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Multiple Myeloma, Gammopathies

Targeting IL-17A in multiple myeloma: a potential novel therapeutic approach in myeloma

Leukemia volume 30, pages 379–389 (2016)Cite this article

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Abstract

We have previously demonstrated that interleukin-17A (IL-17) producing T helper 17 cells are significantly elevated in blood and bone marrow (BM) in multiple myeloma (MM) and IL-17A promotes MM cell growth via the expression of IL-17 receptor. In this study, we evaluated anti-human IL-17A human monoclonal antibody (mAb), AIN457 in MM. We observe significant inhibition of MM cell growth by AIN457 both in the presence and the absence of BM stromal cells (BMSCs). Although IL-17A induces IL-6 production, AIN457 significantly downregulated IL-6 production and MM cell adhesion in MM–BMSC co-culture. AIN457 also significantly inhibited osteoclast cell differentiation. More importantly, in the SCIDhu model of human myeloma administration of AIN457 weekly for 4 weeks after the first detection of tumor in mice led to a significant inhibition of tumor growth and reduced bone damage compared with isotype control mice. To understand the mechanism of action of anti-IL-17A mAb, we report, here, that MM cells express IL-17A. We also observed that IL-17A knockdown inhibited MM cell growth and their ability to induce IL-6 production in co-cultures with BMSC. These pre-clinical observations suggest efficacy of AIN457 in myeloma and provide the rationale for its clinical evaluation for anti-myeloma effects and for improvement of bone disease.

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Acknowledgements

This work is supported by: Department of Veterans Affairs Merit Review Award1 I01 BX001584-01, NIH grants RO1-124929 and PO1-155258 (NCM) and P50-100707, and PO1-78378, (NCM and KCA). JSG is supported by the Department of Veterans Affairs Office of Research and Development through a Career Development Award-2. This work is also supported by MMRF senior award to RHP.

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Authors and Affiliations

  1. Department of Medicine, VA Boston Healthcare System, Harvard Medical School, Boston, MA, USA

    R H Prabhala, M Fulciniti, A Nigroiu, C Pai, S Lee, N S Prabhala, J S Gold & N C Munshi

  2. Department of Medicine, Brigham & Women’s Hospital, Harvard Medical School, Boston, MA, USA

    R H Prabhala, N Rashid, R L Bandi, J S Gold, K C Anderson & N C Munshi

  3. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

    R H Prabhala, M Fulciniti, D Pelluru, P Nanjappa, R Smith, S B Lazo-Kallanian, P G Richardson, J F Daley, K C Anderson & N C Munshi

  4. Department of Medicine, Massachusetts General Hospital, Boston, MA, USA

    S Valet & N Raje

  5. Novartis Institute for Biomedical Research, Cambridge, MA, USA

    S A Ettenberg

  6. Novartis Institute for Biomedical Research, Basel, Switzerland

    F Di Padova

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  1. R H Prabhala
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Prabhala, R., Fulciniti, M., Pelluru, D. et al. Targeting IL-17A in multiple myeloma: a potential novel therapeutic approach in myeloma. Leukemia 30, 379–389 (2016). https://doi.org/10.1038/leu.2015.228

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