ImmunoPET imaging of IGF1R in prostate cancer

Objectives Insulin-like growth factor 1 receptor (IGF1R) plays an important role in proliferation, apoptosis, angiogenesis, and tumor invasion. The expression level of IGF1R is related to resistance to several targeted therapies. Our goal is to develop a PET tracer for imaging of IGF1R in prostate cancer.

Methods Murine antibodies against human IGF1R were generated in BALB/c mice, which were screened in IGF1R-positive MCF-7 cells using flow cytometry as well as in vivo screening in tumor-bearing mice (i.e. biodistribution studies of multiple ⁶⁴Cu-labeled antibody clones). One antibody clone (1A2G11) with the highest affinity for IGF1R was selected and conjugated to NOTA for ⁶⁴Cu-labeling. NOTA-1A2G11 maintained IGF1R specificity/avidity based on flow cytometry. PET/CT imaging and biodistribution of ⁶⁴Cu-NOTA-1A2G11 were conducted in subcutaneous DU-145 (High IGF1R level) and LNCaP (Low IGF1R level) prostate cancer models to evaluate its IGF1R-targeting efficacy and specificity in vivo, which was validated by histology.

Results The antibody production method we adopted could readily produce milligram quantities of anti-IGF1R antibodies for in vivo studies. After both in vitro and in vivo screening, 1A2G11 showed the best IGF1R binding affinity/specificity and lowest non-specific binding. ⁶⁴Cu-labeling was achieved with good yield (>50%) and high specific activity (> 1 Ci/µmol). Serial PET imaging revealed that uptake of ⁶⁴Cu-NOTA-1A2G11 was 2.8±0.7, 10.2±2.6, and 9.6±1.7 %ID/g in IGF1R-positive DU-145 tumors at 4, 24, and 48 h post-injection respectively (n=3), significantly higher than that in IGF1R-negative LNCaP tumors (< 4%ID/g at each time point). Histology studies showed strong correlations between IGF1R expression level in the prostate cancer tumor tissue and tumor uptake of ⁶⁴Cu-NOTA-1A2G11.

Conclusions We have produced a murine antibody that strongly binds to IGF1R, which plays pivotal roles in tumor development and progression. Prominent, persistent, and IGF1R-specific uptake of ⁶⁴Cu-NOTA-1A2G11 in IGF1R-positive prostate tumors was observed, which holds strong potential for future cancer diagnosis, prognosis, and therapy.