BIODISTRIBUTION AND PRECLINICAL RADIOIMMUNOTHERAPY STUDIES USING RADIOLANTHANIDE-LABELED IMMUNOCONJUGATES

Lutetium-177 (Lu-177), samarium-153 (Sm-153), and yttrium-90 (Y-90) 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 Lu-177, Sm-153, and Y-90 using the bifunctional chelating agent PA-DOTA. The authors also review the results of a biodistribution study comparing iodine-125-labeled and Lu-177-labeled CC49 sFv, and the use of Lu-177-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-labeled sFv, particularly in the kidney, where localization of the latter was increased dramatically. Lu-177-CC49 was found to delay the growth of established LS-174T human colon carcinomas in athymic mice at a single dose of 50 mu Ci. Elimination of established tumors was demonstrated over the observation period (77 days) using single administrations of 200 or 350 mu Ci. Dose fractionation experiments revealed that the mice tolerated 750 mu Ci (3 X 250 mu Ci, given weekly), whereas > 50% of the mice died after receiving a single administration of similar to 500 mu Ci. In isotype-matched control experiments, a large differential in the therapeutic effects was observed between Lu-177-labeled control antibody and CC49.