Ubiquitylation-Deficient LAT Polypeptides for TCR Signaling
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current methods for adoptive cell therapy (ACT) face challenges in maintaining T-cell signaling persistence, which is crucial for effective cancer treatment and viral infection management, due to issues like T-cell receptor (TCR) inhibition and limited avidity of T-cells for tumor or viral antigens.
Innovation Solution
The development of non-naturally occurring linker for activation of T-cells (LAT) polypeptides with specific amino acid mutations, such as lysine to arginine substitutions at positions 52 or 204, that are ubiquitylation-deficient, to enhance T-cell receptor signaling persistence and effectiveness.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If T-cells are used for adoptive cell therapy to target cancer or viral antigens, then specific immune response is improved, but T-cell signaling persistence is limited due to TCR inhibition and low avidity
Solution Approach 1:
The invention extracts and modifies the LAT protein by removing specific lysine residues (at positions 52 and/or 204) that are substrates for ubiquitin ligases. This extraction of ubiquitination sites prevents ubiquitin-mediated degradation of LAT, thereby extending T-cell signaling persistence without affecting the specific immune response targeting capability
Solution Approach 2:
The invention changes the chemical parameters of the LAT protein by substituting lysine residues with arginine or alanine at specific positions. This parameter change (amino acid substitution) eliminates ubiquitination sites while maintaining the protein's structural integrity and signaling function, leading to prolonged T-cell activation and cytokine production
2Reliability
If TCR affinity for tumor antigens is increased to improve cancer targeting, then treatment effectiveness is improved, but T-cell inhibition and signaling termination occur more rapidly
Solution Approach 1:
The invention provides beforehand cushioning against TCR signaling termination by engineering LAT proteins resistant to ubiquitin-mediated degradation. This prior protection ensures that even when high-affinity TCRs engage tumor antigens and would normally trigger rapid signaling termination through ubiquitination, the modified LAT protein maintains signaling capability, thereby extending the duration of effective cancer targeting
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
These ubiquitylation-deficient LAT polypeptides increase T-cell receptor signaling, leading to enhanced T-cell viability, proliferation, and cytokine release, allowing for more effective ACT treatments for cancer and viral infections by prolonging immune response.
Implementation Method 1
LAT polypeptides including at least an effective fragment of a full-length mammalian LAT 1 having at least one mutation at one amino acid capable of being ubiquitylated
Data Source
AI summary
LAT (Linker for Activation of T-cells) is a protein involved in signaling through the T-cell receptor (TCR). The invention provides a LAT protein including mutations at ubiquitylation sites that result in an increase in stability of LAT in stimulated and unstimulated cells, and enhanced signaling through the TCR. The invention further provides use for a LAT protein including mutations at ubiquitylation sites for therapeutic and laboratory methods.