A Monoclonal Anti-C5 Antibody Reverses Antiphospholipid Antibody-mediated Thrombosis

Abstract number: OR352

Pierangeli SS, Girardi G, Vega-Ostertag ME, Liu X, Salmon J

We showed that antiphospholipid (aPL)-mediated thrombosis and pregnancy loss are significantly reduced in mice deficient in C3 and C5 complement. We hypothesized that activation of C5 is required for aPL-induced thrombosis. To test this hypothesis, we used an in vivo model of induced thrombosis and vascular injury. We injected CD1 mice with IgG containing aPL(aPL-IgG) (500 µg IP) or control human IgG (IgG-NHS) at time 0 and 48 h. Thirty minutes after each injection with IgG, mice were injected with either 1 mg anti-C5 monoclonal antibody (anti-C5-MoAb) or with a control MoAb. Thrombus dynamics was examined 72 hours after the first injection.

Results:  

In aPL-IgG + control MoAb-treated mice, we observed a significant increase in the size of thrombi compared to mice treated with IgG-NHS and control MoAb (3577.0 ± 1129.0 µm² vs 712.0 ± 272.0 µm²; P = 0.0001). In contrast, when aPL-IgG-treated mice were injected anti-C5 MoAb antibodies, thrombus size was significantly lower than in aPL and control MoAb-treated mice (838.0 ± 222.0 µm² vs 3577.0 ± 1129.0 µm²; P = 0.00005) and not different from mice treated with IgG-NHS and control MoAb or IgG-NHS and anti-C5 MoAb (712.0 ± 272.0 µm² vs 797.0 ± 227.0 µm²). The levels of human aCL antibodies in mice injected with aPL were similar (152.2 ± 14.8 GPL and 135.3 ± 20.3 GPL) in IgG-aPL and control MoAb-treated mice and in IgG-aPL and anti-C5 MoAb-treated mice, respectively. Complement C5 activation is necessary for induction of thrombotic complications by aPL in mice. Complement may be then identified as an important new target for therapy in patients with thrombotic and vascular complications of Antiphospholipid Syndrome (APS). Clinical studies will be needed to confirm these findings in humans.