title: Enzymatically active ADAMTS13 variants are not inhibited by anti-ADAMTS13 autoantibodies: a novel therapeutic strategy?
abstract: ADAMTS13 (a disintegrin and metalloprotease with thrombospondin motifs), a circulating multidomain zinc metalloprotease of the reprolysin subfamily, is critical for preventing von Willebrand factor-platelet interaction under high shear stress conditions. A deficiency of the protease, due to mutations in the ADAMTS13 gene or the presence of antibodies that inhibit the activity of the protease, causes thrombotic thrombocytopenic purpura (TTP). Plasma therapy, the conventional therapy for TTP, may cause serious adverse reactions and is ineffective in some patients. In order to develop new strategies for improving the diagnosis and treatment of TTP, we produced a series of truncated ADAMTS13 proteins in mammalian cells and analyzed their binding with and suppression by the IgG derived from the TTP patients. The results revealed that truncation of the ADAMTS13 protein at its cysteine-rich region eliminated its recognition by the antibodies without abolishing its von Willebrand factor-cleaving activity. This raises the possibility that resistant ADAMTS13 variants may be exploited to circumvent inhibitory antibodies that cause TTP.
authors.affiliation: Division of Hematology, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York 10467, USA.
authors.forename: Wenhua
authors.initials: W
authors.lastname: Zhou
authors.forename: Lingli
authors.initials: L
authors.lastname: Dong
authors.forename: David
authors.initials: D
authors.lastname: Ginsburg
authors.forename: Eric E
authors.initials: EE
authors.lastname: Bouhassira
authors.forename: Han-Mou
authors.initials: HM
authors.lastname: Tsai
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics*; D000071120:ADAMTS13 Protein; D000818:Animals; D001323:Autoantibodies / Q000737:chemistry*; D001792:Blood Platelets / Q000378:metabolism; D019556:COS Cells; D002522:Chlorocebus aethiops; D003545:Cysteine / Q000737:chemistry; D017931:DNA Primers / Q000737:chemistry; D006801:Humans; D007074:Immunoglobulin G / Q000737:chemistry; D047468:Immunoprecipitation; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011697:Purpura, Thrombotic Thrombocytopenic / Q000175:diagnosis / Q000628:therapy; D011994:Recombinant Proteins / Q000737:chemistry; D013696:Temperature; D013997:Time Factors; D014841:von Willebrand Factor / Q000378:metabolism
chemical_list: D001323:Autoantibodies; D017931:DNA Primers; D007074:Immunoglobulin G; D011994:Recombinant Proteins; D014841:von Willebrand Factor; D051722:ADAM Proteins; D000071120:ADAMTS13 Protein; C099604:ADAMTS13 protein, human; D003545:Cysteine