IMPROVED ANTIVIRAL THERAPY: DEVELOPMENT OF FUNCIONAL DE-IMMUNIZED VERSIONS OF INTERFERON ALPHA FOR EMERGIN VIRAL INFECTIONS

SOFÍA GIORGETTI; MARINA ETCHEVERRIGARAY; FRANCES TERRY; WILLIAM MARTIN; ANNE DE GROOT; NATALIA CEAGLIO; MARCOS OGGERO EBERHARDT; EDUARDO MUFARREGE

Buenos Aires

Congreso; Reunión Anual de Sociedades de Biociencias 2021; 2021

Sociedad Argentina de Investigación Clínica (SAIC)

Human interferon α (hIFN-α) are a multigene family of proteins thatconstitutes the current FDA approved therapy for chronic HepatitisB and C virus infections. Additionally, numerous studies have highlightedthese cytokines as candidates for the treatment of emergingviral diseases such as Zika, Chikungunya or Dengue virus infections.Moreover, the pegylated forms of hIFNα2a and hIFNα2b havebeen proposed as therapeutic alternatives to treat infections causedby the acute respiratory syndrome coronavirus2 (SARS-CoV-2).However, a major disadvantage of hIFN-α2b therapy is given by itsshort plasma half-life resulting in the occurrence of severe side effects.To optimize the cytokine?s pharmacokinetic profile, our grouphas developed a highly O-glycosylated IFN, GMOP-IFN, by fusingthe N-terminal end of the cytokine to a peptide containing four potentialO-glycosilation sites.Considering the significant number of reports existent about neutralizingantibodies (NAb) induction after repeated administrations ofhIFN-α, and in order to develop a safer and more efficient IFN therapy,in this study we applied the DeFT (De-immunization of FunctionalTherapeutics) approach to generate functional, de-immunizedversions of GMOP-IFN.Two variants out of four displayed reduced ex vivo immunogenicity,while preserving antiviral function. Moreover, both IFN analogsexhibited null specific antiproliferative activity, which constitutes anadditional highly favorable characteristic when considering the dramaticconsequences associated to hematologic disorders commonlyproduced by hIFN-α therapy.Altogether the results obtained in this work indicate that the newde-immunized GMOP- IFN variants are promising candidates forantiviral therapy, exhibiting reduced immunogenicity, proven in vitroantiviral activity while lacking antiproliferative activity.