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Ex vivo dual gene therapy using human adipocytes secreting anti-HER2 antibody on HER2-positive xenograft tumor models

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Abstract

Background

Although targeted treatments against human epidermal growth factor receptor 2 (HER2) have improved survival in patients with metastatic HER2-positive breast cancer, long and repeated treatment is time-consuming and costly for patients. To reduce these burdens, we developed ex vivo gene-transduced adipocytes that secrete anti-HER2 antibodies and evaluated their anti-tumor effects.

Methods

Ceiling culture-derived proliferative adipocytes (ccdPA) secreting anti-HER2 antibody against domain IV receptors: TRA-ccdPA, and domain II receptors: PER-ccdPA, were constructed using a plasmid lentivirus. Delivery of secreted antibody and its specific binding to HER2 breast cancer were evaluated in vitro and in vivo. To optimize antibody production from ccdPA, different conditions of ccdPA implantation were examined. Anti-tumor efficacy was evaluated in HER2-positive-cancer-inoculated nude mice.

Results

Anti-HER2 antibody against domain II was identified in supernatants from PER-ccdPAs. The optimal method to achieve the highest concentration of antibody in mouse sera was injecting differentiated ccdPA cells into the mammary fat pad. Antibody in supernatants from PER-ccdPAs bound to the surface of HER2-positive breast cancer cells similar to pertuzumab. Antibodies in mouse sera were delivered to HER2-positive breast cancer tumors and tumor necrosis was observed microscopically. One-time administration of combined TRA-ccdPAs and PER-ccdPAs produced antibody continuously in mouse sera, and anti-tumor effects were maintained for the duration of this study in xenograft models. Furthermore, combination therapy significantly suppressed tumor growth compared with a single administration.

Conclusion

Ex vivo gene-transduced adipocytes might be useful for cell-based gene therapy. This system may be a platform for various antibody therapies.

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Acknowledgements

We thank CellGenTech Inc. for their support of this work. We thank Edanz Group (https://en-author-services.edanz.com/ac) for editing a draft of this manuscript. We thank Professor J. Kurebayashi for providing KPL-4.

Funding

This work was supported by MEXT KAKENHI Grant Number JP 18K08588 (H.F.).

Author information

Authors and Affiliations

  1. Department of General Surgery, Chiba University Graduate School of Medicine, 1-8-1, Inohana, Chuo-Ku, Chiba, 260-0856, Japan

    Ryotaro Teranaka, Hiroshi Fujimoto, Takahito Masuda, Takeshi Nagashima, Mamoru Takada, Junta Sakakibara, Hideyuki Yamada, Hiroto Yamamoto & Masayuki Ohtsuka

  2. Center for Advanced Medicine, Chiba University Hospital, 1-8-1, Inohana, Chuo-Ku, Chiba, 260-8677, Japan

    Masayuki Kuroda

  3. CellGenTech, Inc., 1-8-15, Inohana, Chuo-Ku, Chiba, 260-0856, Japan

    Yasuyuki Aoyagi

  4. Department of Plastic, Reconstructive, and Aesthetic Surgery, Chiba University Graduate School of Medicine, 1-8-1, Inohana, Chuo-Ku, Chiba, 260-0856, Japan

    Yoshitaka Kubota

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  1. Ryotaro Teranaka
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  2. Hiroshi Fujimoto
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Correspondence to Hiroshi Fujimoto.

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Teranaka, R., Fujimoto, H., Masuda, T. et al. Ex vivo dual gene therapy using human adipocytes secreting anti-HER2 antibody on HER2-positive xenograft tumor models. Breast Cancer 30, 1018–1027 (2023). https://doi.org/10.1007/s12282-023-01497-8

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  • DOI: https://doi.org/10.1007/s12282-023-01497-8

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