EP-4739707-A1 - IL-1RA BLOCKERS FOR TREATMENT AND PREVENTION OF SEPSIS

Abstract

The invention relates to a pharmaceutical composition comprising an agent capable of inhibiting IL-1Ra activity, for use in prevention or treatment of sepsis associated with systemic fungal infection.

Inventors

• Freigang, Stefan
• GANDER-BUI, Thi Thuy Hang

Assignees

• Universität Bern

Dates

Publication Date

20260513

Application Date

20240705

Claims (7)

1. 1 . A pharmaceutical composition comprising an agent capable of inhibiting IL-1 Ra activity, for use in prevention or treatment of sepsis associated with systemic fungal infection.
2. 2. The pharmaceutical composition for use according to claim 1 , wherein the systemic fungal infection is infection by Candida albicans.
3. 3. The pharmaceutical composition for use according to claim 1 or 2, wherein the agent capable of inhibiting IL-1 RA is a ligand to IL-1 Ra selected from a monoclonal antibody and an antibody-like molecule.
4. 4. The pharmaceutical composition for use according to claim 3, wherein the agent capable of inhibiting IL-1 RA is an IL-1 RA neutralizing antibody or neutralizing antibody-like molecule.
5. 5. The pharmaceutical composition for use according to claim 1 or 2, wherein the agent capable of inhibiting IL-1 RA is an oligonucleotide agent capable of inhibiting IL-1 RN gene expression.
6. 6. The pharmaceutical composition for use according to claim 5, wherein the oligonucleotide agent is capable of hybridizing to a mRNA encoding IL-1 Ra.
7. 7. The pharmaceutical composition for use according to claim 5 or 6, wherein the oligonucleotide agent is selected from an antisense oligonucleotide, a gapmer, an siRNA and a shRNA.

Description

IL-1 Ra Blockers for Treatment and Prevention of Sepsis This application claims the right of priority of European applications 23183633, filed 5 July 2023, and 23215259, filed 8 December 2023, both of which are incorporated herein by reference in their entirety. Field The present invention relates to the medical use of IL-1 Ra blockers in management of sepsis associated with systemic fungal infection. Background Sepsis is a severe, life-threatening condition triggered by microbial dissemination via the bloodstream and a maladapted systemic inflammatory response. Although fungal sepsis is less frequent, invasive fungal infections have particularly high mortality rates. Candida albicans represents the most common cause of fungal bloodstream infection; and despite adequate antifungal treatment, the overall mortality is 30-40%, exceeding 60% in critically ill patients. C. albicans is normally contained by epithelial barrier immunity and occurs as commensal in half of the population. Inborn errors of immunity highlight the importance of IL-17-mediated pathways to avert mucocutaneous colonization, whereas functional neutrophil responses are critical to prevent systemic infection (Puel A. (2020), Hum Genet. 139, 1011-1022; Desai JV, Lionakis MS. (2018), Curr Clin Microbiol Rep. 5, 181-189). Accordingly, individuals with immunosuppression due to hematologic malignancies, organ transplantation, AIDS, or prolonged intensive care hospitalization are highly susceptible to invasive candidiasis. However, preceding systemic viral infections, or medical interventions that compromise physiological barrier function, such as indwelling devices, parenteral nutrition, and abdominal surgery, may predispose otherwise immuno-competent hosts to disseminated Candida infection. Given the high mortality of invasive fungal infections, the emergence of drug resistant strains, and an increasing number of high-risk patients, there is great interest in defining underlying disease mechanisms in order to develop novel therapeutic strategies. Inflammation is the physiological innate response to tissue damage aiming to eliminate the injuring agent and restore internal homeostasis. Both, the dynamics and the composition of its powerful effector functions must be precisely adapted to the characteristics of the invading pathogen in order to provide appropriate defense mechanisms that ensure pathogen clearance while avoiding extensive tissue damage. Therefore, interacting networks of pro- and anti-inflammatory cytokines orchestrate the differentiation and recruitment of functionally distinct immune cell populations. Moreover, there are negative feedback mechanisms, so-called immune checkpoints, which signal disproportionate immune activation and dampen the inflammatory process to prevent immunopathology. However, sepsis is characterized by a derailment of such pro- and antiinflammatory pathway homeostasis with concurrent hyper-inflammation and immune paralysis, resulting in a dysfunctional systemic inflammatory response, multi-organ damage, and failure to contain pathogen replication. The prototypical pro-inflammatory cytokine interleukin-1 (IL-1 ) initiates and coordinates local and systemic inflammatory responses by activating the IL-1 receptor (IL-1 R) on immune and non- immune cells. Both IL-1 cytokines, IL-1 a and IL-10, are quintessential for antimicrobial immunity, including to C. albicans. Still, excessive IL-1 production is associated with severe acute and chronic inflammatory conditions, such as autoinflammatory syndromes, rheumatoid arthritis, sepsis, or metabolic disorders. Accordingly, IL-1oc and IL-10 are subject to highly complex regulatory mechanisms acting at the transcriptional and posttranslational level, which restrict the generation of the mature cytokines or influence their ability to activate the IL-1 R. The inflammatory effects of bioactive IL-1 a and IL-10 are controlled by the IL-1 R antagonist (IL-1 Ra), an endogenous inhibitor that competes for occupancy of the IL-1 R but does not trigger downstream signaling. One secreted and three intracellular isoforms of IL-1 Ra have been described and are derived from the same IL1RN gene. Adding to the complexity of IL-1 regulation, these individual isoforms are differentially expressed in various cell types. For example, intracellular IL-1 Ra is constitutively expressed in epithelial cells, whereas secreted and intracellular isoforms may be induced in diverse leukocyte subsets in response to pro-inflammatory cytokines, microbial products, or tissue injury. The potency of IL-1 Ra-mediated regulation is evident in the severe inflammatory syndrome of DIRA patients, and is exploited therapeutically for the management of IL-1 -mediated diseases. However, while the molecular pathways that govern the generation and secretion of mature IL-1 are well appreciated, much less is known about the regulatory mechanisms operating at the level of receptor binding, such as IL-1 Ra, particularly w