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

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

Santa Fe

Simposio; IX Simposio Latinoamericano de Tecnología de Cultivos Celulares (IX SLATCC); 2022

Universidad Nacional del Litoral

Human interferon α (hIFN-α) administration constitutes the current FDA approved therapy to treat chronic Hepatitis B and C virus infections. Additionally, numerous studies have highlighted this cytokine as candidate for the treatment of emerging viral diseases such as Zika, Chikungunya or Dengue virus infections. Moreover, the pegylated forms of hIFN-α2a and hIFNα2b have been proposed as therapeutic alternatives to treat infections caused by the acute respiratory syndrome coronavirus2 (SARS-CoV-2). However, a major issue related with hIFN-2b therapy is given by its short plasma half-life. To optimize the cytokine’s pharmacokinetic profile, our group has developed a highly O-glycosylated IFN, GMOP-IFN, by fusing the N-terminal end of the cytokine to a peptide containing four potential O-glycosilation sites. Given that hIFN-α is immunogenic, neutralizing antibodies (NAb) induction is frequently observed after repeated administrations of this biologic. For this reason, in order to develop a safer and more efficient IFN therapy, in this study we applied the DeFT (De-immunization of Functional Therapeutics) approach to develop functional, de-immunized versions of GMOP-IFN. Two variants out of four displayed reduced ex vivo immunogenicity, while preserving antiviral function. Moreover, both IFN muteins exhibited null specific antiproliferative activity, which constitutes an additional highly favorable characteristic when considering the dramatic consequences associated to hematologic disorders commonly produced during hIFN-α therapy. Altogether the results obtained in this work indicate that the new de-immunized GMOP-IFN variants constitute promising candidates for antiviral therapy, exhibiting reduced immunogenicity while lacking antiproliferative properties.