Pharmacological Evaluation of Humanized Anti-Epidermal Growth Factor Receptor, Monoclonal Antibody h-R3, in Patients With Advanced Epithelial-Derived Cancer

Abstract

Epidermal growth factor receptor (EGFR) overexpression has been detected in many tumors of epithelial origin, and it is often associated with tumor growth advantages and poor prognosis. h-R3 is a genetically engineered humanized antibody (mAb) that recognizes an epitope located in the extracellular domain of human EGFR. The antibody exhibited potent in vitro and in vivo antitumor effect on EGFR overexpressing cell lines. To study safety, pharmacokinetics, and biodistribution, 12 patients with advanced epithelial-derived tumors received single intravenous infusion of h-R3 at four dose levels. Safety evaluation was made according to World Health Organization toxicity criteria. For biodistribution, 3 mg of the total dose were labeled with Technetium and then pooled with the rest of the dose. Anterior and posterior whole-body images were acquired using a gamma camera. Blood samples were taken for pharmacokinetics, antiidiotypic response, and for soluble EGFR detection. After hR3 administration, no evidence of severe toxicity was observed. Secondary reactions were mild and moderate and mainly consisted of tremors, fever, and vomiting. No anaphylactic or skin reactions were detected. Qualitative analysis of whole-body images showed that the liver had the highest mAb uptake. Pharmacokinetic analysis revealed that elimination half-lives and the AUC increased linearly with dose, while total body clearance decreased when increasing doses of h-R3. No relation between shed EGFR and mAb clearance was found. No antiidiotypic response against h-R3 was detected. Several phase II trials are now underway to evaluate the efficacy of h-R3 in the treatment of advanced cancer patients.

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

“…13 Nimotuzumab has shown a synergic effect when combined with external bean radiotherapy and it has been well tolerated through the intravenous route for treating the advanced epithelial-derived cancer patients including high-grade glioma patients. [14][15][16][17] Recent data from a phase I/II clinical trial, with 200 mg/week of Nimotuzumab for 6 weeks, administered by IV infusion, combined with external radiotherapy in 24 patients with high grade astrocytoma showed no grade 3/4 adverse events. Four patients achieved complete response, 5 a partial response and 11 stable disease, while the median survival time was 22.17 months for all subjects.…”

Enhancement of the antitumor activity of ionising radiation by nimotuzumab, a humanised monoclonal antibody to the epidermal growth factor receptor, in non-small cell lung cancer cell lines of differing epidermal growth factor receptor status

“…In a preclinical study, nimotuzumab showed marked antiproliferative, proapoptotic, and antiangiogenic effects in tumours that overexpress EGFR (Crombet-Ramos et al, 2002). In early clinical trials, nimotuzumab has shown a longer half-life and a greater area under the curve (AUC) in comparison with other anti-EGFR antibodies (Crombet et al, 2003). A phase I/II trial showed that nimotuzumab was well tolerated and enhanced the curative potential of radiation in patients with advanced head and neck cancer (Crombet et al, 2004).…”

Trial Watch: Monoclonal antibodies in cancer therapy

“…Developed in the early 2000s, nimotuzumab (a humanized IgG1 mAb also known as h-R3) soon demonstrated consistent in vitro and in vivo anticancer properties, 60 boosting an intense wave of clinical test, often relying on the combination of nimotuzumab with radiotherapy. [61][62][63][64] In parallel, nimotuzumab was conjugated to radionuclides including 188 Os, 99 mTc, 188 Re and 177 Lu, and some of the resulting immunoradioconjugates entered clinical tests as diagnostic or therapeutic tools for tumors of epidermal origin. [65][66][67][68] Now, approximately 20 phase I-II clinical studies are investigating the efficacy of nimotuzumab for indications as diverse as glioma, head and neck, colorectal and lung cancer.…”