Recombinant HSV Retargeting With HVEM Adapters for Cancer Cell Entry
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Solution Overview
Problem
Existing oncolytic herpes simplex viruses (HSV) for cancer therapy have limited viral propagation and targeting efficiency, leading to low therapeutic efficacy due to the loss of essential genes and limited retargeting capabilities.
Innovation Solution
A recombinant HSV is engineered with multiple expression cassettes for fused proteins that act as adapters, targeting domains, and modified glycoproteins to enhance infection efficiency and propagation, specifically utilizing HVEM as an entry receptor and inserting cancer-cell-targeting domains into glycoproteins like gB, gC, and gH, while maintaining viral propagation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If genes are deleted from HSV to attenuate pathogenicity, then safety is improved, but viral propagation is limited and therapeutic efficacy decreases
Solution Approach 1:
The patent divides the HSV genome into essential and non-essential regions, selectively deleting only non-essential genes (ICP34.5, ICP47) while preserving essential genes required for viral propagation. This segmentation allows the virus to maintain both attenuated pathogenicity and sufficient replicative capacity for therapeutic efficacy.
Solution Approach 2:
The patent modifies viral parameters by deleting specific genes to change the virus from virulent to attenuated, while carefully controlling the extent of deletion to maintain propagation capability. The balance between gene deletion for safety and gene retention for propagation represents a parameter optimization approach.
2Manufacturing precision
If glycoproteins are modified to enhance cancer cell targeting, then infection specificity is improved, but viral entry efficiency may be reduced
Solution Approach 1:
The patent introduces adapter proteins as intermediaries that bridge the modified glycoproteins and cancer cell surface receptors. These adapters enable specific recognition of cancer cells while maintaining efficient viral entry, resolving the contradiction between targeting specificity and entry efficiency.
Solution Approach 2:
The patent creates composite viral particles with chimeric glycoproteins that combine HSV glycoprotein domains with cancer-targeting domains. This composite structure integrates both entry function and targeting specificity into a single molecular entity, achieving dual objectives simultaneously.
3Adaptability or versatility
If multiple targeting domains are expressed to expand cancer cell coverage, then versatility is improved, but device complexity increases
Solution Approach 1:
The patent designs the viral vector to express multiple adapter proteins with different targeting specificities, enabling a single viral preparation to target multiple cancer cell types simultaneously. This multi-functionality approach expands therapeutic applicability without requiring separate viral vectors for each cancer type.
Solution Approach 2:
The patent combines multiple targeting functions into a single recombinant HSV platform by co-expressing multiple adapters from the same viral genome. This merging approach consolidates what would otherwise require multiple separate viral constructs into one unified therapeutic agent.
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 HSV achieves enhanced infection and propagation efficiency, leading to increased cancer cell death and therapeutic efficacy by targeting multiple cancer cell surface antigens, such as HER2 and EpCAM, with reduced infection of normal cells.
Implementation Method 1
a fused protein of a cancer-cell-targeting domain and an extracellular domain of HVEM... adapters that enable dual targeting of HER2 and EpCAM
Data Source
AI summary
Proposed are a recombinant herpes simplex virus for multiple targeting and the use thereof. Particularly, a recombinant HSV capable of multiple targeting through multiple expression of an adapter, which is a fused protein of a cancer-cell-targeting domain and an extracellular domain of HVEM, a recombinant HSV capable of multiple targeting by having a modified glycoprotein so as to enable retargeting, in addition to being capable of expressing the adapter that is the fused protein of the cancer-cell-targeting domain and the extracellular domain of HVEM, and the use of the virus for anti-inflammatory therapy are disclosed.