title: Identification of a Monoclonal Antibody That Attenuates Antiphospholipid Syndrome-Related Pregnancy Complications and Thrombosis.
abstract: In the antiphospholipid syndrome (APS), patients produce antiphospholipid antibodies (aPL) that promote thrombosis and adverse pregnancy outcomes. Current therapy with anticoagulation is only partially effective and associated with multiple complications. We previously discovered that aPL recognition of cell surface β2-glycoprotein I (β2-GPI) initiates apolipoprotein E receptor 2 (apoER2)-dependent signaling in endothelial cells and in placental trophoblasts that ultimately promotes thrombosis and fetal loss, respectively. Here we sought to identify a monoclonal antibody (mAb) to β2-GPI that negates aPL-induced processes in cell culture and APS disease endpoints in mice. In a screen measuring endothelial NO synthase (eNOS) activity in cultured endothelial cells, we found that whereas aPL inhibit eNOS, the mAb 1N11 does not, and instead 1N11 prevents aPL action. Coimmunoprecipitation studies revealed that 1N11 decreases pathogenic antibody binding to β2-GPI, and it blocks aPL-induced complex formation between β2-GPI and apoER2. 1N11 also prevents aPL antagonism of endothelial cell migration, and in mice it reverses the impairment in reendothelialization caused by aPL, which underlies the non-thrombotic vascular occlusion provoked by disease-causing antibodies. In addition, aPL inhibition of trophoblast proliferation and migration is negated by 1N11, and the more than 6-fold increase in fetal resorption caused by aPL in pregnant mice is prevented by 1N11. Furthermore, the promotion of thrombosis by aPL is negated by 1N11. Thus, 1N11 has been identified as an mAb that attenuates APS-related pregnancy complications and thrombosis in mice. 1N11 may provide an efficacious, mechanism-based therapy to combat the often devastating conditions suffered by APS patients.
authors.affiliation: Center for Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Chieko
authors.initials: C
authors.lastname: Mineo
authors.affiliation: Center for Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Lane
authors.initials: L
authors.lastname: Lanier
authors.affiliation: Center for Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Eunjeong
authors.initials: E
authors.lastname: Jung
authors.affiliation: Center for Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Samarpita
authors.initials: S
authors.lastname: Sengupta
authors.affiliation: Center for Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Victoria
authors.initials: V
authors.lastname: Ulrich
authors.affiliation: Center for Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Sacharidou
authors.affiliation: Center for Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Cristina
authors.initials: C
authors.lastname: Tarango
authors.affiliation: Center for Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Olutoye
authors.initials: O
authors.lastname: Osunbunmi
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Yu-Min
authors.initials: YM
authors.lastname: Shen
authors.affiliation: Department of Medicine, Hospital for Special Surgery, Weill Cornell Medical College, New York, New York, United States of America.
authors.forename: Jane E
authors.initials: JE
authors.lastname: Salmon
authors.affiliation: Department of Pharmacology and the Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.|Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Rolf A
authors.initials: RA
authors.lastname: Brekken
authors.affiliation: Department of Pharmacology and the Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Xianming
authors.initials: X
authors.lastname: Huang
authors.affiliation: Department of Pharmacology and the Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Philip E
authors.initials: PE
authors.lastname: Thorpe
authors.affiliation: Center for Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Philip W
authors.initials: PW
authors.lastname: Shaul
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology*; D016736:Antiphospholipid Syndrome / Q000150:complications* / Q000517:prevention & control; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000473:pathology; D005260:Female; D005327:Fetal Resorption; D006801:Humans; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D011247:Pregnancy; D011248:Pregnancy Complications / Q000517:prevention & control*; D013927:Thrombosis / Q000150:complications* / Q000517:prevention & control; D014327:Trophoblasts / Q000473:pathology
chemical_list: D000911:Antibodies, Monoclonal; D052250:Nitric Oxide Synthase Type III