Cat Immunoglobulin Rodent Models With Selected V Gene Segments
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Solution Overview
Problem
Existing methods for inserting cat immunoglobulin DNA into rodents require extensive genome engineering to insert a large number of V gene segments, which can lead to reduced expression of preferred V gene segments and an inefficient antibody repertoire, limiting the production of therapeutically relevant antibodies.
Innovation Solution
Engineering rodents with a limited number of specifically selected cat IGHV, IGLV, and IGKV gene segments, such as V3-14, V3-11, V3-12, V3-84, V3-20, V3-27, V4-3, V3-N3, V1-124, V1-36, V1-104, V1-33, V1-56, V1-42, V1-41, V3-7, V3-5, V3-13, and V1-126, closer to the constant region to enhance expression and replicate the natural antibody repertoire.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If a large number of V gene segments are inserted into rodents through extensive genome engineering, then the antibody repertoire coverage is improved, but the expression efficiency of preferred V gene segments deteriorates and the complexity of genetic engineering increases
Solution Approach 1:
The patent extracts and selects only the most frequently used and therapeutically relevant V gene segments from the complete cat immunoglobulin repertoire. By taking out the essential subset of V segments (such as V3-14, V3-11, V3-12, V3-84, V3-20, V3-27, V4-3, V3-N3, V3-5 for heavy chains and corresponding light chain segments) that represent the majority of natural cat antibody diversity, the invention achieves high repertoire coverage without the need to insert all possible V segments, thereby maintaining high expression efficiency and reducing genetic engineering complexity
Solution Approach 2:
The patent changes the parameter of V gene segment selection from comprehensive inclusion to frequency-based prioritization. By identifying and selecting V segments based on their frequency of occurrence in natural cat antibodies and their therapeutic relevance, the invention optimizes the balance between repertoire coverage and expression efficiency. This parameter change allows the rodent model to produce antibodies that closely mirror natural cat antibody diversity while avoiding the expression dilution that would result from inserting an excessive number of V segments
2Adaptability or versatility
If a large number of V gene segments are inserted into rodents, then the antibody repertoire diversity is improved, but the device complexity of genome engineering increases
Solution Approach 1:
The invention extracts only the essential V gene segments that are most relevant to cat antibody diversity and therapeutic applications. By removing unnecessary V segments from the complete cat immunoglobulin locus, the patent reduces the genome engineering complexity while preserving the core antibody repertoire diversity needed for generating therapeutically relevant antibodies in rodents
Solution Approach 2:
The patent segments the cat immunoglobulin V gene repertoire into priority groups based on frequency and therapeutic relevance. This segmentation allows for a systematic and manageable insertion strategy, where the most important V segments are inserted first, reducing the overall complexity of the genome engineering process while still achieving comprehensive antibody repertoire coverage
Data Source
AI summary
The present invention relates inter alia to rodents and cells that are engineered to contain the exogenous DNA of cats, their use in medicine and the study of disease, methods for production of rodents and cells, and antibodies and antibody chains produced by such rodents and derivatives thereof.