The Balance Between the Therapeutic Efficacy and Safety of [177Lu]Lu-NeoB in a Preclinical Prostate Cancer Model.

PURPOSE: Radiolabeled NeoB is a promising gastrin-releasing peptide receptor (GRPR)-targeting radiopharmaceutical for theranostics of GRPR-expressing malignancies, e.g., prostate cancer (PCa). The aim of this study was to evaluate the effect of different doses of [177Lu]Lu-NeoB on the balance between therapeutic efficacy and safety in a preclinical PCa model. PROCEDURES: To determine the efficacy of [177Lu]Lu-NeoB, PC-3 xenografted mice received 3 sham injections (control group) or 3 injections of 30 MBq/300 pmol, 40 MBq/400 pmol, or 60 MBq/600 pmol [177Lu]Lu-NeoB (groups 1, 2, and 3, respectively) 1 week apart. To quantify tumor uptake, single-photon emission computed tomography/computed tomography (SPECT/CT) imaging was performed 4 h after the first, second, and third injection on a separate group of animals. For safety evaluations, pancreatic and renal tissues of non-tumor-bearing mice treated with the abovementioned [177Lu]Lu-NeoB doses were evaluated 12 and 24 weeks post-treatment. RESULTS: Treatment of PC-3 tumors with all three studied [177Lu]Lu-NeoB doses was effective. Median survival times were significantly (p < 0.0001) improved for treatment groups 1, 2, and 3 versus the control group (82 days, 89 days, 99 days versus 19 days, respectively). However, no significant differences were observed between treatment groups. Quantification of SPECT/CT images showed minimal differences in the average absolute radioactivity uptake, especially after the third injection. Histopathological analysis revealed no clear signs of treatment-related pancreatic toxicity. For the kidneys, atrophy and fibrosis were observed for one animal from group 1 and a chronic inflammatory response was observed for both animals from group 3 at 24 weeks post-treatment. CONCLUSIONS: Treatment with [177Lu]Lu-NeoB is effective in a preclinical PCa model. Adjusting the administered dose could positively impact the risk-benefit balance as a higher dose might not lead to an increased therapeutic effect, but it may lead to an increase in toxicological effects in healthy organs such as the kidneys.

In Vivo Biodistribution and Efficacy Evaluation of NeoB, a Radiotracer Targeted to GRPR, in Mice Bearing Gastrointestinal Stromal Tumor.

NeoB is a radiotracer targeting the gastrin-releasing peptide receptor (GRPR), a G-protein-coupled receptor expressed in various cancers. The aim of the present study was to evaluate the biodistribution and efficacy of this new therapeutic agent in Gastrointestinal Stromal Tumors (GIST). Eighty-two SCID mice bearing GIST-882 tumors were employed. [177Lu]Lu-NeoB biodistribution was evaluated up to seven days by organ sampling (200 pmol/0.8 MBq, i.v.). For efficacy evaluation, mice received either saline, 400 pmol or 800 pmol of [177Lu]Lu-NeoB (37MBq, 1/w, 3 w, i.v.). SPECT/CT imaging was performed at 24 h, and tumor volume was determined up to 100 days. Elevated and specific [177Lu]Lu-NeoB uptake was found in the GIST tumor, as demonstrated by in vivo competition (19.1 ± 3.9 %ID/g vs. 0.3 ± 0.1 %ID/g at 4h). [177Lu]Lu-NeoB tumor retention (half-life of 40.2 h) resulted in elevated tumor-to-background ratios. Tumor volumes were significantly reduced in both treated groups (p < 0.01), even leading to complete tumor regression at the 400 pmol dose. [177Lu]Lu-NeoB exhibited excellent pharmacokinetics with elevated and prolonged tumor uptake and low uptake in non-target organs such as pancreas. The potential of this new theragnostic agent in different indications, including GIST, is under evaluation in the FIH [177Lu]Lu-NeoB clinical trial.

NeoBOMB1, a GRPR-Antagonist for Breast Cancer Theragnostics: First Results of a Preclinical Study with [67Ga]NeoBOMB1 in T-47D Cells and Tumor-Bearing Mice.

BACKGROUND: The GRPR-antagonist-based radioligands [67/68Ga/111In/177Lu]NeoBOMB1 have shown excellent theragnostic profiles in preclinical prostate cancer models, while [68Ga]NeoBOMB1 effectively visualized prostate cancer lesions in patients. We were further interested to explore the theragnostic potential of NeoBOMB1 in GRPR-positive mammary carcinoma, by first studying [67Ga]NeoBOMB1 in breast cancer models; Methods: We investigated the profile of [67Ga]NeoBOMB1, a [68Ga]NeoBOMB1 surrogate, in GRPR-expressing T-47D cells and animal models; Results: NeoBOMB1 (IC50s of 2.2 ± 0.2 nM) and [natGa]NeoBOMB1 (IC50s of 2.5 ± 0.2 nM) exhibited high affinity for the GRPR. At 37 °C [67Ga]NeoBOMB1 strongly bound to the T-47D cell-membrane (45.8 ± 0.4% at 2 h), internalizing poorly, as was expected for a radioantagonist. [67Ga]NeoBOMB1 was detected >90% intact in peripheral mouse blood at 30 min pi. In mice bearing T-47D xenografts, [67Ga]NeoBOMB1 specifically localized in the tumor (8.68 ± 2.9% ID/g vs. 0.6 ± 0.1% ID/g during GRPR-blockade at 4 h pi). The unfavorably high pancreatic uptake could be considerably reduced (206.29 ± 17.35% ID/g to 42.46 ± 1.31% ID/g at 4 h pi) by increasing the NeoBOMB1 dose from 10 pmol to 200 pmol, whereas tumor uptake remained unaffected. Notably, tumor values did not decline from 1 to 24 h pi; Conclusions: [67Ga]NeoBOMB1 can successfully target GRPR-positive breast cancer in animals with excellent prospects for clinical translation.

68Ga/177Lu-NeoBOMB1, a Novel Radiolabeled GRPR Antagonist for Theranostic Use in Oncology.

Because overexpression of the gastrin-releasing peptide receptor (GRPR) has been reported on various cancer types, for example, prostate cancer and breast cancer, targeting this receptor with radioligands might have a significant impact on staging and treatment of GRPR-expressing tumors. NeoBOMB1 is a novel DOTA-coupled GRPR antagonist with high affinity for GRPR and excellent in vivo stability. The purpose of this preclinical study was to further explore the use of NeoBOMB1 for theranostic application by determining the biodistribution of 68Ga-NeoBOMB1 and 177Lu-NeoBOMB1. METHODS: PC-3 tumor-xenografted BALB/c nu/nu mice were injected with either approximately 13 MBq/250 pmol 68Ga-NeoBOMB1 or a low (∼1 MBq/200 pmol) versus high (∼1 MBq/10 pmol) peptide amount of 177Lu-NeoBOMB1, after which biodistribution and imaging studies were performed. At 6 time points (15, 30, 60, 120, 240, and 360 min for 68Ga-NeoBOMB1 and 1, 4, 24, 48, 96, and 168 h for 177Lu-NeoBOMB1) postinjection tumor and organ uptake was determined. To assess receptor specificity, additional groups of animals were coinjected with an excess of unlabeled NeoBOMB1. Results of the biodistribution studies were used to determine pharmacokinetics and dosimetry. Furthermore, PET/CT and SPECT/MRI were performed. RESULTS: Injection of approximately 250 pmol 68Ga-NeoBOMB1 resulted in a tumor and pancreas uptake of 12.4 ± 2.3 and 22.7 ± 3.3 percentage injected dose per gram (%ID/g) of tissue, respectively, at 120 min after injection. 177Lu-NeoBOMB1 biodistribution studies revealed a higher tumor uptake (17.9 ± 3.3 vs. 11.6 ± 1.3 %ID/g of tissue at 240 min after injection) and a lower pancreatic uptake (19.8 ± 6.9 vs. 105 ± 13 %ID/g of tissue at 240 min after injection) with the higher peptide amount injected, leading to a significant increase in the absorbed dose to the tumor versus the pancreas (200 pmol, 570 vs. 265 mGy/MBq; 10 pmol, 435 vs. 1393 mGy/MBq). Using these data to predict patient dosimetry, we found a kidney, pancreas, and liver exposure of 0.10, 0.65, and 0.06 mGy/MBq, respectively. Imaging studies resulted in good visualization of the tumor with both 68Ga-NeoBOMB1 and 177Lu-NeoBOMB1. CONCLUSION: Our findings indicate that 68Ga- or 177Lu-labeled NeoBOMB1 is a promising radiotracer with excellent tumor uptake and favorable pharmacokinetics for imaging and therapy of GRPR-expressing tumors.

α,ε-Hybrid foldamers with 1,2,3-triazole rings: order versus disorder.

Two epimeric series of foldamers characterized by the presence of a repeating α,ε-dipeptide unit have been prepared and characterized by (1)H NMR and ECD spectroscopies together with X-ray diffraction. The first series contains L-Ala and D-4-carboxy-5-methyl-oxazolidin-2-one (D-Oxd). The other series contains L-Ala and L-Oxd. The L,D series of oligomers forms ordered ß-turn foldamers, characterized by a 311 pattern. The L,L series is not ordered. Simulations show that an ordered L,L trimer lies more than 2 kcal/mol higher than the more stable nonfolded extended conformations. Cu(2+) forms complexes with both series but is not able to order the L,L series. Analysis of the EPR spectra shows that the L,D foldamers bear two types of complexation sites that are assigned as a nitrogen donor of the triazole ring and a carboxylate ligand. The L-Ala-D-Oxd-Tri-CO motif may be introduced in any peptide sequence requiring the presence of a stable ß-turn conformations, like in the study of protein-protein interactions.