title: 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.
abstract: 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 9.1 x 10(-8) M for monkeys and 4.5 x 10(-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 four treated animals without other 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.
authors.affiliation: Centro Nacional para la Producción de Animales de Laboratorio (CENPALAB), Habana, Cuba.
authors.forename: Maria Elene
authors.initials: ME
authors.lastname: Arteaga
authors.forename: Nuris
authors.initials: N
authors.lastname: Ledón
authors.forename: Angel
authors.initials: A
authors.lastname: Casacó
authors.forename: Balia
authors.initials: B
authors.lastname: Pardo
authors.forename: Miriam
authors.initials: M
authors.lastname: García
authors.forename: Magela
authors.initials: M
authors.lastname: Boleda
authors.forename: Lisel
authors.initials: L
authors.lastname: Viña
authors.forename: Romy
authors.initials: R
authors.lastname: Orphee
authors.forename: Osvaldo
authors.initials: O
authors.lastname: Hernández
authors.forename: Consuelo
authors.initials: C
authors.lastname: González
authors.forename: Dasha
authors.initials: D
authors.lastname: Fuentes
authors.forename: Valia
authors.initials: V
authors.lastname: Rodríguez
authors.forename: Lidia
authors.initials: L
authors.lastname: Charro
authors.forename: Farah
authors.initials: F
authors.lastname: Baro
authors.forename: Amparo
authors.initials: A
authors.lastname: Macías
authors.forename: Aylen
authors.initials: A
authors.lastname: Pérez
authors.forename: Yakelin
authors.initials: Y
authors.lastname: Morales
authors.forename: Nelvys
authors.initials: N
authors.lastname: Subirós
authors.forename: Barbara
authors.initials: B
authors.lastname: González
authors.forename: Mayra
authors.initials: M
authors.lastname: Ramos
authors.forename: Leyanis
authors.initials: L
authors.lastname: Rodriquez
authors.forename: Alcides
authors.initials: A
authors.lastname: Ballester-Labrada
authors.forename: Tania
authors.initials: T
authors.lastname: Crombet
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000737:chemistry* / Q000633:toxicity; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000633:toxicity*; D001667:Binding, Competitive; D002522:Chlorocebus aethiops; D004562:Electrocardiography / Q000379:methods; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005071:Evoked Potentials; D005260:Female; D007262:Infusions, Intravenous; D008297:Male; D012867:Skin / Q000187:drug effects* / Q000378:metabolism; D018675:Toxicity Tests