title: A novel dimeric inhibitor targeting Beta2GPI in Beta2GPI/antibody complexes implicated in antiphospholipid syndrome.
abstract: BACKGROUND
  β2GPI 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 β2GPI generated by anti-β2GPI antibodies is pathologically important, in contrast to monomeric β2GPI which is abundant in plasma.
  
  
  RESULTS
  We created a dimeric inhibitor, A1-A1, to selectively target β2GPI in β2GPI/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 β2GPI/antibody complexes with anionic phospholipids and ApoER2. We compared the efficiency of A1-A1 to monomeric A1 for inhibition of the binding of β2GPI/antibody complexes to anionic phospholipids. We tested the inhibition of β2GPI present in human serum, β2GPI purified from human plasma and the individual domain V of β2GPI. We demonstrated that when β2GPI/antibody complexes are formed, A1-A1 is much more effective than A1 in inhibition of the binding of β2GPI to cardiolipin, regardless of the source of β2GPI. Similarly, A1-A1 strongly inhibits the binding of dimerized domain V of β2GPI to cardiolipin compared to the monomeric A1 inhibitor. In the absence of anti-β2GPI antibodies, both A1-A1 and A1 only weakly inhibit the binding of pathologically inactive monomeric β2GPI to cardiolipin.
  
  
  CONCLUSIONS
  Our results suggest that the approach of using a dimeric inhibitor to block β2GPI in the pathological multivalent β2GPI/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.
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Alexey
authors.initials: A
authors.lastname: Kolyada
authors.forename: Chang-Jin
authors.initials: CJ
authors.lastname: Lee
authors.forename: Alfredo
authors.initials: A
authors.lastname: De Biasio
authors.forename: Natalia
authors.initials: N
authors.lastname: Beglova
mesh_terms: D000026:Abortion, Habitual / Q000276:immunology*; D000818:Animals; D016736:Antiphospholipid Syndrome / Q000276:immunology* / Q000628:therapy; D015551:Autoimmunity; D002308:Cardiolipins / Q000737:chemistry; D018360:Crystallography, X-Ray / Q000379:methods; D019281:Dimerization; D004220:Disulfides / Q000737:chemistry; D005260:Female; D006801:Humans; D051379:Mice; D011247:Pregnancy; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D053482:beta 2-Glycoprotein I / Q000037:antagonists & inhibitors / Q000737:chemistry*
chemical_list: D002308:Cardiolipins; D004220:Disulfides; D053482:beta 2-Glycoprotein I