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

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 demonstra...

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Published in:	Cancer biology & therapy Vol. 6; no. 9; pp. 1386 - 1391
Main Authors:	Arteaga, Maria Elene, Nuris Ledon, Nuris, Casaco, Angel, Pardo, Balia, Garcia, Miriam, Boleda, Magela, Vina, Lisel, Orphee, Romy, Hernandez, Osvaldo, Gonzalez, Consuelo, Fuentes, Dasha, Rodriguez, Valia, Charro, Lidia, Baro, Farah, Macias, Amparo, Perez, Aylen, Morales, Yakelin, Subiros, Nelvys, Gonzalez, Barbara, Ramos, Mayra, Rodriquez, Leyanis, Ballester-Labrada, Alcides, Crombet, Tania
Format:	Journal Article
Language:	English
Published:	United States Taylor & Francis 01-09-2007
Subjects:	Animals Antibodies, Monoclonal - adverse effects Antibodies, Monoclonal - chemistry Antibodies, Monoclonal - toxicity Antibodies, Monoclonal, Humanized Antineoplastic Agents - adverse effects Antineoplastic Agents - toxicity Binding Binding, Competitive Biology Bioscience Calcium Cancer Cell Cercopithecus aethiops Cycle Electrocardiography - methods ErbB Receptors - antagonists & inhibitors ErbB Receptors - metabolism Evoked Potentials Female Infusions, Intravenous Landes Male Organogenesis Proteins Skin - drug effects Skin - metabolism Toxicity Tests
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Summary:	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.
ISSN:	1538-4047 1555-8576
DOI:	10.4161/cbt.6.9.4539