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PNAS 104 (20): 8269-8274

Copyright © 2007 by the National Academy of Sciences.


BIOLOGICAL SCIENCES / BIOCHEMISTRY

Directed evolution of gene-shuffled IFN-{alpha} 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*,{dagger}, Glenn N. Dawes*, Douglas R. Guptill*, Robert McCord*, Sridhar Govindarajan*, Ajoy Roy*, Shumin Yang*, Judy Gao*, Yong Hong Chen*, Niels Jørgen Ø. Skartved{ddagger}, Annette K. Pedersen{ddagger}, David Lin*, Christopher P. Locher*, Indrani Rebbapragada*, Anne Dam Jensen{ddagger}, Steven H. Bass*, Torben L. Straight Nissen*, Sridhar Viswanathan*, Graham R. Foster§, Julian A. Symons, and Phillip A. Patten*,{dagger},||

*Maxygen, Incorporated, 515 Galveston Drive, Redwood City, CA 94063; {ddagger}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 to a single heterodimeric receptor and have potent antiviral, antiproliferative, and immune modulatory activities. The diverse effects of the type I IFNs are of differential therapeutic importance; in cancer therapy, an enhanced antiproliferative effect may be beneficial, whereas in the therapy of viral infections (such as hepatitis B and hepatitis C), the antiproliferative effects lead to dose limiting bone marrow suppression. Studies have shown that various members of the natural IFN-{alpha} 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-{alpha} hybrids wherein the ratio of antiviral:antiproliferative and Th1-inducing: antiproliferative potencies are markedly increased with respsect to IFN-con1 (75- and 80-fold, respectively). A four-residue motif that overlaps with the IFNAR1 binding site and is derived by cross breeding with a pseudogene contributes significantly to this phenotype. These IFN-{alpha}s have an activity profile that may result in an improved therapeutic index and, consequently, better clinical efficacy for the treatment of chronic viral diseases such as hepatitis B virus, human papilloma virus, HIV, or chronic hepatitis C.

Key Words: evolved • Hepatitis C


Author contributions: A.D.B.-A. and X.H. contributed equally to 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.

{dagger}Present Address: Achaogen, 7000 Shoreline Court, South San Francisco, CA 94080.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

This article contains supporting information online at www.pnas.org/cgi/content/full/0609001104/DC1.

||To whom correspondence should be addressed. E-mail: ppatten{at}achaogen.com

© 2007 by The National Academy of Sciences of the USA


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