Bispecific VSV-G Engagers: Cell-Type-Specific Viral Vector Delivery

bioRxiv (Weizmann Institute of Science) Israel

Overview

Researchers have developed reversible bispecific engagers that enable cell-type-specific delivery of VSV-G-pseudotyped lentiviral vectors. By utilizing a cell-specific ligand fused to VSV-G-binding domains of LDLR, the platform allows for targeted transduction of specific cells, including the in vivo generation of CAR T cells to control multiple myeloma tumors.

In Depth

Key Findings

The developed bispecific engagers enable the selective delivery of viral vectors to specific cell types, overcoming the lack of specificity in standard VSV-G-pseudotyped lentiviral vectors (LVVs). A trimeric CEACAM8-based engager blocked non-specific VSV infection through LDLR with an IC50 of 16.7 pM while facilitating the lysis of CEACAM6-positive tumor cells. Furthermore, an anti-CD3-based trimeric engager demonstrated high transduction efficiency in non-preactivated T cells within human PBMCs.

Technical Details

The platform utilizes reversible engagers composed of a cell-specific ligand or antibody fused to the VSV-G-binding domains of the LDL receptor (LDLR), which are approximately 40 amino acids in length. The mechanism operates as follows:

• The engager binds to the target cell and the VSV-G protein.
• Following endocytosis, the engager dissociates.
• Unmodified VSV-G is released to ensure the efficient delivery of the vector cargo.

Specific applications include an engager comprising the CEACAM8 N-terminal domain for the selective transduction of CEACAM6-positive epithelial cells.

Background & Context

VSV-G-pseudotyped LVVs are highly efficient for ex vivo gene delivery because they utilize the broadly expressed LDL receptor (LDLR). However, this broad expression prevents the cell-type specificity required for effective in vivo applications. The bispecific engager platform addresses this limitation by redirecting the vector to specific cellular targets.

Significance & Outlook

The platform has demonstrated efficacy in vivo, where engager-mediated CAR T cell generation resulted in the sustained control of human OPM2 multiple myeloma tumors in NSG mice. This technology provides a foundation for advancing in vivo gene therapies, specifically in the fields of in vivo CAR T-cell therapy and tumor-directed oncolytic virotherapy.

Get our weekly technology intelligence — free

Receive an infographic that lets you judge at a glance whether each field’s analysis report is worth reading.

Subscribe Free — Weekly Tech Intelligence

By subscribing, you’ll receive Troy-Technical’s weekly technology intelligence newsletter.

• Your email and selected fields are used only to deliver the newsletter.
• We never share your information with third parties.
• You can unsubscribe anytime via the link in each email.

See our Privacy Policy for details.

Agree & Continue ▶

Takes about a minute · Unsubscribe anytime