Recombinant T Cell Receptors for Shared CCND1 Epitope Targeting
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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 vast number of potential non-mutated antigens, hindering comprehensive analysis of antitumor T cell responses.
Innovation Solution
Development of recombinant T cell receptors (TCRs) that specifically bind to human G1/S-specific cyclin-D1 (CCND1) and include nucleotide sequences that inhibit endogenous TCR expression, allowing for cross-competition and enhanced targeting of CCND1 epitopes, with sequences provided in SEQ ID NOs: 1 and 2.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If comprehensive analyses of T cell responses toward non-mutated antigens are performed, then the number of potential targets increases, but the complexity of analysis increases due to high HLA polymorphism and vast number of antigens
Solution Approach 1:
The patent extracts and focuses on a specific shared antigen (CCND1) from the vast universe of potential non-mutated antigens. By selecting a single well-defined target that is overexpressed in multiple cancer types, the invention simplifies the analysis complexity while maintaining broad applicability across different cancer patients.
Solution Approach 2:
The patent creates a universal TCR solution that can bind to CCND1 epitopes presented by multiple HLA class II alleles (including common ones like DP4, DQ8, DR4). This universal TCR design allows a single therapeutic product to work across diverse HLA backgrounds, eliminating the need for complex individualized analyses for each patient's HLA type.
2Reliability
If T cell therapies target mutated tumor antigens, then patient-specific responses are achieved, but the availability to larger patient cohorts is limited due to neoantigen uniqueness
Solution Approach 1:
Instead of creating unique patient-specific TCRs for each individual's mutated antigens, the patent identifies and targets a shared non-mutated antigen (CCND1) that is commonly overexpressed across many patients. This approach copies the successful strategy of mutation-targeting but applies it to a shared antigen, thereby achieving both patient-specific response reliability and broad cohort availability.
Solution Approach 2:
The patent inverts the conventional approach by not targeting mutated antigens (which are patient-specific but rare) but rather targeting non-mutated antigens (which are shared but previously overlooked). This inversion allows the therapy to achieve broad applicability while maintaining the ability to elicit strong patient-specific immune responses against the shared target.
3Adaptability or versatility
If the specificity of antitumor T cell responses toward non-mutated antigens is analyzed, then broader patient applicability is achieved, but the analysis is hampered by high HLA polymorphism
Solution Approach 1:
The patent changes the approach by selecting a target antigen (CCND1) with specific characteristics: it is overexpressed in multiple cancer types and presents epitopes that can be recognized by TCRs restricted to common HLA class II alleles. By changing the target selection parameters to focus on shared overexpressed antigens rather than mutated antigens, the patent achieves broader patient applicability while simplifying the analysis of T cell responses.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The recombinant TCRs enable robust and safe adoptive T cell therapies that can be applied to a broader cohort of cancer patients, effectively targeting CCND1 epitopes and enhancing cytotoxic T cell-mediated cancer cell targeting.
Implementation Method 1
a first nucleotide sequence encoding a recombinant T cell receptor (TCR) or an antigen binding portion thereof that specifically binds human G1/S-specific cyclin-D1 (CCND1)
Data Source
AI summary
The present disclosure is directed recombinant T cell receptors capable of binding a CCND1 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.