Humanized Antibody Production in Genetically Modified Animals
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Solution Overview
Problem
There is a need for genetically modified animals and cells that can produce humanized antibodies capable of recognizing peptide-MHC complexes for therapeutic purposes, as existing technologies struggle to generate antibodies that effectively target these complexes.
Innovation Solution
The development of genetically modified non-human animals with humanized heavy chain and light chain immunoglobulin loci, which can express human or chimeric MHC protein complexes, allowing for the production of immunoglobulin light chain variable domains that can pair with diverse heavy chain variable domains.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If humanized immunoglobulin loci are introduced into non-human animals, then antibody recognition capability for peptide-MHC complexes is improved, but genetic complexity and manufacturing difficulty increase
Solution Approach 1:
The patent segments the immunoglobulin locus into distinct functional regions: humanized heavy chain locus (IGHV, IGHD, IGHJ genes) and light chain locus (IGKV, IGKJ genes), allowing independent modification and recombination. This segmentation enables precise control over which human genetic elements are introduced while maintaining animal framework structures.
Solution Approach 2:
The patent applies local quality by introducing humanized loci only at specific positions within the animal genome while maintaining the rest of the animal's genetic architecture. The heavy chain and light chain loci are selectively modified with human sequences, creating localized humanized regions that produce human-like antibodies without requiring complete human genome replacement.
2Productivity
If human IGHV, IGHD, and IGHJ genes are introduced at endogenous loci, then production of humanized antibodies is improved, but immunogenicity in humans may increase
Solution Approach 1:
The patent changes the genetic parameters at the immunoglobulin loci by introducing human IGHV, IGHD, and IGHJ genes into non-human animals. This parameter change transforms the antibody repertoire to produce humanized antibodies with reduced immunogenicity, as the antibodies share structural and sequence characteristics with human antibodies.
Solution Approach 2:
The patent creates copies of human immunoglobulin genes within the animal genome. The humanized loci contain replicated human gene sequences (IGHV, IGHD, IGHJ) that can be transcribed and translated to produce human-like antibodies, effectively copying human genetic information into the animal host for therapeutic antibody production.
3Reliability
If humanized immunoglobulin loci are engineered into animals, then therapeutic antibody generation is improved, but time required for animal development increases
Solution Approach 1:
The patent performs preliminary action by pre-engineering the humanized immunoglobulin loci into the animal genome before the animal reaches maturity. The humanized heavy chain and light chain loci are introduced and stabilized in early development stages, allowing the animal to produce humanized antibodies throughout its life without requiring additional time for gene insertion or maturation.
Solution Approach 2:
The patent ensures continuity of useful action by establishing the humanized loci in a way that allows continuous production of humanized antibodies from the animal's entire lifespan. The engineered loci remain active and functional throughout development, eliminating the need for separate antibody production phases and enabling continuous therapeutic antibody generation.
Data Source
AI summary
Genetically modified animals and cells with humanized light chain immunoglobulin locus and/or humanized heavy chain immunoglobulin locus. The animals and cells can also express a human or chimeric (e.g., humanized) major histocompatibility complex (MHC) protein complex.