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

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 Devulapally, Timothy H. Witney, Yan Cheng, Suhas Tikole, Subhendu Chakraborti, Jay Nix, Christopher A. Bonagura, Negin Hatami, Joshua J. Mooney, Tushar Desai, Scott Turner, Richard S. Gaster, Andrea Otte, Brendan C. Visser, George A. Poultsides, Jeffrey Norton, Walter Park, Mark Stolowitz, Kenneth Lau, Eric Yang, Arutselvan Natarajan, Ohad Ilovich, Shyam Srinivas, Ananth Srinivasan, Ramasamy Paulmurugan, Juergen Willmann, Frederick T. Chin, Zhen Cheng, Andrei Iagaru, Fang Li and Sanjiv S. Gambhir ()
Additional contact information
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
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
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

Nature Communications, 2019, vol. 10, issue 1, 1-18

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-11863-w

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