Journal article

Publication year: 2013

Pages: 321-327

Journal: Blood

Volume number: 122

Issue number: 3

ISSN: 0006-4971

Open access status: Green

DOI Link: https://doi.org/10.1182/blood-2012-11-468561

Publisher: American Society of Hematology (ASH Publications)

Abstract: 
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 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.

Harvard Citation style: Bakchoul, T., Greinacher, A., Sachs, U., Krautwurst, A., Renz, H., Harb, H., et al. (2013) 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, Blood, 122(3), pp. 321-327. https://doi.org/10.1182/blood-2012-11-468561

APA Citation style: Bakchoul, T., Greinacher, A., Sachs, U., Krautwurst, A., Renz, H., Harb, H., Bein, G., Newman, P., & Santoso, S. (2013). 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. Blood. 122(3), 321-327. https://doi.org/10.1182/blood-2012-11-468561