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.

Nimotuzumab, a promising therapeutic monoclonal for treatment of tumors of epithelial origin

“…Table 2 provides Kd of the different anti-EGFR monoclonals and the capacity of them to cause acneiform rash. 9 Cetuximab shows higher binding affinities than Nimotuzumab in human and in green monkey placentas. These results could be correlated with the dose-dependent skin toxicity effects observed at all dose levels with Cetuximab in a 39-week repeated-dose study in Cynomolgus monkeys.…”

Nimotuzumab with chemoradiation confers a survival advantage in treatment-naïve head and neck tumors over expressing EGFR

“…In fact analysis show that higher affinity antibodies showed significantly higher skin toxicities. 43 Higher affinity antibodies may bind to antigen in the vicinity of the vessels increasing its toxic effects by reducing the penetration into the tumor. 44 Alternatively, as the model predicts, intermediate affinity antibodies (10 -8 and 10 -9 M) like Nimotuzumab would have maximum tumor uptake and minimum uptake in the normal tissues thereby reducing skin toxicity.…”

Phase I single-dose study of intracavitary-administered Nimotuzumab labeled with 188-Re in adult recurrent high-grade glioma

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