In vivo biodistribution and efficacy evaluation of NeoBOMB1, a theranostic agent targeting GRPR, in mice bearing GastroIntestinal Stromal Tumor.

Objectives: The gastrin-releasing peptide receptor (GRPR), also known as bombesin receptor subtype 2, is a G-protein-coupled receptor expressed in various cancers. Multiple radiolabeled GRPR ligands have been evaluated. Among them, NeoBOMB1 has been shown to exhibit excellent tumor uptake and favorable pharmacokinetics for imaging in mice bearing prostate tumors, and its translational prospects were further supported by the successful visualization of prostate cancer lesions in men using ⁶⁸Ga-NeoBOMB1 and PET/CT¹. The aim of the present study was to evaluate the biodistribution and efficacy of this new theragnostic agent in the setting of Gastrointestinal Stromal Tumors (GIST). The study was conducted within the MITIGATE project (European Community FP7, #602306). Methods. A total of 76 six week old male SCID mice bearing subcutaneous GIST-882 tumors were employed. For the biodistribution substudy (5-6 mice per group), ¹⁷⁷Lu-NeoBOMB1 was injected intravenously (200 pmol/0.8 MBq) and the biodistribution was evaluated by organ sampling and gamma-well counting at several time points (1h, 4h, 24h, 48h, 96h, and 168h). Moreover, the specificity was evaluated at 4h by co-injecting an excess of 40 nmol unlabeled NeoBOMB1. Results were expressed as a percentage injected dose per gram (%ID/g). For the efficacy substudy, control mice were injected with saline (Control group, n=13), whereas treated mice received either 400 pM (400 pM group, n=14) or 800 pM (800 pM group, n=13) of 37 MBq (i.v.) of ¹⁷⁷Lu-NeoBOMB1 once a week for 3 weeks. SPECT/CT imaging was performed at 24h on a subgroup of mice, and tumor volume was determined up to 100 days following ¹⁷⁷Lu-NeoBOMB1 injection.

Results: Biodistribution- At 4h post-injection (pi), elevated ¹⁷⁷Lu-NeoBOMB1 uptake was found in the GIST tumor (19.1 ± 3.9 %ID/g) and the pancreas (8.5 ± 2.0 %ID/g), which was significantly reduced to 0.3 ± 0.1 %ID/g and 0.1 ± 0.0 %ID/g, respectively, by in vivo competition. From 24h to 168h pi, ¹⁷⁷Lu-NeoBOMB1 uptake was lower than 2 %ID/g in all investigated tissues with the exception of the GIST tumor. Indeed, tumor uptake was of 13.4 ± 3.5, 10.5 ± 1.6, 5.9 ± 0.3 and 2.5 ± 0.7%ID/g at 24h, 48h, 96h and 168h, resulting in elevated (>10) tumor-to-kidney, tumor-to-liver and tumor-to-pancreas ratios. Efficacy- GIST-882 tumors were readily observable at 24h by SPECT/CT imaging. Interestingly, ¹⁷⁷Lu-NeoBOMB1 tumor uptake in 400 pM group mice was found to be significantly higher than that observed in 800 pM group mice. Twenty six (26) days following therapy onset, tumor volumes from both 400 pM and 800 pM group were found to be significantly reduced in comparison to control group (p<0.01 for both). Moreover, tumor volume of 400 pM group was found to be lower than that observed in the 800 pM group (p<0.001). At later timepoints, tumour regression was observed in the two treated groups, confirming the efficacy of both peptide mass doses and long-term survival of both treated groups. At the end of the follow up period (100 days after therapy onset) no residual tumor volume was detectable in mice from the 400 pM group (0%), while tumor re-growth was observed in 3 mice from the 800 pM group (23%). No signs of toxicity were detected after injection of ¹⁷⁷Lu-NeoBOMB1, indicating that the radiopharmaceutical was well tolerated by the animals. Conclusions. ¹⁷⁷Lu-NeoBOMB1 exhibited excellent pharmacokinetics with elevated and prolonged tumor uptake and low uptake in non-target organs such as pancreas. When injected at therapeutic doses, ¹⁷⁷Lu-NeoBOMB1 successfully inhibited GIST-882 tumor growth, even leading to complete tumor regression when injected at the 400 pmole dose. No signs of toxicity were detected. Clinical trial will be performed to confirm the potential of this new theragnostic agent in patient with GIST. 1. Nock BA, Kaloudi A, Lymperis E et al. J Nucl Med. 2017 Jan;58(1):75-80.

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