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 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 5 .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 bymaternal anti–HPA-1a antibodies in vivo in amousemodel (PLT clearance after 5 hours; 18% vs 62%, in the presence or absence of NGM-SZ21, respectively, P 5 .013). Deglycosylation of SZ21 abrogates Fc-effector functionswithout interferingwith 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. (Blood. 2013;122(3):321-327)