COMPARATIVE METABOLISM AND RETENTION OF I-125, Y-90, AND IN-111 RADIOIMMUNOCONJUGATES BY CANCER-CELLS

Radiolabeled antibodies have produced encouraging remissions in patien ts with chemotherapy-resistant hematological malignancies; however, th e selection of therapeutic radionuclides for clinical trials remains c ontroversial, In this study, we compared the internalization, lysosoma l targeting, metabolism, and cellular retention of radiolabeled murine and humanized monoclonal antibodies targeting the CD33 antigen (monoc lonal antibodies mP67 and hP67, respectively) on myeloid leukemia cell lines (HEL and HL-60) and of anti-carcinoma antibodies (monoclonal an tibodies hCTM01 and hA33) targeting breast cancer and colorectal carci noma cell lines (MCF7 and Cole 205, respectively), Each antibody was l abeled with I-125 (by the IodoGen method) and with In-111 and Y-90 usi ng macrocyclic chelation technology, Targeted tumor cells were analyze d for retention and metabolism of radioimmunoconjugates using cellular radioimmunoassays, Percoll gradient fractionation of cell organelles, SDS-PAGE, and TLC of cell lysates and culture supernatants, Our resul ts suggest that antibodies are routed to lysosomes after endocytosis, where they are proteolytically degraded, [I-125]monoiodotyrosine is ra pidly excreted from cells after lysosomal catabolism of antibodies rad ioiodinated by conventional methods, whereas small molecular weight In -111 and Y-90 catabolites remain trapped in lysosomes. As a consequenc e of the differential disposition of small molecular weight catabolite s, In-111 and Y-90 conjugates displayed superior retention of radioact ivity compared with I-125 conjugates when tumor cells were targeted us ing rapidly internalizing antibody-antigen systems (e.g., hP67 with HE L cells and hCTM01 with MCF7 cells). When tumor cells were targeted us ing antibody-antigen systems exhibiting slow rates of endocytosis (e.g ., hP67 on HL-60 cells and hA33 on Cole 205 cells), little difference in cellular retention of radioactivity was observed, regardless of whe ther I-125, In-111, or Y-90 was used.