Anti-TNF Safety in Pregnant and Breastfeeding Women With IBD
Anti-TNF Safety in Pregnant and Breastfeeding Women With IBD
The humoral immune system comprises five classes of antibodies; however, the human placenta seems to be impermeable to all except immunoglobulin G (IgG). IgG consists of four subclasses: IgG1, IgG2, IgG3 and IgG4. Most of the IgG in the fetus is of maternal origin, and IgG1 is the most effectively transported subclass.
Both infliximab and adalimumab are IgG1 monoclonal antibodies, while certolizumab is a Fab fragment of IgG1. Immunoglobulins are large hydrophilic molecules with a molecular mass of ~150 kD. Consequently, they cannot be transferred by simple diffusion and require active transport across the placenta via a specific receptor-mediated mechanism.
Transport of IgG across the placenta is regulated by two cellular barriers: the syncytiotrophoblast and the fetal capillary endothelium. The first step in IgG materno-fetal transfer takes place via specific receptor-mediated binding. The receptor, neonatal Fc receptor (FcRn), consists of β-2-microglobulin and a large subunit resembling the α-chains of major histocompatibility complex class I molecules. The Fc portion of IgG has been found to bind with high activity to FcRn at an acidic pH (<6.5), although not at a physiological pH. The syncytiotrophoblast internalizes the IgG-containing fluid into the endosomes, which are gradually acidified, thus enabling IgG to bind to the FcRn present in this compartment. The vesicle then fuses with the membrane on the fetal side of the syncytiotrophoblast, where physiological pH promotes the dissociation of IgG from FcRn.
The role of the second placental barrier, the fetal capillary endothelium, is not yet clear. FcRn is only occasionally or weakly expressed on the endothelium of fetal vessels, suggesting that another mechanism is involved in transport of IgG across this placental layer. As the cells of the endothelium are arranged close together, IgG is thought to be transmitted by a transcellular route, rather than by a paracellular route between the cells of the endothelium.
During the first trimester, the FcRn of the placental syncytiotrophoblast is barely detectable and has not been observed before week 14 of gestation. Very low levels of maternal IgG are present in the villous stroma of the placenta during the first trimester (8–10 weeks). However, some authors have detected transfer of IgG into embryonic tissue as early as 4 weeks, suggesting that IgG is transferred during very early pregnancy by an as yet unidentified alternative mechanism.
Less effective transport through the placenta during the first and second trimesters of pregnancy might be due to the presence of an additional barrier, the cytotrophoblast. This layer divides after the fourth month of pregnancy and becomes less prominent when the placenta matures. FcRn have also been found on the microvillous surface of the human fetal intestine, but only from 18 weeks. Fetal swallowing of amniotic fluid (beginning at 18 weeks of gestation) enables protein clearance. IgG uptake from ingested fluid is thus mediated by fetal intestinal FcRn receptors.
Certolizumab differs from infliximab and adalimumab in that it is a Fab fragment of an anti-TNF monoclonal antibody rather than whole IgG1 antibody. Much higher drug levels were consistently observed in fetal samples from pregnant rats with murinized IgG1 than in those with PEGylated Fab versions of hamster antimurine TNF antibody. Accordingly, some authors have recommended discontinuing infliximab/adalimumab in the third trimester (see below), but continuing certolizumab on schedule up to delivery. Consequently, certolizumab could prove more effective than other anti-TNF therapies if this lack of placental transfer is demonstrated in humans. Nevertheless, although the active placental transport of certolizumab via FcRn is not generally observed, some kind of diffusion might theoretically occur via alternative mechanisms in all three trimesters. In this respect, data from four patients who used certolizumab during pregnancy with the last dose 1–4 weeks before delivery revealed low levels of drug in cord blood and in the infant on the day of birth.
Placental Transport of Anti-TNF Drugs
The humoral immune system comprises five classes of antibodies; however, the human placenta seems to be impermeable to all except immunoglobulin G (IgG). IgG consists of four subclasses: IgG1, IgG2, IgG3 and IgG4. Most of the IgG in the fetus is of maternal origin, and IgG1 is the most effectively transported subclass.
Both infliximab and adalimumab are IgG1 monoclonal antibodies, while certolizumab is a Fab fragment of IgG1. Immunoglobulins are large hydrophilic molecules with a molecular mass of ~150 kD. Consequently, they cannot be transferred by simple diffusion and require active transport across the placenta via a specific receptor-mediated mechanism.
Transport of IgG across the placenta is regulated by two cellular barriers: the syncytiotrophoblast and the fetal capillary endothelium. The first step in IgG materno-fetal transfer takes place via specific receptor-mediated binding. The receptor, neonatal Fc receptor (FcRn), consists of β-2-microglobulin and a large subunit resembling the α-chains of major histocompatibility complex class I molecules. The Fc portion of IgG has been found to bind with high activity to FcRn at an acidic pH (<6.5), although not at a physiological pH. The syncytiotrophoblast internalizes the IgG-containing fluid into the endosomes, which are gradually acidified, thus enabling IgG to bind to the FcRn present in this compartment. The vesicle then fuses with the membrane on the fetal side of the syncytiotrophoblast, where physiological pH promotes the dissociation of IgG from FcRn.
The role of the second placental barrier, the fetal capillary endothelium, is not yet clear. FcRn is only occasionally or weakly expressed on the endothelium of fetal vessels, suggesting that another mechanism is involved in transport of IgG across this placental layer. As the cells of the endothelium are arranged close together, IgG is thought to be transmitted by a transcellular route, rather than by a paracellular route between the cells of the endothelium.
During the first trimester, the FcRn of the placental syncytiotrophoblast is barely detectable and has not been observed before week 14 of gestation. Very low levels of maternal IgG are present in the villous stroma of the placenta during the first trimester (8–10 weeks). However, some authors have detected transfer of IgG into embryonic tissue as early as 4 weeks, suggesting that IgG is transferred during very early pregnancy by an as yet unidentified alternative mechanism.
Less effective transport through the placenta during the first and second trimesters of pregnancy might be due to the presence of an additional barrier, the cytotrophoblast. This layer divides after the fourth month of pregnancy and becomes less prominent when the placenta matures. FcRn have also been found on the microvillous surface of the human fetal intestine, but only from 18 weeks. Fetal swallowing of amniotic fluid (beginning at 18 weeks of gestation) enables protein clearance. IgG uptake from ingested fluid is thus mediated by fetal intestinal FcRn receptors.
Certolizumab differs from infliximab and adalimumab in that it is a Fab fragment of an anti-TNF monoclonal antibody rather than whole IgG1 antibody. Much higher drug levels were consistently observed in fetal samples from pregnant rats with murinized IgG1 than in those with PEGylated Fab versions of hamster antimurine TNF antibody. Accordingly, some authors have recommended discontinuing infliximab/adalimumab in the third trimester (see below), but continuing certolizumab on schedule up to delivery. Consequently, certolizumab could prove more effective than other anti-TNF therapies if this lack of placental transfer is demonstrated in humans. Nevertheless, although the active placental transport of certolizumab via FcRn is not generally observed, some kind of diffusion might theoretically occur via alternative mechanisms in all three trimesters. In this respect, data from four patients who used certolizumab during pregnancy with the last dose 1–4 weeks before delivery revealed low levels of drug in cord blood and in the infant on the day of birth.
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