LBPO.ET04 · 实验与分子治疗 · Late-Breaking
ALETA-001的药代动力学，一项CRUK首次人体1/2期试验，针对既往接受过抗CD19 CAR T细胞治疗的B细胞恶性肿瘤患者
Pharmacokinetics of ALETA-001, a CRUK first-in-human phase I/II trial in patients who have received anti-CD19 CAR T-cell therapy for B-cell malignancies
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摘要 Abstract
中文摘要
背景：抗原丢失或逃逸是抗CD19 CAR T细胞治疗失败的一个主要机制，并导致后续疾病复发。ALETA-001是一种同类首创的CAR T细胞衔接蛋白，能够将抗CD19 CAR T细胞桥连至表达CD20的癌细胞。在成功的临床前研究之后，一项针对B细胞恶性肿瘤患者的ALETA-001首次人体1/2期试验启动。我们报道了这项正在进行的英国癌症研究中心（Cancer Research UK）1/2期研究中ALETA-001的药代动力学。
方法：符合条件的患者被诊断为B细胞恶性肿瘤，且既往接受过抗CD19 CAR T细胞治疗。ALETA-001以2小时静脉输注方式每2周给药一次，患者在第1周期接受0.4-2.0 mg/kg，在后续周期接受2.0-6.0 mg/kg。用于药代动力学分析的样本在给予ALETA-001后0、0.25、2、5、24、72和168小时从第1和第2周期采集，并使用经过验证的ELISA检测进行分析。进行了药代动力学分析以确定包括Cmax、曲线下面积（AUC）、终末消除半衰期（T1/2）、全身清除率（CL）和分布容积（Vz）在内的参数。
结果：表1提供了给予ALETA-001后所获得药代动力学参数的摘要（数据酌情以范围或均值±SD表示）。对0.4-6.0 mg/kg剂量ALETA-001所生成的药代动力学数据的比较表明，在观察到的Cmax和AUC值方面总体呈剂量比例关系。当前患者队列中的药物半衰期估计值表明消除半衰期约为4-7天。
结论：作为首次人体1/2期临床试验的一部分，已生成了同类首创CAR T细胞衔接蛋白ALETA-001的新型药代动力学数据。
表1：ALETA-001药代动力学数据摘要 组别（患者数）剂量（mg/kg）周期 该周期患者数 Cmax（µg/mL）AUC（µg/mL.h）T1/2（h）CL（mL/h）Vz（L）A（6）0.4 1 6 5.31 - 13.70 826 ± 197 104.4 ± 7.8 34.2 ± 8.9 5.2 ± 1.6 2 2 6 24.4 - 40.4 5282 ± 592 136.3 ± 23.1 25.8 ± 5.1 5.17 ± 1.7 B（4）2 1 4 29.5 - 41.4 5657.5 ± 536 170.3 ± 36.4 25.86± 6.0 6.3 ± 2.1 2 3 41.7 - 47.8 6470 ± 1878 133.4 ± 48.8 23.4 ± 5.2 4.3 ± 1.2 6 2 1 77.9 18601 312.5 21.5 9.7
查看英文原文 English abstract
Background: Antigen loss or escape represents a primary mechanism of treatment failure of anti-CD19 CAR T-cell therapy and results in subsequent disease relapse. ALETA-001 is a first-in-class CAR T-cell engager protein that can bridge anti-CD19 CAR T-cells to cancer cells expressing CD20. Following successful preclinical studies, a first-in-human phase I/II trial of ALETA-001 was initiated in patients with B-cell malignancies. We report the pharmacokinetics of ALETA-001 in this ongoing Cancer Research UK phase I/II study.
Methods: Eligible patients were diagnosed with B-cell malignancies and had undergone anti-CD19 CAR T-cell therapy. ALETA-001 was administered intravenously as a 2 hour infusion every 2 weeks, with patients receiving 0.4-2.0 mg/kg in cycle 1, and 2.0-6.0 mg/kg in subsequent cycles. Samples for pharmacokinetic analysis were obtained from cycles 1 and 2 at 0, 0.25, 2, 5, 24, 72 and 168 hours post-ALETA-001 administration, and analyzed using a validated ELISA assay. Pharmacokinetic analysis was carried out to determine parameters including C max , area under the curve (AUC), terminal elimination half-life (T 1/2 ), total body clearance (CL), and volume of distribution (Vz) of ALETA-001.
Results: Table 1 provides a summary of the pharmacokinetic parameters obtained following ALETA-001 administration (data expressed as range or mean ± SD as appropriate). Comparison of pharmacokinetic data generated following ALETA-001 doses of 0.4 - 6.0 mg/kg suggests general dose proportionality in terms of observed C max and AUC values. Estimates of drug half-life in the current patient cohort indicate an elimination half-life of approximately 4-7 days.
Conclusion: Novel pharmacokinetic data for the first-in-class CAR T-cell engager protein ALETA-001 have been generated as part of a first-in-human phase I/II clinical trial.
Table 1: Summary of ALETA-001 pharmacokinetic data Group
(No. Patients) Dose
(mg/kg) Cycle No. of patients in cycle Cmax (µg/mL) AUC (µg/mL.h) T 1/2 (h) CL (mL/h) Vz (L) A (6) 0.4 1 6 5.31 - 13.70 826 ± 197 104.4 ± 7.8 34.2 ± 8.9 5.2 ± 1.6 2 2 6 24.4 - 40.4 5282 ± 592 136.3 ± 23.1 25.8 ± 5.1 5.17 ± 1.7 B (4) 2 1 4 29.5 - 41.4 5657.5 ± 536 170.3 ± 36.4 25.86± 6.0 6.3 ± 2.1 2 3 41.7 - 47.8 6470 ± 1878 133.4 ± 48.8 23.4 ± 5.2 4.3 ± 1.2 6 2 1 77.9 18601 312.5 21.5 9.7
利益披露 Disclosure
M. Galler, None..
D. Jamieson, None.
P. Rennert,
Aleta Biotherapeutics Employment, g., Board of Directors, non-salaried role), Stock Option.
J. Craigen, None..
G. Veal, None.