Patient-derived monoclonal anti-HPA-1a can induce platelet activation through FcγRIIa
- 1Sanquin Blood Supply Foundation, Department Research, Amsterdam, The Netherlands
Abstract
Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a pregnancy-associated disorder caused by maternal alloantibodies targeting paternally inherited human platelet antigens (HPAs). These antibodies traverse the placenta and bind to fetal platelets, causing thrombocytopenia and potentially severe complications including intracranial hemorrhage (ICH). Beyond platelets, antibodies may also target other fetal cells such as endothelial cells and placental trophoblasts thereby exacerbating disease severity. Anti-HPA-1a antibodies, the primary cause of FNAIT, display functional heterogeneity due to differences in epitope specificity, glycosylation, which complicate disease severity prediction. Here, we report the structural and functional characterization of two novel anti-HPA-1a antibodies, D-204 and M-204, derived from a mother with a severe FNAIT case. In comparison to D-204 and other existing anti-HPA-1a antibodies such as B2G1 and 26.4, M-204 bound IIb{beta}3 with different kinetics, reaching only half-maximal binding, as determined by flow cytometry. Notably, only M-204 induced platelet aggregation. To investigate the underlying mechanism behind this aggregation, various antibody formats were generated (Fab, Fab2, bispecific, and IgG-Fc dead). Aggregation required both Fab-arms to engage HPA-1a and intact binding to Fc{gamma}RIIa. Structural models and crystal structures suggest the dual engagement of both Fab-arms is required for Fc{gamma}RIIA-engagement which is a unique feature of M-204 among known HPA-1 monoclonals. Our findings highlight the functional diversity of anti-HPA-1a antibodies and provide new insights into their pathogenic mechanisms.
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BibTeX
@misc{oosterhoff2026patientderived,
title = {{Patient-derived monoclonal anti-HPA-1a can induce platelet activation through FcγRIIa}},
author = {J. J. Oosterhoff and S. R. van Brummelen and M. Giulini and I. M. De Cuyper and R. Visser and R. Kapur and C. Gstoettner and E. DominguezV ega and T. de Vos and S. Hofstede-van Egmond and M. Cragg and M. Wuhrer and L. Porcelijn and M. de Haas and A. M. Bonvin and C. E. van der Schoot and G. Vidarsson},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.10.750554},
url = {https://www.biorxiv.org/content/10.64898/2026.09.10.750554v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Patient-derived monoclonal anti-HPA-1a can induce platelet activation through FcγRIIa
AU - J. J. Oosterhoff
AU - S. R. van Brummelen
AU - M. Giulini
AU - I. M. De Cuyper
AU - R. Visser
AU - R. Kapur
AU - C. Gstoettner
AU - E. DominguezV ega
AU - T. de Vos
AU - S. Hofstede-van Egmond
AU - M. Cragg
AU - M. Wuhrer
AU - L. Porcelijn
AU - M. de Haas
AU - A. M. Bonvin
AU - C. E. van der Schoot
AU - G. Vidarsson
PY - 2026
DA - 2026/09/10
PB - bioRxiv
DO - 10.64898/2026.09.10.750554
UR - https://www.biorxiv.org/content/10.64898/2026.09.10.750554v1
AB - Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a pregnancy-associated disorder caused by maternal alloantibodies targeting paternally inherited human platelet antigens (HPAs). These antibodies traverse the placenta and bind to fetal platelets, causing thrombocytopenia and potentially severe complications including intracranial hemorrhage (ICH). Beyond platelets, antibodies may also target other fetal cells such as endothelial cells and placental trophoblasts thereby exacerbating disease severity. Anti-HPA-1a antibodies, the primary cause of FNAIT, display functional heterogeneity due to differences in epitope specificity, glycosylation, which complicate disease severity prediction. Here, we report the structural and functional characterization of two novel anti-HPA-1a antibodies, D-204 and M-204, derived from a mother with a severe FNAIT case. In comparison to D-204 and other existing anti-HPA-1a antibodies such as B2G1 and 26.4, M-204 bound IIb{beta}3 with different kinetics, reaching only half-maximal binding, as determined by flow cytometry. Notably, only M-204 induced platelet aggregation. To investigate the underlying mechanism behind this aggregation, various antibody formats were generated (Fab, Fab2, bispecific, and IgG-Fc dead). Aggregation required both Fab-arms to engage HPA-1a and intact binding to Fc{gamma}RIIa. Structural models and crystal structures suggest the dual engagement of both Fab-arms is required for Fc{gamma}RIIA-engagement which is a unique feature of M-204 among known HPA-1 monoclonals. Our findings highlight the functional diversity of anti-HPA-1a antibodies and provide new insights into their pathogenic mechanisms.
ER -