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; Sanjiv S Gambhir

doi:10.1038/s41467-019-11863-w

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 MooneyTushar 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, Sanjiv S Gambhir

Imaging Chemistry & Biology

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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.

Original language	English
Article number	4673
Pages (from-to)	4673
Journal	Nature Communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-11863-w
Publication status	Published - 1 Dec 2019

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10.1038/s41467-019-11863-w

s41467-019-11863-wFinal published version, 9.06 MBLicence: CC BY

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Kimura, R. H., Wang, L., Shen, B., Huo, L., Tummers, W., Filipp, F. V., Guo, H. H., Haywood, T., Abou-Elkacem, L., Baratto, L., Habte, F., Devulapally, R., Witney, T. H., Cheng, Y., Tikole, S., Chakraborti, S., Nix, J., Bonagura, C. A., Hatami, N., ... Gambhir, S. S. (2019). Evaluation of integrin αvβ6 cystine knot PET tracers to detect cancer and idiopathic pulmonary fibrosis. Nature Communications, 10(1), 4673. Article 4673. https://doi.org/10.1038/s41467-019-11863-w

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title = "Evaluation of integrin αvβ6 cystine knot PET tracers to detect cancer and idiopathic pulmonary fibrosis",

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.",

author = "Kimura, {Richard H} and Ling Wang and Bin Shen and Li Huo and Willemieke Tummers and Filipp, {Fabian V} and Guo, {Haiwei Henry} and Thomas Haywood and Lotfi Abou-Elkacem and Lucia Baratto and Frezghi Habte and Rammohan Devulapally and Witney, {Timothy H} and Yan Cheng and Suhas Tikole and Subhendu Chakraborti and Jay Nix and Bonagura, {Christopher A} and Negin Hatami and Mooney, {Joshua J} and Tushar Desai and Scott Turner and Gaster, {Richard S} and Andrea Otte and Visser, {Brendan C} and Poultsides, {George A} and Jeffrey Norton and Walter Park and Mark Stolowitz and Kenneth Lau and Eric Yang and Arutselvan Natarajan and Ohad Ilovich and Shyam Srinivas and Ananth Srinivasan and Ramasamy Paulmurugan and Juergen Willmann and Chin, {Frederick T} and Zhen Cheng and Andrei Iagaru and Fang Li and Gambhir, {Sanjiv S}",

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Kimura, RH, Wang, L, Shen, B, Huo, L, Tummers, W, Filipp, FV, Guo, HH, Haywood, T, Abou-Elkacem, L, Baratto, L, Habte, F, Devulapally, R, Witney, TH, Cheng, Y, Tikole, S, Chakraborti, S, Nix, J, Bonagura, CA, Hatami, N, Mooney, JJ, Desai, T, Turner, S, Gaster, RS, Otte, A, Visser, BC, Poultsides, GA, Norton, J, Park, W, Stolowitz, M, Lau, K, Yang, E, Natarajan, A, Ilovich, O, Srinivas, S, Srinivasan, A, Paulmurugan, R, Willmann, J, Chin, FT, Cheng, Z, Iagaru, A, Li, F & Gambhir, SS 2019, 'Evaluation of integrin αvβ6 cystine knot PET tracers to detect cancer and idiopathic pulmonary fibrosis', Nature Communications, vol. 10, no. 1, 4673, pp. 4673. https://doi.org/10.1038/s41467-019-11863-w

TY - JOUR

T1 - Evaluation of integrin αvβ6 cystine knot PET tracers to detect cancer and idiopathic pulmonary fibrosis

AU - Kimura, Richard H

AU - Wang, Ling

AU - Shen, Bin

AU - Huo, Li

AU - Tummers, Willemieke

AU - Filipp, Fabian V

AU - Guo, Haiwei Henry

AU - Haywood, Thomas

AU - Abou-Elkacem, Lotfi

AU - Baratto, Lucia

AU - Habte, Frezghi

AU - Devulapally, Rammohan

AU - Witney, Timothy H

AU - Cheng, Yan

AU - Tikole, Suhas

AU - Chakraborti, Subhendu

AU - Nix, Jay

AU - Bonagura, Christopher A

AU - Hatami, Negin

AU - Mooney, Joshua J

AU - Desai, Tushar

AU - Turner, Scott

AU - Gaster, Richard S

AU - Otte, Andrea

AU - Visser, Brendan C

AU - Poultsides, George A

AU - Norton, Jeffrey

AU - Park, Walter

AU - Stolowitz, Mark

AU - Lau, Kenneth

AU - Yang, Eric

AU - Natarajan, Arutselvan

AU - Ilovich, Ohad

AU - Srinivas, Shyam

AU - Srinivasan, Ananth

AU - Paulmurugan, Ramasamy

AU - Willmann, Juergen

AU - Chin, Frederick T

AU - Cheng, Zhen

AU - Iagaru, Andrei

AU - Li, Fang

AU - Gambhir, Sanjiv S

PY - 2019/12/1

Y1 - 2019/12/1

N2 - 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.

AB - 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.

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DO - 10.1038/s41467-019-11863-w

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SN - 2041-1723

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JO - Nature Communications

JF - Nature Communications

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ER -

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

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