Transplacental delivery of therapeutic proteins by engineered IgG: a step towards perinatal replacement therapy

Background: Transplacental delivery of maternal IgG provides humoral protection during the first months of life until the newborn’s immune system reaches maturity. The materno-fetal 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. Objective: 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 IgG (FabFc) specific for different domains of human factor VIII (FVIII), a therapeutically relevant model antigen. The FabFc were injected with exogenous FVIII to pregnant severe hemophilia A mice or to pregnant mice expressing human FVIII following AAV8-mediated gene therapy. FabFc and FVIII were detected in the pregnant mice and/or fetuses by ELISA and immunohistochemistry. Results: Administration of FabFc to pregnant mice mediated the materno-fetal 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 identify antigen/FabFc complex stability, antigen size and shielding of promiscuous protein patches, as key parameters to foster optimal antigen delivery.Conclusions: Our results pave the way towards 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.