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Blood, 1 April 2004, Vol. 103, No. 7, pp. 2617-2623.
Prepublished online as a Blood First Edition Paper on December 11, 2003; DOI 10.1182/blood-2003-07-2207.
Submitted July 3, 2003
Accepted November 17, 2003
In vivo neutralization of C2 domain specific human anti-Factor VIII by an anti-idiotypic antibody
Jean Guy G Gilles*, Sabrina C Grailly, Marc A De Maeyer, Marc G Jacquemin, Luc P VanderElst, and Jean-Marie R Saint-Remy
Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium
Laboratorium Biomoleculaire Modelling, University of Leuven, Leuven, Belgium
* Corresponding author; email: jeanguy.gilles{at}med.kuleuven.ac.be.
Factor VIII (FVIII) administration elicits specific inhibitory Abs in about 25% of hemophilia A patients. The majority of such Abs react with FVIII C2 domain. mAbBO2C11 is a high-affinity human mAb directed towards the C2 domain, which is representative of a major class of human FVIII inhibitors. Anti-idiotypic Abs were raised to mAbBO2C11 to establish their neutralizing potential towards inhibitors. One mouse anti-idiotypic mAb, mAb14C12, specifically prevented mAbBO2C11 binding to FVIII C2 domain and fully neutralized mAbBO2C11 functional inhibitory properties. Modeling of the 3D conformation of mAb14C12 VH and alignment with the 3D structure of the C2 domain showed putative 31 surface-exposed aminoacid residues either identical or homologous to the C2 domain. These included one C2 phospholipid-binding site, Leu2251-Leu2252, but not Met2199-Phe2200. Forty putative contact residues with mAbBO2C11 were identified. mAb14C12 dose-dependently neutralized mAbBO2C11 inhibitory activity in hemophilia A mice reconstituted with human recombinant FVIII (rFVIII), allowing full expression of FVIII activity. It also neutralized in an immunoprecipitation assay ~50% of polyclonal anti-C2 Abs obtained from 3 out of 6 unrelated patients. mAb14C12 is the first example of an anti-idiotypic Ab that fully restores FVIII activity in vivo in the presence of an anti-C2 inhibitor. The present results establish the in vitro and in vivo proof of concept for idiotype-mediated neutralization of a major class of FVIII inhibitors.
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