Targeting IL-17A in multiple myeloma: a potential novel therapeutic approach in myeloma.
Targeting IL-17A in multiple myeloma: a potential novel therapeutic approach in myeloma.
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DOI：
10.1038/leu.2015.228
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发表时间：
2016-02
期刊：
影响因子：
11.4
通讯作者：
Munshi NC
中科院分区：
文献类型：
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作者：
Prabhala RH;Fulciniti M;Pelluru D;Rashid N;Nigroiu A;Nanjappa P;Pai C;Lee S;Prabhala NS;Bandi RL;Smith R;Lazo-Kallanian SB;Valet S;Raje N;Gold JS;Richardson PG;Daley JF;Anderson KC;Ettenberg SA;Di Padova F;Munshi NC
我们先前已经证明，在多发性骨髓瘤（MM）中，产生白细胞介素-17A（IL-17）的Th 17细胞在血液和骨髓（BM）中显著升高，并且IL-17 A通过表达IL-17受体促进MM细胞生长。在这项研究中，我们评估了抗人IL-17 A人单克隆抗体（mAb），AIN 457在MM中的作用。我们观察到在存在和不存在BM基质细胞（BMSC）的情况下，AIN 457对MM细胞生长的显著抑制。虽然IL-17 A诱导IL-6产生，但AIN 457显著下调MM-BMSC共培养物中的IL-6产生和MM细胞粘附。AIN-457还显著抑制破骨细胞分化。更重要的是，在人骨髓瘤的SCIDhu模型中，与同种型对照小鼠相比，在小鼠中首次检测到肿瘤后每周施用AIN-457持续4周导致肿瘤生长的显著抑制和骨损伤的减少。为了了解抗IL-17 A mAb的作用机制，我们在此报告MM细胞表达IL-17 A。我们还观察到IL-17 A敲低抑制MM细胞生长及其在与BMSC共培养物中诱导IL-6产生的能力。这些临床前观察结果表明AIN 457在骨髓瘤中的疗效，并为其抗骨髓瘤作用和改善骨病的临床评价提供了依据。
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.