Phase I Clinical Evaluation of a Neutralizing Monoclonal Antibody Against Epidermal Growth Factor Receptor in Advanced Brain Tumor Patients: Preliminary Study

Abstract

High levels of growth factors and their receptors have been demonstrated in human tumors. Gliomas and meningiomas are characterized by overexpression of epidermal growth factor receptor (EGF-R). Ior egf/r3, is a neutralizing murine monoclonal antibody (MAb) against EGF-R, and was generated at the Cuban Institute of Oncology. The antibody recognizes EGF-R with high affinity, inhibiting tyrosine kinase activation. A clinical trial was conducted in brain tumor patients to evaluate toxicity, immunogenicity, and clinical benefit of escalating doses of the antibody. Nine patients with histologically confirmed gliomas or meningiomas, who had active or recurrent disease after receiving conventional treatment, received four intravenous doses of ior egf/r3. Total dosages ranged from 160 to 480 mg. As inclusion criteria, radioimmunoscintigraphy with the same MAb labeled with 99mTechnetium (99mTc) was performed. Immune response against the murine antibody was also evaluated. After four doses of ior egf/r3 MAb, no significant toxicity was found, except in one patient who developed a grade 4 allergic adverse event. This reaction was probably related with previous sensitization to the same MAb and the development of human anti-mouse antibodies (HAMA) response. Despite no major objective antitumor responses, eight patients had stable disease on the 6-month evaluation, and two patients remain alive after four years of MAb therapy.

Induction of Immunogenic Apoptosis by Blockade of Epidermal Growth Factor Receptor Activation with a Specific Antibody

“…However, there are clinical observations suggesting that short-term mechanisms such as EGFR signaling inhibition and Ab-dependent cellular cytotoxicity are not the only ones involved. Some studies have indicated that maximal clinical and molecular responses to anti-EGFR Abs may take several months (35)(36)(37). Mechanisms underlying the induction of long-time disease stabilization by EGFR Ab treatment have not been formally investigated.…”

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.…”

Current Methods for Detecting Antibodies against Erythropoietin and Other Recombinant Proteins

“…Abs in serum samples collected during the period of EPO resistance were shown to recognize each of the three recombinant EPOs this patient received-epoetin alfa, epoetin beta, and darbepoetin alpha. Specificity of the assay was confirmed by homologous and heterologous displacement (i.e., competition) with the various recombinant proteins (20,94).…”

“…An indirect ELISA was used by Weber and colleagues to demonstrate the presence of anti-EPO Abs in a patient with Ab-mediated PRCA who had received multiple recombinant EPOs (20,94). Abs in serum samples collected during the period of EPO resistance were shown to recognize each of the three recombinant EPOs this patient received-epoetin alfa, epoetin beta, and darbepoetin alpha.…”