A novel dimeric inhibitor targeting Beta2GPI in Beta2GPI/antibody complexes implicated in antiphospholipid syndrome.

ABSTRACT: ?2GPI is a major antigen for autoantibodies associated with antiphospholipid syndrome (APS), an autoimmune disease characterized by thrombosis and recurrent pregnancy loss. Only the dimeric form of ?2GPI generated by anti-?2GPI antibodies is pathologically important, in contrast to monomeric ?2GPI which is abundant in plasma.We created a dimeric inhibitor, A1-A1, to selectively target ?2GPI in ?2GPI/antibody complexes. To make this inhibitor, we isolated the first ligand-binding module from ApoER2 (A1) and connected two A1 modules with a flexible linker. A1-A1 interferes with two pathologically important interactions in APS, the binding of ?2GPI/antibody complexes with anionic phospholipids and ApoER2. We compared the efficiency of A1-A1 to monomeric A1 for inhibition of the binding of ?2GPI/antibody complexes to anionic phospholipids. We tested the inhibition of ?2GPI present in human serum, ?2GPI purified from human plasma and the individual domain V of ?2GPI. We demonstrated that when ?2GPI/antibody complexes are formed, A1-A1 is much more effective than A1 in inhibition of the binding of ?2GPI to cardiolipin, regardless of the source of ?2GPI. Similarly, A1-A1 strongly inhibits the binding of dimerized domain V of ?2GPI to cardiolipin compared to the monomeric A1 inhibitor. In the absence of anti-?2GPI antibodies, both A1-A1 and A1 only weakly inhibit the binding of pathologically inactive monomeric ?2GPI to cardiolipin.Our results suggest that the approach of using a dimeric inhibitor to block ?2GPI in the pathological multivalent ?2GPI/antibody complexes holds significant promise. The novel inhibitor A1-A1 may be a starting point in the development of an effective therapeutic for antiphospholipid syndrome.

SUBMITTER: Kolyada A 

PROVIDER: S-EPMC3002267 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature