Toward a prophylaxis against fetal and neonatal alloimmune thrombocytopenia: induction of antibody‐mediated immune suppression and prevention of severe clinical complications in a murine model

Tiller, Heidi; Killie, Mette Kjær; Chen, Pingguo; Eksteen, Mariana; Husebekk, Anne; Skogen, Bjøŕn; Kjeldsen‐Kragh, Jens; Ni, Heyu

doi:10.1111/j.1537-2995.2011.03480.x

Cited by 67 publications

(48 citation statements)

References 40 publications

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“…Currently, no specific treatment is available to prevent FNAIT; nor is there any specific therapy. However, a strategy to prevent alloimmune thrombocytopenia by Ab prophylaxis has been proved successful in mice (10), and clinical trials (http://www.profnait.eu) are under way to test the potential of hyperimmune anti-HPA-1a IgG in preventing HPA-1a immunization in connection with pregnancy (9). In principle, HPA-1a-specific mAbs may be as efficient as polyclonal antisera in preventing alloimmunization and could hold important advantages, not the least in terms of tailorability, for enhanced function and as a limitless source of such Abs.…”

Section: Discussionmentioning

confidence: 99%

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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%

“…A prophylactic strategy to prevent FNAIT occurrence using anti-HPA-1a Abs derived from pooled donor plasma has been proposed (9). Such a strategy has been proved to prevent thrombocytopenia in newborn pups in a murine model of FNAIT (10). An attractive source of anti-HPA-1a Abs for eventual FNAIT prophylaxis or therapy would be human mAbs.…”

mentioning

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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“…Although the mechanisms behind this process remain largely unknown, a mouse model of fetomaternal platelet alloimmunization demonstrated that administration of platelet anti-b3 antibodies prevented alloimmunization. 42 Here, we have shown that B2G1 very quickly clears HPA-1a-positive platelets from the circulation and would therefore constitute an ideal candidate to progress on to clinical studies for prophylaxis after delivery in HPA-1a-negative women. If this proved to be effective, one could consider follow-on studies to assess effectiveness of this prophylactic approach during pregnancy, in particular including primigravidae where alloimmunization can lead to significant fetal thrombocytopenia.…”

Section: Discussionmentioning

confidence: 99%

Recombinant HPA-1a antibody therapy for treatment of fetomaternal alloimmune thrombocytopenia: proof of principle in human volunteers

Ghevaert

Herbert

Hawkins

et al. 2013

Blood

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Key Points• Recombinant antibody B2G1Dnab protects platelets from destruction by anti-HPA-1a in the circulation of HPA-1a1b human volunteers.• B2G1Dnab is a potential therapeutic agent for antenatal treatment of fetomaternal alloimmune thrombocytopenia due to HPA-1a antibodies.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 (B2G1Dnab) that competes for binding to the HPA-1a epitope but carries a modified constant region that does not bind to Fcg receptors. In vitro studies with a range of clinical anti-HPA-1a sera have shown that B2G1Dnab blocks monocyte chemiluminescence by >75%. In this firstin-man study, we demonstrate that HPA-1a1b autologous platelets (matching fetal phenotype) sensitized with B2G1Dnab 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 B2G1Dnab as therapy, we show that platelets sensitized with a combination of B2G1 (representing destructive HPA-1a antibody) and B2G1Dnab survive 3 times as long in circulation compared with platelets sensitized with B2G1 alone. This confirms the therapeutic potential of B2G1Dnab. 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. (Blood. 2013;122(3):313-320)

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“…Clinical management of FNAIT is still a challenge (1,3,4,61), but IVIG has been demonstrated to be a useful therapy for this disease. We previously demonstrated that IVIG downregulated both maternal and neonatal circulating levels of anti-platelet antibodies (40), although IVIG did not show antiidiotype activity and did not significantly inhibit the binding of anti-β3 antibodies to platelets (40).…”

Section: Detection Of Anti-β3 or Anti-gpibα Antibodies Via Flow Cytommentioning

confidence: 99%

Maternal anti-platelet β3 integrins impair angiogenesis and cause intracranial hemorrhage

Yougbaré¹,

Lang²,

Hong³

et al. 2015

J. Clin. Invest.

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100

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Toward a prophylaxis against fetal and neonatal alloimmune thrombocytopenia: induction of antibody‐mediated immune suppression and prevention of severe clinical complications in a murine model

Abstract: This work conceptually proves that prophylactic administration of PLT antibodies induces AMIS and prevents poor pregnancy outcome in FNAIT.

Cited by 67 publications

References 40 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

Recombinant HPA-1a antibody therapy for treatment of fetomaternal alloimmune thrombocytopenia: proof of principle in human volunteers

Maternal anti-platelet β3 integrins impair angiogenesis and cause intracranial hemorrhage

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