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Engineering TGF-β Traps: Artificially Dimerized Receptor Ectodomains as High-affinity Blockers of TGF-β Action

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Book cover Transforming Growth Factor-β in Cancer Therapy, Volume II

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

Abstract

Receptor ectodomain-based ligand traps are a new class of candidate therapeutics that can be optimized using protein engineering approaches that are built on an understanding of the interactions between natural receptors and their ligands. We present here a summary of our characterization of TGF-β ligand-receptor interactions using primarily surface plasmon resonance (SPR)-based biosensor analyses. The results of those studies lead us to hypothesize that artificial dimerization of TGF-β receptor ectodomains may provide a bridged-binding avidity effect that promotes stable binding and increased ligand trapping potency. We confirmed this by utilizing a de novo designed heterodimerizing coiled-coil peptide system to generate, and compare in a systematic manner, monomeric and dimeric versions of soluble TGF-β receptor ectodomains. Finally, we discuss how the potency and specificity of artificially dimerized receptor ectodomain-based traps may compare favorably with other classes of TGF-β pathway inhibitors.

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Author information

Authors and Affiliations

  1. Department of Chemical Engineering, Bio-P2 Unit, Polytechnical School of Montreal, Montreal, Quebec, Canada

    Gregory De Crescenzo PhD

  2. Sensium Technologies, Inc., Edmonton, Alberta, Canada

    Heman Chao PhD

  3. Health Sector, Biotechnology Research Institute, The National Research Council of Canada, Montreal, Quebec, Canada

    John Zwaagstra PhD & Maureen D. O’Connor-McCourt PhD

  4. Bioprocess and Health Sectors, Biotechnology Research Institute, The National Research Council of Canada, Montreal, Quebec, Canada

    Yves Durocher PhD

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  1. Gregory De Crescenzo PhD
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  2. Heman Chao PhD
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  3. John Zwaagstra PhD
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  4. Yves Durocher PhD
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  5. Maureen D. O’Connor-McCourt PhD
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Editors and Affiliations

  1. Cancer Training Branch, Office of Centers, Training and Resources, National Cancer Institute, Bethesda, MD

    Sonia B. Jakowlew PhD

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© 2008 Humana Press Inc., Totowa, NJ

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De Crescenzo, G., Chao, H., Zwaagstra, J., Durocher, Y., O’Connor-McCourt, M.D. (2008). Engineering TGF-β Traps: Artificially Dimerized Receptor Ectodomains as High-affinity Blockers of TGF-β Action. In: Jakowlew, S.B. (eds) Transforming Growth Factor-β in Cancer Therapy, Volume II. Cancer Drug Discovery and Development. Humana Press. https://doi.org/10.1007/978-1-59745-293-9_40

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  • DOI: https://doi.org/10.1007/978-1-59745-293-9_40

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-58829-715-0

  • Online ISBN: 978-1-59745-293-9

  • eBook Packages: MedicineMedicine (R0)

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