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The enzymatic activity of
antibodies produced by certain hemophilia A patients seems to explain
their resistance to treatment. These are the conclusions of the work conducted
by Sébastien Lacroix-Desmazes and Srini Kaveri (CNRS/ Inserm Unit
430 directed by Michel Kazatchkine), whose results were published this
week in the New England Journal of Medicine. Hemophiliacs are unable
to synthesize a protein called factor VIII, which is necessary for
the coagulation of blood. Sébastien Lacroix-Desmazes and his colleagues
have shown that patients who become resistant to factor VIII replacement
therapy produce antibodies with an enzymatic activity capable of destroying
this factor. A better understanding of this mechanism should enable the
development of more targeted treatment strategies for hemophilia patients.
Hemophilia, a genetic disorder
that is passed from mother to child, is characterized by severe hemorrhaging.
It is due to a defect in the production of a blood coagulation factor
known as factor VIII. The level of this factor in the blood (the complete
or partial lack thereof) determines the severity of the diseaseŅeither
severe or moderate hemophilia. Treatment consists of giving patients infusions
of replacement factor VIII. However, between 20 to 50% of patients with
severe hemophilia, and 5 to 15% of those with moderate to mild hemophilia,
develop factor VIII antibodies (or factor VIII inhibitors) after
the administration of replacement therapy. The antibodies degrade the
factor VIII and nullify the therapeutic benefits of replacement therapy.
Three years ago, the same team demonstrated that with severe hemophilia,
factor VIII antibodies managed to inactivate the coagulation factor
by chemically dismantling it. This inhibiting mechanism by enzymatic cleavage
(or hydrolysis) offers a different explanation in addition to those proposed
to date, including the inhibition of the effect of factor VIII by
the obstruction of its binding sites. With this study, the researchers
demonstrate that this new type of antibody functions like an enzyme.
To determine the role this inhibiting mechanism plays with respect to
the others in the resistance that some hemophiliacs develop subsequent
to factor VIII replacement therapy, the researchers studied a group
of 24 patients with severe hemophilia A, who, following factor VIII
replacement therapy, had developed factor VIII inhibitory antibodies.
Sébastien Lacroix-Desmazes and his colleagues detected enzymatic
activity in the factor VIII inhibitory antibodies in the blood of
13 of the 24 patients tested (54% of all cases). Their analyses showed
a significant correlation between the rate of enzymatic cleavage of factor VIII
and the factor VIII inhibiting activity measured in the plasma of
the patients.
Thus, this catalytic mechanism is very likely implicated in the factor VIII
inhibiting process.
Hemophilia appears to be the first example in human pathology in which
a link is established between hydrolysis of target molecule (the coagulation
factor) by catalytic antibodies and the appearance of clinical symptoms.
The researchers are now working to develop monoclonal catalytic antibodies
(immunoglobulins), specific factor VIII inhibitors, that would directly
target this factor.
The goal is to better "dissect" the factor VIII cleavage
mechanism of the catalytic antibodies so as to identify the specific cleavage
sites of the immunoglobulins responsible for this catalytic activity.
Ultimately, it is hoped that therapeutic molecules may be found that could
act directly on cleavage sites to inhibit the activity of antibodies against
factor VIII in patients with hemophilia A.
Reference
Lacroix-Desmazes S.(1), Bayry J.(1), Misra N.(1), Horn M.P.(1), Villard
S.(2), Pashov A.(1), Stieltjes N.(3), d’Oiron R.(4), Saint-Remy J.-M.(5),
Hoebeke J.(6), Kazatchkine M.D.(1), Kaveri S.V.(1). The prevalence of
proteolytic antibodies against factor VIII in patients with hemophilia A
and factor VIII inhibitors. The New England Journal of Medicine,
346, 9, February 28, 2002.
(1) Inserm Unit 430,
Hôpital Broussais, Paris.
(2) CNRS UMR5094, Faculté de Pharmacie, Montpellier.
(3) Centre des Hémophiles, Hôpital Cochin, Paris.
(4) Centre d'Hémophiles, Hôpital Bicêtre, Paris.
(5) Center for Molecular and Vascular Biology, Katholieke Universiteit
Leuven, Belgium.
(6) UPR 9021 CNRS, IBMC, Strasbourg.
Researcher
Contacts:
Sébastien Lacroix Desmazes
Srini V. Kaveri
Tel: +33 1 43 95 95 89 (or 63)
Fax: +33 1 45 45 90 59
E-mail: sebastien.lacroix@brs.ap-hop-paris.fr
srini.kaveri@brs.ap-hop-paris.fr
CNRS Department of Life Sciences, Communications Contact
Marie-Pascale Corneloup-Brossollet
Tel: +33 1 44 96 46 48
Fax: +33 1 44 96 49 19
E-mail: marie.corneloup@cnrs-dir.fr
CNRS Press contact :
Martine Hasler
Tel : +33 1 44 96 46 35
E-mail : martine.hasler@cnrs-dir.fr
Inserm Press Contact:
Séverine Ciancia
Tel: +33 1 44 23 60 86
E-mail: ciancia@tolbiac.inserm.fr
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