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

Bakchoul, Tamam; Greinacher, Andreas; Sachs, Ulrich J.; Krautwurst, Annika; Renz, Harald; Harb, Habi; Bein, Gregor; Newman, Peter J.; Santoso, Sentot

doi:10.1182/blood-2012-11-468561

Cited by 48 publications

(41 citation statements)

References 38 publications

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“…This may be achieved by protecting fetal tissues and platelets from potentially damaging anti-HPA-1a Abs with Abs that compete for binding to HPA-1a but lack the ability to activate immune effector functions. This is not a new concept and has been proved to function in principle with HPA-1a-specific mAbs both in a murine model and in human volunteers (35,36). The stable binding of mAb 26.4 to both platelet-derived and trophoblast-derived HPA1a, as demonstrated in this study, could be an additional advantage for therapeutic purposes because anti-HPA-1a Abs have been reported to have possible negative effects on fetal growth, in addition to causing thrombocytopenia in the fetus (5,37).…”

Section: Discussionmentioning

confidence: 99%

Characterization of a Human Platelet Antigen-1a–Specific Monoclonal Antibody Derived from a B Cell from a Woman Alloimmunized in Pregnancy

Eksteen

Tiller

Averina

et al. 2015

The Journal of Immunology

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Human platelet Ag (HPA)-1a, located on integrin β3, is the main target for alloantibodies responsible for fetal and neonatal alloimmune thrombocytopenia (FNAIT) in the white population. There are ongoing efforts to develop an Ab prophylaxis and therapy to prevent or treat FNAIT. In this study, an mAb specific for HPA-1a, named 26.4, was derived from an immortalized B cell from an alloimmunized woman who had an infant affected by FNAIT. It is the only HPA-1a–specific human mAb with naturally paired H and L chains. Specific binding of mAb 26.4, both native and recombinant forms, to platelets and to purified integrins αIIbβ3 (from platelets) and αVβ3 (from trophoblasts) from HPA-1a+ donors was demonstrated by flow cytometry and surface plasmon resonance technology, respectively. No binding to HPA-1a− platelets or integrins was detected. Moreover, the Ab binds with higher affinity to integrin αVβ3 compared with a second HPA-1a–specific human mAb, B2G1. Further in vitro experimentation demonstrated that mAb 26.4 can opsonize HPA-1a+ platelets for enhanced phagocytosis by monocytes, inhibit binding of maternal polyclonal anti–HPA-1a Abs, and weakly inhibit aggregation of HPA-1a–heterozygous platelets, the latter with no predicted clinical relevance. Thus, mAb 26.4 is highly specific for HPA-1a and could potentially be explored for use as a prophylactic or therapeutic reagent for FNAIT intervention and as a phenotyping reagent to identify women at risk for immunization.

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Section: Discussionmentioning

confidence: 99%

Characterization of a Human Platelet Antigen-1a–Specific Monoclonal Antibody Derived from a B Cell from a Woman Alloimmunized in Pregnancy

Eksteen

Tiller

Averina

et al. 2015

The Journal of Immunology

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“…In one study, PNGaseF-deglycosylated monoclonal antibodies were administered to the mother and transferred to the fetus via FcRn, and when in the circulation, it bound to the antigen and blocked further interactions with effector cells of the immune system, in this case alleviating autoimmune disease [72]. This study elegantly demonstrates how the functions of a therapeutic monoclonal antibody can be fine tuned by the modification of the Fc-glycan.…”

Section: • • Igg Glycan Engineeringmentioning

confidence: 95%

Bacterial Glycosidases in Pathogenesis and Glycoengineering

Sjögren

Collin

2014

Future Microbiol.

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Glycosylation is a common post-translational protein modification and many key proteins of the immune system are glycosylated. As the true experts of our immune system, pathogenic bacteria produce enzymes that can modify the carbohydrates (glycans) of the defense mechanisms in order to favor bacterial survival and persistence. At the intersection between bacterial pathogenesis and glycobiology, there is an increased interest in studying the bacterial enzymes that modify the protein glycosylation of their colonized or infected hosts. This is of great importance in order to fully understand bacterial pathogenesis, but it also presents itself as a valuable source for glycoengineering and glycoanalysis tools. This article highlights the role of bacterial glycosidases during infections, introduces the use of such enzymes as glycoengineering tools and discusses the potential of further studies in this emerging field.

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“…Using targeted therapies that go beyond intrauterine transfusions, therapeutic plasma exchange, or intravenous immunoglobulin, can existing maternal RBC or PLT alloantibodies be minimized? [7][8][9][10][11] Although preventing primary RBC alloimmunization or PLT glycoprotein alloimmunization would be ideal, a number of women enter pregnancy already alloimmunized to RBC or PLT glycoprotein antigens through prior transfusion or pregnancy. At present, intrauterine transfusions, therapeutic plasma exchange, and IVIG are among the few effective therapies.…”

Section: Neonatology and Perinatologymentioning

confidence: 99%

2016 proceedings of the National Heart, Lung, and Blood Institute's scientific priorities in pediatric transfusion medicine

et al. 2017

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have the potential to transform the clinical practice of pediatric transfusion medicine. By applying basic, translational, and/or clinical research studies focused in six areas the science of transfusion medicine would be advanced. The six areas were selected based on recognized gaps in knowledge and included neonatology and perinatology, oncology and transplant, chronic transfusion, devices and surgery, intensive care, and trauma and teenage blood donation. The meeting and premeeting teleconferences included 80 participants representing multiple stakeholders, academic medicine, the basic and clinical research community, and the government. The participants had expertise in multiple relevant disciplines including transfusion medicine, pediatrics, neonatology, hematology, surgery, critical care, trauma, internal medicine, epidemiology, and study design. The speakers and participants identified research priorities based on unmet needs in the pediatric transfusion medicine arena and proposed strategies to overcome the knowledge gaps and address unanswered questions. ABBREVIATIONS: ECMO 5 extracorporeal membrane oxygenation; HSCT 5 hematopoietic stem cell transplant; ICU 5 intensive care unit; MRI 5 magnetic resonance imaging; NHLBI 5 5 National Heart, Lung, and Blood Institute; NICHD 5 National Institute of Child Health and Human Development; NISHOT 5 noninfectious serious hazards of transfusion; PICU 5 pediatric intensive care unit; PRT 5 pathogen reduction technology; REDS 5 Recipient Epidemiology and Donor Evaluation Study; SCD 5 sickle cell disease; VAD 5 ventricular assist device. From the

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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

Cited by 48 publications

References 38 publications

Characterization of a Human Platelet Antigen-1a–Specific Monoclonal Antibody Derived from a B Cell from a Woman Alloimmunized in Pregnancy

Characterization of a Human Platelet Antigen-1a–Specific Monoclonal Antibody Derived from a B Cell from a Woman Alloimmunized in Pregnancy

Bacterial Glycosidases in Pathogenesis and Glycoengineering

2016 proceedings of the National Heart, Lung, and Blood Institute's scientific priorities in pediatric transfusion medicine

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