T 细胞大颗粒淋巴细胞白血病患者中使用人源化 Mikβ1 mAb 阻断 IL-15 转呈的 1 期临床试验。
Phase 1 trial of IL-15 trans presentation blockade using humanized Mikβ1 mAb in patients with T-cell large granular lymphocytic leukemia.
机构信息
Metabolism Branch, Center for Cancer Research, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
出版信息
Blood. 2013 Jan 17;121(3):476-84. doi: 10.1182/blood-2012-08-450585. Epub 2012 Dec 3.
Abstract
In the present study, Hu-Mikβ1, a humanized mAb directed at the shared IL-2/IL-15Rβ subunit (CD122) was evaluated in patients with T-cell large granular lymphocytic (T-LGL) leukemia. Hu-Mikβ1 blocked the trans presentation of IL-15 to T cells expressing IL-2/IL-15Rβ and the common γ-chain (CD132), but did not block IL-15 action in cells that expressed the heterotrimeric IL-15 receptor in cis. There was no significant toxicity associated with Hu-Mikβ1 administration in patients with T-LGL leukemia, but no major clinical responses were observed. One patient who had previously received murine Mikβ1 developed a measurable Ab response to the infused Ab. Nevertheless, the safety profile of this first in-human study of the humanized mAb to IL-2/IL-15Rβ (CD122) supports its evaluation in disorders such as refractory celiac disease, in which IL-15 and its receptor have been proposed to play a critical role in the pathogenesis and maintenance of disease activity.
摘要
在本研究中，评估了一种针对白细胞介素 2/白细胞介素 15Rβ 亚基（CD122）共有部分的人源化单克隆抗体 Hu-Mikβ1 在 T 细胞大颗粒淋巴细胞（T-LGL）白血病患者中的作用。Hu-Mikβ1 阻断了表达白细胞介素 2/白细胞介素 15Rβ 和共同γ 链（CD132）的 T 细胞的白细胞介素 15 的转呈，而不会阻断在顺式表达三聚体白细胞介素 15 受体的细胞中的白细胞介素 15 作用。在 T-LGL 白血病患者中，Hu-Mikβ1 给药没有与显著毒性相关，但未观察到主要的临床反应。一名先前接受过鼠 Mikβ1 治疗的患者对输注的抗体产生了可测量的抗体反应。尽管如此，这种针对白细胞介素 2/白细胞介素 15Rβ（CD122）的人源化单克隆抗体的首次人体研究的安全性概况支持其在诸如难治性乳糜泻等疾病中的评估，其中白细胞介素 15 和其受体被认为在疾病发病机制和维持疾病活动中发挥关键作用。
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