title: 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.
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 = .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.
authors: Institute for Immunology and Transfusion Medicine, Ernst Moritz Arndt University, Greifswald, Germany.
authors: Tamam
authors: T
authors: Bakchoul
authors: Andreas
authors: A
authors: Greinacher
authors: Ulrich J
authors: UJ
authors: Sachs
authors: Annika
authors: A
authors: Krautwurst
authors: Harald
authors: H
authors: Renz
authors: Habi
authors: H
authors: Harb
authors: Gregor
authors: G
authors: Bein
authors: Peter J
authors: PJ
authors: Newman
authors: Sentot
authors: S
authors: Santoso
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D016824:Antigens, Human Platelet / Q000276:immunology*; D001692:Biological Transport / Q000187:drug effects; D001792:Blood Platelets / Q000276:immunology*; D004195:Disease Models, Animal; D005260:Female; D006031:Glycosylation / Q000187:drug effects; D006801:Humans; D039661:Integrin beta3; D007518:Isoantibodies / Q000276:immunology*; D017038:Mannosyl-Glycoprotein Endo-beta-N-Acetylglucosaminidase / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D058990:Molecular Targeted Therapy; D010587:Phagocytosis / Q000187:drug effects / Q000276:immunology; D010920:Placenta / Q000187:drug effects / Q000378:metabolism; D011134:Polysaccharides / Q000276:immunology; D011247:Pregnancy; D011485:Protein Binding / Q000187:drug effects; D054098:Thrombocytopenia, Neonatal Alloimmune / Q000097:blood* / Q000188:drug therapy / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D016824:Antigens, Human Platelet; C061248:ITGB3 protein, human; D039661:Integrin beta3; D007518:Isoantibodies; D011134:Polysaccharides; D017038:Mannosyl-Glycoprotein Endo-beta-N-Acetylglucosaminidase
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