Flag’s mRNA Adjuvant Technology Platform

The revolutionary potential of mRNA vaccines was validated during the COVID-19 pandemic and holds strong promise for other anti-infective and anticancer applications. However, unleashing the full potential of mRNA vaccines requires improvements in safety, durability of immune response, and reduction of mRNA load.

While conventional vaccines typically include immunoadjuvants to enhance efficacy, mRNA vaccines rely on the immune-stimulatory properties of their components: lipid nanoparticles (LNPs) and antigen-encoding mRNA. However, the activity of LNPs does not align in time and location with mRNA-driven antigen expression, and the interferon (IFN) response inhibits translation, interfering with antigen production.

Flag Bio addresses these limitations by supplementing mRNA vaccines with mRNA adjuvants that encode immunostimulatory polypeptides. These mRNA-Flag adjuvants are produced simultaneously with the mRNA vaccine's antigens, improving the quality of the immune response and ensuring better protection.

Flag’s mRNA adjuvants are versatile and can be used with any type of mRNA vaccine, regardless of the target pathogen, formulation, or delivery route.

Flag-711: the Lead mRNA Adjuvant

Flag’s lead mRNA adjuvant, Flag-711, is a synthetic RNA with a proprietary composition that encodes a pharmacologically optimized agonist of the innate immunity receptor, Toll-like receptor 5 (TLR5).

Toll-like receptors (TLRs) serve as a critical link between innate and adaptive immunity, making TLR agonists excellent adjuvants. However, none of the FDA-approved TLR agonists can be encoded in mRNA and used as mRNA adjuvants.

The TLR5 agonist, a natural protein (bacterial flagellin), can be encoded in mRNA, enabling the adjuvant to be co-expressed and co-localized with the antigen simultaneously.

Activating TLR5 to boost immunity offers a favorable balance between efficacy and safety compared to other TLRs, as demonstrated in both preclinical studies and clinical trials.

The unique tissue specificity of TLR5 expression, particularly in epithelial cells, makes TLR5 agonists especially attractive for enhancing vaccination against respiratory infections.

TLR5 agonists have also been shown to overcome aging-related immunosenescence, improving vaccine efficacy in older mice and humans.

The structure and composition of Flag-711 incorporate a series of protein engineering advancements developed by Flag’s team. Flag-711 enables cells to produce a deimmunized and secretable TLR5 agonist, extending the immunostimulatory effect to the surrounding microenvironment. Additionally, Flag-711 is designed to allow fusion with an antigen without compromising its TLR5 agonistic properties.

The efficacy of Flag-711 has been demonstrated in preclinical models of anti-flu and anti-COVID-19 mRNA vaccines, showing improved antiviral protection and enabling a significant reduction in the mRNA load per vaccine dose.

History of development of TLR5 agonistic proteins, properties of which are implemented in the design and composition of Flag-711.

Development History of TLR5 Agonistic Proteins and Their Integration into the Design of Flag-711. The design and composition of Flag-711 build upon the extensive history of development and optimization of TLR5 agonistic proteins. These advancements have been systematically refined to enhance their pharmacological properties and immunostimulatory capabilities. For detailed references, please refer to the "Relevant Publications" section.