Identification of a Monoclonal Antibody That Attenuates Antiphospholipid Syndrome-Related Pregnancy Complications and Thrombosis

Chieko Mineo, Lane Lanier, Eunjeong Jung, Samarpita Sengupta, Victoria Ulrich, Anastasia Sacharidou, Cristina Tarango, Olutoye Osunbunmi, Yu Min Shen, Jane E. Salmon, Rolf A. Brekken, Xianming Huang, Philip E. Thorpe, Philip W. Shaul

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)e0158757
JournalPLoS One
Volume11
Issue number7
DOIs
StatePublished - 2016

Fingerprint

pregnancy complications
Antiphospholipid Antibodies
Antiphospholipid Syndrome
Pregnancy Complications
thrombosis
monoclonal antibodies
Thrombosis
Monoclonal Antibodies
antibodies
Glycoproteins
Endothelial cells
glycoproteins
Endothelial Cells
endothelial cells
Trophoblasts
apolipoprotein E
trophoblast
Nitric Oxide Synthase
mice
Fetal Resorption

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Identification of a Monoclonal Antibody That Attenuates Antiphospholipid Syndrome-Related Pregnancy Complications and Thrombosis. / Mineo, Chieko; Lanier, Lane; Jung, Eunjeong; Sengupta, Samarpita; Ulrich, Victoria; Sacharidou, Anastasia; Tarango, Cristina; Osunbunmi, Olutoye; Shen, Yu Min; Salmon, Jane E.; Brekken, Rolf A.; Huang, Xianming; Thorpe, Philip E.; Shaul, Philip W.

In: PLoS One, Vol. 11, No. 7, 2016, p. e0158757.

Research output: Contribution to journalArticle

Mineo, Chieko ; Lanier, Lane ; Jung, Eunjeong ; Sengupta, Samarpita ; Ulrich, Victoria ; Sacharidou, Anastasia ; Tarango, Cristina ; Osunbunmi, Olutoye ; Shen, Yu Min ; Salmon, Jane E. ; Brekken, Rolf A. ; Huang, Xianming ; Thorpe, Philip E. ; Shaul, Philip W. / Identification of a Monoclonal Antibody That Attenuates Antiphospholipid Syndrome-Related Pregnancy Complications and Thrombosis. In: PLoS One. 2016 ; Vol. 11, No. 7. pp. e0158757.
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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.",
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AU - Ulrich, Victoria

AU - Sacharidou, Anastasia

AU - Tarango, Cristina

AU - Osunbunmi, Olutoye

AU - Shen, Yu Min

AU - Salmon, Jane E.

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