IL-1 receptor antagonists

Hamlet BioPharma is developing IL1-antagonists to treat bacterial infections

We  have identified Interleukin-1 beta (IL-1b) as a key immune response determinant in acute cystitis and its inhibition as an effective therapy.

We distinguish two disease end-points of IL-1b activation; 1. Moderate, self-limiting cystitis, resembling sporadic infection in humans. 2. Severe progressive cystitis caused by a new, genetic, IL-1b hyper-activation disorder, resembling severe cystitis in humans.

We successfully treat mice with the severe form of acute cystitis by inhibiting IL-1b or the enzyme MMP-7 that processes IL-1b to its active form. Finally,  elevated levels of these molecules in patient urine suggesting clinical relevance and a potential role as biomarkers of infection.

These findings provide a much needed, new, molecular framework for the treatment of acute cystitis.

Acute cystitis is caused by bacteria that trigger exaggerated IL-1 responses

Susceptible mice with immune defects develop very severe bladder infection with inflammation and high numbers of bacteria

IL1-beta

We have recently provided a comprehensive molecular framework for the pathogenesis and immunotherapy of acute cystitis.

• We identified acute cystitis as disease caused by exaggerated inflammation and provide a new mechanism of inflammation driven by IL-1β overactivation.
• We identified a genetic cause of acute cystitis in mice and show that the loss of the two genes ASC or NLRP3 causes the exaggerated inflammatory response.
• We a new mechanism of IL-1β activation by the enzyme matrix metalloproteinase 7- (MMP-7), which cleaves the inactive pro-form of IL-1β.
• We showed that IL-1β hyper-activation can be inhibited by treatment with an IL-1 receptor antagonist or an MMP inhibitor, suggesting that IL-1β and MMP-7 can be used as new immunotherapeutic targets in acute cystitis.
• We detected elevated levels of IL-1β and MMP-7 in urine samples from patients with acute cystitis, suggesting human relevance.

Based on these findings, we are developing new treatments for patients with acute cystitis – a very common infection affecting around 50 % of all women during their lifetime. It is estimated that 20-30 % will have recurrent episodes, resulting in suffering and cost for society. With increasing antibiotic resistance development in the bacteria that cause acute cystitis, there is an urgent need for new solutions to the treatment of those patients.