O3314: Prenatal Administration of Immunoglobulin-M (IgM) Via Transamniotic Fetal Immunotherapy (TRAFIT)

Background: Immunoglobulin-G (IgG) is the only class of immunoglobulins that can cross the placenta from the mother to the fetus during pregnancy. This limitation is one of the contributing factors to the fetus’ and neonate’s unique vulnerability to certain infections, particularly in the perinatal period. Immunoglobulin-M (IgM) is the first antibody class produced during an immune response, playing a crucial role in early defense mechanisms. Produced by lymphocytes B, IgM also functions as a receptor on the surface of naive B cells in its monomeric form, enabling them to recognize antigens and initiate immune responses. Circulating IgM is characterized by a pentameric (less commonly also hexameric) structure consisting of five antibody units linked together, providing ten antigen-binding sites that increase its avidity for antigens of interest (figure). Such large structure, however, is thought to be the reason why it cannot cross the placenta. The transamniotic route has been shown experimentally to be a viable alternative for the administration of immunoglobulins of the G and A classes to the fetus. In this study, we sought to determine whether IgM is also amenable to transamniotic delivery, at first utilizing a healthy rodent model.

Methods: After IACUC approval, fetuses (n=42) from three time-dated pregnant Sprague-Dawley dams received intra-amniotic injections on gestational day 17 (E17, term=E21-22) of either a solution of human pooled IgM antibodies with a reported half-life of 5 days suspended in saline (n=27), or just saline (n=15), the latter to control for the possibility of IgM interspecies homology. Dams were euthanized at term when samples from anatomical sites relevant to the immune response (specifically, bone marrow, spleen, thymus, and serum) were procured. A semi-quantitative, fluorescent enzyme-linked immunosorbent assay (ELISA) previously validated for the IgM delivered was performed in duplicate in each sample. Statistical analyses included Fisher’s exact and Wilcoxon rank sum tests, both with and without nesting to account for individual mothers (significance set at p< 0.05).

Results: Overall survival was 92.9% (39/42) with no significant differences between the groups. In the non-nested comparisons, significantly elevated relative fluorescence was detected in IgM exposed animals in the spleen, thymus, bone marrow, and serum (all p< 0.001). In the nested comparisons, thymus, bone marrow, and serum in IgM animals remained significant higher (p=0.01 to < 0.001) while spleen levels were not significantly elevated (p=0.064).

Conclusion: Fetal administration of immunoglobulin-M (IgM) is viable via the transamniotic route. Transamniotic fetal immunotherapy (TRAFIT) utilizing IgM may become a valuable minimally invasive alternative for the prevention and/or treatment of select perinatal infections.