Targeting IL-17A in multiple myeloma: a potential novel therapeutic approach in myeloma

Abstract

We have previously demonstrated that interleukin-17A (IL-17) producing Th17 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 absence of BM stromal cells (BMSC). While IL-17A induces IL-6 production, AIN457 significantly down-regulated IL-6 production and MM cell-adhesion in MM-BMSC co-culture. AIN-457 also significantly inhibited osteoclast cell–differentiation. More importantly, in the SCIDhu model of human myeloma administration of AIN-457 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 to 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 knock-down inhibited MM cell growth and their ability to induce IL-6 production in co-cultures with BMSC. These pre-clinical observations suggest efficacy of AIN 457 in myeloma and provide the rationale for its clinical evaluation for anti-myeloma effects and for improvement of bone disease.

A gene expression inflammatory signature specifically predicts multiple myeloma evolution and patients survival

“…A shortlist of 20 candidate genes coding for cytokines/chemokines involved in inflammatory response has been derived by relevant literature, focusing on B lymphocytes (effector/regulatory) or healthy/malignant PCs: IL2, IL6, IL8, IL10, IL12A, IL15, IL17A, EBI3 (IL35), CCL2 (MCP1), CCL3 (MIP1a), CCL5 (RANTES), CSF2 (GM-CSF), VEGFA, TNF, NOS2 (iNOS), IFNG, TNFSF11 (RANK-ligand), LTA (Lymphotoxin A/TNF-b), LTB, TGFB1; 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 (Supplementary Table 2). The expression level of these genes was retrieved from each dataset and used for further analyses.…”

A Unique Role of T Helper 17 Cells in Different Treatment Stages of Multiple Myeloma

“…[16][17][18] Specific anti-IL-17A antibodies can actively inhibit the growth of myeloma cells and inhibit the differentiation of osteoblasts. 14 These results suggest that Th17 cells play a key role in MM, and Th17 cells might be a potential therapeutic target for MM patients. 14,19,20 T.T.M.…”

“…14 These results suggest that Th17 cells play a key role in MM, and Th17 cells might be a potential therapeutic target for MM patients. 14,19,20 T.T.M. and Y.C.Z.…”

“…[11][12][13] Th17 cells and IL-17 play a role in the microenvironment of myeloma and promote the growth of myeloma cells. 12,14,15 They promote the differentiation of osteoclasts, inhibit the differentiation of osteoblasts, break the normal bone balance of MM patients, and accelerate bone destruction. [16][17][18] Specific anti-IL-17A antibodies can actively inhibit the growth of myeloma cells and inhibit the differentiation of osteoblasts.…”

Inhibition of bromodomain and extra-terminal (BET) proteins increases NKG2D ligand MICA expression and sensitivity to NK cell-mediated cytotoxicity in multiple myeloma cells: role of cMYC-IRF4-miR-125b interplay

“…These data add novel information on the immunomodulatory activities displayed by BETi and CBP/EP300-BRi, small molecules already known to modulate the expression of inflammatory cytokines in autoimmunity, to inhibit deregulated osteoclastogenesis during cancer progression and to block Th17 and Treg function, two important T cell subsets in MM pathobiology [58, 63–67]. …”