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Gastrin‐releasing peptide receptors (GRPRs) are overexpressed in prostate cancer and are suitable for targeted radionuclide therapy (TRT). We optimized the bombesin‐derived GRPR‐antagonist PEG 2 ‐RM26 for labeling with  177 Lu and further determined the effect of treatment with  177 Lu‐labeled peptide alone or in combination with the anti‐HER2 antibody trastuzumab in a murine model. The PEG 2 ‐RM26 analog was coupled to NOTA, NODAGA, DOTA and DOTAGA chelators. The peptide‐chelator conjugates were labeled with  177 Lu and characterized  in vitro  and  in vivo . A preclinical therapeutic study was performed in PC‐3 xenografted mice. Mice were treated with intravenous injections (6 cycles) of (A) PBS, (B) DOTAGA‐PEG 2 ‐RM26, (C)  177 Lu‐DOTAGA‐PEG 2 ‐RM26, (D) trastuzumab or (E)  177 Lu‐DOTAGA‐PEG 2 ‐RM26 in combination with trastuzumab.  177 Lu‐DOTAGA‐PEG 2 ‐RM26 demonstrated quantitative labeling yield at high molar activity (450 GBq/μmol), high  in vivo  stability (5 min pi >98% of radioligand remained when coinjected with phosphoramidon), high affinity to GRPR ( K  D  = 0.4 ± 0.2 nM), and favorable biodistribution (1 hr pi tumor uptake was higher than in healthy tissues, including the kidneys). Therapy with  177 Lu‐DOTAGA‐PEG 2 ‐RM26 induced a significant inhibition of tumor growth. The median survival for control groups was significantly shorter than for treated groups (Group C 66 days, Group E 74 days). Trastuzumab together with radionuclide therapy significantly improved survival. No treatment‐related toxicity was observed. In conclusion, based on  in vitro  and  in vivo  characterization of the four  177 Lu‐labeled PEG 2 ‐RM26 analogs, we concluded that  177 Lu‐DOTAGA‐PEG 2 ‐RM26 was the most promising analog for TRT. Radiotherapy using  177 Lu‐DOTAGA‐PEG 2 ‐RM26 effectively inhibited tumor growth  in vivo  in a murine prostate cancer model. Anti‐HER2 therapy additionally improved survival.

Trastuzumab cotreatment improves survival of mice with PC‐3 prostate cancer xenografts treated with the GRPR antagonist 177 Lu‐DOTAGA‐PEG 2 ‐RM26