Oncolytic HSV with CD47 Domain for Systemic Delivery
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Solution Overview
Problem
Current oncolytic virotherapy faces challenges with systemic delivery due to neutralizing antibodies and the host's immune clearance mechanisms, such as the mononuclear phagocyte system and natural killer cells, limiting the effectiveness of herpes simplex virus-based therapies.
Innovation Solution
Modifying herpes simplex virus (HSV) by passing it through immune sera with high levels of anti-HSV antibodies and inserting the extracellular domain of CD47 into the glycoprotein C, which enhances resistance to neutralization and immune clearance, resulting in a more effective systemic delivery and tumor targeting.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If oncolytic HSV is administered by systemic route, then therapeutic coverage is improved, but therapeutic efficacy deteriorates due to immune clearance
Solution Approach 1:
The patent uses CD47 as an intermediary molecule that binds to the 'don't eat me' signal on virus particles, preventing recognition by macrophages and other phagocytic cells. This intermediary mechanism allows systemic delivery of oncolytic HSV to reach tumors without being cleared by the mononuclear phagocyte system, thereby maintaining therapeutic efficacy while achieving broad therapeutic coverage
Solution Approach 2:
The patent converts the harmful effect of pre-existing neutralizing antibodies into a beneficial selection pressure by passaging the virus in the presence of these antibodies. This process selects for viral variants with mutations in neutralizing epitopes, transforming the harmful immune response into a tool for generating antibody-resistant virus strains with improved systemic delivery capabilities
2Reliability
If oncolytic HSV is passaged in immune sera, then resistance to neutralizing antibodies is improved, but virus stability deteriorates
Solution Approach 1:
The patent performs preliminary passaging of the oncolytic HSV in immune sera containing neutralizing antibodies before systemic administration. This preliminary action selects for viral variants with mutations in neutralizing epitopes, pre-adapting the virus to resist immune clearance in vivo. The process stabilizes the virus composition by selecting for consistent antibody-resistant variants while maintaining essential viral functions
Solution Approach 2:
The patent changes the selection parameters during passaging by using immune sera with high titers of neutralizing antibodies. This parameter change creates strong selective pressure that drives the evolution of antibody-resistant viral variants. The process maintains virus stability by selecting for mutations that specifically affect antibody binding sites while preserving critical viral replication and oncolytic functions
3Reliability
If CD47 domain is inserted into glycoprotein C, then resistance to immune clearance is improved, but device complexity increases
Solution Approach 1:
The patent merges the CD47 extracellular domain with the glycoprotein C of HSV by inserting the CD47 coding sequence into the gC gene. This merging creates a chimeric glycoprotein that combines the immune evasion function of CD47 with the essential viral functions of gC. The fusion protein is expressed as a single polypeptide chain, simplifying the overall structure compared to separate molecules while achieving dual functionality
Solution Approach 2:
The modified glycoprotein C serves multiple functions: it maintains the essential viral functions of native gC (such as attachment and entry) while simultaneously providing the immune evasion function of CD47 by binding to 'don't eat me' signals on phagocytic cells. This multi-functionality reduces the need for additional separate immune evasion molecules, thereby reducing overall structural complexity while achieving enhanced resistance to immune clearance
Data Source
AI summary
This invention relates to oncolytic viruses which are more resistant to neutralization and phagocytosis by immune systems, and methods for their preparation and treatment of disorders and diseases (such as cancer) with them. Described herein is an oncolytic Herpes Simplex Virus Type 1 (HSV-1) or Herpes Simplex Virus Type 2 (HSV-2) treated in immune sera that contain a high level of anti-HSV antibodies. In one preferred embodiment, the oncolytic virus includes an extracellular CD47 domain inserted into the N-terminus of a glycoprotein in order to inhibit phagocyte activity. The oncolytic virus is suitable for systemic administration for the treatment of cancer.