Innate immunity is the oldest and most conserved facet of the immune system. It is responsible for an anti-infective response and it has been intrinsically linked to the initiating of inflammation. The inflammatory response is necessary for signalling to the adaptive immune system but it can be self-perpetuating and exaggerated, which leads to deleterious effects, including sepsis and autoimmune diseases. The ability to selectively separate the innate immune system’s inflammatory response from the anti-infective one wasn’t recognized until quite late (with the publication of papers like Medzhitov et al., Nature 447:972-8 in 2007).
The innate immune system is characterized by a number of receptors, such as toll-like receptors [TLRs], nucleotide-binding oligomerization domain [NOD]-like receptors [NLRs], and RIG-I like receptors [RLRs], which recognize various patterns indicative of bacterial, fungal or viral infection, genotoxic stress or tissue damage. The ‘pre-programmed responses elicited by these receptors enable the innate immune system to perform with its hallmark rapidity, with no need for the development of individual ‘memory’.
Only recently has the complexity of the innate immune system been detailed, including the concept of epigenetically controlled ‘trained memory’. Further discoveries of the subtleties in cell type and cell function are ongoing1. As research has shown, triggering the innate immune system results in the initiation of different signalling cascades. Interestingly, some evidence indicates significant consolidation of these signalling networks at the intracellular level. For example, most TLRs signal through either MyD88 or TRIF signalling factors, and even these factors can be linked to each other2,3,4,5.
Because of the complexity of the response, and the late recognition of the distinct inflammatory and anti-infective responses, the clinical potential of targeting innate immunity was largely ignored. Moreover, initial attempts to modulate the innate immune system (e.g., through the use of TLR agonists such as CpG) targeted the receptors and, therefore, turned the entire system on or off, instead of leveraging the differences between the pathways.
Finally, early studies of innate immunity focused entirely on the circulating cells, such as monocytes and neutrophils, and their migration to the site of infection/damage. However, recent studies have identified more nuanced subsets of these cell types, as well as other tissue resident cell types, which also play a significant role1.
Where does innate immunity play a role in disease?
While innate immunity is clearly understood to play a role in fighting infection, its significance in tissue homeostasis is more recently revealed. This can involve, for example, macrophages and innate lymphoid cells. Their interaction with the adaptive immune system through myeloid-derived suppressor cells have also highlighted roles in cancer, atherosclerosis, inflammatory bowel disease, rheumatoid arthritis, fibrosis, neurodegenerative disorders, wound healing and chronic inflammatory lung diseases.
How do Innate Defense Regulators (IDRs) work and how do they compare to other therapeutic innate immune therapies?
IDRs are unique in their approach to innate immune modulation. They target an intracellular convergence point in the signalling networks downstream of most innate immune receptors, and they have demonstrated effects on innate immune responses generated by both circulating and tissue resident cells. The primary impact of IDRs is thought to be through ultimately modulating the spectrum of response of macrophages and the related tissue homeostasis controlled by the macrophages. Importantly, IDRs do not directly recruit macrophages nor bias their development along the M1-M2 spectrum directly. Rather they appear to alter the environment around (signalling to) the macrophages, resulting in a more anti-inflammatory/tissue-healing and anti-infective response.
The primary protein involved in direct binding to the IDR compounds is the p62 protein (also known as sequestosome-1). IDRs specifically bind to the ZZ domain of this scaffold protein, changing the resulting protein signaling complexes that form and encouraging signalling through transcription factors such as C/EBPβ while not unduly perturbing NFκB controlled pathways (see graphic).
This unique mechanism has been shown in animal studies to prime the innate immune system for at least 48-72 hours after a single administration, resulting in enhanced bacterial clearance, enhanced survival, enhanced tissue healing and decreased inflammation (across a broad spectrum of inflammatory and anti-inflammatory signalling mediators).
Given the conserved nature of the innate immune system, it is perhaps not surprising, but certainly gratifying, to have observed that all the modes of action (anti-infective, anti-inflammatory and pro-tissue healing) have been demonstrated in Phase 1 and 2 clinical studies with the lead IDR candidate, dusquetide (see Further Information).
What are the development plans for the IDR technology?
At Soligenix, we are pursuing oral mucositis as the first clinical indication for development of the IDR technology. Oral mucositis is a debilitating side effect of cancer treatment that is triggered by cell killing (of both tumor and normal cells) by chemoradiation therapy and thereafter exacerbated by the inflammatory response of the innate immune system, It ultimately leads to increased infections and tissue damage, and it is a leading cause of the reduced quality of life and medical complications that occur with chemoradiation therapy.
As noted, dusquetide, the lead clinical IDR, has completed Phase 1 and 2 clinical studies and is currently under investigation in a Phase 3 clinical trial recruiting in both the US and Europe. Statistically significant reduction in the duration of oral mucositis was demonstrated in the Phase 2 study. The evaluation of dusquetide in oral mucositis is a fast-track designated programme.
In addition to oral mucositis, IDRs have demonstrated beneficial outcomes in fighting bacterial infection, in both animals and humans, irrespective of the pathogen behind the infection. This is a particularly important finding in the context of emerging and antibiotic resistant disease, and we continue to explore opportunities for development.
It is apparent that given the impact of IDRs on macrophage function in particular and the role of macrophage controlled tissue homeostasis in many diseases, including cancer, there are significant potential opportunities for the development of additional IDR compounds.
For more information on Innate Defense Regulators, visit the Soligenix website.
Gasteiger G, D’Osulado A, Schubert DA, Weber A, Bruscia EM, Hartl D. 2017. Cellular Innate Immunity: An Old Game with New Players. J Innate Immun 9:111-125.
Into, T., Inomata, M., Niida, S., Murakami, Y., Shibata, K., 2010. Regulation of MyD88 aggregation and the myD88-dependent signaling pathway by sequestosome-1and histone deacetylase 6. J. Biol. Chem. 285 (46), 35759–35769.
Park, S., Ha, S.D., Coleman, M., Meshkibaf, S., Kim, S.O., 2013. P62/SQSTM1 enhances NOD2-mediated signaling and cytokine production through stabilizing NOD2 oligomerization. PLoS One 8 (2), e57138.
van der Vaart, M., Korbee, C.J., Lamers, G.E., Tengeler, A.C.1, Hosseini, R., Haks, M.C.,Ottenhoff, T.H., Spaink, H.P., Meijer, A.H., 2014. The DNA damage-regulatedautophagy modulator DRAM1 links mycobacterial recognition via TLR-MyD88to autophagic defense. Cell Host Microbe 15 (6), 753–767.
Kim, J.Y., Ozato, K., 2009. The sequestosome 1/p62 attenuates cytokine gene expression in activated macrophages by inhibiting IFN regulatory factor 8 and TNF receptor-associated factor 6/NF-kappa B activity. J. Immunol. 182 (4),2131–2140.