Comparative metabolism and retention of iodine-125, yttrium-90, and indium-111 radioimmunoconjugates by cancer cells

  • 1 May 1996
    • journal article
    • research article
    • Vol. 56  (9) , 2123-2129
Abstract
Radiolabeled antibodies have produced encouraging remissions in patients with chemotherapy-resistant hematological malignancies; however, the selection of therapeutic radionuclides for clinical trials remains controversial, In this study, we compared the internalization, lysosomal targeting, metabolism, and cellular retention of radiolabeled murine and humanized monoclonal antibodies targeting the CD33 antigen (monoclonal antibodies mP67 and hP67, respectively) on myeloid leukemia cell lines (HEL and HL-60) and of anti-carcinoma antibodies (monoclonal antibodies hCTM01 and hA33) targeting breast cancer and colorectal carcinoma cell lines (MCF7 and Cole 205, respectively), Each antibody was labeled with I-125 (by the IodoGen method) and with In-111 and Y-90 using macrocyclic chelation technology, Targeted tumor cells were analyzed 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 results suggest that antibodies are routed to lysosomes after endocytosis, where they are proteolytically degraded, [I-125]monoiodotyrosine is rapidly excreted from cells after lysosomal catabolism of antibodies radioiodinated by conventional methods, whereas small molecular weight In-111 and Y-90 catabolites remain trapped in lysosomes. As a consequence of the differential disposition of small molecular weight catabolites, In-111 and Y-90 conjugates displayed superior retention of radioactivity compared with I-125 conjugates when tumor cells were targeted using rapidly internalizing antibody-antigen systems (e.g., hP67 with HEL cells and hCTM01 with MCF7 cells). When tumor cells were targeted using 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 whether I-125, In-111, or Y-90 was used.