title: 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.
authors.affiliation: Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN, USA. Electronic address: wjbreslin@lilly.com.
authors.forename: William J
authors.initials: WJ
authors.lastname: Breslin
authors.affiliation: Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN, USA.
authors.forename: Kim G
authors.initials: KG
authors.lastname: Hilbish
authors.affiliation: Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN, USA.
authors.forename: Todd J
authors.initials: TJ
authors.lastname: Page
authors.affiliation: Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Coutant
mesh_terms: D000282:Administration, Intravaginal; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D005333:Fetus / Q000378:metabolism*; D007074:Immunoglobulin G / Q000008:administration & dosage* / Q000097:blood / Q000494:pharmacology*; D007275:Injections, Intravenous; D008297:Male; D008431:Maternal-Fetal Exchange; D010920:Placenta / Q000378:metabolism; D011247:Pregnancy; D011817:Rabbits; D012661:Semen / Q000378:metabolism*; D014621:Vagina / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D007074:Immunoglobulin G
keywords: IgG; Monoclonal antibodies; Placental transfer; Seminal transfer; Vaginal absorption