Type I interferons (IFNs) are encoded by multiple genes (up to 20 in mice) and, although each of these binds to the same receptor, they produce different cellular responses. Each has some antiviral, immunomodulatory, and antiproliferative activity. Because of these important properties, IFNs are used clinically to treat chronic viral infection and cancer. However, high antiviral activity with low antiproliferative activity would be desirable to minimize the side effects of IFN treatment in chronic infection, whereas maximizing antiproliferative activity while minimizing immunoregulatory activity would be desirable in cancer treatment. Brideau-Andersen et al. engineered IFNs by gene shuffling that possessed high antiviral activity but minimal antiproliferative activity. They created a series of IFNs that they call the B9X series and assayed these in three different viral infection assays in cultured cells. They also tested the proteins for stimulation of the differentiation of Th1 cells, which is a desirable response to viral infection, and for antiproliferative effects on a human-derived B cell line (Daudi). By these criteria, two specific engineered IFNs, B9X14 and B9X25, were identified that have very high ratios of antiviral:antiproliferative and Th1-inducing:antiproliferative activities. Receptor binding assays with the Daudi cells indicated that these proteins bound the interferon receptor complex with very high affinity (greater than that of several natural IFN-αs). These results have clinical implications for IFN treatment of chronic viral infection, as well as providing insight into the interaction of IFNs with their receptor.
A. D. Brideau-Andersen, X. Huang, S.-C. Chang Sun, T. T. Chen, D. Stark, I. J. Sas, L. Zadik, G. N. Dawes, D. R. Guptill, R. McCord, S. Govindarajan, A. Roy, S. Yang, J. Gao, Y. H. Chen, N. J. Ø. Skartved, A. K. Pedersen, D. Lin, C. P. Locher, I. Rebbapragada, A. D. Jensen, S. H. Bass, T. L. Straight Nissen, S. Viswanathan, G. R. Foster, J. A. Symons, P. A. Patten, Directed evolution of gene-shuffled IFN-α molecules with activity profiles tailored for treatment of chronic viral diseases. Proc. Natl. Acad. Sci. U.S.A. 104, 8269-8274 (2007). [Abstract] [Full Text]