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J. Biol. Chem., Vol. 279, Issue 39, 40445-40450, September 24, 2004

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An Antibody Specific for Coagulation Factor IX Enhances the Activity of the Intrinsic Factor X-activating Complex^*

Randolf J. Kerschbaumer, Klaudia Riedrich, Martina Kral, Katalin Varadi, Friedrich Dorner¶, Jan Rosing||, and Friedrich Scheiflinger**

From the Pre-Clinical Product Development, Baxter BioScience, Biomedical Research Center, A-2304 Orth/Donau, Austria, Vascular Biology, Baxter BioScience, A-1220 Vienna, Austria, ^¶Global R&D, Baxter BioScience, A-1220 Vienna, Austria, and ^||Cardiovascular Research Institute Maastricht, Maastricht University, 6200MD Maastricht, The Netherlands

During hemostasis the zymogen factor X (FX) is converted into its enzymatically active form factor Xa by the intrinsic FX-activating complex. This complex consists of the protease factor IXa (FIXa) that assembles, together with its cofactor, factor VIIIa, on a phospholipid surface. We have studied the functional properties of a FIXa-specific monoclonal antibody, 224AE3, which has the potential to enhance intrinsic FX activation. Binding of the antibody to FIXa improved the catalytic properties of the intrinsic FX-activating complex in two ways: (i) factor VIIIa bound to the FIXa-antibody complex with a more than 18-fold higher affinity than to FIXa, and (ii) the turnover number (k_cat) of the enzyme complex increased 2- to 3-fold whereas the K_m for FX remained unaffected. The ability of 224AE3 to increase the FXa-generation potential (called the "booster effect") was confirmed in factor VIII (FVIII)-depleted plasma, which was supplemented with different amounts of recombinant FVIII. In the presence of antibody 224AE3 the coagulant activity was increased 2-fold at physiological FVIII concentration and up to 15-fold at low FVIII concentrations. The booster effect that we describe demonstrates the ability of antibodies to function as an additional cofactor in an enzymatic reaction and might open up a new principle for improving the treatment of hemophilia.

Received for publication, May 28, 2004 , and in revised form, July 6, 2004.

^* 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.

^** To whom correspondence should be addressed: Baxter BioScience, Biomedical Research Center, Uferstrasse 15, 2304 Orth/Donau, Austria. Tel.: 43-1-20100-3410; Fax: 43-1-20100-4679; E-mail: scheiff{at}baxter.com.

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