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Evaluation of integrin αvβ6 cystine knot PET tracers to detect cancer and idiopathic pulmonary fibrosis
- Source :
- Nat. Commun. 10:4673 (2019), Nature Communications, Vol 10, Iss 1, Pp 1-18 (2019), Nature communications, vol 10, iss 1, Nature Communications
- Publication Year :
- 2019
- Publisher :
- Nature Publishing Group, 2019.
-
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.<br />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.
- 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
Subjects
Details
- Language :
- German
- Database :
- OpenAIRE
- Journal :
- Nat. Commun. 10:4673 (2019), Nature Communications, Vol 10, Iss 1, Pp 1-18 (2019), Nature communications, vol 10, iss 1, Nature Communications
- Accession number :
- edsair.doi.dedup.....55f7c3dcb7dcefeb331fe79d5b501f2f