Multiple dose toxicity study of the humanized anti-epidermal growth factor receptor monoclonal antibody h-R3...

The h-R3 is a humanized growth factor receptor monoclonal antibody (mAb) in development for the treatment of head and neck tumours in which malignant cells overexpress the Epidermal Growth Factor receptor. The present study was designed to evaluate the toxicity of repeated intravenous doses of the h-R3 mAb in a relevant species demonstrated by the avidin-biotin-peroxidase immunohistochemical (IHC) technique in skin biopsy samples from three Cercopithecus aethiops sabaeus monkeys (green monkeys). Additionally, 18 green monkeys were daily intravenously treated during 14 consecutive days. Monkeys were distributed into three experimental groups with three animals of each sex in each group. Group I received saline solution and served as control group; group II received 2.85 mg/kg of h-R3 mAb; and group III received 11.4 mg/kg of the h-R3 mAb. During the study there were no deaths, neither pathological clinical signs, or variations in the corporal weight curve. The electroneurophysiological and sanguine chemistry results did not evidence alterations related to the assay substance. Areas of haematomas, haemorrhages and inflammation, probably related with the administration procedure, were observed at the administration zones of all animals; this fact could also explain the increase in the neutrophil count of all animals at the end of the study. The electrocardiography study showed that in the 14 days of the study one female monkey, from the higher dose group, shifted its cardiac axis from +60 degrees to + 120 degrees; this finding could be interpreted as a right ventricular elongation due to the relative high daily administered volume. It is concluded that doses up to 11.4 mg/kg of h-R3, intravenously administered during 14 consecutive days to Cercopithecus aethiops sabaeus monkeys do not produce considerable toxic effects in the studied system.