New TLR4 agonists as vaccine adjuvants

The invention relates to the synthesis and the biological/pharmacological activity of new molecules active in stimulating the human receptor TLR4. This receptor is one of the key players in activating inflammation and immune response to bacterial pathogens in humans. The capacity of the synthetic molecules described in the patent (called FP molecules) to stimulate TLR4 and their lack of toxicity, made them interesting lead compounds as immunostimulants for vaccine adjuvants development.

A collaboration is running with Croda/Avanti for the development of nanoformulated FP molecules as vaccine adjuvants to reach the veterinary market and eventually to access to clinical phases.

Modern subunit vaccines need to be adjuvanted to reach the desired intensity and duration of the immune response to the antigen. Despite their key role in the vaccination, adjuvants used as pure molecules or combination of molecules (Adjuvant Systems) now available in the market are limited to a relatively restricted variety of chemical entities. For several reasons, the innovation in the field of adjuvant is very slowly progressing despite the market demand for efficient and save adjuvants.

The small molecules clinically approved for use as adjuvants are basically squalene, saponin and MPLA, a detoxified derivative of the gram-negative bacterial lipopolysaccharide (LPS). MPLA is used in HCV and HPV and has potentially large market opportunities also for other vaccinations. However, the production of MPLA is expensive and laborious due to its long synthesis (24 steps).

In the perspective to develop new adjuvants from natural or synthetic molecules, we have to consider that optimal adjuvants should have:

1. low development and production cost
2. well defined activity and toxicity profile

Given the major limitations to the adjuvant market (i.e. the lack of chemical variety of molecular adjuvants and the expensiveness and low sustainability in the production of molecular adjuvants), our technology offers the following striking advantages:

1. Low cost of production (also appealing for veterinary vaccines)
2. Green/sustainable production
3. Scalability
4. Modular approach consisting in the possibility to modulate the chemical structure and therefore the activity/toxicity profiles of TLR4 agonists (FP molecules)

1. Low production costs (sustainable production, veterinary market)
2. Industrial Scalability at global level
3. New nanoformulation in combination with other available and/or innovative adjuvants
4. Lack of toxicity (FP compounds are glycolipid derivatives with a non-toxic glucosamine core)
5. Modulation of activity/distribution profiles by modification of the simple core structure of TLR4 agonists