March 9, 2023

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

NIS Mountain Hero

Replication-competent oncolytic viruses (OVs) are emerging and promising cancer immunotherapies with demonstrable clinical efficacy.

Viral replication places oncolytic viruses (OVs) in a unique niche in the field of drug pharmacokinetics (PK) as their self-amplification obscures exposure-response relationships. Moreover, standard bioanalytical techniques are unable to distinguish the input from replicated drug products. Here, we combine two novel approaches to characterize PK and biodistribution (BD) after systemic administration of vesicular stomatitis virus pseudotyped with lymphocytic choriomeningitis virus glycoprotein (VSV-GP) in healthy mice. First: to decouple input drug PK/BD versus replication PK/BD, we developed and fully characterized a replication-incompetent tool virus that retained all other critical attributes of the drug. We used this approach to quantify replication in blood and tissues and to determine its impact on PK and BD. Second: to discriminate the genomic and antigenomic viral RNA strands contributing to replication dynamics in tissues, we developed an in situ hybridization method using strand-specific probes and assessed their spatiotemporal distribution in tissues. This latter approach demonstrated that distribution, transcription, and replication localized to tissue-resident macrophages, indicating their role in PK and BD. Ultimately, our study results in a refined PK/BD profile for a replicating OV, new proposed PK parameters, and deeper understanding of OV PK/BD using unique approaches that could be applied to other replicating vectors.

Citation

Richard Dambra, Andrea Matter, Kaitlynn Graca, Saeed Salehin Akhand, Saurin Mehta, Ashlee Bell-Cohn, Joyce M. Swenson, Sadia Abid, Dongyue Xin, Cedric Lewis, Luke Coyle, Min Wang, Kathleen Bunosso, Michelle Maugiri, Richard Ruiz, Corey M. Cirillo, Birgit Fogal, Christine Grimaldi, Adam Vigil, Charles Wood, Joseph Ashour, Nonclinical pharmacokinetics and biodistribution of VSV-GP using methods to decouple input drug disposition and viral replication, Molecular Therapy - Methods & Clinical Development, 2022; doi.org/10.1016/j.omtm.2022.12.013

Authors
Richard Dambra, Andrea Matter, Kaitlynn Graca, Saeed Salehin Akhand, Saurin Mehta, Ashlee Bell-Cohn, Joyce M. Swenson, Sadia Abid, Dongyue Xin, Cedric Lewis, Luke Coyle, Min Wang, Kathleen Bunosso, Michelle Maugiri, Richard Ruiz, Corey M. Cirillo, Birgit Fogal, Christine Grimaldi, Adam Vigil, Charles Wood, Joseph Ashou
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