Systemic and Skin Toxicity in Cercopithecus aethiops sabaeus Monkeys Treated During 26 Weeks with a High Intravenous Dose of the Anti-Epidermal Growth Factor Receptor Monoclonal Antibody Nimotuzumab

Maria Elene Arteaga, Nuris Nuris Ledon, Angel Casaco, Balia Pardo, Miriam Garcia, Magela Boleda, Lisel Vina, Romy Orphee, Osvaldo Hernandez, Consuelo Gonzalez, Dasha Fuentes, Valia Rodriguez, Lidia Charro, Farah Baro, Amparo Macias, Aylen Perez, Yakelin Morales, Nelvys Subiros, Barbara Gonzalez, Mayra Ramos, Leyanis Rodriquez, Alcides Ballester-Labrada and Tania Crombet

volume 6 | issue 9

September 2007
Pages: 1390 - 1395

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Nimotuzumab (h-R3) is a humanized anti-epidermal growth factor receptor monoclonal antibody (mAb) registered for treating head and neck tumours. The present study was designed to evaluate the systemic and skin toxicity of chronic intravenous administration of the h-R3 in a relevant species demonstrated by comparing the h-R3 binding affinity constants (Kd) in microsomal placental fractions from Homo sapiens and Cercopithecus aethiops monkeys using an EGF-Receptor radioligand competition assay. The Kd obtained for Nimotuzumab were 9.1x10-8 M for monkeys and 4.5x10-8 M for humans. Monkeys (n=18) were distributed into 3 groups with 3 animals of each sex in each group. Group I received saline; group II received 2.85 mg/kg of h-R3; and group III received 28.57 mg/kg of the h-R3, which represent 1 and 10 times the human dose, and they were weekly intravenously treated during 26 weeks. During the study there were no deaths. Electroneurophysiological, sanguine chemistry and haematological results did not evidence alterations. Areas of haematomas, probably related with the administration procedure, were observed at the administration zones of all animals. The electrocardiography study showed at the end of the study a slight increase in the cardiac frequency of 4 treated animals without others signs. Unexpectedly, skin biopsies and a detailed clinical inspection of the animals did not detect the presence of cutaneous rash or any other skin toxicity sign reported for the majority of the anti-EGF-R monoclonal antibodies. It is concluded that doses up to 28.5 mg/kg of h-R3, intravenously administered during 26 weeks to Cercopithecus aethiops monkeys, do not produce considerable toxic effects.