title: 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.
authors.affiliation: Center of Molecular Immunology, Hermanos Ameijeiras Hospital, Havana, Cuba. tanias@ict.cim.sld.cu
authors.forename: Tania
authors.initials: T
authors.lastname: Crombet
authors.forename: Leonel
authors.initials: L
authors.lastname: Torres
authors.forename: Elia
authors.initials: E
authors.lastname: Neninger
authors.forename: Mauricio
authors.initials: M
authors.lastname: Catalá
authors.forename: María E
authors.initials: ME
authors.lastname: Solano
authors.forename: Alejandro
authors.initials: A
authors.lastname: Perera
authors.forename: Olga
authors.initials: O
authors.lastname: Torres
authors.forename: Normando
authors.initials: N
authors.lastname: Iznaga
authors.forename: Franz
authors.initials: F
authors.lastname: Torres
authors.forename: Rolando
authors.initials: R
authors.lastname: Pérez
authors.forename: Agustín
authors.initials: A
authors.lastname: Lage
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D001682:Biological Availability; D002277:Carcinoma / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D066246:ErbB Receptors / Q000008:administration & dosage* / Q000097:blood; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D018570:Risk Assessment; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D066246:ErbB Receptors