title: Efficacy of aerosol therapy of lung cancer correlates with EGFR paralysis induced by AvidinOX-anchored biotinylated Cetuximab.
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.
authors.affiliation: Sigma-Tau SpA R and D, Pomezia, Rome, Italy.
authors.forename: Rita
authors.initials: R
authors.lastname: De Santis
authors.affiliation: Sigma-Tau SpA R and D, Pomezia, Rome, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Rosi
authors.affiliation: Sigma-Tau SpA R and D, Pomezia, Rome, Italy.
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Anastasi
authors.affiliation: Sigma-Tau SpA R and D, Pomezia, Rome, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Chiapparino
authors.affiliation: Sigma-Tau SpA R and D, Pomezia, Rome, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Albertoni
authors.affiliation: Sigma-Tau SpA R and D, Pomezia, Rome, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Leoni
authors.affiliation: Sigma-Tau SpA R and D, Pomezia, Rome, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Pelliccia
authors.affiliation: Sigma-Tau SpA R and D, Pomezia, Rome, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Santapaola
authors.affiliation: Sigma-Tau SpA R and D, Pomezia, Rome, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Carollo
authors.affiliation: Takis Srl, Via di Castel Romano, Rome, Italy.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Marra
authors.affiliation: Takis Srl, Via di Castel Romano, Rome, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Aurisicchio
authors.affiliation: Takis Srl, Via di Castel Romano, Rome, Italy.
authors.forename: Brunilde
authors.initials: B
authors.lastname: Arseni
authors.affiliation: Takis Srl, Via di Castel Romano, Rome, Italy.
authors.forename: Maria Lucrezia
authors.initials: ML
authors.lastname: Pacello
authors.affiliation: University La Sapienza, Experimental Medicine Department, Viale Regina Elena, Rome, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Palmieri
authors.affiliation: University La Sapienza, Experimental Medicine Department, Viale Regina Elena, Rome, Italy.
authors.forename: Simone
authors.initials: S
authors.lastname: Battella
authors.affiliation: Sigma-Tau SpA R and D, Pomezia, Rome, Italy.
authors.forename: Fiorella
authors.initials: F
authors.lastname: Petronzelli
authors.affiliation: Sigma-Tau SpA R and D, Pomezia, Rome, Italy.
authors.forename: Ferdinando Maria
authors.initials: FM
authors.lastname: Milazzo
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000280:Administration, Inhalation; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001360:Avidin / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000068818:Cetuximab; D004705:Endocytosis / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D008247:Lysosomes / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016513:Mice, SCID; D000077544:Panitumumab; D055503:Protein Multimerization / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D001360:Avidin; D000077544:Panitumumab; C541485:EGFR protein, mouse; D066246:ErbB Receptors; D000068818:Cetuximab