Codon-Optimized TCR for SSX-2 Targeting
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Solution Overview
Problem
Adoptive cell therapy for cancer faces challenges in generating human T cells with anti-tumor potential and the toxicity of transferred T cells to normal tissues, limiting its widespread application.
Innovation Solution
Development of a codon-optimized nucleic acid sequence encoding a T cell receptor (TCR) with antigenic specificity for synovial sarcoma X Breakpoint (SSX)-2, which also recognizes SSX-3, to create a recombinant expression vector and host cells for use in treating various cancers, minimizing toxicity by targeting cancer cells specifically.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If T cells are transferred to treat cancer, then anti-tumor potential is improved, but toxicity to normal tissues increases
Solution Approach 1:
The T cell receptor is engineered with specific antigen recognition properties to differentiate between cancer cells and normal cells. The TCR is designed to recognize SSX-2 and SSX-3 antigens that are specifically expressed on cancer cells, while not recognizing normal tissues. This localized specificity allows the T cells to attack cancer cells while sparing normal tissues, resolving the contradiction between anti-tumor efficacy and toxicity reduction.
Solution Approach 2:
The patent modifies the T cell receptor parameters by engineering chimeric TCRs with altered antigen recognition specificities. The TCRs are designed to recognize multiple antigens (SSX-2 and SSX-3) with different binding affinities, and the patent optimizes parameters such as antigen binding affinity, T cell activation threshold, and cytokine production levels to enhance cancer cell killing while reducing off-target toxicity to normal tissues.
2Reliability
If T cells with anti-tumor potential are generated, then cancer treatment efficacy is improved, but difficulty in generating such T cells increases
Solution Approach 1:
The patent uses gene transfer technology to copy and introduce engineered TCR genes into patient's own T cells. Rather than attempting to generate de novo T cells with desired specificity, the patent copies functional TCR sequences into autologous T cells, which then acquire the desired anti-tumor specificity. This approach simplifies the manufacturing process by using established gene transfer methods rather than requiring complex in vitro T cell differentiation and selection protocols.
3Adaptability or versatility
If TCR is designed to recognize multiple antigens, then versatility in treating different cancers is improved, but complexity of TCR structure increases
Solution Approach 1:
The patent designs chimeric TCRs that function as multi-functional receptors capable of recognizing multiple different antigens (SSX-2 and SSX-3) through a single receptor structure. The TCR is engineered with variable regions that can bind to different antigen peptides presented by MHC molecules, allowing one TCR to perform multiple recognition functions. This universal design approach enables versatility in treating different cancer types that express different SSX antigens without requiring separate TCRs for each antigen.
Solution Approach 2:
The patent merges the antigen recognition specificities for multiple SSX antigens into a single chimeric TCR molecule. By combining multiple antigen recognition capabilities into one unified receptor structure, the patent achieves multi-antigen recognition while avoiding the complexity of coordinating multiple separate TCRs. The chimeric TCR integrates variable regions from different parental TCRs to create a single molecule with broad antigen specificity, simplifying the overall system architecture.
Data Source
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AI summary
The invention provides an isolated or purified T cell receptor (TCR) having antigenic specificity for synovial sarcoma X Breakpoint (SSX)-2. 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.