Specific Destruction of B Cells Producing Anti-β2-GPI Antibodies: a Novel Therapy for Antiphospholipid Syndrome

Antiphospholipid syndrome (APS) is a systemic autoimmune disorder defined by the presence of distinct clinical features such as excessive clotting events and autoantibodies against phospholipids. In women, complications include recurrent miscarriages. The disease can be mild, but can also develop into Catastrophic Antiphospholipid Syndrome in which there is a storm of coagulation and mortality is about 50%.

It is now understood that most of the “Antiphospholipid” antibodies target β2-Glycoprotein (β2-GPI) - a serum protein that binds anionic phospholipids on cell membranes. This protein exists in two conformations in the body. In serum, domain 1 of the protein interacts with its domain 5 resulting in circularization of the protein; when bound to anionic phospholipids the protein remains “open” exposing epitopes in domain 1 recognized by anti- β2-GPI antibodies. Antibody binding appears to activate the coagulation system resulting in thrombosis. If this occurs in the placenta it may lead to complications of pregnancy, including premature birth.

The current treatment for APS is anticoagulant (warfarin, heparin) and anti-platelet (aspirin) therapy which only deal with some of the symptoms and are unacceptable as long term therapies. We decided to take a novel approach to developing a safer and more effective drug that prevents anti-β2-GPI binding to β2-GPI and may also be used to deliver a cytotoxin to the B-cells producing the anti-β2-GPI antibodies, thus potentially curing the disease. We have used Phage display to find peptides that specifically inhibit the bond between the autoantibodies and β2-GPI and other peptides that bind specifically to anti-β2-GPI.