In Vivo Delivery Has Arrived
With our holistic approach to viral vector research and development and interdisciplinary expertise—including a deep familiarity with viral modalities, viral vector engineering and immunology—Vyriad is leading the way towards an in vivo future that transforms medicine for patients. Our novel G protein retargeting platforms give in vivo therapy developers multiple pathways to success, including VSV-G blinding/detargeting and wild-type G protein capping.
In vivo approaches to CAR T therapies have the potential to address a wide range of diseases, including inherited disorders and diseases with significant unmet needs. While the ex vivo CAR T model was a revolutionary first step toward proving the immense power of cell therapy, in vivo therapies promise to be easier on patients, less logistically challenging and more accessible. Vyriad’s novel in vivo platforms help solve the challenges of opportunity and scale for their CAR T therapeutics partners, allowing patients to receive a simple, single dose of a targeted genetic medicine to edit cells inside their body to achieve a therapeutic outcome.
Innovative approaches to G protein engineering
Vyriad takes a unique approach to in vivo CAR T therapies through a combination of best-in-class in vivo platform options for re-targeting lentiviral vectors, informed by innovations in G protein selection and engineering.
PLATFORM 1: BLINDED, RETARGETED VSV-G
VSV-GVyriad’s blinded VSV-G platform engineers lentivirus with a modified, blinded/retargeted VSV-G envelope that targets T cells. Our blinded VSV-G platform efficiently delivers transgenes to niche-resident T-cells, allowing for lower, more efficient and less toxic dosing with permanent CAR T cell durability.
PLATFORM 2: TRIMERIC ADAPTERS ON G-Link™ PROTEINS
Today’s ex-vivo generated CAR-T cells are manufactured using lentiviral platforms with “unblinded” envelopes requiring the use of stimulatory molecules (e.g. CD3/28 beads) and targeting ligands, which clutters the viral surface, risking off-target activation and lower efficiency. Vyriad’s novel, scalable, plug-and-play G-Link™ protein cap technology simplifies the process. The proprietary G-Link™ protein cap binds to the wild-type G protein detargeting the viral vector by blocking the natural receptors. G-Link™ simultaneously retargets the viral vector to CD3, providing a simple manufacturing access point to in vivo CAR T therapies.
OPTIMAL G PROTEIN SELECTION
There is a diversity of g PROTEINS IN VSV’s virus family with varying characteristics. Vyriad has successfully engineered and re-targeted alternate G proteins, and in the process, identified those that have the most optimal targeting , stabilization and immune-evasion for a clinical application.
INNOVATIVE G PROTEIN ENGINEERING
Vyriad engineers viral vectors to display a ligand with cel-specific binding directly on the surface of VSV-G, which re-targets the vector while retaining the G protein’s cell-fusion function. As a result, re-targeted G proteins archive higher density on the surface of the viral vector than vectors where cell-specific ligands are co-displayed with blinded VSV-G proteins.
Vyriad’s development of viral vectors with optimized and engineered G proteins achieves:
- Improved transduction efficiency, favorable compared to ex vivo infusions
- Highly cell-specific targeting
- Stability and resistance to neutralization by complement in human whole blood
- Long-term durability of therapeutic response
- Greatly reduced time to therapeutic infusion versus ex vivo platforms
Why Lentivirus for viral vectors?
- Established method for ex vivo transduction of T cells for CAR T cell therapy
- Integration of transgenes into the host cell genome provides long-term stable gene expression
- Infects dividing and nondividing cells
- Low immunogenicity
- Compatible with G-protein pseudotyping for specific cell targeting
- Can deliver large amounts of DNA (~8 kb), allowing a wider range of payloads to be incorporated versus non-lentiviral technologies
Overcoming Barriers to In Vivo Delivery
Administering genetic therapies in vivo requires perfecting the delivery vehicle. Limitations of first generation viral vectors have hampered the potential of in vivo therapies:
At Vyriad, world-class science comes together with purposeful collaboration to make highly targeted in vivo CAR T and gene therapy possible with efficiency, stability and durability. Our approach to engineering viral vectors leverages years of experience developing and de-risking viral vector-based therapies.