Engineered T-Cell Receptors for NDC80 CT pMHC Recognition
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Solution Overview
Problem
There is a need for T-cell receptors (TCRs) that are specifically directed to cancer-specific antigens for effective cancer treatment, as existing TCRs often fail to recognize tumor-specific pMHC complexes effectively.
Innovation Solution
Development of engineered TCRs that recognize the NDC80 CT antigen, specifically through peptides with sequences GLNEEIARV and ASSLSGGIYEQY, and their use in generating peptide-specific immune effector cells for targeted cancer therapy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing TCRs are used for cancer treatment, then the treatment can be administered, but the TCRs fail to recognize tumor-specific pMHC complexes effectively
Solution Approach 1:
The patent applies parameter changes by modifying the TCR sequences to create engineered TCRs with specific amino acid sequences (e.g., TCR-alpha: AVQAGSSASKII, TCR-beta: ASSLSGGIYEQY) that are optimized for recognizing specific tumor-associated pMHC complexes. This involves changing the sequence parameters of the TCR to achieve high affinity binding to cancer-specific antigens like NDC80 CT.
Solution Approach 2:
The patent uses copying by isolating and cloning functional TCR sequences from T cells that have been selected for recognizing tumor-specific pMHC complexes. The functional TCR sequences are then copied and introduced into other T cells through transduction, creating engineered TCR-T cell products that inherit the specific recognition capability.
2Reliability
If TCR-engineered T cells are generated with specific sequences, then cancer cell recognition is improved, but the complexity of TCR engineering increases
Solution Approach 1:
The patent applies segmentation by separating the TCR into distinct functional components: the variable regions (VD1-VD4, VJ1-VJ4) that provide antigen recognition, the constant regions that provide structural stability, and the signaling domains (CD3ζ, CD3ε) that trigger cellular responses. This modular segmentation allows independent optimization of each component and simplifies the engineering process.
Solution Approach 2:
The patent uses an intermediary approach by employing lentiviral or retroviral vectors as mediators to transfer the engineered TCR sequences into patient T cells. This intermediary system simplifies the overall process by providing a standardized method for TCR introduction without requiring direct manipulation of the T cells themselves.
Data Source
AI summary
This disclosure provides for engineered T cell Receptors (TCRs), cells comprising the TCRs, and methods of making and using the TCRs. The current disclosure relates to TCRs that specifically recognize epitope(s) from tumor antigen NDC80 CT. Accordingly, aspects of the disclosure relate to an engineered T-cell Receptors (TCRs), nucleic acids encoding the TCRs, and cells comprising the nucleic acids and TCRs. Also provided are compositions comprising the cells, nucleic acids, or engineered TCRs of the disclosure, methods of making the cells and methods of using the embodiments of the disclosure for therapeutic treatments.