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 2013 Jul 18;122(3):321-7
Date
05/07/2013Pubmed ID
23645838Pubmed Central ID
PMC3716199DOI
10.1182/blood-2012-11-468561Scopus ID
2-s2.0-84879304669 (requires institutional sign-in at Scopus site) 41 CitationsAbstract
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.
Author List
Bakchoul T, Greinacher A, Sachs UJ, Krautwurst A, Renz H, Harb H, Bein G, Newman PJ, Santoso SAuthor
Peter J. Newman PhD Professor in the Pharmacology and Toxicology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsAntibodies, Monoclonal
Antigens, Human Platelet
Biological Transport
Blood Platelets
Disease Models, Animal
Female
Glycosylation
Humans
Integrin beta3
Isoantibodies
Mannosyl-Glycoprotein Endo-beta-N-Acetylglucosaminidase
Mice
Mice, Inbred BALB C
Mice, SCID
Molecular Targeted Therapy
Phagocytosis
Placenta
Polysaccharides
Pregnancy
Protein Binding
Thrombocytopenia, Neonatal Alloimmune