By exploiting a natural difference in Stem Cell Factor (SCF), our antibody OpSCF binds and inactivates the inflammatory form of SCF, breaking the feed forward cycle of chronic inflammation. Interrupting this cycle returns the inflamed environment to a quiescent state, allowing tissues to heal.
The Reason Why
Chronic Inflammation and Disease
Acute inflammation is a normal process that allows tissue to repair itself after damage occurs, but requires regulation. Chronic inflammation is a common factor in many diseases that can lead to long-term tissue damage and dysfunction when it is not properly regulated. One of the most severe consequences of chronic inflammation is tissue remodeling and fibrosis that replaces the normal functional tissue with fibroblasts and matrix proteins that do not allow the tissue to function normally. This process can often lead to life threatening organ dysfunction, such as in Chronic Kidney Disease, Idiopathic Pulmonary Fibrosis, scleroderma, steroid resistant asthma, Atopic Dermatitis, and others.
Researchers from the University of Michigan have identified that Stem Cell Factor is part of a common pathway that appears to be a primary driver of chronic inflammation. By inhibiting this critical step in the chronic inflammatory pathway, disease progression can be checked. Opsidio has licensed the technology and continued to develop a novel and specific monoclonal antibody that targets the isoform of Stem Cell Factor that is central to driving chronic. Our goal is to help patients who suffer from a variety of chronic inflammatory diseases.
Why Stem Cell Factor?
The Linch Pin
SCF regulates the severity of inflammation and tissue remodeling. Overexpression of SCF causes chronicity of the destructive response. SCF naturally occurs in 2 forms, SCF220 and SCF248. Our data and others clearly demonstrate that SCF220 is responsible for homeostatic functions, including erythropoiesis, whereas SCF248 expression is associated with the induction and maintenance of inflammation. Our novel data indicate that it is the SCF248 isoform that is upregulated during chronic inflammation and in remodeling diseases using samples from patients with chronic disease. SCF248 leads to the activation of innate immune cells, eosinophils, mast cells, and type 2 innate lymphoid cells (ILC2). SCF binds to a surface receptor, c-Kit, found on these critical inflammatory cells leading to production of numerous pro-inflammatory and fibrotic mediators. This leads to fibroblast activation and production of increased inflammation and remodeling. We have found that the exclusive expression of SCF248 (not SCF220) on myofibroblasts and other structural cells is central to these responses and by targeting SCF248, the activation cycle is broken and tissue inflammation and fibrosis is halted.
Why it works
Opsidio has designed a monoclonal antibody (OpSCF) that specifically targets the SCF248 isoform with high affinity. OpSCF does not bind to SCF220 or the soluble extracellular domain released from the cell surface. OpSCF binds to a region found only in SCF248, and not SCF220, so the “normal” functions of SCF are not affected by OpSCF. This is important since it is the membrane bound form of SCF248 that is essential for immune cell activation. By blocking the membrane form of SCF248, OpSCF prevents the activation of the c-kit-requiring immune cells, blocking the release of inflammatory and pro-fibrotic substances, and returns the tissue towards a normal state, allowing natural repair processes to occur. The interruption of chronic inflammation stops disease progression and allows the tissue to function more normally.
We have further identified the likely mechanism of action for OpSCF that it causes SCF248 to be taken off the cell surface, back inside the cell, and is therefore unavailable to activate c-kit-requiring immune cells. We have shown this using a dye that emits colored light only at the low pH found inside the cells’ internalization mechanism. SCF248 is internalized within minutes. Fibroblasts obtained from the lungs of a patient with IPF express high levels of surface SCF248. The red color in image (C) shows that the SCF248 was uniformly taken inside the patient’s activated fibroblasts. Thus, when OpSCF binds to SCF248, it is taken inside the cell and destroyed, without damaging the cell and resulting in a reduction in c-kit+ immune cell activation at sites of disease.