IP Library › Granted Patent US 12,605,447
Granted Patent B2
US 12,605,447 · App. 19/028,880 · Granted Apr 21, 2026

Stable formulations for radionuclide complexes

Inventors: Sebastian Marx (Dachau, DE); Oliver Leib (Ismaning, DE); Luke Heames (Unterschleißheim, DE); Elena Maria Andreolli (Pavia, IT)
Assignee: ITM Solucin GmbH
A61K47/22A61K51/088A61K2121/00
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Quick Facts
Patent No.
US 12,605,447
App. No.
19/028,880
Granted
Apr 21, 2026
Kind
B2
Abstract

The present invention provides a pharmaceutical composition comprising a radiolabeled complex comprising a radionuclide and a targeting molecule linked to a chelating agent; and a stabilizer against radiolytic degradation comprising ascorbic acid and/or a salt thereof; wherein the composition does not comprise gentisic acid or a salt thereof. The pharmaceutical composition of the present invention provides high stability against radiolytic degradation. The present invention also provides a process for preparing such a pharmaceutical composition.

Claims (39)

1 . A pharmaceutical composition comprising:

a) a radiolabeled complex comprising (i) 177Lu (Lutetium-177) and (ii) a cell-targeting molecule linked to a chelating agent; and

b) a stabilizer against radiolytic degradation comprising 40 to 60 mg/ml of sodium ascorbate, and 1.11 mg/ml±1.1 mg/ml ascorbic acid, wherein the weight ratio of sodium ascorbate:ascorbic acid is between 30:1 and 70:1,

wherein the composition does not comprise (i) gentisic acid or a salt thereof and does not comprise (ii) a sequestering agent, and wherein the composition retains greater than 98% radiochemical purity (RCP) for at least 96 hours after end of synthesis (EOS).

2 . The pharmaceutical composition according to claim 1 , wherein the chelating agent is DOTA.

3 . The pharmaceutical composition according to claim 1 , wherein the targeting molecule binds to PSMA or a somatostatin receptor.

4 . The pharmaceutical composition according to claim 1 , wherein the cell-targeting molecule linked to a chelating agent is DOTATOC or DOTATATE.

5 . The pharmaceutical composition according to claim 1 , wherein the composition is an aqueous solution.

6 . The pharmaceutical composition according to claim 1 , wherein the stabilizer consists of: 40 to 60 mg/ml of sodium ascorbate, and 1.11 mg/ml±1.1 mg/ml ascorbic acid, wherein the weight ratio of sodium ascorbate:ascorbic acid is between 30:1 and 70:1.

7 . The pharmaceutical composition according to claim 1 , wherein the composition comprises a buffer, the buffer comprising water and the sodium ascorbate; with the proviso that the composition does not contain another buffer.

8 . The pharmaceutical composition according to claim 1 , wherein the composition consists of:

a) the radiolabeled complex;

b) sodium ascorbate;

c) ascorbic acid; and

d) water.

9 . The pharmaceutical composition according to claim 1 , wherein the composition consists of:

a) the radiolabeled complex;

b) one or more precursors of the radiolabeled complex;

c) sodium ascorbate;

d) ascorbic acid; and

e) water.

10 . The pharmaceutical composition according to claim 1 , wherein the pharmaceutical composition is free of ethanol.

11 . The pharmaceutical composition according to claim 1 , wherein the stabilizer comprises 51 mg/ml±5.1 mg/ml of sodium ascorbate and 1.11 mg/ml±1.1 mg/ml of ascorbic acid.

12 . The pharmaceutical composition according to claim 1 , wherein the radionuclide is 177Lu, the chelating agent is DOTA, and the targeting molecule is a peptide binding to PSMA or a somatostatin receptor.

13 . The pharmaceutical composition according to claim 12 , wherein the radionuclide is present at a concentration providing volumetric radioactivity of 0.42 GBq/ml±0.04 GBq/ml.

14 . A method for treatment of cancer, wherein the cancer is selected from the group consisting of: prostate cancer, pancreatic cancer, renal cancer, bladder cancer, neuroendocrine tumor, gastroenteropancreatic neuroendocrine tumor, carcinoid tumor, pheochromocytoma, paraganglioma, medullary thyroid cancer, pulmonary neuroendocrine tumor, thymic neuroendocrine tumor, a carcinoid tumor or a pancreatic neuroendocrine tumor, pituitary adenoma, adrenal gland tumors, Merkel cell carcinoma, breast cancer, non-Hodgkin lymphoma, Hodgkin lymphoma, head and neck tumor, urothelial carcinoma (bladder), renal cell carcinoma, hepatocellular carcinoma, GIST, neuroblastoma, bile duct tumor, cervix tumor, Ewing sarcoma, osteosarcoma, small cell lung cancer (SCLC), prostate cancer, melanoma, meningioma, glioma, medulloblastoma, hemangioblastoma, supratentorial primitive, neuroectodermal tumor, esthesioneuroblastoma, functional carcinoid tumor, insulinoma, gastrinoma, vasoactive intestinal peptide (VIP) oma, glucagonoma, serotoninoma, histaminoma, ACTHoma, pheocromocytoma, and somatostatinoma,

the method comprising administering a dose of a pharmaceutical composition according to claim 1 to a subject in need thereof.

15 . The method for treatment of cancer according to claim 14 , wherein the dose provides delivery of 7.5 GBq±10% of radioactivity at injection time, and/or wherein the pharmaceutical composition is provided in a volume of 15 to 20 ml.

16 . A process for preparing the pharmaceutical composition according to claim 1 comprising the following steps:

i) formation of the radiolabeled complex comprising (i) 177Lu (Lutetium-177) and (ii) a cell-targeting molecule linked to a chelating agent; and

ii) formulation of the pharmaceutical composition by addition of sodium ascorbate and ascorbic acid to a concentration of 40 to 60 mg/ml of sodium ascorbate, and to a concentration of 1.11 mg/ml±1.1 mg/ml ascorbic acid, wherein the weight ratio of sodium ascorbate:ascorbic acid is between 30:1 and 70:1,

wherein step (i) is performed in a radiolabeling composition comprising:

a) the 177Lu and the cell-targeting molecule linked to the chelating agent; and

b) a radiolabeling buffer comprising water, sodium ascorbate and ascorbic acid,

wherein the pharmaceutical composition does not comprise (i) gentisic acid or a salt thereof and does not comprise (ii) a sequestering agent, and wherein the composition retains greater than 98% radiochemical purity (RCP) for at least 96 hours after end of synthesis (EOS).

17 . The process according to claim 16 , wherein the radionuclide is present in the radiolabeling composition at a concentration providing volumetric radioactivity of 6.0 to 9.5 GBq/mL.

18 . The process according to claim 16 , wherein the chelating agent is DOTA, and/or wherein the targeting molecule binds to PSMA or a somatostatin receptor, wherein the targeting molecule linked to the chelating agent is present in the radiolabeling composition at a concentration of 100±10 μg/ml.

19 . The process according to claim 16 , wherein the sodium ascorbate, and ascorbic acid are present during step (i) at a weight ratio (sodium ascorbate:ascorbic acid) of 2:1 to 6:1, and ascorbic acid is present during step (i) at a concentration of 1-50 mg/ml, and wherein the sodium ascorbate is present during step (i) at a concentration of 10-100 mg/ml.

20 . The process according to claim 16 , wherein the radiolabeling composition in step (i) has a pH of 4.0-5.5, and/or wherein step (i) is performed at a temperature of 87±4° C., and/or wherein step (i) is performed for 25±3 min.

Assignments (3)
ASSIGNMENT OF SECURITY INTEREST Recorded May 13, 2026
From: LSI FINANCING LLC
To: PERCEPTIVE CREDIT ACQUISITION V LLC
Reel/Frame 075610/0404 →
SECURITY INTEREST Recorded Aug 12, 2025
From: ITM ISOTOPE TECHNOLOGIES MUNICH SE; ITM SOLUCIN GMBH; ITM ONCOLOGICS GMBH
To: LSI FINANCING LLC, AS ADMINISTRATIVE AGENT
Reel/Frame 071992/0914 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 25, 2025
From: MARX, SEBASTIAN; LEIB, OLIVER; HEAMES, LUKE; ANDREOLLI, ELENA MARIA
To: ITM SOLUCIN GMBH
Reel/Frame 070621/0253 →
Priority Claims (1)
WO PCT/EP2020/083363 · Nov 25, 2020 · international
Continuity (2)
Continuation 18254122
Related Publication 20250170243A1 · May 29, 2025
References Cited (52)
US 10596278B2 · de Palo · 2020 [cited by examiner]
US 10756278B2 · Claridge et al. · 2020 [cited by applicant]
EP 2862857A1 · 2015 [cited by applicant]
WO 2013022797A1 · 2013 [cited by applicant]
WO 2014143736A1 · 2014 [cited by applicant]
WO 2015055318A1 · 2015 [cited by applicant]
WO 2018215627A1 · 2018 [cited by applicant]
WO 2020109523A1 · 2020 [cited by applicant]
International Search Report and Written Opinion for Application No. PCT/EP2021/082812, mailed Feb. 25, 2022, 8 pages. [cited by applicant]
Iori Michele et al: Labelling of 90Y- and 177Lu-DOTA-Bioconjugates for Targeted Radionuclide Therapy: A Comparison among Manual, Semiautomated, and Fully Automated Synthesis, Contrast Media & Molecular Imaging, vol. 201… [cited by applicant]
Singh, J. et al., “Stability Constants of Metal Complexes in Solution,” InTech Open, 2019, DOI: http://dx.doi.org/10.5772/intechopen.90183, 19 pages. [cited by applicant]
Liu, S., et al., “Ascorbic Acid: Useful as a Buffer Agent and Radiolytic Stabilizer for Metalloradiopharmaceuticals,” Bioconjugate Chem., 2003, pp. 1052-1056. [cited by applicant]
Examination Report for European Application No. EP21815203.1, as issued by the European Patent Office Feb. 25, 2025. [cited by applicant]
Office Action and Search Report issued by the Russian Patent Office for RU2023116057/04, mailed Apr. 3, 2025. [cited by applicant]
Office Action for corresponding Russian Patent Application No. 2023116057/04(034298), Oct. 7, 2025 (Russian language). [cited by applicant]
English language translation of Office Action for corresponding Russian Patent Application No. 2023116057/04 (034298), Oct. 7, 2025. [cited by applicant]
Bakhareva, A.A. et al., Development of New Chelating Agents for Radiopharmaceuticals, Advances in Chemistry and Chemical Technology, 2019, No. 7 (217), p. 18, 2 pages (In Russian, cited in the Office Action for correspo… [cited by applicant]
Maus, S. et al., Aspects on radiolabeling of 177Lu-DOTA-TATE: After C18 purification re-addition of ascorbic acid is required to maintain radiochemical purity, International Journal of Diagnostic Imaging, Feb. 21, 2014,… [cited by applicant]
De Blois, E. et al., Effectiveness of Quenchers to Reduce Radiolysis of (111)In- Or (177)Lu-labelled Methionine-Containing Regulatory Peptides. Maintaining Radiochemical Purity as Measured by HPLC., Curr Top Med Chem. 2… [cited by applicant]
Breeman, W. A.P., Practical Aspects of labeling DTPA- and DOTA-Peptides with 90Y, 111In, 177Lu, and 68Ga for Peptide-Receptor Scintigraphy and Peptide-Receptor Radionuclide Therapy in Preclinical and Clinical Applicatio… [cited by applicant]
Kerdjoudj, R. et al., Scandium(III) complexes of monophosphorus acid DOTA analogues: a thermodynamic and radiolabelling study with 44Sc from cyclotron and from a 44Ti/44Sc generator, Dalton Trans., 2016, 45, 1398-1409. [cited by applicant]
Chang, S., Overview of Prostate-Specific Membrane Antigen, Rev Urol., 2004, 6 (Suppl 10): S13-S18. [cited by applicant]
Bouchelouche, K. et al., Prostate Specific Membrane Antigen-A Target for Imaging and Therapy with Radionuclides, Discov Med., Jan. 2010; 9(44): 55-61. [cited by applicant]
Hillier, S., et al., Preclinical Evaluation of Novel Glutamate-Urea-Lysine Analogues That Target Prostate-Specific Membrane Antigen as Molecular Imaging Pharmaceuticals for Prostate Cancer, Cancer Res., Sep. 1, 2009;69 … [cited by applicant]
Beneová et al., Preclinical Evaluation of a Tailor-Made DOTA-Conjugated PSMA Inhibitor with Optimized Linker Moiety for Imaging and Endoradiotherapy of Prostate Cancer, J. Nucl. Med, Apr. 16, 2015, 56:914-920. [cited by applicant]
Barrett, J.A. et al., First-in-Man Evaluation of 2 High-Affinity PSMA-Avid Small Molecules for Imaging Prostate Cancer, J Nucl Med., Jan. 9, 2013, 54:380-387. [cited by applicant]
Zechmann, C. et al., Radiation dosimetry and first therapy results with a 1241/131 I-labeled small molecule (MIP-1095) targeting PSMA for prostate cancer therapy, Eur J Nucl Med Mol Imaging, Feb. 28, 2014, 41:1280-1292. [cited by applicant]
Afshar-Oromieh, A. et al., The Theranostic PSMA Ligand PSMA-617 in the Diagnosis of Prostate Cancer by PET/ CT: Biodistribution in Humans, Radiation Dosimetry, and First Evaluation of Tumor Lesions, J Nucl Med., Aug. 20… [cited by applicant]
Weineisen, M. et al., 68Ga- and 177Lu-Labeled PSMA I&T: Optimization of a PSMA-Targeted Theranostic Concept and First Proof-of-Concept Human Studies, J Nucl Med., Jun. 18, 2015. 56:1169-1176. [cited by applicant]
Robu, S. et al., Preclinical Evaluation and First Patient Application of 99mTc-PSMA-I&S for SPECT Imaging and Radioguided Surgery in Prostate Cancer, J Nucl Med., 2017; 58:235-242. [cited by applicant]
Chen, Y. et al., 2-(3-{1-Carboxy-5-[(6-[18F]Fluoro-Pyridine-3-Carbonyl)-Amino]-Pentyl}-Ureido)-Pentanedioic Acid, [18F]DCFPyL, a PSMA-Based PET Imaging Agent for Prostate Cancer, Clin Cancer Res., Dec. 15, 2011, 17 (24)… [cited by applicant]
Giesel, F.L. et al., Eur J Nucl Med Molecular Imaging, F-18 labelled PSMA-1007: biodistribution, radiation dosimetry and histopathological validation of tumor lesions in prostate cancer patients, 2017; 44:678-688. [cited by applicant]
Kelly, J. M. et al., Dual-Target Binding Ligands with Modulated Pharmacokinetics for Endoradiotherapy of Prostate Cancer., J Nucl Med., Sep. 2017, 58(9):1442-1449. doi: 10.2967/jnumed.116.188722. [cited by applicant]
Choy, C. J. et al., 177Lu-Labeled Phosphoramidate-Based PSMA Inhibitors: The Effect of an Albumin Binder on Biodistribution and Therapeutic Efficacy in Prostate Tumor-Bearing Mice, Theranostics, Apr. 27, 2017; 7(7): 192… [cited by applicant]
Capello, A. et al., Tyr3-octreotide and Tyr3-octreotate radiolabeled with 177Lu or 90Y: peptide receptor radionuclide therapy results in vitro, Cancer Biotherapy Radiopharm, Oct. 2003; 18(5): 761-8. [cited by applicant]
Guo, W. et al., 99mTc-HyNIC-Folate: A Novel Receptor-Based Targeted Radiopharmaceutical for Tumor Imaging, J Nucl Med. 1999; 40:1563-1569. [cited by applicant]
Mathias, C. J. et al., Synthesis of [99mTc]DTPA-Folate and Its Evaluation as a Folate-Receptor-Targeted Radiopharmaceutical, Bioconjug Chem., 2000, 11:253-257. [cited by applicant]
Leamon, C. P. et al., Synthesis and Biological Evaluation of EC20: A New Folate-Derived, 99mTc-Based Radiopharmaceutical, Bioconjugate Chem., 2002, 13:1200-1210. [cited by applicant]
Reddy, J. A. et al., Preclinical Evaluation of 99mTc-EC20 for Imaging Folate Receptor-Positive Tumors, J Nucl. Med., May 2004, 45(5):857-866. [cited by applicant]
Müller, C. et al., Preclinical evaluation of novel organometallic 99mTc-folate and 99mTc-pteroate radiotracers for folate receptor-positive tumour targeting, Eur J Nucl Med Mol Imaging, Sep. 2006; 33(9):1007-1016. [cited by applicant]
Müller, C. et al., Synthesis and in Vitro/in Vivo Evaluation of Novel 99mTc(CO)3-Folates, Bioconjug Chem., Apr. 28, 2006; 17:797-806. [cited by applicant]
Siegel, B. A. et al., Evaluation of 111In-DTPA-Folate as a Receptor-Targeted Diagnostic Agent for Ovarian Cancer: Initial Clinical Results, J Nucl Med., May 2003, 44(5):700-707. [cited by applicant]
Mathias, C. J. et al., Receptor-Mediated Targeting of 67Ga-Deferoxamine-Folate to Folate-Receptor-Positive Human KB Tumor Xenografts, Nucl Med Biol. 1999; 26:23-25. [cited by applicant]
Mathias, C. J. et al., Preparation of 66Ga- and 68Ga-labeled Ga(III)-deferoxamine-folate as potential folate-receptor-targeted PET radiopharmaceuticals, Nucl Med Biol., 2003, 30:725-731. [cited by applicant]
Bettio, A. et al., Synthesis and Preclinical Evaluation of a Folic Acid Derivative Labeled with 18F for PET Imaging of Folate Receptor-Positive Tumors, J Nucl Med., Jul. 2006; 47(7):1153-1160. [cited by applicant]
Baum, R. P. et al., 177Lu-3BP-227 for Neurotensin Receptor 1-Targeted Therapy of Metastatic Pancreatic Adenocarcinoma: First Clinical Results, The Journal of Nuclear Medicine, 59(5):809-814, May 2018. [cited by applicant]
Zhang, H. et al., Synthesis and Evaluation of Bombesin Derivatives on the Basis of Pan-Bombesin Peptides Labeled with Indium-111, Lutetium-177, and Yttrium-90 for Targeting Bombesin Receptor-Expressing Tumors, Cancer Re… [cited by applicant]
Bodei, L et al., 177Lu-AMBA Bombesin analogue in hormone refractory prostate cancer patients: a phase I escalation study with single-cycle administrations, Eur J Nucl Med Mol Imaging, 2007, 34(suppl 2): S221, Abstract 4… [cited by applicant]
Hennig, I. M. et al., Substance-P Receptors in Human Primary Neoplasms: Tumoral and Vascular Localization, Int J Cancer, 1995, 61:786-792. [cited by applicant]
Kneifel, S. et al., Individual voxelwise dosimetry of targeted 90Y-labelled substance P radiotherapy for malignant gliomas, Eur J Nucl Med Mol Imaging, Jan. 31, 2007, 34:1388-1395. [cited by applicant]
Cordier, D. et al., Targeted alpha-radionuclide therapy of functionally critically located gliomas with 213Bi-DOTA- [Thi8, Met(O2)11]-substance P: a pilot trial, Eur J Nucl Med Mol Imaging, Feb. 16, 2010, 37:1335-1344. [cited by applicant]
Basu, S. et al. Peptide Receptor Radionuclide Therapy of Neuroendocrine Tumors, Semin Nucl Med, 50:447-464, 2020. [cited by applicant]