Technical Report | Published:

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

Nature Medicine volume 17, pages 16851691 (2011) | Download Citation

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 optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

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

  2. 2.

    , , & Monoclonal antibody successes in the clinic. Nat. Biotechnol. 23, 1073–1078 (2005).

  3. 3.

    , , , & Antibody pretargeting advances cancer radioimmunodetection and radioimmunotherapy. J. Clin. Oncol. 24, 823–834 (2006).

  4. 4.

    , , & Immunotoxin therapy of cancer. Nat. Rev. Cancer 6, 559–565 (2006).

  5. 5.

    , , & Photoimmunotherapy: treatment of animal tumors with tumor-specific monoclonal antibody-hematoporphyrin conjugates. J. Immunol. 130, 1473–1477 (1983).

  6. 6.

    , & Targeted intracellular delivery of photosensitizers. Prog. Biophys. Mol. Biol. 73, 51–90 (2000).

  7. 7.

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

  8. 8.

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

  9. 9.

    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).

  10. 10.

    , & Effect of charge on the interaction of site-specific photoimmunoconjugates with human ovarian cancer cells. Cancer Res. 56, 5205–5210 (1996).

  11. 11.

    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).

  12. 12.

    , , & In vivo target-specific activatable near-infrared optical labeling of humanized monoclonal antibodies. Mol. Cancer Ther. 8, 232–239 (2009).

  13. 13.

    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).

  14. 14.

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

  15. 15.

    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).

  16. 16.

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

  17. 17.

    & 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.

    , & Current clinical and preclinical photosensitizers for use in photodynamic therapy. J. Med. Chem. 47, 3897–3915 (2004).

  19. 19.

    , & Identification of singlet oxygen as the cytotoxic agent in photoinactivation of a murine tumor. Cancer Res. 36, 2326–2329 (1976).

  20. 20.

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

  21. 21.

    , , , & Dynamics of photoinduced cell plasma membrane injury. Biophys. J. 68, 2198–2206 (1995).

  22. 22.

    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).

  23. 23.

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

  24. 24.

    , , , & Herceptin-geldanamycin immunoconjugates: pharmacokinetics, biodistribution, and enhanced antitumor activity. Cancer Res. 64, 1460–1467 (2004).

  25. 25.

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

  26. 26.

    , & Photosensitizer-antibody conjugates for detection and therapy of cancer. Adv. Drug Deliv. Rev. 56, 31–52 (2004).

  27. 27.

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

  28. 28.

    , , & Tumor measurement in the nude mouse. J. Surg. Oncol. 31, 229–234 (1986).

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

  1. Molecular Imaging Program, Center for Cancer Research, National Cancer Institute, US National Institutes of Health, Bethesda, Maryland, USA.

    • Makoto Mitsunaga
    • , Mikako Ogawa
    • , Nobuyuki Kosaka
    • , Lauren T Rosenblum
    • , Peter L Choyke
    •  & Hisataka Kobayashi

Authors

  1. Search for Makoto Mitsunaga in:

  2. Search for Mikako Ogawa in:

  3. Search for Nobuyuki Kosaka in:

  4. Search for Lauren T Rosenblum in:

  5. Search for Peter L Choyke in:

  6. Search for Hisataka Kobayashi in:

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.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Hisataka Kobayashi.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–8 and Supplementary Methods

Videos

  1. 1.

    Supplementary Video 1a

    Real-time observation of Tra-IR700 mediated phototoxic cell death.

  2. 2.

    Supplementary Video 1b

    Real-time observation of Tra-IR700 mediated phototoxic cell death.

  3. 3.

    Supplementary Video 2

    Target specific phototoxicity in response to Tra-IR700 mediated photoimmunotherapy in vitro.

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/nm.2554

Further reading