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Transplacental delivery of therapeutic proteins by engineered immunoglobulin G: a step toward perinatal replacement therapy.
Mimoun, Angelina; Bou-Jaoudeh, Melissa; Delignat, Sandrine; Daventure, Victoria; Reyes Ruiz, Alejandra; Lecerf, Maxime; Azam, Aurélien; Noe, Remi; Peyron, Ivan; Christophe, Olivier D; Lenting, Peter J; Proulle, Valérie; McIntosh, Jenny; Nathwani, Amit C; Dimitrov, Jordan D; Denis, Cécile V; Lacroix-Desmazes, Sébastien.
Afiliación
  • Mimoun A; Institut National de la Santé et de la Recherche Médicale, Centre de Recherche des Cordeliers, CNRS, Sorbonne Université, Université Paris Cité, Paris, France.
  • Bou-Jaoudeh M; Institut National de la Santé et de la Recherche Médicale, Centre de Recherche des Cordeliers, CNRS, Sorbonne Université, Université Paris Cité, Paris, France.
  • Delignat S; Institut National de la Santé et de la Recherche Médicale, Centre de Recherche des Cordeliers, CNRS, Sorbonne Université, Université Paris Cité, Paris, France.
  • Daventure V; Institut National de la Santé et de la Recherche Médicale, Centre de Recherche des Cordeliers, CNRS, Sorbonne Université, Université Paris Cité, Paris, France.
  • Reyes Ruiz A; Institut National de la Santé et de la Recherche Médicale, Centre de Recherche des Cordeliers, CNRS, Sorbonne Université, Université Paris Cité, Paris, France.
  • Lecerf M; Institut National de la Santé et de la Recherche Médicale, Centre de Recherche des Cordeliers, CNRS, Sorbonne Université, Université Paris Cité, Paris, France.
  • Azam A; Institut National de la Santé et de la Recherche Médicale, Centre de Recherche des Cordeliers, CNRS, Sorbonne Université, Université Paris Cité, Paris, France.
  • Noe R; Institut National de la Santé et de la Recherche Médicale, Centre de Recherche des Cordeliers, CNRS, Sorbonne Université, Université Paris Cité, Paris, France.
  • Peyron I; Laboratory for Hemostasis, Inflammation & Thrombosis, Unité Mixed de Recherche, Institut National de la Santé et de la Recherche Médicale, Université Paris-Saclay, Le Kremlin-Bicêtre, France.
  • Christophe OD; Laboratory for Hemostasis, Inflammation & Thrombosis, Unité Mixed de Recherche, Institut National de la Santé et de la Recherche Médicale, Université Paris-Saclay, Le Kremlin-Bicêtre, France.
  • Lenting PJ; Laboratory for Hemostasis, Inflammation & Thrombosis, Unité Mixed de Recherche, Institut National de la Santé et de la Recherche Médicale, Université Paris-Saclay, Le Kremlin-Bicêtre, France.
  • Proulle V; Institut National de la Santé et de la Recherche Médicale, Centre de Recherche des Cordeliers, CNRS, Sorbonne Université, Université Paris Cité, Paris, France; Service d'Hématologie Biologique, Hôpital Cochin, AP-HP Centre, Paris, France.
  • McIntosh J; Deparment of Haematology, UCL Cancer Institute, London, UK.
  • Nathwani AC; Deparment of Haematology, UCL Cancer Institute, London, UK; Katherine Dormandy Haemophilia and Thrombosis Unit, Royal Free London NHS Foundation Trust, London, UK.
  • Dimitrov JD; Institut National de la Santé et de la Recherche Médicale, Centre de Recherche des Cordeliers, CNRS, Sorbonne Université, Université Paris Cité, Paris, France.
  • Denis CV; Laboratory for Hemostasis, Inflammation & Thrombosis, Unité Mixed de Recherche, Institut National de la Santé et de la Recherche Médicale, Université Paris-Saclay, Le Kremlin-Bicêtre, France.
  • Lacroix-Desmazes S; Institut National de la Santé et de la Recherche Médicale, Centre de Recherche des Cordeliers, CNRS, Sorbonne Université, Université Paris Cité, Paris, France. Electronic address: sebastien.lacroix-desmazes@crc.jussieu.fr.
J Thromb Haemost ; 21(9): 2405-2417, 2023 09.
Article en En | MEDLINE | ID: mdl-37271431
BACKGROUND: Transplacental delivery of maternal immunoglobulin G (IgG) provides humoral protection during the first months of life until the newborn's immune system reaches maturity. The maternofetal interface has been exploited therapeutically to replace missing enzymes in the fetus, as shown in experimental mucopolysaccharidoses, or to shape adaptive immune repertoires during fetal development and induce tolerance to self-antigens or immunogenic therapeutic molecules. OBJECTIVES: To investigate whether proteins that are administered to pregnant mice or endogenously present in their circulation may be delivered through the placenta. METHODS: We engineered monovalent immunoglobulin G (FabFc) specific for different domains of human factor VIII (FVIII), a therapeutically relevant model antigen. FabFc was injected with exogenous FVIII into pregnant severe hemophilia A mice or pregnant mice expressing human FVIII following AAV8-mediated gene therapy. FabFc and FVIII were detected in the pregnant mice and/or fetuses by enzyme-linked immunosorbent assay and immunohistochemistry. RESULTS: Administration of FabFc to pregnant mice allowed the maternofetal delivery of FVIII in a FcRn-dependent manner. FVIII antigen levels achieved in the fetuses represented 10% of normal plasma levels in the human. We identified antigen/FabFc complex stability, antigen size, and shielding of promiscuous protein patches as key parameters to foster optimal antigen delivery. CONCLUSION: Our results pave the way toward the development of novel strategies for the in utero delivery of endogenous maternal proteins to replace genetically deficient fetal proteins or to educate the immune system and favor active immune tolerance upon protein encounter later in life.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Inmunoglobulina G / Hemofilia A Tipo de estudio: Prognostic_studies Límite: Animals / Female / Humans / Pregnancy Idioma: En Revista: J Thromb Haemost Asunto de la revista: HEMATOLOGIA Año: 2023 Tipo del documento: Article País de afiliación: Francia Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Inmunoglobulina G / Hemofilia A Tipo de estudio: Prognostic_studies Límite: Animals / Female / Humans / Pregnancy Idioma: En Revista: J Thromb Haemost Asunto de la revista: HEMATOLOGIA Año: 2023 Tipo del documento: Article País de afiliación: Francia Pais de publicación: Reino Unido