- Our Science
Syntimmune builds on more than 25 years of proven science that has identified many of FcRn’s functions.
The neonatal crystallizable fragment receptor – referred to as FcRn — was initially thought to exist only in newborn rodents. It is now understood to be expressed throughout human life. This protein plays a critical role in regulating certain serum proteins, including Immunoglobulin G (IgG) and albumin.
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 the interaction of FcRn with IgG has broad potential applicability.
Research that began more than 25 years ago by our founders and advisors who are leading authorities in FcRn science has, in recent years, culminated in significant mechanistic insights into the role of FcRn in immune-mediated diseases. Many of these concepts have now advanced 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 contributor to these diseases by inappropriately attacking normal cells. Examples of such diseases include systemic lupus erythematosus, inflammatory bowel disease, rheumatoid arthritis and Sjögren’s syndrome. Pathogenic IgG also becomes the dominant driver in many diseases, including pemphigus and warm autoimmune hemolytic anemia. These diseases can be chronic and life-threatening. But there has never been a therapeutic agent approved that specifically targets IgG.
Among its functions, FcRn regulates IgG homeostasis and the ability of IgG as immune complexes to engage innate and adaptive immune responses that are inflammatory. Pathogenic IgG antibodies promote many autoimmune diseases. Therefore, our ability to precisely interrupt IgG interactions with FcRn and dismantle and eliminate the inflammatory activities of this immunoglobulin class has profound implications for the treatment of numerous diseases. In preclinical and early stage clinical studies to date, SYNT001 appeared safe, with rapid onset of clinically meaningful IgG blockade.
Blockade with SYNT001
FcRn has multiple roles in IgG biology. It maintains the circulating levels of IgG and regulates the ability of IgG to mediate inflammation. This makes FcRn a key determinant of IgG-mediated autoimmune 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 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 cardiovascular 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 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 IgG-mediated diseases is simple and elegant.
SYNT001 binds to FcRn specifically at the site where IgG interacts with this receptor. SYNT001 has thus been engineered to block IgG interactions with FcRn and disable FcRn-mediated rescue of IgG and the ability of IgG as an immune complex to trigger innate and adaptive immune functions associated with inflammation. Preclinical and early clinical studies have shown that SYNT001 facilitates clearance of IgG, including its pathogenic forms, and reduces IgG- associated inflammation. Further, SYNT001 accomplishes its effects on IgG without destroying immune cells, impacting other types of immunoglobulin or affecting the levels of albumin, a second substrate for FcRn.
Other Syntimmune drug candidates work in similar fashion. For instance, in preclinical models, SYNT002 blocks albumin’s interactions with FcRn and decreases the levels of albumin-bound toxins without affecting IgG. This gives Syntimmune’s pipeline of drug candidate’s broad applicability and specificity.
FcRn’s ROLE IN REGULATING ALBUMIN
In addition to its critical role in regulating IgG and immune processes, 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 by hepatocytes. Research shows that FcRn plays a key role in directing and maintaining albumin in the bloodstream. FcRn also scavenges albumin from excretion in the kidney and liver. A pivotal insight from the groundbreaking work of the Syntimmune team is that blocking the interaction between FcRn and albumin interrupts this process.
When FcRn is absent or blocked, albumin levels in the bloodstream decrease and albumin is lost into the bile and urine. This allows for more albumin and albumin-bound complexes to be excreted. Using acetaminophen as a model for albumin-bound drugs, it was shown that SYNT002, Syntimmune’s proprietary monoclonal antibody that blocks albumin interactions with FcRn, cleared acetaminophen from the circulation and protected the liver from toxicity. This model indicates the potential for SYNT002 to facilitate the clearance of albumin-bound endo- and exotoxins and protect end-organ tissues.
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.
FcRn’s key role in regulating 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 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 trafficking and signaling receptor. The chart below shows just some of the autoimmune diseases for which 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)