Effective Treatment of Established Human Breast Tumor Xenografts in Immunodeficient Mice with a Single Dose of the -Emitting Radioisotope Astatine-211 Conjugated to Anti-HER2/neu Diabodies

Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
Clinical Cancer Research (Impact Factor: 8.72). 03/2008; 14(3):875-82. DOI: 10.1158/1078-0432.CCR-07-1250
Source: PubMed


Successful radioimmunotherapy strategies depend on selecting radioisotopes with physical properties complementary to the biological properties of the targeting vehicle. Small, engineered antitumor antibody fragments are capable of rapid, highly specific tumor targeting in immunodeficient mouse models. We hypothesized that the C6.5 diabody, a noncovalent anti-HER2 single-chain Fv dimer, would be an ideal radioisotope carrier for the radioimmunotherapy of established tumors using the short-lived alpha-emitting radioisotope (211)At.
Immunodeficient nude mice bearing established HER2/neu-positive MDA-MB-361/DYT2 tumors treated with N-succinimidyl N-(4-[(211)At]astatophenethyl)succinamate ((211)At-SAPS)-C6.5 diabody. Additional cohorts of mice were treated with (211)At-SAPS T84.66 diabody targeting the carcinoembryonic antigen or (211)At-SAPS on a diabody specific for the Müllerian inhibiting substance type II receptor, which is minimally expressed on this tumor cell line.
A single i.v. injection of (211)At-SAPS C6.5 diabody led to a 30-day delay in tumor growth when a 20 muCi dose was administered and a 57-day delay in tumor growth (60% tumor-free after 1 year) when a 45 muCi dose was used. Treatment of mice bearing the same tumors with (211)At-SAPS T84.66 diabody at the same doses led to a delay in tumor growth, but no complete responses, likely due to substantially lower expression of this antigen on the MDA-MB-361/DYT2 tumors. In contrast, a dose of 20 muCi of (211)At-SAPS on the anti-Müllerian-inhibiting substance type II receptor diabody did not affect tumor growth rate, demonstrating specificity of the therapeutic effect.
These findings indicate that diabody molecules can be effective agents for targeted radioimmunotherapy of solid tumors using powerful, short-lived alpha-emitting radioisotopes.

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Available from: Calvin Shaller, Jan 27, 2014
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    • "Diabodies therefore have a high potential for radiotherapy. Indeed, a single intravenous dose of 90Y-labelled diabody inhibited growth rates of established HER2 tumour xenografts in athymic nude mice (Adams et al., 2004), and even more promising results have been reported with an anti-HER2 diabody coupled to the a-emitting radio- isotope 211 At, with 60% tumour-free animals 1 year after a single injection of the conjugate in immunodeficient nude mice bearing established HER2/neu-positive tumours (Robinson et al., 2008). More recently, several teams have shown that it is possible to obtain high affinities using a single variable domain. "
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