First preclinical evaluation of [225Ac]Ac-DOTA-JR11 and comparison with [177Lu]Lu-DOTA-JR11, alpha versus beta radionuclide therapy of NETs

Abstract

Background The [177Lu]Lu-DOTA-TATE mediated peptide receptor radionuclide therapy (PRRT) of neuroendocrine tumors (NETs) is sometimes leading to treatment resistance and disease recurrence. An interesting alternative could be the somatostatin antagonist, [177Lu]Lu-DOTA-JR11, that demonstrated better biodistribution profile and higher tumor uptake than [177Lu]Lu-DOTA-TATE. Furthermore, treatment with alpha emitters showed improvement of the therapeutic index of PRRT due to the high LET offered by the alpha particles compared to beta emitters. Therefore, [225Ac]Ac-DOTA-JR11 can be a potential candidate to improve the treatment of NETs (Graphical abstract). DOTA-JR11 was radiolabeled with [225Ac]Ac(NO3)3 and [177Lu]LuCl3. Stability studies were performed in phosphate buffered saline (PBS) and mouse serum. In vitro competitive binding assay has been carried out in U2OS-SSTR2 + cells for natLa-DOTA-JR11, natLu-DOTA-JR11 and DOTA-JR11. Ex vivo biodistribution studies were performed in mice inoculated with H69 cells at 4, 24, 48 and 72 h after injection of [225Ac]Ac-DOTA-JR11. A blocking group was included to verify uptake specificity. Dosimetry of selected organs was determined for [225Ac]Ac-DOTA-JR11 and [177Lu]Lu-DOTA-JR11. Results [225Ac]Ac-DOTA-JR11 has been successfully prepared and obtained in high radiochemical yield (RCY; 95%) and radiochemical purity (RCP; 94%). [225Ac]Ac-DOTA-JR11 showed reasonably good stability in PBS (77% intact radiopeptide at 24 h after incubation) and in mouse serum (~ 81% intact radiopeptide 24 h after incubation). [177Lu]Lu-DOTA-JR11 demonstrated excellent stability in both media (> 93%) up to 24 h post incubation. Competitive binding assay revealed that complexation of DOTA-JR11 with natLa and natLu did not affect its binding affinity to SSTR2. Similar biodistribution profiles were observed for both radiopeptides, however, higher uptake was noticed in the kidneys, liver and bone for [225Ac]Ac-DOTA-JR11 than [177Lu]Lu-DOTA-JR11. Conclusion [225Ac]Ac-DOTA-JR11 showed a higher absorbed dose in the kidneys compared to [177Lu]Lu-DOTA-JR11, which may limit further studies with this radiopeptide. However, several strategies can be explored to reduce nephrotoxicity and offer opportunities for future clinical investigations with [225Ac]Ac-DOTA-JR11.

Recent advances in the development of 225Ac- and 211At-labeled radioligands for radiotheranostics

“…[ 177 Lu]Lu-DOTA-LM3 and [ 225 Ac]Ac-DOTA-LM3 have shown good tumor regression in clinical studies [ 59 , 60 ]. Recently, the SSTR antagonist [ 225 Ac]Ac-DOTA-JR11 was developed, which showed good tumor accumulation but relatively high uptake in the kidney, liver, and bone [ 61 ]. Among the 225 Ac-labeled octreotide analogs, only [ 225 Ac]Ac-DOTATOC and [ 225 Ac]Ac-DOTATATE have been studied clinically, owing to the overwhelming abundance of clinical data on these scaffolds.…”

Towards Effective Targeted Alpha Therapy for Neuroendocrine Tumours: A Review

“…Most studies used the DOTA chelator (29/43) and the TOC/TATE (37/43)-targeting ligand. Two SSTR antagonists (LM3, JR11) were investigated, in contrast to the conventional agonists [ 40 , 60 ]. Several more recent publications examined SSAs conjugated to a new chelator (via a PEG linker), developed specifically for 203/212 Pb radiopharmaceuticals, and appear to improve the pharmacokinetic properties and stability of chelation [ 46 , 47 , 49 ].…”

“…The highest reported ratio is for [ 212 Pb]Pb-PSC-PEG 2 -TOC, where structural modifications to the chelator and linker result in T:K absorbed dose >2.6. Contrastingly, Handula and collaborators conclude that [ 225 Ac]Ac-DOTA-JR11 is unsuitable for therapy based on a low T:K of 0.34 [ 60 ]. While T:K is a useful parameter, clearly more work is required to properly understand what constitutes effective tumour-absorbed doses and safe renal-absorbed doses for this class of radiopharmaceuticals.…”

Implementing Ac-225 labelled radiopharmaceuticals: practical considerations and (pre-)clinical perspectives

“…Based upon the choice of biological vector and mechanism of action, the dose can be calculated for the targeted and the non-targeted tissues (Handula et al 2023 ). Here the high LET energy deposition influences the biological effects, and was confirmed by radiobiological modeling (Handula et al 2023 ).…”

“…Based upon the choice of biological vector and mechanism of action, the dose can be calculated for the targeted and the non-targeted tissues (Handula et al 2023 ). Here the high LET energy deposition influences the biological effects, and was confirmed by radiobiological modeling (Handula et al 2023 ). While double-stranded DNA breaks are crucial for optimal treatment, it's important to acknowledge that high linear energy transfer (LET) also induces indirect effects and bystander effects, contributing significantly to the efficacy of the therapy (Widel 2017 ).…”