Preclinical molecular imaging to study the biodistribution of antibody derivatives in oncology

The successful use of antibodies for the treatment of cancer has spurred the interest in the development of antibody derivatives, such as Bispecific T-cell engagers (BiTEs) and nanobody constructs. Molecular imaging may facilitate drug development of BiTEs and nanobody constructs and decision making throughout this process. By radiolabeling antibody derivatives with zirconium-89 (89Zr), their pharmacokinetic profile, organ distribution and tumor uptake can be studied non-invasively by 89Zr-PET. In addition, fluorescent labeling of antibody derivatives enables studying their distribution within tumors, at a microscopic level. Furthermore, injecting fluorescently labeled nanobodies, that target tumor tissue, may facilitate real-time visualization of tumors in an intraoperative setting.
Given the overexpression on a variety of tumor cells, EpCAM, CEA and HER3 are interesting targets for BiTEs and nanobodies. In order to facilitate their drug development, an anti-EpCAM BiTE, anti-CEA BiTE and anti-HER3 nanobody construct have been radiolabeled with 89Zr. 89Zr-PET was used to study their organ distribution and tumor uptake. Radiolabeling of the anti-CEA BiTE was additionally used to study its in vivo integrity in serum and tumors. The obtained preclinical data have been used to setup a clinical trial, in which 89Zr-PET is used to study organ distribution and tumor uptake of this anti-CEA BiTE in cancer patients.
This thesis also describes the selection and preclinical evaluation of anti-HER2 nanobodies, fluorescently labeled with IRDye 800CW. Shortly after injection, the best performing nanobody enabled tumor visualization of HER2-positive tumors using optical imaging. It accumulated quicker in these tumors than 800CW-trastuzumab, a fluorescently labeled anti-HER2 drug.