A high-affinity fully human anti-IL-6 mAb, 1339, for the treatment of multiple myeloma.
OBJECTIVE
We investigated the in vitro and in vivo anti-multiple myeloma activity of monoclonal antibody (mAb) 1339, a high-affinity fully humanized anti-interleukin 6 mAb (immunoglobulin G1), alone and in combination with conventional and novel anti-multiple myeloma agents, as well as its effect on bone turnover.


METHODS
We examined the growth inhibitory effect of 1339 against multiple myeloma cell lines in the absence and in the presence of bone marrow stromal cells, alone or in combination with dexamethasone, bortezomib, perifosine, and Revlimid. Using the severe combined immunodeficient (SCID)-hu murine model of multiple myeloma, we also examined the effect of 1339 on multiple myeloma cell growth and multiple myeloma bone disease.


RESULTS
mAb 1339 significantly inhibited growth of multiple myeloma cell in the presence of bone marrow stromal cell in vitro, associated with inhibition of phosphorylation of signal transducer and activator of transcription 3, extracellular signal-regulated kinase 1/2, and Akt. In addition, mAb 1339 enhanced cytotoxicity induced by dexamethasone, as well as bortezomib, lenalidomide, and perifosine, in a synergistic fashion. Importantly mAb 1339 significantly enhanced growth inhibitory effects of dexamethasone in vivo in SCID-hu mouse model of multiple myeloma. mAb 1339 treatment also resulted in inhibition of osteoclastogenesis in vitro and bone remodeling in SCID-hu model.


CONCLUSIONS
Our data confirm in vitro and in vivo anti-multiple myeloma activity of, as well as inhibition of bone turnover by, fully humanized mAb 1339, as a single agent and in combination with conventional and novel agents, providing a rationale for its clinical evaluation in multiple myeloma.
Fulciniti
Mariateresa
M
Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
Hideshima
Teru
T
Vermot-Desroches
Claudine
C
Pozzi
Samantha
S
Nanjappa
Puru
P
Shen
Zhenxin
Z
Patel
Nipun
N
Smith
Ernest S
ES
Wang
Wei
W
Prabhala
Rao
R
Tai
Yu-Tzu
YT
Tassone
Pierfrancesco
P
Anderson
Kenneth C
KC
Munshi
Nikhil C
NC
D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry*; D001842:Bone and Bones / Q000378:metabolism; D045744:Cell Line, Tumor; D003907:Dexamethasone / Q000494:pharmacology; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D015850:Interleukin-6 / Q000378:metabolism*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000276:immunology* / Q000628:therapy*; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism; D010766:Phosphorylation; D050796:STAT3 Transcription Factor / Q000378:metabolism
D000911:Antibodies, Monoclonal; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D003907:Dexamethasone