213Bismuth-labeled nanobodies as a new treatment approach in targeted alpha therapy

Dekempeneer Yana

Promoter

Caveliers Vicky, (VUB), vicky.caveliers@uzbrussel.be

SCK•CEN Mentor

Gysemans Mireille
mireille.gysemans@sckcen.be
+32 14 33 32 80

SCK•CEN Co-mentor

Maertens Dominic
dominic.maertens@sckcen.be
+32 14 33 32 69

Expert group

Radiochemistry

PhD started

2016-10-01

Short project description

Incomplete eradication of residual tumor cells and/or acquired drug resistance against conventional therapies dramatically affect morbidity and mortality of cancer patients. A potential solution could be targeted a-radionuclide therapy (TAT). TAT has the ability to specifically kill isolated cancer cells, and causes little damage to healthy cells, because TAT induces internal radiation using lethal short-range alpha particles. To be successful, the radionuclide that produces such a-particles has to be linked to a targeting molecule, to ensure that this therapeutic agent is only delivered to the tumor cells. In this study, we will exploit the unique combination of the a-particle emitter 213Bi and nanobodies. Nanobodies have been successfully used by the In Vivo Cellular and Molecular Imaging (ICMI) research group of the Vrije Universiteit Brussel (VUB) for both nuclear imaging (1)(2) and targeted therapy (3)(4)(5). Nanobodies could be particularly suited for TAT because of their exceptional binding potential to extracellular targets and fast clearance from healthy tissues. Recently a first clinical trial was completed at the UZ Brussel, evaluating a 68Ga-labeled anti-HER2 nanobody for the detection of HER2 positive tumor lesions in breast cancer patients (6). In the past, the same anti-HER2 nanobody, but radiolabeled with 177Lu has been successfully used as a therapeutic and preclinically validated in several mouse models (5).

213Bi is one of the alpha-emitting radionuclides that shows significant promise for TAT (7)(8)(9). Although it is a radionuclide with a relatively short half-life of 46 minutes, it can be made readily available to the hospital over a minimum of 10 days period when using an  225Ac/213Bi generator (10)(11). Presently, 225Ac (t1/2 = 10 d) is predominantly obtained from the decay of the long-lived 229Th (t1/2 = 7880 y) of which the worldwide availability is limited. However, SCK•CEN is in the possession of 229Th-sources originating from the historical Actinium Project (12). The smallest of these sources is very suited to perform research into the development of a mobile 225Ac/213Bi generator and further use of 213Bi in TAT.

The short half-life of 213Bi has the advantage that the lethal radiation is released rapidly after injection. This characteristic matches with the fast binding and clearance of nanobodies, making both ideal partners for TAT. The combination of 213Bi and nanobodies might become a promising treatment option to target residual and metastatic disease.

This research project will be conducted at the Radiochemistry expert group (RCA) of the Belgian Nuclear Research Centre (SCK•CEN) and the In Vivo Cellular and Molecular Imaging (ICMI) research group of the Vrije Universiteit Brussel (VUB). RCA will use its expertise to develop and validate the 225Ac/213Bi generator. In addition, there will be a focus on radiochemical procedures to develop stable 213Bi-labeled nanobodies. ICMI will contribute through its expertise in the preclinical evaluation of radiolabeled nanobodies. The facilities at ICMI will allow the in vitro and in vivo characterization of developed 213Bi-labeled nanobodies.

Objective

This doctoral research project has the overall aim to develop and validate targeted alpha-radionuclide therapy for the treatment of residual and metastatic disease, through the use of 213Bi-labeled nanobodies.

To test this hypothesis, we first aim to develop a mobile 225Ac/213Bi generator. Secondly, the validated anti-HER2 nanobodies will be radiolabeled with 213Bi for the treatment of HER2 positive breast and ovarian cancer.

At the end of this project, we intent to have a fully optimized and preclinically validated 213Bi-labeled anti-HER2 nanobody. If this strategy can proof itself valuable in the treatment of cancer, it has great potential to be a game-changer in the field of nuclear medicine, as it will open the door to additional targeted alpha-particle therapies.