Idera Pharmaceuticals Present New Data That Show Toll-like Receptor Antagonists Inhibit Inflammasome Activation and Suppress Induction of Interleukin 1 Beta in Autoimmune Disease Models
Top-line data from Phase 2 study of IMO-3100 in psoriasis anticipated by year end
“We are pleased that in the preclinical studies, in addition to
controlling the induction of multiple cytokines such as TNF-α, IL-12,
IL-6, and IL-17 and the consequent downstream signaling, our approach to
blocking TLR-mediated pathways also led to decreased production of
inflammasome components and suppression of IL-1β in disease models,”
said Dr.
In a mouse model of IL-23-induced psoriasis, the inflammasome components NLRP3 and AIM2 were up-regulated and IL-1β was increased compared to control animals. Treatment with an antagonist of TLRs 7, 8, and 9 led to suppression of NLRP3, AIM2, and IL-1β in these animals. In mouse models of NZBW/F1 lupus-prone mice and collagen antibody-induced arthritis, NLRP3 was up-regulated and IL-1β was induced compared to control animals. Treatment with an antagonist of TLRs 7, 8, and 9 led to the suppression of NLRP3 and IL-1β in these animals.
About the Inflammasome and Interleukin 1 beta
Activation of the inflammasome, an intracellular complex that regulates the release of proinflammatory cytokines such as IL-1β in response to exogenous pathogens and endogenous danger signals, is influenced by specific TLR signaling. Inflammasome is a multi-protein complex, and its components include NLRP3 and AIM2 for recognition of cellular nucleic acids. Evidence from studies involving human genetics, human ex vivo mononuclear cell responses, and in vivo and in vitro murine models confirms the importance of the inflammasome and interleukin-1β in the pathogenesis of several inflammatory diseases.
Since the discovery and cloning of IL-1β, this critical proinflammatory mediator implicated in many diseases has been a focus of the pharmaceutical industry. The first successful biologic in this class was a recombinant form of the IL-1 receptor antagonist (RA), a natural inhibitor of IL-1β-mediated inflammation. At least three additional IL-1-targeted biologics have been developed, including a recombinant protein with high affinity for IL-1β and two humanized monoclonal antibodies. [Curr Allergy Asthma Rep. 2010 July; 10(4): 229–235.]
About TLRs and Idera's Pipeline
Toll-like Receptors (TLRs) play a key role in inflammation and immunity. Of the 10 human TLRs identified to date, Idera is developing compounds targeted to TLRs 3, 7, 8, and 9, which are expressed in different cells and serve unique functions. Using its chemistry-based approach, Idera has created novel drug candidates that modulate immune responses through either activation or inhibition of specific TLRs. Inhibition of specific TLRs may be useful in treating autoimmune disorders, such as systemic lupus erythematosus (SLE), psoriasis, and rheumatoid arthritis, by blocking the induction of multiple cytokines and signaling pathways. Idera's lead clinical candidates for application in autoimmune diseases are IMO-3100, an antagonist of TLR7 and TLR9, and IMO-8400, an antagonist of TLRs 7, 8, and 9.
A characteristic of autoimmune diseases such as SLE and psoriasis is the production of immune complexes with self-nucleic acids. These abnormal immune complexes activate TLRs 7, 8, and 9 and induce multiple cytokines that cause further damage to the body's own tissues and organs, thereby releasing more self-nucleic acids. Thus, a pathologic amplification cycle is established, promoting disease maintenance and progression. In preclinical models of several autoimmune diseases, IMO-3100 and IMO-8400 inhibited TLR-mediated immune responses, broke the cycle of disease maintenance and progression through decreases in Th1, Th17 and inflammasome pathways, and led to improvements in multiple measures of disease.
About
Idera Forward Looking Statements
This press release contains forward-looking statements concerning
Source:
Idera Pharmaceuticals, Inc.
Lou Arcudi, 617-679-5517
larcudi@iderapharma.com