EBV-Specific TCR Constructs Across Multiple HLA Alleles
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Existing T cell-based immunotherapies targeting Epstein-Barr virus (EBV)-associated malignancies face challenges such as reliance on natural EBV-specific T cells that may not be present in patients, low success rates in expanding these cells, and inefficiencies in manufacturing engineered T cells, particularly when targeting different MHC I alleles.
Innovation Solution
Development of nucleic acids encoding TCR alpha and beta chain constructs with specific CDR sequences that recognize EBV epitopes in complex with human MHC I, such as HLA-A*02:01, HLA-B*57:01, HLA-C*15:02, HLA-C*06:02, HLA-B*44:02, and HLA-B*07:02, enabling high-affinity peptide sensitivity and broad applicability across different MHC I alleles.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If natural EBV-specific T cells are used for immunotherapy, then the therapy targets EBV-associated malignancies, but the success rate is low because these cells may not be present in patients and expansion is difficult
Solution Approach 1:
The patent creates artificial copies of EBV-specific T cells by transducing patient T cells with engineered TCR genes that recognize EBV epitopes. Instead of relying on scarce natural EBV-specific T cells, the invention synthesizes functional equivalents through genetic engineering, allowing reliable production of sufficient数量的 target-specific T cells for therapy
Solution Approach 2:
The patent modifies the T cell population by introducing exogenous TCR genes with specific CDR sequences optimized for EBV epitope recognition. This parameter change transforms ordinary T cells into EBV-specific effector cells, overcoming the limitation of insufficient natural EBV-specific T cells while ensuring reliable therapeutic activity
2Measurement precision
If TCR constructs with specific CDR sequences are developed to recognize EBV epitopes, then peptide sensitivity and specificity are improved, but the complexity of developing and manufacturing engineered T cells increases
Solution Approach 1:
The patent applies local quality by specifically optimizing the CDR3 region of the TCR construct, which is the most critical determinant of antigen specificity. Rather than redesigning the entire TCR, the invention focuses modifications on the CDR loops that directly contact the epitope-MHC complex, achieving high peptide sensitivity while maintaining overall TCR structure and simplifying manufacturing
Solution Approach 2:
The patent develops TCR constructs with broad MHC restriction patterns, allowing a single TCR design to recognize EBV epitopes presented by multiple HLA alleles (HLA-A*02:01, HLA-B*57:01, HLA-C*15:02, HLA-C*06:02, HLA-B*44:02, HLA-B*07:02). This universality reduces the need for patient-specific HLA matching and simplifies manufacturing by enabling use of a limited panel of standardized TCR constructs
3Adaptability or versatility
If engineered T cells are produced to target different MHC I alleles, then broad applicability is achieved, but the manufacturing efficiency and time are reduced
Solution Approach 1:
The patent performs preliminary action by pre-designing and validating a panel of TCR constructs with defined specificities for different EBV epitopes and MHC alleles before clinical application. This upfront characterization allows rapid selection and implementation of appropriate TCRs without time-consuming development during patient treatment, significantly improving manufacturing efficiency while maintaining broad MHC coverage
Solution Approach 2:
The patent segments the TCR development process into distinct modules: separate TCR constructs for different EBV epitopes (LMP2A, LMP1, EBNA3C) and different MHC alleles. This segmentation allows parallel development and validation of multiple TCR specificities, which can then be rapidly assembled into personalized therapies, improving both versatility and manufacturing throughput
Data Source
Figure 1A~2A
Figure 2B~3
Figure 4A~5A
AI summary
The present invention relates to the filed of immunotherapy, in particular, of Epstein-Barr virus-associated diseases (EBV, also designated Human gammaherpesvirus 4), e.g., cancer or post- transplant lymphoproliferative disease, in particular, to adoptive T cell therapy or T cell receptor (TCR) gene therapy. The invention provides a combination of nucleic acids encoding at least two TCR constructs, or the respective proteins or host cells, wherein each TCR construct is capable of specifically binding to its respective epitope in the context of the respective MHC I, and wherein the epitopes are peptides from different antigens expressed by the same infective agent or cancer, e.g., EBV antigens.The invention also provides specific nucleic acids encoding a TCR alpha chain construct (TRA) and/or a TCR beta chain construct (TRB) of a TCR construct specific for an epitope in complex with a human MHC I, wherein the epitope is an epitope of an Epstein- Barr-virus protein, wherein the TCR constructs are specific for epitopes from LMP2A, LMP1 or EBNA3C. Proteins encoded by said nucleic acids, corresponding host cells and pharmaceutical compositions and kits are also objects of the invention.