The Effects of Interleukin‐6 Signal Blockade on Fertility, Embryo‐fetal Development, and Immunization In vivo

Abstract

Possible effects of interleukin‐6 (IL‐6) on reproductive performance, embryonal development, parturition, and postnatal development have been suggested based on protein/mRNAexpression level of IL‐6 in related organs, but less is known about functions of IL‐6 signals in these areas. Following two different approaches have been employed to investigate the role of IL‐6 signals in fertility and pre‐/postnatal development: administration of a rat anti‐mouse IL‐6 receptor antibody, MR16‐1, to mice as a neutralizing antibody system, and B6.129S2‐Il6tm1Kopf/J (IL‐6 knockout [KO]) mice as a KO system. By intravenously dosing 50 mg/kg of MR16‐1 every 3 days, animals in male and female fertility studies and dams in a pre‐/postnatal development study exhibited plasma MR16‐1 concentrations much higher than the effective plasma concentration, indicating that MR16‐1 exposure was sufficient to completely block IL‐6 signals. The concentration of MR16‐1 in the plasma of fetuses exceeded that in the plasma of pregnant animals, and MR16‐1 concentration in milk was about one‐fourth of that in plasma. Both the transient IL‐6 signal blockade by MR16‐1, and the constitutive IL‐6 signal inhibition using IL‐6 KO mice in a combined fertility and pre‐/postnatal development study, revealed no biologically important effects on fertility, early embryonic development to implantation, or pre‐/postnatal development, including IgG/IgM production by keyhole limpet hemocyanin sensitization. These results indicate that IL‐6 signals have no unique, noncompensable roles in reproduction and development in the whole body system, although contributions of IL‐6 in the signaling network appear to exist, as suggested by previously published investigations.

Tocilizumab use in pregnancy: Analysis of a global safety database including data from clinical trials and post-marketing data

“…Preclinical data from experimental animal studies suggest that blockade of IL-6-receptor signaling induces no apparent biological effects on fertility or pre-/postnatal development [6].…”

Novel genetically-humanized mouse model established to evaluate efficacy of therapeutic agents to human interleukin-6 receptor

“…Yoshida et al reported that first intravenous dosing (2 mg/body) inhibited the production of antibodies to MR16-1 after repetitive intraperitoneal or subcutaneous injections of MR16-1 in NZB/NZW F1 mice29. Sakurai et al also suggested the possibility that tolerance induction would inhibit the production of antibody to drug after finding that antibodies to MR16-1 were detected in some mice treated with 15 mg/kg of MR16-1 intravenously every 3 days but not detected in 50 mg/kg groups30. In our study, however, in Il6ra +/+ -h IL6 transgenic mice expressing only mouse Il6ra, the same doses of tocilizumab produced extremely high titers of anti-tocilizumab antibodies, suggesting that there might be some other mechanism than tolerance induction from a first higher dosing.…”

Immunosuppressives and biologics during pregnancy and lactation

“…Along with animal models, the available case reports and case series have yielded no evidence of teratogenic and/or mutagenic effects or an impact on fertility [96, 97]. An animal study showed an increased risk of spontaneous miscarriages and embryonic/fetal mortality in high doses [98].…”