Enhancement of IFN-alpha2 pharmacokinetic properties through glycoengineering

NATALIA CEAGLIO; MARCOS OGGERO; MARINA ETCHEVERRIGARAY; RICARDO KRATJE

Rosario. Pcia. Santa Fe. Argentina

Congreso; XLII Reunion Anual de la Sociedad Argentina de Investigacion en Bioquimica y Biologiaa Molecular (SAIB); 2006

Sociedad Argentina de Investigación en Bioquímica y Biología Molecular

Interferons are a large family of closely related cytokines that block viral infection, inhibit cell proliferation and modulate cell differentiation. IFN-alpha2 has been approved for the treatment of a number of diseases, including chronic hepatitis B and C, renal cell carcinoma and chronic myelogenous leukemia, among others. However, the clinical use of this cytokine has been restricted due to limitations of the standard interferon alfa formulations, which include rapid absorption from the injection site, large volume of distribution, rapid clearance by the kidney, short serum half-life and significant acute and chronic side effects. Several strategies, including pegylation, have been used to enhance IFN activity by decreasing its clearance and prolonging the duration of the therapeutic action. For this purpose, a glycoengineering approach was used to construct fourteen one-site N-glycosylated IFN-alpha2 analogs which were expressed in CHO cells. The specific biological activity, as well as the degree and pattern of glycosylation, were variable according to the position of the N-glycosylation site. The pharmacokinetic profile of a one-site glycosylated mutein showed a 1.4-fold increase of the area under curve after subcutaneous administration compared to the non-glycosylated cytokine. This strategy may be used in order to obtain hyperglycosylated variants with increased therapeutic activity.