Transgenic Animals with Limited Light Chain Locus for Antibody Production
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Solution Overview
Problem
Current methods for producing humanized antibodies, particularly bispecific antibodies, face challenges such as suboptimal binding affinities, immunogenicity, and difficulties in manufacture due to mispairing issues and the need for iterative experiments to improve properties.
Innovation Solution
Genetically modified animals with a humanized light chain and heavy chain immunoglobulin locus, featuring a limited set of human IGKV and IGKJ genes, allow for efficient pairing of diverse heavy chain variable domains with a limited number of light chain options, enabling the production of antibodies that can specifically bind to multiple antigens without extensive antibody engineering.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If humanization of rodent antibody or phage library methods are used to generate therapeutic antibodies, then humanized antibodies can be produced, but binding affinity is suboptimal and immunogenic epitopes are introduced
Solution Approach 1:
The invention changes the genetic parameters of the antibody-producing system by replacing the rodent light chain variable region genes with human light chain variable region genes in the transgenic animal genome. This parameter change at the DNA level ensures that the produced antibodies have human-like sequences, reducing immunogenicity while maintaining binding affinity through proper human V-J recombination
Solution Approach 2:
The transgenic animals serve themselves by naturally producing humanized antibodies through their own immune system. The animals are immunized with antigens and their B cells naturally undergo V-J recombination and somatic hypermutation to produce high-affinity humanized antibodies, eliminating the need for iterative laboratory experiments
2Adaptability or versatility
If phage libraries are used to discover antibodies, then antibody diversity can be obtained, but non-native pairing of immunoglobulin heavy and light chains occurs and iterative experiments are required
Solution Approach 1:
The transgenic animals perform the antibody discovery function themselves through natural immune responses. When immunized, their B cells undergo V-J recombination and somatic hypermutation in vivo, automatically selecting and optimizing the best antibody variants without requiring iterative laboratory screening
Solution Approach 2:
The invention changes the genetic composition of the animal to include human IGHV, IGHD, IGHJ genes alongside human IGKV and IGKJ genes, creating a humanized immunoglobulin locus that produces native-like human antibody pairs with proper heavy and light chain compatibility
3Adaptability or versatility
If conventional methods are used to produce bispecific antibodies, then dual-target binding can be achieved, but mispairing problems occur during manufacture
Solution Approach 1:
The invention applies local quality control by restricting the light chain repertoire to a limited set of human IGKV and IGKJ genes in the transgenic animal. This creates a controlled environment where specific light chains are preferentially paired with desired heavy chains, reducing mispairing issues in bispecific antibody production
Solution Approach 2:
The invention changes the genetic parameters by limiting the number of light chain variable region genes available for recombination, thereby controlling the pairing specificity and reducing the complexity of manufacturing bispecific antibodies with correct chain associations
Data Source
AI summary
This disclosure relates to genetically modified animals and cells with humanized light chain immunoglobulin locus and/or humanized heavy chain immunoglobulin locus. In one aspect, the endogenous light chain immunoglobulin locus comprises a limit number of human IGKV genes and human IGKJ genes.