- Our Science
Syntimmune builds on more than 30 years of proven science that has identified the functions of the neonatal Fc Receptor.
The neonatal Fc receptor (FcRn) — initially thought to exist only in newborn rodents but now understood to be expressed throughout human life — is a protein that plays a critical role in regulating Immunoglobulin G (IgG) function and its immune responses. Research that began more than 30 years ago has in recent years culminated in significant mechanistic insights into the role of FcRn in immune-mediated diseases. Our founders and advisors are among the world leaders in FcRn science who have advanced many of these concepts to a point where it is now possible to intervene and alter the machinery that drives IgG-mediated autoimmune diseases.
In health, antibodies are part of the body’s arsenal to fight infection from bacteria, foreign substances and other invaders. But in autoimmune disease, the body mistakenly responds to its own normal components and tissues. This provokes an immune response against itself, leading to inflammation and disease. Autoimmune diseases vary widely, and may involve individual organs, similar types of cells that are present in different tissues, or the entire body.
IgG is often a key pathologic driver of these diseases by inappropriately attacking normal cells, but there has never been a therapeutic agent that specifically targets IgG. Examples of such diseases include systemic lupus erythematosus, inflammatory bowel disease, rheumatoid arthritis and Sjögren’s syndrome. Pathologic IgG becomes the dominant driver in some diseases, myasthenia gravis, heparin-induced thrombocytopenia, and immune thrombcytopenia purpura. These diseases can be chronic, degenerative, or life-threatening.
At Syntimmune, we are advancing drug candidates that disrupt the close relationship between FcRn and IgG and thus disabling the critical biological machinery that IgG depends on to cause disease.
THE ROLE OF FcRn IN AUTOIMMUNE DISEASE
Building on foundational research by the Syntimmune team, FcRn is now understood to play a complex role in the genesis of various autoimmune diseases.
Because of the many IgG-mediated autoimmune diseases and the varied roles played by FcRn in the immune response, specific blockade of FcRn interactions with IgG has broad potential applicability.
FcRn’s ROLE IN REGULATING ALBUMIN
In addition to its critical role in regulating IgG and immune processes, the neonatal Fc receptor (FcRn) plays an equally important role in maintaining albumin levels in the body.
Albumin is the most abundant human blood plasma protein, comprising approximately 50 percent of human plasma proteins. Among its many functions, albumin maintains oncotic pressure, functions as an anti-oxidant, and plays an important role by binding and transporting many hormones, drugs and toxins.
Albumin is synthesized in the liver. Research shows that FcRn plays a key role in recycling albumin within hepatocytes from the apical space, where it would enter the bile stream and be excreted to the body, to the towards the basal space, from which it reenters the bloodstream. This scavenging is critical to maintain albumin protein levels.
A pivotal insight from the groundbreaking work of the Syntimmune team is that blocking the interaction between FcRn and albumin interrupts this process. More albumin and albumin-bound complexes enter the biliary system, and albumin is excreted. The team looked at a model albumin-bound drug, acetaminophen, and showed it to be cleared using SYNT002, Syntimmune’s proprietary monoclonal antibody that blocks albumin interaction with FcRn. The process also protected the liver from the toxic effects of acetaminophen. This model indicates the potential for the clearance of albumin bound endo and exotoxins.
Syntimmune is engaged in extensive pre-clinical investigation of SYNT002 and a set of related compounds, including peptide mimetics, to demonstrate their potential in numerous diseases, including chronic kidney disease.
IgG-MEDIATED AUTOIMMUNE DISEASE
FcRn rescues pathogenic IgG from degradation within the lysosome, enabling it to continue to cause autoimmune disease.
Current methods of modulating the levels of pathogenic IgG within patients each have significant drawbacks:
- Plasma exchange is a clinical procedure in which blood is taken from the patient’s body, proteins (including IgG) are removed, and the blood cells and plasma are returned to the body, sometimes with replacement plasma from donors. This is a highly invasive procedure and it carries many risks, such as infection. It must be done on a regular basis to maintain effectiveness.
- Intravenous immunoglobulin therapy (IVIG) is a preparation in which IgG from numerous of donors is pooled and administered through injection. However, IVIG therapy carries a heavy protein and fluid burden with concomitant effects on the kidney, as well as cardiovacular and other risks. IVIG’s mechanism is only partially understood.
- High-dose steroids have long been used as immune suppressants, and can help patients suffering from IgG-mediated autoimmune disease. But they also are associated with severe side effects, including increased blood sugar levels, weight gain, and serious emotional and psychiatric changes.
- Rituximab is a drug that targets the body’s B cells. Although it can decrease pathogenic IgG, it accomplishes this by depleting B cells. Rituximab’s mode of action has delayed onset and sustained effects for many patients with IgG-mediated autoimmune diseases. Rituximab treatment can be associated with dangerous and life-threatening serious adverse events.
Syntimmune’s approach to treating pathogenic IgG is simple and elegant.
SYNT001 binds to FcRn specifically at the site where IgG binds this receptor. Because of this, SYNT001 blocks IgG interactions with FcRn and disables FcRn-mediated rescue of IgG. As a result, the pathogenic immune effects of IgG are diminished.
This process has rapid onset and is reversible. SYNT001 accomplishes the destruction of pathogenic IgG antibodies without destroying any immune cells or affecting the levels of albumin, a second substrate for FcRn, or other immunoglobulin classes.
Other Syntimmune drug candidates work in similar fashion. For instance, SYNT002 blocks albumin’s interactions with FcRn and decreases levels of albumin-bound toxins without affecting IgG. This gives Syntimmune’s pipeline of drug candidates broad applicability.
KEY: | FcRn | IgG | SYNT001
FcRn’s key role in trafficking IgG and other proteins gives our drug candidates broad applicability.
Our lead candidate, SYNT001, has potential applications in IgG-mediated autoimmune diseases in neurology, dermatology and hematology as well as numerous complex-mediated diseases such as systemic lupus erythematosus, inflammatory bowel disease and rheumatoid arthritis.
In addition, FcRn is now recognized to affect IgG-mediated inflammation by a variety of mechanisms. Syntimmune’s position as the leader in FcRn science provides the opportunity to design additional drug candidates that modulate the role of this important trafficing receptor. The chart below shows just some of the autoimmune diseases where Syntimmune’s science can play a role in advancing drug candidates that help patients with unmet medical needs.
Potential indications for Syntimmune drug candidates
COMMON INDICATIONS Physiological system Joint rheumatoid arthritis Gastrointestinal ulcerative colitis, Crohn’s disease Systemic lupus family disorders RARE DISEASES Neurological multifocal motor neuropathy, chronic inflammatory demyelinating polyneuropathy (CIDP), myasthenia gravis Dermatological dermatomyositis, pemphigus, pemphigoid Hematological antiphospholipid syndrome (APS), autoimmune hemolytic anemia (AIHA), thrombotic thrombocytopenia purpura (TTP) heparin-induced thrombocytopenia (HIT), idiopathic thrombocytopenic purpura (ITP) SUPERORPHAN DISEASES Various glomerulonephritis, Goodpasture’s disease, stiff person syndrome