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 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 inflammatory diseases. The lead indications for SelK2 are asthma, a common chronic inflammatory disease of the lungs characterized by episodes of wheezing, breathlessness, chest tightness, and cough; and chronic obstructive pulmonary disease (COPD), a disease triggered when foreign particulate matter such as that produced from cigarette smoke leads to the recruitment of inflammatory cells to the bronchial wall and lumen resulting in progressive loss of lung function.
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 asthma and COPD.
Asthma and COPD
Asthma is a common chronic inflammatory disease of the lungs characterized by episodes of wheezing, breathlessness, chest tightness, and cough, and the disease is often associated with eosinophil-rich airway inflammation. Airway eosinophilia is associated with asthma exacerbations and has been shown to play a role in airway remodeling.
Chronic obstructive pulmonary disease (COPD) represents one of the leading causes of death worldwide, and there are few effective therapies. In COPD, foreign particulate matter such as that produced from cigarette smoke leads to the recruitment of inflammatory cells to the bronchial wall and lumen resulting in progressive loss of lung function. Neutrophilia is a hallmark of COPD and neutrophils are thought to be the key inflammatory cell in the pathogenesis of the disease.
Role of PSGL-1 in Asthma and COPD
The induction and maintenance of inflammation in asthma and COPD are mediated by the recruitment and extravasation of inflammatory cells including eosinophils and neutrophils from the pulmonary circulation to the airways. The initial step in this process involves the tethering and rolling of these cells on the endothelium, mediated by PSGL-1/selectin binding. Alternatively, the binding of activated platelets to PSGL-1 on eosinophils and the subsequent activation of additional adhesion molecules that participate in extravasation have also been implicated. Therefore, PSGL-1/selectin inhibition is a viable therapeutic strategy in the modulation of leukocyte extravasation into the airways in asthma and COPD. Indeed, bimosiamose, a small molecule inhibitor of PSGL-1/selectin interactions, has been shown to significantly reduce the fall in FEV1 during the late phase allergic response in a clinical study. Bimosiamose also led to an attenuation of airway inflammation including a decrease in IL-8, neutrophils and macrophages in patients with COPD. Taken together, these data provide an important proof of principle for selectin directed therapies in respiratory diseases. It is anticipated that the potent PSGL-1 inhibitor SelK2 will prevent extravasation of inflammatory cells into the airways of the lung in patients with allergic asthma and COPD.