Hybrid Light Chain Mouse for Homogeneous Bispecific Antibodies
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Existing methods for producing bispecific antibodies face challenges in achieving homogeneous yields due to difficulties in correct light chain association, relying on in vitro manipulations that are not biologically sensible and do not account for in vivo pairing capabilities.
Innovation Solution
Development of a transgenic mouse expressing a hybrid light chain comprising a human Vκ segment joined to a mouse Jκ segment, allowing for efficient pairing with various heavy chains, including somatically mutated ones, through site-specific integration and avoiding gene rearrangement.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If in vitro methods are used to select and pair light chains with heavy chains, then light chain association can be controlled, but the production yield is low and heterogeneity remains high
Solution Approach 1:
The patent introduces a common light chain as an intermediary component that can pair with multiple different heavy chains. This common light chain serves as a mediator that enables correct heterodimerization of heavy chains while maintaining homogeneity in light chain association, thereby resolving the contradiction between manufacturing precision and productivity
Solution Approach 2:
The patent employs a universal common light chain that can function with multiple different heavy chains having varying antigenic specificities. This multi-functional light chain eliminates the need for separate in vitro pairing procedures for each heavy chain combination, thus improving both homogeneity and production yield simultaneously
2Device complexity
If random light chain association is attempted, then production complexity is reduced, but correct light chain association cannot be achieved
Solution Approach 1:
The patent uses a homogeneous common light chain that is identical across all antibody molecules, ensuring consistent and correct association. This homogeneity in light chain design simplifies the production process while guaranteeing correct pairing, as the common light chain naturally selects the appropriate heavy chain partner without requiring complex control mechanisms
3Adaptability or versatility
If multiple different light chains are used for different heavy chains, then antigenic specificity can be optimized, but heterogeneity within the antibody population increases
Solution Approach 1:
The patent segments the antibody structure into two functional parts: a common light chain that ensures homogeneity and correct pairing, and variable heavy chains that provide diverse antigenic specificities. This segmentation allows each component to fulfill its specific function independently, resolving the contradiction between adaptability and homogeneity
Data Source
AI summary
The present disclosure relates to a transgenic non-human mammal (e.g., mouse) that expresses a common light chain, wherein the transgenic non-human mammal comprises a hybrid light chain locus from which a light chain having a human Vκ joined to a mouse Jκ is expressed. Also provided are methods of making a transgenic non-human mammal capable of expressing a common light chain.