Targeron Technology
Targeting Interferons to Externalized Phosphatidylserine on Diseased Cells
What is Targeron Therapeutics’ Technology
Our strategy first combines two types of interferons (type I and type III IFNs) aimed to amplify and localize host immunity. Type I IFNs are found on most nucleated cells but the type III IFNs are more restricted, where they are expressed mainly on epithelial cells. This combination is expected to boost host immunity at epithelial boundaries.
Action of Interferons is Compartmentalized to Different Tissues
The next unique aspect of our biologics aims to link the type I and type III IFN duets with a phosphatidylserine (PS) targeting domain. In healthy normal cells, almost all of the PS is restricted to the inner membrane and hidden from PS-targeting therapeutics. However, on diseased cells including cancer cells and viral infected cells, the PS becomes pathologically externalized where it can interact with PS-targeting therapeutics. This feature of diseased cells enables them to be selectively and safely targeted by our biologics.
Externalized Phosphatidylserine is a Universal Biomarker for Stressed Cells
The biologics under development by Targeron Therapeutics are based on natural endogenous serum proteins. The Gla and EGF-like domains are derived from Growth Arrest-Specific Gene 6 (Gas6) a ligand for the inhibitory TAM (Tyro-3, Axl, and Mertk) receptors. Upon creation of the recombinant biologics, the receptor binding domain is truncated and in turn replaced by the type I and type III IFN duet, thereby adding a potent immunomodulatory domain to stimulate a strong host immune response on cells with pathological PS externalization.
Therapeutic approaches to targeting externalized phosphatidylserine in cancer
By employing this strategy, we have effectively replaced PS targeting immune suppressing biologics with PS targeting immune stimulatory biologics.
The detailed mechanisms of action involving (i) PS targeting to diseased cells such as cancer cells, (iii) recruitment of a type I IFN that activates immune cells such as macrophages and DCs, and (iii) recruitment of a type III IFN that targets epithelial cells, including the up-regulation of MHC-class I and PDL1 on tumor cells.
Using our lead molecule Gas6-IFN-β-IFN-λ, we show strong anti-tumor responses in a syngeneic mouse model of triple negative breast cancer. Shown in the figure is that combination of the three domains provides superior activity compared to PS-targeting molecules that have a single IFN.
PS-targeting IFN Fusion Proteins for Anti-tumor Applications
