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Evaluation of integrin αvβ6 cystine knot PET tracers to detect cancer and idiopathic pulmonary fibrosis

Author

Listed:
  • Richard H. Kimura

    (Stanford University)

  • Ling Wang

    (Peking Union Medical College)

  • Bin Shen

    (Stanford University)

  • Li Huo

    (Peking Union Medical College)

  • Willemieke Tummers

    (Stanford University)

  • Fabian V. Filipp

    (Helmholtz Zentrum München, Ingolstädter Landstraße 1
    Technical University München, Maximus-von-Imhof-Forum 3)

  • Haiwei Henry Guo

    (Stanford University)

  • Thomas Haywood

    (Stanford University)

  • Lotfi Abou-Elkacem

    (Stanford University)

  • Lucia Baratto

    (Stanford University)

  • Frezghi Habte

    (Stanford University)

  • Rammohan Devulapally

    (Stanford University)

  • Timothy H. Witney

    (Stanford University)

  • Yan Cheng

    (Stanford University)

  • Suhas Tikole

    (Helmholtz Zentrum München, Ingolstädter Landstraße 1
    Technical University München, Maximus-von-Imhof-Forum 3
    Mississippi State University)

  • Subhendu Chakraborti

    (Stanford University)

  • Jay Nix

    (Lawrence Berkeley National Laboratory)

  • Christopher A. Bonagura

    (Art Robbins Instruments)

  • Negin Hatami

    (Stanford University)

  • Joshua J. Mooney

    (Stanford University)

  • Tushar Desai

    (Stanford University)

  • Scott Turner

    (Pliant Therapeutics)

  • Richard S. Gaster

    (Stanford University)

  • Andrea Otte

    (Stanford University)

  • Brendan C. Visser

    (Stanford University)

  • George A. Poultsides

    (Stanford University)

  • Jeffrey Norton

    (Stanford University)

  • Walter Park

    (Stanford University)

  • Mark Stolowitz

    (Stanford University)

  • Kenneth Lau

    (Stanford University)

  • Eric Yang

    (Stanford University)

  • Arutselvan Natarajan

    (Stanford University)

  • Ohad Ilovich

    (Stanford University)

  • Shyam Srinivas

    (Stanford University)

  • Ananth Srinivasan

    (Stanford University)

  • Ramasamy Paulmurugan

    (Stanford University)

  • Juergen Willmann

    (Stanford University)

  • Frederick T. Chin

    (Stanford University)

  • Zhen Cheng

    (Stanford University)

  • Andrei Iagaru

    (Stanford University)

  • Fang Li

    (Peking Union Medical College)

  • Sanjiv S. Gambhir

    (Stanford University)

Abstract

Advances in precision molecular imaging promise to transform our ability to detect, diagnose and treat disease. Here, we describe the engineering and validation of a new cystine knot peptide (knottin) that selectively recognizes human integrin αvβ6 with single-digit nanomolar affinity. We solve its 3D structure by NMR and x-ray crystallography and validate leads with 3 different radiolabels in pre-clinical models of cancer. We evaluate the lead tracer’s safety, biodistribution and pharmacokinetics in healthy human volunteers, and show its ability to detect multiple cancers (pancreatic, cervical and lung) in patients at two study locations. Additionally, we demonstrate that the knottin PET tracers can also detect fibrotic lung disease in idiopathic pulmonary fibrosis patients. Our results indicate that these cystine knot PET tracers may have potential utility in multiple disease states that are associated with upregulation of integrin αvβ6.

Suggested Citation

  • Richard H. Kimura & Ling Wang & Bin Shen & Li Huo & Willemieke Tummers & Fabian V. Filipp & Haiwei Henry Guo & Thomas Haywood & Lotfi Abou-Elkacem & Lucia Baratto & Frezghi Habte & Rammohan Devulapall, 2019. "Evaluation of integrin αvβ6 cystine knot PET tracers to detect cancer and idiopathic pulmonary fibrosis," Nature Communications, Nature, vol. 10(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-11863-w
    DOI: 10.1038/s41467-019-11863-w
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