DEVELOPMENT OF AN ANTIGEN-SPECIFIC B-CELL TOLERAGEN FOR THE TREATMENT OF ANTIPHOSPHOLIPID SYNDROME.

Keith Cockerill, G. Michael Iverson, David Jones, Edward Victoria, David Marquis, Matthew Linnik.

La Jolla Pharmaceutical Company, San Diego, CA 92121

Antiphospholipid antibodies (aPL) are associated with stroke, deep vein thrombosis, myocardial infarction and recurrent fetal loss in a condition known as Antiphospholipid Syndrome (APS). APL's have been implicated at several points in the clotting cascade, including causing a delay in the inactivation of procoagulant factor Va. This suggests a direct involvement of aPL in thrombus formation. Our goal is to develop an antigen-specific B-cell toleragen that reduces pathogenic antibody levels thereby normalizing coagulation function in patients with APS. We show that aPL from patient sera recognize antigenic epitopes on domain 1 (D1) of the plasma protein b2-glycoprotein I. To create a prototype therapeutic toleragen we chemically conjugated recombinant D1 to a tetravalent synthetic platform. In an ex vivo tolerance model using spleen cells from mice immunized with D1-KLH, the tetravalent domain 1 conjugate specifically reduces anti-D1 antibody levels in a dose-dependent manner. Treatment of APS patient sera with the conjugate immunoprecipitates Ig and normalizes factor Va activity in coagulation assays. We conclude that an antigen-specific B-cell toleragen may be developed to reduce pathogenic antibodies in patients with APS.

Presented at the 25th Annual Conference of the La Jolla Immunologists, La Jolla, CA., Nov. 8-9, 1999.