Engineered ApoB-Specific TCRs for Targeting CD4+ T Cells
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Solution Overview
Problem
Current treatments for cardiovascular diseases and/or immune disorders, specifically atherosclerosis-related autoimmune disease, lack effective agents and methods for targeting human apolipoprotein B (APOB)-specific CD4+ T cells.
Innovation Solution
Development of a novel engineered T cell receptor comprising a human apolipoprotein B (ApoB) epitope, engineered to bind specifically to Class II HLA and a peptide, engineered to treat atherosclerosis-related autoimmune disease, comprising a human apolipoprotein B (ApoB) epitope, with a beta chain CDR3 selected from SEQ ID NOS: 179 to 356, and optionally a transmembrane domain, for use in treating atherosclerosis-related autoimmune disease.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If conventional treatments are used for cardiovascular diseases, then general immune modulation is achieved, but specific targeting of APOB-specific CD4+ T cells is lacking
Solution Approach 1:
The T cell receptor is segmented into distinct functional domains: variable regions (Vα and Vβ chains) for antigen recognition, constant regions for signaling, and engineered CDR3 regions for epitope-specific binding. This segmentation allows precise targeting of APOB-specific T cells while maintaining manageable structural organization.
Solution Approach 2:
The CDR3 regions are engineered with specific local amino acid sequences (SEQ ID NOS: 179 to 356) that confer high specificity for binding APOB epitopes in the context of Class II HLA molecules. This local quality enhancement at the binding interface provides targeted specificity without requiring complete redesign of the entire receptor structure.
2Reliability
If engineered T cell receptor with high specificity is developed, then therapeutic effectiveness is improved, but manufacturing and clinical application complexity increases
Solution Approach 1:
The engineered T cell receptor design incorporates universal structural elements from conventional TCRs that can be produced using standard molecular biology techniques. The conserved framework regions and constant domains allow the engineered receptor to be manufactured through established protocols, reducing production complexity while maintaining high therapeutic effectiveness through the engineered variable regions.
Solution Approach 2:
Specific amino acid parameters in the CDR3 regions are changed to achieve high specificity for APOB epitopes, while other parameters (overall structure, constant regions) are maintained at standard values. This selective parameter modification approach enables high therapeutic effectiveness without requiring complete redesign of the manufacturing process.
3Adaptability or versatility
If T cell receptor targets multiple APOB epitopes, then broad immune coverage is achieved, but receptor design complexity increases
Solution Approach 1:
Multiple T cell receptor genes encoding different CDR3 specificities are combined in the same T cell through genetic modification. This merging approach allows a single T cell to recognize multiple APOB epitopes by expressing multiple TCR variants, achieving broad immune coverage without requiring complex single-receptor designs.
Solution Approach 2:
The T cell repertoire is made dynamic by introducing variability in CDR3 sequences that can recognize different APOB epitopes. This dynamic design allows the immune system to adapt and respond to various APOB variants and modifications, achieving versatility through controlled diversity rather than fixed complex structures.
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 engineered T cell receptor effectively targets and modulates APOB-specific CD4+ T cells, providing a therapeutic approach for atherosclerosis-related autoimmune disease.
Implementation Method 1
Peptide presentation on heterodimeric Human Leukocyte Antigen (HLA) Class II molecules (encoded by DP, DQ and DR alpha and beta chain genes) engages epitope-specific αβ T Cell Receptors (TCRs)
Implementation Method 2
an engineered T cell receptor comprising a human T cell beta chain with a CDR3 selected from the amino acid sequence of SEQ ID NOS: 179 to 356 and an alpha chain, wherein the TCR is specific for a human apolipoprotein B (ApoB) epitope
Data Source
AI summary
Provided herein are engineered T cell receptor (TCR) proteins, nucleic acids, vectors, host cells, methods of treating atherosclerosis-related autoimmune disease, and chimeric antigen receptor expressing T cell (CAR-T) comprising a beta chain CDR3 selected from the amino acid sequence of SEQ ID NOS: 179 to 356 and an alpha chain, wherein the TCR is specific for a human apolipoprotein B (ApoB) epitope, antigen-MHC binding portions, and full-length versions of the same.