- Renate Burger1,*,
- Andreas Guenther1,
- Katja Klausz1,
- Matthias Staudinger1,
- Matthias Peipp1,
- Eva Maria Murga Penas2,
- Stefan Rose-John3,
- John Wijdenes4 and
- Martin Gramatzki1
- 1 Division of Stem Cell Transplantation and Immunotherapy, University of Kiel;
- 2 Institute of Human Genetics, University of Kiel;
- 3 Department of Biochemistry, University of Kiel;
- 4 Gen-Probe/Diaclone, France
- ↵* Corresponding author; email:
Interleukin (IL)-6 has an important role in the pathophysiology of multiple myeloma where it supports the growth and survival of the malignant plasma cells in the bone marrow. It belongs to a family of cytokines which use the glycoprotein (gp)130 chain for signal transduction, such as oncostatin M or leukemia inhibitory factor (LIF). Targeting IL-6 in plasma cell diseases is currently evaluated in clinical trials with monoclonal antibodies (mAbs). Here, efforts were made to elucidate the contribution of IL-6 and gp130 signaling in malignant plasma cell growth in vivo. In the xenograft SCID model employing our IL-6-dependent plasma cell line INA-6, the lack of human IL-6 induced autocrine IL-6 production and a proliferative response to other cytokines of the gp130 family. Here, mice were treated with mAbs against human IL-6 (elsilimomab/B-E8), the IL-6R (B-R6), and with an antibody blocking gp130 (B-R3). While treatment of mice with IL-6 and IL-6R antibodies resulted in a modest delay in tumor growth, the development of plasmacytomas was completely prevented with the anti-gp130 antibody. Importantly, complete inhibition was also achieved using F(ab)2-fragments of mAb B-R3. Tumors harbour activated STAT3, and in vitro, the antibody inhibited STAT3 phosphorylation and cell growth stimulated by LIF while being less effective against IL-6. In conclusion, growth of INA-6 plasmacytomas in vivo under IL-6 withdrawal remains strictly dependent on gp130, and other gp130 cytokines may substitute for IL-6. Antibodies against gp130 are able to overcome this redundancy and should be explored for a possible therapeutic window.
- Received February 25, 2016.
- Accepted September 14, 2016.
- Copyright © 2016, Ferrata Storti Foundation