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

Targeted radionuclide therapy is a revolutionary tool for the treatment of 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 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 antibody (NP137) has been tested in various clinical trials. In order to provide a companion test detecting netrin-1 in tumors and allowing selection of therapy-eligible patients, we developed an indium-111-NODAGA-NP137 Single Photon Emission Computed Tomography (SPECT) contrast agent. NP137-111In provided specific detection of netrin-1-positive tumors. The high specificity of NP137 paved the way for the generation of lutetium 177-DOTA-NP137 a novel vectorized radiotherapy. We demonstrate here that NP137-177lu provides important anti-tumor effects in animal models. Together these data support the view that NP137-111In and NP137-177lu may represent original imaging and therapeutic tools against cancers.