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Chimeric T84.66 (cT84.66) is a high-affinity (5 x 10(10) M-1) anti-carcino-embryonic antigen (CEA) IgG1. In a recently completed pretherapy imaging trial, 111In-labeled cT84.66 demonstrated targeting of CEA-producing metastatic sites and low immunogenicity, with human antichimeric antibody (HACA) response in only 1 of 15 patients after a single administration. The purpose of the present study was to evaluate cT84.66-diethylenetriaminepentaacetic acid labeled with 90Y in a dose-escalation Phase I trial. Patients with metastatic CEA-producing malignancies received imaging doses of 5 mCi 111In-labeled cT84.66 first, followed 1-2 weeks later by 5 mg cT84.66 labeled with the therapeutic dose of 90Y. Immediately following the therapeutic infusion, diethylenetriaminepentaacetic acid was administered by continuous i.v. infusion over 3 days at 250 mg/m2 body surface area/24 h. Biodistribution, tumor targeting, absorbed radiation dose estimates, antibody clearance, and HACA response were evaluated through blood samples, 24-h urine collections, and nuclear images performed at serial time points after infusion. To date, three patients with metastatic colorectal cancer have been evaluated at the first dose level of 5 mCi/m2. No side effects were associated with antibody administration. Localization of the antibody to nonhepatic metastatic sites was observed. Size-exclusion high-performance liquid chromatography demonstrated the formation of CEA:antibody complexes in serum in all three patients. A significant variation among patients in the clearance rate of the antibody and complexes from blood to liver was seen, which resulted in a reciprocal relationship between estimated liver dose and red marrow dose. Patients who demonstrated faster clearance to liver demonstrated greater excretion of a low-molecular-weight metabolite through the urine. Two patients developed HACA response, which persisted at 4 months after therapy. At this first dose level, no tumor responses were seen and reversible grade 1 thrombocytopenia was observed in 2 patients. cT84.66 demonstrated effective localization in CEA-producing tumors. Its low immunogenicity after a single administration makes it attractive for further evaluation as a radioimmunotherapeutic agent. However, further evaluation is needed to determine whether its immunogenicity will remain low after multiple administrations. Additionally, in two of the three patients, we identified rapid clearance of the antibody to the liver. This underscores the need to identify, characterize, and understand further those factors that influence the biodistribution and clearance of anti-CEA antibodies to allow for better selection of patients for therapy and rational planning of radioimmunotherapy.

Monoclonal antibody scintigraphy with 111In-ZCE025 was used in presurgical staging of 45 patients prior to abdominal exploration for primary, recurrent or metastatic colorectal carcinoma. A total of 186 lesions were identified, of which 147 were evaluated by abdominal surgery and pathology. Sensitivity was 40.5% (49 of 121) for immunoscintigraphy (IS), 61.2% (74 of 121) for computerized tomography (CT), and 72.7% (88 of 121) for IS and CT combined. The positive predictive value was 83.1% (49 of 59) for IS and 88.1% (74 of 84) for CT. Sensitivity of IS was 100% (23 of 23) for primary tumors, 17.7% (11 of 62) for hepatic metastases, and 41.7% (15 of 36) for extrahepatic abdominal metastases. Of the 50 hepatic lesions evaluated by single-proton emission computerized tomography, 11 were localized by IS. Only one was visualized by planar scintigraphy. Sensitivity of CT was 87% (20 of 23) for primary tumors, 67.7% (42 of 62) for hepatic metastases, and 33.3% (12 of 36) for extrahepatic abdominal metastases. Sensitivity of IS combined with CT was 72.6% (45 of 62) for hepatic and 55.6% (20 of 36) for extrahepatic abdominal metastases. Of 24 malignant lesions measured by the pathologist to be less than 3.0 cm (maximum dimension), 7 (29.2%) were detected by IS and 3 (12.5%) by CT. Of 28 malignant lesions greater than 3.0 cm, 23 (82.1%) were detected by IS and 24 (85.7%) by CT. Overall, IS and CT complemented each other in presurgical staging of colorectal carcinoma. IS was of greater value for identification of extrahepatic and small metastases. CT was more effective for identification of hepatic metastases.