Recombinant Adenovirus p53-Selective Replication
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Solution Overview
Problem
Current adenoviral vectors for cancer therapy, particularly Ad2/5, face limitations due to restricted tropism, pre-existing neutralizing antibodies, liver toxicity, and inability to replicate in mice, hindering systemic and tumor-selective delivery, as well as the lack of tools to modify diverse adenoviral genomes for exploiting their unique properties.
Innovation Solution
Development of recombinant adenoviruses impaired in E1B-55k and E4-ORF3 genes, which are replication impaired in p53-expressing cells but not in p53-impaired cells, allowing targeted cancer therapy and enabling the use of adenoviral vectors beyond Ad2/5 serotypes for systemic administration and tumor-specific replication.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If Ad2/5 adenoviral vectors are used for cancer therapy, then gene delivery capability is established, but tropism is restricted and pre-existing neutralizing antibodies limit systemic application
Solution Approach 1:
The patent changes the serotype parameter of adenoviruses from Ad2/5 to alternative serotypes (Ad1, Ad3, Ad7, Ad35, Ad48, etc.), each with different receptor specificities and tissue tropisms. This parameter change enables broader adaptability and systemic application while maintaining gene delivery capability, directly resolving the contradiction between reliability and adaptability.
2Reliability
If Ad2/5 adenoviral vectors are used for cancer therapy, then initial gene delivery is achieved, but liver toxicity and inflammation limit repeated systemic treatment
Solution Approach 1:
The patent exploits the fact that cancer cells have defective p53 pathways (a harmful defect) and converts it into a selective advantage for viral replication. The E1B-55k and E4-ORF3 impairments cause selective replication in p53-deficient cancer cells while sparing normal cells with functional p53, thereby eliminating liver toxicity and enabling repeated systemic treatment without harmful side effects.
3Reliability
If human adenovirus is used for cancer therapy, then tumor-selective lytic replication is achieved, but inability to replicate in mice precludes evaluation in immune competent GEMMs
Solution Approach 1:
The patent creates adenoviruses with universal replication capability across multiple species (human, mouse, other mammals) by selecting conserved viral genes and utilizing species-crossing serotypes. This enables the same viral construct to function in both human cancer cells and mouse models, allowing evaluation in immune competent GEMMs while maintaining tumor-selective lytic replication through p53 pathway exploitation.
4Adaptability or versatility
If E1B-55k and E4-ORF3 impaired adenoviruses are used, then selective replication in p53-impaired cells is achieved, but viral replication is impaired in p53-expressing cells
Solution Approach 1:
The patent applies local quality by making viral replication efficiency context-dependent: high productivity in p53-impaired cancer cells and suppressed productivity in p53-expressing normal cells. The E1B-55k and E4-ORF3 impairments create local conditions where viral replication is selectively advantageous only in the pathological context of p53-deficient tumors, resolving the contradiction between selective targeting and replication efficiency.
Data Source
Figure 1A~1B
Figure 1C~1D
Figure 2A~2B
AI summary
Anti-cancer adenoviruses, methods of use and methods of making the same are provided herein.