Affinity-Maturated TCRs via Somatic Hypermutation
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Solution Overview
Problem
Current methods for generating T cells with high affinity to tumor antigens are limited by the low affinity of naturally occurring T cell receptors (TCRs) and the challenges of antigen loss variants, MHC restriction, and the replicative potential of cultured T cells, which hinder effective anti-tumor immunity.
Innovation Solution
The method involves subjecting TCR genes to somatic hypermutation directed by Activation Induced Cytidine Deaminase (AID) to increase the affinity of TCRs to their ligands, allowing for the creation of affinity-maturated TCRs that can be used to generate reactive T cells for cancer immunotherapy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If TCR genes are subjected to somatic hypermutation to increase affinity, then the affinity of TCRs to ligands is significantly enhanced, but the complexity of the method increases
Solution Approach 1:
The patent applies somatic hypermutation to alter the amino acid sequence parameters of TCR genes, specifically targeting the complementarity determining regions (CDRs) to change the binding parameters of TCRs to their ligands. This parameter change approach enables affinity maturation by introducing point mutations that enhance binding strength while maintaining specificity.
Solution Approach 2:
The patent uses affinity maturation as an intermediary process between initial TCR generation and final therapeutic application. By introducing a intermediate selection and optimization stage through somatic hypermutation, the method enables gradual improvement of TCR affinity through multiple rounds of mutation and selection, ultimately achieving high-affinity TCRs.
2Ease of manufacture
If naturally occurring TCRs are used, then the method is simple, but the affinity to tumor antigens is low
Solution Approach 1:
The patent fundamentally changes the affinity parameters of TCRs by applying somatic hypermutation to the TCR gene sequences. This introduces deliberate mutations in the CDR regions that alter the binding characteristics, transforming low-affinity naturally occurring TCRs into high-affinity engineered TCRs capable of effectively recognizing tumor antigens.
Solution Approach 2:
The patent performs preliminary affinity maturation through somatic hypermutation before the TCRs are used in therapeutic applications. This advance optimization ensures that the TCRs possess sufficiently high affinity for tumor antigens prior to adoptive cell transfer, preventing the need for subsequent affinity enhancement steps.
3Quantity of substance
If T cells are cultured to expand numbers, then sufficient cells for therapy are obtained, but the replicative potential is limited
Solution Approach 1:
The patent changes the functional parameters of T cells by engineering them to express high-affinity TCRs through somatic hypermutation. This parameter change in TCR affinity enables the T cells to maintain effective antigen recognition and proliferative capacity over extended periods, overcoming the replicative limitations of conventional cultured T cells.
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
This approach significantly enhances the affinity of TCRs to their ligands, enabling more effective anti-tumor immune responses by increasing the functional avidity of T cells, which can recognize and target tumor cells more efficiently, thereby improving the efficacy of adoptive T cell therapy.
Implementation Method 1
subjecting TCR genes to somatic hypermutation directed by Activation Induced Cytidine Deaminase (AID) to increase the affinity of TCRs to their ligands
Data Source
AI summary
The present invention relates to methods and systems for increasing the affinity of a T cell receptor (TCR) to its ligand by subjecting the TCR gene to somatic hypermutation. The present invention further relates to use of affinity maturated TCRs to create T cells reactive against a selected antigen.