Chimeric Receptor Junction Region Modification for Reduced Immunogenicity
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Solution Overview
Problem
Existing chimeric antigen receptors (CARs) used in adoptive cell therapy often induce an immune response in subjects, leading to reduced persistence and efficacy of genetically engineered cells, as the junction region between domains can be immunogenic and trigger host immune responses.
Innovation Solution
A variant chimeric receptor with modified junction regions, featuring specific amino acid modifications, is designed to reduce binding affinity for human leukocyte antigens (HLA) and immunogenicity, thereby minimizing immune responses and enhancing the persistence and activity of engineered cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Device complexity
If the junction region of chimeric antigen receptor is used as originally designed, then the receptor structure is simple and functional, but the junction region is immunogenic and triggers host immune responses
Solution Approach 1:
The patent applies local quality by specifically modifying only the junction region between domains while leaving the rest of the CAR structure unchanged. This targeted approach reduces immunogenicity at the problematic location without affecting the overall functional integrity of the receptor
Solution Approach 2:
The patent changes the amino acid sequence parameters in the junction region to create modified versions with reduced HLA binding affinity. Specific amino acid substitutions are made to alter the peptide sequence while maintaining structural functionality, thereby reducing immune recognition
2Object-affected harmful factors
If amino acid modifications are made in the junction region to reduce HLA binding affinity, then immunogenicity is reduced, but the complexity of receptor design increases
Solution Approach 1:
The patent systematically changes amino acid parameters in the junction region by substituting specific residues to reduce HLA binding affinity while maintaining CAR functionality. This parameter optimization approach balances immunogenicity reduction with design complexity
Solution Approach 2:
The patent creates multiple copy variants of the CAR with different amino acid sequences in the junction region. By generating and testing multiple copies with sequential modifications, the optimal balance between reduced immunogenicity and maintained function is achieved
3Reliability
If the chimeric antigen receptor is administered to treat disease, then therapeutic activity is provided, but the engineered cells exhibit reduced persistence due to immune response
Solution Approach 1:
The patent applies preliminary anti-action by pre-modifying the junction region to reduce immunogenicity before the CAR is administered to the patient. This preventive modification stops the immune response problem before it can develop, allowing for longer cell persistence and sustained therapeutic activity
Solution Approach 2:
The patent converts the harmful immunogenicity of the junction region into a benefit by deliberately modifying it to reduce HLA binding. The originally harmful feature (immunogenic junction) is transformed into an improved feature (reduced immune recognition) through amino acid modifications
Data Source
AI summary
Provided are chimeric receptors for engineering cells for adoptive therapy, including T cells, and the genetically engineered cells. In some embodiments, the chimeric receptors, such as chimeric antigen receptors (CARs) are modified in a junction region by one or more amino acid modifications such that peptide fragments of such region exhibit a lower binding affinity for a human leukocyte antigen (HLA) and/or the region exhibits reduced immunogenicity, including following administration to a subject. In some aspects, also provided are methods and compositions for engineering and producing cells expressing such chimeric receptors, compositions containing the cells, and method for their administration to subjects. In some embodiments, features of the chimeric receptors and engineered cells containing the chimeric receptors result in methods that provide for increased or improved activity, efficacy and/or persistence.