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.

Cancer cell–selective in vivo near infrared photoimmunotherapy targeting specific membrane molecules

Abstract

Three major modes of cancer therapy (surgery, radiation and chemotherapy) are the mainstay of modern oncologic therapy. To minimize the side effects of these therapies, molecular-targeted cancer therapies, including armed antibody therapy, have been developed with limited success. In this study, we have developed a new type of molecular-targeted cancer therapy, photoimmunotherapy (PIT), that uses a target-specific photosensitizer based on a near-infrared (NIR) phthalocyanine dye, IR700, conjugated to monoclonal antibodies (mAbs) targeting epidermal growth factor receptors. Cell death was induced immediately after irradiating mAb-IR700–bound target cells with NIR light. We observed in vivo tumor shrinkage after irradiation with NIR light in target cells expressing the epidermal growth factor receptor. The mAb-IR700 conjugates were most effective when bound to the cell membrane and produced no phototoxicity when not bound, suggesting a different mechanism for PIT as compared to conventional photodynamic therapies. Target-selective PIT enables treatment of cancer based on mAb binding to the cell membrane.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: mAb-IR700 PIT in physics-based cancer therapies.
Figure 2: Target-specific cell death in response to Tra-IR700–mediated PIT in 3T3-HER2 cells.
Figure 3: Target-specific cell death in response to Pan-IR700–mediated PIT in epidermal growth factor receptor (EGFR)-expressing A431 cells.
Figure 4: Tra-IR700–mediated PIT for co-cultured cells either expressing or not expressing HER2.
Figure 5: Pan-IR700–mediated PIT for HER1-expressing tumors in vivo.

References

  1. 1

    Waldmann, T.A. Immunotherapy: past, present and future. Nat. Med. 9, 269–277 (2003).

    CAS  Article  PubMed  Google Scholar 

  2. 2

    Reichert, J.M., Rosensweig, C.J., Faden, L.B. & Dewitz, M.C. Monoclonal antibody successes in the clinic. Nat. Biotechnol. 23, 1073–1078 (2005).

    CAS  Article  PubMed  Google Scholar 

  3. 3

    Goldenberg, D.M., Sharkey, R.M., Paganelli, G., Barbet, J. & Chatal, J.F. Antibody pretargeting advances cancer radioimmunodetection and radioimmunotherapy. J. Clin. Oncol. 24, 823–834 (2006).

    CAS  Article  PubMed  Google Scholar 

  4. 4

    Pastan, I., Hassan, R., Fitzgerald, D.J. & Kreitman, R.J. Immunotoxin therapy of cancer. Nat. Rev. Cancer 6, 559–565 (2006).

    CAS  Article  PubMed  Google Scholar 

  5. 5

    Mew, D., Wat, C.K., Towers, G.H. & Levy, J.G. Photoimmunotherapy: treatment of animal tumors with tumor-specific monoclonal antibody-hematoporphyrin conjugates. J. Immunol. 130, 1473–1477 (1983).

    CAS  PubMed  Google Scholar 

  6. 6

    Sobolev, A.S., Jans, D.A. & Rosenkranz, A.A. Targeted intracellular delivery of photosensitizers. Prog. Biophys. Mol. Biol. 73, 51–90 (2000).

    CAS  Article  PubMed  Google Scholar 

  7. 7

    Carcenac, M. et al. Internalisation enhances photo-induced cytotoxicity of monoclonal antibody-phthalocyanine conjugates. Br. J. Cancer 85, 1787–1793 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. 8

    Vrouenraets, M.B. et al. Development of meta-tetrahydroxyphenylchlorin-monoclonal antibody conjugates for photoimmunotherapy. Cancer Res. 59, 1505–1513 (1999).

    CAS  PubMed  Google Scholar 

  9. 9

    Vrouenraets, M.B. et al. Targeting of aluminum (III) phthalocyanine tetrasulfonate by use of internalizing monoclonal antibodies: improved efficacy in photodynamic therapy. Cancer Res. 61, 1970–1975 (2001).

    CAS  PubMed  Google Scholar 

  10. 10

    Hamblin, M.R., Miller, J.L. & Hasan, T. Effect of charge on the interaction of site-specific photoimmunoconjugates with human ovarian cancer cells. Cancer Res. 56, 5205–5210 (1996).

    CAS  PubMed  Google Scholar 

  11. 11

    Mew, D. et al. Ability of specific monoclonal antibodies and conventional antisera conjugated to hematoporphyrin to label and kill selected cell lines subsequent to light activation. Cancer Res. 45, 4380–4386 (1985).

    CAS  PubMed  Google Scholar 

  12. 12

    Ogawa, M., Regino, C.A., Choyke, P.L. & Kobayashi, H. In vivo target-specific activatable near-infrared optical labeling of humanized monoclonal antibodies. Mol. Cancer Ther. 8, 232–239 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. 13

    Yang, X.D. et al. Eradication of established tumors by a fully human monoclonal antibody to the epidermal growth factor receptor without concomitant chemotherapy. Cancer Res. 59, 1236–1243 (1999).

    CAS  PubMed  Google Scholar 

  14. 14

    Pooler, J.P. & Valenzeno, D.P. The role of singlet oxygen in photooxidation of excitable cell membranes. Photochem. Photobiol. 30, 581–584 (1979).

    CAS  Article  PubMed  Google Scholar 

  15. 15

    Ogawa, M. et al. Dual-modality molecular imaging using antibodies labeled with activatable fluorescence and a radionuclide for specific and quantitative targeted cancer detection. Bioconjug. Chem. 20, 2177–2184 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. 16

    Dougherty, T.J. et al. Photodynamic therapy. J. Natl. Cancer Inst. 90, 889–905 (1998).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. 17

    Wilson, B.C. & Patterson, M.S. The determination of light fluence distributions in photodynamic therapy. in Photodynamic therapy of neoplastic disease, Vol. 1 (ed. Kessel, D.) 129–144 (CRC Press, Boca Raton, Florida, USA, 1990).

  18. 18

    Detty, M.R., Gibson, S.L. & Wagner, S.J. Current clinical and preclinical photosensitizers for use in photodynamic therapy. J. Med. Chem. 47, 3897–3915 (2004).

    CAS  Article  PubMed  Google Scholar 

  19. 19

    Weishaupt, K.R., Gomer, C.J. & Dougherty, T.J. Identification of singlet oxygen as the cytotoxic agent in photoinactivation of a murine tumor. Cancer Res. 36, 2326–2329 (1976).

    CAS  PubMed  Google Scholar 

  20. 20

    Patterson, M.S., Madsen, S.J. & Wilson, B.C. Experimental tests of the feasibility of singlet oxygen luminescence monitoring in vivo during photodynamic therapy. J. Photochem. Photobiol. B 5, 69–84 (1990).

    CAS  Article  PubMed  Google Scholar 

  21. 21

    Thorpe, W.P., Toner, M., Ezzell, R.M., Tompkins, R.G. & Yarmush, M.L. Dynamics of photoinduced cell plasma membrane injury. Biophys. J. 68, 2198–2206 (1995).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. 22

    Kosaka, N. et al. Semiquantitative assessment of the microdistribution of fluorescence-labeled monoclonal antibody in small peritoneal disseminations of ovarian cancer. Cancer Sci. 101, 820–825 (2010).

    CAS  Article  PubMed  Google Scholar 

  23. 23

    Kosaka, N. et al. Microdistribution of fluorescently-labeled monoclonal antibody in a peritoneal dissemination model of ovarian cancer. Proc. SPIE 7576, 757604 (2010).

    Article  Google Scholar 

  24. 24

    Mandler, R., Kobayashi, H., Hinson, E.R., Brechbiel, M.W. & Waldmann, T.A. Herceptin-geldanamycin immunoconjugates: pharmacokinetics, biodistribution, and enhanced antitumor activity. Cancer Res. 64, 1460–1467 (2004).

    CAS  Article  PubMed  Google Scholar 

  25. 25

    Nanus, D.M. et al. Clinical use of monoclonal antibody HuJ591 therapy: targeting prostate specific membrane antigen. J. Urol. 170, S84–S88 (2003).

    Article  PubMed  Google Scholar 

  26. 26

    van Dongen, G.A., Visser, G.W. & Vrouenraets, M.B. Photosensitizer-antibody conjugates for detection and therapy of cancer. Adv. Drug Deliv. Rev. 56, 31–52 (2004).

    CAS  Article  PubMed  Google Scholar 

  27. 27

    Zhong, W. et al. In vivo high-resolution fluorescence microendoscopy for ovarian cancer detection and treatment monitoring. Br. J. Cancer 101, 2015–2022 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. 28

    Euhus, D.M., Hudd, C., LaRegina, M.C. & Johnson, F.E. Tumor measurement in the nude mouse. J. Surg. Oncol. 31, 229–234 (1986).

    CAS  Article  PubMed  Google Scholar 

Download references

Acknowledgements

This research was supported by the Intramural Research Program of the US National Institutes of Health, National Cancer Institute, Center for Cancer Research. We would like to thank C. Regino, T. Hirano and C. Paik for their technical support.

Author information

Affiliations

Authors

Contributions

M.M. conducted experiments, performed analysis and wrote the manuscript. M.O., N.K. and L.T.R. conducted experiments and performed analysis. P.L.C. wrote the manuscript and supervised the project. H.K. planned and initiated the project, designed and conducted experiments, wrote the manuscript and supervised the project.

Corresponding author

Correspondence to Hisataka Kobayashi.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–8 and Supplementary Methods (PDF 878 kb)

Supplementary Video 1a

Real-time observation of Tra-IR700 mediated phototoxic cell death. (MOV 443 kb)

Supplementary Video 1b

Real-time observation of Tra-IR700 mediated phototoxic cell death. (MOV 347 kb)

Supplementary Video 2

Target specific phototoxicity in response to Tra-IR700 mediated photoimmunotherapy in vitro. (MOV 374 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Mitsunaga, M., Ogawa, M., Kosaka, N. et al. Cancer cell–selective in vivo near infrared photoimmunotherapy targeting specific membrane molecules. Nat Med 17, 1685–1691 (2011). https://doi.org/10.1038/nm.2554

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing