Transgenic Mice Human Lambda Light Chain Expression

Resolve Bottlenecks,
Find Innovative SolutionsGenerate Solutions

Solution Overview

Problem

Current genetically modified mice that express fully or partly human antibodies exhibit a bias towards kappa light chain usage, limiting the expression of lambda variable regions, which is necessary for generating epitope-binding proteins.

Innovation Solution

Genetically modified mice are developed to express human lambda variable regions in the context of kappa or lambda light chains by replacing endogenous mouse light chain variable region gene segments with human lambda variable and joining gene segments, allowing for the production of chimeric and human antigen-binding proteins with increased lambda variable usage.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Adaptability or versatility

If endogenous mouse light chain variable region gene segments are replaced with human lambda variable and joining gene segments, then lambda variable usage is increased, but the complexity of genetic modification increases

Engineering Contradiction:

Improvelambda variable usageVSAvoidgenetic modification complexity

Core Design Contradiction:

Adaptability or versatilityVSDevice complexity

Solution Approach 1:

The patent extracts and removes the endogenous mouse light chain variable region gene segments from the immunoglobulin locus, replacing them with human lambda variable and joining gene segments. This extraction approach allows for increased lambda variable usage while managing genetic complexity through targeted modification rather than comprehensive restructuring.

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

The patent changes the genetic parameters of the light chain locus by introducing human lambda variable region gene segments and joining segments, thereby altering the composition and functionality of the immunoglobulin gene structure. This parameter change enables the mice to produce antibodies with human lambda variable regions while maintaining mouse constant regions.

Inventive Principle:

Principle #35Parameter changes

2Reliability

If mice are genetically modified to express fully or partly human antibodies, then human antibody expression is improved, but lambda variable usage is limited due to kappa bias

Engineering Contradiction:

Improvehuman antibody expressionVSAvoidlambda variable usage

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

Instead of attempting to increase kappa light chain expression in humanized mice (the conventional approach), the patent inverts the strategy by introducing human lambda variable region gene segments to replace mouse variable regions. This inversion allows lambda variable usage to increase while maintaining human antibody expression, overcoming the kappa bias that typically limits lambda usage in genetically modified mice.

Inventive Principle:

Principle #13The other way round (Inversion)

Data Source

PatentUS20240327785A1Human lambda light chain mice

Publication Date: 2024.10.03 REGENERON PHARMACEUTICALS INC

AI summary

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.