Universal Light Chain Mice for Bispecific Antibody Pairing
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Solution Overview
Problem
Existing technologies face challenges in selecting light chains that effectively associate and express with humanized heavy chains in mice for developing human therapeutics, particularly for bispecific antibodies, without impairing expression or binding behavior.
Innovation Solution
Genetically engineered mice are developed with humanized heavy and light chain loci, expressing a universal light chain derived from one or two human V gene segments, capable of pairing with affinity-matured human heavy chain variable domains, ensuring male fertility and efficient antibody production.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Device complexity
If a universal light chain repertoire derived from no more than one or two V gene segments is used, then the complexity of selecting suitable light chains for bispecific antibodies is reduced, but the diversity of light chain options is limited
Solution Approach 1:
The patent creates a universal light chain that can function with multiple different heavy chains in bispecific antibody construction. By designing a light chain repertoire from limited V gene segments that can effectively associate with various heavy chains, the system achieves multi-functionality where a single light chain design serves multiple antibody pairing purposes, reducing the need for extensive light chain screening.
2Object-affected harmful factors
If human variable domains are expressed in humanized mice, then the potential for immunogenicity is reduced, but the challenge of selecting compatible light chains increases
Solution Approach 1:
The patent performs preliminary selection and optimization of light chains during the mouse model development stage. By establishing a universal light chain repertoire in the humanized mouse model before actual antibody production, the system pre-solves the compatibility issue, allowing researchers to directly use these pre-selected light chains with various heavy chains without facing the selection challenge during therapeutic development.
3Ease of manufacture
If the light chain locus is humanized with limited V segments, then the ease of producing consistent antibodies is improved, but the repertoire of available light chains is restricted
Solution Approach 1:
The patent changes the parameters of the light chain locus by humanizing it with a specific configuration of limited V gene segments (no more than one or two). This parameter change achieves consistent and reproducible antibody production while the selected V segments are designed to maintain adequate functional diversity through combinatorial pairing with different heavy chains and J segments.
Data Source
AI summary
Mice, tissues, cells, and genetic material are provided that comprise a humanized heavy chain immunoglobulin locus, a humanized light chain locus that expresses a universal light chain, and a gene encoding an ADAM6 or ortholog or homolog or functional fragment thereof. Mice are provided that express humanized heavy chains comprising human variable domains, and that express humanized light chains comprising human variable domains wherein the light chains are derived from no more than one, or no more than two, light chain V and J or rearranged V/J sequences. Fertile male mice that express antibodies with universal light chains and humanized heavy chains are provided. Methods and compositions for making bispecific binding proteins are provided.