Objective: The peptide receptor radionuclide therapy (PPRT) for somatostatin receptor positive (SSTR) neuroendocrine tumors (NETs) has emerged more than 15 years ago. The beta-emitter-PRRT has shown to induce objective response in 30-45% of metastatic NETs patients with hematologic/renal toxicity reduced by dose fractionation. The complete response to therapy is rare due to the heterogeneity of NETs; advanced stage of disease at the time of diagnosis; and patient resistance to nonradioactive octreotide and 90Y/177Lu PRRT developed during the therapy. The targeted alpha-emitter therapy of NETs can overcome these limitations. It can enhance the therapeutic response of patients and decrease side-effect and overcome patient resistance of beta-emitter PRRT without significant acute and mid-term toxicity. The RadioMedix and AREVA Med teams together have recently developed several novel 203Pb-peptide derivatives targeting SSTR(+) cancer cells, 203Pb-AR-RMX. The 203Pb is a gamma emitter (279 keV) with t1/2=51.9 h, suitable for single-photon emission computed tomography (SPECT) imaging. The 203Pb is an ideal surrogate for 212Pb α-particle therapy because both isotopes share identical chemical properties. The objective of these studies were: (1) to evaluate the SSTR targeting properties of novel conjugates 203Pb-AR-RMX; and (2) to determine their PK and biodistribution in vivo in SSTR overexpressing xenographs; and (3) to select lead candidate for further pre-IND clinical studies.

Methods: AR-RMX was manufactured under GMP by Macrocylics Inc. The 203Pb-radiolabeling of AR-RMX was carried out under mild conditions. The SSTR targeting properties of 203Pb-AR-RMX were determined in the cellular uptake/competition studies in AR-42J cancer cells and in vivo in SSTR(+) AR42J xenograph mice.

Results:203Pb-AR-RMX-15 shows exceptionally high tumor-specific accumulation and retention in SSTR(+) AR42J xenograph mice. Tumor uptake of 203Pb-AR-RMX-15 was >14.4 %ID/g at 1h post injection and it remained at this level at least for 24h. The kidneys accumulation of 203Pb-AR-RMX-15 was >13 %ID/g at 1h and varies in different strains of mice but decreased progressively over the 24h. The kidney uptake of agent is similar to previously observed for octreotate labeled with other isotopes. The tumor uptake is significantly higher possible as a result of the change of charge of the 203Pb-AR-RMX-15. The acute hematotoxicity and chronic kidney toxicity is known to limit the doses of 90Y/177Lu PRRT. Preliminary studies of 203Pb-AR-RMX-15 showed that its kidney retention can be reduced by >32% by co-injection of our proprietary AminoMedixTM or Gelofusine-Lysine composition. 203Pb-AR-RMX-15 has shown >98% radio/chemical stability up 7 days post-formulation; no bone marrow uptake of agent was observed in bioD studies of 203Pb AR-RMX-15 done up to 24h post injection. These results allow us to hypothesize that the therapeutic dose of 203Pb/212Pb-AR-RMX-15 is expected to be significantly higher than the dose limiting activity.

Conclusions:203Pb-AR-RMX-15 showed promising results in vitro and in vivo studies and will be further investigated as a 203Pb/212Pb-labeled theranostics agent. Our “theranostics” approach using 203Pb/212Pb-PRRT has a potential to advance image-guided radionuclide therapy that can detect and deliver therapeutic radiation dose precisely to SSTR(+) NETs.

Citation Format: Izabela Tworowska, Tania Stallons, Amal Saidi, Nilesh Wagh, Federico Rojas-Quijano, Paul Jurek, Garry Kiefer, Julien Torgue, Ebrahim Delpassand. Pb203-AR-RMX conjugates for image-guided TAT of neuroendocrine tumors (NETs) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-259. doi:10.1158/1538-7445.AM2017-LB-259