NK Cells Expressing Antigen-Specific TCR Complexes

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Solution Overview

Problem

TCR gene therapy faces challenges due to the heterodimeric nature of the TCR molecule, leading to mispairing of introduced α and β chains with endogenously expressed complementary chains, resulting in unpredictable specificity and potential lethal side effects such as graft-versus-host disease.

Innovation Solution

The use of NK cells expressing an antigen-specific functional T cell receptor (TCR) complex, achieved by transferring gene sequences encoding TCR chains and CD3 chains using viral vectors, enables MHC-restricted antigen-specific cytotoxicity, circumventing the mispairing issue.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If TCR gene therapy is applied to redirect cytotoxic T cells towards selected epitopes of tumor antigens, then antigen-specific cytotoxicity is improved, but mispairing of introduced α and β chains with endogenously expressed complementary chains occurs leading to unpredictable specificity and potential lethal side effects

Engineering Contradiction:

Improveantigen-specific cytotoxicityVSAvoidmispairing side effects

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent uses NK cells as an intermediary host instead of T cells. NK cells naturally lack endogenous TCR chains, so when exogenous TCR α and β chains are introduced, they cannot mispair with complementary chains. This intermediary approach resolves the mispairing problem while maintaining antigen-specific cytotoxicity against tumor antigens.

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The patent extracts the TCR recognition function from T cells and transfers it to NK cells. By removing the TCR from its native T cell context and placing it in NK cells that lack endogenous TCR chains, the invention eliminates the source of mispairing while preserving the desired antigen-specific cytotoxic activity.

Inventive Principle:

Principle #2Taking out (Extraction)

2Productivity

If TCR α and β chains are introduced by gene delivery to achieve antigen specificity, then tumor targeting efficiency is improved, but the heterodimeric nature of TCR causes mispairing with endogenous chains resulting in unpredictable specificity

Engineering Contradiction:

Improvetumor targeting efficiencyVSAvoidTCR pairing specificity

Core Design Contradiction:

ProductivityVSManufacturing precision

Solution Approach 1:

NK cells serve as an intermediary system that allows high-level expression of introduced TCR chains without mispairing. The natural absence of endogenous TCR chains in NK cells ensures that introduced α and β chains pair exclusively with each other, achieving both high productivity in tumor targeting and precise control over TCR specificity.

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The patent changes the cellular context parameter from T cells to NK cells. This parameter change fundamentally alters the pairing environment: T cells have endogenous TCR chains that can mispair, while NK cells lack these chains entirely. This parameter change simultaneously enables high TCR expression levels and ensures correct pairing specificity.

Inventive Principle:

Principle #35Parameter changes

3Productivity

If conventional T cell-based immunotherapy is used to harness cytotoxic capacity, then anti-tumor activity is improved, but risk of serious side effects such as graft-versus-host disease increases

Engineering Contradiction:

Improveanti-tumor activityVSAvoidgraft-versus-host disease risk

Core Design Contradiction:

ProductivityVSObject-affected harmful factors

Solution Approach 1:

The patent uses NK cells as an intermediary effector cell type instead of T cells. NK cells retain potent cytotoxic capacity against tumor cells through mechanisms involving perforin, granzymes, and death receptor pathways, while lacking the TCR-mediated mechanisms that cause GvHD. This intermediary approach preserves anti-tumor productivity while eliminating GvHD risk.

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The patent converts the natural limitation of NK cells (lack of TCR expression) from a disadvantage into a benefit. The absence of endogenous TCR chains in NK cells, which normally limits their antigen-specific recognition capability, becomes advantageous by preventing mispairing and GvHD when exogenous TCRs are introduced. The harm (limited specificity) is converted into benefit (safety from GvHD).

Inventive Principle:

Principle #22Blessing in disguise (Convert harm into benefit)

Data Source

PatentUS20240100095A1Natural killer (NK) cells expressing an antigen-specific functional t cell receptor (TCR) complex, methods for production thereof, and methods for therapeutic use thereof

Publication Date: 2024.03.28 NOVA SOUTHEASTERN UNIVERSITY

AI summary

The invention provides modified Natural Killer (NK) cells expressing an antigen-specific functional T cell receptor (TCR) complex. These NK cells are used for T cell receptor (TCR) gene therapy in order to circumvent any risk of mispairing of the TCR α and β chains and to provide Major Histocompatibility Complex (MHC)-restricted antigen-specific cytotoxicity to the NK cells. The invention additionally provides methods for producing the modified NK cells, therapeutic compositions including the modified NK cells, and methods for using the modified NK cells in therapy of cancer, viral infections, autoimmunity, and graft versus host disease (GvHD).