Nonclinical pharmacokinetics and biodistribution of VSV-GP using methods to decouple input drug disposition and viral...

Area of Science:

• Virology
• Pharmacokinetics
• Immunology

Background:

• Oncolytic viruses (OVs) present unique pharmacokinetic (PK) challenges due to self-amplification, complicating exposure-response assessments.
• Standard bioanalytical methods struggle to differentiate between initial OV administration and viral replication products.

Purpose of the Study:

• To characterize the pharmacokinetics (PK) and biodistribution (BD) of systemically administered vesicular stomatitis virus pseudotyped with lymphocytic choriomeningitis virus glycoprotein (VSV-GP) in mice.
• To develop novel approaches to distinguish input virus from replicated virus and to analyze viral RNA dynamics.
• To elucidate the role of specific cell types in OV PK and BD.

Main Methods:

• Developed a replication-incompetent VSV-GP tool virus to model input drug PK/BD.
• Utilized strand-specific in situ hybridization to differentiate genomic and antigenomic viral RNA strands.
• Quantified viral replication and assessed spatiotemporal distribution in mouse tissues.

Main Results:

• The replication-incompetent virus successfully modeled input VSV-GP PK/BD.
• Viral distribution, transcription, and replication were localized to tissue-resident macrophages.
• A refined PK/BD profile for replicating OVs was established.

Conclusions:

• Tissue-resident macrophages play a critical role in the PK and BD of VSV-GP.
• Novel methodologies enable a deeper understanding of replicating OV behavior.
• The developed approaches can be applied to other replicating viral vectors for PK/BD studies.