文章：

抗FcRH5抗体-药物偶联物DFRF4539A治疗复发或难治性多发性骨髓瘤的I期研究

Phase I study of the anti-FcRH5 antibody-drug conjugate DFRF4539A in relapsed or refractory multiple myeloma

原文发布日期：2019-02-04

DOI: 10.1038/s41408-019-0178-8

类型: Article

开放获取: 是

英文摘要：

FcRH5 is a cell surface marker enriched on malignant plasma cells when compared to other hematologic malignancies and normal tissues. DFRF4539A is an anti-FcRH5 antibody-drug conjugated to monomethyl auristatin E (MMAE), a potent anti-mitotic agent. This phase I study assessed safety, tolerability, maximum tolerated dose (MTD), anti-tumor activity, and pharmacokinetics of DFRF4539A in patients with relapsed/refractory multiple myeloma. DFRF4539A was administered at 0.3–2.4 mg/kg every 3 weeks or 0.8–1.1 mg/kg weekly as a single-agent by intravenous infusion to 39 patients. Exposure of total antibody and antibody-conjugate-MMAE analytes was linear across the doses tested. There were 37 (95%) adverse events (AEs), 8 (21%) serious AEs, and 15 (39%) AEs ≥ grade 3. Anemia (n = 10, 26%) was the most common AE considered related to DFRF4539A. Two cases of grade 3 acute renal failure were attributed to DFRF4539A. There were no deaths; the MTD was not reached. DFRF4539A demonstrated limited activity in patients at the doses tested with 2 (5%) partial response, 1 (3%) minimal response, 18 (46%) stable disease, and 16 (41%) progressive disease. FcRH5 was confirmed to be expressed and occupied by antibody post-treatment and thus remains a valid myeloma target. Nevertheless, this MMAE-based antibody-drug-conjugate targeting FcRH5 was unsuccessful for myeloma.

摘要翻译： 

FcRH5是一种细胞表面标志物，与其他血液恶性肿瘤及正常组织相比，其在恶性浆细胞中表达丰富。DFRF4539A是一种靶向FcRH5的抗体-药物偶联物，携带单甲基澳瑞他汀E（MMAE）——一种有效的抗有丝分裂剂。本项I期研究评估了DFRF4539A在复发/难治性多发性骨髓瘤患者中的安全性、耐受性、最大耐受剂量（MTD）、抗肿瘤活性及药代动力学特征。39例患者通过静脉输注接受0.3–2.4 mg/kg（每三周一次）或0.8–1.1 mg/kg（每周一次）的DFRF4539A单药治疗。总抗体及抗体偶联MMAE分析物的暴露量在测试剂量范围内呈线性关系。共报告37例（95%）不良事件、8例（21%）严重不良事件及15例（39）≥3级不良事件。贫血（10例，26%）是最常见的DFRF4539A相关不良事件。两例3级急性肾衰竭被归因于DFRF4539A。无死亡病例，未达到最大耐受剂量。DFRF4539A在测试剂量范围内疗效有限：2例（5%）部分缓解，1例（3%）轻微缓解，18例（46%）疾病稳定，16例（41%）疾病进展。研究证实FcRH5在治疗后仍有表达并被抗体占据，因此仍是有效的骨髓瘤靶点。然而，这种基于MMAE的靶向FcRH5抗体-药物偶联物治疗骨髓瘤未获成功。

原文链接：

Phase I study of the anti-FcRH5 antibody-drug conjugate DFRF4539A in relapsed or refractory multiple myeloma