Modular Biepitopic CAR-T Cells Using Single-Domain Antibody Mimics
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Solution Overview
Problem
Current CAR-T cell therapies face challenges in effectively targeting multiple tumor-associated antigens due to the complexity of VH and VL domain pairing, reduced expression of simultaneously expressed CARs, and compromised protein folding, leading to treatment failure in solid tumors and relapse in lymphoid malignancies.
Innovation Solution
Development of chimeric antigen receptors comprising a combination of single domain antibody mimics, such as monobodies, affibodies, or DARPins, which recognize two different epitopes of the same tumor antigen or two different tumor antigens, enhancing T-cell specificity and stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If multiple scFvs are linearly assembled in one single CAR format to achieve multi-redirected CAR-Ts, then the ability to recognize multiple epitopes is improved, but protein folding is compromised and expression is reduced
Solution Approach 1:
The patent divides the multi-epitope recognition function into separate single-domain antibody components (each recognizing one epitope) rather than using a single linear scFv construct. These segmented domains are then assembled in a controlled manner to maintain proper folding while achieving multi-epitope targeting.
Solution Approach 2:
The patent creates composite antigen-binding structures by combining multiple single-domain antibody components (such as nanobodies or affibodies) into a unified CAR construct. This composite approach allows each domain to fold independently and correctly while collectively providing multi-epitope recognition capability.
2Adaptability or versatility
If multiple CARs are simultaneously expressed to target multiple TAAs, then the coverage of tumor antigens is improved, but expression levels are reduced and manufacturing complexity increases
Solution Approach 1:
The patent merges multiple antigen-binding functions into a single CAR molecule by incorporating multiple single-domain antibody components within one construct. This consolidation allows simultaneous targeting of multiple TAAs or epitopes while simplifying manufacturing compared to producing and combining multiple separate CAR products.
Solution Approach 2:
The patent designs a universal CAR platform using single-domain antibody components that can be configured to recognize different epitopes or TAAs. This multi-functional design allows one CAR construct to perform multiple targeting functions, reducing manufacturing complexity while maintaining versatility.
3Reliability
If scFv-based antigen receptors are used to target tumor antigens, then T cell activation is achieved, but the complexity of VH and VL domain pairing and stabilization increases manufacturing difficulty
Solution Approach 1:
The patent replaces complex scFv domain pairing requirements with simpler single-domain antibody components (such as nanobodies or affibodies) that do not require VH-VL pairing. These simplified components are easier to manufacture and assemble while maintaining T cell activation capability, effectively substituting a simpler, more manufacturable solution for the complex scFv system.
Data Source
AI summary
Provided herein are biepitopic or bispecific chimeric antigen receptors. The chimeric antigen receptors comprise a combination of single domain antibody mimics. The single domain antibody mimics may be monobodies, affibodies, or DARPins. The disclosed chimeric antigen receptors may recognize two different epitopes of the same tumor antigen. For example, the chimeric antigen receptor may recognize two different epitopes of HER-2 or EGFR. The disclosed chimeric antigen receptors may recognize two epitopes of two different tumor antigens. For example, the chimeric antigen receptor may recognize HER-2 and EGFR. The disclosed chimeric antigen receptors may be expressed in immune cells for use in cancer immunotherapy.