Engineered NK Cells with TCR-BiTE Crossfire Against Antigen Loss

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Solution Overview

Problem

Natural Killer (NK) cells lack T cell receptors (TCRs) and face challenges in expressing recombinant TCRs, which can lead to mispairing and reduced therapeutic efficacy, while conventional TCR-based cell therapy is complex and risky due to competition with endogenous TCRs and mispairing issues.

Innovation Solution

NK cells are engineered to express a TCR-complex and secrete a bispecific protein (BiTE) that recognizes intracellular and extracellular target epitopes, enhancing cytotoxic activity and recruiting endogenous T cells through an autocrine stimulation mechanism.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If T cells are engineered to express recombinant TCRs, then the ability to recognize intracellular target epitopes is improved, but the risk of mispairing and competition with endogenous TCRs increases

Engineering Contradiction:

Improvetarget recognition accuracyVSAvoidmispairing risk

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent segments the TCR complex into separate alpha and beta chain components, each engineered with specific signaling domains. The alpha chain includes CD3zeta signaling motifs while the beta chain includes CD3epsilon signaling motifs, allowing independent expression and assembly that prevents mispairing while maintaining recognition accuracy.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent introduces CD3 signaling chains as intermediary components that mediate between the TCR variable regions and the intracellular signaling machinery. These intermediary CD3 components serve as standardized interfaces that eliminate direct competition between different TCR variants and ensure proper signal transduction.

Inventive Principle:

Principle #24Intermediary (Mediator)

2Reliability

If T cells are used for cell therapy, then the ability to provide cytotoxic activity is improved, but the complexity of manipulating TCRs increases due to heterodimer structure and signaling requirements

Engineering Contradiction:

Improvecytotoxic activityVSAvoidTCR manipulation complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent merges the TCR recognition function with CD3 signaling function into a single engineered receptor construct. The alpha and beta chains are designed to co-express and assemble as a functional unit that combines antigen recognition with intrinsic signaling capability, eliminating the need for separate CD3 chain expression and reducing manipulation complexity.

Inventive Principle:

Principle #5Merging (Combining)

Solution Approach 2:

The engineered TCR constructs are designed with universal signaling domains that can function across different T cell contexts. The CD3zeta and CD3epsilon signaling motifs provide universal intracellular signaling capabilities that work independently of endogenous TCR variations, simplifying the engineering process.

Inventive Principle:

Principle #6Universality (Multi-functionality)

3Adaptability or versatility

If multiple TCRs are introduced into T cells, then the range of target recognition is improved, but the risk of forming mixed dimers and reducing correct TCR expression increases

Engineering Contradiction:

Improvetarget recognition rangeVSAvoidcorrect TCR expression

Core Design Contradiction:

Adaptability or versatilityVSReliability

Solution Approach 1:

The patent segments different TCR specificities into separate alpha-beta chain pairs that can be independently engineered and introduced. Each TCR specificity is maintained as a distinct modular unit with dedicated signaling domains, preventing mixed dimer formation while allowing multiple specificities to co-express in the same cell population.

Inventive Principle:

Principle #1Segmentation

4Reliability

If NK cells are engineered to express TCRs, then the ability to avoid MHC loss evasion is improved, but the challenge of ensuring proper TCR expression without endogenous TCR competition increases

Engineering Contradiction:

Improveimmune response effectivenessVSAvoidTCR expression in NK cells

Core Design Contradiction:

ReliabilityVSEase of manufacture

Solution Approach 1:

The patent introduces CD3 signaling chains as intermediary components that mediate TCR function in NK cells. These intermediary CD3 components serve as standardized signaling interfaces that NK cells can express without endogenous TCR competition, ensuring proper signal transduction while simplifying the engineering process.

Inventive Principle:

Principle #24Intermediary (Mediator)

Data Source

PatentUS20250222030A1NK cells for Cell Therapy

Publication Date: 2025.07.10 UNIV OSLO HF

AI summary

The present disclosure provides NK cells useful for therapy. A Natural Killer (NK)-cell includes nucleic acids for expressing an αβ T-cell Receptor (TCR), CD3ζ, CD3γ, CD3δ and CD3ε in its cell membrane, and a nucleic acid for expressing and secreting a bispecific protein, wherein the bispecific protein includes a first Fv for binding to a first target epitope and a second Fv for binding to a second target epitope, wherein the first Fv specifically binds, under physiological conditions, to an epitope located on the extracellular part of a CD3-chain, and wherein the second Fv specifically binds, under physiological conditions, to an epitope located on target cells.