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Centre Hospitalier Universitaire Reims, Laboratoire d’Immunologie, Unité de Formation et de Recherche Médecine Université de Reims Champugne Ardennes, Pôle Biomolécules IFR53 Reims, France;
Centre National de Référence des Groupes Sanguins, Institute National de Transfusion Sanguine, Paris, France; and
Laboratoire de Biologie et Thérapeutique des Pathologies Immunitaires, Equipe de Recherche Associée 7087, Université Pierre et Marie Curie, Centre National de la Recherche Scientifique, Centre l’etude et de Recherche en Virologie et Immunologie, Paris, France
CR1 (CD35, the C3b/C4b receptor) is a widely distributed membrane
glycoprotein with a unique cluster conformation on the surface of
erythrocytes (E). CR1 on E is responsible for the transport of immune
complexes (IC) to liver and spleen. As a cofactor of the C3b cleavage
by factor I, CR1 is also a potent inhibitor of C activation and
inflammation. In some diseases (systemic lupus erythematosus, hemolytic
anemia, AIDS, etc.) an acquired low level of CR1 on E has been
observed, leading to an impaired clearance of IC. The aim of this study
was to design a heterofunctional molecule that will bind to E and
restore a normal or a supranormal CR1 density on E that could mimic the
unique distribution pattern of CR1 on normal E. For that purpose a new
multimerizing system based on the properties of the C-terminal part of
the 
-chain of the C4 binding protein (C4bp) was used. We first
produced a multimeric soluble CR1 that proved to be a better inhibitor
of in vitro C activation than the monomeric form of CR1, then a
heteromultimeric molecule made of CR1 and single-chain Fv
anti-Rh(D) valences able to attach E and providing E with as much
as a 10-fold increase in CR1 density with the same CR1 distribution
pattern as native E. CR1/single-chain Fv anti-Rh(D)-treated E were
able in vitro to attach as many opsonized IC as native E. These data
open the way for future use of multimeric and heteromultimeric forms of
soluble recombinant CR1 as therapy of IC
diseases.
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