Our clinical development programs are supported by discoveries made by our co-founding scientists who leveraged decades of continuous funding from the National Heart Lung and Blood Institute at the NIH to define and characterize selectin/receptor-mediated cell adhesion and its roll in inflammatory diseases. But this is only part of the story. Work at research institutions around the globe built on these early discoveries continues to further our understanding of these adhesion molecules and their importance in human disease. For Tetherex, this substantial body of work lays the foundation for developing new therapies with the potential for treating thrombotic and inflammatory diseases by blocking PSGL-1 function. Tetherex's lead clinical development program is advancing a humanized monoclonal antibody called SelK2, which targets PSGL-1 and blocks its interactions with both the selectin family of molecules and chemokines involved in unregulated inflammatory responses in thromboembolic and inflammatory diseases. The lead indications for SelK2 are venous thromboembolism, a blood clot occurring inside a vein, with more than 10 million cases worldwide and approximately 350,000 deaths per year in the U.S. alone and Crohn's disease, an inflammatory bowel disease with major unmet needs that severely affects more than 500,000 patients in the U.S.
About the Investigational Drug SelK2
SelK2 is a humanized monoclonal antibody that binds PSGL-1 with high affinity and specificity and blocks its ability to interact with P- and L-selectin as well as its ability to bind chemokines. Tetherex is currently developing SelK2 in both venous thromboembolism and Crohn's disease.
Deep vein thrombosis and pulmonary embolism are collectively referred to as venous thromboembolism (VTE). Venous thromboembolism is a major medical burden affecting millions of people around the world, with approximately one million cases and 300,000 deaths annually in the U.S. alone. Current therapies available for venous thromboembolism include heparin-based compounds, vitamin K antagonists, and factor Xa inhibitors. These therapies target the coagulation system and can therefore result in the feared complication of hemorrhage, which can sometimes be fatal.
Role of PSGL-1 in Venous Thromboembolism
The relationship between venous thromboembolism and vein wall inflammation has been well established. Further, the importance of PSGL-1/P-selectin in the inflammatory process leading to venous thromboembolism has been confirmed in several nonhuman primate studies. Collectively, these studies indicate that inhibition of PSGL-1 interactions with its selectin ligands results in a decrease in thrombosis, and importantly, in the absence of bleeding complications. The level of reduction in thrombosis resulting from PSGL-1/P-selectin inhibition was similar to that of the low-molecular-weight-heparin enoxaparin, which is known to be associated with bleeding.
During total hip and total knee replacement surgeries, endothelial injury and platelet activation result in the upregulation of selectins and disruption of the regulatory mechanisms of hemostasis. Platelets and the endothelium then participate in the formation of blood clots through receptor interactions with PSGL-1. The use of tourniquet in total knee replacement also causes thrombogenic activity. Tetherex is initially conducting a Phase 2 clinical study to evaluate the effect of SelK2 treatment versus enoxaparin on thrombosis and bleeding in patients undergoing total knee replacement.
Crohn's disease, also known as regional enteritis, is a relapsing inflammatory bowel disease (IBD) characterized by destructive, progressive and segmental damage of the gastrointestinal tract. It can affect any part of the gut and can cause complications in other organ systems. Crohn's disease affects about 3.2 per 1,000 people in Europe and North America, being less common in Asia and Africa.
Abdominal pain is typically the initial symptom of Crohn's disease, which is often accompanied by fever, weight loss, diarrhea, flatulence, and bloating. Bloody bowel movements typically are intermittent but in the setting of severe Crohn's colitis, bleeding is copious. Any part of the digestive tract can be affected by Crohn's disease. It is classified by the specific region of the gut affected and by disease behavior.
Crohn's disease is now viewed as an adaptive autoimmune system disorder where T cell involvement attempts to compensate for a defective innate immune system due to a combination of genetic predisposition, bacterial and environmental factors. There is no current therapy for Crohn's disease that can consistently provide a clinical response or maintain disease remission in all patients. Current treatment options aim to disrupt disease destruction and progression and achieve sustained clinical remission through mucosal healing. There remains significant unmet medical need in patients with Crohn's disease for a drug with an improved clinical safety and efficacy profile relative to the currently approved therapies.
Role of PSGL-1 in Crohn's Disease
Migration and adherence of monocytes and macrophages to activated endothelial cells in the intestinal mucosa is mediated by PSGL-1 binding to P-selectin. P-selectin has been demonstrated to be upregulated in the inflamed tissue of Crohn's disease patients and these inflammatory cells play a major role in the development of mucosal inflammation. In addition to binding to the selectin family of molecules, PSGL-1 binds to chemokines, which control lymphocyte recirculation in immune system homeostasis, and a link between chemokines and Crohn's disease has also been established.
Multiple independent studies in several different animal models of Crohn's disease and other inflammatory bowel diseases demonstrate that PSGL-1, through its interactions with both the selectins and chemokines, plays a pivotal role in the initial and ongoing inflammatory response characteristic of these diseases. The ability of the humanized SelK2 monoclonal antibody to block PSGL-1/selectin interactions as well as to inhibit the addressin properties of PSGL-1 establishes the scientific rationale for pursuing SelK2 for the treatment of Crohn's disease.