Theranostic TNFa inhibitors – Theranalpha

Tumor Necrosis Factor alpha (TNFa) is a homotrimeric cytokine of the immune system whose overproduction has been associated with several chronic inflammatory diseases and especially rheumatoid arthritis (RA). Clinically approved inhibitors of TNFa include monoclonal antibodies (infliximab, adalimumab, golimumab and certolizumab) and soluble receptor of TNFa (etanercept), also called biologics which display several drawbacks such as their:
• limited tissue penetration
• modality of administration (subcutaneously every 1 to 4 weeks for all drugs with the exception of the intravenous infliximab)
• high production cost and consequently high prices
• immunogenicity and resulting treatment resistance due to immune reactions
• side effects in particular an increased risk of opportunistic infections
To circumvent these obstacles, different research programs have been conducted to identify small molecule inhibitors of TNFa. Among these works, SPD304 (identified in 2005) constitutes a reference compound that inhibits the activity of TNFa by disrupting TNFa homotrimeric form. SPD304 was not evaluated in vivo likely due to his high toxicity and moderate activity. Despite many efforts, no orally available TNFa inhibitor has been identified so far. To our knowledge, no small molecule inhibitors of TNFa have been previously radiolabelled to provide a radiotracer able to monitor the inflammation process in rheumatoid arthritis.

The global objective of this project is the design, in vitro and in vivo evaluation of a theranostic small molecule inhibitor of TNFa providing simultaneously:
• A therapeutic 19F drug candidate (oral route) characterized by a preclinical “Administration Distribution Metabolism Elimination Toxicity” (ADMET) profile at an efficient therapeutic dose and a proof of concept in an animal model representative of RA pathology (Collagen-induced arthritis).
• A diagnostic 18F drug candidate (IV route) characterized by a preclinical proof of concept in PET imaging in an animal model representative of RA pathology (Collagen-induced arthritis).
The Theranalpha project is based on preliminary work performed by the partners of the project who have identified two hit compounds that inhibit the activity of TNFa in vitro at a concentration 10 times lower than SPD304, which is to our knowledge best result ever reached. By design, these two hit compounds are built using a pyridine unit in order to mark the pyridine moiety by fluorine.
This project is aimed to address several unmet medical needs
• The Theranalpha project could provide inexpensive anti-TNFa therapies administered orally. Currently no marketed anti-TNFa therapy can be administered orally. Oral administration could improve the compliance of treatments or even the possibility of using them earlier in the progression of the disease.
• The Theranalpha project should provide a 18F radiolabeled TNFa tracer to
o 1. Confirm RA pathology by detecting cell-bound and soluble TNFa to localize sites of inflammation in patients suspected to display RA and 2. Demonstrate the presence of an ongoing inflammation process where there is a suspicion of inflammation without a systemic inflammatory response
o Determine the staging of the RA disease by diagnosing the status of activity in inflamed organs or tissues (inflamed joints)
o Determine and predict early the response to therapy. In particular, the evaluation of the non-responsiveness to TNFa-blocking agents could be evaluated based on the detection and localization of cell-bound and soluble TNFa by PET imaging. This point is clearly important due to the high cost of marketed anti-TNFa therapies.
o Carry out the therapeutic follow-up of an anti-TNFa treatment by assessing inflammatory activity state before and during the treatment. This point is clinically important since current anti-TNFa therapies are associated with significant side effects.