Passive Perinatal Immunotherapy via Transamniotic Antibody Delivery
Ashlyn E. Whitlock, MD, Daniel F. Labuz, MD, Ina Kycia, PhD, David Zurakowski, PhD, Dario O. Fauza, MD, PhD
Department of Surgery, Boston Children’s Hospital and Harvard Medical School Boston, MA
Fetal administration of immunoglobulin can mitigate perinatal infections and alloimmune disorders. Indirect delivery via the mother is limited by poor placental transfer while direct fetal administration is morbid. We hypothesized that amniotic-fluid could be an attainable route of administration of therapeutic antibodies to the fetus and neonate.
Fetuses (n=109) from Sprague-Dawley dams (n=9) received volume-matched intra-amniotic injections on gestational day 18 (E18; term=21-22 days) of either saline (n=29), or different concentrations of a suspension of human-IgG antibodies: 5mg/mL (n=28), 10mg/mL (n=28), or 15mg/mL (n=24). At term, the presence of human-IgG was quantified by ELISA in the serum, bone marrow, spleen, thymus, and brain of all neonates, as well in the maternal serum. Statistical analysis was by median regression with Bonferroni-adjusted p<0.008.
Overall survival was 83% (90/109) and similar between groups. Human-IgG was detected in the serum, bone-marrow, spleen, thymus, and brain of all fetuses for all three injected concentrations, but not in saline controls (figure; p<0.001). A dose-dependent relationship between injection concentration and IgG load was noted in the bone-marrow, spleen, and thymus (p=0.004 to <0.001). Human-IgG was also detected in maternal serum (figure).
IgG can reach high levels in the fetal/neonatal circulation after simple intra-amniotic administration. Delivery concentration affects antibody load at select sites. Targeted transamniotic antibody delivery may become a strategy of passive immunotherapy for fetuses and neonates.
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