Radiolabeled single-domain antibody fragments for targeted radionuclide therapy of difficult-to-treat cancers.

Abstract

Most cancer cells are characterized by the (over)expression of certain transmembrane proteins – so called tumor-associated antigens. This dissertation describes the application of targeted radionuclide therapy (TRNT) using single-domain antibody fragments (sdAbs) that recognize these tumor-associated antigens in 2 preclinical models that mimic difficult-to-treat cancers, namely brain metastasis and multiple myeloma. So far, TRNT has mainly been explored using 훽–-emitting radionuclides. However, their long range causes irradiation of neighboring non-target cells. The efficacy of low energy, long range 훽–- and high energy, short range 훼-particle emitting radionuclides was compared in both preclinical models.
Firstly, we describe efforts to generate a novel sdAb targeting EGFRvIII - a mutated form of EGFR - for the targeted treatment of glioblastoma. Despite the implementation of a myriad of panning and screening techniques, no selective anti-EGFRvIII sdAbs could be generated.
Secondly, we evaluated an anti-HER2 sdAb for detection and treatment of HER2-positive brain metastases. We demonstrated the superior efficacy of sdAb-based TRNT compared to two clinically implemented HER2-directed treatments, trastuzumab and ado-trastuzumab-DM1.
Thirdly, we describe the generation and therapeutic potential of 훼- and 훽–-radiolabeled sdAbs as tumor-restrictive vehicles against the murine 5T33MM-idiotypic paraprotein.
Analogously, we assessed the transferability of this approach towards sdAb-based personalized medicine for multiple myeloma. Using patient blood samples, we were able to develop sdAbs targeting patient-specific anti-idiotypic paraproteins that could be used for the targeted eradication of residual, treatment-resistant myeloma cells.

Date of Award	4 Mar 2021
Original language	English
Awarding Institution	Vrije Universiteit Brussel
Supervisor	Nick Devoogdt (Promotor), Matthias D'Huyvetter (Promotor), Anna Orlova (Jury), Benedicte Descamps (Jury), Eline Menu (Jury), Kiavash Movahedi (Jury) & Vicky Caveliers (Jury)