title: CS1, a potential new therapeutic antibody target for the treatment of multiple myeloma.
abstract: OBJECTIVE
  We generated a humanized antibody, HuLuc63, which specifically targets CS1 (CCND3 subset 1, CRACC, and SLAMF7), a cell surface glycoprotein not previously associated with multiple myeloma. To explore the therapeutic potential of HuLuc63 in multiple myeloma, we examined in detail the expression profile of CS1, the binding properties of HuLuc63 to normal and malignant cells, and the antimyeloma activity of HuLuc63 in preclinical models.
  
  
  METHODS
  CS1 was analyzed by gene expression profiling and immunohistochemistry of multiple myeloma samples and numerous normal tissues. HuLuc63-mediated antimyeloma activity was tested in vitro in antibody-dependent cellular cytotoxicity (ADCC) assays and in vivo using the human OPM2 xenograft model in mice.
  
  
  RESULTS
  CS1 mRNA was expressed in >90% of 532 multiple myeloma cases, regardless of cytogenetic abnormalities. Anti-CS1 antibody staining of tissues showed strong staining of myeloma cells in all plasmacytomas and bone marrow biopsies. Flow cytometric analysis of patient samples using HuLuc63 showed specific staining of CD138+ myeloma cells, natural killer (NK), NK-like T cells, and CD8+ T cells, with no binding detected on hematopoietic CD34+ stem cells. HuLuc63 exhibited significant in vitro ADCC using primary myeloma cells as targets and both allogeneic and autologous NK cells as effectors. HuLuc63 exerted significant in vivo antitumor activity, which depended on efficient Fc-CD16 interaction as well as the presence of NK cells in the mice.
  
  
  CONCLUSIONS
  These results suggest that HuLuc63 eliminates myeloma cells, at least in part, via NK-mediated ADCC and shows the therapeutic potential of targeting CS1 with HuLuc63 for the treatment of multiple myeloma.
authors.affiliation: Clinical Pathology, Cleveland Clinic Foundation, Cleveland, Ohio, USA.
authors.forename: Eric D
authors.initials: ED
authors.lastname: Hsi
authors.forename: Roxanne
authors.initials: R
authors.lastname: Steinle
authors.forename: Balaji
authors.initials: B
authors.lastname: Balasa
authors.forename: Susann
authors.initials: S
authors.lastname: Szmania
authors.forename: Aparna
authors.initials: A
authors.lastname: Draksharapu
authors.forename: Benny P
authors.initials: BP
authors.lastname: Shum
authors.forename: Mahrukh
authors.initials: M
authors.lastname: Huseni
authors.forename: David
authors.initials: D
authors.lastname: Powers
authors.forename: Amulya
authors.initials: A
authors.lastname: Nanisetti
authors.forename: Yin
authors.initials: Y
authors.lastname: Zhang
authors.forename: Audie G
authors.initials: AG
authors.lastname: Rice
authors.forename: Anne
authors.initials: A
authors.lastname: van Abbema
authors.forename: Melanie
authors.initials: M
authors.lastname: Wong
authors.forename: Gao
authors.initials: G
authors.lastname: Liu
authors.forename: Fenghuang
authors.initials: F
authors.lastname: Zhan
authors.forename: Myles
authors.initials: M
authors.lastname: Dillon
authors.forename: Shihao
authors.initials: S
authors.lastname: Chen
authors.forename: Susan
authors.initials: S
authors.lastname: Rhodes
authors.forename: Franklin
authors.initials: F
authors.lastname: Fuh
authors.forename: Naoya
authors.initials: N
authors.lastname: Tsurushita
authors.forename: Shankar
authors.initials: S
authors.lastname: Kumar
authors.forename: Vladimir
authors.initials: V
authors.lastname: Vexler
authors.forename: John D
authors.initials: JD
authors.lastname: Shaughnessy
authors.forename: Bart
authors.initials: B
authors.lastname: Barlogie
authors.forename: Frits
authors.initials: F
authors.lastname: van Rhee
authors.forename: Mohamad
authors.initials: M
authors.lastname: Hussein
authors.forename: Daniel E H
authors.initials: DE
authors.lastname: Afar
authors.forename: Marna B
authors.initials: MB
authors.lastname: Williams
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use*; D000920:Antibody-Dependent Cell Cytotoxicity; D045744:Cell Line, Tumor; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology; D016131:Lymphocyte Subsets / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000276:immunology; D010950:Plasma Cells / Q000166:cytology / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D000071176:Signaling Lymphocytic Activation Molecule Family; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D011971:Receptors, Immunologic; C448987:SLAMF7 protein, human; D000071176:Signaling Lymphocytic Activation Molecule Family