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Elotuzumab directly enhances NK cell cytotoxicity against myeloma via CS1 ligation: evidence for augmented NK cell function complementing ADCC

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Abstract

Elotuzumab is a monoclonal antibody in development for multiple myeloma (MM) that targets CS1, a cell surface glycoprotein expressed on MM cells. In preclinical models, elotuzumab exerts anti-MM efficacy via natural killer (NK)-cell-mediated antibody-dependent cellular cytotoxicity (ADCC). CS1 is also expressed at lower levels on NK cells where it acts as an activating receptor. We hypothesized that elotuzumab may have additional mechanisms of action via ligation of CS1 on NK cells that complement ADCC activity. Herein, we show that elotuzumab appears to induce activation of NK cells by binding to NK cell CS1 which promotes cytotoxicity against CS1(+) MM cells but not against autologous CS1(+) NK cells. Elotuzumab may also promote CS1–CS1 interactions between NK cells and CS1(+) target cells to enhance cytotoxicity in a manner independent of ADCC. NK cell activation appears dependent on differential expression of the signaling intermediary EAT-2 which is present in NK cells but absent in primary, human MM cells. Taken together, these data suggest elotuzumab may enhance NK cell function directly and confer anti-MM efficacy by means beyond ADCC alone.

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Acknowledgments

This study was supported by funding from Pelotonia Undergraduate Fellowship Program (Shauna M Collins, Don M Benson, Jr) and Multiple Myeloma Opportunities for Research and Education (Don M Benson, Jr, Craig C Hofmeister, Yvonne A Efebera).

Conflict of interest

Don M Benson has served in an advisory capacity to and received research funding from Bristol Myers Squibb; Gary C Starling is a former employee of Abbott Laboratories; Hakju Kwon and Audie Rice are employees of Abbvie Biotherapeutics Inc. No other authors have conflicts of interest to disclose.

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Authors and Affiliations

  1. Biomedical Sciences Program, The Ohio State University, Columbus, OH, USA

    Shauna M. Collins & Don M. Benson Jr.

  2. The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA

    Courtney E. Bakan, Craig C. Hofmeister, Yvonne A. Efebera, David Ciarlariello, Edward L. Briercheck, Tiffany Hughes, Jianhua Yu & Don M. Benson Jr.

  3. The Ohio State University College of Medicine, Columbus, OH, USA

    Gina D. Swartzel, Shakthi Bhaskar & Don M. Benson Jr.

  4. Division of Hematology, The Ohio State University, Columbus, OH, USA

    Craig C. Hofmeister, Yvonne A. Efebera, Jianhua Yu & Don M. Benson Jr.

  5. Abbvie Biotherapeutics Inc., Redwood City, CA, USA

    Hakju Kwon & Audie Rice

  6. Merck, Palo Alto, CA, USA

    Gary C. Starling

  7. Division of Hematology, 898 Biomedical Research Tower, The Ohio State University Comprehensive Cancer Center, 460 W 12th Ave, Columbus, OH, 43210-1240, USA

    Don M. Benson Jr.

Authors
  1. Shauna M. Collins
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  2. Courtney E. Bakan
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  4. Craig C. Hofmeister
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  7. Gary C. Starling
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  8. David Ciarlariello
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  9. Shakthi Bhaskar
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  10. Edward L. Briercheck
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  11. Tiffany Hughes
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  12. Jianhua Yu
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  13. Audie Rice
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  14. Don M. Benson Jr.
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Correspondence to Don M. Benson Jr..

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Collins, S.M., Bakan, C.E., Swartzel, G.D. et al. Elotuzumab directly enhances NK cell cytotoxicity against myeloma via CS1 ligation: evidence for augmented NK cell function complementing ADCC. Cancer Immunol Immunother 62, 1841–1849 (2013). https://doi.org/10.1007/s00262-013-1493-8

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  • DOI: https://doi.org/10.1007/s00262-013-1493-8

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