Targeting IL-17A in Multiple Myeloma: 2 A Potential Novel Therapeutic Approach in Myeloma. 3 (Running title: Th17 pathway in myeloma) 4

We have previously demonstrated that interleukin-17A (IL-17) producing Th17 cells are 3 significantly elevated in blood and bone marrow (BM) in multiple myeloma (MM) and IL- 4 17A promotes MM cell growth via the expression of IL-17 receptor. In this study, we 5 evaluated anti-human IL-17A human monoclonal antibody (mAb), AIN457 in MM. We 6 observe significant inhibition of MM cell growth by AIN457 both in the presence and 7 absence of BM stromal cells (BMSC). While IL-17A induces IL-6 production, AIN457 8 significantly down-regulated IL-6 production and MM cell-adhesion in MM-BMSC co 9 culture. AIN-457 also significantly inhibited TRAP+ multi-nucleated osteoclast cell– 10 differentiation. In the sub-cutaneous MM xenograft model, we observed significant 11 reduction in tumor volume by pre-treatment with AIN457 compared to isotype control. 12 More importantly, in the SCIDhu model of human myeloma where MM cells grow within 13 the human microenvironment, administration of AIN-457 weekly for 4 weeks after the 14 first detection of tumor in mice led to a significant inhibition of tumor growth as well as 15 reduced bone damage compared to isotype control mice. These pre-clinical in vitro and 16 in vivo observations suggest efficacy of AIN 457, anti-IL-17A human mAb in myeloma 17 and provide the rationale for its clinical evaluation both for anti-myeloma effects as well 18 as for improvement of bone disease