Assessment of fetal exposure risk following seminal excretion of a therapeutic IgG4 (T-IgG4) monoclonal antibody using a rabbit model

Abstract

Studies were conducted in New Zealand White rabbits to assess the seminal transfer, vaginal absorption, and placental transfer of a therapeutic monoclonal antibody (T-IgG4). T-IgG4 was administered by intravenous injection (IV) in males and by IV and intravaginal routes in females. Low levels of T-IgG4 were excreted into seminal plasma (100- to 370-fold lower than serum concentrations) and absorbed following vaginal dosing (three orders of magnitude lower than IV administration). On gestation day 29 (GD29), fetal serum T-IgG4 levels were 1.5-fold greater than maternal levels following IV dosing. The fetal T-IgG4 exposure ratio for seminal transfer vs. direct maternal IV dosing was estimated to be 1.3×10(-8). Applying human serum T-IgG4 exposure data to the model, the estimated human T-IgG4 serum concentration from seminal transfer was 3.07×10(-7)μg/mL, an exposure level at least 1000-fold lower than the T-IgG4-ligand dissociation constant (Kd) and at least seven orders of magnitude lower than the in vivo concentration producing 20% inhibition of the target (EC20). These data indicate that excretion of a T-IgG4 into semen would not result in a biologically meaningful exposure risk to the conceptus of an untreated partner.

An open‐label study in healthy men to evaluate the risk of seminal fluid transmission of denosumab to pregnant partners

“…Currently, limited human data are available to indicate whether male patients who receive a mAb therapeutic such as denosumab should be required to use any form of contraception. The data presented here, together with other recently published data , indicate that the risk of denosumab in seminal fluid resulting in fetal exposure to denosumab is negligible and that any theoretical exposure that might occur is highly unlikely to be pharmacologically relevant. These observations may be generally relevant to the class of therapeutic monoclonal antibodies.…”

“…Further investigation of fetal exposure to an IgG2 mAb following biweekly intravaginal administration to cynomolgus monkeys throughout pregnancy yielded data demonstrating that only 0.01% of the intravaginal dose reaches the maternal circulation during the mid‐to‐late third trimester, with no detectable exposure in the conceptus . Similar results were seen with an IgG4 mAb . These in vivo animal study results indicate that male‐mediated mAb drug transfer may not pose a health risk to the pregnant female partner and her fetus, especially as mAbs are not likely to be bioavailable to the developing conceptus.…”

Developmental Toxicity and Fertility Assessment in Rabbits with Tabalumab: A Human IgG4 Monoclonal Antibody

“…Although the placental transfer of tabalumab was not measured in this study, it is assumed that embryonic-fetal exposure occurred, as the placental transfer of tabalumab was demonstrated in a monkey pre-postnatal development study and humanized monoclonal IgGs have been reported to cross the placenta in rabbits during gestation (Bowman et al, 2013;Breslin et al, 2014), with fetal concentrations reaching or exceeding maternal concentrations toward the end of gestation. The placental transfer of IgG4 during mid to late gestation has been shown to be similar across rabbits, monkeys, and humans, all species with a hemochorial placentation (Bowman et al, 2013).…”

CGRP, Amylin, Immunology, and Headache Medicine

“…The rabbit appears to be an appropriate maternal-fetal model, as all IgG classes appear to cross with greater efficiency than in humans. 110,111 Lily Research Labs reported that excretion of a therapeutic-IgG4 into semen would not result in a biologically meaningful exposure risk to the conceptus of an untreated partner using a rabbit model. 111 In the CGRP therapeutics database in the public domain, there is a single report of a male birth of a galcanezumab-treated father on 300 mg with ankyloglossia, a birth defect that decreases mobility of the tip of the tongue, associated with a pathologically short, thick lingual frenulum.…”

“…110,111 Lily Research Labs reported that excretion of a therapeutic-IgG4 into semen would not result in a biologically meaningful exposure risk to the conceptus of an untreated partner using a rabbit model. 111 In the CGRP therapeutics database in the public domain, there is a single report of a male birth of a galcanezumab-treated father on 300 mg with ankyloglossia, a birth defect that decreases mobility of the tip of the tongue, associated with a pathologically short, thick lingual frenulum. 112 Additionally, no adverse parental, reproductive, or developmental effects were observed in any study at any dose with exposures 14-fold greater than human exposure levels.…”