111In- and 225Ac-Labeled Cixutumumab for Imaging and α-Particle Radiotherapy of IGF-1R Positive Triple-Negative Breast Cancer
| Autor: | Clarence Ronald Geyer, Viswas Raja Solomon, Kris Barreto, Humphrey Fonge, Rufael Chekol, Wayne Hill, Wendy Bernhard, Siddesh V. Hartimath, Elahe Alizadeh |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Radioimmunoconjugate
medicine.drug_class business.industry medicine.medical_treatment Pharmaceutical Science Cixutumumab 02 engineering and technology Pharmacology 021001 nanoscience & nanotechnology Monoclonal antibody 030226 pharmacology & pharmacy Radiation therapy 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine chemistry Growth factor receptor Drug Discovery medicine Molecular Medicine Cytotoxic T cell 0210 nano-technology Receptor business Triple-negative breast cancer |
| Zdroj: | Molecular Pharmaceutics. 16:4807-4816 |
| ISSN: | 1543-8392 1543-8384 |
| Popis: | Insulin growth factor receptor (IGF-1R) is overexpressed in many cancers of epithelial origin, where it confers enhanced proliferation and resistance to therapies targeted at other receptors. Anti-IGF-1R monoclonal antibodies have not demonstrated significant improvements in patient outcomes in clinical trials. Humanized monoclonal antibody cixutumumab (IMC-A12) binds to IGF-1R with low nM affinity. In this study, cixutumumab was conjugated with p-SCN-Bn-DOTA and radiolabeled with 111In or 225Ac for imaging or radiotherapy using a triple-negative breast cancer (TNBC) model SUM149PT. The antibody conjugate showed low nM affinity to IGF-1R, which was not affected by conjugation and radiolabeling procedures. Cixutumumab immunoconjugates were effectively internalized in SUM149PT and were cytotoxic to the cells with an EC50 of 225Ac-cixutumumab (0.02 nM) that was almost 5000-fold less than that of unlabeled cixutumumab (95.2 nM). MicroSPECT imaging of the SUM149PT xenograft showed the highest tumor uptake occurred at 48 h post injection and was 9.9 ± 0.5% injected activity per gram (%IA/cc). In radiotherapy studies, we evaluated the effect of the specific activity of 225Ac-cixutumumab on efficacy following a tail vein injection of two doses (days 0 and 10) of the investigation agent or controls. Cixutumumab (2.5 mg/kg) prolonged the survival of the SUM149PT tumor-bearing mice with a median survival of 87 days compared to the PBS control group (median survival of 62 days). Median survival of high specific activity 225Ac-cixutumumab (8 kBq/μg, 225 nCi, 0.05 mg/kg) was 103.5 days compared to 122 days for low specific activity 225Ac-cixutumumab (0.15 kBq/μg, 225 nCi, 2.5 mg/kg). Additionally, low specific activity radioimmunoconjugate led to complete tumor remission in 2/6 mice. The data suggest that the efficacy of cixutumumab can be enhanced by radiolabeling with 225Ac at a low specific activity. |
| Databáze: | OpenAIRE |
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