Inhibition of thrombotic properties of persistent autoimmune anti-β2GPI antibodies in the mouse model of antiphospholipid syndrome.

Antiphospholipid syndrome (APS) is an autoimmune disorder with increased risk for thrombosis and pregnancy losses. β2-glycoprotein I (β2GPI) is the major antigen for clinically relevant antibodies in APS. We engineered a molecule, A1-A1, which interferes with 2 prothrombotic mechanisms in APS: the binding of β2GPI to negatively charged cellular surfaces and ApoE receptor 2. We studied how A1-A1 affects arterial thrombosis in vivo in lupus-prone (NZW × BXSB)F1 male mice. For the first time, we demonstrated that A1-A1 efficiently reduces thrombus size in vivo in the presence of chronic autoimmune anti-β2GPI antibodies. We have shown that A1-A1 interferes with thrombotic properties of β2GPI/antibody complexes and does not affect normal thrombus formation in the absence of anti-β2GPI antibodies. A1-A1 inhibits prothrombotic properties of β2GPI/antibody complexes in wild-type mice after acute infusion with anti-β2GPI antibodies, as well as in mice expressing persistent autoimmune anti-β2GPI antibodies. A1-A1 reduced thrombus size in a mouse model of APS in the presence of lupus features, suggesting that A1-A1 might effectively interfere with thrombosis not only in primary APS but also in APS secondary to lupus. Our results suggest that A1-A1 could be a prototype for an antithrombotic drug in APS.