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Research ArticleDrug Discovery and Translational Medicine

An Engineered Human Follistatin Variant: Insights into the Pharmacokinetic and Pharmocodynamic Relationships of a Novel Molecule with Broad Therapeutic Potential

Amita Datta-Mannan, Benjamin Yaden, Venkatesh Krishnan, Bryan E. Jones and Johnny E. Croy
Journal of Pharmacology and Experimental Therapeutics March 2013, 344 (3) 616-623; DOI: https://doi.org/10.1124/jpet.112.201491
Amita Datta-Mannan
Departments of Drug Disposition Development/Commercialization (A.D.-M.) Biotechnology Discovery Research (J.E.C.), and Musculoskeletal Research (B.Y., V.K.), Lilly Research Laboratories, Indianapolis, Indiana; Biotechnology Discovery Research (B.E.J.), Applied Molecular Evolution, San Diego, California; and Department of Biology, School of Science, Center for Regenerative Biology and Medicine, Indiana University–Purdue University, Indianapolis, Indiana (B.Y., V.K.)
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Benjamin Yaden
Departments of Drug Disposition Development/Commercialization (A.D.-M.) Biotechnology Discovery Research (J.E.C.), and Musculoskeletal Research (B.Y., V.K.), Lilly Research Laboratories, Indianapolis, Indiana; Biotechnology Discovery Research (B.E.J.), Applied Molecular Evolution, San Diego, California; and Department of Biology, School of Science, Center for Regenerative Biology and Medicine, Indiana University–Purdue University, Indianapolis, Indiana (B.Y., V.K.)
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Venkatesh Krishnan
Departments of Drug Disposition Development/Commercialization (A.D.-M.) Biotechnology Discovery Research (J.E.C.), and Musculoskeletal Research (B.Y., V.K.), Lilly Research Laboratories, Indianapolis, Indiana; Biotechnology Discovery Research (B.E.J.), Applied Molecular Evolution, San Diego, California; and Department of Biology, School of Science, Center for Regenerative Biology and Medicine, Indiana University–Purdue University, Indianapolis, Indiana (B.Y., V.K.)
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Bryan E. Jones
Departments of Drug Disposition Development/Commercialization (A.D.-M.) Biotechnology Discovery Research (J.E.C.), and Musculoskeletal Research (B.Y., V.K.), Lilly Research Laboratories, Indianapolis, Indiana; Biotechnology Discovery Research (B.E.J.), Applied Molecular Evolution, San Diego, California; and Department of Biology, School of Science, Center for Regenerative Biology and Medicine, Indiana University–Purdue University, Indianapolis, Indiana (B.Y., V.K.)
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Johnny E. Croy
Departments of Drug Disposition Development/Commercialization (A.D.-M.) Biotechnology Discovery Research (J.E.C.), and Musculoskeletal Research (B.Y., V.K.), Lilly Research Laboratories, Indianapolis, Indiana; Biotechnology Discovery Research (B.E.J.), Applied Molecular Evolution, San Diego, California; and Department of Biology, School of Science, Center for Regenerative Biology and Medicine, Indiana University–Purdue University, Indianapolis, Indiana (B.Y., V.K.)
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This article has a correction. Please see:

  • Addendum to “An Engineered Human Follistatin Variant: Insights into the Pharmacokinetic and Pharmocodynamic Relationships of a Novel Molecule with Broad Therapeutic Potential” - August 01, 2015

Abstract

Human follistatin is a regulatory glycoprotein with widespread biologic functions, including antiinflammatory activities, wound-healing properties, and muscle-stimulating effects. The role of follistatin in a wide range of biologic activities shows promise for potential clinical application, which has prompted considerable interest in the investigation of the protein as a potential disease-modifying agent. In spite of this potential, the development of follistatin as a broad use biotherapeutic has been severely hindered by a poor understanding and characterization of its pharmacokinetic/pharmacodynamic (PK/PD) relationships. Therefore, to better define these relationships, we performed in-depth analyses of the PK/PD relationships of native follistatin-315 (FST315). Our data indicate that the intrinsic PK/PD properties of native FST315 are poorly suited for acting as a parentally administered biotherapeutic with broad systemic effects. Here, we leveraged protein engineering to modify the PK characteristics of the native molecule by fusing FST315 to a murine IgG1 Fc and removing the intrinsic heparan sulfate-binding activity of follistatin. The engineered variant molecule had ∼100- and ∼1600-fold improvements in terminal half-life and exposure, respectively. In contrast to the native FST315, the variant showed a robust, dose-dependent pharmacological effect when administered subcutaneously on a weekly basis in mouse models of muscle atrophy and degeneration. These studies highlight the underappreciated and critical relationship between optimizing multiple physical and chemical properties of follistatin on its overall PK/PD profile. Moreover, our findings provide the first documented strategy toward the development of a follistatin therapeutic with potential use in patients affected with skeletal muscle diseases.

Footnotes

    • Received November 1, 2012.
    • Accepted December 14, 2012.
  • A.D.-M., B.Y., and J.E.C. contributed equally to this work.

  • dx.doi.org/10.1124/jpet.112.201491.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 344 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 344, Issue 3
1 Mar 2013
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Research ArticleDrug Discovery and Translational Medicine

PK and PD of Novel Engineered Follistatin

Amita Datta-Mannan, Benjamin Yaden, Venkatesh Krishnan, Bryan E. Jones and Johnny E. Croy
Journal of Pharmacology and Experimental Therapeutics March 1, 2013, 344 (3) 616-623; DOI: https://doi.org/10.1124/jpet.112.201491

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Research ArticleDrug Discovery and Translational Medicine

PK and PD of Novel Engineered Follistatin

Amita Datta-Mannan, Benjamin Yaden, Venkatesh Krishnan, Bryan E. Jones and Johnny E. Croy
Journal of Pharmacology and Experimental Therapeutics March 1, 2013, 344 (3) 616-623; DOI: https://doi.org/10.1124/jpet.112.201491
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