Efficacy of aerosol therapy of lung cancer correlates with EGFR paralysis induced by AvidinOX-anchored biotinylated Cetuximab

// Rita De Santis 1 , Antonio Rosi 1 , Anna Maria Anastasi 1 , Caterina Chiapparino 1 , Claudio Albertoni 1 , Barbara Leoni 1 , Angela Pelliccia 1 , Daniela Santapaola 1 , Valeria Carollo 1 , Emanuele Marra 2 , Luigi Aurisicchio 2 , Brunilde Arseni 2 , Maria Lucrezia Pacello 2 , Gabriella Palmieri 3 , Simone Battella 3 , Fiorella Petronzelli 1 and Ferdinando Maria Milazzo 1 1 Sigma-Tau SpA R&D, Pomezia, Rome, Italy 2 Takis Srl, Via di Castel Romano, Rome, Italy 3 University La Sapienza, Experimental Medicine Department, Viale Regina Elena, Rome, Italy Correspondence: Rita De Santis , email: // Keywords : AvidinOX, Cetuximab, lung cancer, aerosol Received : July 09, 2014 Accepted : August 26, 2014 Published : August 31, 2014 Abstract Lung cancer, as well as lung metastases from distal primary tumors, could benefit from aerosol treatment. Unfortunately, because of lung physiology, clearance of nebulized drugs is fast, paralleled by unwanted systemic exposure. Here we report that nebulized AvidinOX can act as an artificial receptor for biotinylated drugs. In nude and SCID mice with advanced human KRAS-mutated A549 metastatic lung cancer, pre-nebulization with AvidinOX enables biotinylated Cetuximab to control tumor growth at a dose lower than 1/25,000 the intravenous effective dose. This result correlates with a striking, specific and unpredictable effect of AvidinOX-anchored biotinylated Cetuximab, as well as Panitumumab, observed on a panel of tumor cell lines, leading to inhibition of dimerization and signalling, blockade of endocytosis, induction of massive lysosomal degradation and abrogation of nuclear translocation of EGFR. Excellent tolerability, together with availability of pharmaceutical-grade AvidinOX and antibodies, will allow rapid clinical translation of the proposed therapy.