A heavily N-glycosylated Interferon alpha analog with enhanced antitumor activity

NATALIA CEAGLIO; MARINA ETCHEVERRIGARAY; RICARDO KRATJE; MARCOS OGGERO

Mar del Plata. Buenos Aires. Argentina

Congreso; XLIII Reunión Anual de la Sociedad Argentina de Investigación en Bioquímica y Biología Molecular (SAIB); 2007

Sociedad Argentina en Investigación en Bioquímica y Biología Molecular (SAIB)

Cabe destacar el trabajo completo correspondiente a esta presentación en formato de póster, y que fue titulado "Nuevos derivados de interferón alfa diseñados por glicoingeniería con propiedades terapéuticas y farmacocinéticas mejoradas” ha recibido PREMIO CEDIQUIFA: 50° ANIVERSARIO de la Facultad de Farmacia y Bioquímica (UBA) en la categoría de trabajo inédito con fecha 11 de diciembre de 2007 (ver constancia adjunta). El resumen a la presentación del congreso es el siguiente: Interferons play a central role in the regulation of cell growth and differentiation. Due to its antiviral, antiproliferative and immunomodulatory effects, IFN-alpha has become a therapeutic agent for the treatment of a wide range of malignant and viral diseases. Yet, rapid systemic clearance of the cytokine demands high and frequent doses, which in turn bring about significant side effects. Besides, as therapeutic levels are difficult to sustain, the effectiveness of IFN-alpha in the therapy of solid tumors is severely compromised. In order to increase the in vivo biological activity of IFN-alpha, a heavily glycosylated derivative, 4N-IFN, was constructed by introducing four N-glycosylation sites via site-directed mutagenesis. Immunoblots of the mutein expressed in CHO cells showed a broad band between 27 and 44 kDa consistent with a great heterogeneity of glycoforms with increased size and charge. Purified 4N-IFN was found to have a 25-fold longer plasma half-life and a 20-fold reduced systemic clearance, in comparison with non-glycosylated IFN-alpha after subcutaneous inoculation in rats. Moreover, in spite of its lower in vitro activity, 4N-IFN showed a markedly enhanced in vivo antitumor activity in human prostate carcinoma implanted in nude mice. This remarkable improvement of 4N-IFN properties caused by glycosylation may confer clinical advantages over conventional IFN therapies.