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A Novel Approach to Improve the Function of FGF21

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Abstract

Background and Objective

Fibroblast growth factor 21 (FGF21) has potent effects on normalizing glucose, lipid, and energy homeostasis, and represents an attractive novel therapy for type 2 diabetes mellitus and obesity. Approaches to improve the pharmacokinetic properties of FGF21, such as conjugation with polyethylene glycol, have been explored for therapeutic development. However, not only is there room for further pharmacokinetic improvements, additional re-engineering approaches to improve the potency and stability of FGF21 have not been reported. Here, we describe a novel approach to modify and improve the function of FGF21 by altering its C-terminal βKlotho interaction domain.

Methods

We first identified Avimer proteins that are capable of binding βKlotho. Then we explored replacing the C-terminal βKlotho interaction domain of FGF21 with a βKlotho-binding Avimer protein.

Results

Such a βKlotho-binding Avimer protein was able to fully complement the C-terminal domain function of FGF21. The resulting FGF21-Avimer fusion is functionally indistinguishable from wild type FGF21, and more tolerant of C-terminal modification.

Conclusion

These results demonstrate a viable strategy to modulate the affinity, potency, and engineering of FGF21, paving the way for further improvements of FGF21 as a therapeutic.

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Acknowledgments

All authors are full time Amgen employees and shareholders. We thank Randy Hecht and Bryan Lemon for their generous gift of reagents, and we thank Ming Wang, Kevin Moore, and Scott Simonet for helpful discussions and critical reading of the manuscript. The Avimer sequence described is in a pending patent (US20110150901).

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Authors and Affiliations

  1. Amgen Inc., 1120 Veterans Blvd., South San Francisco, CA, 94080, USA

    Richard Smith, Amy Duguay, Jennifer Weiszmann, Jamila Gupte, Xinle Wu & Yang Li

  2. Amgen Inc., Thousand Oaks, CA, USA

    Shanaka Stanislaus, Ed Belouski, Ling Cai, Junming Yie & Jing Xu

Authors
  1. Richard Smith
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  2. Amy Duguay
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  3. Jennifer Weiszmann
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  4. Shanaka Stanislaus
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  5. Ed Belouski
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  6. Ling Cai
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  7. Junming Yie
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  8. Jing Xu
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  9. Jamila Gupte
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  10. Xinle Wu
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  11. Yang Li
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Corresponding authors

Correspondence to Richard Smith or Yang Li.

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Smith, R., Duguay, A., Weiszmann, J. et al. A Novel Approach to Improve the Function of FGF21. BioDrugs 27, 159–166 (2013). https://doi.org/10.1007/s40259-013-0013-x

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