About the Company
Selexys Pharmaceuticals Corporation (Selexys) is a privately held company that is developing drugs to treat inflammatory and thrombotic diseases. We are targeting the underlying disease mechanism for these disorders. Our target is the adhesion of white blood cells to sites of inflammation mediated by the binding of two proteins, P-selectin and PSGL-1. The company is in preclinical development of humanized antibodies to P-selectin and PSGL-1 for the treatment of acute and chronic inflammatory and thrombotic disorders. Unregulated inflammatory processes play a major role in the harmful effects of multiple inflammatory disorders.
Chronic Inflammatory Diseases
- Crohn’s Disease
- Ulcerative colitis
- Rheumatoid arthritis
- psoriasis
- asthma, allergic reactions
- cutaneous vasculitis
- chronic obstructive pulmonary disease (COPD)
Ischemia reperfusion injury
- Delayed graft function in organ transplantation
- Heart attack, stroke
Vasoocclusion and thrombosis
- Vasoocclusive pain crisis in sickle cell disease
- Deep venous thrombosis
Stenosis and Restenosis
- Coronary artery bypass graft, stent placement, endarterectomy
- Formation of atherosclerotic plaques
An Overview of Inflammation
Inflammation is the accumulation of white blood cells at sites of injury or infection. Normally the white blood cells release enzymes that destroy pathogens and remodel tissues to repair injury. In inflammatory diseases too many white blood cells accumulate and their destructive power is unleashed on the body's own tissues. Selexys antibodies target and block this first step in inflammation, the adhesion of white blood cells.
Adhesion of White Blood Cells to Sites of Inflammation
This process involves the interaction of a protein called P-selectin and its counter-receptor on white blood cells called PSGL-1. In inflammatory disorders, P-selectin is moved to the surface of endothelial cells and platelets where it can bind to PSGL-1. This causes white blood cells to bind to the site and results in damage to cells and tissues that would otherwise be healthy. P-selectin is very specific to the site and is the initial trigger for multiple complex downstream mediators of inflammation. With P-selectin antagonists, Selexys has the advantage of blocking this process early and preventing or mitigating the effect of unregulated downstream processes.
P-selectin Function in Inflammatory and Thrombotic Diseases
Selectins are required for normal homeostatic responses to infection and inflammation. However, their expression also contributes to undesirable recruitment of leukocytes. Dysregulated expression of P-selectin is a major contributor to many of these disorders. This conclusion is based on a large number of studies in animal models over the past 15 years that have used blocking monoclonal antibodies to P-selectin or genetically engineered mice that lack P-selectin to understand P-selectin function. Over a thousand publications in recent years have documented the contribution of P-selectin to tissue and organ damage associated with inflammation. These studies demonstrate that excessive leukocyte recruitment leads to inflammatory and thrombotic injury in a variety of diseases and that blocking this process has major therapeutic potential.
In many animal models of ischemia-reperfusion injury, P-selectin inhibitors, most commonly antibodies, are given at the time of reperfusion, which is clinically relevant to interventions in patients. For example, blocking P-selectin function markedly reduces tissue damage in many models of ischemia-reperfusion injury that are relevant to myocardial infarction, stroke, and acute and delayed organ transplant rejection. Monoclonal antibodies to P-selectin reduce both leukocyte accumulation and thrombus formation in rat and baboon models of deep venous thrombosis (DVT), and accelerate pharmacological thrombolysis in primate models of arterial thrombosis.
Other P-selectin inhibitors have produced similar results. Recombinant PSGL-Ig (rPSGL-Ig) was used successfully to treat established DVT in baboons. It was also shown that rPSGL-Ig decreased post-thrombotic vein wall fibrosis in established DVT in rats. A small-molecule selectin inhibitor reversed inflammation in two different animal models of established inflammatory skin disease. In another clinically relevant study, P-selectin inhibitors used at time of organ transplantation improve organ function and reduce rejection. In a baboon model of occlusive venous thrombosis, administration of rPSGL-Ig chimera as an antagonist to P-selectin successfully treated the established venous thrombosis without anticoagulation. In another study, rPSGL-Ig also effectively suppressed progression of clinical arthritis, and this was accompanied by protection against damage of joint tissues, possibly by reducing TNF production from inflammatory cells in the synovium. This is overwhelming evidence that P-selectin is a major target for intervention in human inflammatory and thrombotic diseases.
The Role of P-selectin in Vasoocclusion in Sickle Cell Disease
Sickle cell disease is an orphan drug indication with major unmet needs. Patients with sickle cell anemia suffer vasoocclusive complications in which sickled red cells clump and adhere to small vessels blocking blood flow (ischemia) to downstream organs. This causes patients intense pain and repeated hospitalizations. It also leads to progressive multi-organ dysfunction and premature death. There are no effective treatments for ongoing crisis in sickle cell patients.
Murine models of sickle cell anemia have been developed by introduction of transgenes for the human globin proteins, one of which has the mutation found in sickle cell anemia. These mice have sickled red cells and develop vasoocclusive complications. The adherence of sickle red blood cells to the vascular endothelium contributes to vasoocclusion observed in sickle cell disease. In genetically-engineered mice used as a model for human sickle cell disease, there is a selectin-dependent recruitment of leukocytes to inflamed microvessels, where they interact with sickled red cells. Sickle cell mice exposed to hypoxia followed by reoxygenation had higher leukocyte rolling and lower red blood cell velocities in small vessels compared to controls. Injection of an anti-P-selectin monoclonal antibody at the time of reoxygenation not only prevented the increase in these parameters, it also reduced leukocyte rolling and increased red blood cell velocities to levels that approached those in unchallenged control mice. This indicates leukocyte adhesion is reversible by a P-selectin antibody therapy resulting in improved microcirculatory blood flow. Sickle cell disease also promotes increased P-selectin expression in several vascular beds and blocking monoclonal antibodies to P-selectin inhibits the enhanced adherence of normal and sickle red blood cells to thrombin-treated endothelial cells. Several studies using P-selectin-knockout mice have shown that endothelial cell P-selectin contributes to the microcirculatory abnormalities in sickle cell disease.
This evidence strongly supports the development of antibody technology to block P-selectin as a mechanism for preventing or reducing painful vasoocclusion crisis in sickle cell disease. Selexys has rights to develop these technologies and we have preclinical programs underway to address this need.
If you would like to learn more about these studies or discuss partnering or license opportunities, please contact us.