A variety of genetic factors, environmental stresses and age-related changes trigger the innate immune system to inappropriately respond and cause excessive inflammation. This type of chronic inflammation is associated with autoimmune and auto-inflammatory conditions.
Antagonists of NLR Proteins
A spectrum of inflammatory diseases are associated with mutations in the NLR gene family. The NLR family is composed of 23 cytosolic proteins with variable recognition motifs that are responsible for detecting cellular threats using pathogen-associated molecular patterns (PAMP) or damage-associated molecular patterns (DAMP). After recognition, some NLRs change shapes to assemble a multi-protein structure known as an inflammasome, which activates inflammatory processes.
By blocking inflammasome activity, our small-molecule inhibitors may help reduce overactive cytokine production and stop inflammatory signaling. IFM is investigating several members of the NLR family including NLRP1, NLRP3, NLRP6, NLRP10 and NLRC4. By targeting components of the inflammasome, the potential exists for our NLR antagonists to be used for multiple indications and to serve as first-in-class innate immune modulators for the treatment of liver fibrosis/non-alcoholic steatohepatitis (NASH), neurodegeneration/Alzheimer’s disease, cardio-metabolic diseases such as atherosclerosis and type 2 diabetes, gout, age-related macular degeneration and autoimmune diseases that include systemic sclerosis, inflammatory bowel disease (IBD), vitiligo, type 1 diabetes, celiac disease, systemic lupus erythematosus and rheumatoid arthritis.
Antagonists of the cGAS-STING Pathway
The appearance of microbial or aberrant human DNA in the cytosol of cells induces an innate immune response. Fragments of this DNA bind to the cytosolic DNA sensor cGAS, which catalyzes the synthesis of the second messenger 2′3′-cGAMP, which in turn triggers STING-dependent interferon production and signaling. Mutations that activate this pathway cause a variety of autoimmune diseases in humans that are characterized by excessive interferon signaling. This provides strong evidence that the molecules that IFM is developing to block the cGAS/STING pathway will be useful to treat diseases that result from abnormal signals induced by cytosolic DNA, including both rare autoinflammatory and autoimmune diseases like Aicardi-Goutières syndrome and more common conditions such as systemic lupus erythematosus, in which excessive type interferon signaling drives disease.
Cancers grow when tumor cells evade detection by the immune system. Our small-molecule oncology therapies work within the tumor microenvironment to activate innate immune responses, which subsequently alert the adaptive immune system to the tumor’s presence. Not only do these inflammatory signals target the cancer cell for destruction, they also form the basis for immunological memory, which may limit the recurrence of cancer.
Our programs aim to produce agents that can potentially be used as standalone agents and in combination with other treatments, such as checkpoint inhibitors, to induce a more effective and durable response than what is possible with current therapies. Among our current immuno-oncology targets are the key innate immune sensors AIM2 and NLRP1.
Agonists of AIM2
AIM2 (Absent in Melanoma 2) is a cytosolic DNA-sensing protein. In response to DNA fragments in the cytosol, AIM2 changes shape, and like NLR proteins, triggers inflammasome activation leading to release of inflammatory cytokines and causing an immune-activating form of cell death. These responses occur during some infections, when microbial DNA is thought to activate AIM2 leading to a protective innate immune response. AIM2 is notably absent or present at reduced levels in certain tumor types, including colorectal and prostate cancers. Reduced expression levels are thought to be a clue that activation of AIM2 may be detrimental to the survival and growth of some cancers. In addition, activation of AIM2 should help overcome the immunosuppressive tumor microenvironment by recruiting immune cells into the tumor microenvironment and thereby promoting an anti-tumor immune response. Combining an AIM2 agonist with checkpoint inhibitors should improve the effectiveness of immune therapy for difficult-to-treat cancers.