Development of IFNbeta-1a versions with reduced immunogenicity and full in vitro biological activity for the treatment of multiple sclerosis

IFNbeta (recombinant interferon Beta) has been widely used for the treatment of Multiple sclerosis for the last four decades. Despite the human origin of the IFNbeta sequence, IFNbeta is immunogenic, and unwanted immune responses in IFNbeta-treated patients may compromise its efficacy and safety in the clinic. In this study, we applied the DeFT (De-immunization of Functional Therapeutics) approach to producing functional, de-immunized versions of IFNbeta-1a. Two de-immunized versions of IFNbeta-1a were produced in CHO cells and designated as IFNbeta-1a(VAR1) and IFNbeta-1a(VAR2). First, the secondary and tertiary protein structures were analyzed by circular dichroism spectroscopy. Then, the variants were also tested for functionality. While IFNbeta-1a(VAR2) showed similar in vitro antiviral activity to the original protein, IFNbeta-1a(VAR1) exhibited 40% more biological potency. Finally, in vivo assays using HLA-DR transgenic mice revealed that the de-immunized variants showed a markedly reduced immunogenicity when compared to the originator.

Ricotti S, Garay A S, Etcheverrigaray M, Amadeo G I, De Groot A S, Martin W, and Mufarrege E F. (2023) Development of IFNbeta-1a versions with reduced immunogenicity and full in vitro biological activity for the treatment of multiple sclerosis. Clin Immunol 257():109831 . [article]