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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.
AuthorsCedric Ghevaert, Nina Herbert, Louise Hawkins, Nicola Grehan, Philip Cookson, Steve F Garner, Abigail Crisp-Hihn, Paul Lloyd-Evans, Amanda Evans, Kottekkattu Balan, Willem H Ouwehand, Kathryn L Armour, Mike R Clark, Lorna M Williamson
JournalBlood (Blood) Vol. 122 Issue 3 Pg. 313-20 (Jul 18 2013) ISSN: 1528-0020 [Electronic] United States
PMID23656729 (Publication Type: Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antibodies
  • Antigens, Human Platelet
  • ITGB3 protein, human
  • Immunoglobulin G
  • Integrin beta3
  • Mutant Proteins
  • Recombinant Proteins
Topics
  • Antibodies (therapeutic use)
  • Antigens, Human Platelet (immunology)
  • Blood Platelets (immunology)
  • Blood Vessels (pathology)
  • Cell Survival (immunology)
  • Female
  • Flow Cytometry
  • Humans
  • Immunoglobulin G (blood)
  • Integrin beta3
  • Male
  • Mutant Proteins (immunology)
  • Recombinant Proteins (therapeutic use)
  • Software
  • Thrombocytopenia, Neonatal Alloimmune (blood, drug therapy, immunology)

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