Gestation age dependent transfer of human immunoglobulins across placenta in timed-pregnant guinea pigs

Abstract

IntroductionWhen administered during pregnancy, antibodies and other biologic drugs that contain the Fc part of the IgG molecule can traverse the placenta. Although it is generally accepted that the FcRn receptor mediates this process, gaps remain in our understanding of underlying details in humans and in common laboratory animal species.MethodsWe expanded our previous studies in timed-pregnant guinea pigs to both measure the transport of human (h) IgG at earlier gestation ages in vivo and evaluate FcRn function in vitro using Surface Plasmon Resonance (SPR) and Madin–Darby canine kidney cells (MDCK) that express guinea pig (gp) FcRn.ResultsIn timed-pregnant guinea pigs both the average concentration of hIgG in the fetus and its ratio to maternal hIgG concentration increase exponentially with gestation age. Thus, hIgG fetal:maternal concentration ratios increase from an average of 1% to 3%, 17%, and 76% on GD ~26, 35, 46, and 54, respectively. In vitro, gpFcRn immobilized on a solid surface can bind hIgG and gpIgG preparations in a similar manner. All engineered human Fc isotype-specific constructs were internalized by MDCK-gpFcRn cells at significant levels. While not significant, their recycling and hIgG transcytosis by this cell line also trend higher than background controls.DiscussionPregnant guinea pigs exhibit similarities with humans in the degree and timing of trans-placental transfer as well as the ability of their FcRn to bind and internalize hIgG in vitro. Further studies are needed to guide building appropriate systems for the evaluation of FcRn mediated function of human immunoglobulin therapies.

Assessing Zika virus replication and the development of Zika-specific antibodies after a mid-gestation viral challenge in guinea pigs

“…These results suggest that while ZIKV challenge in pregnant guinea pigs did not result in detectable viremia, a subclinical infection sufficient to elicit a robust antiviral antibody response did occur. Additionally, the observed accumulation of anti-ZIKV NS1 in fetal plasma was consistent with previous reports of the timing and kinetics of maternal to fetal transfer of IgG in both guinea pigs and humans [ 36 – 38 ].…”

Passive Immunoprophylaxis for the Protection of the Mother and Her Baby: Insights from In Vivo Models of Antibody Transport

“…We found that the mean maternal concentrations trend progressively lower with increased gestation ( Figure 3(a) and supplemental Table S1) whereas the corresponding mean fetal concentrations progressively increase ( Figure 3(b) , and [ 21 ]). These two variables were negatively correlated ( Figure 3(f) ) and, after log transformation, the relationship was linear (Pearson correlation r = −0.60, p = 0.0008, confidence interval −0.80 to −0.29).…”

“…Previously we showed that pregnant guinea pigs are an appropriate animal model for studying human antibody transfer during pregnancy [ 21 , 23 ]. The additional experimental data we present here enabled us to more precisely measure placental transfer and further demonstrate that this model recapitulates well the time course of the placental transfer of IgG in pregnant women.…”

“…All animal procedures were performed in accordance with protocols approved by the CBER Animal Care and Use Committee as previously described [ 21 ]. Briefly, Hartley Albino (Crl:HA) guinea pigs were purchased from commercial sources and mated to produce timed pregnancies.…”

“…Five days after injection, blood samples were collected from all dams, five of the litters on GD45, and all the litters of GD55 and 65 via cardio- or cordocentesis; whole fetuses were collected from all the remaining animals. Five days after injection was used as the sampling point for multiple reasons that have been addressed before [ 21 ] and included lack of anti-human antibody response. In addition, results from this and previous pharmacokinetic studies [ 23 ] indicated that five days following HepaGam administration in guinea pigs is approximately 1.5 times the half-life of human IgG in this species and thus can be considered equivalent to the time point when C min or trough antibody levels are achieved during IGIV therapy.…”