Condition-Controlled Spliceable CAR Molecule for Hypoxic Tumor Activation

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Solution Overview

Problem

Existing CAR-T cell therapies for solid tumors face challenges due to off-target effects and the need for precise spatiotemporal control of activation, particularly in hypoxic tumor microenvironments, which current external small molecule compounds fail to address effectively.

Innovation Solution

A condition-controlled spliceable chimeric antigen receptor (CAR) molecule that responds to hypoxic conditions, allowing for splicing and activation only in tumor microenvironments, reducing retention in normal tissues and enhancing specificity.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If modular CAR is activated by external small molecule compounds, then the CAR can be controlled to activate, but the activation timing and deactivation timing are difficult to control accurately

Engineering Contradiction:

Improveactivation control reliabilityVSAvoidactivation timing control

Core Design Contradiction:

ReliabilityVSEase of operation

Solution Approach 1:

The patent changes the activation parameter from external small molecule compounds to endogenous hypoxia conditions. The CAR molecule includes a hypoxia-responsive element that responds to oxygen concentration changes in the tumor microenvironment, enabling automatic activation under hypoxic conditions without requiring external compound administration.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The CAR system uses the tumor's own hypoxic microenvironment as the activation trigger. The hypoxia-responsive element in the CAR molecule automatically detects and responds to low oxygen conditions, making the system self-activating based on the pathological characteristics of the tumor without needing external control.

Inventive Principle:

Principle #25Self-service

2Productivity

If CAR-T cells are used for solid tumors, then anti-tumor effects can be achieved, but off-target effects occur due to absence of tumor-specific antigens

Engineering Contradiction:

Improveanti-tumor efficacyVSAvoidoff-target effects

Core Design Contradiction:

ProductivityVSObject-affected harmful factors

Solution Approach 1:

The patent applies local quality by making the CAR activation specific to the hypoxic microenvironment of tumors. The hypoxia-responsive element ensures that CAR-T cells are activated only in regions with low oxygen concentration (tumor sites) and remain inactive in normal tissues with adequate oxygen supply, thereby achieving spatially selective anti-tumor activity.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The CAR molecule is segmented into distinct functional domains including an extracellular domain, transmembrane domain, and intracellular signaling domain with a hypoxia-responsive element. This segmentation allows the CAR to respond specifically to hypoxic conditions while maintaining its antigen recognition and signaling functions.

Inventive Principle:

Principle #1Segmentation

3Adaptability or versatility

If modular CAR design is used, then controllable activation is achieved, but the dependency on external small molecule compounds creates clinical application challenges

Engineering Contradiction:

ImprovecontrollabilityVSAvoidexternal compound administration system

Core Design Contradiction:

Adaptability or versatilityVSDevice complexity

Solution Approach 1:

The patent extracts the activation control mechanism from external small molecule compounds and relocates it to endogenous hypoxia conditions. By removing the dependency on externally administered compounds and replacing it with a response to the tumor's natural hypoxic environment, the system simplifies the clinical application while maintaining controllable activation.

Inventive Principle:

Principle #2Taking out (Extraction)

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 CAR molecule achieves targeted activation in hypoxic tumors, minimizing off-target effects and reducing damage to normal tissues, thereby improving the efficacy of CAR-T cell therapy for solid tumors.

Implementation Method 1

the signal transduction unit comprises a conditional signal response domain, a C-terminal splicing domain and a signaling domain, wherein the conditional signal response domain is an oxygen-dependent degradation domain

Methodology Applied

Scientific EffectOxygen-dependent degradation:

Data Source

PatentUS20250319126A1Condition-controlled spliceable chimeric antigen receptor molecule and application thereof

Publication Date: 2025.10.16 SHANGHAI SINOBAY BIOTECH CO LTD

AI summary

A condition-controlled spliceable chimeric antigen receptor molecule and the use thereof.The spliceable chimeric antigen receptor molecule comprises an antigen recognition unit and a signal transduction unit; the antigen recognition unit comprises an antigen recognition domain, a transmembrane domain, a costimulatory signal domain, an N-terminal splicing domain, and a degrader; and the signal transduction unit comprises a conditional signal response domain, a C-terminal splicing domain, and a signaling domain. Such a condition-controlled spliceable system can achieve splicing of the two units and signaling under a tumor microenvironment signal. The antigen recognition unit can spontaneously/be induced to degrade, thus reducing retention in normal tissues. A signaling unit can respond to a specific condition signal of a tumor microenvironment, and has the characteristics of low expression in a normal tissue environment and high expression in the tumor microenvironment. The condition-controlled spliceable system can achieve preparation of drugs and precise treatment for solid tumors by grafting different functional genes.