Chimeric Receptors With Modular Signaling Domains for Immune Modulation
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Solution Overview
Problem
Current recombinant chimeric receptors (CRs) for immune cell therapies, such as CAR T-cell therapies, lack the ability to fine-tune their activity and functionality, primarily functioning as 'on/off' switches, which limits their effectiveness in treating solid tumors and other diseases where precise immune modulation is required.
Innovation Solution
Development of a new class of chimeric receptors engineered with intracellular signaling domains derived from molecules like BAFF-R, CD40, TACI, CD2, CD7, CD30, and NTB-A, which allow for modulatory functions such as co-stimulatory or inhibitory signals, enabling enhanced immune cell activity and specificity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If traditional recombinant chimeric receptors are used, then the structure is simple and easy to manufacture, but the functionality is limited to binary on/off switching without fine-tuning capability
Solution Approach 1:
The chimeric receptor is divided into distinct functional modules: an extracellular antigen-binding domain, a transmembrane domain, and an intracellular signaling domain. The signaling domain is further segmented into multiple independent signaling sequences that can be independently selected and combined, enabling fine-tuned control of immune cell activation while maintaining modular simplicity in design and manufacturing.
Solution Approach 2:
Different regions of the chimeric receptor are optimized with specific properties: the extracellular domain is designed for high-affinity antigen binding, the transmembrane domain provides stable membrane anchoring, and the intracellular domain contains selectable signaling sequences that provide localized fine-tuning of activation strength. This local optimization enables precise control of receptor functionality without requiring complete redesign of the entire structure.
2Productivity
If chimeric receptors with multiple signaling domains are introduced, then the immune cell activation and proliferation are enhanced, but the manufacturing complexity and cost increase
Solution Approach 1:
The chimeric receptor design incorporates universal signaling sequences from well-characterized immune receptors (such as CD28, 4-1BB, OX40) that can be interchanged to achieve different activation profiles. This multi-functionality allows a single receptor framework to serve multiple therapeutic purposes by simply changing the signaling domain, thereby enhancing immune cell proliferation without proportionally increasing manufacturing complexity.
Solution Approach 2:
The invention enables fine-tuning of immune cell activation by changing the signaling parameters within the intracellular domain. Different signaling sequences provide graded responses ranging from strong activation to moderate modulation, allowing optimization of therapeutic efficacy while using the same basic receptor structure. This parameter-based tuning avoids the need to manufacture entirely different receptor types for different activation levels.
3Reliability
If existing CAR T-cell therapies are used, then the treatment is effective for hematological malignancies, but the efficacy is limited in solid tumors
Solution Approach 1:
The chimeric receptor incorporates dynamic signaling capabilities through selectable intracellular domains that can modulate the strength and duration of activation signals. This dynamic control allows the same receptor framework to be adapted for different disease contexts: strong activation signals for hematological malignancies and fine-tuned modulation for solid tumors, thereby expanding therapeutic efficacy across diverse indications while maintaining reliability in each context.
Data Source
AI summary
This disclosure relates to chimeric receptors (CRs) and their signaling components for the regulation of an immune response. Also provided are nucleic acids encoding the disclosed CRs, recombinant immune cells expressing the same, and pharmaceutical compositions containing the disclosed nucleic acids and/or recombinant cells. Further provided are methods useful for modulating an activity of an immune cell, methods for modulating an immune response in an individual, as well as methods for treating a health condition in an individual in needed thereof