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

Abstract

BackgroundOlaratumab (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.MethodsA 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.ResultsThere 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.ConclusionsThe 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.

PDGFRα monoclonal antibody: Assessment of toxicity in juvenile mice administered a murine surrogate antibody of olaratumab

“…These observations included gasping, increased respiration rate, and/or labored respiration immediately following dosing on PND 7; these findings resolved before the 1-hour postdose observations on the same day. These observations are similar to those noted in the previous EFD studies conducted in CD1 mice with LSN3338786 and may be related to an adverse drug reaction due to immune complex formation at low dose levels of surrogate antibody (Luffer-Atlas et al, 2018).…”

“…The low dose was selected to provide an approximate 2Â margin to the human projected efficacious dose. The low dose was the lowest feasible dose due to the potential for immune complex formation previously observed in the EFD study (Luffer-Atlas et al, 2018).…”

“…An important aspect of the pilot juvenile study was to determine if SC injection of LSN3338786 beginning on PND 1 followed by a repeat dose frequency of once every 3 days would generate systemic exposure in neonatal mice similar to serum exposure previously observed in maternal mice administered LSN3338786 by intravenous (IV) injection beginning on Gestation Day (GD) 6 in the reproductive toxicity study (Luffer-Atlas et al, 2018). A direct comparison of TK parameters from the EFD study on GD 15 reveals that maternal mice administered dose levels of 50 and 150 mg/kg by IV injection exhibited mean AUC 0-72hr of 10,600 and 29,600 μg•hr/mL, respectively.…”

“…Given the short life expectancy of patients in the studied and proposed indications, Lilly initially opted to follow the ICH S9 guidance to ensure the safety of olaratumab in patients. It was therefore proposed to health authorities that available nonclinical safety data with olaratumab, as well as data from clinical trials in adults, in conjunction with the extensive literature review and the results from previous embryo-fetal development studies in mouse using the surrogate molecule (Luffer-Atlas et al, 2018) would establish adequate safety for olaratumab administration in pediatric patients with advanced cancer. However, EMA noted the weight of evidence may not provide adequate detection of postnatal effects of the drug, thus based on this feedback a juvenile animal study was conducted.…”

“…Because olaratumab does not bind to mouse or rabbit PDGFRα, traditional rodent or rabbit EFD studies with human olaratumab would not have been informative to assess risk. Alternatively, LSN3338786 is a human anti‐mouse PDGFRα antibody that binds to the mouse PDGF receptor with similar affinity as olaratumab has for the human PDGF receptor thus the EFD study was conducted in CD1 mice with this surrogate antibody of olaratumab (Luffer‐Atlas, Reddy, Hilbish, Grace, & Breslin, 2018). The use of the murine monoclonal antibody (mAb) surrogate in a mouse model of reproductive toxicity avoided both the technical and ethical issues associated with a nonhuman primate model for developmental toxicity testing when the available scientific information already demonstrates a high risk for reproductive toxicity.…”