Advantages of CYN 101
- Cancer Targeting: Specifically Targets Cancer Cells via Laminin Receptor
- Naturally Apoptotic: Kills Targeted Cancer Cells Without Affecting Normal Cells
- Non Immunogenic: No Neutralizing Antibody Effects Seen to Date
- Replication Defective: Engineered to Infect Only Once
- RNA Genome: No Insertion in Host Genome — No Mutagenesis
- Ability to Re-Target: Monoclonal Antibodies (Protein A); Single Chain Antibodies; Other Peptides and Ligands
- Payload Delivery: Can be Engineered to Include Therapeutic Payload: TK, Interferons, Interleukins, SiRNAs, etc…
General
The CYN 101 vector is similar to the wild-type virus except that it has been rendered replication defective. Once it infects a cell, the RNA will code for protein products, but the virus does not “repackage” itself and come out of the host cell to infect again. The vector is highly cytotoxic, killing every cell it infects by triggering apoptosis (programmed cell-death). The vector can be customized in a number of ways, including targeting and inclusion of payloads, although no customization is necessary to have a therapeutic effect in some cancers.
Systemic Delivery
The wild-type virus is naturally transmitted in blood and can survive in the blood stream, thereby allowing for systemic administration of CYN 101 via intravenous or intraperitoneal injection. This represents a distinct advantage over other vectors that are lysed in plasma such as lentiviral systems.
Targeting
The high affinity laminin receptor (LAMR) is the natural target of the wild-type virus and the vector. While the LAMR is expressed by nearly every mammalian cell, it is over-expressed in many solid tumors. In normal cells, the LAMRs are occupied by laminin, thereby blocking binding by the vector. When the LAMR is over-expressed in cancer, the binding sites become available for very specific binding and infection by the vector only to cancer cells.
The vector can also be custom targeted. One product opportunity covered by the NYU IP involves expression of the IgG binding domain of Protein A derived from staphylococcus aureus into the vector envelope. When combined with select monoclonal antibodies, the vector can be re-targeted to sites expressing proteins recognized by the antibody.
Other substitutions can be made on the viral envelope with single-chain antibodies, peptides, oligosaccharides, or other targeting molecules to provide other targeting capabilities.
Little to No Immunogenicity
To date no antibodies have been observed with CYN 101. Proteins on the surface of the vector may not be recognized as foreign and thus no immune response is mounted.
Apoptotic Characteristic
CYN 101 is naturally apoptotic, enabling its use as a cancer therapeutic (cytotoxic) even without a gene payload, as has been demonstrated in animal experiments.
RNA Vector
The Sindbis genome is RNA, which is not incorporated in the host DNA. There is little to no risk of insertional mutagenesis.
Vector is Replication Defective in Host Cells
CYN 101 is engineered to be replication defective. This may have regulatory advantages in addition to the therapeutic advantages.
Production
CYN 101 is manufactured by transfection of the vector RNA into mammalian cells and purified via column chromatography. Scalable manufacturing methods have been developed, and are currently being optimized to produce therapeutically relevant titers in sufficient quantities for clinical trials.
Rapid Gene Expression
Activation of vector gene expression has been demonstrated in twelve to fifteen hours post-infection, allowing for a variety of therapeutic and diagnostic applications.
Imaging
The vector has been custom constructed with florescent reporter genes and with the thymidine kinase gene, which enables tracking of vector infection of tumor cells using PET scan technology. This may allow diagnosis of cancer, as well as monitoring of therapy and tumor shrinkage in “real-time”. Because the vector can be administered systemically, the imaging vectors can be used to identify metastases.
Large Inserts Possible
Two genes have been inserted because of the large insert size of Sindbis vectors (approximately 12 kilobase). Insertion of regulatory elements is achievable.
