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3. A first-in-human trial on the safety and immunogenicity of COVID-eVax, a cellular response-skewed DNA vaccine against COVID-19

Author

Aurisicchio, Luigi, Brambilla, Nadia, Cazzaniga, Marina E., Bonfanti, Paolo, Milleri, Stefano, Ascierto, Paolo A., Capici, Serena, Vitalini, Cristina, Girolami, Federica, Giacovelli, Giampaolo, Caselli, Gianfranco, Visintin, Michela, Fanti, Francesca, Ghirri, Matteo, Conforti, Antonella, Compagnone, Mirco, Lione, Lucia, Salvatori, Erika, Pinto, Eleonora, Muzi, Alessia, Marra, Emanuele, Palombo, Fabio, Roscilli, Giuseppe, Manenti, Alessandro, Montomoli, Emanuele, Cadossi, Matteo, and Rovati, Lucio C.

Published
2023
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5. COVID-eVax, an electroporated DNA vaccine candidate encoding the SARS-CoV-2 RBD, elicits protective responses in animal models

Author

Conforti, Antonella, Marra, Emanuele, Palombo, Fabio, Roscilli, Giuseppe, Ravà, Micol, Fumagalli, Valeria, Muzi, Alessia, Maffei, Mariano, Luberto, Laura, Lione, Lucia, Salvatori, Erika, Compagnone, Mirco, Pinto, Eleonora, Pavoni, Emiliano, Bucci, Federica, Vitagliano, Grazia, Stoppoloni, Daniela, Pacello, Maria Lucrezia, Cappelletti, Manuela, Ferrara, Fabiana Fosca, D’Acunto, Emanuela, Chiarini, Valerio, Arriga, Roberto, Nyska, Abraham, Di Lucia, Pietro, Marotta, Davide, Bono, Elisa, Giustini, Leonardo, Sala, Eleonora, Perucchini, Chiara, Paterson, Jemma, Ryan, Kathryn Ann, Challis, Amy-Rose, Matusali, Giulia, Colavita, Francesca, Caselli, Gianfranco, Criscuolo, Elena, Clementi, Nicola, Mancini, Nicasio, Groß, Rüdiger, Seidel, Alina, Wettstein, Lukas, Münch, Jan, Donnici, Lorena, Conti, Matteo, De Francesco, Raffaele, Kuka, Mirela, Ciliberto, Gennaro, Castilletti, Concetta, Capobianchi, Maria Rosaria, Ippolito, Giuseppe, Guidotti, Luca G., Rovati, Lucio, Iannacone, Matteo, and Aurisicchio, Luigi

Published
2022
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9. Dynamics of humoral and cellular response to three doses of anti-SARS-CoV-2 BNT162b2 vaccine in patients with hematological malignancies and older subjects

Author

Laquintana, Valentina, primary, Mottini, Carla, additional, Marchesi, Francesco, additional, Marcozzi, Benedetta, additional, Terrenato, Irene, additional, Sperandio, Eleonora, additional, de Latouliere, Luisa, additional, Carrieri, Francesca, additional, Pimpinelli, Fulvia, additional, Pontone, Martina, additional, Pellini, Raul, additional, Campo, Flaminia, additional, Conti, Laura, additional, Accetta, Celeste, additional, Mandoj, Chiara, additional, Petrone, Fabrizio, additional, Di Bella, Ornella, additional, Vujovic, Branka, additional, Morrone, Aldo, additional, Compagnone, Mirco, additional, Principato, Eugenia, additional, Pinto, Eleonora, additional, Papa, Elena, additional, Falcucci, Paolo, additional, La Malfa, Antonia, additional, Pallocca, Matteo, additional, De Marco, Federico, additional, Piaggio, Giulia, additional, Ciliberto, Gennaro, additional, Mengarelli, Andrea, additional, and di Martino, Simona, additional

Published
2024
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10. Isolation and Characterization of Neutralizing Monoclonal Antibodies from a Large Panel of Murine Antibodies against RBD of the SARS-CoV-2 Spike Protein

Author

D’Acunto, Emanuela, primary, Muzi, Alessia, additional, Marchese, Silvia, additional, Donnici, Lorena, additional, Chiarini, Valerio, additional, Bucci, Federica, additional, Pavoni, Emiliano, additional, Ferrara, Fabiana Fosca, additional, Cappelletti, Manuela, additional, Arriga, Roberto, additional, Serrao, Silvia Maria, additional, Peluzzi, Valentina, additional, Principato, Eugenia, additional, Compagnone, Mirco, additional, Pinto, Eleonora, additional, Luberto, Laura, additional, Stoppoloni, Daniela, additional, Lahm, Armin, additional, Groß, Rüdiger, additional, Seidel, Alina, additional, Wettstein, Lukas, additional, Münch, Jan, additional, Goodhead, Andrew, additional, Parisot, Judicael, additional, De Francesco, Raffaele, additional, Ciliberto, Gennaro, additional, Marra, Emanuele, additional, Aurisicchio, Luigi, additional, and Roscilli, Giuseppe, additional

Published
2024
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13. A first-in-human trial on the safety and immunogenicity of COVID-eVax, a cellular response-skewed DNA vaccine against COVID-19

Author

Aurisicchio, L, Brambilla, N, Cazzaniga, M, Bonfanti, P, Milleri, S, Ascierto, P, Capici, S, Vitalini, C, Girolami, F, Giacovelli, G, Caselli, G, Visintin, M, Fanti, F, Ghirri, M, Conforti, A, Compagnone, M, Lione, L, Salvatori, E, Pinto, E, Muzi, A, Marra, E, Palombo, F, Roscilli, G, Manenti, A, Montomoli, E, Cadossi, M, Rovati, L, Aurisicchio, Luigi, Brambilla, Nadia, Cazzaniga, Marina E, Bonfanti, Paolo, Milleri, Stefano, Ascierto, Paolo A, Capici, Serena, Vitalini, Cristina, Girolami, Federica, Giacovelli, Giampaolo, Caselli, Gianfranco, Visintin, Michela, Fanti, Francesca, Ghirri, Matteo, Conforti, Antonella, Compagnone, Mirco, Lione, Lucia, Salvatori, Erika, Pinto, Eleonora, Muzi, Alessia, Marra, Emanuele, Palombo, Fabio, Roscilli, Giuseppe, Manenti, Alessandro, Montomoli, Emanuele, Cadossi, Matteo, Rovati, Lucio C, Aurisicchio, L, Brambilla, N, Cazzaniga, M, Bonfanti, P, Milleri, S, Ascierto, P, Capici, S, Vitalini, C, Girolami, F, Giacovelli, G, Caselli, G, Visintin, M, Fanti, F, Ghirri, M, Conforti, A, Compagnone, M, Lione, L, Salvatori, E, Pinto, E, Muzi, A, Marra, E, Palombo, F, Roscilli, G, Manenti, A, Montomoli, E, Cadossi, M, Rovati, L, Aurisicchio, Luigi, Brambilla, Nadia, Cazzaniga, Marina E, Bonfanti, Paolo, Milleri, Stefano, Ascierto, Paolo A, Capici, Serena, Vitalini, Cristina, Girolami, Federica, Giacovelli, Giampaolo, Caselli, Gianfranco, Visintin, Michela, Fanti, Francesca, Ghirri, Matteo, Conforti, Antonella, Compagnone, Mirco, Lione, Lucia, Salvatori, Erika, Pinto, Eleonora, Muzi, Alessia, Marra, Emanuele, Palombo, Fabio, Roscilli, Giuseppe, Manenti, Alessandro, Montomoli, Emanuele, Cadossi, Matteo, and Rovati, Lucio C

Abstract

The COVID-19 pandemic and the need for additional safe, effective, and affordable vaccines gave new impetus into development of vaccine genetic platforms. Here we report the findings from the phase 1, first-in-human, dose-escalation study of COVID-eVax, a DNA vaccine encoding the receptor binding domain (RBD) of the SARS-CoV-2 spike protein. Sixty-eight healthy adults received two doses of 0.5, 1, or 2 mg 28 days apart, or a single 2-mg dose, via intramuscular injection followed by electroporation, and they were monitored for 6 months. All participants completed the primary safety and immunogenicity assessments after 8 weeks. COVID-eVax was well tolerated, with mainly mild to moderate solicited adverse events (tenderness, pain, bruising, headache, and malaise/fatigue), less frequent after the second dose, and it induced an immune response (binding antibodies and/or T cells) at all prime-boost doses tested in up to 90% of the volunteers at the highest dose. However, the vaccine did not induce neutralizing antibodies, while particularly relevant was the T cell-mediated immunity, with a robust Th1 response. This T cell-skewed immunological response adds significant information to the DNA vaccine platform and should be assessed in further studies for its protective capacity and potential usefulness also in other therapeutic areas, such as oncology.

Published
2023

14. Isolation and Characterization of Neutralizing Monoclonal Antibodies from a Large Panel of Murine Antibodies against RBD of the SARS-CoV-2 Spike Protein.

Author

D'Acunto, Emanuela, Muzi, Alessia, Marchese, Silvia, Donnici, Lorena, Chiarini, Valerio, Bucci, Federica, Pavoni, Emiliano, Ferrara, Fabiana Fosca, Cappelletti, Manuela, Arriga, Roberto, Serrao, Silvia Maria, Peluzzi, Valentina, Principato, Eugenia, Compagnone, Mirco, Pinto, Eleonora, Luberto, Laura, Stoppoloni, Daniela, Lahm, Armin, Groß, Rüdiger, and Seidel, Alina

Subjects
MONOCLONAL antibodies, SARS-CoV-2 Omicron variant, SARS-CoV-2, RECOMBINANT proteins, IMMUNOGLOBULINS, HUMORAL immunity
Abstract

The COVID-19 pandemic, once a global crisis, is now largely under control, a testament to the extraordinary global efforts involving vaccination and public health measures. However, the relentless evolution of SARS-CoV-2, leading to the emergence of new variants, continues to underscore the importance of remaining vigilant and adaptable. Monoclonal antibodies (mAbs) have stood out as a powerful and immediate therapeutic response to COVID-19. Despite the success of mAbs, the evolution of SARS-CoV-2 continues to pose challenges and the available antibodies are no longer effective. New variants require the ongoing development of effective antibodies. In the present study, we describe the generation and characterization of neutralizing mAbs against the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein by combining plasmid DNA and recombinant protein vaccination. By integrating genetic immunization for rapid antibody production and the potent immune stimulation enabled by protein vaccination, we produced a rich pool of antibodies, each with unique binding and neutralizing specificities, tested with the ELISA, BLI and FACS assays and the pseudovirus assay, respectively. Here, we present a panel of mAbs effective against the SARS-CoV-2 variants up to Omicron BA.1 and BA.5, with the flexibility to target emerging variants. This approach ensures the preparedness principle is in place to address SARS-CoV-2 actual and future infections. [ABSTRACT FROM AUTHOR]

Published
2024
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15. Supplementary Video 1 from Nutlin-3a Enhances Natural Killer Cell–Mediated Killing of Neuroblastoma by Restoring p53-Dependent Expression of Ligands for NKG2D and DNAM-1 Receptors

Author

Veneziani, Irene, primary, Infante, Paola, primary, Ferretti, Elisa, primary, Melaiu, Ombretta, primary, Battistelli, Cecilia, primary, Lucarini, Valeria, primary, Compagnone, Mirco, primary, Nicoletti, Carmine, primary, Castellano, Aurora, primary, Petrini, Stefania, primary, Ognibene, Marzia, primary, Pezzolo, Annalisa, primary, Di Marcotullio, Lucia, primary, Bei, Roberto, primary, Moretta, Lorenzo, primary, Pistoia, Vito, primary, Fruci, Doriana, primary, Barnaba, Vincenzo, primary, Locatelli, Franco, primary, and Cifaldi, Loredana, primary

Published
2023
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16. Supplementary Figures from Nutlin-3a Enhances Natural Killer Cell–Mediated Killing of Neuroblastoma by Restoring p53-Dependent Expression of Ligands for NKG2D and DNAM-1 Receptors

Author

Veneziani, Irene, primary, Infante, Paola, primary, Ferretti, Elisa, primary, Melaiu, Ombretta, primary, Battistelli, Cecilia, primary, Lucarini, Valeria, primary, Compagnone, Mirco, primary, Nicoletti, Carmine, primary, Castellano, Aurora, primary, Petrini, Stefania, primary, Ognibene, Marzia, primary, Pezzolo, Annalisa, primary, Di Marcotullio, Lucia, primary, Bei, Roberto, primary, Moretta, Lorenzo, primary, Pistoia, Vito, primary, Fruci, Doriana, primary, Barnaba, Vincenzo, primary, Locatelli, Franco, primary, and Cifaldi, Loredana, primary

Published
2023
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17. Data from Nutlin-3a Enhances Natural Killer Cell–Mediated Killing of Neuroblastoma by Restoring p53-Dependent Expression of Ligands for NKG2D and DNAM-1 Receptors

Author

Veneziani, Irene, primary, Infante, Paola, primary, Ferretti, Elisa, primary, Melaiu, Ombretta, primary, Battistelli, Cecilia, primary, Lucarini, Valeria, primary, Compagnone, Mirco, primary, Nicoletti, Carmine, primary, Castellano, Aurora, primary, Petrini, Stefania, primary, Ognibene, Marzia, primary, Pezzolo, Annalisa, primary, Di Marcotullio, Lucia, primary, Bei, Roberto, primary, Moretta, Lorenzo, primary, Pistoia, Vito, primary, Fruci, Doriana, primary, Barnaba, Vincenzo, primary, Locatelli, Franco, primary, and Cifaldi, Loredana, primary

Published
2023
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18. Supplementary Table 1 from Nutlin-3a Enhances Natural Killer Cell–Mediated Killing of Neuroblastoma by Restoring p53-Dependent Expression of Ligands for NKG2D and DNAM-1 Receptors

Author

Veneziani, Irene, primary, Infante, Paola, primary, Ferretti, Elisa, primary, Melaiu, Ombretta, primary, Battistelli, Cecilia, primary, Lucarini, Valeria, primary, Compagnone, Mirco, primary, Nicoletti, Carmine, primary, Castellano, Aurora, primary, Petrini, Stefania, primary, Ognibene, Marzia, primary, Pezzolo, Annalisa, primary, Di Marcotullio, Lucia, primary, Bei, Roberto, primary, Moretta, Lorenzo, primary, Pistoia, Vito, primary, Fruci, Doriana, primary, Barnaba, Vincenzo, primary, Locatelli, Franco, primary, and Cifaldi, Loredana, primary

Published
2023
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19. Supplementary Figure legend from Nutlin-3a Enhances Natural Killer Cell–Mediated Killing of Neuroblastoma by Restoring p53-Dependent Expression of Ligands for NKG2D and DNAM-1 Receptors

Author

Veneziani, Irene, primary, Infante, Paola, primary, Ferretti, Elisa, primary, Melaiu, Ombretta, primary, Battistelli, Cecilia, primary, Lucarini, Valeria, primary, Compagnone, Mirco, primary, Nicoletti, Carmine, primary, Castellano, Aurora, primary, Petrini, Stefania, primary, Ognibene, Marzia, primary, Pezzolo, Annalisa, primary, Di Marcotullio, Lucia, primary, Bei, Roberto, primary, Moretta, Lorenzo, primary, Pistoia, Vito, primary, Fruci, Doriana, primary, Barnaba, Vincenzo, primary, Locatelli, Franco, primary, and Cifaldi, Loredana, primary

Published
2023
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21. Immunogenicity of COVID-eVax Delivered by Electroporation Is Moderately Impacted by Temperature and Molecular Isoforms

Author

D’Alessio, Federico, primary, Lione, Lucia, additional, Salvatori, Erika, additional, Bucci, Federica, additional, Muzi, Alessia, additional, Roscilli, Giuseppe, additional, Compagnone, Mirco, additional, Pinto, Eleonora, additional, Battistuzzi, Gianfranco, additional, Conforti, Antonella, additional, Aurisicchio, Luigi, additional, and Palombo, Fabio, additional

Published
2023
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22. Co-Delivery of the Human NY-ESO-1 Tumor-Associated Antigen and Alpha-GalactosylCeramide by Filamentous Bacteriophages Strongly Enhances the Expansion of Tumor-Specific CD8+ T Cells

Author

Manco, Roberta, primary, D’Apice, Luciana, additional, Trovato, Maria, additional, Lione, Lucia, additional, Salvatori, Erika, additional, Pinto, Eleonora, additional, Compagnone, Mirco, additional, Aurisicchio, Luigi, additional, De Berardinis, Piergiuseppe, additional, and Sartorius, Rossella, additional

Published
2023
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24. Immunogenicity of COVID-eVax Is Moderately Impacted by Temperature and Molecular Isoforms

Author

D’Alessio, Federico, primary, Lione, Lucia, additional, Salvatori, Erika, additional, Bucci, Federica, additional, Muzi, Alessia, additional, Roscilli, Giuseppe, additional, Conforti, Antonella, additional, Compagnone, Mirco, additional, Pinto, Eleonora, additional, Battistuzzi, Gianfranco, additional, Aurisicchio, Luigi, additional, and Palombo, Fabio, additional

Published
2022
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25. 820 Linear DNA amplicons as a novel antiviral and cancer vaccine strategy

Author

Aurisicchio, Luigi, primary, Conforti, Antonella, additional, Compagnone, Mirco, additional, Salvatori, Erika, additional, Lione, Lucia, additional, Pinto, Eleonora, additional, Shorrock, Clay, additional, Hayward, James, additional, Viscount, Brian, additional, Palombo, Fabio, additional, Sun, Yuhua, additional, and Liang, Ben Minghwa, additional

Published
2022
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26. A Linear SARS-CoV-2 DNA Vaccine Candidate Reduces Virus Shedding in Ferrets

Author

Martins, Mathias, primary, Do Nascimento, Gabriela M., additional, Conforti, Antonella, additional, Noll, Jessica C.G., additional, Impellizeri, Joseph A., additional, Sanchez, Elisa, additional, Wagner, Bettina, additional, Lione, Lucia, additional, Salvatori, Erika, additional, Pinto, Eleonora, additional, Compagnone, Mirco, additional, Viscount, Brian, additional, Hayward, James, additional, Shorrock, Clay, additional, Aurisicchio, Luigi, additional, and Diel, Diego G., additional

Published
2022
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27. DNA-Vaccine-Induced Immune Response Correlates with Lower Viral SARS-CoV-2 Titers in a Ferret Model

Author

Compagnone, Mirco, primary, Pinto, Eleonora, additional, Salvatori, Erika, additional, Lione, Lucia, additional, Conforti, Antonella, additional, Marchese, Silvia, additional, Ravà, Micol, additional, Ryan, Kathryn, additional, Hall, Yper, additional, Rayner, Emma, additional, Salguero, Francisco J., additional, Paterson, Jemma, additional, Iannacone, Matteo, additional, De Francesco, Raffaele, additional, Aurisicchio, Luigi, additional, and Palombo, Fabio, additional

Published
2022
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28. A linear DNA vaccine candidate encoding the SARS-CoV-2 Receptor Binding Domain elicits protective immunity in domestic cats

Author

Conforti, Antonella, primary, Sanchez, Elisa, additional, Salvatori, Erika, additional, Lione, Lucia, additional, Compagnone, Mirco, additional, Pinto, Eleonora, additional, Palombo, Fabio, additional, Sun, Yuhua, additional, Viscount, Brian, additional, Hayward, James, additional, Shorrock, Clay, additional, Diel, Diego G., additional, Impellizeri, Joseph A., additional, and Aurisicchio, Luigi, additional

Published
2022
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29. Immunogenicity of COVID-eVax Delivered by Electroporation Is Moderately Impacted by Temperature and Molecular Isoforms.

Author

D'Alessio, Federico, Lione, Lucia, Salvatori, Erika, Bucci, Federica, Muzi, Alessia, Roscilli, Giuseppe, Compagnone, Mirco, Pinto, Eleonora, Battistuzzi, Gianfranco, Conforti, Antonella, Aurisicchio, Luigi, and Palombo, Fabio

Subjects
CIRCULAR DNA, ELECTROPORATION, IMMUNE response, DNA vaccines, MESSENGER RNA, GENETIC transformation
Abstract

DNA integrity is a key issue in gene therapy and genetic vaccine approaches based on plasmid DNA. In contrast to messenger RNA that requires a controlled cold chain for efficacy, DNA molecules are considered to be more stable. In this study, we challenged this concept by characterizing the immunological response induced by a plasmid DNA vaccine delivered using electroporation. As a model, we used COVID-eVax, a plasmid DNA-based vaccine that targets the receptor binding domain (RBD) of the SARS-CoV-2 spike protein. Increased nicked DNA was produced by using either an accelerated stability protocol or a lyophilization protocol. Surprisingly, the immune response induced in vivo was only minimally affected by the percentage of open circular DNA. This result suggests that plasmid DNA vaccines, such as COVID-eVax that have recently completed a phase I clinical trial, retain their efficacy upon storage at higher temperatures, and this feature may facilitate their use in low-/middle-income countries. [ABSTRACT FROM AUTHOR]

Published
2023
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30. The Nuts and Bolts of SARS-CoV-2 Spike Receptor-Binding Domain Heterologous Expression

Author

Maffei, Mariano, primary, Montemiglio, Linda Celeste, additional, Vitagliano, Grazia, additional, Fedele, Luigi, additional, Sellathurai, Shaila, additional, Bucci, Federica, additional, Compagnone, Mirco, additional, Chiarini, Valerio, additional, Exertier, Cécile, additional, Muzi, Alessia, additional, Roscilli, Giuseppe, additional, Vallone, Beatrice, additional, and Marra, Emanuele, additional

Published
2021
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31. ERAP1 Controls the Interaction of the Inhibitory Receptor KIR3DL1 With HLA-B51:01 by Affecting Natural Killer Cell Function

Author

D’Amico, Silvia, primary, D’Alicandro, Valerio, additional, Compagnone, Mirco, additional, Tempora, Patrizia, additional, Guida, Giusy, additional, Romania, Paolo, additional, Lucarini, Valeria, additional, Melaiu, Ombretta, additional, Falco, Michela, additional, Algeri, Mattia, additional, Pende, Daniela, additional, Cifaldi, Loredana, additional, and Fruci, Doriana, additional

Published
2021
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32. COVID-eVax, an electroporated plasmid DNA vaccine candidate encoding the SARS-CoV-2 Receptor Binding Domain, elicits protective immune responses in animal models of COVID-19

Author

Conforti, Antonella, primary, Marra, Emanuele, additional, Palombo, Fabio, additional, Roscilli, Giuseppe, additional, Ravà, Micol, additional, Fumagalli, Valeria, additional, Muzi, Alessia, additional, Maffei, Mariano, additional, Luberto, Laura, additional, Lione, Lucia, additional, Salvatori, Erika, additional, Compagnone, Mirco, additional, Pinto, Eleonora, additional, Pavoni, Emiliano, additional, Bucci, Federica, additional, Vitagliano, Grazia, additional, Stoppoloni, Daniela, additional, Pacello, Maria Lucrezia, additional, Cappelletti, Manuela, additional, Ferrara, Fabiana Fosca, additional, D’Acunto, Emanuela, additional, Chiarini, Valerio, additional, Arriga, Roberto, additional, Nyska, Abraham, additional, Lucia, Pietro Di, additional, Marotta, Davide, additional, Bono, Elisa, additional, Giustini, Leonardo, additional, Sala, Eleonora, additional, Perucchini, Chiara, additional, Paterson, Jemma, additional, Ryan, Kathryn Ann, additional, Challis, Amy-Rose, additional, Matusali, Giulia, additional, Colavita, Francesca, additional, Caselli, Gianfranco, additional, Criscuolo, Elena, additional, Clementi, Nicola, additional, Mancini, Nicasio, additional, Groß, Rüdiger, additional, Seidel, Alina, additional, Wettstein, Lukas, additional, Münch, Jan, additional, Donnici, Lorena, additional, Conti, Matteo, additional, Francesco, Raffaele De, additional, Kuka, Mirela, additional, Ciliberto, Gennaro, additional, Castilletti, Concetta, additional, Capobianchi, Maria Rosaria, additional, Ippolito, Giuseppe, additional, Guidotti, Luca G., additional, Rovati, Lucio, additional, Iannacone, Matteo, additional, and Aurisicchio, Luigi, additional

Published
2021
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33. Nutlin-3a Enhances Natural Killer Cell–Mediated Killing of Neuroblastoma by Restoring p53-Dependent Expression of Ligands for NKG2D and DNAM-1 Receptors

Author

Veneziani, Irene, primary, Infante, Paola, additional, Ferretti, Elisa, additional, Melaiu, Ombretta, additional, Battistelli, Cecilia, additional, Lucarini, Valeria, additional, Compagnone, Mirco, additional, Nicoletti, Carmine, additional, Castellano, Aurora, additional, Petrini, Stefania, additional, Ognibene, Marzia, additional, Pezzolo, Annalisa, additional, Di Marcotullio, Lucia, additional, Bei, Roberto, additional, Moretta, Lorenzo, additional, Pistoia, Vito, additional, Fruci, Doriana, additional, Barnaba, Vincenzo, additional, Locatelli, Franco, additional, and Cifaldi, Loredana, additional

Published
2021
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35. ERAP1 Controls the Interaction of the Inhibitory Receptor KIR3DL1 With HLA-B51:01 by Affecting Natural Killer Cell Function.

Author

D'Amico, Silvia, D'Alicandro, Valerio, Compagnone, Mirco, Tempora, Patrizia, Guida, Giusy, Romania, Paolo, Lucarini, Valeria, Melaiu, Ombretta, Falco, Michela, Algeri, Mattia, Pende, Daniela, Cifaldi, Loredana, and Fruci, Doriana

Subjects
KILLER cells, HISTOCOMPATIBILITY class I antigens, CELL physiology, T cell receptors, LYMPHOBLASTOID cell lines, RESPONSE inhibition, MAJOR histocompatibility complex
Abstract

The endoplasmic reticulum aminopeptidase ERAP1 regulates innate and adaptive immune responses by trimming peptides for presentation by major histocompatibility complex (MHC) class I molecules. Previously, we have shown that genetic or pharmacological inhibition of ERAP1 on murine and human tumor cell lines perturbs the engagement of NK cell inhibitory receptors Ly49C/I and Killer-cell Immunoglobulin-like receptors (KIRs), respectively, by their specific ligands (MHC class I molecules), thus leading to NK cell killing. However, the effect of ERAP1 inhibition in tumor cells was highly variable, suggesting that its efficacy may depend on several factors, including MHC class I typing. To identify MHC class I alleles and KIRs that are more sensitive to ERAP1 depletion, we stably silenced ERAP1 expression in human HLA class I-negative B lymphoblastoid cell line 721.221 (referred to as 221) transfected with a panel of KIR ligands (i.e. HLA-B*51:01, -Cw3, -Cw4 and -Cw7), or HLA-A2 which does not bind any KIR, and tested their ability to induce NK cell degranulation and cytotoxicity. No change in HLA class I surface expression was detected in all 221 transfectant cells after ERAP1 depletion. In contrast, CD107a expression levels were significantly increased on NK cells stimulated with 221-B*51:01 cells lacking ERAP1, particularly in the KIR3DL1-positive NK cell subset. Consistently, genetic or pharmacological inhibition of ERAP1 impaired the recognition of HLA-B*51:01 by the YTS NK cell overexpressing KIR3DL1*001, suggesting that ERAP1 inhibition renders HLA-B*51:01 molecules less eligible for binding to KIR3DL1. Overall, these results identify HLA-B*51:01/KIR3DL1 as one of the most susceptible combinations for ERAP1 inhibition, suggesting that individuals carrying HLA-B*51:01-like antigens may be candidates for immunotherapy based on pharmacological inhibition of ERAP1. [ABSTRACT FROM AUTHOR]

Published
2021
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39. Anti-tumoral effect of desmethylclomipramine in lung cancer stem cells

Author

Bongiorno-Borbone, Lucilla, Giacobbe, Arianna, Compagnone, Mirco, Eramo, Adriana, De Maria Marchiano, Ruggero, Peschiaroli, Angelo, Melino, Gerry, De Maria Marchiano, Ruggero (ORCID:0000-0003-2255-0583), Bongiorno-Borbone, Lucilla, Giacobbe, Arianna, Compagnone, Mirco, Eramo, Adriana, De Maria Marchiano, Ruggero, Peschiaroli, Angelo, Melino, Gerry, and De Maria Marchiano, Ruggero (ORCID:0000-0003-2255-0583)

Abstract

Lung cancer is the most feared of all cancers because of its heterogeneity and resistance to available treatments. Cancer stem cells (CSCs) are the cell population responsible for lung cancer chemoresistance and are a very good model for testing new targeted therapies. Clomipramine is an FDA-approved antidepressant drug, able to inhibit in vitro the E3 ubiquitin ligase Itch and potentiate the pro-apoptotic effects of DNA damaging induced agents in several cancer cell lines. Here, we investigated the potential therapeutic effect of desmethylclomipramine (DCMI), the active metabolite of Clomipramine, on the CSCs homeostasis. We show that DCMI inhibits lung CSCs growth, decreases their stemness potential and increases the cytotoxic effect of conventional chemotherapeutic drugs. Being DCMI an inhibitor of the E3 ubiquitin ligase Itch, we also verified the effect of Itch deregulation on CSCs survival. We found that the siRNA-mediated depletion of Itch induces similar anti-proliferative effects on lung CSCs, suggesting that DCMI might exert its effect, at least in part, by inhibiting Itch. Notably, Itch expression is a negative prognostic factor in two primary lung tumors datasets, supporting the potential clinical relevance of Itch inhibition to circumvent drug resistance in the treatment of lung cancer.

Published
2015

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