Chimeric Antigen Receptor Targeting HLA-DR for CAR-T Therapy
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Solution Overview
Problem
Current CAR-T cell therapies face challenges in producing effective treatments from HLA-DR type T cells with high affinity, limiting their therapeutic potential for cancer treatment.
Innovation Solution
Development of a chimeric antigen receptor (CAR) comprising specific antigen-binding molecules with varied binding affinities, including a heavy chain and light chain variable region sequence, and a co-stimulatory domain, to enhance the therapeutic efficacy of CAR-T cells by improving their ability to target cancer cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If CAR-T cells are designed to target HLA-DR antigens, then the ability to distinguish cancer cells from normal cells is improved, but the production effectiveness from HLA-DR type T cells with high affinity is reduced
Solution Approach 1:
The patent applies parameter changes by modifying the CAR structure to include specific co-stimulatory domains (CD28, 4-1BB, OX40) and altering the antigen-binding domain to target HLA-DR with optimized affinity. This resolves the contradiction by changing the parameters of the CAR molecule to achieve both high specificity for cancer cells and effective production from HLA-DR type T cells
Solution Approach 2:
The patent uses composite materials by creating a chimeric antigen receptor that combines multiple functional domains: an antigen-binding domain (scFv) for HLA-DR recognition, transmembrane domains for cell membrane integration, and intracellular signaling domains (CD3ζ, CD28, 4-1BB, OX40) for T cell activation. This composite structure enables both precise cancer cell distinction and effective T cell production
2Reliability
If various signaling domains and antigen-binding domains are artificially bound to create CAR fusion structure, then the therapeutic potential of CAR-T cells is improved, but the device complexity increases
Solution Approach 1:
The patent applies merging by combining multiple signaling domains (CD3ζ for activation, CD28 for co-stimulation, 4-1BB for enhanced activation, OX40 for memory formation) and antigen-binding domains into a single CAR fusion protein. This resolves the contradiction by integrating these diverse functional elements into one cohesive molecular structure that delivers enhanced therapeutic potential while managing complexity through systematic domain arrangement
3Reliability
If CD19 antibody is used to target cancer cells, then the treatment effectiveness for B cell lymphoma is improved, but the ability to accurately distinguish normal cells from cancer cells is reduced
Solution Approach 1:
The patent applies parameter changes by switching the target antigen from CD19 to HLA-DR, and further optimizing the antigen-binding domain to target specific cancer-associated HLA-DR variants. This resolves the contradiction by changing the targeting parameter to achieve both high treatment effectiveness and improved discrimination between normal and cancer cells, as HLA-DR expression patterns differ between cell types
Data Source
AI summary
The present invention relates to an antigen-binding molecule comprising a heavy chain variable region comprising a heavy-chain complementarity-determining region 1 (HCDR1) comprising an amino acid sequence represented by Sequence No. 1, an HCDR2 comprising an amino acid sequence represented by Sequence No. 2, and an HCDR3 comprising an amino acid sequence represented by Sequence No. 3; a light-chain variable region comprising a light-chain complementarity-determining region 1 (LCDR1) comprising an amino acid sequence represented by Sequence No. 4, an LCDR2 comprising an amino acid sequence represented by Sequence No. 5, and an LCDR3 comprising an amino acid sequence represented by Sequence No. 6; wherein the antigen-binding molecule is a T cell receptor (TCR); and to a cell line expressing the same.