Resolution of unexpected pregnancy‐related findings in a rat embryofetal development and toxicokinetic study of monoclonal antibodies specific for hCMV

BACKGROUND: Developmental and reproductive toxicity testing is not uniformly warranted for biopharmaceuticals that lack relevant targets in test species. However, RG7667, consisting of two monoclonal antibodies specific for human cytomegalovirus (hCMV), was intended for administration to pregnant women to prevent transmission of CMV to the developing fetus. METHODS: Considering the target indication, a Pilot Embryo Fetal Development/Toxicokinetic study was conducted to assess toxicokinetics in the dam and fetuses and general tolerability. RESULTS: RG7667 administered intravenously to presumed pregnant Sprague-Dawley rats was well tolerated with no clinical signs in any dam and comparable litter sizes and viability across groups. However, at cesarean section, hepatic necrosis and pancreatic edema were identified in two dams administered RG7667, with no clear dose relationship. Investigation of total protein, albumin, and transaminase activity in residual serum from TK samples demonstrated striking hypoproteinemia and elevated transaminases limited to these two dams. Overall, these pathology findings in dams were considered of uncertain relationship to RG7667; therefore, a subsequent Pivotal EFD study was conducted, which did not repeat the liver or pancreatic findings. CONCLUSIONS: The results of the Pivotal study confirmed the lack of overt toxicity, teratogenicity, or effects on litter size and viability when human or humanized monoclonal antibodies that lack an endogenous target are administered IV to rats during pregnancy. With these additional data, we concluded that the unexpected pathology findings in the Pilot study were not specific to RG7667, but rather highlight some clinical pathology and macroscopic/microscopic findings that can occur during pregnancy in rats.