Dose escalation trial of indium-111-labeled anti-carcinoembryonic antigen chimeric monoclonal antibody (chimeric T84.66) in presurgical colorectal cancer patients

Wong, JYC Chu, DZJ Yamauchi, D Odom-Maryon, TL Williams, LE Liu, A Esteban, JM Wu, AM Primus, FJ Beatty, JD Shively, JE Raubitschek, AA

Jyc. Wong et al., Dose escalation trial of indium-111-labeled anti-carcinoembryonic antigen chimeric monoclonal antibody (chimeric T84.66) in presurgical colorectal cancer patients, J NUCL MED, 39(12), 1998, pp. 2097-2104

34

INGLESE

Article

Radiology ,Nuclear Medicine & Imaging","Medical Research Diagnosis & Treatment

JOURNAL OF NUCLEAR MEDICINE

0161-5505 → ACNP

39

12

1998

2097 - 2104

ISI

0161-5505(199812)39:12<2097:DETOIA>2.0.ZU;2-M

Chimeric T84.66 (cT84.66) is a high-affinity(1.16 x 10(11) M-1) IgG1 monocl onal antibody against carcinoembryonic antigen (CEA). The purpose of this p ilot trial was to evaluate the tumor-targeting properties, biodistribution, pharmacokinetics and immunogenicity of In-111-labeled cT84.66 as a functio n of administered antibody protein dose. Methods: Patients with CEA-produci ng colorectal cancers with localized disease or limited metastatic disease who were scheduled to undergo definitive surgical resection were each admin istered a single intravenous dose of 5 mg of isothiocyanato-benzyl diethyle netriaminepentaacetic acid-cT84.66, labeled with 5 mCi of In-111. Before re ceiving the radiolabeled antibody, patients received unlabeled diethylenetr iaminepentaacetic 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 ur ine 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 rat e 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, resu lting in a modification of surgical management. Interpatient variations in serum clearance rates were observed and were secondary to differences in cl earance and metabolic rates of antibody and antibody:antigen complexes by t he 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 Y-90-cT84.66 radiation doses ranging from 0.3 to 193 cGy/mCi. Thirteen patients were evaluated 1-6 mo after infusion for human antichime ric antibody, and none developed a response. No major differences in tumor imaging, tumor uptake, pharmacokinetics or organ biodistribution were obser ved with increasing protein doses, although a trend toward increasing blood uptake and decreasing liver uptake was observed with increasing protein do se. Conclusion: Chimeric T84.66 demonstrated tumor targeting comparable to other radiolabeled intact anti-CEA monoclonal antibodies. Its immunogenicit y after single administration was lower than murine monoclonal antibodies. These properties make In-111-cT84.66, or a lower molecular weight derivativ e, attractive for further evaluation as an imaging agent. Yttrium-90 dosime try 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 prot ein doses of In-111-cT84.66 were not demonstrated, the results do suggest t hat antibody clearance from the blood is driven by hepatic uptake and metab olism, with more rapid blood clearance seen in patients with liver metastas es. These patients with rapid clearance and potentially unfavorable biodist ribution for imaging and therapy may, therefore, be a more appropriate subs et in which to evaluate the role of administering higher protein doses. Thi s underscores the need to further identify, characterize and understand tho se 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.