title: Targeting IL-17A in multiple myeloma: a potential novel therapeutic approach in myeloma.
abstract: We have previously demonstrated that interleukin-17A (IL-17) producing T helper 17 cells are significantly elevated in blood and bone marrow (BM) in multiple myeloma (MM) and IL-17A promotes MM cell growth via the expression of IL-17 receptor. In this study, we evaluated anti-human IL-17A human monoclonal antibody (mAb), AIN457 in MM. We observe significant inhibition of MM cell growth by AIN457 both in the presence and the absence of BM stromal cells (BMSCs). Although IL-17A induces IL-6 production, AIN457 significantly downregulated IL-6 production and MM cell adhesion in MM-BMSC co-culture. AIN457 also significantly inhibited osteoclast cell differentiation. More importantly, in the SCIDhu model of human myeloma administration of AIN457 weekly for 4 weeks after the first detection of tumor in mice led to a significant inhibition of tumor growth and reduced bone damage compared with isotype control mice. To understand the mechanism of action of anti-IL-17A mAb, we report, here, that MM cells express IL-17A. We also observed that IL-17A knockdown inhibited MM cell growth and their ability to induce IL-6 production in co-cultures with BMSC. These pre-clinical observations suggest efficacy of AIN457 in myeloma and provide the rationale for its clinical evaluation for anti-myeloma effects and for improvement of bone disease.
authors: Department of Medicine, VA Boston Healthcare System, Harvard Medical School, Boston, MA, USA.|Department of Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors: R H
authors: RH
authors: Prabhala
authors: Department of Medicine, VA Boston Healthcare System, Harvard Medical School, Boston, MA, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors: M
authors: M
authors: Fulciniti
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors: D
authors: D
authors: Pelluru
authors: Department of Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors: N
authors: N
authors: Rashid
authors: Department of Medicine, VA Boston Healthcare System, Harvard Medical School, Boston, MA, USA.
authors: A
authors: A
authors: Nigroiu
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors: P
authors: P
authors: Nanjappa
authors: Department of Medicine, VA Boston Healthcare System, Harvard Medical School, Boston, MA, USA.
authors: C
authors: C
authors: Pai
authors: Department of Medicine, VA Boston Healthcare System, Harvard Medical School, Boston, MA, USA.
authors: S
authors: S
authors: Lee
authors: Department of Medicine, VA Boston Healthcare System, Harvard Medical School, Boston, MA, USA.
authors: N S
authors: NS
authors: Prabhala
authors: Department of Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors: R L
authors: RL
authors: Bandi
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors: R
authors: R
authors: Smith
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors: S B
authors: SB
authors: Lazo-Kallanian
authors: Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
authors: S
authors: S
authors: Valet
authors: Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
authors: N
authors: N
authors: Raje
authors: Department of Medicine, VA Boston Healthcare System, Harvard Medical School, Boston, MA, USA.|Department of Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors: J S
authors: JS
authors: Gold
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors: P G
authors: PG
authors: Richardson
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors: J F
authors: JF
authors: Daley
authors: Department of Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors: K C
authors: KC
authors: Anderson
authors: Novartis Institute for Biomedical Research, Cambridge, MA, USA.
authors: S A
authors: SA
authors: Ettenberg
authors: Novartis Institute for Biomedical Research, Basel, Switzerland.
authors: F
authors: F
authors: Di Padova
authors: Department of Medicine, VA Boston Healthcare System, Harvard Medical School, Boston, MA, USA.|Department of Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors: N C
authors: NC
authors: Munshi
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D004195:Disease Models, Animal; D006801:Humans; D020381:Interleukin-17 / Q000037:antagonists & inhibitors*; D015850:Interleukin-6 / Q000096:biosynthesis; D008297:Male; D051379:Mice; D009101:Multiple Myeloma / Q000188:drug therapy*; D010010:Osteoclasts / Q000187:drug effects; D053668:Syndecan-1 / Q000032:analysis
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C508717:IL17A protein, human; D020381:Interleukin-17; D015850:Interleukin-6; D053668:Syndecan-1; C555450:secukinumab