From netrin-1-targeted SPECT/CT to internal radiotherapy for management of advanced solid tumors.

ABSTRACT

Targeted radionuclide therapy is a revolutionary tool for the treatment of highly spread metastatic cancers. Most current approaches rely on the use of vectors to deliver radionuclides to tumor cells, targeting membrane-bound cancer-specific moieties. Here, we report the embryonic navigation cue netrin-1 as an unanticipated target for vectorized radiotherapy. While netrin-1, known to be re-expressed in tumoral cells to promote cancer progression, is usually characterized as a diffusible ligand, we demonstrate here that netrin-1 is actually poorly diffusible and bound to the extracellular matrix. A therapeutic anti-netrin-1 monoclonal antibody (NP137) has been preclinically developed and was tested in various clinical trials showing an excellent safety profile. In order to provide a companion test detecting netrin-1 in solid tumors and allowing the selection of therapy-eligible patients, we used the clinical-grade NP137 agent and developed an indium-111-NODAGA-NP137 single photon emission computed tomography (SPECT) contrast agent. NP137-111 In provided specific detection of netrin-1-positive tumors with an excellent signal-to-noise ratio using SPECT/CT imaging in different mouse models. The high specificity and strong affinity of NP137 paved the way for the generation of lutetium-177-DOTA-NP137, a novel vectorized radiotherapy, which specifically accumulated in netrin-1-positive tumors. We demonstrate here, using tumor cell-engrafted mouse models and a genetically engineered mouse model, that a single systemic injection of NP137-177 Lu provides important antitumor effects and prolonged mouse survival. Together, these data support the view that NP137-111 In and NP137-177 Lu may represent original and unexplored imaging and therapeutic tools against advanced solid cancers.