Rationale for Eterna’s IL-10 iMSC Cell Therapy (ERNA-102) in Autoimmune disease
IL-10 is a potent immunoregulatory cytokine first identified as a secreted factor, which inhibited inflammatory cytokine synthesis by activated Th2 cells [1]. Although IL-10 has been shown to exhibit predominantly anti-inflammatory effects, it has been reported to have distinct immunostimulatory functions as well, suggesting that the downstream effects of IL-10 expression is highly nuanced and context dependent.
IL-10 is a homodimeric protein, consisting of two 160 amino acid polypeptides, which specifically interacts with a heterodimeric IL-10R, consisting of IL-10RA and IL-10RB. IL-10 may be expressed by a broad spectrum of adaptive and innate immune cells, including but not limited to, Th1, Th2, Th17, CD8, Treg, B cells (adaptive) and DCs, macrophages, mast cells, NK cells, eosinophils, neutrophils[2]. Epithelial cells – including cancer cells - may also secrete IL-10, which has been implicated as a significant mechanism of tumor-driven immune evasion [3, 4].
Specificity of IL-10 binding and activity is dependent on the high-affinity interaction between IL-10 and IL-10RA (also known as IL-10R1). IL-10RA is mainly expressed on immune cells. When IL-10 binds to and activates IL-10R, activation of JAK and STAT nuclear transcription factors leads to a discrete program of gene expression [5, 6]. In macrophages and other antigen-presenting cells (APCs), IL-10 signaling drives a potent immunosuppressive state characterized by a decrease in antigen presentation and processing, inhibition of pro-inflammatory cytokine and chemokine expression and expression of downstream anti-inflammatory factors such as arginase and soluble IL-1 receptor antagonist (IL-1RA). In macrophages, IL-10 has been shown to induce metabolic reprogramming characterized by inhibition of the pro-inflammatory upregulation of glycose intake and glycolysis, increased removal of dysfunctional mitochondria, suppressed activation of inflammasome and mTOR activity [7]. Although other cell types can respond to IL-10, including B cells and CD8 T cells under certain circumstances, expression levels of IL-10RA are much greater on macrophages, suggesting that they represent the critical target cell, driving the immunosuppressive activity of IL-10 in inflamed tissues.
It is widely appreciated that tissue macrophages are phenotypically plastic and thus represent a critical cellular node orchestrating the balance between an inflammatory milieu state versus a quiescent non-inflamed state [8-11]. Thus, the ability to selectively deliver IL-10 and other anti-inflammatory signals selectively to macrophages in inflamed tissues would represent a powerful and tractable approach to treating a host of inflammatory disease, including rheumatoid arthritis, inflammatory bowel disease, macrophage activation syndromes, systemic sclerosis, neuroinflammatory diseases, inflammatory skin disorders and others.
Unfortunately, despite impressive efficacy in preclinical models, systemic recombinant IL-10 therapy has failed to deliver significant therapeutic benefit in clinical trials in a variety of disease settings, including rheumatoid arthritis, inflammatory bowel disease (Crohn’s disease and ulcerative colitis), acute pancreatitis and psoriasis (reviewed in[6, 12] ). We, hypothesize that the lack of therapeutic benefit is due to insufficient delivery of IL-10 to the inflamed macrophages in the target tissue.
We believe that Eterna’s IL-10_iMSC product can leverage the intrinsic ability of MSCs to home to sites of tissue inflammation and selectively target IL-10 and other anti-inflammatory MSC-derived factors to the site of inflammation, resulting in resolution of pathogenic inflammation and healing.
Mesenchymal stem cells (MSCs) interact with macrophages and deliver polarization signals, through direct cell-cell contact as well as through a plethora of secreted molecules, including IL1RA, IDO, PTX3, TGFβ and PGE2 [13-22]. Interestingly, using a fully human ex vivo culture model, Vasandan et al demonstrated that the effect of MSCs on macrophage polarization was strongly dependent on the initial functional state of the macrophages: naïve macrophages were induced by MSCs to become inflammatory whereas inflammatory macrophages were shifted towards an immunosuppressive phenotype[23]. In addition, this study showed that re-polarization from an inflammatory (M1) to an anti-inflammatory (M2) phenotype was dependent on PGE-2 expression by co-cultured MSCs [23].
Our proprietary synthetic induced MSCs are derived from induced pluripotent stems cells (iPSCs), which have been engineered to express IL-10. In addition, in our ERNA-102 (IL-10_iMSC), we have engineered a bialleic deletion of B2 microglobulin to decrease expression of MHC molecules in order to enhance in vivo persistence of our allogeneic product.
Eterna’s therapeutic hypothesis is that ERNA-102 will selectively home to sites of ongoing inflammation, specifically delivering IL-10 and other anti-inflammatory signals precisely to the critical cellular locus of action: inflammatory macrophages. We anticipate that ERNA-102 will repolarize the macrophages to an anti-inflammatory state, ameliorating inflammation and promoting tissue repair and regeneration. Based on this mechanism of action, we believe that ERNA-102 represents a broad-spectrum, tissue-targeted anti-inflammatory therapeutic.
Eterna’s initial clinical focus will be in rheumatoid arthritis.
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