Dose Escalation Trial of Indium-111-Labeled Anti-Carcinoembryonic Antigen Chimeric Monoclonal Antibody (Chimeric T84.66) in Presurgical Colorectal Cancer Patients

• Published in: The Journal of nuclear medicine (1978) Vol. 39; no. 12; pp. 2097 - 2104
• Main Authors: Wong, Jeffrey Y.C, Chu, David Z.J, Yamauchi, Dave, Odom-Maryon, Tamara L, Williams, Lawrence E, Liu, An, Esteban, Jose M, Wu, Anna M, Primus, F. James, Beatty, J. David, Shively, John E, Raubitschek, Andrew A
• Format: Journal Article
• Language: English
• Published: Reston, VA Soc Nuclear Med 01-12-1998; Society of Nuclear Medicine
• Subjects: Adult; Aged; Animals; Antibodies, Monoclonal - adverse effects; Biological and medical sciences; Carcinoembryonic Antigen - immunology; Colorectal Neoplasms - diagnostic imaging; Colorectal Neoplasms - pathology; Colorectal Neoplasms - radiotherapy; Colorectal Neoplasms - surgery; Combined treatment; Diseases of the digestive system; Female; Humans; Immunoglobulin G - adverse effects; Indium Radioisotopes - adverse effects; Indium Radioisotopes - pharmacokinetics; Indium Radioisotopes - therapeutic use; Liver Neoplasms - diagnostic imaging; Liver Neoplasms - secondary; Lymphatic Metastasis; Male; Medical sciences; Metabolic Clearance Rate; Mice; Middle Aged; Neoplasm Metastasis; Pilot Projects; Radiography; Radioimmunotherapy; Radionuclide Imaging; Radiopharmaceuticals - adverse effects; Radiopharmaceuticals - pharmacokinetics; Radiopharmaceuticals - therapeutic use; Radiotherapy Dosage; Radiotherapy, Adjuvant; Radiotherapy. Instrumental treatment. Physiotherapy. Reeducation. Rehabilitation, orthophony, crenotherapy. Diet therapy and various other treatments (general aspects); Sensitivity and Specificity; Tissue Distribution; Treatment. General aspects; Tumors; Rectal disease; Radiolabelling; Monoclonal antibody; Bioavailability; Malignant tumor; Radiotherapy; Indium; Dose activity relation; Colonic disease; Carcinoembryonic antigen; Rectum; Immunoradiotherapy; Digestive diseases; Intestinal disease; Clinical trial; Colon; Preoperative; Pharmacokinetics
• ISSN: 0161-5505; 1535-5667

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.
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.
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.
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.