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Detection of colorectal polyps in humans using an intravenously administered fluorescent peptide targeted against c-Met

Nature Medicine volume 21, pages 955–961 (2015)Cite this article

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Abstract

Colon cancer prevention currently relies on colonoscopy using white light to detect and remove polyps, but small and flat polyps are difficult to detect and frequently missed when using this technique. Fluorescence colonoscopy combined with a fluorescent probe specific for a polyp biomarker may improve polyp detection. Here we describe GE-137, a water-soluble probe consisting of a 26–amino acid cyclic peptide that binds the human tyrosine kinase c-Met conjugated to a fluorescent cyanine dye. Intravenous administration of GE-137 leads to its accumulation specifically in c-Met–expressing tumors in mice, and it is safe and well tolerated in humans. Fluorescence colonoscopy in patients receiving intravenous GE-137 enabled visualization of all neoplastic polyps that were visible with white light (38), as well as an additional nine polyps that were not visible with white light. This first-in-human pilot study shows that molecular imaging using an intravenous fluorescent agent specific for c-Met is feasible and safe, and that it may enable the detection of polyps missed by other techniques.

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Figure 1: GE-137 chemical and optical properties and testing in a rodent model of colon cancer.
Figure 2: Experimental system for combined WL and NIR fluorescence colonoscopy in humans.
Figure 3: Simultaneous WL and FL images of representative lesions of the various morphological and histological subtypes found.
Figure 4: c-Met expression analysis by immunohistochemistry using an antibody specific for the extracellular domain of c-Met.
Figure 5: c-Met expression in normal colon and an adenomatous polyp as detected by immunohistochemistry and GE-137.

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Acknowledgements

The authors would like to acknowledge the contributions of T. Attramadal, E. Johannesen and H. Dirven, who were the Project Leaders at GE Healthcare in the screening, lead selection and the translational/early clinical phases of the project, respectively. GE Healthcare AS received support for the GE-137 project from The Research Council of Norway grant no. 192984/BIA and SkatteFUNN grant no. 201108. F.W.B.v.L. and T.B. were supported by the The Netherlands Organisation for Scientific Research (NWO) VIDI (grant no. STW BGT11272) and a Postdoctoral Molecular Imaging Scholarship from the Education and Research Foundation for Nuclear Medicine and Molecular Imaging.

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Authors and Affiliations

  1. Centre for Human Drug Research, Leiden, the Netherlands

    Jacobus Burggraaf, Ingrid M C Kamerling, Lenneke Schrier, Marieke L de Kam & Andrea J Kales

  2. GE Healthcare, Oslo, Norway

    Paul B Gordon, Ragnar Bendiksen, Bård Indrevoll, Roger M Bjerke, Siver A Moestue, Marit Swaerd-Nordmo, Geir Torheim, Liv-Ingrid Ødegårdstuen & Andrew Healey

  3. GE Global Research Centre, Niskayuna, New York, USA

    Siavash Yazdanfar

  4. Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, the Netherlands

    Alexandra M J Langers, Philip W Voorneveld & James C H Hardwick

  5. Pathology Diagnostics Ltd., St. John's Innovation Centre, Cambridge, UK

    Madhuri V Warren

  6. Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands

    Hans Morreau

  7. Department of Radiology, Leiden University Medical Center, Leiden, the Netherlands

    Tessa Buckle & Fijs W B van Leeuwen

  8. GE Healthcare, Amersham, UK

    Grethe T Dalsgaard

Authors
  1. Jacobus Burggraaf
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Contributions

J.B., I.M.C.K. and P.B.G. designed the pharmacological studies; B.I., M.S.-N. and L.-I.Ø. developed the probe and the drug product; and R.B., R.M.B., S.A.M., A.H. and G.T.D. conducted the preclinical testing. L.S. and A.J.K. performed recruitment and safety testing for the clinical studies. M.L.d.K. performed the statistical analyses. H.M. performed the histopathological analysis of polyps. M.V.W. performed the c-Met immunohistochemical analysis. F.W.B.v.L., P.W.V. and T.B. performed the ex vivo direct fluorescence imaging studies. A.H., S.Y. and G.T. designed the method for assessing the imaging characteristics of the probe and developed the colonoscopy system. P.B.G., A.M.J.L. and J.C.H.H. designed the clinical studies, A.M.J.L. and J.C.H.H. performed the clinical studies, and J.C.H.H. wrote the manuscript.

Corresponding author

Correspondence to James C H Hardwick.

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Competing interests

P.B. Gordon, R. Bendiksen, B. Indrevoll, R.M. Bjerke, S.A. Moestue, S. Yazdanfar, G. Torheim, M. Swaerd-Nordmo, G.T. Dalsgaard, L.-I. Ødegårdstuen and A. Healey are all currently employed by GE Healthcare or were employed by GE Healthcare during the study. The following authors declare no conflict of interest: J. Burggraaf, I.M.C. Kamerling, L. Schrier, M.L. de Kam, A.J. Kales, A.M.J. Langers, M.V. Warren, H. Morreau, P.W. Voorneveld, T. Buckle, F.W.B. van Leeuwen, and J.C.H. Hardwick.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–6, Supplementary Tables 1–4 & Supplementary Methods (PDF 4164 kb)

Supplementary Video 1

Video showing the two endoscopic images obtained simultaneously with white light and with near infrared fluorescence imaging (Green image) from a patient at colonoscopy. The first frame of the video details the characteristics of the colonic polyp shown in the video. (AVI 2485 kb)

Supplementary Video 2

Video showing the two endoscopic images obtained simultaneously with white light and with near infrared fluorescence imaging (Green image) from a patient at colonoscopy. The first frame of the video details the characteristics of the colonic polyp shown in the video (AVI 2531 kb)

Supplementary Video 3

Video showing the two endoscopic images obtained simultaneously with white light and with near infrared fluorescence imaging (Green image) from a patient at colonoscopy. The first frame of the video details the characteristics of the colonic polyp shown in the video (AVI 2577 kb)

Supplementary Video 4

Video showing the two endoscopic images obtained simultaneously with white light and with near infrared fluorescence imaging (Green image) from a patient at colonoscopy. The first frame of the video details the characteristics of the colonic polyp shown in the video (AVI 2368 kb)

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Burggraaf, J., Kamerling, I., Gordon, P. et al. Detection of colorectal polyps in humans using an intravenously administered fluorescent peptide targeted against c-Met. Nat Med 21, 955–961 (2015). https://doi.org/10.1038/nm.3641

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