Non-activated T Cells Expressing Virus-Specific TCR

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Solution Overview

Problem

Current antiviral therapies for HBV, such as nucleoside/nucleotide analogues and IFN-α, are expensive and have severe side effects, and adoptive T cell therapies can cause toxicity due to cytotoxicity against normal tissues and cross-reactivity with endogenous proteins.

Innovation Solution

Engineering non-activated T cells to express a virus-specific T Cell Receptor (TCR) with reduced expression of cytotoxic factors like perforin and granzyme, allowing them to inhibit viral replication while minimizing cytotoxicity to infected cells.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If activated T cells are engineered to express virus-specific TCR, then antiviral efficacy is improved, but cytotoxicity to normal tissues increases causing toxicity

Engineering Contradiction:

Improveantiviral efficacyVSAvoidcytotoxicity to normal tissues

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent changes the activation state parameter of T cells from activated to non-activated, which fundamentally alters the expression level of cytotoxic factors. Non-activated T cells express low levels of perforin and granzyme, thereby reducing cytotoxicity to normal tissues while retaining the ability to inhibit viral replication through other mechanisms such as cytokine production and modulation of infected cell function.

Inventive Principle:

Principle #35Parameter changes

2Reliability

If T cells are engineered to express high levels of cytotoxic factors, then viral replication inhibition is improved, but toxicity to host increases

Engineering Contradiction:

Improveviral replication inhibitionVSAvoidtoxicity to host

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The patent changes the expression level parameter of cytotoxic factors in T cells by maintaining them in a non-activated state. This parameter change allows the T cells to inhibit viral replication through non-cytotoxic mechanisms such as secretion of antiviral cytokines (IFN-γ, TNF-α) and modulation of infected cell metabolism, thereby achieving viral control without host tissue damage.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent extracts the cytotoxic function from the antiviral function by using non-activated T cells that do not rely on cytotoxicity for viral inhibition. The antiviral effect is achieved through separate mechanisms (cytokine secretion, metabolic modulation) that are independent of perforin and granzyme-mediated cell killing, thus separating the beneficial antiviral effect from the harmful cytotoxic effect.

Inventive Principle:

Principle #2Taking out (Extraction)

Data Source

PatentUS11576932B2Non-activated t cells expressing exogenous virus-specific T cell receptor (TCR)

Publication Date: 2023.02.14 LION TCR PTE LTD

AI summary

The present invention relates to T cells, in particular a non-activated T cell, comprising an exogenous nucleic acid encoding a T cell Receptor (TCR) specific for a virus. An embodiment of the invention is directed to a non-activated (resting) T cell expressing Hepatitis B virus (HBV) envelope s183-191 TCR capable of inhibiting viral replication and which shows reduced expression of perforins and/or granzymes in response to stimulation as compared to an activated T cell expressing the said TCR. Also encompassed are methods for producing such cells, compositions, pharmaceutical compositions and kits comprising such cells and medical uses thereof.