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 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.
Arteaga
Maria Elene
ME
Centro Nacional para la Producción de Animales de Laboratorio (CENPALAB), Habana, Cuba.
Ledón
Nuris
N
Casacó
Angel
A
Pardo
Balia
B
García
Miriam
M
Boleda
Magela
M
Viña
Lisel
L
Orphee
Romy
R
Hernández
Osvaldo
O
González
Consuelo
C
Fuentes
Dasha
D
Rodríguez
Valia
V
Charro
Lidia
L
Baro
Farah
F
Macías
Amparo
A
Pérez
Aylen
A
Morales
Yakelin
Y
Subirós
Nelvys
N
González
Barbara
B
Ramos
Mayra
M
Rodriquez
Leyanis
L
Ballester-Labrada
Alcides
A
Crombet
Tania
T
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