title: Elotuzumab directly enhances NK cell cytotoxicity against myeloma via CS1 ligation: evidence for augmented NK cell function complementing ADCC.
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.
authors.affiliation: Biomedical Sciences Program, The Ohio State University, Columbus, OH, USA.
authors.forename: Shauna M
authors.initials: SM
authors.lastname: Collins
authors.forename: Courtney E
authors.initials: CE
authors.lastname: Bakan
authors.forename: Gina D
authors.initials: GD
authors.lastname: Swartzel
authors.forename: Craig C
authors.initials: CC
authors.lastname: Hofmeister
authors.forename: Yvonne A
authors.initials: YA
authors.lastname: Efebera
authors.forename: Hakju
authors.initials: H
authors.lastname: Kwon
authors.forename: Gary C
authors.initials: GC
authors.lastname: Starling
authors.forename: David
authors.initials: D
authors.lastname: Ciarlariello
authors.forename: Shakthi
authors.initials: S
authors.lastname: Bhaskar
authors.forename: Edward L
authors.initials: EL
authors.lastname: Briercheck
authors.forename: Tiffany
authors.initials: T
authors.lastname: Hughes
authors.forename: Jianhua
authors.initials: J
authors.lastname: Yu
authors.forename: Audie
authors.initials: A
authors.lastname: Rice
authors.forename: Don M
authors.initials: DM
authors.lastname: Benson
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology*; D015153:Blotting, Western; D049109:Cell Proliferation; D005434:Flow Cytometry; D006801:Humans; D047468:Immunoprecipitation; D007371:Interferon-gamma / Q000378:metabolism; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation; D009101:Multiple Myeloma / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000071176:Signaling Lymphocytic Activation Molecule Family; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D012333:RNA, Messenger; D011971:Receptors, Immunologic; C103572:SH2D1B protein, human; C448987:SLAMF7 protein, human; D000071176:Signaling Lymphocytic Activation Molecule Family; D014157:Transcription Factors; C546027:elotuzumab; D007371:Interferon-gamma