Chimeric Antigen Receptor with Catalytic Signaling Domain
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current cancer immunotherapies, such as CAR-T cell therapy, face challenges in treating solid tumors due to the complex immunosuppressive tumor microenvironment and high tumor heterogeneity, where cancer cells use 'don't eat me' signaling molecules like PD-L1 to inhibit immune cell functions, hindering effective treatment.
Innovation Solution
A chimeric antigen receptor (CAR) is designed with an extracellular target molecule binding domain, an intracellular signaling domain containing catalytic domains, and a transmembrane domain to enhance immune cell activation and killing of cancer cells by bypassing immune checkpoint inhibition, specifically targeting PD-1/PD-L1 signaling pathway to re-activate immune cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CAR-T cell therapy is used to treat solid tumors, then immune cell activation and cancer cell killing ability are improved, but the immunosuppressive tumor microenvironment and immune checkpoint inhibition (PD-1/PD-L1 signaling) worsen treatment effectiveness
Solution Approach 1:
The patent introduces an intermediate signaling component that mediates between the CAR activation and the immune checkpoint inhibition. The chimeric antigen receptor is designed to include additional signaling domains that can overcome the suppressive PD-1/PD-L1 pathway by providing alternative activation signals that bypass the checkpoint blockade, thereby restoring immune cell function in the immunosuppressive microenvironment.
Solution Approach 2:
The patent employs a composite chimeric antigen receptor structure that combines multiple functional domains including antigen recognition, co-stimulation, and checkpoint blocking capabilities. This composite receptor integrates different signaling pathways (e.g., CD3ζ for activation, CD28 or 4-1BB for co-stimulation, and PD-1 domain for checkpoint blocking) into a single molecular entity that can simultaneously perform multiple functions to overcome tumor immune evasion.
2Ease of manufacture
If the CAR structure is simplified to improve manufacturing, then device complexity is reduced, but the ability to bypass immune checkpoint inhibition and re-activate immune cells is compromised
Solution Approach 1:
The patent merges multiple functional domains into a single chimeric antigen receptor molecule, combining antigen recognition (scFv), co-stimulation (CD28 or 4-1BB), and checkpoint blocking (PD-1 domain) into one integrated structure. This merging approach maintains the complex functionality needed to bypass immune checkpoint inhibition while streamlining the manufacturing process by producing a single recombinant protein rather than multiple separate components.
Solution Approach 2:
The chimeric antigen receptor is designed with universal multi-functionality, where a single receptor molecule performs antigen recognition, T cell activation, co-stimulation, and immune checkpoint blocking simultaneously. The standardized modular design allows the same basic structure to be applied across different cancer types and targets, maintaining versatility while simplifying manufacturing through a platform approach.
3Reliability
If the CAR targets multiple signaling pathways to overcome immune evasion, then immune cell re-activation is improved, but the device complexity increases
Solution Approach 1:
The chimeric antigen receptor is segmented into distinct functional modules: an extracellular antigen recognition domain (scFv), a transmembrane domain, and an intracellular signaling domain composed of separate functional units (CD3ζ for activation, CD28 or 4-1BB for co-stimulation, and PD-1 for checkpoint blocking). This segmentation allows each module to perform its specific function independently while maintaining overall structural integrity and simplifying the design process through modular assembly.
Solution Approach 2:
The chimeric antigen receptor incorporates dynamic signaling capabilities where the intracellular domain can adaptively respond to different activation states. The signaling domains are designed to provide graded responses based on the level of antigen engagement and co-stimulation, allowing the receptor to dynamically adjust its signaling output to overcome varying degrees of immune checkpoint inhibition while maintaining structural consistency.
Data Source
AI summary
A chimeric antigen receptor includes a) an extracellular target molecule combination domain, used for a specific-binding target molecule; b) an intracellular signaling domain including at least one intracellular activation signaling domain and/or at least one intracellular detection signaling domain; and c) a transmembrane domain, used to connect the extracellular target molecule combination domain and the intracellular signaling domain, and fix the two domains on a cell membrane. Activation of the intracellular signaling domain at least relies on combination of the extracellular target molecule combination domain with the target molecule, and the intracellular activation signaling domain contains a molecule or a fragment having a catalytic functional group. The present chimeric antigen receptor combines various means to create and apply an artificial molecular machine, thus having the strengths of an immune checkpoint inhibitor and of cell therapy at the same time, and providing a solution for improving treatment of solid tumors.