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Viral transduction of the HER2-extracellular domain expands trastuzumab-based photoimmunotherapy for HER2-negative breast cancer cells

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Abstract

The prognosis of HER2-positive breast cancer has been improved by trastuzumab therapy, which features high specificity and limited side effects. However, trastuzumab-based therapy has shortcomings. Firstly, HER2-targeted therapy is only applicable to HER2-expressing tumors, which comprise only 20–25 % of primary breast cancers. Secondly, many patients who initially respond to trastuzumab ultimately develop disease progression. To overcome these problems, we employed virus-mediated HER2 transduction and photoimmunotherapy (PIT) which involves trastuzumab conjugated with a photosensitizer, trastuzumab-IR700, and irradiation of near-infrared light. We hypothesized that the gene transduction technique together with PIT would expand the range of tumor entities suitable for trastuzumab-based therapy and improve its antitumor activity. The HER2-extracellular domain (ECD) was transduced by the adenoviral vector, Ad-HER2-ECD, and PIT with trastuzumab-IR700 was applied in the HER2-negative cancer cells. Ad-HER2-ECD can efficiently transduce HER2-ECD into HER2-negative human cancer cells. PIT with trastuzumab-IR700 induced direct cell membrane destruction of Ad-HER2-ECD-transduced HER2-negative cancer cells. Novel combination of viral transduction of a target antigen and an antibody-based PIT would expand and potentiate molecular-targeted therapy even for target-negative or attenuated cancer cells.

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Abbreviations

DMEM:

Dulbecco’s modified Eagle’s medium

ECD:

Extracellular domain

HER2:

Human epidermal growth factor receptor type 2

MOI:

A multiplicity of infection

NIR:

Near infrared

PBS:

Phosphate-buffered saline

PI:

Propidium iodide

PIT:

Photoimmunotherapy

SDS:

Sodium dodecyl sulfate

SQ:

Self-quenched

Tra-IR700:

Trastuzumab-IR700

XTT:

The sodium 3′-[1-(phenylaminocarbonyl)-3,4-tetrazolium]-bis(4-methoxy-6-nitro) benzene sulfonic acid hydrate

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Acknowledgments

We thank Tomoko Sueishi for her technical support. This study was supported by grants-in-aid from the Ministry of Education Culture, Sports, Science and Technology, Japan (Toshiyoshi Fujiwara, Hiroshi Tazawa, Shunsuke Tanabe, and Shunsuke Kagawa) and grants from the Ministry of Health, Labor and Welfare, Japan (Toshiyoshi Fujiwara).

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmacological Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan

    Kyoko Shimoyama, Shunsuke Kagawa, Michihiro Ishida, Shinichiro Watanabe, Kazuhiro Noma, Kiyoto Takehara, Hiroshi Tazawa, Yuuri Hashimoto, Shunsuke Tanabe & Toshiyoshi Fujiwara

  2. Center for Innovative Clinical Medicine, Okayama University Hospital, Okayama, Japan

    Hiroshi Tazawa

  3. Department of Palliative Care, Okayama University Hospital, Okayama, Japan

    Junji Matsuoka

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

    Hisataka Kobayashi

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  1. Kyoko Shimoyama
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  2. Shunsuke Kagawa
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Corresponding author

Correspondence to Shunsuke Kagawa.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Morphological change induced immediately after Tra-IR700 mediated PIT in HER2-ECD transduced breast cancer cells captured as a time-lapse movie (MP4 4920 kb)

The cellular membrane injury that was caused in 1. MDA-MD-231 cells and 2. MCF7 cells immediately after Tra-IR700 mediated PIT is shown (MP4 4644 kb)

Fig. S1

Adenoviral transduction of GFP protein into breast cancer cells. Fluorescence microscopic analysis of (a) MCF7 cells and (b) MDA-MB-231 cells that were transduced with GFP using Ad-GFP at the indicated MOIs. Most cells were transduced with GFP at an Ad-GFP MOI of 50 (PPT 468 kb)

Fig. S2

Microscopic analysis of the effect of Tra-IR700 mediated PIT on Saos2 cells infected with Ad-HER2-ECD. (a) Phase contrast analysis of the morphology of Ad-HER2-ECD-infected Saos2 cells immediately after PIT using 6 J or 24 J, and 24 h after PIT using 24 J. (b) PI staining of Ad-HER2-ECD-infected Saos2 cells 5 days after Tra-IR700 mediated PIT using 15 J. PI staining indicates plasma membrane destruction of Saos2 cells following treatment (PPT 284 kb)

Fig. S3

Effect of Tra-IR700-mediated PIT on cell viability of SK-BR-3 and Saos2 cells. (a) HER2-positive SK-BR-3 cells were treated with trastuzumab or with Tra-IR700 in combination with NIR irradiation as indicated and cell viability was measured using the XTT assay after 72h. The suppression of cell viability by Tra-IR1700 plus NIR (24 J) was significantly higher than that induced by trastuzumab or by any of the control groups. (b) Saos2 cells transduced with Ad-HER2-ECD were treated with Tra-IR700 mediated PIT () or with seven control conditions and cell viability was quantified after 72h using the XTT assay. Only the Ad-HER2-ECD transduced cells treated with Tra-IR700-mediated PIT (24 J) showed cell death that was significantly higher than that induced in any of the other groups (PPT 141 kb)

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Shimoyama, K., Kagawa, S., Ishida, M. et al. Viral transduction of the HER2-extracellular domain expands trastuzumab-based photoimmunotherapy for HER2-negative breast cancer cells. Breast Cancer Res Treat 149, 597–605 (2015). https://doi.org/10.1007/s10549-015-3265-y

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