1. Evaluation of integrin αvβ6 cystine knot PET tracers to detect cancer and idiopathic pulmonary fibrosis
- Author
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Joshua J. Mooney, Subhendu Chakraborti, Bin Shen, Brendan C. Visser, Ohad Ilovich, Fabian V. Filipp, Timothy H. Witney, Christopher A. Bonagura, Ramasamy Paulmurugan, Juergen K. Willmann, Jeffrey A. Norton, Fang Li, Ling Wang, Zhen Cheng, S. Srinivas, Lotfi Abou-Elkacem, Thomas Haywood, Scott Turner, Arutselvan Natarajan, Walter G. Park, Eric J Yang, H. Henry Guo, Frederick T. Chin, Andrei Iagaru, Negin Hatami, Willemieke S. Tummers, Richard S. Gaster, Richard H. Kimura, George A. Poultsides, Frezghi Habte, Mark L. Stolowitz, Kenneth Lau, Yan Cheng, Rammohan Devulapally, Andrea Otte, Ananth Srinivasan, Jay C. Nix, Sanjiv S. Gambhir, Lucia Baratto, Suhas Tikole, Tushar J. Desai, and Li Huo
- Subjects
0301 basic medicine ,Integrins ,General Physics and Astronomy ,Crystallography, X-Ray ,Idiopathic pulmonary fibrosis ,0302 clinical medicine ,Neoplasms ,Medicine ,lcsh:Science ,Lung ,Cancer ,screening and diagnosis ,Multidisciplinary ,Crystallography ,medicine.diagnostic_test ,biology ,Cystine knot ,Magnetic Resonance Imaging ,Healthy Volunteers ,3. Good health ,ddc ,Detection ,medicine.anatomical_structure ,Positron emission tomography ,030220 oncology & carcinogenesis ,Respiratory ,Biomedical Imaging ,4.2 Evaluation of markers and technologies ,Biodistribution ,Science ,Integrin ,Bioengineering ,Article ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Rare Diseases ,Antigens, Neoplasm ,Clinical Research ,Humans ,Antigens ,X-ray crystallography ,business.industry ,Diagnostic markers ,General Chemistry ,medicine.disease ,Idiopathic Pulmonary Fibrosis ,4.1 Discovery and preclinical testing of markers and technologies ,030104 developmental biology ,Positron-Emission Tomography ,Cancer research ,biology.protein ,X-Ray ,Neoplasm ,Cancer imaging ,lcsh:Q ,Protein design ,Molecular imaging ,business ,Solution-state NMR - 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., Knottin is a cystine knot peptide. Here, the authors develop a knottin-based tracer for positron emission tomography and demonstrate its ability to detect cancer and idiopathic pulmonary fibrosis through selective binding to integrin αvβ6.
- Published
- 2019