Exogenous TdT Animal Models for Higher Antigen Receptor Diversity
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Solution Overview
Problem
There is a need for genetically engineered non-human animals with increased antigen receptor diversity to improve the production of therapeutic antigen binding molecules, such as antibodies and T cell receptors, to enhance their therapeutic potential.
Innovation Solution
Genetically modified non-human animals are engineered to include an exogenous nucleic acid encoding terminal deoxynucleotidyltransferase (TdT), which increases antigen receptor diversity by catalyzing template-independent nucleotide additions during V(D)J recombination in B and T lymphocytes, leading to enhanced expression of human antigen binding molecules like antibodies, T cell receptors, and chimeric antigen receptors.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If non-human animals are genetically engineered to increase antigen receptor diversity, then the production of therapeutic antigen binding molecules is improved, but the genetic modification complexity increases
Solution Approach 1:
The patent segments the approach by introducing specific exogenous nucleic acids (TdT encoding sequences) into the animal genome rather than attempting comprehensive genetic modification. This targeted segmentation allows increased antigen receptor diversity through specific enzymatic activity while avoiding the complexity of modifying multiple genomic loci simultaneously.
Solution Approach 2:
The patent uses terminal deoxynucleotidyltransferase (TdT) as an intermediary enzyme to achieve increased antigen receptor diversity. By introducing exogenous TdT encoding nucleic acids, the system mediates the desired effect (increased diversity) through a specific biochemical mechanism (template-independent nucleotide addition) without requiring direct modification of multiple antigen receptor genes.
2Adaptability or versatility
If exogenous TdT is introduced to enhance antigen receptor diversity, then therapeutic antibody diversity is improved, but the risk of off-target effects increases
Solution Approach 1:
The patent applies local quality by expressing exogenous TdT specifically in B cells and T cells through cell-type-specific promoters or regulatory elements. This localized expression ensures that TdT activity is confined to the relevant lymphocyte populations where V(D)J recombination occurs, minimizing off-target effects in other tissues while maintaining enhanced antigen receptor diversity in the intended cells.
Solution Approach 2:
The patent implements preliminary action by introducing exogenous TdT encoding nucleic acids into the animal genome during embryonic development or early life stages. This allows the transgene to be established and expressed in a controlled manner during critical windows of lymphocyte development, ensuring proper integration and regulation before the animal reaches maturity, thereby reducing potential off-target effects.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The modified animals exhibit increased antigen-receptor diversity, resulting in improved production of therapeutic antibodies and TCRs, enhancing their therapeutic efficacy and diversity.
Implementation Method 1
terminal deoxynucleotidyltransferase (TdT), which increases antigen receptor diversity by catalyzing template-independent nucleotide additions during V(D)J recombination
Data Source
AI summary
Provided herein are methods and compositions related to non-human animals that express exogenous Terminal Deoxynucleotidyltransferase (TdT).