title: Due to interleukin-6 type cytokine redundancy only glycoprotein 130 receptor blockade efficiently inhibits myeloma growth.
abstract: 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.
authors.affiliation: Division of Stem Cell Transplantation and Immunotherapy, Department of Internal Medicine II, Christian-Albrechts-University Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany r.burger@med2.uni-kiel.de.
authors.forename: Renate
authors.initials: R
authors.lastname: Burger
authors.affiliation: Division of Stem Cell Transplantation and Immunotherapy, Department of Internal Medicine II, Christian-Albrechts-University Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Günther
authors.affiliation: Division of Stem Cell Transplantation and Immunotherapy, Department of Internal Medicine II, Christian-Albrechts-University Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Klausz
authors.affiliation: Division of Stem Cell Transplantation and Immunotherapy, Department of Internal Medicine II, Christian-Albrechts-University Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Staudinger
authors.affiliation: Division of Stem Cell Transplantation and Immunotherapy, Department of Internal Medicine II, Christian-Albrechts-University Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Peipp
authors.affiliation: Institute of Human Genetics, Christian-Albrechts-University Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany.
authors.forename: Eva Maria Murga
authors.initials: EM
authors.lastname: Penas
authors.affiliation: Department of Biochemistry, Christian-Albrechts-University of Kiel, Medical Faculty, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Rose-John
authors.affiliation: Gen-Probe/Diaclone SAS, Besançon, France.
authors.forename: John
authors.initials: J
authors.lastname: Wijdenes
authors.affiliation: Division of Stem Cell Transplantation and Immunotherapy, Department of Internal Medicine II, Christian-Albrechts-University Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Gramatzki
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D020732:Cytogenetic Analysis; D050822:Cytokine Receptor gp130 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D051379:Mice; D009101:Multiple Myeloma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019947:Receptors, Interleukin-6 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D016207:Cytokines; D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D050822:Cytokine Receptor gp130