PDGFRα monoclonal antibody: Assessment of embryo-fetal toxicity and time-dependent placental transfer of a murine surrogate antibody of olaratumab in mice.

BACKGROUND

Olaratumab (Lartruvo™) is a recombinant human IgG1 monoclonal antibody that specifically binds PDGFRα. The maternal and in utero embryo-fetal toxicity and toxicokinetics of a human anti-mouse PDGFRα antibody (LSN3338786) were investigated in pregnant mice.

METHODS

A pilot study was used to set doses for the definitive study. In the definitive study, mice were administered vehicle, 5, 50, or 150 mg/kg LSN3338786 by intravenous injection on gestation days (GD) 6, 9, 12, and 15. Fetal tissues and/or serum samples were collected on GD 10, 12, 15, and 18 to evaluate exposure of antibody.

RESULTS

There were no adverse maternal effects at 50 and 150 mg/kg although maternal deaths and adverse clinical signs were observed at 5 mg/kg. LSN3338786 crossed the placenta as early as GD 10 during organogenesis. Elimination half-life of LSN3338786 in dams decreased between GD 6 and 15. On GD 18, fetal serum concentrations of antibody were substantially higher than maternal serum concentrations at all doses. Increased incidences of malformations consisting of open and partially open eye and increased incidences of skeletal variation frontal/parietal additional ossification site occurred in fetuses from mid- and high-dose groups.

CONCLUSIONS

The majority of transplacental migration of antibody occurred in concert with rapid maternal serum clearance before parturition. The no-observed effect level for teratogenicity of 5 mg/kg was associated with GD 15 maternal serum concentrations 3-11 times lower than clinical exposure of olaratumab, suggesting that olaratumab may cause fetal harm when administered to pregnant women.