Catenated VAR2CSA Protein for CAR-T Cell Stability

Resolve Bottlenecks,
Find Innovative SolutionsGenerate Solutions

Solution Overview

Problem

Current CAR-T cell therapies face challenges such as poor persistence of CAR-T cells and loss of CD19 antigens on tumor cells, leading to limited efficacy and safety concerns like cytokine release syndrome.

Innovation Solution

The development of a catenated VAR2CSA recombinant protein with enhanced stability and affinity for tumor-specific antigen placenta-like chondroitin sulfate A (pl-CSA), which is used in a chimeric antigen receptor cell system to improve anti-tumor activity and safety.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If a normal VAR2CSA recombinant protein (wild-type) is used, then the CAR-T cell system can be constructed, but the protein stability and affinity for pl-CSA are insufficient

Engineering Contradiction:

Improveprotein stabilityVSAvoidprotein structure complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The VAR2CSA protein is divided into functional domains (binding domain, SpyTag, p53dim domain, SpyCatcher) that can independently fold and function. This segmentation allows each domain to contribute specifically to overall protein stability and affinity without requiring the entire protein to be perfectly optimized, thereby improving reliability while managing structural complexity.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent creates a composite protein structure by fusing VAR2CSA binding domain with SpyTag and SpyCatcher modules. This composite design combines the antigen-binding capability of VAR2CSA with the self-assembling and stabilizing properties of SpyTag/SpyCatcher, resulting in enhanced protein stability and affinity for pl-CSA while maintaining manageable structural complexity through modular architecture.

Inventive Principle:

Principle #40Composite materials

2Duration of action of moving object

If CAR-T cell therapy is applied, then anti-tumor activity is achieved, but poor persistence of CAR-T cells and loss of CD19 antigens limit efficacy

Engineering Contradiction:

ImproveCAR-T cell persistenceVSAvoidanti-tumor efficacy

Core Design Contradiction:

Duration of action of moving objectVSReliability

Solution Approach 1:

The patent modifies the antigen target from CD19 to placenta-like chondroitin sulfate A (pl-CSA), which is constitutively expressed on tumor cells and does not undergo down-regulation or loss through mutation. This parameter change in target antigen selection ensures continuous recognition and binding by CAR-T cells, thereby extending CAR-T cell persistence and maintaining reliable anti-tumor efficacy over time.

Inventive Principle:

Principle #35Parameter changes

3Reliability

If high affinity for tumor antigen is achieved, then anti-tumor activity is enhanced, but toxic side effects like cytokine release syndrome increase

Engineering Contradiction:

Improveanti-tumor activityVSAvoidcytokine release syndrome

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent engineering the VAR2CSA binding domain to have high affinity specifically for pl-CSA on tumor cells, while the overall CAR-T cell activation and cytokine release are regulated by local control mechanisms in the CAR structure and signaling pathways. This localized high affinity binding to the specific antigen target enhances anti-tumor activity without proportionally increasing systemic toxic effects, as the binding specificity confines the strong interaction to the tumor cell surface.

Inventive Principle:

Principle #3Local quality

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 catenated VAR2CSA recombinant protein significantly enhances the stability and affinity of CAR-T cell systems, leading to stronger and more durable anti-tumor activity with reduced risk of toxic side effects.

Implementation Method 1

Due to the formation of an isopeptide bond by spontaneous amide-bond condensation of a short peptide SpyTag with its protein ligand SpyCatcher

Methodology Applied

Scientific EffectAmide-bond condensation: Chemical Bonding

Data Source

PatentUS20250073269A1Catenated VAR2CSA recombinant protein, preparation method therefor, and use thereof

Publication Date: 2025.03.06 CAS LAMVAC (GUANGZHOU) BIOMEDICAL TECH CO LTD

AI summary

Provided is a catenated VAR2CSA recombinant protein, a preparation therefor and a use thereof. The catenated VAR2CSA recombinant protein comprises a binding domain, SpyTag, a p53dim structural domain, and SpyCatcher, which are randomly arranged. The binding domain comprises a structural domain, in the VAR2CSA protein, binding to placenta-like chondroitin sulfate A. The catenated VAR2CSA recombinant protein has high stability and affinity to the tumor-specific antigen placenta-like chondroitin sulfate A, and can be effectively used in the field of tumor immunotherapy, such as immune cell therapy.