OC 08.1 - GC1126A, a novel ADAMTS13 mutein that evades autoantibody as a superior therapy for acquired thrombotic thrombocytopenic purpura (aTTP)

Background: Acquired thrombotic thrombocytopenic purpura (aTTP) is a rare, life-threatening blood disorder that forms blood clots in small blood vessels. aTTP occurs when the body starts producing antibodies that block the enzyme called ADAMTS13, which plays a role in the cleavage of von Willebrand factor (vWF). ADAMTS13 autoantibodies of aTTP patients’ plasma recognize epitopes in all ADAMTS13 domains and most patients have autoantibodies against the cysteine-rich and spacer domains.

Aims: This study aims to identify the ADAMTS13 muteins resistant to ADAMTS13 autoantibodies and to evaluate variants via in vitro, in vivo and ex vivo studies.

Methods: We generated mutein panels using an ADAMTS13 crystal structure by Molecular Dynamics simulation, 3D point cloud scanning and direct evolution method. Variants were screened with autoantibody binding and ADAMTS13 activity assays. Selected muteins were further evaluated pharmacodynamic biomarkers and pharmacokinetics properties in aTTP-mimic mouse model and C57BL/6 mice, respectively. Ex vivo study was performed using Korean aTTP patients’ plasma.

Results: GC1126A was the most effective variant with escaping autoantibodies and had a longer half-life than controls. In aTTP-mimic mouse model, GC1126A-treated group showed dramatic recovery of platelet counts and LDH levels with higher residual activity of ADAMTS13. In addition, GC1126A improved platelet recovery at a low dose compared to ADAMTS13 or Cablivi, showing more prolonged effectiveness than Cablivi. For the preliminary result of ex vivo study using aTTP patients’ plasma samples, GC1126A exhibited higher residual activity in aTTP patient plasma compared to ADAMTS13 and this effect seemed to be more observable with high titer autoantibodies.

Conclusion(s): Our data showed that a novel recombinant protein GC1126A recovers PD biomarkers by evading ADAMTS13 autoantibodies through in vitro and in vivo studies and remains higher ADAMTS13 residual activity in aTTP patients’ plasma. GC1126A could be a potential new therapeutic treatment option for aTTP patients.