Monoclonal antibody (MAb) B72.3 IgG was radiolabeled with 131I and administered to female athymic NCr-nu mice bearing the LS-174T human colon adenocarcinoma xenograft to determine if fractionation of MAb dose had any advantage in tumor therapy. In the LS-174T xenograft, only approximately 30%-60% of tumor cells express the B72.3-reactive TAG-72 antigen. The LS-174T xenograft was used to reflect the heterogeneity of the TAG-72 antigen often seen in biopsy specimens from patients. In contrast to a single 600-muCi dose of 131I-B72.3 IgG where 60% of the animals died from toxic effects, two 300-muCi doses of 131I-B72.3 IgG (total of 600 muCi) reduced or eliminated tumor growth in 90% of mice, with only 10% of the animals dying from toxic effects. Dose fractionation even permitted escalation of the dose to three doses (each 1 wk apart) of 300 muCi of 131I-B72.3 IgG (for a total of 900 muCi), resulting in even more extensive tumor reduction or elimination and minimal toxic effects. The use of an isotype-matched control MAb revealed a nonspecific component to tumor growth retardation, but the use of the specific B72.3 IgG demonstrated a much greater therapeutic effect. Tumors that had escaped MAb therapy were analyzed for expression of the B72.3-reactive TAG-72 antigen with the use of the immunoperoxidase method; they were shown to have the same antigenic phenotype as the untreated tumors. We verified tumor elimination by killing the test animals after a 7-week observation period and performing histologic examination of tumor sites. We also monitored toxic effects by histologic examination of numerous organs, including bone marrow. These studies thus demonstrate the advantage of dose fractionation of a radiolabeled MAb for tumor therapy. We anticipate that the concept of dose fractionation can be practically applied in radioimmunotherapeutic clinical trials with the development and use of recombinant-chimeric MAbs and modified constructs.

131I-COL-1 is well tolerated, except for hematologic toxicity. These data suggest that patients with highly elevated circulating CEA levels and/or increased tumor bulk may clear 131I-labeled COL-1 more rapidly from the circulation and experience less myelosuppression.

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Lutetium‐177 (177Lu), samarium‐153 (153Sm), and yt‐trium‐90 (90Y) are members of the family of elements known as lanthanides or rare earths. Monoclonal antibody CC49, a murine immunoglobulin (Ig) G1, which is reactive with the tumor‐associated antigen TAG‐72, previously has been shown to react with a wide range of human carcinomas. The authors review here the comparative biodistributions of CC49 IgG and F(ab′)2 fragments labeled with 177Lu, 153Sm, and 90Y using the bifunctional chelating agent PA‐DOTA. The authors also review the results of a biodistribution study comparing iodine‐125‐labeled and 177Lu‐labeled CC49 sFv, and the use of 177Lu‐CC49 IgG in an experimental therapy model. Chelation and conjugations gave similar yields, and the labeled proteins showed similar retention of immunoreactivity regardless of the isotope used for both IgG and F(ab′)2. Biodistribution data obtained in athymic mice bearing LS‐174T human colon carcinoma xenografts likewise showed no differences among the three radioisotopes for both IgG and F(ab′)2. Femur uptake of radioactivity was lower than previously reported for other radiolanthanide immunoconjugates. Different metabolic patterns were observed for radioiodinated versus radiometal‐la‐beled sFv, particularly in the kidney, where localization of the latter was increased dramatically. 177Lu‐CC49 was found to delay the growth of established LS‐174T human colon carcinomas in athymic mice at a single dose of 50 μCi. Elimination of established tumors was demonstrated over the observation period (77 days) using single administrations of 200 or 350 μCi. Dose fractionation experiments revealed that the mice tolerated 750 μCi (3 × 250 μCi, given weekly), whereas > 50% of the mice died after receiving a single administration of ∼ 500 μCi. In iso‐type‐matched control experiments, a large differential in the therapeutic effects was observed between 177Lu‐la‐beled control antibody and CC49. Cancer 1994; 73:993–8.