Phase I clinical evaluation of a neutralizing monoclonal antibody against epidermal growth factor receptor.
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.
Center of Molecular Immunology, Clinical Immunology Division, P.O. Box 16040, Havana 11600, Cuba. Taniac@ict.cim.sld.cu
T
T
Crombet
O
O
Torres
E
E
Neninger
M
M
Catalá
N
N
Rodríguez
M
M
Ramos
E
E
Fernández
N
N
Iznaga
R
R
Pérez
A
A
Lage
D000328:Adult; D000368:Aged; D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000096:biosynthesis; D000910:Antibodies, Heterophile / Q000096:biosynthesis; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000276:immunology / Q000493:pharmacokinetics / Q000627:therapeutic use; D000912:Antibodies, Neoplasm / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use; D000918:Antibody Specificity; D002277:Carcinoma / Q000000981:diagnostic imaging* / Q000532:radiotherapy / Q000628:therapy; D015331:Cohort Studies; D003131:Combined Modality Therapy; D004797:Enzyme-Linked Immunosorbent Assay; D066246:ErbB Receptors / Q000276:immunology*; D005260:Female; D005334:Fever / Q000139:chemically induced; D005500:Follow-Up Studies; D006207:Half-Life; D006801:Humans; D007022:Hypotension / Q000139:chemically induced; D008175:Lung Neoplasms / Q000000981:diagnostic imaging / Q000532:radiotherapy / Q000628:therapy; D008297:Male; D051379:Mice; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000276:immunology*; D009369:Neoplasms / Q000000981:diagnostic imaging* / Q000532:radiotherapy / Q000628:therapy; D009500:Neutralization Tests; D016719:Radioimmunodetection; D016499:Radioimmunotherapy; D019275:Radiopharmaceuticals / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D012449:Safety; D013045:Species Specificity; D013667:Technetium / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D014018:Tissue Distribution
D000888:Antibodies, Anti-Idiotypic; D000910:Antibodies, Heterophile; D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm; D009363:Neoplasm Proteins; D019275:Radiopharmaceuticals; D013667:Technetium; D066246:ErbB Receptors