PEGylated Domain I of Beta-2-Glycoprotein I Inhibits the Binding, Coagulopathic, and Thrombogenic Properties of IgG From Patients With the Antiphospholipid Syndrome.
PEGylated Domain I of Beta-2-Glycoprotein I Inhibits the Binding, Coagulopathic, and Thrombogenic Properties of IgG From Patients With the Antiphospholipid Syndrome.
复制标题
DOI：
10.3389/fimmu.2018.02413
复制
发表时间：
2018
影响因子：
7.3
通讯作者：
Rahman A
中科院分区：
文献类型：
--
作者：
McDonnell TCR;Willis R;Pericleous C;Ripoll VM;Giles IP;Isenberg DA;Brasier AR;Gonzalez EB;Papalardo E;Romay-Penabad Z;Jamaluddin M;Ioannou Y;Rahman A
APS是一种自身免疫性疾病，其中抗磷脂抗体（aPL）引起血管血栓形成和妊娠发病率。在APS患者中，aPL通过其N-末端结构域I（DI）结合血清β 2-糖蛋白I（β2GPI）发挥致病作用。我们以前表明，细菌表达的重组DI抑制来自APS患者血清的IgG（APS-IgG）的生物学作用。DI太小（7 kDa）而不能成为可行的治疗剂。向小分子中添加聚乙二醇（PEG化）可延长血清半衰期，降低蛋白水解靶向，并可降低免疫原性。这是一种定制药代动力学参数的常用方法，已用于临床许多疗法的生产。然而，分子的PEG化可能降低其生物活性，并且PEG基团的大小可能改变活性和半衰期延长之间的平衡。在这里，我们实现了生产的重组DI（PEG-DI）的位点特异性聚乙二醇化，并描述了在体外和体内的三个不同大小的PEG基团的变体的活动。所有变体均能抑制APS-IgG在ELISA中与完整β2GPI的结合，改变人血浆的凝血性质，并促进小鼠血栓形成和组织因子表达。这些发现为将DI发展成为APS的一流治疗方法迈出了重要的一步。
APS is an autoimmune disease in which antiphospholipid antibodies (aPL) cause vascular thrombosis and pregnancy morbidity. In patients with APS, aPL exert pathogenic actions by binding serum beta-2-glycoprotein I (β2GPI) via its N-terminal domain I (DI). We previously showed that bacterially-expressed recombinant DI inhibits biological actions of IgG derived from serum of patients with APS (APS-IgG). DI is too small (7 kDa) to be a viable therapeutic agent. Addition of polyethylene glycol (PEGylation) to small molecules enhances the serum half-life, reduces proteolytic targeting and can decrease immunogenicity. It is a common method of tailoring pharmacokinetic parameters and has been used in the production of many therapies in the clinic. However, PEGylation of molecules may reduce their biological activity, and the size of the PEG group can alter the balance between activity and half-life extension. Here we achieve production of site-specific PEGylation of recombinant DI (PEG-DI) and describe the activities in vitro and in vivo of three variants with different size PEG groups. All variants were able to inhibit APS-IgG from: binding to whole β2GPI in ELISA, altering the clotting properties of human plasma and promoting thrombosis and tissue factor expression in mice. These findings provide an important step on the path to developing DI into a first-in-class therapeutic in APS.
登录
查看更多内容
影响因子：
--
作者：
通讯作者：
--
影响因子：
4.4
作者：
Iverson, GM;Reddel, S;Linnik, MD
通讯作者：
Linnik, MD
影响因子：
10.4
作者：
Ioannou, Y.;Romay-Penabad, Z.;Pierangeli, S.
通讯作者：
Pierangeli, S.
影响因子：
27.4
作者：
Fleischmann R;Vencovsky J;van Vollenhoven RF;Borenstein D;Box J;Coteur G;Goel N;Brezinschek HP;Innes A;Strand V
通讯作者：
Strand V
影响因子：
7.5
作者：
Petri, M
通讯作者：
Petri, M