Radiolabeled Nanobodies as Theranostic Tools in Targeted Radionuclide Therapy of Cancer

The principle of targeted radionuclide therapy (TRNT) is based on the specific delivery of cytotoxic radiation to tumor cells, with minimal uptake in healthy tissues. This can be achieved by delivering a radiolabeled vector molecule to a surface-protein that is unique or overexpressed on tumor cells, but is not or much less present on healthy tissue. Essential for efficient TRNT is the use of radionuclides that are able to elicit high delivery of energy within their close surrounding. Nanobodies have shown to be functional after connection to chelating agents for radionuclide complexation, making them suitable for TRNT. In this thesis, we developed 177Lu-labeled anti-HER2 nanobodies for the treatment of human epidermal growth factor receptor 2(HER2)+cancer. Radiolabeled nanobodies accumulate intensely in kidneys. For therapeutic purposes with long-lived radioisotopes, this accumulation could lead to important renal toxicity. We assessed strategies to reduce renal retention of nanobodies. An optimized 177Lu-labeled anti-HER2 nanobody format was evaluated for TRNT in mice with HER2+tumor xenografts. We generated and characterized anti-idiotype nanobodies for imaging of disease progression and for TRNT of multiple myeloma. We described the generation of anti-prostate-specific membrane antigen (PSMA) nanobodies as a new vector molecule for imaging and TRNT of PSMA+ prostate cancer.