TCR Complex Without Binding Domain for Tumor Targeting
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Solution Overview
Problem
Current cancer immunotherapies, including CAR T cells and antibody-based therapies, face limitations such as restricted recognition spectrum of TCRs, risk of autoantigen recognition, severe side effects, and development of tumor escape variants.
Innovation Solution
Development of a T cell receptor (TCR) complex comprising a TCR alpha and beta polypeptide devoid of an antigen-binding domain, combined with a CD3 polypeptide lacking a heterologous antigen-binding domain, enabling presentation on the surface of T cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If TCRs are used for cancer immunotherapy, then anti-tumor activity is achieved, but risk of autoantigen recognition and hybridization increases
Solution Approach 1:
The patent extracts and removes the variable regions (Vα and Vβ) that contain antigen-binding specificity from the TCR structure. This leaves only the constant regions (Cα and Cβ) which maintain structural integrity and signaling function but cannot bind antigens, thereby eliminating autoantigen recognition risk while preserving T cell activation capability
Solution Approach 2:
The patent introduces an Fc region of an antibody as an intermediary component that can be engineered to bind specifically to tumor-associated antigens. This Fc region replaces the native antigen-binding variable regions, allowing specific tumor targeting without the risk of endogenous TCR autoantigen recognition
2Reliability
If CAR T cells are used for therapy, then tumor targeting is improved, but severe side effects and cytokine release syndrome occur
Solution Approach 1:
The patent modifies only the extracellular antigen-binding portion of the receptor (using Fc region instead of variable regions) while preserving the native TCR signaling structure and intracellular domains. This localized modification maintains physiological signaling pathways and avoids the excessive activation and cytokine release associated with CAR T cells
3Adaptability or versatility
If exogenous TCR is introduced to T cell, then antigen recognition capability is enhanced, but hybridization between exogenous and endogenous chains occurs
Solution Approach 1:
The patent removes the variable regions from the TCR that would otherwise pair with either endogenous or exogenous chains. By eliminating these regions entirely and replacing them with Fc regions, the patent prevents hybridization between exogenous TCR chains and endogenous TCR chains, ensuring stable and predictable receptor function
Solution Approach 2:
The patent uses the Fc region of antibodies as a template or copy of a well-characterized binding domain that can be engineered with desired specificity. This Fc-based approach copies the successful antigen-binding strategy from antibodies while avoiding the complexities and instabilities of TCR variable region engineering
Data Source
AI summary
Engineered T cell receptor (TCR) complex and methods of using same are provided. Accordingly, there is provided a TCR comprising a TCR alpha polypeptide and a TCR beta polypeptide, wherein the TCR is devoid of a binding domain, wherein the TCR alpha and beta polypeptides comprise amino acid modifications enabling presentation of the TCR as a TCR complex on a surface of a T cell expressing same. Also provided are polynucleotides encoding the TCR. T cells expressing the TCR complex and methods of using same.