Somatostatin analogues have been examined as a treatment for somatostatin receptor overexpressing tumors for years; specifically, octreotate (TATE) and octreotide (TOC). Several versions of these analogues coupled to beta or gamma nuclides are currently used as imaging agents, as treatments with peptide receptor radionuclide therapy (PRRT) for patients with neuroendocrine tumors or are being explored in preclinical and clinical settings. Our study describes the use of 212 Pb-DOTAMTATE, the octreotate analogue, in combination with 212 Pb, the parent of an alpha emitter. Preclinical studies demonstrated tumor targeting of 212 Pb-DOTAMTATE of >20% ID/g up to 24 hours post drug injection. The addition of kidney protection agents, including L-lysine and L-arginine decreases drug accumulation in the kidneys and the addition of ascorbic acid to the chelation mixture reduces oxidation of the drug product. 212 Pb-DOTAMTATE displays a favorable toxicity profile with single-dose injections of 20 mCi showing 100% survival and with nontoxic cumulative doses up to 45 mCi, when fractionated into three smaller doses of 15 mCi. In an initial efficacy study, a single 10 mCi injection of 212 Pb-DOTAMTATE extended the mean survival 2.4-fold. Efficacy was enhanced by giving three treatment cycles of 212 Pb-DOTAMTATE and reducing the time between injections to two weeks. Efficacy was optimized further by the addition of a chemo-sensitizing agent, 5-fluorouracil, given in combination with three cycles of 10 mCi 212 Pb-DOTAMTATE. These conditions led to 79% of the animals being tumor free at the end of the 31-week study suggesting that 212 Pb-DOTAMTATE alone or in combination with a chemotherapeutic may have positive clinical implications.

Relapse of chronic lymphocytic leukaemia and non-Hodgkin's lymphoma after standard of care treatment is common and new therapies are needed. The targeted alpha therapy with 212 Pb-NNV003 presented in this study combines cytotoxic α-particles from 212 Pb, with the anti-CD37 antibody NNV003, targeting B-cell malignancies. The goal of this study was to explore 212 Pb-NNV003 for treatment of CD37 positive chronic lymphocytic leukaemia and non-Hodgkin's lymphoma in preclinical mouse models.An anti-proliferative effect of 212 Pb-NNV003 was observed in both chronic lymphocytic leukaemia (MEC-2) and Burkitt's lymphoma (Daudi) cells in vitro. In biodistribution experiments, accumulation of 212 Pb-NNV003 was 23%ID/g and 16%ID/g in Daudi and MEC-2 tumours 24 h post injection. In two intravenous animal models 90% of the mice treated with a single injection of 212 Pb-NNV003 were alive 28 weeks post cell injection. Median survival times of control groups were 5-9 weeks. There was no significant difference between different specific activities of 212 Pb-NNV003 with regards to therapeutic effect or toxicity. For therapeutically effective activities, a transient haematological toxicity was observed. This study shows that 212 Pb-NNV003 is effective and safe in preclinical models of CD37 positive chronic lymphocytic leukaemia and non-Hodgkin's lymphoma, warranting future clinical testing.

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

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