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Directed evolution of gene-shuffled IFN- molecules with activity profiles tailored for treatment of chronic viral diseases
Amy D. Brideau-Andersen*,
Xiaojian Huang*,
Siu-Chi Chang Sun*,
Teddy T. Chen*,
Diane Stark*,
Ian J. Sas*,
Linda Zadik*,,
Glenn N. Dawes*,
Douglas R. Guptill*,
Robert McCord*,
Sridhar Govindarajan*,
Ajoy Roy*,
Shumin Yang*,
Judy Gao*,
Yong Hong Chen*,
Niels Jørgen Ø. Skartved,
Annette K. Pedersen,
David Lin*,
Christopher P. Locher*,
Indrani Rebbapragada*,
Anne Dam Jensen,
Steven H. Bass*,
Torben L. Straight Nissen*,
Sridhar Viswanathan*,
Graham R. Foster,
Julian A. Symons¶, and
Phillip A. Patten*,,||
*Maxygen, Incorporated, 515 Galveston Drive, Redwood City, CA 94063; Maxygen, Anpartsselskab, Agern Alle 1, DK-2970 Hoersholm, Denmark; ¶Roche Palo Alto LLC, 3431 Hillview Avenue, Palo Alto, CA 94304; and Queen Mary's School of Medicine and Dentistry, Institute of Cell and Molecular Science, The Royal London Hospital, 4 Newark Street, London E1 2AT, England
Edited by Peter G. Schultz, The Scripps Research Institute, La Jolla, CA, and approved March 26, 2007
Received for publication November 4, 2006.
Abstract:
Type I IFNs are unusually pleiotropic cytokines that bind toa single heterodimeric receptor and have potent antiviral, antiproliferative,and immune modulatory activities. The diverse effects of thetype I IFNs are of differential therapeutic importance; in cancertherapy, an enhanced antiproliferative effect may be beneficial,whereas in the therapy of viral infections (such as hepatitisB and hepatitis C), the antiproliferative effects lead to doselimiting bone marrow suppression. Studies have shown that variousmembers of the natural IFN- family and engineered variants,such as IFN-con1, vary in the ratios between various IFN-mediatedcellular activities. We used DNA shuffling to explore and confirmthe hypothesis that one could simultaneously increase the antiviraland Th1-inducing activity and decrease the antiproliferativeactivity. We report IFN- hybrids wherein the ratio of antiviral:antiproliferativeand Th1-inducing: antiproliferative potencies are markedly increasedwith respsect to IFN-con1 (75- and 80-fold, respectively). Afour-residue motif that overlaps with the IFNAR1 binding siteand is derived by cross breeding with a pseudogene contributessignificantly to this phenotype. These IFN-s have an activityprofile that may result in an improved therapeutic index and,consequently, better clinical efficacy for the treatment ofchronic viral diseases such as hepatitis B virus, human papillomavirus, HIV, or chronic hepatitis C.
Key Words: evolved • Hepatitis C
Author contributions: A.D.B.-A. and X.H. contributed equallyto this work; A.D.B.-A., X.H., S.-C.C.S., D.S., A.D.J., T.L.S.N.,S.V., G.R.F., J.A.S., and P.A.P. designed research; A.D.B.-A.,X.H., S.-C.C.S., T.T.C., D.S., L.Z., G.N.D., D.R.G., R.M., S.Y.,J.G., Y.H.C., N.J.Ø.S., A.K.P., C.P.L., I.R., A.D.J.,and S.V. performed research; A.D.B.-A., X.H., S.-C.C.S., T.T.C.,D.S., I.J.S., G.N.D., D.R.G., R.M., S.G., A.R., S.Y., J.G.,Y.H.C., N.J.x.S., A.K.P., D.L., C.P.L., I.R., A.D.J., S.H.B.,T.L.S.N., S.V., and P.A.P. analyzed data; and A.D.B.-A., S.V.,and P.A.P. wrote the paper.
Present Address: Achaogen, 7000 Shoreline Court, South San Francisco,CA 94080.
molecules with activity profiles tailored for treatment of chronic viral diseases
,
Glenn N. Dawes*,
Douglas R. Guptill*,
Robert McCord*,
Sridhar Govindarajan*,
Ajoy Roy*,
Shumin Yang*,
Judy Gao*,
Yong Hong Chen*,
Niels Jørgen Ø. Skartved
,
Annette K. Pedersen
,
Julian A. Symons¶, and
Phillip A. Patten*
family and engineered variants, such as IFN-con1, vary in the ratios between various IFN-mediated cellular activities. We used DNA shuffling to explore and confirm the hypothesis that one could simultaneously increase the antiviral and Th1-inducing activity and decrease the antiproliferative activity. We report IFN-
Present Address: Achaogen, 7000 Shoreline Court, South San Francisco, CA 94080. 
