Recombinant MUC5AC T Cell Receptors With Endogenous TCR Suppression
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Solution Overview
Problem
Existing T cell therapies targeting mutated tumor antigens are limited by the uniqueness of neoantigens to each patient, and the high polymorphism of HLA genes hampers comprehensive analysis of antitumor T cell responses toward non-mutated antigens, making it difficult to develop efficacious and safe therapies for a broader patient cohort.
Innovation Solution
Development of recombinant T cell receptors (TCRs) that specifically bind to human MUC5AC, utilizing nucleotide sequences encoding alpha and beta chains with defined CDR regions and incorporating siRNAs to inhibit endogenous TCR expression, enabling cross-competition for binding and targeting shared antigens.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If T cell therapies target mutated tumor antigens, then patient-specific efficacy is improved, but broad applicability deteriorates due to uniqueness of each patient's neoantigens
Solution Approach 1:
The patent develops TCRs that recognize shared non-mutated antigens (such as MUC5AC) that are universally expressed across multiple cancer types and patients, rather than patient-specific mutated antigens. This allows a single TCR construct to provide therapeutic efficacy across broad patient populations, resolving the contradiction between patient-specific efficacy and broad applicability.
Solution Approach 2:
Instead of following the conventional approach of targeting mutated antigens (which provides patient-specific efficacy but limited broad applicability), the patent inverts the strategy by targeting non-mutated shared antigens. This inversion enables the therapy to achieve broad applicability while maintaining efficacy through the design of TCRs with high specificity for the shared antigen and controlled cross-reactivity.
2Measurement precision
If comprehensive analysis of antitumor T cell responses toward non-mutated antigens is performed, then shared antigen identification is improved, but the sheer number of non-mutated antigens and HLA polymorphism cause analysis difficulty
Solution Approach 1:
The patent extracts and focuses on specific shared non-mutated antigens (such as MUC5AC) that are commonly expressed across cancer types, rather than attempting to analyze all possible non-mutated antigens. By selecting and concentrating on these key shared antigens, the complexity of analysis is reduced while maintaining the ability to identify targets with broad applicability.
Solution Approach 2:
The patent applies local quality by designing TCRs with highly specific binding characteristics for particular epitopes of shared antigens. The TCRs are engineered to recognize specific HLA-class II restricted epitopes with defined binding affinities, allowing precise characterization of T cell responses to specific antigen regions while managing the overall complexity of antigen-HLA diversity.
3Productivity
If recombinant TCRs are designed to cross-compete with endogenous TCRs, then T cell redirection to cancer cells is improved, but endogenous TCR expression must be inhibited
Solution Approach 1:
The patent employs preliminary action by incorporating nucleotide sequences that inhibit endogenous TCR expression into the recombinant TCR construct. This preliminary inhibition of endogenous TCRs ensures that when the recombinant TCR is expressed, it can effectively redirect T cells to cancer cells without competition from endogenous TCRs, thereby improving targeting efficiency while managing the complexity of gene expression control through integrated design.
Data Source
AI summary
The present disclosure is directed recombinant T cell receptors capable of binding a MUC5AC epitope and nucleic acid molecules encoding the same. In some aspects, 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 aspects, the methods comprise treating a cancer in a subject in need thereof.