Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

A membrane antibody receptor for noninvasive imaging of gene expression

Gene Therapy volume 13, pages 412–420 (2006)Cite this article

Abstract

Monitoring gene expression is important to optimize gene therapy protocols and ensure that the proper tissue distribution is achieved in clinical practice. We developed a noninvasive imaging system based on the expression of artificial antibody receptors to trap hapten-labeled imaging probes. Functional membrane-bound anti-dansyl antibodies (DNS receptor) were stably expressed on melanoma cells in vitro and in vivo. A bivalent (DNS)2-diethylenetriaminepentaacetic 111Indium probe specifically bound to cells that expressed DNS receptors but not control scFv receptors. Importantly, the 111In probe preferentially localized to DNS receptors but not control receptors on tumors in mice as assessed by gamma camera imaging. By 48 h after intravenous injection, the uptake of the probe in tumors expressing DNS receptors was 72 times greater than the amount of probe in the blood. This targeting strategy may allow noninvasive assessment of the location, extent and persistence of gene expression in living animals and in the clinic.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  1. Hoffman RM . In vivo imaging with fluorescent proteins: the new cell biology. Acta Histochem 2004; 106: 77–87.

    Article  CAS  PubMed  Google Scholar 

  2. Misteli T, Spector DL . Applications of the green fluorescent protein in cell biology and biotechnology. Nat Biotechnol 1997; 15: 961–964.

    Article  CAS  PubMed  Google Scholar 

  3. Yang M, Baranov E, Jiang P, Sun FX, Li XM, Li L et al. Whole-body optical imaging of green fluorescent protein-expressing tumors and metastases. Proc Natl Acad Sci USA 2000; 97: 1206–1211.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Jacobs Jr WR, Barletta RG, Udani R, Chan J, Kalkut G, Sosne G et al. Rapid assessment of drug susceptibilities of Mycobacterium tuberculosis by means of luciferase reporter phages. Science 1993; 260: 819–822.

    Article  CAS  PubMed  Google Scholar 

  5. Leo BM, Li X, Balian G, Anderson DG . In vivo bioluminescent imaging of virus-mediated gene transfer and transduced cell transplantation in the intervertebral disc. Spine 2004; 29: 838–844.

    Article  PubMed  Google Scholar 

  6. Ray P, De A, Min JJ, Tsien RY, Gambhir SS . Imaging tri-fusion multimodality reporter gene expression in living subjects. Cancer Res 2004; 64: 1323–1330.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. de Vries EF, van Dillen IJ, van Waarde A, Willemsen AT, Vaalburg W, Mulder NH et al. Evaluation of [18F]FHPG as PET tracer for HSVtk gene expression. Nucl Med Biol 2003; 30: 651–660.

    Article  CAS  PubMed  Google Scholar 

  8. Gambhir SS, Barrio JR, Wu L, Iyer M, Namavari M, Satyamurthy N et al. Imaging of adenoviral-directed herpes simplex virus type 1 thymidine kinase reporter gene expression in mice with radiolabeled ganciclovir. J Nucl Med 1998; 39: 2003–2011.

    CAS  PubMed  Google Scholar 

  9. Tjuvajev JG, Finn R, Watanabe K, Joshi R, Oku T, Kennedy J et al. Noninvasive imaging of herpes virus thymidine kinase gene transfer and expression: a potential method for monitoring clinical gene therapy. Cancer Res 1996; 56: 4087–4095.

    CAS  PubMed  Google Scholar 

  10. Gambhir SS, Bauer E, Black ME, Liang Q, Kokoris MS, Barrio JR et al. A mutant herpes simplex virus type 1 thymidine kinase reporter gene shows improved sensitivity for imaging reporter gene expression with positron emission tomography. Proc Natl Acad Sci USA 2000; 97: 2785–2790.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Richard JC, Zhou Z, Ponde DE, Dence CS, Factor P, Reynolds PN et al. Imaging pulmonary gene expression with positron emission tomography. Am J Respir Crit Care Med 2003; 167: 1257–1263.

    Article  PubMed  Google Scholar 

  12. Tjuvajev JG, Avril N, Oku T, Sasajima T, Miyagawa T, Joshi R et al. Imaging herpes virus thymidine kinase gene transfer and expression by positron emission tomography. Cancer Res 1998; 58: 4333–4341.

    CAS  PubMed  Google Scholar 

  13. Johnson AA, Ray AS, Hanes J, Suo Z, Colacino JM, Anderson KS et al. Toxicity of antiviral nucleoside analogs and the human mitochondrial DNA polymerase. J Biol Chem 2001; 276: 40847–40857.

    Article  CAS  PubMed  Google Scholar 

  14. Morin KW, Duan W, Xu L, Zhou A, Moharram S, Knaus EE et al. Cytotoxicity and cellular uptake of pyrimidine nucleosides for imaging herpes simplex type-1 thymidine kinase (HSV-1 TK) expression in mammalian cells. Nucl Med Biol 2004; 31: 623–630.

    Article  CAS  PubMed  Google Scholar 

  15. Bonini C, Ferrari G, Verzeletti S, Servida P, Zappone E, Ruggieri L et al. HSV-TK gene transfer into donor lymphocytes for control of allogeneic graft-versus-leukemia. Science 1997; 276: 1719–1724.

    Article  CAS  PubMed  Google Scholar 

  16. Russo V, Tanzarella S, Dalerba P, Rigatti D, Rovere P, Villa A et al. Dendritic cells acquire the MAGE-3 human tumor antigen from apoptotic cells and induce a class I-restricted T cell response. Proc Natl Acad Sci USA 2000; 97: 2185–2190.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Haack K, Linnebacher M, Eisold S, Zoller M, von Knebel Doeberitz M, Gebert J . Induction of protective immunity against syngeneic rat cancer cells by expression of the cytosine deaminase suicide gene. Cancer Gene Ther 2000; 7: 1357–1364.

    Article  CAS  PubMed  Google Scholar 

  18. Haberkorn U, Oberdorfer F, Gebert J, Morr I, Haack K, Weber K et al. Monitoring gene therapy with cytosine deaminase: in vitro studies using tritiated-5-fluorocytosine. J Nucl Med 1996; 37: 87–94.

    CAS  PubMed  Google Scholar 

  19. Barrio JR, Satyamurthy N, Huang SC, Keen RE, Nissenson CH, Hoffman JM et al. 3-(2′-[18F]fluoroethyl)spiperone: in vivo biochemical and kinetic characterization in rodents, nonhuman primates, and humans. J Cereb Blood Flow Metab 1989; 9: 830–839.

    Article  CAS  PubMed  Google Scholar 

  20. MacLaren DC, Gambhir SS, Satyamurthy N, Barrio JR, Sharfstein S, Toyokuni T et al. Repetitive, non-invasive imaging of the dopamine D2 receptor as a reporter gene in living animals. Gene Therapy 1999; 6: 785–791.

    Article  CAS  PubMed  Google Scholar 

  21. Bunzow JR, Van Tol HH, Grandy DK, Albert P, Salon J, Christie M et al. Cloning and expression of a rat D2 dopamine receptor cDNA. Nature 1988; 336: 783–787.

    Article  CAS  PubMed  Google Scholar 

  22. Wolf G . Vitamin A functions in the regulation of the dopaminergic system in the brain and pituitary gland. Nutr Rev 1998; 56: 354–355.

    Article  CAS  PubMed  Google Scholar 

  23. Beom S, Cheong D, Torres G, Caron MG, Kim KM . Comparative studies of molecular mechanisms of dopamine D2 and D3 receptors for the activation of extracellular signal regulated kinase. J Biol Chem 2004; 279: 28304–28314.

    Article  CAS  PubMed  Google Scholar 

  24. Strange PG . Aspects of the structure of the D2 dopamine receptor. Trends Neurosci 1990; 13: 373–378.

    Article  CAS  PubMed  Google Scholar 

  25. Weissleder R, Moore A, Mahmood U, Bhorade R, Benveniste H, Chiocca EA et al. In vivo magnetic resonance imaging of transgene expression. Nat Med 2000; 6: 351–355.

    Article  CAS  PubMed  Google Scholar 

  26. Liao KW, Chen BM, Liu TB, Tzou SC, Lin YM, Lin KF et al. Stable expression of chimeric anti-CD3 receptors on mammalian cells for stimulation of antitumor immunity. Cancer Gene Ther 2003; 10: 779–790.

    Article  CAS  PubMed  Google Scholar 

  27. Cheng TL, Liao KW, Tzou SC, Cheng CM, Chen BM, Roffler SR . Hapten-directed targeting to single-chain antibody receptors. Cancer Gene Ther 2004; 11: 380–388.

    Article  CAS  PubMed  Google Scholar 

  28. Liao KW, Lo YC, Roffler SR . Activation of lymphocytes by anti-CD3 single-chain antibody dimers expressed on the plasma membrane of tumor cells. Gene Therapy 2000; 7: 339–347.

    Article  CAS  PubMed  Google Scholar 

  29. Chen IY, Wu JC, Min JJ, Sundaresan G, Lewis X, Liang Q et al. Micro-positron emission tomography imaging of cardiac gene expression in rats using bicistronic adenoviral vector-mediated gene delivery. Circulation 2004; 109: 1415–1420.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Levenson VV, Transue ED, Roninson IB . Internal ribosomal entry site-containing retroviral vectors with green fluorescent protein and drug resistance markers. Hum Gene Ther 1998; 9: 1233–1236.

    Article  CAS  PubMed  Google Scholar 

  31. Yu Y, Annala AJ, Barrio JR, Toyokuni T, Satyamurthy N, Namavari M et al. Quantification of target gene expression by imaging reporter gene expression in living animals. Nat Med 2000; 6: 933–937.

    Article  CAS  PubMed  Google Scholar 

  32. Chou WC, Liao KW, Lo YC, Jiang SY, Yeh MY, Roffler SR et al. Expression of chimeric monomer and dimer proteins on the plasma membrane of mammalian cells. Biotechnol Bioeng 1999; 65: 160–169.

    Article  CAS  PubMed  Google Scholar 

  33. Liao KW, Chou WC, Lo YC, Roffler SR . Design of transgenes for efficient expression of active chimeric proteins on mammalian cells. Biotechnol Bioeng 2001; 73: 313–323.

    Article  CAS  PubMed  Google Scholar 

  34. Martell A, Smith RM . Critical Stability Constants, vol. 6. Plenum Press: New York, 1986.

    Google Scholar 

  35. Coloma MJ, Morrison SL . Design and production of novel tetravalent bispecific antibodies. Nat Biotechnol 1997; 15: 159–163.

    Article  CAS  PubMed  Google Scholar 

  36. Morrison SL, Porter SB, Trinh KR, Wims LA, Denham J, Oi VT . Variable region domain exchange influences the functional properties of IgG. J Immunol 1998; 160: 2802–2808.

    CAS  PubMed  Google Scholar 

  37. Northrop JP, Bednarski M, Barbieri SO, Lu AT, Nguyen D, Varadarajan J et al. Cell surface expression of single chain antibodies with applications to imaging of gene expression in vivo. Eur J Nucl Med Mol Imaging 2003; 30: 1292–1298.

    Article  CAS  PubMed  Google Scholar 

  38. Farinas J, Verkman AS . Receptor-mediated targeting of fluorescent probes in living cells. J Biol Chem 1999; 274: 7603–7606.

    Article  CAS  PubMed  Google Scholar 

  39. Andrianaivo F, Lecocq M, Wattiaux-De Coninck S, Wattiaux R, Jadot M . Hydrodynamics-based transfection of the liver: entrance into hepatocytes of DNA that causes expression takes place very early after injection. J Gene Med 2004; 6: 877–883.

    Article  CAS  PubMed  Google Scholar 

  40. Wang CH, Jawan B, Lee TH, Hung KS, Chou WY, Lu CN et al. Single injection of naked plasmid encoding alpha-melanocyte-stimulating hormone protects against thioacetamide-induced acute liver failure in mice. Biochem Biophys Res Commun 2004; 322: 153–161.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This study was supported by grants from the National Research Program for Genomic Medicine, National Science Council, Taipei, Taiwan (NSC92-3112-B-037-001 and NSC-93-3112-B-010-019) and the Genomic and Proteomic Program, Academia Sinica, Taipei, Taiwan (94M007-2).

Author information

Author notes

  1. S R Roffler and H-E Wang: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan

    S R Roffler & B-M Chen

  2. Department of Medical Radiation Technology and Institute of Radiological Sciences, National Yang-Ming University, Taipei, Taiwan

    H-E Wang & H-M Yu

  3. School of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung, Taiwan

    W-D Chang, C-M Cheng & T-L Cheng

  4. MedicoGenomic Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan

    W-D Chang, C-M Cheng & T-L Cheng

  5. Chia Nan University of Pharmacy and Science, Taninan, Taiwan

    Y-L Lu

Authors
  1. S R Roffler
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. H-E Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. H-M Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. W-D Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. C-M Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Y-L Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. B-M Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. T-L Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to T-L Cheng.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Roffler, S., Wang, HE., Yu, HM. et al. A membrane antibody receptor for noninvasive imaging of gene expression. Gene Ther 13, 412–420 (2006). https://doi.org/10.1038/sj.gt.3302671

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gt.3302671

Keywords

This article is cited by

Search

Advanced search

Quick links