EpCAM-Targeted AAV/shEGFR Complex for Cancer Treatment
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Solution Overview
Problem
Current methods for delivering shRNA to cancer cells face challenges such as short persistence due to degradation and low efficiency, and existing viral vectors like AAV have limitations in selective targeting of specific diseased tissues due to non-specific tropism.
Innovation Solution
A viral complex comprising a viral vector capable of delivering shRNA that suppresses EGFR expression, conjugated with an anti-EpCAM antibody, which specifically targets cancer cells overexpressing EpCAM, allowing for selective delivery and reduced immune response.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If synthetic siRNA is used for gene suppression, then the method is easy to prepare and has high target selectivity, but the persistence is very short (2-4 days) due to degradation by nucleases and dilution during cell division
Solution Approach 1:
The patent combines synthetic siRNA with AAV viral vectors to create a composite delivery system. The AAV vector protects the siRNA from nuclease degradation and enables long-term persistence (several weeks) while maintaining the ease of synthesis and target selectivity of synthetic siRNA.
Solution Approach 2:
The AAV viral vector serves as an intermediary carrier that delivers the synthetic siRNA into target cells. This mediator protects the siRNA from degradation in the extracellular environment and facilitates its entry into cells, thereby extending its persistence duration.
2Duration of action of moving object
If retroviral vectors (adenovirus, lentivirus) are used for long-term gene silencing, then persistence can occur for several weeks, but in vivo stability cannot be guaranteed due to immune responses, viral gene insertion into host genome, and induction of mutations
Solution Approach 1:
The patent extracts the essential function of retroviral vectors (long-term persistence) while removing their harmful components (immune responses, genomic integration, mutation induction) by using AAV vectors that provide similar persistence without these adverse effects.
Solution Approach 2:
The patent converts the potential harm of viral delivery (immune responses, genomic integration) into a benefit by selecting AAV vectors that have minimal immunogenicity and do not integrate into the host genome, thereby achieving long-term persistence without compromising in vivo stability.
3Reliability
If AAV vectors are used for delivery, then immune responses are minimized and infection efficiency in non-dividing cells is high, but selective delivery to specific diseased tissue is difficult due to extensive host tropism
Solution Approach 1:
The patent modifies the AAV vector to have different properties in different locations: it maintains its inherent low immunogenicity and high non-dividing cell infection efficiency, while adding tissue-specific targeting capability through antibody conjugation to achieve selective delivery to cancer tissues.
Solution Approach 2:
The patent creates a composite structure by conjugating anti-EpCAM antibodies to the AAV vector surface. This composite enables the vector to maintain its favorable immune profile while gaining selective targeting capability for EpCAM-expressing cancer cells.
4Object-affected harmful factors
If conventional AAV vectors are used, then they do not have harmful pathogenicity and do not replicate in infected cells, but they cannot selectively target cancer tissue due to non-specific tropism
Solution Approach 1:
The patent introduces an anti-EpCAM antibody as an intermediary targeting molecule that directs the AAV vector to cancer cells. The antibody serves as a mediator that bridges the AAV vector and the EpCAM receptor on cancer cell surfaces, enabling selective targeting without altering the inherent safety profile of AAV.
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 viral complex effectively suppresses EGFR expression in cancer cells, inducing apoptosis and reducing tumor volume and weight, while avoiding immune responses, thus providing a safe and effective anticancer treatment.
Implementation Method 1
an anti-epithelial cell adhesion molecule (EpCAM) antibody conjugated to the viral vector, which specifically targets cancer cells overexpressing EpCAM
Implementation Method 2
RNA interference (RNAi) refers to a phenomenon in which double strand RNA consisting of sense RNA having a sequence homologous to the mRNA of a target gene and antisense RNA having a sequence complementary thereto is introduced to a cell, etc. to selectively induce degradation of the mRNA of a target gene or suppress the expression of a target gene
Data Source
AI summary
The present invention relates to a viral complex comprising a viral vector capable of delivering shRNA that suppresses an expression of epidermal growth factor receptor (EGFR) to a cell and an anti-epithelial cell adhesion molecule (EpCAM) antibody conjugated to the viral vector, a pharmaceutical composition for preventing or treating cancer, comprising the viral complex, and a method for treating cancer, comprising administering the viral complex or the pharmaceutical composition to a subject in which a cancer disease has occurred and overexpressing EpCAM. The anti-EpCAM antibody-AAV2/shEGFR complex provided in the present invention significantly reduces the expression level of EGFR in tumor cells overexpressing EpCAM without inducing an immune response in vivo, thereby inducing death of tumor cells, and thus, it can be widely utilized in more effective and safe cancer treatment.