We report here two cases of breastfeeding patients who required the use of biologics due to signs of worsening disease postpartum. The transfer of the IgG1 monoclonal antibodies, RTX and canakinumab, into breast milk was expected to be low due to the low content of IgG in human breast milk . The predominant immunoglobulin in breast milk is IgA, ranging from about 900 µg/ml in colostrum to about 400 µg/ml in mature milk [6, 7]. By contrast, the content of IgG in mature breast milk is approximately 1/20 of the IgA levels . Among the IgG subclasses, IgG1 represents the lowest proportion in mature milk, with levels of about 5 µg/ml . The concentrations of RTX and canakinumab in breast milk were clearly < 1 µg/ml, as confirmed previously in other studies on RTX [8, 9]. These data confirm the low transfer of IgG1 monoclonal antibodies into breast milk. Similarly, low concentrations of various other biologics (e.g. infliximab, certolizumab, adalimumab, golimumab, ustekinumab, natalizumab) have been found in the breast milk of women receiving treatment, independent of application mode, half-life or time to maximum serum concentration, emphasizing that IgG-based molecules all pass poorly into breast milk [10, 11].
What matters to our breastfeeding patients is the question of whether this minimal transfer of canakinumab or RTX into breast milk is clinically relevant to their infant. An estimate widely used to express the drug exposure of the breastfed infant is the RID. The low concentrations of canakinumab and RTX in the breast milk of our patients and the weight-adjusted maternal doses translated into a reassuring median RID of < 0.1%. In partially breastfed infants, as in case 2, the RID ratio is overestimated. Generally, drugs with a RID of < 10% are regarded as safe when breastfeeding . However, the RID is a theoretical estimate, not a real-time measurement of drug transfer into the infant’s bloodstream. The uncertainty revolves around the question of whether these low quantities of monoclonal antibodies swallowed by the suckling infant can be absorbed by the gastrointestinal tract and detected in the infant’s bloodstream. Binding sites of IgG molecules, such as the neonatal Fc receptor (FcRn), are indeed expressed across different species and on different tissues, such as the placenta and intestinal epithelial cells , the latter providing the prerequisite for intestinal absorption. In rodents, passive immunity of the neonate via protective IgG is delivered via the placenta as well as through breast milk. However, the situation in humans is clearly in favour of the transplacental pathway [7, 12], as shown by therapeutic serum levels of IgG monoclonal antibodies such as canakinumab, infliximab or adalimumab in neonates after in-utero exposure during late gestation [13,14,15]. Fetal exposure can be reduced by avoiding the biologic drug during the third trimester, or even beyond gestational week 20, as in our patient with MWS. The transplacentally acquired canakinumb level in the infant’s cord blood was clearly below therapeutic levels  and continued to decrease, becoming undetectable despite repeated maternal doses during the observed lactation period. This underlines the poor intestinal absorption of monoclonal IgG antibodies. Similar pharmacokinetics have been described in one breastfed infant exposed to infliximab during pregnancy and lactation . By contrast, a subtherapeutic serum level of infliximab was found in one breastfed infant 5 days after the maternal infusion; however, no detectable drug levels were seen in the sera of two other breastfed infants after maternal treatment with adalimumab or infliximab . In our patients, there were no detectable levels of canakinumab or RTX in the sera of the breastfed infants. Gastrointestinal proteolysis is likely to be the predominant mechanism destroying the integrity of luminal monoclonal IgG antibodies, thereby explaining the poor oral bioavailability of these biologics as a whole.
In conclusion, increasing data on the pharmacokinetics of biologics in lactating patients aids the shared decision-making process. Our cases reveal minimal transfer of canakinumab and RTX into breast milk, and no detectable levels of these biologics in the bloodstream of the breastfed infants. Thus, we conclude that canakinumab and RTX can be used to maintain disease control in breastfeeding patients. However, more pharmacokinetic data are needed in this field. Notably, it remains to be determined whether the transfer of monoclonal antibodies into breast milk can be altered in different clinical scenarios, such as in prematurely born infants or in the case of mastitis, with a possible increase in paraepithelial transfer of larger molecules.