Traffic Signal Timing and Optimization

Epidermal growth factor receptors (EGFR) are overexpressed in triple-negative breast cancer (TNBC) and are an attractive target for the development of theranostic radiopharmaceuticals. We studied anti-EGFR panitumumab labeled with ¹¹¹In (panitumumab-DOTA-¹¹¹In) for SPECT/CT imaging and Meitner-Auger electron (MAE) radioimmunotherapy (RIT) of TNBC. Panitumumab-DOTA-¹¹¹In was bound, internalized, and routed to the nucleus in MCF7, MDA-MB-231/Luc, and MDA-MB-468 human breast cancer (BC) cells dependent on the EGFR expression level (1.5 × 10⁴, 1.7 × 10⁵, or 1.3 × 10⁶ EGFR/cell, respectively). The absorbed dose in the nuclei of MCF7, MDA-MB-231/Luc, and MDA-MB-468 cells incubated with 4.4 MBq of panitumumab-DOTA-¹¹¹In (20 nM) was 1.20 ± 0.02, 2.2 ± 0.1, and 25 ± 2 Gy, respectively. The surviving fraction (SF) of MDA-MB-231/Luc cells treated with panitumumab-DOTA-¹¹¹In (10-300 nM; 1.5 MBq/μg) was reduced as the absorbed dose in the cell increased, with clonogenic survival reduced to an SF = 0.12 ± 0.05 at 300 nM corresponding to 12.7 Gy. The SFs of MDA-MB-468, MDA-MB-231/Luc, and MCF7 cells treated with panitumumab-DOTA-¹¹¹In (20 nM; 1.7 MBq/μg) were <0.01, 0.56 ± 0.05, and 0.67 ± 0.04, respectively. Unlabeled panitumumab had no effect on SF, and irrelevant IgG-DOTA-¹¹¹In only modestly reduced the SF of MDA-MB-231/Luc cells but not MCF7 or MDA-MB-468 cells. The cytotoxicity of panitumumab-DOTA-¹¹¹In was mediated by increased DNA double-strand breaks (DSB), cell cycle arrest at G2/M-phase and apoptosis measured by immunofluorescence detection by flow cytometry. MDA-MB-231/Luc tumors in the mammary fat pad (MFP) of NRG mice were clearly imaged with panitumumab-DOTA-¹¹¹In by microSPECT/CT at 4 days postinjection (p.i.), and biodistribution studies revealed high tumor uptake [18 ± 2% injected dose/g (% ID/g] and lower normal tissue uptake (<10% ID/g). Administration of up to 24 MBq (15 μg) of panitumumab-DOTA-¹¹¹In to healthy NRG mice caused no major hematological, renal, or hepatic toxicity with no decrease in body weight. Treatment of NOD SCID mice with MDA-MB-231 tumors with panitumumab-DOTA-¹¹¹In (22 MBq; 15 μg) slowed tumor growth. The mean time for tumors to reach a volume of ≥500 mm³ was 61 ± 5 days for RIT with panitumumab-DOTA-¹¹¹In compared to 42 ± 6 days for mice treated with irrelevant IgG₂-DOTA-¹¹¹In (<i>P</i> < 0.0001) and 35 ± 3 days for mice receiving 0.9% NaCl (<i>P</i> < 0.0001). However, tumors regrew at later time points. The median survival of mice treated with panitumumab-DOTA-¹¹¹In was 70 days versus 46 days for IgG₂-DOTA-¹¹¹In (<i>P</i> < 0.0001) or 40 days for 0.9% NaCl (<i>P</i> < 0.0001). We conclude that panitumumab-DOTA-¹¹¹In is a promising theranostic agent for TNBC. Increasing the administered amount of panitumumab-DOTA-¹¹¹In and/or combination with radiosensitizing PARP inhibitors used for treatment of patients with TNBC may provide a more durable response to RIT.

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