TY - JOUR
T1 - Identification of a monoclonal antibody that attenuates antiphospholipid syndrome-related pregnancy complications and thrombosis
AU - Mineo, Chieko
AU - Lanier, Lane
AU - Jung, Eunjeong
AU - Sengupta, Samarpita
AU - Ulrich, Victoria
AU - Sacharidou, Anastasia
AU - Tarango, Cristina
AU - Osunbunmi, Olutoye
AU - Shen, Yu Min
AU - Salmon, Jane E.
AU - Brekken, Rolf A.
AU - Huang, Xianming
AU - Thorpe, Philip E.
AU - Shaul, Philip W.
N1 - Funding Information:
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.
Funding Information:
This work was supported by National Institutes of Health (http://www.nhlbi.nih.gov), R01HL109604 and T32 HL098040; The Hartwell Foundation (http://www.thehartwellfoundation.org), grant# unavailable; The Children?s Medical Center Foundation (https://give.childrens.com), grant# unavailable; The Effie Marie Cain Scholarship (URL not available), grant# unavailable. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. This work was also supported by a sponsored research agreement from Peregrine Pharmaceuticals, Inc. (www.peregrineinc.com), grant# unavailable. Peregrine Pharmaceuticals, Inc., played a role in the preparation of the manuscript and the decision to submit it for publication. They had no role in study design, or collection, analysis and interpretation of data. We are indebted to Mr. Mohamed Ahmed for technical assistance. We are also indebted to Dr. Eugene Frenkel (UT Southwestern, Department of Internal Medicine) for his assistance recruiting APS patients through support from the Raymond Nasher Cancer Research Fund.
Funding Information:
Funding: This work was supported by National Institutes of Health (http://www.nhlbi.nih.gov),
Funding Information:
decision to publish, or preparation of the manuscript. This work was also supported by a sponsored research agreement from Peregrine Pharmaceuticals, Inc. (www.peregrineinc.com), grant# unavailable. Peregrine Pharmaceuticals, Inc., played a role in the preparation of the manuscript and the decision to submit it for publication. They had no role in study design, or collection, analysis and interpretation of data.
Publisher Copyright:
© 2016 Mineo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2016/7
Y1 - 2016/7
N2 - 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.
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 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.
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U2 - 10.1371/journal.pone.0158757
DO - 10.1371/journal.pone.0158757
M3 - Article
C2 - 27463336
AN - SCOPUS:85024388342
VL - 11
JO - PLoS One
JF - PLoS One
SN - 1932-6203
IS - 7
M1 - e0158757
ER -