Evaluation of integrin αvβ6 cystine knot PET tracers to detect cancer and idiopathic pulmonary fibrosis
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 .
- Authors:
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- Publication Date:
- Research Org.:
- Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC), Basic Energy Sciences (BES); Canary Foundation; National Institutes of Health (NIH); National Cancer Institute (NCI); GRFP NSF National Science Foundation; Science Alliance on Precision Medicine and Cancer Prevention; National Natural Science Foundation of China (NSFC); Beijing Municipal Science & Technology Commission; CAMS Innovation Fund for Medical Science
- OSTI Identifier:
- 1619577
- Alternate Identifier(s):
- OSTI ID: 1580946
- Grant/Contract Number:
- AC02-05CH11231; SC0008397; NCI U01 CA210020; CA154887; CRN-17-427258; 81571713; Z151100003915133; 2016-I2M-4-003
- Resource Type:
- Published Article
- Journal Name:
- Nature Communications
- Additional Journal Information:
- Journal Name: Nature Communications Journal Volume: 10 Journal Issue: 1; Journal ID: ISSN 2041-1723
- Publisher:
- Nature Publishing Group
- Country of Publication:
- United Kingdom
- Language:
- English
- Subject:
- 60 APPLIED LIFE SCIENCES
Citation Formats
Kimura, Richard H., Wang, Ling, Shen, Bin, Huo, Li, Tummers, Willemieke, Filipp, Fabian V., Guo, Haiwei Henry, Haywood, Thomas, Abou-Elkacem, Lotfi, Baratto, Lucia, Habte, Frezghi, Devulapally, Rammohan, Witney, Timothy H., Cheng, Yan, Tikole, Suhas, Chakraborti, Subhendu, Nix, Jay, Bonagura, Christopher A., Hatami, Negin, Mooney, Joshua J., Desai, Tushar, Turner, Scott, Gaster, Richard S., Otte, Andrea, Visser, Brendan C., Poultsides, George A., Norton, Jeffrey, Park, Walter, Stolowitz, Mark, Lau, Kenneth, Yang, Eric, Natarajan, Arutselvan, Ilovich, Ohad, Srinivas, Shyam, Srinivasan, Ananth, Paulmurugan, Ramasamy, Willmann, Juergen, Chin, Frederick T., Cheng, Zhen, Iagaru, Andrei, Li, Fang, and Gambhir, Sanjiv S. Evaluation of integrin αvβ6 cystine knot PET tracers to detect cancer and idiopathic pulmonary fibrosis. United Kingdom: N. p., 2019.
Web. doi:10.1038/s41467-019-11863-w.
Kimura, Richard H., Wang, Ling, Shen, Bin, Huo, Li, Tummers, Willemieke, Filipp, Fabian V., Guo, Haiwei Henry, Haywood, Thomas, Abou-Elkacem, Lotfi, Baratto, Lucia, Habte, Frezghi, Devulapally, Rammohan, Witney, Timothy H., Cheng, Yan, Tikole, Suhas, Chakraborti, Subhendu, Nix, Jay, Bonagura, Christopher A., Hatami, Negin, Mooney, Joshua J., Desai, Tushar, Turner, Scott, Gaster, Richard S., Otte, Andrea, Visser, Brendan C., Poultsides, George A., Norton, Jeffrey, Park, Walter, Stolowitz, Mark, Lau, Kenneth, Yang, Eric, Natarajan, Arutselvan, Ilovich, Ohad, Srinivas, Shyam, Srinivasan, Ananth, Paulmurugan, Ramasamy, Willmann, Juergen, Chin, Frederick T., Cheng, Zhen, Iagaru, Andrei, Li, Fang, & Gambhir, Sanjiv S. Evaluation of integrin αvβ6 cystine knot PET tracers to detect cancer and idiopathic pulmonary fibrosis. United Kingdom. https://doi.org/10.1038/s41467-019-11863-w
Kimura, Richard H., Wang, Ling, Shen, Bin, Huo, Li, Tummers, Willemieke, Filipp, Fabian V., Guo, Haiwei Henry, Haywood, Thomas, Abou-Elkacem, Lotfi, Baratto, Lucia, Habte, Frezghi, Devulapally, Rammohan, Witney, Timothy H., Cheng, Yan, Tikole, Suhas, Chakraborti, Subhendu, Nix, Jay, Bonagura, Christopher A., Hatami, Negin, Mooney, Joshua J., Desai, Tushar, Turner, Scott, Gaster, Richard S., Otte, Andrea, Visser, Brendan C., Poultsides, George A., Norton, Jeffrey, Park, Walter, Stolowitz, Mark, Lau, Kenneth, Yang, Eric, Natarajan, Arutselvan, Ilovich, Ohad, Srinivas, Shyam, Srinivasan, Ananth, Paulmurugan, Ramasamy, Willmann, Juergen, Chin, Frederick T., Cheng, Zhen, Iagaru, Andrei, Li, Fang, and Gambhir, Sanjiv S. Mon .
"Evaluation of integrin αvβ6 cystine knot PET tracers to detect cancer and idiopathic pulmonary fibrosis". United Kingdom. https://doi.org/10.1038/s41467-019-11863-w.
@article{osti_1619577,
title = {Evaluation of integrin αvβ6 cystine knot PET tracers to detect cancer and idiopathic pulmonary fibrosis},
author = {Kimura, Richard H. and Wang, Ling and Shen, Bin and Huo, Li and Tummers, Willemieke and Filipp, Fabian V. and Guo, Haiwei Henry and Haywood, Thomas and Abou-Elkacem, Lotfi and Baratto, Lucia and Habte, Frezghi and Devulapally, Rammohan and Witney, Timothy H. and Cheng, Yan and Tikole, Suhas and Chakraborti, Subhendu and Nix, Jay and Bonagura, Christopher A. and Hatami, Negin and Mooney, Joshua J. and Desai, Tushar and Turner, Scott and Gaster, Richard S. and Otte, Andrea and Visser, Brendan C. and Poultsides, George A. and Norton, Jeffrey and Park, Walter and Stolowitz, Mark and Lau, Kenneth and Yang, Eric and Natarajan, Arutselvan and Ilovich, Ohad and Srinivas, Shyam and Srinivasan, Ananth and Paulmurugan, Ramasamy and Willmann, Juergen and Chin, Frederick T. and Cheng, Zhen and Iagaru, Andrei and Li, Fang and Gambhir, Sanjiv S.},
abstractNote = {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 .},
doi = {10.1038/s41467-019-11863-w},
journal = {Nature Communications},
number = 1,
volume = 10,
place = {United Kingdom},
year = {Mon Oct 14 00:00:00 EDT 2019},
month = {Mon Oct 14 00:00:00 EDT 2019}
}
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