Development of 188Re-based radiopharmaceuticals for theranostic treatment of melanoma

Beliš Marek

Promoter

Vandenberghe Stefaan, stefaan.vandenberghe@ugent.be

SCK•CEN Mentor

Van Hecke Karen
karen.van.hecke@sckcen.be
+32 14 33 32 75

SCK•CEN Co-mentor

Aerts An
an.aerts@sckcen.be
+32 14 33 23 90

Expert group

Radiochemistry

PhD started

2017-10-16

Short project description

The current approach of radionuclide based targeted therapy is mainly by the use of β-emitters bound to targeting molecules such as monoclonal antibodies. This is due to the availability and the favourable characteristics of many β-emitting nuclides. Other therapeutic particle emissions are Auger electrons, α-particles and conversion electrons.

Rhenium-188 (188Re) is a promising radionuclide for radiotherapeutic applications. It emits β--particles with a maximum energy of 2.12 MeV (Kodina, 1990) (Knapp F. L., 1993). These β--particles have a maximum range of about 10 mm in soft tissue. 188Re is particularly well suited for radiotherapy when effective deep tissue penetration is required. In addition, it emits a 155 keV γ-ray, which can be used for imaging with current SPECT (single-photon emission computed tomography) systems without imposing a high external dose risk for medical workers. The gamma radiation can be conveniently used for evaluation of biokinetics and dosimetric estimations. Because its possible simultaneous application as both therapeutic and diagnostic agent, 188Re is a so-called theranostic radionuclide.

188Re is obtained carrier-free as 188Re perrhenate solution from a 188W/188Re radioisotope generator (Knapp F. M., 1994) (Knapp F. B., 1999) (Knapp F. L., 1993) (Kodina, 1990). The parent nuclide, 188W, is produced by double neutron capture of enriched tungsten targets in a high flux reactor such as BR2.

188Re and 99mTc have similar chemical properties and in particular a similar complexation chemistry, and therefore 99mTc can be interchanged in 99mTc-labelled carrier molecules by 188Re and vice versa. 99mTc is world-wide the most used radionuclide for medical diagnosis and the knowledge on 99mTc-based systems can be readily transformed to 188Re-based analogues. The use of 188Re as a theranostic radionuclide or 99mTc/188Re as a theranostic radionuclide pair offers the potential for personalized medicine by applying pre-therapy low-dose imaging followed by high-dose therapy in selected patients (Srivastava, 2013).

The potential of 188Re in therapeutic radiopharmaceuticals has been shown already for bone metastases and hepatocellular carcinoma. This project will focus on melanoma, which is a malignancy of melanocytes, pigment (melanin)-producing cells situated predominately in skin. It is an especially troublesome frequently occurring cancer, is regularly metastatic at diagnosis and predominately affects an active population between 30-50 years old. Until recently, chemotherapy offered little hope for metastatic melanoma. Signal inhibitors targeting B-RAF result in relatively short responses. Immunotherapy is very promising for some patients but at the cost of very serious side effects. Therefore there remains an opportunity for radionuclide therapy, and this is an underdeveloped field (Norain & Dadachova, 2016).

Objective

This doctoral research project has the overall aim to develop and validate radionuclide therapy for the treatment of metastatic melanoma (both primary tumour and metastatic lesions) by 188Re-labelled carrier molecules based on quantitative imaging and dosimetry. At the end of this project, we intent to have preclinically validated 188Re-labelled carrier molecules for theranostic treatment of melanoma.

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Appropriate selective carrier molecules are essential in this story to target specific cancer cells. Several carriers have been developed, labelled with therapeutic isotopes 131I, 90Y, 177Lu and more recently alpha-emitters such as 213Bi, 211At and 225Ac in preclinical experiment and early phase clinical trials in melanoma (Raja, et al., 2007). Three categories of carrier molecules are possible to use:

  1. Monoclonal antibodies, or fragments, targeting at melanoma-associated antigens such as HMW MAA, 6D2 or GD3 (Klein, et al., 2013);
  2. Peptides such as MSH (melanocyte-stimulating hormone) analogues or melanin-binding decapeptide 4B4 (Miao, Owen, Fisher, Hoffmann, & Quinn, 2005);
  3. Small molecules binding to components intra- or extracellular, such as the melanin binding benzamide (MIP-1145, BA52) (Joyal, et al., 2010) (Mier, et al., 2014).

This project will focus on category 2 & 3 carrier molecules (peptides and small molecules).

The radiolabelling of the carrier molecules with 188Re will be performed using bifunctional chelating agents such as MAG3, HYNIC and DTPA that form stable complexes with 188Re (Liu, 2008) (Sugiura, 2014). Such chelating agents have the advantage that they can bind to metals, but also possess a chemically reactive functional group so they can be covalently bound to the carrier molecule. The stability of the 188Re-labelled carrier molecules will have to be assessed in vitro and in vivo. Finally, the imaging and therapeutic potential has to be demonstrated.

Project work packages (WPs) include:

  1. Optimization of radiochemical procedures for the labelling of the carrier molecule(s) by selection and validation of appropriate bifunctional chelating agents, selecting an appropriate perrhenate reduction method, and selecting the most suitable labelling approach. Readouts will be yield (overall yield and yield of the individual steps) and purity after labelling.
  2. Assessment of the radiochemical stability of 188Re-labelled carrier molecules in storage and physiological conditions.
  3. In vitro studies on tumour cell lines, with a clear view on specificity of binding, affinity, and degree of internalisation.
  4. Development of quantitative imaging methodology for 188Re. This includes phantom studies to determine energy window optimization, collimator choice and corrections for high energy contamination. Based on the images obtained with microSPECT, maps of dose distribution are determined with convolution based or Monte Carlo methods. This WP will also assess the feasibility of a model with the sole theranost 188Re versus the tandem 99mTc/188Re.
  5. In vivo studies in different human tumour xenografted mouse models for melanoma to assess the stability, biodistribution, tissue penetration and tumour targeting.
  6. In vivo toxicity studies (histopathology and analysis of functional parameters in serum or urine) based on the outcome of biodistribution studies (WP5).
  7. Therapeutic efficacy of 188Re-labelled carrier molecules in relevant preclinical cancer mouse models.

This research project will be conducted by the Radiochemistry group (RCA) of the Belgian Nuclear Research Centre (SCK•CEN) and the IMIT (Innovative Molecular Imaging and Therapy) consortium of the University of Gent (UGent). RCA will provide the 188Re isotope and develop stable 188Re-labelled carrier molecules. UGent will provide the carrier molecules and perform preclinical evaluation of the 188Re-labelled carrier molecules by in vitro and in vivo characterisation. In a later stage of the project, in vitro and in vivo characterisation could be complemented by analogous studies performed at SCK•CEN.

An important and major part of the work is centred around work packages 1&2 and will be carried out in the Radiochemistry expert group of SCK•CEN. The work related to the other work packages will be carried out in the first stage of the project in the IMIT consortium (Radiopharmacy, MEDISIP and Infinity lab and Nuclear Medicine groups of UGent) and in a later stage of the project possibly at SCK•CEN.

References

Joyal, J., Barret, J., Marquis, J., Chen, J., Hillier, S., Maresca, K., et al. (2010). Preclinical evaluation of an 131I-labeled benzamide for targeted radiotherapy. Cancer Res, 70(10), 4045-4053.

Klein, M., Lotem, M., Peretz, T., Zwas, S., Mizrachi, S., Liberman, Y., et al. (2013). Safety and Efficacy of 188-Rhenium-Labeled Antibody to Melanin in Patients with Metastatic Melanoma. Journal of Skin Cancer, 2013, 1-8.

Knapp, F. B. (1999). Rhenium radionuclides for therapeutic radiopharmaceutical development. Therapeutic applications of radiopharmaceuticals, Proceedings of the International Seminar, Hyderabad, India, 1999, (pp. 59-66).

Knapp, F. L. (1993). Patentnr. Patent 5,186,913. US.

Knapp, F. M. (1994). The continuing important role of radionuclide generator systems for nuclear medicine. European Journal of Nuclear Medicine, 21(10), 1151-1165.

Kodina, G. T. (1990). Production and investigation of rhenium-188 generator. In M. B. Nicolini, Technetium and Rhenium in Chemistry and nuclear Medicine (pp. 635-641).

Liu, S. (2008). Bifunctional Coupling Agents for Radiolabeling of Biomolecules and Target-Specific Delivery of Metallic Radionuclides. Adv Drug Deliv Rev, 60(12), 1347-1370.

Miao, Owen, N., Fisher, D., Hoffmann, T., & Quinn, T. (2005). Therapeutic afficacy of a 188Re-labeled alpha-melanocyte-stimulating hormone peptide analog in murine and human melanoma-bearing mouse models. j. Nucl. Med., 46, 121-129W.

Mier, W., Kratochwil, C., Hassel, J., Giesel, F., Beijer, B., Babich, J., et al. (2014). Radiopharmaceutical therapy of patients with metastasized melanoma with the melanin-binding benzamide 131I-BA52. J.Nucl.Med.Mol.Imaging, 55, 9-14.

Norain, A., & Dadachova, E. (2016). Targeted radionuclide therapy of melanoma. Seminars of Nucl. Med., 46, 250-259.

Raja, C., Graham, S., Rizvi, S., Song, E., Goldschmith, H., Thompson, J., et al. (2007). Interim analysis of toxicity and response in phase 1 trial of systemic targeted alpha terapy for metastatic melanoma. Cancer Biol. Ther., 6(6), 846-852Y.

Srivastava, S. M. (2013). Therapeutic Radionuclides: Production, Physical Characteristics, and Applications. In R. Baum, Therapeutic Nuclear Medicine. Springer-Verlag, Berlin, Heidelberg.

Sugiura, G. K. (2014). Radiolabeling Strategies for Tumor-Targeting Proteinaceous Drugs. Molecules, 19, 2135-2165.