CS1, a potential new therapeutic antibody target for the treatment of multiple myeloma.
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.
Hsi
Eric D
ED
Clinical Pathology, Cleveland Clinic Foundation, Cleveland, Ohio, USA.
Steinle
Roxanne
R
Balasa
Balaji
B
Szmania
Susann
S
Draksharapu
Aparna
A
Shum
Benny P
BP
Huseni
Mahrukh
M
Powers
David
D
Nanisetti
Amulya
A
Zhang
Yin
Y
Rice
Audie G
AG
van Abbema
Anne
A
Wong
Melanie
M
Liu
Gao
G
Zhan
Fenghuang
F
Dillon
Myles
M
Chen
Shihao
S
Rhodes
Susan
S
Fuh
Franklin
F
Tsurushita
Naoya
N
Kumar
Shankar
S
Vexler
Vladimir
V
Shaughnessy
John D
JD
Barlogie
Bart
B
van Rhee
Frits
F
Hussein
Mohamad
M
Afar
Daniel E H
DE
Williams
Marna B
MB
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
D000911:Antibodies, Monoclonal; D011971:Receptors, Immunologic; C448987:SLAMF7 protein, human; D000071176:Signaling Lymphocytic Activation Molecule Family