TSHαβ CAR-T Receptor Architecture for Persistent TSHR Targeting
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Solution Overview
Problem
CAR-T cell therapies for solid tumors face challenges due to lack of effective antigenic targets and immunogenicity, leading to poor therapeutic efficacy and tumor recurrence.
Innovation Solution
Development of a non-immunogenic CAR-T cell targeting the thyroid-stimulating hormone receptor (TSHR) using a chimeric antigen receptor (CAR) with an extracellular domain composed of TSH protein α and β subunits, incorporating a linker peptide and intracellular costimulatory domains, to enhance persistence and tumor cell killing.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CAR-T cells are constructed using traditional scFv sequences from monoclonal antibodies, then they can effectively target tumor cells, but they exhibit high immunogenicity causing clearance by the patient's immune system
Solution Approach 1:
The patent changes the fundamental parameter of the antigen-binding domain from heterologous scFv sequences to the patient's own TSH protein sequence. This parameter change eliminates immunogenicity while preserving target recognition capability, as the patient's immune system recognizes TSH as self-protein rather than foreign antigen.
Solution Approach 2:
The patent uses the natural TSH protein structure as a template to design the CAR antigen-binding domain. By copying the native TSH amino acid sequence and structure, the CAR molecule mimics the patient's own hormone, enabling it to bind TSHR on thyroid cancer cells without triggering immune rejection.
2Productivity
If CAR-T cells are constructed with high immunogenicity, then they can be easily recognized and activated, but they are rapidly cleared by the patient's immune system reducing therapeutic efficacy
Solution Approach 1:
The patent fundamentally changes the immunogenicity parameter from high to low by using self-protein TSH sequence. This allows the CAR-T cells to maintain tumor-killing activity while avoiding immune clearance, thereby sustaining therapeutic efficacy over time.
3Manufacturing precision
If traditional CAR molecules are used for solid tumors, then they can target tumor cells, but they suffer from short survival time and poor therapeutic efficacy
Solution Approach 1:
The patent changes the antigen-binding domain parameter from immunogenic scFv to non-immunogenic TSH protein sequence. This parameter change resolves the contradiction by enabling both accurate tumor targeting through TSHR binding and extended survival time by avoiding immune system recognition and clearance.
Data Source
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AI summary
The present invention provides a CAR-T cell constructed on the basis of a natural protein TSH. The present invention provides a chimeric antigen receptor constructed on the basis of a TSHα subunit and TSHβ subunit tandem structure, a CAR-T cell, and a use thereof. The TSHαβ-CAR-T cell of the present invention can kill TSHR-positive thyroid cancer cells in a targeted manner, and has no immunogenicity, so that the TSHαβ-CAR-T cell has the prospect of being used in the treatment of thyroid cancer.