BCMA-Specific VCAR Compositions Using Single-Domain Antibodies
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Solution Overview
Problem
There is a long-felt need for a method to direct the specificity of immune cells without using traditional antibody sequences or fragments thereof.
Innovation Solution
The development of chimeric antigen receptors (CARs) comprising an ectodomain with an antigen recognition region, a transmembrane domain, and an endodomain with a costimulatory domain, utilizing single domain antibodies such as VHHs, which can be bi- or tri-specific, and potentially including a hinge and signal peptide.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If traditional antibody sequences are used for antigen recognition, then the immune cell specificity is established, but the device complexity and manufacturing difficulty increase
Solution Approach 1:
The patent extracts only the essential antigen-binding domain from traditional antibodies, using single-domain antibodies (sdAbs) instead of full antibody sequences. This extraction maintains antigen recognition capability while eliminating the complexity of traditional antibody structures, resulting in simpler CAR designs with reduced amino acid sequences that are easier to manufacture and engineer.
Solution Approach 2:
The CAR is segmented into distinct functional modules: a single-domain antibody for antigen recognition, a transmembrane domain for membrane anchoring, and an intracellular signaling domain for immune activation. This segmentation allows each component to be optimized independently and facilitates modular assembly, reducing overall complexity while maintaining reliability.
2Reliability
If traditional antibody sequences are used, then antigen recognition is achieved, but the manufacturing precision and ease of manufacture decrease
Solution Approach 1:
By extracting the minimal essential antigen-binding region into single-domain antibodies, the patent creates sequences that are shorter and simpler to synthesize. This extraction maintains full antigen recognition capability while significantly improving ease of manufacture through reduced sequence length and simplified genetic constructs.
Solution Approach 2:
The patent changes the parameter of antibody sequence length and complexity by using single-domain antibodies instead of traditional multi-domain antibody structures. This parameter change results in more compact sequences that are easier to clone, express, and manufacture with higher precision.
3Device complexity
If single domain antibodies are used in CARs, then the device complexity is reduced, but the antigen recognition specificity may be compromised
Solution Approach 1:
The patent carefully extracts only the most critical antigen-binding residues and structural elements into the single-domain antibody framework. This selective extraction preserves the essential specificity-determining regions while removing non-essential portions, maintaining antigen recognition capability despite the reduced structure.
Solution Approach 2:
The single-domain antibodies are designed with enhanced local quality in the antigen-binding region, concentrating the specificity-determining features in optimized local structures. This allows the simplified overall structure to maintain high antigen recognition specificity through localized structural optimization.
Data Source
AI summary
Disclosed are VHH chimeric antigen receptors (VCARs), VCAR transposons encoding VCARs of the disclosure, cells modified to express VCARs of the disclosure, as well as methods of making and methods of using the same for adoptive cell therapy.