Therapeutic advantages of Auger electron- over β-emitting radiometals or radioiodine when conjugated to internalizing antibodies

Recent studies suggest a higher anti-tumour efficacy of internalizing monoclonal antibodies (MAbs) when labelled with Auger electron emitters, as compared with beta-emitters. The aim of this study was to compare the anti-tumour efficacy and toxicity of the internalizing MAb, CO17-1A, labelled with Auger electron emitters (I-125, In-111) versus conventional beta(-)-emitters (I-131, Y-90) in a colon cancer model, and to assess whether the residualizing radiometals may have therapeutic advantages over the conventionally iodinated conjugates. Biodistribution studies of I-125-, In-111- or Y-88-labelled CO17-1A were performed in nude mice bearing subcutaneous human colon cancer xenografts. For therapy, the mice were injected with either unlabelled or I-125-, I-131-, In-111- or Y-90-labelled CO17-1A IgG(2a), whereas control groups were left untreated or were given a radiolabelled isotype-matched irrelevant antibody. The influence of internalization was assessed by comparing the results with those obtained with an anti-carcinoembryonic antigen (CEA) antibody which does not internalize to a relevant extent. The maximum tolerated activities (MTA) and doses (MTD) of each agent were determined. Myelotoxicity and potential second-organ toxicities, as well as tumour growth, were monitored. Bone marrow transplantation (BMT) was performed in order to enable dose intensification. Radiometals showed significantly better tumour-to-blood ratios than the respective iodinated conjugates. The MTAs of I-131- and I-125-CO17-1A without artificial support were 11.1 MBq (300 mu Ci) and 111 MBq (3 mCi), respectively; the MTA of the metals was reached at 4 MBq (100 mu Ci) for Y-90-, and at 85 MBq (2.3 mCi) for In-111-CO17-1A. Myelotoxicity was dose limiting in all cases. BMT enabled an increase in the MTA to 15 MBq (400 mu Ci) of I-131-labelled CO17-IA, to 4.4 MBq (120 mu Ci) of Y-90-labelled CO17-IA, and to 118 MBq (3.2 mCi) of In-111-labelled CO17-1A, while the MTA of I-125-CO17-1A had not been reached at 185 MBq (5 mCi) with BMT. Whereas no significant therapeutic effects were seen with unlabelled CO17-1A, tumour growth was retarded significantly with its radiolabelled forms. The therapeutic results were significantly (P<0.01) better with both Auger electron emitters (I-125 and In-111) than with the p-emitters, and, in accordance with the biodistribution data, a trend towards better therapeutic results was found with radiometals (more complete remissions) as compared with radioiodine. In contrast, at equitoxic doses, no significant difference was observed in the therapeutic efficacy of I-131- versus I-125-labelled non-internalizing anti-CEA antibody, F023C5. These data suggest that, at equitoxic doses, the therapeutic efficacy of internalizing MAbs labelled with Auger electron emitters, such as I-125 or In-111, is superior to that of internalizing MAbs labelled with conventional beta-emitters. The lower toxicity of Auger electron emitters may be due to the short path length of their low-energy electrons, which can reach the nuclear DNA only if the antibody is internalized las is the case in antigen-expressing tumour tissue, but not in the stem cells of the red marrow).