CLDN18A2-Targeting CAR-T Cells for Solid Tumor Therapy
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Solution Overview
Problem
CAR-T cell immunotherapy for solid tumors faces challenges such as immunological toxicity and 'on-target off-tumor' toxicity due to sustained activation of CAR-T cells, necessitating the identification of appropriate antigenic targets for effective tumor cell elimination with minimal toxicity.
Innovation Solution
Development of a chimeric antigen receptor (CAR) specifically targeting human CLDN18A2, comprising an extracellular binding region, transmembrane region, and intracellular signaling region, which is genetically engineered into immune effector cells to recognize and target CLDN18A2-positive tumor cells while minimizing recognition of normal tissues.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CAR-T cells are used to target solid tumors, then antitumor activity is improved, but immunological toxicity and on-target off-tumor toxicity increase
Solution Approach 1:
The patent applies local quality by designing the CAR structure with distinct functional domains: the extracellular binding region specifically recognizes CLDN18A2 on tumor cells, while the intracellular signal region is engineered to modulate activation strength. This spatial differentiation of functions within the CAR molecule allows selective antitumor activity while reducing unwanted toxicity effects on normal tissues.
Solution Approach 2:
The patent employs parameter changes by modifying the intracellular signaling domain composition and configuration of the CAR. Different signal regions with varying activation strengths are tested and optimized to achieve the right balance between effective tumor cell lysis and minimization of sustained activation that causes toxicity. The signaling parameters are tuned to prevent excessive immune activation.
2Reliability
If CAR-T cells are sustained activated to eliminate tumor cells, then antitumor efficacy is improved, but macrophage activation syndrome and immunological toxicity occur
Solution Approach 1:
The patent applies periodic action by designing the CAR signaling domain to provide controlled, regulated activation rather than sustained continuous activation. The intracellular signal region is engineered to deliver immune activation signals in a controlled manner that achieves tumor cell elimination while preventing the sustained intense activation that leads to macrophage activation syndrome and immunological toxicity.
3Measurement precision
If CAR-T cells recognize target antigen on normal tissues, then specificity is improved, but on-target off-tumor toxicity increases
Solution Approach 1:
The patent applies local quality by ensuring the extracellular binding region of the CAR is highly specific for CLDN18A2, while the intracellular signal region is designed with moderated activation strength. This creates a system where normal tissues expressing low levels of CLDN18A2 are recognized with high specificity but do not trigger strong toxic responses, as the signaling domain requires a threshold level of activation that is only reached on tumor cells.
Data Source
AI summary
A chimeric antigen receptor (CAR) cell specifically targeting human Claudin18.2 (CLDN18A2), a preparation method and an application thereof are provided. The extracellular binding region of the CAR includes a protein specifically recognizing CLDN18A2 that has any one of the amino acid sequences as shown in SEQ ID NOS: 2-5 or any one of the amino acid sequences of the variants having 70%-99% identity with the amino acid sequences shown by the SEQ ID NOS: 2-5. The immune effector cell modified by the CAR can be used to treat tumors.