Inhibition of HPA-1a alloantibody-mediated platelet destruction by a deglycosylated anti-HPA-1a monoclonal antibody in mice: toward targeted treatment of fetal-alloimmune thrombocytopenia.
نویسندگان
چکیده
Fetal/neonatal alloimmune thrombocytopenia (FNAIT) is often caused by maternal alloantibodies against the human platelet antigen (HPA)-1a, which opsonizes fetal platelets (PLTs). Subsequent PLT destruction is mediated via the Fc part of the alloantibodies. The monoclonal antibody (mAb) SZ21 binds to the HPA-1a epitope and inhibits the binding of maternal alloantibodies. However, it also promotes complement activation and phagocytosis. Deglycosylation of antibodies abrogates the Fc-related effector functions. We modified the N-glycan of SZ21 by endoglycosidase F. The in vivo transplacental transport of N-glycan-modified (NGM)-SZ21 was not impaired. When injected into pregnant mice, both native-SZ21 and NGM-SZ21 were transported equally into fetal circulation (8.9% vs 8.7%, respectively, P = .58). Neither the binding properties of NGM-SZ21 to HPA-1a in surface plasmon resonance, nor the inhibition of anti-HPA-1a-induced PLT phagocytosis, were affected by N-glycan modification. NGM-SZ21 prevented PLT destruction induced by maternal anti-HPA-1a antibodies in vivo in a mouse model (PLT clearance after 5 hours; 18% vs 62%, in the presence or absence of NGM-SZ21, respectively, P = .013). Deglycosylation of SZ21 abrogates Fc-effector functions without interfering with placental transport or the ability to block anti-HPA-1a binding. Humanized, deglycosylated anti-HPA-1a mAbs may represent a novel treatment strategy to prevent anti-HPA-1a-mediated PLT destruction in FNAIT.
منابع مشابه
Inhibition of HPA-1a alloantibody-mediated platelet destruction by a deglycosylated anti-HPA-1a monoclonal antibody: towards targeted treatment of fetal-alloimmune thrombocytopenia
متن کامل
Plenary Paper PLATELETS AND THROMBOPOIESIS Inhibition of HPA-1a alloantibody-mediated platelet destruction by a deglycosylated anti–HPA-1a monoclonal antibody in mice: toward targeted treatment of fetal-alloimmune thrombocytopenia
• The study describes a potential novel treatment of fetal alloimmune thrombocytopenia by dissecting the effector activities of an epitopespecific IgG antibody. • Neither the in vivo transplacental transport nor the inhibiting properties of the blocking antibody are impaired by the N-glycan modification. Fetal/neonatal alloimmune thrombocytopenia (FNAIT) is often caused by maternal alloantibodi...
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Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a severe disease that is caused by maternal alloantibodies generated during pregnancy or at delivery as a result of incompatibility between maternal and fetal human platelet antigens (HPAs) inherited from the father. Antibody-mediated immune suppression using anti-HPA-1a immunoglobulins is thought to be able to prevent FNAIT caused by HP...
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عنوان ژورنال:
- Blood
دوره 122 3 شماره
صفحات -
تاریخ انتشار 2013