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Brideau-Andersen, Amy D.; Huang, Xiaojian; Sun, Siu-Chi Chang; Chen, Teddy T.; Stark, Diane; Sas, Ian J.; Zadik, Linda; Dawes, Glenn N.; Guptill, Douglas R.; McCord, Robert; Govindarajan, Sridhar; Roy, Ajoy; Yang, Shumin; Gao, Judy; Chen, Yong Hong; Skartved, Niels Jørgen Ø.; Pedersen, Annette K.; Lin, David; Locher, Christopher P.; Rebbapragada, Indrani; Jensen, Anne Dam; Bass, Steven H.; Nissen, Torben L. Straight; Viswanathan, Sridhar; [...]

Directed evolution of gene-shuffled IFN-α molecules with activity profiles tailored for treatment of chronic viral diseases

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  • Media type: E-Article
  • Title: Directed evolution of gene-shuffled IFN-α molecules with activity profiles tailored for treatment of chronic viral diseases
  • Contributor: Brideau-Andersen, Amy D.; Huang, Xiaojian; Sun, Siu-Chi Chang; Chen, Teddy T.; Stark, Diane; Sas, Ian J.; Zadik, Linda; Dawes, Glenn N.; Guptill, Douglas R.; McCord, Robert; Govindarajan, Sridhar; Roy, Ajoy; Yang, Shumin; Gao, Judy; Chen, Yong Hong; Skartved, Niels Jørgen Ø.; Pedersen, Annette K.; Lin, David; Locher, Christopher P.; Rebbapragada, Indrani; Jensen, Anne Dam; Bass, Steven H.; Nissen, Torben L. Straight; Viswanathan, Sridhar; [...]
  • imprint: Proceedings of the National Academy of Sciences, 2007
  • Published in: Proceedings of the National Academy of Sciences
  • Language: English
  • DOI: 10.1073/pnas.0609001104
  • ISSN: 0027-8424; 1091-6490
  • Keywords: Multidisciplinary
  • Origination:
  • Footnote:
  • Description: <jats:p>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-α 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-α 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-αs 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.</jats:p>
  • Access State: Open Access