Recombinant Oncolytic Virus Targeting CD133 Tumor Stem Cells

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Solution Overview

Problem

Current cancer therapies are ineffective against tumor stem cells, which are resistant to chemotherapy and have high regenerative potential, leading to the incurability of many cancer types.

Innovation Solution

Development of recombinant oncolytic viruses with a binding domain specific for the tumor stem cell marker CD133, which targets and inhibits the growth and metastasis of tumors, enhancing oncolytic potential by modifying the measles virus to use CD133 as a receptor and reducing its specificity for natural receptors like CD46 and SLAM, while incorporating a suicide gene for enhanced therapeutic effects.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional cancer therapies are used, then treatment of differentiated tumor cells is achieved, but tumor stem cells remain resistant and cause recurrence

Engineering Contradiction:

Improvecure rateVSAvoidchemotherapy resistance

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The invention modifies the measles virus to express a chimeric H protein with localized CD133-binding capability. The H protein contains the native measles H sequence (residues 1-566) fused to a CD133-binding scFv sequence (residues 567-662), creating a localized binding domain that specifically targets CD133+ tumor stem cells while leaving other tumor cells unaffected. This localized modification enables selective targeting of the resistant stem cell population.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The invention changes the receptor specificity parameter of the measles virus by replacing or modifying the H protein's natural receptor-binding domain. The chimeric H protein alters the virus's binding parameters to recognize CD133 instead of the native SLAM or CD46 receptors, fundamentally changing which cell population the virus infects and destroys.

Inventive Principle:

Principle #35Parameter changes

2Manufacturing precision

If oncolytic viruses are engineered to target specific cell markers, then tumor cell specificity is improved, but virus complexity increases

Engineering Contradiction:

Improvetumor cell targeting specificityVSAvoidvirus structure

Core Design Contradiction:

Manufacturing precisionVSDevice complexity

Solution Approach 1:

The invention creates a composite viral envelope protein by fusing the measles virus H protein with a CD133-binding single-chain variable fragment (scFv). This chimeric H protein combines the membrane fusion function of the native H protein with the specific binding capability of the anti-CD133 scFv, creating a single integrated protein that performs both functions. The scFv is linked via a flexible linker to the H protein, forming a functional composite structure.

Inventive Principle:

Principle #40Composite materials

3Manufacturing precision

If measles virus is modified to use CD133 as receptor, then tumor stem cell targeting is achieved, but specificity for natural receptors must be reduced

Engineering Contradiction:

ImproveCD133 targeting specificityVSAvoidinfection efficiency

Core Design Contradiction:

Manufacturing precisionVSProductivity

Solution Approach 1:

The invention modifies the receptor binding parameters of the measles virus H protein by introducing a CD133-binding scFv domain. This parameter change redirects the virus's tropism from natural receptors (SLAM, CD46) to the artificial CD133 receptor on tumor stem cells, fundamentally altering which cells the virus can infect and replicate in.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The chimeric H protein acts as an intermediary that bridges the virus and the CD133 receptor. The scFv portion of the H protein serves as a mediator that specifically recognizes and binds to CD133, enabling the virus to attach to and enter CD133+ tumor stem cells. This intermediary binding domain replaces the need for natural receptor interaction while maintaining viral entry function.

Inventive Principle:

Principle #24Intermediary (Mediator)

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 recombinant oncolytic viruses specifically target and kill tumor stem cells, significantly increasing oncolytic potential, effectively inhibiting tumor growth and metastasis with minimal damage to non-neoplastic tissue, making previously incurable cancer types treatable.

Implementation Method 1

recombinant oncolytic viruses comprising a binding domain specific for a cell marker for a tumor stem cell can be utilized to specifically target/attack tumor stem cells

Methodology Applied

Scientific EffectAntigen-antibody binding:

Data Source

PatentEP2680867B1Enhanced tumor therapy by tumor stem cell targeted oncolytic viruses

Publication Date: 2018.08.15 BUNDESREPUBLIK DEUTSCHLAND

Figure 1A~1B
Figure 2A~2C
Figure 3A~3D

AI summary

The invention relates to recombinant oncolytic viruses that target tumor stem cells and various uses of these recombinant viruses. In particular, an oncolytic virus comprising a recombinant binding domain specific for a tumor stem cell marker is disclosed. Furthermore, the use of such oncolytic viruses for the treatment of cancer is disclosed.