Inducible T-cell co-stimulator ligand (ICOSL) blockade leads to selective inhibition of anti-KLH IgG responses in subjects with systemic lupus erythematosus.
Inducible T-cell co-stimulator ligand (ICOSL) blockade leads to selective inhibition of anti-KLH IgG responses in subjects with systemic lupus erythematosus.
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DOI：
10.1136/lupus-2016-000146
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发表时间：
2016
影响因子：
3.9
通讯作者：
Chung JB
中科院分区：
文献类型：
--
作者：
Sullivan BA;Tsuji W;Kivitz A;Peng J;Arnold GE;Boedigheimer MJ;Chiu K;Green CL;Kaliyaperumal A;Wang C;Ferbas J;Chung JB
在系统性红斑狼疮（SLE）受试者中评价AMG 557（一种人抗诱导型T细胞共刺激配体（ICOSL）单克隆抗体）单次和多次给药的安全性、耐受性、药代动力学（PK）和药效学（PD）。轻度、稳定型SLE患者（n=112）入组两项临床试验，以评价AMG 557单次（1.8-210 mg皮下或18 mg静脉）和多次（6 - 210 mg皮下每隔一周（Q2 W）×7）给药的效果。 受试者接受两次1 mg皮内注射（间隔28天）匙孔血蓝蛋白（KLH）（一种新抗原），以评估AMG 557的PD效应。 评估了安全性、PK、靶标占有率、抗KLH抗体应答、淋巴细胞亚群分析和SLE相关生物标志物以及临床结局。AMG 557表现出可接受的安全性特征。PK特性与针对细胞表面靶点的抗体一致，在较低浓度下观察到非线性PK，在较高浓度下观察到线性PK。AMG 557的靶结合率具有剂量依赖性和可逆性，在本试验中达到最大结合率。观察到抗AMG 557抗体，但无中和抗体，对药物水平无影响。AMG 557给药后观察到抗KLH IgG应答显著降低，抗KLH IgM应答或总体IgG水平无明显变化。淋巴细胞亚群或SLE相关生物标志物和临床指标未见明显变化。抗KLH IgG的选择性降低证明了AMG 557在SLE受试者中的PD效应与ICOS通路的生物学一致，并支持AMG 557作为自身免疫性疾病潜在治疗药物的进一步研究。NCT 02391259和NCT 00774943。
To evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of single-dose and multiple-dose administration of AMG 557, a human anti-inducible T cell co-stimulator ligand (ICOSL) monoclonal antibody, in subjects with systemic lupus erythematosus (SLE). Patients with mild, stable SLE (n=112) were enrolled in two clinical trials to evaluate the effects of single (1.8–210 mg subcutaneous or 18 mg intravenous) and multiple (6 –210 mg subcutaneous every other week (Q2W)×7) doses of AMG 557. Subjects received two 1 mg intradermal injections 28 days apart of keyhole limpet haemocyanin (KLH), a neoantigen, to assess PD effects of AMG 557. Safety, PK, target occupancy, anti-KLH antibody responses, lymphocyte subset analyses and SLE-associated biomarkers and clinical outcomes were assessed. AMG 557 demonstrated an acceptable safety profile. The PK properties were consistent with an antibody directed against a cell surface target, with non-linear PK observed at lower concentrations and linear PK at higher concentrations. Target occupancy by AMG 557 was dose dependent and reversible, and maximal occupancy was achieved in the setting of this trial. Anti-AMG 557 antibodies were observed, but none were neutralising and without impact on drug levels. A significant reduction in the anti-KLH IgG response was observed with AMG 557 administration without discernible changes in the anti-KLH IgM response or on the overall IgG levels. No discernible changes were seen in lymphocyte subsets or in SLE-related biomarkers and clinical measures. The selective reduction in anti-KLH IgG demonstrates a PD effect of AMG 557 in subjects with SLE consistent with the biology of the ICOS pathway and supports further studies of AMG 557 as a potential therapeutic for autoimmune diseases. NCT02391259 and NCT00774943.