PMID- 27463336 OWN - NLM STAT- MEDLINE DCOM- 20170717 LR - 20181113 IS - 1932-6203 (Electronic) IS - 1932-6203 (Linking) VI - 11 IP - 7 DP - 2016 TI - Identification of a Monoclonal Antibody That Attenuates Antiphospholipid Syndrome-Related Pregnancy Complications and Thrombosis. PG - e0158757 LID - 10.1371/journal.pone.0158757 [doi] LID - e0158757 AB - 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 beta2-glycoprotein I (beta2-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 beta2-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 beta2-GPI, and it blocks aPL-induced complex formation between beta2-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. FAU - Mineo, Chieko AU - Mineo C AD - Center for Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America. FAU - Lanier, Lane AU - Lanier L AD - Center for Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America. FAU - Jung, Eunjeong AU - Jung E AD - Center for Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America. FAU - Sengupta, Samarpita AU - Sengupta S AD - Center for Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America. FAU - Ulrich, Victoria AU - Ulrich V AD - Center for Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America. FAU - Sacharidou, Anastasia AU - Sacharidou A AD - Center for Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America. FAU - Tarango, Cristina AU - Tarango C AD - Center for Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America. FAU - Osunbunmi, Olutoye AU - Osunbunmi O AD - Center for Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America. FAU - Shen, Yu-Min AU - Shen YM AD - Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America. FAU - Salmon, Jane E AU - Salmon JE AD - Department of Medicine, Hospital for Special Surgery, Weill Cornell Medical College, New York, New York, United States of America. FAU - Brekken, Rolf A AU - Brekken RA AD - Department of Pharmacology and the Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America. AD - Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America. FAU - Huang, Xianming AU - Huang X AD - Department of Pharmacology and the Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America. FAU - Thorpe, Philip E AU - Thorpe PE AD - Department of Pharmacology and the Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America. FAU - Shaul, Philip W AU - Shaul PW AD - Center for Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America. LA - eng GR - R01 HL109604/HL/NHLBI NIH HHS/United States GR - T32 HL098040/HL/NHLBI NIH HHS/United States PT - Journal Article DEP - 20160727 PL - United States TA - PLoS One JT - PloS one JID - 101285081 RN - 0 (Antibodies, Monoclonal) RN - EC 1.14.13.39 (Nitric Oxide Synthase Type III) SB - IM MH - Antibodies, Monoclonal/*immunology MH - Antiphospholipid Syndrome/*complications/prevention & control MH - Cells, Cultured MH - Endothelium, Vascular/pathology MH - Female MH - Fetal Resorption MH - Humans MH - Nitric Oxide Synthase Type III/metabolism MH - Pregnancy MH - Pregnancy Complications/*prevention & control MH - Thrombosis/*complications/prevention & control MH - Trophoblasts/pathology PMC - PMC4963039 COIS- Competing Interests: RAB, XH and PET were consultants for Peregrine Pharmaceuticals, Inc., and their efforts on the project were partially funded by Peregrine Pharmaceuticals, Inc. YMS served as a speaker for Janssen for Xarelto, which is an oral anticoagulant, and for Alexion for Soliris, which is being studied for catastrophic APS. JES was a consultant for Alexion. These competing interests do not alter the authors' adherence to PLOS ONE policies on sharing data and materials. The authors have no additional declarations regarding possible competing interests. EDAT- 2016/07/28 06:00 MHDA- 2017/07/18 06:00 PMCR- 2016/07/27 CRDT- 2016/07/28 06:00 PHST- 2016/01/07 00:00 [received] PHST- 2016/06/21 00:00 [accepted] PHST- 2016/07/28 06:00 [entrez] PHST- 2016/07/28 06:00 [pubmed] PHST- 2017/07/18 06:00 [medline] PHST- 2016/07/27 00:00 [pmc-release] AID - PONE-D-16-00759 [pii] AID - 10.1371/journal.pone.0158757 [doi] PST - epublish SO - PLoS One. 2016 Jul 27;11(7):e0158757. doi: 10.1371/journal.pone.0158757. eCollection 2016.