EPHB4-Targeted CAR-T Lymphocytes for Solid Tumor Killing

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Solution Overview

Problem

Insufficient research and clinical application of CAR-T cell therapies for solid tumors, particularly neuroblastoma and osteosarcoma, necessitate the identification of cancer antigens highly expressed in tumors for targeted therapy.

Innovation Solution

Development of a chimeric antigen receptor (CAR) specific to the EPHB4 receptor, utilizing the EphrinB2 extracellular domain for targeted recognition and activation of T cells, which are then genetically modified using a piggyBac transposon method to enhance therapeutic efficacy.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional CAR-T cell therapy is applied to solid tumors, then T cells can recognize tumor antigens, but the therapeutic efficacy is insufficient due to lack of highly specific tumor antigens

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidtumor antigen specificity

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The invention changes the target parameter from conventional tumor antigens to EPHB4 receptor, which is highly expressed in solid tumors including osteosarcoma. By selecting a specific receptor parameter (EPHB4) that is differentially expressed between tumor and normal tissues, the CAR-T cells achieve both high therapeutic efficacy and tumor-specific adaptability

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention uses an intermediary approach by employing a single-chain antibody (scFv) against EPHB4 as the antigen recognition domain in the CAR construct. This intermediary scFv enables T cells to indirectly recognize and target EPHB4-expressing tumor cells, bridging the gap between T cell receptors and tumor antigens with high specificity

Inventive Principle:

Principle #24Intermediary (Mediator)

2Strength

If CAR-T cells are genetically modified to enhance cytocidal effect, then tumor cell killing ability increases, but the complexity of genetic modification increases

Engineering Contradiction:

Improvecytocidal effectVSAvoidgenetic modification complexity

Core Design Contradiction:

StrengthVSDevice complexity

Solution Approach 1:

The CAR construct is segmented into distinct functional domains: an extracellular antigen recognition domain (scFv against EPHB4), a transmembrane domain, and an intracellular signaling domain. This segmentation allows for modular genetic modification, where each domain can be independently optimized and assembled, reducing overall genetic complexity while maintaining strong cytocidal effect

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The CAR-T cell employs a composite receptor structure combining elements from different sources: the scFv domain from antibody technology, the transmembrane and signaling domains from T cell receptor components. This composite approach integrates the high specificity of antibodies with the cytocidal capability of T cells, achieving both strong tumor killing and manageable genetic complexity through proven modular components

Inventive Principle:

Principle #40Composite materials

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 EPHB4-specific CAR-T cells effectively target and kill tumor cells expressing EPHB4, demonstrating high specificity and cytocidal effects, with minimal adverse events.

Implementation Method 1

Methodology Applied

Scientific EffectTransposon-mediated gene transfer:

Data Source

PatentEP3556855B1Chimeric antigen receptor gene-modified lymphocyte having cytocidal effect

Publication Date: 2026.01.14 SHINSHU UNIVERSITY

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AI summary

An object of the present invention is to provide a therapeutic strategy in the solid tumor area and a means useful therefor to further advance the clinical application of CAR therapy. There is prepared a gene-modified lymphocyte which expresses a chimeric antigen receptor having an EphrinB2 extracellular domain at the antigen recognition site.