Recombinant NDV with HN Mutations for Oncolytic Activity
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Solution Overview
Problem
Current oncolytic Newcastle Disease Virus (NDV) strains have limitations in therapeutic effectiveness and safety, necessitating the development of improved strains with enhanced killing capabilities while maintaining safety for normal cells.
Innovation Solution
Recombinant NDV strains are engineered to carry foreign genes encoding antibodies or antigen-binding parts targeting specific cancer-related proteins, such as PD-L1, VEGF-A, KIRs, LAG-3, NKG2A, GITR, OX40, and IL-12, along with mutations in the HN, M, F, and L proteins to enhance replication and immunological response in cancer cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current oncolytic NDV strains are used, then cancer cells can be selectively targeted and killed, but therapeutic effectiveness is limited and safety for normal cells cannot be fully ensured
Solution Approach 1:
The patent applies parameter changes by introducing specific mutations in the HN, M, F, and L proteins of the NDV strain. These mutations alter the viral parameters to enhance replication efficiency and oncolytic activity in cancer cells while maintaining safety for normal cells. The mutations in the F protein (fusion protein) and L protein (RNA polymerase) specifically improve viral replication and immunological response without compromising the selective targeting capability.
Solution Approach 2:
The patent creates a composite viral construct by engineering the NDV to carry foreign genes encoding antibodies or antigen-binding parts (such as anti-PD-L1, anti-VEGF-A, anti-KIRs) alongside the mutated viral proteins. This composite structure combines the oncolytic properties of NDV with the therapeutic effects of the incorporated antibodies, enhancing overall therapeutic effectiveness while maintaining the selective safety profile through the inherent tumor-specific replication of NDV.
2Reliability
If NDV is engineered to carry foreign genes encoding antibodies, then immunological response is enhanced, but device complexity increases
Solution Approach 1:
The patent merges multiple therapeutic functions into a single viral vector. The NDV genome is engineered to simultaneously carry mutations for enhanced replication (in HN, M, F, L proteins) and foreign genes encoding therapeutic antibodies or antigen-binding parts. This merging approach delivers multiple therapeutic effects (oncolysis plus immune modulation) through one agent, enhancing immunological response while avoiding the need for separate administration of multiple therapies.
Solution Approach 2:
The engineered NDV strain serves multiple functions: it replicates selectively in cancer cells (inherent NDV property), enhances replication through protein mutations (F and L proteins), and delivers therapeutic antibodies or antigen-binding parts (foreign genes). This multi-functionality allows a single viral construct to perform oncolysis, immune stimulation, and targeted therapy delivery, reducing the need for multiple separate treatments.
3Productivity
If mutations are introduced in HN, M, F, and L proteins to enhance replication, then oncolytic potential increases, but risk of losing safety profile increases
Solution Approach 1:
The patent applies local quality by introducing mutations specifically in the HN, M, F, and L proteins that are crucial for viral replication and oncolytic activity, while maintaining the integrity of other viral components that ensure safety. The mutations are localized to specific functional domains (such as the fusion protein F and RNA polymerase L) to enhance replication without affecting the fundamental tumor-selective replication mechanism that provides safety for normal cells.
Data Source
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AI summary
The invention relates to transgene expressing Newcastle Disease Viruses (NDV), which have been demonstrated to possess significant oncolytic activity against mammalian cancers and/or an improved safety profile. The invention provides novel oncolytic viruses through the use of genetic engineering, including the transfer of foreign genes or parts thereof, such as genes encoding Atezolizumab or Bevacizumab. The present invention also provides nucleic acids encoding a reverse genetically engineered (rg-)NDV comprising one or more of these foreign genes and having a mutation in the HN gene, said mutation allowing replication of said rgNDV in a cancer cell to a higher level than replication of an otherwise identical rgNDV not having said mutation in the HN gene.