Dual-Target CAR-T Lymphocyte for Leukemia Relapse Prevention
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Solution Overview
Problem
Current CAR-T cell therapies for treating acute lymphoblastic leukemia, such as CAR-T19, face challenges with relapse due to loss of CAR-T cells or antigen target, leading to ineffective identification and elimination of malignant cells.
Innovation Solution
Development of a T lymphocyte with a chimeric antigen receptor comprising specific single-chain antibodies, linker peptides, and immune co-stimulatory segments, which recognizes CD19 and CD22 antigens, enhancing tumor cell killing and reducing cytokine secretion for safer in vivo treatment.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CAR-T19 therapy is used to treat B-ALL, then complete remission rate is improved, but relapse occurs due to loss of CD19 antigen target
Solution Approach 1:
The chimeric antigen receptor is designed to recognize multiple antigens (CD19 and CD22) simultaneously through dual single-chain antibodies, enabling the T lymphocyte to target both CD19-positive and CD22-positive leukemia cells. This multi-functionality prevents relapse due to antigen loss, as the T cell can still recognize and kill cells that have lost CD19 expression.
Solution Approach 2:
The chimeric antigen receptor constructs a composite structure by integrating two different single-chain antibodies (anti-CD19 and anti-CD22) with linker peptides and transmembrane domains. This composite design allows the receptor to bind multiple antigen types, thereby overcoming the limitation of single-antigen targeting and reducing the risk of relapse.
2Productivity
If CAR-T19 therapy is used to treat B-ALL, then tumor cell elimination is improved, but cytokine secretion increases causing safety issues
Solution Approach 1:
The patent modifies the intracellular signaling domain of the chimeric antigen receptor by selecting specific co-stimulatory sequences (such as 4-1BB or CD28) and adjusting their arrangement. This parameter change in the signaling pathway optimizes the balance between tumor cell killing efficiency and cytokine secretion levels, reducing excessive immune activation while maintaining therapeutic efficacy.
3Adaptability or versatility
If single-chain antibodies are arranged with multiple linker peptides, then antigen recognition capability is improved, but receptor structure complexity increases
Solution Approach 1:
The chimeric antigen receptor is segmented into distinct functional modules: extracellular single-chain antibody regions for antigen binding, linker peptide regions for structural flexibility, transmembrane regions for cell membrane insertion, and intracellular signaling regions for immune activation. This segmentation allows each component to perform its specific function efficiently while maintaining overall structural organization despite the increased complexity of multi-antigen recognition.
Data Source
AI summary
Provided is a T lymphocyte. The T lymphocyte expresses a chimeric antigen receptor, and includes an extracellular region. The extracellular region includes a first single-chain antibody, a second single-chain antibody, a first linker peptide, and a CD8 hinge region. The first linker peptide is arranged between the first single-chain antibody and the second single-chain antibody. The first single-chain antibody includes a first heavy chain variable region, a first light chain variable region, and a second linker peptide. The second linker peptide is arranged between the first heavy chain variable region and the first light chain variable region. The second single-chain antibody includes a second heavy chain variable region, a second light chain variable region, and a third linker peptide. The third linker peptide is arranged between the second heavy chain variable region and the second light chain variable region. The first linker peptide has a repeated amino acid sequence of GGGGS, and the second linker peptide and the third linker peptide independently have 2-6 repeated amino acid sequences of GGGGS, respectively.