Intravascular survival of red cells coated with a mutated human anti-D antibody engineered to lack destructive activity

Armour, Kathryn L.; Parry-Jones, D. R.; Beharry, N.; Ballinger, James R.; Mushens, Rosey; Williams, Russell B.; Beatty, Cynthia; Stanworth, S; Lloyd-Evans, Paul; Scott, Marion L.; Clark, Mike; Peters, A. M.; Williamson, Lorna M.

doi:10.1182/blood-2005-03-0989

Cited by 28 publications

(45 citation statements)

References 28 publications

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“…This is in keeping with the in vitro data showing that this antibody does not cause FcRmediated effector cell activation. 29,35 In a previous study to assess survival of red cells sensitized with an anti-D (Fog-1) carrying the same G1Dnab constant region, 36 Fog-1G1Dnab-sensitized red cells pooled in the spleen before reappearing in the circulation after 3 to 4 hours. We did not have the opportunity to use a g camera to confirm where the platelets went following re-injection but the curve obtained in the first few hours post-injection suggests this may happen for platelets too, with a trough reached at 20 minutes and subsequent rise reaching a plateau at 2 hours.…”

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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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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“…Preclinical studies suggest that this human HPA‐1a antibody may be able to block the harmful effect of most maternal HPA‐1a antibodies (manuscript in preparation). RBC survival studies in humans have shown that a monoclonal anti‐D antibody equipped with the same biologically inactive Fc domain is unable to trigger the destruction of D+ RBCs 41 . Human studies with the modified HPA‐1a antibody will follow.…”

Section: Discussionmentioning

confidence: 99%

Management and outcome of 200 cases of fetomaternal alloimmune thrombocytopenia

et al. 2007

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“…With regard to efficacy, we have previously demonstrated improved intravascular survival in RhD-positive healthy volunteers of autologous red cells sensitized with an RhD antibody containing the same Δnab constant region compared with red cells sensitized with the parent IgG1 RhD antibody (52), showing that the encouraging results demonstrated in vitro in the CL assay translate to an in vivo protective effect in humans. Whether these results also apply to platelets sensitized with the modified anti-HPA-1a will be assessed in a forthcoming human volunteer study.…”

Section: Figurementioning

confidence: 98%

Developing recombinant HPA-1a–specific antibodies with abrogated Fcγ receptor binding for the treatment of fetomaternal alloimmune thrombocytopenia

Ghevaert

Wilcox²,

Fang³

et al. 2008

J. Clin. Invest.

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Fetomaternal alloimmune thrombocytopenia (FMAIT) is caused by maternal generation of antibodies specific for paternal platelet antigens and can lead to fetal intracranial hemorrhage. A SNP in the gene encoding integrin β3 causes a clinically important maternal-paternal antigenic difference; Leu33 generates the human platelet antigen 1a (HPA-1a), whereas Pro33 generates HPA-1b. As a potential treatment to prevent fetal intracranial hemorrhage in HPA-1a alloimmunized pregnancies, we generated an antibody that blocks the binding of maternal HPA-1a-specific antibodies to fetal HPA-1a1b platelets by combining a high-affinity human HPA-1a-specific scFv (B2) with an IgG1 constant region modified to minimize Fcγ receptor-dependent platelet destruction (G1Δnab). B2G1Δnab saturated HPA-1a + platelets and substantially inhibited binding of clinical HPA-1a-specific sera to HPA-1a + platelets. The response of monocytes to B2G1Δnab-sensitized platelets was substantially less than their response to unmodified B2G1, as measured by chemiluminescence. In addition, B2G1Δnab inhibited chemiluminescence induced by B2G1 and HPA-1a-specific sera. In a chimeric mouse model, B2G1 and polyclonal Ig preparations from clinical HPA-1a-specific sera reduced circulating HPA-1a + platelets, concomitant with transient thrombocytopenia. As the Δnab constant region is uninformative in mice, F(ab′) 2 B2G1 was used as a proof of principle blocking antibody and prevented the in vivo platelet destruction seen with B2G1 and polyclonal HPA-1a-specific antibodies. These results provide rationale for human clinical studies.

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Intravascular survival of red cells coated with a mutated human anti-D antibody engineered to lack destructive activity

Cited by 28 publications

References 28 publications

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

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

Management and outcome of 200 cases of fetomaternal alloimmune thrombocytopenia

Developing recombinant HPA-1a–specific antibodies with abrogated Fcγ receptor binding for the treatment of fetomaternal alloimmune thrombocytopenia

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