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Purpose: The angiotensin converting enzyme-2 (ACE2)—entry receptor of SARS-CoV-2—and its homologue, the angiotensin-converting enzyme (ACE), play a pivotal role in maintaining cardiovascular homeostasis. Potential changes in ACE2 expression levels and dynamics after SARS-CoV-2 infection have been barely investigated. The aim of this study was to develop an ACE2-targeting imaging agent as a noninvasive imaging tool to determine ACE2 regulation. Methods: DOTA-DX600, NODAGA-DX600 and HBED-CC-DX600 were obtained through custom synthesis and labeled with gallium-67 (T1/2 = 3.26 d) as a surrogate radioisotope for gallium-68 (T1/2 = 68 min). ACE2- and ACE-transfected HEK cells were used for the in vitro evaluation of these radiopeptides. The in vivo tissue distribution profiles of the radiopeptides were assessed in HEK-ACE2 and HEK-ACE xenografted mice and imaging studies were performed using SPECT/CT. Results: The highest molar activity was obtained for [67Ga]Ga-HBED-CC-DX600 (60 MBq/nmol), whereas the labeling efficiency of the other peptides was considerably lower (20 MBq/nmol). The radiopeptides were stable over 24 h in saline (> 99% intact peptide). All radiopeptides showed uptake in HEK-ACE2 cells (36–43%) with moderate ACE2-binding affinity (KD value: 83–113 nM), but no uptake in HEK-ACE cells (< 0.1%) was observed. Accumulation of the radiopeptides was observed in HEK-ACE2 xenografts (11–16% IA/g) at 3 h after injection, but only background signals were seen in HEK-ACE xenografts (< 0.5% IA/g). Renal retention was still high 3 h after injection of [67Ga]Ga-DOTA-DX600 and [67Ga]Ga-NODAGA-DX600 (~ 24% IA/g), but much lower for [67Ga]Ga-HBED-CC-DX600 (7.2 ± 2.2% IA/g). SPECT/CT imaging studies confirmed the most favorable target-to-nontarget ratio for [67Ga]Ga-HBED-CC-DX600. Conclusions: This study demonstrated ACE2 selectivity for all radiopeptides. [67Ga]Ga-HBED-CC-DX600 was revealed as the most promising candidate due to its favorable tissue distribution profile. Importantly, the HBED-CC chelator enabled 67Ga-labeling at high molar activity, which would be essential to obtain images with high signal-to-background contrast to detect (patho)physiological ACE2 expression levels in patients. [ABSTRACT FROM AUTHOR]

Purpose: It was previously demonstrated that radiation effects can enhance the therapy outcome of immune checkpoint inhibitors. In this study, a syngeneic breast tumor mouse model was used to investigate the effect of [177Lu]Lu-DOTA-folate as an immune stimulus to enhance anti-CTLA-4 immunotherapy. Methods: In vitro and in vivo studies were performed to characterize NF9006 breast tumor cells with regard to folate receptor (FR) expression and the possibility of tumor targeting using [177Lu]Lu-DOTA-folate. A preclinical therapy study was performed over 70 days with NF9006 tumor-bearing mice that received vehicle only (group A); [177Lu]Lu-DOTA-folate (5 MBq; 3.5 Gy absorbed tumor dose; group B); anti-CTLA-4 antibody (3 × 200 μg; group C), or both agents (group D). The mice were monitored regarding tumor growth over time and signs indicating adverse events of the treatment. Results: [177Lu]Lu-DOTA-folate bound specifically to NF9006 tumor cells and tissue in vitro and accumulated in NF9006 tumors in vivo. The treatment with [177Lu]Lu-DOTA-folate or an anti-CTLA-4 antibody had only a minor effect on NF9006 tumor growth and did not substantially increase the median survival time of mice (23 day and 19 days, respectively) as compared with untreated controls (12 days). [177Lu]Lu-DOTA-folate sensitized, however, the tumors to anti-CTLA-4 immunotherapy, which became obvious by reduced tumor growth and, hence, a significantly improved median survival time of mice (> 70 days). No obvious signs of adverse effects were observed in treated mice as compared with untreated controls. Conclusion: Application of [177Lu]Lu-DOTA-folate had a positive effect on the therapy outcome of anti-CTLA-4 immunotherapy. The results of this study may open new perspectives for future clinical translation of folate radioconjugates. [ABSTRACT FROM AUTHOR]

Purpose: The L1 cell adhesion molecule (L1CAM) is considered a valuable target for therapeutic intervention in different types of cancer. Recent studies have shown that anti-L1CAM radioimmunotherapy (RIT) with Cu- and Lu-labelled internalising monoclonal antibody (mAb) chCE7 was effective in the treatment of human ovarian cancer xenografts. In this study, we directly compared the therapeutic efficacy of anti-L1CAM RIT against human ovarian cancer under equitoxic conditions with the radiolanthanide Lu and the potential alternative Tb in an ovarian cancer therapy model. Methods: Tb was produced by neutron bombardment of enriched Gd targets. Tb and Lu were used for radiolabelling of DOTA-conjugated antibodies. The in vivo behaviour of the radioimmunoconjugates (RICs) was assessed in IGROV1 tumour-bearing nude mice using biodistribution experiments and SPECT/CT imaging. After ascertaining the maximal tolerated doses (MTD) the therapeutic impact of 50 % MTD of Lu- and Tb-DOTA-chCE7 was evaluated in groups of ten mice by monitoring the tumour size of subcutaneous IGROV1 tumours. Results: The average number of DOTA ligands per antibody was 2.5 and maximum specific activities of 600 MBq/mg were achieved under identical radiolabelling conditions. RICs were stable in human plasma for at least 48 h. Lu- and Tb-DOTA-chCE7 showed high tumour uptake (37.8-39.0 %IA/g, 144 h p.i.) with low levels in off-target organs. SPECT/CT images confirmed the biodistribution data. Tb-labelled chCE7 revealed a higher radiotoxicity in nude mice (MTD: 10 MBq) than the Lu-labelled counterpart (MTD: 12 MBq). In a comparative therapy study with equitoxic doses, tumour growth inhibition was better by 82.6 % for the Tb-DOTA-chCE7 than the Lu-DOTA-chCE7 RIT. Conclusions: Our study is the first to show that anti-L1CAM Tb RIT is more effective compared to Lu RIT in ovarian cancer xenografts. These results suggest that Tb is a promising candidate for future clinical applications in combination with internalising antibodies. [ABSTRACT FROM AUTHOR]