CAR Linker Domain Optimization for Solid Tumor Targeting
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Solution Overview
Problem
Current CAR T cell therapies face limitations in targeting and treating solid tumors due to challenges in accessing solid tumor microenvironments and developing effective CAR-T cells that target cancer cells expressing solid-tumor specific antigens.
Innovation Solution
A chimeric antigen receptor (CAR) is designed with a linker domain of 12 to 228 amino acids, specifically optimized to target dysfunctional P2X7 receptors, which are selectively expressed by cancer cells, enhancing the efficacy of CAR-expressing immune cells in recognizing and killing a wide range of cancer cell types.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If a CAR is designed with a specific linker domain length to optimize antigen recognition, then the ability to recognize and target dysfunctional P2X7 receptors is improved, but the ability to effectively target diverse solid tumor types remains limited
Solution Approach 1:
The patent systematically varies the linker domain length parameter (testing multiple lengths including 12, 22, 32, 42, 52, 62, 72, 82, 92, 102, 112, 122, 132, 142, 152, 162, 172, 182, 192, 202, 212, and 228 amino acids) to identify the optimal length for P2X7 receptor recognition. This parameter optimization enables the CAR to effectively recognize dysfunctional P2X7 receptors across diverse solid tumor types including prostate, breast, ovarian, lung, and pancreatic cancers.
2Reliability
If CAR T cells are used to treat haematological cancers, then high response rates are achieved, but treatment of solid tumours remains limited due to T cell access issues and hostile microenvironment
Solution Approach 1:
The patent optimizes the local properties of the CAR molecule by specifically designing the linker domain composition and length to enable effective P2X7 receptor recognition in the solid tumor microenvironment. The linker domain is engineered with specific amino acid sequences that allow the CAR to navigate the hostile solid tumor environment while maintaining antigen recognition capability, thereby overcoming the limitations that prevent CAR T cells from effectively treating solid tumors.
3Adaptability or versatility
If a linker domain is made longer to increase flexibility for antigen binding, then antigen recognition capability is improved, but the structural stability and proper orientation of the CAR may be compromised
Solution Approach 1:
The patent systematically optimizes the linker domain length parameter to find the balance point between flexibility and stability. By testing multiple linker lengths and evaluating CAR expression, antigen recognition, and cytotoxic activity, the patent identifies the optimal linker domain length that provides sufficient flexibility for antigen binding while maintaining structural stability and proper CAR orientation on the T cell surface.
Data Source
AI summary
The present invention relates to an optimized chimeric antigen receptor (CAR), and genetically modified cells expressing the same, that can target a diverse range of cancer types. More specifically, the CAR has an optimized linker length that facilitates the targeting and lyse of a wide range of cancer cell types by CAR expressing T cells.