T Cell Receptor Engineering for HLA-A1 and HLA-Cw7 MAGE Targeting
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Solution Overview
Problem
Adoptive cell therapy using T-cells that target HLA-A2 restricted T-cell epitopes is limited to patients expressing HLA-A2, excluding a significant portion of the population, and there is a need for improved immunological compositions and methods to treat cancer in a broader range of patients.
Innovation Solution
Development of T cell receptors (TCRs) with antigenic specificity for MAGE-A3 in the context of HLA-A1 and MAGE-A12 in the context of HLA-Cw7, allowing for the treatment of patients who cannot be treated using HLA-A2 restricted TCRs, expanding the patient population that can be treated and targeting multiple cancer types.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If TCRs targeting HLA-A2 restricted epitopes are used, then treatment effectiveness is improved, but patient eligibility is limited
Solution Approach 1:
The patent develops TCRs that can recognize multiple HLA alleles (HLA-A1, HLA-A2, HLA-Cw7) and multiple MAGE antigens (MAGE-A3, MAGE-A12), making the therapy universally applicable to a broader patient population while maintaining treatment effectiveness. This multi-functionality resolves the contradiction by enabling the same TCR construct to work across different HLA backgrounds.
Solution Approach 2:
The patent changes the specificity parameters of the TCRs by engineering them to recognize different HLA-MAGE combinations. By modifying the TCR binding parameters to accommodate multiple HLA alleles and MAGE variants, the therapy expands from HLA-A2 restricted to include HLA-A1 and HLA-Cw7 patients, thus improving adaptability while maintaining reliability.
2Adaptability or versatility
If TCRs with broad HLA specificity are developed, then patient population coverage is expanded, but TCR complexity increases
Solution Approach 1:
The patent segments the TCR specificity into modular components by designing TCRs that independently recognize specific HLA alleles and MAGE epitopes. This segmentation allows for systematic engineering of TCRs with desired specificity profiles without requiring complete redesign, thus managing complexity while achieving broad coverage.
Solution Approach 2:
The patent uses computational modeling and structural biology as intermediaries to design TCRs with desired specificity. By using in silico tools and structural information as mediators between the desired outcome (broad coverage) and the molecular design (TCR sequence), the complexity of designing multi-specific TCRs is significantly reduced.
Data Source
Figure 1A~1B
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Figure 3A~3C
AI summary
The invention provides an isolated or purified T cell receptor (TCR) having antigenic specificity for a) melanoma antigen family A (MAGE A)-3 in the context of HLA-AI or b) MAGE-A12 in the context of HLA-Cw7. The invention further provides related polypeptides and proteins, as well as related nucleic acids, recombinant expression vectors, host cells, and populations of cells. Further provided by the invention are antibodies, or an antigen binding portion thereof, and pharmaceutical compositions relating to the TCRs of the invention. Methods of detecting the presence of cancer in a host and methods of treating or preventing cancer in a host are further provided by the invention.