are provided that are a source of somatically mutated human λ variable sequences useful for making antigen-binding proteins. Compositions and methods for making antigen-binding proteins that comprise human λ variable sequences, including human antibodies, are provided.

主权项

1. A method for making an antibody comprising a human λ variable domain, the method comprising the steps of:
(a) exposing a genetically modified mouse to an antigen, wherein the genetically modified mouse has a genome that comprises an endogenous λ light chain immunoglobulin locus comprising:
i) a deletion of a first endogenous Vλ-Jλ-Cλ gene cluster; andii) a replacement of a fragment of endogenous Vλ and Jλ gene segments in a second endogenous Vλ-Jλ-Cλ gene cluster with human Vλ and Jλ gene segments, wherein the human Vλ and Jλ gene segments comprise at least one human Vλ gene segment and at least one human Jλ gene segment, and wherein the human Vλ and Jλ gene segments are operably linked to a mouse λ constant (Cλ) gene; (b) allowing the genetically modified mouse to develop an immune response to the antigen; and (c) isolating from the mouse of (b) an antibody specific for the antigen, wherein the antibody comprises a human λ variable domain derived from the human Vλ and Jλ gene segments.