Engineered TCRs Targeting HPV 16 E6/E7 Epitopes
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Solution Overview
Problem
Current therapeutic agents targeting HPV 16-expressing cells or cancers are inadequate, necessitating improved solutions for effectively targeting cancer cells infected with human papillomavirus, particularly those expressing HPV 16 E6 and E7 oncoproteins.
Innovation Solution
Development of T cell receptors (TCRs) and engineered cells expressing these receptors that specifically bind to peptide epitopes of HPV 16 E6 and E7 in the context of major histocompatibility complex (MHC) molecules, enabling targeted cytotoxic activity against HPV 16-expressing cancer cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current therapeutic agents are used to target HPV 16-expressing cells, then treatment is provided, but the efficacy is inadequate and cross-reactivity occurs
Solution Approach 1:
The TCRs are designed with specific complementarity determining regions (CDRs) that provide localized high-affinity binding to HPV 16 E6 and E7 peptide epitopes. The CDR3 regions in particular are engineered to recognize specific anchor residues in the peptide-MHC complex, ensuring selective binding to HPV 16-expressing cells while avoiding cross-reactivity with other HPV types or healthy cells.
Solution Approach 2:
The patent employs systematic variation of CDR amino acid sequences to optimize binding affinity and specificity parameters. By modifying individual amino acid residues in the CDR regions, the TCRs achieve enhanced binding strength (affinity) to HPV 16 epitopes while maintaining selectivity, thereby improving therapeutic efficacy without increasing cross-reactivity.
2Reliability
If TCRs are engineered to bind HPV 16 E6 and E7 epitopes, then specificity is improved, but immunogenicity risk increases
Solution Approach 1:
The TCR variable regions, particularly the CDR3 segments, are engineered with specific amino acid compositions that enhance peptide-MHC recognition while minimizing immunogenicity. The localized optimization of binding interfaces allows high specificity for HPV 16 epitopes without triggering unwanted immune responses against the TCR itself.
Solution Approach 2:
The TCRs are constructed as composite molecules combining human framework regions with engineered CDR sequences. This composite structure maintains compatibility with the human immune system while providing the necessary specificity for HPV 16 recognition, thereby reducing immunogenicity risk compared to fully non-human TCRs.
3Reliability
If therapeutic agents are designed to target cancer cells, then treatment effectiveness improves, but the complexity of the therapy increases
Solution Approach 1:
The patent extracts and isolates the specific CDR regions responsible for HPV 16 epitope recognition, separating them from the need for complex whole-virus vaccines or multifactorial therapeutic regimens. By focusing on the critical binding interface elements, the therapy achieves high effectiveness through a more streamlined approach.
Solution Approach 2:
The TCRs are produced as recombinant proteins or genetically engineered into T cells, creating standardized copies of the therapeutic agent. This copying approach allows for consistent manufacturing and dosing, reducing the complexity associated with personalized or highly variable therapeutic interventions while maintaining treatment effectiveness.
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 TCRs demonstrate high and consistent expression and functional activity on human T cells, achieving effective cytotoxicity against HPV 16-expressing cancer cells with improved efficacy and reduced risk of cross-reactivity or immunogenicity, even at low effector-to-target ratios.
Implementation Method 1
T cell receptors (TCRs), such as recombinant TCRs, that bind a peptide epitope of HPV 16 E6 or E7, in the context of a major histocompatibility complex (MHC) molecule
Data Source
AI summary
Provided herein are binding molecules, such as those that recognize or bind a peptide epitope of a cancer antigen, such as expressed on a cancer cell, including cells infected with human papilloma virus (HPV) or that contain HPV DNA sequences and/or those that recognize or bind a peptide epitope of HPV 16 E6 or E7, in the context of a major histocompatibility complex (MHC) molecule. Among the provided binding molecules are T cell receptors (TCRs) or antibodies, including antigen-binding fragments thereof, that bind or recognize such peptide epitopes. The present disclosure further relates to engineered cells comprising such binding molecules, e.g., TCRs or antibodies (and chimeric antigen receptors containing the antibodies), and uses thereof in adoptive cell therapy.