Due to interleukin-6 type cytokine redundancy only glycoprotein 130 receptor blockade efficiently inhibits myeloma growth
| Autor: | Renate Burger, Matthias Peipp, Martin Gramatzki, John Wijdenes, Katja Klausz, Matthias Staudinger, Andreas Günther, Stefan Rose-John, Eva Maria Murga Penas |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
medicine.drug_class Biology Plasma cell Monoclonal antibody Mice 03 medical and health sciences Cell Line Tumor Cytokine Receptor gp130 medicine Animals Humans Interleukin 6 Autocrine signalling Cell Proliferation Interleukin-6 Cytokine redundancy Antibodies Monoclonal Articles Hematology Glycoprotein 130 Receptors Interleukin-6 Xenograft Model Antitumor Assays Molecular biology Disease Models Animal 030104 developmental biology medicine.anatomical_structure Cytogenetic Analysis biology.protein Cancer research Cytokines Signal transduction Multiple Myeloma Leukemia inhibitory factor Signal Transduction |
| Zdroj: | Haematologica. 102:381-390 |
| ISSN: | 1592-8721 0390-6078 |
| DOI: | 10.3324/haematol.2016.145060 |
| Popis: | Interleukin-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 130 chain for signal transduction, such as oncostatin M or leukemia inhibitory factor. Targeting interleukin-6 in plasma cell diseases is currently evaluated in clinical trials with monoclonal antibodies. Here, efforts were made to elucidate the contribution of interleukin-6 and glycoprotein 130 signaling in malignant plasma cell growth in vivo. In the xenograft severe combined immune deficiency model employing our interleukin-6-dependent plasma cell line INA-6, the lack of human interleukin-6 induced autocrine interleukin-6 production and a proliferative response to other cytokines of the glycoprotein 130 family. Herein, mice were treated with monoclonal antibodies against human interleukin-6 (elsilimomab/B-E8), the interleukin-6 receptor (B-R6), and with an antibody blocking glycoprotein 130 (B-R3). While treatment of mice with interleukin-6 and interleukin-6 receptor antibodies resulted in a modest delay in tumor growth, the development of plasmacytomas was completely prevented with the anti-glycoprotein 130 antibody. Importantly, complete inhibition was also achieved using F(ab’)2-fragments of monoclonal antibody B-R3. Tumors harbor activated signal transducer and activator of transcription 3, and in vitro, the antibody inhibited leukemia inhibitory factor stimulated signal transducer and activator of transcription 3 phosphorylation and cell growth, while being less effective against interleukin-6. In conclusion, the growth of INA-6 plasmacytomas in vivo under interleukin-6 withdrawal remains strictly dependent on glycoprotein 130, and other glycoprotein 130 cytokines may substitute for interleukin-6. Antibodies against glycoprotein 130 are able to overcome this redundancy and should be explored for a possible therapeutic window. |
| Databáze: | OpenAIRE |
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