Modular CAR Signaling via Separate Transmembrane Chains
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Solution Overview
Problem
Current CAR designs are rigid, combining fixed costimulatory domains in cis, which limits flexibility and control over the CAR-generated signal, and may not effectively mimic natural T cell activation.
Innovation Solution
A 'mix and match' approach is proposed where different signaling and costimulatory domains are present on separate chains within the same CAR complex, allowing for increased flexibility and control of the CAR signal through transmembrane-mediated interactions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If costimulatory domains are combined in cis on the same intracellular protein domain, then the CAR structure is simplified and easier to manufacture, but the flexibility and control of the CAR-generated signal is reduced
Solution Approach 1:
The CAR is divided into separate chains: a first chain with a signaling domain and a second chain with a costimulatory domain. This segmentation allows independent optimization of each domain's function while maintaining overall CAR complexity manageable through modular assembly.
Solution Approach 2:
The invention creates a universal CAR design where different signaling domains (CD3ζ, FcεRIγ) and costimulatory domains (CD28, 4-1BB, OX40, ICOS) can be combined in various configurations. This multi-functionality allows the same basic CAR structure to serve multiple therapeutic purposes by simply changing the domain combinations.
2Reliability
If fixed costimulatory domains are used in cis, then the CAR design is more stable and reliable, but the ability to mimic natural T cell activation is reduced
Solution Approach 1:
The invention introduces dynamic control mechanisms where the costimulatory domain expression can be regulated independently from the signaling domain. This allows the CAR to adapt its signaling characteristics based on cellular context, better mimicking the dynamic nature of natural T cell activation while maintaining structural stability.
Solution Approach 2:
The invention uses an intermediary mechanism where the costimulatory domain on the second chain interacts with endogenous ligands on the cell surface, rather than requiring direct cis-interaction. This intermediary approach allows more flexible and physiologically relevant signaling while maintaining design stability.
3Productivity
If different costimulatory domains are used to yield different kinetics and persistence, then the CAR can be optimized for specific therapeutic outcomes, but the CAR structure becomes more complex
Solution Approach 1:
By segmenting the CAR into separate chains for signaling and costimulation, the invention enables independent selection and optimization of different costimulatory domains (CD28 for rapid response, 4-1BB for persistence, etc.) without increasing overall structural complexity. Each domain can be tailored for specific kinetic profiles while maintaining modular simplicity.
Data Source
AI summary
The present application relates to the field of immunotherapy, more particularly to the field of chimeric antigen receptors (CARs). Currently, second and third generation CAR designs are quite rigid in that they combine fixed costimulatory domains in cis on the same intracellular protein domain. Trans signaling is not equivalent as costimulatory receptors have different expression levels or stoichiometry. Here, a ‘mix and match’ approach is proposed where different signaling and costimulatory domains are present on separate chains within the same CAR complex, allowing increased flexibility and control of the nature and strength of the CAR-generated signal. Also proposed are polynucleotides, vectors encoding the transmembrane polypeptide chains and cells expressing such CARs. These cells are particularly suitable for use in immunotherapy, and strategies to treat diseases such as cancer using these cells are also provided.