Coiled-Coil Spacer Domain for Multimeric CAR Design
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Solution Overview
Problem
Current chimeric antigen receptors (CARs) face limitations in targeting cancer cells with antigens expressed at low density due to high affinity binding domains, which restrict their ability to induce activation in the presence of low antigen density, and existing spacers like IgG1 hinge are inflexible and require whole domain structures, limiting vector construction and CAR design flexibility.
Innovation Solution
The use of a coiled-coil spacer domain in CARs allows for multimerization, increasing sensitivity to low-density antigens by forming complexes such as dimers, trimers, or higher oligomers, and enabling incremental spacer length adjustments, enhancing vector efficiency and flexibility in CAR design.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Strength
If high affinity binding domains are used in CARs, then binding strength to antigen is improved, but ability to induce activation in response to low density antigen is worsened
Solution Approach 1:
The patent combines multiple CAR molecules into multimeric complexes (dimers, trimers, or higher oligomers) through the coiled-coil spacer domain. This merging of multiple binding domains increases overall avidity for low-density antigens while maintaining the ability to induce T-cell activation, resolving the contradiction between binding strength and activation capability.
Solution Approach 2:
The invention creates composite CAR structures by fusing the coiled-coil spacer domain (derived from cartilage oligomeric matrix protein) with antigen-binding domains and signaling domains. This composite design enables multimerization while preserving both high binding affinity and activation induction capability, allowing the CAR to function effectively against low-density antigens.
2Stability of the object's composition
If whole domain structures like IgG1 hinge are used as spacers, then structural stability is improved, but design flexibility and vector construction efficiency are worsened
Solution Approach 1:
The patent extracts only the essential coiled-coil spacer domain from the cartilage oligomeric matrix protein, removing unnecessary bulk while retaining the multimerization capability. This extracted spacer element provides structural stability through coiled-coil formation while enabling flexible design and efficient vector construction, as it can be easily incorporated into various CAR configurations without requiring whole domain structures.
Solution Approach 2:
The invention changes the structural parameters of the spacer by using a compact coiled-coil domain instead of large immunoglobulin domains. This parameter change reduces the overall size and complexity of the CAR construct while maintaining structural stability through the coiled-coil motif's inherent stability, thereby improving both design flexibility and vector construction efficiency.
3Device complexity
If classical homodimer CAR structure is used, then simplicity of construction is improved, but flexibility in antigen binding specificity and stoichiometry is worsened
Solution Approach 1:
The patent creates a universal CAR platform based on the coiled-coil spacer that can accommodate multiple different antigen-binding specificities within the same multimeric structure. The coiled-coil domain serves as a universal connector that can link different scFv variants, allowing flexible stoichiometry and multiple binding specificities while maintaining relatively simple construction through standardized spacer sequences.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
This approach results in a hyper-sensitive CAR that can effectively target and activate T-cells against low-density antigens, improving cancer therapy by allowing targeting of more cancers and reducing cancer escape, with increased avidity and flexibility in CAR design.
Implementation Method 1
The coiled-coil domain enables the multimerization of a plurality of CAR-forming polypeptides and/or accessory polypeptides
Data Source
AI summary
The present invention provides a chimeric antigen-receptor (CAR)-forming polypeptide comprising: (i) an antigen-binding domain; (ii) a coiled-coil spacer domain; (iii) a transmembrane domain; and (iv) an endodomain. The invention also provides a multimeric CAR formed by association of a plurality of CAR-forming polypeptides by virtue of association of their coiled-coil spacer domains.