Recombinant gp100 T Cell Receptors With Endogenous TCR Suppression
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Solution Overview
Problem
Existing T cell therapies targeting non-mutated antigens face challenges due to the high polymorphism of HLA genes and the lack of comprehensive analyses of antitumor T cell responses, limiting their applicability to a broader cohort of cancer patients.
Innovation Solution
Development of recombinant T cell receptors (TCRs) that specifically bind to the non-mutated antigen gp100, associated with particular HLA alleles, and include nucleotide sequences that inhibit endogenous TCR expression, enabling cross-competition for binding and enhancing therapeutic efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If T cell therapies target mutated tumor antigens, then clinical responses are induced in cancer patients, but the therapies are limited to individual patients due to the uniqueness of neoantigens
Solution Approach 1:
The patent develops TCRs that recognize shared non-mutated antigens (gp100) that are universally expressed across multiple cancer types and patients, rather than patient-specific mutated antigens. This universal antigen targeting approach enables a single TCR construct to treat multiple patients with different cancers, achieving both clinical efficacy and broad applicability
2Adaptability or versatility
If comprehensive analyses of antitumor T cell responses toward non-mutated antigens are conducted, then shared antigens can be identified for broader therapy applicability, but the high polymorphism of HLA genes and large number of non-mutated antigens hamper such analyses
Solution Approach 1:
The patent extracts and focuses on a specific shared antigen (gp100) and its associated HLA alleles from the complex landscape of thousands of non-mutated antigens and HLA polymorphisms. By selecting a representative shared antigen with common HLA restriction, the patent simplifies the analysis while still achieving broad applicability across multiple patients
3Reliability
If endogenous TCR expression is inhibited to enable cross-competition for binding, then therapeutic efficacy is enhanced, but the complexity of the gene therapy increases
Solution Approach 1:
The patent incorporates nucleotide sequences that inhibit endogenous TCR expression directly into the TCR gene construct. This preliminary suppression of endogenous TCR prevents competitive interference with the therapeutic TCR, ensuring that the introduced TCR dominates the antigen recognition and thereby enhances therapeutic efficacy
Data Source
AI summary
The present disclosure is directed recombinant T cell receptors capable of binding a gp100 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.