title: Dose escalation trial of indium-111-labeled anti-carcinoembryonic antigen chimeric monoclonal antibody (chimeric T84.66) in presurgical colorectal cancer patients.
abstract: Chimeric T84.66 (cT84.66) is a high-affinity (1.16x10(11) M(-1)) IgG1 monoclonal antibody against carcinoembryonic antigen (CEA). The purpose of this pilot trial was to evaluate the tumor-targeting properties, biodistribution, pharmacokinetics and immunogenicity of 111In-labeled cT84.66 as a function of administered antibody protein dose.
  
  
  METHODS
  Patients with CEA-producing colorectal cancers with localized disease or limited metastatic disease who were scheduled to undergo definitive surgical resection were each administered a single intravenous dose of 5 mg of isothiocyanatobenzyl diethylenetriaminepentaacetic acid-cT84.66, labeled with 5 mCi of 111In. Before receiving the radiolabeled antibody, patients received unlabeled diethylenetriaminepentaacetic acid-cT84.66. The amount of unlabeled antibody was 0, 20 or 100 mg, with five patients at each level. Serial blood samples, 24-hr urine collections and nuclear images were collected until 7 days postinfusion. Human antichimeric antibody response was assessed up to 6 mo postinfusion.
  
  
  RESULTS
  Imaging of at least one known tumor site was performed in all 15 patients. Fifty-two lesions were analyzed, with an imaging sensitivity rate of 50.0% and a positive predictive value of 76.9%. The antibody detected tumors that were not detected by conventional means in three patients, resulting in a modification of surgical management. Interpatient variations in serum clearance rates were observed and were secondary to differences in clearance and metabolic rates of antibody and antibody:antigen complexes by the liver. Antibody uptake in primary tumors, metastatic sites and regional metastatic lymph nodes ranged from 0.4% to 134% injected dose/kg, resulting in estimated 90Y-cT84.66 radiation doses ranging from 0.3 to 193 cGy/mCi. Thirteen patients were evaluated 1-6 mo after infusion for human antichimeric antibody, and none developed a response. No major differences in tumor imaging, tumor uptake, pharmacokinetics or organ biodistribution were observed with increasing protein doses, although a trend toward increasing blood uptake and decreasing liver uptake was observed with increasing protein dose.
  
  
  CONCLUSIONS
  Chimeric T84.66 demonstrated tumor targeting comparable to other radiolabeled intact anti-CEA monoclonal antibodies. Its immunogenicity after single administration was lower than murine monoclonal antibodies. These properties make 111In-cT84.66, or a lower molecular weight derivative, attractive for further evaluation as an imaging agent. Yttrium-90 dosimetry estimates predict potentially cytotoxic radiation doses to select tumor sites, which makes 90Y-cT84.66 also appropriate for further evaluation in Phase I radioimmunotherapy trials. Although clinically important changes in biodistribution, pharmacokinetics and tumor targeting with increasing protein doses of 111In-cT84.66 were not demonstrated, the results do suggest that antibody clearance from the blood is driven by hepatic uptake and metabolism, with more rapid blood clearance seen in patients with liver metastases. These patients with rapid clearance and potentially unfavorable biodistribution for imaging and therapy may, therefore, be a more appropriate subset in which to evaluate the role of administering higher protein doses. This underscores the need to further identify, characterize and understand those factors that influence the biodistribution and clearance of radiolabeled anti-CEA antibodies, to allow for better selection of patients for therapy and rational planning of radioimmunotherapy.
authors.affiliation: Division of Radiation Oncology, City of Hope National Medical Center and Beckman Research Institute, Duarte, California 91010, USA.
authors.forename: J Y
authors.initials: JY
authors.lastname: Wong
authors.forename: D Z
authors.initials: DZ
authors.lastname: Chu
authors.forename: D
authors.initials: D
authors.lastname: Yamauchi
authors.forename: T L
authors.initials: TL
authors.lastname: Odom-Maryon
authors.forename: L E
authors.initials: LE
authors.lastname: Williams
authors.forename: A
authors.initials: A
authors.lastname: Liu
authors.forename: J M
authors.initials: JM
authors.lastname: Esteban
authors.forename: A M
authors.initials: AM
authors.lastname: Wu
authors.forename: F J
authors.initials: FJ
authors.lastname: Primus
authors.forename: J D
authors.initials: JD
authors.lastname: Beatty
authors.forename: J E
authors.initials: JE
authors.lastname: Shively
authors.forename: A A
authors.initials: AA
authors.lastname: Raubitschek
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000911:Antibodies, Monoclonal / Q000009:adverse effects; D002272:Carcinoembryonic Antigen / Q000276:immunology; D015179:Colorectal Neoplasms / Q000000981:diagnostic imaging / Q000473:pathology / Q000532:radiotherapy* / Q000601:surgery*; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000009:adverse effects; D007205:Indium Radioisotopes / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008113:Liver Neoplasms / Q000000981:diagnostic imaging / Q000556:secondary; D008207:Lymphatic Metastasis; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D008875:Middle Aged; D009362:Neoplasm Metastasis; D010865:Pilot Projects; D011859:Radiography; D016499:Radioimmunotherapy; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D011879:Radiotherapy Dosage; D018714:Radiotherapy, Adjuvant; D012680:Sensitivity and Specificity; D014018:Tissue Distribution
chemical_list: D000911:Antibodies, Monoclonal; D002272:Carcinoembryonic Antigen; D007074:Immunoglobulin G; D007205:Indium Radioisotopes; D019275:Radiopharmaceuticals; C116410:indium 111-cT84.66 monoclonal antibody