INITIAL EXPERIENCE EVALUATING (90)YTTRIUM-RADIOLABELED ANTICARCINOEMBRYONIC ANTIGEN CHIMERIC T84.66 IN A PHASE-I RADIOIMMUNOTHERAPY TRIAL

Chimeric T84.66 (cT84.66) is a high-affinity (5 x 10(10) M(-1)) anti-c arcinoembryonic antigen (CEA) IgG1, In a recently completed pretherapy imaging trial, In-111-labeled cT84.66 demonstrated targeting of CEA-p roducing metastatic sites and low immunogenicity, with human antichime ric antibody (HACA) response in only 1 of 15 patients after a single a dministration, The purpose of the present study was to evaluate cT84.6 6-diethylenetriaminepentaacetic acid labeled with Y-90 in a dose-escal ation Phase I trial, Patients with metastatic CEA-producing malignanci es received imaging doses of 5 mCi In-111-labeled cT84.66 first, follo wed 1-2 weeks later by 5 mg cT84.66 labeled with the therapeutic dose of Y-90, Immediately following the therapeutic infusion, diethylenetri aminepentaacetic acid was administered by continuous i.v. infusion ove r 3 days at 250 mg/m(2) 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 collect ions, and nuclear images performed at serial time points after infusio n. To date, three patients with metastatic colorectal cancer have been evaluated at the first dose level of 5 mCi/m(2), No side effects were associated with antibody administration, Localization of the antibody to nonhepatic metastatic sites was observed. Size-exclusion high-perf ormance liquid chromatography demonstrated the formation of CEA:antibo dy complexes in serum in all three patients, A significant variation a mong 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 demonst rated faster clearance to liver demonstrated greater excretion of a lo w-molecular-weight metabolite through the urine. Two patients develope d HACA responses, which persisted at 4 months after therapy, At this f irst dose level, no tumor responses were seen and reversible grade 1 t hrombocytopenia was observed in 2 patients. cT84.66 demonstrated effec tive localization in CEA-producing tumors, Its low immunogenicity afte r a single administration makes it attractive for further evaluation a s a radioimmunotherapeutic agent. However, further evaluation is neede d to determine whether its immunogenicity will remain low after multip le administrations. Additionally, in two of the three patients, we ide ntified rapid clearance of the antibody to the liver, This underscores the need to identify, characterize, and understand further those fact ors that influence the biodistribution and clearance of anti-CEA antib odies to allow for better selection of patients for therapy and ration al planning of radioimmunotherapy.