Chimeric Antigen Receptor Targeting NKG2DL for Solid Tumor Therapy

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Solution Overview

Problem

Current CAR-T cell therapies face challenges in targeting solid tumors due to the lack of specific tumor antigens and the risk of activating normal cells, leading to off-target effects and reduced efficacy in treating solid tumors.

Innovation Solution

Development of a chimeric antigen receptor (CAR) targeting human NKG2DL, comprising a specific sequence of the NKG2D protein ligand, which includes modifications to enhance binding and killing efficiency, specifically designed for T cells to recognize and target NKG2DL-expressing tumor cells.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If CAR-T cells target common tumor antigens, then they can recognize and kill tumor cells, but they may also activate normal cells expressing similar antigens, causing off-target effects and reduced specificity

Engineering Contradiction:

Improvetumor cell recognition accuracyVSAvoidoff-target effects on normal cells

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies local quality by designing CAR-T cells with highly specific local recognition capability against NKG2DL, which is locally expressed on stressed tumor cells. The CAR construct includes a specifically engineered extracellular domain that recognizes NKG2DL with high affinity, ensuring that the killing action is localized precisely to tumor cells expressing this ligand while sparing normal cells that do not express NKG2DL.

Inventive Principle:

Principle #3Local quality

2Reliability

If CAR-T cells are designed for high specificity to avoid off-target effects, then safety is improved, but the availability of suitable tumor-specific targets is limited

Engineering Contradiction:

Improvetumor cell targeting specificityVSAvoidapplicability to different tumor types

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent applies universality by demonstrating that NKG2DL is a pan-tumor target expressed across multiple cancer types including solid tumors and hematologic malignancies. The CAR-T cell construct designed against NKG2DL can therefore be universally applied to treat various tumor types, making the therapy both specific and versatile simultaneously.

Inventive Principle:

Principle #6Universality (Multi-functionality)

Solution Approach 2:

The patent applies parameter changes by modifying the CAR construct parameters, specifically engineering the extracellular domain to recognize NKG2DL with optimized binding affinity and specificity. This parameter optimization enables the CAR-T cells to achieve high specificity while maintaining broad applicability across different tumor types that express NKG2DL.

Inventive Principle:

Principle #35Parameter changes

3Productivity

If CAR-T cells require high antigen expression specificity for effective killing, then tumor cell destruction is improved, but the persistence and efficacy in solid tumors are reduced due to antigen heterogeneity

Engineering Contradiction:

Improvetumor cell killing efficiencyVSAvoidimmune cell persistence in tumor microenvironment

Core Design Contradiction:

ProductivityVSDuration of action of stationary object

Solution Approach 1:

The patent applies this principle by utilizing NKG2DL, which is transiently expressed on tumor cells under stress conditions. The CAR-T cells are designed to recognize and kill these stressed tumor cells efficiently, and can be rapidly replenished or reactivated as new stressed cells appear, maintaining persistent anti-tumor activity without requiring long-term antigen expression on individual tumor cells.

Inventive Principle:

Principle #27Cheap short-living objects (Disposable)

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 modified CAR-T cells demonstrate a killing efficiency of 40-70% against NKG2DL-positive tumor cells at an effector-to-target ratio of 10:1, significantly improving the persistence and cytotoxicity of immune cells, particularly for cancers like liver, ovarian, and lung cancer.

Implementation Method 1

a chimeric antigen receptor (CAR) targeting human NKG2DL, comprising a specific sequence of the NKG2D protein ligand, which includes modifications to enhance binding and killing efficiency

Methodology Applied

Scientific EffectProtein-ligand binding:

Implementation Method 2

Methodology Applied

Scientific EffectImmune-mediated cytotoxicity:

Data Source

PatentUS11090335B2Chimeric antigen receptor targeting human NKG2DL and methods of preparing said receptor and pharmaceutical composition

Publication Date: 2021.08.17 NANJING KAEDI BIOTHERAPEUTICS LTD

AI summary

A chimeric antigen receptor targeting to human NKG2DL, its encoding sequence, and its modified immune response cells, and the preparation and application thereof are provided. This invention constructs a chimeric antigen receptor targeting to NKG2DL and its modified immune response cell based on the NKG2D molecule. The amino acid sequence of the chimeric antigen receptor targeting the human NKG2DL is sequentially connected by the following amino acid sequences from an amino terminal to a carboxy terminal: an amino acid sequence of a guiding sequence, an amino acid sequence of human NKG2D, an amino acid sequence of a human CD8 hinge region, an amino acid sequence of a human CD8 transmembrane region, an amino acid sequence of a human 4-1BB intracellular domain and an amino acid sequence of a human CD3 zeta domain.