Elotuzumab directly enhances NK cell cytotoxicity against myeloma via CS1 ligation: evidence for augmented NK cell function complementing ADCC |
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Authors: | Shauna M. Collins Courtney E. Bakan Gina D. Swartzel Craig C. Hofmeister Yvonne A. Efebera Hakju Kwon Gary C. Starling David Ciarlariello Shakthi Bhaskar Edward L. Briercheck Tiffany Hughes Jianhua Yu Audie Rice Don M. Benson Jr. |
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Affiliation: | 1. Biomedical Sciences Program, The Ohio State University, Columbus, OH, USA 2. The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA 3. The Ohio State University College of Medicine, Columbus, OH, USA 4. Division of Hematology, The Ohio State University, Columbus, OH, USA 5. Abbvie Biotherapeutics Inc., Redwood City, CA, USA 6. Merck, Palo Alto, CA, USA 7. Division of Hematology, 898 Biomedical Research Tower, The Ohio State University Comprehensive Cancer Center, 460?W 12th Ave, Columbus, OH, 43210-1240, USA
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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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