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J. Biol. Chem., Vol. 280, Issue 48, 39934-39941, December 2, 2005

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Enzymatically Active ADAMTS13 Variants Are Not Inhibited by Anti-ADAMTS13 Autoantibodies

A NOVEL THERAPEUTIC STRATEGY?^*

Wenhua Zhou, Lingli Dong, David Ginsburg, Eric E. Bouhassira¶, and Han-Mou Tsai1

From the Division of Hematology, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York 10467, the Departments of Genetics and Internal Medicine, Howard Hughes Medical Institute and Life Sciences Institute, University of Michigan, Ann Arbor, Michigan, 48109, and ^¶Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York 10461

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.

Received for publication, May 4, 2005 , and in revised form, August 22, 2005.

^* This study was supported by National Institutes of Health Grants R01HL62136 and R01HL72876. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Division of Hematology, Montefiore Medical Center, 111 E. 210th St., Bronx, NY 10467. Tel.: 718-920-4410; Fax: 78-881-7108; E-mail: htsai{at}montefiore.org.

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