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An Improved and High Throughput Respiratory Syncytial Virus RSV Micro-neutralization Assay
Published on: January 26, 2019
Antibody neutralization of retargeted measles viruses
Patrycja J Lech1, Roland Pappoe2, Takafumi Nakamura3
1Department of Molecular Medicine, 200 1st Street SW, Guggenheim Building 18, Mayo Clinic, Rochester, MN, USA.
Abstract:
The measles virus (MV) vaccine lineage is a promising oncolytic but prior exposure to the measles vaccine or wild-type MV strains limits treatment utility due to the presence of anti-measles antibodies. MV entry can be redirected by displaying a polypeptide ligand on the Hemagglutinin (H) C-terminus. We hypothesized that retargeted MV would escape neutralization by monoclonal antibodies (mAbs) recognizing the H receptor-binding surface and be less susceptible to neutralization by human antisera. Using chimeric H proteins, with and without mutations that ablate MV receptor binding, we show that retargeted MVs escape mAbs that target the H receptor-binding surface by virtue of mutations that ablate infection via SLAM and CD46. However, C-terminally displayed domains do not mediate virus entry in the presence of human antibodies that bind to the underlying H domain. In conclusion, utility of retargeted oncolytic measles viruses does not extend to evasion of human serum neutralization.
Insights
Retargeted measles virus (MV) can evade some antibodies, but not all. This oncolytic virus therapy shows promise, though human serum neutralization remains a challenge for measles virus treatments.
Area of Science:
- Virology
- Immunology
- Oncolytic Virus Therapy
Background:
- Measles virus (MV) is a promising oncolytic virus for cancer treatment.
- Pre-existing anti-measles antibodies limit MV therapy efficacy.
- Antibody neutralization poses a significant hurdle for MV-based treatments.
Purpose of the Study:
- To investigate if retargeting MV via its Hemagglutinin (H) C-terminus can evade antibody neutralization.
- To determine if modified MV can escape neutralization by monoclonal antibodies (mAbs) and human antisera.
- To assess the potential of retargeted MV as an oncolytic therapy resistant to immune responses.
Main Methods:
- Engineered chimeric Hemagglutinin (H) proteins for MV retargeting.
- Introduced mutations to ablate wild-type MV receptor binding (SLAM and CD46).
- Tested retargeted MV neutralization by specific mAbs and human sera.
Main Results:
- Retargeted MVs successfully escaped neutralization by mAbs targeting the H receptor-binding surface.
- Mutations ablating SLAM and CD46-mediated infection contributed to mAb escape.
- Retargeted MVs did not evade virus entry neutralization by human antibodies binding to the underlying H domain.
Conclusions:
- Retargeting MV via H C-terminus allows escape from specific neutralizing antibodies.
- This strategy does not confer resistance to neutralization by broader human serum antibodies.
- The utility of retargeted oncolytic measles viruses is limited in evading human serum neutralization.
