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

Abstract

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 (125I, (111)In) versus conventional beta(-)-emitters (131I, 90Y) in a colon cancer model, and to assess whether the residualizing radiometals may have therapeutic advantages over the conventionally iodinated conjugates. Biodistribution studies of 125I-, (111)In- or 88Y-labelled CO17-1A were performed in nude mice bearing subcutaneous human colon cancer xenografts. For therapy, the mice were injected with either unlabelled or 125I-, 131I-, (111)In- or 90Y-labelled CO17-1A IgG2a, 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 131I- and 125I-CO17-1A without artificial support were 11.1 MBq (300 microCi) and 111 MBq (3 mCi), respectively; the MTA of the metals was reached at 4 MBq (100 microCi) for 90Y-, and at 85 MBq (2.3 mCi) for (111)In-CO17-1A. Myelotoxicity was dose limiting in all cases. BMT enabled an increase in the MTA to 15 MBq (400 microCi) of 131I-labelled CO17-1A, to 4.4 MBq (120 microCi) of 90Y-labelled CO17-1A, and to 118 MBq (3.2 mCi) of (111)In-labelled CO17-1A, while the MTA of 125I-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 (125I and (111)In) than with the beta-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 131I- versus 125I-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 125I or (111)In, 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 ...

[Lys40(Ahx-DTPA-111In)NH2]-Exendin-4 Is a Highly Efficient Radiotherapeutic for Glucagon-Like Peptide-1 Receptor–Targeted Therapy for Insulinoma

“…A number of chemotherapeutic compounds (e.g., bleomycin) and antibodies (e.g., anti -epidermal growth factor receptor, anti-CD74, and anti-HER2) have been labeled with 111 In and tested in both cellular and animal xenograft models with moderate therapeutic effects (14 -17). A higher antitumor efficacy of Auger electron emitters compared with h-emitting radiometals or 131 I have also been detected when conjugated to internalizing antibodies (18). A clinical study investigating the effect of [ 111 In-DTPA]octreotide in patients with neuroendocrine tumors has revealed a low incidence of clinical side effects, yet only a moderate therapeutic response to the radiopeptide (19).…”

Ionizing radiation delivered by specific antibody is therapeutic against a fungal infection

“…Increasing the RIT dose by several-fold will often not improve the survival of the host, and can hasten death because of radiation injury. In experimental RIT, the MTA is usually defined as the highest possible activity under the respective conditions that does not result in any mouse deaths, with the next higher dose level resulting in at least 10% of the mice dying from radiation injury (40). Hence, our ability to increase the RIT dose by 300% indicates a large therapeutic window.…”

Radioimmunotherapy of Solid Tumors by Targeting Extra Domain B Fibronectin: Identification of the Best-Suited Radioimmunoconjugate

“…The question of which format should be used for radioimmunotherapy was often addressed using different targets and different radioimmunoconjugates (45,46) but still remains unsolved. Additionally, therapeutic isotopes were compared at their MTAs to find the most suited dose rate and effectiveness (47,48). Whereas some have recommended iodinated Fab fragments (47), we came to the conclusion that the I-131-labeled small immunoprotein is the most suitable radioimmunoconjugate for ED-B fibronectin -targeted radioimmunotherapy.…”