Soluble analog of ApoER2 targeting beta2‐glycoprotein I in immune complexes counteracts hypertension in lupus‐prone mice with spontaneous antiphospholipid syndrome

Abstract

To cite this article: Kolyada A, Ke Q, Karageorgos I, Mahlawat P, Barrios DA, Kang PM, Beglova N. Soluble analog of ApoER2 targeting beta2-glycoprotein I in immune complexes counteracts hypertension in lupus-prone mice with spontaneous antiphospholipid syndrome.J Thromb Haemost 2016; 14: 1298-307. Essentials(NZWxBXSB)F1 male mice develop antibodies beta2-glycoprotein I (b2GPI) and hypertension. A1-A1 is a soluble analogue of ApoE receptor 2 with a high affinity for b2GPI/antibody complexes. A1-A1 improved blood pressure and arterial elastance in (NZWxBXSB)F1 male mice. A1-A1 had no adverse effects on the hemodynamics of healthy mice.Summary. Background: Antiphospholipid syndrome (APS) is diagnosed based on the presence of antiphospholipid antibodies and clinical thrombosis or fetal loss during pregnancy. Lupus-prone (NZWxBXSB)F1 male mice are the mouse model of spontaneous APS. They develop antib2GPI antibodies, microinfarcts and hypertension. ApoER2 is a receptor that contributes to anti-b2GPI-dependent thrombosis in APS by down-regulating endothelial nitric oxide synthase activation. Objectives: A1-A1 is a small protein constructed from two identical ligand-binding modules from ApoER2, containing the binding site for b2GPI. We studied how treatment with A1-A1 affects the development of hypertension in (NZWxBXSB)F1 male mice. Methods: We treated (NZWxBXSB)F1 male mice with A1-A1 for up to 4 weeks and examined changes in hemodynamics by left ventricular pressure-volume loop measurements. Results: We observed improvements in blood pressure in the A1-A1 treated mice. A1-A1 prevented the deterioration of arterial elastance by decreasing systemic resistance and improving vessel compliance. We did not detect any adverse effects of the treatment in either male mice or in apparently healthy female (NZWxBXSB)F1 mice. Conclusions: We demonstrated that A1-A1, which is a soluble analog of ApoER2 that binds pathological b2GPI/anti-b2GPI complexes, has a positive impact on hemodynamics in lupus-prone mice with spontaneous anti-b2GPI antibodies and hypertension.

16th International Congress on Antiphospholipid Antibodies Task Force Report on Antiphospholipid Syndrome Treatment Trends

“…More recently, the group achieved longer-term delivery of A1-A1 in (NZW x BXSB) F1 mice by implanting a subcutaneous osmotic pump. 169 This led to a reduction in blood pressure in the mice – though this method may not be acceptable to patients. Unlike TIFI, there is currently no evidence that A1-A1 inhibits aPL-induced fetal loss in mice.…”

PEGylated Domain I of Beta-2-Glycoprotein I Inhibits Thrombosis in a Chronic Mouse Model of the Antiphospholipid Syndrome

“…An alternative approach has been described in a series of papers from the group of Kolyada and colleagues ( 29 – 32 ). They have taken advantage of the fact that the A1 domain of the apolipoprotein E receptor 2 (ApoER2) binds to DV.…”

“…In the mouse model experiments, 84% of A1-A1 had been lost from the blood within an hour ( 30 ). In a subsequent experiment in (NZWxBXSB1)F1 mice, this problem was counteracted by use of a subcutaneous osmotic pump to deliver the agent continuously over 2-4 weeks ( 32 ). A reduction in the blood pressure of the mice was reported, but thrombosis was not an outcome of this study ( 32 ).…”

“…In a subsequent experiment in (NZWxBXSB1)F1 mice, this problem was counteracted by use of a subcutaneous osmotic pump to deliver the agent continuously over 2-4 weeks ( 32 ). A reduction in the blood pressure of the mice was reported, but thrombosis was not an outcome of this study ( 32 ). It is unlikely that patients would accept use of such a device for a treatment that is essentially preventative, and there are no reports of chemical modification of A1-A1 to increase serum half-life.…”

Domain I of β2GPI is capable of blocking serum IgA antiphospholipid antibodies binding in vitro: an effect enhanced by PEGylation

“…12 This has led to a spate of research into novel therapeutics for APS. [13][14][15] These novel therapeutics target b2GPI rather than the clotting cascade, and the majority of research has been carried out on the IgG subclass. This study used one of these novel therapeutics (Domain I) and its modified forms (PEGylated DI) to test whether it was possible to disrupt the binding of patient IgA antibodies to b2GPI immobilized in an ELISA.…”