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7-27-16 Shaul/Brekken/Thorpe/etal article: Fhu/Bavi vs. APS-related Pregnancy Complications & Thrombosis (PLOS ONE multidisciplinary Open Access journal)...

7-27-16/PLoS One: “Identification of a Monoclonal Antibody That Attenuates Antiphospholipid Syndrome-Related Pregnancy Complications & Thrombosis”
http://www.ncbi.nlm.nih.gov/pubmed/27463336 Rec.1-7-16, Acc.6-21-16, Pub.7-27-16
Mineo C1, Lanier L1, Jung E1, Sengupta S1, Ulrich V1, Sacharidou A1, Tarango C1, Osunbunmi O1, Shen YM2, Salmon JE3, Rolf Brekken 4,5, Xianming Huang 4, Philip Thorpe 4, Philip W Shaul 1
1 Ctr. for Pulmonary & Vascular Biology, Dept of Pediatrics, UTSW-MC/Dallas
2 Dept of Internal Medicine, UTSW-MC/Dallas
3 Dept of Medicine, Hosp. for Special Surgery, Weill Cornell Medical College, NYC
4 Dept of Pharmacology & the Hamon Ctr forTherapeutic Oncology Res., UTSW-MC/Dallas
5 Dept of Surgery, UTSW-MC/Dallas
**Dr. Philip Shaul: https://profiles.utsouthwestern.edu/profile/16558/philip-shaul.html
**PLOS ONE Journal: a multidisciplinary Open Access journal http://journals.plos.org/plosone
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 B2-glycoprotein I (B2-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 B2-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 [1N11 is Fully-Human Bavituximab, aka PGN635/AT004] does not, and instead 1N11 prevents aPL action. Coimmunoprecipitation studies revealed that 1N11 decreases pathogenic antibody binding to B2-GPI, and it blocks aPL-induced complex formation between B2-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.
DISCUSSION:
...The potential clinical impact of 1N11 in patients with APS is substantial. aPL are positive in 10% of all patients with deep vein thrombosis, in 11% of all patients with myocardial infarction, and in 13% of all patients with stroke [62]. In addition, despite oral anticoagulation therapy, individuals with a laboratory diagnosis of APS have a 44% likelihood of suffering a thrombotic event within 10 years [63]. As importantly, although the reported rates of bleeding complications vary widely for APS patients receiving anticoagulation, the incidence can be as high as 10% [64]. The impact of APS on pregnancy is also considerable. It has been estimated to complicate 5–7% of all pregnancies, and despite current anticoagulation therapy, the rate of fetal loss in APS is 18%, IUGR occurs in 13–33% of APS pregnancies, and the rate of prematurity is 16–50%, with an average gestational age of 31 weeks [65–70]. Moreover, when anticoagulation is chosen as a means to combat any of the numerous complications of APS, major dilemmas remain regarding the level of anticoagulation to target and the duration of therapy [71]. Spring-boarding from the present discovery of 1N11 as a highly-effective, mechanism-based treatment for APS in a comprehensive series of mouse models of APS-related disorders, clinical studies of 1N11 now warrant consideration.
FULL ARTICLE: http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0158757