Engineered TCRs Targeting MAGEA4 Peptide-HLA Complex
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Solution Overview
Problem
Current cancer therapies lack specific targeting mechanisms to effectively recognize and destroy cancer cells, particularly those expressing MAGEA4 protein, which is upregulated in various cancers, due to limitations in identifying and characterizing tumor-associated antigens and their corresponding T-cell receptors.
Innovation Solution
Development of novel T-cell receptors (TCRs) specifically designed to bind to the MAG-003 peptide-HLA molecule complex, including engineered alpha and beta chains with enhanced binding affinity and stability, for use in treating proliferative diseases such as lung, renal, and breast cancers by enhancing T-cell recognition and killing of tumor cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional cancer therapies are used, then treatment can be administered, but they lack specific targeting mechanisms to effectively recognize and destroy cancer cells
Solution Approach 1:
The patent modifies the T-cell receptor structure by engineering specific amino acid substitutions in the CDR regions, particularly CDR3, to enhance binding affinity and specificity for the MAG-003 peptide-HLA-A*02:01 complex. This parameter change in the molecular structure enables reliable cancer cell targeting while maintaining feasibility of manufacturing through standard protein engineering techniques
Solution Approach 2:
The engineered TCR acts as an intermediary molecule that bridges the gap between the T-cell and the tumor-associated antigen MAGEA4 presented by HLA-A*02:01. This specialized receptor enables specific recognition and binding, providing the missing targeting mechanism that conventional therapies lack
2Manufacturing precision
If T-cell receptors are engineered to enhance binding affinity, then targeting effectiveness improves, but the complexity of development and characterization increases
Solution Approach 1:
The patent applies local quality changes by introducing specific amino acid substitutions only in the CDR regions of the TCR, particularly in CDR3 which is most critical for antigen recognition. This localized engineering approach enhances binding affinity without requiring complete redesign of the entire TCR structure, thereby managing development complexity while achieving improved manufacturing precision
Solution Approach 2:
The patent employs partial action by focusing engineering efforts on specific key residues rather than attempting to optimize the entire TCR structure. By targeting only the most critical binding interface regions, the patent achieves enhanced affinity while avoiding the excessive complexity that would result from comprehensive structural optimization
3Duration of action of stationary object
If TCRs are designed for high stability and prolonged half-life, then therapeutic effectiveness improves, but the engineering requirements become more stringent
Solution Approach 1:
The patent applies preliminary action by pre-engineering stabilizing mutations in the TCR structure before therapeutic application. Specific amino acid substitutions are introduced in advance to enhance structural stability and extend half-life, allowing the TCR to maintain functionality throughout the therapeutic process without requiring complex post-manufacturing modifications
4Measurement precision
If specific T-cell receptors targeting MAGEA4 are developed, then cancer cell recognition improves, but the difficulty of identifying and characterizing appropriate antigens increases
Solution Approach 1:
The patent uses copying by creating recombinant TCR sequences based on previously identified natural TCRs that recognize MAGEA4. By cloning and engineering these known specific sequences, the patent achieves high measurement precision in cancer cell recognition while avoiding the need to de novo identify and characterize new antigens, thereby reducing the difficulty of antigen characterization
Data Source
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AI summary
The present description relates to T-cell receptors (TCRs) binding to tumor-associated antigens (TAAs) for targeting cancer cells, T-cells expressing same, methods for producing same, and methods for treating cancers using same. In particular, the present description relates to TCRs and their variants that bind to HLA class I or II molecules with a peptide, such as MAG-003 have the amino acid sequence of KVLEHVVRV (SEQ ID NO:1). The present description further relates to peptides, proteins, nucleic acids and cells for use in immunotherapeutic methods. In particular, the present description relates to the immunotherapy of cancer. The present description furthermore relates to tumor-associated T-cell peptide epitopes, alone or in combination with other tumor-associated peptides that can for example serve as active pharmaceutical ingredients of vaccine compositions that stimulate anti-tumor immune responses, or to stimulate T-cells ex vivo and transfer into patients. Peptides bound to molecules of the major histocompatibility complex (MHC), or peptides as such, can also be targets of antibodies, soluble T-cell receptors, and other binding molecules.