Phase I Clinical Evaluation of a Neutralizing Monoclonal Antibody against Epidermal Growth Factor Receptor

Abstract

Ior egf/r3, a neutralizing monoclonal antibody (mAb) against Epidermal Growth Factor Receptor (EGFR) was generated at the Cuban Institute of Oncology. Immunoscintigraphic studies in 148 patients with this 99-m Technetium (99Tc) labeled mAb, showed a high sensitivity and specificity for in vivo detection of epithelial tumors. To study safety, pharmacokinetic and immunogenicity of ior egf/r3 at high doses, a phase I clinical trial was conducted. Nineteen patients with advanced epithelial tumors received 4 mAb intravenous infusions at 6 dose levels: from 50 to 500 mg. Previously, immunoscintigraphic images using the same mAb labeled with 99Tc were acquired. Blood samples were collected for pharmacokinetic analysis and HAMA response. After mAb therapy, objective response was classified according to WHO criteria. Ior egf/r3 was well tolerated in spite of the high-administered doses. Only a severe adverse reaction consisting of hypotension and lethargy was observed. In 13 patients, selective accumulation of 99Tc-labeled mAb was observed at the site of the primary tumor or the metastasis. Pharmacokinetic analysis revealed that elimination half-life and the area under the time-concentration curve increased linearly with dose. HAMA response was detected in 17 patients. After 6 months of mAb therapy, 4 patients had stable disease. One patient had a tumor partial remission after 3 cycles of ior egf/r3.

Antidrug Antibody Formation in Oncology: Clinical Relevance and Challenges

“…In oncology, the effects of modifications to the treatment regimen are conflicting. Among the nine studies that reported ADA formation for different doses, the majority found that ADA Antidrug Antibody Formation in Oncology CME formation was not dose-dependent [21,71,[84][85][86], and only two studies confirmed a decrease in ADA formation with higher doses [17,19].…”

Interspecies scaling of the monoclonal anti‐EGF receptor ior EGF/r3 antibody disposition using allometric paradigm: is it really suitable?

“…In fact, the ior EGF/r3 immunohistochemical stained pattern was similar to that obtained by the standard anti-EGF receptor monoclonal antibody from Amersham [3]. Currently, the murine MAb ior EGF/r3, like many other anti-EGF receptor monoclonal antibodies, is the subject of pre-clinical and clinical studies in order to gain insight into its possible therapeutic uses [4][5][6][7]. Also, these molecules as radiotracers may be of diagnostic importance for monitoring different epithelial tumours [8][9][10].…”

“…Assumptions underlying allometric scaling include the absence of species-specific clearance mechanisms and the absence of nonlinearities in the disposition. However, evidence of both first-order and dose-dependent kinetic has been found previously [4,6]. Moreover, the limited biotransformation could be questionable because cleavage products (i.e.…”

“…The clinical trial was conducted at the 'Hermanos Ameijeira' Hospital (Havana, Cuba). The protocol was approved by the Institutional Review Board of the hospital (Hospital Ethic Committee) and also by the National Regulatory Authority of the Republic of Cuba [4].…”

Immunotherapy as a strategy for the treatment of non-small-cell lung cancer

“…In stage IIIB/IV NSCLC, three trials [10,33,34] evaluated the effect a vaccine consisting of human EGF had on patients’ overall survival. The vaccine consisted of the full-length human EGF protein complexed to the Neisseria meningitides P64K protein for added immunogenicity.…”