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Some factor VIII inhibitor antibodies recognize a common epitope
corresponding to C2 domain amino acids 2248 through 2312, which overlap a
phospholipid-binding site
D Scandella, GE Gilbert, M Shima, H Nakai, C Eagleson, M Felch, R Prescott, KJ Rajalakshmi, LW Hoyer and E Saenko
Holland Laboratory, American Red Cross, Rockville, MD 20855, USA.
The finding that human factor VIII (fVIII) inhibitor antibodies with C2
domain epitopes interfere with the binding of fVIII to phosphatidylserine
(PS) suggested that this is the mechanism by which they inactivate fVIII.
We constructed a recombinant C2 domain polypeptide and demonstrated that it
bound to all six human inhibitors with fVIII light chain specificity. Thus,
some antibodies within the polyclonal anti-light chain population require
only amino acids within C2 for binding. Recombinant C2 also partially or
completely neutralized the inhibitor titer of these plasmas, demonstrating
that anti-C2 antibodies inhibit fVIII activity. Immunoblotting of a series
of C2 deletion polypeptides, expressed in Escherichia coli, with inhibitor
plasmas showed that the epitopes for human inhibitors consist of a common
core of amino acid residues 2248 through 2312 with differing extensions for
individual inhibitors. The epitope of inhibitory monoclonal antibody (MoAb)
ESH8 was localized to residues 2248 through 2285. Three human antibodies
and anti-C2 MoAb NMC-VIII/5 bound to a synthetic peptide consisting of
amino acids 2303 through 2332, a PS- binding site, but MoAb ESH8 did not.
These antibodies also inhibited the binding of fVIII to synthetic
phospholipid membranes of PS and phosphatidylcholine, confirming that the
blocked epitopes contribute to membrane binding as well as binding to PS.
In contrast, MoAb ESH8 did not inhibit binding. As the maximal function of
activated fVIII in the intrinsic factor Xase complex requires its binding
to a phospholipid membrane, we propose that fVIII inhibition by anti-C2
antibodies is related to the overlap of their epitopes with the PS-binding
site. MoAb ESH8 did not inhibit fVIII binding to PS-containing membranes,
suggesting the existence of a second mechanism of fVIII inhibition by
anti-C2 antibodies.
Volume 86,
Issue 5,
pp. 1811-1819,
09/01/1995
Copyright © 1995 by The American Society of Hematology
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