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Connective tissue diseases
Visualisation of interstitial lung disease by molecular imaging of integrin αvβ3 and somatostatin receptor 2
  1. Janine Schniering1,
  2. Martina Benešová2,3,
  3. Matthias Brunner1,
  4. Stephanie Haller2,
  5. Susan Cohrs2,
  6. Thomas Frauenfelder4,
  7. Bart Vrugt5,
  8. Carol A Feghali-Bostwick6,
  9. Roger Schibli2,3,
  10. Oliver Distler1,
  11. Cristina Mueller2,3,
  12. Britta Maurer1
  1. 1 Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, Zurich, Switzerland
  2. 2 Center for Radiopharmaceutical Sciences, Paul Scherrer Institute, Villigen, Switzerland
  3. 3 Department of Chemistry and Applied Biosciences, ETH Zurich, Zurich, Switzerland
  4. 4 Institute of Diagnostic and Interventional Radiology, University Hospital Zurich, Zurich, Switzerland
  5. 5 Institute of Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland
  6. 6 Division of Rheumatology & Immunology, Medical University of South Carolina, Charleston, South Carolina, USA
  1. Correspondence to Dr Britta Maurer, Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, Zurich 8091, Switzerland; Britta.Maurer{at}usz.ch

Abstract

Objective To evaluate integrin αvβ3 (alpha-v-beta-3)-targeted and somatostatin receptor 2 (SSTR2)-targeted nuclear imaging for the visualisation of interstitial lung disease (ILD).

Methods The pulmonary expression of integrin αvβ3 and SSTR2 was analysed in patients with different forms of ILD as well as in bleomycin (BLM)-treated mice and respective controls using immunohistochemistry. Single photon emission CT/CT (SPECT/CT) was performed on days 3, 7 and 14 after BLM instillation using the integrin αvβ3-targeting 177Lu-DOTA-RGD and the SSTR2-targeting 177Lu-DOTA-NOC radiotracer. The specific pulmonary accumulation of the radiotracers over time was assessed by in vivo and ex vivo SPECT/CT scans and by biodistribution studies.

Results Expression of integrin αvβ3 and SSTR2 was substantially increased in human ILD regardless of the subtype. Similarly, in lungs of BLM-challenged mice, but not of controls, both imaging targets were stage-specifically overexpressed. While integrin αvβ3 was most abundantly upregulated on day 7, the inflammatory stage of BLM-induced lung fibrosis, SSTR2 expression peaked on day 14, the established fibrotic stage. In agreement with the findings on tissue level, targeted nuclear imaging using SPECT/CT specifically detected both imaging targets ex vivo and in vivo, and thus visualised different stages of experimental ILD.

Conclusion Our preclinical proof-of-concept study suggests that specific visualisation of molecular processes in ILD by targeted nuclear imaging is feasible. If transferred into clinics, where imaging is considered an integral part of patients’ management, the additional information derived from specific imaging tools could represent a first step towards precision medicine in ILD.

  • interstitial lung disease
  • nuclear imaging
  • biomarkers
  • integrin
  • somatostatin receptor

https://doi.org/10.1136/annrheumdis-2018-214322

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    Footnotes

    • CM and BM contributed equally.

    • Handling editor Josef S Smolen

    • Contributors JS made substantial contributions to the conception of the study, and the acquisition, analysis and interpretation of data, and was involved in drafting and revising the manuscript. MBe, MBr, SC, TF, BV and CAFB were centrally involved in the acquisition and analysis of data and in revising the manuscript. RS and OD made contributions to the conception and design of the study, interpretation of data and revision of the manuscript. CM and BM made substantial contributions to conception and design of the study and were centrally involved in the acquisition, analysis and interpretation of data and in drafting and revising the manuscript. All authors have given final approval of the version to be published.

    • Funding This work was supported by the Swiss National Science Foundation (Grant: CRSII3_154490), Hartmann-Mueller Foundation.

    • Competing interests JS, MBe, MBr, SH, SC, RS, CM, CAF-B and TF have no competing interests to declare. OD had consultancy relationship and/or has received research funding from Actelion, AnaMar, Bayer, Boehringer Ingelheim, ChemomAb, EspeRare Foundation, Genentech/Roche, GSK, Inventiva, Italfarmaco, Lilly, medac, MedImmune, Mitsubishi Tanabe Pharma, Novartis, Pfizer, Sanofi, Sinoxa and UCB in the area of potential treatments of scleroderma and its complications. In addition, OD has a patent mir-29 for the treatment of systemic sclerosis licensed. The real or perceived potential conflicts listed above are accurately stated. BM had grant/research support from AbbVie, Protagen and Novartis, and congress support from Pfizer, Roche and Actelion. In addition, BM has a patent mir-29 for the treatment of systemic sclerosis licensed. The real or perceived potential conflicts listed above are accurately stated.

    • Patient consent Obtained.

    • Ethics approval All animal experiments were approved by the cantonal authorities and performed according to the Swiss animal welfare guidelines. All studies with human biosamples were approved by the local ethics committees and the local institutional review boards.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data sharing statement All data from this study were published in the article or in the online supplementary information.

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