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

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.