title: Recombinant HPA-1a antibody therapy for treatment of fetomaternal alloimmune thrombocytopenia: proof of principle in human volunteers.
abstract: Fetomaternal alloimmune thrombocytopenia, caused by the maternal generation of antibodies against fetal human platelet antigen-1a (HPA-1a), can result in intracranial hemorrhage and intrauterine death. We have developed a therapeutic human recombinant high-affinity HPA-1a antibody (B2G1Δnab) that competes for binding to the HPA-1a epitope but carries a modified constant region that does not bind to Fcγ receptors. In vitro studies with a range of clinical anti-HPA-1a sera have shown that B2G1Δnab blocks monocyte chemiluminescence by >75%. In this first-in-man study, we demonstrate that HPA-1a1b autologous platelets (matching fetal phenotype) sensitized with B2G1Δnab have the same intravascular survival as unsensitized platelets (190 hours), while platelets sensitized with a destructive immunoglobulin G1 version of the antibody (B2G1) are cleared from the circulation in 2 hours. Mimicking the situation in fetuses receiving B2G1Δnab as therapy, we show that platelets sensitized with a combination of B2G1 (representing destructive HPA-1a antibody) and B2G1Δnab survive 3 times as long in circulation compared with platelets sensitized with B2G1 alone. This confirms the therapeutic potential of B2G1Δnab. The efficient clearance of platelets sensitized with B2G1 also opens up the opportunity to carry out studies of prophylaxis to prevent alloimmunization in HPA-1a-negative mothers.
authors: National Health Service (NHS) Blood and Transplant, Cambridge, United Kingdom.
authors: Cedric
authors: C
authors: Ghevaert
authors: Nina
authors: N
authors: Herbert
authors: Louise
authors: L
authors: Hawkins
authors: Nicola
authors: N
authors: Grehan
authors: Philip
authors: P
authors: Cookson
authors: Steve F
authors: SF
authors: Garner
authors: Abigail
authors: A
authors: Crisp-Hihn
authors: Paul
authors: P
authors: Lloyd-Evans
authors: Amanda
authors: A
authors: Evans
authors: Kottekkattu
authors: K
authors: Balan
authors: Willem H
authors: WH
authors: Ouwehand
authors: Kathryn L
authors: KL
authors: Armour
authors: Mike R
authors: MR
authors: Clark
authors: Lorna M
authors: LM
authors: Williamson
mesh_terms: D000906:Antibodies / Q000627:therapeutic use*; D016824:Antigens, Human Platelet / Q000276:immunology; D001792:Blood Platelets / Q000276:immunology; D001808:Blood Vessels / Q000473:pathology; D002470:Cell Survival / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D039661:Integrin beta3; D008297:Male; D050505:Mutant Proteins / Q000276:immunology; D011994:Recombinant Proteins / Q000627:therapeutic use*; D012984:Software; D054098:Thrombocytopenia, Neonatal Alloimmune / Q000097:blood / Q000188:drug therapy* / Q000276:immunology
chemical_list: D000906:Antibodies; D016824:Antigens, Human Platelet; C061248:ITGB3 protein, human; D007074:Immunoglobulin G; D039661:Integrin beta3; D050505:Mutant Proteins; D011994:Recombinant Proteins
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