Recombinant T Cell Receptors for Shared Tumor Antigen Targeting
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Solution Overview
Problem
Existing T cell therapies targeting mutated tumor antigens are limited by their uniqueness to individual patients, and the high polymorphism of HLA genes hampers comprehensive analyses of antitumor T cell responses toward non-mutated antigens, necessitating the development of TCRs that can bind shared non-mutated antigens like tyrosinase, MAGE-A1, MART1, MAGE-A3, and SSX2.
Innovation Solution
Development of recombinant T cell receptors (TCRs) that specifically bind to the epitopes of tyrosinase, MAGE-A1, MART1, MAGE-A3, and SSX2, associated with particular HLA alleles, and include nucleotide sequences that inhibit the expression of endogenous TCRs, enabling cross-competition for binding and targeting these antigens.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If T cell therapies target mutated tumor antigens, then they can induce clinical responses in cancer patients, but they are limited by their uniqueness to individual patients and cannot be broadly applied
Solution Approach 1:
The patent develops TCRs that recognize shared non-mutated antigens (tyrosinase, MAGE-A1, MART1, MAGE-A3, SSX2) that are expressed across multiple cancer types and patients, rather than patient-specific mutated antigens. This universal approach allows a single TCR product to treat multiple patients with different cancer types, resolving the contradiction between individual efficacy and broad applicability
Solution Approach 2:
The patent changes the target antigen parameter from mutated (patient-specific) to non-mutated shared antigens that are commonly expressed across different cancer types. By selecting antigens that are both tumor-associated and widely expressed, the therapy maintains clinical efficacy while achieving broader applicability across patient cohorts
2Loss of information
If comprehensive analyses of T cell responses toward non-mutated antigens are conducted, then shared antigens can be identified for broad therapy applicability, but the high polymorphism of HLA genes hampers such analyses
Solution Approach 1:
The patent extracts and focuses on specific HLA allele-antigen combinations that have been identified as clinically relevant (e.g., HLA-A*02:01 with SSX2, HLA-B*18:01 with MART1). By selecting representative allele-antigen pairs rather than attempting to analyze all possible HLA polymorphisms, the patent overcomes the complexity barrier while still achieving comprehensive coverage of clinically important targets
Solution Approach 2:
The patent develops TCRs with specific local characteristics tailored to particular HLA alleles and antigen epitopes. Each TCR is optimized for its specific HLA-restricted antigen target, allowing precise recognition while accommodating HLA polymorphism through allele-specific design rather than attempting a universal solution
3Reliability
If endogenous TCR expression is inhibited to enable recombinant TCR function, then TCR gene therapy efficacy is enhanced, but potential off-target effects may arise
Solution Approach 1:
The patent incorporates nucleotide sequences that inhibit endogenous TCR expression as part of the recombinant TCR construct design. This preliminary inhibition of endogenous TCRs ensures that the recombinant TCRs will be the primary functional receptors, enhancing therapy efficacy while the inhibition mechanism is built into the therapeutic construct itself rather than applied as a separate intervention
Data Source
AI summary
The present disclosure is directed recombinant T cell receptors capable of binding a tyrosinase epitope, a MAGA-A1 epitope, a MART1 epitope, a MAGE-A3 epitope, or an SSX2 epitope and nucleic acid molecules encoding the same. In some embodiments, the nucleic acid molecules further comprise a second nucleotide sequence, wherein the second nucleotide sequence or the polypeptide encoded by the second nucleotide sequence inhibits the expression of an endogenous TCR. Other aspects of the disclosure are directed to vectors comprising the nucleic acid molecule and cells comprising the recombinant TCR, the nucleic acid molecule, or the vector. Still other aspects of the disclosure are directed to methods of using the same. In some embodiments, the methods comprise treating a cancer in a subject in need thereof.