Phase I study of the anti-CD40 humanized monoclonal antibody lucatumumab (HCD122) in relapsed chronic lymphocytic leukemia
Phase I study of the anti-CD40 humanized monoclonal antibody lucatumumab (HCD122) in relapsed chronic lymphocytic leukemia
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DOI：
10.3109/10428194.2012.681655
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发表时间：
2012-11-01
影响因子：
2.6
通讯作者：
O'Brien, Susan
中科院分区：
文献类型：
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作者：
Byrd, John C.;Kipps, Thomas J.;O'Brien, Susan
Lucatumumab是一种完全人源化的抗CD 40抗体，可阻断CD 40 L与CD 40的相互作用，并介导抗体依赖性细胞介导的细胞毒性（ADCC）。我们在慢性淋巴细胞白血病（CLL）的I期临床试验中评估了lucatumumab。26例复发性CLL患者入组5个不同的剂量队列，每周给药一次，持续4周。Lucatumumab的最大耐受剂量（MTD）为3.0 mg/kg。4.5 mg/kg和6.0 mg/kg剂量组4例患者发生3级或4级无症状淀粉酶和脂肪酶水平升高。在入组的26例患者中，17例患者病情稳定（平均持续时间76天，范围29-504天），1例患者结节性部分缓解持续230天。CLL细胞上CD 40受体的饱和度在所有剂量组给药后均一致，但在3.0 mg/kg或更高剂量组的谷值时间点也持续存在。在MTD时，第一次输注后Lucatumumab的中位半衰期为50小时，第四次输注后为124小时。总之，lucatumumab在3.0 mg/kg剂量下具有可接受的耐受性、支持长期给药的药代动力学和药效学靶点拮抗作用，但表现出最小的单药活性。lucatumumab在CLL中的未来努力应侧重于基于组合的治疗。
Lucatumumab is a fully humanized anti-CD40 antibody that blocks interaction of CD40L with CD40 and also mediates antibody-dependent cell-mediated cytotoxicity (ADCC). We evaluated lucatumumab in a phase I clinical trial in chronic lymphocytic leukemia (CLL). Twenty-six patients with relapsed CLL were enrolled on five different dose cohorts administered weekly for 4 weeks. The maximally tolerated dose (MTD) of lucatumumab was 3.0 mg/kg. Four patients at doses of 4.5 mg/kg and 6.0 mg/kg experienced grade 3 or 4 asymptomatic elevated amylase and lipase levels. Of the 26 patients enrolled, 17 patients had stable disease (mean duration of 76 days, range 29-504 days) and one patient had a nodular partial response for 230 days. Saturation of CD40 receptor on CLL cells was uniform at all doses post-treatment but also persisted at trough time points in the 3.0 mg/kg or greater cohorts. At the MTD, the median half-life of lucatumumab was 50 h following the first infusion, and 124 h following the fourth infusion. In summary, lucatumumab had acceptable tolerability, pharmacokinetics that supported chronic dosing and pharmacodynamic target antagonism at doses of 3.0 mg/kg, but demonstrated minimal single-agent activity. Future efforts with lucatumumab in CLL should focus on combination-based therapy.