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

Recent studies suggest a higher anti-tumour efficacy of internalizing monoc lonal antibodies (MAbs) when labelled with Auger electron emitters, as comp ared with beta-emitters. The aim of this study was to compare the anti-tumo ur efficacy and toxicity of the internalizing MAb, CO17-1A, labelled with A uger electron emitters (I-125, In-111) versus conventional beta(-)-emitters (I-131, Y-90) in a colon cancer model, and to assess whether the residuali zing radiometals may have therapeutic advantages over the conventionally io dinated conjugates. Biodistribution studies of I-125-, In-111- or Y-88-labe lled CO17-1A were performed in nude mice bearing subcutaneous human colon c ancer xenografts. For therapy, the mice were injected with either unlabelle d or I-125-, I-131-, In-111- or Y-90-labelled CO17-1A IgG(2a), whereas cont rol groups were left untreated or were given a radiolabelled isotype-matche d irrelevant antibody. The influence of internalization was assessed by com paring the results with those obtained with an anti-carcinoembryonic antige n (CEA) antibody which does not internalize to a relevant extent. The maxim um tolerated activities (MTA) and doses (MTD) of each agent were determined . Myelotoxicity and potential second-organ toxicities, as well as tumour gr owth, were monitored. Bone marrow transplantation (BMT) was performed in or der 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 m u 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 t he 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 C O17-1A, while the MTA of I-125-CO17-1A had not been reached at 185 MBq (5 m Ci) with BMT. Whereas no significant therapeutic effects were seen with unl abelled CO17-1A, tumour growth was retarded significantly with its radiolab elled forms. The therapeutic results were significantly (P<0.01) better wit h 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 t herapeutic 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 t hat, at equitoxic doses, the therapeutic efficacy of internalizing MAbs lab elled with Auger electron emitters, such as I-125 or In-111, is superior to that of internalizing MAbs labelled with conventional beta-emitters. The l ower toxicity of Auger electron emitters may be due to the short path lengt h of their low-energy electrons, which can reach the nuclear DNA only if th e antibody is internalized las is the case in antigen-expressing tumour tis sue, but not in the stem cells of the red marrow).