A Phase 1 study of the safety, pharmacokinetics and anti-leukemic activity of the anti-CD123 monoclonal antibody CSL360 in relapsed, refractory or high-risk acute myeloid leukemia
A Phase 1 study of the safety, pharmacokinetics and anti-leukemic activity of the anti-CD123 monoclonal antibody CSL360 in relapsed, refractory or high-risk acute myeloid leukemia
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DOI：
10.3109/10428194.2014.956316
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发表时间：
2015-05-01
影响因子：
2.6
通讯作者：
Roberts, Andrew W.
中科院分区：
文献类型：
--
作者：
He, Simon Z.;Busfield, Samantha;Roberts, Andrew W.
急性髓性白血病（AML）原始细胞表达高水平的白细胞介素-3（IL-3）受体-α（CD 123）。CSL 360是一种重组嵌合免疫球蛋白G（1）（IgG（1）），抗CD 123单克隆抗体（MoAb），可中和IL-3，并在体外显示出抗白血病活性。这项I期研究在40例晚期AML患者中评估了5个剂量水平（0.1-10.0 mg/kg）的CSL 360每周一次静脉给药持续12周的安全性、药代动力学和生物活性。除轻度输注反应外，CSL 360耐受性良好。未达到最大耐受剂量。半衰期为4.9天，曲线下面积（AUC）和最大浓度（Cmax）随剂量成比例增加。>= 3.0 mg/kg的剂量导致CD 123的完全饱和和下调以及对IL-3的离体增殖反应性的消除，表明IL-3信号传导的充分阻断。两名患者有反应，一名患者在17次给药后完全缓解。CSL 360特异性结合CD 123，但在大多数患者中不诱导抗白血病活性。虽然安全，但单克隆抗体阻断CD 123功能作为治疗策略是不够的。
Acute myeloid leukemia (AML) blasts express high levels of interlekin-3 (IL-3) receptor-alpha (CD123). CSL360 is a recombinant, chimeric immunoglobulin G(1) (IgG(1)), anti-CD123 monoclonal antibody (MoAb) that neutralizes IL-3 and demonstrates anti-leukemic activity in vitro. This phase 1 study assessed safety, pharmacokinetics and bioactivity of weekly intravenous CSL360 for 12 weeks in 40 patients with advanced AML across five dose levels (0.1-10.0 mg/kg). Other than mild infusion reactions, CSL360 was well tolerated. The maximal tolerated dose was not reached. The half-life was 4.9 days, and the area under the curve (AUC) and maximum concentration (Cmax) increased proportionally with dose. Doses >= 3.0 mg/kg resulted in complete saturation and down-regulation of CD123 and abolition of ex vivo proliferative responsiveness to IL-3, indicating adequate blockade of IL-3 signaling. Two patients responded, with one remaining in complete remission after 17 doses. CSL360 bound CD123 specifically, but did not induce anti-leukemic activity in most patients. While safe, MoAb blockade of CD123 function is insufficient as a therapeutic strategy.