Development of new theragnostic radiopharmaceuticals for EGFR(+) and KRAS mutated tumors

JÖRI WEHRMÜLLER; MANUEL SZTEJNBERG; ROGER SCHIBLI; DAILENYS ESPINOSA MARTINEZ; NOEMI NEVARES; MARTIN BEHE; JULIA MILENA GALLINO FERNÁNDEZ; CLARISA LOPEZ BULARTE; JOSE LUIS CRUDO; LUCIA LAURA POLICASTRO

Congreso; REUNIÓN DE SOCIEDADES DE BIOCIENCIAS 2020; 2020

The epidermal growth factor receptor (EGFR) is one of the most exploredcancer associated molecules due to its overexpression in various types ofcancers. Nowadays, there are approximately 10 compounds on the market targetingEGFR. However, their effectiveness is limited in patient subpopulation withspecific genetic characteristics and due to acquired resistance.Radioimmunotherapy (RIT) is based on radiolabeled proteins targetingcancer-associated structures. Besides antibodies, alternative protein formatswith different pharmacokinetic characteristic such as nanobodies (VHH) havebeen explored for radionuclides diagnosis in the recent years. The aim of thisproject is to obtain a novel radiopharmaceuticals based in 177Luand VHH against EGFR receptor (VHH-EGFR) for theragnostic application. First,we labelled a monomeric VHH-EGFR with 177Lu and characterized itsperformance in kras mutated and wild type cancer cells in colony assay. Theresults showed a specific and significative therapeutic effect in kras mutatedrespect wild type kras cancer cells. However, for in vivo application,it is necessary to slightly increase its size in order to avoid quick renalclearance and achieve a therapeutic effect. Atthis moment, we are working in different strategies to slightly increase nanobodysize, for instance adding an albumin binder or perform VHH dimers to improve itspharmacokinetic and therapeutic effect in future in vivo experiments.