Phase I study of a bispecific ligand-directed toxin targeting CD22 and CD19 (DT2219) for refractory B-cell malignancies.
Phase I study of a bispecific ligand-directed toxin targeting CD22 and CD19 (DT2219) for refractory B-cell malignancies.
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DOI：
10.1158/1078-0432.ccr-14-2877
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发表时间：
2015-03-15
期刊：
影响因子：
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通讯作者：
Vallera DA
中科院分区：
文献类型：
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作者：
Bachanova V;Frankel AE;Cao Q;Lewis D;Grzywacz B;Verneris MR;Ustun C;Lazaryan A;McClune B;Warlick ED;Kantarjian H;Weisdorf DJ;Miller JS;Vallera DA
新型双特异性配体导向毒素 (BLT) DT2219 由白喉毒素 (DT) 的催化和易位增强结构域与针对人 CD19 和 CD22 的抗体的双特异性单链可变片段 (scFV) 之间的重组融合组成。我们进行了一项 1 期剂量递增研究，以评估 DT2219 在复发/难治性 B 细胞淋巴瘤或白血病患者中的安全性、最大耐受剂量 (MTD) 和初步疗效。每隔一天 2 小时内静脉注射 DT2219，共 4 剂。在九个剂量组中，剂量从 0.5 μg/kg/天递增至 80 μg/kg/天，直到观察到剂量限制毒性 (DLT)。 25 名患有表达 CD19 和/或 CD22 的成熟或前体 B 细胞淋巴恶性肿瘤的患者参加了该研究。患者接受过中位数的 3 次化疗，其中 8 名患者接受了失败的造血移植。所有患者均接受单疗程DT2219治疗；一名患者被撤回。最常见的不良事件 (AE) 包括体重增加、低白蛋白、转氨酶和发烧，均为短暂的 1-2 级，发生在较高剂量组（≥40 μg/kg/天）的患者中。两名受试者在 40 和 60 μg/kg 的剂量水平下经历了 DLT。 2 名患者出现持久的客观反应； 1例在2个周期后完全缓解。相关研究显示中和抗体的发生率出人意料地低（30%）。我们确定了一种新型免疫毒素DT2219的安全性，并确定其生物活性剂量在40-80 μg/kg/天×4之间。计划进行一项探索 DT2219 重复课程的第二阶段研究。
The novel bispecific ligand-directed toxin (BLT) DT2219 consists of a recombinant fusion between the catalytic and translocation enhancing domain of diphtheria toxin (DT) and bispecific single chain variable fragments (scFV) of antibodies targeting human CD19 and CD22. We conducted a phase 1 dose escalation study to assess the safety, maximum tolerated dose (MTD), and preliminary efficacy of DT2219 in patients with relapsed/refractory B cell lymphoma or leukemia. DT2219 was administered intravenously over 2 hours every other day for 4 total doses. Dose was escalated from 0.5 μg/kg/day to 80 μg/kg/day in nine dose cohorts until a dose limiting toxicity (DLT) was observed. Twenty-five patients with mature or precursor B-cell lymphoid malignancies expressing CD19 and/or CD22 enrolled to the study. Patients received median 3 prior lines of chemotherapy and 8 failed hematopoietic transplantation. All patients received a single course of DT2219; one patient was retreated. The most common adverse events (AE) including, weight gain, low albumin, transaminitis and fevers were transient grade 1-2 and occurred in patients in higher dose cohorts (≥40 μg/kg/day). Two subjects experienced DLT at dose levels 40 and 60 μg/kg. Durable objective responses occurred in 2 patients; one was complete remission after 2 cycles. Correlative studies showed a surprisingly low incidence of neutralizating antibody (30%). We have determined the safety of a novel immunotoxin DT2219 and established it's biologically active dose between 40-80 μg/kg/day ×4. A phase II study exploring repetitive courses of DT2219 is planned.