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

Richard H. Kimura(Stanford University), Ling Wang(Chinese Academy of Medical Sciences & Peking Union Medical College), Bin Shen(Stanford University), Li Huo(Chinese Academy of Medical Sciences & Peking Union Medical College), Willemieke S. Tummers(Stanford University), Fabian V. Filipp(Helmholtz Zentrum München), H. 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), Subhendu Chakraborti(Stanford University), Jay C. Nix(Lawrence Berkeley National Laboratory), Christopher A. Bonagura, Negin Hatami(Stanford University), Joshua J. Mooney(Stanford University), Tushar Desai(Stanford University), Scott Turner(Pliant (United States)), Richard S. Gaster(Stanford University), A Otte(Stanford University), Brendan C. Visser(Stanford University), George A. Poultsides(Stanford University), Jeffrey A. Norton(Stanford University), Walter G. Park(Stanford University), Mark L. Stolowitz(Stanford University), Kenneth H. 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), Jürgen K. Willmann(Stanford University), Frederick T. Chin(Stanford University), Zhen Cheng(Stanford University), Andrei Iagaru(Stanford University), Fang Li(Chinese Academy of Medical Sciences & Peking Union Medical College), Sanjiv S. Gambhir(Stanford Medicine)
Nature Communications
October 14, 2019
10.1038/s41467-019-11863-w
Cited by 114Open Access
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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 αvβ 6 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 α v β 6 .

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